CN1838946A - Pharmaceutical formulations of amyloid inhibiting compounds - Google Patents

Abstract

Therapeutic formulations and methods for inhibiting amyloid deposition in a subject, whatever its clinical setting, are described. Therapeutic formulations and methods for preventing or treating amyloidosis and/or amyloid-related disease are also described.

Description

The pharmaceutical preparation of amyloid inhibiting compounds

Related application

The application requires to enjoy the priority of following patent application: in the United States Patent (USP) provisional application case the 60/480th of application on June 23rd, 2003, No. 984 (attorney NBI-152-1), the United States Patent (USP) provisional application case the 60/512nd of 17 applications October in 2003, No. 116 (attorney NBI-152-2) (above-mentioned two parts of applications all are entitled as " pharmaceutical preparation of amyloid inhibiting compounds "), and on June 18th, 2004 the U.S. Patent application 10/XXX that is entitled as " pharmaceutical preparation of amyloid inhibiting compounds " that applied for, XXX number (attorney NBI-152).

The application is involved in the United States Patent (USP) provisional application case the 60/436th that is entitled as " conjoint therapy that is used for the treatment of the Alzheimer connection " of December 24 applications in 2002, No. 379 (attorney NBI-154-1), United States Patent (USP) provisional application case the 60/482nd in application on June 23rd, 2003, No. 214 (attorney NBI-154-2), No. the 10/746th, 138, the novel patent application case of U.S. utility (attorney NB I-154) in December 24 applications in 2003, and the International Patent Application PCT/CA2003/002011 (attorney NBI-154PC) that is entitled as " therapeutic agent that is used for the relevant treatment of diseases of β-starch albumen ".The application relates to the United States Patent (USP) provisional application case the 60/482nd of application on June 23rd, 2003, the United States Patent (USP) provisional application case the 60/512nd of No. 058 (attorney NBI-156-1), on October 17th, 2003 application, the U.S. patent application case 10/XXX that is entitled as " improved drug candidate and preparation method thereof " of No. 135 (attorney NBI-156-2) (above-mentioned two parts of applications all are entitled as " synthetic method that is used to prepare the chemical compound for the treatment of amyloidosis ") and application on June 8th, 2004, XXX number (attorney NBI-156).The application also relates to the United States Patent (USP) provisional application case the 60/480th of application on June 23rd, 2003, the United States Patent (USP) provisional application case the 60/512nd of No. 918 (attorney NB I-149-1), on October 17th, 2003 application, the U.S. patent application case 10/XXX that is entitled as " method of treatment protein condenses disorder " of No. 017 (attorney NBI-149-2) and on June 18th, 2004 application, XXX number (attorney NBI-149).The application also relates to the United States Patent (USP) provisional application case the 60/480th of application on June 23rd, 2003, No. 906 (attorney NBI-162-1), the United States Patent (USP) provisional application case the 60/512nd of 17 applications October in 2003, No. 047 (attorney NBI-162-2), the U.S. patent application case 10/XXX of application on June 18th, 2004, the U.S. Patent application 10/XXX of XXX number (attorney NBI-I62A) and on June 18th, 2004 application, XXX number (attorney NBI-162B) (above-mentioned application all is entitled as " compositions and the method that are used for the treatment of the relevant disease of amyloid "); And the United States Patent (USP) provisional application case the 60/480th of application on June 23rd, 2003, the United States Patent (USP) provisional application case the 60/512nd of No. 928 (attorney NBI-163-1), on October 17th, 2003 application, the U.S. patent application case 10/XXX of No. 018 (attorney NBI-163-2) and on June 18th, 2004 application, XXX number (attorney NBI-163) (above-mentioned application all is entitled as " compositions and the method for the disease that the treatment amyloid is relevant with epilepsy "; The application also relates to the method for the treatment of amyloidosis (No. 08/463,548, U.S. patent application case now is United States Patent (USP) U.S5,972,328, attorney NCI-003CP4).

Above-mentioned patent application or patent mode is by reference comprised in this application clearly in full, and this includes, but are not limited to description, claims, summary and image, form and the accompanying drawing of these patent applications or patent.

Background of invention

Amyloidosis is meant a kind of pathological condition that is in the amyloid fibril that is characterised in that.Amyloid relates to one group and appears at various in many various disease but the generic term of particular proteins deposit (in the born of the same parents or born of the same parents outer).Although their appearance is diversified, all amyloid beta depositions all have common morphological characteristic, by specific dyestuff (for example Congo red) dyeing, and have red-green birefringence feature after the dyeing in polarized light.They also enjoy common ultrastructure feature and common X-ray diffraction and infrared spectrum.

The disease that amyloid is relevant can be limited to an organ or spread all over a plurality of organs.First kind of situation is called as " locality amyloidosis ", and second kind of situation is called as " SA ".

Some amyloid diseases can be paroxysmal, occur but most these diseases all are forms with a kind of complication of disease of preexist.For example, primary amyloid degeneration (AL amyloid) can occur under the condition of the pathological condition that any other does not occur, perhaps can be accompanied by plasma cell dyscrasia or multiple myeloma and occurs.

Secondary amyloidosis is accompanied by chronic infection (for example pulmonary tuberculosis) or chronic inflammatory disease (for example rheumatoid arthritis) usually and shows effect.A kind of familial form of secondary amyloidosis also sees the familial amyloidosis of other types, for example, and familial Mediterranean fever (FMF).The amyloidosis of this familial type be by gene genetic and be common among the specific crowd.In constitutional and secondary amyloidosis, all in a plurality of organs, find deposition, and thereby be considered to general amyloid disease.

" local amyloidosis " is those amyloidosis of tending to influence single tract.The feature of different amyloids also is the proteinic type in this deposition.For example, neurodegenerative disease (for example itch, bovine spongiform encephalitis, creutzfeldt-jakob disease etc.) is characterised in that the appearance and the accumulation of the protease opposing agent form of a kind of prion protein in the central nervous system.Similarly, Alzheimer---another neurodegenerative disease---is characterised in that neural inflammatory plaque and neurofibril disorder.In this case, being found in amyloid plaque in parenchyma and the blood vessel is formation of deposits by fibril A amyloid beta matter.Other disease, for example maturity-onset diabetes (type ii diabetes) is characterised in that the localized accumulated of the amyloid fibril in the pancreas.

In case form these amyloids, just there are not a kind of known and well accepted therapy or therapeutic scheme to dissolve the amyloid beta deposition thing significantly in position, prevent further amyloid beta deposition or prevention to cause amyloid beta deposition.

Each amyloidosis protein has and can stand conformation change and form β-layer form, and form can be in extracellular or cell sedimentary insoluble fibril.Each amyloidosis protein, although the amino acid sequence difference, have form fibril and with other the bonded common trait of composition (for example proteoglycan, amyloid P and supplemental components).In addition, although the proteinic amino acid sequence of each amyloidosis is inequality, but but demonstrate similarity, such as the zone of the ability that can partly (be called the GAG binding site) and other zones that promote β-layer formation in conjunction with the glycosaminoglycans (GAG) of proteoglycan.Proteoglycan for almost spread all in the body everywhere all size and the macromole of structure.They can be found in the interior lacuna of born of the same parents, on the cell surface, and can be used as the parts of fine extracellular matrix.All the basic structure of proteoglycan comprises a core protein and at least a, but usually multiple, is connected to the polysaccharide chain (GAGs) on the core protein.Had been found that many different GAGs, this comprises chondroitin sulfate, dermatan sulfate, keratan sulfate, heparin and hyaluronic acid element (hyaluronan).

In specific situation, the amyloid fibril is in case deposition just can become poisonous to cell on every side.For example, verified: the Ap fibril that forms senile plaque is relevant with dead neuronal cell, poor nutrition aixs cylinder, astrocytosis and microglioma in the Alzheimer object.When testing in vitro, the arithmetical series peptide of oligomerization (solvable) and fibril as shown can an activation process of trigger (brain macrophage), this will explain microglioma and the brain inflammation of being found in the patient's who has Alzheimer brain.Oligomerization and fibril A β peptide all can also cause neuronal cell death external.For example consult, MP Lambert etc., Proc.Natl.Acad.Sci.USA 95,6448-53 (1998).In the amyloidosis of another type of in the type ii diabetes patient, being found, when amyloidosis protein IAPP forms oligomerization form or fibril form, demonstrated in external meeting and caused β-islet cells toxicity.Therefore, the appearance of the IAPP in type ii diabetes patient's pancreas has caused the loss of β islet cells (Langerhans) and the organ dysfunction that can cause insulinemia.

The amyloidosis and the β of another kind of type ₂Microglobulin is correlated with and is found among the patient who carries out hemodialysis for a long time.The patient who accepts hemodialysis for a long time can form β in canalis carpi and in the tissue that is rich in collagen in a plurality of joints ₂The microglobulin fibril.This will cause serious pain, ankylosis and joint to be expanded.

Amyloidosis also is the feature of Alzheimer.Alzheimer is a kind of serious brain diseases that causes the gradual loss of memory, and this disease causes peralytic dementia, physiological defect and death in a relatively long time.Along with the aged tendency of population of developed country, Alzheimer's disease patient's quantity has reached high ratio.

Suffer the patient of Alzheimer in the manhood, to produce a progressive peralytic dementia, and be attended by three main structural changes: the neuronic divergence loss of a plurality of parts of brain at brain; Be called as the sedimentary accumulation of intracellular protein of neurofibril disorder; And the sedimentary accumulation of the exoprotein that is called as amyloid or senile plaque, and be accompanied by lopsided teleneuron (poor nutrition aixs cylinder) and activation microglia (microglioma and astrocytosis).A main component of these amyloid plaques is amyloid-β peptide (Ap), and this is a kind of 39～43 amino acid whose protein that produce by the division of amyloid beta protein precursor albumen (APP).Carried out extensive studies, for example consulted, Selkoe, Trends in CellBiology 8,447-453 (1998) at the sedimentary association of A β in the Alzheimer.AD results from endoplasmic reticulum (" ER "), Golgi body or the nuclear usually-and amyloid precursor protein in the lysosome passage is (" during the metabolism of APP ") handles, and secreted into one 40 (" A β 1-40 ") or 42 (" the individual amino acid whose peptide (Selkoe of A β 1-42 ") usually, Annu.Rev.Cell Biol.10,373-403 (1994)).A β supports by following aspect as the effect of a main cause of Alzheimer: the sedimentary appearance of A β outside the born of the same parents in the senile plaques of Alzheimer, the growth of AD in the cell of implicit variation Alzheimer related gene (for example amyloid precursor protein, presenilin-1 I and presenilin-1 II) increases, and born of the same parents' outer solvable (oligomerization) or fibrillar AD are for the toxicity of the cell in cultivating.For example consult Gervais, Eur.Biopharm.Review, 40-42 (autumn calendar year 2001); May, DDT6,459-62 (2001).Although the symptomatiatria for Alzheimer has been arranged, this moment, this disease can't obtain prevention or healing.

Alzheimer is characterised in that diffusion and neural inflammatory plaque, large cerebrovascular disease and neurofibrillary tangles.Plaque and blood vessel amyloid are considered to be described to spread or the proteinic formation of deposits of insoluble A beta amyloid of fibril.The oligomerization A β of solubility and fibrillar A β are considered to neurotoxicity and struvite.

The amyloidosis of another type is a brain amyloid angiopathy (CAA).CAA is the specificity deposition of amyloid-beta fibril in leptomingeal and cortex tremulous pulse, small artery and venous tube wall.Its common and Alzheimer, mongolism and natural aging, and the various familial diseases relevant with apoplexy or peralytic dementia are relevant (consults Frangione etc., Amyloid:J.Protein Folding Disord.8, Suppl.1,36-42 (2001)).

The therapy that is used for the treatment of the amyloid disease at present almost is symptomatiatria all, and clinical effectiveness temporary transient or part can only be provided.Can the part mitigation symptoms although described some pharmaceutical preparatioies, still there is not a kind of comprehensive pharmacotherapy to be used for the prevention and the treatment of Production Example such as Alzheimer at present.

Summary of the invention

The invention provides the method, compositions and the preparation that are used for the treatment of amyloidosis.Method of the present invention comprises taking to this object and a kind ofly can suppress sedimentary therapeutic combination of amyloid or preparation.

Therefore, the compositions and methods of the invention can be used in inhibition the sedimentary amyloidosis disease of amyloid wherein take place.Method of the present invention can be used for the treatment of the amyloid distortion or can prophylactically be used for amyloidosis susceptible patient in treatment.

On the one hand, method of the present invention to small part deposits to suppress amyloid based on the interaction that suppresses between amyloidosis protein and the basement membrane component.In specific instantiation, the component of this basement membrane is a kind of glycoprotein or proteoglycan, preferred agrin, perlecan or Heparan sulfate proteoglycan.Employed treatment chemical compound can hinder the basement membrane component to be attached to the proteinic target site of amyloidosis in the method for the present invention, thereby suppresses the amyloid deposition.In other instantiation, employed treatment chemical compound can improve amyloid clear from brain in the method for the present invention, thereby suppresses the amyloid deposition.In other instantiation, employed treatment chemical compound can suppress amyloid (for example, by solvable or insoluble amyloid, for example fibril in the method for the present invention; By the amyloid deposition and/or by amyloid-β, the nervus retrogression degeneration or the cytotoxicity that cause as described here).

Aspect preferred, the present invention relates to the purposes of alkyl sulfonic acid in the relevant treatment of diseases of amyloid.

Therefore, on the one hand, the present invention relates to a kind of sedimentary method of patient amyloid that is used for suppressing, it comprises the treatment preparation of taking effective dose to this object, described treatment preparation contains a kind of being made into significantly to be reduced or prevents the bad treatment chemical compound of gastrointestinal tolerant, thereby suppresses the amyloid deposition.

On the other hand, the present invention relates to the method for the disease (for example A β-relevant disease) that amyloid is relevant among a kind of treatment or the prevention patient, it comprises the treatment preparation of taking a kind of therapeutic dose to this object, described treatment preparation contains a kind of being made into significantly to be reduced or prevents the bad treatment chemical compound of gastrointestinal tolerant, thus treatment or the relevant disease of prevention amyloid.

On the other hand, the present invention relates to a kind of sedimentary method of amyloid that is used for suppressing object, it comprises the treatment preparation of taking a kind of effective dose to this object, described treatment preparation contains a kind of treatment chemical compound that gastrointestinal tolerant is bad that is made into significantly to reduce or prevent, thereby the interaction that this chemical compound suppresses between amyloidosis protein and the basement membrane component deposits to suppress amyloid.

Another aspect of the present invention comprises a kind of sedimentary method of amyloid that suppresses in the object, it comprises the treatment preparation of taking a kind of effective dose to this object, described treatment preparation contains a kind of treatment chemical compound that gastrointestinal tolerant is bad that is made into significantly to reduce or prevent, thereby this treatment chemical compound can suppress that amyloid causes (for example by solubility or insoluble starch shape albumen, for example fibril causes; Cause nervus retrogression degeneration or cytotoxicity as described here) by amyloid deposition and/or by amyloid-β.

On the other hand, chemical compound of the present invention relates to a kind of sedimentary method of amyloid that is used for suppressing object, it comprises the treatment preparation of taking a kind of effective dose to this object, described treatment preparation contains a kind of treatment chemical compound that gastrointestinal tolerant is bad that is made into significantly to reduce or prevent, thereby this treatment chemical compound improves amyloid from cleaning up between brain.

In yet another aspect, the present invention relates to a kind of sedimentary method of amyloid that is used for suppressing object, it comprises the treatment preparation to the oral a kind of effective dose of patient, and described treatment preparation contains a kind of treatment chemical compound that gastrointestinal tolerant is bad that is made into significantly to reduce or prevent.

Another aspect of the present invention is a kind of sedimentary pharmaceutical composition of amyloid that is used for suppressing object, it comprise contain a kind of be enough to suppress in the object the sedimentary amount of amyloid be made into significantly reduce or prevent the treatment chemical compound that gastrointestinal tolerant is bad, and the treatment preparation of pharmaceutically acceptable carrier.

Another aspect of the present invention relates to a kind of pharmaceutical composition that is used for the treatment of amyloidosis, it comprise a kind of be enough to suppress in the object the sedimentary amount of amyloid be made into significantly to reduce or prevent the treatment chemical compound that gastrointestinal tolerant is bad and the treatment preparation of pharmaceutically acceptable carrier.

On the other hand, the present invention relates to a kind of pharmaceutical composition that is used for the treatment of or prevents the relevant disease of amyloid (for example relevant disease of A β), it comprise a kind of contain be enough to prevent or treatment target in the relevant disease of amyloid be made into significantly to reduce or prevent treatment chemical compound and the pharmaceutically acceptable carrier that gastrointestinal tolerant is bad.

Another aspect, the present invention relates to a kind of sedimentary method of the amyloid that has the sedimentary patient of amyloid that is used to reduce, this method comprises the treatment preparation of taking a kind of effective dose to this object, described treatment preparation contains a kind of treatment chemical compound that gastrointestinal tolerant is bad that is made into significantly to reduce or prevent, thereby reduces patient's amyloid deposition.

Another aspect of the present invention relates to a kind of chemotactic factor and bonded method of glycosaminoglycans that is used for suppressing object, it comprises to this object takes a kind of treatment preparation, described treatment preparation contains a kind of being made into significantly reduces or prevents the treatment chemical compound that gastrointestinal tolerant is bad, thereby has suppressed combining of chemotactic factor and glycosaminoglycans.

Another aspect of the present invention relates to the interactional method of a kind of mediator's apoplexy due to endogenous wind antibacterial and glycosaminoglycans, and it comprises to this object takes the treatment preparation that containing of a kind of effective dose is made into significantly to reduce or prevent the treatment chemical compound that gastrointestinal tolerant is bad.

In yet another aspect, the present invention relates to a kind of method that is used at mankind's treatment bacterial infection, it comprises the treatment preparation to the oral a kind of effective dose of the mankind, and described treatment preparation contains a kind of treatment chemical compound that gastrointestinal tolerant is bad that is made into significantly to reduce or prevent.

On the other hand, the present invention relates among a kind of patient of adjusting the interactional method of virus and glycosaminoglycans, it comprises the treatment preparation of taking a kind of effective dose to this object, and described treatment preparation contains a kind of treatment chemical compound that gastrointestinal tolerant is bad that is made into significantly to reduce or prevent.

Another aspect of the present invention relates to the method for a kind of patient's of treatment viral infection, and it comprises to this object takes the treatment preparation that containing of a kind of effective dose is made into significantly to reduce or prevent the treatment chemical compound that gastrointestinal tolerant is bad.

Another aspect of the present invention relates to a kind of prevention, treatment or suppresses the method for the brain amyloid angiopathy in the object, it comprises takes a kind of effective dose treatment preparation, and described treatment preparation contains a kind of treatment chemical compound that gastrointestinal tolerant is bad that is made into significantly to reduce or prevent.

On the other hand, the present invention relates to the method for a kind of prevention, treatment or inhibition brain amyloid angiopathy, it comprises cells of vascular wall is contacted with a kind of treatment preparation, described treatment preparation contains a kind of being made into significantly to be reduced or prevents the treatment chemical compound that gastrointestinal tolerant is bad, thereby brain amyloid angiopathy has obtained prevention, treatment or inhibition.

On the other hand, the present invention relates to the method for a kind of prevention, treatment or inhibition brain amyloid angiopathy, it comprises cells of vascular wall is contacted with a kind of treatment preparation, described treatment preparation contains a kind of being made into significantly to be reduced or prevents the treatment chemical compound that gastrointestinal tolerant is bad, thereby brain amyloid angiopathy has obtained prevention, treatment or inhibition.

Another aspect of the present invention relates to a kind of prevention, treatment or suppresses the method for the Alzheimer in the object, it comprises the treatment preparation of taking a kind of effective dose to this object, and described treatment preparation contains a kind of treatment chemical compound that gastrointestinal tolerant is bad that is made into significantly to reduce or prevent.

Another aspect of the present invention relates to the Alzheimer in a kind of prevention, treatment or the inhibition object, it comprises the treatment preparation of taking a kind of effective dose to this object, described treatment preparation contains a kind of being made into significantly to be reduced or prevents the treatment chemical compound that gastrointestinal tolerant is bad, thereby Alzheimer has obtained prevention, treatment or inhibition.

On the other hand, the present invention relates to a kind of sedimentary pharmaceutical composition of amyloid that is used for suppressing object of packing, it comprises a kind of container that is made into significantly to reduce or prevent the treatment chemical compound that gastrointestinal tolerant is bad that contains that keeps the treatment effective dose; And this is used for suppressing the operation instructions of the sedimentary chemical compound of amyloid of object.

Aspect another, the present invention relates to a kind of pharmaceutical composition that is used for the treatment of the amyloidosis in the object of packing, it comprises a kind of container that is made into significantly to reduce or prevent the treatment chemical compound that gastrointestinal tolerant is bad that contains that keeps the treatment effective dose; And this is used for the treatment of the operation instructions of the chemical compound of the amyloidosis in the object.

Aspect another, the present invention relates to a kind of pharmaceutical composition that is used for the treatment of the Alzheimer in the object of packing, it comprises a kind of container that is made into significantly to reduce or prevent the treatment chemical compound that gastrointestinal tolerant is bad that contains that keeps the treatment effective dose; And this is used for the treatment of the operation instructions of the chemical compound of the Alzheimer in the object.

Another aspect of the present invention be a kind of packing be used for the treatment of the medicine for treating viral infections compositions, it comprises that one keeps the treatment effective dose to contain a kind of container that is made into significantly to reduce or prevent the treatment preparation of the treatment chemical compound that gastrointestinal tolerant is bad; And this is used for the treatment of the operation instructions of the chemical compound of viral infection.

On the other hand, the present invention relates to a kind of pharmaceutical composition that is used for the treatment of bacterial infection of packing, it comprises that a maintenance contains a kind of container that is made into significantly to reduce or prevent the treatment preparation of the treatment chemical compound that gastrointestinal tolerant is bad for the treatment of effective dose; And the operation instructions of this treatment chemical compound that is used for the treatment of.

On the other hand, what the invention belongs to a kind of packing is used for chemokine inhibiting and the bonded pharmaceutical composition of glycosaminoglycans, and it comprises that keeps a kind of a kind of treatment preparation that is made into significantly to reduce or prevent the treatment chemical compound that gastrointestinal tolerant is bad of containing of effective dose for the treatment of; And this is used for the operation instructions of chemokine inhibiting and the bonded treatment chemical compound of glycosaminoglycans.

Another aspect the present invention relates to a kind of manufacturing and comprises and be mixed with a kind of described method of treatment preparation for the treatment of the treatment chemical compound and the pharmaceutically acceptable carrier of effective dose, and it is bad with remarkable reduction or prevention gastrointestinal tolerant wherein to prepare this treatment preparation.

On the other hand, the present invention relates to a kind of 3-amino-1-propane sulfonic acid that comprises greater than 5 weight %.

On the other hand, the present invention relates to a kind of pharmaceutical preparation, its comprise a kind of treat chemical compound with greater than the other reagent of 1 weight %.

On the other hand, the present invention relates to the sedimentary method of amyloid among a kind of inhibition patient, it comprises the treatment preparation of taking a kind of effective dose to this object, and described treatment preparation comprises the treatment chemical compound that a kind of preparation has enteric coating, thereby has suppressed the amyloid deposition.

On the other hand, the present invention relates to the sedimentary method of amyloid among a kind of inhibition patient, it comprises the treatment preparation of taking a kind of effective dose to this object, described treatment preparation comprises the treatment chemical compound that a kind of preparation has the reagent of the release that can change this treatment chemical compound, thereby has suppressed the amyloid deposition.

In addition, another aspect of the present invention is a kind of sedimentary pharmaceutical composition of amyloid that is used for suppressing object, and it comprises the treatment chemical compound that a kind of preparation has enteric coating, thereby has suppressed the amyloid deposition.

On the other hand, the present invention relates to a kind of sedimentary pharmaceutical composition of amyloid that is used for suppressing object, it comprises the treatment chemical compound that a kind of preparation has the reagent of the release that can change this treatment chemical compound, thereby has suppressed the amyloid deposition.

On the other hand, the present invention relates to a kind of method of preparing the bad pharmaceutical composition that has strengthened of gastrointestinal tolerant, it comprises: a kind of treatment chemical compound of preliminary election is mixed with a kind of pharmaceutically acceptable carrier, remarkable reduction or the prevention gastrointestinal tolerant bad ability that preliminary election should the treatment chemical compound wherein, thus the bad pharmaceutical composition that has strengthened of gastrointestinal tolerant formed.

On the other hand, the present invention relates to the method for the disease that amyloid is relevant among a kind of prevention or the treatment patient, it comprises the treatment preparation of taking a kind of effective dose to this object, described treatment preparation comprises the treatment chemical compound that a kind of preparation has enteric coating, thus prevention or the relevant disease of treatment amyloid.

On the other hand, the present invention relates to the method agent of the disease that amyloid is relevant among a kind of prevention or the treatment patient, it comprises the treatment preparation of taking a kind of effective dose to this object, described treatment preparation comprises the treatment chemical compound that a kind of preparation has the reagent of the release that can change this treatment chemical compound, thereby prevents or treated the relevant disease of amyloid.

On the other hand, the present invention relates to the pharmaceutical composition of the disease that amyloid is relevant among a kind of prevention or the treatment patient, it comprises the treatment preparation of taking a kind of effective dose to this object, and described treatment preparation comprises the treatment chemical compound that a kind of preparation has enteric coating.

Another aspect the present invention relates to a kind ofly be used for preventing or the pharmaceutical composition of the disease that the amyloid of treatment target is relevant, and it comprises the treatment chemical compound that a kind of preparation has the reagent of the release that can change this treatment chemical compound.

The detailed content of invention

The present invention relates to be used for the treatment of method, compositions and the preparation of amyloidosis.Method of the present invention comprises to this object takes a kind of treatment preparation that can suppress the sedimentary treatment chemical compound of amyloid.Therefore, (for example the invention particularly relates to the treatment preparation, comprise alkyl sulfonic acid) in the prevention of the relevant disease of amyloid or the purposes in the treatment, the disease that wherein said amyloid is relevant especially comprises Alzheimer, brain amyloid angiopathy, inclusion body myositis, degeneration of macula, Tang Shi innate stupid disease, mild cognitive damage and type ii diabetes.

I. the relevant disease of amyloid

The present invention relates to comprise the pharmaceutical composition or the purposes of preparation in the relevant treatment of diseases of amyloid for the treatment of chemical compound.The disease that many amyloid are relevant is known, and undoubtedly exists.

AA (reactivity) amyloidosis

Usually, AA amyloidosis is many a kind of clinical manifestations that can evoke the disease of lasting acute phase response.This disease comprises chronic inflammation disease, chronic part or general bacterial infection and malignant tumor.The modal form of reactive or secondary (AA) amyloidosis is considered to the result of long-standing diseases associated with inflammation.For example, the patient who suffers from rheumatoid arthritis or familial Mediterranean fever (a kind of genetic diseases) can be developed and AA amyloidosis." AA amyloidosis is " with " " but mutual alternative ground uses secondary (AA) amyloidosis term.

The AA fibril generally includes fragment that the 8000 daltonian proteolysis divisions that serum amyloid A protein (ApoSAA) arranged form, a kind of mainly for adapting to therefore synthetic circulation apolipoprotein in the hepatocyte as IL-1, IL-6 and TNF of this cell.In case secretion, ApoSAA just cooperates with HDL.The fibriilar deposition of AA can spread all in the body, and preferred soft tissue organs.Kidney is a deposition site normally, and liver and spleen also may be affected.In heart, gastrointestinal tract and skin, also can find this deposition.

The disease of essence that can cause producing AA amyloidosis is including, but not limited to diseases associated with inflammation, for example rheumatoid arthritis, juvenile chronic arthritis, ankylosing spondylitis, chronic eczema, psoriasis arthrosis, conjunctivo-urethro-synovial syndrome, adult's Chauffard-Still disease, Behcet and Crohn disease.The AA deposition can also cause owing to chronic bacterial infection, for example be caused by leprosy, pulmonary tuberculosis, bronchiectasis, decubital ulcer, chronic pyelonephritis, osteomyelitis and intestinal lipodystroph.Some malignant tumor also can cause AA fibril amyloid deposition.This comprises for example Huo Qijin Lin Shi crust tumor, kidney malignant tumor, intestinal lung and urogenital tract malignant tumor, rodent ulcer and hairy cell leukemia.Other the disease that may be correlated with in AA amyloidosis be CastlemanShi disease and Schnitzler syndrome.

AL amyloidosis (primary amyloidosis)

The AL amyloid deposition dyscrasia with any bone-marrow-derived lymphocyte blood lineage almost usually is relevant, and this comprises from plasmacytic malignant tumor (multiple myeloma) to optimum monoclonal gammopathy.Sometimes, the sedimental existence of amyloid may be the dyscrasic leading indicator of essence.At Current Drug Targets, 2004, described amyloidosis among the 5159-171 in detail.

The sedimentary fibril of AL amyloid is made up of monoclonal immunoglobulin light chain or its fragment.More particularly, this fragment comes from the N-end group district (κ or λ) of light chain and comprises all or part of that it can be by (VL) scope.Deposition usually occurs in the stroma, causes arthrosis, immune dyscrasia, myeloma and the recessive dyscrasia in periphery and autonomy neuropathy, carpal tunnel syndrome, macroglossia, restrictive cardiomyopathy, big joint.Yet it should be noted that: nearly all tissue, particularly internal organs for example kidney, liver, spleen and heart all may be related to.

Heritability whole body amyloidosis

Many hereditary SAs are arranged.Although be rare relatively disease, adult onset symptom and their hereditary pattern (normally autosome is arranged) cause continuing of this disease in many crowds.Usually, this syndrome is attributable to the point mutation that causes producing albuminous degeneration heritability peptide or proteinic precursor protein at this.Table 1 has been summarized the fibril compositions of the exemplary form of these diseases.

The exemplary amyloid fibril compositions-relevant disease of table 1-

Fibril peptide/protein	The genetic variant	Clinical syndrome
			Derive from the ATTR protein and the fragment of transthyretin	Met30, other many kinds	Familial amyloid shape albumen polyneuropathy (FAP), (being mainly peripheral nervous)
Derive from the ATTR protein and the fragment of transthyretin	Thr45，Ala60，Ser84， Met111，Ile122	Be not with chaotic outstanding, the familial amyloid shape albumen polyneuropathy of neuropathic heart, senile systemic amyloidosis, Tenosynovium
			The N-end group fragment of ApoA 1 (AapoAI)	Arg26	Familial amyloid shape albumen polyneuropathy (FAP), (being mainly peripheral nervous)

Table 1 (continuing)

The N-end group fragment of Apoliproprot ein A1 (AapoAI)	Arg26, Arg50, Arg60, other	(being mainly the internal organs confusion) of Ostertag type, non-neuropathic
			Apolipoprotein aii		Familial amyloidosis
Lysozyme (Alys)	Thr56，His67	(being mainly the internal organs confusion) of Ostertag type, non-neuropathic
			Fibrous root α chain fragment	Leu554，Val526	The skull neuropathy that has lattice corneal dystrophy
Gelsolin fragment (Age1)	Asn187，Tyr187	The skull neuropathy that has lattice corneal dystrophy
			Cystatin c fragment (ACys)	Glu68	Hereditary cerebral hemorrhage (brain amyloid angiopathy)-Iceland's type
The amyloid beta matter (A β) that comes from amyloid precursor protein (APP)	Gln693	Hereditary cerebral hemorrhage (brain amyloid angiopathy)-Dutch type
			The amyloid beta matter (A β) that comes from amyloid precursor protein (APP)	Ile717，Phe717，Gly717	The familial Alzheimer
The amyloid beta matter (A β) that comes from amyloid precursor protein (APP), for example, bPP 695	Gln618	Alzheimer, Tang Shi innate stupid disease, hereditary cerebral hemorrhage and amyloidosis, Dutch type

Table 1 (continuing)

The amyloid beta matter (A β) that comes from amyloid precursor protein (APP)	Asn670，Leu671	Familial peralytic dementia-possible Alzheimer
			Derive from the prion protein (PrP, APrPsc) (51-91 insert) of Prp precursor protein	Leu102，Val167， Asn178，Lys200	Familial Creutz Fil spy-Jakob's disease; Gerstmann-Str_ussler-Scheinker syndrome (heritability spongiform encephalopathy, prion disease)
Be derived from the proteinic AA of serum A amyloid A (ApoSAA)		Familial Mediterranean fever, advantage kidney confusion (autosome degeneration)
			Be derived from the proteinic AA of serum A amyloid A (ApoSAA)		Muckle-Well syndrome, nephropathy, deaf and dumb, urticaria, limbs pain
Unknown		The cardiomyopathy that has lasting atrial standstill
			Unknown		Skin deposits (bulla, pimple, pus skin)
Be derived from the AH amyloid protein (γ I) of heavy chain immunoglobulin	AγI	Myeloma association amyloidosis
			ACal amyloid protein from (urging) thyrocalcitonin	(urging) thyrocalcitonin	Thyroid medullary carcinoma

Table 1 (continuing)

AANF amyloid protein from atrial natriuretic peptide		Isolated atrial amyloid
			Be derived from the Apro of prolactin antagonist		Prolactinoma
Be derived from the Abri/ADan of ABri peptide		Britain and Denmark's familial peralytic dementia

Data are from Tan SY, Pepys MB.Amyloidosis.Histopathology, 25 (5), 403-414 (in November, 1994), WHOPS term sub-committee, the term of amyloid and amyloidosis.Bulletin of the World HealthOrganisation 1993; 71:10508; With Merlini etc., Clin Chem Lab Med2001; 39 (11): 1065-75.

The data of table 1 are exemplary, rather than to the restriction of scope of the present invention.For example, described the independently point mutation of transthyretin gene kind above 40, it can cause the clinical form that is similar to familial amyloid shape albumen polyneuropathy all.

Usually, also heritability amyloid disease can take place once in a while, and the disease of heritability and sporadic form all shows the similarity relevant with amyloid.For example, the most general form of secondary AA amyloidosis can take place owing to lasting inflammation once in a while, and does not get in touch with familial Mediterranean fever.Hereinafter the generality discussion about heritability amyloid disease also can be used for sporadic amyloidosis.

Transthyretin (TTR) is a kind of protein of 14 kilodaltons, and it is also sometimes referred to as prealbumin.It produces by liver and choroid plexus, and brings into play function in transmission thyroxin and vitamin A.These proteinic at least 50 mutation, it is characterised in that separately single amino acids changes, and is all relevant with the various forms of familial amyloid shape albumen polyneuropathy.For example, use proline to replace leucine at 55 and cause neuropathic a kind of radical especially form; Use methionine to replace leucine at 111 and in the danish type patient, cause serious heart disease.

Isolating amyloid deposit shows from the patient's that suffers from SA heart tissue: this deposit is made up of the heterogeneous mixture of TTR and fragment thereof, it is called as ATTR respectively, and its whole sequence has all obtained sign.ATTR fibril component can be from this plaque, extracted, and their structure and sequence (for example, Gustavsson, A. etc., Laboratory Invest.73:703-708,1995 can be measured according to methods known in the art; Kametani, F. etc., Biochem.Biophys.Res.Commun.125:622-628,1984; Pras, M. etc., PNAS 80:539-42,1983).

(people who for example has point mutation among Glye → Arg26, Trpo → Arg50, the Leu → Arg60) shows a kind of this protein apolipoprotein AI or its segmental sedimentary amyloidosis (" Ostertag type ") of being characterised in that at molecule ApoA 1.These patients have low-level high density lipoprotein (HDL) and have peripheral neuropathy or renal failure.

(for example the sudden change in the α chain of Ile → Thr56 or Asp → His57) is the basis of the heritability amyloid of the another kind Ostertag type non-neuropathic that sees Britain family in the α of this enzyme lysozyme series.In this description, the fibril (Alys) of the antalzyme protein matter of variation is deposited, and the patient demonstrates impaired renal function usually.Different with most of fibrils described herein formation property protein, this protein (Benson, M.D. etc., CIBA Fdn.Symp.199:104-131,1996) occur with a kind of integral body (unsegmented) form usually.

Light chain immunoglobulin tends to form the gathering of various forms, this (for example comprises the filamentous form, AL amyloidosis and AH amyloidosis), granular form (light chain storage disorders (LCDD), heavy chain storage disorders (HCDD) and weight chain storage disorders (LHCDD)), crystal habit (for example, the day after tomorrow Farconi syndrome) and microtubular form (for example cryoglobulinemia).AL and AH amyloidosis are respectively that insoluble defibrillation dimension and/or their the segmental formation by light chain immunoglobulin and heavy chain shows.In the AL fibril, for example the ratio of viscosities κ chain of λ VI chain (λ 6 chains) is big to find the λ chain.λ III chain also has slight rising.Merlini etc., CLIN CHEM LABMED 39 (11): 1065～75 (2001).

The feature of heavy chain amyloidosis (AH) is the proteinic gathering of heavy chain amyloid of IgG1 subclass usually.Eulitz etc., PROC NATL ACAD SCI USA 87:6542～46 (1990).

As if more showing of the light chain of amyloidosis and non-amyloidosis: the former can comprise makes the Protein Folding instability and promotes accumulative displacement group or substituted radical.It is different significantly that AL and LCDD and other amyloid disease have, and this is thereby they have relative advantages of small integral monoclonal light chain or its fragment, and described light chain is that the tumor expansion by the B cell of antibody manufacturing forms.AL assembles normally well-ordered λ chain.It is the relative unordered gathering with the λ chain of κ chain that fibril LCDD assembles, and great majority are κ, in some cases, is mainly κ IV.Bellotti etc., J0URNAL OF STRUCTURALBIOLOGY 13:280-89 (2000).What have amyloidosis and heavy chain non-amyloidosis among the patient of AH amyloidosis more demonstrates the component of losing and/or changing.Eulitz etc., PROC NATL ACAD SCI USA 87:6542-46 (1990) (pathogenic heavy chain, it is characterized in that molecular mass significantly is lower than non-amyloidosis heavy chain) and Solomon AMJHEMAT 45 (2) 171～6 (1994) (the amyloidosis heavy chain is characterized in that only comprising the VH-D part of non-amyloidosis heavy chain).

Therefore, detect or monitoring suffers from or the patient's of susceptible AL, LCDD, AH etc. potential method includes but not limited to immunity inspection blood plasma or urine, to detect amyloidosis light chain or heavy chain, for example, amyloid γ, amyloid κ, amyloid κ iv, amyloid, otherwise the existence of amyloid γ 1 or inhibition deposition.

Cerebral amyloidosis

The most frequent type of amyloid in brain mainly comprises Ap peptide fibril, causes and the relevant peralytic dementia of sporadic (nongenetic) Alzheimer.In fact, the incidence rate of sporadic Alzheimer substantially exceeds the genetic form that is indicated as.Yet, all closely similar at these two type Central Plains Fibrinopeptide formation property plaques.Cerebral amyloidosis comprise pathogen wherein be the structure of brain (comprising its ingredient) of amyloid or function disease, disease, condition of illness, and other are unusual.The brain scope that infects in the relevant disease of amyloid can be to comprise the substrate of vasculature or comprise function or the soft tissue of tissue regions or neuron itself.The patient need not the diagnosis of the certainty of the relevant disease of the amyloid accepting to confirm particularly.Term " disease that amyloid is relevant " comprises cerebral amyloidosis.

Amyloid-β peptide (" A β ") is deutero-39～43 the amino acid whose peptides of proteolysis from the larger protein that is called as beta amyloid precursor protein (" β APP ").Sudden change among the β APP causes the familial form of Alzheimer, Tang Shi innate stupid disease, brain amyloid angiopathy and alzheimer disease, it is characterized in that the brain deposition of the plaque formed as hereinafter further specifically described A β fibril and other components.The sudden change of the known APP relevant with Alzheimer occurs near the cleavage site near β or gamma secretase, or in A β inside.For example, position 717 is near β or the splitted position of gamma-secretase of the APP in being processed into A β, and position 670/671 is near the splitted position of beta-secretase.Sudden change in any of these residue may cause Alzheimer, and this estimation is by causing that generation causes from the increase of the amount of 42/43 amino acid form of the A of APP β.The familial form of Alzheimer only accounts for 10% of patient's total number of persons.Most Alzheimer occur as sporadic case, wherein APP and A β do not have any sudden change.The structure and the sequence of the A β peptide of all lengths are known in this area.Can make this peptide according to the method that this area suppresses, perhaps extract this peptide (for example, Glenner and Wong, Biochem.Biophys.Res.Comm.129,885-90 (1984) from brain in accordance with known methods.In addition, can obtain various forms of peptides from commercial source.APP expresses in most cells and continuous destructive metabolism.The approach of main destructive metabolism causes discharging the soluble outer function fragment of a kind of known APPs α for be called the cut-out of the APP of alpha-secretase enzyme by a kind of quilt in A β sequence temporarily.The formation of A β peptide has been got rid of in this cut-out.With respect to this non-amyloidosis approach, can also be respectively by suppress for β-and gamma-secretase in the cut-out of the N of A β end or C end, subsequently A β is discharged into born of the same parents' external space.Up to the present, proved that BACE is a kind of beta-secretase (Vasser etc., Science 286:735～741,1999) and has shown presenilin-1 and gamma-secretase active relevant (De Strooper etc., Nature, 391,387～90 (1998)).These 39～43 amino acid whose peptides produce by β and gamma secretase order this amyloid precursor protein of albuminolysis (APP) is arranged.Although A β 40 is a kind of principal modes that produce, total 5～7% A β be (Cappi etc., Int.J.Biochem., Cell Biol.31,885～89 (1999)) that the form with A β 42 exists.

As if the length of A β peptide change its biochemistry/physiological property significantly.Specifically, be highly hydrophilic other two of the C of A β 42 end, this may improve the accumulative tendentiousness of A β 42.For example proof such as Jarrett is external, compare with A β 40, A β 42 assembles very fast, and this shows that long A β may be a kind of important pathological protein (Jarret etc. that relate to the nerve plaque in the Alzheimer, Biochemistry 32,4693～97 (1993)); Ann.N.Y.Acad.Sci.695 such as Jarret, 144～48 (1993)).Recently further supported this hypothesis for the analysis of the contribution of the A β of the concrete form in the Alzheimer of gene family.For example be connected to APP on the FAD " " mutant form (APP V7171) has optionally improved the generation (Suzuki etc. of A β 42/43 with respect to A β 40 in London, Science, 264,1336～40 (1994)), and APP (APPK670N/M671L) " " mutant form has improved the level (Citron etc. of A β 40 and A β 42/43 in Sweden, Nature, 360,672～674 (1992)); Cai etc., Science 259,514～16, (1993)).In addition, the sudden change that also should observe the FAD connection in presenilin-1-1 (" PS-1 ") or presenilin-1-2 (" PS-2 ") gene will cause the optionally increase (Borchelt etc. of A β 42/43 rather than A β 40, Neuron 17,1005～13 (1996)).This discovery obtains the further conclusive evidence of the following fact: express optionally raising (Borchelt, the op cit. of the transgenic mouse models of PS mutant at brain A β 42; Duff etc., Neurogeneration 5 (4), and 293～98 (1996)).Thereby obtain about the hypothesis of the etiology of Alzheimer be: since the increase of the generation of A β 42 or release cause or A β 42 brain concentration in the increase or the attenuating of cleaning up be a origin cause of formation sexual behavior part in this nosopathology.

Verified various mutations position in A β or APP and relevant with peralytic dementia or cerebral hemorrhage clinically.The disease that exemplary CAA is relevant includes but not limited to: Iceland's type has the heritability cerebral hemorrhage (HCHWA-I) of amyloidosis, the Dutch mutation (HCHWA-D of HCHWA; The sudden change of A β); The Flanders sudden change of A β; The arctic sudden change of A β; Italy's sudden change of A β; The Iowa sudden change of A β; Heritability Britain peralytic dementia; And heritability Denmark peralytic dementia.CAA can be sporadic.

Unless possess description, term as used in this specification " degeneration of amyloid-beta sample " and " degeneration of amyloid sample " or the like are meant albuminoid degeneration protein or peptide, amyloid beta precursor protein matter or peptide, intermediate and modify body or fragment.Especially, " A β " is meant any peptide of the proteolysis processing and manufacturing of app gene product, and particularly relevant with amyloid pathology peptide comprises a β 1-39, a β 1-40, a β 1-41, a β 1-42 and a β 1-43.In order to name conveniently, " A β 1-42 " is called as " A β (1-42) " here or is called " A β 42 " simply or " A β 42 " (and also be same for the amyloid peptide of discussed herein any other).Here employed term " beta amyloid albumen ", " amyloid-β " and " A β " are synonym.

Unless otherwise mentioned, term " amyloid " is meant amyloidosis protein, peptide or its fragment, it can be dissolved in (for example, monomeric or oligomerization) or insoluble (for example, have the structure of fibril or in the amyloid plaque).For example consult MP Lambert etc., Proc.Nat ' l Acad.Sci.USA 95,6448～53 (1998)." amyloidosis " or " amyloid disease " or " disease that amyloid is relevant " is meant a kind of pathological conditions that the amyloid fiber occurs that is characterised in that." amyloid " is a generic term, is meant to see a kind of different of many various disease but particular proteins deposition (in the cell or extracellular).Although their form is changeable, all amyloid deposition all has common morphological characteristic, uses dyestuff (for example Congo red) dyeing, and is characterised in that is demonstrating red green birefringent phenomenon after the dyeing in polarized light.They also have common superstructure feature or common X-ray diffraction and infrared spectrum.

Gelsolin is and fragment and the bonded calbindin of actin filament.Proteinic position 187 (for example, Aspo → Asn; Asp → sudden change Tyr) causes the form of heritability SA, and this finds among Finland patient and Holland and the Japanese usually.In ill individuality, the fibril that forms from gelsolin fragment (Agel) comprises amino acid/11 73-243 (68kDa carboxyl end groups fragment) usually and deposits blood vessel and basement membrane, cause cerneal dystrophy and and then develop into the skull neuropathy of peripheral neuropathy, poor skin nutrition and change and the deposition (Kangas in other organs, H. wait Human Mol.Genet.5 (9): 1237～1243,1996).

Other mutein, the cystatin c (Acys) of for example the mutant α chain of Fibrinogen (AfibA) and variation also form fibril and produce the feature of heritability disease.The AfibA fibril forms the precipitation that is characterised in that the non-neuropathic heritability amyloid that has nephropathy; Acys is sedimentary to be characterised in that a kind of heritability brain amyloid angiopathy (Isselbacher, Harrison ' s Principles ofInternal Medicine, McGraw-Hill, San Francisco, 1995 that are reported in Iceland; Benson etc.).In at least some pathology, the patient who suffers from brain amyloid angiopathy (CAA) has demonstrated has the amyloid fibril (Nagai that comprises a kind of cystatin c and the proteinic not mutated strain of amyloid-beta, A. etc., Molec.Chem.Neuropathol.33:63-78,1998).

Think that now the prion disease of some form is heritable, this has accounted for the case up to 15%, and once be considered to its infective (Baldwin etc. of right and wrong in essence before this, inResearch Advances in Alzheimet ' s Disease and RelatedDisorders, John Wiley and Sons, New York, 1995).In heritability and sporadic prion disease, patient produces by normal prion protein (PrP ^CS) the plaque formed of improper equivalents.

A kind of dominant mutant isoform, PrPsc, be also referred to as AScr, be different from normal cell protein in the synthetic and high beta-pleated sheet content of deposition, back translation in insoluble, the secondary lysosome that the toleration that proteinase is degenerated, cleaning agent are extracted out, set up at least 5 cause creutzfeldt-Jacob disease (CJD),, Gerstmann-Straussler-Scheinker syndrome (GSS) and serious familial insomnia's (FFI) heritability contact.(Baldwin, the method for supra) extract the fibril peptide from the itch fibril, measuring sequence and make this peptide is known (for example, Beekes, M. etc., J.Gen.Virol.76:2567～76,1995) in this area.

For example, a kind of form of GSS be connected in the PrP of codon 102 sudden change, and telencephalic GSS separates with the sudden change of codon 117.Sudden change in codon 198 and 217 causes the form of a kind of GSS, and wherein neuritis's plaque is characterised in that Alzheimer comprises PrP rather than A β peptide.The familial CJD of some form is with relevant in the sudden change of codon 200 and 210; In familial CJD and FFI, found in codon 129 and 178 sudden change (Baldwin, supra).

Cerebral amyloidosis

The local deposits of amyloid is very common at brain (particularly in more old individuality).The most frequent type of amyloid in brain mainly comprises a kind of β peptide fibril, and it causes peralytic dementia or accidental (nongenetic) Alzheimer.The cerebral amyloidosis of normal generation is sporadic or familial.For example, the generation of sporadic Alzheimer and sporadic CAA is considerably beyond familial A β and CAA.In addition, can't distinguish the sporadic form and familial form (the different of them only are the heritability gene mutation whether occurs) of disease; For example, even if the amyloid plaque that in sporadic and familial A β, forms and clinical symptoms be not identical, also be very similar.

Brain amyloid angiopathy (CAA) is meant that the specificity of amyloid fibril on leptomingeal and outer cutaneous artery, arteriole and wall of vein deposits.Its common and Alzheimer, mongolism and natural aging, and the various family diseases relevant with apoplexy or peralytic dementia are relevant (consults Frangione etc., Amyloid:J.ProteinFolding Disord.8, Suppl.1,36-42 (2001)).CAA can be sporadic or genetic.

Senile systemic amyloidosis

Amyloid deposition general or focus increases with advancing age.For example, in the heart tissue of more old individuality, find the fibril of wild type transthyretin (TTR) usually.These may asymptomatic, clinically be mourned in silence, and perhaps may cause heart failure.Asymptomatic filamentous focus deposition also may occur in brain (Ap), prostate (β ₂Microglobulin) in corpora amylacea, joint and the seminal vesicle.

The amyloidosis (DRA) that dialysis is relevant

In the patient who accepts secular hemodialysis or peritoneal dialysis, also can develop usually by β ₂The fibrillated plaque of microglobulin (pzM).β ₂Microglobulin be a kind of polypeptide of 11.8 kilodaltons and be a kind of exist with all nucleated cell on the antigenic light chain of I level MHC.In normal circumstances, unless impaired renal function, β ₂M is distributed in this intercellular substance usually, at this moment β ₂M is sent in the tissue, and polymerization forms the amyloid fibril there.The inefficacy of clearance (for example in the situation of impaired renal function) causes the deposition in carpal bone tunnel and other positions (mainly being in the rich collagen tissue in the joint).Different with other fibrillin matter, β ₂The M molecule is not to produce by the division than long precursor protein, and is present in the fibril with unsegmented form usually.(Benson，supra)。The maintenance of verified this amyloid precursor and accumulation are the processes of the most basic main diseases originality of DRA.DRA is characterised in that the osteoarthritis (for example ankylosis, pain, expansion etc.) in peripheral joint.β in the tissue ₂The isotype of M, the β of saccharifying ₂M or β ₂The polymer of M is that modal amyloidosis form is (with original β ₂M is opposite).Different with the amyloidosis of other types, β ₂M is limited in the osteoarthrosis position to a great extent.The internal organs deposition is very rare.Sometimes, these depositions may relate to blood vessel and other important regions of anatomy.

Be used to remove β although have ₂The improved method of M, but the blood plasma β of most patient ₂M concentration still is significantly higher than the normal person.The β that these have improved ₂M concentration causes the relevant amyloidosis (DRA) of diabetes usually and causes dead cormorbidities.

Islet amyloid shape protein polypeptide and diabetes

Before a century, islets of langerhans hyaline degeneration (amyloid deposition) has been described first, this is because found fibrous proteins gathering (Opie, EL., JExp.Med., 5:397-428,1901) in the pancreas of serious hyperglycemia patient.Today, islet amyloid shape albumen (mainly being made up of islet amyloid shape protein polypeptide (IAPP)) or amylin are to surpass 90% feature organization pathology labelling in all type ii diabetes (have another name called non-insulin-dependent diabetes mellitus, or NIDDM) pathology.These fibrillar accumulations are because islet amyloid shape protein polypeptide (IAPP) or amylin (a kind of 37 amino acid whose polypeptide come from a kind of bigger precursor peptide that is called preceding IAPP) cause.

IAPP secretes jointly with corresponding β cell with insulin and urgees to secrete agent.These pathological characters and insulin-dependent (I type) diabetes are not got in touch and are the consistent features that is diagnosed as the various clinical symptoms type of NIDDM (type ii diabetes).

The longitudinal study of cat is shown with immunocytochemical study to monkey: the proteic violent rising of islet amyloid shape and gathering of insulin secretion β cell are reduced relevant, and have improved the order of severity of disease.In recent years, transgenic research has confirmed the relation between the formation of IAPP plaque and β apoptosis and the dysfunction, and this shows: the amyloid deposition is to improve a principal element of the order of severity of type ii diabetes.

Shown that also IAPP causes β-islet cells toxicity in external meeting, this shows in II type or type i diabetes patient's (back islet transplantation) pancreas and loss and the organ dysfunction that the IAPP fibril can cause β cell islets of langerhans (Langerhans) occur.In the type ii diabetes patient, the accumulation of pancreas IAPP will cause forming oligomerization IAPP, thereby cause the IAPP-amyloid to increase so that insoluble fibre is sedimentary, the destruction that this finally causes the insulin of islets of langerhans to produce sexual cell causes depletion and inefficacy (Westermark, the P. of β cell, Grimelius, L., Acta Pats.Microbiol.Scand., sect.A.81:291-300,1973, de Koning, EJP., Deng, Diabetologia 36:378-384,1993; And Lorenzo, A., etc., Nature 368:756-760,1994).IAPP as the sedimentary accumulation of fibroid also can owing in deposition, capture IAPP increase in the blood plasma the preceding IAPP that finds usually and the ratio of IAPP.Can prove the minimizing of β cell by hyperglycemia and insulinemia.This β cell mass loss needing may cause insulinize.

Can treat because the death or the caused disease of dysfunction of the cell of particular type by the healthy cell of transplanting correlation type to the patient.This method has been used to type i diabetes people's treatment.Usually, before transplanting, cultivate the pancreas islet cells from donor, reclaim or reduce their immunity then at after separating external.Yet in many examples, because the death of transplanted cells, islet cell transplantation is unsuccessful.The reason that success rate is low is IAPP, and it can form the toxicity oligomer.Adverse effect can be by in the born of the same parents or the accumulation of the outer fibril oligomer of born of the same parents cause.The IAPP oligomer can form fibril and at external pair cell toxigenicity.In addition, the IAPP fibril also may be grown behind cell transplantation, and causes the death and the dysfunction of cell.Even be not characterised in that in the situation that fibriilar disease occurs when patient that cell is accepted to transplant from the donor of health suffers from, also still can this thing happens.For example, chemical compound of the present invention also can be used for preparation according to cell and tissue as the transplanting of the described method of international patent application (PCT) WO01/003680.

The level of concentration, proinsulin/insulin and the C-peptide of IAPP/IAPP before chemical compound of the present invention can also be stablized.In addition, the result of the biomarker of effectiveness, different tests (for example arginine-insulin secretion test, glucose tolerance test, insulin resistant degree and sensitivity tests) all can reduce and/or the sedimental cumulative labelling of amyloid as β cell quality.This medicine can also use together with other the medicine towards insulin resistance, the manufacturing of liver property glucose and insulin secretion.This chemical compound can be by keeping the β cell function preventing insulin treatment, and can be used to keep islet transplantation.

The deutero-amyloidosis of hormone

The endocrine organ can hold the amyloid deposit, particularly in older individuals.The hormone secretion tumor can also comprise the deutero-amyloid plaque of hormone, and its fibril is made up of for example thyrocalcitonin (medullary thyroid carcinoma) and atrial natriuretic peptide polypeptide hormones such as (isolated atrial amyloids).These protein sequences and structure are known in the art.

Various amyloidosis

Have various other forms of amyloid disease, it is usually expressed as the local deposits of amyloid.In general, these diseases cause narrow spectrum fibril predecessor's part to produce usually or metabolism lacks, or particular organization (for example joint) tends to the fibril deposition.This paroxysmal sedimentary example comprises warty AL amyloid, skin amyloid, the amyloid that the endocrine amyloid is relevant with tumor.The disease that other amyloid is relevant comprises as described in Table 1 those, for example familial amyloid shape albumen polyneuropathy (FAP), old SA, Tenosynovium, familial amyloidosis, the Ostertag type, the amyloidosis of non-neuropathic, the skull neuropathy, hereditary cerebral hemorrhage, familial peralytic dementia, chronic dialysis, familial Creutz Fil spy-Jacob disease, the Gerstmann-Straussler-Scheinker syndrome, the heritability spongiform encephalopathy, prion disease, familial Mediterranean fever, the Muckle-Well syndrome, nephropathy, deaf, urticaria, limb pain, cardiomyopathy, the skin precipitation, multiple myeloma, optimum monoclonal gammopathy, maccoglobulinaemia, myeloma with amyloidosis, medullary thyroid carcinoma, isolatism atrium amyloid and diabetes.

Can therapeutic ground or prophylactically take chemical compound of the present invention and form, assemble with fibril with treatment or deposit relevant disease, and regardless of its clinical symptoms.Chemical compound of the present invention uses following mechanism to improve the relevant lysis of amyloid, and these mechanism include but not limited to: reduce amyloid fibril formation or sedimentary speed; Dwindle the sedimentary degree of amyloid; Suppress, reduce or prevention amyloid fibril formation; Forbid the inflammation that amyloid causes; Improve amyloid from cleaning up between brain; Or the protection cell is avoided (oligomer or fibrillar) toxicity that amyloid causes.

In an instantiation, can therapeutic ground or the chemical compound/preparation of the present invention of taking prophylactically form, assemble or deposit relevant disease with amyloid-β fibril with treatment.Chemical compound of the present invention can use following mechanism to be used to improve the disease relevant with amyloid-β (this inventory is illustrative, rather than restrictive): reduce amyloid-β fibril and form or sedimentary speed; Dwindle the sedimentary degree of amyloid-β; Suppress, reduce or prevent that amyloid-β fibril from forming; Suppress nervus retrogression degeneration or cytotoxicity that amyloid-β causes; Amyloid-β that inflammation-inhibiting causes; Improve amyloid-β cleaning up from brain; Or the bigger metabolism of promotion A β.

Chemical compound of the present invention can control effectively amyloid-β along their inlet enter brain (along the infiltration of blood brain barrier) or from around deposition.When at acting by their periphery,, chemical compound promote A β to clean up from brain thereby can changing the balance of the A β in brain and blood plasma.The increase of cleaning up of A β from brain will cause the attenuating of A β brain concentration, thereby promote the sedimentary minimizing of A β.In addition, the chemical compound that sees through brain can be controlled deposition by directly acting on brain A β, for example by holding it in a kind of non-filamentous form or promoting it to break away from from brain.This chemical compound APP that can slow down handles; Can improve the fibriilar degeneration of A β by macrophage or by neuronal cell; Maybe can reduce the manufacturing of A β by activatory microglia.These chemical compounds can also prevent A β interference cell surface and thereby prevention neurotoxicity, nervus retrogression degeneration or the inflammation in the brain.

In a preferred instantiation, this method also is used to treat Alzheimer (for example, sporadic or familial A β).Can also be prophylactically or therapeutic ground use this method to handle sedimentary other the clinical disease of amyloid-β, Tang Shi innate stupid disease individuality and suffer from brain amyloid angiopathy (" CAA "), hereditary cerebral hemorrhage or early stage Alzheimer for example.In another instantiation, this method is used to dispose the damage of slight understanding.

Mild cognitive damage (" MCI ") is a kind of disease with following feature: still have measurable damage in state gentleness aspect the thinking skill, its inevitable and not paretic appearance exists related.MCI usually but must not cause the secondary Alzheimer.

In addition, proved that APP and the undesired accumulation of amyloid-beta protein in muscle fiber and sporadic occlusion body myositis (IBM) exist pathology related (Askanas, V. etc., (1996) Proc.Natl.Acad.Sci.USA 93:1314-1319; Askanas, V. etc. (1995) Current Opinion in Rheumatology 7:486-496).Therefore, chemical compound of the present invention can be prophylactically or therapeutic ground be used for the wherein undesired sedimentary treatment of diseases of amyloid-beta protein on non-neural position, for example by transmit this compounds for treating IBM to muscle fiber.

In addition, verified, A β is relevant with the abnormal born of the same parents' external sediment that is called as the choroid wart, and wherein the basal surface along the retinal pigment epithelium accumulates in the individuality with relevant degeneration of macula (ARMD) of age.

ARMD be a kind of in older individuality irreversible vision loss.It is believed that A β deposition can be the important component part (Johnson etc. of the nosogenetic local inflammation incident of the atrophy, choroid wart source of students and the ARMD that cause the retinal pigment epithelium, Proc.Natl.Acad.Sci.USA 99 (18), and 11830～5 (2002)).

In another instantiation, the invention still further relates to the method for in object (preferred people), treating or preventing the relevant disease of amyloid, it comprises: take a kind of following formula: compound of therapeutic dose or the chemical compound of the opposite description in this description to object, thereby reduce or inhibition amyloid fibril formation or deposition, nervus retrogression degeneration or cytotoxicity.In another instantiation, the present invention relates to a kind of method of in object (preferred people), treating or preventing the relevant disease of amyloid, it comprises to object takes the following formula of therapeutic dose or the chemical compound that this description is described in addition, thereby (for example suffering from cerebral amyloidosis, Alzheimer, Tang Shi innate stupid disease or brain amyloid angiopathy) the patient in improve or stable cognitive function, or prevent, slow down or stop the further deterioration of cognitive function.The quality of the daily life of all right these objects of these chemical compounds.

Treatment chemical compound of the present invention can be by for example stablizing blood glucose, prevention or reducing loss, minimizing or the prevention of β cell quality because the hyperglycemia that the loss of β cell mass causes is treated the amyloidosis relevant with type ii diabetes with the manufacturing of adjusting (for example improve or stable) insulin.The ratio of the concentration of IAPP/IAPP before chemical compound of the present invention can also be stablized.

Treatment chemical compound of the present invention can also by stablize renal function, reduce albuminuria, improve Ccr (for example at least 50% higher or at least 100% or higher) or by causing relieve chronic diarrhoea, weight increase (for example, 10% or bigger) treatment AA (Secondary cases) amyloidosis and/or AL (constitutional) amyloidosis.

II. method of the present invention

In an instantiation, the present invention includes a kind of sedimentary method of object amyloid that is used for suppressing, it comprises a kind of treatment preparation that comprises treatment chemical compound described herein of taking effective dose to this object, thereby suppresses the amyloid deposition.Therefore, in another instantiation, the present invention relates in a kind of treatment target with prevention amyloid relevant disease, for example the A β disease of being correlated with, method, it comprises the treatment preparation of taking comprising of a kind of therapeutic dose of treatment chemical compound of the present invention to object

Can therapeutic ground or prophylactically take preparation of the present invention and form, assemble or deposit relevant disease with amyloid-β fibril with treatment.Preparation of the present invention can use following mechanism to do in order to cover the process (this inventory is illustrative and nonrestrictive) of the relevant disease of amyloid-β: reduce amyloid-β fibril and form or sedimentary speed; Dwindle the sedimentary degree of amyloid-β; Suppress, reduce or prevention amyloid-β fibril formation; Suppress nervus retrogression degeneration or cytotoxicity that amyloid-β causes; Amyloid-β that inflammation-inhibiting causes; Or increase amyloid-β cleaning up from brain.

Preparation of the present invention can be controlled after inlet enters brain (after infiltration cerebrovascular wall) or effectively from amyloid-β deposition of periphery.Be not subject to any theory, when from doing the time spent on every side, the chemical compound of preparation of the present invention can change the A β balance between brain and the blood plasma, thereby promotes A β is cleaned up from brain.A β will cause the minimizing of A β brain concentration from the increase of cleaning up of brain, and thereby help the sedimentary minimizing of A β.Perhaps; the chemical compound of the preparation of the present invention of infiltration brain can be by directly to brain A β effect; for example, perhaps protect cell to avoid the influence of the poisonous effect of A β, with the control deposition by holding it in non-fibril form or promoting it from the cleaning up of brain.In another instantiation, this chemical compound can also prevent the amyloid protein combination of soluble form or oligomerization form or fibril form or adhere to cell surface and cause cell injury or poisoning.

In a special instantiation, this method is used to treat Alzheimer (for example, sporadic or familial A β).All right preventative or therapeutic ground uses this method to treat for example sedimentary clinical symptoms of amyloid-β in the object of Tang Shi innate stupid disease individuality and brain amyloid angiopathy (" CAA ") or hereditary cerebral hemorrhage.

In the instantiation of some, treatment preparation of the present invention can suppress the interaction between amyloidosis protein and the basement membrane component (for example glycoprotein or proteoglycan), thereby suppresses the amyloid deposition.Can be by external in conjunction with test, for example this description (embodiment 5) or United States Patent (USP) U.S5,164, method described in 295 (it is reference that this patent is drawn in full at this) is measured the interactional ability between chemical compound inhibition amyloidosis protein of the present invention and glycoprotein or the proteoglycan basement membrane component.

The present invention relates to a kind of sedimentary method of object amyloid that is used for suppressing, it comprises the treatment preparation described herein of taking a kind of effective dose to this object, and this treatment preparation comprises a kind of treatment chemical compound that contains at least one and replacement or unsubstituted aromatics or the covalently bound sulfonate ester group of aliphatic molecules.

In another instantiation, the present invention includes a kind of chemokine inhibiting and bonded method of glycosaminoglycans of being used for, it comprises the treatment preparation that contains treatment chemical compound described herein to taking.

In another instantiation, the present invention relates to a kind of interactional method of in the mankind, regulating between antibacterial and the glycosaminoglycans, it comprises to the mankind takes a kind of treatment preparation that comprises treatment chemical compound described herein.Therefore, the present invention relates to a kind of method that is used at mankind's treatment bacterial infection, it comprises to the mankind takes a kind of treatment preparation that comprises treatment chemical compound of the present invention.In a specific instantiation, the present invention relates to the method that a kind of treatment is subjected to the object of chlamydia torment, it comprises to object takes the treatment preparation that comprises treatment chemical compound described herein.

In another instantiation, the present invention includes a kind of virus of controlled plant and interactional method of glycosaminoglycans of being used for, it comprises to object takes a kind of treatment preparation that comprises treatment chemical compound described herein.More generally, another instantiation of the present invention is a kind of method that is used for the treatment of viral infection in the object, and it comprises to object takes a kind of treatment preparation that comprises treatment chemical compound of the present invention.In a specific instantiation, the present invention suffers the method for the object of HSV for a kind of treatment, and it comprises to object takes a kind of treatment preparation that comprises treatment chemical compound described herein.

In addition, example of the present invention is the sedimentary method of amyloid that a kind of minimizing suffers from the sedimentary object of amyloid, this method comprises a kind of treatment preparation that comprises treatment chemical compound described herein of taking effective dose to this object, thereby reduces the amyloid deposition in the object.

Another instantiation of the present invention relates to a kind of prevention, treatment or suppresses the method for the brain amyloid angiopathy in the object, and it comprises to object takes a kind of treatment preparation that comprises treatment chemical compound of the present invention.In addition, the present invention includes a kind of method that is used to prevent, treat or suppress brain amyloid angiopathy, it comprises cells of vascular wall is contacted with the treatment preparation that comprises treatment chemical compound of the present invention, thus prevention, treatment or suppress brain amyloid angiopathy.In addition, the present invention includes a kind of method that is used to prevent, treat or suppress brain amyloid angiopathy, it comprises cells of vascular wall is contacted with the treatment chemical compound of treatment preparation of the present invention, thus prevention, treatment or suppress brain amyloid angiopathy.

Described " the sedimentary inhibition of amyloid " for example comprises minimizing, prevents or stop, and the amyloid of fibrilization forms, suppress or slow down further amyloid deposition in the suffer from amyloidosis object of (for example having had the amyloid deposition), and reduce or reverse amyloid fibrillation or the deposition in the object of the amyloidosis that continues.For example, the degree that amyloid deposition suppresses estimates by should being used for immediately, and this degree is positioned at following scope, and it for example comprises: eliminate the amyloid deposition basically fully or reduce the amyloid deposition.The sedimentary inhibition of amyloid is with respect to a untreated object, perhaps measure with respect to an object of before treatment, treating, perhaps by (for example being by diabetics or cerebral amyloidosis patient, Alzheimer or brain amyloid angiopathy patient) observable clinically improvement, cognitive function stable of pancreatic function or minimizing that cognitive function further reduces (for example, prevention, slow down or the development of tissue disease) or for example improvement of the parameter of the concentration of A β or the tau among the CSF, measure.In some instantiation; can suppress the amyloid deposition by following effects; for example: the interaction, the nervus retrogression degeneration of cleaning up or suppressing owing to amyloid cause or the cytotoxicity of raising amyloid beta from brain that suppress between amyloidosis protein and the basement membrane component (for example pass through solvable or undissolved amyloid; fibril for example; by amyloid deposition and/or amyloid-beta, as described here) or the protection brain avoid the adverse effect of A β.

Term " basement membrane " is meant the extracellular matrix that comprises glycoprotein and proteoglycan, and it comprises laminin, IV Collagen Type VI, fibrinolysin collection, polyprotein, perlecan and Heparan sulfate proteoglycan (HSPG).In an instantiation, suppress amyloid beta deposition by the interaction of disturbing amyloidosis protein and glycosaminoglycans sulfuric ester (for example HSPG).Known glycosaminoglycans sulfuric ester is present in all types of amyloids (consults Snow, A.D. etc., Lab.Invest.56,120～123 (1987)) and amyloid beta deposition and HSPG deposition takes place in the animal model of amyloidosis simultaneously (consult Snow, A.D. etc., Lab.Invest.56,665～675 (1987)).

" treatment " of an employed here object comprises: be in treatment, cure, or alleviate, change, remedy, improve, improve, or influence this disease or disease, the symptom of disease or disease, the perhaps purpose of the risk of this disease or disease (or susceptibility), apply or take compositions of the present invention to object, apply or take compositions of the present invention for the cell or tissue of taking from object, described object suffers from amyloid relevant disease or disease, symptom with this disease or disease perhaps is in (perhaps susceptible) among the danger of this disease or disease.Term " treatment " is meant in damage, pathological condition or treatment of conditions or any successful sign in covering, it comprises any objective or subjective parameter, and for example symptom alleviates, alleviates, weakens or make the more tolerable for object of this damage, pathological condition or disease; Reduce the speed of degenerating or failing; Make that the maximal end point of degenerating is not weaker; Improve the physics or the psychologic status of object; Perhaps, prevent paretic outbreak in some cases.The treatment of symptom or improvement can be based on subjective or objective parameters, and this comprises: the result of physical examination, spirit assessment or recognition tests (for example CDR, MMSE, ADAS-Cog) or other tests known in the art.For example, speed or the degree of the alleviating cognitive decline peralytic dementia of successfully having treated object of method of the present invention by reducing cognitive decline.

In an instantiation, term " treatment " comprises that the CDR grade with object remains its baseline grade or 0.In another instantiation, term " treatment " comprise with " CDR " grade of object low about 0.25 above, about 0.5 or above, about 1.0 above, about 1.5 or above, about 2.0 above, about 2.5 or above or about 3.0 or more than.In another instantiation, term " treatment " also comprises with the historical control group to be compared, and reduces the speed of the CDR grade rising of object.In another instantiation, this term comprise the raising speed of the CDR grade of object reduced the historical control group or do not treat matched group raising speed about 5% or above, about 10% or above, about 20% or above, about 25% or above, about 30% or above, about 40% or above, about 50% or above, about 60% or above, about 70% or above, about 80% or above, about 90% or above or about 100%.

In another instantiation, term " treatment " also comprises the score of maintenance object in MMSE.The MMSE score with object that comprises term " treatment " improves 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 minutes.This term also comprises with the historical control group to be compared, the speed of the reduction of the MMSE score of reduction object.In another instantiation, this term comprise the MMSE score of object can be reduced historical control group or untreated matched group about 5% or still less, about 10% or still less, about 20% or still less, about 25% or still less, about 30% or still less, about 40% or still less, about 50% or still less, about 60% or still less, about 70% or still less, about 80% or still less, about 90% or still less or about 100% or still less.

In another instantiation, term " treatment " also comprises the score of maintenance object in ADAS-Cog.Term " treatment " comprises the score of object in ADAS-Cog reduced at about 1 or more, about 2 or more, about 3 or more, about 4 or more, about 5 or more, about 7.5 or more, about 10 or more, about 12.5 or more, about 15 or more, about 17.5 or more, about 20 or more, perhaps about 25 or more.This term also comprises with the historical control group to be compared, the speed of the raising of the ADAS-Cog score of raising object.In another instantiation, this term comprise the raising speed of the ADAS-Cog score C DR grade of object reduced the historical control group or do not treat matched group raising speed about 5% or above, about 10% or above, about 20% or above, about 25% or above, about 30% or above, about 40% or above, about 50% or above, about 60% or above, about 70% or above, about 80% or above, about 90% or above or about 100%.

In another instantiation, term " treatment ", for example for AA or AL amyloidosis, comprise the rising of serum creatinine Cl, for example Ccr improve 10% or more, 20% or more, 50% or more, 80% or more, 90% or more, 100% or more, 150% or more, 200% or more.Term " treatment " also comprises and alleviates the kidney third property syndrome (NS).It also comprise slow down chronic diarrhea and/or with weight increase 10% or more, 15% or more or 20% or more.

Without wishing to be bound by theory, in some respects, pharmaceutical composition of the present invention comprises can prevent or suppress the chemical compound that the amyloid fibril forms in brain or other vitals (local action) or whole health (general action).Pharmaceutical composition of the present invention can be after they enter brain (at the infiltration blood brain barrier) or control amyloid beta deposition effectively from periphery.When from peripheral action, the chemical compound of pharmaceutical composition can change the balance of the amyloidosis peptide between brain and the blood plasma, and promotes the amyloidosis peptide to discharge from brain.It also has clean up (or the catabolism) that is beneficial to amyloid protein (solvable), and prevent owing to reduce the amyloid protein pond in specific organ (for example, liver, spleen, pancreas, kidney, joint, brain etc.) that then the amyloid fibril from forming and deposition.The amyloidosis peptide will cause the reduction of amyloidosis peptide brain concentration from the increase of the discharge of brain, and thereby promote the amyloidosis peptide to deposit.Especially, this reagent level or this reagent that can reduce amyloid peptide (for example A β 40 in CSF and the blood plasma and A β 42) can reduce the level of amyloid peptide (for example, A β 40 among the CSF and A β 42) and improve its level in blood plasma.Perhaps; the chemical compound of infiltration brain can be controlled deposition by directly acting on the cerebral amyloidosis peptide; for example by holding it in non-filamentous form or promoting its removing from brain; by improving its degeneration in brain, perhaps avoid the adverse effect of amyloidosis peptide by the protection brain cell.The concentration of amyloid protein that can also cause a kind of reagent reduces (that is, in specific organ, do not obtain triggering the amyloid fibril and form or deposit required critical concentration).In addition, chemical compound described herein can suppress or reduce the interaction of amyloid and cell surface component (for example glycosaminoglycans or proteoglycan basement membrane component).This chemical compound can also the prevention of amyloid protein peptide in conjunction with or be adhered on the cell surface, this combination is a kind of known cell injury or toxic process of causing.Similarly, this chemical compound can block the neurotoxic that cytotoxicity that amyloid causes or Microglial activation or amyloid cause, or suppresses the inflammation that amyloid causes.This chemical compound can also reduce amyloid aggregation, fibril forms or sedimentary speed or amount, and perhaps this chemical compound can reduce the degree of amyloid beta deposition.Above-mentioned mechanism of action should not be considered to the restriction to scope of the present invention, and can not have to implement the present invention under the condition of above-mentioned information.

Term " significantly " or " significantly " are meant variation that can notice or measurable amount or increase are taking place aspect the discernible characteristic, perhaps wherein this variation will be that can notice, measurable or unacceptable influence, for example injurious effects.Similarly, term " reduce significantly or prevention gastrointestinal tolerant bad " comprise gastrointestinal tolerant bad notice or measurable minimizing or prevention, that is, opposite with the situation of minimizing that can't notice or immeasurablel or prevention.For example, pain that feel sick, vomitus is relevant with gastrointestinal or uncomfortable for a long time number of times can be used as measurement treatment preparation of the present invention to the bad minimizing of gastrointestinal tolerant or the influence of prevention.In addition, the term ability of treatment preparation " can the appreciable impact " is meant the ability that influence this treatment preparation, but does not influence this ability in a kind of unacceptable mode on the degree of damaging interests, and so ability that can this healing potion of appreciable impact.

" adjusting of amyloid beta deposition " comprises the enhancing that aforesaid inhibition and amyloid beta deposition or fibril form.Therefore, term " adjusting " comprises 1) prevention or stop the amyloid to form or accumulation, suppress or slow down further amyloid aggregation in (for example the having had amyloid aggregation) object that suffers amyloidosis, and reduce or reverse and suffering amyloidosis, and 2) improve amyloid beta deposition, for example increase in the body or the speed and the amount of external amyloid beta deposition.Amyloid enhancing property chemical compound can be used in the animal model of amyloidosis, for example, is used for causing the sedimentary development of animal amyloid in the short period of time or is used for improving the amyloid deposition within the time of selecting.Amyloid strengthens the screening test that the property chemical compound can be used to suppress in the body chemical compound of amyloidosis, for example in animal model, and the test cell line of amyloidosis and in vitro tests.The test of the chemical compound that this chemical compound can be used to for example to provide faster or more responsive.The adjusting of amyloid aggregation is to measure with respect to untreated object or with respect to the object before the treatment.

The preparation of the treatment function that the system that comprises term " treatment preparation " can realize being scheduled to (for example prevent, treat or suppress amyloidosis), and can reduce or prevent gastrointestinal tolerant bad (being nausea and vomiting).Minimizing that gastrointestinal tolerant is bad or prevention can be for example, depend under one's belt direct physics contact or to central nervous system's indirect central action.

In the instantiation of some, minimizing that gastrointestinal tolerant is bad or prevention depend on the treatment chemical compound of taking to object at least.In an instantiation, the treatment compound-base with a kind of treatment function that caters to the need is selected in its minimizing or the bad ability of prevention gastrointestinal tolerant and is included in the treatment preparation.In the instantiation of some, this chemical compound is carried out modification so that make the treatment chemical compound with the bad ability of needed treatment function and minimizing or prevention gastrointestinal tolerant.For example, can carry out structural modification (for example add suitable substituent group or change pharmaceutically acceptable counter ion) or preparation again to this chemical compound, so that this chemical compound has desirable treatment function and minimizing or the bad ability of prevention gastrointestinal tolerant.

In some other instantiation, minimizing that gastrointestinal tolerant is bad or prevention not merely depend on the treatment chemical compound of taking to object.For example, in an instantiation, minimizing that gastrointestinal tolerant is bad or prevention also do not rely on and have formula 3-amino-1-propane sulfonic acid ester/X, and wherein X is a counter ion, perhaps forms ester with sulfonate, chemical compound, for example 3-amino-1-propane sulfonic acid or its sodium salt.In a special instantiation of the present invention, other reagent is depended in minimizing that gastrointestinal tolerant is bad or prevention, for example enteric coating or improvement releasing agent.

In another instantiation, in this treatment preparation, comprise at least a other reagent, wherein this other reagent is different from this treatment chemical compound.At a specific instantiation, this other reagent gives the characteristic of at least a needs of this treatment preparation.At a special instantiation, the characteristic that this needs, minimizing or prevention gastrointestinal tolerant are bad at least in part.Therefore, in an other instantiation, other reagent can be to be used for this treatment preparation, with independently or with other minimizing or prevent Intolerant method, reduce or the prevention gastrointestinal tolerant bad.For example, because any possible gastrointestinal tolerant that the treatment preparation causes is bad, this tablet can be enteric coating or can will discharge fast any of stomach or enteral with control treatment chemical compound as the modification release reagent in order to be protected from.

In example of the present invention, minimizing that gastrointestinal tolerant is bad or prevention can also be finished by the local discomfort that reduces or prevent high pH value (wherein this high pH value produces during chemical compound dissolves in the stomach owing to treating after taking this treatment chemical compound) to cause.As another extra advantage of treatment preparation of the present invention, the bad minimizing of gastrointestinal tolerant also can cause the compliance of the improvement of medication object (for example patient).

In another special instantiation, treatment chemical compound of the present invention is an alkyl sulfonic acid.Term " alkyl sulfonic acid " comprises and replacing or unsubstituted alkyl sulfonic acid and replacement or unsubstituted hexyl alkyl sulfonic acid.It is worthy of note amino substituted compound, and the present invention relates to replace or unsubstituted amino substituted alkyl sulfonic acid and replacement or the unsubstituted amino low alkyl group sulfonic acid that replaces that an one example is 3-amino-1-propane sulfonic acid.Be also pointed out that term as used in this specification " alkyl sulfonic acid " is interpreted as the synonym of " alkane sulfonic acid ".

In the instantiation of some, the present invention relates to replace or unsubstituted alkyl sulfonic acid, replacement or unsubstituted alkyl sulphuric acid, replacement or unsubstituted alkyl thiosulfonic acid, replacement or unsubstituted alkyl thiosulfuric acid or its ester, comprise its pharmaceutically acceptable salt.For example, the present invention relates to a kind of chemical compound, promptly replace or unsubstituted alkyl sulfonic acid or its ester or amide, comprise its pharmaceutically acceptable salt.In another instantiation, the present invention relates to a kind of chemical compound, promptly replace or unsubstituted low alkyl group sulfonic acid or its ester or amide, comprise its pharmaceutically acceptable salt.Similarly, the present invention includes a kind of chemical compound, promptly (replacement-or unsubstituted-amino-) substituent group low alkyl group sulfonic acid or its ester or amide, comprise its pharmaceutically acceptable salt.In another instantiation, this chemical compound is low alkyl group sulfonic acid or its ester or the amide of (replacement-or unsubstituted-amino-)-replace, and comprises its pharmaceutically acceptable salt.

Verified: the compositions of alkyl sulfonic acid (for example comprising 3-amino-1-propane sulfonic acid and salt thereof) is useful for the treatment of the relevant disease (comprising Alzheimer and brain amyloid angiopathy) of amyloid beta.Consult WO 96/28187, WO 01/85093 and U.S. Pat 5,840,294.

One group of example of alkyl sulfonic acid has following structure

Wherein Y (has formula-NR for amino ^aR ^b, R wherein ^aAnd R ^bBe hydrogen, alkyl, aryl or heterocyclic radical, perhaps R independently of one another ^aAnd R ^bForm a ring residue that in ring, has 3～8 atoms with the nitrogen-atoms that is connected with them) or sulfonic group (have formula-SO ₃ ^-X ⁺), n is 1～5 integer, and X is hydrogen or cation (for example sodium).Some exemplary alkyl sulfonic acids comprise following compounds:

In some cases, this alkyl sulfonic acid is a kind of " micromolecule ", that is, a kind ofly itself be not the product (for example, protein, ribonucleic acid or terminal transferase) of genetic transcription or translation and have lower molecular weight, for example less than about 2500.In other situation, this chemical compound can a kind of biological product of formula, for example antibody or immune peptide.

Alkyl sulfonic acid can prepare by for example general reaction process described in the following document: US5,643,562; US5,972,328; US5,728,375; US5,840,294; US4,657,704; With United States Patent (USP) provisional application case the 60/482nd, No. 058 (application on June 23rd, 2003, attorney NBI-156-1), United States Patent (USP) provisional application case the 60/512nd, No. 135 (applications on October 17th, 2003, attorney NBI-156-2), all be entitled as " synthetic method that is used to prepare the chemical compound for the treatment of amyloidosis ", and U.S. patent application case 10/_, _, number (on June 18th, 2004 application, attorney NBI-156, be entitled as " improved drug candidate and preparation method thereof ", its content mode by reference comprises in this application in full, perhaps by revising its method, uses the initiation material that obtains easily, reagent and conventional synthetic method.In these reactions, can also use itself known but NM variation.For example, described in this description and compound functions that have identical general aspects and structural equivalents (wherein, one or more substituent groups having been carried out can not causing the effectiveness of essence character or this chemical compound the simple change of adverse effect) can prepare by the various known methods in this area.

In general, chemical compound of the present invention can perhaps by it is made amendment, for example use the initiation material, reagent and the conventional synthesis step that obtain easily to synthesize by for example hereinafter described conventional method method.In these reactions, can also use itself known but NM herein variation.Described in this description and compound functions that have identical general aspects and structural equivalents wherein, have carried out can not causing adverse effect simply to change to the effectiveness of essence character or this chemical compound to one or more substituent groups.Reagent of the present invention can be easily according to synthetic route described herein and draft, as shown in the concrete steps that provided.Yet those skilled in the art will recognize: can use other the synthetic route that is used to form reagent of the present invention, and the following content that provides only is for example, rather than limitation of the present invention.For example consult " Comprehensive OrganicTransformations ", R.Larock work, VCH publishing house (1989).To recognize further that also various protections or deprotection strategy are a kind of common ways (for example consulting " Protective Groupsin Organic Synthesis ", Greene and Wuts work) of this area.Association area those of skill in the art will recognize the selection (for example, amine and carboxyl-protecting group) of any specific protecting group will depend on this protection residue under the subsequent reactions condition stability and will understand suitable selection.Those skilled in the art's further instruction is selected from following a large amount of Chemistry Literature: " Chemistry of the AminoAcids ", J.P.Greenstein and M.Winitz work, John Wiley﹠amp; Sons, Inc., New York (1961); " ComprehensiveOrganic Transformations ", R.Larock work, VCH publishing house (1989); T.D.Ocain etc., J.Med.Chem., 31,2193-99 (1988); E.M.Gordon etc., J.Med.Chem.31,2199～10 (1988); " Practice of PeptideSynthesis ", M.Bodansky and A.Bodanszky work, Springer-Verlag, New York (1984); " Protective Groups in Organic Synthesis ", T.Greene and P.Wuts work (1991); " Asymmetric Synthesis:Construction of Chiral Molecules Using AminoAcids ", G.M.Coppola and H.F.Schuster work, John Wiley﹠amp; Sons, Inc., New York (1987); " The Chemical Synthesis of Peptides ", J.Jones, Oxford University Press, New York (1991); " Introductionof Peptide Chemistry ", P.D.Bailey work, John Wiley﹠amp; Sons, Inc., New York (1992).

Here chemical constitution is to draw according to this area standard commonly used.Therefore, when the atom of a drafting, carbon atom for example, reading removes to have a unsaturated valence link, and then this valence link is considered to satisfy valence link by hydrogen atom, comes even if hydrogen atom there is no need to be drawn significantly.The structure of some chemical compounds of the present invention comprises three-dimensional carbon atom.Should be understood that: unless possess explanation, the isomer of this asymmetric generation (for example all enantiomer or diastereomer) is also included within the scope of the present invention.That is, except as otherwise noted, any chiral carbon center can be (R)-or (S)-spatial chemistry.Separating technology that can be by classics is by the synthetic this isomer that obtains pure basically form of spatial chemistry control.

In addition, when suitable, alkene can comprise E-or Z-isomery.In addition, chemical compound of the present invention can the non-solvent form, exist with solvation form and polymorphous form (for example, comprising pseudopolymorphic forms) of acceptable solvent (for example water, THF, ethanol etc.).Term " solvation " expression comprises the gathering of the molecule of the molecule of one or more chemical compounds and one or more medicine solvent (for example water, ethanol etc.).

Can be included in the chemical compound described in the following document as other example of the chemical compound of chemical compound of the present invention: United States Patent (USP) provisional application case the 60/480th, No. 906 (applications on June 23rd, 2003, attorney NBI-162-1) and United States Patent (USP) provisional application case the 60/512nd, No. 047 (application on October 17th, 2003, attorney NBI-162-2), U.S. patent application case 10/_, _, (application on June 18th, 2004, attorney NBI-162A) and U.S. Patent application the 10/th, _, number (on June 18th, 2004 application, attorney NBI-162B), all be entitled as " compositions and the method for the disease that the treatment amyloid is relevant "; And United States Patent (USP) provisional application case the 60/480th, No. 928 (applications on June 23rd, 2003, attorney NBI-163-1), United States Patent (USP) provisional application case 60/512, No. 018 (application on October 17th, 2003, attorney NBI-163-2), U.S. patent application case 10/_, _, (application on June 18th, 2004, attorney NBI-163), all be entitled as " compositions and the method for the disease that the disease that the treatment amyloid is relevant is relevant with Epileptogenesis ".

In an instantiation, the present invention relates to a kind of compositions with treatment chemical compound (chemical compound that promptly has formula I-A) to small part:

Wherein

R ¹Being one replaces or unsubstituted cycloalkyl, aryl, cycloalkyl aryl, dicyclo or three rings, dicyclo or three ring condensed ring radical or replacement or unsubstituted C ₂-C ₁₀Alkyl;

R ²Be selected from hydrogen, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, aralkyl, thiazolyl, triazolyl, imidazole radicals, benzothiazolyl and benzimidazolyl;

Y is SO ₃ ^-X ⁺, OSO ₃ ^-X ⁺, or SSO ₃ ^-X ⁺

X ⁺Be hydrogen, cation radical or ester forming group (that is, as prodrug);

And L ¹And L ²Independently for replacing or unsubstituted C ₁-C ₅Alkyl or do not exist, or its pharmaceutically acceptable salt, condition is to work as R ¹During for alkyl, L ¹Do not exist.

In another instantiation, the present invention relates to a kind of compositions with treatment chemical compound (chemical compound that promptly has formula II-A) to small part:

Wherein:

R ¹For replacing or unsubstituted ring, dicyclo, three ring or benzheterocycle or replacement or unsubstituted C ₂-C ₁₀Alkyl.

R ²Be hydrogen, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, aralkyl, thiazolyl, triazolyl, imidazole radicals, benzothiazolyl and benzimidazolyl, perhaps with R ¹Link to each other and form a heterocycle;

Y is SO ₃ ^-X ⁺, OSO ₃ ^-X ⁺, or SSO ₃ ^-X ⁺

X ⁺Be hydrogen, cation radical or ester forming residue;

M is 0 or 1;

N is 1,2,3 or 4;

L replaces or unsubstituted C ₁-C ₃Alkyl or do not exist, or its pharmaceutically acceptable salt, condition is to work as R ¹During for alkyl, L does not exist.In a specific instantiation, n is 3 or 4.

In another instantiation, the present invention relates to a kind of compositions with treatment chemical compound (chemical compound that promptly has formula III-A) to small part:

Wherein:

A is nitrogen or oxygen;

R ¹¹For hydrogen, become salt cation, ester forming group ,-(CH2) _x-Q, or when A is nitrogen, A and R11 form natural or non-natural amino acid residue or its salt or ester together;

Q is hydrogen, thiazolyl, triazolyl, imidazole radicals, benzothiazolyl or benzimidazolyl;

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

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

R ³, R ^3a, R ⁴, R ^4a, R ⁵, R ^5a, R ⁶, R ^6a, R ⁷And R ^7aBe hydrogen, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aromatic yl alkyl carbonyl, aryl carbonyl, alkoxy carbonyl group, cyano group, halogen, amino, tetrazole radical independently of one another, or two R groups on the adjacent ring atom and annular atoms form a two key together.In a specific instantiation, n is 3 or 4.In the instantiation of some, R ³, R ^3a, R ⁴, R ^4a, R ⁵, R ^5a, R ⁶, R ^6a, R ⁷And R ^7aOne of be formula III a-A residue:

Wherein:

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

R ^A, R ^B, R ^C, R ^DAnd R ^EBe independently selected from hydrogen, halogen, hydroxyl, alkyl, alkoxyl, halogenated alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, cyano group, thiazolyl, triazolyl, imidazole radicals, tetrazole radical, benzothiazolyl and benzimidazolyl; And pharmaceutically acceptable salt and ester.In the instantiation of some, described chemical compound is not 3-(4-phenyl-1,2,3,6-tetrahydrochysene-1-pyridine radicals)-1-propane sulfonic acid.

One become ester group or residue comprise when in conjunction with the time can form the group of ester.The example of this base comprises replacement or unsubstituted alkyl, aryl, thiazolinyl, alkynyl or cycloalkyl.The special embodiment of possible ester comprises methyl, ethyl and the tert-butyl group.In addition, the example of salt-forming cation comprises the pharmaceutically acceptable salt described in this description and lithium, sodium, potassium, magnesium, calcium, barium, zinc, ferrum and ammonium.In another instantiation, this salt-forming cation is a sodium salt.

In another instantiation, the present invention relates to a kind of compositions with treatment chemical compound (chemical compound that promptly has formula IV) to small part:

Wherein:

A is nitrogen or oxygen;

R ¹¹For hydrogen, become salt cation, ester forming group ,-(CH2) _x-Q, or when A is nitrogen, A and R11 form natural or non-natural amino acid residue or its salt or ester together;

Q is hydrogen, thiazolyl, triazolyl, imidazole radicals, benzothiazolyl or benzimidazolyl;

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

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

R ⁴, R ^4a, R ⁵, R ^5a, R ⁶, R ^6a, R ⁷And R ^7aBe hydrogen, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aromatic yl alkyl carbonyl, aryl carbonyl, alkoxy carbonyl group, cyano group, halogen, amino, tetrazole radical independently of one another, R ⁴And R ⁵Form two key, perhaps R with the carbon atom that links to each other with them ⁶And R ⁷Form two keys with the carbon atom that links to each other with them;

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

R ⁸, R ⁹, R ¹⁰, R ¹¹And R ¹²Be independently selected from hydrogen, halogen, hydroxyl, alkyl, alkoxyl, halogenated alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, cyano group, thiazolyl, triazolyl, imidazole radicals, tetrazole radical, benzothiazolyl and benzimidazolyl and pharmaceutically acceptable salt thereof and ester.In a specific instantiation, n is 3 or 4.

In another instantiation, the present invention relates to a kind of compositions with treatment chemical compound (chemical compound that promptly has formula V-A) to small part:

Wherein:

A is nitrogen or oxygen;

R ¹¹For hydrogen, become salt cation, ester forming group ,-(CH2) _x-Q, or when A is nitrogen, A and R11 form natural or non-natural amino acid residue or its salt or ester together;

Q is hydrogen, thiazolyl, triazolyl, imidazole radicals, benzothiazolyl or benzimidazolyl;

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

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

Aa is natural or non-natural amino acid residue;

M is 0,1,2 or 3;

R ¹⁴Hydrogen or protecting group;

R ¹⁵Be hydrogen, alkyl or aryl, and pharmaceutically acceptable salt and prodrug, in a special instantiation, n is 3 or 4.

In another instantiation, the present invention relates to a kind of compositions with treatment chemical compound (chemical compound that promptly has formula VI-A) to small part:

Wherein:

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

A is nitrogen or oxygen;

R ¹¹For hydrogen, become salt cation, ester forming group ,-(CH2) _x-Q, or when A is nitrogen, A and R11 form natural or non-natural amino acid residue or its salt or ester together;

Q is hydrogen, thiazolyl, triazolyl, imidazole radicals, benzothiazolyl or benzimidazolyl;

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

R ¹⁹Be hydrogen, alkyl or aryl;

Y ¹Be oxygen, sulfur or nitrogen;

Y ²Be carbon, nitrogen or oxygen;

R ²⁰Be hydrogen, alkyl, amino, thiazolinyl, alkynyl, cycloalkyl, aryl, aralkyl, thiazolyl, triazolyl, tetrazole radical, imidazole radicals, benzothiazolyl or benzimidazolyl;

R ²¹Be hydrogen, alkyl, amino, thiazolinyl, alkynyl, cycloalkyl, aryl, aralkyl, thiazolyl, triazolyl, tetrazole radical, imidazole radicals, benzothiazolyl or benzimidazolyl; If or Y ²Be oxygen, then do not exist;

R ²²Be hydrogen, alkyl, amino, thiazolinyl, alkynyl, cycloalkyl, aryl, aralkyl, thiazolyl, triazolyl, tetrazole radical, imidazole radicals, benzothiazolyl or benzimidazolyl; If or Y ¹Be nitrogen, then R ²²Be hydrogen, hydroxyl, alkoxyl or aryloxy group; If Y ¹Be sulfur, then R ²²Do not exist; If or Y ¹Be nitrogen, R ²²And R ²¹Couple together and form a ring residue;

Or its pharmaceutically acceptable salt.In a specific instantiation, n is 3 or 4.

In another instantiation, the present invention relates to a kind of compositions with treatment chemical compound (chemical compound that promptly has formula VII-A) to small part:

A)

Wherein:

N is 2,3 or 4;

A is nitrogen or oxygen;

R ¹¹For hydrogen, become salt cation, ester forming group ,-(CH2) _x-Q, or when A is nitrogen, A and R11 form natural or non-natural amino acid residue or its salt or ester together;

Q is hydrogen, thiazolyl, triazolyl, imidazole radicals, benzothiazolyl or benzimidazolyl;

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

G is a direct key or oxygen, nitrogen or sulfur;

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

M is 0 or 1;

R ²⁴Be selected from hydrogen, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, aroyl, alkyl-carbonyl, aminoalkyl carbonyl, cycloalkyl, aryl, aralkyl, thiazolyl, triazolyl, imidazole radicals, benzothiazolyl and benzimidazolyl;

Each R ²⁵Be independently selected from hydrogen, halogen, cyano group, hydroxyl, alkoxyl, mercaptan, amino, nitro, alkyl, aryl, carbocylic radical or heterocyclic radical, and pharmaceutically acceptable salt.In a specific instantiation, n is 3 or 4.

Additional compounds for example comprises, the treatment chemical compound of formula (II-B):

Wherein:

X is oxygen or nitrogen;

Z is C=O, S (O) ₂, or P (O) OR ⁷

M and n are 0,1,2,3,4,5,6,7,8,9 or 10 independently of one another;

R ¹And R ⁷Independently of one another for hydrogen, metal ion, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, with X form a natural or non-natural amino acid residue residue or-(CH ₂) _p-Y;

Y is hydrogen or the heterocyclic radical that is selected from thiazolyl, triazolyl, tetrazole radical, imidazole radicals, benzothiazolyl and benzimidazolyl;

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

R ²Be hydrogen, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, alkyl-carbonyl, aryl carbonyl or alkoxy carbonyl independently of one another;

R ³Be independently selected from hydrogen, amino, cyano group, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl heterocyclic radical, replacement or unsubstituted aryl, heteroaryl, thiazolyl, triazolyl, tetrazole radical, imidazole radicals, benzothiazolyl or benzimidazolyl and pharmaceutically acceptable salt, ester and prodrug.

In another instantiation, m is 0,1 or 2.In another instantiation, n is 0,1 or 2, for example, and 1 or 2.In another instantiation, R ³Be aryl, heteroaryl or phenyl.In another instantiation, Z is S (O) ₂

In another instantiation, the present invention of the present invention is formula (II-B)

Wherein:

X is oxygen or nitrogen;

M and n are 0,1,2,3,4,5,6,7,8,9 or 10 independently of one another;

R ¹For hydrogen, metal ion, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl or one with X form natural or alpha-non-natural amino acid residue residue or-(CH ₂) _p-Y;

Y is hydrogen or the heterocyclic radical that is selected from thiazolyl, triazolyl, tetrazole radical, imidazole radicals, benzothiazolyl and benzimidazolyl;

Each R ⁴Be independently selected from hydrogen, halogen, cyano group, hydroxyl, mercaptan, amino, cyano group nitro, alkyl, aryl, carboxyl or heterocyclic radical;

R ²Be hydrogen, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, alkyl-carbonyl, aryl carbonyl or alkoxy carbonyl independently of one another;

J does not exist or for oxygen, nitrogen, sulfur or a residue of divalent, includes but not limited to low-grade alkylidene, alkylene oxide group, alkylidene amino, alkylidene sulfenyl, alkylene oxide group alkyl, alkylidene amino alkyl, alkylidene alkylthio, thiazolinyl, alkene oxygen base, alkenyl amino or thiazolinyl sulfenyl; With

Q is 1,2,3,4 or 5, and pharmaceutically acceptable salt and prodrug.In a specific instantiation, n is 1 or 2.

In another instantiation, treatment chemical compound of the present invention is formula (III-B) chemical compound:

Wherein:

X is oxygen or nitrogen;

M and n are 0,1,2,3,4,5,6,7,8,9 or 10 independently of one another;

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

R ¹For hydrogen, metal ion, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl or one with X form natural or alpha-non-natural amino acid residue residue or-(CH ₂) _p-Y;

Y is hydrogen or the heterocyclic radical that is selected from thiazolyl, triazolyl, tetrazole radical, imidazole radicals, benzothiazolyl and benzimidazolyl;

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

R ²Be hydrogen, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, alkyl-carbonyl, aryl carbonyl or alkoxy carbonyl;

R ⁵Be selected from hydrogen, halogen, amino, nitro, hydroxyl, carbonyl, mercaptan, carboxyl, alkyl, alkoxyl, alkoxy carbonyl, acyl group, alkyl amino and acyl amino;

J does not exist or for oxygen, nitrogen, sulfur or a residue of divalent, includes but not limited to low-grade alkylidene, alkylene oxide group, alkylidene amino, alkylidene sulfenyl, alkylene oxide group alkyl, alkylidene amino alkyl, alkylidene alkylthio, thiazolinyl, alkene oxygen base, alkenyl amino or thiazolinyl sulfenyl; With its pharmaceutically acceptable salt, ester and prodrug.In a specific instantiation, n is 1 or 2.

In another instantiation, treatment chemical compound of the present invention is:

B).

Wherein:

X is oxygen or nitrogen;

M and n are 0,1,2,3,4,5,6,7,8,9 or 10 independently of one another;

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

R ¹For hydrogen, metal ion, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl or one with X form natural or alpha-non-natural amino acid residue residue or-(CH ₂) _p-Y;

Y is hydrogen or the heterocyclic radical that is selected from thiazolyl, triazolyl, tetrazole radical, imidazole radicals, benzothiazolyl and benzimidazolyl;

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

R ²Be hydrogen, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, alkyl-carbonyl, aryl carbonyl or alkoxy carbonyl;

R ⁵Be selected from hydrogen, halogen, amino, nitro, hydroxyl, carbonyl, mercaptan, carboxyl, alkyl, alkoxyl, alkoxy carbonyl, acyl group, alkyl amino and acyl amino; And

Its pharmaceutically acceptable salt, ester and prodrug.In another instantiation, m is 0.In a specific instantiation, n is 1 or 2.

In another instantiation, the present invention relates to the treatment chemical compound of formula (V-B):

Wherein:

Z is C=O, S (O) ₂, or P (O) OR ⁷

R ¹For hydrogen, metal ion, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl or one with X form natural or alpha-non-natural amino acid residue residue or-(CH ₂) _pOne Y;

Y is hydrogen or the heterocyclic radical that is selected from thiazolyl, triazolyl, tetrazole radical, imidazole radicals, benzothiazolyl and benzimidazolyl;

M and n are 0,1,2,3,4,5,6,7,8,9 or 10 independently of one another;

R ²Be hydrogen, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, alkyl-carbonyl, aryl carbonyl or alkoxy carbonyl; And

R ⁶Being one is substituted or the unsubstituted heterocyclic residue.In another instantiation, m is 0 or 1.In another instantiation, n is 0 or 1.In another instantiation, R ⁶Be thiazolyl, azoles base, pyrazolyl, indyl, pyridine radicals, thiazinyl, thienyl, benzothienyl, glyoxalidine base, dihydro-thiazolyl, azoles quinoline base, thiazolinyl, tetrahydro-pyrimidine base or piperazine base.In another instantiation, Z is S (O) ₂In a specific instantiation, n is 1 or 2.

In some instantiation of the present invention, treatment preparation of the present invention also may comprise pharmaceutically acceptable non-active ingredient and have the treatment chemical compound of formula 3-amino-1-propane sulfonic acid ester/X (wherein X is counter ion or forms ester with sulfonate), wherein this ester or counter ion comprise respectively can appreciable impact should the minimizing of treatment preparation or prevent the alcohol radical of the bad ability of gastrointestinal tolerant or the atom or the residue of positively charged.In a preferred instantiation, this cation group is that hydrogen (H) and this chemical compound are 3-amino-1-propane sulfonic acid.At some in other the instantiation, this hydrogen is by being replaced by a pharmaceutically acceptable cation or an alcohol radical or its equivalent, and this chemical compound be one should acid salt or ester.

The pharmaceutically acceptable salt of this treatment chemical compound or ester can not reduce or the bad ability of prevention gastrointestinal tolerant by appreciable impact treatment preparation within the scope of the invention.For example, this cation can be a pharmaceutically acceptable alkali metal, alkaline-earth metal, more ion (for example aluminium ion), polycation counter ion or the ammonium of high price, and alcohol radical can be a pharmaceutically acceptable alcohol radical.In a special instantiation, pharmaceutically acceptable salt is a sodium salt, yet, also can consider other salt in its pharmaceutically acceptable scope.

In general, the treatment chemical compound that is suitable for treatment preparation of the present invention comprises at least one and replacement or unsubstituted aryl or the covalently bound sulfonate group of fat-based.

In another instantiation, this treatment chemical compound has at least one and replacement or the covalently bound sulfonate group of unsubstituted fat-based.In a similar instantiation, this treatment chemical compound has at least two and replacement or the covalently bound sulfonate group of unsubstituted fat-based.In another instantiation, this treatment chemical compound has at least one and replacement or the covalently bound sulfonate group of unsubstituted low alkyl group.In similar instantiation, this treatment chemical compound has at least two and replacement or the covalently bound sulfonate group of unsubstituted low alkyl group.

In another instantiation, this treatment chemical compound has at least one and the amino covalently bound sulfonate group of fat-based that replaces.In similar instantiation, this treatment chemical compound has at least two covalently bound sulfonate groups of fat-based that replace with amino.In another instantiation, this treatment chemical compound has at least one amino covalently bound sulfonate group of low alkyl group that replaces.In similar instantiation, this treatment chemical compound has at least two covalently bound sulfonate groups of low alkyl group that replace with amino.

" sulfonate group " as used herein be with carbon atom bonded-SO ₃-H or-SO ₃The X group, wherein X is cation radical or ester group.Similarly, " sulfonic acid " has one and the bonded SO of carbon atom ₃The H group." sulfuric ester " as used herein have one with carbon atom bonded-O-H or-OX, wherein X is cation radical or ester group.And " sulphuric acid " chemical compound have one with carbon atom bonded-OH.According to the present invention, suitable cation group can be a hydrogen atom.In some cases, this cation group can be in fact under physiology's pH value being group on the electropositive treatment chemical compound, for example amino.

This comprise one with the covalently bound cation group chemical compound of this treatment chemical compound itself be called as " inner salt " or " amphion ".For example, can under suitable condition, form chemical compound 3-amino-1-propane sulfonic acid from an inner salt or amphion.

Unless otherwise defined, chemical residue herein can be replacement or unsubstituted.In some instantiations, term " replacement " is meant that this molecule that can allow that this residue has outside the dehydrogenation that is positioned on this residue realizes that the substituent non-limiting instance of substituent group of its intended function is selected from following residue: straight or branched alkyl (preferred C ₁-C ₅), cycloalkyl (preferred C ₃-C ₈), alkoxyl (preferred C ₁-C ₆), alkylthio (preferred C ₁-C ₆), thiazolinyl (preferred C ₂-C ₆), alkynyl (preferred C ₂-C ₆), heterocyclic radical, carbocylic radical, aryl (for example; phenyl), aryloxy group (for example; phenoxy group), aralkyl (for example; benzyl), aryloxy alkyl (for example, phenoxyalkyl), arylacetamide base, alkylaryl, heteroarylalkyl, alkyl-carbonyl and aryl carbonyl or other this acyl group, heteroaryl carbonyl or heteroaryl, (CR ' R ") _0-3NR ' R " (for example ,-NH ₂), (CR ' R ") _0-3CN (for example ,-CN) ,-NO ₂, halogen (for example ,-F ,-Cl ,-Br or-I), (CR ' R ") _0-3C (halogen) ₃(for example ,-CF ₃), (CR ' R ") _0-3CH (halogen) ₂, (CR ' R ") _0-3CH ₂(halogen), and (CR ' R ") _0-3CONR ' R ", (CR ' R ") _0-3(CNH) NR ' R ", and (CR ' R ") _0-3S (O) _1-2NR ' R ", (CR ' R ") _0-3CHO, (CR ' R ") _0-3(CR ' R ") _0-3H, (CR ' R ") _0-3S (O) _0-3R ' (for example ,-SO ₃H ,-OSO ₃H), (CR ' R ") _0-3O (CR ' R ") _0-3H (for example ,-CH ₂OCH ₃With-OCH ₃), (CR ' R ") _0-3S (CR ' R ") _0-3H (for example ,-SH and-SCH ₃), (CR ' R ") _0-3OH (for example ,-OH), (CR ' R ") _0-3COR ', (CR ' R ") _0-3(replacing or unsubstituted phenyl), and (CR ' R ") _0-3(C ₃-C ₈Cycloalkyl), (CR ' R ") _0-3CO ₂R ' (for example ,-CO ₂H) or (CR ' R ") _0-3OR ' group, or the amino acid whose side chain of any natural origin; Wherein R ' and R " be hydrogen, C independently of one another ₁-C ₅Alkyl, C ₂-C ₅Thiazolinyl, C ₂-C ₅Alkynyl and aryl." substituent group " can also comprise for example halogen; carboxyl; the alkyl-carbonyl oxygen base; aryl carbonyl oxygen base; alkoxy-carbonyl oxy; aryloxycarbonyl oxygen base; carboxylate; alkyl-carbonyl; alkoxy carbonyl; amino carbonyl; alkyl thiocarbonyl; alkoxyl; phosphate ester; phosphonate group; the phosphonous acid ester group; cyano group; amino (comprises alkyl amino; dialkyl amido; arylamino; ammonia diaryl base; with basic arylamino); acyl amino (comprises alkyl-carbonyl-amino; aryl-amino-carbonyl; carbamoyl and urea groups); imino group; sulfydryl; the alkyl sulfenyl; artyl sulfo; carbothioic acid ester; sulfuric ester; sulfonate group; sulfamoyl; sulfonamido; nitro; trifluoromethyl; azido; heterocyclic radical; aralkyl and aromatic radical or heteroaryl residue.

Should be appreciated that, " replacement " and " being substituted " comprises following implicit prerequisite, that is, this replacement is consistent with the atom and the substituent valence link that allows of replacement, and this replacement obtains a stable chemical compound, for example can spontaneously not transform by rearrangement, cyclisation, elimination etc." replacement " as used in this specification includes the substituent group of all permissions of organic compounds.Aspect a broad, the substituent group that is allowed includes the aliphatic of organic compounds and carbocylic radical and heterocyclic radical, aromatics and the non-aromatic substituent of ring family, straight chain and side chain.The substituent group of this permission can be one or more identical or different for suitable organic compound.

In the instantiation of some, a substituent group for example can be selected from: halogen, trifluoromethyl, nitro, cyano group, C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₁-C ₆Alkyl-carbonyl oxygen base, aryl carbonyl oxygen base, C ₁-C ₆Alkoxy-carbonyl oxy, aryloxycarbonyl oxygen base, C ₁-C ₆Alkyl-carbonyl, C ₁-C ₆Alkoxy carbonyl, C ₁-C ₆Alkoxyl, C ₁-C ₆Alkyl sulfenyl, artyl sulfo, heterocyclic radical, aralkyl and aryl (comprise heteroaryl.

Treatment chemical compound of the present invention in general is a micromolecule." micromolecule " is meant that this chemical compound itself is not the product of genetic transcription or translation (for example, protein, RNA or DNA).Preferably " micromolecule " is meant a low molecular weight compound, for example less than 7500 atomic mass units, is more preferably less than 5000 atomic mass units, is more preferably less than 1000 atomic mass units.

The term " amine " of institute's term or " amino " are meant formula-NR replacement or unsubstituted in this description ^aR ^b, R wherein ^aAnd R ^bBe hydrogen, alkyl, aryl or heterocyclic radical independently of one another, R ^aAnd R ^bForm a ring residue that in ring, has 3～8 atoms with the nitrogen-atoms that is connected with them.Therefore, except as otherwise noted, term " amino " comprises the ring amino residue, for example piperidyl or pyrrolidinyl.Therefore, term as used in this specification " alkyl amino " expression has the alkyl that connects superincumbent amino.Suitable alkyl amino base have 1～about 12 carbon atoms,, the group of 1～about 6 carbon atoms for example.Term " amino " comprises wherein nitrogen-atoms and at least one carbon or covalently bound chemical compound of hetero atom or residue.Term " dialkyl amido " comprises the group that nitrogen-atoms wherein is connected with two alkyl at least.Term " arylamino " and " ammonia diaryl base " comprise the nitrogen that nitrogen-atoms wherein links to each other with at least 1 or 2 aryl respectively.Term " alkyl aryl amino " is meant the amino that is connected with at least one alkyl or at least one aryl.Term " alkyl amino alkyl " is meant alkyl, thiazolinyl or the alkynyl that is replaced by alkyl amino.Term " amide " or " amino carbonyl " comprise chemical compound or the residue that wherein comprises a nitrogen-atoms that links to each other with the carbon of carbonyl or thiocarbonyl.

Term " fat-based " comprises the organic compound that is characterised in that the straight or branched with 1～22 carbon atom.Fat-based comprises alkyl, thiazolinyl and alkynyl.This chain can be ramose or crosslinked.Alkyl comprises the saturated hydrocarbons with one or more carbon atoms, comprises straight chained alkyl and branched alkyl.Term " alcyl " comprises the closed-loop structure of three or more carbon atom.

Alcyl is included as the cycloalkanes of saturated cyclic hydrocarbons or naphthalene, undersaturatedly has the cyclenes of two or more pairs of keys and have a triple-linked ring acetylene.They do not comprise aromatic group.Naphthenic embodiment comprises cyclopropane, cyclohexane extraction and Pentamethylene..The embodiment of cyclenes comprises cyclopentadiene and cyclo-octatetraene.Alcyl also comprises polycyclic ring, for example, and condensed ring structure and the alcyl that replaces, for example alcyl of alkyl replacement.Multi-ring or multi-ring group comprises two or more rings (for example: cycloalkyl, cycloalkenyl group, cycloalkynyl radical, aryl or heterocyclic radical), and wherein one or more carbon are that two adjacent rings are common, for example should ring fused rings or volution.The ring that connects by non-adjacent atom is called as " bridged ring ".

" alkyl " as used in this specification comprises the saturated hydrocarbyl with one or more carbon atoms, straight chained alkyl, for example, methyl, ethyl, propyl group, butyl, amyl group, hexyl, heptyl, octyl group, nonyl, decyl etc.Cycloalkyl (or " cycloalkyl " or " alcyl " or " carbocylic radical "), for example, cyclopropyl, cyclopenta, cyclohexyl, suberyl, ring octyl group etc.The alkyl of side chain, for example, the isopropyl tert-butyl group, sec-butyl, isobutyl group etc.; The alkyl that alkyl replaces, for example cycloalkyl of alkyl replacement and the alkyl of naphthenic substituent.

Therefore, for example the present invention relates to replacement or unsubstituted alkyl sulfonic acid, i.e. replacement or unsubstituted straight chained alkyl sulfonic acid, replacement or unsubstituted cycloalkyl sulfonic acid and replacement or unsubstituted branched alkyl sulfonic acid.

In the instantiation of some, the alkyl of a straight or branched can have 30 or less carbon atom in main chain, for example for straight chain C ₁-C ₃₀And for side chain C ₃-C ₃₀In the instantiation of some, the alkyl of a straight or branched may have 20 or carbon atom still less in its main chain, for example for straight chain C ₁-C ₂₀, or for side chain C ₃-C ₂₀, and, more particularly, be for example 18 or still less carbon atom.

In addition, the example of cycloalkyl has 4～10 carbon atoms in their circulus, for example has 4～7 carbon atoms in this link structure.

Term " low alkyl group " is meant the alkyl that has 1～8 carbon atom in chain, and the cycloalkyl that has 3～8 carbon atoms in ring structure.Unless carbon number possesses explanation, " rudimentary " in " low alkyl group " is meant that this residue has at least 1 and be less than 8 carbon atoms.In the instantiation of some, the low alkyl group of straight or branched in its main chain, have 6 or carbon atom still less (for example, for straight chain C ₁-C ₆, for side chain C ₃-C ₆), for example, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl and the tert-butyl group.Similarly, cycloalkyl can have 3～8 in the link structure, for example 5～6 carbon atoms." C ₁-C ₆Alkyl " in term " C ₁-C ₆" be meant that alkyl comprises 1～6 carbon atom.

In addition, unless otherwise mentioned, the term alkyl comprises " unsubstituted alkyl " and " alkyl of replacement ", and wherein the latter is meant that alkyl has the substituent group of the hydrogen on one or more carbon atoms of replacing on this hydrocarbon main chain.This substituent group for example can comprise, thiazolinyl; alkynyl; halogen; carboxyl; the alkyl-carbonyl oxygen base; aryl carbonyl oxygen base; alkoxy-carbonyl oxy; aryloxycarbonyl oxygen base; carboxylate; alkyl-carbonyl; aryl carbonyl; alkoxy carbonyl; amino carbonyl; alkyl amino-carbonyl; dialkyl amino carbonyl; alkyl thiocarbonyl; alkoxyl; phosphate-based; phosphonate group; the phosphonous acid ester group; cyano group; amino (comprises alkyl amino; dialkyl amido; arylamino; ammonia diaryl base; and alkyl aryl amino); acyl amino (comprises alkyl-carbonyl-amino; aryl-amino-carbonyl; carbamoyl and urea groups); imino group; sulfydryl; the alkyl sulfenyl; artyl sulfo; the thiocarboxylic acid ester group; sulfate group; alkyl sulphonyl; sulfonate group; sulfonamides; sulfonamide; nitro; trifluoromethyl; cyano group; azido; heterocyclic radical; alkylaryl; or aryl (comprising heteroaryl).

Term " thiazolinyl " and " alkynyl " are meant the undersaturated fat-based that is similar to alkyl, comprise straight or branched and ring structure, but it comprises at least one two keys or triple bond respectively.Suitable thiazolinyl and alkynyl comprise having 2～about 12 carbon atoms, preferred 2～about 6 carbon atoms.

Term " aryl " comprises the undersaturated cyclic hydrocarbon that contains one or more rings.Usually, term " aryl " comprises can contain zero to four heteroatomic 5-or 6-person's monocyclic aryl, for example is selected from: benzene, pyrroles, furan, thiophene, thiazole, isothiazole, imidazoles, triazole, pyrazoles, azoles, different azoles, pyridine, pyrazine, pyridazine and pyrimidine etc.In addition, term aryl comprises multi-ring group, for example derived from the group of three rings, dicyclo, for example assorted fast quinoline of naphthalene, benzothiazole, benzodiazole, benzothiazole, benzimidazole, benzothiophene, methylene dioxy phenyl group, quinoline, isoquinolin, naphthopyridine, indyl, benzofuranyl, fast quinoline base, denitrogenation or indolizine.

These have heteroatomic aryl and are also referred to as " aryl-heterocyclic ", " heteroaryl " or " heteroaryl " in ring structure.

Aryl can also with alicyclic ring or nonaromatic heterocyclic radical bridge joint, to form one multi-ring (for example, tetralin).In ring structure, have heteroatomic aryl and can also be called as aryl-heterocyclic, heterocycle, heteroaryl or heteroaromatics, wherein, for example comprise that the ring of any formation is combined with an atom or non-carbon atom.This ring can be saturated or unsaturated and can comprise one or more pairs of keys.The example of some heterocyclic radicals comprises pyridine radicals, furyl, thienyl, morpholinyl and indyl.

Term " hetero atom " comprises any atom except carbon and hydrogen.Preferred hetero atom is nitrogen, oxygen, sulfur and phosphorus.

Heterocyclic radical comprises that also the closed-loop structure of one or more atoms in its medium ring is an element except carbon, for example nitrogen, sulfur or oxygen.Heterocyclic radical can be saturated or unsaturated and heterocyclic radical for example pyrroles and furan can have armaticity.They comprise condensed ring structure example such as quinoline and isoquinolin.Other examples of heterocyclic radical comprise pyridine and purine.The example of assorted aromatic radical and heterolipid cyclic group also have 1～3 independent or condensed 3 Yuans to about 8 Yuans and have one or more N, O or the ring of S atom, for example coumarin base, quinolyl, pyridine radicals, pyrazinyl, pyrimidine radicals, furyl, pyrrole radicals, thienyl, thiazolyl, azoles base, imidazole radicals, indyl, benzofuranyl, benzothiazolyl, tetrahydrofuran base, THP trtrahydropyranyl, piperidyl, morpholinyl and pyrrolidinyl.

III. treatment preparation of the present invention

The invention still further relates to a kind of sedimentary pharmaceutical composition of amyloid that is used for suppressing object, it comprises a kind of defined treatment preparation of this description and pharmaceutically acceptable carrier that is enough to suppress the amount of the amyloid beta deposition in the object.

In another instantiation, the present invention relates to a kind of pharmaceutical composition that is used for the treatment of amyloidosis, it comprises a kind of defined treatment preparation of this description and a kind of pharmaceutically acceptable carrier that is enough to the sedimentary amount of amyloid in the object that suppresses.

In another instantiation, the present invention relates to a kind of pharmaceutical composition that is used for the treatment of or prevents amyloid related diseases (for example type ii diabetes) or A ss related diseases (for example alzheimer's disease, brain amyloid angiopathy, occlusion body myositis, degeneration of macula, Down's syndrome and hereditary cerebral hemorrhage), it comprise a kind of contain be enough to prevent or treatment target in amyloid related diseases be made into significantly to reduce or prevent the treatment chemical compound that gastrointestinal tolerant is bad and the treatment preparation of pharmaceutically acceptable carrier.

In the instantiation of some, the present invention treats the treatment chemical compound of preparation and the binding site of basement membrane glycoprotein in the amyloidosis protein or proteoglycan interacts, thereby and suppresses the amyloidosis protein bound to this basement membrane component.Basement membrane glycoprotein and proteoglycan comprise laminin, IV Collagen Type VI, fibrinolysin, agrin, perlecan and heparan sulfuric ester proteoglycan (HSPG).In a specific instantiation, this treatment chemical compound suppresses the interaction between amyloidosis protein and agrin, perlecan or the HSPG.In addition, motivation (consulting for example Cardi and Weintraub (1989), Arteriosclerosis 9:21～32) for the binding site of the unanimity of HSPG has also been described in amyloidosis protein.

Therefore, the present invention includes a kind of sedimentary pharmaceutical composition of amyloid that is used for suppressing object of packing, it comprises a container described herein that keeps the treatment effective dose; And the description that is used for suppressing the sedimentary chemical compound of amyloid of object.In the instantiation of some, the disease relevant with this amyloid beta deposition is selected from Alzheimer, brain amyloid angiopathy, occlusion body myositis, degeneration of macula, Tang Shi syndrome, mild cognitive damage, type ii diabetes and hereditary cerebral hemorrhage.

Term " container " comprises any accepter that is used to suppress this treatment preparation.For example, in an instantiation, this container is a packing that comprises said preparation.In other instantiation, this container is not the packing that comprises said preparation, that is, this container is an accepter, for example comprise this packing preparation or unpackaged directly and the box or the bottle of the operation instructions of preparation.In addition, packing technique also is well known in the art.Should be understood that the operation instructions of this treatment preparation can be contained on the packing that contains said preparation, and this description and this packaged products form a functional relationship that has improved.Yet, should be understood that this description can comprise and relate to the information that chemical compound is implemented its expectation function (for example minimizing or prevention gastrointestinal tolerant are bad).

In another instantiation, the present invention includes a kind of pharmaceutical composition that is used for the treatment of the amyloidosis in the object of packing, it comprises a chemical compound container described herein that keeps the treatment effective dose; And the description that is used for the treatment of the chemical compound of the amyloidosis in the object.

In another instantiation, what the present invention relates to a kind of packing is used for the treatment of the medicine for treating viral infections compositions, and it comprises and keeps a kind of container for the treatment of the treatment preparation described herein of effective dose; And the description of using the chemical compound of this compound treats viral infection.

Another instantiation of the present invention relates to a kind of pharmaceutical composition that is used for the treatment of bacterial infection of packing, and it comprises a container that keeps the treatment preparation of the present invention of treatment effective dose; And the description of using the chemical compound of this compound therapeuticing bacteria infection.

On the other hand, what the invention belongs to a kind of packing is used for chemokine inhibiting and the bonded pharmaceutical composition of glycosaminoglycans, and it comprises that keeps an a kind of treatment preparation of the present invention for the treatment of effective dose; And use this to be used for the description of chemokine inhibiting and the bonded treatment chemical compound of glycosaminoglycans.

Treatment preparation of the present invention can also comprise two or more treatment combination of compounds.Therefore, the present invention relates to a kind of treatment preparation that is used for the treatment of Alzheimer, it comprises 3-amino-1-propane sulfonic acid and second medicine at other symptoms (for example supervention symptom of Alzheimer).In the instantiation of some, should " second medicine " can be cholinesterase inhibitor, for example acetylcholinesterase or butyrylcholinesterase inhibitor, for example, Romotal, donepezil, rivastigmine or galantamine.In another instantiation, second medicine can be NMD antagonist, for example memantine.

In another instantiation, this second medicine can be an antioxidant, vitamin E, estrogen, non-steroidal anti-inflammatory reagent (for example aspirin or naproxen), cholesterol modifier for example Si Tajing or gingko.

Treatment preparation of the present invention can also further comprise a kind of pharmaceutically acceptable carrier.Pharmaceutically acceptable carrier as used herein comprises the activity compatible of any sugar-coat, antibiotic and antifungal agents and absorption delay reagent etc. and this chemical compound and to can accepting on the object physiology, and can this treatment preparation of appreciable impact realize its expectation function or can appreciable impact treatment preparation do not reduce or the reagent of the ability that the prevention gastrointestinal tolerant is bad.They can also in said composition, comprise additional active substance, as long as can appreciable impact not be somebody's turn to do the ability for the treatment of preparation minimizing or prevention of emesis.

Active substance is to take with the effect of the treatment effective dose that is enough to suppress the amyloid beta deposition in this object.With respect to untreated object, a kind of " treatment effective dose " preferably suppresses about at least 20%, more preferably about at least 40%, more preferably about at least 60% and more preferably about at least 80% with amyloid beta deposition.Can assess the ability that this chemical compound suppresses amyloid beta deposition in an animal model system, described animal model system can be estimated the effectiveness in the amyloid beta deposition in suppressing human diseases.Perhaps, can suppress the interactional ability between amyloidosis protein and the basement membrane component by checking this chemical compound, for example as U.S. Pat 5,164,295 is described, its mode is by reference comprised in this application clearly, perhaps by assess the ability that this chemical compound suppresses amyloid beta deposition as embodiment 5 described mass spectrums.

Term " object " comprises and amyloidosis wherein can take place or infect the amyloid disease easily, for example Alzheimer Down's syndrome, mild cognitive damage, CAA, (β that dialysis is relevant ₂M) powder sample degeneration, supervention (AA) amyloidosis, constitutional (AL) amyloidosis, hereditary amyloidosis, diabetes, or the like active organism.The example of object comprises the mankind, monkey, cattle, sheep, goat, Canis familiaris L. and cat.Term " object " comprises that animal (for example, mammal, for example, cat, Canis familiaris L., horse, pig, cattle, goat, sheep, rodent, for example white mice or rat, rabbit, Sciurus vulgaris, Bears, primate (for example chimpanzee, monkey, gorilla and the mankind)), and chicken, duck, Beijing duck, goose and genetically modified organism.

In some instantiation of the present invention, this object need be treated by method of the present invention, and is selected for the treatment based on these needs.Need treatment to as if technical affirmation, and comprise being proved to be and have a kind of disease or the disease relevant with amyloid-deposition or amyloidosis, and has a symptom of this disease or disease, perhaps among the danger for this disease or disease, and will expect, based on diagnosis, for example internal medicine diagnosis, can be benefited from treating (for example cure, fully recover, prevent, alleviate, alleviate, change, remedy, improve, improve or influence the symptom of this disease or disease and this disease or disease or the danger of disease or disease).

Can use known step, the dosage and the cycle of suppressing the amyloid beta deposition in the object are being taken compositions of the present invention to object.Can be according to various factors, amount, patient's age, sex and the body weight of sedimentary amyloid and the ability that this treatment chemical compound is suppressed at the amyloid beta deposition in the object of the clinical site in object for example is to change the effective dose of this treatment chemical compound of realizing that therapeutic effect is required.Can adjust dosage range so that best therapeutic response to be provided.For example, can take a plurality of independent dosage or can reduce dosage in proportion every day according to the emergency of treatment situation.A non-limiting instance of the effective dose of treatment chemical compound of the present invention (for example 3-amino-1-propane sulfonic acid) is 1～500mg/kg body weight/day.Ordinary skill can be studied relevant factor arbitrarily and need not the effective dose of over-drastic test decision treatment chemical compound.

Can change the actual dose level of the active component in the pharmaceutical composition of the present invention, so that obtain and can effectively realize needed therapeutic response to specific patient, compositions and medication pattern, and to the amount of the avirulent active component of patient.

Especially, selected dosage level will depend on various factors, this comprise secretion speed, the treatment of activity, the administration time of employed specific chemical compound of the present invention, employed chemical compound persistent period, with employed specific chemical compound combination other medicine, chemical compound or materials used, the patient's age of being treated, sex, weight, condition, general health situation and previous medical science such as history of disease in well-known factor.

Doctor with this area common skill, for example doctor or veterinary can easily determine the effective dose of needed pharmaceutical composition.For example, this doctor or veterinary can be lower than the dosage of the chemical compound of the present invention that the pharmaceutical composition of the dosage of realizing that required therapeutic effect is required uses from use, progressively increase dosage, until obtaining needed effect.

The mode of medication can influence the composition of effective dose.Can before or after the amyloidosis outbreak, take this treatment preparation.In addition, can be per diem or take a plurality of independent dosage and staggered dosage continuously, perhaps can fuse this dosage continuously, perhaps can be bolus injection.In addition, can increase or reduce the dosage of this treatment preparation in proportion according to the situation of treatment or prevention.

In specific instantiation, for the ease of taking and the concordance of dosage, it is particularly advantageous that said composition is made dosage unit form.Dosage unit form as used herein is meant the physically discrete unit of the dosage unit that is suitable as the object that is used for this treatment; Its each self-contained a kind of in conjunction with required pharmaceutical carrier produce required therapeutic effect and the treatment chemical compound of the scheduled volume that calculates.The specification of dosage unit form of the present invention be by the decision of following factor and directly depending on: (a) feature of the uniqueness of this treatment chemical compound and realize specific therapeutic effect; (b) this inherent limitation of technology that is used for the treatment of the treatment chemical compound of the amyloid beta deposition in the object of mixing/preparation.

Another aspect of the present invention comprises and is used for the treatment of amyloidosis, suppresses amyloid beta deposition; Or prevention or treatment amyloid related diseases, for example, A β-relevant disease, for example, Alzheimer, brain amyloid angiopathy, occlusion body myositis, degeneration of macula, Down's syndrome, the mild cognitive damage, and hereditary cerebral hemorrhage, pharmaceutical composition above-described treatment preparation can be included in and a kind ofly contain pharmaceutically acceptable carrier and be formulated into remarkable minimizing or prevention gastrointestinal tolerant bad amount, be enough to treat or suppress the amount of amyloidosis, or be enough to suppress sedimentary amount, or be enough to prevent or treat the pharmaceutical composition of treatment chemical compound of the amount of amyloid related diseases.In an instantiation, treatment preparation of the present invention comprises having formula 3-amino-the treatment chemical compound of 1-propane sulfonic acid ester/X (wherein X is counter ion or forms ester with sulfonate), wherein this ester or counter ion comprise respectively can appreciable impact should the minimizing of treatment preparation or prevent the alcohol radical of the bad ability of gastrointestinal tolerant or the atom or the residue of positively charged.A preferred instantiation of cation group is that hydrogen, H+ and this chemical compound are 3-amino-1-propane sulfonic acid.

In another instantiation, the present invention relates to a kind of method of preparing the bad pharmaceutical composition that has strengthened of gastrointestinal tolerant, it comprises: a kind of treatment chemical compound of preliminary election is mixed with a kind of pharmaceutically acceptable carrier, remarkable reduction or the prevention gastrointestinal tolerant bad ability that preliminary election should the treatment chemical compound wherein, thus the bad pharmaceutical composition that has strengthened of gastrointestinal tolerant formed.

Term " gastrointestinal tolerant is bad strengthen pharmaceutical composition " comprises containing based on it and significantly reduces or the pharmaceutical composition of the selected treatment chemical compound of the present invention of ability preliminary election chemical compound that the prevention gastrointestinal tolerant is bad.

IV. administration

Preparation of the present invention comprises and is suitable for oral preparation.Said preparation can exist with the unit formulation form easily, and can prepare by methods known in the art.Can be mixed together the amount that is generally the chemical compound that produces therapeutic effect with the amount of the active component of making the single dose form with carrier material.Usually, since 1%, this amount is about 1%～99% active component, preferably approximately 5%～70%, most preferably about 10%～about 30%.

Prepare these preparations or method for compositions and comprise chemical compound of the present invention and carrier, and the blended step of one or more auxiliary agents.In general, can prepare said preparation by the following method: chemical compound of the present invention and liquid-carrier or pulverizing solid carrier or two kinds evenly and are nearly mixed, then, if desired, form.

Being fit to oral preparation of the present invention can be capsule, cachet, pill, tablet, lozenge (use a kind of spice base, be generally sucrose and arabic gum or Tragacanth), powder, granule; Or

Be dissolved in solution or suspension in aqueous or the non-aqueous liquid; Perhaps oil-in-water or Water-In-Oil liquid emulsion; Perhaps elixir or syrup; Perhaps lozenge (use inactive alkali, example gel and glycerol or sucrose and arabic gum) or collutory or the like form, the chemical compound of the present invention of its each self-contained a kind of scheduled volume is as active component.Can also pill, the form of electuary or paste takes chemical compound of the present invention.

In being suitable for oral solid dosage forms of the present invention (capsule, tablet, pill, dragee, powder, granule or the like), this active component mixes with one or more pharmaceutically acceptable carriers, for example sodium citrate or dicalcium phosphate or any following carrier: filler or supplement, for example starch, lactose, sucrose, glucose, mannitol or silicic acid; Binding agent, for example carboxymethyl cellulose, alginate, gel, polyvinyl pyrrolidone, sucrose or arabic gum; Wetting agent, for example glycerol; Disintegrating agent is agar, calcium carbonate, Rhizoma Solani tuber osi or tapioca, alginic acid, some esters of silicon acis and sodium carbonate for example; Solution blocker, for example paraffin; Absorb accelerator, for example quaternary ammonium compound; Wetting agent, for example spermol and glyceryl monostearate; Adsorbent drug, for example Kaolin and Bentonite; Lubricant, for example stone powder, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl and composition thereof; And coloring agent.In capsule, tablet and pill, this pharmaceutical composition also may comprise buffer agent.The solid composite that can also use similar type uses this excipient as lactose or toffee and high molecular weight polyethylene glycol etc. as filler and hard filling capsule.

When oral, chemical compound of the present invention is effective.Therefore, preferred route of administration is oral.This therapeutic active substance can be coated with a kind of material and avoid the effect of the condition that acid and other can this chemical compound of passivation to protect this chemical compound.Can prepare chemical compound of the present invention to guarantee normal distribution in vivo.For example, blood brain barrier (BBB) has been got rid of the chemical compound of many highly-hydrophilics, and in order to guarantee that treatment chemical compound of the present invention passes BBB, can be formulated in them in the liposome.Make the method for liposome and consult for example U.S.4,522,811, US5,374,548 and US5,399,331 liposomees can comprise one or more residues (targeting residue) that optionally are discharged in specific cells and the organ, and thereby provide targeted drug release (to consult for example V.V.Ranade (1989), J.Clin.Pharmacol.29:685).Exemplary residue comprises folic acid and biotin (consulting for example US5416016, Low etc.), mannoside (Umerzawa etc., (1988) Biochem.Biophys.Res.Commun.153:1038); Antibody (P.G.Bloeman etc. (1995) FEBS Lett.357:140; M.Owais etc. (1995) Antimicrob.Agents Chemother.39:180); Surface protein A receptor (Briscoe etc. (1995) Am.J.Physiol, 1233:134); Gp 120 (Schreier etc., (1994) J.Biol.Chem.269:9090); Consult K.Keinanen again; M.L.Laukkanen (1994) FEBS Lett 346:123; J.J.Killion; I.J.Fidler (1994), Immunomethods 4:273.

In order to take this treatment chemical compound, may essential this chemical compound be coated with or take a kind of material preventing inactivation with this chemical compound; For example, can take this treatment chemical compound in suitable carrier, for example liposome or diluent to object.Liposome comprises W/O/W CGF and conventional liposome (Strejan etc., J.Meuroimmunol.7,27 (1984)).

Can orally chemical compound be should treat, for example, inert diluent or absorbable edible carrier used.The composition of this treatment chemical compound and other can also be enclosed in the hard or soft gelatine capsule, be pressed into tablet or directly be included in the diet of this object.For oral administration, this treatment chemical compound can comprise excipient and use with absorbable form.The percentage ratio of this treatment chemical compound certainly is different with preparation in the compositions.The amount of the treatment chemical compound in this treatment in the useful compositions is the amount that can access appropriate dosage.

The pharmaceutically acceptable carrier of term comprises a kind of pharmaceutically acceptable material, compositions or carrier, for example liquid or solid filler, diluent, excipient, solvent or compression material, it relates in object transportation or carries chemical compound of the present invention so that can realize the function of its expection.Usually, this chemical compound is carried or is transported to the part of another organ or health from the part of an organ or health.Each " carrier " compatible with other compositions of preparation, can not the meaning of patient harm on; On the meaning that can not influence the bad ability of minimizing of treatment preparation or prevention gastrointestinal tolerant, be " acceptable " perhaps.Some examples that can be used as pharmaceutically acceptable carrier material comprise: sugar, for example lactose, dextrose plus saccharose; Starch, for example corn starch and potato starch; Cellulose and derivant thereof, for example sanlose, ethyl cellulose and cellulose acetate; The powder Tragacanth; Fructus Hordei Germinatus; Gel; Pulvis Talci; Excipient, for example cocoa butter and suppository wax; Oils, for example Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, safflower oil, Oleum sesami, olive oil, Semen Maydis oil and Oleum Glycines; Glycol, for example propylene glycol; Polyhydric alcohol, for example glycerol, Sorbitol, mannitol and Polyethylene Glycol; Ester, for example ethyl oleate and ethyl laurate; Agar; Buffer agent, for example magnesium hydroxide and aluminium hydroxide; Alginic acid; Pyrogen-free water; Isotonic saline solution; Ringer ' s solution; Ethanol; Buffer solution; And employed compatible material in the medicine of other nontoxic this areas inhibition.

In said composition, can also there be wetting agent, emulsifying agent and lubricant, for example sodium lauryl and magnesium stearate, and coloring agent, demoulding system, sugar-coat agent, sugaring, flavoring agent and spice, antiseptic and antioxidant.

The example of pharmaceutically acceptable antioxidant comprises: water miscible antioxidant, for example ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite or the like; The antioxidant that oil is molten, for example anti-bad blood acyl cetylate, butylated hydroxyanisol (BHA), 2,6-ditertbutylparacresol (BHT), lecithin, propyl lactate, alpha-tocopherol, with metallo-chelate reagent, for example citric acid, ethylenediaminetetraacetic acid (EDTA), Sorbitol, tartaric acid, phosphoric acid etc.

Can be by randomly suppressing or the molded tablet made from one or more auxiliary agents.(for example can use binding agent, gel or HYDROXY PROPYL METHYLCELLULOSE), lubricant, inert diluent, antiseptic, disintegrant (for example, sodium starch glycolate or crosslinked sanlose), surface-active or dispersant prepare compressed tablet.Can be by making this molded tablet in the suitable wherein molded moistening powder compounds of use inert liquid diluent that reaches.

Can be randomly with tablet, pharmaceutical composition of the present invention with other solid dosage forms, for example dragee, capsule, pill and preparation of granules become sugar-coat or housing, for example known other sugar-coats in enteric coating and pharmaceutical technology field.The HYDROXY PROPYL METHYLCELLULOSE that can also use different proportion is for example prepared these chemical compounds so that needed release characteristic, other polymer matrix, liposome or microsphere to be provided, so as to provide active component wherein slowly or controlled release.Can keep membrane filtration or by comprising that before use the aseptic solid composite or other the sterile injectable medium that can be dissolved in the sterilized water come it is sterilized by antibacterial for example.These compositionss can also randomly comprise opacifier, and/or can be included in the gastrointestinal specific part, randomly in the mode that postpones, only or the reagent of preferred release of active ingredients.The example of the embedding compositions that can be used comprises polymer and wax.If suitable, this active component can also be the little seal form with one or more above-mentioned excipient.

Except chemical compound of the present invention, powder can also comprise excipient, for example lactose, Pulvis Talci, silicic acid, aluminium hydroxide, calcium silicates and polyamide powder, or the mixture of these materials.

The liquid dosage form that is used for oral chemical compound of the present invention comprises pharmaceutically acceptable Emulsion, microemulsion, solution, suspension, syrup and elixir.Except that this active component, this liquid dosage form can comprise this area inert diluent commonly used, for example water or other solvent; Solubilizing agent and emulsifying agent, for example ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 butylene glycol; Oils (particularly Semen Gossypii, Semen arachidis hypogaeae, corn, antibacterial, Chinese olive tree, caster and Semen Sesami oils); The sorbitan of glycerol, tetrahydrofuran base alcohol, Polyethylene Glycol and fatty acid ester, and composition thereof.Except inert diluent, this Orally administered composition can also comprise adjuvant, for example wetting agent, emulsifying or suspending agent, sweeting agent, flavoring agent, coloring agent, aromatic and antiseptic.

Except active substance, suspension can comprise suspending agent, for example ethoxylated isostearyl alcohol, polyethylene glycol oxide Sorbitol and sorbitan ester, microcrystalline Cellulose, inclined to one side aluminium hydroxide, Bentonite, agar and Tragacanth and composition thereof.

These compositionss can also comprise adjuvant, for example antiseptic, wetting agent, emulsifying agent and dispersant.Prevention to action of microorganisms can be by comprising various antibacterial and antifungal agent, and for example para shellfish, chlorobutanol, phenol sorbic acid etc. are realized.Comprise isotonic reagent in compositions, for example sugar, sodium chloride etc. also are desirable.In addition, can be by the reagent that postpone to absorb, for example aluminum monostearate and gel, the absorption that prolongs the injectable medicine.

Can also be with compositions topical of the present invention in object, for example by directly said composition being laid or is spread out on the epidermis or epithelial tissue of object, perhaps by " plaster " transdermal administration.This compositions comprises for example detergent, emulsifiable paste, solution, gel and solid.These topical compositions preferably include effective amount, and are for example about at least 0.1%, preferably approximately 1%～about 5% chemical compound of the present invention.The suitable carrier that is used for topical is preferably with by perspiring or being immersed in continuous film that water removes and the form of protective layer is retained in skin.Usually, this carrier is organically in essence and can makes this treatment have no to disperse or dissolve therein.This carrier can comprise pharmaceutically acceptable lubricant, emulsifying agent, thickening agent, solvent or the like.

In an instantiation, based on the weight of preparation, this medicine preparation comprises greater than about 0.1% for example greater than about 1%, for example greater than about 2%, for example greater than about 3%, for example greater than about 4%, for example greater than about 5%, for example greater than about 10%, for example greater than about 20%, for example greater than about 30%, for example greater than about 40%, for example greater than about 50%, for example greater than about 60%, for example greater than about 70%, for example greater than about 80%, for example greater than about 90%, for example greater than about 95%, for example greater than about 99% treatment chemical compound, for example alkyl sulfonic acid, for example 3-amino-1-propane sulfonic acid chemical compound.In a specific instantiation, this medicine preparation comprises the preparation of this treatment chemical compound weight of about 12.6% ± 0.5%.In another specific instantiation, this medicine preparation comprises the preparation of this treatment chemical compound weight of about 95.2% ± 0.5%.The remainder of this pharmaceutical preparation is other reagent composition described herein again.

In another instantiation, weight based on preparation, this medicine preparation comprises greater than about 1%, for example greater than about 2%, for example greater than about 3%, for example greater than about 4%, for example greater than about 5%, for example greater than about 6%, for example greater than about 7%, for example greater than about 8%, for example greater than about 9%, for example greater than about 10%, for example greater than about 20%, for example greater than about 30%, for example greater than about 40%, for example greater than about 50%, for example greater than about 60%, for example greater than about 70%, for example greater than about 80%, for example greater than about 90%, for example greater than about 95%, for example greater than about 99% other reagent, for example a kind of reagent or enteric coating that changes the release of treatment chemical compound.Should be appreciated that these percents are scopes independent or that mix other reagent that apply one or more said preparations.Therefore, in some instantiation, other reagent can be the treatment preparation that is used for giving good characteristic, for example, with independently or with other minimizing or prevent Intolerant method, reduce or the prevention gastrointestinal tolerant bad.Other exemplary reagent have been described herein.For example, because any possible gastrointestinal tolerant that the treatment preparation causes is bad, this tablet can be enteric coating or can will discharge fast any of stomach or enteral with control treatment chemical compound as the modification release reagent in order to be protected from.In a specific instantiation, based on the weight of said preparation, this medicine preparation comprises this other reagent of about 9.3 ± 0.5%.In another specific instantiation, based on the weight of said preparation, this medicine preparation comprises this other reagent of about 8.8 ± 0.5%.In another specific instantiation, based on the weight of said preparation, this medicine preparation comprises this other reagent of about 5.6 ± 0.5%.

In specific instantiation of the present invention, this treatment chemical compound is selected from: change the reagent of the release of this treatment chemical compound, for example HYDROXY PROPYL METHYLCELLULOSE (HPMC); Fluidizer/diluent; The esters of silicon acis crystallite; Filler, for example double alkali yl calcium is phosphate-based; Binding agent/disintegrating agent, for example Starch_1500; Lubricant, for example stearic acid powder or magnesium stearate; Interior sugar-coat, for example Opadry_II is white; Outer sugar-coat, for example Opadry_II is white and Opadry_ is transparent; Enteric coating, for example Acrylezet_, and combination arbitrarily.Following material is that (West Point, PA) company buys: Starch_1500, Opadry_II are white, the transparent Acryleze_ of Opadry_ from Colorcon.Several instantiation of the present invention has been discussed in following example.

Equivalent technical solutions

Those skilled in the art use and are no more than conventional test and the content of this explanation, can recognize, maybe can determine a plurality of equivalent technical solutions of concrete steps described herein, instantiation, claim and embodiment.These equivalent technical solutions are considered as included in the scope of the present invention, and comprise these technical schemes by appended claim.

It will also be appreciated that when providing numerical value or scope to be, for example, age, dosage and blood levels that object is overall, all numerical value and scope that these numerical value and scope are included all are included in scope of the present invention.In addition, all fall into the numerical value of this scope, and the upper and lower bound of the scope of a numerical value is considered to, and application of the present invention considers.

Combination by reference

The application in full employed bulletin patent, disclosed patent application all by reference mode in conjunction with in this application.Should understand, any chemical compound described herein and in the application that is considered to " related application " part all falls within the scope of the present invention, and it is included by the present invention, and, at least for these purposes by clearly in conjunction with in this application, and for other purposes by further clearly in conjunction with in this application.

Embodiment

Further specify the present invention by following embodiment, but these embodiment should not be considered to further restriction of the present invention.

Embodiment 1-is used for oral capsule

In table 2, provide 100mg and 400mg white capsular unit formulation.

Table 2:100mg and the capsular unit formulation of 400mg

Composition	Grade	Function	Capsule (mg/ capsule)
								100	400
3-amino-1-propane sulfonic acid, sodium salt	MS*	Active component	100mg	400mg
					Calcium carbonate	NF	Filler	4.45	17.8
Magnesium stearate	NF	Lubricant	0.55	2.2

* MS: manufacture criterion level; NF: country's prescription level; USP: American Pharmacopeia level.

The result of some research shows: 3-amino-1-propane sulfonic acid sodium salt of taking solid dosage forms (capsule) is relevant with gastrointestinal symptom (being regurgitation and vomiting).Test in addition shows that this gastrointestinal symptom to small part is owing to the local excitation that causes at the too high pH value that amino-1-propane sulfonic acid sodium salt was produced between breaking-in period under one's belt is caused.The test (solid dosage forms) of other that carry out on one's body Canis familiaris L. has shown that the toleration of free acid is better than sodium-salt form.

In addition, the moisture absorption person's character of sour form makes it be called a kind of active drug ingredient of needs.For example, because any possible gastrointestinal tolerant that sour form causes is bad, this tablet can be enteric coating and can will discharge fast any of harmonization of the stomach enteral with the control medicine as the modification release reagent in order further to be protected from.

Example 2-enteric coating tablet

According to the white enteric coating tablet of following formulation 100mg and 400mg, wherein because its density is low and fluffy, by using water particleization with drug substance (this drug substance is removed sodium manufacturing by using ion exchange) densification.The unit preparation of 100mg and 400mg enteric coating tablet is provided in table 3.

The enteric coating tablet of the unit formulation of the table 3:100mg and 400 U.S.

Composition	Grade	Function	Capsule (mg/ capsule)
								100mg	400mg
Core
					3-amino-1-propane sulfonic acid, sodium salt	MS*	Active component	100	400
Silicified microcrystalline cellulose	NF	Fluidizer/diluent	350.00	70.00
					Calcium hydrogen phosphate	USP	Filler	158.40	112.00
HYDROXY PROPYL METHYLCELLULOSE (HPMC)	USP	Drug release modifier	70.00	70.00
					Starch _ 1500	NF	Bonding agent/disintegrating agent	11.10	37.50
The stearic acid powder	NF	Lubricant	7.00	7.00
					Magnesium stearate	NF	Lubricant	1.80	0.018
Sugar-coat
					Opadry_II is white	MS*	Interior sugar-coat	14.00	14.00
Acryleze_	MS*	Enteric coating	42.00	42.00
					Gross weight			756.00	756.00

* MS: manufacture criterion level; NF: country's prescription level; USP: American Pharmacopeia level.

100 milligrams of enteric coating tablets external (rate of dissolution) and the PK data source 1 used in first phase I research show that these tablets will cause acceptable pK and good tolerability.

Example 3-modification discharges sugar coated tablet

Clinical research shows that enteric coating and drug release modifier will be significant in medicine (metabolism) kinetics (PK) feature of medicine and the effect in the toleration thereof.Therefore, in order to obtain specific specific pharmaceutical properties (aspect PK, toleration and product stability), drug release modifier is formulated in the tablet.For the physical stability (in acceptability of filming and moistureproof ability) of improving product, under the condition of quickening, modify this enteric coating system by the amount and the outer sugar-coat of adding that increase enteric coating.

The modification of preparation 50mg concentration discharges sugar coated tablet, it comprises volume material p-amino-1-benzenesulfonic acid and inactive composition (silicified microcrystalline cellulose, calcium hydrogen phosphate), HYDROXY PROPYL METHYLCELLULOSE, starch, stearic acid, magnesium stearate, and Opadry_II white (outer sugar-coat and interior sugar-coat) and Acryleze_).Provide the 50mg modification to discharge the unit formulation of sugar coated tablet in the table 4.

Table 4:50mg modification discharges the unit formulation of sugar coated tablet

Composition	Grade	Function	Quantity/sheet (mg)	Quantity/crowd (kg)
					Core
3-amino-1-propane sulfonic acid, sodium salt	MS*	Active component	50.00	0.500
					Silicified microcrystalline cellulose	NF	Fluidizer/diluent	174.73	1.746
Calcium hydrogen phosphate	USP	Filler	79.42	0.794
					HYDROXY PROPYL METHYLCELLULOSE (HPMC)	USP	Drug release modifier	35.00	0.350
Starch _ 1500	NF	Bonding agent/disintegrating agent	5.55	0.056
					The stearic acid powder	NF	Lubricant	3.50	0.036
Magnesium stearate	NF	Lubricant	1.80	0.018
					Weight			350.00	3.500
Sugar-coat
					Opadry_II is white	MS*	Interior sugar-coat	7.00	0.072
Acryleze_	MS*	Enteric coating	35.0	0.360
					Opadry_ is transparent	MS*	Outer sugar-coat	3.50	0.036
Gross weight			395.50	3.974

* MS: manufacture criterion level; NF: country's prescription level; USP: American Pharmacopeia level.

Embodiment 4-modification discharges sugar coated tablet

Sugar-coat to the preparation among the embodiment 3 carries out some trickle changes: use the outer sugar-coat of the transparent conduct of 0padry_ among the embodiment 3, and white to substitute Opadry_II, and 0padry_II still is used as interior sugar-coat in vain.To transparent similar, Opadry_II is a kind of HPMC class preparation with sealing function in vain, and thereby similarly has a moistureproof ability of raising enteric coating (Acryleze_).

The sugar-coat system change of outer sugar-coat is a kind of method of being convenient to amplify this product formulation size, promptly, by preventing that the outer sugar-coat of spray gun during carrying out the transition to coating method from enteric coating from applying the obstruction during step applies step to outer sugar-coat, promote to be applied to the transition of another sugar-coat from a sugar-coat

Provide the 50mg modification to discharge sugar coated tablet in the table 5 and be used for unit formulation

Table 5:50mg modification discharges the unit formulation of sugar coated tablet

Composition	Grade	Function	Quantity/sheet (mg)	Quantity/crowd (kg)
					Core
3-amino-1-propane sulfonic acid, sodium salt	MS*	Active component	50.00	0.500
					Silicified microcrystalline cellulose	NF	Fluidizer/diluent	174.73	1.746
Calcium hydrogen phosphate	USP	Filler	79.42	0.794
					HYDROXY PROPYL METHYLCELLULOSE (HPMC)	USP	Drug release modifier	35.00	0.350
Starch _ 1500	NF	Bonding agent/disintegrating agent	5.55	0.056
					The stearic acid powder	NF	Lubricant	3.50	0.036
Magnesium stearate	NF	Lubricant	1.80	0.018
					Weight			350.00	3.500
Sugar-coat
					Opadry_II is white	MS*	Interior sugar-coat	7.00	0.072
Acryleze_	MS*	Enteric coating	35.0	0.360
					Opadry_II is white	MS*	Outer sugar-coat	3.50	0.036
Gross weight			395.50	3.974

* MS: manufacture criterion level; NF: country's prescription level; USP: American Pharmacopeia level.

The dissolving characteristic of measuring according to the method (American Pharmacopeia 25, method B, the 2017th page) of American Pharmacopeia shows that the rate of dissolution of two kinds of 50mg modifications release sugar coated tablets (embodiment 3 and 4) is suitable.

In addition, in order to improve outward appearance, that is, white has prepared following modification release coated tablet by increasing the white amount of Opadry_II.

Table 6:50mg modification discharges the unit formulation of sugar coated tablet

Composition	Grade	Function	Quantity/sheet (mg)	Quantity/crowd (kg)
					Core
3-amino-1-propane sulfonic acid, sodium salt	MS*	Active component	50.00	0.500
					Silicified microcrystalline cellulose	NF	Fluidizer/diluent	174.73	1.746
Calcium hydrogen phosphate	USP	Filler	79.42	0.794
					HYDROXY PROPYL METHYLCELLULOSE (HPMC)	USP	Drug release modifier	35.00	0.350
Starch _ 1500	NF	Bonding agent/disintegrating agent	5.55	0.056
					The stearic acid powder	NF	Lubricant	3.50	0.036
Magnesium stearate	NF	Lubricant	1.80	0.018
					Weight			350.00	3.500
Sugar-coat
					Opadry_II is white	MS*	Interior sugar-coat	7.00	0.072
Acryleze_	MS*	Enteric coating	35.0	0.360
					Opadry_II is white	MS*	Outer sugar-coat	7.00	0.072
Gross weight			399.00	4.004

* MS: manufacture criterion level; NF: country's prescription level; USP: American Pharmacopeia level.

Embodiment 5-mass spectral analysis

Can use mass spectrum as described below (" MS ") method of testing to measure chemical compound combines with amyloid is fibriilar.

Sample preparation is become to comprise 20% alcoholic acid aqueous solution, and the dissolved A β 40 of the test compounds of 20 μ M and 20uM adjusts to 7.4 (± 0.2) by adding 0.1% sodium hydrate aqueous solution with pH value.Use Waters ZQ 4000 mass spectrographs by this solution of electro-spray ionization mass spectral analysis then.Introduce this sample with the flow velocity direct impregnation of 25L/min at this sample of preparation in 2 hours.For all analyses, the source temperature is remained on 70 ℃, and voltage is remained on 20V.Use Masslynx 3.5 software data processings.

Resulting MS test data provides the understanding of chemical compound and the bonded ability of A β.

Claims (127)

1. one kind is used for suppressing the sedimentary method of object amyloid, it comprises the treatment preparation of taking a kind of effective dose to this object, described treatment preparation contains a kind of treatment chemical compound that gastrointestinal tolerant is bad that is made into significantly to reduce or prevent, thereby suppresses the amyloid deposition.

2. the method for claim 1, wherein this treatment preparation further comprises and a kind ofly selects it significantly to reduce in advance or the treatment chemical compound of the ability that the prevention gastrointestinal tolerant is bad.

3. the method for claim 1, wherein this treatment preparation further comprises a kind of minimizing or the bad other reagent of prevention gastrointestinal tolerant.

4. method as claimed in claim 3, wherein this this other reagent is enteric coating.

5. method as claimed in claim 3, wherein this other reagent is a kind of reagent that changes the release of treatment chemical compound.

6. the method for claim 1, wherein this treatment preparation comprises a kind of treatment chemical compound that contains at least one and replacement or unsubstituted aromatic molecule or the covalently bound sulfonate group of aliphatic molecules.

7. another aspect of the present invention relates to a kind of prevention in object, treats or suppresses this amyloid related diseases, it comprises the treatment pharmacy amount agent of taking a kind of effective dose to this object, the agent of described treatment pharmacy amount contains a kind ofly to be become significantly to reduce or prevent the treatment chemical compound that gastrointestinal tolerant is bad by the pharmacy amount, thereby prevention, treats or suppress this amyloid related diseases.

8. method as claimed in claim 7, wherein this amyloid related diseases is A β-relevant disease.

9. method as claimed in claim 7, wherein therapeutic ground or prophylactically dispose this amyloid related diseases.

10. method as claimed in claim 7, wherein this amyloid related diseases is selected from Alzheimer, brain amyloid angiopathy, occlusion body myositis, degeneration of macula, Down's syndrome, mild cognitive damage and hereditary cerebral hemorrhage.

11. method as claimed in claim 7, wherein this amyloid related diseases is a type ii diabetes.

12. as claim 1 or 7 described methods, thereby the interaction that wherein should treat between chemical compound inhibition amyloidosis protein and the basement membrane component suppresses amyloid beta deposition.

13. the method for claim 1, wherein this treatment preparation also may comprise the treatment chemical compound with formula 3-amino-1-propane sulfonic acid ester/X (wherein X is counter ion or forms ester with sulfonate) of the amount that is enough to suppress amyloid beta deposition, wherein this ester or counter ion comprise respectively can appreciable impact should the minimizing of treatment preparation or prevent the alcohol radical of the bad ability of gastrointestinal tolerant or the atom or the residue of positively charged.

14. method as claimed in claim 13, wherein this treatment chemical compound is 3-amino-1-propane sulfonic acid.

15. method as claimed in claim 7 wherein should be replacement or unsubstituted alkyl sulfonic acid, replacement or unsubstituted alkyl sulphuric acid, replacement or unsubstituted alkyl thiosulfonic acid, replacement or unsubstituted alkyl thiosulfuric acid by the treatment chemical compound.Or its pharmaceutically acceptable salt.

16. method as claimed in claim 7 wherein should be replacement or unsubstituted alkyl sulfonic acid or its pharmaceutically acceptable salt by the treatment chemical compound.

17. method as claimed in claim 7 wherein should be replacement or unsubstituted low alkyl group sulfonic acid or its pharmaceutically acceptable salt by the treatment chemical compound.

18. method as claimed in claim 7 should the treatment chemical compound be alkyl sulfonic acid or its pharmaceutically acceptable salt of (amino replacement or unsubstituted)-replacement wherein.

19. method as claimed in claim 7 should the treatment chemical compound be low alkyl group sulfonic acid or its pharmaceutically acceptable salt of (amino replacement or unsubstituted)-replacement wherein.

20. the described method of claim 7, wherein this treatment chemical compound has following structure:

Wherein Y is-NR ^aR ^bOr-SO ₃ ^-X ⁺, n is 1～5 integer, and X ⁺Be hydrogen or cation, R ^aAnd R ^bBe selected from hydrogen, alkyl, aryl or heterocyclic radical independently of one another, or R ^aAnd R ^bForm a ring residue that in ring, has 3～8 atoms with the nitrogen-atoms that is connected with them.

21. the described method of claim 7, wherein this treatment chemical compound has following structure:

22. method as claimed in claim 7, wherein this treatment chemical compound is 3-amino-1-propane sulfonic acid.

23. method as claimed in claim 13 is wherein as embodiment 1, embodiment 2, embodiment 3 or this treatment preparation of embodiment 4 preparations.

24. as each described method of claim 1～23, the wherein oral treatment chemical compound that is somebody's turn to do.

25. method that is used for suppressing the amyloid beta deposition of object, it comprises the treatment preparation of taking a kind of effective dose to this object, described treatment preparation contains a kind of treatment chemical compound that gastrointestinal tolerant is bad that is made into significantly to reduce or prevent, thereby the interaction between this treatment chemical compound inhibition amyloidosis protein and the basement membrane component is to suppress amyloid beta deposition.

26. method that is used for suppressing the amyloid beta deposition of object, it comprises the treatment preparation of taking a kind of effective dose to this object, described treatment preparation contains a kind of treatment chemical compound that gastrointestinal tolerant is bad that is made into significantly to reduce or prevent, thereby this treatment chemical compound suppresses nervus retrogression degeneration or cytotoxicity that amyloid causes.

27. sedimentary method of amyloid that is used for suppressing object, it comprises the treatment preparation of taking a kind of effective dose to the patient, described treatment preparation comprises a kind of treatment chemical compound that gastrointestinal tolerant is bad that is made into significantly to reduce or prevent, thereby should improve the clearance rate of amyloid from brain by the treatment chemical compound.

28. as each described method of claim 25～27, what wherein this treatment preparation also may comprise the amount that is enough to suppress amyloid beta deposition has formula 3-amino-1-propane sulfonic acid ester/X, wherein X is counter ion or forms ester with sulfonate, the treatment chemical compound, wherein this ester or counter ion comprise respectively can appreciable impact should the minimizing of treatment preparation or prevent the alcohol radical of the bad ability of gastrointestinal tolerant or the atom or the residue of positively charged.

29. as each described method of claim 25～27, wherein should treatment chemical compound for replacing or unsubstituted alkyl sulfonic acid, replacement or unsubstituted alkyl sulphuric acid, replacement or unsubstituted alkyl thiosulfonic acid, replacement or substituted alkyl thiosulfuric acid not.Or its pharmaceutically acceptable salt.

30. each described method of claim 25～27 wherein should be replacement or unsubstituted alkyl sulfonic acid or its pharmaceutically acceptable salt by the treatment chemical compound.

31. each described method of claim 25～27 wherein should be replacement or unsubstituted low alkyl group sulfonic acid or its pharmaceutically acceptable salt by the treatment chemical compound.

32. each described method of claim 25～27 should treatment chemical compound be alkyl sulfonic acid or its pharmaceutically acceptable salt of (replace or not substituted-amino)-replacement wherein.

33. each described method of claim 25～27 should treatment chemical compound be low alkyl group sulfonic acid or its pharmaceutically acceptable salt of (replace or not substituted-amino)-replacement wherein.

34. the described method of claim 28, wherein this treatment chemical compound has following structure:

Wherein Y is-NR ^aR ^bOr-SO ₃ ^-X ⁺, n is 1～5 integer, and X ⁺Be hydrogen or cation, R ^aAnd R ^bBe selected from hydrogen, alkyl, aryl or heterocyclic radical independently of one another, or R ^aAnd R ^bForm a ring residue that in ring, has 3～8 atoms with the nitrogen-atoms that is connected with them.

35. the described method of claim 28, wherein this treatment chemical compound has following structure:

36. method as claimed in claim 28, wherein this treatment chemical compound is 3-amino-1-propane sulfonic acid.

37. as each described method of claim 25～36, the wherein oral treatment chemical compound that is somebody's turn to do.

38. sedimentary method of amyloid that is used for suppressing object, it comprises the treatment preparation to the oral a kind of effective dose of patient, described treatment preparation comprises a kind of treatment chemical compound that gastrointestinal tolerant is bad that is made into significantly to reduce or prevent, thereby suppresses amyloid beta deposition.

39. method as claimed in claim 38, what wherein this treatment preparation also may comprise the amount that is enough to suppress amyloid beta deposition has formula 3-amino-38-propane sulfonic acid ester/X, wherein X is counter ion or forms ester with sulfonate, the treatment chemical compound, wherein this ester or counter ion comprise respectively can appreciable impact should the minimizing of treatment preparation or prevent the alcohol radical of the bad ability of gastrointestinal tolerant or the atom or the residue of positively charged.

40. method as claimed in claim 39, wherein this treatment chemical compound is 3-amino-1-propane sulfonic acid.

41. as claim 1,25,26 or 27 described methods, it further comprises this treatment chemical compound of taking in a kind of pharmaceutically acceptable carrier.

42. method as claimed in claim 39 is wherein as embodiment 1, embodiment 2, embodiment 3 or this treatment preparation of embodiment 4 preparations.

43. method as claimed in claim 41 wherein will be treated chemical compound and be taken with the reagent that is selected from following reagent: the reagent, fluidizer/diluent, filler, binding agent/disintegrating agent, lubricant, interior sugar-coat, outer sugar-coat, enteric coating and the combination in any thereof that change the release of treatment chemical compound.

44. method as claimed in claim 43, the reagent that wherein changes the release of treatment chemical compound is HYDROXY PROPYL METHYLCELLULOSE (HPMC).

45. method as claimed in claim 43, wherein this fluidizer/diluent is a silicified microcrystalline.

46. method as claimed in claim 43, wherein this filler is a calcium hydrogen phosphate.

47. method as claimed in claim 43, wherein this binding agent/disintegrating agent is starch _ 1500.

48. method as claimed in claim 43, wherein this lubricant is the stearic acid powder.

49. method as claimed in claim 43, wherein this lubricant is a magnesium stearate.

50. method as claimed in claim 43, wherein this internal layer is an Opadry_II white.

51. method as claimed in claim 43, wherein this external coating is white Opadry_II or transparent Opadry_.

52. method as claimed in claim 43, wherein this enteric coating is Acryleze.

53. the sedimentary pharmaceutical composition of amyloid that is used for suppressing object, its comprise a kind of contain the amount that is enough to suppress the amyloid beta deposition in the object be made into significantly to reduce or prevent the treatment chemical compound that gastrointestinal tolerant is bad and the treatment preparation of pharmaceutically acceptable carrier.

54. a pharmaceutical composition that is used for the treatment of amyloidosis, its comprise a kind of contain the amount that is enough to the amyloidosis in the treatment target be made into significantly to reduce or prevent the treatment chemical compound that gastrointestinal tolerant is bad and the treatment preparation of pharmaceutically acceptable carrier.

55. a pharmaceutical composition is used for the treatment of or prevents amyloid related diseases, it comprise a kind of contain be enough to prevent or treatment target in amyloid related diseases be made into significantly to reduce or prevent the treatment chemical compound that gastrointestinal tolerant is bad and the treatment preparation of pharmaceutically acceptable carrier.

56. pharmaceutical composition as claimed in claim 55, wherein this amyloid related diseases is the A ss related diseases.

57. pharmaceutical composition as claimed in claim 55, wherein the calcium amyloid related diseases is selected from Alzheimer, brain amyloid angiopathy, occlusion body myositis, degeneration of macula, Down's syndrome, mild cognitive damage and hereditary cerebral hemorrhage.

58. pharmaceutical composition as claimed in claim 55, wherein this amyloid related diseases is a type ii diabetes.

59. as each described pharmaceutical composition of claim 53～58, wherein the existing amount of this treatment preparation is enough to suppress amyloidosis protein and the interaction between the basement membrane component in the object and suppress amyloid beta deposition, and a kind of pharmaceutically acceptable carrier.

60. as each described pharmaceutical composition of claim 53～58, wherein the existing amount of this treatment preparation is enough to suppress nervus retrogression degeneration or the cytotoxicity that amyloid causes, and a kind of pharmaceutically acceptable carrier.

61. as each described pharmaceutical composition of claim 53～58, wherein the existing amount of this treatment preparation is enough to improve with the removing of amyloid beta from brain, and a kind of pharmaceutically acceptable carrier.

62. as each described pharmaceutical composition of claim 53～58, wherein this treatment preparation also may comprise the treatment chemical compound with formula 3-amino-38-propane sulfonic acid ester/X of the amount that is enough to suppress amyloid beta deposition and pharmaceutically acceptable carrier ester wherein X be a counter ion or form ester that wherein this ester or counter ion do not comprise respectively and can appreciable impact treatment preparation to reduce or alcohol radical or the electropositive atom and the residue of the ability that the prevention gastrointestinal tolerant is bad with sulfuric ester.

63., wherein should be replacement or unsubstituted alkyl sulfonic acid, replacement or unsubstituted alkyl sulphuric acid, replacement or unsubstituted alkyl thiosulfonic acid, replacement or unsubstituted alkyl thiosulfuric acid or its pharmaceutically acceptable salt by the treatment chemical compound as each described pharmaceutical composition of claim 53～58.

64., wherein should be replacement or unsubstituted alkyl sulfonic acid or its pharmaceutically acceptable salt by the treatment chemical compound as each described pharmaceutical composition of claim 53～58.

65., wherein should be replacement or unsubstituted low alkyl group sulfonic acid or its pharmaceutically acceptable salt by the treatment chemical compound as each described pharmaceutical composition of claim 53～58.

66., should the treatment chemical compound be alkyl sulfonic acid or its pharmaceutically acceptable salt of (replacing or unsubstituted amino)-replacement wherein as each described pharmaceutical composition of claim 53～58.

67., should the treatment chemical compound be low alkyl group sulfonic acid or its pharmaceutically acceptable salt of (replacing or unsubstituted amino)-replacement wherein as each described pharmaceutical composition of claim 53～58.

68. as each described pharmaceutical composition of claim 53～58, wherein this treatment chemical compound has following structure

Wherein Y is-NR ^aR ^bOr-SO ₃ ^-X ⁺, n is 1～5 integer, and X ⁺Be hydrogen or cation, R ^aAnd R ^bBe selected from hydrogen, alkyl, aryl or heterocyclic radical independently of one another, or R ^aAnd R ^bForm a ring residue that in ring, has 3～8 atoms with the nitrogen-atoms that is connected with them.

69, pharmaceutical composition as claimed in claim 62, wherein this treatment chemical compound has following structure:

70. pharmaceutical composition as claimed in claim 62, wherein this treatment chemical compound is 3-amino-1-propane sulfonic acid.

71. pharmaceutical composition as claimed in claim 62 is wherein as embodiment 1, embodiment 2, embodiment 3 or this treatment preparation of embodiment 4 preparations.

72., wherein will treat chemical compound and take: the reagent, fluidizer/diluent, filler, binding agent/disintegrating agent, lubricant, interior sugar-coat, outer sugar-coat, enteric coating and the combination in any thereof that change the release of treatment chemical compound with the reagent that is selected from following reagent as the described pharmaceutical composition of claim 70.

73. as the described pharmaceutical composition of claim 72, the reagent that wherein changes the release of treatment chemical compound is HYDROXY PROPYL METHYLCELLULOSE (HPMC).

74. as the described pharmaceutical composition of claim 72, wherein this fluidizer/diluent is a silicified microcrystalline.

75. as the described pharmaceutical composition of claim 72, wherein this filler is a calcium hydrogen phosphate.

76. as the described pharmaceutical composition of claim 72, wherein this binding agent/disintegrating agent is starch _ 1500.

77. as the described pharmaceutical composition of claim 72, wherein this lubricant is the stearic acid powder.

78. as the described pharmaceutical composition of claim 72, wherein this lubricant is a magnesium stearate.

79. as the described pharmaceutical composition of claim 72, wherein this internal layer is white Opadry_II.

80. as the described pharmaceutical composition of claim 72, wherein this external coating is white Opadry_II or transparent Opadry_.

81. as the described pharmaceutical composition of claim 72, wherein this enteric coating is Acryleze.

82. sedimentary method of amyloid that minimizing suffers from the sedimentary object of amyloid, this method comprises the treatment preparation of taking a kind of effective dose to this object, described treatment preparation contains a kind of treatment chemical compound that gastrointestinal tolerant is bad that is made into significantly to reduce or prevent, thereby reduces the amyloid deposition in the object.

83. chemotactic factor and bonded method of glycosaminoglycans that is used for suppressing object, it comprises to the patient takes a kind of treatment preparation, described treatment preparation comprises that a kind of being made into significantly reduce or prevent the treatment chemical compound that gastrointestinal tolerant is bad, thus the combining of chemokine inhibiting and glycosaminoglycans.

84. the interactional method of mediator's apoplexy due to endogenous wind antibacterial and aminopolysaccharide, it comprises to the mankind takes the treatment preparation that containing of a kind of effective dose is made into significantly to reduce or prevent the treatment chemical compound that gastrointestinal tolerant is bad.

85. a method that is used at mankind's treatment bacterial infection, it comprises the treatment preparation to the oral a kind of effective dose of the mankind, and described treatment preparation contains a kind of treatment chemical compound that gastrointestinal tolerant is bad that is made into significantly to reduce or prevent.

86. as the method for claim 85, wherein this bacterial infection is a chlamydia.

87. an interactional method of regulating among the patient virus and aminopolysaccharide, it comprises the treatment preparation of taking a kind of effective dose to this object, and described treatment preparation contains a kind of treatment chemical compound that gastrointestinal tolerant is bad that is made into significantly to reduce or prevent.

88. a method for the treatment of patient's viral infection, it comprises to this object takes the treatment preparation that containing of a kind of effective dose is made into significantly to reduce or prevent the treatment chemical compound that gastrointestinal tolerant is bad.

89. as the described method of claim 88, wherein this viral infection is HSV.

90. a prevention, treatment or suppress the method for the brain amyloid angiopathy in the object, it comprises the treatment preparation of taking a kind of effective dose, and described treatment preparation contains a kind of treatment chemical compound that gastrointestinal tolerant is bad that is made into significantly to reduce or prevent.

91. method that is used to prevent, treat or suppress brain amyloid angiopathy, it comprises cells of vascular wall a kind ofly is made into significantly to reduce or prevents that the treatment preparation of the treatment chemical compound that gastrointestinal tolerant is bad from contacting with containing, thus prevention, treatment or suppress brain amyloid angiopathy.

92. method that is used to prevent, treat or suppress brain amyloid angiopathy, it treatment chemical compound that comprises the treatment preparation that cells of vascular wall is bad with being mixed with minimizing or prevention gastrointestinal tolerant contacts, thus prevention, treatment or inhibition brain amyloid angiopathy.

93. the method for Alzheimer in prevention or the treatment target, it comprises the treatment preparation of taking a kind of effective dose to this object, and described treatment preparation contains a kind of treatment chemical compound that gastrointestinal tolerant is bad that is made into significantly to reduce or prevent.

94. the sedimentary pharmaceutical composition of amyloid that is used for suppressing object of a packing, it comprises a kind of container that is made into significantly to reduce or prevent the treatment chemical compound that gastrointestinal tolerant is bad that contains that keeps the treatment effective dose; And the description that is used for suppressing the sedimentary chemical compound of amyloid of object.

95. as the pharmaceutical composition of the described packing of claim 94, wherein relevant with amyloid beta deposition disease is selected from Alzheimer, brain amyloid angiopathy, occlusion body myositis, degeneration of macula, Down's syndrome, mild cognitive damage and hereditary cerebral hemorrhage.

96. as the pharmaceutical composition of the described packing of claim 94, wherein relevant with amyloid beta deposition disease is a type ii diabetes.

97. a packing be used for the treatment of the sedimentary pharmaceutical composition of amyloid in the object, it comprises a kind of container that is made into significantly to reduce or prevent the treatment chemical compound that gastrointestinal tolerant is bad that contains that keeps the treatment effective dose; And the description that is used for the treatment of the sedimentary chemical compound of amyloid in the object.

98. a packing be used for the treatment of the medicine for treating viral infections compositions, it comprises that one keeps the treatment effective dose to contain a kind of container that is made into significantly to reduce or prevent the treatment preparation of the treatment chemical compound that gastrointestinal tolerant is bad; And the description of using the chemical compound of this compound treats viral infection.

99. the pharmaceutical composition that is used for the treatment of bacterial infection of a packing, it comprises that one keeps the treatment effective dose to contain a kind of container that is made into significantly to reduce or prevent the treatment preparation of the treatment chemical compound that gastrointestinal tolerant is bad; And the description of using the chemical compound of this compound therapeuticing bacteria infection.

100. a packing be used for chemokine inhibiting and the bonded pharmaceutical composition of aminopolysaccharide, it comprises that one keeps a kind of and treats containing of effective dose and be made into significantly to reduce or prevent the treatment preparation of the treatment chemical compound that gastrointestinal tolerant is bad; And use this to be used for the description of chemokine inhibiting and the bonded treatment chemical compound of aminopolysaccharide.

101. a manufacturing comprises the method for the treatment preparation that is mixed with a kind of treatment chemical compound for the treatment of effective dose and pharmaceutically acceptable carrier, it is bad with remarkable reduction or prevention gastrointestinal tolerant wherein to prepare this treatment preparation.

102. a pharmaceutical preparation, it comprises the 3-amino-1-propane sulfonic acid greater than 5 weight %.

103. as the described pharmaceutical preparation of claim 102, wherein said preparation comprises the 3-amino-1-propane sulfonic acid greater than 10 weight %.

104. as the described pharmaceutical preparation of claim 102, wherein said preparation comprises the 3-amino-1-propane sulfonic acid greater than 20 weight %.

105. as the described pharmaceutical preparation of claim 102, wherein said preparation comprises the 3-amino-1-propane sulfonic acid greater than 30 weight %.

106. as the described pharmaceutical preparation of claim 102, wherein said preparation comprises the 3-amino-1-propane sulfonic acid greater than 50 weight %.

107. as the described pharmaceutical preparation of claim 102, wherein said preparation comprises the 3-amino-1-propane sulfonic acid greater than 80 weight %.

108. as the described pharmaceutical preparation of claim 102, wherein said preparation comprises the 3-amino-1-propane sulfonic acid greater than 95 weight %.

109. and a kind of pharmaceutical preparation, its comprise a kind of treat chemical compound with greater than the other reagent of 1 weight %.

110. as the described pharmaceutical preparation of claim 109, wherein said preparation comprises this other reagent greater than 2 weight %.

111. as the described pharmaceutical preparation of claim 109, wherein said preparation comprises this other reagent greater than 3 weight %.

112. as the described pharmaceutical preparation of claim 109, wherein said preparation comprises this other reagent greater than 4 weight %.

113. as the described pharmaceutical preparation of claim 109, wherein said preparation comprises this other reagent greater than 5 weight %.

114. as the described medicine preparation of claim 109, wherein this other reagent is enteric coating.

115. as the medicine preparation of claim 109, wherein this other reagent is a kind of reagent that changes the release of treatment chemical compound.

116. one kind is used for suppressing the sedimentary method of object amyloid, it comprises the treatment preparation of taking a kind of effective dose to the patient, and described treatment preparation comprises the treatment chemical compound that a kind of preparation has enteric coating, thereby suppresses the amyloid deposition.

117. sedimentary method of amyloid that is used for suppressing object, it comprises the treatment preparation of taking a kind of effective dose to the patient, described treatment preparation comprises the treatment chemical compound that a kind of preparation has the reagent of the release that can change this treatment chemical compound, thereby has suppressed the amyloid deposition.

118. the sedimentary pharmaceutical composition of amyloid that is used for suppressing object, it comprises that a kind of preparation has the treatment chemical compound of enteric coating, thereby suppresses the amyloid deposition.

119. the sedimentary pharmaceutical composition of amyloid that is used for suppressing object, it comprises the treatment chemical compound that a kind of preparation has the reagent of the release that can change this treatment chemical compound, thereby has suppressed the amyloid deposition.

120. a method of preparing the bad enhanced pharmaceutical composition of gastrointestinal tolerant, it comprises:

A kind of treatment chemical compound of preliminary election is mixed with a kind of pharmaceutically acceptable carrier, and wherein this treatment chemical compound is based on its remarkable minimizing or prevents the bad ability of gastrointestinal tolerant to select, and forms the bad enhanced pharmaceutical composition of a kind of gastrointestinal tolerant.

121. as claim 90,91 or 92 described methods, wherein this brain amyloid angiopathy relates to Alzheimer, Down's syndrome, natural aging or or the familial disease relevant with apoplexy or peralytic dementia.

122. one kind is used for preventing or the method for the amyloid related diseases of treatment target, it comprises the treatment preparation of taking a kind of effective dose to the patient, described treatment preparation comprises the treatment chemical compound that a kind of preparation has enteric coating, thus prevention or treatment amyloid related diseases.

123. the method for amyloid related diseases in prevention or the treatment target, it comprises the treatment preparation of taking a kind of effective dose to this object, described treatment preparation comprises the treatment chemical compound that a kind of preparation has the reagent of the release that can change this treatment chemical compound, thereby prevents or treated amyloid related diseases.

124. one kind is used for preventing or the pharmaceutical composition of the amyloid related diseases of treatment target, it comprises that a kind of preparation has the treatment chemical compound of enteric coating.

125. a pharmaceutical composition that is used at patient's prevention or treatment amyloid related diseases, it comprises the treatment chemical compound that a kind of preparation has the reagent of the release that can change this treatment chemical compound, thereby has suppressed the amyloid deposition.

126. a prevention, treatment or suppress the method for the Alzheimer in the object, it comprises the treatment preparation of taking a kind of effective dose to this object, described treatment preparation contains a kind of treatment chemical compound that gastrointestinal tolerant is bad that is made into significantly to reduce or prevent, thus prevention, treatment or inhibition Alzheimer.

127. the pharmaceutical composition that is used for the treatment of the Alzheimer in the object of a packing, it comprises a kind of container that is made into significantly to reduce or prevent the treatment chemical compound that gastrointestinal tolerant is bad that contains that keeps the treatment effective dose; And the description that is used for the treatment of the sedimentary chemical compound of amyloid in the object.