CN1787822A - Compouds and uses thereof in modulating amyloid beta - Google Patents
Compouds and uses thereof in modulating amyloid beta Download PDFInfo
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- CN1787822A CN1787822A CN 200480012784 CN200480012784A CN1787822A CN 1787822 A CN1787822 A CN 1787822A CN 200480012784 CN200480012784 CN 200480012784 CN 200480012784 A CN200480012784 A CN 200480012784A CN 1787822 A CN1787822 A CN 1787822A
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Abstract
Novel compounds, compositions, and kits are provided. Methods of modulating Abeta levels, and methods of treating a disease associated with aberrant Abeta levels are also provided.
Description
Related application
[0001] this application has required the U.S. Provisional Application that proposes May in 2003 14 number 60/470,884 and the rights and interests of the U.S. Provisional Application that proposes in December 22 in 2003 number 60/532,260, and the full content that is incorporated herein every application as a reference.
Invention field
[0002] provides chemical compound, the using method of pharmaceutical composition and these chemical compounds.In one embodiment, these chemical compounds are used for the treatment of neurodegenerative disease (neurodegenerativediseases).
Background of invention
[0003] only supplying to help the reader understanding in information that this provided and the list of references of being quoted, is not to constitute to admit that any list of references or information are prior aries of the present invention.
[0004] neurodegenerative disease is with selective neuronal group's destruction or is degraded to the disease of feature.Exemplary neurodegenerative disease comprises Alzheimer (AD), and parkinsonism is (PD) for example, Huntington Chorea (HD), and prion disease, cerebral amyloid angiopathy (CAA) and mild cognitive damage (MCI).Neurodegenerative disease is relevant with carrying out property nervous system dysfunction, and often causes the maincenter of catching an illness or the atrophy of peripheral nervous system structure.
[0005] Alzheimer (AD) (alzheimer ' s diease) is a kind of carrying out property neurodegenerative disease, and this disease is the main cause that surpasses 65 years old crowd's dementia the age.This sick clinical symptoms starts from slight impermanent memory problem.Along with the development of the state of an illness, the difficulty on memory, language and the direction deteriorates into the independent degree of exercising Functional Capability of disturbing this people.Other can discrepant symptom, comprises muscular spasm and epilepsy.From initial memory loss symptom to death, AD the duration on average be 10 years.
[0006] feature of AD shows as the loss of a large amount of neuronal cells in some brain districts of AD patient's brain and the deposition of protein substance.These deposits comprise neurofibrillary tangles and amyloid-beta speckle.The main protein composition of amyloid-beta speckle is A β.
[0007] inferred that accumulation that A β increases works significantly to the pathogeny of AD, and the accumulation that A β increases is also relevant with other amyloidosis and nervous disorders, for example, parkinson disease, Down's syndrome, diffusion Lu Yi body disease is benumbed on the carrying out property nuclear, with hereditary amyloidosis cerebral hemorrhage-Dutch type (HCHWA-D) (Hereditary Cerebral Hemorrhage withAmyloidosis-Dutch Type), cerebral amyloid angiopathy (CAA) and mild cognitive damage (MCI).Can find the supportive evidence of A β role in AD the Down's syndrome patient on one's body, these Down's syndromes patient has been developed symptom and the pathological process of similar AD after 40 years old.Such patient showed the amyloid plaques of similar AD before other AD paresthesia epilepsy, show that the accumulation that A β increases is initial pathogenic incident.Cumulative evidence is from the evaluation to various sudden changes in AD for other hint A β peptide (A β peptides), and these sudden changes cause that A β is decided to be to form on the cell of certain type of heritability AD (AD of family, or FAD) at those to be increased.The FAD individuality accounts for 10% of all AD cases, and shows more Zao disease symptoms than sporadic AD patient usually.
[0008] A β peptide is from the course of processing of amyloid precursor protein (APP).The mRNA that produces the app gene on comfortable No. 21 chromosome produces about 10 possible isotypes (isoforms) through alternative splicing, and wherein three (APP695,751 and 770 aminoacid isotypes) preponderate in brain.APP695 is the shortest in three kinds of isotypes, and mainly is created in the neuron.APP751 contains Kunitz protease inhibitor (KPI) domain and APP770 contains KPI domain and MRC-OX2 antigenic structure territory, and they mainly are found on the non-neuronal neurogliocyte (glial cells).
[0009] main APP isotype is list-transmembrane protein (single-transmembraneproteins), is made up of the outer amino terminal domain of born of the same parents (approximately 590-680 aminoacid) and a kytoplasm tail (about 55 aminoacid) that contains transportation signal (trafficking signals) in the born of the same parents.In APP, A β peptide sequence partly is positioned at the born of the same parents outer end of cell membrane, and part extends to strides in the film district.APP isotype 695,751 is shared identical A β with 770, is striden film and born of the same parents' intracellular domain.
[0010] APP betransported (trafficked) by the constitutive secretion approach, its experience translation post-treatment (post-translational processing) comprises the cutting by two kinds of approach: amyloid approach (amyloidogenic pathway) and non-amyloid approach (non-amyloidogenic pathway) there.In non-amyloid approach, APP is cut by the alpha-secretase enzyme action in the A beta structure territory, discharges a kind of excretory big solubility N-terminal fragment (sAPP α) and a kind of non-amyloid C-terminal fragment (C83) of being used for.Because cutting occurs in the A beta structure territory, so the alpha-secretase enzyme action in the non-amyloid approach cuts the formation of having got rid of A β.Cut the gamma-secretase cutting in the predicted subsequently membrane spaning domain of C-terminal fragment of the APP that (C83) produced by the alpha-secretase enzyme action, produce the non-amyloid fragments of peptides (22-24 residue) that is known as p3.
[0011] in the amyloid approach, at the top, aminoterminal A beta structure territory of definition A β peptide, APP is cut by beta-secretase (BACE1 or BACE2 enzyme).BACE1 or BACE2 cutting produce short solvable N-end, sAPP β and amyloid C-terminal fragment (C99).In addition, BACE1 is 10 aminoacid (between amino acid/11 0 and 11) cutting APP after the top in A beta structure territory also, produces a terminal solvable fragment of long N-and short C-terminal fragment (C89).By gamma-secretase, promptly presenilin genes relies on enzyme (presenilin-dependent enzyme), and C89 or C99 are further cut, and produces the A β peptide of different length.
[0012] principal mode of the A β that is found from the speckle of AD brain is 40 kinds of A β 42 and A β.The kind that A β 42 is initial deposition in the brain speckle is highly susceptible in vitro assembling.Therefore, be accumulated as with A β in the therapy of the disease of feature or obstacle in development treatment, 42 kinds of the A β of 4 amyloid especially may become a kind of feasible target (viable target).
[0013] present, the Therapeutic Method of not curing AD or treating AD effectively, the approved medicine of minority comprises Aricept, Exelon, Cognex and Reminyl, the most a lot ofly alleviates effect.Based on the dependency between A β accumulation, neurone loss and the AD, regulate A β level, for example reduce the level of pathogenicity A β kind, show it is a kind of feasible pattern that speckle formed and minimized neuronal cell death that reduces.Therefore, the chemical compound of regulating A β level is existed medical need.Really, such chemical compound is useful to treatment such as the such neurodegenerative disorders of AD.
Summary of the invention
[0014], has been found that treating the helpful new compound of a lot of diseases according to the present invention.The compositions and the test kit that comprise this new compound have also been introduced.
[0015] an aspect of of the present present invention provides and has active chemical compound to regulating amyloid-β (amyloid-beta) (A β) level.Therefore, such chemical compound is applicable to treatment and the unusual relevant disease of A β level, and/or with the relevant disease of any situation of A β horizontal adjustment generation therapeutic effect.Preferably, the chemical compound here is helpful to treatment such as the such neurodegenerative disorders of AD.
Detailed Description Of The Invention
[0016] unless other definition is arranged, identical at these all used technology and scientific terminology with the implication of those skilled in the art institute common sense.The full content of all patents, application, disclosed application and other publication is incorporated herein by reference.
I. invention chemical compound
[0017] the invention provides new compound, and the acceptable salt of materia medica and its prodrug (prodrugs), described new compound has the structure corresponding to formula (I):
(A)-L
A-(B)-L
B-(C)-L
C-(D)
(I)
Wherein:
A is:
Wherein, each E independently is N, NR, C, CR
1, S or O, condition is that to be no more than four E are hetero atoms,
R is a hydrogen, replaces or substituted alkyl not, replaces or substituted alkenyl base not, replace or unsubstituting polysulfide yl, replace or unsubstituting alkoxy, replace or substituted alkyl amide groups not, replace or substituted alkyl amino not, replace or the unsubstituted ring alkyl, or replacement or unsubstituting aromatic yl;
Each R
1Independent is hydrogen, halogen, replace or substituted alkyl not, replace or substituted alkenyl base not, replace or unsubstituting polysulfide yl, replace or unsubstituting alkoxy, replace or substituted alkyl amide groups not, replace or substituted alkyl amino not, replace or substituted-amino not, replace or the unsubstituted ring alkyl, or replacement or unsubstituting aromatic yl;
Or A is:
Wherein, each M independently is selected from CR
1Or N, condition is that to be no more than three M are N, and
B is:
Wherein, each M independently is CR
2Or N, condition is that to be no more than three G are N;
Each R
2Independently be selected from hydrogen, halogen replaces or substituted alkyl not, replaces or substituted alkenyl base not, replaces or unsubstituting polysulfide yl, replaces or unsubstituting alkoxy, replaces or substituted alkyl amide groups not, replaces or substituted alkyl amino not, replaces or substituted-amino not;
Or B constitutes condensed ring system with A;
C is:
Wherein, J is selected from CR
3, O, S, N and NR;
Each K independently is N, NR, C or CR
3
Each R
3Independent be hydrogen, and halogen replaces or substituted alkyl not, replaces or the unsubstituted ring alkyl, replaces or unsubstituting aromatic yl, replaces or substituted heteroaryl not, replaces or unsubstituting alkoxy, and restrictive condition for working as C is
The time, R
3Be not-NH
2
Or C is:
Wherein each M independently is selected from CR
1Or N, condition is that to be no more than three M are N;
D is:
Wherein each E independently is N, NR, C, CR
1, S or O, condition is that to be no more than four E are hetero atoms;
Or D is:
Wherein each M independently is selected from CR
5Or N, condition is that to be no more than three M are N;
Each R
5Independently be selected from hydrogen, halogen replaces or substituted alkyl not, replaces or substituted alkenyl base not, replace or unsubstituting polysulfide yl, replace or unsubstituting alkoxy, replace or the unsubstituted ring alkyl, replace or unsubstituting heterocycle, replace or unsubstituting aromatic yl, replace or substituted heteroaryl not, or replace or substituted-amino not, replace or substituted alkyl amino not;
L
AFor arbitrarily, when existing, be covalent bond or junctional complex (linker), be selected from :-C=C-,-C=C-,-(C (R ')
2)
z-,-O-,-O-(C (R ')
2)
z-,-S-,-NR '-,-NH-(C (R ')
2)
z-,-N=N-,-C (O)-,-C (O) NR '-,-O-C (O)-,-O-C (O)-O-,-O-C (O)-NR '-,-NR '-C (O)-,-NR '-C (O)-O-,-NR '-C (O)-NR '-,-S-C (O)-,-S-C (O)-O-,-S-C (O)-NR '-,-S (O)-,-S (O)
2-,-O-S (O)
2-,-O-S (O)
2-O-,-O-S (O)
2-NR '-,-O-S (O)-,-O-S (O)-O-,-O-S (O)-NR '-,-O-NR '-C (O)-, O-NR '-C (O)-O-,-O-NR '-C (O)-NR '-,-NR '-O-C (O)-,-NR '-O-C (O)-O-,-NR '-O-C (O)-NR '-,-O-NR '-C (S)-,-O-NR '-C (S)-O-,-O-NR '-C-(S)-NR '-,-NR '-O-C (S)-,-NR '-O-C (S)-O-,-NR '-O-C (S)-NR '-,-O-C-(S)-,-O-C (S)-O-,-O-C (S)-NR '-,-NR '-C (S)-,-NR '-C (S)-O-,-NR '-C (S)-NR '-,-S-S (O)
2-,-S-S (O)
2-O-,-S-S (O)
2-NR '-,-NR '-O-S (O)-,-NR '-O-S (O)-O-,-NR '-O-S (O)-NR '-,-NR '-O-S (O)
2-,-NR '-O-S (O)
2-O-,-NR '-O-S (O)
2-NR '-,-O-NR '-S (O)-,-O-NR '-S (O)-O-,-O-NR '-S (O)-NR '-,-O-NR '-S (O)
2-O-,-O-NR '-S (O)
2-NR '-,-O-NR '-S (O)
2-,-O-P (O) (R ')
2-,-S-P (O) (R ')
2-and-NR '-P (O) (R ')
2-, wherein, each R ' independence is hydrogen, replaces or unsubstituted alkyl, replaces or unsubstituted alkenyl, replaces or unsubstituted alkynyl, replace or unsubstituted cycloalkyl, and z is 1-10;
L
BIndependent is covalent bond or junctional complex, is selected from :-C=C-,-C ≡ C-,-(C (R ')
2)
z-,-O-,-O-(C (R ')
2)
z-,-S-,-NR '-,-NH-(C (R ')
2)
z,-N=N-,-C (O)-,-C (O) NR '-,-O-C (O)-,-O-C (O)-O-,-O-C (O)-NR '-,-NR '-C (O)-,-NR '-C (O)-O-,-NR '-C (O)-NR '-,-S-C (O)-,-S-C (O)-O-,-S-C (O)-NR '-,-S (O)-,-S (O)
2-,-O-S (O)
2-,-O-S (O)
2-O-,-O-S (O)
2-NR '-,-O-S (O)-,-O-S (O)-O-,-O-S (O)-NR '-,-O-NR '-C (O)-,-O-NR '-C (O)-O-,-O-NR '-C (O)-NR '-,-NR '-O-C (O)-,-NR '-O-C (O)-O-, NR '-O-C (O)-NR '-,-O-NR '-C (S)-,-O-NR '-C (S)-O-,-O-NR '-C (S)-NR '-,-NR '-O-C (S)-,-NR '-O-C (S)-O-,-NR '-O-C (S)-NR '-,-O-C (S)-,-O-C (S)-O-,-O-C (S)-NR '-,-NR '-C (S)-,-NR '-C (S)-O-,-NR '-C (S)-NR '-,-S-S (O)
2-,-S-S (O)
2-O-,-S-S (O)
2-NR '-,-NR '-O-S (O)-,-NR '-O-S (O)-O-,-NR '-O-S (O)-NR '-,-NR '-O-S (O)-,-NR '-O-S (O)
2-O-,-NR '-O-S (O)
2-NR '-,-O-NR '-S (O)
2-,-O-NR '-S (O)-O-,-O-NR '-S (O)-NR '-,-O-NR '-S (O)
2-O-,-O-NR '-S (O)
2-NR '-,-O-NR '-S (O)
2-,-O-P (O) (R ')
2-,-S-P (O) (R ')
2-and-NR '-P (O) (R ')
2-, wherein, each R ' independence is hydrogen, replaces or unsubstituted alkyl, replaces or unsubstituted alkenyl, replaces or unsubstituted alkynyl, replace or unsubstituted cycloalkyl, and z is 1-10;
L
CBe-O--S-,-S (O)
2-,-NR-,-C (O)-,-(C (R ')
2)
z-or-C (S)-;
Restrictive condition is, when A is
The time, L
ANot-C (O) NH-,-CH
2NH-,-CH
2-O-or-C (O) N (CH
3)-; And
The described chemical compound of formula (I) is not
[0018] just as used in this, mention certain element, for example hydrogen or H mean the isotope that comprises that this element is all.For example, comprise hydrogen or H if a group is defined, it also can comprise deuterium and/or tritium.In the structure that is provided, wherein nitrogen-atoms appears as bivalence herein, should think that this nitrogen-atoms is that trivalent and the 3rd substituent group are hydrogen.
[0019] unless special mark, chemical compound of the present invention can have asymmetric center, also may be, or enantiomer occurs with the mixture of stereoisomer or with independent diastereomer, its all isomeric forms is included among the present invention.Chemical compound of the present invention comprises all conformers.Chemical compound of the present invention also can one or more tautomers form exist, both comprised single tautomer, comprise tautomers mixture again.
[0020] phrase " alkyl " refers to any organic group group of any molecule that its carbon atom can be directly connected to here to be occurred." substituted hydrocarbon radical " refers to according to the substituted hydrocarbyl group of the following definition that provides.Hydrocarbyl group comprises saturated and unsaturated hydrocarbons, straight chain and branched chain aliphatic hydrocarbons, cyclic hydrocarbon and aromatic hydrocarbons.
[0021] phrase " replacement " refers to by displaced atom of another one substituent group or atomic group.Phrase " replacement " comprises other replacement of any level, for example, one-replace, two-replace, three-replacing, four-replacement or five-replace is the chemistry permission in this such replacement.Replacement can occur in any chemistry can and the position and any atom on, for example replacement on carbon or any hetero atom.For example, the chemical compound of replacement is the displaced chemical compound of key that one or more keys of connecting its contained hydrogen or carbon atom are connected non-hydrogen and/or non-carbon atom.
[0022] phrase " alkyl " refers to the hydrocarbyl chain that contains 1-20 carbon atom.Phrase " alkyl " comprises straight chained alkyl, methyl for example, ethyl, propyl group, butyl, amyl group, hexyl, heptyl, octyl group, nonyl, decyl, undecyl, dodecyl, and analog.Alkyl also comprises the branched chain isomer of straight chained alkyl, and the group that is provided by following example is provided :-CH (CH
3)
2,-CH (CH
3) (CH
2CH
3) ,-CH (CH
2CH
3)
2,-C (CH
3)
3,-C (CH
2CH
3)
3,-CH
2CH (CH
3)
2,-CH
2CH (CH
3) (CH
2CH
3) ,-CH
2CH (CH
2CH
3)
2,-CH
2C (CH
3)
3,-CH
2C (CH
2CH
3)
3,-CH (CH
3) CH (CH
3) (CH
2CH
3) ,-CH
2CH
2CH (CH
3)
2,-CH
2CH
2CH (CH
3) (CH
2CH
3) ,-CH
2CH
2CH (CH
2CH
3)
2,-CH
2CH
2C (CH
3)
3,-CH
2CH
2C (CH
2CH
3)
3,-CH (CH
3) CH
2CH (CH
3)
2,-CH (CH
3) CH (CH
3) CH (CH
3)
2With-CH (CH
2CH
3) CH (CH
3) CH (CH
3) (CH
2CH
3).Therefore, alkyl comprises primary alkyl, secondary alkyl and tertiary alkyl.Preferred alkyl comprises having 1-16 carbon atom, or the alkyl of 1-3 carbon atom, for example, and methyl, ethyl, propyl group and-CH (CH
3)
2
[0023] phrase " substituted alkyl " refers to according to the substituted alkyl of above-mentioned definition.The example of " substituted alkyl " group includes, but are not limited to, and halogen atom replaces carbon or hydrogen atom, for example trifluoromethyl; Oxygen atom on the group replaces carbon or hydrogen atom, hydroxyl for example, alkoxyl, aryloxy group, and ester group; Sulphur atom on the group replaces carbon or hydrogen atom, mercapto for example, alkyl and aryl sulfur, sulfuryl, sulfonyl and sulfoxide group; Nitrogen-atoms on the group replaces carbon or hydrogen atom, amine for example, amide, alkylamine, dialkylamine, N-oxidation of alkyl, imidodicarbonic diamide and enamine; Silicon atom on the group replaces carbon or hydrogen atom, trialkyl silyl (trialkylsilyl) for example, and di alkylaryl is silica-based, the silica-based and thriaryl-silicon of alkyl diaryl; Replace carbon or hydrogen atom with other various hetero atoms.In addition, substituted alkyl can be in conjunction with one or more carbon atoms.
[0024] phrase " alkenyl " refers to and contains 2-20 carbon atom and at least one carbon-to-carbon double bond (hydrocarbon chain C=C-).Phrase " alkenyl " comprises straight alkenyl, and the branched chain isomer of straight alkenyl.Preferably, alkenyl contains 1-8 two key.Phrase " substituted alkenyl base " refers to according to the substituted alkenyl of definition that is as above provided.
[0025] phrase " alkynyl " refers to the hydrocarbon chain that contains 2-20 carbon atom and at least one carbon-to-carbon triple bond (C ≡ C-)." alkynyl " comprises straight-chain alkynyl, and the branched chain isomer of straight-chain alkynyl.Preferably, alkynyl contains 1-8 triple bond.Phrase " substituted alkynyl " refers to according to the definition substituted alkynyl that is as above provided.
[0026] phrase " cycloalkyl " refers to 3-20 carbon atom and contains the alicyclic moiety of the saturated and unsaturated bond quantity of any chemistry permission.Preferably, cycloalkyl contains 4-7 carbon atom.Cycloalkyl includes but not limited to, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, ring octyl group and analog.Phrase " substituted cycloalkyl " refers to according to the substituted cycloalkyl of definition that is as above provided.Substituted cycloalkyl can have one or more atoms that replaced by the straight or branched alkyl, and may further include the cycloalkyl that is comprised the condensed ring replacement by other ring.The example of the cycloalkyl that is replaced by condensed ring comprises, but be not limited to, adamantyl (adamantyl), norborny (norbornyl), bicyclo-[2.2.2] octyl group, naphthalane base (decalinyl), tetrahydro naphthyl and 2,3-indanyl, bornyl, camphene base (camphenlyl), different camphene base (isocamphenyl) and carenyl (carenyl).Typical substituted cycloalkyl can be single the replacement or repeatedly replacement, for example, but is not limited to 2,2-, 2,3-, 2,4-, 2,5-, or 2,6-two substituted cyclohexyls, or single replacement, two replaces or three replacement norborny or suberyl, and for example, these groups can be by alkyl, alkoxyl, amino, sulfo-or halogen replace.
[0027] phrase " ring alkylidene " refers to the divalent cycloalkyl that contains 3-20 carbon atom, and phrase " substituted ring alkylidene " refers to the one or more substituent ring alkylidene that further contains as above-mentioned.
[0028] phrase " heterocyclic radical ", " heterocyclic " or " heterocycle " refer to that to have an annular atoms at least be heteroatomic non-aromatics cyclic hydrocarbon compound.Heterocyclic radical comprises monocycle, dicyclo and the polycyclic compound that contains 3-20 annular atoms, and wherein one or more annular atomses are hetero atom, for example, but is not limited to N, O and S.Heterocyclic radical comprises any level, and other is saturated.For example, heterocyclic radical comprises the first ring of the unsaturated 3-8 that contains 1-4 nitrogen-atoms; The first ring of saturated 3-8 that contains 1-4 nitrogen-atoms; The condensation unsaturated heterocycle base that contains 1-4 nitrogen-atoms; The first ring of unsaturated 3-8 that contains 1-2 oxygen atom and 1-3 nitrogen-atoms; The first ring of saturated 3-8 that contains 1-2 oxygen atom and 1-3 nitrogen-atoms; The unsaturated condensation heterocyclic radical that contains 1-2 oxygen atom and 1-3 nitrogen-atoms; The first ring of unsaturated 3-8 that contains 1-3 sulphur atom and 1-3 nitrogen-atoms.Preferred heterocyclic radical contains 5 or 6 yuan of rings.The heterocyclic radical example includes, but are not limited to morpholine and piperazine.Phrase " substituted heterocyclic radical " or " substituted heterocycle " refer to according to the substituted heterocyclic radical of the top definition that provides.
[0029] phrase " heterocycle alkylidene (heterocyclene) " or " heterocycle alkylidene (heterocyclylene) " refer to the divalent heterocycle (promptly containing ring) that contains 3-20 carbon atom, and " substituted heterocycle alkylidene (substituted heterocycloalkylene) " refers to and further contain aforesaid one or more substituent heterocycle alkylidene.
[0030] phrase " aryl " refers to the monocyclic aryl that can comprise 5-20 carbon atom.Aryl comprises, but is not limited to phenyl, xenyl, anthryl and naphthenyl.Phrase " substituted aryl " refers to according to the substituted any aryl of definition that is as above provided.For example, substituted aryl can be in conjunction with one or more carbon atoms, oxygen atom, and nitrogen-atoms and/or sulphur atom, and comprise that one or more aromatics carbon of aryl wherein and one replace and/or the bonded aryl of substituent methyl, alkenyl or alkynyl not.This comprises that wherein thereby two carbon atoms of aryl are arranged (for example, dihydro naphthyl or tetrahydro naphthyl) with two atoms of alkyl, alkenyl or alkynyl in conjunction with the key that becomes that defines a condensed ring system.Therefore, phrase " substituted aryl " includes, but not limited to tolyl, hydroxyphenyl etc.
[0031] phrase " arlydene " refers to the divalent aryl that contains 3-20 carbon atom, and phrase " replacement arlydene " refers to and further contains aforesaid one or more substituent arlydene.
[0032] phrase " heteroaryl " refers to by carbon atom with such as N, the 3-20 unit aromatic ring that the such hetero atom of S and O is formed, or (ii) contain carbon atom and such as N, and heteroatomic 8-10 unit's dicyclo or polycyclic system that S and O are such, wherein having a ring in bicyclic ring system at least is aromatic ring.Heteroaryl ring can be connected on any hetero atom or carbon atom.Typically heteroaryl compound comprises, for example, and imidazole radicals, pyridine radicals, pyrazinyl, pyrimidine radicals, thiophenyl, thiazolyl, furyl, pyrido furyl, pyrimido furyl, pyrido thienyl, pyridazine bithiophene base, Bi Ding Bing oxazolyl, pyridazine Bing oxazolyl, Mi Ding Bing oxazolyl, the pyrido thiazolyl, pyridazine benzothiazolyl, pyrrole radicals, pyrrolinyl, imidazole radicals, pyrazolyl, pyridine radicals, dihydropyridine base, pyrimidine radicals, pyrazinyl, pyridazinyl, triazolyl (4H-1 for example, 2,4-triazolyl, 1H-1,2,4-triazolyl and 2H-1,2, the 4-triazolyl), tetrazole radical (for example 1H-tetrazole radical and 2H tetrazole radical), pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, indyl, isoindolyl, indolinyl, indolizine base (indolizinyl), benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazole Ji ， oxazolyl ， isoxazolyl ， oxadiazole base (Li Evil 1,2,4-di azoly, 1,3,4-oxadiazole base and 1,2,5-oxadiazole base), benzoxazolyl, Ben Bing oxadiazole base benzoxazinyl (for example 2H-1,4-benzoxazinyl), thiazolyl, isothiazolyl, thiadiazine base (for example 1,2,3-thiadiazine base, 1,2,4-thiadiazine base and 1,2,5 thiadiazine bases).Phrase " substituted heteroaryl " refers to according to the substituted heteroaryl of definition that is as above provided.
[0033] phrase " heteroarylidene " refers to and contains one or more hetero atoms (N for example, O, S, or similar atom) as the part of aromatic ring, have the divalent aryl of 3-20 carbon atom with the typical case, and " replacement heteroarylidene " refers to and further contains aforesaid one or more substituent heteroarylidene.
[0034] phrase " alkoxyl " refers to oxygen containing alkyl or cycloalkyl, as defined above.
[0035] phrase " alkylamidoalkyl " refers to as defined above and contains-C (O) NR
2Alkyl, wherein each R independently is a hydrogen, alkyl, cycloalkyl, aryl, heteroaryl etc.And alkylamidoalkyl comprises that wherein R and N constitute the concrete example of a ring structure together.
[0036] phrase " amino " refers to-NR
2, wherein each R independently is a hydrogen, alkyl, cycloalkyl, aryl, heteroaryl etc.And amino comprises that wherein R and N constitute the concrete example of a ring structure together.
[0037] phrase " alkyl amino " refers to and contains an amino as defined above alkyl, and alkyl as defined above.
[0038] phrase " halogen " refers to F, Cl, Br or I.
[0039] phrase " junctional complex (linker) " refer to anyly can be used to add, in conjunction with or connect two or more alkyl, substituted hydrocarbon radical, contain heteroatomic substituted hydrocarbon radical, or contain the chemical part that replaces heteroatomic alkyl.Typical junctional complex comprises-C=C--C ≡ C-,-(C (R ')
2)
z-,-O-,-O-(C (R ')
2)
z-,-S-,-NR '-,-NH-(C (R ')
2)
z-,-N=N-,-C (O)-,-C (O) NR '-,-O-C (O)-,-O-C (O)-O-,-O-C (O)-NR '-,-NR '-C (O)-,-NR '-C (O)-O-,-NR '-C (O)-NR '-,-S-C (O)-,-S-C (O)-O-,-S-C (O)-NR '-,-S (O)-,-S (O)
2-,-O-S (O)
2-,-O-S (O)
2-O-,-O-S (O)
2-NR '-,-O-S (O)-,-O-S (O)-O-,-O-S (O)-NR '-,-O-NR '-C (O)-,-O-NR '-C (O)-O-,-O-NR '-C (O)-'-,-NR '-O-C (O)-,-NR '-O-C (O)-O-,-NR '-O-C (O)-NR '-,-O-NR '-C (S)-,-O-NR '-C (S)-O-,-O-NR '-C (S)-NR '-,-NR '-O-C (S)-,-NR '-O-C (S)-O-,-NR '-O-C (S)-NR '-,-O-C (S)-,-O-C (S)-O-,-O-C (S)-NR '-,-NR '-C (S)-,-NR '-C (S)-O-,-NR '-C (S)-NR '-,-S-S (O)
2-,-S-S (O)
2-O-,-S-S (O)
2-NR '-,-NR '-O-S (O)-,-NR '-O-S (O)-O-,-NR '-O-S (O)-NR '-,-NR '-O-S (O)
2-,-NR '-O-S (O)
2-O-,-NR '-O-S (O)
2-NR '-,-O-NR '-S (O)-,-O-NR '-S-(O)-O-,-O-NR '-S (O)-NR '-,-O-NR '-S (O)
2-O-,-O-NR '-S (O)
2-NR '-,-O-NR '-S (O)
2-,-O-P (O) (R ')
2-,-S-P (O) (R ')
2-and-NR '-P (O) (R ')
2-, wherein, each R ' independence is hydrogen, replaces or unsubstituted alkyl, replaces or unsubstituted alkenyl, replace or unsubstituted alkynyl, or replacement or unsubstituted cycloalkyl, and z is 1-10.Here embodiment preferred comprises the chemical compound of formula (I), wherein L
CFor-NH-.
[0040] comprise the chemical compound of formula (I) in the embodiment of this introduction, wherein A and B together, or B and C constitute a condensed ring system together.Exemplary condensed ring system comprises
[0041] phrase " condensed ring system " refers to by thick and to together two or three rings, for example bicyclo-or three-ring system.Exemplary condensed ring system comprises, naphthyl for example, 1-carbolinyl (1-carbolinyl) and analog; With substituted ring system for example biphenyl, phenylpyridyl, hexichol piperazinyl (diphenylpiperazinyl) and analog.
[0042] here embodiment preferred comprises the chemical compound of formula (I), and wherein D is
And d is 0-5.Each R
5Preferred embodiment, when existing, independently be selected from halogen, replace or unsubstituted C
1-C
5Alkyl replaces or unsubstituted C
1-C
5Alkoxyl replaces or unsubstituted 5-6 unit heteroaryl, or N (R ")
2, wherein each R is " for independently replacing or do not replace C
1-C
5Alkyl or C
3-C
10Cycloalkyl.The embodiment of D further comprises wherein D and R
5Constitute the chemical compound of a condensed ring system together.The embodiment of preferred D is selected from
Or
[0043] embodiment preferred comprises the chemical compound of formula (I) herein, and wherein C is
For example, the embodiment of C can be selected from
Or
Preferred embodiment comprises the chemical compound of formula (I), and wherein C is
[0044] embodiment preferred comprises the chemical compound of formula (I) herein, and wherein B is
And b is 0-2.For example, the embodiment of B can be selected from
Or
Preferred embodiment comprises the chemical compound of formula (I), and wherein B is selected from
Or
Each R wherein
2Independently be selected from halogen or replacement or unsubstituted C
1-C
5Alkyl.
[0045] embodiment preferred comprises the chemical compound of formula (I) herein, and wherein A is
Wherein F is CH or N.The embodiment of preferred A comprises wherein R
1Be halogen or replacement or unsubstituted C
1-C
5The chemical compound of alkyl.
[0046] embodiment preferred of this place introduction comprises the chemical compound that has corresponding to the structure of formula (II):
[0047] other embodiment preferred comprises the chemical compound that has corresponding to the structure of formula (III) herein:
[0048] further preferred embodiment comprises the chemical compound that has corresponding to the structure of formula (IV) herein:
[0049] herein further embodiment preferred comprise the chemical compound that has corresponding to the structure of formula V:
[0050] particularly preferred embodiment comprises the chemical compound that has corresponding to the structure of formula (VI) herein:
[0051] embodiment of being introduced comprises compositions, and it contains the chemical compound and the pharmacological-acceptable carrier of formula (I); And test kit (kits), it contains the chemical compound and the operation instruction thereof of formula (I).
II. the preparation of chemical compound
What [0052] introduce below is the exemplary overall plan of preparation The compounds of this invention.Provide among more detailed synthetic schemes the embodiment here.Because according to method well known to those of ordinary skill in the art, chemical compound herein can be prepared easily, so replacement or a lot of methods except that the following synthetic schemes of introducing can be used to prepare chemical compound herein.
[0053] chemical compound similar of the derivant in this description disclosure scope with chemistry, can be by conventional modification method mentioned herein, using suitable raw material to prepare, is conspicuous to its selection to those skilled in the art.
A. conventional condensation scheme
[0054] containing the chemical compound of aminothiazole or amino azoles part (3) herein can be by preparing in conjunction with α-halogenated ketone derivatives (1) and suitable thiourea or carbamide compound (2).For example, following scheme 1 has been described a conventional scheme for preparing the thiazolamine chemical compound.For example, by changing ring A, B and D and control scheme 1 are to prepare chemical compound of the present invention.
Scheme 1
[0056] in addition, utilize for example NH of simple thiourea
2-C (=S)-NH
2Also can carry out condensation reaction with various α-bromoketone derivant.As the route institute example of scheme 2, conjugation reaction can take place at coupling agent (coupling agent) with the carboxylic acid derivates that contains ring D (5) in the amine of generation (4) when existing, generate amido link chemical compound (6).
Scheme 2
B. the preparation of α-bromoketone derivant
[0056] scheme 1 employed preferred halogenation ketone derivatives comprises α-bromoketone derivant.Shown in the following scheme 3, the bromination of suitable alkyl ketone causes the formation of α-bromoketone derivant.
Scheme 3
[0059] therefore, by ring A in the change scheme 3 and B part, can prepare multiple α-bromoketone derivant.For example, its medium ring A is that imdazole derivatives and ring B are that the α-bromoketone derivant of phenyl derivatives (1a) can be according to scheme 4 preparation.And for example, scheme 4 also can be used for preparing the α that its medium ring A is triazole or thiazole-bromoketone derivant.
Scheme 4
[0060] its medium ring A is non-aromatic derivative, and for example piperazine is that the α-bromoketone derivant of phenyl derivatives can utilize the bromination of corresponding ketone easily to prepare with ring B.
C. the preparation of thiourea derivative
[0059] in scheme 1 described conventional condensation reaction, uses thiourea or urea, and can utilize scheme 5 preparation thiourea or ureas.Usually, can pass through suitable amine, for example anil joins in the suitable isothiocyanate compound and prepares urea derivative.
Scheme 5
[0060] thiourea derivative 7 or 8 is fit to and α-bromoketone derivant condensation.And 7 or 8 corresponding urea derivative also is suitable for use in the conventional condensation of introducing in this place.
D. the optional synthetic route for preparing the aminothiazole that replaces
[0061] except such scheme 1 and scheme 2 described conventional condensation routes, also can use Suzuki coupling (Suzuki coupling) reaction of the modification shown in the following scheme 6 to prepare the thiazole and the pyridine derivate of various replacements.
Scheme 6
[0062] aminothiazole derivs prepares by the modification that utilizes scheme 6, shown in following scheme 7.Notice that all one-tenth key condition and scheme 6 is identical in the scheme 7.
Scheme 7
III. regulate the method for the method of A β and the treatment disease relevant with A β
[0063] an aspect of of the present present invention relates to the method and the method for treatment with the disease that A β level is relevant unusually of regulating A β level, and its use has corresponding to the chemical compound of the structure of formula (VII) and drug acceptable salt and its prodrug:
(A
1-L
A1)
0-1-(B
1)-L
B1-(C
1)-L
C1-(D
1)
(VII)
Wherein:
A
1Choose wantonly, when existing, be 5 yuan or 6 yuan and replace or unsubstituted cycloalkyl, heterocyclic radical (heterocyclyl), aryl, heteroaryl, ring alkylidene, heterocycle alkylidene (heteroclylene), arlydene or heteroarylidene;
B
1Be 5 yuan or 6 yuan and replace or unsubstituted ring alkylidene heterocycle alkylidene (heteroclylene), arlydene, or heteroarylidene; Or B
1With A
1Together, form a condensed ring system;
C
1Being 5 yuan or 6 yuan replaces or unsubstituted arlydene or heteroarylidene;
D
1Be 5 yuan or 6 yuan and replace or unsubstituting aromatic yl heteroaryl, arlydene, or heteroarylidene; With
L
A1Choosing wantonly, when existing, is covalent bond or junctional complex;
Each L
B1And L
C1Independent is covalent bond or junctional complex;
The described chemical compound of its Chinese style (VII) is regulated A β level.
[0064] preferred methods herein comprises the chemical compound of use formula (VII), wherein:
A
1Choose wantonly, when existing be:
Wherein, each E independently is N, NR, C, CR
1, S or O, condition is that no more than four E is a hetero atom;
R is a hydrogen, replaces or unsubstituted alkyl, replaces or unsubstituted alkenyl, replace or unsubstituted alkynyl, replace or unsubstituted alkoxyl, replace or the unsubstituted alkyl amide groups, replace or unsubstituted alkyl amino, replace or unsubstituted cycloalkyl, or replacement or unsubstituted aryl;
Each R
1Be hydrogen, halogen, replace or unsubstituted alkyl, replace or unsubstituted alkenyl, replace or unsubstituted alkynyl, replace or unsubstituted alkoxyl, replace or the unsubstituted alkyl amide groups, replace or unsubstituted alkyl amino, replace or unsubstituted amino, replace or unsubstituted cycloalkyl, or replacement or unsubstituted aryl;
Or A
1, when existing, be:
Wherein, each M is independently selected from CR
1Or N, condition is that to be no more than three M are N; With
B
1Be:
Wherein each G is CR independently
2Or N, condition is that to be no more than three G are N;
Each R
2Independently be selected from hydrogen, halogen replaces or unsubstituted alkyl, replace or unsubstituted alkenyl, replace or unsubstituted alkynyl, replace or unsubstituted alkoxyl, replace or the unsubstituted alkyl amide groups, replace or unsubstituted alkyl amino, replace or unsubstituted amino;
C
1Be:
Wherein J is selected from CR
3, O, S, N and NR;
Each K is N, NR, C or CR independently
3
R
3Be hydrogen, halogen replaces or unsubstituted alkyl, replaces or unsubstituted cycloalkyl, replaces or unsubstituted aryl, replace or unsubstituted heteroaryl, or replacement or unsubstituted alkoxyl;
Or C
1Be:
Wherein each M is independently selected from CR
1Or N, condition is that to be no more than three M are N;
D
1Be:
Wherein each E independently is N, NR, C, CR
1, S or O, condition is that to be no more than four E are hetero atoms;
Or D
1Be:
Wherein each M is independently selected from CR
5Or N, condition is that to be no more than three M are N;
Each R
5Be independently selected from hydrogen, halogen replaces or unsubstituted alkyl, replaces or unsubstituted alkenyl, replace or unsubstituted alkynyl, replace or unsubstituted alkoxyl, replace or unsubstituted cycloalkyl, replace or unsubstituted heterocycle, replace or unsubstituted aryl, replace or unsubstituted heteroaryl, replace or unsubstituted amino, or replacement or unsubstituted alkyl amino;
L
A1, when existing, and each L
B1And L
C1Be covalent bond or junctional complex independently, be selected from-C=C-,-C-C-,-(C (R ')
2)
z-,-O-, O (CR ')
2)
z-,-S-,-NR '-,-NH-(C (R ')
2)
z,-N=N-,-C (O)-,-C (O) NR '-,-O-C (O)-,-O-C (O)-O-,-O-C (O)-NR '-,-NR '-C (O)-,-NR '-C (O)-O-,-NR '-C (O)-NR '-,-S-C (O)-,-S-C (O)-O-,-S-C (O)-NR '-,-S (O)-,-S (O)
2-,-O-S (O)
2-,-O-S (O)
2-O-,-O-S (O)
2-NR '-,-O-S (O)-,-O-S (O)-O-,-O-S (O)-NR '-,-O-NR '-C (O)-,-O-NR '-C (O)-O-,-O-NR '-C (O)-NR '-,-NR '-O-C (O)-,-NR '-O-C (O)-O-,-NR '-O-C (O)-NR '-,-O-NR '-C (S)-,-O-NR '-C (S)-O-,-O-NR '-C (S)-NR '-,-NR '-O-C (S)-,-NR '-O-C (S)-O-,-NR '-O-C (S)-NR '-,-O-C (S)-,-O-C (S)-O-,-O-C (S)-NR '-,-NR '-C (S)-,-NR '-C (S)-O-,-NR '-C (S)-NR '-,-S-S (O)
2-,-S-S (O)
2-O-,-S-S (O)
2-NR '-,-NR '-O-S (O)-,-NR '-O-S (O)-O-,-NR '-O-S (O)-NR '-,-NR '-O-S (O)
2-,-NR '-O-S (O)
2-O-,-NR '-O-S (O)
2-NR '-,-O-NR '-S (O)-,-O-NR '-S (O)-O-,-O-NR '-S (O)-NR '-,-O-NR '-S (O)
2-O-,-O-NR '-S (O)
2-NR '-,-O-NR '-S (O)
2-,-O-P (O) (R ')
2-,-S-P (O) (R ')
2-and-NR '-P (O) (R ')
2-, wherein, each R ' independence is hydrogen, replaces or unsubstituted alkyl, replaces or unsubstituted alkenyl, replace or unsubstituted alkynyl, or replacement or unsubstituted cycloalkyl and z is 1 to 10.
[0065] preferred methods herein comprises the chemical compound of use formula (VII), wherein L
C1Be-O-,-S-,-S (O)-,-S (O)
2-,-NR '-,-C (O)-,-(C (R ')
2)
2-or-C (S)-.
[0066] preferred herein embodiment comprises use corresponding to formula (II), (III), (IV), (V) or chemical compound (VI) regulate the method for the method of A β level and treatment and the disease that A β level is relevant unusually.
[0067] phrase " amyloid beta " or " A β " refer to a kind of peptide from human or other species, its (a) produced by processing or cutting APP, and be amyloid (amyloidogenic), (b) be one of the peptide composition of amyloid-beta speckle, (c) be 43-aminoacid sequence (the aminoacid 672-714 of APP770 of A β; Gene bank is included numbering P05067), be a kind of as (a) (d), (b) or (c) fragment of described peptide, and/or (e) contain one or more with (a), (b), (c) or (d) relevant adding, removal or replacement.In the art, A β also is known as β AP, A β P or β A4.Be generally～4.2Kd protein derived from the proteoclastic A β of APP peptide, its typical length is a 39-43 aminoacid, and this depends on the terminal point of carbonyl end, and this terminal point shows its inhomogeneity.Yet, contain less than 39 amino acid whose A β peptides, for example A β 38, A β 37 and A β 34 also can exist.
[0068] A β peptide can pass through the generation of amyloid (amyloidogentic) APP processing approach, and wherein APP is cut by the active of beta-secretase (BACE) and one or more gamma-secretases.A β peptide comprises that those 672 positions that start from APP770 and those start from the peptide of 682 positions of APP770 (for example, see also gene bank and include numbering P05067).Usually, as used herein, " A β " comprises any He all A β peptides, unless amino acid residue is designated, for example, such as 1-43 (A β 43), 1-42 (A β 42), 1-40 (A β 40), 1-39 (A β 39), 1-38 (A β 38), 1-37 (A β 37), 1-34 (A β 34), 11-43,11-42,11-40,11-39,11-38,11-37,11-34 and other.The different A β peptide of all lengths is known as A β " kind (species) " at this.
[0069] phrase " amyloid precursor protein (amyloid precursor protein) " or " APP " refer to and can carry out Proteolytic enzyme processing or cut the protein that produces A β by one or more processing or cleavage reaction.APP comprises that all pass through the isotype that alternative splicing (alternativesplicing) produces, and it is typically distinguished by amino acid whose quantity in concrete isotype.For example, APP comprises APP695, APP751 and APP770.For example, other isotype of APP comprises APP714, L-APP752, L-APP733, L-APP696, L-APP677, APP563 and APP365.
[0070] APP comprises that also all contain the isotype of sudden change, and this sudden change is found under AD family and other amyloidosis condition.For example, these sudden changes comprise Sweden (Lys670Asn, Met671Leu) two sudden changes, London sudden change (Val717Ile), Indiana sudden change (Val717Leu), Val717Phe, Val717Gly, Ala713Thr, Ala713Aal, Austria's sudden change (Thr714Ile), Iran's sudden change (Thr714Ala), France's sudden change (Val715Met), Germany's sudden change (Val715Ala), Florida sudden change (Ile716Val), Ile716Thr, Australia's sudden change (Leu723Pro), Flanders sudden change (Ala692Gly), Holland's sudden change (Glu693Gln), arctic sudden change (Glu693Gly), Italy's sudden change (Glu693Lys), Iowa sudden change (Asp694Asn) and amyloidosis-Dutch type (Dutch-type) sudden change (Glu693Gln).(all herein numberings are relevant with the APP770 form).
[0071] term " APP " further comprises and contains protein that one or more relevant with above-mentioned isotype add, remove or replace and from the app proteins of human and other species.Unless specify specific isotype, be commonly referred to as from APP any species, that any and all isotypes that suddenly change or do not suddenly change are arranged at this used APP.
[0072] phrase " amyloid precursor protein fragment " refers to by one or more processing or cleavage reaction is processed or cutting produces any part of APP of A β.The amyloid precursor fragment of APP comprises the beta-secretase cleavage site usually, and when cutting, this site produces the N-end of A β, perhaps gamma-secretase cleavage site, when cutting, this site produces the C-end of A β, perhaps comprises beta-secretase and gamma-secretase cleavage site simultaneously.Exemplary starches sample precursor fragment comprises the APPC-terminal fragment that is named as C99 and C89, and lacks the part of some or all of C-terminal residues, and this residue remains in the cytosol usually.
[0073] phrase " amyloid precursor protein (APP), the source of its amyloid precursor fragment and/or A β " refers in vivo anyly, exsomatizes or the sv material that contains APP, its amyloid precursor fragment and/or A β.For example, the organism that a kind of " source " can be a kind of work (comprises human patients, or laboratory or veterinary animal), its sample (for example the tissue or body fluid, or its extract), cell (for example primary cell or cell line, or its extract), the outer medium of born of the same parents or substrate or environment or isolating protein.
[0074] " regulate (modulate) " about the phrase of A β level or " regulating (modulating) " (for example A β 43, A β 42, A β 40 to refer at least a A β peptide, A β 39, A β 38, A β 37, A β 34,11-43,11-42,11-40,11-39,11-38,11-37,11-34 etc.) quantity can increase with detecting or reduce; A β peptide relative populations not of the same race (for example ratio of A β 42 and A β 40) can increase with detecting or reduce; The A β peptide of specific form (for example monomer, oligomer or fibril form; In solution or accumulate on the speckle; In a special conformation; Deng) quantity or relative populations can increase with detecting or reduce; And/or the A β peptide of specific position (for example in the born of the same parents, film relevant or the outer position of born of the same parents, or in special organization or body fluid) quantity or relative populations can increase with detecting or reduce.In preferred embodiments, with the minimizing of A β 42 or A β 40 levels, or the increase of A β 37 or A β 38 levels, adjusting can detect.For example, with respect to reference levels, by increasing or be reduced by at least quantity or the relative populations of the A β of a kind of A β of 5%, total A β or specific form, for example 10%, 20%, 30%, 40%, 50%, 75%, 90% or more, be can be certified to the adjusting of A β level.Adjusting can be to increase or reduce, and this increase or minimizing have significant difference statistically with respect to reference levels.
[0075] phrase " contact (contacting) " refers to two or more materials is taken place or direct or indirect contact.Contact can occur in vivo, in vitro or in vitro.For example, by the treatment or the preventive dosage (prophylactic administration) of chemical compound, APP, its starch precursor fragment and/or A β source or BACE activity human or other animal are originated, and can both contact with chemical compound.For example, by chemical compound is imported the incubation base, the APP of tissue, tissue extract or cell, its starch precursor fragment and/or A β source can contact with chemical compound.For example, by chemical compound and fluid premixing, be that for example APP, its starch precursor fragment and/or the A β source of the outer medium of born of the same parents can contact with chemical compound fluid.
[0076] phrase " treatment (treating) " or " treatment (treatment) " one or more symptoms of referring to a kind of disease or disease improve or any mode of useful variation, no matter be permanent or temporary transient mode, this can give the credit to using of chemical compound herein or compositions or relevant with using of chemical compound or compositions herein.This term comprises any drug use, comprise that the prevention that the development of one or more symptoms of disease wherein or disease is prevented from, delays or reduces uses, no matter be permanent or temporary transient mode, this can give the credit to using of chemical compound or relevant with using of chemical compound.In one embodiment of the invention, treatment comprises any drug use of chemical compound here, be used for the treatment of with change or unusual A β generation, catabolism, processing and/or level be the disease or the obstacle of feature.
[0077] phrase " with the relevant disease of unusual A β level " refers to any situation, and (for example A β 43, A β 42, A β 40, A β 39 to it is characterized in that at least a A β peptide, A β 38, A β 37, A β 34,11-43,11-42,11-40,11-39,11-38,11-3,11-34 etc.) quantity unusual; The relative populations of A β peptide not of the same race unusual (for example ratio of 42 couples of A β 40 of A β); The A β peptide of specific form (monomer for example, oligomer, or fibril form; In solution or accumulate on the speckle; In a special conformation; Deng) quantity or relative populations unusual; And/or specific position (for example in the born of the same parents, film relevant or the outer position of born of the same parents, or in special organization or body fluid) quantity or the relative populations of A β unusual.The unusual quantity of one or more A β peptides, A beta form and/or A β may be with to be in situation normal, no morbid state relevant.With the A β level that changes be the disease of feature and obstacle in this area and/or described herein be known, for example, comprise Down's syndrome, parkinson disease, diffusion Lu Yi body disease, benumb on the carrying out property nuclear, hereditary amyloidosis cerebral hemorrhage-Dutch type (Hereditary CerebralHemorrhage with Amyloidosis-Dutch Type (HCHWA-D)), cerebral amyloid angiopathy (CAA) and mild cognitive damage (MCI).Embodiment of the present invention comprise for example method of AD diseases associated of any and unusual A β level of treatment.Chemical compound of the present invention can be applied to a main body, and treat (comprising prevention or improvement) and the A β generation, the fibril formation/deposition that change, degrade and/or remove, or the relevant situation of isotype of any variation of A β.
[0078] preferably, chemical compound of the present invention is used for the treatment of neurological disorder, includes, but are not limited to neurodegenerative conditions and other dementia or wound situation.Exemplary neurological disorder can comprise diffusibility Lu Yi body disease, Pick disease, multisystem degeneration (Xia-De syndrome), motor neuron, comprise amyotrophic lateral sclerosis, the degeneration ataxia, cortical basal ganglionic degeneration (cortical basaldegeneration), amyotrophic lateral sclerosis-Parkinson-Dementia syndrome (ALS-Parkinson ' s-Dementia complex of Guam), subacute sclerosing panencephalitis, Huntington Chorea, synucleinopathies, former carrying out property aphasia, striatonigral degeneration, Ma-Yue disease/spinocerebellar ataxia 3 types and olivopontocerebellar degeneration, tourette's disease, oblongata and pseudobulbar paralysis, spinal cord and spinal cord oblongata amyotrophy (Kennedy's disease), primary lateral sclerosis, family's spastic paraplegia, Wei-Huo disease, Ku-Wei syndrome, amaurosis idiotica familiaris, sandhoff disease, family's spastic paraplegia, Wo-Ku-Wei syndrome, spastic paraparesis, progressive multifocal leukoencephalopathy, prion disease (comprises Ke-Ya syndrome, Ge-Shi-Sha disease, the fatal insomnia of family of Kuru disease), dull-witted and other situation of following memory to lose, for example vascular dementia of age related, arteriosclerotic leukoencephalopathy under the subacute cortex (Bin Sineiwangge disease), the dementia of endocrine or metabolism origin, head trauma and dispersivity brain injury dementia, dementia pugilistica and frontal lobe dementia, cerebral ischemia or cerebral infarction (infaction), comprise the inaccessible and thrombosis obturation of embolus, and the intracranial hemorrhage of any kind (includes, but are not limited to peridural, subdural, subarachnoid and IC) and intracranial and spinal column in infringement (include, but are not limited to dampen, penetrate, shear force, oppress and tear).
IV. other treatment is used
[0079] chemical compound of the present invention and compositions can be used for treatment or improve various disorders.In one embodiment, can be used for the chemical compound of therapeutic use and compositions in target tissue (be brain, treatment neural degeneration obstacle, other generate the concrete peripheral organ of amyloid situation) and have quite high bioavailability and quite low toxicity.Those of ordinary skills can utilize standardized method to assess the materia medica acceptability of chemical compound described herein.
[0080] for example, chemical compound of the present invention can be used for treating cancer or other is the disease of feature with the abnormal cell hypertrophy, inflammation, antibacterial or viral infection, autoimmune disease, acute pain, myalgia, neuropathic, anaphylaxis, sacred disease, dermatosis, cardiovascular diseases, diabetes, gastrointestinal disease, depression, endocrine or other disease that is feature with unusual hormone catabolism, obesity, osteoporosis or other bone disorders, pancreatic diseases, epilepsy or epilepsy disease, erection disturbance or sexual dysfunction, ophthalmology obstacle or oculopathy, the cholesterol imbalance, hypertension or hypotension, migraine or headache, obsession, Panic disorder, anxiety neurosis, post-traumatic stress disorder, chemicals dependence or addiction etc.
[0081] also can be used for prevention or treatment amyloidosis at the chemical compound that this provided.Amyloidosis comprises that be all situations of feature with amyloid beta deposition to brain or periphery, comprises and rheumatism, and idiopathic disease, heredopathia, inflammation infects sick relevant with malignant diseases amyloidosis.For example, amyloidosis disease comprises the situation relevant with the A β level of above-mentioned variation (Alzheimer for example, Down's syndrome, HCHWA-D, cerebral amyloid angiopathy (CAA), damage (MCI) etc. with mild cognitive), and familial amyloid sample polyneuropathy, familial amyloid sample cardiomyopathy (Danish type), isolating cardiac amyloidosis (isolated cardiacamyloid), amyloid angiopathy, the senile amyloidosis of general, familial general amyloidosis, light chain amyloidosis (AL), dialysis dependency amyloidosis, renal amyloidosis, the amyloidosis Protein virus encephalopathy of being correlated with, diabetes (wherein amylin may deposit on kidney or the pancreas), atrium amyloidosis and hypophysis amyloidosis.
[0082] those of ordinary skills can determine to use chemical compound described herein or compositions to its useful other disease and obstacle.
V. pharmaceutical composition
[0083] phrase " materia medica acceptable carrier " refers to any carrier of the known suitable specific application mode of those of ordinary skills.In addition, chemical compound can be formed in the drug alone active component in the compositions, perhaps also can combine with other active component.
[0084] phrase " the acceptable salt of materia medica " refers to and is applicable to any salt pref of doing medicinal application.The acceptable salt of materia medica comprises amine salt, for example, and N, N '-dibenzyl-ethylenediamin, chlorination procaine (chloroprocaine), choline, ammonia, diethanolamine and other hydroxylamine, 1, the 2-ethylenediamine, N-methylglucosamine, procaine, N-dibenzyl phenethylamine, 1-is right-chloro-benzyl-2-pyrrolidine-1 '-the ylmethyl benzimidazole, diethylamine and other alkylamine, piperazine, Tris etc.; Alkali metal salt, for example, lithium, potassium, sodium etc.; Alkali salt, barium for example, calcium, magnesium etc.; Transition metal salt, zinc for example, aluminum etc.; Other slaine, sodium hydrogen phosphate for example, disodium hydrogen phosphate etc.; Mineral acid, hydrochloride for example, sulfate etc.; And acylate, acetate for example, lactate, malate, tartrate, citrate, Ascorbate, succinate, butyrate, valerate, fumarate etc.
[0085] phrase " prodrug " refers to chemical compound, and it is metabolised to by one or more steps or process after using on the live body, or be converted into have biology, the compound form of medicine or therapeutic activity.Can prepare prodrug by revising the existing functional group of chemical compound, mode is this modification or with the operation of routine or be cracked into chemical compound described herein in vivo.For example, prodrug comprises chemical compound of the present invention, and wherein hydroxyl, amino or sulfydryl combine with other group, when compound administration on one's body the time, can cleavedly form free hydroxyl, free amino group respectively to mammal, or free sulfydryl.For example, typical prodrug comprises ester, enol ether, enol ester, acetate, formates, benzoate derivant, and the analog of the alkohol and amine functional group in the The compounds of this invention.By understanding drug effect process and the drug metabolism in live body, those of ordinary skills, in case know a kind of chemical compound that pharmacologic activity is arranged, the prodrug that just can design this chemical compound (for example, please refer to Nogrady (1985) MedicinalChemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392).
[0086] compositions herein comprises the chemical compound that one or more are mentioned herein.In one embodiment, chemical compound is made into suitable pharmaceutical preparation, for example solution, suspension, tablet, dispersible tablets, ball, capsule, powder, slow releasing agent or elixir are used for oral, or in sterile solution or suspension, be used for parenteral admistration, and transdermal patch preparation (transdermal patchpreparation) and Diskus.In one embodiment, utilize technology known in the art and process that above-claimed cpd is made pharmaceutical composition (for example, seeing also AnselIntroduction to Pharmaceutical Dosage Forms, Fourth Edition 1985,126).
[0087] in compositions, one or more chemical compounds of valid density or its materia medica can be accepted derivant and mix with the pharmaceutical carrier that is fit to.Before being made into dosage form, as mentioned above, chemical compound can be corresponding salt, ester, enol ether or enol ester, acetal, ketal, ortho esters (orthoesters), hemiacetal, hemiketal, acid, alkali, solvate, hydrate or prodrug by development.The concentration of chemical compound in compositions is effective burst size, in case use, this dosage can treat, prevents or improve by one or more symptom of treatment disease or obstacle.
[0088] in one embodiment, compositions is made into single dose and uses.For preparing a kind of compositions, in selected carrier,, make that the disease of being treated is alleviated, prevents by valid density dissolving, suspension, dispersion or the fractional chemical compound of mixed weight, perhaps one or more symptoms are improved.
[0089] to when the patient do not have adverse side effect by treatment, reactive compound is added in the pharmacological-acceptable carrier with the amount that is enough to bring into play effective therapeutical effect.By herein and the disclosed WO of PCT 04/018997 described, system in vivo and in vitro, test compounds can the decision treatment of experience ground go up effective concentration, infers human using dosage then thus.
[0090] concentration of reactive compound in pharmaceutical composition will depend on absorption, inactivation and the drainage rate of reactive compound, the physicochemical characteristics of chemical compound, the known other factors of dosage and dosage and those of ordinary skills.
[0091] in one embodiment, a kind ofly treat effective dosage and should produce the serum-concentration of about 0.1ng/ml to the active component of about 50-100 μ g/ml.In another embodiment, the pharmaceutical composition dosage that should provide be every day every kilogram of about 0.001mg of human body body weight to about 2000mg.The pharmaceutical dosage unit mode is made into, every dosage unit form provides about 0.01mg, 0.1mg or 1mg to about 500mg, 1000mg or 2000mg, in one embodiment, every dosage unit mode provides and is approximately 10mg to the active component of about 500mg or the compositions of necessary component.
[0092] active component can applied once, maybe can be divided into many low doses and use by interval.Should be appreciated that accurate dose and treatment the duration treated the function of disease, and can utilize known testing scheme or, determine empirically according to from live body or the in vitro deduction of test data.Should be noted that concentration and dose value also change with the order of severity of the disease that will improve.Further be to be understood that; for any special main body; the personnel's that will implement according to individual need and enforcement or supervision group compound professional judgement; adjust concrete dosage control in time; and; in this concentration range of setting forth only is exemplary, is not scope or the use that is intended to limit compositions required for protection.
[0093] under the not enough situation of its dissolubility of compound exhibits, can use the method for dissolved compound.These methods are the known methods of those of ordinary skills, include but not limited to, use cosolvent, and for example dimethyl sulfoxide (DMSO) uses surfactant, for example TWEEN
, or be dissolved in the sodium bicarbonate aqueous solution.The derivant of chemical compound, for example the prodrug of chemical compound also can be used for preparing drug composition effective.
[0094] mixing in a single day or adding chemical compound, formed mixture can be a solution, suspension, emulsion etc.The form of formed mixture depends on several factors, comprises the dosing mode and the dissolubility of chemical compound in selected carrier or media (vehicle) of expection.Valid density will be enough to improve the symptom of disease, obstacle or the situation of being treated, and can the decision of experience ground.
[0095] provides pharmaceutical composition to be used for bestowing the human and animal, for example contain the tablet that an amount of chemical compound or its materia medica can be accepted derivant, capsule by the unit dose mode, ball, powder, granule, sterile parenteral solutions or suspension and oral administration solution or suspension, and oil-water emulsion.In one embodiment, Drug therapy reactive compound and derivant thereof are produced and use by unit dose mode or multiple dose mode.Unit dose mode used herein refers to the unit of the physical separation that is suitable for human and animal's main body, as known in the art, can pack separately.Each unit dose contains the therapeutical active compound of scheduled volume of the required therapeutic effect of enough generations and essential pharmaceutical carrier, media or diluent.The example of unit dose mode comprises the tablet or the capsule of ampoule and syringe and independent packing.The unit dose mode can its part or its times amount be applied.The multiple dose mode is a plurality of identical unit dose modes, and it is packaged in the independent container, uses in the unit dose mode of separating.The example of multiple dose mode comprises phial, tablet or capsule bottle, or pint or gallon bottle.Therefore, the multiple dose mode is a plurality of unit dose that concentrate in the packing.
[0096] for example, the medicine of liquid can be used compositions can be by dissolving in carrier, disperse or mix above-mentioned reactive compound and optional medicine adjuvant, forms solution or suspension and prepares, carrier is water for example, saline, D/W, glycerol, ethylene glycol, ethanol etc.If necessary, the pharmaceutical composition that use also can contain minor amounts of non-toxic auxiliary substances, for example wetting agent, emulsifying agent, solubilizer, pH buffer agent etc., for example, acetate, sodium citrate, cyclodextrin (cyclodextrine) derivant, sorbitan monolaurate, triethanolamine sodium acetate, triethanol amine oleate and other such reagent.
[0097] practical methods of the such dosage mode of preparation is known or conspicuous to those of ordinary skills; For example, please refer to Remington ' s Pharmaceutical Science, Mack Publishing Company, Easton, Pa., 15th Edition, 1985.
[0100] can prepare and contain active component in 0.005%-100% (wt%) scope and remainder the dosage mode or the compositions of supplying by non-toxic carrier.Preparing these method for compositions is that those of ordinary skills are known.The compositions that expection is used can contain 0.001%-100% (wt%) active component, in one embodiment, is 0.1%-95% (wt%), in another embodiment, is 75%-85% (wt%).
A. Orally administered composition
[0101] oral drugs dosage mode is solid-state, gel or liquid state.Solid-state dosage mode is a tablet, capsule, granule, and loose powder.The kind of oral tablet comprises compression, chew lozenge and can be the tablet of enteric, sugar-coat or film clothing.Capsule can be hard or soft gelatine capsule, and granule and loose powder can non-effervescent or the effervescent mode provide, and in conjunction with known other component of those of ordinary skills.
1. oral solid composition
[0102] in certain embodiments, dosage form is solid-state dosage mode, in one embodiment, is capsule or tablet.Tablet, ball, capsule, lozenge etc. can contain one or more following components, or the chemical compound of similar quality: binding agent; Lubricant; Diluent; Fluidizer; Disintegrating agent; Coloring agent; Desulfurizing agent; Fumet; Wetting agent; An emetic coating; Film coating.The example of binding agent comprises microcrystalline Cellulose, gum tragacanth, glucose solution, Acacia farnesiana Willd. slurry, gelatin solution, molasses, polyvinylpyrrolidine, polyvidone (povidon), polyvinylpyrrolidone, sucrose and paste.Lubricant comprises Talcum, starch, magnesium stearate or calcium, Lycopodiaceae and stearic acid.Diluent comprises, for example lactose, sucrose, starch, Kaolin, salt, mannitol and dicalcium phosphate.Fluidizer includes but not limited to silica sol.Disintegrating agent comprises intersection carmethose (crosscarmellose sodium), glycolic acid Starch Sodium, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxy methyl cellulose.Coloring agent comprises, for example, and any water solublity FD that is identified by approval and C dyestuff, its mixture; Be suspended in water solublity FD and C dyestuff in the hydrated alumina.Desulfurizing agent comprises sucrose, lactose, mannitol and artificial desulfurizing agent, for example glucide and any amount spray drying spice.Fumet comprises natural perfume material and the synthetic compound mixture that for example extracts the fruit from plant, and these chemical compounds produce pleasant sensation, for example, but are not limited to Herba Menthae and methyl salicylate.Wetting agent comprises PGML, dehydrating sorbitol monooleate, single month silicic acid diethylene glycol ester and polyoxyethylene lauryl ether (polyoxyethylene lauralether).Emetic-coatings comprises fatty acid, fat, and wax, lac contains ammonia lac and Cellacefate.Film coating comprises hydroxyethyl-cellulose, sodium carboxy methyl cellulose, Macrogol 4000 and Cellacefate.
[0103] chemical compound, or its materia medica can accept derivant and can be provided in a kind of compositions, the said composition protection it-avoid the stomach sour environment.For example, compositions can be made into to wrap in the enteric coating, and enteric coating can be kept its integrity under one's belt, and at the enteral release of active compounds.Compositions also can be prepared from conjunction with antacid and other such component.
[0104] when the dosage unit mode is capsule, except that containing the above-mentioned type material, it can comprise the liquid-carrier such as fatty oil.In addition, the dosage unit mode can comprise the material of other various modification dosage unit physical forms, for example sugar-coat and other enteric agent.Chemical compound also can be as elixir, suspension, and syrup, sheet, spray agent, the composition of chewing gum etc. is applied.Syrup removes and contains the active ingredient beyond the region of objective existence, can contain sucrose as desulfurizing agent and some antiseptic, dyestuff and coloring agent and spice.
[0105] active substance also can mix with other active substance that can not weaken required effect, or mixes with the material that replenishes required effect, for example, and antacid, H2 blocker and diuretic.Active component refers to that chemical compound described herein or its materia medica can accept derivant.Can comprise higher concentration, calculate by weight and to reach about 98% active component.
[0106] in all embodiments, tablet and capsule can be by coatings, and just as known to persons of ordinary skill in the art, purpose is to relax or keep the dissolving of active component.Therefore, for example, can come coating with traditional intestinal absorption coating, for example phenylo salicylic acid, wax and Cellacefate.
2. oral fluid composition
[0107] liquid oral dose mode comprises aqueous solution, emulsion, and suspension, regeneration is from the solution of non-granulae effervescentes and/or suspension and the regeneration effervescent formulation from granulae effervescentes.For example, aqueous solution comprises elixir and syrup.Emulsion or be oil-in-water or for Water-In-Oil.
[0108] elixir is limpid and the aqueous alcohol preparation of sweet taste.The pharmacological-acceptable carrier that is used for elixir comprises solvent.Syrup is the aqueous solution of spissated sugar, sucrose for example, and can contain antiseptic.Emulsion is two-phase system, and wherein a kind of liquid is dispersed in another liquid in the mode of little liquid pearl.The pharmacological-acceptable carrier that is used in the emulsion is on-aqueous liquid, emulsifying agent and antiseptic.Suspension uses acceptable suspending agent of materia medica and antiseptic.Be used for materia medica non-granulae effervescentes, the liquid oral dose mode of renewable one-tenth and can accept material, comprise diluent, sweeting agent and wetting agent.The materia medica that is used for granulae effervescentes, the liquid oral dose mode of renewable one-tenth can receive material and comprise organic acid and carbon dioxide source.Coloring agent and fumet are used in all above-mentioned dosage modes.
[0109] solvent comprises glycerol, Sorbitol, ethanol and syrup.Examples of preservatives comprises glycerol, methyl and propyl parabene, benzoic acid, sodium benzoate and ethanol.The on-aqueous liquid example that is used for emulsion comprises mineral oil and cottonseed oil.The example of emulsifying agent comprises gelatin, Acacia, gum tragacanth, bentonite and such as the such surfactant of Tween-81.Suspending agent comprises sodium carboxy methyl cellulose, pectin, gum tragacanth, Veegum and Acacia.Desulfurizing agent comprises sucrose, syrup, glycerol and such as the so artificial desulfurizing agent of glucide.Wetting agent comprises propylene glycol monostearate, dehydrating sorbitol monooleate, single month silicic acid diethylene glycol ester and polyoxyethylene lauryl ether.Organic acid comprises citric acid and tartaric acid.Carbon dioxide source comprises sodium bicarbonate.Coloring agent comprises any water solublity FD and C dyestuff of being identified by approval, and composition thereof.Fumet comprises natural perfume material and the synthetic compound mixture that for example extracts the fruit from plant, and these chemical compounds produce pleasant sensation.
[0110] for solid-state dosage mode, in one embodiment, solution or suspension in for example isobutyl carbonate third rare ester, vegetable oil or triglyceride are sealed in the gelatine capsule.U.S. Patent number 4,328,245,4,409,239 and 4,410,545 disclose such technical scheme, preparation and its encapsulation.Liquid towards dosage mode, for example the solution in Polyethylene Glycol can be accepted for example water dilution of liquid carrier by the materia medica of capacity, so that measure easily when using.
[0111] in addition, by the dissolving of reactive compound or salt or be distributed to vegetable oil, ethylene glycol, triglyceride, in propylene glycol ester (for example isobutyl carbonate third rare ester) and other such carrier, and these solution or suspension are encapsulated in the hard or soft capsule shells, to prepare liquid state or half-solid-state oral formulations.Other useful dosage form is included in United States Patent (USP) RE28,819 and 4,358,603 described those.Briefly, such dosage form includes but not limited to that those contain the chemical compound that this place provides, the dosage form of the list of dialkylization or ployalkylene glycol and one or more antioxidants, and described chemical compound includes but not limited to 1, the 2-dimethoxymethane, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether., tetraethylene glycol dimethyl ether (tetraglyme), Polyethylene Glycol-350-dimethyl ether, Polyethylene Glycol-550-dimethyl ether, Polyethylene Glycol-750-dimethyl ether, wherein 350,550 and 750 refer to the approximate mean molecule quantity of Polyethylene Glycol, described antioxidant for example 2,6-ditertbutylparacresol (BHT), tert-butyl group hydroxyanisol (butylated hydroxyanisole) (BHA), propyl gallate, vitamin e, hydroquinone, Hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thio-2 acid and its ester, and dithiocarbamates.
[0112] other dosage form includes but not limited to aqueous alcohol solutions, and it comprises the acceptable acetal of materia medica.The alcohol that is used for these dosage forms is the acceptable water-miscible solvent that contains one or more oh groups of any materia medica, includes but not limited to ethylene glycol and ethanol.Acetal includes but not limited to two (low alkyl) acetal, for example acetaldehyde diethyl acetal of low alkyl aldehydes.
B. injectable, solution and emulsion
[0113] be feature with the injection in one embodiment, also consider parenteral admistration at this, itself or be subcutaneous injection, intramuscular injection or intravenous injection.Can prepare injectable with traditional mode, or be liquid solution or for suspension, be fit to the solid-state form that exists with solution in the liquid or suspension before its injection, or be emulsion.Injectable, solution and emulsion also contain a kind of and multiple excipient.Suitable excipient for example has water, salt, glucose, or ethanol.In addition, if desired, the pharmaceutical composition that is applied also can contain a spot of nontoxic auxiliary substance, for example wetting agent or emulsifying agent, pH buffer agent, stabilizing agent, solubilizing agent and other such auxiliary agent, for example such as sodium acetate, sorbitan monolaurate, Emulphor FM and cyclodextrin.
[0114] implants a kind of slow release and slow-released system and also be taken into account, so that keep a kind of stable dosage level (seeing also United States Patent (USP) 3,710,795) at this.Briefly, be scattered in a kind of solid-state internal matrix (inner matrix) at the chemical compound that this provided, for example, polymethyl methacrylate, poly-butylacrylic acid methyl ester, plasticising or unplasticised polyvinyl chloride, plasticising nylon, the plasticising polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, vinyl-vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicon-carbon acid esters (silicone carbonate) copolymer, hydrophilic polymer is acrylate and methacrylate hydrogel for example, ossein, the polyvinyl acetate of the pure and mild crosslink part hydrolysis of crosslinked polyethylene, it by outside polymeric membrane around, this polymeric membrane is polyethylene for example, polypropylene, the ethylene/propylene copolymer, the ethylene/ethyl acrylate copolymer, ethylene/vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, neoprene, chlorinated polyethylene is rare, polyvinyl chloride, the copolymer of vinyl chloride and vinyl acetate, vinylidene chloride, ethylene and third rare, from poly-polyethylene terephthalate (ionomer polyethylene terephthalate), butyl rubber, epichlorohydrin rubber, ethylene/vinyl alcohol copolymer, the copolymer of ethylene/vinyl acetate/vinyl alcohol terpolymer and ethylene/vinyl ethoxy-ethanol (vinyloxyethanol), this material can not dissolve in body fluid.Chemical compound diffuses through outside polymeric membrane with a controllable step of rate of release.The percentage ratio height of reactive compound in this parenteral composition depends on the character that it is concrete, and the needs of the activity of chemical compound and main body.
[0115] parenteral admistration of compositions comprises intravenous, subcutaneous and intramuscular dispensing.The parenteral admistration preparation comprises the sterile liquid that is used to inject, aseptic dry soluble preparation, for example freeze dried loose powder, and it only combined with solvent before using; Comprise the tablet that subcutaneous injection is used, the sterile suspension that is used to inject, only before using with bonded aseptic dry soluble preparation of solvent and aseptic emulsion.Solution can be aqueous, or water-free.
[0116] if intravenous dispensing, suitable carriers comprises normal saline and phosphate-buffered salt (PBS) and contains thickening agent and the solution of solubilizing agent, glucose for example, and Polyethylene Glycol and polypropylene glycol, and composition thereof.
[0117] pharmacological-acceptable carrier that is used for parenteral administration comprises moisture media, non-hydrophily is situated between, antibacterial, isotonic agent, buffer, antioxidant, local anesthetic, suspending agent and dispersant, emulsifying agent, hidden (sequestering) agent or sequestration (chelating) agent and other medicines are learned acceptable material.
[0118] moisture media (aqueous vehicle) example comprises sodium chloride injection, and Green's injection waits and oozes glucose injection, sterilized water injection, glucose and lactic acid Green injection.Non-water parenteral media comprises the fixed oil (fixed oils) of plant source, cottonseed oil, Semen Maydis oil, Oleum sesami and Oleum Arachidis hypogaeae semen.Antibacterial in bacteriostatic or the fungus inhibition condensation product (concentrations) must be added in the parenteral administration that is packaged in the multi-dose container, antibacterial comprises phenol or cresol, mercurial, benzyl alcohol, chlorobutanol, methyl and propyl para-hydroxybenzoate, thiomersalate, benzalkonium chloride (benzalkoniumchloride) and benzethonium chloride.Isotonic agent comprises sodium chloride and glucose.Buffer comprises phosphate and citrate.Antioxidant comprises sodium bisulfate.Local anesthetic comprises procaine hydrochloride.Suspending agent and dispersant comprise sodium carboxymethyl cellulose, hydroxypropyl emthylcellulose and polyvinylpyrrolidone.Emulsifying agent comprises Polysorbate 80 (TWEEN
80).Hidden (sequestering) agent of metal ion or sequestration (chelating) agent comprise EDTA.Pharmaceutical carriers also comprises the vinyl alcohol as the water miscibility media, polyvinyl alcohol and propylene glycol; With the sodium hydroxide that is used to adjust pH value, hydrochloric acid, citric acid or lactic acid.
[0119] regulates the pharmacologic activity compound concentrations, so that injection provides effective amount to produce required pharmacodynamics effect.Dosage depends on age, weight and the situation of patient or animal accurately, and this is well known in the art.
[0120] the unit dose parenteral administration be loaded into the peace cut open, phial or the band syringe needle syringe in.The preparation of the parenteral admistration that is useful on must be aseptic, as known in the art and practice.
[0121] as an illustration, to contain the aseptic aqueous solution of reactive compound be a kind of effective dosing mode for vein or arterial infusion.Another embodiment is to inject on demand containing the sterilized water of active substance or oil solution or suspension, to produce required pharmacodynamics effect.
[0122] injectable is designed to part and systemic administration.In one embodiment, effective dosage is prepared to its concentration and is at least about 0.1%w/w to about 90%w/w or bigger in the treatment, and in certain embodiments, the reactive compound that surpasses 1%w/w is applied to by treated tissue.
[0123] chemical compound can suspend with micropowder shape or other shape that is fit to, or can be produced more easily molten biologically active prod by development or produce prodrug.The shape of the mixture that forms depends on several factors, comprises the method for application and the dissolubility of chemical compound in selected carrier or media of expection.Valid density will enough be used to improve the symptom of disease, and can the decision of experience ground.
C. freeze dried loose powder
[0124] also interested in freeze dried loose powder herein, it can be reproduced into solution, emulsion and other mixture and use.They also can be reconstructed and be made solid or gel.
[0125] by dissolving chemical compound mentioned herein in suitable solvent, perhaps its materia medica can be accepted derivant and prepares aseptic, freeze dried loose powder.This solvent can contain the excipient that improves stability, or the other medicines composition of loose powder or the actified solution that made by loose powder.Operable excipient includes but not limited to, glucose, sorbitol, fructose, Semen Maydis pulp, xylitol, glycerol, glucose, sucrose, or other appropriate formulation.Solvent also can contain buffer, known this type of buffer of citrate, sodium phosphate or potassium phosphate or other those of ordinary skills for example, and in one embodiment, it is approximately pH neutral.Under the standard conditions that those of ordinary skills know, carry out solution aseptic filtration subsequently, carry out lyophilization then, required preparation is provided thus.In one embodiment, formed solution is dispensed into and carries out lyophilization in the phial.Each phial contains the chemical compound of single dose or multiple dose.Freeze dried loose powder can be stored under the suitable environment, and for example about 4 ℃ are arrived room temperature.
[0126] this freeze dried loose powder and water reconstruct injection, and a kind of dosage form that is used for parenteral admistration is provided.For realizing reconstructing, freeze dried loose powder is added in sterilized water or other suitable carriers.Accurately amount depends on selected chemical compound.This amount can rule of thumb determine.
D. local application
[0127] preparation of local mixture (topical mixtures) as be used for local and systemic administration as described in.Formed mixture can be a solution, suspension, and emulsion or analog, and be made into frost (creams), gel, ointment, emulsion, solution, elixir, lotion, suspension, tincture is stuck with paste foam, aerosol, washing liquid, spraying, suppository, binder, the dosage form of transdermal patches (dermalpatches) or other any suitable local application.
[0128] chemical compound or its materia medica can be accepted derivant and be made into aerosol, are used for local application, for example (for example, see also the special US4 of the U.S. by sucking, 044,126,4,414,209 and 4,364,923, these patents have been described and have been discharged the especially aerosol of asthma of steroid therapy inflammation).The dosage form that is administered to respiratory tract can be the form of aerosol or aerosol apparatus solution, perhaps for spraying the fine powder of usefulness, its separately or with other inert carrier for example lactose combine and use.In the case, in one embodiment, the diameter of dosage form particle is less than 50 microns, in one embodiment less than 10 microns.
[0129] chemical compound can be made into local or a certain specific part is used, and for example locally applies to skin and mucosa, for example in eye, with the form of gel, frost, lotion, uses in eye or the brain pond or uses in the spinal column.Be used for transdermal delivery (transdermal delivery) and be used for eye or mucosa, or the local application that is used to suck treatment also is taken into account.Also can use the nose solution (nasal solutions) of independent reactive compound, or can accept the nose solution of the reactive compound of excipient in conjunction with other medicines.
[0130] these solution, especially those are intended to be used for the solution of ophthalmology, can be made into the isosmotic solution of 0.01%-10% (volume %) in conjunction with the salt that is fit to, and its pH is about 5-7.
E. the compositions of other route of administration
[0131] other method of application, for example transdermal patch (transdermal patches) comprises that ionotherapy and electrophoretic apparatus and rectal administration also are taken into account at this.
[0132] percutaneous ointment comprises that ionotherapy and electrophoretic apparatus are well known to those of ordinary skill in the art.For example, such paster (patches) is disclosed in United States Patent (USP) 6,267, in 98,6,261,595,6,256,533,6,167,301,6,024,975,6,010,715,5,985,317,5,983,134,5,948,433 and 5,860,957.
[0133] for example, the drug dose mode of rectal administration is the rectal suppository that acts on whole body, capsule and tablet.Refer to the solids of putting into rectum at this used rectal suppository, this solids melts under body temperature or is softening, discharges one or more pharmacology or therapeutic activity component.The employed materia medica of rectal suppository can be accepted material for improving substrate (base) or the media and the medium of fusing point.The example of substrate comprises cupu oil (cupu oil), glycerol-gelatin, the suitable mixture of monoglyceride, double glyceride and the triglyceride of Polyethylene Glycol (Polyethylene Glycol) and fatty acid.Can use the compositions of various different substrates.The medium that can improve the suppository fusing point comprises spermaceti and wax.Can pass through compression method or molding, the preparation rectal suppository.The weight of rectal suppository is approximately 2-3gm (mg) in one embodiment.
[0134] use same materia medica can accept material, and the same method manufacturing of utilization and peroral dosage form is used for the tablet and the capsule of rectal administration.
F. target dosage form
[0135] at the chemical compound that this provided, or its pharmacology can accept derivant and also can be prepared to, being target by other position of particular tissues, receptor or health of treatment main body.Many such target methods are well known to those of ordinary skill in the art.All such target methods are taken into account at this, are used for this compositions.The limiting examples of relevant target method sees also United States Patent (USP) 6,316, and 652,6,274,552,6,271,359,6,253,872,6,139,865,6,131,570,6,120,751,6,071,495,6,060,082,6,048,736,6,039,975,6,004,534,5,985,307,5,972,366,5,900,252,5,840,674,5,759,542 and 5,709,874.
[0136] in one embodiment, the liposome suspension comprises the liposome of target tissue, and for example the liposome of target tumor also is suitable as pharmacological-acceptable carrier.These carriers can prepare according to the known method of those of ordinary skills.For example, the liposome dosage form can be by United States Patent (USP) 4,522,811 described preparations.Briefly, (MLV ' s) such liposome can be by forming at dry egg lecithin of flask interior and brain Phosphatidylserine (mol ratio is 7: 3) such as the multi-disc medium.Add the solution that said chemical compound forms in the phosphate buffered saline (PBS) (PBS) of no bivalent cation, rock flask and only be broken up into up to liquid film.Wash formed media, to remove unencapsulated chemical compound, be centrifuged into ball, and then be suspended among the PBS.
G. therapeutic alliance
[0137] in another embodiment, chemical compound can be by co-administered or use in proper order with another kind of therapeutic agent.These therapeutic agents comprise those known therapeutic agents that is used for the treatment of, prevents and improve amyloidosis and neurodegenerative disease and obstacle symptom.Such therapeutic agent comprises, but be not limited to donepezil hydrochloride (donepezil hydrochloride) (Aracept), tartaric acid Rivastigmine (rivastigmine tartrate) (Exelon), (romotal) tacrinehydrochloride (Cognex) and galanthamine hydrobromide (galantamine hydrobromide) are (Reminyl).
VI. test kit
[0138] according to a further aspect in the invention, provide test kit.According to the present invention, this test kit comprises the packing that contains chemical compound of the present invention or compositions.
[0139] phrase " packing " refers to any container that contains chemical compound described herein or compositions.In preferred embodiments, packing can be box or packaging material (wrapping).The packing material that is used for the packaged pharmaceuticals goods is well known to those of ordinary skill in the art, for example, sees also United States Patent (USP) 5,323,907,5,052,558 and 5,033,252.The drug packages examples of materials includes, but not limited to blister bag (blister pack), bottle, pipe, inhaler, pump, bag, bottle, container, syringe, any packaging material of bottle and suitable selected dosage form and expection dosing mode and treatment.
[0140] test kit also contains and is not contained within the packing, but is attached to the article of packing outside, for example pipet.
[0141] test kit can randomly comprise operation instruction, is used for chemical compound of the present invention or compositions be administered to suffering from the main body that needs the treatment situation.Test kit also can comprise the chemical compound operation instruction of using through administrative organization's approval, for example U.S. food and FAD.Test kit also can be chosen label or the product insert (product inserts) that contains The compounds of this invention wantonly.Packing and/or any product insert can be approved through administrative organization itself.Test kit can be included in the packing chemical compound that exists with solid phase or liquid phase (for example buffer that this was provided).Test kit also can comprise the buffer that is used for the used solution of preparation manipulation method and liquid is transferred to pipet another container from a kind of container.
[0142] test kit also can randomly contain one or more chemical compounds that are useful on therapeutic alliance described herein.In certain embodiments, packing is the container that is used for the intravenous dispensing.In other embodiment, chemical compound provides in inhaler.In other embodiment, chemical compound is to provide with polymeric matrix or with the liposome form.
VII. assessing compound is regulated the activity of A β level
[0143] chemical compound described herein comprises the chemical compound of regulating A β level.Can utilize a lot of assay methods known in the art and/or described herein to come assessing compound to regulate the activity of A β level.Usually, the source of APP or its fragment and/or A β contacts reasonable time with chemical compound, and A β level estimated directly or indirectly, and is as described below.To in the A β of A β level in the presence of the chemical compound and appropriate control thing level (for example media tester (vehicle control) or positive control (positive control)) relatively measure chemical compound and whether regulate A β level.
A.APP, amyloid precursor fragment and/or A β source
[0144] being used for assessing compound regulates the APP of A 'beta ' activity, amyloid precursor fragment and/or A β source and depends on detected product and the character that will measure.For example, assessing compound to regulate the activity of APP or the segmental gamma-secretase cutting of amyloid precursor, can use APP C-terminal fragment, for example C99 corresponding to the beta-secretase cleaved products.When any and all APP generation stage assessing compounds, the APP of preferred complete length.
[0145] is used for the active proper A PP of assessing compound, amyloid precursor fragment and/or A β source and (for example comprises the live test animal, natural and transgenic animal), and tissue (for example brain), tissue extract, body fluid (for example, blood, blood plasma, cerebrospinal fluid, urine etc.) with from the primary cell of human and experimental animal.Other source comprises the outer medium of recombinant cell lines, cellular lysate (complete cell extract, membrane-bound fragment etc.) and born of the same parents.On some is used, can be used alternatingly the APP or the A β of basic purification.Chorista, produce and keep former generation and reconstitution cell, preparation lysate, and the method for the protein purification compatible with the A beta determination all is methods known in the art.
[0146] is of the influence of direct or indirect assessing compound, uses and contain APP or its amyloid precursor fragment, and have the ability that it is separated albumen and process in the organism that produces A β and the organism external source the generation of A β peptide, secretion and/or degraded.For assessing compound to the A beta form (for example, monomer, oligomeric or fibril form or structure), the influence of fibril deposition and fibril degraded, use and contain the A beta monomers, interior or the organism external source of oligomer or fibriilar organism, generation APP or the segmental cell of amyloid precursor randomly can be contained in this source.
B. transgenic animal
[0147] can express any required wild type and saltant APP, amyloid precursor fragment or A β isotype to the active useful transgenic animal of assessing compound, as described herein.The animal that is produced can be advantageously as model, the especially Alzheimer of human diseases and other neural degeneration and with the model of amyloidosis diseases associated.Transgenic animal include, but are not limited to rodent, comprise mice, rat and hamster, sheep, goat, chicken, pig, cattle, monkey, primates and other non-human mammal.
[0148] randomly, animal further known one or more of external source ground expression participates in the gene of APP processing or degradation pathway, for example wild type and saltant presenilin genes (presenilin) (PS-1 or PS-2), BACE, IDE and/or enkephalinase (neprilysin), and/or one or more relate to pathogenetic other gene, for example tau gene.
[0149] can be in a organized way in institute, or only in selected tissue (for example system organization), in any or all developmental stage, and the physiology, super-or inferior-physiology's level, come expression alien gene by suitably selecting to regulate element (regulatory elements).Transgenic animal further can be that exogenous gene is pure and mild, hemizygous, heterozygosis or chimeric.Transgenic animal can contain exogenous gene and endogenous homologue (endogenous counterpart), or are replaced by endogenous homologue (for example by " hammering into (knock in) " method).Standardization test handbook has been described the method that produces transgenic animal, for example, comprises Hogan et al., (1994), Manipulating the Mouse Embryo:A Laboratory Manual, 2nd ed., ColdSpring Harbor Laboratory, New York.
[0150] transgenic animal of expression AAP are known in the art, comprise the Tg2576 mice, this muroid contains Sweden (Lys670Asn, Met671Leu) the human APP695 of two sudden changes (Hsiao et al. (1996) the Science 274:99-102 under the control of hamster prion protein promotor gene; U.S.Patent No.5,877,399); V717F PDAPP mice, this muroid contain human APP695 (Val717Phe) (Games et al. (1995) the Nature 373:523-527 under the control of platelet derived growth factor (PDGF) chain gene promoter; U.S.Patent No.5,811,633); With the C100 mice, this muroid contains terminal 100 aminoacid (Neve et al. (1996) the Neurobiol.Aging 17:191-203 of neurotoxicity C-of the APP under dystrophin nervous system promoter (dystrophin neural promoter) control; U.S.Patent Nos.5,672,805).Other transgenic animal of expressing APP are described for example at United States Patent (USP) 5,612, and 486,5,850,003,5,387,742,6,037,521,6,184,435,6,187,992,6,211,428 and 6,340, described in 783; Emilien, et al., (2000) Arch.Neuro.57:176-181 summarizes it.
C. cell
[0151] is used for the active cell of assessing compound and can expresses interior giving birth to or any required wild type of reorganization or suddenly change APP and/or A β isotype, as described here.Cell can be from any animal primary cell or cell line (cell lines), this animal comprises human and other mammal, for example above-mentioned transgenic animal.Cell can be any different lineage, it for example neurally is (cortex neural maincenter cell for example, Microglial (microglia), neuroglia, astrocyte), fibroblast, lymphocyte and epithelial cell, perhaps can be all can or pluripotent cell (see also Freshney, R.I. (2000) " Culture of AnimalCells:A Manual of Basic Technique; " 4th ed., Wiley-Liss).A kind of active example cell that is suitable for estimating the chemical compound of regulating A β is SH-SY5Y-APP751, and embodiment has herein partly described this cell line.Further exemplary cells is HGB, gives birth to APP (endogenous APP) in it is expressed.
[0152] the exemplary primary cell that is suitable for estimating the compound activity of regulating A β is the mixing brain incubation thing (mixed brain cultures) from the Tg2576 transgenic mice, and perhaps other expresses the transgenic animal of APP.For example,, separate cerebral tissue, then by former generation neuron incubation standardization program incubation cell, with preparation mixing brain incubation thing with papain by dissecting cerebral tissue from about 17 days mice embryos.
[0153] maybe can induce under the control of adjusting element in suitable formation, APP, amyloid precursor fragment or coding A β nucleic acid can be by various well-known transfection methods by instantaneous or stably import primary cell or cell line (Sambrook and Russell (2000) " MolecularCloning:A Laboratory Manual " Cold Spring Harbor Laboratory Press; Ausubel et al. (eds.) (current edition) " Current Protocols in MolecularBiology " John Wiley ﹠amp; Sons.).
D. directly estimate the mensuration of A β level
[0154] can utilize the mensuration of direct evaluation A β level to come assessing compound to regulate the ability of A β.Therefore, can be by measuring the quantity of concrete A β peptide (A β 43, A β 42, A β 40, A β 39, A β 38, A β 37, A β 34,11-43,11-42,11-40,11-39,11-38,11-37,11-34 etc.); By measuring the quantity of all A β; By measuring the quantity (for example ratio of A β 42 and A β 40) of concrete A β peptide with respect to second kind of A β peptide; A β by measuring particular form (monomer for example, oligomer or fibril form; In solution or accumulate on the speckle, medium at special tectonic) quantity or relative populations, and/or A β by measuring ad-hoc location is (for example in the born of the same parents, film relevant or born of the same parents are outer, or in special organization or body fluid) quantity or relative populations, come assessing compound to regulate the ability of A β.
[0155] a lot of methods known in the art can be used for specific A β kind or form in the ground measuring samples, or the quantity or the relative populations of total A β peptide.In these methods, mark and/or measure the level of the next quantitative A β of calibration curve that produces in optional can the use by the standard of utilizing dose known amounts.
[0156] for example, can utilize the immunologic detection method that adopts A β-specific antibodies (for example monoclonal or polyclonal antibody, single-chain antibody, chimeric antibody, bifunctional antibody, humanized antibodies, CDR-grafted antibody, the optional support of CDR-grafting (alternative scaffolds), with and Fab).Such antibody may optionally be specific to concrete A β kind or form.For example, at the N-of A β end, the C-end, or the antigen at conjugated antigen decision position (epitope) can be used for detecting simultaneously the multiple isotype of A β on the center or near it.Exemplary antigen includes, but not limited to 6E10, B436, the antibody of opposing A β 12-28,21F12, A387, Clone GB-10 and A β-40 antibodies selective.And the antibody of any required epitope of any A β kind can prepare with the described well-known method in this area easily.
[0157] antibody or bonding agent (binding agent) randomly can be detected ground mark, and perhaps, if use second kind of antibody or bonding agent, second antibody or bonding agent can be detected ground mark.Exemplary detectable label comprises radioactive, fluorescence, noctilcent, chemiluminescent label.Detect the method for this class label, and the method for or qualitative determination binding peptide quantitative based on such detection is well known in the art.
[0158] the suitable immunologic detection method of measuring A β level is the method that those of ordinary skills know.Typical method comprises, but be not limited to, immunoprecipitation is (optional in conjunction with electrophoretic separation, or degeneration or native gel, or mass spectral analysis), western hybrid method (westernhybridization), immunocytochemistry, based on the method for fluorescence resonance energy transmission (FRET), and various forms of enzyme-linked immunosorbent assay (ELISA).For measuring any type of A β (for example no matter A β is a monomer, oligomeric or fibril form, and the structure of A β), can use non-degeneration isolating environment (for example non-degeneration electrophoresis or chromatography).For the level of measuring concrete A β kind, can carry out the electrophoresis method (urea-bis-bicine-SDS based electrophoresis) of carbamide-two-two (ethoxy) glycine SDS base, this electrophoresis method can be used for A β 37, A β 38, A β 39, A β 40, Ars2-42 and A β-42 kind of (Wiltfang et al., (2001) J.Biol.Chem., 276:42645-42657).
[0159] can easily be suitable for being used in combination with the non-antibody base medium that combines A β such as immunologic detection method recited above, these non-antibody base media are A β-conjugated protein, its segment for example, and micromolecular compound.Protein and chemical compound in conjunction with A β are known in the art, perhaps can be discerned by the Screening test of routine.
[0160] can use any mensuration to be deposited on the method for A β quantity in the live organism tissue, comprise formation method (imaging methods), for example multiphoton microscope method and positron scattering x-ray tomography art.For example, preparation is striden across blood-brain barrier, and highly affine in conjunction with the amyloid beta deposition thing, preparation is thio-flavin-T analog 2-[4 '-(methylamino) phenyl for example] benzothiazole (Mathis et al. (2002) Bioorg.Med.Chef.Lett.12:295-298) and the deutero-methoxyl group-X04 of Congo red (Klunk et al. (2002) J; Neuropathol.Exp.Neurol.61:797-805).
E. the mensuration of Indirect evaluation A β level
[0161] in addition, can utilize the mensuration of Indirect evaluation A β level to come assessing compound to regulate the ability of A β.Those of ordinary skills can determine suitable assay method to estimate the adjusting of A β level.For example, the quantity that APP is not cut in assessment, or the quantity of the APP elaboration products of non-A β.
[0162] therefore, chemical compound be can assess and quantity or the relative populations of APP regulated, and/or the quantity or the relative populations of the cleaved products of alpha-secretase enzyme (for example sAPP α or C83), and/or alpha-secretase enzyme and gamma-secretase (for example p3) are united the quantity or the relative populations of the product of cutting, and/or beta-secretase (sAPP β, C99, or C89) quantity or the relative populations of cleaved products.The method that the method for the quantity of measurement APP or APP elaboration products is known in the art comprises and utilizes suitable antibody, to the similar immune detecting measuring of said determination A β.
[0163] provides the following example, further illustrate embodiment of the present invention.These embodiment are also non-limiting, and should not be interpreted as limiting any aspect of the present invention.
Embodiment
[0164] unless otherwise indicated, all solvents and reagent all from Aldrich ChemicalCompany (Milwaukee, WI).
[0165] uses
1HNMR spectrophotometer architectural feature.Use residual
1Interior mark is done at the H solvent peak, at deuterated chloroform (CDCl
3) or water (D
2O) in, proton magnetic resonance (PMR) (
1HNMR) spectrum is recorded on the Varian 300MHz NMR spectrometer.
[0166] the correct quality and the purity of use Applied Biosystems AP150X mass spectrograph and Shimadzu HPLC systematic analysis purifying compounds.Typical case's gradient (gradient) is for using the mobile phase of the acetonitrile/water 1-99% more than 4 minutes, and the trifluoroacetic acid of 0.035-0.050% is added into mobile phase.Gradient is moved under the speed of 7ml/min, passes through Chromalith
TMSpeedRodRP-18e, 4.6 * 50mm chromatographic column.By observing (M+H
+) ion (M+1), confirm the structure of chemical compound.Wavelength place at 220nm and 254nm absorbs by ultraviolet, with the purity of assessing compound.Purity percentage ratio is based on the integration of peak area on the chromatograph.
Embodiment 1
The preparation of typical α-bromoketone derivant
[0167] by with typical thiourea condensation, prepare typical α-bromoketone derivant.Following description is the illustrative methods that is used for synthetic typical α-bromoketone derivant.
A.2-bromo-1-[4-(4-methyl-imidazoles-1-yl)-phenyl]-ethyl ketone (ethanone) (10)
[0168] in the round flask of a 100ml, with 4-acetylbenzene ylboronic acid (820mg, 5mmol, 2.0eq) and 4-methyl isophthalic acid H-imidazoles (205mg, 2.5mmol 1.0eq) are dissolved in the DMF/CH of 22ml
2Cl
2In the solution (1: 10).Add in this reactant mixture then Glacial acetic acid copper (681mg, 3.75mmol, 1.5eq), 4 molecular sieves (sieves) (1.875g) and pyridine (pyridine) (0.4ml, 5mmol, 2.0eq).At room temperature (air, room temp) in the air, stirring reaction 16 hours, LC-MS judges that reaction finishes this moment.Filter this product by Celite, use methanol wash, utilize silica gel chromatography (ISCO system, 0-5% methanol/ethyl acetate) purification, thereby produce chemical compound 9 (200mg, yield are 40%).
[0169] (200mg 1mmol) is dissolved in acetic acid (2mL) solution that is calculated by weight to 30% hydrogen bromide with chemical compound 9.In this solution, dropwise add bromine (160mg, 1mmol).Reaction was at room temperature stirred 2 hours.Reactant mixture be introduced in the frozen water (～5g).Required product is precipitated to get off.Filter solid sediment, with the frozen water washing, by the vacuum pump drying, produce a kind of xanchromatic solid product 10 (120mg, HOAc salt) then, this product does not need purification can continue subsequently step.
B.2-bromo-1-[4-(4-methyl-imidazoles-1-yl)-phenyl]-third-1-ketone (40)
[0170] will be dissolved in 4-methyl-imidazoles among the DMSO (1.72g, 21mmol, 1.05eq) and 1-(4-fluoro-phenyl)-third-1-ketone (3.04g, 20mmol, solution 1.0eq) and Anhydrous potassium carbonate (K
2CO
3) (5.52g, 40mmol is 2.0eq) in 90 ℃ of following stirred overnight (overnight).This moment, LC-MS judges that reaction finishes.After the cooling, reactant mixture is poured in the frozen water (～50g).Required product is precipitated to get off, filtering precipitate, and use cold water washing, and carry out drying by vacuum pump then, produce a kind of yellow solid product 11 (2.14g, yield 50%).Adopt to above-mentioned similar mode chemical compound 11 is carried out the bromination processing and generates chemical compound 12.
[0171] similar to above-mentioned steps, 1-(3,4-two fluoro-phenyl)-third-1-ketone and 4-methyl-imidazoles reacting generating compound 13.Adopt aforesaid mode that chemical compound 13 is carried out bromination and handle to generate { 4-[3-fluoro-4-(4-methyl-imidazoles-1-yl)-phenyl]-thiazol-2-yl }-(5-isopropyl-4-methoxyl group-2-methyl-phenyl)-amine (14).
C.2-bromo-1-[4-(4-ethyl-imidazo-5-yl-)-phenyl]-ethyl ketone (16)
1.5-ethyl-4-tosyl-2-azoles quinoline (15)
[0172] with fine-powdered Cyanogran. (NaCN) (0.098g, 2mmol) add the tosyl methyl isocyanate (TosMIC, 3.90g, 20mmol) and propionic aldehyde (1.5mL 20.4mmol) in the stirred suspension of the dried ethanol of 60mL (EtOH).Reactant mixture becomes limpid, and the white crystals of azoles quinoline began to be precipitated out in 15 minutes.Continued stirring reaction 30 minutes.Filtering mixt washed with ether-hexane (1: 1) before drying.Obtain yield and be 81% chemical compound 15 (4.1g).Utilize
1H NMR is at CDCl
3In, confirm structure.LC-MS：[M+1]＝254。Purity is greater than 98%.
2.4-ethyl imidazol(e) (16)
[0173] in a pressure bottle, (1.1g, 4.3mmol) the dried methanol (MeOH) that is dissolved in saturated ammonia is (30mL) in the solution with chemical compound 15.Between 100-110 ℃, reactant mixture was stirred 18 hours.With solvent evaporation,, utilize CH by flash chromatography (flash chromatography) purified product
2Cl
2-MeOH eluting.Chemical compound 16 is separated, its be light yellow oily (yield 72%, 0.3g).At CDCl
3The middle utilization
1H NMR confirms the structure of chemical compound, adopts TLC at CH
2Cl
2Purification among the-MeOH (9: 1).Purity is greater than 95%.
(3.1-[4-4-ethyl imidazol(e)-1-yl)-phenyl]-ethyl ketone (17)
[0174] (0.068g is in 60% oil dispersion, and (0.180g in DMF 1.8mmol) (6mL) solution, at room temperature stirs 1.7mmol) to add chemical compound 16 with NaH.Mixture is stirred 15 minutes, adding 4 '-acetyl fluoride ketone (0.215g, DMF 1.56mmol) (2mL) solution.At 80 ℃ reactant mixture was heated 1 hour, cooling then, dilute with water then extracts with EtOAc.With salt water washing organic layer, drying, and evaporation obtains a kind of yellow solid.The at room temperature very fast crystallization of chemical compound 17 forms white needle-like crystals.Yield is 0.270g, 67%.At CDCl
3The middle utilization
1HNMR confirms the structure of chemical compound 17.LC-MS：[M+1]＝215。Purity is greater than 98%.
4.2-bromo-1-[4-(4-ethyl-imidazo-5-yl-)-phenyl]-ethyl ketone (18)
[0175] with ketone 17 (0.160g 0.66mmol) is dissolved in 30% acetic acid/hydrogen bromide (5mL), add then bromine (0.104g, 0.66mmol).Reactant mixture was at room temperature stirred 1 hour, pour into then (10mL) in the cold water.With ethyl acetate (20mL) extraction product.Water and the bonded organic layer of salt water washing, drying, evaporation produces a kind of yellow solid, and from ethyl acetate: crystallize out the chemical compound 18 that produces 0.170g (77%) the hexane (1: 1).At CDCl
3The middle utilization
1H NMR confirms the structure of chemical compound 18.LC-MS：[M+1]＝294。Purity is greater than 95%.
D.2-bromo-1-[6-(4-methyl-imidazoles-1-yl)-pyridin-3-yl]-ethyl ketone (20)
(1.1-[6-4-methyl-imidazoles-1-yl)-pyridin-3-yl]-ethyl ketone (19)
[0176] with 1-(6-chloro-pyridin-3-yl)-ethyl ketone (7.00g, 45.16mmol) and 4-methylimidazole (11.11g 135.50mmol) mixes in DMSO (35ml), adds K then
2CO
3Mixture is heated 22 hours under 110 ℃, and stirs fast.With the reactant mixture cool to room temperature, be poured into (400ml) in the frozen water then, and vigorous stirring 15 minutes.The precipitate that produces is collected on the filter, and the water thorough washing.The material that is generated is dried under vacuum, produces a kind of dark brown solid 19 (6.1g, 67%).LC/MS：[M+1]
+＝202.2.C
11H
11N
3O＝201.2。
1H?NMR(DMSO-d6)300MHzδ2.18(3H，s)，2.63(3H，s)，7.72(1H，s)，7.87(2H，d，J＝9.0Hz)，8.41(2H，d，J＝9.0Hz)，8.51(1H，s)，8.98(1H，s)。
2.2-bromo-1-[6-(4-methyl-imidazoles-1-yl)-pyridin-3-yl]-ethyl ketone (20)
[0177] chemical compound 19 is suspended among the 30%HBr/AcOH (75ml).In greater than 1 hour time, dropwise add bromine (4.82g, 30.30mmol).At room temperature, reaction is stirred 2 hours.Reactant mixture is poured in the frozen water of 600mL and fast and stirred 15 minutes.The precipitate that is generated is collected on the filter and washes with water.Air-dry chemical compound, producing a kind of is yellow solid 20 (10.6g, 80%).LC/MS：[M+1]
+＝281.1.C
11H
10BrN
3O：2HBr＝442.0。
1H NMR (DMSO-d6) 300MHz δ 2.36 and 2.37 (6H, two s), 5.06 (2H, s), 8.16 (1H, d, J=9.0Hz), 8.29 (1H, s), 8.69 (1H, d, J=9.0Hz), 9.15 (1H, s), 9.93 (1H, s).
E.1-[4-(5-bromo-thiazol-2-yl)-phenyl]-ethyl ketone (1221) and 2-bromo-l-[4-(5-bromo-thiazol-2-yl)-phenyl]-ethyl ketone (1222)
(1.1-[4-5-bromo-thiazol-2-yl)-phenyl]-ethyl ketone (1221)
[0178] with the 2-bromo thiazole (1g 6.1mmol) puts into flask, add toluene: EtOH (4: 1,80mL: 20mL), add then 4-acetylbenzene ylboronic acid (1.2g, 7.32mmol), sodium carbonate (2.16g, 20.4mmol) and water (3mL).Fed bubbling nitrogen 30 minutes, and made the reactant mixture degassing.Add Pd (PPh subsequently
3)
4, and under 80 ℃, reactant mixture was heated 17 hours, then reactant mixture is cooled to room temperature.Add EtOAc (3 * 100mL) and water (100mL).Water (100mL), saline (100mL) washing organic extract, and pass through MgSO
4Drying is filtered, and utilizes column chromatography (120g ISCO cylinder) purification.Chemical compound 1219 is separated, and is a kind of white powder (974mg, 79%, C
11H
9NOS Mass Calculation value: 203.3, observation: 204.2[M+1]).(160mg, 1mmol) before, (204mg 1mmol) is dissolved in the acetic acid (3mL) of 30%HBr with chemical compound 1219 earlier dropwise adding bromine.Reactant mixture at room temperature is stirred 6 hours, is introduced into then in the frozen water, stirred 10 minutes, and filtering precipitate.Chemical compound 1221 is separated, and is a kind of yellow powder (257mg, 92%, C
11H
8BrNOS Mass Calculation value: 281.2, observation: 282.1[M+1]).
2.2-bromo-1-[4-(5-bromo-thiazol-2-yl)-phenyl]-ethyl ketone (1222)
[0179] utilize and top described identical step, with 2, (809mg is 4.94mmol) for beginning to prepare chemical compound 1220 for 5-two bromo thiazoles.1-[4-(5-bromo-thiazol-2-yl)-phenyl]-ethyl ketone 1220 is separated, and is a kind of dark yellow powder (500mg, 43%, C
11H
8BrNOS Mass Calculation value: 283.2, observation: 284.1[M+1]).2-bromo-1-[4-(5-bromo-thiazol-2-yl)-phenyl]-ethyl ketone 1222 is separated, and is dark yellow powder (436mg, 77%, C
11H
7BrNOS Mass Calculation value: 360.1, observation: 361.6[M+1]).
[0180] (α-bromoketone) derivant is the exemplary illustration of the bromoketone chemical compound of all preparations to list in α-bromoketone in the table 1 below.
Table 1
Embodiment 2
The preparation of thiourea derivative
[0181] combines the preparation thiourea derivative with the aryl isothiocyanate derivatives by anil.Most of aniline compounds all are that commerce can get, and/or synthesize with well-known method.
[0182] a kind of exemplary aniline, 5-(N, N dimethylamine)-2-methyl-aniline prepares according to following typical itineraries.This process also is used for synthetic other 5-(N, N dimethylamine)-2-methyl-aniline analog.
[0183] in a 350mL vial (glass bomb), with 4-methyl-3-nitro aniline (25.0g, 164.5mmol) and bromoethane (44.8g 411.2mmol) is dissolved among the DMF, with the preparation chemical compound 29, diethyl-(4-methyl-3-nitro benzene)-amine.Add a big stirring rod and K
2CO
3(56.75g, 411.2mmol).Tightly cover bottle (bomb) and place in 80 ℃ the oil bath.Then with reactant mixture vigorous stirring 40 hours.Follow reaction mixture and uncap, material is separated out between EtOAc (400mL) and water (300mL).Water layer mixes EtOAc layer water (500mL) washed twice with EtOAc (150mL) washed twice, with saline (500mL) washing once.Then the EtOAc layer is passed through MgSO
4Carry out drying, filter and be condensed into a kind of black liquor.Carry out silica gel chromatography, purified product with the 5%EtOAc/ hexane.Concentrate pure fraction, produce a kind of orange liquid compound 29 (20.8g, 61%).LC/MS：[M+H]
+＝209.1.C
11H
16N
2O
2＝208.2。
1H?NMR(CDCl
3)300MHzδ1.16(t，6H，J＝6.9Hz)，2.44(s，3H)，3.35(q，4H，J＝6.9Hz)，6.76(2d，1H，J＝3.0Hz)，7.09(2d，1H，J＝0.6Hz)，7.25(d，1H，J＝3.0Hz)。
[0184] (20.8g 100.0mmol) is dissolved in MeOH: CH with chemical compound 29
2Cl
2In, and in ice bath, be cooled to 0 ℃.In greater than 90 minutes time, 1 part of ground of 1 gram adds NiCl
2-6H
2O (4.0g, 16.8mmol) and NaBH
4(11.0g, 297.3mmol).TLC confirms that reaction finishes.Decompression removes down and desolvates, and with the material resuspending in CH
2Cl
2(500mL) and silica gel in.Under reduced pressure remove then and desolvate till material presents loose Lycoperdon polymorphum Vitt powder.Powder is placed in the funnel, and with EtOAc (500mL) thorough washing.Formed solution is condensed to a kind of yellow liquid, uses 30%EtOAc/ hexane eluting in silicagel column, this yellow liquid of purification.Under reduced pressure, pure fraction is mixed and concentrate and form a kind of lilac liquefied compound 30 (15.3g, 85%).LC/MS：[M+H]
+＝179.2。C
11H
168N
2＝178.2。
1H?NMR(CDCl
3)300MHzδ1.13(t，6H，J＝6.9Hz)，2.04(s，3H)，3.27(q，4H，J＝6.9Hz)，3.51(broad?s，2H)，6.05(d，1H，J＝2.4Hz)，6.11(two?d，1H，J＝2.4Hz)，6.86(d，1H，J＝8.1Hz)。
[0185] by with typical α-bromoketone derivant condensation, prepare following typical thiourea derivative.The following example process that is used for preparing thiourea derivative of classifying as.
A.2-methyl-5-pyrroles-1-base-phenyl-thiourea (32)
[0186] (6.4mmol 1.04g) puts into 10ml dry acetone (acetone), under agitation adds 2-methyl-5-pyrroles-1-base-aniline apace with the isothiocyanic acid benzoyl ester.Reaction is stirred 2 hours under 40 ℃, is introduced in the excessive trash ice then and vigorous stirring.Collect formed solid, fully use the cold water eluting, use hexane wash subsequently, air-dry then.Product 31 (yield 90%) is directly used in following step without being further purified.
[0187] in 10% the NaOH aqueous solution that a chemical compound 31 is added (～80 ℃) of preheatings stir.After stirring whole night, mixture is poured on ice excessive.With concentrated hydrochloric acid pH value is adjusted into 5-6.Collect the coprecipitate of formed benzoic acid and required product 32, and use cold water washing, use hexane wash then, to remove benzoic acid.Product (yield 80%) is entered subsequent reaction by air-dry without being further purified.
B.4-hydroxyl-2,5-dimethyl-phenyl-thiourea (34)
[0188] (33mmol 5.38g) puts into the 30ml dry acetone, under agitation adds aniline apace with the isothiocyanic acid benzoyl ester.Reaction is stirred 2 hours under 40 ℃, is introduced in the excessive trash ice then and vigorous stirring.Collect formed solid, fully use the cold water eluting, use hexane wash subsequently, air-dry then.Product 33 (yield is greater than 80%) is directly used in following step without being further purified.
[0189] in the 10%NaOH aqueous solution that (～80 ℃) that a chemical compound 33 is added preheating stir.After stirring whole night, mixture is poured on ice excessive.With concentrated hydrochloric acid pH value is adjusted into 5-6.Collect the coprecipitate of formed benzoic acid and required product 34, and use cold water washing, use hexane wash then, to remove benzoic acid.Product (～80% yield) is entered subsequent reaction by air-dry without being further purified.
C. (4-ethyoxyl-2,5-dimethyl-phenyl)-thiourea (39)
1.4-hydroxyl-2,5-dimethyl-phenyl-t-butyl carbamate (35)
[0190] respectively with Boc anhydride (Bis(tert-butoxycarbonyl)oxide) (22mmol, 4.8g) and TEA (30mmol 4.17mL) adds 4-amino-2, and (20mmol is in 40ml THF solution 2.74g) for 5-dimethyl-phenol.At room temperature after the stirred overnight, concentrated reaction mixture is removed THF, and with in residue water-soluble once more (50mL) and the ethyl acetate (80mL).With ethyl acetate (3 * 50mL) aqueous layer extracted.Blended organic layer is carried out drying by sodium sulfate.Except that after desolvating,, produce title compound 35 (90% yield) with flash chromatography (ISCO system, 5-40% ethyl acetate/hexane) purifying crude product.
2. (4-ethyoxyl-2,5-dimethyl-phenyl)-t-butyl carbamate (36)
[0191] with potassium carbonate (K
2CO
3, 8mmol, 1.1g) and bromoethane (4.8mmol, (4mmol is in 5ml DMF solution 948g) 523mg) to add chemical compound 35.At 60 ℃, after the stirred overnight, add entry (2mL) and dissolve unreacted potassium carbonate, use ethyl acetate (3 * 10mL) extractive reaction mixture then.Mix organic layer and carry out drying by sodium sulfate.Except that after desolvating,, produce title compound 36 (90% yield) with flash chromatography (0-30% ethyl acetate/hexane) purifying crude product.
3.4-ethyoxyl-2,5-dimethyl-aniline (37)
[0192] (950mg is in 10ml dichloromethane solution 3.6mmol) trifluoroacetic acid (5mL) to be added chemical compound 36.Reactant mixture is stirred 2 hours.At this moment, LC-MS shows that reaction finishes.The inspissation reaction flask desolvates and most of TFA to remove.Residue then more than 24 hours, is produced the title compound 37 as tfa salt by further drying in high vacuum furnace.
[0193] uses the synthetic method of preparation chemical compound 33 recited above and 34, synthetic compound 38 and 39.
D.N, N-ethyl-2,5-dimethyl-benzene-1,4-diamidogen-thiourea (44)
1. (4-amino-2,5-dimethyl-phenyl)-t-butyl carbamate (40)
[0194] respectively with boc anhydride (Boc
2O) (33mmol, 7.2g) and TEA (45mmol 6.26mL) adds 2,5-dimethyl-benzene-1, (30mmol is in 40ml THF solution 4.1g) for the 4-diamidogen.At room temperature after the stirred overnight, concentrated reaction mixture to be removing THF, and with residue in the water-soluble once more and ethyl acetate.With ethyl acetate (3 * 80mL) aqueous layer extracted.Organic layer is mixed and carry out drying by sodium sulfate.Except that after desolvating,, produce title compound 40 (greater than 90% yield) with flash chromatography (5-50% ethyl acetate/hexane) purifying crude product.
2. (4-diethylamine-2,5-dimethyl-phenyl)-t-butyl carbamate (41)
[0195] with potassium carbonate (K
2CO
3, 15mmol, 2.07g) and bromoethane ((5mmol is in 3mL DMF solution 1.18g) 0.93mL) to add chemical compound 40 for 12.5mmol, 1.36g.Reaction is stirred whole night under 70 ℃.Add entry (3mL) and dissolve unreacted potassium carbonate, with ethyl acetate (3 * 10mL) extractive reaction mixture.Mix organic layer and carry out drying by sodium sulfate.Except that after desolvating,, produce title compound 41 (75% yield) with flash chromatography (0-30% ethyl acetate/hexane) purifying crude product.
3.N, N-diethyl-2,5-dimethyl-benzene-1,4-diamidogen (42)
[0196] in the 2ml dichloromethane solution with trifluoroacetic acid (1mL) adding 41.Reactant mixture is stirred 2 hours.At this moment, LC-MS shows that reaction finishes.Concentration response desolvates and most of TFA to remove.Residue then more than 24 hours, is produced the title compound 42 as tfa salt (100% yield) by further drying in high vacuum furnace.
[0197] uses and above-mentioned preparation chemical compound 33 synthetic method similar, come synthetic compound 43 and 44 from 42 with 34.
E.N, N-diethyl-4,6-dimethyl-benzene-1,3-diamidogen-thiourea (49)
1. (5-amino-2,4-dimethyl-phenyl)-t-butyl carbamate (45)
[0198] respectively with the boc anhydride (33mmol, 7.2g) and TEA (45mmol 6.26mL) adds 2,6-dimethyl-benzene-1, (30mmol is in 40mL THF solution 4.1g) for the 3-diamidogen.At room temperature after the stirred overnight, concentrated reaction mixture is to remove THF, and residue is dissolved in water and the ethyl acetate once more.With ethyl acetate (3 * 80mL) aqueous layer extracted.Organic layer is mixed, and carries out drying by sodium sulfate.Except that after desolvating,, produce title compound 45 (95% yield) with flash chromatography (5-50% ethyl acetate/hexane) purifying crude product.
2. (5-diethylin-2,4-dimethyl-phenyl)-t-butyl carbamate (46)
[0199] (5mmol adds potassium carbonate (K in 3mL DMF solution 1.18g) at chemical compound 45
2CO
3, 15mmol, 2.07g) and bromoethane (12.5mmol, 1.36g, 0.93mL).Reaction is stirred whole night under 70 ℃.Add entry (3mL) and dissolve unreacted sodium carbonate, then (3 * 10mL) extract with ethyl acetate with reactant mixture.Organic layer is mixed, and carries out drying by sodium sulfate.Except that after desolvating,, produce title compound 46 (80% yield) with flash chromatography (0-30% ethyl acetate/hexane) purifying crude product.
3.N, N-diethyl-4,6-dimethyl-benzene-1,3-diamidogen (47)
[0200] (1.16g adds trifluoroacetic acid (5mL) in 10mL dichloromethane solution 4.0mmol) at chemical compound 46.Reactant mixture is stirred 2 hours.This moment, LC-MS shows that reaction finishes.Reaction is concentrated to remove and desolvates and most of TFA.Residue then more than 24 hours, is produced the title compound 46 (100% yield) as tfa salt by further drying in high vacuum furnace.
[0201] uses and above-mentioned preparation chemical compound 33 and 34 similar synthetic method, from 47 synthetic compounds 48 and 49.
F.2-methyl-5-bromophenyl thiourea (50)
[0202] 2-methyl-5-bromaniline (10.8g, 58.4mmol) and isothiocyanic acid benzoyl ester (9.5g, 58.4mmol) combination in acetone (Acetone), and be heated backflow (reflux) 30 minutes.Reaction is cooled and is introduced in the frozen water of stirring.Mixture is stirred 15 minutes, forms a kind of precipitate then, and this precipitate is filtered, and in vacuo by air-dry 1 hour.The yellow powder that is generated then is suspended in 5% the NaOH aqueous solution, and is stirred 18 hours under 80 ℃.Reaction is cooled, and then is introduced in the frozen water of stirring (400ml).After stirring in frozen water 1 hour, the white solid that is produced is by vacuum filtration, and by dry 1 hour of air vacuum filter (air vaccum filter), produces a kind of white solid mixture 51 (10.1g, 71%).LC/MS：[M-H]
-＝244.1。C
8H
9BrN
2S＝245.1。
1H?NMR(DMSO-d6)300MHzδ2.14(s，3H)，7.17(d，1H，J＝8.4Hz)，7.31(d，1H，J＝7.8Hz)7.45(s，1H)，9.24(broad?s，1H)。
Thiourea (thiourea urea) derivant of listing in [0203] in the table 2 is collected for the example of all thiourea compounds that are produced.
Table 2
Embodiment 3
The condensation of typical case's α-bromoketone and exemplary thiourea
[0204] typical α-bromoketone derivant (0.08mmol; See also " bromoketone (the bromoketone) " row in the following table 3) combine in 1mL DMF solution with 4-diethylamine-2 methyl-phenyl-thiourea 67 (0.08mmol).At 70 ℃, use optional vortex stirring reaction 4-6 hour.After the cool to room temperature, reactant mixture is directly injected reversed-phase HPLC (Gilson 215), at a C
18Use acetonitrile/water/TFA gradient separations title product (title product) in the chromatographic column.Title product is concentrated in a vacuum as a kind of tfa salt.
Table 3
[0205] following { 4-[6-(4-methyl-imidazoles-1-yl)-pyridin-3-yl]-thiazol-2-yl }-(2-methyl-5-pyrroles-1-base-phenyl)-amine and its typical analog are according to being produced to above-mentioned similar step.Usually, 32 of 0.1mmol be dissolved in the 1ml DMF solution with various α-bromoketone derivant (seeing also down tabulation 4 " bromoketone (bromoketone) " is listed as).Be reflected at and be stirred 6 hours under 70 ℃.After the cool to room temperature, in reversed-phase HPLC, use acetonitrile/water/TFA gradient and C
18Immobile phase purification reaction mixture.Product is separated, and concentrates then, produces title mixture (title product), is a kind of tfa salt.
Table 4
[0206] according to method same as described above, prepare various typical N, N-diethyl-2,5-dimethyl-N '-4-[4-(4-methyl-imidazoles-1-yl)-phenyl]-thiazol-2-yl }-benzene-1,4-diamine compound and its exemplary analog.This reacts employed typical bromoketone and lists in down in the tabulation 5 with the synthesising title compound that is produced.
Table 5
[0207] according to method same as described above, prepare various typical N, N-diethyl-4,6-dimethyl-N '-4-[4-(4-methyl-imidazoles-1-yl)-phenyl]-thiazol-2-yl }-benzene-1,3-diamine compound and its exemplary analog.This reacts employed typical bromoketone and lists in down in the tabulation 6 with the synthesising title compound that is produced.
Table 6
[0208] various typical α-bromoketone derivant is to combine with thiourea derivative 34 with above-mentioned similar methods, and exception is that (0.1mmol 37.5mg) is dissolved in the 0.5mLDMF dissolving condensation product subsequently.With sodium carbonate (K
2CO
3, 0.2mmol, 27.6mg) and bromoethane (0.12mmol 13mg) adds in the solution.Reaction at room temperature is stirred whole night.Remove after the unreacted sodium carbonate, utilize reversed-phase HPLC, use acetonitrile/water/TFA gradient and C
18Immobile phase, the purification reaction mixture is to separate and then concentrated title product.This reacts employed typical bromoketone and lists in down in the tabulation 7 with the synthesising title compound that is provided.
Table 7
[0209] utilizes different alkyl bromides, use and top described similar chemical process, synthetic 87 (observation [M+1]=431.4, value of calculation [M+1]=431.6)
[0210] typical thiourea derivative (seeing also " thiourea (thiourea) " row of table 8) and 2-bromo-1-(4-(4-methyl-piperazine-1-yl)-phenyl)-second-1-ketone 88 chemical combination prepare the following aminothiazole analog that typically contains piperazinyl.Use following exemplary route, the cited typical title chemical compound of preparation table 8.
[0211] common, 0.1mmol 2-bromo-1-(4-(4-methyl-piperazine-1-yl)-phenyl)-second-1-ketone is dissolved in the anhydrous N of 1.0mL, in the dinethylformamide (DMF), and add the 0.1mmol thiourea.Mixture under 70 ℃ by whirling motion agitating heating 4 hours.After the cool to room temperature, reactant mixture is directly injected the reversed-phase HPLC chromatographic column, uses 1-99% acetonitrile/water/0.05TFA gradient more than 10 minutes.The required fraction that contains title compound is concentrated through fast vacuum (speedvac).Measure through HPLC, all title compound purity are 95%.
Table 8
[0212] typical thiourea derivative (seeing also " thiourea " row of table 9) and 2-bromo-1-(4-imidazoles-1-base-phenyl) second-1-ketone 22 chemical combination prepare the following aminothiazole analog that typically contains imidazole radicals.With illustrative methods same as described above, the cited typical title compound of preparation table 9.
Table 9
[0213] use also can prepare the analog that contains pyrrolidinyl with above-mentioned similar methods.A kind of exemplary pyrrolidinyl analogs, chemical compound 1201, be by 0.1mmol 2-bromo-1-(4-pyrrolidine-1-base-phenyl) second-1-ketone is dissolved in the 1.0mL dry DMF, and add 0.1mmol (3-methyl mercapto (methylsulfanyl)-phenyl)-thiourea and prepare.Mixture under 70 ℃ by whirling motion agitating heating 4 hours.After the cool to room temperature, reactant mixture is directly injected the reversed-phase HPLC chromatographic column, uses 1-99% acetonitrile/water/0.05TFA gradient more than 10 minutes.Required fraction is concentrated through fast vacuum (speedvac).Measure through HPLC, the purity of chemical compound 1201 is 95%.
[0214] except containing the thiazole analog, to use and above-mentioned similar methods, the analog that contains oxazolidone also prepares by condensation aryl urea derivative and bromoketone derivant.A kind of exemplary oxazolidone analog, [4-(4-imidazoles-1-base-phenyl)-azoles-2-yl]-(4-methoxyl group-phenyl)-amine 1202, and exemplary analog is by following exemplary path of preparing.
[0215] in this typical method, blended bromoketone (0.2g, 0.75mmol) and carbamide (0.375g 2.26mmol) is dissolved by 1.5mL DMF in a seal glass test tube.Mixture is heated under 85-90 ℃ and stirred 24 hours.After reaction is cooled to room temperature, use the DMF diluted reaction mixture, and directly inject the reversed-phase HPLC post, use 1-99%CH3CN/ water/0.05%TFA gradient more than 10 minutes.Utilize fast vacuum (speedvac) to concentrate the product that contains required fraction, and from hexane/EtOAc (1: 1), precipitate, be further purified and obtain 0.140g (56%) white solid chemical compound 1202.In DMSO, utilize
1H NMR confirms the structure of chemical compound, its LC-MS[M+1]=333.The purity that HPLC measures is greater than 95%.
Embodiment 4
The preparation of typical case's thiazole
A. the substituent adding of annulus and N-
[0216] various typical N-replacement chemical compound of containing thiazole prepares by the exemplary route shown in following.And this route has shown another kind of method, and by this method, annulus is added on the typical thiazolium compounds.
[0217] in exemplary route as follows, bromoketone 22 and 4-bromo-phenylthiourea are by generating 1203 with example 3 described similar methods condensations.N-acidylate subsequently generates 1204, and N-alkanisation has afterwards generated 1205.In addition, heterocycle further is added to 1203 or 1205, generates 1209 or 1206 and 1207 respectively.
1. (4-bromophenyl)-(4-(4-imidazoles-1-base phenyl)-thiazol-2-yl)-t-butyl carbamate (1204)
[0218] with chemical compound 1203 (400mg, 1.0mmol) at the nitrogen atmosphere low suspension in anhydrous pyridine (5mL), add then di-t-butyl bicarbonate (di-tert-butyldicarbonate) (262mg, 1.2mmol).Reactant mixture at room temperature is stirred 16 hours (becoming limpid after being reflected at 5 minutes), is introduced in the frozen water afterwards.After stirring 10 minutes, filtering mixt, and precipitate bled dry 2 hours.Chemical compound 1204 is separated as a kind of white powder (460mg).Expection mass spectral analysis=497; Observation=498[M+1].
2.4-bromophenyl-(4-(4-imidazoles-1-base phenyl)-thiazol-2-yl)-(2-TMS-ethoxyl methyl)-amine (1208)
[0219] chemical compound 1204 is put into dry DMF (7mL) under nitrogen atmosphere, add then NaH (35mg, 95% powder, 1.38mmol).After at room temperature stirring 10 minutes, and adding 2-(trimethyl silyl) ethoxymethyl chloride (0.25mL, 1.38mmol).Reactant mixture at room temperature is stirred 3 hours, adds entry (50mL) and EtOAc (3 * 50mL) then carefully.Water (100mL), saline (100mL) washing organic extract carry out drying by magnesium sulfate, and filter.Under vacuum, remove and desolvate, generate a kind of yellow oily chemical compound 25, this chemical compound after coagulation (530mg) in a moment.
1H NMR (300MHz, DMSO, δ inppm)-0.07 (s, 9H), 0.93 (t, J=7.8Hz, 2H), 3.69 (t, J=7.5Hz, 2H), 5.32 (s, 2H), 7.11 (s, 1H), 7.44-7.50 (m, 3H), 7.65 (d, J=6.3Hz, 2H), 7.68 (d, J=5.7Hz, 2H), 7.78 (d, J=0.9Hz, 1H), 7.97 (d, J=8.4Hz, 2H), 8.30 (s, 1H). expection mass spectral analysis=527; Observation=528[M+1].
3. (4-(4-imidazoles-1-yl-phenyl)-thiazol-2-yl)-(4-piperidines-1-base-phenyl)-amine (1209)
[0220] in using the heating gun drying bottle (heat-gun dried vial) of nitrogen purging, will (+/-)-(10mg 0.015mmol) is dissolved in (1mL) in the dry toluene to BINAP.After 2 minutes, with Pd
2(dba)
3(3mg, 0.0025mmol), chemical compound 1208 (53mg, 0.1mmol) and piperidines (11mg 0.12mmol) adds in the reaction flask.After at room temperature stirring 5 minutes, (14mg, 0.14mmol), reactant mixture is heated 18 hours under 90 ℃, by the filter of one 0.45 μ m, carries out the HPLC purification subsequently then to add NaOtBu.Chemical compound 1209 is as a kind of brown oil be separated (1.3mg).Expection mass spectral analysis=401; Observation=402[M+1].
4. (4-bromophenyl)-ethyl-(4-(imidazoles-1-base phenyl)-thiazol-2-yl)-amine (1205)
[0221] chemical compound 1203 is put into dry DMF (7mL) under nitrogen atmosphere, add then NaH (powder of 17mg 95%, 0.65mmol).After at room temperature stirring 10 minutes, (0.05mL, 0.65mmol), reactant mixture is stirred 2 hours under 90 ℃, adds entry (50mL) and EtOAc (3 * 50mL) then carefully to add bromoethane.Water (100mL), saline (100mL) washing organic extract carry out drying by magnesium sulfate, and filter.Under vacuum, remove and desolvate, generate a kind of light yellow solid chemical compound 1205 (200mg).Expection mass spectral analysis=425; Observation=426[M+1].
5.N-ethyl-(4-(4-imidazoles-1-base phenyl)-thiazol-2-yl)-(4-piperidines-1-base phenyl)-amine (1206)
[0222] in using the heat gun drying bottle of nitrogen purging, will (+/-)-(10mg 0.015mmol) is dissolved in (1mL) in the dry toluene to BINAP.After 2 minutes, add Pd
2(dba)
3(3mg, 0.0025mmol), chemical compound 1205 (43mg, 0.1mmol) and piperidines (11mg, 0.12mmol).After at room temperature stirring 5 minutes, (14mg, 0.14mmol), reactant mixture is heated 23 hours under 90 ℃, by the filter of one 0.45 μ m, carries out the HPLC purification subsequently then to add NaOtBu.Chemical compound 1206 is as a kind of brown oil be separated (12mg).Expection mass spectral analysis=429; Observation=430[M+1].
6.N-ethyl-(4-(4-imidazoles-1-base-phenyl)-thiazol-2-yl)-(4-morpholine-4-base-phenyl)-amine (1207)
[0223] in using the heat gun drying bottle of nitrogen purging, will (+/-)-(10mg 0.015mmol) is dissolved in (1mL) in the dry toluene to BINAP.After 2 minutes, add Pd
2(dba)
3(3mg, 0.0025mmol), chemical compound 1205 (43mg, 0.1mmol) and morpholine (11mg, 0.12mmol).After at room temperature stirring 5 minutes, (14mg, 0.14mmol), reactant mixture is heated 23 hours under 90 ℃, by the filter of one 0.45 μ m, carries out the HPLC purification subsequently then to add NaOtBu.Chemical compound 1207 is as a kind of brown oil be separated (21mg).Expection mass spectral analysis=431; Observation=432[M+1].
B. the adding of non-loop section
[0224] except loop section, after bromoketone derivant and the thiourea derivative condensation, acyclic functional group can be added to typical thiazolium compounds.Shown in the following illustrative route, the N-alkylation takes place and generates 1209 in thiazole 1208.Add N, N dimethylamine generates 1210, N-takes place subsequently go protection (N-deprotection), generates 1211.
1.N
*1, N
*1-diethyl-4-methyl-N
*-3
*-4-[4-(4-methyl-imidazoles-1-yl)-phenyl]-thiazol-2-yl }-N
*3
*-(2-TMS-ethoxyl methyl)-benzene-1,3-diamidogen (1210)
[0225] with three (diphenyl methylene acetone) two palladiums (0) (Pd
2(dba)
3) (0.066g, 0.146mmol), three (tert-butyl group) phosphine (P (t-Bu)
3) (the hexane solution of 0.44ml 10%, 0.146mmol), (1.62 are dissolved in the 15ml toluene for the dried toluene solution of chemical compound 1209,2.92mmol), diethylamine (0.90ml, 8.76mmol) and tert-butyl group sodium oxide (sodium tert-butoxide) (NaOtBu) (0.420g 4.38mmol) adds in drying sealing (screw-capped) phial of a band stirring rod together.Use the nitrogen wash phial, and it is sealed tightly.Mixture is stirred 1 hour in 90 ℃ oil bath then.Under reduced pressure remove toluene.Material is suspended in CH once more
2Cl
2In silica gel.Then under reduced pressure, remove CH
2Cl
2, so that chemical compound is absorbed on the silica gel.Utilize the column chromatography purification product then,, produce a kind of light yellow semi-solid product 1210 (0.842g, 52%) with EtOAc/ hexane eluting.LC/MS：[M+1]
+＝548.4.C
30H
41N
5OSSi＝547.8。
2.N
*, N
*1-diethyl-4-methyl-N
*-3
*-4-[4-(4-methyl-imidazoles-1-yl)-phenyl]-thiazol-2-yl }-N
*3
*-(2-TMS-ethoxyl methyl)-benzene-1,3-diamidogen (1211)
[0226] chemical compound 1210 is dissolved in DMF (5ml) and the 2M hydrochloric acid solution (5ml), and at room temperature stirred 1.5 hours.Then utilize the reversed-phase HPLC purified product.Under reduced pressure mix pure fraction and be concentrated into exsiccation.The substance dissolves that is produced is in CH
2Cl
2(250ml), and, wash once with saline (100mL) with saturated sodium bicarbonate (100mL) washed twice.Organic facies is carried out drying by magnesium sulfate, under reduced pressure filters and concentrates, and generates a kind of white solid 1211 (alkali-free) (0.610g, 51%).LC/MS：[M+H]
+＝418.5.C
24H
27C
5S＝417.5。
3.N
*1, N
*1-diethyl-4-methyl-N
*-3
*-4-[4-(4-methyl-imidazoles-1-yl)-phenyl]-thiazol-2-yl]-N
*3
*-(2-TMS-ethoxyl methyl)-benzene-1, the dihydrochloride of 3-diamidogen
[0227] (0.610g 1.46mmol) is partially dissolved among the MeOH (2ml) with chemical compound 1211 (alkali-free).Add 2M HCl/Et then
2(1.46ml, 2.92mmol), solution becomes is clear for O.Use nitrogen current with the volume of solution concentration to minimum.Add Et then
2O (5ml) grinds to form white solid with chemical compound, by Et
2O (5ml) washed twice is used the nitrogen current drying.Then material is dissolved in once more and does Et
2Among the O (1.5ml), heating a little simultaneously.Cooling mixture, compound crystal.Crystal is collected on the filter, uses Et
2O (1ml) washed twice, vacuum drying produces a kind of white solid dihydrochloride (0.320g, 26%).LC/MS：[M+1]
+＝418.5。C
24H
27N
5S·2HCl＝490.5。
1H NMR (DMSO-d6) 300MHz δ 1.09-1.36 (6H, t, J=6.9Hz), 2.34 and 2.36 (6H, two s), (3.51 4H, broad s), 7.42 (2H, t, J=8.4Hz), 7.57 (1H, s), 7.79 (2H, d, J=9.0Hz), 8.07 (1H, t, J=1.2Hz), 8.19 (2H, d, J=9.0Hz), 8.57 (1H, s), 9.69 (1H, d, J=1.8Hz), 9.68 (1H, s).
[0228] by various bromoketone derivants and thiourea derivative are used similar methods, synthetic one group of chemical compound that contains ring-type, non-annularity and N-alkylation thiazole comprises following exemplary compounds 1212, and dihydrochloride (0.032g, 97%).LC/MS：[M+1]
+＝433.4.C
24H
28N
6S.2HCl＝505.5。
1H NMR (DMSO-d6) 300MHz δ 0.856 (3H, t, J=7.2Hz), 1.07-1.23 (5H, m), 2.35 and 2.38 (6H, two s), 3.43and 3.54 (4H, two broad s), 7.41 (2H, broad s), 7.73 (1H, s), 8.03 (1H, d, J=9.0Hz), 8.24 (1H, s), 8.62 (1H, broad s), 8.75 (1H, d, J=8.7Hz), 9.12 (1H, d, J=1.8Hz), (9.80 1H, broad s), 9.90 (1H, d, J=1.5Hz).
C. typical C-connection thiazole
[0229] except that N-connects thiazole,, prepares the thiazole that various C-connect by exemplary route as follows.
(1.2-3,4-two chloro-phenyl)-thioacetamide (1213)
[0230] hydrogen sulfide (gas) bubbling is added (3, the 4-Dichlorobenzene base)-acetonitrile (1.86g, 10mmol, 1.0eq)) and triethylamine (TEA) (10mmol, in ethanol 1eq) (10ml) solution, about 1 hour.After 1 hour, sealed reaction mixture, and stirred overnight at room temperature.TLC shows that most of nitrile is converted into thioacetamide (thioacteamide).By nitrogen being blasted reactant mixture 30 minutes, remove excessive H
2S.Concentrated reaction mixture then, and utilize silica gel chromatography (ISCO system, 30-60% ethyl acetate/hexane) purification reaction mixture, produce title compound (1213) (55% yield).
(2.2-3,4-two chloro-benzyls)-4-[4-(4-methyl-imidazoles-1-yl)-phenyl]-thiazole (1214)
[0231] with thioacetamide 1213 (0.08mmol) and 2-bromo-1-[4-(4-methyl-imidazoles-1-yl)-phenyl]-ethyl ketone (0.08mmol) 10 is dissolved among the 1ml DMF.Be reflected at and be stirred 6 hours under 70 ℃.After the cool to room temperature, reactant mixture is directly injected reversed-phase HPLC (Gilson 215), uses acetonitrile/water/TFA gradient and C
18Immobile phase separates, and concentrates then, produces title product 1214, is tfa salt.
Embodiment 5
The preparation of typical triazolyl and furyl aminothiazole compounds
[0232] use following exemplary conventional route, preparation contains the chemical compound of triazolyl and furyl.
[0233] adopts the typical triazolyl aminothiazole compounds of following path of preparing.
1.N
*1
*-[4-(4-azido-phenyl)-thiazol-2-yl]-N
*4
*, N
*4-diethyl-2-methyl-benzene-1,4-diamidogen (1216a)
[0234] (0.300g is 1.24mmol) with (4-lignocaine-2-methyl-phenyl)-thiourea 75 (0.293g, 1.24mmol) chemical combination in the scintillation vial of a 20mL band stirring rod for 4-azido-bromoacetophenone (bromoacetophenone) 28.Add anhydrous EtOH (5ml), in 65 ℃ of oil baths, with mixture agitating heating 2.5 hours.Generate the limpid solution of a kind of black.Cool off this solution, under reduced pressure remove EtOH, generate the oil of a kind of purple, this oil is at room temperature placed 2 days post crystallizations, produces a kind of purple solid 1216a (0.465g, 99%).LC/MS：[M+1]
+＝379.0.C
20H
22N
6S＝378.5。
2.1-(-{ 4-[2-(4-lignocaine-2-methyl-phenylamino)-thiazole-4-yl]-phenyl }-1H-[1,2,3] thiazole-4-yl)-ethanol (1218a)
[0235] with chemical compound 1216a (0.100g, 0.26mmol), sodium ascorbate (SodiumAscorbate) (0.005g, 0.026mmol), copper sulphate pentahydrate (II) (0.001g, 0.0026mmol) and but-3-yn-2-ol (0.018g 0.26mmol) adds in the phial that a spiral cover that stirring rod arranged.The tert-butyl alcohol (1ml) and water (1ml) are added in the phial, and lid is tight.At room temperature mixture was by vigorous stirring 16 hours.Decompression moves down desolvates, and the residue that is generated is dissolved among the DMF (1.5ml) once more.Utilize the reversed-phase HPLC separated product then.Under reduced pressure concentrate pure fraction, produce ditrflouroacetate salt 1218a (0.038g, 21%).LC/MS：[M+1]
+＝449.1。C
24H
28N
6OS＝448.5。
[0236] the following step is used to prepare typical furyl aminothiazole compounds, N
*1
*, N
*1
*-diethyl-N
*3
*-[4-(4-furan-3-base-phenyl)-thiazol-2-yl]-4-methyl 1-benzene-1,3-diamidogen (1217a).
[0237] with N
*3
*-[4-(4-bromo-phenyl)-thiazol-2-yl]-N
*1
*, N
*1
*-diethyl-4-methyl-benzene-1, and the 3-diamidogen (104mg, 0.25mmol) (1215a) places flask, adding toluene: EtOH (4: 1,12mL: 3mL), add 3-furan boric acid (34mg then, 0.30mmol), sodium ascorbate (80mg, 0.75mmol) and water (1mL).Utilize nitrogen bubble to pass through reactant mixture 30 minutes, make the reactant mixture degassing.Add Pd (PPh subsequently
3)
4(29mg, 0.025mmol), reactant mixture is heated 17 hours under 80 ℃, then cool to room temperature.Add EtOAc (3 * 100mL) and water (100mL).Water (100mL), saline (100mL) washing organic extract carry out drying by magnesium sulfate, use column chromatography purification (40g ISCO cylinder).Title compound is as a kind of yellow powder be separated (40mg, 40%, C
24H
25N
3O
5The Mass Calculation value of S: 403.5.Observed value: 404.1[M+1]).
Embodiment 6
Typical invention chemical compound
[0238] table 10 has been enumerated the synthetic typical compound of exemplary route that utilizes among the foregoing description 1-5.
Table 10
Table 10
Table 10
Table 10
Table 10
Table 10
Table 10
Table 10
Table 10
Table 10
Table 10
Table 10
Table 10
Table 10
Table 10
Table 10
Table 10
Table 10
Table 10
Table 10
Table 10
Table 10
Table 10
Table 10
Table 10
Table 10
Table 10
Table 10
Table 10
Table 10
Table 10
Table 10
Table 10
Table 10
Table 10
Table 10
Table 10
Table 10
Table 10
Table 10
Table 10
Embodiment 7
Estimate the ELISA mensuration that A β regulates
[0239] activity of A β 42 and A β 40 levels in the outer medium of the adjusting of sandwich ELISA algoscopy (the sandwich ELISA assay) assessing compound below use born of the same parents.
A. the preparation of cell
[0240] by using the DNA of the human APP751 of coding that is included among the carrier pcDNA.1, stable transfection is from the human SH-SY5Y cell of ATCC (including numbering CRL-2266), and the neuroblastoma cell that produces expression APP is.Cell is laid down on (～20,000SH-SY5Y-APP transfectional cell/hole) on the 384-orifice plate, allows to adhere at least 18 hours.Washed cell in the culture fluid (DMEM, 10%FBS, 100 units/ml penicillin, 0.1mg/ml streptomycin) then, and add the culture fluid that 30 μ l contain the debita spissitudo chemical compound.
B. the calculating of chemical compound usefulness (potency)
[0241] chemical compound is suspended among the DMSO (media).Use a concentration of chemical compound, promptly 30 μ M carry out just measuring, to measure the activity whether chemical compound has A β 42 levels that reduce the outer medium of born of the same parents.Chemical compound is added in the cell, and cell was by incubation 18-22 hour in the presence of chemical compound.If A β 42 levels (estimating as following sandwich ELISA) of the outer medium of the cell born of the same parents that contact with this compound concentration are less than about 60% of the outer level (negative control) of the cell born of the same parents that only contact with media, to measure the chemical compound of certain limit concentration so, to measure the usefulness (being the IC50 value of chemical compound) that chemical compound reduces A β 42 and A β 40 levels.
[0242] for measuring the usefulness that chemical compound reduces A β 42 levels of the outer medium of born of the same parents, six variable concentrations with chemical compound are handled cell (differing 1/2 log10 dilution (log dilutions)), calculate the concentration that A β 42 levels are reduced to the maximum half that reduces of A β 42 levels.
[0243] same, for measuring the usefulness that chemical compound reduces A β 40 levels of the outer medium of born of the same parents, adopt the variable concentrations of chemical compound, pair cell is handled, and calculates the concentration that A β 40 levels are reduced to the maximum half that reduces of A β 40 levels.
[0244] reduces the selectivity degree of A β 42 levels of the outer medium of born of the same parents for measuring chemical compound with respect to A β 40 levels that reduce the outer medium of born of the same parents, comparative compound reduces A β 42 levels and chemical compound reduces the usefulness of A β 40 levels, and is expressed as a times selectivity (fold selectivity).A β 40 levels minimizing as the outer medium of carpogonium is not more than 50%, then uses the maximum concentration (for example 30 μ M) of test compound in calculating.
C. the ELISA that estimates A β level measures
[0245] utilizes A β 42 or A β 40 antibodies selectives as capture antibody, measure the A β level of estimating the outer medium of born of the same parents from the supernatant (supernatant) in tissue culture ware hole by sandwich ELISA.Before beginning to carry out immunoassay, be used in 25 μ l among the TBS～A β 42 or the A β 40 selectivity monoclonal antibody bags of 5 μ g/ml are spent the night by the microtitration 384-orifice plate of white.
[0246] for estimating the level of A β 42 in the sample supernatant, in the first set reaction of sandwich assay, use A β 42 selectivity monoclonal antibody A387 (first antibody or capture antibody), the 35-42 aminoacid (please refer to WO 04/018997) of this antibody opposing A β.For estimating the level of A β 40 in cell conditioned medium liquid, in the first set reaction of sandwich assay, use A β 40 selectivity monoclonal antibody B113, the 30-40 aminoacid (please refer to WO04/018997) of this antibody recognition A β.
[0247] be used in second antibody in the sandwich assay, the B436 (please refer to WO 04/018997) of the amino acid/11-12 of opposing A β reacts with A β 40 and A β 42 peptides.Combine with alkali phosphatase as the second antibody that detects antibody.Utilize a kind of in the presence of alkali phosphatase the luminous existence or the shortage of measuring antibodies of radiative substrate, this substrate is CDP-Star chemical luminous substrate (Applied Biosciences).
[0248] after being spent the night with the capture antibody bag under 4 ℃, assay plate is by the BAS/TBS of 50 μ l 1%, and Fraction V sealing (Sigma, St.Louis, MO).The assay plate three times that contains cell with 50 μ l TBS/0.1%Tween-20 washing, the supernatant of self-organizing cultivation in future plate hole is transferred to antibody sandwich plate (supernatant of 20 μ l is added bag by in the plate of A β 42 antibodies selectives, the supernatant adding of 10 μ l is wrapped by in the plate of A β 40 antibodies selectives) then.Cell conditioned medium liquid and assay plate are at room temperature by incubation 2 hours.Wash assay plate three times with 50 μ l TBS/0.1%Tween-20 then.After the washing, with 25 μ l and alkali phosphatase (～0.5ug/ml is in 1%TBS) bonded anti--A β
1-12, with hole incubation 2.5 hours at room temperature.With 50 μ l TBS/0.1%Tween-20 washing holes three times, add 25 μ l CDP-Star chemical luminous substrates (Tropix, Inc.), and incubation 20 minutes at room temperature.Upward carry out quantitatively at Analyst HT (Molecular Devices Corp.) luminous.
[0249] data show with respect to the acceptable signal of the positive control hole background that obviously distinguishes over medium control value (vehicle controls) (～7-20 is (fold) doubly).A β 42 peptides are measured a very big range of linearity, and it is approximately the 75-2000pg/ hole; HDR (high dynamicrange), it is (signal: background), be about 3-30 times of background in the range of linearity; The muting sensitivity limit, it is less than the selectivity of 20pg/ hole and A β 42, and it is for being higher than about 1000 times of other A β peptide at least, and this makes this method can carry out the chemical compound that high throughput screening is regulated A β 42 levels.
[0250] Xia Mian table 11 has been enumerated exemplary compounds mentioned herein, and these chemical compounds show activity in above-mentioned A β 42 and/or the A β 40 active biological external tests that reduce.The usefulness data representation of typical compound is as follows: A=＜0.2uM; B=0.2uM-1.0uM; C=1.1uM-5.0uM; D=5.1uM-10uM; E=10.1 μ M-30 μ M; The activity of detectable minimizing A β 40 when F=concentration is approximately 30 μ M.
[0251] table 12 further specifies typical compound mentioned herein, A β 42 that these compound exhibits reduce when concentration is approximately 30 μ M and/or A β 40 activity.
Table 11
Table 11
Table 11
Table 11
Table 11
Table 11
Table 11
Table 11
Table 11
Table 11
Table 11
Table 11
Table 11
Table 11
Table 11
Table 11
Table 11
Table 11
Table 11
Table 11
Table 11
Table 11
Table 12
Table 12
Table 12
Embodiment 8
The chemical compound Cytotoxic evaluation
[0252] is the cytotoxicity of assessing compound, remove the cell conditioned medium liquid of crossing with compound treatment, described in top embodiment 7, and adding calculating by volume contains 10% cell survival ability indicator (cell viability indicator) dyestuff AlamarBlue
TMThe solution of (Biosource, San Diego).Cell at 37 ℃ by incubation 3 hours, read the fluorescence on CytoFluor (AppliedBiosystems) spectrophotometer afterwards, this spectrophotometer uses excite light filter (excitation filter) and a 580-nm of a 530-nm to launch light filter (emission filter).With respect to control cells, the cell of the compound treatment shown in the table 11 shows that AlamarBlue fluorescence reduction is less than 40%.
Embodiment 9
Estimate the FRET mensuration that A β regulates
[0253] use homogeneous phase time discrimination fluorescence (HTRF) algoscopy, assessing compound is regulated the active as follows of A β 40 in the outer medium of born of the same parents and A β 42 levels.
[0254] the SH-SY5Y-APP cell is laid in the plate and uses compound treatment, as described in above-mentioned embodiment, exception is, for measuring the usefulness of chemical compound, 11 kinds of variable concentrations with chemical compound are handled cell, by 1/4th logarithms intervals (quarter-log intervals), the typical case uses the Cmax of 1,3 or 10 μ M.HTRF is analyzed, the supernatant from handling cell of 5 or 10 μ l is joined the antibody centering of the labelling of 10 or 15 μ l, total amount is 20 μ l, and at 4 ℃ of following incubation 20-24 hours.Traget antibody to or be used to estimate the 8000pgB436-XL665 and the 400pg B113 europium of A β 40 levels, or being used to estimate the 8000pgB436-XL665 and the 400pg A387 europium of A β 42 levels, it is diluted in 50mM NaPO4,0.2%BSA, 0.5M KF, pH are in 7 the solution.On BMG Rubystar, read the fluorescent value at 620nm and 665nm place.For formulating the concentration-response curve, measure the read-around ratio of each concentration, and as the percentage ratio curve plotting of the reading of untreated cell at 665/620nm, A β 42 or A β 40 levels are reduced to the usefulness that concentration that maximum minimizing is worth a half is calculated as chemical compound.
[0255] the present invention in this explanation can not have by concrete disclosed any or some elements at this in shortage, is implemented under the situation of any restriction or some restrictions.Used term and expression formula are as descriptive term, and also unrestricted, and use such term and expression formula to be not intended to shown in the eliminating and more any equivalents of described feature or its part, and will recognize, within the requirement of the scope of the invention, various modifications all are possible.Therefore, be to be understood that, although the present invention is specifically open by embodiment preferred and optional feature, but the modification of notion disclosed herein and change can be used by those of ordinary skills, and such modification and change are considered to be within the scope of the present invention that claims limit.
[0256] or article, patent, patent application and all other file and the electronic information quoted mentioned at this, all introduced at this, as a reference, it is quoted degree and specifically and is separately shown as each independent publication and be incorporated herein by reference document.The applicant keeps will be from any and all material of any such article, patent, patent application or other file and the right that information usefully adds this application.
[0257] can specifically do not disclosed any or some elements at this in shortage in this illustrated the present invention, be implemented aptly under the situation of any restriction or some restrictions.Therefore, for example, term " comprises (comprising) ", and " comprising (including) ", " containing (containing) ", wait and should be understood by popularity, and also unqualified.In addition, be used as descriptive term at this used term and expression formula, and it is unrestricted, and use such term and expression formula to be not intended to shown in the eliminating and more any equivalents of described feature or its part, and will recognize, within scope of the presently claimed invention, various modifications all are possible.Therefore, be to be understood that, although the present invention is specifically open by preferred embodiment and optional feature, but the modification of notion disclosed herein and change can be used by those of ordinary skills, and such modification and change are considered to be within the scope of the present invention that claims limit.
[0258] at this present invention has been carried out extensive and general description.Each narrower kind and the next grouping that drops within general the disclosing also constitutes a part of the present invention.This comprises the general description of the present invention that has the restricted type clause, or has the general description of the present invention of removing the negative qualification of any main body from kind, no matter whether the material of being removed is specifically quoted at this.
[0259] in addition, feature wherein of the present invention or aspect are described according to Markush groups, persons of ordinary skill in the art will recognize that therefore the present invention also is described according to Markush groups member's single member or subordinate group.
[0260] illustrated in other embodiment claim below.
Claims (42)
1. chemical compound and pharmacological-acceptable salt thereof and its prodrug, described chemical compound has the structure corresponding to formula (I):
(A)-L
A-(B)-L
B-(C)-L
C-(D)
(I)
Wherein:
A is:
Wherein each E independently is N, NR, C, CR
1, S or O, condition is that to be no more than 4 E are hetero atoms;
R is a hydrogen, replaces or substituted alkyl not, replaces or substituted alkenyl base not, replace or unsubstituting polysulfide yl, replace or unsubstituting alkoxy, replace or substituted alkyl amide groups not, replace or substituted alkyl amino not, replace or the unsubstituted ring alkyl, or replacement or unsubstituting aromatic yl;
Each R
1Be hydrogen, halogen, replace or substituted alkyl not, replace or substituted alkenyl base not, replace or unsubstituting polysulfide yl, replace or unsubstituting alkoxy, replace or substituted alkyl amide groups not, replace or substituted alkyl amino not, replace or substituted-amino not, replace or the unsubstituted ring alkyl, or replacement or unsubstituting aromatic yl;
Or A is:
Wherein, each M independently is selected from C R
1Or N, condition is that to be no more than 3 M are N; With
B is:
Wherein, each G independently is CR
2Or N, condition is that to be no more than 3 G are N;
Each R
2Independently be selected from hydrogen, halogen replaces or substituted alkyl not, replaces or substituted alkenyl base not, replaces or unsubstituting polysulfide yl, replaces or unsubstituting alkoxy, replaces or substituted alkyl amide groups not, replaces or substituted alkyl amino not, replaces or substituted-amino not;
Or B and A constitute a condensed ring system together;
C is:
Wherein J is selected from CR
3, O, S, N and NR;
Each K independently is N, NR, C or CR
3
Each R
3Be hydrogen, halogen replaces or substituted alkyl not, replaces or the unsubstituted ring alkyl, replaces or unsubstituting aromatic yl; Replace or substituted heteroaryl not, or replacement or unsubstituting alkoxy, its restrictive condition is for as C being
The time, R
3Be not-NH
2
Or C is
Wherein, each M independently is selected from CR
1Or N, condition is that to be no more than 3 M are N;
D is:
Wherein, each E independently is selected from N, NR, C, CR
1, S or O, condition is that to be no more than 4 E are hetero atoms;
Or D is:
Wherein, each M independently is selected from CR
5Or N, condition is that to be no more than 3 M are N;
Each R
5Independently be selected from hydrogen, halogen replaces or substituted alkyl not, replaces or substituted alkenyl base not, replace or unsubstituting polysulfide yl, replace or unsubstituting alkoxy, replace or the unsubstituted ring alkyl, replace or unsubstituting heterocycle, replace or unsubstituting aromatic yl, replace or substituted heteroaryl not, replace or substituted-amino not, replace or substituted alkyl amino not;
L
AFor arbitrarily, when existing, be covalent bond or junctional complex, be selected from-C=C--C=C-,-(C (R ')
2)
z-,-O-,-O-(C (R ')
2)
z-,-S-,-NR '-,-NH-(C (R ')
2)
z-,-N=N-,-C (O)-,-C (O) NR '-,-O-C (O)-,-O-C (O)-O-,-O-C (O)-NR '-,-NR '-C (O)-,-NR '-C (O)-O-,-NR '-C (O)-NR '-,-S-C (O)-,-S-C (O)-O-,-S-C (O)-NR '-,-S (O)-,-S (O)
2-,-O-S (O)
2-,-O-S (O)
2-O-,-O-S (O)
2-NR '-,-O-S (O)-,-O-S (O)-O-,-O-S (O)-NR '-,-O-NR '-C (O)-,-O-NR '-C (O)-O-,-O-NR '-C (O)-NR '-,-NR '-O-C (O)-,-NR '-O-C (O)-O-,-NR '-O-C (O)-NR '-,-O-NR '-C (S)-,-O-NR '-C (S)-O-,-O-NR '-C-(S)-NR '-,-NR '-O-C (S)-,-NR '-O-C (S)-O-,-NR '-O-C (S)-NR '-,-O-C-(S)-,-O-C (S)-O-,-O-C (S)-NR ' ,-NR '-C (S)-,-NR '-C (S)-O-,-NR '-C (S)-NR ' ,-S-S (O)
2-,-S-S (O)
2-O-,-S-S (O)
2-NR '-,-NR '-O-S (O)-,-NR '-O-S (O)-O-,-NR '-O-S (O)-NR '-,-NR '-O-S (O)
2-,-NR '-O-S (O)
2-O-,-NR '-O-S (O)
2-NR '-,-O-NR '-S (O)-,-O-NR '-S (O)-O-,-O-NR '-S (O)-NR '-,-O-NR '-S (O)
2-O-,-O-NR '-S (O)
2-NR '-,-O-NR '-S (O)
2-,-O-P (O) (R ')
2-,-S-P (O) (R ')
2-and-NR '-P (O) (R ')
2-, wherein, each R ' independence is hydrogen, replaces or unsubstituted alkyl, replaces or unsubstituted alkenyl, replaces or unsubstituted alkynyl, replace or unsubstituted cycloalkyl, and z is 1-10;
L
BIndependent is covalent bond or junctional complex, is selected from-C=C--C ≡ C-,-(C (R ')
2)
z-,-O-,-O-(C (R ')
2)
z-,-S-,-NR '-,-NH-(C (R ')
2)
z,-N=N-,-C (O)-,-C (O) NR '-,-O-C (O)-,-O-C (O)-O-,-O-C (O)-NR '-,-NR '-C (O)-,-NR '-C (O)-O-,-NR '-C (O)-NR '-,-S-C (O)-,-S-C (O)-O-,-S-C (O)-NR '-,-S (O)-,-S (O)
2-,-O-S (O)
2-,-O-S (O)
2-O-,-O-S (O)
2-NR '-,-O-S (O)-,-O-S (O)-O-,-O-S (O)-NR '-,-O-NR '-C (O)-,-O-NR '-C (O)-O-,-O-NR '-C (O)-NR '-,-NR '-O-C (O)-,-NR '-O-C (O)-O-,-NR '-O-C (O)-NR '-,-O-NR '-C (S)-,-O-NR '-C (S)-O-,-O-NR '-C (S)-NR '-,-NR '-O-C (S)-,-NR '-O-C (S)-O-,-NR '-O-C (S)-NR '-,-O-C (S)-,-O-C (S)-O-,-O-C (S)-NR '-,-NR '-C (S)-,-NR '-C (S)-O-,-NR '-C (S)-NR '-,-S-S (O)
2-,-S-S (O)
2-O-,-S-S (O)
2-NR '-,-NR '-O-S (O)-,-NR '-O-S (O)-O-,-NR '-O-S (O)-NR '-,-NR '-O-S (O)-,-NR '-O-S (O)
2-O-,-NR '-O-S (O)
2-NR '-,-O-NR '-S (O)
2-,-O-NR '-S (O)-O-,-O-NR '-S (O)-NR '-,-O-NR '-S (O)
2-O-,-O-NR '-S (O)
2-NR '-,-O-NR '-S (O)
2-,-O-P (O) (R ')
2-,-S-P (O) (R ')
2-and-NR '-P (O) (R ')
2-, wherein, each R ' independence is hydrogen, replaces or unsubstituted alkyl, replaces or unsubstituted alkenyl, replaces or unsubstituted alkynyl, replace or unsubstituted cycloalkyl, and z is 1-10;
L
CFor-O-,-S-,-S (O)-,-S (O)
2-,-NR-,-C (O)-,-(C (R ')
2) Z-, or-C (S)-;
Restrictive condition is for as A being
The time, L
ANot-C (O) NH-,-CH
2NH-,-CH
2-O-or-C (O) N (CH
3)-; With
The described chemical compound of formula (I) is not
2. the described chemical compound of claim 1, wherein A and B constitute a condensed ring system together.
3. the described chemical compound of claim 1, wherein B and C constitute a condensed ring system together.
4. the described chemical compound of claim 1, wherein D is
And d is 0-5.
5. the described chemical compound of claim 4, wherein each R
5Independently be selected from halogen, replace or do not replace C
1-C
5Alkyl replaces or does not replace C
1-C
5Alkoxyl replaces or does not replace 5 yuan to 6 yuan heteroaryls, replace or not substituted-amino and-N (R ")
2, wherein each R is " independent of replacing or do not replace C
1-C
5Alkyl or C
3-C
10Cycloalkyl.
6. the described chemical compound of claim 5, wherein D and R
5Constitute a condensed ring system together.
7. the described chemical compound of claim 4, wherein D is
8. the described chemical compound of claim 7, wherein, R
5Independently be selected from halogen, replace or do not replace C
1-C
5Alkyl replaces or does not replace C
1-C
5Alkoxyl, replace or do not replace 5 yuan to 6 yuan heteroaryls and-N (R ")
2, wherein each R is " independent of replacing or do not replace C
1-C
5Alkyl or C
3-C
10Cycloalkyl.
9. the described chemical compound of claim 1, wherein L
CFor-NH-.
10. the described chemical compound of claim 1, wherein C is
11. the described chemical compound of claim 10, wherein C is
12. the described chemical compound of claim 11, wherein C is
13. the described chemical compound of claim 10, wherein C is selected from
14. the described chemical compound of claim 1, wherein B is
15. the described chemical compound of claim 14, wherein B is selected from
Or
16. the described chemical compound of claim 15, wherein B is selected from
17. the described chemical compound of claim 16, wherein each R
2Independently be selected from halogen or replacement or do not replace C
1-C
5Alkyl.
18. the described chemical compound of claim 1, wherein A is
Wherein F is CH or N.
19. the described chemical compound of claim 18, wherein R
1Be halogen or replacement or do not replace C
1-C
5Alkyl.
20. the described chemical compound of claim 1, it has the structure corresponding to formula (II):
21. the described chemical compound of claim 20, it has the structure corresponding to formula (III):
22. the described chemical compound of claim 21, it has the structure corresponding to formula (IV):
23. the described chemical compound of claim 22, it has the structure corresponding to formula V:
24. the described chemical compound of claim 23, it has the structure corresponding to formula (VI):
25. a compositions, it comprises described chemical compound of claim 1 and pharmacological-acceptable carrier.
26. a cover test kit, it comprises described chemical compound of claim 1 and operation instruction.
27. method of regulating amyloid-β (A β) level, comprise that the source with amyloid precursor protein (APP) or its fragment and/or A β contacts with its prodrug with the chemical compound and the pharmacological-acceptable salt of effective quantity, described chemical compound has the structure corresponding to formula (VII):
(A
1-L
A1)
0-1-(B
1)-L
B1-(C
1)-L
C1-(D
1)
(VII)
Wherein:
A
1For optional, when existing, be 5 yuan or 6 yuan and replace or the unsubstituted ring alkyl, heterocycle, aryl, heteroaryl, ring alkylidene, heterocycle alkylidene, arlydene, or heteroarylidene;
B
1Be 5 yuan or 6 yuan and replace or the unsubstituted ring alkylidene heterocycle alkylidene, arlydene, or heteroarylidene; Or B and A constitute a condensed ring system together;
C
1Be 5 yuan or 6 yuan and replace or do not replace arlydene or heteroarylidene;
D
1Be 5 yuan or 6 yuan and replace or unsubstituting aromatic yl heteroaryl, arlydene, or heteroarylidene; With
L
A1For optional, when existing, be covalent bond or junctional complex;
Each L
B1And L
C1Independent is covalent bond or junctional complex;
The described chemical compound of its Chinese style (VII) is regulated A β level.
28. the described method of claim 27, wherein
A
1For optional, when existing be:
Wherein, each E independently is N, NR, C, CR
1, S or O, condition is that to be no more than 4 E are hetero atoms;
R is a hydrogen, replaces or substituted alkyl not, replaces or substituted alkenyl base not, replace or do not replace hydroxy alkynyl, replace or unsubstituting alkoxy, replace or substituted alkyl amide groups not, replace or substituted alkyl amino not, replace or the unsubstituted ring alkyl, replace or unsubstituting aromatic yl;
Each R
1Be hydrogen, halogen, replace or substituted alkyl not, replace or substituted alkenyl base not, replace or unsubstituting polysulfide yl, replace or unsubstituting alkoxy, replace or substituted alkyl amide groups not, replace or substituted alkyl amino not, replace or substituted-amino not, replace or the unsubstituted ring alkyl, replace or unsubstituting aromatic yl;
Or A
1, when existing be:
Wherein each M independently is selected from CR
1Or N, condition is that to be no more than 3 M be N; With
B
1Be:
Wherein each G independently is CR
2Or N, condition is that to be no more than 3 G be N;
Each R
2Independently be selected from hydrogen, halogen replaces or substituted alkyl not, replaces or substituted alkenyl base not, replaces or do not replace hydroxy alkynyl, replaces or unsubstituting alkoxy, replaces or substituted alkyl amide groups not, replace or substituted alkyl amino not,
C
1Be:
Wherein, J is selected from CR
3, O, S, N and NR;
Each K independently is N, NR, C or CR
3With
R
3Be hydrogen, halogen replaces or substituted alkyl not, replaces or the unsubstituted ring alkyl, replaces or unsubstituting aromatic yl, replace or substituted heteroaryl not, or replacement or unsubstituting alkoxy;
Or C
1For:
Wherein each M independently is selected from CR
1Or N, condition is that to be no more than 3 M be N;
D
1Be:
Each E independently is selected from N, NR, C, CR
1, S or O, condition is that to be no more than 4 E be hetero atom;
Or D
1For:
Wherein each M independently is selected from CR
5Or N, condition is that to be no more than 3 M are N;
Each R
5Independently be selected from hydrogen, halogen, replace or substituted alkyl not, replace or substituted alkenyl base not, replace or unsubstituting alkoxy, replace or the unsubstituted ring alkyl, replace or unsubstituting heterocycle, replace or the unsubstituted ring aryl, replace or substituted heteroaryl not, replace or substituted-amino not, or replace or substituted alkyl amino not;
L
A1, when existing and each L
B1And L
C1Independent is covalent bond or junctional complex, is selected from-C=C--C=C-,-(C (R ')
2)
z-,-O-,-O-(CR '
2)
z,-S-,-NR '-,-NH-(C R '
2)
z,-N=N-,-C (O)-,-C (O) NR '-,-O-C (O)-,-O-C (O)-O-,-O-C (O)-NR '-,-NR '-C (O)-,-NR '-C (O)-O-,-NR '-C (O)-NR '-,-S-C (O)-,-S-C (O)-O-,-S-C (O)-NR '-,-S (O)-,-S (O)
2-,-O-S (O)
2-,-O-S (O)
2-O-,-O-S (O)
2-NR '-,-O-S (O)-,-O-S (O)-O-,-O-S (O)-NR '-,-O-NR '-C (O)-,-O-NR '-C (O)-O-,-O-NR '-C (O)-NR '-,-NR '-O-C (O)-,-NR '-O-C (O)-O-,-NR '-O-C (O)-NR '-,-O-NR '-C (S)-,-O-NR '-C (S)-O-,-O-NR '-C (S)-NR '-,-NR '-O-C (S)-,-NR '-O-C (S)-O-,-NR '-O-C (S)-NR '-,-O-C (S)-,-O-C (S)-O-,-O-C (S)-NR '-,-NR '-C (S)-,-NR '-C (S)-O-,-NR '-C (S)-NR '-,-S-S (O)
2-,-S-S (O)
2-O-,-S-S (O)
2-NR '-,-NR '-O-S (O)-,-NR '-O-S (O)-O-,-NR '-O-S (O)-NR '-,-NR '-O-S (O)
2-,-NR '-O-S (O)
2-O-,-NR '-O-S (O)
2-NR '-,-O-NR '-S (O)-,-O-NR '-S (O)-O-,-O-NR '-S (O)-NR '-,-O-NR '-S (O)
2-O-,-O-NR '-S (O)
2-NR '-,-O-NR '-S (O)
2-,-O-P (O) (R ')
2-,-S-P (O) (R ')
2-and-NR '-P (O) (R ')
2-, wherein each R ' independence is hydrogen, replaces or substituted alkyl not, replaces or substituted alkenyl base not, replace or unsubstituting polysulfide yl, or replacement or unsubstituted ring alkyl, and z is 1-10.
29. the described method of claim 28, wherein L
C1For-O-,-S-,-S (O)-,-S (O)
2-,-NR-,-C (O)-,-(C (R ')
2) z-or-C (S)-.
30. the described method of claim 29, wherein said chemical compound has the structure corresponding to formula (II):
31. the described method of claim 30, wherein said chemical compound has the structure corresponding to formula (III):
32. the described method of claim 31, wherein said chemical compound has the structure corresponding to formula (IV):
33. the described method of claim 32, wherein said chemical compound has the structure corresponding to formula V:
34. the described method of claim 33, wherein said chemical compound has the structure corresponding to formula (VI):
35. the method for a treatment and the unusual horizontal diseases associated of A β comprises chemical compound and pharmacological-acceptable salt and its prodrug to the effective quantity of administered, described chemical compound has the structure corresponding to formula (VII):
(A
1-L
A1)
0-1-(B
1)-L
B1-(C
1)-L
C1-(D
1)
(VII)
Wherein:
A
1For optional, when existing, be 5 yuan or 6 yuan and replace or the unsubstituted ring alkyl, heterocyclic radical, aryl, heteroaryl, ring alkylidene, heterocycle alkylidene, arlydene, or heteroarylidene;
B
1Be 5 yuan or 6 yuan and replace or the unsubstituted ring alkylidene heterocycle alkylidene, arlydene, or heteroarylidene; Or B and A constitute a condensed ring system together;
C
1Be 5 yuan or 6 yuan and replace or do not replace arlydene or heteroarylidene;
D
1Be 5 yuan or 6 yuan and replace or unsubstituting aromatic yl heteroaryl, arlydene, or heteroarylidene; With
L
A1For optional, when existing, be covalent bond or junctional complex;
Each L
B1And L
C1Independent is covalent bond or junctional complex;
The described chemical compound of its Chinese style (VII) is regulated A β level.
36. method according to claim 35, wherein
A
1For optional, when existing be:
Wherein, each E independently is N, NR, C, CR
1, S or O, condition is that to be no more than 4 E are hetero atoms;
R is a hydrogen, replaces or substituted alkyl not, replaces or substituted alkenyl base not, replace or do not replace hydroxy alkynyl, replace or unsubstituting alkoxy, replace or substituted alkyl amide groups not, replace or substituted alkyl amino not, replace or the unsubstituted ring alkyl, or replacement or unsubstituting aromatic yl;
Each R
1Be hydrogen, halogen, replace or substituted alkyl not, replace or substituted alkenyl base not, replace or unsubstituting polysulfide yl, replace or unsubstituting alkoxy, replace or substituted alkyl amide groups not, replace or substituted alkyl amino not, replace or substituted-amino not, replace or the unsubstituted ring alkyl, or replacement or unsubstituting aromatic yl;
Or A
1, when existing be:
Wherein each M independently is selected from CR
1Or N, condition is that to be no more than 3 M be N; With
B
1Be:
Wherein each G independently is CR
2Or N, condition is that to be no more than 3 G be N;
Each R
2Independently be selected from hydrogen, halogen replaces or substituted alkyl not, replaces or substituted alkenyl base not, replaces or do not replace hydroxy alkynyl, replaces or unsubstituting alkoxy, replaces or substituted alkyl amide groups not, or replaces or substituted alkyl amino not;
C
1Be:
Wherein, J is selected from CR
3, O, S, N and NR;
Each K independently is N, NR, C or CR
3With
Each R
3Be hydrogen, halogen replaces or substituted alkyl not, replaces or the unsubstituted ring alkyl, replaces or unsubstituting aromatic yl, replace or substituted heteroaryl not, or replacement or unsubstituting alkoxy;
Or C
1For:
Wherein each M independently is selected from CR
1Or N, condition is that to be no more than 3 M be N;
D
1Be:
Each E independently is selected from N, NR, C, CR
1, S or O, condition is that to be no more than 4 E be hetero atom;
Or D
1For:
Wherein each M independently is selected from CR
5Or N, condition is that to be no more than 3 M are N;
Each R
5Independently be selected from hydrogen, halogen, replace or substituted alkyl not, replace or substituted alkenyl base not, replace or unsubstituting alkoxy, replace or the unsubstituted ring alkyl, replace or unsubstituting heterocycle, replace or the unsubstituted ring aryl, replace or substituted heteroaryl not, replace or substituted-amino not, or replace or substituted alkyl amino not;
L
A1, when existing and each L
B1And L
C1Independent is covalent bond or junctional complex, is selected from-C=C--C=C-,-(C (R ')
2)
z-,-O-,-O-(CR '
2)
z,-S-,-NR '-,-NH-(CR '
2)
z,-N=N-,-C (O)-,-C (O) NR '-,-O-C (O)-,-O-C (O)-O-,-O-C (O)-NR '-,-NR '-C (O)-,-NR '-C (O)-O-,-NR '-C (O)-NR '-,-S-C (O)-,-S-C (O)-O-,-S-C (O)-NR '-,-S (O)-,-8 (O)
2-,-O-S (O)
2-,-O-S (O)
2-O-,-O-S (O)
2-NR '-,-O-S (O)-,-O-S (O)-O-,-O-S (O)-NR '-,-O-NR '-C (O)-,-O-NR '-C (O)-O-,-O-NR '-C (O)-NR '-,-NR '-O-C (O)-,-NR '-O-C (O)-O-,-NR '-O-C (O)-NR '-,-O-NR '-C (S)-,-O-NR '-C (S)-O-,-O-NR '-C (S)-NR '-,-NR '-O-C (S)-,-NR '-O-C (S)-O-,-NR '-O-C (S)-NR '-,-O-C (S)-,-O-C (S)-O-,-O-C (S)-NR '-,-NR '-C (S)-,-NR '-C (S)-O-,-NR '-C (S)-NR '-,-S-S (O)
2-,-S-S (O)
2-O-,-S-S (O)
2-NR '-,-NR '-O-S (O)-,-NR '-O-S (O)-O-,-NR '-O-S (O)-NR '-,-NR '-O-S (O)
2-,-NR '-O-S (O)
2-O-,-NR '-O-S (O)
2-NR '-,-O-NR '-S (O)-,-O-NR '-S (O)-O-,-O-NR '-S (O)-NR '-,-O-NR '-S (O)
2-O-,-O-NR '-S (O)
2-NR '-,-O-NR '-S (O)
2-,-O-P (O) (R ')
2-,-S-P (O) (R ')
2-and-NR '-P (O) (R ')
2-, wherein each R ' independence is hydrogen, replaces or substituted alkyl not, replaces or substituted alkenyl base not, replace or unsubstituting polysulfide yl, or replacement or unsubstituted ring alkyl, and z is 1-10.
37. the described method of claim 36, wherein L
C1For-O-,-S-,-S (O)-,-S (O)
2-,-NR-,-C (O)-,-(C (R ')
2)
z-, or-C (S)-.
38. the described method of claim 37, wherein said chemical compound has the structure corresponding to formula (II):
39. the described method of claim 38, wherein said chemical compound has the structure corresponding to formula (III):
40. the described method of claim 39, wherein said chemical compound has the structure corresponding to formula (IV):
41. the described method of claim 40, wherein said chemical compound has the structure corresponding to formula V:
42. the described method of claim 41, wherein said chemical compound has the structure corresponding to formula (VI):
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US47088403P | 2003-05-14 | 2003-05-14 | |
| US60/470,884 | 2003-05-14 | ||
| US60/532,260 | 2003-12-22 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210015057.XA Division CN102584813B (en) | 2003-05-14 | 2004-05-14 | Compound and the purposes in regulating amyloid beta thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1787822A true CN1787822A (en) | 2006-06-14 |
Family
ID=36784996
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200480012784 Pending CN1787822A (en) | 2003-05-14 | 2004-05-14 | Compouds and uses thereof in modulating amyloid beta |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN1787822A (en) |
| ZA (1) | ZA200509153B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101815713A (en) * | 2007-08-31 | 2010-08-25 | 卫材R&D管理有限公司 | Polycyclic compound |
| CN102209537A (en) * | 2008-11-10 | 2011-10-05 | 弗·哈夫曼-拉罗切有限公司 | Heterocyclic gamma secretase modulators |
| CN102325765A (en) * | 2009-02-06 | 2012-01-18 | 奥索-麦克尼尔-詹森药品公司 | Novel substituted bicyclic heterocyclic compounds as gamma secretase modulators |
| WO2012136111A1 (en) * | 2011-04-02 | 2012-10-11 | 中国人民解放军军事医学科学院毒物药物研究所 | Phenylpropionic acid compound, preparation method therefor and medicinal use thereof |
| CN105524056A (en) * | 2016-01-05 | 2016-04-27 | 中山大学肿瘤防治中心 | Aminothiazole compound, and preparation method and application thereof |
| CN105636588A (en) * | 2013-08-09 | 2016-06-01 | Ngc药物公司 | Formulations containing gamma secretase modulators |
-
2004
- 2004-05-14 CN CN 200480012784 patent/CN1787822A/en active Pending
-
2005
- 2005-11-11 ZA ZA200509153A patent/ZA200509153B/en unknown
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101815713A (en) * | 2007-08-31 | 2010-08-25 | 卫材R&D管理有限公司 | Polycyclic compound |
| CN101815713B (en) * | 2007-08-31 | 2013-09-11 | 卫材R&D管理有限公司 | Polycyclic compound |
| CN102209537A (en) * | 2008-11-10 | 2011-10-05 | 弗·哈夫曼-拉罗切有限公司 | Heterocyclic gamma secretase modulators |
| CN102325765A (en) * | 2009-02-06 | 2012-01-18 | 奥索-麦克尼尔-詹森药品公司 | Novel substituted bicyclic heterocyclic compounds as gamma secretase modulators |
| CN102325765B (en) * | 2009-02-06 | 2014-12-24 | 杨森制药公司 | Novel substituted bicyclic heterocyclic compounds as gamma secretase modulators |
| WO2012136111A1 (en) * | 2011-04-02 | 2012-10-11 | 中国人民解放军军事医学科学院毒物药物研究所 | Phenylpropionic acid compound, preparation method therefor and medicinal use thereof |
| CN103097367A (en) * | 2011-04-02 | 2013-05-08 | 中国人民解放军军事医学科学院毒物药物研究所 | Phenylpropionic acid compound, preparation method therefor and medicinal use thereof |
| CN103097367B (en) * | 2011-04-02 | 2014-12-03 | 中国人民解放军军事医学科学院毒物药物研究所 | Phenylpropionic acid compound, preparation method therefor and medicinal use thereof |
| CN105636588A (en) * | 2013-08-09 | 2016-06-01 | Ngc药物公司 | Formulations containing gamma secretase modulators |
| CN105524056A (en) * | 2016-01-05 | 2016-04-27 | 中山大学肿瘤防治中心 | Aminothiazole compound, and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200509153B (en) | 2006-08-30 |
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