Title of Invention | "NITROGEN-CONTAINING HETEROARYL DERIVATIVES" |
---|---|
Abstract | The present invention relates to preventives or remedies for Alzheimer"s disease and to amyloid protein fibril-ivormatlon inhibitors which include at least one One ntrogen-containing heteroaryl compound or physiologically-permitted salt thereof as an active ingredient. Furthermore, the present invention also relates to nitrogen-containing heteroaryl derivatives with .specified substituents which are valuable as preventives or remedies for Alzheimer"s disease, or as amyloid protein fibril-formation inhibitors. |
Full Text | This invention relates to nitrogen-containing heteroaryl derivatives. [Technical Field] The present invention relates to preventives or remedies for Alzheimer's disease and to amyloid protein fibril-formation inhibitors which include at least one nitrogen-containing heteroaryl compound or physiologically-permitted salt thereof as an active ingredient. Furthermore, the present invention also relates to nitrogen-containing heteroaryl derivatives with specified substituents which are valuable as preventives or remedies for Alzheimer's disease, or as amyloid protein fibril-formation inhibitors.,/ [Technical Background] ß-Amyloid protein (hereinafter referred to as Aß) is a major structural component of the senile plaques strikingly present in the brains of patients with Alzheimer's disease, and it is an insoluble peptide comprising 39 to 43 amino acids. It is produced by enzymic cleavage from ß-amyloid protein precursor protein. From recent detailed pathological research into the brains of patients with Alzheimer's disease it is reported that, in the process of the occurrence of dementia, first of all there is a build-up of Ap within the brain of the patient, which triggers the formation ot: senile plaques, and after the passage of a • :<:ins iderable number of years there occurs neurofibrillary degeneration followed by neuronal degenerative loss rev. neurosci. vol.12> Furthermore, it is reported that Ap which comprises 40 •:in>ino acids (Ap 1-40) and its active central portion peptide (AP 25-35) cause degeneration and death of rat primary hippocampal neurons in an in vitro experimental system and specifically lower the cellular MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] reduction capacity [see, respectively, Science, Vol.250, .VV'ri (1990) and J. Neurochem. , Vol.65, 2585 (1995)]. A:-:, examples of the cells exhibiting a lowering of the MTT reduction capacity due to AP, there are foetal rat hippocampal neurons, PC12 cells and HeLa cells, etc. consequently, by measuring activity in inhibiting this lowering of the MTT reduction capacity due to Ap in such •jells, it is possible to investigate substances which inhibit the damaging action of AP on nerve cells. Mow, long-term potentiation (hereinafter referred to as LTP) is a phenomenon in which, by hippocampal nerve fibre electrical stimulation at high frequency for a short time, the synapse reaction strength is increased ever a prolonged period, and it is regarded as a model lor learning and memory. It is reported that, in hippocampal sections, Ap has an LTP impairing action [J. Neurosci. Res. Vol.60, 65 (2000), Proc. -Natl. Acad. Sci. UHA, Vol.95, 6448 (1998), etc]. Furthermore, it is reported that, in a transgenic mouse overexpressing Ap, i/IT in the hippocampus is inhibited compared to normal mouse and, in a learning behaviour test, the memory and iearning capacity are lowered [Science, Vol.274 mm ( 1996) ] . Consequently, by investigating substances which inhibit LTD impairment due to Ap in the hippocampus, it is j-M-sibie to investigate substances which lessen memory i rnpa i rmen t caused by Ap. A|> is regarded as at least one of the causes of the occurrence of Alzheimer's disease, so a substance which inhibits the impairment of nerve cells induced by AP would be etfective as a preventive or remedy for A i. z he liner ' s disease. Examples of known compounds which suppress nerve cell : Illnesses which are characterized by the extracellular deposition in various organs and tissues of polymerized amyloid protein which adopts a specific fibrillar .-•structure are generally classified as amyloidosis. The protein from which this amyloid is composed is, for example, in Alzheimer's disease, AP which is deposited in the brain; in type 2 diabetes, it is amylin which is deposited in the pancreas; in familial amyloid neuropathy, it is serum prealbumin (transthyretin) which i r; deposited in the peripheral nerves; it is iinmunoglobulin light chain-derived AL protein in the r.ase of ainyloidosis accompanying primary and multiple myeloma; and it is AA protein in the case of secondary ainyloidosis, etc. [See, for example") Sipe, J.D., Annu. Rev. Eiochem., Vol.61, 947-97 (1992), etc.] tic. tact that the amyloid protein in the course of .ibril-format ion produces a p-sheet structure is known u be a characteristic common to many amyloid proteins. See, for example, Sipe, J.D., Annu. Rev. Biochem. , Vol.61, 947-97 (1992), etc.] A|J> .is a typical amyloid protein, and it accumulates in "he brains of Alzheimer's disease patients, forming senile plaques. Within the senile plaques, a (3-sheet structure is adopted and fibril formation occurs, and there is known to be characteristic staining by dyes such as tnioflavin and Congo red which denote a librillar structure. Furthermore, it is known that with Mic adoption of the p-sheet structure and fibril i.> •!mat ion, A(3 shows toxicity to cultured nerve cells [Pike, C.J. et al, J. Neurosci. Vol.13, 1676-1687 ( 1.993) ] 11. is also known that the amylin, which is the main st ructural component of the amyloid protein deposited in rbe pancreas in type 2 diabetes, adopts a p-sheet structure and forms fibrils, which show toxicity to pancreatic [i-cells [Lorenzo, A. et al, Nature, Vol.368, 7M,-760 (1994) ] . i1 is reported that amyloid proteins such as A(3 and amylin both exhibit cytotoxicity by adopting a p-sheet structure and forming fibrils, and by lowering the cell MTT reduction capacity. Consequently,, it is thought that compounds which inhibit this fibril formation by amyloid proteins like Ap and amylin would inhibit their cell toxicity. Furthermore, since the mechanism of such manifestation of cytotoxicity is common to a number of amyloid proteins, it is believed that drugs which inhibit; the cytotoxicity of certain amyloid proteins and suppress fibril-formation could also inhibit cytotoxicity and fibril-formation in other amyloid proteins. Thus, as well as Alzheimer's disease and type 2 diabetes, by suppressing fibril-formation of amyloid protein this will be effective as a preventive or remedy h. »r, for example, immunoglobulinic amyloidosis, reactive familial amyloidosis, dialysis-related senile amyloidosis, cerebrovascular hereditary cerebral haemorrhage with Creutzfeldt-Jakob disease, bovine encephalitis (BSE), scrapie, medullary carcinoma of the thyroid, insulinoma, localized atrial arnvloid, amyloidosis cutis, localized nodu'lar amyloidosis and other types of amyloidosis, preferably .for Alzheimer's disease, type 2 diabetes, dialysis-related amyloidosis, familial amyloidosis, Creutzfeldt-rakob disease and BSE, and in particular for Alzheimer's disease or type 2 diabetes. Known examples of compounds which inhibit amyloid protein fibril-formation include variant peptide (W096/28471), imino-aza-anthracyclinone derivatives derived from anthrazalone (W098/32754), thionaphthalene derivatives with a specific structure (JP-A-9-95444) and i.aochr oman compounds (JP-A-2000-198781) . As compounds winch inhibit fibril-formation by Ap in particular from amongst, the amyloid proteins, there are known iAp5 [Nat. Med., Vol.4, 822-826 (1998)], and PTI-00703 [Neurobiol. Aqing, Vol.19 (Suppl 4) 1070 (1998). However, these compounds have a structure which is completely different ; r oin the nitrogen-containing heteroaryl compounds which ,.ti:e the effective component of the amyloid protein 1. ibr il-f ormat ion inhibitors of the present invention. With regard to nitrogen-containing heteroaryls, 3-[[4-[(2-fluoro-5-methylphenyl)amino]-2-pyrimidinyl]amino]-phenol and 4-[[6-[(2,5-dichlorophenyl)amino]-4-pyrlmidinyl ] amino] -phenol are disclosed as having an ,-inticancer action (WOOO/12485, WOOO/12486, etc), and the analogous 4,6-dianilino-pyrimidine derivatives are also disclosed as having an anticancer action (Japanese Patent Publication (PTC) No.9-506363). Moreover, 4,4'-I(6-methyl-2,4-pyrimidinediyl)diimino]bisphenol, 4,4'-j (6-amino-1,3,5-triazine-2,4-diyl)diimino]bisphenol and 1, 4'-[2,4-pyrimidinediyldiimino]bisphenol are disclosed a:; having an antibacterial action or anti-HIV action [J. Indian Chem. Soc. Vol.58 [5], 512-13 (1981), Acta Cienc. Indioa. Chem. Vol.11[1], 66-70 (1985), J. Med. Chem. Vol.9(3), 423-4, (1966), W099/36410, W099/50250]. Moreover, it has been disclosed that triazine derivatives with a 4-position derivative have an impeding action for kinase which is an enzyme catalysing the reaction to produce ATP by transfer of a phosphoryl q roup within the cell, and are valuable in the treatment of Alzheimer's disease, etc (W001/25220). Disclosure of the Invention] The present inventors have carried out a painstaking otudy with the objective of developing preventives or remedies lor Alzheimer's disease which have powerful activity and are highly safe, and they have discovered that nitrogen-containing heteroaryl compounds have an outstanding action in inhibiting the lowering of MTT induction capacity and in inhibiting long-term ). Furthermore, the present inventors have also carried out painstaking study with the objective of developing highly active arid highly safe drugs which can suppress amyloid protein fibril-formation and can suppress eytotoxicity brought about by the amyloid protein, and they have discovered that nitrogen-containing heteroaryl compounds have an outstanding inhibitory action in terms o! amyloid protein fibril-formation, and also have 'a Mbrillar amyloid protein breakdown action and are •-.'-'iluabie as preventives or remedies for amyloidosis, for •e.--.ample Alzheimer's disease and type 2 diabetes. The Present, invention has also been perfected based on this discovery. This invention provides preventives or remedies for Alzheimer's disease, or amyloid protein fibril-formation inhibitors, which include at least one nitrogen-eontaining heteroaryl compound, or pharmacologically permitted salt thereof, as an active ingredient. it also provides nitrogen-containing heteroaryl derivatives which possess specified groups. Specifically, the nitrogen-containing heteroaryl compounds which are an active ingredient of the Alzheimer's disease preventives or remedies, or of the amyloid protein fibril-formation inhibitors, of the present invention, have the following general formula (In this (formula remove) H and R each independently represent a hydrogen atom o i: a C._,; alky I group, ZJ and Z" each independently represent a hydrogen atom, C,-,, alkyl group, Ci-e alkoxy group, halo-Ci-e alkyl group or halogen atom, X represents a CVf, alkoxy group, mercapto group, Ci-e ai kylthio group, amino group, mono- or di-Ci-e alkylamino qroup, hydroxy group or halogen atom, Z' and Z1 each independently represent a hydrogen atom or halogen atom, and A .represents a group of formula (II) to (VI) below. (formula remove) N (V or N= R10 R11 (VI) In formulae (II) to (VI) above, R. represents a hydrogen atom, gi-s alkyl group, Ci_6 -u.koxy group, mercapto group, Ci-e alkylthio group, amino qsoup, mono- or di-Cj-e alkylamino group or hydroxy qroup, ( R represents a hydrogen atom or alkyl group, K' represents a hydrogen atom, Ci-e alkyl group, Ci_6 dlkoxy group, mercapto group, Ci-e alkylthio group, amino group, mono- or di-Ci-e alkylamino group or hydroxy group, H and R8 each independently represent a hydrogen atom, f'j., alkyl group, Ci-6 alkoxy group, mercapto group, Ci-e alkylthio group, amino group or mono- or di-Ci-6 a] kylamino group, H represents a gj.-o alkyl group, Ci-e alkoxy group, mercapto group, Ci_6 alkylthio group, amino group, mono-or di-Gi-f. alkylamino group or hydroxy group, and l;-"' and R:1 each independently represent a hydrogen atom, (' . alkyl group, CV6 alkoxy group, Ci-e alkylthio group, 01 morro- or di-Ci_f, alkylamino group. it: general formula (VIII) below Furthermore, amongst the compounds (I), the nitrogen-containing heteroaryl derivatives of the following general formula (VII) below (formula remove) (formula remove) and A 71 72 74 it , L, , L, , the .above formulae, R1, R , R , nave r. he same meanings as above, and Z6 represents a c, alkoxy group or a halogen atom. -C( alkyl group" denoted by R1, R2, R3, R5, R6, R7, R1' , R':, Z1 and Z% or the Ci~C6 alkyl portion of -C. aikoxy group" denoted by R3, R7, R8, R9, Z1, Z' may be, for example, a methyl, ethyl, iuopropyl, butyl, isobutyl, s-butyl, t-butyl, 1-rnethylbutyl, 2-methylbutyl, 3-methylbutyl, 1.,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-!!i« :t' hyi pentyl, 3-methylpentyl, 4-methylpentyl, 1/1-' I imethyibuty! , 1,2-dimethylbutyl, 1,3-dimethylbutyl, .', 2-dimethylbutyl, 2, 3-dimethylbutyl, 3, 3-dimethylbutyl, i ~t:t hylbutyl, 2-ethylbutyl, 1,1, 2-trimethylpropyl or 1,2,2-trimethylpropyl group. Excepting the alkyl group and the alkyl portion of the alkoxy group in the 'ioi:init ions of R1, R2, R3, R9, R10 and R11, and the alkyl : ,rt.ion of the alkoxy group in the definitions of R6 and ;; , it is preferably a Ci_4 alkyl group, more preferably i -nothyl or ethyl group, and in particular a methyl The alkyl group and the alkyl portion of the alkoxy i.:ic} group in the definitions of R1 and R2 are preferably a methyl or ethyl group. The alkyl qroup in the definition of R3 is preferably a C: r. alkyl group, more preferably a d-4 alkyl group, and still more preferably an ethyl, propyl or isopropyl qroup. The alkyl portion of the alkoxy group in the (i( -i inition of R"' is preferably a Ci-4 alkyl group and m-re preferably a Ci-3 alkyl group. Tho alkyl portion of the alkoxy group in the definition oi R' is preferably a Ci-3 alkyl group, and more preferably a methyl or ethyl group. The alkyl qroup in the definition of R9 is preferably a (';.'•: a iky.I group, more preferably a C2-4 alkyl group and still more preferably an ethyl, propyl, isobutyl, s-bi.ityl or t-butyl group. The alkyl portion of the alkoxy qroup in the definition of R9 is preferably a Ci-4 alkyl qroup, more preferably a methyl, ethyl or butyl group, .ind in particular a butyl group. The aikyl group and the alkyl portion of the alkoxy qroup in the definitions of R10 and R11 are preferably a ' '. . • a ! ky.l qroup . The alkyl portion of the alkoxy group in the definition •of ZT is preferably a Ci-3 alkyl group. The "halogen atom" in the definitions of Z1, Z2, Z3, Z4, and Z" is for example a fluorine, chlorine, bromine or iodine atom, preferably a fluorine or chlorine atom, ,.md in particular a chlorine atom. The C\-(, alkyl portion of the "halo-Ci-e alkyl group" in the definitions of Z1 and Z2 is the same as in the case ot the Ci-», alkyl group above, and the halogen portion is the .same as the halogen atom above. Examples are the Muoromethyl, difluoromethyl, trifluoromethyl, ehloromethyl, dichloromethyl, trichloromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 1-chloroethyl, 2-chloroethyl, 1,1-dichloroethy] and 1,2-dichloroethyl group, with the 11uoromethyl, difluoromethyl, trifluoromethyl, tjhloromethyl, dichloromethyl, trichloromethyl, 1-' ; uoroethyl arid 1-chloroethyl group being preferred, and i:he trif luoromethyl group further preferred. The C.-o alkyl portion of the "Ci-e alkylthio group" in the definitions of R3, R6, R7, R8, R9, R10, R11 and Z3 is the same as the Ci-6 alkyl group above, and examples are 1 methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, s-butylthio and t-butylthio. Excluding the alkyl portion of the thioalkyl group in the definitions of R3, R6, R10, R11 and Z3, a Ci_4 alkylthio is preferred, more preferably the methylthio or •••t.hylthio group, and in particular the methylthio group. With regard to the alkyl portion of the thioalkyl group in the definitions of R3, R6, R10, R11 and Z3, this is preferably a Ct-3 alkyl group, with the methylthio group being particularly preferred. C •...,, alkyl portion of the "mono- or di-Ci_6 alkylamino group" in the definitions of R3, R6, R7, R8, R9, R10, R11 and Z' is the same as the Ci-6 alkyl group above, examples being the methylamino, ethylamino, propylamino, dimethylami.no, methylethylamino, methylpropylamino, diethylamino, ethylpropylamino and dipropylamino groups. F.xoept in the case of R3 and R9, the methylamino, > - .'•:. i.s preferably a CY-4 alkoxy group, Ci_4 alkylthio group ;••;• hydroxy group, more preferably a d-2 alkoxy group, '.:.-;• alkylthio group or hydroxy group, with a hydroxy group particularly preferred. In the case of the compounds of the present invention it-presented by general formula (I) or (VII) above, the |-'..l lowing preferred compounds can be cited. : . The compounds where R1 and R2 are each independently ,-: hydrogen atom or a Cj._2 alkyl group, 2} The compounds where R1 and R2 are hydrogen atoms, -> ; The compounds where A is a group represented by iormula (II) (where R* is a hydrogen atom, Ci-s alkyl, Ci_ lkylthio or mono- or di-Cj-3 alkylamino group, and R 4 is a hydrogen atom or nitro group), a group represented by formula (III) (where R5 and R6 are each independently a hydrogen atom or Cj.-2 alkyl group) , a group of formula ;. !V) (where R ' and R8 are each independently a hydrogen aiom or C\ aikyl group), a group of formula (V) (where R is a C| -, aikyl, Ci-4 alkoxy or a Ci_4 alkylthio group), i n oi a group of. formula (VI) (where R10 and R11 are each dependently a hydrogen atom or Ci_3 alkyl group), •1': The compounds where A is a group of formula (II) (whore FT is a hydrogen. atom, Ci_5 alkyl, Ci_3 alkylthio or mono- or di-Ci_^ alkylamino group, and R4 is a hydrogen atom or nitro group), a group of formula (III) (where R' is a hydrogen atom and R6 is a methyl or ethyl group) , a group of formula (IV) (where R7 and R8 are hydrogen atoms), a group of formula (V) (where R9 is a C;-:] alkoxy or €1-4 alkylthio group), or a of: 1: or mul a (VI) (where R10 and R11 are hydrogen l'j} The compounds where A is a group of formula (II) (where R is a hydrogen atom, Ci_4 alkyl or amino group, rind R4 is a hydrogen atom or nitro group) or a group of formula (V) (where R9 is a C2-4 alkyl or a butoxy group), to The compounds where A is a group of formula (II) ;ohorc R'• is ,iii ethyl, propyl, isopropyl or amino group and R' is a hydrogen atom, or R3 is a hydrogen atom and K" is a nitro group) or a group of formula (V) (where R9 is a ('.;.-.! alkyi group), ,' i The compounds where Z1 and Z2 are each independently ..i hydrogen at:om or para-position fluorine atom, chlorine , it.orn or (T-. alkyl group, Z: is a meta-position hydroxy group (in the case of compound (I) ) , or the hydroxy group on the phenyl ring to which Z1 is bonded is in the meta-position (in the case of compound (VII)) and XT and Z' are hydrogen atoms, H) The compounds where Z1 and Z2 are each a hydrogen atom or para-position methyl group, Z' is a rneta-position hydroxy group (in the case of compound (I), or the hydroxy group on the phenyl ring to which Z1 is L>onded is in the meta-position (in the case ot compound (VII) ), and Z'1 and Z; are hydrogen atoms. i',ik:inq these together, for example combinations of 2), to 6) and 8) are preferred. Amongst these • • iu r the r p re ferred. Moreover, in the case of the compounds (VIII), there can be cited i; the compounds where R1 and R2 are each independently a hydrogen atom or Ci-:; alkyl group, ,".: i the compounds where R1 and R2 are hydrogen atoms, •n the compounds where R3 is a hydrogen atom, Ci-s a. i. kyl, 0|- ••'! the compounds where RJ is a hydrogen atom, Ci-4 alkyl of amino group, 5} the compounds where R3 is an ethyl, propyl, i.:.; o p r o p y 1 r (, '•: the compounds where Zb is a Ci_4 alkoxy group, iluorine atom or chlorine atom, and 7) the compounds where Z6 is a methoxy group, ethoxy f! r o u p c.) r c h 1. o r i n e atom. hiking these together, for example combinations of 2), -c to ';•) and 7) are preferred. Amongst these combinations, the combination of 2), 5) and 7) is 11.1 r t h e r preferred. The compounds of the present invention of general 1ormuia ([), (VII) or (VIII) possess within the same molecule a phenolic hydroxy group, which is a weakly acidic group, and an amino group or alkylamino group, •:'tc, which is a weakly basic group, so they form physiologically permitted salts when reacted with a comparatively strong base or acid. Examples of such ;. salts such as the acetate, fumarate and maleate. The hyrlrochloride, nitrate, sulphate and phosphate are preferred. Moreover, where the compounds of the present invention -ind t.heir pharmacologically permitted salts form soivates (such as hydrates), then these too are included w.i thin the scope of the invention. Tables I to _) below give specific examples of preferred .•(impounds represented by aforesaid general formulae (I), '"./I I) or (VIII). The compounds shown in Tables 1 to 5 have the formulae denoted by (1) to (5) respectively. With regard to the abbreviations employed below, Me moans the methyl group, Et means the ethyl group, Pr means the propyl group, iPr means the isopropyl group, Bu means the butyl group, iBu means the isobutyl group, sBu means the s-butyl group, tBu means the t-butyl H°-T -r(OH)n Ry (formula remove)Rz [where R: , Ry and R/: are the same or different, and each represent a hydrogen atom or a Ci-4 alkyl group (preferably Rv:, Ry and R2 are the same or different, and each represent a hydrogen atom or a methyl group; more preferably, Rx, Ry and Rz are methyl groups), and n is 1 <. are known compounds for oxdmple jp-a-5-32654 and possess an outstanding action in inhibiting a lowering of the mtt reduction capacity ltp impairment hippocampus they valuable as alzheimer disease preventives or remedies.> (Table Rermove)(Table Rermove)Amongst the above compounds, the preferred compounds are Exemplified Compound Nos 1-1-1-27, 1-29-1-30, 1-32, 1-36-1-37, 1-40-1-41, 1-56, 1-58, 1-60, 1-62, 1-68-1-69, 1-71-1-72, 1-74—1-75, 1-86-1-109, 1-114 -1-116, 1-120-1-122, 1-127-1-136, 1-147-1-153, 1-155-1-156, 1-158-1-165, 1-173-1-175, 1-178-1-183, 1-200—1-203, 2-1-2-3, 2-6-2-8, 2-11-2-13, 2-16-2-18, 2-21-2-23, 2-31-2-33, ,2-36-2-38, 2-41-2-43, 2-46-2-48, 2-56-2-58, 2-61-2-63, 2-66 ~2-68, 2-71-2-73, 2-76—2-78, 2-81-2-83, 2-86-2-88, 2-91-2-93, 2-96-2-98, 2-101-2-109, 3-1-3-3, 3-6-3-8, 3-11-3-13, 3-16-3-18, 3-21-3-23, 3-26-3-32, 4-1 — 4-3, 4-6-4-8, 4-11 — 4-13, 4-16-4-18, 4-21-4-23, 4-26-4-28, 4-31-4-33, 4-36-4-38, 4-41-4-43, 4-46-4-48, 4-51 — 4-53, 4-56 -4-58, 4-61-4-63, 4-66-4-68, 4-71-4-73, 4-76-4-78, 4-81 — 4-83, 4-85-4-88, 4-91-4-93, 4-96-4-98, 4-101-4-103, 4-106 — 4-108, 4-111-4-113,4-116-4-118,4-121-4-123,4-126-4-128,4-131-4-133, 4-136-4-138,4-141-4-143,4-146 — 4-148,4-151-4-153,4-156-4-158, 4-1 61 - 4-1 63, 4-1 66- 4-168, 4-171-4-1 73, 4-176-4-178, 4-181 -4-183, 4-186-4-188,4-191-4-193,4-196-4-198,4-201 — 4-203,4-206 — 4-208, 4-211-4-225, 4-228-4-230, 4-233-4-235, 4-238-4-240, 2-243-4-245, 4-248-4-250,4-253-4-255,4-258 — 4-260,4-263 — 4-265,4-268-4-270, 4-273-4-275, 4-278-4-280, 4-283 — 4-285, 4-288—4-290, 4-303-4-305, 4-308-4-310,4-313-4-315,4-318-4-320,4-323—4-325,4-328-4-330, 4-353-4-355, 4-358-4-360, 5-1-5-7, 5-12-5-17, 5-24-5-29, 5-35-5-40, 5-46-5-49, 5-54-5-57, 5-64-5-65 and the following are further pref erred: -1--1~1~6, 1-11-1-12, 1-20-1-26, 1-30, 1-71, 1-87, 1-89, .1-91-1-93, 1-100-1-106, 1-127-1-131, 1-147-1-150, 1-152-1-153, 1-155 -1-156, 1-161, 1-173, 1-178-1-181, '2-1, 2-6, 2-1K 2-16, 2-21, 2-31, 2-36, 2-41, 2-46, 2-56, 2-61, 2-66, 2-71, 2-76, 2-81, 2-86, 2-91, 2-96, 2-102-2-107, 3-1, 3-6, 3-11, 3-16, 3-21, 3-26-3-28, 3-31-3-32, 4-1, 4-6, 4-11, 4-16, 4-21, 4-26, 4-31, 4-36, 4-41, 4-46, 4-51, 4-56, 4-61, 4-66, 4-71, 4-76, 4-81, 4-85-4-86, 4-91, 4-96, 4-101, 4-106, 4-111, 4-116, 4-121, 4-126, 4-131, 4-136, 4-141, 4-14-6, 4-151, 4-156, 4-201, 4-206, 4-211-4-222, 4-263, 4-303, 4-313, 4-353, 4-358, 5-1-5-6, 5-12-5-17, 5-24-5-29, 5-35 — 5-39, ,5-54— 5-55, 5-64-5-65 with the following being still further preferred: - 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, 1-22, 1-30, 1-71, 1-161, 1-173, 2-1, 2-11, 4-6, 4-11, 4-26, 4-31, 4-36, 4-81, 4-212, and 5-1 in particular, the following :- 1-1 : N, N ' -bis ( 3-hydroxyphenyl ) pyrimidine-4 , 6-diamine 2-methyl-N,N' -bis ( 3-hydroxyphenyl) pyrimidine-4 , 6-- diamine •L_ 3. 2-ethyl-N,N' -bis (3-hydroxyphenyl) pyrimidine-4 , 6- d iainine 1-4 : 2-propyl-N,N' -bis ( 3-hydroxyphenyl) pyrimidine-4, 6- diarnine I-', : 2-isopropyl-N,N ' -bis (3-hydroxyphenyl) pyrimidine- 2-butyl-N, N' -bis (3-hydroxyphenyl ) pyrimidine-4 , 6- diamine 1 22 : 2-cimino-N, N ' -bis (3-hydroxyphenyl)pyrimidine-4, 6- i'i i amine ]- 173: N,N'-bis(3-hydroxyphenyl)-5-nitropyrimidine-4,6- i.l i amine 2-1: N,N'-bis(3-hydroxyphenyl)pyrimidine-2,4-diamine 1 -( : b-ethyl-N,N'-bis(3-hydroxyphenyl)-1,3,5-triazine- •1 -'I 1 : N, N ' -bis (3-hydroxyphenyl) -6-propyl-l, 3,5- t riazine-2, 4-diamine 4-26: 6-isobutyl-N,N'-bis(3-hydroxyphenyl)-1,3,5- « t riazine-2,4-diamine 4-31: 6-s-butyl-N,Nr-bis(3-hydroxyphenyl)-1,3,5-r. riazine-2, 4-diamine 4-36: 6-t-butyl-N,N'-bis(3-hydroxyphenyl)-1,3,5- t i: i a z i ne - 2,4- di ami ne •1 -212 : 6-ethyl-N, N ' -bis ( 3-hydroxy-4-methylphenyl) - i , .-:, !.)-1 riazine-2, 4-diamine and !'.- i : N , N ' -bi s ( 3-hydroxyphenyl) pyridazine-3, 6-diamine, and most preferably 2-methyl-N,N'-bis(3-hydroxyphenyl)pyrimidine-4,6-diamine ,>i id N,N'-bis(3-hydroxyphenyl)pyridazine-3,6-diamine. (Mode of Practising the Invention] 'i'he nitrogen-containing heteroaryl compounds represented by general formulae (I) of the present invention and the nitrogen-containing heteroaryl derivatives represented by general formulae (VII) and (VIII) are either known compounds (for example WOOO/12485 pamphlet) or they can be produced by the following method using known compounds as the starting materials. Method A (IX) (X) stage A-l (XI) stage A-2 (Table Rermove) (XII) NH Q1 Tn the above formulae, R1, R2, Z1, Z2, Z3, Z4, Z5 and A n.ive the same meanings as above, and X1 and X' each lepresents a halogen atom (preferably a chlorine atom, oromine atom or iodine atom, and more preferably a • Til or ine atom) . Stage A-l is a stage for the production of a compound of general formula (XI) by the reaction between a halogen compound of general formula (IX) and an aminophenol of general formula (X) in an inert solvent. The inert solvent used is not particularly restricted providing it does not impede the reaction, and to some extent dissolves the starting materials. Examples i:;ci.ude aliphatic hydrocarbons such as hexane, heptane, 1iqroin and petroleum ether; aromatic hydrocarbons such .•is benzene, toluene and xylene; halo-hydrocarbons such .::; dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; nitriles such as acetonitrile and propionitrile; ethers such as diethyl ether, diisopropyl ether, 1 orrahydrofuran, dioxane, dimethoxyethane and diethylene qlycoi dimethyl ether; amides such as formamide, dimethylformamide, dimethylacetamide, N-methyl-2-nyrrclidone and hexamethyIphosphoramide; sulphoxides such as dimethylsulphoxide and sulfolane; and alcohols such as methanol, ethanol, propanol, 2-ethoxyethanol and •-1 nitoxyethanol. The ethers, amides and alcohols are pieterred, in particular dioxane, diethylene glycol dimethyl ether, dimethylformamide, dimethylacetamide, 2-erhoxyethanol or 2-butoxyethanol. This stage can be carried out with the optional addition of a base, such as an organic base like triethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)-uviidine, or an alkali metal carbonate such as sodium carbonate or potassium carbonate. An organic base is preferred. The reaction temperature will differ with the starting material compounds and the solvent but, normally, it is 0 /:00°C and preferably 50-170°C. The reaction time will vary with the reaction temperature, the starting material compounds and the solvent but, normally, it is in the range from 10 minutes to 24 hours, and preferably 30 minutes to 8 hours. Following the end of the reaction, the target material o,in )::>e obtained from the reaction mixture by the usual methods. For example, following the end of the reaction the solvent is distilled off and water poured onto the residue obtained, then extraction performed with a water-immiscible solvent (such as benzene, ether, ethyl acetate or the like), after which the extraction liquid is washed with water and dried with anhydrous magnesium sulphate. By then distilling off the solvent, the target compound is obtained. The target compound thus obtained can, where necessary, be further purified by the usual methods, such as column chromatography, etc. The aminophenol (X) used in stage A-l is either a known compound or can be readily produced by known methods : see J. Am. Chem. Soc., Vol.47, 1712-1718 (1925), J. iotorocyclrc Chem., Vol.26, 1255-1259 (1989), Synthesis, 1446-1450 (1997), J. Chem. Soc., 3017-3020 (1949), J. Chem. Soc., 2426-2430 (1951)]. slacje A-2 is a stage for the production of the target compound (T), and this is achieved by performing .reaction between the compound of general formula (XI) ai;d an amine of general formula (XII) in the same way as )n stage A-l. In the case where compound (X) and compound (XII) are the same compound, then it is possible to obtain the desired compound (I) by carrying out reaction in the same way as in stage A-l using at least 2 mol (preferably 2-3 mol) of compound (X) per mol of halo-corn pound (IX) . The amine of general formula (XII) used in stage A-2 is '• ] r.her. a known compound or is readily produced by known methods [Synth. Commun., Vol.30, 3639-3644 (2000)]. The compound (IXa) where, in the compound of general formula (IX) employed in stage A-l, A is a group of i-'rmula (V) and R!* is a Ci_6 alkyl group, can be produced l;v i i;(: following method B. Method B X3 N ^N stage B-l (Table Rermove) XIII) in the above formulae, X1 and X2 have the same meanings is above, and X' represents a halogen atom (preferably a vhlorine atom, bromine atom or iodine atom, and more a chlorine atom) , and R12 is a Ci-6 alkyl 01 aqe B-l is a stage based on a known method [Helv. uch as trimethylaluminium; an organo-zinc reagent such as dimethylzinc; or an organo-copper reagent such as Lithium dimethyl-cuprate; preferably an organo-lithium r After the completion of the reaction, the target compound is obtained from the reaction mixture by the usual methods. For example, the reaction mixture is concentrated or extracted with a water-immiscible organic solvent (such as benzene, ether, ethyl acetate «a the like), followed by drying with anhydrous magnesium sulphate, after which the solvent is distilled (iff. Where required, the target material thus obtained can be further purified by normal methods, for example by column chromatography. The compound of general formula (IX) used in stage A-l i-an also be produced by the following method C. Method C stage C-l OH A—OH *> X1 A X2 halogenating agent (XIV) (IX) In the above formulae, X1, X2 and A have the same meanings as above. ."'vine 0-1 i s a stage based on a known method [J. Org. enem., Vol. 17, 1320-1327 (1952); J. Org. Chem. , Vol.18, ..'Vi-tjL.,6 (19b:i); J. Am. Chem. Soc. Vol.79, 2230-2232 •' : ''7! ] by the reaction between a compound of general tormula (XIV) and a halogenating agent (such as a ' .hionyl halide such as thionyl chloride; a phosphorus tnhalide such as phosphorus trichloride, phosphorus t i.1bromide or phosphorus triiodide; a phosphorus p";i!t ahalide such as phosphorus pentachloride, phosphorus I. >f>ntabromide or phosphorus pentaiodide; or a phosphorus oxyhalide such as phosphorus oxychloride, phosphorus oxybromide or phosphorus oxyiodide; in particular with phosphorus oxychloride) either in the absence of solvent of in the presence of an inert solvent (such as an • •! i phat ic hydrocarbon such as hexane or heptane; an :;ornatic hydrocarbon such as benzene or toluene; a halo-i \T.i roearbon such as dichloroethane or dichlorobenzene; i!, other such as diethyl ether or diethylene glycol oiniethyl ether; or an organic base such as N-rnethylmorphol ine, triethylamine, N-me'thyl-piperidine, pyridine, quinoline or dimethylaniline; preferably in an organic base or in the absence of solvent, and in particular in dimethylaniline), at 20-180°C (preferably ~'0-150°0) for from 1 hour to 24 hours (preferably 3 to 5 o.'urs) . Ln the case where no solvent is employed, the reaction is carried out using excess of the halogenating 11 q e n t . i concentrated Or extracted with a water-immiscible orqanic solvent (such as benzene, ether, ethyl acetate or the like), followed by drying with anhydrous magnesium sulphate, after which the solvent is distilled r^:i and the target material obtained. Where required, Mie target material thus obtained can be further purified by normal methods, for example by column chromatography. In the case where the nitrogen-containing heteroaryl compounds of general formula (I) of the present invention, or pharmacologically permitted salts thereof, , ire used as preventives or remedies for Alzheimer's di.sease or as amyloid protein -fibril-formation inhibitors, they can be administered orally in the form of tablets, capsules, granules, powders or syrups, etc, or parent erally in the form of injections or .suppositories, etc, either on their own or after mixing with suitable pharmacologically-permitted fillers, d i 1 uen t s or the 1 i ke . These pharmaceutical preparations are produced by known methods using additives such as fillers/excipients (examples of which are organic fillers like lactose, sucrose, glucose, mannitol, sorbitol or other sugar or .?. uqar derivative; corn starch, potato starch, a-starch, •"I'-'Xtrin or other such starch or starch derivative; ;.• i yst al line cellulose or other such cellulose no-rivative; gum Arabic; dextran; pullulan or the like; and inorganic fillers like light silica, synthetic aluminium silicate, calcium silicate, magnesium metasilicate or other silicic acid derivative; calcium hydrogen phosphate or other phosphate; calcium carbonate or other carbonate; calcium sulphate or other sulphate, -.'-• the like), lubricants (examples of which are stearic acid and metal stearates like calcium stearate and magnesium stearate; talc; colloidal silica; beeswax, sperm whale wax and other such waxes; boric acid; adipic ,n:id; sulphates such as sodium sulphate;- glycol; fumaric ic.ici; sodium benzoate; DL-leucine; sodium i.-iuryisulphate, magnesium laurylsulphate and other such I •iiirylsulphates; silicic anhydride, silicic acid hydrate and other silicas; and also the aforesaid starch derivatives), binders (examples of which are hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, macrogol and compounds identical !• trie aforesaid fillers), disintegrating agents u'oliulose derivatives such as hydroxypropyl cellulose with a Jow degree of substitution, carboxymethyl cellulose, calcium carboxymethyl cellulose and internally-crosslinked sodium carboxymethyl cellulose; carboxymethyl starch, sodium carboxymethyl starch, >••} osslinked polyvinyl pyrrolidone and other such ' .-nernica ily-rnodif led starch/cellulose or the like), ..fnij Lsif iers (for example bentonite, veegum and other types of colloidal clay; magnesium hydroxide, aluminium hydroxide and other such metal hydroxides; sodium lauryl sulphate, calcium stearate and other such anionic surfactants; benzalkonium chloride and other types of cat ionic surfactants; and polyoxyethylene alkyl ether, poiyoxyethylene sorbitan fatty acid ester, sucrose fatty .-ic.id ester arid other such nonionic surfactants), stabilizers (methyl paraben, propyl paraben and other such p-hydroxybenzoic acid esters; chlorobutanol, benzyl alcohol, phenyl ethyl alcohol and other such alcohols; benzalkonium chloride; phenol, cresol and other such phenols; thimerosal; dehydroacetic acid; and sorbic acid), correctives/corrigents (such as the normally used .sweeteners, acidic taste-conferrers, spices and the like), diluents and other such additives. The amount used will differ according to the symptoms, aqe, etc, but when administered orally to an adult there oan be used an amount between a lower limit of 1 mg (preferably 10 mg) and an upper limit of 1,000 mg (preferably 500 mg) per time, and when administered intravenously there can be used an amount between a lower limit of 0.5 mg (preferably 5 mg) and an upper limit of 500 mg (preferably 250 mg) per time, from once to ;.;ix times per day according to the symptoms. [Optimum Mode for Practising the Invention] Bolow, the present invention is explained in still further detail by providing some production examples, experimental and preparation examples, but the invention is not to be restricted to these. (Pro d uc t i o n E x amp1e 1) (-.-fc'.t hyl-N, N ' -bis ( 3-hydroxyphenyl) -I, 3, 5-triazine-2, 4-diamine (Exemplified Compound No. 4-6) !1A) 2,1-dichloro-6-ethyl-l,3,5-triazine Tins compound was prepared based on a known method [Helv. Chern. Acta, 33, 1365-1369 (1950)]. That is to say, 2 , 4 , 6-trichloro-l, 3, 5-triazine (4.61 g, 25.0 rnmol) was dissolved in benzene (50.0 mL) under an atmosphere of nitrogen and the solution cooled with an ice bath. While stirring the solution, ethylmagnesium bromide i •:.(.} M ether solution, 10.0 mL) was slowly added over 20 minutes and stirring carried out for a further 30 minutes while ice cooling. The reaction was monitored by thin layer chrornatography and, following the end of the reaction, saturated aqueous ammonium chloride solution (20.0 mL) was added to the reaction liquid and stirring carried out. Ether (200 mL) was also added and liquid separation performed. The organic layer obtained was removed, washed with distilled water (20.0 mL) and risen with saturated sodium chloride solution (20.0 mL) , alter which drying was carried out with anhydrous magnesium sulphate. By distilling off the solvent under reduced pressure, the crude target compound was i )1 rtained. The crude compound thus obtained was purified using silica gel chromatography (elution solvent: hexane/ethyl acetate == 100/1, v/v) and the target compound obtained (2. 67 g, 60% yield) . 6-ethyl-N,N'-bis(3-hydroxyphenyl)-1,3,5-triazine- Aiter dissolving 3-aminophenol (2.18 g, 20 mmol) in 1/4-'.i ; oxane (20.0 mL), 2, 4-dichloro-6-ethyl-l, 3, 5-triazine (;.78 g, 10 rnmol) was added and stirring carried out for 3 hours at 100°C under a nitrogen atmosphere. :'\,'llowinq the end of the reaction, the solvent was (i, stilled off under reduced pressure and the residue purified using silica gel column chromatography (elution solvent: methylene chloride/methanol = 20/1, v/v) and the target compound obtained (2.26 g, yield 70%). 'H NMR spectrum (DMSO, 400MHz), Mass spectrum (El), m/z: 323 (M+) (Production Example 2) /-Kthyl-N,N'-bis(3-hydroxyphenyl)pyrimidine-4, 6-diamine I Exempl if ied Compound No. 1-3) I 2 A) 4 , 6-dichloro-2-ethylpyrimidine Preparation was carried out based on a known method [J. Or.g., Vol.18, 653-656 (1953)]. That is to say, an •••••xcess amount. of phosphoryl chloride (6.34 mL, ,'0.0 rnmol) was added to 2-ethyl-lH-pyrimidine-4, 6-dione •; . .-1(1 q, 10.0 mmol) and the reaction mixture heated under reflux for 2 hours. After the solid material had completely dissolved, the reaction mixture was cooled to room temperature, and the unreacted phosphoryl chloride distilled off under reduced pressure. The residue was ,.idded to finely crushed ice (200 g) and left. After the ice had melted, ether (200 mL) was added to the reaction mixture, and liquid separation performed. The organic layer obtained was removed, washed with distilled water (20.0 mL) and then with saturated aqueous sodium chloride solution (20.0 mL), after which drying was performed with anhydrous magnesium sulphate. By d:.:.: tilling off the solvent under reduced pressure, crude rarget compound was obtained (1.68 g, crude yield 95%). t!hv crude 'compound obtained was used in the next reaction without further purification. 2-ethyl-N,N'-bis(3-hydroxyphenyl)pyrimidine-4,6- A;tei: dissolving 3-aminophenol (1.09 g, 10.0 mmol) in 2-ethoxyethanol (5.0 mL) , 4 , 6-dichloro-2-ethylpyrimidine 10.89 g, 5.0 mmol) was added and stirring carried out for b hours at 130°C. The reaction was monitored by thin layer chromatography .siid, following the end of the reaction, the solvent was distilled off under reduced pressure. The residue was purified using silica gel column chromatography (elution solvent: methylene chloride/methanol = 20/1, v/v) and the target compound obtained (0.97 g, yield 60%). 'H NMR spectrum (DMSO, 400MHz), Mass spectrum (El), m/z: 322 (M+) I I:> i" o d u c t i o n E x amp 1 e 3 ) ,,.-Methyl-N- ( 3-hydroxyphenyl) -N1 - (3-methoxyphenyl) - pvi irnidine-4 , 6-diamine (Exemplified Compound No. 1-108) '. )A; 2-methyl-4-chloro-6- (3-hydroxyphenylamino) -pyrimidine ••I, 6-(iichloro-2-methylpyrimidine (1.63 g, 10.0 mmol) prepared based on the method described in Production Kxarnple 2A above using 2-methyl-lH-pyrimidine-4, 6-dione in;-Lead of t: he 2-ethyl-lH-pyrimidine-4, 6-dione, was .-,.:r;wiy added to a 2-ethoxyethanol (5.0 mL) solution of '3-aminophenol (1.09 g, 10.0 mmol) and the reaction mixture heated for 4 hours at 130°C. The reaction was monitored by thin layer chromatography and, following i lie end of the reaction, the reaction mixture was cooled to room temperature and the precipitated white powder filtered off. The crude product filtered off was used in the subsequent reaction without further purification (1.76 g, crude yield 75%). 'H NMR spectrum (DMSO, 400 MHz), Mass spectrum (El), m/z: 234 (M-H+) 1 Hi X-methyl-N- (3-hydroxyphenyl) -N ' - ( 3-methoxyphenyl) -pyrimidine-4,6-diamine 2-methyl-4-chloro-6-(3-hydroxyphenylamino)pyrimidine sO.71 u, 3.0 mmol) was added to a 2-ethoxyethanol f'.'.O rrtL) solution of 3-methoxyaniline (0.37 g, 3.0 mmol) under a nitrogen atmosphere and the reaction mixture ::i. irred for ':. The reaction was monitored by thin layer chromatography and, at the end of the reaction, the solvent was H.! stilled off under reduced pressure. The residue was purified usinq silica gel column chromatography (elution solvent: methylene chloride/methanol = 20/1, v/v) and the target compound obtained (0.48 g, yield 50%) 'H NMR spectrum (CDC1,, 400 MHz), J - 8.0 Hz). • Mass spectrum (El), m/z: 322 (M+) •(Production Example 4) ;.-'-Methyl-N, N ' -bis ( 3-hydroxyphenyl) pyrimidine-4 , 6-diamine ^exemplified Compound No. 1-2) This compound was obtained (yield 60%) based on the av'thod described in Production Example 2B using 4,6-dichloro-2-methylpyrimidine instead of the 4,6-dichloro-2-ethylpyrimidine. 'H NMR spectrum (DMSO, 400 MHz), s). Mass spectrum (El), m/z: 308 (M+) (Production Example 5) H,N'-bis(j-hydroxyphenyl)pyrimidine-4,6-diamine ihxemplilied Compound No. 1-1) This compound was obtained (yield 60%) based on the method described in Production Example 2B using 4,6-dichloropyrimidine instead of the 4, 6-dichloro-2- ethylpyrimidine. 'H NMR spectrum (DMSO, 400 MHz), s)0 Mass spectrum (El), m/z: 294 (M+) ; i'.i:oduction Example 6) 1 •!, N ' -bi s ( 3-hydroxyphenyl) pyrimidine-2 , 4-diamine ; l-ixemp 1 i f ied Compound No . 2-1) This compound was obtained (yield 80%) based on the method described in Production Example 2B using 2,4-dichloropyrimidine instead of the 4,6-dichloro-2- •v hy Ipyr imidine . 'IINMR spectrum (DMSO, 400 MHz), Mass spectrum (El), m/z: 294 (M+) ': , n-i"uinet hyl-N, N ' -bis ( 3-hydroxyphenyl) pyrimidine-2 , 4-diarnirie (Exemplified Compound No. 2-11) Tfiis compound was obtained (yield 78%) based on the method described in Production Example 2B using 2,4- ' i. chluro-'-j, 6-dimethylpyrimidine instead of the 4,6- 'H NMR spectrum (DMSO, 400 MHz), S : 2.12(3H, s), 2.37C3H, s), 6.49C1H, dd, J = 1.6, 8.2 Hz), 6.67(2H, i), 6.88UH, t, J = 1.6 Hz), 6.94-7.20C2H, i), 7.06(1H, d, J=8.2Hz), 7.18UH, t, J = 8.2Hz), 9. 40-9. 60(4H, brs)0 Mass spectrum (El), m/z: 322 (M+) (i'roduction Example 8) 2-Butyl-N,N'-bis(3-hydroxyphenyl)pyrimidine-4,6-diamine '.Exemplified Compound No. 1-6) This compound was obtained (yield 73%) based on the method described in Production Example 2B using 4,6- d.j chloro-2-butylpyrimidine instead of the 4,6-dichloro- 2-ethylpyrimidine. '1INMR spectrum (DMSO, 400MHz), s). Mass spectrum (El), m/z: 350 (M+) - i- rc'pyi-M, N ' -bis ( 3-hydroxyphenyl) pyrimidine-4 , 6-diamine (Exemplified Compound 1-4) This compound was obtained (yield 68%) based on the inethoa described in Production Example 2B using 4,6-d i.chi 'HNMR spectrum (DMSO, 400 MHz), iidss spectrum (El), m/z: 336 (M+) •, i' r odu c t i o n F,xamp 1 e 1 (3) N, N'-his(3-hydroxyphenyl)-6-propyl-l,3,5-triazine-2,4-diamine (Exemplified Compound 4-11) This compC'Lind was obtained (yield 62%) based on the method described in Production Example IB using 2,4- dichloro-6-propyl-l,3,5-triazine instead of the 2,4-dichloro-6-ethyl-1,3,5-triazine. 'It NMR spectrum (DMSO, 400MHz), Mass spectrum (El), m/z: 337 (M+) i'Production Example 11) N--et.hy.L-N, N ' -bis ( 3-hydroxyphenyl) -2-methylpyrimidine-'•'!, (i-d iamino (Exemplified Compound No. 1-30) it This compound was obtained (yield 45%) based on the nethod described in Production Example 3B using 3-'•••i.hylaminophenol instead of the 3-methoxyaniline. 'H NMR spectrum (DMSO, 400 MHz), 1,N'-bis(3-hydroxyphenyl)pyridazine-3,6-diamine Exemplified Compound 5-1) 'his compound was obtained (yield 55%) based on the ic-thod described in Production Example 2B using 3,6- dichloropyridazine instead of the 4,6-dichloro-2-et.hylpyrimidine. >H NMR spectrum (DMSO, 400MHz), 5 : 6.28(2H, dd, 1 = 2.2, 7. 7 Hz), 6.96-7.07(4H, m), 7.06 (2H, s), 7.44(2H, t, J = 2.2 Hz), 8.78UH, s), 9.23UH, s). Mass spectrum (El), m/z: 294 (M+) (Production Example 13) . -Ami.no-N, N ' -bis ( 3-hydroxyphenyl) pyrimidine-4, 6-diamine (Kxemplif led Compound No. 1-22) • This compound was obtained (yield 55%) based on the mot hod described in Production Example 2B using 2-amino- ethylpyrimidine. Ml NMR spectrum (DMSO, 400 MHz), 6 : 5.49UH, s), 6.35(2H, d, J -8.0 Hz), 6.75(2H, brs), 6. 77-6. 86(4H, •), 6.96(2H, t, J = 8.0 Hz), 9. 14C2H. brs), 9.36(2H, brs). Mass spectrum (FAB), m/z: 310 (M+H+) (!' r o du c t io n K xamp1e 14) .2-Me thy It hi o-N , N ' -bis ( 3-hydroxyphenyl) pyrimidine-4 , 6-diamine (Exemplified Compound No. 1-20) This compound was obtained (yield 62%) based on the method described in Production Example 2B using 4,6- d :i chloro-2-methylthio-pyrimidine instead of the 4,6- 'H NMR spectrum (DMSO, 400 MHz), 6 :2.48(3H, s), 5.9K1H, s), 6. 39 (2H, dd, J = 1.4, 8.0 Hz), 6.92(2H, d, J = 8. 0 Hz), 6.99(2H, m), 7.06C2H, t, J = 8.0 Hz), 9.0K2H, s), 9.3K2H, s). Mass spectrum (El), m/z: 340 (M+) (Production Example 15) 2-Methylthio-N,N'-diethyl-N,N'-bis(3-hydroxyphenyl)-pyrimidine-4,6-diamine (Exemplified Compound No.1-71) This compound was obtained (yield 43%) based on the method described in Production Example 2B using 4,6-dichloro-2-methylthio-pyrimidine instead of the 4,6-dichloro-2-ethylpyrimidine, and using 3-ethylaminophenol instead of the 3-aminophenol. 'HNMR spectrum (DMSO, 400 MHz), Mass spectrum (El), m/z: 396 (M+) (Production Example 16) 6-Butoxy-N,N'-bis(3-hydroxyphenyl)-1,3,5-triazine-2,4-diamine (Exemplified Compound No. 4-81) This compound was obtained (yield 62%) based on the method described in Production Example IB using 6-butoxy-2,4-dichloro-l,3,5-triazine (10.0 mmol) instead of the 2,4-dichloro-6-ethyl-l,3,5-triazine. 'HNMR spectrum (DMSO, 400MHz), Mass spectrum (FAB), m/z: 368 (M+H+) (!' i o d u c t i o n E x amp 1 e 17) 6-Butoxy-N,N'-diethyl-N,N'-bis(3-hydroxyphenyl)-1,3,5-rriazine-2,4-diamine (Exemplified Compound No. 4-85) This compound was obtained (yield 47%) based on the method described in Production Example IB using 6-hutoxy-2,4-dichloro-l,3,5-triazine instead of the 2,4-dichloro-6-ethyl-l,3,5-triazine, and using 3-oLhyldminophenol instead of the 3-aminophenol. 'HNMR spectrum (DMSO, 400MHz), fi:0.83(3H, t, J = 7.3Hz), 1.08(8H. m), 1.24C2H, in), 1.52(2H, i), 3.79(4H, m), 4.02(2H, m), 6.60-6.70(6H, b), 7.15C2H, t, J = 8.0 Hz). Mass spectrum (FAB), m/z: 424 (M+H+) (Production Example 18) N,N'-bis(3-hydroxyphenyl)-5-nitropyrimidine-4,6-diamine (Exemplified Compound No. 1-173) This compound was obtained (yield 80%) based on the method described in Production Example 2B using 4,6-<:1 j.chloro-t instead of the> 2 - e t h v 1 p y r i m i. d i n e . 'H NMR spectrum (DMSO, 400 MHz), 8 : 6.65(2H, n), 7.95(2H, m), 7.10 -7. 22(4H, m). 8.20C1H, s), 9.60(2H, a). 10.80C2H, brs). Mass spectrum (El), m/z: 339 (M+) iProduction Example 19) N,N'-bis(3-hydroxy-2-methylphenyl)pyrimidine-4,6-diamine (Exemplified Compound No. 1-86) This compound was obtained (yield 40%) based on the method described in Production Example 2B using 4,6-dichloropyrimidine instead of the 4, 6-dichloro-2-elhylpyrimidine, and using 3-amino-2-methylphenol Instead of the 3-aminophenol. 'H NMR spectrum (DMSO, 400 MHz), a : 1.95C6H, s), 5.48 (IB, s), 6.6K2H, d, J = 5.3 Hz), 6.73(2H, d, J = 5.3 Hz), 6.92(2H, d, J = 5.3 Hz), 8.00(1H, s), 8.290H, s), 9.30(1H, brs). Mass spectrum (El), m/z: 322 (M+) (Production Example 20) N, N'-(3-hydroxy-2-methylphenyl)pyrimidine-2,4-diamine (Exemplified Compound No. 2-101) This compound was obtained (yield 50%) based on the method described in Production Example 2B using 2,4-dichloropyrimidine (0.74 g, 5.00 mmol) instead of the 4,6-dichloro-2-ethylpyrimidine, and using 3-amino-2-methylphenol instead of the 3-aminophenol. Mass spectrum (El), m/z: 322 (M+) reduction Example 21 N, N'-bis(3~hydroxy-4-methoxyphenyl)pyrimidine-4,6-diamine (Exemplified Compound No. 1-88) Tliis compound was obtained (yield 67%) based on the method described in Production Example 2B using 4,6-dichloropyrimidine instead of the 4,6-dichloro-2-ethylpyrimidine, and using 3-amino-4-methoxyphenol instead of the 3-aminophenol. 'H NMR spectrum (DMSO, 400 MHz), 8 : 3.73(6H, s), 5.93OH, s), 6.8K4H. n), 7.00(2H, s), 8.120H, s), 8. 71 OH, brs), 8.990H. brs). Mass spectrum (El), m/z: 354 (M+) (Production Example 22) ^-Methyl-N,N'-bis(3-hydroxyphenyl)pyrimidine-2,4-diamine (Exemplified Compound 2-6) This compound was obtained (yield 71%) based on the method described in Production Example 2B using 2,4-dichloro-6-methylpyrimidine instead of the 4,6-dichloro- 2-ethylpyrimidine. 'H NMR spectrum (DMSO, 400 MHz), d :2.36(3H, s), 6.170H, s), 6.460H, dd, 1 = 1.9. 8. 5 Hz), 6.500H, dd, J = 1.9, 8.5 Hz), 6.940H, s), 7.01-7. 12(3H, n), 7.20(2H, t, J = 8. 5 Hz), 9. 35 OH, s), 9. 44 OH, s), 9.500H, brs), 9.800H, brs). Mass spectrum (El), m/z: 308 (M+) (Production Example 23) ^-Methyl-N-(3-chlorophenyl)-N'-(3-hydroxyphenyl)-pyrimidine-4,6-diamine (Exemplified Compound 1-161] This compound was obtained (yield 57%) based on the method described in Production Example 3B using 3-ehloroaniline instead of the 3-methoxyaniline . 'II NMR spectrum (CDC1,. 400 MHz), Mass spectrum (El), m/z: 326 (M+) (['reduction Example 24) /-Methyl-N, N ' -bis (4, 6-dif luoro-3-hydroxyphenyl ) - pyr imidine-4 , 6-diamine (Exemplified Compound No. 1-171) This compound was obtained (yield 57%) based on the method described in Production Example 2B using 4,6-'lichloro-2-methylpyrimidine instead of the 4, 6-dichloro-2-ethyipyrimrdine, and using 5-amino-2, 4-dif luorophenol instead of the 3-aminophenol . ih NMR spectrum (DMSO, 400 MHz), 6 : 2.30C3H, s), 5.77(1H, s), 7. 2K2H, t. 3JHF = 11.0 Hz), 7.4K2H, t, «JHF = 8.8 Hz), 8.58(2H, brs), 9.79(2H, brs), Maws spectrum (El), m/z: 380 (M+) ; ['reduction Example 25) : -1 sop ropy 1-N, N ' -bis (3-hydroxyphenyl) pyr imidine-4 , 6-liamine (Exemplified Compound No. 1-5) 'his compound was obtained (yield 65%) based on the 'iethod described in Production Example 2B using 4,6- 1 i chloro-2-isopropylpyrimidine instead of the 4,6- i ichloro-2-ethylpyrimidine . 41 NMR spectrum (CD3OD, 400 MHz), 5 : 1. 32 (6H, d, J = 6. 9 Hz), 2. 88 (1H, septet, J = 6.9 Hz), 6.08UH, s), 6.47(2H, ddd, J = 0.9, 2.2, 8.1 Hz), 6.90C2H, ddd, J = 0.9, 2.2, 8.1 Hz), 6.98C2H, t, J = 2.2 Hz), 7. 09(2H, t, J - 8. 1 Hz), Mass spectrum (El), m/z: 336 (M+) (Production Example 26) 2-Methyl-N , N ' -bis ( 3-hydroxy-5-trif luoromethylphenyl ) -pyr imidine-4 , 6-diamine (Exemplified Compound No. 1-90) compound was obtained (yield 43%) based on the method described in Production Example 2B using 4,6-dichloro-2-methylpyrimidine instead of the 4 , 6-dichloro-/'-ethylpyrimidine, and using 3-amino-5-trif luoromethyl- phenol instead of the 3-aminophenol . 'H NMR spectrum (CD,OD, 400 MHz), d : 2.46(3H, s), 6. OS (1H, s), 6.68(2H, m), 7.30(2H, n) , 7.34(2H, t, J = 2.0 Hz). Mass spectrum (El), m/z: 444 (M+) (!' r odu ct i on Kxamp 1 e 27) N,N'-bis(3-hydroxyphenyl)-6-methyl-l, 3, 5-triazine-2,4-di.amine (Exemplified Compound No. 4-1) This compound was obtained (yield 73%) based on the method described in Production Example IB using 2,4-d:i chloro-6-methyl-l, 3, 5-triazine instead of the 2,4- dichloro-b-el. liyl-1, 3, 5-triazine . 'H NMR spectrum (DMSO, 400 MHz), 5 : 2.29(3H, s), 6.43(2H, dd, J = 2.4, 8.0 Hz), 7.06C2H. t, J = 8.0 Hz), 7.13C2H, brs), 7.30(2H, d, J = 8.0 Hz), 9.27(2H, brs), 9.53(2H, brs). Mass spectrum (El), m/z: 309 (M+) (Production Example 28) f.-Butyl-N, N ' -bis (3-hydroxyphenyl) -1,3, 5-triazine-2, 4-c] i amine (Exemplified Compound No. 4-21) This compound was obtained (yield 68%) based on the method described in Production Example IB using 6-butyl-'.•'., 4-dichloro-l, 3, 5-triazine instead of the 2,4-dichloro-6-ethyl-1,3,5-triazine. 41 NMR spectrum (DMSO) 400 MHz), 6:0.92(3H, t, J = 7.3Hz), 1.37(2H, sextet, J = 7/3 Hz), 1.73(2H, quintet, J = 8.0 Hz), 2.5K2H, n). 6. 42(2H, dd, J - 2.5, 8.0 Hz), 7.05(2H, t, J = 8.0 Hz), 7.13(2H, s), 7.3K2H, d, J = 8.0 Hz), 9.26(2H, brs), 9.5K2H, brs). Mass spectrum (El), m/z: 351 (M+) (Production Example 29) N,N'-dimethyi-N,N'-bis(3-hydroxyphenyl)pyrimidine-4,6-diamine (Exemplified Compound No. 1-28) This compound was obtained (yield 43%) based on the method described in Production Example 2B using 4,6-dichloropyrimidine instead of the 4,6-dichloro-2-ethylpyrimidlne, and using 3-methylaminophenol instead ;:.:. t: he 3-ami nophenol. 'II NMR spectrum (DMSO, 400 MHz), (5 : 3.28(6H, s), 5.50UH, s), 6.54 -6. 64 (6H, m), 7. 1K2H, t, J = 8.0 Hz), 8.21(1H, s), 9.50(2H, brsK Mass spectrum (El), m/z: 340 (M+ 2~Methyl-N,N'-dimethyl-N,N'-bis(3-hydroxyphenyl)- pyrimidine-4,6-diamine (Exemplified Compound No. 1-31) This compound was obtained (yield 45%) based on the method described in Production Example 2B using 4,6-• lichloro-2-methylpyrimidine instead of the 4,6-dichloro-,•:-fthy l.pyrimidine, and using 3-methylaminophenol instead or the 3-cirriinophenol. 'H NMR spectrum (DMSO, 400 MHz), brs)» Mass spectrum (El), m/z: 336 (M+) (Production Example 31) (>- I sobutyl-N, N ' -bis (3-hydroxyphenyl) -1,3, 5-triazine-2, 4-ciiamine (Exemplified Compound No. 4-26) This compound was obtained (yield 50%) based on the method described in Production Example IB using 6-isoDutyl-2,4-dichloro-l,3,5-triazine instead of the 2,4-dichloro-6-et hyl-1,3,5-triazine. 'H NMR spectrum (DMSO, 400 MHz), 6 : 0. 99 (6H, d, J = 6. 8 Hz), 2. 42 (1H, a), 2.49(2H, d, J = 7.2 Hz), 6.54(2H, dd, J = 1.5, 8.0 Hz), 7.00 ~7.09(2H, fli), 7.1K2H, t, J = 8.0 Hz), 7.21 (2H, i). Mass spectrum (El), m/z: 351 (M+) 6-Ethyl-N,N'-bis(3-hydroxy-4-methylphenyl)-1,3,5-triazine-2,4-diamine (Exemplified Compound No.4-212) This compound was obtained (yield 55%) based on the method described in Production Example IB using 3-amino-j-methylphenol {sic} instead of the 3-aminophenol. 'H NMR spectrum (DMSO, 400 MHz), 7.02(2H, d, 1-8.0 Hz). Mass spectrum (El), m/z: 351 (M+) i i' r od u c tion Examp1e 33) 6-t-Butyl-N,N'-bis(3-hydroxyphenyl)-l,3,5-triazine-2,4-diamine (Exemplified Compound No. 4-36) This compound was obtained (yield 48%) based on the method described in Production Example IB using 6-t-butyl-2,4-dichloro-l,3,5-triazine instead of the 2,4- d.i ohloro-b-et.hyl-1, 3, 5-triazine. 'H NMR spectrum (DMSO, 400 MHz), d :1.32(9H, s), 6.43(2H, dd, J - 2. 0, 8.0 Hz), 7.06(2H, t, J = 8.0 Hz), 7.20(2H, brs), 7.34(2H, d, J = 8.0 Hz), 9.27(2H, brs), 9.39(2H, brs). Mass spectrum (El), m/z: 351 (M+) (1.! r o d u c t i o n E x a mp 1 e 34) b-s-Butyl-N, N'-bis(3-hydroxyphenyl)-1,3,5-triazine-2,4-diamine (Exemplified Compound No. 4-31) This compound was obtained (yield 52%) based on the method described in Production Example IB using 6-s- butyl-2 , 4-dichloro-l,3,5-triazine instead of the 2,4-dichloro-6-ethyl-l,3,5-triazine. 'H NMR spectrum (DMSO, 400 MHz), 5:0.90(3H, t, J = 7.4Hz), 1.26(3H, d, J = 6.4 Hz), 1.59(1H, ddq, J = 6.4, 7.4, 14.0 Hz), 1.83(1H, ddq, J = 6.4, 7.4, 14.0 Hz), 2.600H, ddq, J = 6. 4 , 6 . 4 , 6 . 4 Hz), 4.00(2H, brs), 6.5K2H, d, J = 7.2 Hz), 7.09(2H, d, J - 7.5 Hz), 7.12(2H, s), 7.27C2H, d, J - 7.5 Hz), 9.40UH, brs), 9.90UH, brs). Mass spectrum (El), m/z: 351 (M+) (Example 1) Action in inhibiting the lowering of MTT reduction capacit y The HeLa cells employed were purchased from the Uainippon Pharmaceutical Co. The HeLa cells were seeded by suspension in MEM (Minimum essential medium; produced by the Sigma Chemical Co.) containing ]0"> inactivated FBS (foetal bovine serum) such that there were 1,000 per well in a 96-well nncroplate, and then culturing was carried out overnight in an incubator at 37°C in the presence of 5% C02. The test compound was dissolved in dimethyl sulphoxide (DMSO) and diluted with the MEM medium so that the final ~ :r>ncentration of DMSO was no more than 0.1 wt%, and added to the cells seeded the previous day. A solution oi. (^-amyloid protein (Apl-40: produced by the Sigma Chemical Co.) dissolved in MEM medium was added so the final A|31-40 concentration was 100 ng/mL. Overnight culturing was carried out using an incubator at 37°C in Lhe presence of S'a CC>2, with 100 ja,L/well of MEM medium containing 5v deactivated FBS. Now, prior to use, the Apl-40 had been dissolved in buffer and left overnight so that the amyloid coagulated. In order to determine the percentage inhibition of the v.f-st compound, cells alone, cells where Apl-40 had been ,.u:ided, and cells where only the test compound had been added, were also incubated overnight under the same conditions. The following day, there was added 10 jaL/well of MTT [3-!1, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium hrornide: produced by Wako Pure Chemical Industries] prepared at a concentration of 5 mg/mL with phosphate buffered saline (PBS), and incubation carried out for 2 hours at 37°C in the presence of 5% CC>2. The medium was then eliminated and the formazan dye produced measured colorirnetricaily (A570 nm-A650 nm) using a Microplate Reader (produced by the Molecular Devices Co.), by dissolving with the addition of 100 (4.L per well of isopropanol. In this way, the change in the MTT reduction capacity of the HeLa cells was measured. '['he percentage inhibition (%) by the test compound was determined from the following formula. inhibition (',) [(a - b) / (a - c) ] x 100 wlie re MTT reduction capacity when untreated h - MTT reduction capacity when A(3l-40 and the test c omp o u n d are added (..: - MTT reduction capacity when only Afil-40 is added T.ible 6 shows the action in inhibiting the lowering of the MTT reduction capacity by A01-40 (100 nM) in HeLa cells, denoted by the 50% inhibitory concentration As can seen from Table 6, the compounds of the present invention show outstanding action in inhibiting a Lowering of the MTT reduction capacity. Table 6 Test Compound IC50 (urn) compound of Production Example 1 3.5 compound of Production Example 2 1 .9 compound of Production Example 4 6.0 compound of Production Example 5 9.6 compound of Production Example 6 6.7 compound of Production Example 8 5.5 compound of Production Example 9 2.4 compound of Production Example 10 4.2 compound of Production Example 13 5.5 compound of Production Example 18 3.8 compound of Production Example 27 2.4 compound of Production Example 33 2.2 compound of Production Example 34 4.1 compound of Production Example 35 2.1 compound of Production Example 36 5.8 When testing was carried out by the same method as above using 4 - ( 7-hydroxy-2 , 4 , 4-trimethyl-chroman-4-yl ) benzene- i,.j-diol, and the action in suppressing the lowering of MTT tunction measured as the 50% inhibitory concentration (IC50), the measured result obtained was '•,'/. UM. (Example 2) Action in suppressing long-term potentiation inhibition The method for testing the suppression of the impairment (c long-term potentiation was based on that described in .1. Neurosci. Vol.20, 2003-10 (2000). That is to say, acute1 sections of thickness 400 jj,m were prepared from ' ::he hippocampus of the brains of 3-4 week old male Wistar rats. These acute sections were immersed in ,-iitificial cerebrospinal fluid in which p-amyloid protein (Apl-42: produced by the Sigma Chemical Co.) and compound from Production Examples I or 12 'had been •dissolved, and pretreatment carried out for 5 hours. In the measurement using the compound from Production Kxample 1, the concentration of the A(3l-42 in the artificial cerebrospinal fluid was 500 nM and the concentration of the compound from Production Example 1 w.is 1 (.tg/mL. In the measurement using the compound from rreduction Example 12, the concentration of the A(3l-42 in the artificial cerebrospinal fluid was 1 |J,M and the concentration of the compound from Production Example 12 vms 3 fiq/mL. Now, the AJ31-42 was used after coagulation •:) f. the amyloid by leaving overnight. !()0 pulses 01 high frequency stimulation at 100 Hz were ripplied to the pretreated acute sections, and the field excitatory postsynaptic potential: fEPSP) measured by an extracellular recording method. The fEPSP was measured at 30 second intervals following .implication of the high frequency stimulation and the iEPSP slope (units [%]) measured. The average values of the slope over 0-20 minutes, 20-40 minutes and 40-r>0 minutes were determined. This test was repeated five i Lines over. The results are shown in Table 7. In the 4 -able, the figures are the average values ± standard deviation for the five averages obtained in the five 'ests. "Test. 1" shows the measurements employing the compound from Production Example 1 and "Test 2" shows the measurements employing the compound from Production Example 12. "A(3" denotes the Apl-42. A.; controls, measurements were made of the fEPSP [mV] under the same conditions for acute sections pretreated with the artificial cerebrospinal fluid alone, acute sections pretreated with the artificial cerebrospinal fluid in which Apl-42 had been dissolved, and acute sections pretreated with artificial cerebrospinal fluid in which only the compound from Production Example 1 or i:; had been dissolved, and then the average value of the I. EPSP slope ['A ] obtained. Table 7 Test 1 Control group A|l(500nM) Prod. Ex. 1 compound* (lug/mL) Value of fEPSP Slope [%] 0-20 20-40 40-60 minutes minutes minutes 158.815.2 157.5±4.2 155.615.4 145.815.8 136.114.0 113.0+2.6 155.313.4 156.513.9 155.815.0 A|H50()nM) +I'rod.Hx. I compound (l)ng/mL) 150.018.4 149.616.9 151.217.5 cst (.'ontrol group Prod. Ex. 12 compound** (3 u.g/mL) A(i( li-tM) + Prod. Ex. 12 compound (3 ug/mL) 145.815.8 136.114.0 113.0+2.6 132.318.8 114.416.4 103.715.4 175.317.4 162.919.8 160.8110.3 161.712.6 148.113.1 146.214.6 Notes: :|:Prod.Ex. 1 compound = compound from Production Example 1 !l:*Prod.Ex.!2 compound = compound from Production Example 12 in the control group, by applying high frequency stimulation, an increase in the synapse transmission was confirmed over a 60 minute period. However, in the nroup where the sections had been pretreated for 5 hours w:tn A^l-42, while long-term potentiation was induced i:s maintenance was impaired. In contrast, by pretreating for 5 hours with A(3l-42 Together with the compound synthesized in Production Example 1 or in Production Example 12, which is inactive on its own, the impairment of the LTP due to the Apl-42 w a s s u p p r e s s e d . As can be seen in Table 7, the compounds of the present invention show an outstanding suppression action against i. he impairment of synapse transmission produced by Ap. Average values of the fEPSP slope [%] were determined in the same way as in the test method described above, for 4-(7-hydroxy-2,4,4-trimethyl-chroman-4-yl)benzene-1,3-diol (Compound A in the table) . The measured values obtained are shown below. ( 'ontrol group ( 'ompound A ( l(.ig/mL) A(H 1 f.iM) + ( 'ompound A ( 1 )ig/mL) Table 8 Value of fEPSP Slope [%] 0-20 20-40 40-60 minutes minutes minutes 158.715.1 157.514.1 155.515.3 133.519.5 123.816.6 122.8 ±7.1 168.6+13.0 146.6115.9 149.7 ±16.1 159.516.6 142.815.4 137.3+4.5 (Example 3) Ap fibril-formation inhibiting action and fibrillar Ap breakdow n a c ti on The A(> fibril-formation inhibiting action and fibrillar Ap breakdown action were evaluated using the thioflavin binding assay method. The details of the test method are based on the method described in J. Biol. Chem. Vol.274, 25945-25952 (1999). i n the measurement of the inhibition of A(3 fibril-format, ion, the concentration of the Afil-42 was 25 fj,M and the concentration of the compound synthesized in Production F.xample 4 or Production Example 12 was 100 ng/rriL in each case. The measurement of the Ap fibril-formation inhibiting action was carried out [.'.•I lowing incubation for 2 days at 37°C of the Apl-42 a , one and of the Apl-42 to which the compound . ynLhesizecl in Production Example 4 or Production Example 12 had been added,. i;' In the measurement of the fibrillar Ap breakdown action, i.lie concentration of the Apl-42 was 25 |^M and the .•oncentrat ion of the compound synthesized in Production Ixample •'! or Production Example 12 was 100 |ag/mL in each :'fise. After incubating the Apl-42 for 2 days or 3 days at 37°C, the compound synthesized in Production Example 1 or Production Example 12 was or was not added, and then further incubation performed for 2 days, after -vhich measurement of the fibrillar Ap breakdown action /^cii; performed. The measurements of the Ap fibril-formation inhibiting action and of the fibrillar AP breakdown action were carried out by placing a 100 (j,L sample obtained by p r et reatment as described above, plus 800 (.iL of d.i stilled water, 1 mL of glycine (100 mM) and 50 fiL of ihioflavin (100 f-iM) in a cuvette, and measuring the !iuoresoence at an excitation wavelength of 435 nm and a fluorescence wavelength of 490 nm. The results are shown in Table 9. The figures in the rai:ne show the calculated percentages taking the iiuorescent intensity obtained when the fluorescence of t he sample obtained by incubating Apl-42 (25 jo,M) alone by the above method, and measured at an excitation wavelength of 435 nm and a fluorescence wavelength of 440 nm, was taken as 100. The figures are in the form of the average value ± standard deviation, for the three to nine averages obtained in three to nine tests. In the table, "Test 3" shows the measurements using the compound 1 rorn Production Example 4, and "Test 4" shows the measurements using the compound from Production Example 12. "Ap" is for the A01-42. Table 9 Test 3 fibril-formation inhibiting action (fluorescent intensity %) fibrillar breakdown action (fluorescent intensity %) Ap(25uM) + Prod.Hx. 4 compound* (100|j.g/mL) Test 4 A(S(25(.iM) A|K25u,M)+Prod. Ex. 12 compound" (100^g/mL) 100.00 ±1.18 16.26 ±5.30 100.00 + 2.24 1.69 ±1.324 100.00 ± 8.88 30.63 ±1.26 100.00 ± 2.07 28.49 ±5.17 Notes: *Prod.Ex.4 compound = compound from Production Example 4 **Prod.Ex.l 2 compound = compound from Production Example 12 With A|i by itself, strong thioflavin fluorescence was confirmed. This shows that AP forms fibrils. However, in the samples obtained by adding the compound from Production Example 4 or from Production Example 12 prior to fibril formation, there was a weakening of the thioflavin fluorescence, indicating that the AP fibril-formation was inhibited. The same results were also obtained with samples obtained by adding the compound (- rom Production Example 4 or Production Example 12 after r :bril. formation, indicating that there was a fibrillar A (3 breakdown action. As. shown in Table 8 {sic}, as well as the compounds of me present invention acting to inhibit Ap fibril-rormation, it is clear that they also act to break down formed A|3 fibrils . (Preparation Example 1) A powder preparation comprising the compound from Production Example 1 when '. q vf the compound from Production Example 1, :-M'r q > :> I: lactose and 100 g of corn starch are mixed m.qother, ri powder preparation is obtained. (Preparation Example 2) Granules 'comprising the compound from Production Example 1 /•-iter mixing <:> g of the compound from Production Example I, H6b g ot lactose and 100 g of hydroxypropyl cellulose ••'. r low degree of substitution, 300 g of 10% aqueous hydroxypropyi cellulose solution is added and kneading performed. The mixture is extruded and granulated using a granulator, and then dried to obtain a granular preparation (granules). (Preparation Example 3) Capsules of the compound of ;\! eduction Example 1 Alter mixing together 5 g of the compound from Production Example 1, 115 g of lactose, 58 g of corn starch and 2 g of magnesium stearate using a V-shape ii; ixer, No.! capsule containers are filled with 180 mg ^quantities oi the mixture and capsules obtained. (Preparation Example 4) Tablets of the compound of Production Example 1 AMer mixing together 5 g of the compound from Production Example 1, 90 g of lactose, 34 g of corn .--•larch, 20 q of crystalline cellulose and 1 g of magnesium stearate in a blender, tableting is carried cut with a tableting machine and tablets obtained. [industrial Application Potential] The drugs of the present invention which contain a compound of general formula (I) are outstanding in their c.ict ion in suppressing the fall in MTT reduction capacity brought about by [i-amyloid protein, and in inhibiting impairment of long-term potentiation of hippocampal nerve cells, so they are useful as preventatives or remedies for Alzheimer's disease. The amyloid protein fibril-formation inhibitors of the piesent invention are outstanding in their action in inhibiting amyloid protein fibril-formation and in their fibrillar amyloid protein breakdown action, so they are valuable as preventatives or remedies for amyloidosis, .such as Alzheimer's disease, type 2 diabetes, i rnmunoqlobulinic amyloidosis, reactive amyloidosis, '. ..uriiiial amyloidosis, dialysis-related amyloidosis, eeiiile amyloidosis, cerebrovascular amyloidosis, hereditary cerebral haemorrhage with amyloidosis, Ci eutzfeldt-Jakob disease, bovine spongiform encephalitis (BSE), scrapie, medullary carcinoma of the thyroid, insulinoma, localized atrial amyloid, umyloidosiK eutis and localized nodular amyloidosis, 1 .'i. oierably tor Alzheimer's disease, type 2 diabetes, siia lysis-related amyloidosis, familial amyloidosis, Creutzfeldt-Jdkob disease and BSE, in particular for Alzheimer's disease and type 2 diabetes. K1.: i.: I:hermorc, the nitrogen-containing heteroaryl derivatives of the present invention and their iharmacoloqically permitted salts are valuable as i ieventives or remedies for Alzheimer's disease of warmblooded animals (in particular humans), or as amyloid protein fibril-formation inhibitors. WE CLAIM: 1. Nitrogen-containing heteroaryl derivatives in the treatment of Alzheimer's disease represented by the following general formula (VII) (Formula Removed) where R1 and R2 each independently represent a hydrogen atom or C1-6 alkyl group, Z1 and 7? each independently represent a hydrogen atom, C1-6 alkyl group, C1-6 alkoxy group, halogen atom or halo-C1-6 alkyl group, Z4 and Z5 each independently represent a hydrogen atom or halogen atom, and A represents a group of formula (II) to (VI) below (Formula Removed) where R3 represents a hydrogen atom, C1-6 alkyl group, C1-6 alkoxy group, mercapto group, C1-6 alkylthio group, amino group, mono- or di-C1-6 alkylamino group or hydroxy group, R4 represents a hydrogen atom or nitro group, R5 represents a hydrogen atom or C1-6 alkyl group, R6 represents a hydrogen atom, C1-6 alkyl group, C1-6 alkoxy group, mercapto group, C1-6 alkylthio group, amino group, mono- or di-C1-6 alkylamino group or hydroxy group, R7 and R8 each independently represent a hydrogen atom, C1-6 alkyl group, C1-6 alkoxy group, mercapto group, C1-6 alkylthio group, amino group or mono- or di-C1-6 alkylamino group, R9 represents a C1-6 alkyl group, C1-6 alkoxy group, mercapto group, C1-6 alkylthio group, amino group, mono- or di-C1-6 alkylamino group or hydroxy group, and R10 and R11 each independently represent a hydrogen atom, C1-6 alkyl group, C1-6 alkoxy group, C1-6 alkylthio group, or mono- or di-C1-6 alkylamino group), or pharmacologically permitted salts thereof such as herein described with the proviso that where the compound is of formula V, it is not 2-amino-4,6-di-(meta-hydroxyphenylam.ino)-s-triazine or 2-amino-4,6-di-(hydroxytolyamino) -s-triazine. 2. Nitrogen-containing heteroaryl derivatives or pharmacologically permitted salts thereof as claimed in Claim 1, where R1 and R2 are each independently a hydrogen atom or C1-2 alkyl group. 3. Nitrogen-containing heteroaryl derivatives or pharmacologically permitted salts thereof as claimed in Claim 2, where R1 and R2 are hydrogen atoms. 4. Nitrogen-containing heteroaryl derivatives or pharmacologically group of formula (II) where R3 is a trydrogen atom, C1-5 alkyl, C1-3 alkylthio or mono- or di-C1-3 alkylamino group, and R4 is a hydrogen atom or nitro group), a group of formula (III) where R5 and R6 are each independently a hydrogen atom or C1-2 alkyl group, a group of formula (IV) where R7 and R8 are each independently a hydrogen atom or C1-2 alkyl group, a group of formula (V) where R9 is a C1-5 alkyl, C1-4 alkoxy or a C1-4 alkylthio group, or a group of formula (VI) where R10 and R11 are each independently a hydrogen atom or C1-3 alkyl group. 5. Nitrogen-containing heteroaryl derivatives or pharmacologically permitted salts thereof as claimed in any one of Claims 1 to 3, where A is a group of formula (II) where R3 is a hydrogen atom, C1-5 alkyl, C1-3 alkylthio or mono- or di-Ci-3 alkylamino group, and R4 is a hydrogen atom or nitro group, a group of formula (III) where R5 is a hydrogen atom and R6 is a methyl or ethyl group, a group of formula (IV) where R7 and R8 are hydrogen atoms, a group of formula (V) where R9 is a C1-5 alkyl, C1-4 alkoxy or C1-4 alkylthio group, or a group of formula (VI) where R10 and R11 are hydrogen atoms. 6. Nitrogen-containing heteroaryl derivatives or pharmacologically permitted salts thereof as claimed in any of Claims 1 to 3, where A is a group of formula (II) where R3 is a hydrogen atom, C1-4 alkyl or amino group, and R4 is a hydrogen atom or nitro group or a group of formula (V) where R9 is a C2-4 alkyl or a butoxy group. 7. Nitrogen-containing heteroaryl derivatives or pharmacologically permitted salts thereof as claimed in any of Claims 1 to 3, where A is a group of formula (II) where R3 is an ethyl, propyl, isopropyl or amino group and R4 is a hydrogen atom, or R3 is a hydrogen atom and R4 is a nitro group or a group of formula (V) where R9 is a C2-4 alkyl group. 8. Nitrogen-containing heteroaryl derivatives or pharmacologically permitted salts thereof as claimed in any 01 Claims I to 7, where Z1 and Z2 are each independently a hydrogen atom or para-position fluorine atom., chlorine atom or C1-2 alkyl group, the hydroxy group on the phenyl ring to which Z1 is bonded is in the meta-position, and Z4 and Z5 are hydrogen atoms. 9. Nitrogen-containing heteroaryl derivatives or pharmacologically permitted salts thereof as claimed in any of Claims 1 to 8, where Z1 and Z2 are each independently a hydrogen atom or para-position fluorine atom, chlorine atom or C1-2 alkyl group, the hydroxy group on the phenyl ring to which Z1 is bonded is in the meta-position, and Z4 and Z5 are hydrogen atoms. 10. Nitrogen-containing heteroaryl derivatives or pharmacologically permitted salts thereof as claimed in any of Claims 1 to 7, where Z1 and Z2 are hydrogen atoms or para-position methyl groups, the hydroxy group on the phenyl ring to which Z1 is bonded is in the meta-position, and Z4 and Z5 are hydrogen atoms. 11. A nitrogen-containing heteroaryl derivative as claimed in Claim 1 which is selected from any of the following, or pharmacologically permitted salts thereof; N,N'-bis(3-hydroxyphenyl)pyrimidine-4,6-diamine, 2 -methyl- N, N' -bis(3 -hydroxyphenyl) pyrimidine-4,6-diamine, 2-ethyl-N,N'-bis(3-hydroxyphenyl)pyrirmdine-4,6-diamine, 2-propyl-N,N'-bis(3-hydroxyphenyl)pyrirnidine-4,6-diamine, 2-isopropyl-N,N'-bis(3-hydroxyphenyl)pyrimidine-4,6-diamine, 2-butyl-N,N'-bis(3-hydroxyphenyl)pyrimidine-4,6-diamine, 2-amino-N N'-bis(3-hyaroxyphenyl)pyrimidine-4,6-diamine, N,N'-bis(3-hydrophenyl)-5-nitropyrimidine-4,6-diamine, N, N' -bis (3 -hy droxyphenyl) pyrimidine- 2,4-diamine, 6-ethyl-N,N'-bis(3-hydroxyphenyl)-l,3,5-triazine-2,4-diamine, N,N'-bis(3-hydroxyphenyl)-6-propyl-l, 3,5-triazine-2,4-diamine, 6-isobutyl-N,N'-bis(3-hydroxyphenyl)-1,3,5-triazine-2,4-diamine, 6-sec-butyl-N,N'-bis(3-hydroxyphenyl}-1,3,5-triazine- 2,4-diamine, 6-tert-butyl-N,N'-bis(3-hydroxyphenyl)-1,3,5-triazine-2,4-diamine, 6-ethyl-N,N'-bis(3-hydroxy-4-methylphenyl)-l,3,5-triazine-2,4-diamine and N, N' -bis (3 -hydroxyphenyl) pyridazine- 3,6-diamine. 12. A nitrogen-containing heteroaiyl derivative as claimed in Claim 1 selected from the following, or pharmacologically permitted salts thereof; 2-methyl-N,N'-bis(3-hydroxyphenyl)pyrimidine-4,6-diamine and N,N'-bis(3-hydroxyphenyl)pyridazine-3,6-diamine. |
---|
1578-DELNP-2004-Claims-(02-12-2010).pdf
1578-delnp-2004-claims-(11-06-2008).pdf
1578-DELNP-2004-Claims-(28-05-2008).pdf
1578-DELNP-2004-Correspondence-Others-(04-06-2008).pdf
1578-delnp-2004-correspondence-others-(11-06-2008).pdf
1578-DELNP-2004-Correspondence-Others-(20-04-2010).pdf
1578-delnp-2004-correspondence-others.pdf
1578-delnp-2004-description (complete)-11-06-2008.pdf
1578-delnp-2004-description (complete)-28-05-2008.pdf
1578-delnp-2004-description (complete).pdf
1578-DELNP-2004-Form-1-(02-12-2010).pdf
1578-DELNP-2004-Form-1-(28-05-2008).pdf
1578-DELNP-2004-Form-2-(02-12-2010).pdf
1578-DELNP-2004-Form-2-(28-05-2008).pdf
1578-DELNP-2004-Form-3-(28-05-2008).pdf
1578-DELNP-2004-GPA-(28-05-2008).pdf
1578-delnp-2004-pct-notificatian.pdf
1578-delnp-2004-pct-search report.pdf
1578-DELNP-2004-Petition-138-(28-05-2008).pdf
Patent Number | 245132 | |||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Indian Patent Application Number | 1578/DELNP/2004 | |||||||||||||||||||||
PG Journal Number | 01/2011 | |||||||||||||||||||||
Publication Date | 07-Jan-2011 | |||||||||||||||||||||
Grant Date | 04-Jan-2011 | |||||||||||||||||||||
Date of Filing | 07-Jun-2004 | |||||||||||||||||||||
Name of Patentee | BTG INTERNATIONAL LTD., | |||||||||||||||||||||
Applicant Address | 10 FLEET PLACE, LIMEBURNER LANE, LONDON EC4M 7SB, U.K. | |||||||||||||||||||||
Inventors:
|
||||||||||||||||||||||
PCT International Classification Number | C07D237/20 | |||||||||||||||||||||
PCT International Application Number | PCT/JP02/12265 | |||||||||||||||||||||
PCT International Filing date | 2002-11-25 | |||||||||||||||||||||
PCT Conventions:
|