TW200930396A - Method of making and using adenosine analogue - Google Patents

Abstract

This document describes compounds, extracts, and pharmaceutical compositions relating to Gastrodia spp., and methods for the treatment subjects having metabolic disorder or medical conditions such as Huntington's disease, a trinucleotide repeat disease or abnormal blood glucose levels.

Description

200930396 VI. Description of the invention: [Technical field to which the invention pertains] The present invention relates to a related compound, an extract and a pharmaceutical composition of the genus Gastrodia elata, and for the treatment of a metabolic disorder or such as a dinosaur (Huntington's) The disease of the disease, the method of the disease. [Prior Art] The Huntington's disease (HD) system is a non-sexually associated neurodegenerative disease characterized by chorea, dementia, and psychiatric symptoms. When the disease occurs, the concentration and short-term memory will decrease, and the involuntary movements of the head, trunk and limbs will increase. Walking, Lu language and swallowing ability deteriorated. Eventually it will die from complications caused by suffocation, infection or heart failure. The cause of the lesion is an extension of the CAG trinucleotide on the exon of the Huntington's Disease Collaborative Research Group. Normal chromosomes have 35 or fewer CAG repeats at their N-terminus, while HD is a repeat of 36 or more. The excess CAG was repeatedly translated into a polyglutamine amide fragment (polyQ) of the Htt protein. When the CAG is repeated more than 36 times, several brain regions (especially in the striatum) undergo special degradation. The formation of Htt aggregates in peripheral tissues (including blood cells), liver and kidney, and changes in overall gene expression have also been reported (Borovecki, F. et al. (2005); Panov, et al. (2005). ) : Ishiguro, et al. (2001)). Evidence from different laboratories indicates that mutant Htt forms aggregates and causes aberrations in protein-protein interactions (Bate, G. (2003)). Although some therapeutic agents with general effects have been reported, there is a continuing need in the art for the effective treatment of HD 3 200930396. [Summary of the Invention]

^ ^Please find out that certain gastrodia elata (αe/αία) (-traditional Chinese medicine) extracts and related compounds have surprising effects in treating Huntington's disease and hyperglycemia. For example, administration of gastrodia elata extract delays the progression of the motor performance of the f-Dutton's disease-transforming mouse model and prolongs their lifespan (Example 2). Similarly, treatment with Gastrodia elata extract protects cells from apoptosis induced by serum deficiency (Example 1). Furthermore, administration of Gastrodia elata extract to R6/2 mice reduced the concentration of glucose in the elevated blood (Example 4) and reduced the formation of aggregates in the liver (Example 5 >). Furthermore, these compounds isolated from the extracts slow down several major symptoms of schizophrenia in these mice (including exercise, weight loss, and shortened lifespan) (Example 6) and prevention of pei2 cell Apoptosis was induced by serum deficiency (Example 5). In various embodiments, the invention provides a compound represented by the following structural formula:

B/C, R4 ^ its pharmaceutically acceptable salts and their solvates (s〇lvate). Ring A is optionally substituted with R3; B is a selectively substituted aryl or heteroaryl; Group C is a bond or a selectively substituted cycloaliphatic, heterocyclic aryl or heteroaromatic R and R are each a bond or a selectively substituted alkylene, such as a C1-C4 alkene group; 4 200930396 X is -Ο-, -S-, -SS-, -S (O)-, -S〇2-, -NRa-, -C(0)NRa-, -NRaC(0)-, -NRaS02- or -S02NRa-; R3 and R4 are -OH, i, respectively -CN, _n〇2, -ORa, -RbORa, -C(0)Ra, -0C(0)Ra, -C(0)0Ra, -SRa, -RbSRa, -OC(S)Rd, -C (S) ORa, -C(0)SRa, _C(8)SRa, B(ORa)2, -S(0)Ra, -S02Ra, -S03Ra, -〇S02Ra, _〇s〇3Ra, -P〇2RaRb, -OP 〇2RaRb, -P〇3RaRb, -〇p〇3RaRb, _N(RaRb), Ο

-C(0)N(RaRb), -C(0)NRaNRbS02Rc, -C(〇)NRaS02Rc, C(0)NR CN, -S02N(RaRb), -S02N(RaRb), _NReC(0)Ra or - NReC(0)ORa; and R-R are each a -H or a selectively substituted aliphatic, cycloaliphatic, heterocyclyl, benzoinyl, aryl, heteroaryl; or -N() RR) - is a selectively substituted heterocyclic group. In each of the embodiments, at least one of the groups 1 and R2 may be a selectively substituted olefin |, for example, #C1_C4 olefin A. In some embodiments, the R and R systems are each a C1 匸 4 埽 hydrocarbon group. In various embodiments, the X system may be _NRa_, _Ra_, -NRaC(〇)-, _NRaS〇24_S〇2NRa... for example, -NH_. In some implementations, the 'X system can be called. In some embodiments, the x system can be -s-, -s(o)- or _s〇2_, for example, _s_. In each of the embodiments, R3 and R4 are independently dentate, Guan, C1-C4, _SH, c1-C4 thiol, c〇2h, SOI, _P〇3H2 or _(10)3H2. In some embodiments, Γ' and R4 = less: one is - 〇H or grandchild. In some embodiments, R and R are the same functional groups, such as _〇H. In various embodiments, Ring B may be a selectively substituted phenyl group, a biphenyl group, a naphthyl group, a silk, an onion group, an imidazolyl group, a decyl group, a porphinyl group, a bite, and a Base, bite base, pyrim'idyi, 5 200930396 π 喃 基, n 嗤 、, π 洛 洛, 吼 基, ° 嗤 嗤, 坐 坐, 口 0 0 sit ( Oxazolyl), isoxaz〇lyl, 1,2,3-trisal, 1,2,4-triazolyl, imidazolyl, thienyl, pyrimidine, quinazolinyl, anthracene 〇 基, tetradecyl, benz〇thienyl, benzoxanthyl, fluorenyl, quinolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, Benzoisoxazolyl, benzimidazolyl, quinolyl, isoquinolyl, decyl or isodecyl.

In each embodiment, the ring C is selectively substituted: C3-C8 cycloalkyl, chelated, thiazolinyl, oxazolidinyl, terrible Thiazolidinyl, tetrahydrocarbamate, tetrahydrothiophenyl, morph〇iino, thiomorpholino, pyrrolidinyl, pyridyl, 0-cylidine Base, thiazolidinyl, furanosyl form of glucose, mannose, galactose, allose, altrose, glucosamine, idose or tartanose; or pyranosyl form Glucose, mannose, galactose, allose, altrose, isoglucose, idose or talose. In each embodiment, the compound is represented by the following structural formula.

- wherein the ring D is selectively substituted or fused to another ring. In the case of the application, the compound can be expressed as a file.

In certain embodiments, the compound can be expressed as 丫~3'2丫, 0 6 200930396. In a particular embodiment, the compound can be expressed as

In some embodiments, the compound is

In various embodiments, the compound can be represented by the following formula:

Wherein B' is a selectively substituted heteroaryl group, and C' is a selectively substituted heterocyclic group. In various embodiments, B' is a selectively substituted pyrimidinyl or fluorenyl group. In each embodiment, C' and R4 may be a selectively substituted furanose or D-pyranose form of glucose, mannose, galactose, arganose, altrose, isoglucose, Idose or talose. In some embodiments, the compound is represented by the following structural formula:

In some embodiments, the -NH-B'-C'-R4 system may be a selective substituted ribonucleoside or deoxyribonucleoside. In some embodiments, the compound is: 7 200930396

HO OH In some embodiments, both R1 and R2 are a selectively substituted olefinic group such as a C1-C4 olefin group. In some implementations, X is not in some implementations, x = is -s-. In some implementations, χ is not -s_s_. In some implementations, X is not _S(〇)_ or _s〇2_. In some implementations, X is not -NRa-. In some implementations, χ is not _c(〇)NRa_ or -NRaC(0)-. In some implementations, χ is not _NRas -S02NRa- 〇 ^ In some implementations, the 'X system is. In some implementations, the X system is -S-. In some implementations, the tether is _s_s_. In some embodiments, the X system is _S(〇) sound S (V. In some embodiments, the X system is -NRa-. In some implementations, the lanthanide system is _c(〇)NRa_ Or -NRaC(9)·. In some implementations, the lanthanide is Vision-S02NRa-. ^ ❿ In the partial crane-like towel, the r1r4 system is at least one view. In some implementations, 'and the R4 system are the same. ^ In some embodiments, R3 & r4 is at least one of the embodiments, and the RlR4 system, at least one is not _〇H. In some implementations, 'and R4 is at least one is not or _n〇2. In the implementation of the Ministry of Gas, at least one of Rl R4 is not visual,

:L〇=V3C(〇)r _〇C(〇)Ra or, Qing. In the partial implementation of the L sample, at least one of the R AR systems is not _SRa, RbSR =)r, 04Ra, -cw^^^, and at least one of R and the ruler is not 4_B(〇Ra)2. In some aspects of the 200930396, at least one of R3 and R4 is not _s(〇)Ra, _s〇2Ra, -SO#, -〇S〇2Ra or -osoy. In some embodiments, at least one of r3 and R is not -PC^RaRb, _〇p〇2RaRb, _p〇sRaRb or -OP〇3RaRb. In some embodiments, at least one of R3 and R4 is not -N(RaRb), -C(9)N(RaRb), _c(〇)NRaNRbs〇2RC, -C(0)NRaS〇2Rc or -C(0)NRaCN . In some embodiments, at least one of R3 and R4 is not _S〇2N (RV^_s〇2N(RaRb)e is in some embodiments, and at least one of R3 and R4 is not _NRcc(〇)Ra Or -NRcC(0)0Ra. In some embodiments, at least one of R3 and R4 is a halogen. In some embodiments, at least one of 'R3 and R4 is _CN or _; ^〇2. In the aspect, at least one of 'R3 and R4 is _〇Ra, -RbORa, _C(0)Ra, _〇C(〇)Ra or -C(0)〇Ra. In some implementations, 'R3 and R4 At least one of _SRa, _RbsRa, _c(S)Ra, -OC(S)Ra, -C(S)〇Ra, -C(0)SRa or -C(S)SRa. In some implementations At least one of R3 and R4 is _B(〇Ra;) 2. In some embodiments, at least one of R3 and R4 is _S(〇)Ra, _s〇2Ra, -S03Ra, -OS〇2Ra or -〇S〇3Ra. In some embodiments, at least one of R3 and R4 is -P〇2RaRb, _〇p〇2RaRb, _p〇3RaRb or -〇P〇3RaRb. In some embodiments, R3 and At least one of R4 is -N(RaRb), -C(〇)N(RaRb), _C(0)NRaNRbS02Rc, -C(0)NRaS02Re or _c(0)NRaCN. In some embodiments, r3 And at least one of R4 is -S〇2N (RaRb) or -S02N (RaRb). In some embodiments, at least one of R3 and R4 is _NRcC(〇)Ra or -NRcC(O)0Ra. In the embodiment, the compound is an isolated compound, for example, the compound is a pure compound, a compound contained in a pharmaceutical composition, and one is contained in a day of genus 9 200930396 spp. The compound in (Gastrodia e!ata)) is in some embodiments, when R1 and R2 are the same methyl group, B is phenyl, C is a bond, and both R3 and R4 are located at R1. And the base of R2 is 'X is not -0-' -S-, or -S(O)-. For example, in some embodiments, the compound is not bis(4-hydroxyphenylindenyl)ether, bis(4-hydroxyphenylindenyl) sulfide or bis(4-hydroxybenzyl)sulfoxide. In some embodiments, the compound is not a gastrodin, a gastrodioside or a parishin. The present invention also provides a medicinally acceptable extract of the genus Gastrodia (Ga ❹, for example, Gastrodia elata e/flia), which can be prepared by any method known in the art, for example, extraction with an organic solvent (e.g., sterol, Ethanol, water/ethanol, water/sterol, acetone, methyl ethyl ketone, acetonitrile or other similar solvent). Extraction stratification of these extracts is also provided. Gastrodia can be any species of the genus Gastrodia, including Gastrodia elata, Gastrodia cunninghamil, Gastrodia aff. sesawo/ofe·?, and others, but not limited to the above species. @ A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition comprises the compound. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable extract of the genus Gastrodia (e.g., Gastrodia elata). A method of treating a patient suffering from Huntington's disease, in each embodiment, comprising administering to the patient an effective amount of a compound and/or a pharmaceutically acceptable gastrodia (eg, gastrodia β/βΜ) An extract, or a pharmaceutical composition thereof. A method of treating a patient suffering from an abnormality in blood glucose concentration, in each embodiment, comprising administering to the patient an effective amount of a compound and/or a pharmaceutically acceptable gastrodia (eg, gastrodia elata (Gfl versus e/α) ^ϊ)) 200930396 Extract, or a pharmaceutical composition thereof. The patient's abnormal blood glucose concentration may present hyperglycemia, and in each embodiment, the aforementioned patient has one or more diseases such as Huntington's disease, trinucleoside repeat (including SCA1, SCA2, SCA3, SCA6, SCA7, SCA17, dentate, dentatorubralpallidoluysian atrophy and spinal muscular atrophy, type 1 diabetes, type 2 diabetes, cardiovascular disease, X syndrome, obesity-related hyperglycemia Symptoms, excessive appetite, hyperglycemia or steroid-induced hyperglycemia or other. A method of controlling the activity of a patient's A2a receptor, in each embodiment, comprising administering to the patient an effective amount of the compound and/or medically acceptable genus (eg, gastrodia elata). An extract, or a pharmaceutical composition thereof. In some embodiments, the dosage of the compound, extract or pharmaceutical composition administered to the patient is effective to treat a disease modulated by the A2a receptor by, for example, increasing the activity of the A2a receptor. These diseases include, for example, chronic heart failure, peripheral tissues (including liver, kidney, and heart) ischemia and sepsis. A method of controlling the concentration of cyclic adenosine phosphate in a patient, in each embodiment, comprising administering to the patient an effective amount of a compound and/or a pharmaceutically acceptable gastrodia (eg, gastrodia elata) An extract, or a pharmaceutical composition thereof. In some embodiments, the dose of the compound administered to the patient is effective to increase the concentration of cyclic adenosine monophosphate in the patient (eg, extensively or in localized cells or tissues). In some embodiments, the dose of the compound, extract or pharmaceutical composition applied to the patient is effective for treating a disease regulated by adenosine monophosphate in the patient', for example, by increasing the adenosine monophosphate in the patient. The concentration of phosphoric acid is achieved. Such diseases include chronic heart failure, ischemia of the surrounding tissues (including liver, kidneys, and heart) and sepsis. 11 200930396 In the case of sigma, the pharmaceutical composition contains 4 drugs acceptable. The medicine can be used to connect the water/ethanol extract or compound of Tianma.

^人#包3 In various embodiments of the method for treating a patient's disease, 1俜^ contains an effective dose of the compound, J extract or medicine, and the group: treatment of the T-listening disorder: Hunting The chorea, repeat 4 blood glucose concentration abnormality, or can be controlled by the 4, α2 VIII receptor activity or control the concentration of cyclic adenosine monophosphate in the patient. In some embodiments, the disease is Huntington's disease: sputum, triple repeat or abnormal blood glucose concentration. In some heart samples, the disease is Huntington's disease. In some implementations, the disease is hyperglycemia, type 1 diabetes, type 2 diabetes, heart, vascular disease, snoring syndrome, obesity-related hyperglycemia, hyperphagia associated with hyperphagia, or steroids. Induced hyperglycemia is a condition selected from the group consisting of Scai, SCA2, SCA3, SCA6, SCA7, SCA17, dentate red globus pallidus atrophy and spinal muscular atrophy. Group of trinucleotide repeats. In some embodiments, the disease is selected from the group consisting of chronic heart failure, peripheral tissue ischemia, and sepsis, wherein the compound, extract, or pharmaceutical composition is effective to increase patient Α 2 Α receptor activity or increase The patient has a cyclic adenosine monophosphate concentration. θ The details of one or more embodiments of the present invention are set forth in the following drawings and embodiments. Other features, objects, and advantages of the invention are apparent from the embodiments, drawings, or claims. The patent application scope of one part of the disclosure is 12 200930396. The drawings and the description of the specific embodiments of the present invention are intended to Gastrodia (GosiroiZ/fle/plus alpha) is widely used in Asia for at least 1500 years. Traditionally, it is used to treat headaches, dizziness, numbness and phlegm, especially cramps such as epilepsy and tetanus. Base - For its effective medical use in the treatment of epilepsy, many studies have been conducted to explore its role in preventing neurological damage. For example, it has been reported that gastrodin (a component of gastrodia elata (〇 〇 e e/αία)) changes the GABA metabolism in the gerbil hippocampus (An et al. (2003)). Furthermore, in the gerbil ischemia model and the kainic-acid treated mouse model, the ether fraction of the methanol extract of Gastrodia elata has neuronal damage in the hippocampus. Protective effects (Kim, et al. (2001); Kim, et al. (2003)). The E. sinensis lysate can significantly reduce the neuronal cell death induced by β-amyloid (Kim, et al. (2003)). Similarly, by using a mouse ❹ model treated with alginate, Hsieh and his colleagues demonstrated that administration of gastrodia elata extract not only significantly reduced the number of cramps' but also delayed the start time (HSieh, etal ( 2001)). This anti-creep effect of Gastrodia elata is achieved by regulating its free radical scavenging activity (Hsieh, et al. (2000)). In addition, a gastrodone extract of Gastrodia elata prevents serum-deprived apoptosis of PC12 cells by inhibiting JNK activity (Huang, et al, (2004)). In the present study, we demonstrate that the addition of partially purified Gastrodia extract or two novel compounds purified from Gastrodia elata in drinking water of mice can significantly improve HD in the R6/2 gene transfer HD mouse model. Symptoms (Mangiarini, et. Al. (1996)). 13 200930396 200930396 申请人 Applicants have also found that certain gastrodia elata (a traditional Chinese medicine) extract and its related compounds have surprising results in the treatment of conditions such as Huntington's disease and hyperglycemia. For example, administration of gastrodia elata extract may delay further deterioration of the motor performance of the Huntington's disease gene-transferred mice' and improve their lifespan (Example 2). Similarly, treatment with Gastrodia elata extract protects cells from apoptosis induced by serum deficiency (Example 1). Furthermore, treatment of R6/2 mice with Gastrodia elata extract reduced the glucose concentration in the elevated blood (Example 4) and reduced the formation of mutant Htt aggregates in the liver (Example 5). Furthermore, compounds isolated from these extracts delay several major symptoms of Huntington's disease in these mice (including exercise degeneration, weight loss, and shortened life) (Example 6) and prevent PC12 cell factor Apoptosis caused by serum withdrawal (Example 5). Suitable protecting groups for use in the present invention provide protection and deprotection in the synthesis and reaction conditions (e.g., for protecting R3 and R4 groups in the synthesis of a compound), which are known in the art. For example, at Greene* Wuts (1991). For example, particular embodiments of suitable hydroxy protecting groups include alkyl ethers (e.g., fluorenyl, ethyl alkoxyalkyl ethers (e.g., decyloxymethyl), decane ethers (e.g., Triterpenoids and other similar protecting groups, but are not limited thereto. The term 'is〇lated, as used in the present invention, refers to a character-dependent reaction mixture or biological resource ( For example, gastrodia elata) ° purification. For example, - partially purified or isolated compounds are isolated from the reaction mixture or by a gassed towel by a single step separation, recrystallization, affinity purification or other known in the art. Purification of the hydrazine stage. For example, in a special embodiment, the method is purified by a high pressure liquid chromatography apparatus. The aliphatic group used in the present invention is a chain-like, branched or ring-shaped 200930396 , shape. An aromatic hydrocarbon which is fully saturated or contains one or more unsaturated units. A monoalkyl group is a saturated aliphatic group. Generally, a linear or branched aliphatic group has from 1 to 1 carbon atom. Preferably, it has from j to about 4 An atom, and a cyclic aliphatic group (for example, a cycloaliphatic group represented by B or C) has from 3 to about 5 carbon atoms, preferably from 3 to about 8 carbon atoms. A fatty group is preferably a straight chain or Branching base 'for example: methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, tert-butyl, pentyl, hexyl, heptyl or octyl, or one having 3 to a cycloalkyl group of about 8 carbon atoms. A C1_C4 linear or branched alkyl group or an alkoxy group or a -wei group or an oxo group is also referred to as "lower alkyl group, or "lower alkoxy group," A functional group substituted with _F, -α or -I is a "lower haloalkyl group, or a "lower haloalkoxy group"; a sulfhydryl group-lower filament is substituted with _ ;; or the like 2. The "alkylene" used in the present invention, (for example, an olefin group represented by Rl^R), is a linkage-extension bond represented by _(CH2)n4, wherein the η system is 1 to An integer of 1 ,, preferably i to 4. The term "aryl" as used herein (for example, an aryl group represented by B or C) means a C6-C14 carbocyclic aromatic group such as phenyl, and the like. The aromatic group also contains a fused polycyclic aromatic earth = a carbocyclic aromatic ring which is fused with its fresh, Wei- or ring-fat &, for example, naphthyl, anthracenyl, fluorenyl and the like. The term "heteroaromatic group," (for example, a heteroaromatic group as indicated by Β), refers to a heteroaromatic ring of 5-14 members which is a U or a Ο Ν Ν hetero atom. An example package of a heteroaromatic group. "^isoCazolyl, thienyl, furyl, fluorenyl, pyridyl, pyrimidine, pyrazolyl, pyrrolyl, pyrazinyl, thiazolyl, isothiazide V (tetra), iso. Similar to the ternary group, accepting oxime:, thiol, thienyl, pyrimidinyl, quinazolinyl, fluorenyl, tetrazolyl ^ 15 15 200930396 Other analogs. Heteroaryl also contains a fused polycyclic aromatic ring A system wherein one carbocyclic aromatic or heteroaromatic ring is fused to one or more other aromatic rings. Examples include benzothienyl, benzofuranyl, & fluorenyl, quinolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl: benzisoxazolyl, benzimidazolyl, Quinoline, isoquinolyl, indole and isoindolyl. Particular examples of heterocyclic groups include heteroaryl nucleobases such as fluorenyl derivatives (eg, 2-aminoamine-6(9H)-one, 6-amino-(9Η) κ, or Other similar and pyrimidinyl derivatives (eg, aminopyrimidine-2(111)-one, 5-pyridylpyrimidine bite-2,4(1Η,3Η).dione, or other analogs). -Used by the present invention Non-aromatic heterocyclic groups (eg, hetero-riff) are non-materials, which include one or more examples, or S heteroatoms in the ring. These rings may be five members, six members, two or Examples of the eight-membered ring include: sputum, sputum = quilt, tetrahydrocarbyl, tetrahydrothiophenyl, succinct = = yl, azozinyl, thiol, sulfhydryl, cyclogalactose , allose, glucosamine, mannose, or the like) and bis, glucose, idose (10) thiol- to-aryl, cyclo-, heterocyclyl, stupid selective substituents • Substituted 'suitable drug-active substituents. - ΐ ΐ ΐ ΐ ΐ ΐ ( ( ( ( ( ( ( ( ( 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四The valence can be formed with a -burning group - a single bond; a carbon atom of a valence (eg, _C(-H)=) (for example: _CrH, (for example, singular) =), having a divalent 43⁄4) ) can form one or two single bonds to link 200930396 to one or two substituents (for example: -C(alkyl)(H)-, -C(alkyl)(Br)-), or form a pair a bond to a substituent (e.g., -C(=0)-), and analogs thereof. The substituents contemplated by the present invention comprise only those substituents which form a stable compound. For example, a suitable substituted carbon atom Selective substituents (for example, substituents represented by a selective substituent of R1, R, B) include -F, -Cl, -Br, -I, -CN, -N〇2, -〇Ra, - C(0)Ra, -0C(0)Ra, -C(0)ORa, -SRa, -C(S)Ra, -〇C(S)Ra, -C(S)ORa, -C(0) SRa, -C(S)SRa, -B(ORa)2, _S(0)Ra, -S02Ra ' -S03Ra ' -0S02Ra ' -0S03Ra > -P02RaRb ' -OP02RaRb ' -P03RaR b ' -〇P〇3RaRb > -N(RaRb) ' ❹

-C(0)N(RaRb), -C(0)NRaNRbS02Re, -C(0)NRaS02Rc, -C(0)NRaCN, -S02N(RaRb), -SO hetero aRb), _NrC(0)Ra, - NRcC(0)0Ra > -NRcC(0)N(RaRb) . -C(NRc)-N(RaRb) > -NRd-C(NRc)-N(RaRb), -NRaN(RaRb), _CRC= CRaRb, _c = CRa. = CRaRb^ = NRa> = N〇Ra> = NNRa^ Selectively substituted, selectively substituted Wei, selective aliphatic, selectively substituted cycloaliphatic, selected a cyclic group, a selectively substituted methyl group, a substituted or a selectively substituted heteroaryl group, the (10) is substituted or a selectively substituted aliphatic group, selective = 'selectivity The substituted heterocyclic group, the selectively substituted aromatic group or the 盥-R Rabb, or the substituted substituted fly, together with N(RR), is a selective substituted R4 and The nitrogen atom of two covalent bonds (for example, R3.R and the nitrogen atom in the functional group represented by R, R., UR, heteroaroyl or transradyl) Selectively selected 17 200930396 Red-substituted aliphatic group, selective system substituted ring aliphatic group, selection By a heterocyclic group of j, a selectively substituted benzyl group, a selectively substituted aromatic group, a selectively substituted heteroaryl group, _CN, _N〇2, _〇Ra, <(〇?, _0C(0)Ra, _C(〇)〇Ra, taste, _s(〇)Ra, _s〇2Ra, -S03R, -N(RaRb), _C(0)N(RaRb), _c(0)NRaNRbS02Rc, • -C(0)NRaS〇2Rc > -C(〇)NRaCN > -S02N(RaRb) > -S02N(RaRb) > -NRcC(〇)Ra x -NRcC(0)0Ra ^ -NReC(0 N(RaRb), and the like. A nitrogen heteroaryl or a non-aromatic heterocyclic ring may be substituted by oxygen to form an N-oxide. For example: pyridyl N-oxide, piperazine Pyridyl N-oxide, or other analogs. For example, in various embodiments, a ring nitrogen atom in a nitrogen-containing heterocyclic or heteroaryl group can be substituted to form an N-oxide. The invention also encompasses pharmaceutically acceptable salts of the disclosed compounds. These compounds may have one or more protons of sufficient acidity to react with a suitable organic or inorganic base to form a base addition salt. When a compound has a hydrogen atom bonded to an oxygen source , A nitrogen atom or a sulfur atom, the compounds can be expected to also include salts thereof, because when the argon atoms are reacted with a suitable organic or inorganic base to form a base addition salt. Base addition salts include those derived from inorganic bases and organic bases, among which inorganic bases such as ammonium or alkali metal or hydroxides, carbonates, bicarbonates, and the like of soil metals, and Organic bases such as alkoxides, alkaneamines, alkyl and arylamines, and the like. Such bases for the preparation of the salts of the present invention include sodium hydroxide, hydrazine hydroxide, hydrazine hydroxide, potassium carbonate, and the like. For example, pharmaceutically acceptable salts include those monovalent salts formed by reacting a compound of the present invention with one equivalent of a suitable base (ie, the compound has a single negative charge and can be used as a pharmaceutically acceptable relative cation (eg, 200930396 monovalent cation) Balanced, or a divalent salt formed by reaction with two equivalents of a suitable base (ie, the compound has two negative charges that can be accepted by two pharmaceutically acceptable relative cations (eg, two pharmaceutically acceptable monovalent cations or a single drug) Accept divalent cations) balance). Examples include Li+, Na+, K+, Mg2+, Ca2+, and NR4+, wherein each R is a hydrogen, a selectively substituted aliphatic group (eg, monohydroxyalkyl, aminoalkyl, or ammonium alkyl) Or a selectively substituted aromatic group; or, the two R groups together form a selectively substituted non-aromatic heterocyclic ring which is selectively fused to an aromatic ring. In general, the pharmaceutical acceptable cations are Li+, Na+, K+, NH3(C2H5OH)+ or N(CH3)3(C2H5OH)+. The compounds disclosed herein have a sufficiently detectable functional group, such as an amine group, which is formed by revealing that the compound reacts with an organic or inorganic acid to form an acid addition salt. An acid generally used to form an acid addition salt from a compound having a base includes an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, or the like; and an organic acid; and an organic acid For example, phthalic acid, sulphuric acid, oxalic acid, p-benzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, or the like. Examples of such salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monophosphonates, doubles. Hydrogen phosphates, "partic acid salts, pyrophosphates, vapors, bromines, iodides, acetates, propionates, citrates, octanoates, Acrylates, formates, isobutyrates, hexanoates, heptanoates, propiates, oxalates, malonates, succinates, suberates , a lipoate, a fumarate, a maleate, a butyne-1,4-diate, a hexyne-1,6-diate, a benzoate, Gas benzoate, mercapto benzoate, dinitrophenyl phthalate, hydroxybenzoate, decyl benzoate, phthalate, 19 200930396 sulfonate, diterpenes Benzene sulfonate, stupid acetate, phenylpropionate, phenylbutyrate, citrate, lactate, 7-light butyrate, glycolate, tartrate, methanesulfonate, Acrylic Tread acid, naphthalene-1-sulfonate, naphthalene-2-renewal, mandelate, or other the like. The invention also encompasses pharmaceutically acceptable solvates. The term "solvate" as used in the present invention means that a compound of the present invention or a salt thereof may further comprise a stoichiometric or non-stoichiometric solvent (such as water or an organic solvent) which is formed by non-covalent molecules. The power to combine. The invention also includes a pharmaceutical composition comprising the disclosed compounds. A "pharmaceutical composition" comprising a disclosed compound is administered to a patient in combination with an acceptable pharmaceutical carrier as part of a pharmaceutical composition. The formulation of the compound to be administered will vary depending on the choice of route of administration (eg, oral (eg, lozenges, capsules, tablets, solutions, or the like), intravascular, intraperitoneal, intramuscular, subcutaneous, non-oral, oral Cheek, cranial or cerebrospinal, eyeball (eg, solution, ointment, or included in an implant or contact lens), nose (eg, solution, spray, aerosol, or the like), throat, lung (eg, gas) Sol), intravaginal, anal, preparation as an implant or depot, as a surface coating for implanting a medical device, as a topical solution, latex, capsule, cream, ointment or Other analogues). Suitable pharmaceutical carriers may contain inert ingredients which will not react with the compound. For example, standard pharmaceutical formulation techniques described in Remington's Pharmaceutical Science (2005) can be used. Suitable pharmaceutical carriers for parenteral administration include, for example, sterile water, physiological test water, antibacterial saline (about 0.9% mg/mL benzyl alcohol in saline), phosphate buffered saline, Hank's solution, lactated Ringer's Ringers-lactate and other analogues. A method of encapsulating a composition (e.g., in a coating of hard gelatin or cyclamate) is known in the art (Baker, et al. 20 200930396 (1986)). It will be readily understood that certain of the compounds disclosed herein may be obtained in the form of different stereoisomers (e.g., diastereomers and enantiomers), and the present invention encompasses All of the isomeric forms of the unexposed compound, as well as racemic "mixtures, and methods of treating patients with both pure isomers and mixtures thereof (including rotatory mixtures). Stereoisomers can be separated and isolated by any suitable method, such as chromatography. ❹ In various embodiments, the method of treating a patient having Huntington's disease comprises administering to the patient an effective amount of a compound and/or a pharmaceutically acceptable extract of the genus Gastrodia (eg, Gastrodia elata). Or a pharmaceutically acceptable composition thereof. In various embodiments, the method of treating a patient having an abnormal blood glucose concentration comprises administering to the patient an effective amount of a compound and/or an extract of a pharmaceutically acceptable gastrodia (eg, Gastrodia elata). Or a pharmaceutically acceptable composition thereof. Patients with abnormal blood glucose glucose concentrations may exhibit hyperglycemia' and in each embodiment may have one or more diseases, such as Huntington's disease, type 1 diabetes, type 2 diabetes, Cardiovascular disease, X syndrome, obesity. Glucosamine hypersensitivity, hyperphagic hypersensitivity associated with excessive appetite, or steroid-induced hyperglycemia or other similar conditions. In various embodiments, the method of controlling patient A2A receptor activity comprises administering to the patient an effective amount of a compound and/or a pharmaceutically acceptable gastrodia (eg, gastrodia (Gosiroi/z'cf e/αία)) An extract, or a pharmaceutically acceptable composition thereof. In some embodiments, the dose of the compound, extract or pharmaceutical composition administered to the patient is effective to treat a disease modulated by a sputum receptor in a patient, for example, by increasing the activity of the a2a receptor. . 21 200930396 In each embodiment, a method for regulating a concentration of acyclic adenosine monophosphate in a patient comprises administering to the patient an effective amount of a compound and/or a pharmaceutically acceptable gastrodia (eg, an extract of Gastrodia elata, or a pharmaceutical thereof) The composition is received. In some embodiments, the dose of the compound administered to the patient is effective to increase the concentration of cyclic adenosine monophosphate in the patient or the tissue in a particular cell or tissue. In some embodiments, administration The dose of the compound, extract or pharmaceutical composition of the patient can effectively treat a disease caused by adenosine monophosphate in a patient, for example, by increasing the concentration of acyclic adenosine monophosphate in the patient. Method for preparing scorpion benzene extract

The underground stems of Gastrodia elata (B1 ·) were purchased from local Chinese medicine stores in Taipei. The gastrodia elata flakes were extracted overnight with an aqueous solution of ethanol (60 ° C). The crude extract was concentrated under reduced pressure using a vacuum rotary concentrator. The dried sample was introduced into an ion column chromatography (DIAION® HP20, HP21, Mitsubishi Chemical, Tokyo, Japan) and flushed with water to a gradient of sterol. Screening of each fractions was carried out by the activity of protecting PC 12 cells from programmed death induced by lack of serum. The eluate having this activity was combined and purified with a SEPHADEX® LH-20 column (Pharmacia LKB, Biotechnology AB, Uppsala Sweden). Two fractions of T1-C and T1-11 active ingredients were obtained by repeated extraction with methanol. High Pressure Liquid Chromatography uses: Merck PUROSPHER® RP-18e ( Merck KGaA

Life Science & Analytics, Darmstadt, Germany ), (250x4.6 mm) column, UV 270-nm detector, with a flow rate of 0.5 mL/min, 70% to 40% water/methanol gradient gradient 40 Minutes, then rinsed with 40% 22 200930396 to 20% water/sterol for 5 minutes to observe the chemical profiles of the different batches. Cell Culture The PC 12 cell line was ordered from the American Type Culture Collection (ATCC, Manassas, VA, USA) and survived with supplements - 10% Ma Qiqing and 5% fetal bovine serum Dulbecco's Modified Eagle

Medium (DMEM) and cultured in a carbon dioxide incubator * * (5%) at 37 °C. The Striatal Progenitor cell line (ST14A) was obtained from Dr. E. Cattaneo (University of Milano, Italy) and cultured in a culture chamber of 33 ° C, 10% carbon dioxide - 90% air, as described in the previous literature (Ehrlich). , etal. (2001)). MTT assay PC12 cells were washed three times with phosphate buffered saline (PBS) and resuspended in DMEM. The suspended cells were plated into 96-well plates (1 x 10 cells per well) and then administered with the indicated agents. After 21 hours of application, 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrapyrazine (MTT) was added to the medium (〇, 5 mg). In /mL), it was further cultured at 37 ° C for 3 hours. After the medium was removed, 100 μl of dimercaptosulfoxide (DMSO) was added to each well to dissolve 曱臜 (f0rmazan) crystals, followed by a micro-enzyme-linked immunosorbent assay (ELISA). The reader measures the absorbance at 570 nm and 630 nm for each well. Animal sputum administration Male R6/2 mice and littermate control groups were mated with female control mice (B6CBAF1/J). The experimental mouse is made by Jackson Laboratories,

Bar Harbor’ ME’ USA was purchased. The progeny were identified by PCR genotyping technique using the genomic DNA obtained from the tail tissue 23 200930396, which uses the primers located in the transgenic genes (5'-CCGCTCAGGTTCTG CTTTTA-3' and 5,-GGCTGAGGAAGCTGAGGAG-3). To confirm that the number of CAG repeats is kept at about 150. A total of 67 R6/2 gene-transferred mice were used in this study. The animals were housed in the Institute of Biomedical Science Animal Care Facility on a 12-hour day/dark cycle. Each injection of the designated drug is administered between 13: 〇〇 and 18:00, and the measurement of the body weight of the mouse is recorded before the daily feeding. The operation of the animal experiment is based on the Academia Sinica Institutional Animal Care and Utilization Committee > ° Roadrod performance The motor coordination system was evaluated using a roller device (UGO BASILE, Comerio' Italy) for more than 2 minutes at a constant speed (12 rpm) (Carter, et al. (1999)). All mice were trained for two days at six weeks to make them aware of the roller device. These animals were tested three times a week at 7-12 weeks of age. In each test, the animal is placed in the device after the rotation is initiated. Drops due to delays are automatically recorded. Each mouse will be tested three times with a maximum of two minutes per test. Immunostoichiometry and sputum: Brain containing striatum (interaural 5.34mm/front || (bregma) 1.54mm to both ears 3.7mm / anterior subsection (30μιη) and liver section (20μιη) To perform stoichiometric analysis. Single-antibody immunostaining was performed using the imatin-biotin-peroxidase complex method (ABC method) described in the prior art (Wu, et al. (1998)). It can be used for multiple antibodies when diluted 1:2000. 24 200930396 anti-ubiquitin antiserum (DakoCytomation Denmark A/S » Glostrup » Denmark) ° Three different kinds of the same brain The sections were labeled with anti-ubiquitin antiserum and counterstained with thiol green, and a total of six mice in each test were analyzed at 12 weeks of age, with at least 1200 and 300 counts per mouse. Cells' to determine the ubiquitination of striatal cells and hepatocytes

Htt collection. The third panel is a representative representation of the striatum labeled with ubiquitin in 12-week-old R6/2 mice given control drinking water from the periphery. Scale bar: 2^111. Figure 3B is a representation of the striatum labeled with ubiquitin in 12-week-old R6/2 mice containing gastrodia elata extract (5 mg/mL) of drinking water. Scale bar: 25μιηη. The third C picture shows the distribution of neuronal intranuclear inclusions (Nils) in 12-week-old R6/2 mice given control drinking water or drinking water containing gastrodia elata extract (5 mg/mL) from the surrounding area. The percentage bar graph of the striatum cells is described in "Materials and Methods". Scale bar: 25μιηη. **Use the Student's t-test to compare with the R6/2 mice that are given the age of vehicie.

The mice were sacrificed by cervical dislocation, and blood samples (1 to 1.5 mL) of each mouse were collected in EDTA blood tubes, and blood glucose concentration was utilized by ABBOTT.

The Alcyon 300i analyzer (ABBOTT Labs, Abbott Park, IL, USA) was measured. - Tandem mass spectrometer screening of amino acids in jk solution: Sample collection was performed by infiltrating the blood (25 μl) of the tail vein of 10.5-week-old R6/2 mice into filter paper (s&S 903; Schleicher & 25 200930396

Shuell, Dassel, Germany). Before the analysis, the blood system was firstly analyzed by the paper, and then a series of mass spectrometers (Qyatro Micro; Micromass, Beverly, ΜΑ, USA) were used as described in the previous literature (Wu, et al. (2004)). The concentration of the amino acid was detected. Example 1: Application of Gastrodia elata extract protects cells from apoptosis induced by lack of serum We have previously found that Am-R-specific agonists particularly improve the main symptoms of several HDs (Chou, et al. (2005)) . In addition, Gastrodia elata extract not only inhibits apoptosis induced by serum withdrawal of PC 12 cells but also activates Am-R (Huang, et al. (2004)). In this study, we first operated partial purification of different eluates of Gastrodia elata as described in the “Methods”. The water/ethanol extract of the gastrodia elata extract was then introduced into DIAION® HP-20 column chromatography and eluted with a gradient of water to methanol. As shown in the first panel, several lysates extracted by sterol, T1-2 and T1_3) showed activity to protect PC12 from apoptosis induced by serum withdrawal. The most effective educt system is Τ1 -3 effluent. Example 2: Applying Gastrodia elata extract to promote motor coordination in R6/2 mice 生命 Lifetime The therapeutic effects of T1-3 lysate on R6/2 mice are discussed herein. The mice were subjected to T1_3 effluent (additional drinking water 5 mg/mL) between 4 weeks and 12 weeks. As shown in the second figure, the R6/2 HD mouse completes the roller test. The ability of the entire process (12Gs) is reduced at 1 () week. The addition of Tl_3 lysate to drinking water reduced the progression of the motor-coordinated test in the squirrel's gift-bearing round. The second B-picture shows the life cycle of the dirty mouse, and the month is moderately extended due to the 1_3 effluent. From the observed behavior or performance of the average animal (IV) T1-3 26 200930396 administered in this study has no toxic effects. Example 3: Application of Gastrodia elata extract to reduce nuclear recruitment in R6/2 mouse neurons. T1-3 lysate was used to discuss its effect on nuclear formation (Nils) in neuronal cells. Since the ΝΠ2 line observed in the brain of R6/2 mice is ubiquitinated (Meade, et al. (2002)), 12-week-old R6/2 mice treated with chronic Τ1·3 treatment Brain sections were stained with anti-ubiquitin antibodies and then counterstained with methyl green. The third to the right of C to show that supplementation of Τ1-3 resulted in a significant decrease in the percentage of Nils in the striatal cells of R6/2 mice. It is speculated that the application of Gastrodia elata delayed the formation of Nils in HD rats. Wild type mice were not found in the brain.

Nil (Chou, et al. (2005) J Neurochem 93, 310-20). Example 4: Applying Gastrodia elata extract will reduce the elevated glucose concentration in the blood of R6/2 mice. All the laboratories, including our own research, HD patients and HD mice have blood glucose. High disease (Chou, et ai, (2005);

Podolsky, et al. (1972); Duan, et al. (2003)). Because inhibition of hyperglycemia has been shown to be associated with improvements in neuronal deficits in HD patients (Duan et al.), we discuss whether chronic glucose administration of T1_3 normalizes blood glucose concentrations in R6/2 mice. As in an earlier literature (HUrlbert, et al. (1999)), compared to wild-type mice, the concentration of glucose in blood at the age of six weeks was increased by one = 匕 1 force: The blood glucose concentration was observed to be significantly greater than the movement coordination defect τ 2 f (second A map). The fourth graph shows that concentrated production, which shows that the abnormally high glucose in the Ti-i, LR6/2 mice will improve glucose regulation and energy metabolism. 27 200930396 Table 1. Blood amino acid concentration of R6/2 mice and wild-type mice. Composition of WT (CON) N= 20 R6/2 (CON) N= 24 R6/2 (RG) N= 14 Arg 31.30 Soil 3.24** 78.60 ± 6.41 49.87 ± 9.96 Ala 258.39 ± 25.76+ 383.30 ± 24.23 303.75 ± 54.31 Cit 22.51 Soil 3.46Λ 41_38± 4J9 37.49 ± 8.70 Orn 12.02 ± 2.05* 24.25 Soil 5.02 27.88 ± 4_99 Gin 253.92 ±29.10 * 471.71 ± 70.86 570.44 ± 110.31 Glu 153.24 ± 15.22* 230.80 ± 17.18 164.92 ± 28.22* Gly 187.99 ± 14.54+ 309.86 ± 20.52 274.04 ± 45.02 His 4.23 ± 0.66 3.27 Soil 0.38 3.36 Soil 0.64 Met 13.79 Soil 1_33* 28.55 Soil 1.79 26.92 ± 5.04 Phe 75.09 ± 6.63* 97.28 Soil 3.03 70.40 ± 10.03* Pro 738.22 ± 99.42 812.81 ± 52.68 546.90 ± 87.47 * Ser 30.87 ± 2.75** 60.31 Earth 3.60 41.20 ± 4.621^ Thr 65.38 ± 7.00 74.07 ± 5_27 53.45 ± 6.77 a Trp 32.65 ± 3.18+ 46.49 ± 4.35 31.46 Earth 5.68* Tyr 47.09 ± 4.1^" 75.82 ± 4.82 48.85 ± 7.01** Val 153.54 ± 16.43 192.61 ± 13.99 131.33 ±20.17* Asp 72.81 ± 23.06 54.95 ± 6.9 9 141.04 ± 26.00*

Example 5: Applying Gastrodia elata extract reduces the Htt collection in the liver of HD rats. Since abnormal metabolism may contribute to HD lesions, we further analyzed the concentration of amino acids in the blood. As shown in Table 1, 12 of the 17 tested amino acids in R6/2 mice were significantly higher than the wild type. Supplementation of T1-3 eluate will normalize 7 of the increased concentrations of amino acids in R6/2 mice. Since abnormal amino acid metabolism may cause liver dysfunction (Holm, et al. (1999)), we study liver 28 200930396

Formation of Htt aggregates (Htt aggregates). As previously reported (Tanaka, et al. 2004), Htt aggregates were observed in the liver of R6/2 mice (figure A). Chronic supplementation reduces Htt aggregates in the liver of HD rats (figure B). This protective effect is associated with previous neuronal damage induced by ischemia and Alzheimer's disease (Kim, et al. (2001); Kim, et al. (2003) Phytother Res; Kim, et al (2003) J Ethnopharmacol; Hsieh, et al. (2001)) showed a consistent neuroprotective effect of gastrodia. Example 6: The isolated component of the active gastrodia elata extract protects PC12 cells from apoptosis and may act as an agonist of A2A-R.

The active T1-3 effluent was mixed, fractionated, and purified by Sephadex LH-20 column chromatography (sixth image). 14 known compounds (including gastrodin, patriotine, 4-hydroxybenzyl alcohol, 4,4'-dihydroxybenzyl sulfoxide, 4-hydroxyphenyl decane, bis(4-hydroxyphenyl fluorenyl) Ether, 4-hydroxybenzyl ether, tetrahydroxybenzyl-methyl ether, trimethylcitrate, 4-aminobenzazole, urine, adenine, 5-(hydroxyl) 2-furanoaldehyde and Tl-C (Taguchi, et al. (1981); Lin, et al (1996) Phytochemistry 42, 549-551; Hayashi, et al. (2002); Huang, et al. 2005), Xiao, et al. (2002)), and a previously unseparated composition (Tl-11) were identified. These isolated proshes were tested for their ability to prevent apoptosis induced by serum. Of the 15 compounds, two compounds (T1-C and T1-11) have activity to protect PC12 cells from programmed death (Figure 7A). T1-C and T1-11 are analyzed in T1-3. About 5% and 0.2%, respectively. Although it is a relatively small amount of composition, Tl-11 has more potential to protect PC12 cells from apoptosis than T1-C. Interestingly, for ST14A cells ( Ehrlich, et al. (2001)) No Administration of T1-C 29 200930396 or T1-11 increased the amount of intracellular CAMP, as did the A2A-R selective agonist CGS2168. In addition, the cAM? response was induced by A2A-R-dependent antagonists. (CSC, Figure 7B) inhibition. Therefore, it is believed that T1-C and Tl_ll function like A2A-R agonists. Example 7: The isolated component of active gastrodia elata extract maintains the movement of R6/2 mice. Performance, reduction of «reduction of sputum and prolongation of life from four weeks, regardless of the application of Tl-C (0.5 gm / mL) or Tl-ll (0.05 mg / mL) in drinking water, make R6/2 mice The motor coordination estimated by the roller test significantly delayed further deterioration (Figure 8A). In addition, both compounds improved body weight loss and prolonged life in R6/2 mice. Control, T1-C and T1-11 treatment The average survival time of the mice was 94.9 ± 2.5, 106·7 ± 4.6, and 104.9 ± 5.2 days, respectively (mean soil SEM, η = 7 to 8; eighth C chart). Example 8: Single of active gastrodia elata extract Structure of the composition component 舆 Properties The structure of the two active components (T1-C and Τ1-11) is based on spectral data, especially 1D and 2D NMR spectroscopy data. Analysis. High performance liquid chromatography system used to monitor the activity of different batches of chemical cross-sectional flow of analyte. The chromatogram of the active lysate showed separation of the active components with a residence time T1-C of 40.91 minutes and a T1-11 of 22.03 minutes. The isolated T1-C is a colorless needle, and its molecular formula is CmHmC^S, which is obtained by high-resolution ionization mass spectrometry (HREIMS) at /w/z 247.0751(Μ++Η) and 13C NMR data. Eight-hydrogen deficiency (IHD). The infrared spectrum was observed to be absorbed by the radical (3285 cm·1) and the aromatic group (1604 and 1600 cm·1). Nuclear magnetic resonance spectroscopy and qualitative analysis revealed that the structure of T1-C is a symmetry person 30 200930396

, 1H NMR spectrum indicates a 1,4-disubstituted phenyl [(5 7.09 and 6.72 (4H each, d, "7=8·5Ηζ)]) and two benzylic thiomethylene protons (benzylic thiomethylene proton) [(5 3.53 ( 4H, s) ]. c NMR, DEPT and HMQC analysis revealed two oxidized sp2 aromatic carbon atoms [d 157.4(s)], two of the six aromatic carbon atoms completely substituted for sp2 carbon atoms And two sulfoximine-based carbon atoms. The HMBC spectrum of T1-C reveals from H-7 to Cl, C-2(6); from H-2(6) to Cl, C-3(5) and C -4 cross peaks. From the above results, it is speculated that the T1-C compound should be constructed as 4,4'-dihydroxybenzoinyl sulfide:

T1-C: mp 126~128°C; IR (KBr) max: 3285, 1604, 1600, 1509, 1214, 1089, 841, 815 cm-1; 1H NMR (CD3OD) δ 3.53 (4 H, s, H -7), 6.72 and 7.09 (4H each, d, J=8.5 Hz, H-3(5) and H-2(6)); 13C NMR (CD3OD) δ 35.9 (t, C-7), 116.1 ( d, C-3(5)), 130.5 (s, C-1), 131.1 (d, C-2(6)), 157.4 (s, C-4); EIMS m/z (%) 246 (M+ , 35), 200 (15)i 107 (1〇〇)_ HREIMS m/z 246.0717 (calcd for C14H1402S: 246.0715). Compounds with the same structure as Tl-C have been chemically analyzed in an earlier gastrodia elata extract The literature reveals (Xiao, et al. (2002)). Conversely, 'T1-11 has not been identified before. It was identified by its HRFABMS in m/z374.1361 (M++H) and 13C NMR data as having the molecular formula C17H1905N5. Colorless and amorphous powder. Its IR spectrum indicates that it has hydroxyl groups (3327, 1125, 1065 cm-1) and an aromatic system (1630, 1610, 1585 cm-1). The 4 and 13C NMR spectra showed an adenosine-like pattern, but the signal generated by the substitution of the p-hydroxybenzylamino group for one of the T-11 amine groups [<5h 4.60 (2H, t, J=6.0 Hz) ), 31 200930396 6.65 and 7.12 ( 2H each,d, "7=8.5 Hz, H-3,, (5") and H-2, '(6,,)); 5c42.4(t, H-7 ,,), 114.9 (d, C-3,, (5,,)), 128.6 (d, C-2 "(6")), 130.8 (s, C_l")]. The binding of the p-hydroxybenzylamine group can be further determined by the correlation of H-7" and C-l", C-2"(6") and C-6 of HMBC. The structure of T1-11 (2-(6-(4-hydroxybenzylamino)-9H-indotyl)-5-(hydroxymethyl)tetrahydrofuran-3,4·diol) has the following structure:

HO 0H Τ1-11: mp 216~218°C; IR (KBr) max: 3327, 3164, 2927, 1630, 1514, 1125, 1065, 815 cm-1; 1H NMR (DMSO-d6) δ 3.54 and 3.64 ( 1H each, m, H-5'), 3.95 (1H, t, J=1.8 Hz, H-4,), 4.13 (1H, m, H-3'), 4.60 (3H, m, H-2, , -7"), 5.87 (1H, d, J = 5.5 Hz, H-1'), 6.65 and 7.12 (2H each, d, J = 8.5 Hz, H-3" (5") and H-2" (6")), 8.19 and 8.33 (1H each, s, H-2 and H-8), 8.28, 9.19 (1H each, br s, OH and NH); 13CNMR (DMSO-d6) 6 42.4 (t, C-7M), 61.7 (t, C-5'), 70.7 (d, C-3*), 73.5 (d, C-2'), 85.9 (d, C>4,), 88.0 (d, C -1'), 114.9 (d, C-3" (5")), 120.4 (s, C-5), 128.6 (d, C-2" (6")), 130.8 (s, C-Γ) , 139.8 (d, C-8), 148.4 (s, C-4), 152.3 (d, C-2), 154.5 (s, C-6), 156.1 (s, C4"); FABMS m/z ( %) 374 (M++1, 28), 242 (15), 154 (95), 136 (83), 56 (100); HRFABMS m/z 374.1361 (calcd for C17H1905N5: 374.1388). Example 9: Compound Synthetic Scheme Loops The compounds described herein can also be obtained from readily available starting materials by standard chemical synthesis methods. A synthesis process as an embodiment is as follows. In a coupling step, the starting material is combined with the precursors 32 200930396 precursor groups X1 and X2 to form a link:

X1 X2

Selective protection step - ❹ X2, B〆 R4 coupling

R4pg coupling

Y

Deprotect PGR3<Jr r1, v-r2, /c

B, r4pg

For example, when X of the compound is -O-, it can be formed by selecting a pair of equivalent xVx2 (e.g., a hydroxyl group and a halogen or a metal oxide and a halogen) under suitable reaction conditions to form an ether. Formation (eg, Larock, RC (1999, page 890-895). Similarly, when the compound X is -s-, it can be separated from the valence of xVx2 (eg, thiol or thioolate) De-based (eg halogen); this compound can be further oxidized, converting -S- to -S(0)- or -S02-. X is -C(0)NRa-, _NRaC(0)-', -NRaS02- or The compound of -S〇2NRa- can be prepared from a starting material in which one of X1 and X2 is an amine and the other is a derivative of an amine-reactive group or a sulfonyl group. For example, an acid halide ), suifonylhalide or other analogs' and react under conditions suitable for the formation of guanamine or sulfonamide (for example: Larock, RC (1999, page 1953-1954)). X is a disulfide. The compound of (disulfide) can be prepared by reduction and purification when χι/χ2 is _SH. The compound of X is _NRa- can be selected by X/X彳The number (such as an amine group and a halogen) is formed under reaction conditions suitable for the denaturation or aromatization of an amine (for example: Larock, RC (1999, page 33 200930396 779-784). Depending on the reaction conditions, the R3|R4 group can be used. Forming pg r3 and pg_r4 by unmodified reaction, or selectively protecting, each of which

PGf is an appropriate protecting group. For example, when R3 and R4 are -OH, the protecting group is a benzyl ether, a weiji silk, a weiji ether or the like. The standard can be used to convert a substituent (e.g., Rule 3 and R4) from an easily obtainable value (e.g., i, a thiol or the like) to another valence. See, for example, Larock, 1999. Example 10: Synthesis route of T1-C

1.NaOH

® (4-methoxyphenyl)methanethiol is stirred in ethanol and sodium hydroxide to form sodium (4-methoxyphenyl)methanethiolate. One equivalent of 1-(methylmethyl)-4-methoxybenzene was added to the mixture and stirred overnight. Thereafter, the reaction mixture was added with a diluted acid to terminate the reaction, and the obtained product was bis(4-decyloxybenzyl) sulfide. The bis(4-methoxybenzyl) sulfide is then reacted with hydrogen bromide in acetonitrile to remove the decyl protecting group, followed by neutralization and purification of the bis(4-decyloxyphenyl) group. Things. 34 200930396

Example 11: Synthesis route of T1-11

Adenine ribose nucleus (2-(6-amino-9H-indole-9-yl)-5-(pyridyl)tetrahydrofuran-3,4-diol) and 4-methoxybenzidine The gas reacted overnight in the dichloroethane. After completion of the reaction, a portion of the benzoicone was reduced to a methylene group in a slight excess of lithium aluminum hydride in ethanol. The resulting compound is deprotected with hydrogen bromide in acetonitrile to form the product 2-(6-(4-pyridinylamino)_9Η_η吟吟_9_ ❹))-5-(yl fluorenyl)tetra Hydrogen π von _3,4 diol (Tl-l 1 ). Example 12: Efficacy of T1-11 in Inflammatory Materials 舆 Method 'Cell Culture Primary stellate cells (astrocyte) were purified from neonatal (1-2 day old) R6/2 HD mouse brain (see Mangiarini, L. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Ce//87, 493-506 (1996)), and with its litter small 35 200930396 As a WT control group. Briefly, the cortex was carefully removed and digested with 〇5〇/0 TG-EDTA (Gibco, Grand Island, NY, USA) for 10 minutes at 37 ° C, then gently pipetted with a pipette. Make a physical separation 'and pass through a nylon mesh of 70 μιη holes. The cells were then placed in a poly-L-lysine-coated plate and de-activated with fetal calf serum (FBS) and 1% penicillin/streptomycin in DMEM medium (Dulbecco's) with 1% ν/ν heat added. Modified Eagle medium ; Gibco) was grown at 37 ° C in a humidified atmosphere containing 5% CO 2 . Progeny were identified by PCR-based genotyping techniques using the genomic DNA extracted from the tail of the mouse and the primer pair of Jackson Laboratory (5'-CCGCTCAGGTTCT GCTTTTA-3, and 5,-GGCTGAGGAAGCTGAGGAG-3). The performance of the variant Htt was measured using mouse anti-human Htt monoclonal antibody (EM48) (1:200 dilution, Chemicon International, Temecula, CA, USA). The purity of the primary stellate cell culture was determined using immunohistochemical staining using an anti-stellate cell-specific antibody (GFAP, 1:1000 dilution, Sigma, St. Louis, MO, USA) or anti-antibody. Microgel-specific labeled antibody (anti-CDllb, 1:200 dilution, Serotec, Oxford, UK). At 30 DIV, 99% of the primary cultured cells were positive for GFAP, and no CD11b positive cells (i.e., microglia) were found (data not shown). Dr. SFTzeng from National Cheng Kung University (Taiwan, Taiwan) generously presented a microglia cell line (BV2 cells, see Mazzolla, R., ei a/. Enhanced resistance to Cryptococcus neoformans infection induced by chloroquine in a murine model of meningoencephalitis. Antimicrob Agents Chemother 41 , 802-807 (1997))#,^^ Add DIO/Cl2 medium (Gibco, CA, USA) with lOQ/oI^BS (Hy-Clone) in an incubator at 37 ° C, in which the incubator The gas has 5% C02 and 95% air. 36 200930396 11 Hyun Sodium Sulfate (SDS)-Polyacrylic Acid Gel Electrophoresis and Western Deuteration Method The protein concentration was determined by Bio_Rad Protein Assay Dye Reagent Concentrate (Bio-Rad, Hercules, CA, USA). The sample was loaded into an 8% SDS_polyacrylamide gel and separated. Electricity

- After the end of the bath, the gel was transferred to a nitrocellulose membrane and blocked with a 3% 珏8 solution in PBS (131 〇 ^ 〇, then with the specified antibody at 4. ❹ effect overnight The membrane and a secondary antibody conjugated to a peroxidase were then co-cultured for 1 hour at room temperature and washed three times with TBST (0.2 MTris-base, 1.37 M NaCl and 0.1% Tween 20) to generate an immune response. The band was followed by a non-radioactive luminescence method (ECL, available from Fujifilm, Tokyo, Japan). In Western blot analysis, we used a 1:1000 anti-iNOS (BD Bioscience, CA, USA) Diluted solution. Nitrogen dioxide (NO) in the case of measuring NO production 'cells (5xl〇5 cells/dose) are in the presence of the target drug with lipopolysaccharide (LPS, 0.5 pg/mL) • Handling for 72 hours. As for the production of NO, it is used in a modified

The Griess reagent (Sigma, MO, USA) was evaluated in the amount of N02- (the stable end product of the NO formation process) according to the manufacturer's instructions. The medium was mixed with an equal amount of lx modified Griess reagent for 15 minutes. The absorbance at 540 nm was then monitored. NO production is normalized by the amount of protein in the same well, which is expressed as a percentage of the signal of WT stellate cells under control (untreated) conditions. 37 200930396 Results and discussion

Inflammation is involved in the pathology of a variety of traumatic and neurodegenerative diseases, including Huntington's disease (see Calabrese, V., Boyd-Kimball, D., Scapagnini, G. & Butterfield, DA Nitric oxide and cellular stress response in brain Aging and neurodegenerative disorders: the role of vitagenes. In Vivo 18, 245-267 (2004); Deckel, AW Nitric oxide and nitric oxide synthase in Huntington's disease. J Neurosci Res 64, 99-107 (2001)), therefore, nerve The inflammatory mechanism is an important drug target for many degenerative diseases (Sastre, M" Klockgether, T. & Heneka, MT Contribution of inflammatory processes to Alzheimer's disease: molecular mechanisms. Int J Dev Neurosci 24, 167-176 (2006); Blanco, AM & Guerri, C. Ethanol intake enhances inflammatory mediators in brain: role of glial cells and TLR4/IL-1RI receptors. Front Biosci 12, 2616-2630 (2007) ; Marchetti, B., et al. Glucocorticoid receptor-nitric Oxide crosstalk and vulnerability to experimental parkinsonism: pivotal role for glia-neur On interactions. Brain Res Brain Res Rev 48, 302-321 (2005); Barbeito, LH, et al. A role for astrocytes in motor neuron loss in amyotrophic lateral sclerosis. Brain Res 47, 263-274 (2004); and Beattie MS Inflammation and apoptosis: linked therapeutic targets in spinal cord injury. 10, 580-583 (2004)). The cell types responsible for the inflammatory response in the brain are stellate cells and microgel cells. Therefore, when we tested the effects of T1-11 on inflammation, we used primary stellate cells purified from wild-type (WT) and R6/2-J2 mice (a mouse model of Huntington's disease). And a micro 38 200930396 gel cell strain (BV2). The expression of inducible nitric oxide synthase (iNOS) and the production of nitric oxide (NO) are used as inflammatory markers as proposed in other literature (see Barbeito, LH, et al. A role for Astrocytes in motor neuron loss in amyotrophic lateral sclerosis. Brain Res Brain Res Rev 47, 263-274 (2004)) ° In several pathological inflammatory processes (such as septic shock, multiple organ failure, and chronic alcoholism), NO It produces a number of toxic factors, such as peroxynitrite, which play a key role (see Blaneo, AM & Guerri, C. Ethanol intake enhances inflammatory mediators in brain: role of glial cells and TLR4/ IL-1RI receptors. Front Biosci 12, 2616-2630 (2007) ; Chandra, A., Enkhbaatar, P., Nakano, Y., Traber, LD & Traber, DL Sepsis: emerging role of nitric oxide and selectins. Clinics 61, 71-76 (2006)) ° As shown in the ninth figure, low concentrations of bacterial toxins (lipopolysaccharide, LPS) will make iNOS expression and NO production in stellate cells obvious. Plus. The primary stellate cells received from R6/2-J2 mice had higher iNOS expression and NO production than wild mice, which is consistent with the hypothesis that chronic inflammation occurs in HD. Most importantly, T1-11 effectively inhibits inflammation caused by LPS (Fig. 9). Similarly, T1-11 also reduces iNOS induction (iNOS induction) and NO production by BPS in BV2 cells (Fig. 10). Since the inflammatory response is associated with astrocyte recruitment and/or microglial activation, and involves many degenerative diseases (such as Alzheimer's disease, Parkinson's diseases, spinal cord trauma, muscle atrophy) The amyotrophic lateral sclerosis, the findings of the present invention suggest that T1-11 can produce beneficial effects in neuronal diseases/injuries associated with inflammation and its systemic diseases such as sepsis in 200930396. Example 13, Synthesis of T1-11 The two active compounds Tl-C (1) and T1-11 (2) have been purified from the Chinese herb Tianma () and characterized, indicating that they have neuroprotective effects. (See Huang, NK, Lin, YL, Cheng, JJ & Lai, WL Gastrodia data prevents rat pheochromocytoma cells from serum-deprived apoptosis: the role of the MAPK family. Life Sci 75, 1649-1657 (2004) and Huang, NK, et al. Neuroprotective principles from Gastrodia elata. 70, 571-574 (2007)). Traditional Chinese medicine uses the underground stems of gastrodia to improve memory, ease sleep disorders, and protect heart function. Some researchers have suggested that gastrodia can prevent neuronal damage under several conditions (see An, SJ·, et al. Gastrodin determines immunoreactivities of gamma-aminobutyric acid shunt enzymes in the hippocampus of seizure-sensitive gerbils. J Neurosci Res 71 , 534-543 (2003) ; Kim, HJ, Moon, KD, Oh, SY, Kim, SP & Lee, SR Ether fraction of methanol extracts of Gastrodia data, a traditional medicinal herb, protects against kainic acid-induced neuronal damage In the mouse hippocampus. Neurosci Lett^lAt, 65-68 (2001)) ; Kim, HJ, Lee, SR & Moon, KD Ether fraction of methanol extracts of Gastrodia elata, medicinal herb protects against neuronal cell damage after transient global ischemia In gerbils. Phytother Res 17, 909-912 (2003); Kim, HJ, Moon, KD, Lee, DS & Lee, SH Ethyl ether fraction of Gastrodia elata Blume protects amyloid beta peptide-induced cell 200930396 death. JEthnopharmacol 84, 95-98 (2003); Hsieh, CL, et al. Anticonvulsive and free radi Cal scavenging activities of Gastrodia elata Bl. in kainic acid-treated rats. Am J Chin Med 29, 331-341 (2001) ; Hsieh, C.L., et al.

Anticonvulsive and free radical scavenging activities of vanillyl alcohol in ferric chloride-induced epileptic seizures in Sprague-Dawley rats. Life Sci 67, 1185-1195 (2000)). Ο

Tl-C

❹ Due to the limited content of Tl-11 in plant sources (~0.0 01 °/〇 for dry plant material), we use organic synthesis as a necessary means to obtain a sufficient amount of T1 -11 for subsequent organisms. ^ As shown in the subsequent flow chart, the adenosine analog T1-11 (Compound 2) is in the presence of diisopropylethylamine (DIEA) with 4-phenylbenzoguanamine hydrochloride (6) It is synthesized by the substitution reaction of 6_ehlG〒rine rib〇nUCle〇Side (7), and the yield is high. Since the amine hydrochloride 6 has no commercially available product, it is a two-stage reaction from the 4th benzene, and the inter-cloth product is the corresponding line 5. Therefore, the foregoing

Hydrogenation under the catalysis of Pd/C gave a 1H*13C NMR spectrum of the amine hydrochlorides I, 2 and 5 as shown in the eleventh: The TM1 synthesized above is derived from the natural ones (see Calabrese, V" Boyd-Kimball, D" 41 200930396

Scapagnini, G. & Butterfield, D.A. Nitric oxide and cellular stress response in brain aging and neurodegenerative disorders: the role of vitagenes. In Vivo 18, 245-267 (2004)). Synthesis of TM1 (/-(4-dihydroxybenzyl)aminopurine ribonucleoside, A^-G-dihydroxybenzy Uaminopurine riboside)

❹

NH2OH.HCI, NaOAc, EtOH - rt, 6 h, 70%

NOH 5

N-propanol, DIEA, 60oC, 7h, 78% 10% Pd/C, H2 EtOH, HCI, 4 h

The following is a specific embodiment of synthesizing TM1 according to the above flow chart. © Unless otherwise indicated, all reagents and solvents are reagent grades and are used without further purification. THF and diethyl ether are taken up from Na/diphenone, while CH2C12 is distilled off from CaH2. ' The absorbance of the solution was measured using a Perkin Elmer Lamda 35 UV-Vis spectrophotometer. Fluorescence spectra were measured using an AMINCO. Bowman Series 2 spectrophotometer. The melting point was recorded using a Yanaco micrometer. use

Nicolet Magna 550-11 § Recorded infrared (IR) spectra. NMR spectra were obtained using a Parian Unity Plus-400 (400 MZz) in which the chemical shift values (δ) were recorded relative to the following values in parts per million: δ Η 7.24/dc 77.0 at CHC13/CDC13 (t 42 200930396 line), (CH3)2CO/(CD3)2CO is δΗ 2.05/δ. 29.92, at CH3〇H/CD3OD is δΗ 3.31/5C 49.0, and at (CH3)2SO/(CD3)2SO is δκ 2.49 (m) / 5C 39.5 (m). A splitting pattern with multiple bees can be reported as s (single peak), d (doublet), t (triplet), q (quadruple), m (multiplet), br (wide) . Coupling constants (represented by Hz). ESI-MS experiments were performed on a Bruker Daltonics - BioTOF 111 high-resolution mass spectrometer. Analytical thin-layer chromatography (TLC) was performed on an E· Merck silica gel 60 F254 plate. (0.25 mm) ❹. Use UV, anisaldehyde or ninhydrin spray to visualize the compound. Column chromatography is used with 70-230 mesh; The column was carried out. The experiments sensitive to air or moisture were carried out under argon. All the glass was dried in an oven for more than 2 hours, and was cooled to room temperature in a desiccator before use. 妒-(4-dihydroxyl Benzoyl) adenosine (2) (see Trivedi, BKB, CJ; Bristol, JA; Hamilton, HW; Patt, WC; Kramer, WJ; φ Johnson, S. A.; Bruns, R. F.; Cohen, DM; Ryan, MJ N6-Substituted adenosine receptor agonists: potential antihypertensive agents. J. Med. Chem 34, 1043-1049 (1991); Golisade, AW, J.; Herforth, C.; Jomaab, H.; 'Linka, A. Bioorg. . Anti-malarial activity of N6-substituted adenosine derivatives. Part I. Med. Chem. 10 , 769-777 (2002)) 43 200930396

4-hydroxybenzylamine hydrochloride 6 (395 mg '2.5 mmol), 6-chloro-purine ribonucleoside 7 (143 mg, 0.5 mmol) and two in 1-propanol (25 mL) Isopropylethylamine (2 mL, 12 mmol) was heated to 70 ° C for 6 hours. The mixture was concentrated under reduced pressure and triturated with water to give a white solid, which was filtered to give the desired adenosine 2 (151 mg, 81%). C17H19N505; white powder, mp 208.7-209.2 0C; [α] 20 〇 = -64.5 (DMSO, 1 = 10 cm); TLC (MeOH/EtOAc (1:9)) Rf = 03; !H NMR (DMSO-i /6, 400 MHz) δ 9.22 (1 H, s), 8.34 (1H, s), 8.30 (1 H, s s), 8.18 (1 H, s), 7.12 (2 H, d, J= 8.0 Hz ), 6.65 (2 H, d, J = 8.0 Hz), 5.86 (1 H, d, /= 5.6 Hz), 5.41 (2 H, m), 5.18 (1 H, d, 5.6 Hz), 4.60 (2 H, m), 4.13 (1 H, q, J= 4.6, 7.4 Hz), 3.95 (1 H, q, 3.4, 6.2 Hz), 3.66 (1 H, m), 3.53 (1 H, m); 13C NMR (DMSO-i/6, 400 MHz) δ 155.3, 153.6, 151.6, 147.6, 139.1, 129.5, 127.9 (2 x), 119.2, 114.4 (2 x), 87.6, 85.6, 73.3, 70.5, 61.5, 42.4; ESI-MS calcd for C17H20N5O5: 374.1459, found: m/z 374.1412 (M+ + H). Each of the documents described in the present invention is incorporated by reference in its entirety. A series of embodiments of the present invention have been disclosed as above, however, it will be readily understood that various modifications may be made without departing from the spirit and scope of the invention. Other embodiments are defined by the scope of the following patent application. [Simple diagram of the diagram] The first panel is a bar graph showing the viability of PC12 cells, which is expressed as a percentage of the MTT metabolic measurement (leftmost strip) of the serum-containing control group. The group lacking serum is the second strip from the left. The PC12 cell line lacking jk clear was subjected to methanol extract (D1, 1-1, T1-2 and T1-3) for 24 hours, wherein the aforementioned sterol extract contained different doses of gastrodia elata extract. # When compared with the serum-containing control group, /><0.05. The second A picture is the roller test result, which is a graph of the number of seconds on the age of the mouse. The R6/2 mice are given from the surrounding area to the control drinking water (CON, n=ll) or containing the gastrodia elata extract (GE ' 5 mg/mL, n=12) drinking water. The second B-line is a graph of the percentage of survival versus the age of the mice, in which R6/2 mice were given control drinking water (CON, n=ll) or containing gastrodia elata extract (GE, 5 mg/mL, n) from four weeks old. =12) drinking water. The third panel is a representative representation of the striatum labeled with ubiquitin in 12-week-old R6/2 mice given control drinking water from the periphery. Scale bar: 25μπι. The third map is a representative representation of the striatum labeled with ubiquitin in 12-week-old R6/2 mice containing gastrodia elata extract (5 mg/mL) of drinking water. Scale bar: 25μιηη. The third C-picture is from 12-week-old R6/2 mice given control drinking water or drinking water containing gastrodia elata extract (5 mg/mL) from the periphery to the striatum cells expressing the accumulation of neurons in the nucleus of neurons. Percentage bar graphs, quantitative methods are described in "Materials and Methods". Scale bar: 25 μιη. ** Use Student's t-test 'when compared with 45 200930396 R6/2 mice given the age of the agent, ρ<第四.〇ι. The fourth picture shows the wild mouse control group, the R6/2 small gas control group, and the blood of R6/2 mice containing the gastrodia elata extract (5 mg/mL) drinking water from the surrounding area. A graph of the concentration of glucose in the middle (mg/dL) versus age. The blood sample is collected and blood glucose is measured during the indicated period, as described in "Methods, Methods". / -, Figure 5A is a representative figure of the liver labeled with ubiquitin in R6/2 mice from the periphery of the control drinking water. Scale bar: ❽ 25μιη. The fifth map is a representation of the liver labeled with ubiquitin in 12-week-old R6/2 mice containing gastrodia elata extract (5 mg/mL) of drinking water from the periphery. Scale bar: 25μιηη. The fifth C-graph is a bar graph showing the percentage of Htt aggregates in liver cells expressing 12-week-old r6/2 small gas from control drinking water or drinking water containing gastrodia elata extract (5 mg/mL) from the surrounding area. Quantitative methods are described in Materials and Methods. ** Use the Student's t-test to compare with the R6/2 mice that were administered with media at the indicated age. φ The sixth figure is a chromatogram of the active effluent of the gastrodia elata extract. HPLC conditions include Merck RP-18e (250 x 4.6 mm) column ", phase ladder, 70% to 4% water/sterol for 40 minutes, then 4% to 2 inches/water/ Sterol 5 points #, flow rate 〇 5 mL / min, detection wavelength 27 〇 nm. The positions of the two active compositions (T1-C and T1-11) are indicated by arrows. Figure 7A shows the cell viability after administration of T1_c or T1-11 to Pci2 cells after serum withdrawal, expressed as a percentage of the MTT metabolism of the pci2 cell control group as a percentage. The PC 12 cell line after serum withdrawal was treated with the indicated dose of the indicated drug or not with the indicated drug for 24 hours. Cell viability was measured by the MTT assay and expressed as a percentage of the MTT activity measured by the serum-containing group as a percentage of 46 200930396. Data points represent the mean ± SEM of at least three independent experiments (n = 3 to 6). Figure 7B shows the ST14A cell control group and the cell cAMP of ST14A cells after 20 minutes of CGS21680 (CGS, 10μΜ), Τ1-(: (ΙΟμΜ) or Τ1-11 (26.8μΜ) at room temperature. The content of bar graph. The measurement of cell cAMP content is as described in the specification. ~ Figure 8A shows the drinking water (CON, 1% DMS0, n=8) and Ή-C (0.5) from the surrounding area. Mg/mL, dissolved in 1% DMS0, n=7) drinking water, or R6/2 mouse roller containing T1-11 (0.05 mg/mL, dissolved in 1% DMS0, n=8) drinking water Test results chart. Figure 8B shows control drinking water (CON, 1% DMS0, n=8) from the surrounding area, containing T1-C (0.5 mg/mL, dissolved in 1% DMS0, n=7) Drinking water, or R6/2 mouse body weight chart containing Tl-11 (〇·〇5 mg/mL, dissolved in 1% DMS0, η=8) drinking water. The eighth C picture is from the periphery Control drinking water (CON, 1% DMS0, η=8), drinking water containing T1-C (0.5 mg/mL, dissolved in 1% DMS0, n=7), or containing Tl-11 (0.05 # mg /mL, a percentage of survival of R6/2 mice in drinking water dissolved in 1〇/〇DMSO, η=8). The presence of Τ1-11 effectively inhibits the inflammation induced by LPS. The primary stellate cells (30 DIV) received from wild-type (WT, Α) or R6/2 mice (Β) are present at the specified concentration of TM1. In the case of LPS (0.5 pg/mL) for 48 hours (Α, Β) or 72 hours (C). Western blot analysis was used to measure the amount of iNOS protein in whole cell lysate (one behavior 2 〇 Kg ) (Α,Β). The yield of NO under the corresponding conditions was measured using the Griess method, which is expressed as a percentage of the signal obtained from 47 200930396 wild-type stellate cells under control conditions (untreated). T-test and Mann-Whitney rank sum test, when compared with wild-type lysate, /? < 0·01. The tenth figure shows that T1-11 will reduce LPS in BV2 cells. Induction of iNOS and production of NO. The BV2 cell line was treated with LPS (0.5 pg/mL) for 72 hours (C) in the presence of the indicated concentration of ~T1-11. Measurement by Western blot analysis The amount of iNOS protein in whole cell lysates (2〇^g/row) (A, B). Measured using the Griess method. NO production under conditions, which is expressed as a percentage of 100% of the signal obtained from control cells (untreated). Figure 11 is a 1H NMR spectrum of Compound 1 (CD3 〇 D, 400 MHz). Figure 12 is a 13C NMR spectrum of Compound 1 (CD3〇D, 4〇〇 MHz). The thirteenth chart is the 1H NMR spectrum of Compound 2 (DMSO-i/5, 400 MHz). ❿ Figure 14 shows the 13C NMR spectrum of Compound 2 (DMSO-A, 4 〇〇 MHz). Figure 15 is a 1H NMR spectrum of Compound 5 (DMSO-A, 400 MHz) 〇 ' Figure 16 is a 13C NMR spectrum of Compound 5 (DMSO-4, 400 MHz). [Main component symbol description] None 48

Claims (1)

200930396 VII. Scope of application for patents. 1. A method for mitigating or treating a neurodegenerative disease, which is carried out in a mammalian patient in need thereof, and comprises administering to the aforementioned patient an individual or a dose containing an effective amount Synthetic N6_(4-hydroxyphenylhydrazino)adenosine (τι-ll) or a pharmaceutically acceptable salt or solvate thereof is used as a pharmaceutical composition as a pharmaceutically active agent. 2. The method of claim 1, wherein the neurodegenerative disease is Huntington's disease. The method of claim 1, wherein the aforementioned N6-(4-basic methyl) adenosine is a synthetic compound. 4. A method of modulating inflammation comprising performing on a mammalian patient in need thereof and comprising administering to said patient an effective amount of isolated or synthesized N6-(4-hydroxybenzyl) A pharmaceutical composition of adenosine (T1-11) or a pharmaceutically acceptable salt or solvate thereof as a pharmaceutically active agent. 5. The method of claim 4, wherein the aforementioned inflammatory system occurs in the central nervous system (CNS). 6. The method of claim 4, wherein the aforementioned inflammatory system occurs in the brain. The method of claim 4, wherein the inflammatory cell line is associated with astreocyte recruitment and/or activation of microglia. 8. The method of claim 4, wherein the aforementioned inflammatory system is associated with a neurological disorder. 9. The method of claim 4, wherein the aforementioned regulation refers to reduction or inhibition. 51 200930396 10. A method for producing N6-(4-hydroxyphenylhydrazino)adenosine of the following formula, r It comprises the following steps: a) a compound of formula I 4-nonoxyphenyl fluorenyl compound represented by formula II II is condensed, wherein R! represents a leaving group to prepare a compound of formula III b) reduction of the compound of the formula III to give the compound of the formula IV 200930396 and the U ίν compound deprotected to prepare ν6-(4-carbylbenzyl) = the method of claim 10, wherein the aforementioned leaving group = Patent (4) The method described in Item 1G, wherein the aforementioned squirting milk roll. Ο ϊ ί ί ί ί ί ί ί ί 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 14. The method of claim 10, wherein the gasification solution is as described in claim 10, wherein the reducing step is in the lowering of the gas and the lowering of a C1-C4. It is carried out in the presence of an alcohol solvent. 16. The method of claim 1, wherein the aforesaid deprotection step is carried out in the presence of hydrobromide and acetonitrile. 17. A method of producing N6-(4-hydroxyphenylhydrazino) adenosine of the formula OH OH OH which comprises a compound of formula 7 7 OH OH 53 200930396 with compound of formula 6 The step of condensing. 18. The method of claim 17, wherein the compound of the above formula 6 is prepared by the following steps: a) a compound of formula 4 Conversion to compound of formula 5 b) hydrogenation of a compound of formula 5 to give a compound of formula 6. 19. The method of claim 17, wherein the condensation step is carried out in the presence of a C1-C4 lower alcohol and a base. 20. The method of claim 19, wherein the base is diisopropylethylamine (DffiA). 54