TW200400042A - Therapeutic methods and uses of sapogenins and their derivativers - Google Patents

Abstract

The invention discloses therapeutic methods and uses of certain steroidal sapogenins, related compounds and derivatives thereof, in the treatment of non-cognitive neurodegeneration, non-cognitive neuromuscular degeneration, motor-sensory neurodegeneration or receptor dysfunction or loss in the absence of cognitive, neural and neuromuscular impairment.

Description

200400042

[Technical field to which the invention belongs] The present invention relates to saponin compounds, related compounds and uses and treatment methods thereof. , Κ, saponin, related compounds and their derivatives are used to treat non-cognitive neurodegeneration, non-cognitive neuromuscular degeneration, motor sensory nerve degradation or receptor abnormality or loss. On the other hand, the present invention relates to a composition for the treatment. [Prior technology] Cognitive dysfunction is a feature of dementia conditions and symptoms, such as Alzheimer's disease (AD), senile dementia of the Alzheimer's type (SDAT)), Lewy body dementia and vascular dementia. Minor cognitive abnormalities are also characteristic of some non-dementia conditions and symptoms, such as: mi 1 d cognitive impairment (MCI), age-associated memory impairment (AAMI), Autism and neuroimpairment. Non-cognitive neurodegeneration (ie, neurodegeneration in the absence of cognitive impairment), non-cognitive neuromuscular degeneration (ie, neuromuscular degradation in the absence of cognitive impairment), and motor sensory neurodegeneration are characteristic of the following conditions and symptoms' For example · Parkinson's disease, muscular dystrophy (including: shoulder-humerus type progressive

200400042 V. Description of the invention (2) Facioscapulohumeral muscular dystrophy (FSH) 'Duchenne muscular dystrophy, Becker muscular dystrophy and Brucell muscular dystrophy Bruce, s muscular dystrophy), Fuch's dystrophy, myotonic dystrophy, corneal dystrophy, reflex sympathetic dystrophy syndrome ( RSDSA)), neurovascular dystrophy, myasthenia gravis, Lambert Eaton disease, Huntington's disease, amyotrophic lateral sclerosis (Amyotrophic lateral sclerosis (ALS)), and multiple sclerosis (mu 11 ip 1 e sclerosis) ° Φ receptor dysfunction or loss — especially nicotinic and / or scopolamine Muscarinic acetyl choline receptors and / or dopaamine receptors Disorders or loss of e receptors and / or adrenoceptors are characteristic of some or all of the conditions and symptoms described above. Receptor disorders or loss in the absence of cognition, neurological and neuromuscular defects are also characteristic of the following conditions and symptoms, such as: postural hypotension (chrono hypotension), chronic fatigue syndrome, asthma (Asthma), susceptibility to heart failure and macular degeneration

3002-5563-PF (Nl), Chiumeow.ptd Page 7 200400042 V. Description of the invention (3) Due to the increase in life expectancy and the control of sporadic diseases, the above-mentioned conditions and symptoms are gradually increasing in all societies Increasing and serious problems, among which demographics of older ethnic groups are continuing to increase. What is urgently needed are agents that can treat or help manage and prevent these diseases. DE-A-4303214, incorporated by reference, discloses the treatment of viral diseases by saponins and sapogenins, but no data is provided for those skilled in the art to select specific classes of compounds to treat any specific Viral diseases. World Patent No. WO-A-99 / 16786, incorporated by reference, discloses the use of certain saponins and saponin compounds in the treatment of dementia. World Patent Nos. WO-A-99 / 48482, WO-A-99 / 48507, WO-A-01 / 23406, WO-A-0 / 23407, WO -A-0 1/23408 relates to the use of certain saponins, saponin ligands and their derivatives in the treatment of cognitive disorders and related symptoms. Chinese Patent Application No. CN-A- 1 09603 1 (Chinese Patent Application No. CN-A- 1 0 960 3 1), incorporated by reference, is disclosed in the / 3-adrenaline and M-type bile energy receptors (adregergic and Bioactivity of spirostane sapogenin and sarsasapogenin under the two-way regulation of M-cholinergic receptors. No specific pharmaceutical activity is provided. However, in 1988, the synthesis and applications of π isotopically labeled compounds (Synthesis and Applications of

3002-5563-PF (Nl), Chiuffie〇w Ptd Page 8 200400042 V. Description of the Invention (4)

Isotopical ly Label led Compounds) "page 315-320, Yi et al. Describe the use of salsa saponin in the treatment of Alzheimer's disease. There are some so-called " spectrum " diseases (, spectro⑽ " dis〇 rder), these diseases have a wide range of symptoms combined with relative severity. The severity of each symptom and specific combination of symptoms will vary from person to person, and will vary according to the stage of development of the disease. For example, in cases of Parkinson's disease, myasthenia gravis, Lambert Eaton's disease, postural hypotension, and chronic fatigue, cognitive impairment is one of the secondary symptoms that may occur, including secondary symptom. One, but not the primary symptom (primary Symptom). Furthermore, these symptoms are not viral diseases of dementia. Many such diseases are so-called " spectrum " diseases. Therefore, in many cases, there is no need to treat cognitive disorders (eg, dementia). The present invention is based on our findings. Some saponins and their derivatives (including saponin) have amazing disease-modifying activities. "(DiSeaSeiodizing activity), can resist non-cognitive neuroization, non-cognitive neuromuscular Degeneration, motor sensory neurodegeneration, and receptor impairment or loss in the absence of cognition, neurological and neuromuscular deficiencies: effective prevention and change of these symptoms. This finding can improve non-viral disorders that are not the main symptoms Treatment of sexually transmitted diseases p. "T Kaifeng" Japanese disease [Summary of the invention] Brief description of the present invention According to the form of the present invention, the present invention provides an active agent (as defined herein

200400042 V. Use of the invention (5) ^ Active agents are used to treat or prevent human or non-human animals ^ suffering or susceptible symptoms, or to prepare a combination for treating or preventing the symptoms, (such as a pharmaceutical combination Food, food, food supplements and beverages), these symptoms are (1) non-cognitive neurodegeneration, (ii) non-cognitive neuromuscular degeneration, (丨 丨 i) motor sensory neurodegeneration, and (iv) lack of cognitive receptors Disorders or loss, neurological and neuromuscular defects. "· Active agent" refers to the compounds of the following general formulae I, II and I, as the saponin ligand derivative defined in the following references, the derivative has at least one defined X group substituent, Sugar-subsituted derivatives of such compounds (sugar-subs ti tu t ed der iva ti ves), all stereoisomers and racemic mixtures thereof, all pharmaceutically Acceptable pro-drugs and salts, and all mixtures and combinations thereof. Formula I:

3002-5563-ίΨ (Ν1), Qii umeow ptd p. 10 200400042

^ 10 R, # 13 'Rule 18, Rule 19' Rule 20 'Ru, R, 9 Individual Rule 21, R22, Rule 23, Rule 24, R26 Composition is hydrogen (Η), OH, = (?, M r5, r6, R ?, R27 ^ 28 av29 av30 x 1V31 ^ 1V32 ruc ^, / atom (holaatom), (Me-S-) (Me ~ S0-) ^ (MeSOo- ^), m, 1X: 2) , NH2-, MeS02NH-, alkyl, or the absence of A, 々〇 »子 I or OR, where R is an alkyl or acyl group; ", R12 ,, R15, R16, R17, r25, r33 may be hydrogen, 0H, a halogen atom, (Me-S-), (Me-SO-), (MeS02-), N3-, NH2-, MeSOgNH- ', or not present, or Is ⑽, where R is an alkyl group or fluorenyl group; -R〇 di represents an optional double bond, wherein, in addition to the above,

3002-5563-PF (Nl); Chiumeow.ptd Page 11 200400042 V. Description of the invention (7)-One of R33 and R14 is a thiol group Molecular formula (I I):

^ 14 In the general formula (II): Heart, r2, r3, r4, r5, r6, r7, r8, r10, r13, r18, r19, r20-heart, R2, R3, R4, R2I, R22, R23 , R24, R26, R27, AV28, AV29, AV30, AV31, 1V32 Don't be nitrogen 'OH' = 0 '_ Atom' (Me_S-) '(Me_S0-)' (MeS02-), N3-, NH2-, MeS02NH-, alkyl , 0R (where R is alkyl or fluorenyl), or does not exist; -R9 'Rll' R12 'Rl4 5 Rl5' Rl6 'Rl7' R25 'R33' R35 may be hydrogen 'OH, _ atom, (Me- S-), (Me-SO-), (MeS02_), N3-, NH2-,

MeS02NH-, alkyl, OR (wherein R is alkyl or fluorenyl), or does not exist,

3002-5563-PF (Nl), Chiun] ew ptd Page 12 200400042 V. Description of the invention (8)… represents an arbitrary double bond, wherein, in addition to the above,-one of Rm and L is an alkyl group; Formula III:

m in the general formula (I II):-R1, R2, R3, R4, R5, R6 5 R7, r8 ^ 10 J Rl3, Rl4 1 'feet 18 5 feet 19, feet 20, R21, ^ 22 1 ^ 23 5 ^ 24, R26 '^ 27' feet 28, I h,] ^ 30 5 feet 31 5 feet 32, feet 33, R34, feet 35 5 feet 36 'feet 37 are hydrogen, OH 1 2: 0, halogen atoms , (Me-S-), (Me-S0-), (MeS02-), N3-9nh2-, MeS02NH-, alkyl, 0R (, where R is alkyl or fluorenyl), or does not exist; -Heart '' Rn 'Ruler 12' Ruler 15 'Ruler 16 5 ^ 17 ^ 25 May be hydrogen, OH, halogen atom, (Me-S-), (Me-S0-), (MeS02 ~), n3- nh2 -, MeS02NH-, alkyl, 0R (wherein R is alkyl or fluorenyl), or does not exist;

3002-5563-PF (Nl); Chiumeow.ptd Page 13 200400042 V. Description of the invention (9) • • represents any double bond, in addition to the above, one of R33 and Rm is Alkyl; and the stereochemistry of R25 is in orientation; especially saponin ligand derivatives (but not specifically steroid helix alkane | hormone ligand derivatives) have at least one X group substituent, Where X is selected from the group consisting of:-a halogen atom,-(Me-S-), (Me-S0-), (Me-S02-), -N3-, NH2-, MeS02NH-, and · -An alkyl group; and a derivative form of any of the above compounds, wherein the carbon atom at position 3 (ie, the carbon atom to which Rs is attached, or the same position as the saponin ligand derivative without a molecular formula defined above), or the molecular formula In (II) and (III), the carbon atoms at positions 3 and '26 (that is, the carbon atoms linked by &), or each of the carbon atoms at positions 3 and 26, will carry a 0-sugar moiety. Among them, the sugar group is a mono, di or trisaccharide (saccharide). The sugar-derived derivative form of a saponin active agent generally refers to saponin in the conventional art. As used herein, "car b < phy dr ate 1 'specifically includes such sugar groups. The active agent used in the present invention is preferably a non-estrogenic steroidal sapogenins ), Saponin, and derivatives thereof as defined above, including all of its physiologically acceptable prodrugs

200400042 V. Description of the Invention αο) Substances and salts. The active agent may be produced naturally or non-naturally. According to conventional techniques and the following description, by modifying side groups and / or side atoms of a naturally occurring compound, a non-naturally occurring active agent can be appropriately prepared. The present invention also provides the same method for treating human and non-human animals, and provides a composition containing the active agent for use in the treatment method. If necessary, the active agent of the present invention may add one or more activities Agents and then administered together, these active agents include cholinesterase inhibitors, dopamine agonists (e.g., L-dopa), catechol oxygen methyl groups COT inhibitors, monoamine oxidase B inhibitors (ΜΑ0-B inhibitors), anti-cholinergics, acetyl chol ine agoni sts, serotonin agonists, α -Amino-3-hydroxy-5-fluorenyl isoxapentine- 4-propanoic acid receptor agonists (AMPA receptor agonists), γ-aminobutyric acid receptor agonists (N-fluorenyl- NMDA receptor agonists, θ-adrenoceptor agonists, digoxin, dobutamine, anti-inflammatory drugs -inflammatories), neurotrophic factors, statins, adenosine A2a receptor agonists, acid sugar reductase inhibitors

3002-5563-PF (Nl), Chiumeow.ptd Page 15 200400042 V. Description of the invention (11) · Preparations (aldose reductase inhibi tors), immunomodulators: (immunomodulators), cannabi noid agonists, Interferon or tricyclic ant i-depressants ° This activator can be used to treat and prevent humans and non-human animals from suffering or susceptible to non-cognitive neurodegeneration, non-cognitive neuromuscular degeneration Symptoms and diseases such as motor sensory nerve degeneration, or impairment or loss of receptors. Examples of such symptoms and diseases are described below. Therefore, 'for one or more of the symptoms and diseases mentioned above that are susceptible to or susceptible to humans and non-human animals, the present invention also provides the use of an activator (as defined therein) for the treatment or prevention of such symptoms, or provides an activator Use in the preparation of a composition for treating or preventing the symptoms. [Embodiment] Detailed description of the present invention Examples of active agents Several kinds of active agents are specifically described below: 1. The compound of the above general formula I, wherein: R1'R3, m r13, r18, r19, r2. ,and also

'22' 'R24' R26 'R27,', ', R3. , &Amp;, heart 2 are W lice, 0H, = 0, _ atom, (Me-s-), (Me —so —), (Me_s〇2 one),%-'NH2-, MeS〇2NH- Alkyl or absent, or OR, where R is alkyl or fluorenyl; 9 ^ 11 ^ 12 heart 4 'Rl5' heart 6 'Ri7' R25, R33 can be hydrogen, 0H, halogen

200400042 V. Description of the invention (12) Atom, (Me-S-), (Me ~ s〇-)

MeS02NH-, alkyl or absent, represents an arbitrary double bond, (Me-S02-), N3-, NH2-, or OR, where R is alkyl or fluorenyl wherein, in addition to the above,- One of R33 and Rm is a alkynyl group, and the stereochemistry of R25 is located at the position 2. The compound of the above general formula I, one of which is R1 'R2' R3 'R4' R5, R6, R7, R8,

Rl0 ’R

R v18

R 19 ^ 20 is R22 'R23' R24 'R26OH' = 0, halogen atom, (Me_s_), (Me — so —) '1 (two s〇: y' N3 ~, NH2 ~ 5MeS02NH ^ 5 -¾ yz t- 4-, 〇 is a ′ group or a fluorenyl group; & group may not exist, or it is OR ′ of 21 hydrogen v27

R 28 v29 t ’r3]

_R9 'K12' R15 'R16' R17 is hydrogen, -Rh, R14, R25, R33 may be hydrogen, 0H, _ atom, (Me-SO-), (Me-S02 ~), n3—, Nh2— , MeS〇2NH ~ alkyl, or absent 'or OR' where r is alkyl or fluorenyl; • .. represents an arbitrary double bond, wherein, in addition to the above, one of R33 and Rl4 Is an alkyl group, and the stereochemistry of R25 is in the / 3 position; 3. The compound of the above general formula I, wherein:

200400042 V. Description of the Invention (13) • ···················································· The stereochemistry of R is cold, and in addition to the above, at least one of Rs or R23 is an X group, and the possible remaining substituents are hydrogen, 0H, = 0, and OR, where R is alkyl or fluorene Or is absent, and X is selected from the group consisting of:-a halogen atom,-(Me-S-), (Me-SO-), (Me-S02-), and -N3, NH2_, MeS02NH-- Benzyl; 4. The compound of the above general formula I, wherein: ^ 21 = ^ 22 = ^ 23 = ^ 24 ~ ^ 14 = R33 = fluorenyl,

25 ~ ^ 26 = K27 = R28 = ^ 29 ^ Rqh = J M3 AM5 _1M6 ~ AM7

Rl8 = ruler 19 l31 R32 = hydrogen = represents a single bond,-the stereochemistry of R25 is in the cold direction, and in addition to the above,

RfR2 di to / 1: each is an X group. Possible remaining substituents are hydrogen, 0H = 0, and OR, where R is an alkyl or amidino group, and X is selected from the following groups:- A halogen atom,-(Me-S-), (Me-SO-), (Me —s〇2 —), and

200400042 V. Description of the invention (14) -N3, NH2_, MeS02NH--sulphonyl group; 5. The compound of the above general formula II, wherein: -h, R2, R3, R4, R5, R6, R7, R8, R10, Ru , R18, Rl9, ', ruler 21' ^ 22 '' 'R24' ^ 26 '^ 27' '' heart '^ 3 ()' 'R32, R34 are hydrogen, OH, = 0, ii atom, (Me -S-), (Me-SO-), (Me-S02-), N3-, NH2-, MeS02NH-, alkyl, OR (where r is an alkyl group or an alcohol group), or does not exist; -R9 'Ru' R12 'R14' R15 'R16' R17 'R25' R33 'R35 can be hydrogen, OH, halogen atom, (Me-S-), (Me-SO-), (Me-S02-), N3- , NH2-, MeS02NH-, alkyl, OR (wherein R is alkyl or fluorenyl), or does not exist; ... represents an arbitrary double bond, wherein, in addition to the above, one foot 33 and Rl4 One of them is the base group, and the stereochemistry of R25 is located at the / 5 position; 6 · The compound of the above general formula II, and its carbohydrate derivative, are compounded: ',

200400042

-R34 is hydrogen, OH, = 0, and OR (wherein r is alkyl, adduct); earth carbohydrate -Rn, R14, R25, R33, R35 may be hydrogen, 0H, halogen atom, ("(Me-SO-), (Me-S02-), n3-, NH2-, MeS02NH ~, ^^ 8 ~) OR (wherein R is alkyl or fluorenyl), or does not exist; & '... represents an arbitrary double bond, in which, in addition to the above, one of R33 and Rh is an alkyl group, and the stereochemistry of r25 is located in various directions; 7. The compound of the above general formula II, and its carbohydrate : 物 物 和 生物, 20 ~ ^ 21 ~ ^ 22 = ^ 23 = ^ 24 = ^ 25 = ^ 26 = ^ 27 = ^ 28 = ^ 29 =-rh = fluorene

Is -0H or -0R, where R is an alkyl group, fluorenyl or r35 is hydrogen or does not exist, the compound ^ represents any double bond, and the fluorenyl group above can be a mirror image isomer clockwise ) Or counterclockwise and the stereochemistry of R25 is in the orientation. In addition to the above, R3 / R2f has: X groups, possible remaining substituents are hydrogen, = 0, and OR (where R is an alkyl or Fluorenyl or absent), and X is selected from the group consisting of ...

200400042 V. Description of the invention (16)-Halogen atom '-(Me-S-), (Me-SO-), (Me-S02-), and -N3, NH2-, MeS02NH-alkyl; 8 · Above Compounds of general formula II and their carbohydrate derivatives' where: ~ R! = R2 = R4 = = 20 = ruler 21 = knife 2 = = 1 ^ 4 = R25 = R26 = R27 = R28 = R29 = ruler 30 = Kl = heart 2 _ hydrogen '-RH = R33 = methyl-R34 is -OH or -OR, where R is alkyl, fluorenyl or carbohydrate' and-R35 is hydrogen or absent, • ·. Means any And the stereochemistry of R25 is in the / 3 position, and in addition to the above, at least one of & or X is an X group, and the possible remainder is 0, and OR (where R is an alkyl group) Or fluorenyl or non-existent horse lice, 0H, and X is selected from the group consisting of: '-halogen atom,-(Me-S-), (Me-S0-), (Me ~ S〇2-) , And -N3, NH2-, MeS02NH--carbyl;

3002-5563-PF (N1); Chiumeow.ptd Page 21 200400042 V. Description of the invention (17), R33, R34, R35, R36, R37 are hydrogen, 0H, = 0, halogen atom,: (Me-S -), (Me ~ S0-), (Me-S02-), N3-, NH2-, MeS02NH-, alkyl, OR (where R is alkyl or fluorenyl), or does not exist; -R9, Ru 'R12, R15, R16, Rn, R25 may be hydrogen, 0H, halogen atom, (Me-S-), (Me-S0-), (MeS02-), N3_, NH2-, MeS02NH-, ^ group, OR (Where R is an alkyl group or a fluorenyl group), or does not exist; • ·. Represents an arbitrary double bond, wherein, in addition to the above, one of -r33 and r14 is an alkyl group, and the stereochemistry of R25 is located at Cold orientation; k 10 · The compound of the above general formula III, wherein: -R 丨, R2, R3, R4, R5, r6, r7, r8, R10, r13, r14, r18, r19, R20, R21, R22, R23 , R24, r26, r27, r28, r29, r30, R31, r32, R33, R35, R36, R37 are hydrogen, OH, = 0, halogen atom, (Me-S-), (Me-S0-) (Me-S02-), n3-, Nh2—, MeSO2NH_, alkyl, OR (where R is alkyl or fluorenyl), or does not exist; -R9, Rl2, Rule 15, R16, R17 = hydrogen-R34 is hydrogen, OH, = 0, -atom, (Me —s —), (Me —so—), (Me-S02-), N3-, NH2-, MeS02NH- , Alkyl, OR (wherein R is alkyl, fluorenyl, or carbohydrate), or does not exist; Read Dream -Rn, R25 can be hydrogen, 0H, _ atom, (Me_s—), (Me — s 〇-), (Me-S02-), N3-, NH2-, MeS02NH-, alkyl, OR (where R is alkyl or fluorenyl), or does not exist; • ·. Represents any double bond,

3002-5563-PF (N1), Chiumeow.ptd Page 22, 200400042 V. Description of the invention (18) In addition to the above,-one of R33 and Xin 4 is a calcined group and the stereochemistry of R25 is located at / 3 orientation; 11. The compound of the above general formula III, and its carbohydrate derivatives, where: = R2 = R4 = R5-R6-R7 = R8 = R10 = Rn = R9 = R12-R13 = = = = = ^ 20 = K21 = R22 = ^ 23 ^ ^ 24 = ^ 25 = ^ 26 = ^ 27 = ^ 28 = ^ 29 ^ ^ 3〇 = R31 = R32 = R33 = H 5-R14 = 曱 -R34 is -OH or -OR, where R is a alkynyl group or a carbohydrate and R35 is hydrogen or does not exist, R37 is hydrogen, -0H or = 0 R36 is hydrogen or -0H • ·. Represents a single bond, and -carbon 25 The fluorenyl group on (C25) may be a mirror image isomer clockwise (R) or counterclockwise (S) structure and the stereochemistry of R25 is in the yS orientation. In addition to the above, at least one of R3 or dagger 3 is X Possible remaining substituents are hydrogen, 0H, = 0, and 0R, where R is alkyl or fluorenyl or absent, and X is selected from the group consisting of:-a halogen atom,-(Me-S -), (Me-SO-), (Me-S02-), and -N3, NH2-, MeS02NH--alkyl ;

3002-5563-PF (Nl), Chiumeow.ptd Page 23, 200400042 V. Description of the invention (19) 1 2 · The compound of the above general formula III and its carbohydrate derivative, wherein: -R1 = R2 = R4 = R5 = R6 = R7 = R8 = R10 = R11 = R9 = R12 = Ri3 = Ri5 = Ri6 = Ri7 = R18 = R19 = R 2. = R21 = R22 = R23 = R24 = R25 = R26 = R27: R28 = R29: = r3. -R14 = R33 = fluorenyl-R34 is -OH or -OR, where R is alkyl, fluorenyl or carbohydrate, and R35 is hydrogen or absent, R37 is hydrogen, -0H or = 0, R36 is hydrogen or -0H 〇 represents a single bond,-the fluorenyl group on carbon 2 5 (C 2 5) may be a mirror image isomer clockwise (r) or counterclockwise (S) structure and the stereochemistry of R25 is in the cold direction, except for the above In addition to the above, at least one of R3 or R23 is an X group, and the possible remaining substituents are hydrogen, 0H = 0, and 0R, wherein R is an alkyl group or a fluorenyl group or does not exist, and X is selected from the following groups Groups: -halogen atom,-(Me-S-), (Me-S0-), (Me-S02-), and -N3, NH2-, MeS02NH--carbon groups; 13 · Special substituted saponin ligands (Substituted sapogenins), but does not specifically refer to the steroid spirane saponin casein f, in which at least one of the saponin ligands of the 0H group is replaced by X, and X is

3002-5563.PF (Nl), Chiumeow.ptd Page 24 200400042

Contained groups:-halogen atom,-(Me-S-), (Me-S0-) '(Me-S02-), and-N3, N H2 _, Me S 02 N Η-, and- Group 1 4 · Special saponin ligands as defined above, but do not specifically refer to spiron steroid-containing saponin ligands, in which the halogen atom in the definition of X # 敦 ^ 1 5 · Substituted saponin ligands selected from the following: 3 cold-fluoro-5 / 5, 20〇 :, 22〇 :, 251 ^ -spirostane (3 cold 411 ^ 〇-5 stone, 20 α, 22 a, 25R -spirostane), 3,3-difluoro-5 dots, 20 α 22 a 25R-spiral burn (3,3-difluoro-5 / 3,20 α, 22 a, 25R-spirostane), 3 α-methyl Scutellaria amine group 5 / 3,20 α, 22 a, 25R-spiral burn (3 α-methylsulphonylamino-5 0,20α, 22 a, 25R-spirostane), 3 α-triazole-5 cold , 20 α, 22 a, 25R-spiral burn (3 a-azido-5 A, 20 a, 22 a, 25R-spirostane), 3 α-amino-5 / 3, 20 a, 22 a, 25R- Spirosteroid (3 a-amino-5 / 3, 20 α, 22 α, 25R-spirostane), its stereoisomers and racemic mixtures, and its pharmaceutically acceptable prodrugs and salts; 16. Substituted saponin compounds, wherein the parent saponin is replaced with at least one X group as defined above, and the parent saponin is selected from sarsasapogenin, episa Earl sarsasapogenin, smilagenin, episilagenin '' and grace

3002-5563-PF (Nl); Chiumeow.ptd page 25 200400042 V. Description of the invention (21) Zosapogenin-D (partial transliteration anzurogenin-D); 1 7. Compound of general formula I a:

(ia) — wherein the R group is selected from hydrogen; alky 1 carbonyl; alkoxycarbonyl; aikylcarbamoyl; or arylcarbonyl; or suiph 〇 (H03S)); phosphono ((Η0) 2P (0)-); or a mono-, di- or tri-saccharide; wherein any alkyl group can be optionally aryl, amine, mono or di Alkylamine (mono- or di-alky amino), carboxylic acid residue (carboxyiic acid res i due (-C00H)); or any resulting combination for substitution. 1 8 · As above 1 to 1 17 Derivative forms of the compounds defined in item 7, where the carbon atom at position 3, or the carbon atom at position 3 m in the molecular formulas η and hi, the carbon atom at position 2 or each in position 3 and The carbon atoms of 2 and 6 each carry a 0-sugar group, wherein the sugar group is a mono-, di- or tri-saccharide, for example, a monoaldulose or ketose with 5 or 6 carbon atoms (mON. aldose or ketose), preferably cyclic furanose (cycHsed

3002-5563-PF (Nl), Chiumeow.ptd Page 26, 200400042 V. Description of the invention (22) Furanose and pyranose forms, or optical isomerism with D or L Alpha or / 3 anomers, or any combination of di- and tri-oligosaccharides; acylated forms of sugar residues are also included in the "sugar" class; appropriate sugars Including glucose, mannose, fructose, galactose, maltose, cellobiose, sucrose, rhamnose, xylose (Xylose), arabinose (arabinose), fucose, quinovose, apiose, lactose, galactose-glucose, glucose-arabinose, trehalose-glucose, Rhamnose-glucose, glucose-glucose-glucose, glucose-rhamnose, mannose-glucose, glucose- (rhamnose) -glucose, glucose- (rhamnose) -rhamnose, glucose- (glucose) -Glucose, galactose- (rhamnose ) —Galactose and its tritiated (for example: a c e t y 1 a t e d) derivative. In the definition of the above compounds: the amino group of the alkyl group, the monoalkylamino group (mo no-alky ami no) and the dialkylamino group are preferably monosubstituted at the α position of the alkyl group. Radical (mono-substituent). The carboxyl (—C00H) substituent of an optionally present alkyl group may be located at the terminal of the alkyl group or at any other position. The "'" alkyl group (alky 1) π refers to an aliphatic hydrocarbon group, and the aliphatic hydrocarbon group may be a straight or branched chain having about 1 to 20 broken atoms. The alkyl chain preferably has 1 to about

3002-5563-PF (Nl); Chiumeow.ptd Page 27 200400042 V. Description of the invention (23) 12 broken atoms. Branching refers to the attachment of one or more lower alkyl groups (eg, methyl, ethyl, or propyl) to a linear alkyl chain. Low alkyl π means about 1 to 4 carbon atoms in a straight or branched chain. Examples of alkyl groups include: fluorenyl, ethyl, n-propyl (n — pr〇py 丨), isopropyl (i-propyl), n-butyl, third butyl (t-butyl), second butyl (s-butyl), n-pentyl, η-pentyl. • 'Aryl' refers to any group containing an aromatic or fused rings system, and preferably contains up to 2 carbon atoms. Phenyl is an example of an aryl group. The aryl group can be arbitrarily, for example, a halogen atom (such as chlorine or molybdenum), an alkyl group, a hydroxyl group, a hydroxy group, an alkoxy group, an amine group, a nitro group, a halogenated amino group ( acylamin〇), carboxyl group and alkoxycarbonyl group—single or multiple substitution, respectively. π carboxylic acid residue " refers to Weyl-C00H. π 醯 group " Refers to H-C0- or alkyl-C0- groups, where alkyl is defined as follows. The fluorenyl group preferably contains a lower alkyl group, and examples of the fluorenyl group include formyl, acetyl, propanoyl, 2-methylpropanoyl, and butanyl ( (butanoyl) and palmitoyl; "optionally substituted" means that the previously mentioned groups may be substituted with one or more substituents, which may be the same or different Substituents, and with respect to the parent group being substituted, it is best to have one or more small molecules (for example: less than the largest molecule

Page 28 3002-5563-PF (Nl), Chiumeow.ptd 200400042 V. 20% of the description of the invention (24)); Suitable substituents include halogen atoms (for example: gas or bromine), alkyl, ring Alkyl, hydroxyl, alkoxy, amino, halogenated amino, aryl, aromaticamino, carboxyl, alkoxycarbonyl, aralkoxycarbonyl, heteroaryl epoxy Heteraralkoxycarbonyl, and optionally substituted carbamoyl, the size of which is preferably as described above; " Pharmaceutically acceptable π means within the scope of sound examination and veterinary diagnosis, suitable for use in Contact human and other animal cells without causing inappropriate toxicity, irritation, allergic reactions and similar reactions, and have a reasonable benefit / risk ratio. "Pharmaceutically acceptable prodrug" refers to a prodrug of a compound that is suitable for use in contact with cells of humans and other animals within the scope of sound inspection and veterinary diagnosis without causing undue toxicity or irritation , Allergic reactions and similar reactions, and a reasonable benefit / risk ratio, and effective effects, such as zwitterionic forms of the compound. "Prodrug," refers to the rapid transformation of the compound in vivo (invivo). The parent compound having the above-mentioned molecular formula, for example, is achieved by hydrolys is in blood. Through metabolic cleavage, functional groups can be rapidly transformed into a series of groups that react with carboxyl groups in the body. Since the metabolic cleavage group of a compound is easily cleaved in vivo, a compound with such a group acts as a prodrug. A complete discussion of prodrugs is listed in the following literature: Design 〇f Prodrug, Η · Bundgaard, ed ·, Elsevier, 1985;

Methods in Enzymo1ogy, K. Widder et a 1, Ed

3002-5563-PF (Nl); Chiumeow.ptd page 29 200400042 V. Description of the invention (25)

Academic Press, 42, p. 309-396, 1985; A Textbook of

Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard, ed., Chapter 5; Design and Applications of Prodrugs ρ 113-191, 1991; Advanced Drug Delivery Reviews, H. Bundgard, 8, p. 1-38, 1992 ; Journal of Pharmaceutical Sciences, 77, p.285, 1988; Chem, Pharm. Bull., N. Nakeya et al, 32, p. 692, 1984; Pro-drugs as Novel Delivery

Systems, T. Higuchi and V. Stella, Vol. 14 of the ACS Symposium Series, and Biorevcrsible Carriers in Drug Design, Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, 1 987, all of which are incorporated by reference. Literature; " Pharmaceutically acceptable salts " refers to the relatively non-toxic, inorganic and organic acid addition salts and base addition sa 11 s compounds in the present invention. During purification, these salts can be prepared in situ. Especially after the free base form purified compounds are reacted with appropriate organic or inorganic acids, respectively, and then the salts are separated to form acid additions. Synthetic salts. See S. M. Berge, et al., Pharmaceutical Salts, J. Pharm. Sci., 66: P. 1-19 (1977), which is incorporated herein by reference. The acid form (acid form The purified compounds are reacted with appropriate organic or inorganic bases, respectively, and then the salts are separated to form base addition salts. The base addition salts include pharmaceutically acceptable metal and amine salts. Appropriate acid addition salts Examples of classes are And some

3002-5563-PF (Nl); Chiumeow.ptd page 30 200400042 Description of the invention (26) Salts formed by the reaction of the following acids, which are as follows: hydrochloric acid, sulfuric acid, phosphonic acid and nitric acid. Examples of suitable base addition salts are those formed by reaction with the following types of salts: sodium hydroxide (sod i um hydroxide), potassium hydroxide and ammonium hydroxide ) 〇 A better class of active agents are compounds of general formula Ia. In some compounds of formula la, the fluorenyl group at 'carbon 25 has a counterclockwise (S) structure. These compounds of the present invention are salsa saponin and episa salsa saponin or derivatives thereof. In other compounds of the formula la, the methyl group of carbon 25 has a clockwise (R) structure; these compounds of the present invention are isoamidine saponin and epiisoamidine saponin or derivatives thereof. The -0R in the above molecular formula la may be selected from the following groups (unless appended but excluded from the book). · Hydroxyl, ethyl formate (ethoxycarbonyloxy), acetate, amber Succinate, cinnamat e, P-cobate

(ferulate), propionate, butyrate, valerate, isovalerate, caproate, isocaproate, diethyl Diethy lacetate, octanoate, decanoate, laurate, myristate, palmitate, stearate (stearate), benzoate, pheny lacetate, phenylpropionate, cinnamate, p-nitrophenylhydrazone

3002-5563-PF (Nl); Chiumeow.ptd Page 31, 200400042 V. Description of the invention (27)-(p-ni trobenzoy loxy), 3, 5-dinitrobenzyloxy (3, 5- dini trobenzoy loxy), p-chlorobenzoyloxy, 2,4-dichlorobenzoy loxy, P-bromobenzoy loxy ), M-bromobenzoyloxy, m-bromobenzoyloxy, p-methoxybenzoy loxy, phtha 1 y 1, glycinate, aminopropyl Salts (alaninate), valinates (phenylalaninate), isoleucinate (isoleucinate), methioninate (argionate), argininate (argininate), Asparaginate, aspartate, cysteinate, glutamate, histidinate, lysinate ), Prolinate, serine, threoninate, tryptophanate, tyrosina te), fumara t e or maleate (ma 1 ea te). Particularly preferred compounds of general formula Ia and their pharmaceutically acceptable salts are as follows:

Salsa sapon saponin ethyl formate (cathylate) salsa saponin acetate salsa saponin succinate and its pharmaceutically acceptable salt salsa saponin glycinate and Its pharmaceutically acceptable salts

3002-5563-PF (Nl), Chiumeow.ptd Page 32

200400042 V. Description of the invention (28) Salsa saponin ammonia salsa saponin valsarsa saponin benzene salsa saponin isosarsa saponin different table salsa saponin table salsa saponin table Table Salsa soap table Salsa soap table Salsa soap table Salsa soap table Salsa soap table Salsa soap table Salsa soap table Salsa soap table Deeds, sweets, sweets, sweets, sweets, sweets, sweets, sweets, sweets, sweets, sweets, sweets, sweets, sweets, sweets, sweets, sweets, sweets, sweets, sweets, sweets, sweets, sweets, sweets, sweets, sweets, sweets, sweets Glycolyl propionate and its pharmaceutically acceptable amine salt and its pharmaceutically acceptable aminopropionate and its medicinal leucine salt and its pharmaceutically acceptable methionine salt and its pharmaceutical ethyl acetate succinate Salt and its pharmaceutically glycine salt and its pharmaceutically aminopropionate salt and its pharmacological phenylaminopropionate salt and its pharmacy isoleucine salt and its pharmacoisothione salt And its medicine, formic acid (cathylate acetate succinate and its pharmacological glycine and its pharmacological aminopropionate and its pharmacological valine and its Phenylaminopropionate and its isoleucine and its pharmaceutically acceptable saltsAcceptable saltsAcceptable saltsAcceptable saltsAcceptable saltsAcceptable salts Acceptable Salts Acceptable Salts Acceptable Salts Pharmaceutically Acceptable Salts Acceptable Salts Acceptable Salts Acceptable Salts Acceptable Salts Salt acceptable salt pharmaceutically acceptable salt pharmaceutically acceptable salt

3002-5563-PF (Nl), Chiumeow.ptd Page 33, 200400042 V. Description of the invention (29) Isozyme soap glycogen isomethionine salt and its pharmaceutically acceptable salt Ethyl isothiophene ethyl acetate (cathylate) Ethyl isothiophene saponin acetate Acetyl isothiophene saponin succinate and its pharmaceutically acceptable salt Amine acid salt and its pharmaceutically acceptable salt Epiisocyanogenol Glycoside aminopropionate and its pharmaceutically acceptable salt Glycogen phenylaminopropionate and its pharmaceutically acceptable salt Glycoside isoleucine and its pharmaceutically acceptable salt Glycogen isomerase and its pharmaceutically acceptable salts. Regarding saponin (R is sugar) compounds of the general formula Ia, the following compounds are particularly preferred: salsa saponin, episa salsa Each of the compounds has a zero sugar group at position 3, and the sugar group is selected from the group consisting of Glucose, mannose, fructose, galactose, maltose, cellobiose, sucrose, rhamnose, xylose, arabinose, trehalose, isorhamnetose, celery sugar, lactose, galactose-glucose, glucose-arabic Sugar, trehalose-glucose, rhamnose-glucose, glucose-glucose-glucose, glucose-rhamnose, mannose-glucose, glucose- (rhamnose glucose, glucose- (rhamnose) -rhamnose, Glucose- (glucose) -glucose, galactose- (rhamnose) -galactose and its tritiated (eg, acetylated) derivatives. Examples of other suitable activators include 16, 22-epoxy fecal-3 Cold-alcohol (16,22-epoxycoprostan-3 / 3-ol)

3002-5563-PF (Nl); Chiumeow.ptd page 34 200400042

(smi1agenone), prodrugs and salts of feces. Composition and use of sterol (coprosteroi) and its pharmaceutically acceptable Therefore the present invention can provide a method for treating or preventing the following symptoms, including non-tolerance neurodegeneration, #cognitive neuromuscular degeneration, motor sensory nerve , Or abnormal or loss of receptors in the absence of cognition, nerves or deities' & muscle & injuries (specially proposed but not limited to the above specific disease conditions). The method includes administering to the human or non-human animal an effective dose of an active agent (as defined herein) or a pharmaceutically acceptable salt thereof. The active agent can be in a composition containing the active agent and any appropriate added ingredients (formula, formula, formula, and formula).忒 The composition may be a pharmaceutical composition (medicine), food, food supplement or beverage. This composition may comprise a mixture of the specified compounds, and / or a pharmaceutically acceptable salt thereof. According to another aspect of the present invention, the present invention provides a composition having an activity to combat and treat non-cognitive neurodegeneration, non-cognitive neuromuscular degeneration, motor sensory neurodegeneration, or deficiencies in humans and non-human animals. Cognitive receptor abnormalities or loss' neurological or neuromuscular damage. The composition comprises an effective amount of an active agent compound. "Pharmaceutical composition" in the context of the present invention means active agents and pharmaceutically acceptable vehicles, diluents, adjuvants, excipients, or excipients ( vehicles), for example: preservatives, fillers, decomposing agents, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, perfumes, antibacterials

200400042 V. Description of the Invention (31) " ---- Agents, antifungal agents, lubricants and dispensing agents, the use of these additives is based on the mode of administration and Depending on the dosage form. The items such as 'food', 'food supplements' and 'drinks' used here have general meanings and are not limited to the preparation of pharmaceuticals.

. The dosage of the active agent can vary widely depending on the severity of the symptoms to be treated or prevented. The selection of the proper dose is a general and well-known technique and will not cause any confusion. For example, the dose of the active agent may be greater than about 0.1 mg / kg of body weight, or, for example, greater than 0.3 mg / kg of body weight, preferably once a day. More typically, the dose will be between! * ^ Mg / kg, for example, doses between i and 0, preferably once a day. In humans, a suitable dose is about 70 to 700 mg per day. "Pharmaceutically acceptable dosage form" means a dosage form of a compound or composition of the present invention 'including tablets (^ a b 1 e t s), sugar-coated bonds, powders, elixirs, syrups, liquid preparations (Hquid

preparations), including suspensions, sprays, inhalants, tablets, lozenges, emulsions, solutions, granules, capsules and suppositories. Liquid preparations are also used for injection, including \ Purpose, quality, and body preparations (liposome preparations). For related technology and detailed description, please refer to Remington, Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, latest edition. In general ' A reference herein that illustrates a particular class of compounds includes within its scope a description of a mixture of two or more such compounds. The present invention provides human or non-human animals suffering from or susceptible to the following diseases

200400042

(I) non-cognitive neurodegeneration, (i 丨) non-cut ^ non-δ tolerance neurons become very destined, (iii) motor sensory neurodegeneration, or (i ν) lack of "Snail No. 5 tolerance" Treatment of body disorders or loss, neurological and neuromuscular defects, knots; Parkinson's disease, encephalitis, Parkinsonism, depression, depression Schizophrenia 1C

(schizophrenia), muscular insufficiency (including progressive shoulder muscular dystrophy, Duchenne muscular dystrophy, Baker's muscular dystrophy, and Brucell muscular dystrophy), Fuch, s insufficiency Disease, tonic muscular dystrophy, corneal dystrophy, reflex sympathetic insufficiency, neurovascular dystrophy, myasthenia gravis, Lambert Eaton disease, Huntington's disease, motor neuron disease (including muscular atrophy) Lateral sclerosis 'Multiple sclerosis, Postural hypotension, Traumatic neurodegeneration after stroke or accident (eg Trauma of the head or spinal nerves), Batten's disease' Cockayne syndrome, Down syndrome, cort icobasal gang 1 ionic degeneration, multiple system atrophy, cerebral atrophy, olive bridge Cerebellar atrophy

(olivopontocerebellar atrophy), dentatorubral atrophy, pallidoluysian atrophy, spondylosis and atrophy (sp i nobu 1 bar atrophy), optic neuritis subacute sclerosis Sclerosing pan-encephalitis (SSPE), attention deficit

200400042 V. Description of the invention (33) disorder), post-virai encephaHtis, post-policy myelitis syndrome, Fahrs syndrome 'J 〇ubert syndrome, Gerber II Guillain-Barre syndrome, iissencephaly, pediatric stroke (Moyamoya di sease), neuronal migration disorders, autism, polyglutamine disease, Niemann Pick disease, progressive multifocal leukoencephalopathy, pseudotumor cerebri, Refsum disease '' Zellweger syndrome syndrome), supranuclear palsy, Friedreich's ataxia, spinocerebellar ataxia type 2, Rhett syndrome, Shy- Drager syndrome (Shy-Drager syndrome), tuberous sclerosis, Pikes disease (Pi ck, s disease), chronic fatigue syndrome, neuropathies (including hereditary neuropathy 'diabetic neuropathy and mitotic neuropathy (mit 〇ticneur 〇pathy)), degenerative proteins Prion-based neurodegeneration (including Creutzfeldt-Jakob disease (CJD), variant CJD, new variant CJD, and bovine spongiform encephalopathy ( BSE)), family

3002-5563-PF (Nl), Chiumeow.ptd Page 38 200400042 V. Description of the invention (34) Genetic insomnia (GSS), fatal familial insomnia (FFI), kuru and Alper's syndrome), Joseph's disease ( Joseph's disease), acute disseminated myelitis

encephalomyelitis), arachnoiditis, vascuiar lesions of the central nervous system, loss of extremity neuronal function :, Charcoal-Marley-Dous Disease (Charcot-Marie-Tooth di sease), susceptible heart failure, asthma, and macular degeneration ° Therefore, the present invention includes the treatment or prevention of the above-mentioned human or non-human animals A method of disease and condition, which method comprises administering to said individual or non-human animal an effective active agent as defined herein, and said active agent is also used in the preparation of a composition to achieve said treatment or prevention. In Parkin's Autism, Chronic Syndrome, the symptoms commonly used in the treatment of autism do not degenerate or lose muscle, and the present invention treats the use of heterozygous cups, sexual fatigue and any other symptoms Existence, saponin on motor sensory meridian and any cognitive compound,

Parkinson's disease after encephalitis, postural hypotension syndrome, myasthenia gravis, related to Lambert-Eaton. He is related to the present invention and is already in the art. 4 The present invention is subject to the proviso, not the cognitive For the symptoms of non-cognitive neurodegeneration, non-cognitive dementia, or neuroregeneration or lack of cognition in the lack of cognition 4 I = lack of cognition, the symptoms presented by individuals are secondary or complementary. The preparation of episodium saponin and salsa saponin

200400042 V. Raw materials available on the description of invention (35). Suppliers include companies such as Sigma Aldrich, Research Plus Inc., and Steraloids Inc. The preparation methods of these raw materials are also described in the literature (for example, the preparation of episarsa saponin is described in JACS ρ 5225 (1 959)). Reduction of sarsasapogenone by metal hydride reducing agen t can be used to produce episa salsagen. The method of Lajis et al., Steroids, 1 993, 58, 38 7-389 · can be used to prepare sarsasapogenone. The unsubstituted saponin and saponin compounds as the original raw materials also exist in some natural plants, especially the genus Asparagus, Asparagus, Anemarrhena, Yucca Or Agave. The heterophylla saponin or salsa saponin used in the present invention may be in the form of an extract of a plant of the genus 'Asparagus', Asparagus, Yuga, Genus or Agave, or a dry powdered plant raw material. The method of preparing the active agent is a well-known conventional technique. Reference can be made to the examples in WO-A-02 / 07922 1 (wherein Examples 5 to 16 describe the salsa saponin ethyl acetate 'episa salsa saponin ethyl acetate, episa salsa saponin Succinate salt, isoamyl saponin glycyrrhizin ethyl acetate, episarsasapogenin glycinate hydrochloride, salsa saponin glycinate hydrochloride, _ acid surface different loan deeds Diaminoglycine Glycolate, Hydrochloric Acid Epithelium Compared with Dimethogan: Type: = (epismilagenin L-alaninate), Epimedium Hydrochloride Saponin Glycogen Left-Lead Methionate, Epimedium Hydrochloride Episulfonate Hydrochloride L-isoleucine, Epiisopic Hydrochloride Sodium Glycogen, Levophenylaminopropionate, and Epiisopic Hydrochloride

3002-5563-PF (Nl); Chiuraeow.ptd page 40 200400042 V. Description of the invention (36) Glycogen left methionine salt). Compounds of formula la (except those with R = H) can be prepared from compounds of R = H by conventional techniques. A preferred reaction is a nucleophilic substitution reaction in which a compound having 0H at position 3 is reacted with a compound of formula LR, and R is selected from an alkylcarbonyl group; a oxycarbonyl group; an alkylaminofluorenyl group; or an arylcarbonyl group; Any alkyl group can optionally be aryl, amine, mono-alkyl-amino, di-alkyl-amino, carboxylic acid residue (_C00H), or any resulting L's cooperating substitution; and L is a leaving group, suitable for nucleophilic substitution. The L-R compound may be a carboxylic acid, or, where appropriate, an anhydride, or an acyl halide (e.g., a fluorenyl gas). For example, when R is a cathy late (ethoxycarbonyl) group, the LR compound may suitably be ethyl ch1 oro f orma te. O This reaction is appropriate for a base (for example: (Pyridine), and optionally in the presence of an acid (eg, hydrochloric acid). The details of the nucleophilic substitution reaction are conventional techniques. Refer to Example RC Larock, in Comprehensive Organic Trans format ions, VCH publishers, 1 989. 〇 Dihydrosarsasapogenin can be prepared using the method described in Marker and Rohrmann (1939), Sterol LIII; Sa The side chain structure of elsa saponin can be found in J. Am. Chem. Soc. 61, pp 846-851. It can be prepared using the method described in Scheer et al., (1955)

30C2-5563-PF (Nl) ^ Chiumeow.ptd page 41 200400042 V. Description of the invention (37) 16, 22-Epoxy solids 3-Alcohol. The isomerism of the carbon 25 isomerism of heterogenous saponin and salsa saponin can be seen in J. Am. Chem. Soc. 77, pp 641-646 · 〇

The reaction described here must protect the functional group of the reaction (this functional group must be present in the final product, such as hydroxyl, carboxyl, or amine) to prevent it from participating in unnecessary reactions. Traditional protecting groups can be used in accordance with standard procedures. Related content can refer to TW Green and PGM Wuts, in " Protective Groups in Organic Chemistry 丨 丨, John Wiley & Sons, 1991; JFW McOmie in " Protective Groups in Organic Chemistry 丨 ', Plenum Press, 1 9 73 ·. In order to protect the amine substituent in the compound of the formula L-R (where R is an amine substitution), an alkoxycarbonyl protecting group is preferably used. Through the action of this protecting group, the amine group in the synthesis step functions like an alkoxycarbonylamino group until deprotection in an acidic dry solvent.

The compound so prepared can be obtained again from the reaction mixture in a conventional manner. For example, to remove the solvent from the reaction mixture by distillation, or, if necessary, after distilling off the solvent from the reaction mixture, pouring the residue into water, followed by extraction with a water-soluble solvent and distilling off the solvent of the extract, The compound can be recovered. In addition, if necessary, the product is further purified using conventional techniques, examples of which are recrystallisation, reprecipitation or various chromatography techniques, especially column chromatography or 2. preparative thin layer chromatography

3002-5563-PF (N1), Chiumeow ptd p. 42 200400042

chromatography) 〇 Discussion on the basis of activity (Discussi〇n

Activity) of the Basis for the choice of treatment function under the present invention, ^ ^ ^ ^ ^ Xi Dao Yue Diao is from some new observation reports, these. ^ ^ Ϊ́η In order to understand the basic principles of the present invention, this article will summarize This also observes the dying, dying, T, reporting and explains how to predict the therapeutic activities in the present invention within the scope of the active agents defined above. + Diosgenin 70, epidermal saponin saponin, salsa saponin and episa salsa saponin repair muscarinic acetylcholine receptors and adrenaline receptors ( loss of adrenoceptors), and the cell displays such receptors in vitro. These results show that these compounds repair the receptor to a normal degree of cellular receptor loss (Example 1). In in vitro tests, salsa saponin, episa salsagen ethyl acetate 'episarsa saponin, episaponin saponin, and saponin saponin were used to prevent rats Chemically-induced neurodegeneration of cortical neurones. These results show that these compounds are neuroprotective compounds in vitro and prevent neurodegeneration and nerve defects (Example 2). In in vitro tests, salsa saponin, isocapsid saponin, 16, 22-epoxy fecal-3H-alcohol, smilagenone, isopyridine hydrochloride Chesaponin glycinate and faecal hormone reverse chemically induced neurodegeneration in rat cortical neurons. These results show

200400042

It is shown that the compound reverses sensory nerve degeneration and nerve defect in vitro (Example Isozygium saponin reverses chemically induced apoptosis in neurons, proving that the compound can resist apoptosis in vitro (ant i- apoptot ic) and has neuroprotective effects (Example 4). In vitro tests, Isozyme saponin and Salsa saponin increase the axon production of rat cortical neurons (neuri te outgrow) (axis Number of axons and axon branches), proving that they have a neurotrophic effect in vitro (Example 5) ° In the in vitro test, mesenchephalic dopaminergic neurones in the brain, the heterogeneous deduction of Ganyuan and Sa Ersaponin prevents and reverses neurotoxin-induced neurodegeneration, which is 1-methyl-4-phenylpyridinium (MPP +). These results demonstrate that these compounds are Can prevent and reverse neurodegeneration and nerve defects in vitro (Examples 6 and 7). In vitro tests, salsa saponin and isopyrazine saponin reversed the spinal motility of rats Neuronal degeneration in the chemically arched one in spinal motor neurones. These results demonstrate that these compounds reverse the neurodegeneration and nerve defects of motor neurons in vitro (Example 8). Cognitive ability in vivo In the cognitive ability test, salsa saponin, episa salsa saponin ethyl formate and isopyrazogena saponin reduced the false response in aged rats. This result is similar to the compounds administered to the aged rats. Oxytocin

200400042 V. Description of the invention (40) The increase in base receptor density is related. These results demonstrate that these compounds reverse neurological deficits in vivo (Example 9). Isozyme saponin and salsa saponin reversed the decrease in muscarinic acetylcholine and dopamine receptors and decrease of brain derived neurotrophic factor (BDNF) in aged animals. These results demonstrate that the compound reverses motor sensory neurodegeneration and neurological deficits and has neurotrophic properties in vivo (Example 9). In the cognitive ability test in vivo, episalen saponin ethyl formate, salsa saponin ethyl formate, episasar saponin and epiisobarium saponin Will reduce the number of erroneous reactions in young rats exposed to neurotoxic agents (ibotenic ac id and amy loid), and increase brain muscarinic acetylcholine receptors Body density. These results demonstrate that these compounds reverse nerve defects in vivo (Example 10). In a mouse model of amyotrophic lateral sclerosis and Charcoal-Marie-Dous disease, heterozygous saponin and salsa saponin increase mouse survival and improve motor sensory neurodegeneration and nerve defects (Example 11). In short, these compounds slow or reverse the degeneration of certain neurons. These include: reversal of harmful changes in the cell body, atrophy of neuron extension (axons), reduced release of neurotrophic factors (such neurotrophic factors as: brain-derived neurotrophic factor, nerve growth factor (NGF), Neurotrophins-3 (NT-3), neurotrophins 4/5 (NT4 / 5) and other neurotrophins (neurotrophins), transforming growth factor-cold super-family neurotrophic factors (e.g. :

3002-5563-? F (Nl), Chiumeow.ptd Page 45 200400042 V. Description of the invention (41) Ciliary neurotrophic factor ,, Neuronal toxicity or death: = 'White t disease inhibitory factor (LIF)), and ίΐ Ξ: 1 axonal a, and prevent neurotoxicity. These compounds slow down or reverse the cholinergic and dopaminergic groups. 0: Reduced function, for example, reducing muscarinic acetylcholine ^ M ^^^^^^^^^^^^. In addition, we found that neuroprotection and receptor loss silk ^ τ # is used for active regulation, which reverses the previously deteriorating condition to a suspended or young state, preventing continuous deterioration. In addition, we found that the reversal of the apoptotic effect of the compound appears to be in cell life (cel 1

The non-neoplastic domain is regulated and may cause neoplasia. Based on the above data, the activity against disease states (^ ctivUyj has been listed in this specification. In addition, the above data shows that Ke Yueji will not have serious or life-threatening side effects such as cancer. The active agent is typically non- Estrogenic (n 〇 _ 〇estr 〇gen 丨 c) active agents. The conventional techniques described above show a reasonable basis for the predictions made on the extension of the above observations, as well as showing the "active agents," items included in the invention Reasonable prediction of the therapeutic activity of the 'relevant chemical structure and derivatives'.

In the conventional technology and pharmacology, sugars, esters and other groups at appropriate positions (especially at positions 3 and / or 26) on steroid molecules can be easily cleaved by hydrolysis in the body, and Other carbon atoms are expected to have the same effect. In addition, in the conventional technology and pharmacology, according to the pH value of the body fluid in which the active agent is present, the salts of the "active agent" used herein 'free acid and free base are immediately converted to each other in the body. , Public

3002-5563-PF (Nl) iChiumeow ptd Page 46 200400042

It is well known that the side group substituents which are expressed in a wide form can exist in a complex (Carbon Skeleton), and generally have a poor influence on the pharmacological activity of the structure, and the wood will not affect the size of the molecule. Time. People ’s ~~ especially when the side group is smaller than the whole for all these reasons, the scope of this patent application is appropriate, and the data is the basis for reasonable and credible predictions. May Book Length: Useful Pharmacology Tests collected and presented here

Individuals have reached the limit of key embedding. It is generally believed that one of the physiological effects of the active agent is: t, adding God, nutrient factors (such as brain-derived neurotrophic factors, or neurogenic factors or their receptors). The ability to synthesize, release, or reduce the rate of degradation. Some of these effects on growth factors may be due to the effect of compounds on cytosolic or nuclear receptors or the binding of chemokines to the promoter region, which directly affect the mRNA of growth factors. ) Production rate, or the result of increasing another material fact factor. In addition, the compound appears to modulate receptors. For example, some compounds prevent the loss of muscarinic acetylcholine and dopamine receptors in the brain. The general phase # 泫 compound is not sufficient to correct its effect by correcting the number or function of the receptors or the conversion rate.

In order to make the above and other objects, features, and advantages of the present invention more comprehensible, the following describes the preferred embodiments in detail with the accompanying drawings as follows: Example 1 Receptor loss in in vitro tests Repair

200400042 V. Description of the Invention (43) In this paper, Ethyl Isozyme Sodium Glycolate Ethyl Ester, Salsa Saponin Ethyl Formate, Ethyl Salsa Ethyl Sodium Ethyl Formate, Ethyl Salsenogen Ethyl Succinate, Epiisocyanate Glycogen Acetate and Salsa Saponin for Muscarinic Acetylcholine Receptor (m) in Chinese Hamster Ovary Cells (CHO cel 1) or / 92 and m3 Receptor in Chinese Hamster Ovary Cells Impact on performance. Among them, for the m receptor, the Chinese hamster ovary cells were transfected with a vector (vec 10 Γ), or for the yj 2 and m3 receptors, the Chinese hamster ovary cells were co-transfected with the vector (co-transfected) ). The results are described in Table 1 and FIG. 1 below. For m receptors, during the culture period in which Chinese hamster ovary cells were infected with a vector transfer, Episaponin Ethyl Glycogenate, Ethyl Salsa Ethyl Formate, Ethyl Salsa Ethyl Formate Ethyl esters, episarsaponin succinate, and salsa saponin, each compound prevents a decrease in the number of m receptors. For cold 2 and ... receptors, the density of m3 receptors did not change during the culture period when Chinese hamster ovary cells were co-transfected with this medium; the density of ^ 2 adrenergic receptors decreased. Cultured with episodium sapogenin acetate (Figure n does not significantly change the density of m3 receptors; but it obviously prevents the decrease of adrenergic receptors. Table 1 Effects of salsa saponin ethyl acetate, episarsa saponin ethyl acetate, episa salsa saponin succinate, and salsa saponin on the repair of m-type acetylcholine receptor density

Page 48 200400042 V. Description of the invention (44) Compound obstruction (microMr. MicroM) Activity activity Ethyl isocyanate ethyl acetate 10 salsa ethyl acetate 10 ++ episal Salsa Sodium Ethyl Ethyl Acetate 10 ++ Table Salsa Soap Ethyl Acetate 10 ++ Salsa Soap 10 ++ So 'this experiment shows episodium acetic acid ethyl acetate, salsa soap Ethyl Acetate of Ethyl Acetate, Ethyl Salmonate Ethyl Acetate, Ethyl Salmonate Succinate, Ethyl Salmonate Acetate and Salsagenin Can Prevent Receptor Number Over Time Decreased, and when the number of receptors in the cell is reduced, the number of receptors can also be restored to a normal amount. Example 2 The neuroprotective effects of salsa saponin, episa salsa saponin ethyl acetate, episa salsa saponin, episaponin saponin and heterosaponin saponin on neurons The purpose of the study was to detect the exposure of salsa saponin, episalsa saponin ethyl formate, episa Salsa saponin, episarizine saponin and heterosaponin saponin to primary cortical neurons. Effect of glutamate (known as glutamate on neurodegeneration) in rat survival.

The rat cortical neurons were cultured for 10 days; on day 10, the medium was changed to serum-free defined medium. On day 12, 24 hours before exposure to glutamate, the culture medium was washed away and the compound (Saline was tested with a positive control (/ 3-oestradiol)). Salsa saponin, episa salsa saponin, ethyl acetate, episa salsa saponin, heterosaponin saponin and heterosaponin saponin) or an excipient control group (dioxin (DMS0), 25%) or negative control

3002-5563-PF (Nl), Chiume ow. Ptd page 49 200400042 V. Description of the invention (45) Group (diosgenin) fresh medium replacement. The culture was exposed to glutamate on day 13. After the incubation period, i.e. after 24 hours of glutamate exposure, the medium is washed off and placed in fresh medium, supplemented with appropriate compounds or excipients to assess its protective effect. By measuring the activity of lactate dehydrogenase (LDH), the survival rate of neuronal cells can be evaluated. The release of the activity in the culture medium was measured after 24 hours of administration of the test compound or exposure to glutamate and test compound using a CytoTox 96 non-radioactive kit, and measured at the wavelength of light absorption. It was quantified at 450 nm. After the rat primary cortical culture was exposed to glutamate, the cortical neurons degraded significantly, and 24 hours after treatment, it was demonstrated that cortical neurons increased due to the release of lactate dehydrogen to the culture medium. Pretreatment with compounds (p r e -1 r e a t e d) in primary cortical cultures for 24 hours also significantly reduced the neurodegeneration induced by glutamate (Figure 2; Table 2). Table 2-Salsa saponin, Salsa saponin ethyl acetate, Salsa saponin, heterosaponin saponin and heterosaponin saponin for nerves caused by glutamate Impact of degradation

3002-5563-PF (N1); Chiumeow.ptd Page 50 200400042 V. Description of the invention (46) Conditional mean 値 standard error mean (Meant sem) (%) Control group 100 + glutamate 66 ± 3 + Glutamate + sarsasapogen (30nM) 79 ± 3 control group 100 + glutamate 65 ± 3 + glutamate + episalsaponin ethyl formate (30 nM) 74 ± 3 control Group 100 + glutamate 68 ± 4 + glutamate + episarsa saponin (30_ 88 ± 3 Control group 100 + glutamate 71t 2 + glutamate + episodium sapogenin (30_ 79 ± 2 control group 100 + glutamate 68 ± 4 + glutamate + isovitchid saponin (30nM) 91 ± 4 control group 100 + glutamate 68t 4 + glutamate + Lai 30_ Negative control group 72 ± 4 In the in vitro test of rat primary cortical neurons, salsa saponin, episarizine saponin ethyl acetate, episarizine saponin, epiphenomenon Both saponin and isozogenin have obvious neuroprotective effects, preventing the phenomenon of neurodegeneration caused by ammonium salt. Example 3 Salsa saponin, isoxanogen saponin, 16, 22-epoxy fecal-3 / 3-alcohol, isopyridine soap Reversal of neurodegeneration in neurons by ketones, isopyridyl saponin glycyrrhizin glycinate and faecal sterols as described above, exposure to glutamate (100 micromoles (// M); 10 minutes) In rat primary cortical culture, after 24 hours, it was found that the activity of lactic acid dehydrogenation was increased, indicating a significant neurodegeneration phenomenon.

3002-5563-PF (Nl), Chiunieow.ptd Page 51, 200400042 V. Description of the invention (47) Compared with neurons exposed to glutamate, give 1 7/3 after exposure to glutamate -Estradiol, whose lactic acid dehydrogenation activity is significantly reduced, which shows a significant neuroprotective effect. Similarly, compared with neurons exposed to glutamate, salsa saponin, isopyrazine saponin, 16,2 2 -epoxy scum-3 / 3-ol, isoamidine The dehydrogenation activity of lactic acid dehydrogenase was significantly reduced after decoglycosides, isopsogapogenol glycylglycinate and faecol, which showed a significant neuroprotective effect (Table 3). Table 3-Effects of different compounds on cortical neurons previously exposed to glutamate

3002-5563-PF (Nl), Chiumeow.ptd Page 52 200400042 V. Description of the invention (48) Conditional mean 値 standard error mean (Meant sem) (%) Control group 100 ± 4 Amine salt [100 " M] 66t 2 glutamate + 17 /?-Estradiol [3nM] 69t 2 glutamate residual salt + 17-estradiol [30nM] 75 ± 5 control group 100 ± 1 glutamate [100 " M] 67 ± 3 glutamate + salsa glutamate [3nM] 101 ± 3 glutamate + salsa glutamate [30nM] 112 ± 1 glutamate + isoglutamate S Ganyuan [3nM] 109 ± 6 glutamate + isoamidine glycoside [30nM] 104 ± 1 control group 100 ± 8 glutamate [100 " M] 40 ± 1 glutamate + saponin [30nM. Negative control group] 49t 6 control group 100 ± 5 glutamate [100 " M] 64 ± 4 glutamate + 16.22-epoxy septic-30-alcohol [3nM] 114 ± 7 shoe glutamate + 16 · 22-ring Oxygen-3β-alcohol [30nM] 134 ± 7 glutamate + isoamylglyceride [3nM] 119 ± 7 glutamate + isoamylglyceride [30nM] 119 ± 4 Control group 100 ± 4 glutamate [100〇θΜ] 58 ± 3 glutamate + isozanche hydrochloride glycan glycinate [3ηΜ] 117 ± 4 glutamate + isozanche hydrochloride Glycinate [30ηΜ] 141t 6 glutamate + faecol [3ηΜ] 126 ± 5 glutamate + faecol [30ηΜ] 116 ± 4 In short, salsa saponin, isopyridine soap Glycogen, 16,22-epoxy faecal-3zol-ol, Isotriazol Glycoside, Isotriazol Hydrochloride Glycoside Glycolate and Fecal Stereol Reverse Glutamate in Rat Primary Cortical Neurons Acid-induced neurodegeneration shows its therapeutic potential for neurodegenerative diseases. Example 4 The anti-apoptotic effect of Isoprostogenous saponin on neurons

3002-5563-F ¥ (Nl), Ch! Iimeow.ptd Page 53 200400042 V. Description of the Invention (49) The purpose of this study was to detect that in the primary cortical culture of rats, the exogenous depletion of Ganyuan in Anti-apoptotic effect on sulphur degassing Swen protein cells (marker of week death)). Primary culture of cortical neurons. Rat cortical neurons were cultured for 6 days. On the sixth day, glutamate (100 micromoles; 10 minutes) was added. Then the culture was washed off and the medium was replaced with Fresh culture medium of isobaric saponin or excipient control group (dimethylacerene, 0.25%) After 6 hours, the activity of thiocystine plum-3 was measured to assess apoptosis Case. From the colorimetric caspase-3 substrate, acetyl-aspartic acid-glutamic acid-valine-aspartic acid p-nitropyridine -Asp-Glu-Va and Asp p-ni troani 1 ide) interrupt the activity of nitrate protein Teng-3 > Relative thiocystine The concentration of thiocystine protein can also be optically dense, 1 382-1 388, 1 202- 1 2 1 4, Neurons show glutathione induced by isoamidine saponin glycanamine, and sulfur can be detected by p-ni troani 1 ine Cystic. P-Nitroaniline has a high absorption value at 40 5nM. Protein-3 activity is measured at optical density. In addition to the standardization of the relative activity of -3, the proteinity of the samples was measured (Du et al., J Neurochem., 69 1997; Sawada et al., Faseb J., i4 2000). Xenoglycerol reverses the increase of cysteine protein-3 activity induced in rat primary cortex and has anti-apoptotic effects (Table 4). Table 4-Effect of Isozygium saponin on the activity of serotonin-3 in cortical neurons

3002.5563-PF (Nl); Chiumeow.ptd p. 54 200400042

Conditional thiocysteine protein activity (percent of control group) Control group 100 + Fibrate 131 Aminate + Isotriazapogenin (300ηΜ) 105 Example 5 The neurodegenerative disease is characterized by a progressive neuron Loss and reduction of nerve & axons. Agents that can trigger axonal formation can promote the connection between Kobe and Amp, and improve the symptoms of neurodegeneration (K a t z ma n e t a 1 Faseb J., 5, 278-286, 1991). > Exposing rat primary cortical neurons to 17/3 / 3-estradiol (0.3, 3, 30 pM) will significantly increase the length of axons (Table 5), exposing atmospheric primary cortical neurons At 17/5-estradiol (3, 30 pM) significantly increased the percentage of neurons exhibiting axons (Table 6). Exposure of rat primary cortical neurons to heterogenous saponin and salsa saponin (0.3, 3, 30 pM) will significantly increase the length of axons and the percentage of neurons that show axons ( Tables 5 and 6). All in all, the heterozygous saponin and salsa saponin have a neurotrophic effect in vitro. Table 5-Measurement of the effects of 17-estradiol, isoprostyl saponin and salsa saponin on the axon length using optical micrometry

200400042 V. Description of the invention (51) Conditional length control group 100t 4 estradiol (0.3pM) 154t 5 17 stone-estradiol (3 ports ") 163 ± 4 17 厶 -estradiol (30pM) 183 ± 5 iso Takisapogenol (〇3pM) 159t 5 Isotopsylsaponin (3pM) 190t 8 Isotopigenin (3〇pM) 204t 6 Salsa saponin (〇3pM) 177 ± 5 Salsa Saponin (3pM) 197t 5 Salsa saponin (30pM) 211t 6 Table 6-17 / 3-The effect of estradiol, isopyrazine and salsa saponin on the number of neurons showing axons Condition number control group Alt 2 17 / 3-estradiol (0.3 卩 gate) 48 ± 2 17 / 3-estradiol (3-port gate) 60 ± 2 17 / 5-estradiol (30 ′ “59 ± 2 Isevitazone saponin (〇3pM) 63 ± 2 Isomazia saponin (3pM) 63 ± 2 Isevitaza saponin (30pM) 66 ± 2 Salsa saponin (〇3pM) 55t 2 sa Salsa saponin (3pM) 61 ± 1 Salsa saponin (30pM) 62 ± 2 # Example 6 In the model of Parkinson's disease in vitro, heterosaponin and salsa saponin prevent large Mesencephalic dopaminergic neurons in mice are exposed to neurotoxin, 1-fluorenyl-4-benzyl Neural Degeneration After Baseline Ratio Change (MPP +).

3002-5563-PF (N1); Chiumeow.ptd Page 56 200400042 V. Description of the invention (52) From neurotoxin, 1-fluorenyl-4-phenyl D specific bite, 1-methyl-4phenyl-1 , 2,3,6-tetrahydro B specific bite (1-methyl-4-phenyl-l, 2,3,6-tetrahydropyridine, M PTP) -induced damage in neurodegenerative diseases (for example: Parkinson's Disease) presents a degenerative phenomenon of striatum dopaminergic neurons (Nigr 0 striata 1 dopaminergic neurones) (My tin 1 i neou et al., Science, 225, 529-53 1, 1 9 84). The most significant biochemical changes caused by this toxin include reduction of dopamine and its metabolites in substantia nigra pars compacta and caudate nucleus (Burns et al., Proc Natl Acad Sci USA, 80 , 4546-4550, 1 98 3), and a reduction in dopamine uptake during the production of striatum synaptosomal (Heikki la et a 1., J Neurochem., 44, 310- 3 1 3, 1 985 ) 〇 Pretreatment of dopaminergic neurons with isoamidine saponin and salsa saponin will significantly reduce exposure to specific groups compared to the 1-fluorenyl-4-phenylpyridine group alone. The neuron death phenomenon after dopaminergic neurotoxin bumethyl-4-phenylpyridine (2 / zM). Glial cell line-derived neurotrophic factor (G D N F) and fine-derived neurotrophic factor, and molecules related to neuron growth were used as positive control groups. Compared with neurons exposed to p-methyl: 4-phenylpyridine alone, pretreatment with isopyrifosyl saponin and salsa saponin significantly increased neuron survival (Table 7). Table 7-Treatment with brain-derived neurotrophic factor and glial cell neurotrophic factor ’heterologous saponin and salsa saponin

3002-5563-PF (N1), Chiumeow ptd Page 57 200400042 V. Description of the invention (53)-Effect of 4-benzylpyridine dopaminergic neurons Conditional survival control group 1001: 3 + 1-methyl- 4-phenyl0 [£ (2 / ^ M) 55 ± 3 + 1-methyl-4-phenylpyridine (2y M) + brain-derived neurotrophic factor (1 85ηΜ) & Shen glia Neurotrophic Factor (〇17 啲) 122 ± 7 +1 -methyl-4 · phenylpyridine (2 " Μ) + Isobaric® Ganyuan (3〇ηΜ) 98 ± 4 + 1-methyl-4 -Phenylpyridine (2y Μ) + _ saponin (30ηΜ) 89t 3

In the Parkinson's disease model in vitro, pre-treatment with isoamidine saponin and salsa could significantly prevent the development of specific dopaminergic neurotoxin i-methyl-4-phenylamidine specific bite Of neurons degenerate, demonstrating their neuroprotective effect. Example 7 In vitro saponin is also inverse hormone 1-fluorenyl-4 and the neurons of specific neurons alone with Gan and Sal are exposed as specific neurons. As compared with neurons, the neurons are stored in Table 8- In the model of Parkinson's disease with the brain's heterozygous disease, the neurons produced by the heterozygous saponin and doxaminergic neurons of the rat midbrain after exposure to neural crest-phenylpyridine (MPP) Degradation. Treatment of dopaminergic neurons with the isopyrrolidine-4, phenyl D ratio bite group can significantly reduce the amenorrheic toxin buylyl-4-phenylpyridine (mpp + k2) After ^ death. Glial neurotrophic factor and brain-derived branch, molecules related to neuronal growth, and 17/5 -estradiol

Control group. Compared with those who were exposed to 1-methyl_4-benzyl roar alone, the addition of heterosexual saponin and salsa saponin significantly increased the activity (Table 8). Derived neurotrophic factor and neurotrophic region of glial cells saponin, salsa saponin and 17-estradiol for exposure

200400042 V. Description of the invention (54) Effects of dopaminergic neurons in p-methyl-4-benzylpyridine Conditional survival control group 100 ± 6 + 1-methyl-4-phenylpyridine (2 RenM) 76 ± 4 + 1-methyl-4-phenylpyridine (2 # Μ) + brain-derived neurotrophic factor (185M) & glial cell neurotrophic factor (0.17ηM) 98 ± 5 + 1-methyl-4-benzene Gyridoxine (2 to Μ) + Hexathione (0 03ηΜ) 111t 6 + 1-methyl-4-phenylpyridine (2ρ Μ) + Salsa (0 03ηΜ) 112 ± 6 + Methyl-4-phenylpyridine (2β Μ) + 17β-estradiol (0 03ηΜ) 106 ± 5 Exposure to 1-methyl-4-phenylpyridine not only caused a significant reduction in the amount of dopaminergic energy, but also caused the axis Burst reduction. This study showed that heterozygous saponin and salsa saponin significantly increased the number of axons of neurons in vitro (Table 9). These results show that this compound reverses motor neuron degeneration. Table 9-Impact of saponin and salsa saponin on the percentage of axons of dopaminergic neurons exposed to albino-4-phenylpyridine (2 // Μ) Conditional axon control group 41 ± 4 + 1-methyl-4-phenylpyrazine (2 # 1 \ / 1) 27 ± 5 + 1-methyl-4-phenylpyridoxine (2 # M) + isocyanate (0 03nM ) 41 ± 4 + 1-methyl-ptophenylpyridine (2 # M) + Salsa saponin; (0 03η Μ) 43 ± 4 Example 8 Salsa and saponin Neuroprotective effects of spinal motor neurons The purpose of this study was to determine the survival of primary spinal motor neurons in rats exposed to glutamate by salsa and saponin Patterns cause neurodegeneration. 17 yS_estradiol and brain-derived neurotrophic factor were used as the positive control group.

3002-5563-PF (Nl), Chi ptd page 59 200400042 V. Description of the invention (55) Primary culture of spinal motor neurons according to the method described by Marti nou et al. Neuron, 8, 737-744, 1992 Rat motor neurons were prepared, the culture medium was removed on day 1Q, and the culture was exposed to glutamate (4 micromolar) at 37 ° C for 10 minutes. After exposure to amidolate, the

Dulbecco modified Eagle medium was used to wash the culture and then placed in fresh medium containing the test compound. After 48 hours, the degree of degeneration of spinal motor neurons can be determined by measuring the dehydrogenation of lactic acid released into the above-mentioned medium. Results After 48 hours of post-treatment exposure to facial glutamate, an increase in hydrogen release into the culture medium showed a degenerative phenomenon of rat primary spinal cord exercise-female. The treatment of rat primary spinal neurons treated with salsa saponin or iso-saponin saponin for 48 hours resulted in neurodegeneration caused by facial amines (Table 10). There is a significant reduction in hydration. Table 10-Effect of salsa and saponin on the spinal cord-Neurodegeneration induced by glutamate Zhong Jingyuan

200400042 V. Description of the invention (56) Conditioned neurodegeneration system group + dimethyl sulfene [0.25%] 100t 1 acid salt [4 micromole] + dimethyl sulfene [〇25%] 94 ± 1 _ acid Salt + brain-derived neurotrophic factor [3_] 148 ± 8 bond amine salt + 17/3-estradiol [〇 · 〇3ηΜ] 102 ± 2 glutamate + 17 / 3-estradiol [3ηΜ] 110 ± 1 acid salt + 17/3 -estradiol [300ηΜ] 116t 6 glutamate + salsa saponin [〇〇3ηΜ] 123 ± 2 amine salt + salsa saponin [3ηΜ] 137 ± 1 _ Amine salt + Salsa saponin [300ηΜ] 136t 6 Sodium acid salt + Isozygium saponin [0.03ηΜ] 128 ± 4 Sodium salt + Isodiazol saponin [3ηΜ] 154t 1 Hydrazine + Isotriazogenol [300_] 144t 4 In this in vitro motor nerve degeneration model, salsa saponin and Isotriazologen are reversed by glutamine in rat spinal motor neurons Acid-induced neurodegeneration. Example 9 In the second half of life (about 40 years of age in humans), the density of neurons in the brain decreases (Selkoe, D J, Sci. Am. 267, 134-142, 1 9 9 2). The change in cortical function is due to the decrease in the number of neurons, their interconnections and neurotrophins (eg, brain-derived neurotrophic factors; Bothwell, M, Functional interactions of neurotrophins and neurotrophin receptors, Annu.

Rev · Neurosci ·, 18, 223-253, 1 995), decreased acetylcholine depletion in the body, degree (Qin test and nicotinic receptor) and / or reduced binding function in the cortical area (Rinne et al ., Brain Res ... 1985; Selkoe, DJ, Sci. Am. 267, 134-142, 1992).

3002-5563-PF (Nl), Chiuraeow ptd 200400042 V. Description of the invention (57) In addition, older rats (Biegon et al., Neurobiol · Aging ·, 10, 305-3 1 0, 1 989) and human (Rinne et al., Brain Res., 336, 19-25, 1985) hippocampus (Narang, N, Mech. Ageing Dev., 78, 221-239, 1995) and patterns In the striatum, binding of muscarinic acetylcholine receptors was significantly reduced. In addition, in Alzheimer's disease, reduced choline activity and amyloid plaque depos iti on (von der Kammer et al., Biochem. Soc. Symp. 13, 140, 200 1 )related. Other neurodegenerative diseases, such as Parkinson's disease, exhibit reduced dopaminergic activity (Drukarch et al., Expert. Opin. Investig. Drugs, 10, 1 855-1 868, 200 1) 〇 Oral administration to the elderly Rats (Sprague-Daw ley rats, 20 months old) Salsa saponin 'episarsa saponin ethyl acetic acid ethyl ester or ossinoglycan, which will reverse aging between two or three months Features that change during the process, such as impairments in learning and memory, decreased acetylcholine and dopamine receptors in the mycotoxin test, and decreased brain-derived neurotrophic factors in neurotrophins. The aged rats were divided into different groups, one group was the control group, and the other groups were given salsa saponin, episarsa saponin ethyl formate or isopyrida saponin (18 kg kg-1 day) -1, ^ = 1 〇) 2-3 months. The other control group (n = 1 14) was young rats that were not administered. The medicaments given each day were mixed in the smallest amount of food, and each rat was fed separately every morning. The mouth uses Y-maze apparatUS for learning and memorizing. formula. A row of copper is on the laminate (f 1 00 r) of each arm of the Y-shaped electric maze.

200400042 V. Description of the invention (58) The rod can supply current to the copper rod when necessary, and adjust it to the required voltage. Each arm is 45 cm long and has a 15 watt (W) lamp at its end 'which turns on when needed. After 3 months of administration, each rat was trained for 7 consecutive days in the following manner. During each training period, the rats were placed in one arm of a gamma-type electrical maze, and after resting for 2 minutes, a current was supplied to the copper rod, and at the same time, the arm light clockwise turned on to show the unstimulated area (non- stimulation area). If the rat enters that arm, it is recorded as a correct response, otherwise it is recorded as a wrong response. This stimulus response test (s t i mu 1 at i on-response test) was repeated 20 times a day, with a break of 5 seconds between each successive test. After 20 tests on the seventh day, the number of correct responses is used to indicate learning ability (the higher the number, the better the learning ability). The rats were then allowed to rest for 30 days' and this step was repeated. After a 30-day rest period, 20 additional tests were performed, and the number of correct responses was used to indicate memory ability. Next, the muscarinic acetamidine receptor density in the brain was measured. The tissue was prepared as follows: After decapitating the rat, the brain was quickly removed, iced in dry ice, and transferred to a refrigerator. The brain is homogenized, and its particulate matter is finally suspended in the buffer. The muscarinic acetylcholine receptor density was measured by a dual competitive ligand binding assay (d u a 1-s i t e competitive ligand binding assay). The results are shown in Figures 3 and 4 ° Y-type electric maze experiments showed that the learning ability and memory of aged rats were weakened. After administering Salsa saponin ’to the elderly rat ’s salsa saponin ethyl acetate and isoamidine saponin, it was repaired.

3002-5563 · PF (N1), Chiunieow ptd page 63 200400042 V. Description of the invention (59) Learning and memory ability of rats. The muscarinic acetylcholine receptors in elderly rats are dense, and there is a significant decrease. Salsa saponin, episalsa saponin ethyl formate and isoamidine saponin repair muscarinic acetylcholine receptor density. Compared with aged rats (Di and D2 were 129 · 2 ± 36 · 8; 153 · 8 ± 40.5 fmol / mg protein), young rats showed significantly higher dopamine (D) 1 and ^ receptor densities. (157.5 ± 33 · 2; 200 · 6 soil 50.9 fmol / mg protein). In contrast, the a and 込 receptor densities were repaired in aged rats given 3 months of isocyanate saponin and salsafu tc (iso ± male saponin group was 177 ± log; 217 ± (45.7 fmol / mg protein; salsa histamine groups were 172.0 ± 44 · 〇; 20.4 ± 60.5 fmol / mg protein). Qimingcaibi ratio (i.2 ° 5 ± 0.2i9ng / g tissue) ’young rat month, brain-derived neurotrophic factor with a more pronounced shoulder (1 · 647 ± Guiguang dagger tissue). In contrast, the brain-derived neurotrophic factor was partially repaired in aged rats given Isozygium saponin and Safar Gengguang \ 11; degrees (respectively: .342 ± 0.07; 14io ± o.232ng / G factor-derived God operates in the elderly with large "neural defects: reduced brain pamine receptor density; elephant. &Amp; and the toxicine acetylcholine with multiple examples 1 10 In the silent mode and the taxi mode, the neurotoxic agents (㈣, Λ crane Λ.) Are used. In this brain, this will lead to the loss of neurons, and the receptors will be injected into the rats as soon as possible Before cognitive impairment

3002-5563-PF (Nl); CTiiumeow.ptd page 64 uses Alzheimer's disease as a model of neurodegeneration. 200400042 V. Research Note (60) of Yan Jiu shows the vascular nucleus in the rat brain ( nucleus vasalis) After topical injection of Dianfen powder, it can cause cholinergic insufficiency and behavioral defects for up to 2 months (Giovannelli et al., 1995:

MeuToscience, ㉞, 78b 792). In addition, injecting amyloid-like amyloid together with a small amount of amanitamic acid into the hippocampus of rats, not only near the injection site, but also away from the injection site, neuron loss and glial cells penetration ( Morimoto et al., 1 998: Neuroscience, 8J, 479-487) 〇 Our research uses Morimoto's method (Morimoto et al., 1 998: Neuroscience, M, 479-48 7), and with some modifications # (以Unilateral injections replace bilateral injections). Three-month-old Sprague Daw ley rats were randomly divided into different groups, and a stereotaxic instrument (Stoelting Co ·) was used to complete the class of Dianfen / 3! _4Q and crane cream acid (both from S i gma ) Injection, its positioning coordinates are AP =-0.5 mm (mm) (from the center line to the right), L =-2.8 mm (from the front of the front (bregma)), η = -7 · 0 mm ( From the dura mater to the ventral surface). Each rat was administered at a dose of 1 microliter of 1) saline solution containing 4 micrograms of amyloid Aw and 1 microgram of amanitaic acid. The injection was completed in 20 minutes, the needle was withdrawn after 10 minutes, and the skin was sutured. The eight groups are: the control group (surgery group) given physiological saline for surgery (model group) (the control group was given amyloid callose and amanitamic acid) and the model group + episarsa saponin ethyl ester (18 mg / kg / day) * Mode group + Salsa saponin ethyl formate (18 mg / kg / day) *

3002-5563-PF (N1), Chiumeow ptd Page 65 200400042 V. Description of the invention (61) Model group + episarsaponin ethyl succinate (18 mg / kg / day) (comparative group) Model group + Episarsa saponin (18 mg / kg / day) * model group + episarizine saponin (18 mg / kg / day) * model group + saponin (ie negative control group, 18 mg / kg Kg / day) * Compounds consistent with the invention

Ethyl salsa saponin ethyl acetate, Ethyl salsa saponin ethyl formate, Ethyl salsa saponin ethyl succinate (control compound), Ethyl salsa saponin, Isoprosaline Yuan and saponin (all doses are 18 mg / kg / day) are fed through a gastric tube in a stable suspension in sodium carboxymethylcellulose (CMC-Na) (0.5%) Rats were fed once a day. The rats in the control group and the model group were given the same volume of sodium carboxymethylcellulose (0.5%) once a day. Twenty days before the operation, medications and excipients were started for two months. The density of the methamphetamine acetylcholine receptor was evaluated next. The brain sample was homogenized, centrifuged, and then the particulate matter after centrifugation at 27,000 X g was homogenized and measured. The concentration of quinolyl diphenyl glycolate (3H-QNB) is selected in the saturation range. After incubation and separation, the combined fraction was measured by a liquid scintillation counter. Step-Through Test: learning to memory. The effects of test compounds on learning and memory were estimated using avoidance methods. A 60 × 60 X 15 cm box is divided into two rooms equally. One dark room has a copper rod base and will be charged when used (40 V ac). The other is a bright room without charge. There is an opening (hole) between the two chambers for rats to pass through. Every Oxygen is

200400042 Continuous: This experiment was performed on days. The first day of training: first let the rats cope with the photo in the first 3 minutes, and then put the rats into the bright t so that their backs face the holes between the two chambers. ”Charge the copper rod in the dark room for 5 minutes. . The next day was tested. Record 5. The number of times the rat crossed the hole. Decreased number of crossings indicates that the scopolamine acetylcholine receptors in the control group were remembered. Epsalza saponin formic acid ethyl purpose, disaponin saponin formate low-vinegar, episalsa saponin and epiphenanthrene saponin make muscarinic acetamidine receptor density in the brain There was a significant increase, while saponin and episarsalol ethyl succinate did not significantly change the muscarinic acetylcholine receptor density. Therefore, this experiment shows that the effect of the compound of the present invention is to normalize the number of receptors', that is, when the compound is administered to an animal in which the amount of the receptor is reduced, the compound tends to repair the number of receptors to a normal amount. The error response (number of errors) of the neurodegeneration model group within 5 minutes was significantly higher than that of the control group, indicating that the number of memory cells, episarizine saponin ethyl acetate ethyl formate, and ethyl formate all reduced the false antisaponin ethyl succinate, respectively. No salt can be found in Table 1 1 (see Table 11). Representation of different kinds of saccharin ‘Salsa saponin and salsa saponin should be counted, while saponin and sarsal saponin reduce the number of false reactions.

200400042 V. Description of the invention (63) Group M-type receptor density learning and dilemma avoidance method (fmol 庵 克 ®white matter) Error number control group (n = 10) S ^ S (n = 1〇7 — Taxi _Sa 1 yuan loses Σ1 purpose (n = 1 ϋ) + _ Spirit1 |) 6 ^ 0_ 艺 龅 (η = 11) + 袠 _function 1¾¾¾ based Hi auto-salt (n = 11) + _ cap acid_ € Ermen = Er + Everything in a Different Way. Gan Yuan (n = i 1) + 酣 膑 1 控 _ (11 二 8) 859 ± 101 713 ± " 48 877t 89 ^ 916 ± 158 * 774 ± 79 869 ± 104 * 877t 90 * 770 ± 68 0 60t 〇70 4 00t 2 40 1 36t 0 92 ^ 1 36 ± 1 03 ^ 3 73 ± 1 35 1 50 ± 1 18 too 1 73 ± 0 9 ”3 75 ± 1 49 Wo J Unpaired Student t test was used for statistical analysis. 氺 indicates p < 0 · 0 5 〇 Example 11

Amyotrophic lateral sclerosis is a progressive and lethal neurodegenerative disease that causes motor neuron degeneration, skeleton atrophy, par alysis, and death. The cause of the disease is he terogeneous: some forms of human amyotrophic lateral sclerosis are due to mutations in the Cu / Zn superoxide dismutase (SOD-1) gene. Animal models of this disease include copper-zinc superoxide dismutase gene (S0D-ltransgenic mice over-expressing SOD-1 gene) overexpressing copper-zinc superoxide dismutase gene and progressive motor neuropathy

Progressive motor neuropathy (pmn, model of Charcoal-Marie-Dous disease) mice. Heterozygium saponin and salsa saponin increase life span and improve superoxide dismutase in mice with amyotrophic lateral sclerosis and Charcoal-Marie-Dous disease (Figure 5) Behavioral deficiencies in mice with progressive motor neuropathy (Figure 6) (behavi〇ural

3002-5563-PF (Nl); Chiumeow.ptd p. 68 200400042 V. Description of the invention (64) deficit). Although the present invention has been disclosed as above with preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make various modifications and retouches without departing from the spirit and scope of the present invention. Therefore, the present invention The scope of protection shall be determined by the scope of the attached patent application.

3002-5563-PF (Nl), Chiumeow ptd, page 69, 200400042, simple illustration. Figure 1 shows the co-transfected cell line in Chinese hamster ovary-point 2 / m3 (CH0- / 3 2 / m3). line) On the fifth day, the effect of episaponin saponin acetate on m3 and cold 2 adrenergic receptor density. Fig. 2 shows the nerves of salsa saponin, episa salsagen ethyl succinate and iso-saponin saponin on glutenate salt arches in rat primary cortical neurons S Impact of degradation. The third chart shows the effects of salsa saponin, episa salsazone ethyl acetate (ethoxylate), and debenture on the learning capacity and memory of elderly rats. The fourth graph shows the effects of salsaben, episasargen saponin ethyl acetate (ethoxylated oxygen), and isoparaben saponin on the number of muscarinic receptors. Fig. 5 is a graph showing the survival curve of mice after the oral administration of copper-zinc superoxide dismutase (sQpq) mice isoprosamin. Fig. 6 shows the survival curve of mice after oral administration of salsa saponin to mice with progressive motor neuron disease (pmn).

3002-5563-PF (Nl); Chiumeow.ptd p. 70

Claims (1)

200400042 6. Scope of patent application 1. Use of one or more active agents, the active agent is selected from the following compounds: A. Formula I compounds: 0) In the general formula (I): -Rj 5 R2 5 R3? R4 JJ 9 5 ^ 10? ^ 13 5 ^ 18? ^ 19 1 ^ 20 R2I 'R22' R23 'R24' R26 'R27' R28 '' 5 cores 0 ′ Ruler 31 ′ R32 are hydrogen, OH, = 0, halogen atom, (Me-S-), (Me-S0-), (Me-S02-), N3-, NH2-, MeS02NH-, Alkyl, either absent, or OR, where R is alkynyl or alkynyl;-9 'Rll' heart 2 'Rl4' heart 5 'Rl6' heart 7 '^ 25' 'can be nitrogen'. H, halogen atom, (Me-S-), (Me-SO-), (Me-S02-), N3-, NH2-, MeS02NH-, alkyl, or not present, or OR (where R is Alkyl or 3002-5563-PF (N1) ^ Chiumeow ptd page 71 200400042 VI. Patent application scope 醯); 2 represents an arbitrary double bond, in addition to the above, one of-R33 and 1 ^ 4 is burned B. Compounds of formula II: In the general formula (II): -Heart, R2, R3, R4, R5, R6, R7, R8, R10, R13, R18, R19, R20, R21, R22, R23, R24 5 R26 'R27 5 R28' R29 'R30' .R31 'R32' R34 are hydrogen, OH, = 0, li atom, (Me-S-), (Me-S0-), (Me-S02_), N3-, NH2-, MeS02NH-, Alkyl, OR (wherein R is alkyl or fluorenyl), or is absent; 3002-5563-PF (Nl), Chiumeow.ptd Page 72, 200400042 6. Scope of patent application-R9, Rn, R12, R14, R15, R16, Rn, ruler 25, R33, R35 can be hydrogen, OH, tooth atom , (Me-S-), (Me-SO-), (MeS02_), N3-, Guan 2-, MeS02NH-, alkyl, OR (wherein R is alkyl or fluorenyl), or does not exist; Represents an arbitrary double bond, wherein, in addition to the above, one of-R33 and R14 is an alkyl group; a compound of formula III: In the general formula (III): 9 R2 5 R3 J R4 5 R5 5 κβ 5? 5 ^ 10 5 ^ 13 5 K14 5 Ri8 5 1 ^ 19 feet 20 'R2I' R22 'R23' R24, R26 5 R27 5 R28 'R29' R30 'R3I' R32 5 R33, R34, R35, D6, R; n are hydrogen, 0H, = 0, halogen atom, (Me-S-), (Me-SO-), (Me -S02 ~), N3-, NH2-, MeS02NH-, alkynyl '0R (wherein R is alkynyl or alkynyl)' or does not exist; 3002-5563-PF (N1); Chiumeow.ptd 页 Page 73, 2004.00242. Application scope: R9, Rn, R12, R15, R16, R17, the heart may be hydrogen, 0H, halogen atom, (Me-S- ), (Me-S0-), (Me-S02-), N3-, NH2-, MeS02NH ,, alkyl, OR (wherein R is alkyl or fluorenyl), or does not exist; two: any Double bond 'wherein, in addition to the above,-one of R33 and R14 is an alkyl group, and the stereochemistry of r25 is in the Θ position; D. a saponin ligand derivative having at least one X group substituent, t X is selected from the group consisting of: -Halogen atom,-(Me-S-), (Me-SO-), (Me-S〇2-), -N3, -NH2, MeS02NH, and -alkyl; and E · derivatives of any of the above compounds Form, where the carbon atom at position 3, or the carbon atom at position 3 in the formulae II and III, the carbon atom at position 26 or each of the carbon atoms at positions 3 and 26 have _ zeros A sugar group, wherein the sugar group is a mono, di or trisaccharide; All its stereoisomers and racemic mixtures, all its pharmaceutically acceptable pro-drugs and salts, and all their mixtures and combinations' are used to treat or prevent human or non-human animals from suffering from or Susceptible symptoms, or compositions for treating or preventing these symptoms, which are (i) non-cognitive neurodegeneration, (ii) non-cognitive neuromuscular degeneration, (1 1 1) motor sensory neurodegeneration, or ( iv) Abnormal or loss of receptors in the absence of cognition, neurological and neuromuscular defects. 3002-5563-PF (N1); Chiumeow.ptd p. 74 200400042 You Zhongxi, No. 1 in the scope of the patent application, the active agent using the active agent 'or at least one of the active agents is selected from the following: a • compound of the above general formula I, wherein: R V201, R2 R3: 'I, R6, R7, R8, R1. , R13, R18, b, R2 A ^ OH in Γ, R26, R27, R28, R29, R- one, _ atom, (Me — S-), (Me-so-), (Me_S0), two- 'I-' MeSOjH-, fluorenyl or absent (where alkyl or fluorenyl); ^^ A'Ru '^, R14, ri5, Ru atom, (Me-S-), (Me-SO-) MeSC ^ NH-' or alkyl group; or Rn, R25, R33 can be hydrogen, OH, from, (Me-S02-), n3-, NH2-, or OR (wherein r is an alkyl group or a halogen atom represents an arbitrary double bond, where 'in addition to the above,-R33 and Rl4 One is a thiol group and the stereochemistry of R25 is located at the / 5 position; b. The compound of the above general formula I, wherein: 113 19 仄 20 L are I -R !, R2, R3, R4, R5, R6, r7, R8, Ri0 R21, R22, R23, R24, ', R27,', R29, 1, 3. , IV31 7 R32 ..... hydrogen, OH, = 0, ii atom, (Me —S-), (Me-SO-;), (MeS02-) N3- 'NH2-' MeS02NH-, alkyl or Does not exist, or is OR (wherein) ^ alkyl or ethyl); 200400042 VI. The scope of the patent application is based on the presence or absence of (Me-S0-), (Me-S02-), N3-, NH2-, MeS02NH-, or OR (wherein R is alkyl or fluorenyl); Two represents an arbitrary double bond, wherein, in addition to the above, one of-'and R14 is an alkyl group, and the stereochemistry of R25 is in the / 3 position; c. The compound of the above general formula I, where = R2 = R4 = R5 = R6 = R7 = R8 = R10 = R11 20 = R21 = R22 = R23 = R24 = R25 = R26 = R27 = R28 = R29 = R3Q = R31 = R32 = R33 = hydrogen,-one of R33 and R14 is Methyl, two: represents a single bond,-the fluorenyl group on carbon 2 5 (C25) can be a mirror image isomer clockwise (R) or counterclockwise (S) structure and the stereochemistry of R25 is in the / 3 position, except In addition to the above, at least one of R3 or D3 is an X group, and the possible remaining substituents are hydrogen, 0H, = 0, and 0R, wherein R is a alkynyl group or a fluorenyl group or does not exist, and X is selected from The following groups are included:-a halogen atom,-(Me-S-), (Me-S0 ~~), (Me-S02_), and -N3, NH2-, MeS02NH-alkyl; d. The above general formula Compound of I, where: r19 = r R! = R2 = R4 = R5 = R6 = R7 = R8 = R1 〇 = R !! = R9 = Rj 2 = Rj 3 = Rj 5 = Ri 6 = R 17 l18 3002-5563-PF (Nl); Chiumeow.ptd Page 76 200400042 VI. Patent application scope 20 = R21 = · I = R ι22 R23-= R9C; = R 2r = R97 = R9R = R? Q = Rqn = R .qi = R c24 v25 ^ 27 28 v29 ^ 31 ^ 32 hydrogen 33 methyldi represents a single bond 5-R25 stereochemistry at / 3 position In addition to the above, at least one of R3 4R23 is an X group, possible The remaining substituents are hydrogen, 0H = 0, and 0R, where R is alkyl or fluorenyl or absent, and X is selected from the group consisting of:-a halogen atom,-(Me ~~ S-), ( Me-S0-), (Me-S〇2-) 'and -N3, NH2-, MeS02NH-alkyl; e. Compounds of the above general formula II, wherein: -h, R2, R3, R4, R5, R6, R7, R8, R1Q, R13 and R 18 R 19 (20 R 21 R 22 l23, 24 v26 R 27 (28 (29 l30 ^ 32 v34 other than hydrogen, OH, = 0, _ atom, (Me-S -), (Me-S0-) (Me-S02-), N3-, NH2- or fluorenyl), or the absence of MeS02NH-, alkyl, 0R (wherein R is an alkane R1 1V9 1V11 1V12, 1V14, 1V15 OH, _ atom, (Me-S-) can be hydrogen, R16? R17? R25 5 R33 iv35 (Me-S0-) (Me-S02 -), N3 NH2-, MeS02NH-, alkyl, 0R (where the R is an alkyl or acyl) exists; represents two optional double bond, wherein in addition to the above, or 3002-5563-PF (Nl), Chiumeow.ptd Page 77 200400042 VI. Application scope-one of R33 and 1 ^ 14 is a calcined group 'and the stereochemistry of R25 is in the / 5 position; f. The general formula II above Compounds or carbohydrate derivatives thereof, in which: -R !, R2, R3, R4, R5, R6, R7, R8 ^ 21 hydrogen av22 OH M3 1V18 AV19 AV20 (23 'feet 24' R26 '' ' R28 '' '' 'hi, heart 2 are: 0, _ atom, (Me-S-), (Me-SO-), (Me-S02-), N3-, NH2-, MeS02NH-, alkyl 0R (wherein R is alkyl or fluorenyl), or does not exist;-R9 'Rl2' Rl5 'Rl6' Rl7 is hydrogen '-R34 is hydrogen, OH, = 0, and 0R (wherein R is alkyl , Fluorenyl or carbohydrate), and -Rn, R14, R25, R33, R35 can be hydrogen, 0H, halogen atom, (Me-S-), (Me-S0-), (Me-S0?-), NH9 MeS02NH-, alkyl OR (wherein R is alkyl or fluorenyl), or does not exist; two represents an arbitrary double bond, wherein, in addition to the above, one of R33 and R14 is an alkyl group, And the stereochemistry of R25 is located in Lu G. The compound of the above general formula II or a carbohydrate derivative thereof, wherein: -heart = R2 = R4: R5 = R6 = R7 = R8 = R10 = RU = _p_p_p_p_n_D_ Π _ D 20 — K21 — K22 — K23 — K24 — K25 — K26 — K27 — K HRl3 28 ~ ^ 29 L30 M5 ~ 1V16 " " 1V17: feet 31 = feet 32 = feet 33 dihydrogen-r14 = hydrazone 3002-5563-PF (Nl), Chiumeow.ptd Page 78 200400042 VI. Patent application scope -R34 is -0H or -0R, where R is an alkyl group, amidino group or a carbohydrate, and R35 is hydrogen or does not exist Two represents an arbitrary double bond, the fluorenyl group on carbon 25 may be a mirror image isomer clockwise (R) or counterclockwise (S) structure, and the stereochemistry of r25 is located in the azimuth. In addition to the above, R3 or At least one of R23 is an X group, the possible remaining substituents are hydrogen, 0H, = 0, and OR, where R is alkyl or fluorenyl or absent, and X is selected from the group consisting of:-halogen Atoms,-(Me-S-), (Me-S0-), (Me_S02-), and -N3, NH2-, MeS02NH-alkyl; h · the compound of formula II above or a carbohydrate derivative thereof, Where: ~ Rl = R2 = R4 = R5 = R6 = R7 = R8 = Rl0 = Rll = R9 = Rl2 == R13 == R15 = R16 = R17 = R18 = R19 = R 2〇 = R2i = R22 = R23 = R24 45 = R26 = R27 = R28 = R29 = R30 = r3i = i one 14 = R33 = fluorenyl '-R34 is -0H or -0R' where R is alkyl, fluorenyl or carbohydrate, and R35 is nitrogen Or the absence of two represents an arbitrary double bond, while the three-dimensionality of R25 々 degree in orientation, and in addition to the above, 3002-5563-PF (N1), Chiumeow.ptd Page 79 200400042 6. At least one of R3 or R23 is X group, and the possible remaining substituents are hydrogen, 0H, = 0, and 0R, among which R Is an alkyl group or a fluorenyl group or is absent, and X is selected from the group consisting of:-a halogen atom,-(Me-S-), (Me-S0-), (Me-S02-), and -N3, NH2-, MeS02NH--alkyl; i. Compounds of the above general formula III, wherein:-R !, R2, R3, R4, R5, R6, R7, R8, R1 (), R13, r14, r18, r19, Ruler 2. 'Ruler 21, ruler 22, ruler 23, ruler 24' ruler 26 'ruler 27' ^ 28 'R29, R3〇, R31, R32, R33, R34, ruler 35, R36, R37 are hydrogen' 〇H '= 〇 , Halogen atom, (Me-S-), (Me-SO-), (Me-S02-), N ", NH2-, MeS02NH-, alkyl, OR (wherein R is alkyl or fluorenyl) ' Or does not exist; -R9, Rn, R12, R15, R16, Ri7 'can be hydrogen, OH, halogen atom, (Me-S-), (Me-S0-), (MeS02-), N3-, NH2-, MeS02NH-, alkyl, OR (wherein R is alkyl or fluorenyl), or does not exist; two represents any double bond, wherein, except for the above, one of L 'and L is alkyl 'And the stereochemistry of R25 is located in the Θ position; j · The compound of the above general formula III or its carbohydrate derivative, wherein:-Ri, R2, R3, R4, R5, r6 ,,', R13, R14, r18, R19 , R20, R21, R22, R23, R24, R26, R27, R28, R29, R30, R31, R32, 3002-5563-PF (Nl); Chiumeow.ptd Page 80 200400042 6. Scope of patent application 'R35, R36, R37 are hydrogen, 0H, = 0, halogen atom, (Me-S-), (Me —S0—), (Me-S02-), N3-, NH2-, MeS02NH-, alkyl, OR (wherein r is alkyl, fluorenyl, or carbohydrate), or does not exist; R9, R15, R16, R17 are hydrogen, R34 is mu'OH, = 〇, _ atom, (Me-S-), (Me-SO-), (MeS02-) ,, NH2-, MeS02NH-, alkyl, 〇R (Wherein R is alkyl or fluorenyl), or does not exist; Ru, R25 may be hydrogen, OH, i atom, (Me-S-), (Me-S0-), (Me-S02-) ' , NH2-, MeS02NH-, alkynyl, OR (wherein R is alkynyl or fluorenyl), or does not exist; two represents an arbitrary double bond, wherein, in addition to the above, one R33 and & 4 where One is an alkyl group, and the stereochemistry of R25 is located in the direction; k · The compound of the above general formula π I, where-· R!-R2 = R4 = R5 = r6 = r7 = r8 = ri〇 = r " = 仏= ri2 = ri3 = ri5 = r16 = r17 = ri8 = r19 = R 20-R21 = R22 = R23 = R24 = r25 = r26 = r2? = r28 = r29 = r3. = R31 = R32 = R33 = Hydrogen '-Rl4 = Hexyl' -R34 is -OH or -OR, where r is an alkyl, fluorenyl or carbohydrate, and R35 is hydrogen or the absence of R37 is nitrogen, -0H Or = 〇R36 is nitrogen or -〇Η 2: represents a single bond, the fluorenyl group on -carbon 25 can be a mirror image isomer clockwise (R) or counterclockwise (s) junction 3002-5563-PF (Nl), Chiumeow ptd Page 81 200400042 6. The scope of the patent application, and the stereochemistry of R25 is located in the β position. In addition to the above, at least one of Rs or & The remainder is taken as 20, and yttrium, the opposite of which is an alkyl group or an alcohol group or does not exist, and for the wind, X is selected from the group consisting of: -tooth atom,-(Aie-S-), (Afe-SO -), (Me_s〇2_), and -N3, NH2-, MeS02NH-alkyl OH one foot 1 9 of the compound of the above general formula u I or the magnetic milk A /, water compound derivatives, I · 20 = K2I = R22 = R23 I & 4 = R33 = methyl 5 = R6 = R7-R8 = R1〇.Rii == Rd == R ^: r24Hr27 = R28 = r R 1 ^ Ri3 = Rl5 = R16 = R17 = Rl8 = R19 = R • 29 ίν3〇- R31 == M9 " K20 Hydrogen-R34 is -OH or -OR, where R35 is hydrogen or there is no xylyl group or carbohydrate and R37 is hydrogen _〇H or = 〇foot 36 is hydrogen or -〇Η The second represents a single bond, the fluorenyl group on carbon 25 may be a mirror I, and the structure of clockwise (R) or counterclockwise (S) structure, and The stereochemistry of R25 is located at the point position. In addition to the above, 3002-5563-PF (Nl), Chiume ow ptd page 82 200400042 VI. Application scope & or at least one of R23 is X group. Possible remaining substituents are hydrogen, 0H, = 0, and OR, where R is alkyl or fluorenyl or not Is present, and X is selected from the group consisting of:-a halogen atom,-(Me-S-), (Me-S0-), (Me-S02-), and -N3, NH2-, MeS02NH-- * m. Substituted saponin ligands, wherein at least one OH group of the saponin ligand is substituted with X, X is selected from the group consisting of:-a halogen atom,-(Me-S-), (Me- S0-), (Me-S02-), -N3, NH2-, MeS02NH-, and-alkynyl; η · saponin ligands as defined above, wherein the halogen atom in the definition of X is a fluorine atom; Substituted saponin ligands selected from the following: 3 cold-fluoro-5 cold, 20 °: 220, 251 ° -helix < is alkane (3041111′-5-5, 2061, 22 (2,251 ^- 3011 * 〇513116), 3,3-difluoro-5 3,200 :, 22〇 :, 251 ^ -spirosteroid (3,3-difluoro-5 // 3,20 α, 22 (^, 25 {^ -5011'〇3 七 & 1 ^), 3 ^ -fluorenylsulfonamido: 50, 2〇 «, 22 a, 25R-spiral g (3 a-methylsul phonylamino-5 / 3,20 α, 22 α, 25R-spirostane) '3 α -Trisamidine-5 / 3,20 α, 22 α, 25R-spiral retention (3 α -azido-5 / 3,20 α , 22 a, 25R-spirostane), 3 α-amino-5 / 3,20 α, 22 a, 25R-spirostane (3 a-amino-5, 3002-5563-PF (Nl), Chiumeow.ptd, page 83, 200400042 6. Application scope of patent 20 α, 22 a, 25R-spirostane), and its stereoisomers and racemic mixtures' and pharmaceutically acceptable precursors Drugs and salts; ρ · substituted saponin compounds, in which the parent saponin compound f (parent sapogenin) is then substituted with at least one X group as defined above, and the substituted saponin compound is selected from Salsa soap Yuan, episalic saponin, isoparagrin saponin, epizoa saponin, and Enzrozagogen -CKanzurogenin-D); q. Compounds of general formula I a: The R group in Xin is selected from hydrogen; alkylcarbonyl; alkoxycarbonyl, aikylcarbamoyl; or arylcarbonyl; or thiocarbonyl (suiph〇 (H03S) )); Phosphono ((H0) 2P (0)-); or mono, di or 'trifuran; where any of the alkyl groups can optionally be aryl, test group, mono or diamine (Mono-or di-alkyl-amino), carboxylic acid residue (-C00H), or any resulting tie-up substitution; and 3002 · 5563-ίΨ (Ν1), Chiumeow.ptd page 84 200400042 6. Application for patent scope r. Derivative form of the compound as defined in items a to q above, in which the carbon atom at position 3, or, in the formula II The carbon atom at position 3, the carbon atom at position 2 or each of the carbon atoms at positions 3 and 26 in III and III carry a 0-sugar group, wherein the sugar group is mono, di or tri Sugar, and its tritiated derivatives. 3. Use of the active agent according to item 1 or 2 of the scope of the patent application, wherein the active agent, or at least one of the active agents, is selected from the compounds of the general formula Ia. 4. The use of an active agent as described in the scope of any previous patent application, wherein the active agent, or at least one of the active agents is selected from the group consisting of: salsa saponin, salsa saponin ethyl acetate, salsa Salsa saponin acetate, salsa saponin succinate and pharmaceutically acceptable salts thereof, salsa saponin glycinate and pharmaceutically acceptable salts thereof, salsa saponin amino group Propionate and its pharmaceutically acceptable salts, salsa saponin valinate and its pharmaceutically acceptable salts, salsa saponin phenylaminopropionate and its pharmaceutically acceptable Salts, salsa saponin isoleucine and its pharmaceutically acceptable salts, salsa saponin isosulfonate and its pharmaceutically acceptable salts, episarsa saponin , Ethyl salsa saponin ethyl acetate, Ethyl salsa saponin acetate, Ethyl salsa saponin succinate and pharmaceutically acceptable salts thereof, 3002-5563-PF (N1); Chiumeow.ptd Page 85 200400042 6. Scope of patent application: Salsa saponin glycinate and its pharmaceutically acceptable salts, salsa saponin aminopropionic acid Salts and pharmaceutically acceptable salts thereof, episalsa saponin valinate and pharmaceutically acceptable salts thereof, episalsa saponin phenylaminopropionate and pharmaceutically acceptable salts thereof Salts, episarsa saponin isoleucine and its pharmaceutically acceptable salts, episarsa saponin isomethionine and its pharmaceutically acceptable salts, isopyridine soap Ganyuan, Isozyme Sodium Glycolate Ethyl Ester, Isozyme Sodium Glycogen Acetate, Isozyme Sodium Glycogen Succinate and Its Pharmaceutically Acceptable Salts, Isozyme Sodium Glycogen Glycine Salt and its pharmaceutically acceptable salts, Isozyme saponin glycylan aminopropionate and its pharmaceutically acceptable salts, Isozyme saponin glycylide valinate and its pharmaceutically acceptable salts , Isozyme saponin glycylide phenylamino propionate and its pharmaceutically acceptable salts, Isozyme saponin glycylide isoleucine and its pharmaceutically acceptable Accepted salts, isoamidine saponin isoamylthione salt and pharmaceutically acceptable salts thereof, epiammonium saponin saponin, epiammonium saponin ethylammonium acetate, epiammonium Acetylglycolide acetate, Epicisocyanatoglycoside succinate and its pharmaceutically acceptable salts, Epicisocyanatoglycoside glycine succinate and its pharmaceutically acceptable salts, Epicisolate Acetyl saponin glycinyl amino propionate and its pharmaceutically acceptable salts, Episexogenin saponin saponin valinate and its pharmaceutically acceptable salts, Episopogenin saponin saponin phenylamino Propionate and its pharmaceutically acceptable salts 3002o563-PF (Nl) Xhiumeow ptd Page 86 200400042 VI. Application for patents, episodium glutamate, glycogen isoleucine and its pharmaceutically acceptable salts Thionine salts and their pharmaceutically acceptable salts; In any of the above active agents, the carbon atom at position 3 of the saponin of salsa saponin, episa salsa saponin, iso-sapogenin and epi-isosapogenin has a carbon atom at position 3. Sugar group, wherein the sugar group is selected from glucose, mannose, fructose, galactose, malt bran, cellobiose, sucrose, rhamnose, xylose, arabinose, trehalose, isorhamnetin, Celery sugar, lactose, galactose-glucose, glucose-arabinose, trehalose-glucose 'rhamnose-glucose, glucose-glucose-glucose, glucose-rhamnose, mannose-glucose, glucose- (rhamnoglucose , Glucose- (rhamnose) -rhamnose, glucose- (glucose) -glucose, galactose- (rhamnose) -galactose and its tritiated derivatives; 16, 22-epoxy fecal solid-30,000 ―Alcohol, smilagenone, fecal sterols, and pharmaceutically acceptable prodrugs and their salts. 5. The use of the active agent as described in any one of the previous application areas, wherein the active agent is present and selected from pharmaceutical compositions, foods, food supplements, and beverages. 6. The use of the active agent as described in any of the previous patent applications, where the active agent is present with one or more added active agents. 7. The use of the active agent as described in item 6 of the scope of the patent application, wherein one or more of the added active agents are selected from the group consisting of cholinesterase inhibitors, dopamine agonists, and dopamine agonists. 3002-5563-PF (Nl), Chiumeow.ptd 200400042 VI. Application scope of patents (eg, L-dopa), catechin oxygen-position transferases (COMT inhibitors), monoamine oxidase B inhibitors (MAO-B inhibitors), anticholinergic drugs (anti -cholinergics), acetylcholine agonists, serotonin agonists, α-amino-3 -meryl-5-amidinoisoxialyl-4-propionate receptor agonists (AMPA receptor agonists), χ-aminobutyric acid receptor agonists, N-fluorenyl-D-aspartic acid receptor agonists (NMDA receptor agonists), epinephrine receptor agonists (/ 5-adrenoceptor agonists), digitalis (digoxin), dobutamine, anti-inflammatories, neurotrophic factors, statins, adenosine A2a Adenosine A2a receptor agonists, aldose reductase inhibitors, immunomodulators, cannabinoid agonists, interferon 0 (interferori / 5) or tricyclic Anti-depressants (tricyclic anti-depressants) 〇8 · The use of active agents as described in any of the previous patent applications, in which humans or non-human animals suffer from or are susceptible to any of the following diseases: Parkinson's disease Parkinson's disease (depression), schizophrenia, muscular dystrophy (including progressive shoulder and humerus type muscular dystrophy ', Duchenne muscular dystrophy, Baker's muscular dystrophy And Brucell muscular insufficiency), Fuch, s insufficiency, tonic muscular dystrophy, 3002-5563 * PF (Nl), Chiumeow.ptd, page 88, 200400042 6. Application scope of patent Corneal dystrophy, reflex sympathetic insufficiency, neurovascular dystrophy 'myasthenia gravis, Lambert Eaton's disease, Handing Dayton syndrome, motor neuron disease (including amyotrophic lateral sclerosis), multiple sclerosis, postural hypotension, traumatic neurodegeneration following a stroke or accident (eg, trauma to the head or spinal nerves), Batten, s disease '' Cockayne syndrome, Down syndrome, corticobasal ganglionic degeneration, multiple system atrophy ), Cerebral atrophy (cerebrai atrophy), olivopontocerebellar atrophy, dentatorubral atrophy, pallidoluysian atrophy, spinal cord and bulbar atrophy (spinobulbar atrophy) , Optic neuritis, sub-acute sclerosing encephalitis (sc 1 eros i ng pan-encepha 1 iti s (SSPE)), attention deficit disorder, post-viral encephalitis, post-poliomyelitis syndrome, Fahr's syndrome, Joubert syndrome, Geba Guillain-Barre syndrome, ligsencephaly, pediatric stroke (Moyamoya disease), neuronal migration disorders, autism syndrome, polyglutamine disease , Niemann Pick disease, progressive multifocal leukoencephalopathy 3002-5563-F ^ (N1), Chiumeow.ptd Page 89 200400042 VI. Progressive multifocal ieukoencephal〇pathy, pseudotumor cerebri, Refsum disease, tile Zellweger syndrome, supranuclear paiSy, Friedreich's ataxia, spinocerebellar ataxia type 2, rhett syndrome (Rhett syndrome), Shy-Drager syndrome (Shy-Drager syndrome), tuberous sclerosis, Pick's disease (Pick, s disease), chronic fatigue syndrome, neuropathies (including hereditary neuropathies ( hereditary neuropathy) 'Diabetic neuropathy and mi tot ic neuropathy), prion-based neurodegeneration (including Creutzfeldt-Jakob disease (CJD), variants CJD '' new variant CJD, Bovine Bull (Bo vine spongiform encephalopathy (BSE)), familial genetic insomnia (GSS), fatal familial insomnia (FFI), kuru and Alper's syndrome, Joseph's disease, acute disseminated encephalomyelitis ), Spinal nerve insects (arachnoiditis), vascular lesions of the central nervous system (vascular lesions of the central nervous system), extreme loss of neuron function (loss of extremity neuronal function), Charcoal-Marley-Duss Disease (Charcot-Marie-Tooth 3002-5563-PF (Nl) .Chiumeow.ptd Page 90 200400042 3002-5563-PF (N1), Chiumeow.ptd p. 91