TWI357816B - Therapeutic methods and uses of sapogenins and the - Google Patents

Description

1357816 IX. Description of the invention: [Technical field to which the invention pertains] The present invention relates to the use and treatment of saponin ligands, related compounds and derivatives thereof. Saponin ligands, related compounds and their derivatives are used to treat non-cognitive neurodegeneration, non-cognitive neuromuscular degeneration, motor sensory neurodegeneration, or stylistic abnormalities or loss. In another aspect, the invention relates to a composition for use in the treatment. [Prior Art] Cognitive dysfunction is dementia

• Characteristics of conditions and symptoms, such as: Alzheimer's disease (Alzheimer, S • disease (AD)), Alzheimer's disease (senUe dementia of the Alzheimer's type (SDAT)), Levi's Lewy body dementia and vascular dementia. Cognitive abnormalities with a small βρ degree are also characteristic of certain non-dementia conditions and symptoms, such as mild cognitive impairment (MCI), age-associal: ed mem〇ry impairment ( AAMI)), autism and neurological disorder (neur〇impairment). Non-cognitive neurodegeneration (ie, neurodegeneration in the absence of cognitive impairment), non-cognitive neuromuscular degeneration (ie neuromuscular degeneration in the absence of cognitive impairment) and motor sensory neurodegeneration are characteristic of the following conditions and symptoms' eg. Parkinson, s disease, muscular dystrophy (including: shoulder-shoulder-type progressive muscle 3002-5563A-PF 5 1357816 > € facioscapulohumeral muscular dystrophy (FSH) Duchens muscular dystrophy (Duchenne muscular)

Dystrophy), Becker muscular dystrophy and Bruce 's muscular dystrophy, Fuch's dystrophy, tonic muscular atrophy ( Myotonic dystrophy), corneal dystrophy, ref lex sympathetic dystrophy syndrome (RSDSA), neurovascular dystrophy, myasthenia gravis, lambert Lambert Eaton disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis. Receptor dysfunction or loss—especially nicotinic and/or muscarinic acetylcholine receptors and/or dopamine receptors and/or The disorder or loss of adrenergic receptors (adrenoceptors) is characteristic of some or all of the above conditions and symptoms. In the absence of cognitive impairment or loss of the receptor, neurological and neuromuscular defects are also characteristic of the following conditions and symptoms, such as: postural hypotension, chronic fatigue syndrome, asthma (asthma), Susceptibility to heart failure and macular degeneration ° 3002-5563A-PF 6 ; expected increase in 1 ife expectancy and for sporadic; control of disease 'the above conditions and symptoms In all societies, it is increasing and serious. The demographic data of older people is continuing to work... What is urgently needed is an agent that can treat or help treat and prevent these diseases. DE-A-4 303 214, which is incorporated by reference, discloses the treatment of saponins and sapogenins for viral diseases but does not provide data for those skilled in the art to select specific classes of compounds to treat any particular virus. Sexual disease. The use of certain saponins in combination with saponin in the treatment of dementia is disclosed in the World Patent Publication No. WO-A-99/16786, which is incorporated herein by reference. U.S. Patent No. WO-A-99/48, 482, WO-A-99/48, 507, WO-A-01/23406, WO-A-01/23407, WO-A-01/23407, incorporated herein by reference. A-0 1/23408 relates to the use of certain saponins, saponin and its derivatives in the treatment of cognitive impairment and related symptoms. Chinese Patent Application No. CN-A-1 096031, which is incorporated by reference, discloses cold-adrenalin and M-type biliary receptors (y3-adregergic and M-cholinergic) Under the bidirectional regulation of receptors, the biological activity of spirostane sapogenin and sa rs a sapogen in 0 does not provide specific pharmaceutically active activity. However, in 1998, the synthesis and application of isotopically labeled compounds (Synthesis and Applications of

Isotopically Labelled Compounds)" 315-320

3002-5563A-PF 7 1357816, Yi et al. describe the use of salsa soap in the treatment of Alzheimer's disease. There are some so-called "spectrums", which have a wide range of symptoms combined with relative severity. The combination of the severity of each symptom and the specific symptoms will vary from person to person, depending on The stage of development of the disease will also vary. For example, in cases of Parkinson's disease, myasthenia gravis, Lambert Eaton, postural hypotension, and chronic fatigue syndrome, although cognitive impairment is likely to occur 2 times One of the symptoms (secondary Symptom), but not the main symptom (primary sy is tom). In addition, these symptoms are not viral diseases or dementia. Many of these diseases are called "spectrum, disease. Therefore, in many cases, there is no need to treat cognitive impairment (eg, dementia). The present invention is based on our findings, and certain pheromone and its derivatives (including 4) have amazing disease repair activity (d1Sease-nH3difying aGtivUy), which is resistant to non-cognitive neurodegeneration, non-cognitive nerves. Muscle degeneration, motor sensory nerve degeneration, and prevention of receptor dysfunction in the absence of cognition Sensen A long loss of 'neural and neuromuscular defects, thus effectively preventing and improving this ^, lameness - symptoms. This finding can improve the treatment of non-viral, spectral and non-fragmented diseases that are not the main symptoms of certain cognitive disorders. BRIEF DESCRIPTION OF THE DRAWINGS A brief description of the present invention The present invention provides a use of an active agent (as defined herein) for the treatment or prevention of human and non-human animals.

3002-5563A-PF 8 1357816 Symptoms or predisposition to prepare a composition (eg, pharmaceutical composition, food, food supplement, and beverage) for treating or preventing the condition (i) non-cognitive neurodegeneration (ii) non-cognitive neuromuscular degeneration, (iii) motor sensory neurodegeneration, (iv) lack of cognitive receptor impairment or loss, neurological and neuromuscular defects. "Active agent" means a compound of the formula: u, and π, as defined in the following referenced saponin derivatives, which have at least one defined @X-based substituent, such as Sugar-substituted derivatives of such compounds as defined, all stereoisomers and racemic mixtures of all pharmaceutically acceptable prodrugs (pro- Drugs) combined with salts, and all their mixtures. Formula I:

Ruler 3, R4, R5, R6, R7 R23 ' R24 » R26 > R27 '

Rfi ’ R 丨. , Rl3, R丨8, R丨9, β2〇, .28 » :2i), R3D, R31, R32 Individual 3002-5563A-PF 9 1357816 Composition of hydrogen (Η) ' 〇H,=〇,_ atom (hola atom), (Me-S_), (Me-S0-) '(MeS〇2-), N3-, NH2-, MeSOaNH-, alkyl (alkyl), or absent or '〇R, where r is an alkyl group or an acyl group; _Rg ' R1 1 ' R12 ' R i 4,R) 5 ' R! 6,R, 7,R25,R33 may be nitrogen, 〇H, halogen atom, (Me -s-), (Me-S0-), (MeS〇2-), N3-, NH2-, MeS〇2NH-, alkyl, or absent, or OR, wherein R is alkyl or decyl; • .· indicates an arbitrary double bond (op tional doubl e bound),

Wherein, in addition to the above, one of -R33 and Rl4 is a burnt group; the molecular formula (Π):

1 2 ' R3 ' R4 ' R5 ' R6 ' R? ' Re, r丨. , Ri3 ’ Ri8, Rig, r2. , R2 丨, R22, R23, R24 ' R26 ' R", R28, R2g, R3., R31, R32, R34 are hydrogen, OH, =0, i! atom, (Me_s_), (Me_s〇_), (MeS〇2_), ...' NH2-, MeS〇2NH-, alkyl, 〇R (wherein alkyl or fluorenyl), or absent;

3002-5563A-PF 丄乃7816 9 ' Ru ' Rl2 ' Rl4 ' Rl5 ' Rl6, R17, R25, R33, R35 can be argon, OH, halogen atom '(Me-S-), (Me_s〇_), ( MeS〇2_), N3_, NH2_ .,

MeS〇2NH- 'burning base' 〇i{ (wherein R is an alkyl group or a fluorenyl group)' or not; f · represents an arbitrary double bond, wherein, in addition to the above,

One of -R33 and Rm is an alkyl group; Formula 111:

• Κι , κ: 7, 8 feet, Rl. ’ R13, R丨4, κ丨8, Κ",

R20, R21, R 22 J R23, R24 5 r. ^ Κ 6 ′ R” ′ R28, R29, R3, R31, R32, ^33, R34, R35, R36, {{37 public from one

7 knives are hydrogen, OH, = 〇, _ atoms, (Me_s (Me-SO-), (MeS〇2-), I Μττ J , NH2-, MeS 〇 2NH-, alkyl, 〇R (复中R is alkyl or fluorenyl), formula, /, ' or absent; -Rg, Rii, R12, Ris ' R16, R p

Rz5 can be hydrogen, OH, _ atom, (Me_s_, (Me-SO-), (MeS〇2-), N3-Nm ^ S },

, Nl- , MeSO·-, depot, 0R (its 3002-5563A-PF 11 1357816 • R is alkyl or sulfhydryl), or absent; • • • represents any double bond, of which, in addition to the above In addition, one of -R33 and Ru is an alkyl group; and the stereochemistry of R25 is located at $orientation; especially a saponin derivative (but not specifically steroidal snail) Φ ligand has at least one X-based substituent, wherein X is a group selected from the group consisting of: - a halogen atom, -(Me-S-), (Me-SO-), (Me-S〇 2-), -N3-, NH2-, MeSChNH-, and -alkyl; and a derivative form of any of the above compounds, wherein the carbon atom at position 3 (ie, the carbon atom to which R3 is bonded, or the above definition a molecular formula of saponin with the same position of each derivative), or a carbon atom of positions 3 and 26 (ie, the carbon atom to which R34 is bonded) of the formulae (11) and (111), or carbon of each position 3 and 26 The atom will have a sucrose group (〇_sugar(四) 丨 ,, in which the glycosyl group is a single 'di or saccharide. The form of the sugar derivative of the active agent generally refers to saponin in the prior art. As used herein, "carbohydrate (jrate), especially includes such a glycosyl group. The active agent used in the present invention is the most A non-estrogen steroidal sapogenins, a serotonin, and a derivative, a substance, and a salt thereof, as defined above, including all physiologically acceptable prodrugs thereof. The active agent may be produced naturally or unnaturally. It is produced non-naturally. According to the prior art and the following description, the side group of the compound produced by modifying the scorpion

Side groups and/or side atoms (Side A

Twiae atoms), a non-naturally occurring active agent can be suitably prepared. Human animals, the same method is also provided in the present invention for treating humans and non-

And providing a composition comprising the active agent for use in the method of treatment described. If desired, the active agents of the present invention may be administered with one or more active agents, including: cholinesterase inhibitors, dopamine agonists (eg, cholinesterase inhibitors) (eg, : levodopa L-dopa), catechol oxy-transferase (COMT inhibitors), monoamine oxidase B inhibitors (MA〇_B inhibitors), anti-cholinergics, antibiotics Acetylcholine agon i sts, serotonin agonists, AMPA receptor agonists, 7"-amino GABA receptor agonists, NMDA receptor agonists, adrenoceptor agonists (f-adrenoceptor agonists), foxglove ( Digoxin), dobutamine, anti-inflammatories, neurotrophic factors, statins, adenoid A2a receptor agonist 3002-5563A-PF 13 1357816 (adenosine A2a rece Ptor agonists), aldose reductase inhibitors, immunomodulators, cannabinoid agoni sts, inter f eron or tricyclic antidepressants (tricyclic anti-depressants) ° This activator can be used to treat and prevent non-cognitive neurodegeneration, non-cognitive neuromuscular degeneration, motor/sensory neurodegeneration, or receptor impairment or loss in humans and non-human animals. Symptoms and diseases. Examples of such symptoms and diseases are described below. Thus, the present invention also provides for the use of an activating agent (as defined therein) for treating or preventing the condition, or for providing an activator, for one or more of the symptoms and diseases of the human or non-human animal previously described. Use in the preparation of a composition for treating or preventing this condition. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS DETAILED DESCRIPTION OF THE INVENTION Examples of Active Agents Several active agents are specifically described below: 1. A compound of the above formula I, wherein: -R1 ' ' R3, r4, r5, r6, r7, R8 ' R Hey. , Ri3, Ri8, Ri9, R2. , R21 L ' r23 ' R24 ' R2B ' R„ ' R28 ' Rzg ' R3e ' ^ are respectively hydrogen, 〇H, =0, halogen atom, (Me_s_), (Me —s〇—), (Me_s〇2_) , I—, Nth—, MeS〇2NH—, alkyl or absent, or 〇r, wherein R is alkyl or fluorenyl; 3002-5563A*-pf 14 1357816 -R9 ' Rh ' R12 ' Ru, Rl5, Ri6, Ri7, R25, R33 can be gas, helium atom, (Me-s-), (Me-s〇-), (Me-S〇2-), N3-, NH2-, MeS〇haloyl or There is no 'or 〇R, where R is an alkyl group or a fluorenyl group; '•.. represents an arbitrary double bond, wherein 'except as described above, one of -R33 and R14 is an alkyl group, and the R25 is a stereo Chemistry is located in a million directions;

2. A compound of the above formula I, wherein:

Rl9 ’ R2. , 匕2 are e, S〇2,), 0R, where -Ri ' R2 ' R3, R4, R5, r6, r7, r8, R10 ' r13, ruler 8, R21, R22, R23 ' R24, R26 , R27, R28, R29, R3〇, r31, hydrogen, OH ' =0, halogen atom, (U-), (Me-S0~), (secret Na_, Nlh- ' MeSOzNH-, alkyl, or non-existent 'Or R is a base or a base; -Rs ' Rl2,Ri5,Rl6, R17 is hydrogen, -Rii,Ru ' R25 ' R33 can be hydrogen, 〇H, _ atom, (Me~s~), — a), (Me_S〇2_), Ns- 'NH2-, MeSOzNH- 'alkyl' or absent, or OR, wherein R is alkyl or fluorenyl; ... denotes an arbitrary double bond, wherein In addition to the above, one of - 33 and Rm is an alkyl group, and the stereochemistry of Rm is in the β orientation; 3. The compound of the above formula I, wherein: -Rl = R2 = R4 = R5 = R6 = K7 = R8 = Rl〇 = Rn=R9 = Rl2 = Rl3 = Ri5 = ^16=;pi7_p ^32 = 1^33=Gas: R20 = R21=R22 = R23 = ^24 = K25 = R26 = R27 = R28 = R29 = R30 = ^3i=: 3002-5563A-PF 15 1357816 咄33 and R,4 One of them is methyl (ch3) ..· represents a single bond, -carbon 25 (C2 5) The (S) structure of the methyl group can be a mirror image isomer clockwise (only 彡 or counterclockwise - R25 stereochemistry is located in the stone orientation, and in addition to the above,

W R23 has at least one of X groups, and the possible remaining substituents are hydrogen, 〇H = 〇, and OR, wherein R is a base or a aryl group or is absent, and X is selected from the group consisting of: - a halogen atom, _(Me-S-), (Me-S〇-) '(Me_s〇2_), and -N3 > NH2-» MeS〇2NH--alkyl; 4. a compound of the above formula i, Where: mR5=R6=R7=R8=Rl((=Rn=R9=Ri2=Ri3=Ri5=Ri6n (4) m=R23=R24=R25=R26=R27=R28=R29=m=hydrogen, -R]4 = R 3 3 = methyl, climbing / , -R25 is located in the salient position, and in addition to the above, R3 or R23 has at least one of the X groups, and the possible remaining substituents are hydrogen, (10) = 〇' and '0R, wherein r is alkyl or fluorenyl or absent, and X is selected from the group consisting of: -halogen, 3002-5563A-PF 16 Ο丄ϋ -(Me-S_),( l), n), and -N3 > jyjfj2_ , MeS〇2NH--alkyl; 5. The compound of the above formula, wherein: 1 R2 ' L, R4 ' r5 ' Re, R?, Re, Ri. ,,Heart,&,,R: 'R" ' R23 ' R24,R26,R2" L,R29,R3e,R3I,r32,R34 The knife is hydrogen ' OH' =0' South Atom, Me_s _), (Me_s〇), (Me_s〇2), 3 NH2-, MeS〇2NH-, alkyl, (wherein R is alkyl or acyl), or absent;

Rg ' R",R12 ' R" ' R15 ' Rl6 ' R" ' R25,I,—may be nitrogen, 〇H, quotient atom' (Me-S-), (Me-S〇-), (Me_s〇 2_), n3_, NHz one,

MeS〇2m, GR (where u is a burnt group or a silk), or absent; II·- represents an arbitrary double bond, wherein, in addition to the above, - R33 and R "one of them is an alkyl group, Whereas the stereochemistry of Rw is in the 泠 orientation; 6. The compound of the above formula 11 and its carbohydrate derivatives are:

R8,Ri〇' r13,r18 ' R19 ' R20, R21 > R22 > r23 > r24 > r26 is hydrogen ' OH, =0, halogen atom N3-, NH2-, MeSOAH-, or absent; 1 K" ' R28 ' R29 ' R3., R31, R32 respectively '(Me-S-) '(Me_s〇_), (Me_s〇2 a), alkyl group OR (where R is alkyl or sulfhydryl ), -R9 1 Ri

Rl5 'Ru ' R17 is hydrogen 3002-5563A-PF 17 1357816 -R34 is hydrogen ' OH ' =0 ' and 〇r (where r is alkyl, sulfhydryl or carbohydrate); -Rn, R14, R25, R33 , R35 may be hydrogen, hydrazine H, halogen atom, (Me_s_), (Me-S0-), (Me-S〇2-), N3_ 'NH2_, MeS〇2NH_, alkyl, 〇R (where R is Or a non-existent; ... denotes an arbitrary double bond, wherein, in addition to the above, one of -R33 and Rm is a unitary group, and the stereochemistry of R25 is in a non-oriented position; a compound of the formula II, and a carbohydrate derivative thereof, wherein: =m=R23m=R27=R28=R29=m=R3 -Ru=methyl

-R34 is -0H or -OR, wherein R is an alkyl group, a thiol group or a carbohydrate, and R35 is nitrogen or non-existent, 22 represents an arbitrary double bond, and a thiol group on a carbon 25 (C25) For the mirror image isomers clockwise (R) or inverse (S) structure. Ten and R25 stereochemistry is located in no orientation, except for the above, one of R3 or U is one of X groups, and the possible remaining substituents are Hydrogen, hydrazine, =0, and 0R (wherein R is alkyl or fluorenyl or absent), and X is selected from the group consisting of: 3002-556 3A - PF 18 1357816 - functional atom, _ (Me- S-) '(Me_SO-) '(Me-S〇2-), and _N3, Nth- , MeSOzNH-; base 8. The compound of the above formula 11 and its carbohydrates are produced in the street: -Ri =R2 = R4 = R5=R6=R7 = R8 = R10=Rn=R9=R12=Ri3=Ri5=Ri6 = R]7 = Rig=Ri =R2〇= R2丨= R22 = R23=R24 = R25=R2s = R27 = R28 = R29 = R3() = R3i = R32 = hydrogen, _Rl4 = R33 = methyl - R "is -OH or -〇R ' where R is alkyl, sulfhydryl or carbohydrate and -R35 is Hydrogen or absent, ... denotes an arbitrary double bond, and the stereochemistry of R25 is in the calling position, except for the above Further, at least one is an X group, and the remaining remaining substituents are hydrogen, 〇h = 〇' and 0R (wherein R is an alkyl group or a sulfhydryl group 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-, MeS〇2NH--alkyl; a compound, wherein: ', R丨9, -Ri, R2, R3, R4, r5, r6, r7,, Ri., 3002-5563A-PF 19 1357816 R20, R21, R22, R23, ί 24' R26 ' I?27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37 are hydrogen ' 〇H ' =0, halogen atom, (Me-S-), (Me-S0-), (Me-S〇2-), N3- 'NH2-, MeSChNH- 'alkyl, 〇R (wherein R is alkyl or sulfhydryl), or absent; -R9, Rii' Ri2' R15, Rie, R"' R' can be hydrogen ' 0H' tooth atom, (Me-S-), (Me-S〇-), (MeSCh-), N3- 'NH2-, MeSChNH-, alkyl group, (where R is Alkyl or fluorenyl), or absent; • ·. means any double bond,

Wherein, in addition to the above, one of _R33 and Rm is an alkyl group and the stereochemistry of R25 is in the orientation; 10. The compound of the above formula, wherein: -Rl, R2 ' R3 ' ' R5 ' Re , ' R8 , R 丨. ' R13,, R丨8, R丨9, R20 > R2I > R22 ' R23 * ^24 * ^26 * ^27 5 R28 > Rag » R30 > R31 > ^32 R33, R35, R36, R" is hydrogen '0H ' = 〇' halogen atom, (n_), (Me-S0-), (Me-S0r) 'Nr, NH2-, MeS〇2NH- 'alkyl, 0R (where R is an alkane Base or thiol)' or absent; -R9, R丨2, R15, Ri6, Rl7=nitrogen-R34 is hydrogen, OH, =〇, _ atom, (Me~S~), (Me-S〇- ), (Me_s〇2), Ns-, ΝΗπ, MeSChNH- 'alkyl, 〇R (where r is alkyl, sulfhydryl or carbohydrate), or absent; -Rh ' R25 can be hydrogen, 0Η , atom atom '(Me-S-), (no-), (Me-S〇2-), Nr, NH2-, MeS〇2NH-, alkyl, 〇R (wherein R is alkyl or fluorenyl) ), or does not exist; 20

3002-5563A-PF ratio 7816 II represents an arbitrary double bond, wherein 'except for the above, one of ~R33 and R14 is an alkyl group, and the stereochemistry is in a non-azimuth; Π. the compound of the above formula And its carbohydrate derivatives, of which:

Ri r Bu R4=nm=Rii=Rg=Ri2m6m n=R22=R23=R24=R25=R26=R27=R28=mm, 1u=曱A 34 is -oh or -〇R, where R is an alkane a group, a thiol or a carbohydrate, and R35 is hydrogen or absent, R37 is hydrogen, _〇H or =〇 is hydrogen or -0H ' = _ represents a single bond, and

- the sulfhydryl group on carbon 25 (C25) may be a mirror image of a clockwise (or counterclockwise (S) structure and the stereochemistry of Rw is not oriented, except for the above, at least one of R3 or R23 The x group, the possible remaining substituent is hydrogen, 〇H =0' and OR' wherein r is alkyl or sulfhydryl or absent, and X is selected from the group consisting of: - a halogen atom, and - (Me -S-) '(Me-S0-), (Me-S〇2-), 3002-5563A-PF 21 1357816 -N3 , NH2- , MeS〇2NH--alkyl; 12. Compound of the above formula III And its carbohydrate derivatives, where: -Rl=R2 = R4 = R5 = R6 = R7 = R8-Rl0 = Rll = R9 = Rl2 = Rl3 = Rl5 = Rl6 = Rl7 = Rl8 = Rl9 = R20 = R2 1= R22 = R23 = R24 = R25 = R26 = R27 = R28 = R29 = R3〇 = R3l = R32 = Rig = R2〇 = hydrogen, - Rl4 = R33 = methyl - R34 is -0H or -OR 'where R is burnt a group, a thiol or a carbohydrate, and R35 is hydrogen or absent, is hydrogen, -0H or =0 R36 is hydrogen or -OH ... represents a single bond,

The thiol group on -3⁄4 25(C25) may be a clockwise (r) or counterclockwise (S) structure of the mirror image isomer and the stereochemistry of R25 is in the point orientation, except for the above, R3 or R" has at least One is an X group, and the remaining remaining substituents are hydrogen, 〇H, =0' and 0R, wherein 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-SCh-) ' and -N3, NH2-, MeSOzNH-3002-5563A-PF 22 丄丄Ο-burning base; 13.Specially take us The substituted sapogenins of this generation, but not specific to the steroid-like snail saponin, in which at least one of the 0H bases of the urgency is replaced by X, and X a group selected from the group consisting of: - a halogen atom, _(Me-S-), (Me-S〇-), (Me_s〇2_), and

-N3 'NH2- ' MeSOzNH-, and -alkyl; 14. The specific saponin ligand defined above, but does not specifically refer to the steroid helicin ligand, wherein the halogen atom in the definition of 纟χ refers to the gas atom ; 15_Substituted saponin saponin selected from the following materials: 3 no-fluoro-5$ 20 α, 22 a,25R-spirostane), 3, 3-difluoro-5 $,20 α,22 α ,25R - Spiral leaver (3, 3-di fluoro-5 /3 , 20 α , 22 ^:, 25 ft-5 - 11' 〇 513116) '3 〇: -Methylsulfonylamino-5 0,2〇 <2'22 ο:,25R-spiral alkane (3 α -methylsulphonylamino-5 /3,20 a ,22 a , 25R-spirostane), 3 a -triazole-5 /3,20 a,22 a , 25R-spiral leave-burning (3 a -azido-5 no, 20 a, 22 a,25R-spir os tane)' 3a -amino- 5y5, 20a, 22a, 25R-spiral brothel (3α-amino-5々 , 20α, 22α, 25R-spirostane), and stereoisomers and racemic mixtures thereof, and pharmaceutically acceptable prodrugs and salts thereof;

3002-5563A-PF 23 1357816 16. A substituted saponin ligand wherein the parent sapogenin is subsequently substituted with at least one of the X groups defined above, and the parent saponin is selected from the group consisting of Sal. Sarsasapogenin, episarsasapogenin, smi lagenin 'epismi lagenin, and Enzro soapy-D ( Partially transliterated anzurogenin-D); 17. Compound of formula la:

(la) wherein the R group is selected from the group consisting of hydrogen; alky 1 car bony 1; alkoxycarbonyl; aikylcarbamoyl; or arylcarbonyl; or sulfur Daichi (Suiph〇 (H〇3S)); phosphonic acid (phosphono ((Η0)2Ρ(0)-); or mono-, di- or tri-saccharide; wherein any of the alkyl groups can be used, 3⁄4 to the ground a group, an amine group, a mono-or di-alkyl-amino group, a carboxylic acid residue (-C00H), or any combination of the resulting ones. a derivative form of the compound defined in the above items 1 to 17, wherein the carbon atom at position 3, or the carbon atom at position 3 in the formula π and ΠΙ, the carbon atom at position 26 or each at positions 3 and 26 3002 -5563A-PF 24 1357816 The carbon atom 'has a 〇-saccharide group, wherein the sugar group is a single 'di or disaccharide', for example, a single-stranded ketone or ketone with 5 or 6 carbon atoms ( Mon〇aldose or ketose), preferably in the form of cyclised furanose and pyranose, or optical isomer with]) or L (optical isomer) Ism) alpha or 0 first-order isomer (anomei), or any combination of its two and three oligosaccharides (aciigosaccharide); acylated forms of sugar residues are also included in "sugar," Among the 'sweet sugars' include I] glucose mannose, fructose galactose, mal tose, cellobiose, hemp Sugar (sucrose), rhamnose, xylenose 'arabinose, trehalose' (qucose) 'iso-rhamnose (qUinovose), sprout sugar (api〇se), milk . 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 oximation (eg acety 1 ated) a derivative. In the definition of the above compound: an amine group of an alkyl group optionally present, Amine Cmonc ^ alkyl ~ amino) with a dialkyl amino group is preferably mono-substituted in the square of the position of the alkyl substituent (m〇n〇_substi " tuent). The carboxyl (-C00H) substituent of the optionally present alkyl group may be at the end of the alkyl group or at any other position. 3002-5563A-PF 25 1357816 Alkyl, which means an aliphatic hydrocarbon group (4) begging. Hydr〇Carbon group) The aliphatic hydrocarbon group may be a linear or branched chain having from about 〇 to 2 碳 carbon atoms. Preferably, the alkyl chain has from # i to about 12 carbon atoms. Branch means that one or more of the lower bases (1〇町 〇叩3) (for example, methyl, ethyl or propyl) are attached to a linear alkyl chain. ''Low-burning group'' refers to about 4 carbon atoms in a straight or branched chain, and examples of the alkyl group include methyl, ethyl, n-propyl (n_pr〇pyl), and isopropyl (ι-propyl). ), n-butyl (n-butyl), t-butyi, t-butyl, n-pentyl, 3-pentyl. aryl (ary 1)'' Any group comprising an aromatic ring or a fused rings system preferably having a carbon atom of 12. The phenyl group is an example of an aryl group. The aryl group may optionally be - for example, a halogen atom (eg, gas or bromine) 'alkyl" cycloalkyl, hydroxy, alkoxy 'amine' nitro, acylamin ,, carboxy and epoxy The carbonyl group (aik〇XyCarb〇ny 1)—either mono- or poly-substituted, respectively. The carboxylic acid residue refers to the slow-based C00H. "Wheat base" means an H-C0- or alkyl-CO- group wherein the alkyl group is as defined below. The brewing base preferably comprises a low alkyl group, and examples of the mercapto group include formyl 'acetyi', propyl group (pr〇pan〇y 1 ), 2-methylpropenyl group (2- Methylpr〇panoyl), butanoyl and pa 1mi toy 1; optionally ly substituted means that one or more of the groups mentioned in the previous 3002-5563A-PF 26 1357816 may be substituted by one or more Substituents, the substituents may be the same or different substituents, and with respect to the parent group being substituted, preferably one or more small molecules (eg, smaller than the largest molecule)

20%) of a substituent; suitable substituents include a halogen atom (eg alkyl 'cycloalkyl, hydroxy, alkoxy, amine, decylamino, aryl, aroylamino, carboxy, ring Alkoxycarbonyl 'aralk〇xyCarbonyl, heteroaralkoxycarbonyl, and optionally substituted carbamoyl, preferably in size as described above; pharmaceutically acceptable Refers to cells that are suitable for contact with humans and other animals within the scope of a sound examination and veterinary diagnosis without causing undue toxicity, irritation, allergic reactions and similar reactions, and having a reasonable benefit/risk ratio ( Benefit/risk rati "a pharmaceutically acceptable prodrug, a precursor to a compound that is suitable for use in contact with humans and pea-healed cells, within the scope of health and veterinary diagnostics. Does not cause undue toxicity, irritation, allergic reactions and similar reactions, and has a reasonable benefit/risk ratio, M-effective effects such as zwitterionic forms of the compound zwitteri〇nir, ",, nie forms)." prodrugs

By means of a compound in vivo (inviv 〇), it is converted into a parent compound of the above formula, which is, for example, by hydrolysis in the blood to achieve this. Anti-庵 ^ long time. Through metabolic cleavage, the functional groups are rapidly converted into a series of groups reactive with sulfhydryl groups in the body. Since the compound J? Xie cleavage group is easily cleaved in vivo, the compound I having such a group acts to drive the drug. A complete discussion of 3002-5563A-PF 27 1357816 related prodrugs is listed in Design of Prodrug, H. Bundgaard, ed., Elsevier, 1 985; Methods in Enzymo 1 ogy, K. Widder et al, Ed. 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 p.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 herein; "pharmaceutically acceptable salts" are meant to be relatively non-toxic, inorganic and organic acid addition salts, and base addition salts in the present invention. (base addition sa 1 ts) compound. These salts can be formulated in situ during the final isolation and purification of the compounds. In particular, the free base form of the purified compound is separately reacted with a suitable organic or inorganic acid, and then the salt is separated to form an acid addition salt. Reference s. M. Berge, e1: al..

Pharmaceutical Salts, J. Pharm. Sci., 66: p. 1-19 (1 977), incorporated herein by reference. After the acid compound (acid f〇rm) is separately reacted with an appropriate organic or inorganic reaction, the salt is separated, 3002-5.563A-PF 28 1357816 • A base addition salt can be formed. Base addition salts include pharmaceutically acceptable metal and amine salts. Examples of suitable acid addition salts are those formed by reaction with the following acids: hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid. Examples of suitable base addition salts are those formed by reaction with the following bases: sodium hydroxide (s〇dium hydr〇xide), potassium hydroxide and ammonium hydroxide (amm〇nium hydroxide) ° A better class of active agents are compounds of formula la. In some of the compounds of formula la, the methyl group of carbon 25 is a counterclockwise (S) structure; these compounds of the invention are salsa soaps and table salsa or derivatives thereof. In other compounds of the formula la, the methyl group of carbon 25 is a clockwise (R) structure, and the compounds of the present invention are isomeric glycosaminoglycans. The -OR in the above formula la may be selected from the following groups (unless otherwise attached): hydroxyl group, cathylate (ethoxycarbonyloxy), acetate, crotonic acid Succinate, cinnamate, ferulate, propirate, butyrate, valerate, isovaierate ,caproate _isocaproate, diethylacetate, octanate, decanoate, laurate, stem citrate (myristate), paimitate, stearate, benzoate, phenylacetate 3002-5563A-PF 29 1357816 (phenylacetate), phenylpropionate 'cinnamate, p-ni trobenzoyloxy, 3, 5-dinitrobenzoyloxy, p-benzoquinoneoxy (p-chlorobenzoyloxy) , 2, 4-di-chlorobenzoyloxy, Yue brewing stupid bromo-yloxy (p-bromobenzoy1oxy), inter-bromo-phenyl Yue brewing yloxy (m-bromobenzoyloxy), oxybenzone Yue Yue acyl oxygen (p-methoxybenzoyloxy), xylylene acyl (phthaly1), glycine sleep

(glycinate), alaninate, valinate, phenylalaninate, isoammonium acid salt (18〇1611 (:111 & 6), methyl sulfide Amorphate (111161; 111〇11111 & 16), argininate, asparaginate, aspartate, cysteine, Glutamate, histidinate, lysine salt __ (ysysinate) 'prolinate, serinate' butylamine (threoninate) , tryptophanate 'tyrosinate, fumarate or maleate. The compound of formula la and its pharmaceutically acceptable salt are especially preferred. The classes are as follows: Salsa soap dollar salsa soap ethyl formate (cathy late) salsa soap yuan acetate 3002-5563A-PF 30 1357816 尔萨息元素 ό 及其 and its pharmaceutically acceptable salt萨萨_萨四元甘胺酸 and its pharmaceutically acceptable salt 尔尔萨皂元 aminopropionic acid And a pharmaceutically acceptable salt thereof, salsa saponin and its pharmaceutically acceptable salt salsa soap phenylaminopropionate and pharmaceutically acceptable salt thereof Soap-based isoleucine salt and its pharmaceutically acceptable salt π

Salsa 4 yuan iso-methionine salt and its pharmaceutically acceptable salt table salsa soap table table salsa soap element ethyl formate (cathy iate) table 1 salsa soap yuan acetate table Salsa saponin and its pharmaceutically acceptable salts, salsa saponin and its pharmaceutically acceptable salts Acceptable salts, salsa saponin and its pharmaceutically acceptable salts, salsa phenyl aminopropionate and pharmaceutically acceptable salts thereof 4-membered isoleucine salt and pharmaceutically acceptable salt thereof, salsa saponin isomethionine salt and pharmaceutically acceptable salt thereof, saponin, saponin, saponin, saponin Ester (ca1;hylate) isoindole saponin acetate sulphate succinic acid succinate and pharmaceutically acceptable salts thereof isoindole saponin glycosides and pharmaceutically acceptable salts thereof Isocyanium sulphate aminopropionate and pharmaceutically acceptable salt thereof, iszide saponin valine and pharmaceutically acceptable salt thereof 3002-5563A-PF 31 1357816 Isoflavone phenylaminopropionate and pharmaceutically acceptable salt thereof, isoindole, isocyanine, and pharmaceutically acceptable salt thereof And its pharmaceutically acceptable salts, saponins, saponins, succinic acid, ethyl succinic acid, ethyl succinic acid, ethyl succinic acid, ethyl succinic acid Salts and pharmaceutically acceptable salts thereof, isoindole saponin glycosides and pharmaceutically acceptable salts thereof, and pharmaceutically acceptable salts thereof Salt isoforms and pharmaceutically acceptable salts thereof Isoleucine salt and pharmaceutically acceptable salt thereof, isoindole, isomethionine salt, and pharmaceutically acceptable salt thereof, relating to saponin (R is a sugar) compound of formula la The special priority is listed as the compound 1 ersa 4 yuan, the table (four) saponin, the qi saponin ^ disc table subtraction " ganyuan, each of the carbon atoms in the ... with 値0 a group in which the sugar group is selected from the group consisting of glucose, mannose, fructose, galactose 'maltose' fiber double enzyme 'severe sugar' rhamnose, xylose, allah + 'sea syrup, isoflavone, order sugar , lactose, galactose-glucose, glucose-arabinose, Oohu her sea 4 sugar 1 glucose 'rhamnose-glucose, glucose-glucose-glucose, grapefruit e-gumose _ paper plum sugar, mannose-glucose , glucose-(rhamnose)_glucose, glucosamine-(supplementary sugar)-rhamnose, glucose-(glucose)-glucose, galactose-series sugar lacto-lipid)-galactose and its deuterated C For example: acetylated derivatives.

3002-5563A-PF 32 1357816 Other examples of suitable activators include 16, 22-epoxy fecal solids _3 stone monool (16,22-ep〇xyCoprostan-3 no 〇〇, isoindole _ smi Lagenone), copropster(1) and its pharmaceutically acceptable prodrugs and salts. Composition and use

The present invention therefore provides a method of treating or preventing the following symptoms, including non-cognitive neurodegeneration, non-cognitive neuromuscular degeneration, motor neurosensory degeneration or receptor abnormalities or loss in the absence of cognition, neurological or neuromuscular damage ( In particular, but not exclusively, the particular disease conditions described above are included. The method comprises administering to the human or non-human animal an effective amount of an active agent (as defined herein) or a pharmaceutically acceptable salt thereof. The active agent can be administered in the form of a composition comprising the active agent and any suitable additional ingredients. The composition may be a pharmaceutical composition (agent), 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 invention, the invention provides a composition which is active to combat and treat non-cognitive neurodegeneration in humans and non-human animals, non-cognitive neuromuscular degeneration, motor neuropathy, or lack thereof Cognitive receptors are heterozygous, long-lasting, neurological or neuromuscular damage. The composition comprises an effective amount of an active agent compound. A "pharmaceutical composition" in the context of the present invention means an active agent, and a pharmaceutically acceptable vehicle, a diluent, an adjuvant, an excipient, or an excipient (Vehlcles). ) 'Example: Preservatives' fillers, decomposers, wetting agents 3002-5563A-PF 33 1357816 (wetting agents), emulsifiers, suspending agents, sweeteners, flavoring agents, perfuming agents , antibacterial agents 'ant i fungal agents, lubricanting agents and dispensing agents, the use of these additives depends on the mode of administration and dosage form. Items such as “food”, “food supplement” and “beverage,” have general meaning and are not limited to the formulation of pharmaceuticals. The dosage of the active agent is broad and depends on the severity of the symptoms of the condition to be treated or prevented. The choice of the appropriate dosage is a general, conventional technique that does not cause problems. For example, the dose of active agent may be greater than about 毫克 1 mg / kg body weight ' or such as ' greater than 0.3 mg / kg body weight, preferably administered once a day. More typically, the dosage will be between about 1 and 25 mg/kg. For example, the dosage is between about 1 and 10, preferably once a day. In the case of the human body, a convenient dose is about 70 to 700 grams per day. "Pharmaceutically acceptable dosage form" means that the compound φ or the dosage form of the composition 'includes tablets, dragees, powders, elixirs, syrups, liquid preparations (1 iqUid preparations), Including suspensions, sprays, inhalers, tablets, lozenges, emulsions, granules, capsules and suppositories. Liquid preparations are also used for injection, including liposome preparations. (liposome preparations). For related techniques and detailed description, please refer to Remington, Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, latest edition. « In general, the reference to a specific class of compounds is described here at 3002-5563A- PF 34 1357816 An illustration of a mixture of two or more such compounds in its scope. The present invention provides (i) non-cognitive neurodegeneration, which is caused by human or non-human animals after suffering from or susceptible to: (丨丨) Non-cognitive neuromuscular degeneration (丨丨丨) motor sensory neurodegeneration, or (iv) lack of cognitive receptor impairment or loss, nerves and gods Treatment for muscle defects, including Parkinson's disease (P〇stencephal i tic Parkinsonism), depression (depressi〇n), schizophrenia (schizophrenia), muscle dystrophy (including skin) Scapular limb progressive muscular atrophy, Du Xian's muscle dystrophy, Becker's muscle dystrophy and Brucella muscle dystrophy, Fuch's dystrophy, tonic muscular atrophy, corneal dystrophy 'Reflective sympathetic dystrophy, neurovascular malnutrition, myasthenia gravis' Lambert Eton, Huntington's disease, motor neuron disease (including amyotrophic lateral sclerosis, multiple sclerosis, postural Hypotension' Traumatic neurodegeneration after a stroke or accident (eg, trauma to the head or spinal nerves), Batten's disease, Cockayne syndrome, Down's syndrome ( Down syndrome) 'c〇rticobasal gangl ionic degeneration' multiple system atrophy, brain atrophy (cerebral atr Ophy), olivopontocerebellar atrophy, dentatorubral atrophy, pallidoluysian atrophy, spinal cord and spinal dystrophy (spinobulbar atrophy), optic neuritis (optic) Neuritis), subacute sclerosing encephalitis (sclerosing pan-encephalitis 35

3002-5563A-PF 1357816 (SSPE)), attention deficit disorder, post-viral encephal it is, post-poliomyelitis syndrome, Fahr's Syndrome, Joubert syndrome, Guillain-Barre syndrome, lissencephaly, Moyamoya disease, neur〇nal migration disorders > autism syndrome, more Facial amine amide

(polyglutamine disease), Niemann Pick disease 'progressive multifocal 1eukoencepha1opathy, pseudotumor cerebri' Refsum disease, Waddenbo Zellweger syndrome, supranuclear palsy, Friedreich's ataxia, spinocere bellar ataxia type 2, Reiter syndrome ( Rhett syndrome), Shy-Drager syndrome, tuberous sclerosis, pick, s disease, chronic fatigue syndrome, neuropathies (including hereditary neuropathy) Neuropathy), diabetic neuropathy and mitotic neuropathy, prion-based neurodegeneration (including Creutzfeldt-Jakob disease (CJD), variant CJD) (variant CJD) 'New variant CJD , Mad 3002-5563A-PF 36 1357816 Bovine spongiform encephalopathy (BSE), family Genetic insomnia (GSS), fatal family insomnia (FFI), kuru and

Alper's syndrome), Joseph's disease, acute disseminated encephalomyelitis 'arachn〇iditis, vascular injury of the central nervous system (vascular iesi〇ns) 〇f the

Central nervous system), loss of extreme neuronal function (1〇33 of extremity neuronal function), Charcot-Marie-Tooth disease, susceptibility to heart failure, asthma (asthma) , as well as macular degeneration (macuiar degenerati〇n). The invention thus includes a method of treating or preventing a disease or condition afflicted or predisposed by a human or non-human animal as described above, the method comprising administering to the individual or non-human animal an active agent as defined herein, and the active agent It is also used in the preparation of compositions for the treatment or prevention described. Parkinson's disease after Parkinson's encephalitis, postural hypotension autism 'chronic fatigue syndrome, myasthenia gravis, with Lambert _ Eaton: commensurate, and any other related to the present invention and already in It is disclosed in the prior art: In the symptoms of its treatment method, 'the invention is subject to the book of the book, the symptoms of non-cognitive dissociation are not present, 'for non-cognitive neurodegeneration, non-cognitive nerves', meat degradation', motor sensory nerve degeneration or lack of Cognitive Absence of Absent Receptors: In the case of loss and also symptoms such as sacral muscle defects, 'any cognitive abnormalities presented by the individual and treated are secondary or subsidized. The preparation of the compound used in the present invention is the same as that of the 4th glutinous rice.

3002-5563A-PF 37 1357816 Raw materials available on the 'Supply' include Sigma Aldrich, I^e seareh Plus Inc• and Steraloids Inc. The preparation of these materials is also described in the literature (for example, the preparation of the table salsa soap is described in JACS p. 5225 (1 959)). The table salsa soap element can be obtained by reducing the sarsasapogenone via a hydrogen storage alloy reducing agent (hydrogen reduction agent). The sarsasapogenone can be obtained by the method of Ujis et al., Steroids, 1 993' 58' 387-389. Lu as the starting material of unsubstituted saponin and saponin is also present in some natural plants, especially the genus Asparagus, Asparagus, Anemarrhena, Yucca Or the genus Agave. The isoindole or salsa soap element used in the present invention may be an extract of the genus genus, asparagus, genus, genus, yucca or agave, or a dry powdery plant. raw material. Methods of preparing active agents are well known in the art. Reference can be made to the examples in WO-A-02/079221 (Examples 5 to 6 of which describe the salicinic acid ethyl ester, the table salsa soap ethyl formate, the table salsa soap 70 amber Acid salt, ethyl sulphate, ethyl acetate, episarsasapogenin glycinate hydrochloride, salsa saponin, glycosyl hydrochloride, hydrochloric acid, salicylate Amino acid salt, epismilagenin L-alaninate, acesulfame hydrochloride, lysine hydrochloride, acetophenone hydrochloride, left flavonoid Isoleucine salt, hydrochloric acid, singularly, saponin, left-form amino-propionate, and hydrochloric acid, divorced soap, 3002-5563A-PF 38 1357816, glyphate left-type methionine salt). Compounds of formula la (except those having 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 〇jj at position 3 is reacted with a compound of formula LR, r is selected from an alkylcarbonyl group; an aerobic group, an amidino group; or an arylcarbonyl group; Let any alkyl group be arbitrarily aryl 'amino' monoalkylamine (m〇n〇_alky hamin〇), dialkyl-amino-carboxylic acid residue (-c〇 〇H), or any resulting knot-coupling substitution; and L is a leaving group (ieaving gr0Up), suitable for nucleophilic substitution. The L-R compound may be a carboxylic acid' or, where appropriate, an anhydride or a syrylate (e.g., a chlorinated chloride). For example, when R is a cathylate (ethoxycarbonyl) group, the L-R compound may suitably be ethyl chloroformate °

This reaction is suitably carried out in an assay (for example: U pyridine) and is optionally carried out in the presence of an acid such as hydrochloric acid. The details of the nucleophilic substitution reaction are conventional techniques. Reference can be made to the example RC Larock. , in Comprehensive Organic Transformations, VCH publishers, 1989. The dihydrosarsasapogenin can be obtained by the method described by Marker and Rohrmann (1939), Sterol LIII; the side chain structure of Salsa soap is visible in J. Am. Chem. Soc. 61, ρρ 846-851. Using the method described in Scheer et al., (1955), the carbon of 16,22-3002-5563A-PF 39 1357816 epoxy manure--3-ol can be obtained. 25 isomerism can be seen in J. Am. Chem. Soc. 77, ρρ 64 646. The reactions described herein must protect the functional groups of the reaction (which need to be present in the final product, such as hydroxyl, carboxyl or amine groups) to avoid their involvement in unnecessary reactions. Traditional protecting groups can be used in accordance with standard procedures. For related content, please refer to TW Green and PGM Wuts,in “Protective

Groups in Organic Chemistry", John Wiley & Sons, 1991; JFW McOmie in Protective Groups in Organic

Chemistry", Plenum Press, 1 973. In order to protect the amino substituents in the LR compound of formula (wherein r is an amino group substitution), it is preferred to use a pyrocarbonyl protecting group. Through the action of this protecting group, in the synthesis step The amine group functions as an alk〇xycarb〇nylamino group until deprotection in an acidic dry solvent. The compound thus obtained can be re-recovered from the reaction mixture by conventional means. For example, the solvent in the reaction mixture is removed by steaming, or, if necessary, after the solvent in the reaction mixture is removed by steaming, the residue is poured into water, followed by extraction with a water-soluble solvent and distillation to remove the extract. The solvent can then be re-acquired. Further, if necessary, the product can be further purified using conventional techniques, examples of which are recrystallisation, reprecipitation or various chromatographic techniques. In particular, column chromatography or preparative thin layer chromatography (preparative thin layer 3002-5563A-PF 40 1357816 Chromatography) ° t Discussion of the basis of activity (Discussic) n Qf the Basis kr the

Activity) The therapeutic functions underlying the present invention are derived from a number of new observations, which are described in detail in the following examples. In order to understand the basic principles of the present invention, these observations will be summarized herein, and explain how to predict the claimed therapeutic activities of the present invention under the scope of the active agents defined above, 菝 菝 菝 菝 皂 皂 , , The loss of muscarinic acetylcholine receptors and adrenergic receptors (adrenoce Ptors) in the cells of Salsa soap and salsa soap cells Such receptors are expressed in vitro. These results show that these compounds repair receptors to a normal extent of cellular receptor loss (Example 1). In vitro (in vitro) test, salsa soap, table salsa φ elemental ethyl formate, table salsa soap yuan 'isolated 菝 皂 皂 甘 以及 以及 以及 以及 以及 以及Chemically induced neurodegeneration of rat cortical neurons. These results show that these compounds are neuroprotective compounds in vitro as well as preventing neurodegeneration and neurological deficits (Example 2) ° In vitro experiments, salsa soap, heterosexual dividends '16 22-epoxy fecal solid-l-alcohol, smi lagenone, isoindole, sulphate, glycosylamine and fecal sterol reverse the chemically-induced nerves of rat cortical neurons Degradation ^ These results show that 3002-5563A-PF 41 1357816 S Hai compounds reverse sensory neurodegeneration and neurological deficits in vitro (Example 3). Indigo-saponin reverses chemically-induced apoptosis in neurons (apopt〇S1S), demonstrating that this compound is resistant to apoptosis in vitro 111:1-30 (^1: 〇1:1(:) And neuroprotective (Example 4). In vitro, isoindole and salsa soap increased axonal production of rat cortical nerve 7C (neurite 〇utgr〇wth) (number of axons and Axon branches), demonstrating their neurotrophic effects in vitro (Example 5). In in vitro tests of mesenchephalic dopaminergic neurones, isoflavones and salsa soap Meta-prevention and reversal of neurotoxin-induced neurodegeneration. The neurotoxin is methyl _4_phenylpyridine (Bu 1^1:1^ Bu 411^1^1?71^(^11111111(^ ?? +)) These results demonstrate that these compounds prevent and reverse neurodegeneration and neurological deficits in vitro (Examples 6 and 7). In vitro, salsa soap and isoindole saponins reversed rats Chemically induced in spinal motor neurons (spinal m〇t〇r neurones) Neurodegeneration. These results demonstrate that these compounds reverse neuronal degeneration and neurological deficits in motoneurons in vitro (Example 8). In vivo cognitive ability test (c〇gnitive abi lity test), Thrall Sa soap, table salsa saponin ethyl citrate and iso-saponin will reduce the false response in aged rats, this result is related to the administration of compounds in aged rats, the poison in the rat brain Alkali acetylcholine was associated with increased physique. These results demonstrate that these compounds reverse 3002-5563A-PF 42 1357816 nerve defects in vivo (Example 9). Isoniazid and salsa soap reversal of aging animals Reduction of muscarinic acetylcholine receptors and dopamine receptors and reduction of brain derived neurotrophic factor (BDNF) • These results demonstrate that the compound reverses motor sensory neurodegeneration and nerves in vivo Defects and neurotrophic properties (Example 9). In the in vivo cognitive ability test (c〇gnitive abilitytest), table salsa soap element ethyl formate, Sa Essence of Ethyl Ethyl Ester, Table Salsa Soap and Epirubicin will reduce exposure to neurotoxic agents (ib〇tenic aCid and amyloid) The number of false responses in young rats, and increased the density of muscarinic acetylcholine receptors in the brain. These results demonstrate that these compounds reverse the neurological deficit in vivo (Example 1). In a mouse model of amyotrophic lateral sclerosis and Charcot-Marie-Dies disease, isoforms and salsa saponins increase mouse survival and φ improve motor sensory neurodegeneration and nerves Defect (Example 丨丨). In short, these compounds slow or reverse the regression of certain neurons. These include: reversal of deleterious changes in the cell body, atrophy of neuronal extension (axons), and decreased release of neurotrophic factors such as brain-derived neurotrophic factor, nerve growth factor (NGF), Neurotrophin-3 (NT-3), neurotrophins such as neurotrophin 4/5 (NT4/5), and TGF-Θ super-family neur〇tr〇phic fact〇 Rsx eg: ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), and god 3002-5563A-PF 43 1357816

Metatoxicity or death (apoptosis). These compounds have enormous neuroprotective properties that stimulate axon formation and prevent neurotoxicity. These compounds also slow or reverse the reduction in cholinergic and dopaminergic functions, for example, reducing the density of muscarinic acetophenone 2 and dopamine receptors. In addition, we have found that the reversal of neuroprotection and receptor loss is an active regulation that reverses the worsening state of the past into a normal or young state, preventing continued deterioration. In addition, we found that the reversal of the apoptotic effect of this compound appears to be regulated in cell life (non-neoplasticd〇main) and may cause neoplasia. Based on the above data, The activity related to the disease state is listed in the present specification. In addition, the above data shows that there may be no serious or life-threatening side effects such as cancer, and the active agent is typically non-estrogen (n 〇n_〇estr〇genic) Active Agents The above-described prior art shows a reasonable basis for the prediction of the extension of the above observations, as well as the inclusion of the active agent, within the project, the relevant chemical structure Reasonable prediction of therapeutic activity with derivatives. In conventional techniques and pharmacology, sugars, esters and other groups in place on the steroid molecule (especially at positions 3 and/or 26), in vivo It can be easily cleaved by hydrolysis, and the other carbon atoms of the molecule also have the same effect as the 'month B. In addition, in the conventional technology and pharmacology, according to the active agent The pH of the body fluid present, as used herein, "active agent, range of salts, free acid and free base are immediately converted into each other in vivo. Furthermore, it is well known to formulate pendant substituents in the form of a broad form. The complex alkane 3002-5563A-PF 44 1357816, complex carb〇n skeleton, is present and generally does not adversely affect the pharmacological activity of the structure, especially when the pendant group is smaller than the size of the entire molecule. For all of these reasons, the scope of the patent application for the beneficial pharmacological activity set forth in this application is appropriate, and the test data collected and presented herein is the basis for reasonable and reliable prediction. Without wishing to be bound by theory, it is generally believed One of the active agents is used to increase the ability of neurotrophic factors (eg, brain-derived neurotrophic factors and/or nerve growth factors or their receptors) to synthesize, release, or reduce the rate of degradation. These are on growth factors. The effect may be due to the action of the compound on the cytosolic or nuclear receptor (cytosolic or nuclear recept〇r), or the association of the compound to the promotion Immediately after the promoter region, the growth rate of the messenger ribonucleic acid (mRNA) is produced, or the result of adding another material factor. In addition, the compound seems to regulate the receptor, for example, some Compounds • Prevent or reverse the loss of muscarinic choline and dopamine receptors in the brain. Generally, this compound exerts its effect by correcting the deficiency in the number or function of the receptor or the rate of conversion. The above and other objects, features, and advantages will be more apparent and understood. The preferred embodiments of the invention are described in the following description. Ethyl isophthalic acid ethyl sulphate, salsa soap carboxylic acid 3002-5563A-PF 45 1357816 ethyl ester, table salsa saponin ethyl citrate, table salsa soap succinate, different菝 皂 皂 醋酸 醋酸 与 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔Impact. Wherein, for the m receptor, the Chinese hamster ovary cells are trans-charged by a vector, or, for the absence of the 2 and m3 receptors, the Chinese sputum oxygen or nest cells are co-metastatically infected with the vector (co -t ran s fee ted). The results are shown below in Table 1 and in the culture of Chinese hamster ovary cells during a medium-transfer infection, given epirubicin, ethyl sulphate, ethyl salicylate, and salsa saponin. Ethyl ester, table salsa soap succinate, and each compound of Salsa, prevent the reduction of the number of m receptors. For cold 2 and adult, the density of m3 steroids did not change during the culture of Chinese hamster ovary cells cotransfected with this vector; the density of cold 2 adrenergic receptors decreased. The isoforms of the saponin acetate (Fig. 1:) were not significantly modified = the density of the m3 receptor; it was expected to significantly prevent the reduction of the w-adrenergic receptor. Table and table different deeds 4 Gan Yuan m b a!, Salsa 4 yuan love B cool, 矣 ethyl ester, table salsa soap succinate, 盥 藤 藤 藤 straight, table salsa saponin The effect of the repair of formic acid 〃 For the m-type acetylcholine receptor density _ compound surface difference by the saponin saponin ethyl sulphate salsa soap a pot ΓΕΤϊ 1 agricultural degree (micromolar 7 ~ ϋΐΓ ^ ^ Γ ΤΓ ~ ~ ~^ Activity (activity) ++

Therefore, this experiment shows that the table is different from ethyl sulphate, ethyl sulphate, ethyl sulphate, ethyl sulphate, ethyl sulphate, table salsa saponin A' table salsa soap abalone 3002-5563A-PF 46 /010 Acid salt, main field # can prevent receptors can also repair the recipient, reduce the saponin acetate and salsa soap: decrease with time 'at the same time when the number of receptors in the cell to normal. Example 2: = Table Salsa soap element formic acid ethyl vinegar, table salsa soap cell table \ and neuroprotective effect of heterosexual saponin in neurons B / research purpose in the detection of salsa Yuan, Table Salsa, elemental formic acid, 曰' table salsa Xiyuan, the difference between the different 娄 娄 娄 与 与 异 异 对于 对于 对于 对于 对于 对于 对于 初级 初级 初级 初级 初级 初级 初级 初级 初级 初级 初级 初级 初级 大鼠 大鼠 大鼠 大鼠 大鼠 大鼠 大鼠 大鼠 大鼠The impact of the rate /. ❹ initiates culture of rat cortical neurons for 1G days; on day 1G, the medium is changed to Serum-free defined medium. On the 12th day, 24 hours before exposure to glutamate, the medium was washed off and tested with a positive control group (positlve c〇ntr〇1) (10,000-〇estradiol). Compound (Salsa soap, table salsa soap element ethyl formate, table salsa soap A 'isolated saponin and isoindole saponin) or excipient control group (dimethyl Replace the fresh medium with Aachen (DMS〇), 25%) or the negative control group (diosgenin). The culture was exposed to glutamate on day 13. After the incubation period, i.e., after exposure to glutamate for 24 hours, the medium was washed off and placed in a fresh medium, supplemented with an appropriate compound or vehicle to evaluate its protective effect. The survival rate of neuronal cells can be assessed by measuring the activity of lactate dehydration (LDH). The release of active in the medium is given to the test compound or to the glutamate and test compound 24 3002-5563A-PF 47 1357816

After an hour, it was measured using a CytoTT 96 non-radioactive kit (CytnT L〇1〇x 96 non-radioactive kit) and quantified when the absorbance wavelength (wavpi eiength absorbance) was 450 nm. Cortical neurons were significantly degraded after exposure of the rat primary cortical culture to glutamate, and 24 hours after treatment, it was demonstrated that cortical neurons were increased by dehydrogenation of the pore acid to the medium.

The pre-treatment of the primary cortical culture μ with the compound also significantly reduced the neurodegeneration induced by the lysamine (Fig. 2). Table 2 - Salsa soap, table salsa saponin ethyl formate, table salsa soap, singularity and isoindole saponin for the effects of glutamate-induced neurodegeneration, Mean weight of the condition ±±^^~ (Meanis. e. m) (%) Control group 100 + glutamate 66 + 3 + face amine + salsa soap (3〇nM) 79 ± 3 Control group ϊοό + glutamate 65+3 decanoic acid salt + table 瘙尔萨 soap element ethyl formate (30nM) 74±3 control group ϊοό + glutamate 68±4 + crocodamine + Table Salsa soap element (30nM) 88+3 Tanning group Ϊ 00 ~~ + glutamate ~- 71±2 + glutamate + epiruthenium saponin (30nM) 79+2 Control group 100 + glutamate 68+4 + glutamate + isoindole saponin (3〇nM) 91+4 control group 100 ~ ~ + glutamate 68 ± 4 + glutamate + soap ( 30nM) Negative control group 72±4 'In the in vitro test of rat primary cortical neurons, salsa soap, 3002-5563A-PF 48 1357816 table salsa saponin ethyl citrate, table salsa soap Yuan's isoforms, saponins, and saponins, all have obvious neuroprotective effects. Salt neurodegeneration caused the phenomenon. Example 3 • Salsa soap, different borrowed sugar, 16,22-epoxy fecal solid-3/3-alcohol, isodecyl sulphonate, isoindole sulphate Reversal of neurodegeneration in neurons with fecal sterol as described above, exposure to glutamate (100 micromolar (#M); 10 ® minutes) of rat primary cortical culture, after 24 hours It was found that the activity of dehydrogenation of lactic acid increased, indicating significant neurodegeneration. Compared with glutamate-exposed neurons, the activity of dehydrogenation of lactate was significantly reduced after exposure to glutamine and given 7 7 /3 -estradiol, which showed significant neuroprotective effects. . Similarly, compared with the glutamate-exposed neurons, the salsa soap, isoindole, 1,6,22_epoxy fecal solid-3/3-ol, isoindole soap After the ketone, the isoindole, the glucosamine glycolate and the sterol, the lactic acid dehydrogenation activity was significantly reduced, which showed significant neuroprotective effects (Table 3). Table 3 - Effect of different compounds on cortical neurons pre-exposed to glutamate. Mean ± standard error average (Meanis. e. m) (%) Control group 100 ± 4 glutamate [100/zM] 66+2 glutamate +17々-estradiol [3nM] 69+2 glutamate +17/3-estradiol [30 he] 75±5 control group 100±1 glutamate [100 #M] 67±3 glutamate + salsa soap element [3nM] 101+3 faceted acid salt + salsa soap element [30nM] 112+1 3002-5563A-PF 49 1357816 glutamate + Isophthalic acid [3nM] 109±6 glutamate + isoindole saponin [30nM] 104±1 control group 100±8 glutamate [100#M] 40±1 glutamate + soapy [30nM, negative control group] 49+6 control group 100±5 glutamate [100//M] 64±4 glutamate+16, 22-epoxy fecal solid-3/3-ol [3nM] 114+7 glutamate +16, 22-epoxy fecal solid-3 cold-alcohol [30nM] 134±7 glutamate + isoindole saponin [3nM] 119±7 glutamic acid Salt + isoindole saponin [30nM] 119±4 control group 100±4 glutamate [100//M] 58±3 glutamate + isophthalic acid saponin glycosaminoglycan [3nM 117±4 faceted amine salt + isophthalic acid saponin glycine Salt [30nM] 141±6 glutamate + fecal sterol [3nM] 126±5 glutamate + fecal sterol [30nM] 116±4 In short, salsa soap, isoindole, 16, 22-epoxy fecal solid-3/5-alcohol, isoindole, saponin hydrochloride and fecal sterol reverse the surface of rat primary cortical neurons The induced neurodegeneration manifests its therapeutic potential for neurodegenerative diseases. Example 4

The anti-apoptotic effect of isoindole saponin in neurons The purpose of this study was to detect caspase-3 in the primary cortical culture of rats. Anti-apoptotic effect on (cells > markers of weekly death). Primary culture of cortical neurons Culture rat cortical neurons for 6 days, add glutamate (100 μmol; 10 min) on day 6, then wash off the culture and replace the medium with Isophthalic acid or excipient-controlled group (dimethyl sulfoxide, 〇. 25%) 3002-5563A-PF 50 1357816 of fresh medium 'after 6 hours, the measurement of thiocysteine peptone-3 Activity to assess the condition of apoptosis. From colorimetric caspase-3 substrate, acetamidine-aspartate-glutamate-valine-aspartate p-nitroanilide (acety) The activity of thiocysteine peptone-3 was detected by interrupting p-nitroaniline on Asp-Glu-Val-Asp p-nitroani1ide. p-Nitroaniline has a high absorption at 405 nM. The relative thiocysteine protein plum-3 activity was measured by optical density. In addition to normalizing the relative activity of thiocysteine protein plum-3, the protein concentration of the sample can also be measured by optical density (Duet al., J Neurochem., 69, 1382-1388, 1997; Sawada et al., Faseb J., 14, 1202-1214, 2000). Isoglutinin-induced reversal of alanine-induced increase in thiocysteine-3 activity in rat primary cortical neurons, indicating that saponins have an anti-apoptotic effect (Table 4). The serotonin-induced thiocysteine protein 晦-3 activity in cortical neurons

Condition thiocysteine protein marinating activity (% of control group) ΟΟ ΟΟ "

+ glutamate + isoindole (3〇〇nnn) Example 5 Neurodegenerative diseases are characterized by a gradual loss of neurons and a decrease in neuronal processes (axons). Agents that can trigger axon production can be Promotes the connection between neurons and improves the symptoms of neurodegeneration (Katzman illusion.,

Faseb J., 5, 278-286, 1991). 3002-5563Α-ΡΓ 51 1357816 Exposure of rat primary cortical neurons to estradiol (〇·3, 3, 30 pM) significantly increased the length of axons present (Table 5), and the primary cortical neurons of rats Exposure to 17/3-estradiol (3,30 pM) significantly increased the percentage of neurons expressing axons (Table 6). Exposure of rat primary cortical neurons to isoforms and salsa soap (0.3, 3, 30 pM) significantly increased the length of axons present and the percentage of neurons expressing axons (Table) 5 and 6). All in all, the different sugars and salsa soaps have a nutritional effect on the body in vitro. Table 5 - Measurement of the effect of 17/3-estradiol, isoindole, and salsa soap on axon length using optical micrometry. Conditional length control group 100 ± 4 17 ^ - female Glycol (0·3ρΜ) 154±5 17/3-estradiol (3pM) 163±4 17/5-estradiol (30卩1^) 183±5 isoindole saponin (〇·3ρΜ) 159+5 菝 菝 皂 甘 ( (3ρΜ) 190±8 菝 菝 皂 甘 204 204 204 204 204 204 204 204 204 204 204 204 204 204 204 204 204 204 204 204 204 204 204 萨尔 萨尔 萨尔 萨尔 萨尔 萨尔 197 197 197 197 197 197 197 197 197 197 197 197 197 197 197 5 Salsa soap (30ρΜ) 211±6

Table 6-17/3-Estradiol, isoindole saponin and salsa saponin on the number of neurons expressing axons Condition number control group 47+2 17 call-estradiol (0. 3ρΜ 48+2 17yS-estradiol (3ρΜ) 60±2 17/3-estradiol (30ρΜ) 59±2 isoindole saponin (0.3ρΜ) 63±2 isoindole saponin (3ρΜ) 63±2 isoindole saponin (30ρΜ) 66±2 3002-5563A-PF 52 1357816 salsa soap (0.3pM) 55±2 salsa soap (3pM) 61±1 salsa soap (30pM) 62±2 Example 6 In a model of Parkinson's disease in vitro, isoflavin and melabinol preventive neurons in the midbrain (mesencephai ic) dopaminergic neurons in rats exposed to the nerve Neurode degeneration (neurot〇xin), neuronal degeneration after 1_mercapto_4_phenylindole ratio (MPP+). By neurotoxin '-methyl-4-phenylpyridine, 1-mercapto-4

-I,2,3,6-tetrahydro π H:(I-methyl-4-phenyl-l,2,3,6-tetrahydropyridine' MPTP) metabolite-induced damage in neurodegenerative diseases (eg Pa In the case of Jinsen's disease, degeneration of striatum dopaminergic neurones (Mytinlineou et al., Science, 225, 529-531, 1984). The most significant biochemical changes caused by this toxin include dopamine and its metabolites in the substantia nigra pars compacta and caudate nucleus (Burns et al., Proc Natl Acad Sci USA·, 80 , 4546-4550, 1983), and a reduction in dopamine uptake in the manufacture of striatum synapses (Heikkia et al., J Neurochem., 44, 310-313, 1985). Compared with the 1-methyl-4-phenylpyridine group alone, pretreatment with doxaminergic neurons and salsa soap can significantly reduce exposure to specific dopaminergic neurotoxins. Neuronal death after diterpene-4-phenylpyridine (2 μ Μ). Glial cell line-derived neurotrophic factor (GDNF) 3002-5563A-PF 53 1357816 Both molecules related to brain-derived neurotrophic factor and neuronal growth were used as positive control groups. The survival of neurons was significantly increased by pretreatment with isoforms and salsa soaps compared to neurons exposed to 1-mercapto-4_phenylpyridine alone (Table 7). Table 7 - E, the source of the neurotrophic factor and the glial cell neurotrophic factor, isoindole, and salsa soap pretreatment for dopaminergic nerves exposed to 1-methyl-4-phenylpyridine Effect of element _ conditional survival control group 100+3 +1_methyl-4 phenylpyridine----- 55+3 & glial cell neurotrophic factor (〇. 17πΜ, 122+7 卜 甲基 methyl 4 base D than bite (2^^ extracting saponin (3〇ηΜ) 98+4 +1-methyl 4 base D than biting saponin (3〇ηΜ) 89+3 Parkinson's disease pattern in vitro Among them, pretreatment with saponins and salsa soap can significantly prevent neuronal degeneration after exposure to specific dopaminergic neurotoxin, methyl-4-phenylpyridine, and prove its neuroprotective effect. Example 7 In a model of Parkinson's disease in vitro, heteroglycemic saponins and salsa soaps also reversed the dopaminergic neurons of the atmospheric midbrain during exposure to the neurotoxin, methyl-4-phenylpyridine (3), After the neurodegeneration produced, compared with the 丨-methylphenylpyridine group alone, treated with saponins and salsa soap Dopaminergic neurons, which reduce the death of neural crests after exposure to a specific neurotoxin, methyl + phenyl bite (Mpp+) (2 " M). Glial neurotrophic factors and brain-derived neurotrophic factors, and nerves The molecule related to the growth of the element, with the 17 stone _ female 23002-5563A-PF 54 leaven as a positive control group. 盥 /, early exposure to 1-mercapto-4-phenylpyridine than the neural crest, given Survival of isoforms plus neurons (Table 8) β, 70 and salsa soap elements will be significantly increased, salsa soap and 17 lux-estradiol glial cell neurotrophic factor, isoindole The influence of the element on the dopaminergic energy of Tailu in the methyl-4-phenylpyridine

Table 8 - Giving brain-derived neurotrophic factor fish

+ 甲基methyl-4-phenyl 1- & glial cell neurotrophic factor early rn 17 ^ s nutrient factor (1. 85nM) 丄1 _ Tian Gan J nLL.A/Λ~~ΓΓΓ——:

Exposure to 1-methyl-4-cylinder ΠΗ·-* T soil 4 base [] bite not only caused a significant decrease in the amount of dopaminergic energy, but also reduced the percentage of axons. This study shows that the different ratios of dimethoate and salsa 4 in vitro significantly increase the number of axons of neuronal S f 9_isosarsal soap, for exposure to diterpenoids + benzene regulations (2 #M) (Table 9), these results show that the compound reverses motor neuron degeneration. Conditions -... Axon percentage control group __ 41±4 +1-mercapto-4-phenylpyridyl (2 // M) ------ 27±5 +1-methyl-4-phenyl Batch D (2#M) + Iso-saponin (〇〇3nM) 41±4 + memethyl-4-phenylpyridine (2 // M) + salsa 43±4 Example 8 Salsa Neuroprotective effects of saponins and xenobiotics in spinal motor neurons The purpose of this study was to examine salsa saponins and isoindole saponins in rats with primary spinal motor motility exposed to glutamate Meta-survival, 3002-5563A-PF 55 1357816 It is known that this motor neurodegenerative pattern can cause neurodegeneration. The control group was positive for 17 7 _ estradiol and brain-derived neurotrophic factor. Primary cultures of spinal motor neurons Prepare rat motor neurons according to the method described in Martinou et al., Neuron, 8, 737-744, 1992, remove media on day 10, and specify at 37 °C. Culture medium was exposed to glutamate (4 micromolar) for 10 minutes in the medium. After exposure to glutamate, the culture was washed with Dulbecco modified Eagle med i um at 37 ° C and placed in fresh medium containing the test compound. After 48 hours, the degree of degeneration of spinal motor neurons was determined by measuring the dehydrogenation of lactic acid released into the above medium. Results After exposure to glutamate, 48 hours of post-treatment, an increase in dehydrogenation of lactate into the medium showed significant deterioration of the primary spinal motor neurons in rats.

Rat primary spinal motor neurons were treated with salsa soap or isoforms for 48 hours, and neurite-induced neurodegeneration was significantly reduced (Table 10). Table 10 - Effect of salsa soap and isoindole on the neurodegeneration induced by glutamate in spinal motor neurons. Neurodegenerative control group + dimethyl sulfoxide [0. 25%] 100 +1 glutamate [4 micromolar] + dimethyl sulfoxide [0. 25%] 94+1 glutamate + brain-derived neurotrophic factor [3nM] 148+8 glutamate + 17 stone -Estradiol [0· 03nM] 102+2 glutamate +170-estradiol [3ηΜ] 110±1 glutamate +17/3-estradiol [30〇1^] 116±6 3002 -5563A-PF 56 1357816 glutamate + salsa soap [0. 03nMJ 123+2 glutamate + salsa soap bnM] 137 ± 1 sulphate + salsa soap [300nM ] 136±6 glutamate + isoindole saponin [0. 〇3nM] 128+4 glutamate + iso-saponin [3nM] 154+1 glutamate + isoindole甘元 [300nM] 144±4 In this in vitro motor neurodegenerative model, salsa soap and heterosexual saponins reversed the neurodegeneration induced by faceamine in rat spinal motor neurons. Example 9

In the latter half of life (about 40 years old in humans), the density of neurons in the brain is reduced (Selkoe, D J, Sci. Am. 267, 134-U2, 1 9 9 2). Changes in cortical function are due to a decrease in the number of neurons, which are reduced in interconnection, neurotrophins (eg, brain-derived neurotrophic factor; Bothwel1, M, Functional interactions of neurotrophins and neurotrophin receptors, Annu. Rev. Meurosci·' 18' Reduction of 223-253,1 995), decreased receptor density (test and nicotinic receptors) and/or reduced binding function in the cortical region (Rinne et al., Brain Res., 336, 19) -25, 1985; Selkoe, 〇J' Sci. Am. 267, 134-142, 1992). In addition, older rats (Biegon et al., Neurobio 1. Aging·, 10, 305-31 0, 1 989) and humans (Rinne et al., Brain Res., 336, 19-25) , 1985) The hippocampus (1^ mouth 〇〇 & 111 mouth 115) (Heart 犷 &11; 1 ^, ^ 16 〇 11 · Ageing Dev., 78, 221-239, 1995) and striatum In the striatum, the binding of the muscarinic acetylcholine receptor is markedly reduced. In addition, in Alzheimer's disease, 'the activity of bile test is reduced with amyloid plaque deposition 3002-5563A-PF 57 1357816 (amyloid β plaque deposition) (von der Kammer et al Biochem. Soc. Symp. 13 卜 140 , 200 1) related. Other neurodegenerative diseases, such as Parkinson's disease, exhibit a characteristic of reduced dopaminergic activity (Drukarch et al., Expert. Opin. Investig. Drugs 10, 1855-1868, 2001). Oral administration to elderly rats (SpragUe_J) awley rats, 2 months old) Salsa soap Yuan's table salsa soap element ethyl formate or isoindole, between two or three months It will reverse the characteristics that will change during the aging process, such as: learning and memory deficits - muscarinic acetylcholine and dopamine receptor reduction and neurotrophin brain-derived neurotrophic factor reduction. The old rats were divided into different groups' one group as the control group, and the other groups were given salsa soap yuan, table salsa soap element ethyl formate or isoindole saponin (18 mg kg -1 day -) , n=1〇) 2_3 months. Another group of control groups = young rats that were not administered. Each dose of the drug is mixed in a minimum amount of food, and each rat is fed separately each morning.

The Y_maze apparatus is used for learning and memory testing. On the floor of each arm of the Y-type electric maze, when there is a row of copper rods, the current is supplied to the copper rods and adjusted to the required voltage. Each arm is 45 cm long and has a 15 watt (1) lamp at its end. This light turns on when needed. J,,·°乐<3 months later, according to the following method, 7 days of training for each sale, each +- 旻 机 在 在 在 在 在 在 在 将 将 将 将 将 将 将 将 将 将 将 将 将 将 将 将 将 将 将 将 将 将 将 将 将 将After 2 minutes, a current is supplied to the copper rod 'at the same time, and the light of the slanting direction/needle direction branch # lights up to show the non-stimulation area, ts L ,

If the rat enters that arm, 3002-5563A-PF 58 1357816 δ has been recorded as a correct response reSp〇nse), otherwise it is recorded as a worst response. The st imu 1 at ion-response test was repeated 20 times a day, with a break of 5 seconds between each successive test. After 20 tests on day 7, the correct number of responses is used to indicate learning ability (the higher the number, the better the learning ability). Then let the rats rest for 30 days and repeat this step. After 20 more days of rest and 30 tests, the correct number of responses is used to indicate memory ability. Next, the muscarinic acetylcholine receptor density in the brain was measured. The tissue was prepared as follows: The rats were decapitated and 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 the dud_site competitive ligand binding assay. The results are shown in Figures 3 and 4. Y-type electrical maze experiments showed that the learning ability and memory of aged rats were weakened. The rats were given learning and memory ability after giving the aged rats Salsa, the table of salsa soap ethyl formate and the isoindole. The density of muscarinic acetylcholine receptors in aged rats was significantly decreased. Salsa soap yuan, table Salsa 矣 罕 罕 酉 酉 乙 曰 曰 曰 曰 修复 修复 修复 修复 修复 修复 修复 修复 修复 修复 修复 修复 修复 修复 修复 修复 修复 修复 修复 修复 修复 修复 修复Compared with aged rats (D, and D2 were 1 29 2±36 8 ; 1 53 8 ± 40. 5 fmol/mg protein), the young rats showed significantly higher dopamine (D) 1 and 2 receptor densities. (1 57 5±33.2; 2〇〇6±3002-5563A-PF 59 丄357816 50.9^01/mg protein). In contrast, the density of (1) and Dz receptors was restored in the aged rats given saponin and salsa soap 70 for 3 months (177±10. 9 ; 217; ±45. 7fm〇l/mg protein; salsa soap group is 172 〇±44 〇; 2〇6 4±6〇5fm〇i/mg protein). Compared with aged rats (UOhO.Uhg/gram tissue), young rats showed a higher degree of brain-derived neurotrophic factor (丨.647 ± 277277 ng/g tissue). In contrast, the degree of brain-derived neurotrophic factor was partially restored in the aged rats given the different saponins and salsa saponins* for 3 months (1·342±〇·〇7, respectively; .410 ± 0.232 ng / gram of tissue). Therefore, the compound reverses the neurological deficit in aged rats, the decrease in the degree of brain-derived I. neurotrophic factor, and the decrease in the density of muscarinic acetylcholine and dopamine receptors. Example 1 Mode in which Alzheimer's disease mode is neurodegenerative The Alzheimer's disease pattern in one body is a pattern of neurodegeneration. In this mode, nerve agents (amyloid sputum and amanita citrate) are injected into the brain of rats, which leads to loss of neurons, loss of receptors and cognitive impairment. Previous studies have shown that local injection of starch into the nucleus vasalis in the rat brain; 3, after 2 months, leads to hypofunction and behavioral deficits in cholinergic (Giovannelli et al., 1995) Neuroscience, 78 792). In addition, the starch-like starch was not injected into the hippocampus of rats together with a small amount of amanita citrate, not only in the vicinity of the injection, but also in the loss of neurons and nerves away from the injection site.

3002-5563A-PF i357816 Infiltration of glial cells (M〇rim〇t〇 et al, ι 998: • Neuroscience, ^4, 479-487). Our study used Morimoto's method (M〇rin)〇tc) et al, - 1998: Neuroscience' 479-487) with some modifications (to-binary injection instead of bilateral injection). The 3-month-old Sprague Dawley rats were randomly divided into different groups, and the starch-like heart 4 was performed with a stere〇taxic instrument (Stoelting Co.). Injection with amanita tannin (both from Sigma) with a positioning coordinate of Ap = _〇5 mm# (mm) (from the midline to the right), L=_2·8 mm (from the front® (bregma) back ), H = -7.0 mm (from the dura mater to the ventral direction). Each rat is administered at a dose of 4 μg of amyloid-like heart per 1 μl of U1) of physiological saline. "With 1 microgram of amanita citrate. 纟In 20 minutes, the needle is taken out after 1 minute." The skin is sutured. The eight groups are: the control group for the treatment of physiological saline (control group) • the model group (the control group is given the starch-like call and the amanita tannin) mode group + table salsa soap Ethyl formate (18 mg/kg/day) wood mode group + salsa soap element ethyl formate (18 mg/kg/day)* mode group + table salsa soap element ethyl succinate (18 mg /kg/day) (comparison group) Mode group + table salsa soap (18 mg / kg / day) wood mode group + table iso- 菝 矣 矣 矣 (18 mg / kg / day) 氺 model group (ie negative control group, 18 mg/kg/day) * Compounds consistent with the present invention

3002-5563A-PF 61 1357816 will be the table salsa soap element f acid ethyl ester, salsa soap element ethyl formate, table salsa special ethyl succinate (control compound), table salsa soap , different forms of I, Gan and Sugan (all doses are 18 mg / kg / day) in a stable suspension in slow methylcellulose sodium (CMC_Na) (〇. 5%) through the stomach tube ( Gastric tube) Rats were fed once a day. The same volume of sodium carboxymethylcellulose (〇. 5%) was administered to the control group and the model group rats once a day. Two days before the operation, medication and excipients were given for two months.

Next, we assessed the density of the sputum test. The brain sample was homogenized, centrifuged, and then the 27,000 X g centrifuged granular material was rehomogenized and measured. The concentration of quinolyl glycolate (3H_QNB) is selected to be in the saturation range. After incubation and separation, the bound fraction was metered by a liquid scintillation counter.

Avoid 0Tep-ihrough Test): Learning and memory. The effect of test compounds on learning and memory was assessed using the darkness method. An X X 15 cm box is equally divided into two chambers. One dark room has a copper rod base. When used, it charges (40 V ac) and the other is bright room, Tian ~ & Dan 1; There is an opening (hole) between the two chambers for passage by the rat. Each experiment was performed for two consecutive days. The first day of training: the first 3 minutes to allow the rat to fit in the box =, then put the rat into the bright room, so that it faces the hole between the two room kings, and charges the copper rod of the dark room 5 minute. The next day, the test was performed to record the number of times the rat crossed the hole within 5 minutes. A decrease in the number of crossings indicates a hyperactivity of memory. The neurotoxicity pattern of muscarinic acetylcholine in the brain is significantly lower than that of the control group. Table Salsa saponin ethyl citrate, Satay with 啁 啁 皂 7L formic acid 3002-5563A-PF 62 1357816 ester, table salsa soap and table 菝 菝 皂 皂 甘 使 使 使 使There was a significant increase in the density of acetylcholine receptors, while the concentration of scorpion sulphate and ethyl succinate did not significantly change the density of muscarinic choline receptors. Thus, this experiment shows that the action of the compound of the present invention is such that the amount of the receptor is normalized, i.e., when the compound is administered to an animal having a reduced amount of the receptor, the compound has a tendency to repair the number of receptors to a normal amount. In the neurodegenerative model group, the error response (number of errors) within 5 minutes was significantly higher than that of the control group, indicating a memory defect (see Table 11). Epirubicin saponin®, table salsa saponin ethyl citrate, table salsa soap and salsa saponin ethyl citrate reduce the number of false reactions, respectively Ersa soap element ethyl succinate did not reduce the number of false reactions. Table 11 Group Μ type receptor density learning and memory avoidance method (fmol / mg / protein) error number control group (n = 10) 859 ± 101 0. 60 ± 0. 70 mode group (n = 10) 713 + 48 4. 00+2. 40 + table salsa soap decanoic acid ethyl ester (n=10) 877+89* 1.36+0. 92* + salsa soap element ethyl formate (η=11) 916± 158* 1.36±1.03* + table salsa soap element ethyl succinate salt (η=11) 774±79 3. 73±1.35 + table salsa soap element (η=10) 869+104* 1.50± 1.18* + table isoindole saponin (η=11) 877+90* 1.73±0_91 wood + soap (negative control group η=8) 770±68 3.75±1.49 using unpaired Student t test for statistical analysis,* Represents ρ<0· 05. Example 11 Amyotrophic lateral sclerosis is a progressive lethal neurodegenerative disease that causes motor neuron degeneration, skeletal atrophy, paralysi s and death. The cause of this disease is heterologous 3002-5563A-PF 63 1357816: some forms of human amyotrophic lateral sclerosis are due to Cu/Zn super〇xide dismutase (SOD-1). Gene mutations. Animal models of this disease include SOD-ltransgenic mice over-expressing SOD-1 gene and progressive motor neuropathy (Excessively Exciting SOD-1 Gene) Pr〇gressive m〇t〇r neiiropathyMpnm, model of Xia Ke-Mali-Dos Disease) mice. Alizarin saponins and salsa soaps increase life span and improve superficial dismutase mice in amyotrophic lateral sclerosis and Schaco-Marley-Dies disease mode (Figure 5) Behavioral (behavioural deficit) condition in mice with progressive motor neuropathy (Figure 6). While the present invention has been described above by way of a preferred embodiment, it is not intended to limit the invention, and the present invention may be modified and modified without departing from the spirit and scope of the invention. The scope of protection is subject to the definition of the scope of the patent application. [Simple description of the diagram] Figure 1 shows the co-transfected cell line in the Chinese hamster ovary _θ2/ιη3αΗ0-;3 2/ιη3) on the fifth day. The effect of acetate on the density of m3 and stone 2 adrenergic receptors. Figure 2 shows the salicin-induced neuron in the primary C〇riiCal neurons of the salsa saponin, the selevar saponin and the saponin. The effects of degradation. 3002-5563A-PF 64 1357816 Figure 3 shows the learning ability and memory of Salsa soap, table salsa soap ethyl formate (B' oxycarbonyloxy) and isoindole saponin for aged rats influences. • Figure 4 shows the effect of salsa soap, the amount of sulphuric acid ethyl citrate (ethyl oxycarbonyloxy) and isoindole saponin on the number of muscarinic receptors. Figure 5 is a graph showing the survival curves of mice after oral administration of copper sulphate superoxide dismutase (S0D-1) mice. Figure 6 shows the survival curves of mice after oral administration of progressive motor neuron disease (pmn) ® mouse salsa soap. [Main component symbol description] No 0

3002-5563A-PF 65

Claims (1)

135.7816 April 20曰 Correction replacement page No. 097110333 X. Application for special bacteria: 1. One or more for the treatment or prevention of humans and animals (i) Non-cognitive degeneration I (u) Non-cognitive neuromuscular degeneration, (ii) motor sensory neurodegeneration, Or (1V) an active agent lacking cognitive abnormality or loss of neurological and neuromuscular defects 'except for the above stereochemical positions, including all stereoisomers, racemic mixtures' pharmaceutically acceptable prodrugs and salts And a combination thereof, wherein the active agent is selected from the group consisting of the following compounds of formula I a: a compound of formula I a: (la) wherein the R group is selected from the group consisting of hydrogen; alkyl car bony 1, alkoxycarbonyl, alkylcarbamoyl, or arylcarbonyl, or thio a group (sulpho (HO2S)), a phosphonic acid group (phosphono ((Η0)2Ρ(0)-), or a mono-, di- or trisaccharide, wherein any alkyl group may optionally be an aryl group, an amine group, a single Or a mono- or di-alkyl-amino group, a carboxylic acid residue (-C00H), or a combination thereof as described above. 2. As described in claim 1 The active agent, wherein the one or 3002-5563A-PF1 66 1357816 was corrected on April 20, 2001. The replacement of 贞 097110333 is based on a plurality of compounds selected from: Salsa soap, salsa soap ethyl formate ( Cathylate), salsa soap acetate, salsa soap succinate and pharmaceutically acceptable salts thereof, salsa soap glycinate and pharmaceutically acceptable salts thereof, sal Sa-species aminopropionate and its pharmaceutically acceptable salts Protonate and its pharmaceutically acceptable salt, salsa soap, amino acid propionate and pharmaceutically acceptable salt thereof, salsa soap isocyanine salt and pharmacy thereof Acceptable salts 'Salsa soap isomethionine and its pharmaceutically acceptable salts, table salsa soap, table calsa late, cathy late, table Salsa soap element acetate 'table salsa soap succinate and its pharmaceutically acceptable salts, table salsa soap glycinate and its pharmaceutically acceptable salts, table sal Saponin aminopropionate and eight drugs are available for the salt, the salsa saponin and its pharmaceutically acceptable salts, and the salsa phenylaminopropionic acid Salts and pharmaceutically acceptable salts thereof, esaresa saponin isoleucine and pharmaceutically acceptable salts thereof, essa saponin isomethionine and pharmaceutically acceptable thereof Accepted salts, saponins, saponins, cathy late, isoflavone acetate, isoindole succinic acid succinate and their pharmaceutically acceptable accept Salts, iso-detailed glycine-glycinates and pharmaceutically acceptable salts, iso-glycolic aminopropionates and pharmaceutically acceptable salts thereof, and iso (four)-named Ganyuan Lysine and pharmaceutically acceptable salts thereof, saponin phenylaminopropionate and pharmaceutically acceptable salt thereof, iso-saponin iso- leucine and Pharmaceutically acceptable salts, isomeric glycosides, isomethionine salts, and pharmaceutically acceptable salts thereof, 3002-5563A-PF1 67 I35781^〇97n〇333 Ptfe Wi 1 April 20 Correction to replace the H-class 'differentially different saponins, singularity l-Igan yoghurt UathyUte.), the lycopene saponin acetate, the different forms of the stagnation Pharmaceutically acceptable salts, genus, saponins, saponins, glycosides, pharmaceutically acceptable salts thereof, and pharmaceutically acceptable salts thereof, and pharmaceutically acceptable salts thereof Salts, iso-details, special-glyphate and alkaloids: Lexically acceptable salts, different forms of decoction, Glycine base, amino acid propionate, and scientifically acceptable salts, tables By means of the glyco-alkaline isoleucine salt and its accommodating salt, epirubicin, methionine and its pharmaceutically acceptable salts, quinone and monoglycan derived The substance, which is derived from: Salsa, the saponin, the saponin, the singularity, the singularity, the singularity of the singularity, the carbon atom of the i3 in each of the compounds a glycose group, wherein the sugar group is selected from the group consisting of: glucose, mannose 'fructose, galactose, malt mash, fiber double _, bismuth sugar, rhamnose, xylose, arabinose, trehalose, and different mice Li sugar? Vegetable sugar, lactose, galactose _ glucose, grape ^ Arab Sugar, sea bath sugar - glucose, rhamnose - glucose, glucose - glucose - glucose glucose - rhamnose, mannose - glucose, glucose - (rhamnose) - (iv) sugar, glucose - (rhamnose) - rhamnose, glucose - (glucose) - glucoside rhamnose - 'galactose and its deuterated derivatives, and the pharmaceutically acceptable salts described above. 3. The active agent according to claim 1, wherein the mono-, di- or trisaccharide is a mono- or saccharide having 5 or 6 carbon atoms, or a ring thereof. The stagnation of sucrose or _form or its two or three enzymes, or any sputum. ^ 3002-5563A-PF1 68 丄竹/816 April 20 100 100 曰 替换 替换 第 第 第 333 333 333 333 333 333 333 333 333 333 333 333 333 333 333 333 333 333 333 333 333 333 333 333 333 333 333 333 333 333 333 333 333 333 333 333 333 333 333 333 It is selected from the group consisting of pharmaceutical compositions, σ, each of $μα J °0, food supplement composition and beverage 0. 5. The active agent as described in the patent application scope 1 jg %, +, Zhagule 1 Wherein the active agent is present together with one or more additional active agents. 6. The active agent of claim 5, wherein the one or more added active agents are selected from the group consisting of cholinesterol inhibitors (cholinesterase inhibitors), dopamine agonists, catechol oxotransferases (c〇MT inhibitors) 'monoamine oxidase b inhibitors (MA〇_B inhibi1; 〇rs), anticholinergic drugs (anti -chol inergics), acetylcholine agonists, serotonin agonists (ser〇t〇nin agonists) 'α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid AMPA receptor agonists '7-aminobutyric acid agonists, N-methyl-D-aspartate agonists, adrenergic receptors Agonists (cold-adrenoceptor agonists), digoxin, dobutamine, anti-inf lammatories 'neurotrophic factors, statins, Adenosine A2a receptor agonists, aldose reductase inhibitors, immunomodulators, cannabinoid agonists, interferon i nter f eron /5 ) or tricyclic anti-depressants ° 3002-5563A-PF1 69 1357816 No. 097 Π 0333 April 20, 100 Correction Replacement Page 7. For the scope of the patent application For treating or preventing a human or non-incorporated active agent, wherein the active human animal disease comprises: Parkinson's disease after Parkinson's disease encephalitis (postencephalitic) Parkinsonism), depression (depressi〇n), schizophrenia (schizophrenia) 'mechanical dystrophy (including shoulder and shoulder type progressive muscular dystrophy, Du Xian's muscle dystrophy, Becker's muscle dystrophy and Cloth. Muscle dystrophy] Fuch's dystrophy, tonic muscular atrophy, corneal dystrophy, reflex sympathetic dystrophy, neurovascular malnutrition, myasthenia gravis, Lambert Eaton, Huntington's disease, motor neuron disease (including amyotrophic lateral sclerosis), multiple sclerosis, postural hypotension, traumatic neurodegeneration after stroke or accident (eg, head 4 or spinal nerve trauma) ) 'Batten, s disease, sC/ckayne syndrome, Down syndrome' pedigree basal ganglia degeneration (c〇rtic〇basai) Gangl ionic degeneration), multiple system atrophy 'cerebral atrophy', ritual bridge month 小 小 ® % oli oli oli oli oli oli oli oli dent dent dent dent dent dent dent dent dent dent dent dent dent dent dent dent dent dent dent dent dent dent dent dent dent dent dent dent dent dent dent dent dent dent dent dent dent dent dent dent dent dent dent dent dent dent ), pallidus atrophy, spinal cord and spinobulbar atrophy, optic neuritis, sclerosing pan-encephalitis (SSPE), attention deficit disorder ( Attraction deficit disorder) 'post-viral encephalitis, post-poliomyelitis syndrome, 3002-5563A-PF1 70 1 April 20 correction replacement page 1357716_ _ Fahr's syndrome, Joubert syndrome, Guillain-Barre syndrome' iissencephaiy, Moyamoya disease, neuronal migration disorders, autism syndrome , polyglutamine amide group (polyglutamine disease), Niemann pick disease 'progressive multifocal leukoencepha1opathy, pseudotumor cerebri 'Refsum disease' Zellweger syndrome, supranuclear palsy 'Friedreich' s ataxia, spinocere bellar ataxia type 2, Ritter Rhett syndrome 'Shy-Drager syndrome, tuberous sclerosis, Pick, s disease' chronic fatigue syndrome, neuropathies (including hereditary neuropathy) (heredi tary neuropathy), diabetic neuropathy and mitotic neuropathy, prion-based neurodegeneration (including Creutzfeldt-Jakob disease (CJD), variant Variant CJD, a new variant of CJD (new var) Iant CJD), Bovine spongiform encephalopathy (BSE), family genetic insomnia (GSS), lethal family insomnia (FFI), kuru and A1 per's syndrome) Joseph, s Disease), 急3002-5563A-PF1 71 1357816 No. 097110333 April 20, 100 correction of replacement of page disseminated encephalomyelitis, spinal nerve arachnoiditis, central nervous system vascular injury ( Vascular lesions of the central nervous system), loss of extreme neuronal function (ioss ' 〇f extremity neuronal function), Charcot-Marie-Tooth disease, susceptibility to heart failure , asthma (asthma) and macular 1 ar degeneration. 8. The active agent of claim 7, wherein the active agent is for treating or preventing Parkinson's disease. 9. The active agent of claim 7, wherein the active agent is for treating or preventing amyotrophic lateral sclerosis (ALS) and other motor neurone disease. The active agent of claim 7, wherein the active agent is used to treat or prevent a mental disorder (schiz〇phrenia). 11. The active agent of claim 7, wherein the active agent is for treating or preventing depression. 72 3002-5563A-PF1