KR20120128596A - Theraputic methods and uses of sapogenin and their derivatives - Google Patents

Abstract

The present invention relates to certain non-cognitive neurodegeneration, non-cognitive neuromuscular degeneration, neurodegeneration or motor dysfunction of motor neurosensory organs, or receptor dysfunction or loss in the absence of impairment of cognitive, neurological and neuromuscular. To a method for use and treatment of certain steroidal sapongenins, related compounds and derivatives thereof in the

Description

Therapeutic method and use of sapongenin and derivatives thereof {THERAPUTIC METHODS AND USES OF SAPOGENIN AND THEIR DERIVATIVES}

The present invention relates to methods for and treatment of sapongenin, related compounds and derivatives thereof.

Sapogenin, related compounds, and derivatives thereof include non-cognitive neurodegeneration, non-cognitive neuromuscular degeneration, and motor-sensory of motor-sensory organs. neurodegeneration, or treatment in receptor dysfunction or loss. In a further aspect, the invention also relates to a composition used in such a therapy.

Cognitive dysfunction is a hallmark of dementia diseases and syndromes such as Alzheimer's disease (AD), Alzheimer's form of senile dementia (SDAT), Lewy body dementia and vascular dementia. to be. More mild cognitive dysfunctions, such as mild cognitive impairment (MCI), age-associated memory impairment (AAMI), autism, and neuroimpairment, are also specific non- Dementia diseases and syndromes.

Non-cognitive neurological defects (ie, neurological defects in the absence of cognitive dysfunction), non-cognitive neuromuscular defects (ie, neuromuscular defects in the absence of cognitive dysfunction), and neurological defects of motor-sensory organs are associated with Parkinson's disease. ; Muscle dystrophy; Muscular dystrophy, including facioscapsulohumeral muscular dystrophy (FSH), Duchenne muscular dystrophy, Becker muscular dystrophy, and Bruce's muscular dystrophy; Fuchs' dystrophy; Myotonic dystrophy; Corneal dystrophy; Reflex sympathetic dystrophy syndrome (RSDSA); Neurovascular dystrophy; Myasthenia gravis; Lambert Eaton disease; Huntington's disease; Amyotrophic lateral sclerosis (ALS); And diseases and syndromes such as multiple sclerosis.

Loss of receptors—particularly loss of nicotine and / or muscarinic receptors and / or dopamine receptors and / or adrenoceptors—characterizes some or all of the diseases and syndromes described above. Have Loss of the receptor in the absence of cognitive, neurological and neuromuscular damage, as well as postural hypotension, chronic fatigue syndrom, asthma, susceptibility to heart failure and muscle degeneration ( diseases and syndromes such as muscular degeneration).

The above diseases and syndromes are very serious in all societies, because the expectation of life, the treatment of acquired diseases, and the demographic aspect of the elderly are increasing.

DE-A-4303214, which is incorporated by reference of the present invention, discloses the use of saponins and sapongenins in the treatment of viral diseases, but those of ordinary skill in the art are interested in certain specific viral diseases. There is no data describing whether a particular group of compounds can be selected.

WO-A-99 / 16786 suggests the use of certain saponins and sapongenins in the treatment of dementia, which is incorporated by reference herein.

In WO-A-99 / 48482, WO-A-99 / 48507, WO-A-01 / 23406, WO-A-01 / 23407, WO-A-01 / 23408, treatment of cognitive dysfunction and related diseases The use of specific saponins, sapongenins and derivatives thereof is described in the following, which is incorporated by reference of the present invention.

In Chinese Patent Application No. CN-A-1096031, the bioactivity of spirostane sapogenin and sarsasapogenin in the two types of regulation of β-adrenergic and M-cholinergic receptors is described. Although described, no specific pharmaceutical activity is shown. This is reflected as a reference of the present invention. However, "Synthesis and Application of Isotopically Labeled Compounds", 1998, p. 315-320, Yi et al., Describe the use of salsa saponenin in the treatment of senile dementia. Doing.

Many of these diseases are called "spectrum" diseases, and the combination of symptoms is wide and there is a wide range of relative severity. The severity of each symptom and the combination of a particular symptom may vary depending on the individual and the individual and on the stage of disease progression. Cognitive dysfunction, such as Parkinson's disease, myasthenia gravis, Lambert Eaton's disease, postural hypotension and chronic fatigue syndrome, is not a primary symptom, although it appears as one of several possible symptoms of secondary symptoms. In addition, these diseases are not viral diseases or dementia. Thus, in many cases, treatment of cognitive dysfunction (eg, dementia) is not necessary.

The present invention provides surprising activity for certain sapongenin and its derivatives, including saponins, for noncognitive neurodegeneration, noncognitive neuromuscular degeneration, and neurodegeneration of motor neurosensory organs as well as receptor loss in the absence of cognitive, neurological and neuromuscular damage. Based on the findings of having activity, it is now possible to actively prevent and reverse these diseases. These findings have enabled improved treatment of diseases in certain non-viral, spectral and non-spectral, cognitive neurodegenerations that are not primary symptoms.

According to one aspect of the invention, i) non-cognitive neurodegeneration, ii) non-cognitive neuromuscular degeneration, iii) neurodegeneration of the motor-sensory organ, iv) receptors in the absence of cognitive, neurological and neuromuscular defects For the treatment or prevention of humans and non-human animals suffering from or susceptible to dysfunction or loss, methods of making or treating or preventing compositions (eg, pharmaceutical compositions, foods, food supplements and beverages) To provide for the use of an active drug (as defined herein).

The expression "active drug" denotes a compound represented by the following formulas (1), (2) and (3), wherein X radical substituents, sugar-substituted derivatives of such compounds as defined below, all stereoisomers thereof And derivatives derived from one or more such as those defined as racemic mixtures, pharmaceutically acceptable pro-drugs and salts thereof, and all mixtures and combinations thereof, as defined below Derivatives.

[Formula 1]

In which R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₁₀ , R ₁₃ , R ₁₈ , R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ , R ₂₆ , R ₂₇ , R ₂₈ , R ₂₉ , R ₃₀ , R ₃₁ , and R ₃₂ are independent of each other, and H, OH, = O, a halogen atom, (Me-S-), ( Me-SO-), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH-, alkyl; Or unsubstituted; Or OR, wherein R is an alkyl group or acyl group,

R ₉ , R ₁₁ , R ₁₂ , R ₁₄ , R ₁₅ , R ₁₆ , R ₁₇ , R ₂₅ , and R ₃₃ represent H, OH, a halogen atom, (Me-S-), (Me-SO-), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH-, an alkyl group; Or unsubstituted; Or OR, wherein R is an alkyl group or acyl group,

... represents an arbitrary double bond,

In addition to the above,

R ₃₃ or R ₁₄ One is an alkyl group;

[Formula 2]

In which R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₁₀ , R ₁₃ , R ₁₈ , R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ , R ₂₆ , R ₂₇ , R ₂₈ , R ₂₉ , R ₃₀ , R ₃₁ , R ₃₂ and R ₃₄ are independent of each other, H, OH, = O, a halogen atom, (Me-S-) , (Me-SO-), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH-, an alkyl group, OR, wherein R is an alkyl or acyl group, or unsubstituted;

R ₉ , R ₁₁ , R ₁₂ , R ₁₄ , R ₁₅ , R ₁₆ , R ₁₇ , R ₂₅ , R ₃₃ and R ₃₅ represent H, OH, a halogen atom, (Me-S-), (Me-SO- ), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH-, an alkyl group, OR, wherein R is an alkyl group or an acyl group, or unsubstituted;

... represents an arbitrary double bond,

In addition to the above,

One of R ₃₃ or R ₁₄ is an alkyl group;

(3)

Where R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₁₀ , R ₁₃ , R ₁₄ , R ₁₈ , R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ , R ₂₆ , R ₂₇ , R ₂₈ , R ₂₉ , R ₃₀ , R ₃₁ , R ₃₂ , R ₃₃ , R ₃₄ , R ₃₅ , R ₃₆ and R ₃₇ are independent of each other, H, OH, = 0, halogen atom, (Me-S-), (Me-SO-), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH-, alkyl group, OR (where R is Alkyl group or acyl group) or unsubstituted;

R ₉ , R ₁₁ , R ₁₂ , R ₁₅ , R ₁₆ , R ₁₇ and R ₂₅ are H, OH, halogen atoms, (Me-S-), (Me-SO-), (Me-SO _2- ) , N _3- , NH _2- , MeSO ₂ NH-, an alkyl group, OR, wherein R is an alkyl group or an acyl group, or unsubstituted;

... represents an arbitrary double bond,

In addition to the above,

One of R ₃₃ or R ₁₄ is an alkyl group; And

The stereochemistry of R ₂₅ is β-orientation;

Sapogenin derivatives, which are not specifically excluded but are steroidal spirostane sapongenin derivatives derived from one or more X radical substituents,

Where X is

Halogen atoms,

-(Me-S-), (Me-SO-), (Me-SO _2- ),

N _3- , NH _2- , MeSO ₂ NH-, and

-Selected from the group consisting of alkyl groups; And

Derivatives of any of the above compounds, wherein the 3-position carbon atom (i.e. in which R ₃ is substituted for carbon or in the sapogenin derivative not defined in the above formula), or in the case of formulas 2 and 3 , The carbon atom at the 3-position, at the 26-position (ie having R ₃₄ substituted in the carbon) or at the 3- and 26-positions respectively has O-sugar units, where sugar groups (sugar group) are monosaccharides, disaccharides or trisaccharides.

Sugar-carrying derivative forms of saponenin active drugs are generally mentioned in the prior art, such as sapogenin. The expression "carbohydrate" includes specifically such sugar groups in the present invention.

The active drug used in the present invention is a non-estrogenic steroidal sapongenin, saponin and derivatives thereof within the above definition, preferably including all physiologically acceptable pro-drugs and salts thereof.

Such active drugs may be naturally occurring or non-naturally occurring. Non-naturally occurring active drugs are well known in the art and are prepared by modifying the side groups and / or side atoms of naturally occurring compounds, as described below.

The present invention also relates to providing a method for the treatment of human and non-human animals, and a composition comprising an active drug for use in said method of treatment.

The active drug of the present invention may be, if necessary, one or more cholinesterase inhibitors, dopamine agonists (eg, L-dopa), COMT inhibitors, MAO-B inhibitors, anti-cholinergic agents (anti-cholinergics), acetylcholine agonists, serotonin agonists, AMPA receptor agonists, GABA receptor agonists, NMDA receptor agonists, β-adrenergic receptor agonists, digoxin, dobutamine, anti-inflammatory agents ( anti-inflammatories, neurotrophic factors, statins, adenosine A2a receptor antagonists, aldose reductase inhibitors, immunomodulators, cannabinoids It may also be co-administered with additional active drugs such as a cannabinoid agonist, interferon β or tricyclic anti-depressant.

The active drug is a human suffering from or susceptible to diseases and disorders characterized by non-cognitive neurodegeneration, non-cognitive neuromuscular degeneration, neurodegeneration of motor-sensory organs, or receptor dysfunction or loss. And therapeutically or prophylactically applied to non-human animals.

Accordingly, the present invention also relates to compositions (eg, pharmaceutical compositions, foods, food supplements and beverages) for the treatment or prevention of humans and non-human animals suffering from or susceptible to one or more such diseases and disorders. Produce; Or to provide for the use of an active drug (as defined herein) in prophylaxis or treatment.

Examples of active drugs

The classification of active drugs is specifically indicated in the following:

1. A compound represented by Chemical Formula 1,

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₁₀ , R ₁₃ , R ₁₈ , R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ , R ₂₆ , R ₂₇ , R ₂₈ , R ₂₉ , R ₃₀ , R ₃₁ And R ₃₂ are independent of each other, and H, OH, ═O, halogen atom, (Me-S—), (Me-SO—), (Me-SO ₂ —), N _3- , NH _2- , MeSO ₂ NH-, an alkyl group; Or unsubstituted; Or OR, wherein R is an alkyl or acyl group,

R ₉ , R ₁₁ , R ₁₂ , R ₁₄ , R ₁₅ , R ₁₆ , R ₁₇ , R ₂₅ and R ₃₃ represent H, OH, a halogen atom, (Me-S-), (Me-SO-), ( Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH-, alkyl; Or unsubstituted; Or OR, wherein R is an alkyl or acyl group,

... represents an arbitrary double bond,

In addition to the above,

One of R ₃₃ or R ₁₄ is an alkyl group; And

The stereochemistry of R ₂₅ is β-orientation;

2. As a compound represented by Formula 1,

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₁₀ , R ₁₃ , R ₁₈ , R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ , R ₂₆ , R ₂₇ , R ₂₈ , R ₂₉ , R ₃₀ , R ₃₁ And R ₃₂ are independent of each other, and H, OH, ═O, halogen atom, (Me-S—), (Me-SO—), (Me-SO ₂ —), N _3- , NH _2- , MeSO ₂ NH-, alkyl; Or unsubstituted; Or OR, wherein R is an alkyl or acyl group,

R ₉ , R ₁₂ , R ₁₅ , R ₁₆ and R ₁₇ = H,

R ₁₁ , R ₁₄ , R ₂₅ and R ₃₃ are H, OH, halogen atoms, (Me-S-), (Me-SO-), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH—, alkyl; Or unsubstituted; Or OR, wherein R is an alkyl or acyl group,

... represents an arbitrary double bond,

In addition to the above,

One of R ₃₃ or R ₁₄ is an alkyl group; And

The stereochemistry of R ₂₅ is β-orientation;

3. A compound represented by Chemical Formula 1,

-R ₁ = R ₂ = R ₄ = R ₅ = R ₆ = R ₇ = R ₈ = R ₁₀ = R ₁₁ = R ₉ = R ₁₂ = R ₁₃ = R ₁₅ = R ₁₆ = R ₁₇ = R ₁₈ = R ₁₉ = R ₂₀ = R ₂₁ = R ₂₂ = R ₂₃ = R ₂₄ = R ₂₅ = R ₂₆ = R ₂₇ = R ₂₈ = R ₂₉ = R ₃₀ = R ₃₁ = R ₃₂ = R ₃₃ = H,

One of R ₃₃ or R ₁₄ is an alkyl group;

-... represents a single bond,

The methyl group at C _{25 is} in the R or S orientation,

The stereochemistry of R ₂₅ is β-orientation; And

In addition to the above,

At least one or more of R ₃ or R ₂₃ is an X radical and may be left as a substituent which is H, OH, ═O, and OR, wherein R is an alkyl or acyl group, or unsubstituted, and X Is selected from the group consisting of halogen atoms, (Me-S-), (Me-SO-), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH- and alkyl groups,

4. As a compound represented by Formula 1,

R ₁ = R ₂ = R ₄ = R ₅ = R ₆ = R ₇ = R ₈ = R ₁₀ = R ₁₁ = R ₉ = R ₁₂ = R ₁₃ = R ₁₅ = R ₁₆ = R ₁₇ = R ₁₈ = R ₁₉ = R ₂₀ = R ₂₁ = R ₂₂ = R ₂₃ = R ₂₄ = R ₂₅ = R ₂₆ = R ₂₇ = R ₂₈ = R ₂₉ = R ₃₀ = R ₃₁ = R ₃₂ = H,

R ₃₃ = R ₁₄ = CH ₃ ;

-... represents a single bond,

The stereochemistry of R ₂₅ is β-orientation; And

In addition to the above,

At least one or more of R ₃ or R ₂₃ is an X radical and may be left as a substituent which is H, OH, ═O, and OR, wherein R is an alkyl or acyl group, or unsubstituted, and X Is selected from the group consisting of a halogen atom, (Me-S-), (Me-SO-), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH-, and an alkyl group,

5. As a compound represented by Formula 2,

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₁₀ , R ₁₃ , R ₁₈ , R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ , R ₂₆ , R ₂₇ , R ₂₈ , R ₂₉ , R ₃₀ , R _{31 ,} R ₃₂ and R ₃₄ are independent of each other, H, OH, = O, a halogen atom, (Me-S-), (Me -SO-), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH-, an alkyl group, OR, wherein R is an alkyl or acyl group, or unsubstituted;

R ₉ , R ₁₁ , R ₁₂ , R ₁₄ , R ₁₅ , R ₁₆ , R ₁₇ , R ₂₅ , R ₃₃ and R ₃₅ represent H, OH, a halogen atom, (Me-S-), (Me-SO- ), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH-, an alkyl group, OR, wherein R is an alkyl or acyl group, or unsubstituted;

... represents an arbitrary double bond,

In addition to the above,

One of R ₃₃ or R ₁₄ is an alkyl group; And

The stereochemistry of R ₂₅ is β-orientation;

6. As a compound represented by the formula (2) and carbohydrate derivatives thereof,

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₁₀ , R ₁₃ , R ₁₈ , R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ , R ₂₆ , R ₂₇ , R ₂₈ , R ₂₉ , R ₃₀ , R _{31 ,} and R ₃₂ are independent of each other and include H, OH, = O, a halogen atom, (Me-S-), (Me-SO -), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH-, an alkyl group, OR, wherein R is an alkyl or acyl group, or unsubstituted;

R ₉ , R ₁₂ , R ₁₅ , R ₁₆ , R ₁₇ = H,

R ₃₄ is H, OH, ═O, and OR, wherein R is an alkyl group, acyl group or carbohydrate group; And

R ₁₁ , R ₁₄ , R ₂₅ , R ₃₃ , and R ₃₅ are H, OH, a halogen atom, (Me-S-), (Me-SO-), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH-, an alkyl group, OR, wherein R is an alkyl group or acyl group, or unsubstituted;

... represents an arbitrary double bond,

In addition to the above,

One of R ₃₃ or R ₁₄ is an alkyl group;

The stereochemistry of R ₂₅ is β-orientation;

7. As a compound represented by the formula (2) and carbohydrate derivatives thereof,

R ₁ = R ₂ = R ₄ = R ₅ = R ₆ = R ₇ = R ₈ = R ₁₀ = R ₁₁ = R ₉ = R ₁₂ = R ₁₃ = R ₁₅ = R ₁₆ = R ₁₇ = R ₁₈ = R ₁₉ = R ₂₀ = R ₂₁ = R ₂₂ = R ₂₃ = R ₂₄ = R ₂₅ = R ₂₆ = R ₂₇ = R ₂₈ = R ₂₉ = R ₃₀ = R ₃₁ = R ₃₂ = R ₃₃ = H,

R ₁₄ = CH ₃ ;

R ₃₄ = -OH or -OR, wherein R = alkyl, acyl or carbohydrate, and

-R ₃₅ = H or unsubstituted,

-Represents an arbitrary double bond, and

The methyl group at C _{25 is} in the R or S configuration, and

The stereochemistry of R ₂₅ is β-orientation; And

In addition to the above,

At least one or more of R ₃ or R ₂₃ is an X radical and may be left as a substituent which is H, OH, ═O, and OR, wherein R is an alkyl or acyl group, or unsubstituted, and X Is selected from the group consisting of a halogen atom, (Me-S-), (Me-SO-), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH-, and an alkyl group,

8. As a compound represented by the formula (2) and carbohydrate derivatives thereof,

R ₁ = R ₂ = R ₄ = R ₅ = R ₆ = R ₇ = R ₈ = R ₁₀ = R ₁₁ = R ₉ = R ₁₂ = R ₁₃ = R ₁₅ = R ₁₆ = R ₁₇ = R ₁₈ = R ₁₉ = R ₂₀ = R ₂₁ = R ₂₂ = R ₂₃ = R ₂₄ = R ₂₅ = R ₂₆ = R ₂₇ = R ₂₈ = R ₂₉ = R ₃₀ = R ₃₁ = R ₃₂ = H,

R ₁₄ = R ₃₃ = CH ₃ ;

R ₃₄ = -OH or -OR, wherein R = alkyl, acyl or carbohydrate, and

-R ₃₅ = H or unsubstituted,

-Represents an arbitrary double bond, and

The stereochemistry of R ₂₅ is β-orientation; And

In addition to the above,

At least one or more of R ₃ or R ₂₃ is an X radical and may be left as a substituent which is H, OH, ═O, and OR, wherein R is an alkyl or acyl group, or unsubstituted, and X Is selected from the group consisting of a halogen atom, (Me-S-), (Me-SO-), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH-, and an alkyl group,

9. As a compound represented by Formula 3,

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₁₀ , R ₁₃ , R ₁₄ , R ₁₈ , R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ , R ₂₆ , R ₂₇ , R ₂₈ , R ₂₉ , R ₃₀ , R _{31 ,} R ₃₂ , R ₃₃ , R ₃₄ , R ₃₅ , R ₃₆ and R ₃₇ are independent of each other, H, OH, = O, a halogen atom, (Me-S-), (Me-SO-), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH-, an alkyl group, OR, where R is alkyl or Acyl group) or unsubstituted;

R ₉ , R ₁₂ , R ₁₅ , R ₁₆ , R ₁₇ and R ₂₅ are H, OH, halogen atoms, (Me-S-), (Me-SO-), (Me-SO _2- ), N ₃ -, NH _2- , MeSO ₂ NH-, an alkyl group, OR, wherein R is an alkyl or acyl group, or unsubstituted;

... represents an arbitrary double bond,

In addition to the above,

R ₃₃ or R ₁₄ is an alkyl group; And

The stereochemistry of R ₂₅ is β-orientation;

10. As the compound represented by Formula 3,

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₁₀ , R ₁₃ , R ₁₄ , R ₁₈ , R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ , R ₂₆ , R ₂₇ , R ₂₈ , R ₂₉ , R ₃₀ , R _{31 ,} R ₃₂ , R ₃₃ , R ₃₄ , R ₃₅ , R ₃₆ and R ₃₇ are independent of each other, H, OH, = O, a halogen atom, (Me-S-), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH-, an alkyl group, OR where R is an alkyl or acyl group, or substituted Not;

R ₉ , R ₁₂ , R ₁₅ , R ₁₆ , R ₁₇ = H,

R ₃₄ = H, OH, = 0, halogen atom, (Me-S-), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH-, an alkyl group, OR, where R is an alkyl group , An acyl group, or a carbohydrate group) or unsubstituted;

R ₁₁ , and R ₂₅ are H, OH, = 0, halogen atom, (Me-S-), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH-, an alkyl group, OR ( Wherein R is an alkyl group or acyl group) or unsubstituted;

... represents an arbitrary double bond,

In addition to the above,

One of R ₃₃ or R ₁₄ is an alkyl group; And

The stereochemistry of R ₂₅ is β-orientation;

11. As a compound represented by the formula (3) and carbohydrate derivatives thereof,

R ₁ = R ₂ = R ₄ = R ₅ = R ₆ = R ₇ = R ₈ = R ₁₀ = R ₁₁ = R ₉ = R ₁₂ = R ₁₃ = R ₁₅ = R ₁₆ = R ₁₇ = R ₁₈ = R ₁₉ = R ₂₀ = R ₂₁ = R ₂₂ = R ₂₃ = R ₂₄ = R ₂₅ = R ₂₆ = R ₂₇ = R ₂₈ = R ₂₉ = R ₃₀ = R ₃₁ = R ₃₂ = H,

R ₁₄ = CH ₃ ;

R ₃₄ = -OH or -OR, where R = alkyl, acyl or carbohydrate

, And

-R ₃₅ = H or unsubstituted,

R ₃₇ = H, -OH or = O,

R ₃₆ = H or -OH,

-Represents a single bond, and

The methyl group at C _{25 is} in the R or S configuration, and

The stereochemistry of R ₂₅ is β-orientation; And

In addition to the above,

At least one or more of R ₃ or R ₂₃ is an X radical and may be left as a substituent which is H, OH, ═O, and OR, wherein R is an alkyl or acyl group, or unsubstituted, and X Is selected from the group consisting of a halogen atom, (Me-S-), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH- and an alkyl group,

12. As the compound represented by the formula (3) and carbohydrate derivatives thereof,

R ₁ = R ₂ = R ₄ = R ₅ = R ₆ = R ₇ = R ₈ = R ₁₀ = R ₁₁ = R ₉ = R ₁₂ = R ₁₃ = R ₁₅ = R ₁₆ = R ₁₇ = R ₁₈ = R ₁₉ = R ₂₀ = R ₂₁ = R ₂₂ = R ₂₃ = R ₂₄ = R ₂₅ = R ₂₆ = R ₂₇ = R ₂₈ = R ₂₉ = R ₃₀ = R ₃₁ = R ₃₂ = H,

R ₁₄ = R ₃₃ = CH ₃ ;

R ₃₄ = -OH or -OR, where R = alkyl, acyl or carbohydrate

, And

-R ₃₅ = H or unsubstituted,

R ₃₇ = H, -OH or = O,

R ₃₆ = H or -OH,

-Represents a single bond, and

The methyl group at C _{25 is} in the R or S configuration, and

The stereochemistry of R ₂₅ is β-orientation; And

In addition to the above,

At least one or more of R ₃ or R ₂₃ is an X radical and may be left as a substituent which is H, OH, ═O, and OR, wherein R is an alkyl or acyl group, or unsubstituted, and X Is selected from the group consisting of a halogen atom, (Me-S-), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH- and an alkyl group,

13. Substituted sapogenin, in particular steroidal spirostane sapogenin, does not exclude wherein at least one OH-group of sapogenin is substituted with X, where X is a halogen atom, (Me-S- ), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH-, and an alkyl group;

14. Sapogenin as defined above, in particular steroidal spirostane sagogenin, does not exclude where the halogen atom defined by X is a fluorine atom;

15. (3β-fluoro-5β, 20α, 22α, 25R-spirostane), (3,3-difluoro-5β, 20α, 22α, 25R-spirostane), (3α-methylsulfonylamino -5β, 20α, 22α, 25R-spirostane), (3α-azido-5β, 20α, 22α, 25R-spirostane), (3α-amino-5β, 20α, 22α, 25R-spirostane) And substituted sapogenins selected from stereoisomers and racemic mixtures thereof, pharmaceutically acceptable pro-drugs and salts thereof;

16. Substituted sapogenin, wherein the parent sapogenin is selected from salsa sapogenin, episalsa sapogenin, smilagenin, epismilagenin, and anzurogenin-D. Substituted with one or more X radicals as defined;

17. A compound represented by the following formula (4):

[Formula 4]

Wherein R group is a hydrogen atom; Alkylcarbonyl; Alkoxycarbonyl; Alkyl carbamoyl; Or arylcarbamoyl; Or sulfo (HO ₃ S); Phosphono ((HO) ₂ P (O)-); Or monosaccharides, disaccharides or trisaccharides; Wherein any alkyl group is selected from those optionally substituted with aryl, amino, mono- or di-alkyl-amino, carboxylic acid residues (-COOH), or any combination thereof;

18. Derivative forms of compounds as defined in items 1 to 17 above, wherein the carbon atom is in the 3-position, or in the case of Formulas 2 and 3, the carbon atom is the 3-position, the carbon atom is The carbon atoms at the 3- and 26-positions have O-sugar units in which the sugar group is monosaccharide, disaccharide or trisaccharide, for example mono aldose having 5 or 6 carbon atoms, Or in ketose, preferably in cyclized furanose or pyranose form, or in α or β anomers and contain D or L optical isomers, or their di- and tri-oligosakas Any combination of rides; Acylated forms of sugar residues are also included in the term "sugar"; Examples of suitable sugars include glucose, mannose, fructose, galactose, maltose, cellobiose, sucrose, rhamnose, xylose, arabinose, Fucose, quinovose, apiose, lactose, galactose-glucose, glucose-arabinose, fucose-glucose, rhamnose-glucose, glucose-glucose-glucose, glucose-rhamnose, Mannose-glucose, glucose- (rhamnose) -glucose, glucose- (rhamnose) -rhamnose, glucose- (glucose) -glucose, galactose- (rhamnose) -galactose and its acylation (e.g. acetylation) ) Derivatives.

In the definition of the above compound:

Optionally, the amino, mono-alkyl-amino and di-alkyl-amino substituents of the alkyl group are preferably present as mono-substituents at the α position of the alkyl group.

Optionally, the —COOH substituent of the alkyl group may be present at the terminal or any other position of the alkyl group.

"Alkyl" means a linear or branched aliphatic hydrocarbon group having 1 to 20 carbon atoms in the chain. Preferred alkyl groups are those having 1 to 12 carbon atoms in the chain. Branched form means that at least one lower alkyl group, such as methyl, ethyl or propyl group, is attached to a linear alkyl chain. "Lower alkyl" means one to four carbon atoms in the chain, either linear or branched. Examples of the alkyl group include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, s-butyl, n-pentyl, 3-pentyl and the like.

"Aryl" is any type of group, including aromatic ring or fused ring modes, preferably up to 12 carbon atoms. One example of an aryl group is a phenyl group. Also optionally selected by substituents independently selected from, for example, halo (e.g., chloro or bromo), alkyl, cycloalkyl, hydroxy, alkoxy, amino, nitro, acylamino, carboxy and alkoxycarbonyl groups of the aryl group. Mono- or poly-substituted.

"Carboxylic acid residue" means a -COOH group.

"Acyl group" means an H-CO- or alkyl-CO- group, where the alkyl group is as defined above. Preferably, the acyl group includes a lower alkyl group. Examples of such acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and palmitoyl.

"Optionally substituted" means that the group may be substituted with one or more of the same or different substituents, preferably with respect to the substituted parent group, For example, one or more substituents having a size of 20% or less of the largest particle dimension; Suitable substituents are halo (chloro, or bromo), alkyl, cycloalkyl, hydroxy, alkoxy, amino, acylamino, aryl, aroylamino, carboxy, alkoxycarbonyl, aralkoxycarbonyl, heteroaralkoxy Carbonyl (heteroaralkoxycabonyl) and optionally substituted carbamoyl, preferably within the size defined above;

"Pharmaceutically tolerated" is suitable for use in contact with human and lower animal cells without excessive toxicity, irritation, allergic reactions, etc. in the negative medical and veterinary judgment aspects, proportional to the ideal benefit / risk ratio . "Pharmaceutically acceptable pro-drug" means a prodrug of the compound, used in contact with cells of humans and lower animals without negative toxicity, irritation, allergic reactions, etc. in negative medicinal and veterinary judgment aspects. Suitable to be proportional to the ideal benefit / risk ratio, they are not only effective for their intended use, but are also zwitterionic forms of the compounds. The term "pro-drug" refers to a compound that is rapidly delivered in vivo to prepare a parent compound of the formula, for example hydrolyzed in blood It is by. Functional groups that can be delivered rapidly by metabolic cleavage produce in vivo a class of groups that react with carboxyl groups. In this case, metabolic cleaved groups in the compound are cleaved in vivo, so that the compound having such a group acts as a prodrug. A review of prodrugs can be provided at: Design of Prodrugs, H. Bundgaard, ed., Elsevier, 1985; Methods in Enzymatics, K. Widder et al, Ed., Academic Press, 42, p. 309-396, 1985; Textbooks on Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard, ed., Chapter 5; Design and Application of Prodrugs p.113-191; Inventory of Advanced Drug Delivery, H. Bundgard, 8, p.1-38, 1992; Journal of Pharmaceutical Science, 77, p. 285, 1988; Chem. Pharm. Bull., N. Nakeya et al, 32, p. 692, 1984; Prodrugs in Novel Delivery Systems, T. Higuchi and V. Stella, Vol. 14 of the A.C.S. Symposium Series, and Bioreversible Carriers in Drug Design, Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press; 1987, these materials are incorporated by reference of the present invention.

By "pharmaceutically acceptable salts" is meant a relatively non-toxic, inorganic and organic acid addition salt, and base addition salt of a compound of the invention. Such salts may be prepared in situ in the final separation and purification steps of the compound. In particular, acid addition salts can be prepared respectively by reacting the purified compound in free base form with a suitable organic or inorganic acid and separating the prepared salts. See, eg, S. M. Berge, et al., Pharmaceutical Salts, J. Pharm. See Sci., 66: p.1-19 (1977), which is incorporated herein by reference. Base addition salts may also be prepared respectively by reacting the purified compound in acid form with a suitable organic or inorganic base and separating the prepared salts. Base addition salts include pharmaceutically acceptable metal and amine salts. Examples of suitable acid addition bases are those formed with salts selected from hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid. Examples of suitable base addition salts are those formed from bases selected from sodium hydroxide, potassium hydroxide and ammonium hydroxide.

Particularly preferred species of active drug are the compounds represented by the above formula (4).

In the compound of formula 4, the methyl group of C ₂₅ is in the S configuration, and such compounds of the present invention are salsa saginogenin and episalsa pogenin or derivatives thereof. In other compounds represented by formula (4), the methyl group of C ₂₅ is in the R configuration, and such compounds of the invention are smilagenin and epismilagenin or derivatives thereof.

In formula (4), -OR is selected from the following (unless excluded from any condition): hydroxy, cathylate (ethoxycarbonyloxy), acetate, succinate, propionate, butyrate, valerate, Isovalate, caproate, isocaproate, diethyl acetate, octanoate, decanoate, laurate, myristate, palmitate, stearate, benzoate, phenylacetate, Phenylpropionate, cinnamate, p-nitrobenzoyloxy, 3,5-dinitrobenzoyloxy, p-chlorobenzoyloxy, 2 2,4-dichlorobenzoyloxy, p-bromobenzoyloxy, m-bromobenzoyloxy, p-methoxybenzoyloxy , Phthalyl yl), glycinate, alaninate, avalinate, phenylalaninate, isoleucinate, methioninate, arginate, Aspartate, cysteinate, glutaminate, histidinate, lysinate, prolinate, serinate, threonate ( threoninate, tryptophanate, tyrosinate, fumerate and maleate.

The compound of Formula 4 and pharmaceutically acceptable salts thereof are particularly preferably the following compounds (unless excluded by preconditions):

Salsa saponogenin,

Salsa saponenin catylate,

Salsa saponenin acetate,

Salsa saponogenin succinate and pharmaceutically acceptable salts thereof

Salsa saponogenin glycinate and pharmaceutically acceptable salts thereof,

Salsa saponenin alaninate and pharmaceutically acceptable salts thereof,

Salsa saponogenin valateate and pharmaceutically acceptable salts thereof,

Salsa saponogenin phenylalanine and pharmaceutically acceptable salts thereof,

Salsapogenin isoleucinate and pharmaceutically acceptable salts thereof,

Salsapogenin methioninate and pharmaceutically acceptable salts thereof,

Episalsa saponogenin,

Episalsa saponogenine citrate,

Episalsa saponogenin acetate,

Episalsasapogenin succinate and pharmaceutically acceptable salts thereof,

Episalsasapogenin glycinate and pharmaceutically acceptable salts thereof,

Episalsasapogenin alaninate and pharmaceutically acceptable salts thereof,

Episalsasapogenin valinates and pharmaceutically acceptable salts thereof,

Episalsasapogenin phenylalanine and pharmaceutically acceptable salts thereof,

Episalsa sapongenin isoleucinate and pharmaceutically acceptable salts thereof,

Episalsasapogenin methioninate and pharmaceutically acceptable salts thereof,

Smilagenin,

Smilagenin catylate,

Smilagenin acetate,

Smilagenin succinate and pharmaceutically acceptable salts thereof

-Smilagenin glycinate and pharmaceutically acceptable salts thereof,

Smillagenin alaninate and pharmaceutically acceptable salts thereof,

Smilagenin valateate and pharmaceutically acceptable salts thereof,

Smillagenin phenylalanine and pharmaceutically acceptable salts thereof,

Smillagenin isoleucinate and pharmaceutically acceptable salts thereof,

Smillagenin methioninate and pharmaceutically acceptable salts thereof,

-Epismilagenin,

Epismilagenin catylate,

-Epismilagenin acetate,

Epismilagenin succinate and pharmaceutically acceptable salts thereof,

Epismilagenin glycinate and pharmaceutically acceptable salts thereof,

-Epismilagenin alaninate and pharmaceutically acceptable salts thereof,

Epismilagenin valateate and pharmaceutically acceptable salts thereof,

-Epismilagenin phenylalanineate and pharmaceutically acceptable salts thereof,

Epismilagenin isoleucinate and pharmaceutically acceptable salts thereof,

-Epismilagenin methioninate and pharmaceutically acceptable salts thereof.

The saponin (R = sugar) of the compound represented by the formula (4) is particularly preferably the following compound: salsa saponenin, episalsa saponenin, smilagenin and epismilagenin, in each case a 3-position carbon source It has O-sugar units, where sugar groups are glucose, mannose, fructose, galactose, maltose, cellobiose, sucrose, rhamnose, and xyl Xylose, arabinose, fucose, quinoose, apiose, lactose, galactose-glucose, glucose-arabinose, fucose-glucose, rhamnose-glucose, Glucose-glucose-glucose, glucose-rhamnose, mannose-glucose, glucose- (rhamnose) -glucose, glucose- (rhamnose) -rhamnose, glucose- (glucose) -glucose, galactose- (rhamnose) -galactose And acylations thereof (eg It is selected from tilhwa) derivatives.

Further examples of suitable active drugs include 16,22-epoxycoprostan-3βol, smilagenone, coprosterol and pharmaceutically acceptable pro-drugs and salts thereof.

Composition and Uses

Accordingly, the present invention is directed to non-cognitive neurodegeneration, non-cognitive neuromuscular degeneration, neurodegeneration of motor neuron-sensory organs or the absence of cognitive, neurological and neuromuscular damage in accordance with their needs in humans or non-human animals. Provided and enabled to provide a method for treating or preventing medicament, said method comprising administering to said human or non-human animal an effective amount of said active drug (as defined herein) or a pharmaceutically acceptable salt thereof Include.

Such active drugs may be administered in the form of a composition comprising the active drug and any additional suitable ingredients. Examples of such compositions are pharmaceutical compositions (pharmaceuticals), foods, food supplements, or beverages. Such compositions may include mixtures of certain compounds, and / or pharmaceutically acceptable salts thereof.

According to a further aspect of the invention, a human or non-human in noncognitive neurodegeneration, noncognitive neuromuscular degeneration, neurodegeneration of motor-sensory organs or in the absence of receptor dysfunction or loss in the absence of cognitive, neurological and neuromuscular damage Provided are uses of a composition comprising an active drug in the treatment of an animal, which includes an effective amount of a compound of the active drug.

In the present invention, the "pharmaceutical composition" includes an active drug and a pharmaceutically acceptable carrier; diluent; Adjuvant; Excipients; Or preserving agents, additives, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, perfuming agents, antibacterial agents, antibacterial agents, lubricants and dispensing agents; Same excipients, depending on the nature of the mode of administration and dosage form.

The terms "foodstuff", "food supplement" and "beverage" as used herein have their general meaning and are not limited to pharmaceutical preparation.

The dosage of the active drug can vary widely depending on the intensity of the condition being treated or prevented. Selection of the appropriate dosage can be carried out by the skilled artisans without undue difficulty. The dose of active drug is preferably administered once a day, for example at least about 0.1 mg per weight (kg), for example at least about 0.3 mg per weight (kg). More generally, it is preferred to administer between 1 and 25 mg / kg body weight once per day, for example between about 1 and 10 mg. The composition may be suitably formulated in unit dosage form so that it is suitable for administration to the patient in unit dosage form between about 1 to 10 mg / kg. For human use, the formulations may conveniently be applied between about 70 and 700 mg per day.

"Pharmaceutically acceptable formulation" means a formulation of a compound or composition of the present invention and includes a tablet; Dragees; powder; Elixirs; syrup; Injectable liquid preparations, including liposome preparations, as well as liquid preparations, including suspensions, sprays, inhalable tablets, lozenges, emulsions, potions, granules, capsules, and suppositories Include. Formulation techniques can be found in Remington, Pharmaceutical Science, Mack Publishing Co., Easton, PA, latest edition.

In general, references in which one of a particular group of compounds is present include a range of two or more mixtures of such compounds.

The present invention provides for the treatment of i) noncognitive neurodegeneration, ii) noncognitive neuromuscular degeneration, iii) neurodegeneration of motor neuron-sensory organs, or iv) cognitive, neurological and neuromuscular damage. Providing a treatment in a human or non-human animal patient suffering from or susceptible to any of the following diseases, the disease comprising: Parkin's disease; Postencephalitic parkinsonism after encephalitis; Depression; Schizophrenia; Muscular dystrophy, including facioscapsulohumeral muscular dystrophy (FSH), Duchenne muscular dystrophy, Becker muscular dystrophy, and Bruce's muscular dystrophy; Fuchs' dystrophy; Myotonic dystrophy; Corneal dystrophy; Reflex sympathetic dystrophy syndrome (RSDSA); Neurovascular dystrophy; Myasthenia gravis; Lambert Eaton disease; Huntington's disease; Diseases of motor neuron sensory organs, including amyotrophic lateral sclerosis (ALS); Multiple sclerosis; Positional hypotension; Traumatic neurodegeneration (eg, by seizure or by accident (eg, head injury or spinal cord injury by mental shock)); Batten's disease; Cacayne syndrome (Cockayne syndrom); Down syndrom; Corticobasal ganglionic degeneration; Multiple system atrophy; Oribopontocerebellar atrophy; Dentatorubral atrophy; Palidoluysian atrophy; Spinobulbar atrophy; Optic neuritis; Sclerosing pan-encephalitis (SSPE); Attention deficit disorder; Post-viral encephalitis; Post-poliomyelitis syndrom; Farr's syndrom; Juubert syndrome (Joubert syndrom); Guillain-Barre syndrom; Lissencephaly; Moyamoya disease; Neuromigration disorders; Autistic syndrom; Polyglutamine disease; Niemann-Pick disease; Progressive multifocal leucoencephalopathy; Pseudotumor cerebri; Refsum disease; Zellweger syndrom; Supranuclear palsy; Friedreich's ataxia; Spinocerebellar ataxia type 2; Rhett syndrome; Shy-Drager syndrom; Tuberous sclerosis; Pick's disease, chronic fatigue syndrome; Neuropathies, including hereditary neuropathy, diabetic neuropathy, and mitotic neuropathy; Creutzfeldt-Jakob disease (CJD), modified Creutzfeldt-Jakob disease (variant CJD), bovine spongiform encephalopathy (BSE), Gersmann-Straeussler-Scheinker Syndrom (GSS), Famili Fatal Prion-based neurodegeneration, including Insomnia, kuru, and Alper's syndrom; Joseph's disease; Acute disseminated encephalomyelitis; Arachnoiditis; Vascular lesions of the central nervous system; Loss of extremity neuronal function; Charcot-Marie-Tooth disease; It is susceptible to heart failure, asthma and macular degeneration.

Accordingly, the present invention encompasses methods for treating or preventing such diseases and disorders in humans or non-human animals suffering from or susceptible to such diseases, which include an effective amount of an active drug as defined herein. And administering to the human or non-human animal, as well as the use of the active drug in the preparation of the composition for the treatment or prophylaxis.

For Parkin's disease, encephalitis Parkin's disease, postural hypotension, autism, chronic FED, myasthenia gravis and Lambert Eaton's disease, as well as any other diseases within the scope of the disease states referred to herein, It is related to the present invention as described in the above, or described as recognized in the prior art in the art, or it is obvious to be an effective treatment, and the present invention is free of symptoms of cognitive dysfunction; Or secondary or incidentally non-cognitive neurodegeneration due to any symptom of cognitive dysfunction present in the patient to be treated; Noncognitive neuromuscular degeneration; Neurodegeneration of motor-sensory organs; Or conditions of receptor dysfunction or loss in the absence of cognitive, neurological and neuromuscular damage.

Preparation of Compounds Used in the Present Invention

Smilagenin, epismilagenin, and salsa saponogenin are commercially available materials. Suppliers of such materials include Sigma Aldrich, Research Plus Inc. and Stealoid Inc. A method for the preparation of these materials can be found in the paper entitled Preparation of Episalsa saponogenin as shown in JACS p.5225 (1959). Episalsasapogenin can be prepared by reducing salsapogenone using a metal hydride reducing agent. Salsa saponogenone can be prepared using the method of Lajis et al, Steroids, 1993, 58, 387-389.

In addition, unsubstituted sapongenins used as starting materials include the famous genus, plant species such as Smilax, Asparagus, Anemarrhena, Yucca, or Agave. species, naturally occurring species. Here, smilagenin or salsa saponogenin is used in accordance with the present invention, in the form of plant extract or dry powdered plant material, Smilax, Asparagus, Anemarrhena, It is derived from a plant genus such as Yucca or Agave.

Methods of making active drugs are well known to those of ordinary skill in the art. Examples of such drugs include, but are not limited to, WO-A-02 / 79221 (as in Examples 5 to 16, salsa saponenin catylate, episasa sapogenin catylate, episasa sapogenin succinate, episilagenin catylate, Episalsasapogenin glycinate hydrochloride, Salsasapogenin glycinate hydrochloride, Epismilagenin glycinate hydrochloride, Epismilagenin L-alanine hydrochloride, Epismilagenin L-valinate hydrochloride, Epi It describes a method for preparing smilagenin L-isorucinate hydrochloride, epismilagenin L-phenylalanine hydrochloride and epismilagenin L-methioninate hydrochloride. The compound represented by the formula (4) may be prepared using a conventional technique from a compound having R = H, when different from that of R = H.

A preferred reaction is a nucleophilic substitution reaction, which reacts with a compound containing OH at the 3-position with a compound represented by the following formula (5):

[Chemical Formula 5]

L-R

Wherein R is alkylcarbonyl; Alkoxycarbonyl; Alkyl carbamoyl; Or arylcarbamoyl, or wherein any alkyl group is optionally substituted with aryl, amino, mono alkyl-amino, di-alkyl-amino, carboxylic acid residue (-COOH), or any combination thereof ; And L is a living group under conditions suitable for nucleophilic substitution.

Examples of L-R compounds are carboxylic acids or, if appropriate, anhydrides, or acyl halides (eg acyl chloride). For example, where R is a citrate (epoxycarbonyl) unit, the L-R compound will be suitably ethyl chloroformate.

The reaction will be carried out under a base such as pyridine, optionally in the presence of an acid such as hydrochloric acid.

The detailed reaction of the nucleophilic substitution reaction is already well known, see, for example, RC Larock, in Comprehensive Organic Transformations, VCH publishers, 1989.

Dihydrosalsasapogenin is described by Marker and Rohmann (1939), STerols L; The structure of the side chain of sarsasapogenin, J. Am. Chem. Soc. 61, pp846-851 will be prepared using the method described. 16,22-epoxycoprostan-3β-ol is described in Scheer et al, (1955), The C-25 isomerism of smilagenin and sarsasapogenin: J. Am. Chem. Soc. 77, pp641-646.

In the methods described herein, it is necessary to protect with reactive functional groups, for example hydroxy, carboxy or amino groups of such functional groups, these being those required in the final product to avoid unwanted precipitation in the reaction. to be. Conventional protective groups will be used to conform to the standard particles. For example, TW Green and PGM Wuts are described in "Protective groups in organic chemistry", John Wiley & Sons, 1991; See JFW McOmie, "Protective groups in organic chemistry", Plenum Press, 1973. In the compound LR represented by Formula 5, wherein R is amino-substituted, the protective amino substituent is preferably an alkoxycarbonyl protective group, whereby the amino functional group is dissolved in a dry solvent during the synthesis step. It is present as an alkoxycarbonylamino group (preferably t-butoxycarbonylamino) until deprotection in acidic conditions.

Thus, the prepared compounds may be recovered from the reaction mixture in a conventional manner, for example, by distillation of the solvent from the reaction mixture, or if necessary, the solvent is distilled from the reaction mixture and then the residue is brought into water. After pouring, it is prepared by extracting with a water-mixing solvent and distilling the solvent from the extract. In addition, if desired, the product may be purified by conventionally well known techniques such as recrystallization, reprecipitation, or various chromatography techniques, detectable column chromatography or preliminary tin layer chromatography (TLC).

Activity ( activity Based on

Therapeutic usages underlying the present invention result from a number of novel medical examinations, as described in detail in the Examples below. To understand the theoretical principles of the present invention, it would be useful to summarize such findings as to how to anticipate the therapeutic activity claimed in the present invention beyond the scope of the active drug defined above.

Smilagenin, epismilagenine, salsa saponogenin and episasa sagenogenin restore the loss of muscarinic acetylcholine receptors and adrenergic receptors in cells that express these receptors in vitro. These results show that the compounds restore towards receptor loss of normal cells (Example 1).

Salsa sapogenin, episalsa sapogenin catylate, episasa sagenogenin, epismilagenin and smilagenin prevent chemically induced neurodegeneration in rat cortical neurons in vitro. These results indicate that these compounds are neuroprotective and prevent neurodegeneration and nerve damage in vitro. (Example 2)

Salsasapogenin, smilagenin, 16,22-epoxycoprostan-3β-ol, smilagenone, smilagenin glycinate hydrochloride, and coprosterol may be found in rat cortical neurones in vitro. Reverses chemically induced neurodegeneration These results indicate that these compounds reverse sensory neurodegeneration and nerve damage in vitro. (Example 3)

Smilagenin converts chemically induced apoptosis in neurons, which shows anti-apoptotic and neuroprotective properties in vitro. (Example 4)

Smilagenin and salsa saponogenin exhibit their neurotrophic effects in vitro, thereby increasing the growth of neurites (neurite number and in neural in vitro) in rats. Neurite branch)). (Example 5)

Smilagenin and salsa saponogenin induce neurotoxin-induced neurodegeneration (neurotoxin 1-methyl-4-phenylpyridinium (MPP +)) in vitro in mesenchephalic dopaminergic neurons These results indicate that these compounds prevent or reverse neurodegeneration and nerve damage in vitro. (Examples 6 and 7)

Salsa saponogenin and smilagenin reverse chemically induced neurodegeneration in vitro in rat spinal motor neurons. These results indicate that the compounds reverse neurodegeneration and neuronal damage of motor neurons in vitro (Example 8).

Salsa saponenin, episasa saponenin catylate and smilagenin reduce the number of false responses in in vitro experiments on cognitive abilities of old rats, which are found in the bone marrow of old rats treated with the tested compounds. Correlated with increasing muscarinic acetylcholine receptor density. These results indicate that the compounds reverse neuronal damage in vivo. (Example 9)

Smilagenin and salsapogenin reverse the decay in the brain derived from neurotrotrophic factor (BDNF) and decrease in muscarinic acetylcholine and dopamine receptors in older animals. These results indicate that these compounds reverse the neurodegeneration, neuronal damage and neurotrophic of motor neurosensory organs in vivo (Example 9).

Episalsasapogenin Cartylate, Salsasapogenin Carthylate, Episalsasapogenin and Epismilagenin were tested in vivo for the cognitive abilities of young rats exposed to neurotoxin drugs (aibothenic acid and amyloid β). It reduces the number of false positives and increases the muscarinic acetylcholine receptor density in the spinal cord. These results indicate that the compounds reverse neuronal damage in vivo. (Example 10)

Smilagenin and salsa saponogenin enhance survival and neurodegeneration and neurological damage of motor-sensory organs in rat models of amyotrophic lateral hardening layer (ALS) and Charcot-Marie-Tooth disease. (Example 11)

In summary, these compounds have been known to slow or reverse certain aspects of neuronal degeneration. This includes reversal of reverse changes in the cell body; Atrophy of nerve expansion; Neurotropins (eg BDNF, NGF, NT-3, NT4 / 5), TGF-β super-family neurotrophic factors (eg GDNF) and neurokines (eg CNTF, LIF) Reduction of neurotrophic factor release; And reversal of neurotoxicity or apoptosis. The compounds have potent neuroprotective properties, accumulation of neurite growth, and prevention of neurotoxicity. Such compounds have been known to slow or reverse the decrease in cholinergic and dopamine function, such as a decrease in muscarinic acetylcholine and dopamine receptor density. In addition, we have found that the neuroprotective and reversal of the receptor loss effect is actually a modifiable effect, which reverses the deterioration of the past to normal or young by protecting the continuously worsening condition. . In addition, we found that the reversal of the killing effect of these compounds can be regulated in the non-neoplastic domain of the cell cycle and does not induce neoplasia.

The above data means that it can strongly respond to the disease state already described in the present invention. In addition, the data have been observed to be free of serious or life-threatening side effects such as cancer.

The prior art described above represents a negative-based and negative prediction of therapeutic activity with respect to related chemical structures and derivatives encompassed by the term "active drug" in the present invention as an extension of the above observations.

Other groups suitable for sugar, ester and steroid molecules, particularly at the 3- and / or 26-positions, are readily cleaved by hydrolysis in vivo, and this same effect can be expected at other carbon atoms of the molecule. Pharmacology and are well known in the art. In addition, salts, free acids and free bases included within the term "active drug" as used in the present invention are body fluids in which the active drug is present in vivo. It is known that it can be easily converted to each other depending on the pH of the. In addition, the side group substituents in the various forms of range do not actually adversely affect the pharmacological activity of the structure, and may be present in the carbon skeleton complex, especially when the size of the side group is small compared to the size of the entire molecule. Known.

For these reasons as above, the claims which show the benefits of the pharmacological activity produced in the present invention are reasonable and are based here on the certainty and reliability from the experimental data present.

In one precondition, the compound reduces the rate of degeneration of neurotrophic factors, such as the brain derived from growth factors and / or nerve growth factors, and with the brain derived from growth factors and / or nerve growth factors. Increase the production or release of the same neurotrophic factor. This effect on growth factors may be due to a direct effect on the rate of production of cellular substrates or nuclear receptors, or mRNA, which is a growth factor, as a result of binding of compounds in the stimulant domain or increased production of other material factors. Because of the effect of the compound.

In addition, the compounds have been shown to modulate receptors. For example, some of these compounds have been found to prevent or reverse the loss of muscarinic acetylcholine or dopamine receptors in the brain, which compounds modify the number of receptors or the ability to correct deficiencies in function or trunover. It is thought to be due.

Sapogenin, compounds related thereto, and derivatives thereof of the present invention may be used for non-cognitive neurodegeneration, non-cognitive neuromuscular degeneration, and neurodegeneration of motor-sensory organs. (motor-sensory neurodegeneration), or therapy in receptor dysfunction or loss.

1 shows the effect of epismilagenin acetate on 5 day old m3 and β2 adrenergic receptor densities in CHO-β2 / m3 co-infected cell stems.
Figure 2 shows the effects of salsa saponogenin, episalsa saponogenin citrate and smilagenin on glutamate-induced neurodegeneration in the early cortical neurons of rats.
Figure 3 shows the effect of salsa saponogenin, episasa saponogenin citrate and smillagenin on the learning ability and memory of old mice.
Figure 4 shows the effect of salsa sapogenin, episasa sagogenin catylate, and smilagenin on the number of muscarinic receptors.
Figure 5 shows the survival profile of SOD-1 mice after oral administration of smilagenin.
Figure 6 shows the survival profile of pmn rats after oral administration of salsa saponogenin.

In order to describe the present invention without limiting the embodiment, the accompanying drawings and examples are shown as follows. However, the invention is not intended to limit the claims in any other way.

Example  1: in vitro experiment ( in vitro Recovery of receptor loss in

epismilagenin catylate, salsa saponenin on the expression of muscarinic acetylcholine receptor (m) in CHO cells or β2 and m3 receptors of CHO cells infected with carriers for m receptors or co-infected with carriers for β2 and me receptors The effects of cartilate, episalsa saponogenin catylate, episalsa saponogenin succinate, and salsa saponenin were investigated.

The results are shown in the following Table 1 and Figure 1. During the incubation cycle, CHO cells were infected with carriers for m receptors and treated with epismilagenin catylate, salsa saponenin catylate, episasa saponenin catylate, episasa saponogenin succinate, and salsa saponenin, respectively. The reduction of the number was prevented. CHO cells were simultaneously infected with carriers for β2 and m3 receptors during the culture cycle, while the density of m3 receptors remained unchanged, while the density of β2 adrenergic receptors decreased. Incubation with epismilagenin acetate did not significantly change the density of m3 receptors, but significantly prevented the reduction of β2 adrenergic receptors.

Restorative Effect of Epismilagenin Cartilate, Salsa Saponenin Cartilate, Episalsa Saponenin Cartilate, Episalsa Sagenogenin Succinate, and Salsa Sagenenin on the m-acetylcholine Receptor Density compound Concentration [microM] Activity Epismilagenin Cartylate 10 ++ Salsa-Sapogenin Cartylate 10 ++ Episalsa Saponogenine Cartylate 10 ++ Episalsasapogenin Succinate 10 ++ Salsa saponenin 10 ++

Thus, in this experiment, epismilagenine cartilate, salsa saponenin catylate, episasa saponenin catylate, episasa saponenin succinate, and salsa saponenin, respectively, can prevent the decrease in the number of receptors over time, Given to cells that have decreased receptor levels, they have shown a tendency to restore receptor numbers to normal levels.

Example  2 : Salsa saponenin , Episalsa saponogenin Cartylate , Episalsa saponogenin , Epi Smilagenin and Smilagenin  Neuroprotection in neurons neuroprotective ) effect

The purpose of this experiment was to examine the effects of salsa saponogenine, episalsa saponenin catylate, episalsa sapogenin, epismilagenin and smilagenin on the survival of paranormal neurons in rats exposed to glutamate known to cause neurodegeneration. It was.

Rat cortical neurons were incubated for 10 days, and on day 10, the medium was switched to serum-free medium. On day 12, 24 hours prior to exposure to glutamate, the cultures were washed and the medium was washed with positive controls (β-oestradial), test compounds (salsapogenin, episalsasapogenin catylate, episalsasapogenin, epismilagenin And fresh medium, including silagenin), or excipient control (DMSO, 0.25%), or negative control, diosgenin.

On day 13, the cultures were exposed to glutamate. After the incubation period, the cultures were washed and placed on fresh medium supplemented with relevant compounds or excipients that could enhance their protective effect 24 hours after glutamate exposure.

Cell survival of neurons was tested by measuring the lactate dehydrogenase (LDH) activity released in the medium 24 hours after test compound treatment or glutamate plus test compound exposure using the CytoTox 96 non-radioactive kit. The absorption wavelength at 450 nm was measured and quantified.

Exposing the rat's initial cortical culture with glutamate resulted in significant degeneration in cortical neurons, and 24 hours post-treatment appeared due to increased release of lactate dehydrogenase into the culture medium.

Early cortical cultures pretreated with compounds for 24 hours showed a significant reduction in glutamate-induced neurodegeneration. (Figure 2, Table 2)

Effects of salsa saponogenin, episalsa sapogenin catylate, episalsa sapogenin, epismilagenin and smilagenin in the prevention of glutamate-induced neurodegeneration Condition Mean ± s.e.m (%) Control group 100 + Glutamate 66 ± 3 + Glutamate + salsapogenin (30nM) 79 ± 3 Control group 100 + Glutamate 65 ± 3 + Glutamate + Episalsa Saponogenin Cartylate (30 nM) 74 ± 3 Control group 100 + Glutamate 68 ± 3 + Glutamate + episalsasapogenin (30nM) 88 ± 3 Control group 100 + Glutamate 71 ± 2 + Glutamate + epismilagenin (30nM) 79 ± 2 Control group 100 + Glutamate 68 ± 4 + Glutamate + smilagenin (30 nM) 91 ± 4 Control group 100 + Glutamate 68 ± 4 + Glutamate + diocegenin (30nM) negative control 72 ± 4

Salsa saponenin, episalsa saponenin catylate, episasa saponenin, epismilagenin and smilagenin all have excellent neuroprotective effects against glutamate-induced neurodegeneration in in vitro experiments of rat superficial cortical neurons. Indicated.

Example 3: In the neuronal salsa sandpaper genin, Smila genin, 16,22- epoxy Corp. as Stan -3β- ol, Smila genon, Smila genin Glycinate Reversal of neurodegeneration by hydrochloride and coprosterol

As mentioned above, it can be seen that the lactate dehydrogenase activity measured after 24 hours by exposing rats' first cortical cultures to glutamate (100 μM; 10 min) shows significant neurodegeneration. After exposure to glutamate, treatment with 17β-oestradial showed a significant decrease in LDH activity compared to neurons exposed to glutamate, indicating an important neuroprotective effect. Similarly, when treated with salsasapogenin, smilagenin, 16,22-epoxycoprostan-3β-ol, smilagenone, smilagenin glycinate hydrochloride and coprosterol, compared to neurons exposed to glutamate, There is a significant reduction in LDH activity, which also implies a significant neuroprotective effect. Table 3

Effect of various compounds on epidermal neurons prior to exposure to glutamate Condition Mean ± s.e.m (%) Control group 100 ± 4 Glutamate [100 μM] 66 ± 2 Glutamate + 17βoestradiol [3 nM] 69 ± 2 Glutamate + 17βoestradiol [30 nM] 75 ± 5 Control group 100 ± 1 Glutamate [100 μM] 67 ± 3 Glutamate + salsa saponogenin [3 nM] 101 ± 3 Glutamate + salsa saponogenin [30 nM] 112 ± 1 Glutamate + smilagenin [3 nM] 109 ± 6 Glutamate + smilagenin [30 nM] 104 ± 1 Control group 100 ± 8 Glutamate [100 μM] 40 ± 1 Glutamate + diosgenin [30 nM, negative control] 49 ± 6 Control group 100 ± 5 Glutamate [100 μM] 64 ± 4 Glutamate + 16,22-epoxycoprostan-3βol [3 nM] 114 ± 7 Glutamate + 16,22-epoxycoprostan-3βol [30 nM] 134 ± 5 Glutamate + smilagenone [3 nM] 119 ± 7 Glutamate + smilagenone [30 nM] 119 ± 4 Control group 100 ± 4 Glutamate [100 μM] 58 ± 3 Glutamate + smilagenin glycinate hydrochloride [3 nM] 117 ± 4 Glutamate + smilagenin glycinate hydrochloride [30 nM] 141 ± 6 Glutamate + coprosterol [3 nM] 126 ± 5 Glutamate + coprosterol [30 nM] 116 ± 4

In conclusion, salsasapogenin, smilagenin, 16,22-epoxycoprostan-3β-ol, smilagenone, smilagenin glycinate hydrochloride and coprosterol in rat superficial epidermal neurons are neurons induced by glutamate Reversal of degeneration suggests treatment potential in neurodegenerative disorders.

Example  From 4 neurons Smilagenin  Semi-examination ( anti - apoptotic ) effect

The purpose of this experiment was to determine the anti-apoptotic effect of smilagenin on caspase-3 activity, a marker of apoptosis, in rat epidermal cultures exposed to glutamate.

Primary culture of epidermal neurons

Rat cortical neurons were incubated for 6 days, and on day 6, glutamate (100 μM), 10 min was added. The cultures were then washed and the medium was replaced for 6 hours with fresh medium containing smilagenin or excipient control (DMSO, 0.25%). After 6 hours of treatment, apoptosis was measured by measuring caspase 3 activity. Caspase 3 activity was determined by cleavage of p-nitroaniline from a color-based caspase-3 substrate, acetyl-ASp-Glu-Val-Asp p-nitroanilide. Relative caspase-3 activity was determined by optical density, and in addition, the relative activity of caspase-3 quantified the hydrogen concentration of the sample, which was also measured as optical density. (Du et al, J Neurochem., 69, 1382-1388, 1997; Sawada et al, Faseb J., 14, 1202-1214, 2000)

Smilagenin reverses the increase in glutamate-induced caspase-3 activity in rat paragonal neurons, confirming that smilagenin exhibits an anti-apoptotic effect. Table 4

Effect of Smilagenin on Glutamate-induced Caspase-3 Activity in Cortical Neurons Condition Caspase activity (% of control) Control group 100 + Glutamate 131 + Glutamate + smilagenin (300 nM) 105

Example  5

Neurodegenerative disorders are characterized by gradual loss of neurons and degeneration of neuronal processes. Drugs that induce the natural outgrowth of neurites are facilitated by the formation of new relationships between neurons and improving symptoms of neurodegenerative diseases. (Katzman et al, Faseb J., 5,278-286, 1991)

Exposure to 17β-oestradial (0.3,3,30 pM) significantly increased the extant length of neurites in rat paracortical neurons. (Table 5) Exposure to 17β-oestradial (3,30 pM) The percentage of neurons exposing neurites in superparasitic cortical neurons was significantly increased (Table 6). Significantly increased the percentage of neurons revealing length and neurites (Tables 5 and 6).

In conclusion, smilagenin and salsa saponogenin were confirmed to have neurological effects through in vitro experiments.

Effect of 17β-oestradial, smilagenin and salsa saponogenin on neurite length measured using optical microscopy Condition Mean ± s.e.m (%) Control 100 ± 4 17β-oestradial (0.3 pM) 154 ± 5 17β-oestradial (3 pM) 163 ± 4 17β-oestradial (30 pM) 183 ± 5 Smilagenin (0.3 pM) 159 ± 5 Smilagenin (3 pM) 190 ± 8 Smilagenin (30 pM) 204 ± 6 Salsa saponenin (0.3 pM) 177 ± 5 Salsa saponenin (3 pM) 197 ± 5 Salsa saponenin (30 pM) 211 ± 6

Effect of 17β-oestradial, smilagenin, and salsa saponogenin on the number of neurons that show neurites Condition Mean ± s.e.m (%) Control 47 ± 2 17β-oestradial (0.3 pM) 48 ± 2 17β-oestradial (3 pM) 60 ± 2 17β-oestradial (30 pM) 59 ± 2 Smilagenin (0.3 pM) 63 ± 2 Smilagenin (3 pM) 63 ± 2 Smilagenin (30 pM) 66 ± 2 Salsa saponenin (0.3 pM) 55 ± 2 Salsa saponenin (3 pM) 61 ± 1 Salsa saponenin (30 pM) 62 ± 2

Example  6

Smilagenin and salsa saponogenin are neurons developed by exposure to Neutrotoxin, 1-methyl-4-phenylpyridinium (MPP +), in rat middle brain dopaminergic neurons, an in vitro model of Parkinson's disease. Denaturation was prevented.

Injury caused by the metabolite of neurotoxin, MPP +, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is associated with neurodegenerative disorders such as Parkinson's disease. It mimics the neurodegeneration of the observed nigrostriatal dopaminergic neurons. (Mytinlineou et al, Science, 225, 529-531, 1984) The most dominant biochemical changes induced by these toxins are the substantia nigra pars compacta and the nucleus nucleus (Burns et al, Reduced levels of dopamine and its metabolites, and nigrostriatal synaptosomal preparations (heikkila et al, J Neurochem., 44,310-) in Proc natl Acad Sci USA, 80,4546-4550, 1983). 313, 1985).

Pretreatment of dopaminergic neurons with smilagenin and salsapogenin significantly reduced neuronal disappearance due to exposure of certain dopaminergic neurotoxins MPP + (2 μM) when compared to MPP + alone. Glial cell stem-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), and molecules related to neuronal growth were used as positive controls. Pretreatment with smilagenin and salsapogenin showed a significant increase in neuron survival compared to neurons exposed to MPP + alone, suggesting an important neuroprotective effect (Table 7).

Pretreatment Effects of BDNF and GDNF, Smilagenin and Salsasapogenin on Dopamine Neurons After MPP + (2μM) Exposure Condition Mean ± s.e.m (%) Control 100 ± 3 + MPP + (2 μM) 55 ± 3 + MPP + (2 μM) + BDNF (1.85 nM) & GDNF (0.17 nM) 122 ± 7 + MPP + (2 μM) + smilagenin (30 nM) 98 ± 4 + MPP + (2 μM) + salsa sapogenin (30 nM) 89 ± 3

In vitro models of Parkinson's disease pretreated with smilagenin and salsa saponogenin significantly prevent neuronal degeneration following exposure to certain dopaminergic neurotoxins, MPP +, a neuroprotective effect It means to represent.

Example  7

In addition, smilagenin and salsa saponogenin are caused by exposure to neurotoxin 1, -methyl-4-phenylpyridinium (MPP +) in dorsal brain dopaminergic neurons in rats, an in vitro model of Parkinson's disease. Neurodegeneration was reversed.

Dopaminergic neurons treated with smilagenin and salsapogenin significantly reduced the death of neurons by exposure to certain dopaminergic neurotoxin MPP + (2 μM) compared to that treated with MPP + alone. Glial cell stem-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), molecules related to neuronal growth, and 17β-oestradial were used as positive controls. Treatment with smilagenin and salsapogenin showed a marked increase in neuronal survival compared to neurons exposed with MPP + alone.

Effects of BDNF and GDNF, Smilagenin, Salsasapogenin and 17β-oestradial Treatment in Dopaminergic Neurons After MPP + (2μM) Exposure Condition Mean ± s.e.m (%) Control 100 ± 6 + MPP + (2 μM) 76 ± 4 + MPP + (2 μM) + BDNF (1.85 nM) & GDNF (0.17 nM) 98 ± 5 + MPP + (2 μM) + smilagenin (30 nM) 111 ± 6 + MPP + (2 μM) + salsa sapogenin (30 nM) 112 ± 6 + MPP + (2 μM) + 17β-oestradial (30 nM) 106 ± 5

Exposure to MPP + showed a significant decrease in the percentage of neurites as well as a significant decrease in dopaminergic number. These studies showed that smilagenin and salsa saponogenin significantly increased the number of neurites in in vitro experiments of neurons, as shown in Table 9. These results indicate that the compound reverses motor neuron degeneration.

Effect of Neurites Percentage of Smilagenin and Salsasapogenin on Dopamine Neurons After MPP + (2μM) Exposure Condition Mean ± s.e.m (%) Control 41 ± 4 + MPP + (2 μM) 27 ± 5 + MPP + (2 μM) + smilagenin (0.03 nM) 41 ± 4 + MPP + (2 μM) + salsa sapogenin (0.03 nM) 43 ± 4

Example  8 motor neurons in the spine Salsa saponenin  And Smilagenin  Neuroprotective effect

The purpose of this experiment was to evaluate the effects of salsa saponogen and smilagenin on the survival of paravertebral motor neurons in rats exposed to glutamate known to cause neurodegeneration in a model of motor neurodegeneration.

Primary culture of motor neuron of spine

Rat motor neurons were prepared according to the method described in Maritinou et al, Neuron, 8, 737-744. On day 10, the medium was removed and the cultures were exposed to glutamate (4 μM) in defined medium for 37 to 10 minutes. After exposure to glutamate, the medium was washed with Dulbecco modified with Eagle medium at 37 and then placed in fresh culture medium containing test compounds. After 48 hours, the limit of motor neuron degeneration of the spine was measured by measuring the content of lactate dehydrogenase (LDH) released into the culture medium as above.

result

Significant degeneration of motor neuron neurons in the rat paravertebral spine after exposure to glutamate was post-treated for 48 hours, indicating increased lactate dehydrogenase release into the culture medium.

Spinal motor neuron neurons in the first-time rats treated with salsa saponogenin or smilagenin for 48 hours significantly reduced neurodegeneration induced by glutamate. Table 10

Effects of Smilagenin and Salsa Sapogenin on Glutamate-induced Neurodegeneration in Motor Neurons of the Spine Condition Mean ± s.e.m (%) Control + DMSO (0.25%) 100 ± 1 Glutamate [4 μM] + DMSO [0.25%] 94 ± 1 Glutamate + BDNF [3 nM] 148 ± 8 Glutamate + 17β-oestradiol [0.03 nM] 102 ± 2 Glutamate + 17β-oestradiol [3 nM] 110 ± 1 Glutamate + 17β-oestradiol [300 nM] 116 ± 6 Glutamate + salsa sapogenin [0.03 nM] 123 ± 2 Glutamate + salsapogenin [3 nM] 137 ± 1 Glutamate + salsapogenin [300 nM] 136 ± 6 Glutamate + smilagenin [0.03 nM] 128 ± 4 Glutamate + smilagenin [3 nM] 154 ± 1 Glutamate + smilagenin [300 nM] 144 ± 4

Salsa saponogenin and smilagenin have been shown to reverse glutamate-induced neurodegeneration in in vivo experiments of rat spinal motor neurons, a model of motor neuron degeneration.

Example  9

In the second half of life (from humans, 40 years old), the density of neurons decreases in the brain (Selkoe, D J. Sci. Am. 267, 134-142, 1992). The number of neurons, their interrelationship, and their reduction in neurotrophin, such as the brain derived from neurotrophic factors (BDNF; Bothwell, M, Functional interactions of neurotrophins and neurotrophin receptors, Annu. Rev. Neurosci., 18-223-253, 1995), decreases in acetylcholine receptor density (muscarinic and nicotinic) and / or cortical regions (Rinne et al, Brain Res., 336, 19-25, 1985; Selkoe, DJ , Sci. Am. 267, 134-142, 1992). Moreover, as we age, muscarinic acetylcholine receptor binding is observed in hippocampus, Narang, N, Mech.Aging Dev., 78, 221-239, 1995 and striatum of old rats (Beigon et al, Neurobiol, Aging., 10, 305-310, 1989), and humans (Rinne et al, Brain Res., 336, 19-25, 1985). In addition, in Alzheimer's disease, a decrease in cholinerogenic activity is associated with the deposition of amyloid β plaques (von der Kammer et al, Biochem. Soc. Symp. 131-140, 2001). Other neurodegenerative disorders, such as Parkinson's disease, are characterized by a decrease in dopaminergic activity (Drukarch et al, Expert. Opin. Investig. Drugs, 10, 1855-1868, 2001).

Impairment in learning and memory, muscarinic acetylcholine and dopamine by oral administration of salsa saponenin, episasa saponenin catylate or smilagenin to Sprague-Dawley rats 20 month old for 2 or 3 months Reduction in receptors, and reduction in Neutropin BDNF, modifications characteristic of the aging process are reversed.

Old Sprague-Dawley rats were separated into different groups, and one control group and the other group were treated with salsa saponenin, episalsa saponenin catylate or smilagenin (18 mg / kg.day, n = 10) for 2-3 months. It was. Untreated young rat controls (n = 14) were included in this experiment. Daily doses of the drug were mixed with a minimum amount of food and administered to each rat in divided portions each morning.

Learning and memory experiments were performed using the Y-maze instrument. The copper rod was aligned on the underside of each arm of the Y-maze, applying an electrical current of the appropriate voltage as needed. Each upper limb is 45 cm long, with a 15 W lamp at the end and turned on whenever necessary. After 3 months of drug administration, each rat was trained continuously for 7 days as follows. During each training session, rats are placed in one upper limb of the Y-maze, left for 2 minutes, then an electrical current is applied to the copper rod, and the non-stimulation site is illuminated to the right or to the lamp of the upper limb. To indicate. If the rat entered the upper limb, it was recorded as one correct response, otherwise it was recorded as one wrong response. These stimulation-response tests were repeated 20 times daily, each with 5 seconds of rest between two consecutive tests.

After 20 tests on day 7, the number of correct responses was used as an expression of learning ability (the higher the number, the higher the learning ability). The rats were then rested for 30 days, then this process was repeated once more. After a 30-day rest period, the number of correct responses in 20 tests was used as a measure of memory.

Muscarinic acetylcholine receptor density in the brain was measured. Tissues were prepared as follows. The rats were chopped, the brains were quickly removed, lyophilized and transferred to the freezer. The brain was homogenized and finally the pellet was floated in buffer.

A dual-site competitive ligand binding assay was used by measuring the muscarinic acetylcholine receptor density.

The results are shown in the following figures 3 and 4. The Y-maze experiments showed that both the learning and memory were impaired in old mice. However, after administration of salsa saponogenin, episalsa saponenin catylate and smilagenin to old mice, learning and memory were restored. Muscarinic acetylcholine receptor density was markedly reduced in old mice. Salsa saponenin, episasa saponenin catylate and smilagenin have substantially restored the number of muscarinic acetylcholine receptors.

For young mice, significantly higher dopamine (D) 1 and 2 receptor densities (157.7 ± 33.2; 200.6 ± 50.9 fmol / mg) compared to old mice (129.2 ± 36.8; 153.8 ± 40.5 fmol / mg protein, D1 and D2, respectively) protein, respectively). In contrast, old rats treated with smilagenin and salsa saponenin for three months showed D1 and D2 receptor densities (smilagenin 177 ± 10.9; 217 ± 45.7 fmol / mg protein, salsa saponogenin 172.0 ± 44.0; 206.4 ± 60.5, respectively). Was restored.

In addition, young rats showed significantly higher BDNF levels (1.647 ± 0.277 ng / g tissue) compared to old mice (1.205 ± 0.219 ng / g tissue). In contrast, old mice treated with smilagenin and salsa saponogenin for 3 months partially restored BDNF levels (1.342 ± 0.07; 1.410 ± 0.232 ng / g tissue, respectively).

Thus, these compounds reversed neuronal damage, a decrease in BDNF levels, and a decrease in muscarinic acetylcholine and dopamine receptor density that occurred in old mice.

Example  10

Alzheimer's Disease Model as a Neurodegeneration Model

An in vivo model of Alzheimer's disease was used as a neurodegeneration model. In this model, neurotoxin drugs (amyloid beta and ibothenic acid) were injected into the rat brain because it led to receptor loss and cognitive damage in the brain. Previous studies have shown that local injection of amyloid β in the nucleus vasalis of the rat brain causes cholinergic hypofunction and impaired behavior of choline up to 2 months postoperatively (Giovannelli et al., 1995: Neuroscience, 66, 781-792.). In addition, co-injection of a small amount of amyloid β ibothenic acid into the hippocampus of rats results in loss of neurons due to infiltration of distant Glia cells as well as close to the injected site. (Morimoto et al., 1995: Neuroscience, 84, 479-487).

In the study of the present invention, the Morimoto method (Morimoto et al., 1998: Neuroscience, 84, 479-487) was used with minor modifications (alone instead of both injections). Three month old Sprague Dawley rats were randomly divided into different groups. Infusion of amyloid β1-40 and ibothenic acid (both purchased from Sigma) was performed using a stereotaxic instrument (produced by Stoelting). Coordinate is AP = -0.5mm (right side of the middle line). , L = -2.8 mm (rear from bregma), and H = -7.0 mm (lower part of the endocardium). Dose for each rat was amyloid 1-40 (4 μg) and ibothenic acid (1 μg) in 1 μl saline. Injection was completed within 20 minutes and the needle was removed after 10 minutes. The skin was then sutured.

The eight groups are:

-Control (control) manipulated by injecting normal saline

Model (control infused with amyloid β + ibothenic acid)

-Model + Episalsa sapongenin Cartylate (18mg / kg / day) *

Model + salsa saponogenine carboxylate (18 mg / kg / day) *

-Model + Episalsa sapongenin ethyl succinate (18mg / kg / day) * (comparative)

-Model + Episalsa saponogenin (18mg / kg / day) *

Model + Epismilagenin (18mg / kg / day) *

Model + Diosgenin (ie negative control, 18 mg / kg / day) *

Where * is a compound consistent with the present invention.

Episalsa saponenin cartylate, Salsa saponenin cartylate, Episalsapogenin ethyl succinate (comparative compound), Episalsasapogenin, epismilagenine and diosgenin (all of these are 18 mg / kg / day) Was administered to animals via a gastric tube in a stable suspension of CMC-Na (0.5%) once daily. Control and model groups were administered in the same volume of CMC-Na (0.5%) once daily. Drugs and excipients were administered for 2 months beginning 20 days prior to administration.

Muscarinic acetylcholinergic receptor density was measured. Brain samples were homogenized, centrifuged, and centrifuged samples at 27000 × g were re-homogenized and used for measurement. The concentration of 3H-QNB was chosen in the saturation range. After incubation and separation, the binding portion was measured with a liquid scintillation calculator.

Step test: The memory effect of the test compound was evaluated through step test. A box of 60 × 15 × 15 cm was divided into equally sized spaces, one of which was electrically applied (40 V ac), using copper rod bases in the dark space, while the other was not energized into the bright spaces. A passage (hole) was placed between the two spaces to allow the rat to pass. The experiment was performed for two days in succession using each rat. The first day was practiced; The rats were then allowed to acclimate to the box for the first three minutes, then placed in a bright room, with the back of the mouse facing the aisle, and in dark spaces the copper rods were energized for five minutes. On the second day, the number of traverses for 5 minutes was recorded as the period for testing. The improvement of memory was determined by the decrease in the number of crossings.

The density of muscarinic receptors in the brain of the neurodegenerative model was observed to be significantly lower than the control. Episalsa saponenin catylate, salsa saponenin catylate, episasa sapogenin and epismilagenin have been found to significantly increase muscarinic acetylcholinergic receptor density in the brain, whereas diosgenin and episalsa saponogenin ethyl Succinate did not show a significant change in muscarinic acetylcholinergic receptor density. Thus, through these experiments, the compounds of the present invention play a role in normalizing the number of receptors, i.e., when added to animals with reduced receptor levels, the compounds of the present invention maintain the normal number of receptors. It seems to be prone.

Within 5 minutes, many error numbers were higher in the neurodegeneration model group than in the control group, indicating memory impairment (see Table 11 below). Each epismilagenine, episalsa saponenin catylate, episalsa sapogenin and salsa saponenin catylate can be seen to significantly reduce the number of such false responses, while diosgenin and episalsa saponenin ethyl Succinate is not all effective in reducing the number of false responses.

group Muscarinic Receptor Density
(fmol / mg / protein) Learning and memory test through steps
(Error No) Control (n = 10) 859 ± 101 0.60 ± 0.70 Model (n = 10) 713 ± 48 4.00 ± 2.40 Model + episalsa saponogenine citrate (n = 10) 877 ± 89 * 1.36 ± 0.92 * Model + salsa saponogenine citrate (n = 11) 916 ± 158 1.36 ± 1.03 * Model + episalsa saponogenine ethyl succinate (n = 11) 774 ± 79 3.73 ± 1.35 Model + episalsa saponogenin (n = 10) 869 ± 104 * 1.50 ± 1.18 * Model + epismilagenin (n = 11) 877 ± 90 * 1.73 ± 0.91 * Model + Diosgenin (n = 8) 770 ± 68 3.75 ± 1.49 Statistical analysis using t-test of unpaired students.
* Means p <0.05.

Example  11

Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disorder that causes degeneration of motor neurons, skeletal atrophy, stroke and death. The incidence of this disease is heterogeneous: Cu / Zn superoxide dismutase (SOD-1) gene degeneration causes several forms of ALS in humans. Animal models for this disease include SOD-1 transgenic mice expressing the SOD-1 gene and mice with progressive motor neuron (pmn, Charcot-Marie-Tooth model). Smilagenin and salsa saponogenin increased lifespan and enhanced behavioral disturbances in SOD mice (Figure 5) and pmn mice (Figure 6), two models of ALS and Charcot-Marie-Tooth disease.

The invention has been described broadly above. However, one of ordinary skill in the art will recognize that the spirit and scope of the present invention and its accompanying patents can be readily modified and changed.

Claims (8)

Iii) noncognitive neurodegeneration, ii) noncognitive neuromuscular degeneration, iii) neurodegeneration of motor-sensory organs, iii) suffering from or suffering from receptor dysfunction or loss in the absence of cognitive, neurologic and neuromuscular defect For the easy treatment or prevention of human and non-human animals, the following compounds A) to E), all stereoisomers and racemic mixtures thereof, all pharmaceuticals thereof, in the treatment or prophylaxis, or in the preparation of the composition Use of at least one active drug selected from acceptable pro-drugs and salts, and all mixtures and combinations thereof:
A) a compound represented by the following formula (1);
Formula 1

In which R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₁₀ , R ₁₃ , R ₁₈ , R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ , R ₂₆ , R ₂₇ , R ₂₈ , R ₂₉ , R ₃₀ , R ₃₁ , and R ₃₂ are independent of each other, and H, OH, = O, a halogen atom, (Me-S-), ( Me-SO-), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH-, alkyl; Or unsubstituted; Or OR, wherein R is an alkyl group or acyl group,
R ₉ , R ₁₁ , R ₁₂ , R ₁₄ , R ₁₅ , R ₁₆ , R ₁₇ , R ₂₅ , and R ₃₃ represent H, OH, a halogen atom, (Me-S-), (Me-SO-), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH-, an alkyl group; Or unsubstituted; Or OR, wherein R is an alkyl group or acyl group,
... represents an arbitrary double bond,
In addition to the above,
R ₃₃ or R ₁₄ One is an alkyl group;

B) a compound represented by Formula 2;
Formula 2

In which R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₁₀ , R ₁₃ , R ₁₈ , R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ , R ₂₆ , R ₂₇ , R ₂₈ , R ₂₉ , R ₃₀ , R ₃₁ , R ₃₂ and R ₃₄ are independent of each other, H, OH, = O, a halogen atom, (Me-S-) , (Me-SO-), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH-, an alkyl group, OR, wherein R is an alkyl or acyl group, or unsubstituted;
R ₉ , R ₁₁ , R ₁₂ , R ₁₄ , R ₁₅ , R ₁₆ , R ₁₇ , R ₂₅ , R ₃₃ and R ₃₅ represent H, OH, a halogen atom, (Me-S-), (Me-SO- ), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH-, an alkyl group, OR, wherein R is an alkyl group or an acyl group, or unsubstituted;
... represents an arbitrary double bond,
In addition to the above,
One of R ₃₃ or R ₁₄ is an alkyl group;

C) a compound represented by Formula 1;
(3)

Where R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₁₀ , R ₁₃ , R ₁₄ , R ₁₈ , R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ , R ₂₆ , R ₂₇ , R ₂₈ , R ₂₉ , R ₃₀ , R ₃₁ , R ₃₂ , R ₃₃ , R ₃₄ , R ₃₅ , R ₃₆ and R ₃₇ are independent of each other, H, OH, = 0, halogen atom, (Me-S-), (Me-SO-), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH-, alkyl group, OR (where R is Alkyl group or acyl group) or unsubstituted;
R ₉ , R ₁₁ , R ₁₂ , R ₁₅ , R ₁₆ , R ₁₇ and R ₂₅ are H, OH, halogen atoms, (Me-S-), (Me-SO-), (Me-SO _2- ) , N _3- , NH _2- , MeSO ₂ NH-, an alkyl group, OR, wherein R is an alkyl group or an acyl group, or unsubstituted;
... represents an arbitrary double bond,
In addition to the above,
One of R ₃₃ or R ₁₄ is an alkyl group; And
The stereochemistry of R ₂₅ is β-orientation;

D) Sapongenin derivatives derived from one or more X radical substituents, wherein X is
Halogen atoms,
-(Me-S-), (Me-SO-), (Me-SO _2- ),
N _3- , NH _2- , MeSO ₂ NH-, and
-Selected from the group consisting of alkyl groups; And

E) derivatives of any form of the compound, wherein the carbon atom is 3-positioned; Or in the case of Chemical Formulas 2 and 3, each carbon atom at the 3-position, the 26-position, or each of the 3- and 26-positions has an O-sugar unit, which is a sugar group ( sugar groups) are monosaccharides, disaccharides or trisaccharides. The method of claim 1,
Use, characterized in that the active drug, or at least one active drug, is selected from a) to r):
a) a compound represented by Chemical Formula 1,
R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₁₀ , R ₁₃ , R ₁₈ , R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ , R ₂₆ , R ₂₇ , R ₂₈ , R ₂₉ , R ₃₀ , R ₃₁ And R ₃₂ are independent of each other, and H, OH, ═O, halogen atom, (Me-S—), (Me-SO—), (Me-SO ₂ —), N _3- , NH _2- , MeSO ₂ NH-, an alkyl group; Or unsubstituted; Or OR, wherein R is an alkyl or acyl group,
R ₉ , R ₁₁ , R ₁₂ , R ₁₄ , R ₁₅ , R ₁₆ , R ₁₇ , R ₂₅ and R ₃₃ represent H, OH, a halogen atom, (Me-S-), (Me-SO-), ( Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH-, alkyl; Or unsubstituted; Or OR, wherein R is an alkyl or acyl group,
... represents an arbitrary double bond,
In addition to the above,
One of R ₃₃ or R ₁₄ is an alkyl group; And
The stereochemistry of R ₂₅ is a compound that is β-oriented;

b) as a compound represented by Formula 1,
R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₁₀ , R ₁₃ , R ₁₈ , R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ , R ₂₆ , R ₂₇ , R ₂₈ , R ₂₉ , R ₃₀ , R ₃₁ And R ₃₂ are independent of each other, and H, OH, ═O, halogen atom, (Me-S—), (Me-SO—), (Me-SO ₂ —), N _3- , NH _2- , MeSO ₂ NH-, alkyl; Or unsubstituted; Or OR, wherein R is an alkyl or acyl group,
R ₉ , R ₁₂ , R ₁₅ , R ₁₆ and R ₁₇ = H,
R ₁₁ , R ₁₄ , R ₂₅ and R ₃₃ are H, OH, halogen atoms, (Me-S-), (Me-SO-), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH—, alkyl; Or unsubstituted; Or OR, wherein R is an alkyl or acyl group,
... represents an arbitrary double bond,
In addition to the above,
One of R ₃₃ or R ₁₄ is an alkyl group; And
The stereochemistry of R ₂₅ is a β-orientation;

c) As the compound represented by Formula 1,
-R ₁ = R ₂ = R ₄ = R ₅ = R ₆ = R ₇ = R ₈ = R ₁₀ = R ₁₁ = R ₉ = R ₁₂ = R ₁₃ = R ₁₅ = R ₁₆ = R ₁₇ = R ₁₈ = R ₁₉ = R ₂₀ = R ₂₁ = R ₂₂ = R ₂₃ = R ₂₄ = R ₂₅ = R ₂₆ = R ₂₇ = R ₂₈ = R ₂₉ = R ₃₀ = R ₃₁ = R ₃₂ = R ₃₃ = H,
One of R ₃₃ or R ₁₄ is an alkyl group;
-... represents a single bond,
The methyl group at C _{25 is} in the R or S orientation,
The stereochemistry of R ₂₅ is β-orientation; And
In addition to the above,
At least one or more of R ₃ or R ₂₃ is an X radical and may be left as a substituent which is H, OH, ═O, and OR, wherein R is an alkyl or acyl group, or unsubstituted, and X Is a halogen atom, a compound selected from the group consisting of (Me-S-), (Me-SO-), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH- and an alkyl group;

d) as a compound represented by Formula 1,
R ₁ = R ₂ = R ₄ = R ₅ = R ₆ = R ₇ = R ₈ = R ₁₀ = R ₁₁ = R ₉ = R ₁₂ = R ₁₃ = R ₁₅ = R ₁₆ = R ₁₇ = R ₁₈ = R ₁₉ = R ₂₀ = R ₂₁ = R ₂₂ = R ₂₃ = R ₂₄ = R ₂₅ = R ₂₆ = R ₂₇ = R ₂₈ = R ₂₉ = R ₃₀ = R ₃₁ = R ₃₂ = H,
R ₃₃ = R ₁₄ = CH ₃ ;
-... represents a single bond,
The stereochemistry of R ₂₅ is β-orientation; And
In addition to the above,
At least one or more of R ₃ or R ₂₃ is an X radical and may be left as a substituent which is H, OH, ═O, and OR, wherein R is an alkyl or acyl group, or unsubstituted, and X Is a compound selected from the group consisting of a halogen atom, (Me-S-), (Me-SO-), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH-, and an alkyl group,

e) As a compound represented by Formula 2,
R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₁₀ , R ₁₃ , R ₁₈ , R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ , R ₂₆ , R ₂₇ , R ₂₈ , R ₂₉ , R ₃₀ , R _{31 ,} R ₃₂ and R ₃₄ are independent of each other, H, OH, = O, a halogen atom, (Me-S-), (Me -SO-), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH-, an alkyl group, OR, wherein R is an alkyl or acyl group, or unsubstituted;
R ₉ , R ₁₁ , R ₁₂ , R ₁₄ , R ₁₅ , R ₁₆ , R ₁₇ , R ₂₅ , R ₃₃ and R ₃₅ represent H, OH, a halogen atom, (Me-S-), (Me-SO- ), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH-, an alkyl group, OR, wherein R is an alkyl or acyl group, or unsubstituted;
... represents an arbitrary double bond,
In addition to the above,
One of R ₃₃ or R ₁₄ is an alkyl group; And
The stereochemistry of R ₂₅ is a β-orientation;

f) As the compound represented by the formula (2) and carbohydrate derivatives thereof,
R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₁₀ , R ₁₃ , R ₁₈ , R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ , R ₂₆ , R ₂₇ , R ₂₈ , R ₂₉ , R ₃₀ , R _{31 ,} and R ₃₂ are independent of each other and include H, OH, = O, a halogen atom, (Me-S-), (Me-SO -), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH-, an alkyl group, OR, wherein R is an alkyl or acyl group, or unsubstituted;
R ₉ , R ₁₂ , R ₁₅ , R ₁₆ , R ₁₇ = H,
R ₃₄ is H, OH, ═O, and OR, wherein R is an alkyl group, acyl group or carbohydrate group; And
R ₁₁ , R ₁₄ , R ₂₅ , R ₃₃ , and R ₃₅ are H, OH, a halogen atom, (Me-S-), (Me-SO-), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH-, an alkyl group, OR, wherein R is an alkyl group or acyl group, or unsubstituted;
... represents an arbitrary double bond,
In addition to the above,
One of R ₃₃ or R ₁₄ is an alkyl group;
The stereochemistry of R ₂₅ is a β-orientation;

g) a compound represented by the formula (2) and a carbohydrate derivative thereof, wherein:
R ₁ = R ₂ = R ₄ = R ₅ = R ₆ = R ₇ = R ₈ = R ₁₀ = R ₁₁ = R ₉ = R ₁₂ = R ₁₃ = R ₁₅ = R ₁₆ = R ₁₇ = R ₁₈ = R ₁₉ = R ₂₀ = R ₂₁ = R ₂₂ = R ₂₃ = R ₂₄ = R ₂₅ = R ₂₆ = R ₂₇ = R ₂₈ = R ₂₉ = R ₃₀ = R ₃₁ = R ₃₂ = R ₃₃ = H,
R ₁₄ = CH ₃ ;
R ₃₄ = -OH or -OR, wherein R = alkyl, acyl or carbohydrate, and
-R ₃₅ = H or unsubstituted,
-Represents an arbitrary double bond, and
The methyl group at C _{25 is} in the R or S configuration, and
The stereochemistry of R ₂₅ is β-orientation; And
In addition to the above,
At least one or more of R ₃ or R ₂₃ is an X radical and may be left as a substituent which is H, OH, ═O, and OR, wherein R is an alkyl or acyl group, or unsubstituted, and X Is a compound selected from the group consisting of a halogen atom, (Me-S-), (Me-SO-), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH-, and an alkyl group,

h) As a compound represented by the formula (2) and carbohydrate derivatives thereof,
R ₁ = R ₂ = R ₄ = R ₅ = R ₆ = R ₇ = R ₈ = R ₁₀ = R ₁₁ = R ₉ = R ₁₂ = R ₁₃ = R ₁₅ = R ₁₆ = R ₁₇ = R ₁₈ = R ₁₉ = R ₂₀ = R ₂₁ = R ₂₂ = R ₂₃ = R ₂₄ = R ₂₅ = R ₂₆ = R ₂₇ = R ₂₈ = R ₂₉ = R ₃₀ = R ₃₁ = R ₃₂ = H,
R ₁₄ = R ₃₃ = CH ₃ ;
R ₃₄ = -OH or -OR, wherein R = alkyl, acyl or carbohydrate, and
-R ₃₅ = H or unsubstituted,
-Represents an arbitrary double bond, and
The stereochemistry of R ₂₅ is β-orientation; And
In addition to the above,
At least one or more of R ₃ or R ₂₃ is an X radical and may be left as a substituent which is H, OH, ═O, and OR, wherein R is an alkyl or acyl group, or unsubstituted, and X Is a compound selected from the group consisting of a halogen atom, (Me-S-), (Me-SO-), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH-, and an alkyl group;

i) as a compound represented by Formula 3,
R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₁₀ , R ₁₃ , R ₁₄ , R ₁₈ , R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ , R ₂₆ , R ₂₇ , R ₂₈ , R ₂₉ , R ₃₀ , R _{31 ,} R ₃₂ , R ₃₃ , R ₃₄ , R ₃₅ , R ₃₆ and R ₃₇ are independent of each other, H, OH, = O, a halogen atom, (Me-S-), (Me-SO-), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH-, an alkyl group, OR, where R is alkyl or Acyl group) or unsubstituted;
R ₉ , R ₁₂ , R ₁₅ , R ₁₆ , R ₁₇ and R ₂₅ are H, OH, halogen atoms, (Me-S-), (Me-SO-), (Me-SO _2- ), N ₃ -, NH _2- , MeSO ₂ NH-, an alkyl group, OR, wherein R is an alkyl or acyl group, or unsubstituted;
... represents an arbitrary double bond,
In addition to the above,
R ₃₃ or R ₁₄ is an alkyl group; And
The stereochemistry of R ₂₅ is a β-orientation;

j) as a compound represented by the formula (3) or a carbohydrate derivative thereof,
R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₁₀ , R ₁₃ , R ₁₄ , R ₁₈ , R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ , R ₂₆ , R ₂₇ , R ₂₈ , R ₂₉ , R ₃₀ , R _{31 ,} R ₃₂ , R ₃₃ , R ₃₄ , R ₃₅ , R ₃₆ and R ₃₇ are independent of each other, H, OH, = O, a halogen atom, (Me-S-), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH-, an alkyl group, OR where R is an alkyl or acyl group, or substituted Not;
R ₉ , R ₁₂ , R ₁₅ , R ₁₆ , R ₁₇ = H,
R ₃₄ = H, OH, = 0, halogen atom, (Me-S-), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH-, an alkyl group, OR, where R is an alkyl group , An acyl group, or a carbohydrate group) or unsubstituted;
R ₁₁ , and R ₂₅ are H, OH, = 0, halogen atom, (Me-S-), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH-, an alkyl group, OR ( Wherein R is an alkyl group or acyl group) or unsubstituted;
... represents an arbitrary double bond,
In addition to the above,
One of R ₃₃ or R ₁₄ is an alkyl group; And
The stereochemistry of R ₂₅ is a β-orientation;

k) as a compound represented by Formula 3,
R ₁ = R ₂ = R ₄ = R ₅ = R ₆ = R ₇ = R ₈ = R ₁₀ = R ₁₁ = R ₉ = R ₁₂ = R ₁₃ = R ₁₅ = R ₁₆ = R ₁₇ = R ₁₈ = R ₁₉ = R ₂₀ = R ₂₁ = R ₂₂ = R ₂₃ = R ₂₄ = R ₂₅ = R ₂₆ = R ₂₇ = R ₂₈ = R ₂₉ = R ₃₀ = R ₃₁ = R ₃₂ = H,
R ₁₄ = CH ₃ ;
R ₃₄ = -OH or -OR, wherein R = alkyl, acyl or carbohydrate, and
-R ₃₅ = H or unsubstituted,
R ₃₇ = H, -OH or = O,
R ₃₆ = H or -OH,
-Represents a single bond, and
The methyl group at C _{25 is} in the R or S configuration, and
The stereochemistry of R ₂₅ is β-orientation; And
In addition to the above,
At least one or more of R ₃ or R ₂₃ is an X radical and may be left as a substituent which is H, OH, ═O, and OR, wherein R is an alkyl or acyl group, or unsubstituted, and X Is a halogen atom, a compound selected from the group consisting of (Me-S-), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH- and an alkyl group;

l) a compound represented by Formula 3 and a carbohydrate derivative thereof,
R ₁ = R ₂ = R ₄ = R ₅ = R ₆ = R ₇ = R ₈ = R ₁₀ = R ₁₁ = R ₉ = R ₁₂ = R ₁₃ = R ₁₅ = R ₁₆ = R ₁₇ = R ₁₈ = R ₁₉ = R ₂₀ = R ₂₁ = R ₂₂ = R ₂₃ = R ₂₄ = R ₂₅ = R ₂₆ = R ₂₇ = R ₂₈ = R ₂₉ = R ₃₀ = R ₃₁ = R ₃₂ = H,
R ₁₄ = R ₃₃ = CH ₃ ;
R ₃₄ = -OH or -OR, wherein R = alkyl, acyl or carbohydrate, and
-R ₃₅ = H or unsubstituted,
R ₃₇ = H, -OH or = O,
R ₃₆ = H or -OH,
-Represents a single bond, and
The methyl group at C _{25 is} in the R or S configuration, and
The stereochemistry of R ₂₅ is β-orientation; And
In addition to the above,
At least one or more of R ₃ or R ₂₃ is an X radical and may be left as a substituent which is H, OH, ═O, and OR, wherein R is an alkyl or acyl group, or unsubstituted, and X Is a halogen atom, a compound selected from the group consisting of (Me-S-), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH- and an alkyl group;

m) substituted sapogenin, wherein at least one or more OH-groups of the sapogenin are substituted with X, wherein X is a halogen atom, (Me-S-), (Me-SO _2- ), N _3- , NH _2- , MeSO ₂ NH-, and an alkyl group selected from the group consisting of;

n) a compound defined above, wherein the halogen atom in the definition of X is a fluorine atom;

o) (3β-fluoro-5β, 20α, 22α, 25R-spirostane), (3,3-difluoro-5β, 20α, 22α, 25R-spirostane), (3α-methylsulfonylamino -5β, 20α, 22α, 25R-spirostane), (3α-azido-5β, 20α, 22α, 25R-spirostane), (3α-amino-5β, 20α, 22α, 25R-spirostane) And substituted sapogenins selected from stereoisomers and racemic mixtures thereof, pharmaceutically acceptable pro-drugs and salts thereof;

p) substituted sapogenin, wherein the parent sapogenin is selected from salsa saponinin, episalsa sapogenin, smilagenin, epismilagenin, and anzurogenin-D Sapogenin substituted with one or more X radicals as defined;

q) a compound represented by the following formula (4):
Formula 4

Wherein R is a hydrogen atom; Alkylcarbonyl; Alkoxycarbonyl; Alkyl carbamoyl; Or arylcarbamoyl; Or sulfo (HO ₃ S); Phosphono ((HO) ₂ P (O)-); Or monosaccharides, disaccharides or trisaccharides; Wherein any alkyl group is selected from those optionally substituted with aryl, amino, mono- or di-alkyl-amino, carboxylic acid residues (-COOH), or any combination thereof;

r) in the form of a derivative of a compound as defined in the items a) to q) above, in the 3-position carbon atom or in the case of formulas 2 and 3, the 3-position carbon atom, the 26-position carbon atom Or the carbon atoms at the 3- and 26-positions respectively have an O-sugar moiety wherein the sugar group is a monosaccharide, a disaccharide or a trisaccharide. 3. The method according to claim 1 or 2,
The active drug, or at least one active drug, characterized in that selected from the compound represented by the formula (4). 4. The method according to any one of claims 1 to 3,
The active drug, or one or more active drugs
Salsa saponogenin,
Salsa saponenin catylate,
Salsa saponogenin acetate,
Salsa saponogenin succinate and pharmaceutically acceptable salts thereof,
Salsa saponogenin glycinate and pharmaceutically acceptable salts thereof,
Salsa saponogenin alaninate and pharmaceutically acceptable salts thereof,
Salsa saponogenin valateate and pharmaceutically acceptable salts thereof,
Salsa saponogenin phenylalanine and pharmaceutically acceptable salts thereof,
Salsa sapogenin isoleucinate and pharmaceutically acceptable salts thereof,
Salsasapogenin methioninate and pharmaceutically acceptable salts thereof,
Episalsa saponogenin,
Episalsa saponogenin catylate,
Episalsasapogenin acetate,
Episalsasapogenin succinate and pharmaceutically acceptable salts thereof,
Episalsasapogenin glycinate and pharmaceutically acceptable salts thereof,
Episalsasapogenin alaninate and pharmaceutically acceptable salts thereof,
Episalsasapogenin valinate and pharmaceutically acceptable salts thereof,
Episalsasapogenin phenylalanineate and pharmaceutically acceptable salts thereof,
Episalsasapogenin isoleucinate and pharmaceutically acceptable salts thereof,
Episalsasapogenin methioninate and pharmaceutically acceptable salts thereof,
-Smilagenin,
Smilagenin catylate,
Smilagenin acetate,
Smilagenin succinate and pharmaceutically acceptable salts thereof,
Smillagenin glycinate and pharmaceutically acceptable salts thereof,
Smilagenin alaninate and pharmaceutically acceptable salts thereof,
Smilagenin valateate and pharmaceutically acceptable salts thereof,
Smilagenin phenylalanineate and pharmaceutically acceptable salts thereof,
Smillagenin isoleucinate and pharmaceutically acceptable salts thereof,
Smillagenin methioninate and pharmaceutically acceptable salts thereof,
-Epismilagenin,
Epismilagenin catylate,
-Epismilagenin acetate,
Epismilagenin succinate and pharmaceutically acceptable salts thereof
Epismilagenin glycinate and pharmaceutically acceptable salts thereof,
Epismilagenin alaninate and pharmaceutically acceptable salts thereof,
Epismilagenin valinate and pharmaceutically acceptable salts thereof,
Epismilagenin phenylalanineate and pharmaceutically acceptable salts thereof,
Epismilagenin isoleucinate and pharmaceutically acceptable salts thereof,
Epismilagenin methioninate and pharmaceutically acceptable salts thereof;
A saponin derivative of salsa saponogenin, episasa saponogenin, smilagenin and epismilagenin, in which case the 3-position carbon atom has an O-sugar unit, wherein the sugar group is glucose, mannose , Fructose, galactose, maltose, cellobiose, sucrose, rhamnose, xylose, arabinose, fucose, quinobose ( quinovose, apiose, lactose, galactose-glucose, glucose-arabinose, fucose-glucose, rhamnose-glucose, glucose-glucose-glucose, glucose-rhamnose, mannose-glucose, glucose- (rhamnose) ) -Glucose, glucose- (rhamnose) -rhamnose, glucose- (glucose) -glucose, galactose- (rhamnose) -galactose and acylated (eg acetylated) derivatives thereof;
16,22-epoxycoprostan-3β-ol, smilagenone, coprosterol and pharmaceutically acceptable pro-drugs and salts thereof. The method according to any one of claims 1 to 4,
Wherein said active drug is present in a composition selected from pharmaceutical compositions, foods, food supplements and beverages. The method according to any one of claims 1 to 5,
The active drug is characterized in that it is present together with one or more additional active drugs. The method according to claim 6,
The one or more additional active drugs include cholinesterase inhibitors, dopamine agonists, COMT inhibitors, MAO-B inhibitors, anti-cholinergics, acetylcholine agonists, serotonin agonists , AMPA receptor agonists, GABA receptor agonists, NMDA receptor agonists, β-adrenergic receptor agonists, digoxin, dobutamine, anti-inflammatories, neurotrophic factors, statins ), Adenosine A2a receptor antagonists, aldose reductase inhibitors, immunomodulators, cannabinoid agonists, interferon β or tricyclic anti-sedatives ( tricyclic anti-depressant). 8. The method according to any one of claims 1 to 7,
The human or non-human animal may be Parkin's disease; Posten cephalitic parkinsonism; Depression; Schizophrenia; Muscular dystrophy, including facioscapsulohumeral muscular dystrophy (FSH), Duchenne muscular dystrophy, Becker muscular dystrophy, and Bruce's muscular dystrophy; Fuchs'dystrophy; Myotonic dystrophy; Corneal dystrophy; Reflex sympathetic dystrophy syndrome (RSDSA); Neurovascular dystrophy; Myasthenia gravis; Lambert Eaton disease; Huntington's disease; Diseases of motor neuron sensory organs, including amyotrophic lateral sclerosis (ALS); Multiple sclerosis; Positional hypotension; Traumatic neurodegeneration (eg, by seizure or by accident (eg, head injury or spinal cord injury by mental shock)); Batten's disease; Cacayne syndrome (Cockayne syndrom); Down syndrom; Corticobasal ganglionic degeneration; Multiple system atrophy; Oribopontocerebellar atrophy; Dentatorubral atrophy; Palidoluysian atrophy; Spinobulbar atrophy; Optic neuritis; Sclerosing pan-encephalitis (SSPE); Attention deficit disorder; Post-viral encephalitis; Post-poliomyelitis syndrom; Farr's syndrom; Juubert syndrome (Joubert syndrom); Guillain-Barre syndrom; Lissencephaly; Moyamoya disease; Neuromigration disorders; Autistic syndrom; Polyglutamine disease; Niemann-Pick disease; Progressive multifocal leucoencephalopathy; Pseudotumor cerebri; Refsum disease; Zellweger syndrom; Supranuclear palsy; Friedreich's ataxia; Spinocerebellar ataxia type 2; Rhett syndrome; Shy-Drager syndrom; Tuberous sclerosis; Pick's disease; Chronic fatigue syndrome; Neuropathies, including hereditary neuropathy, diabetic neuropathy, and mitotic neuropathy; Creutzfeldt-Jakob disease (CJD), modified Creutzfeldt-Jakob disease (variant CJD), bovine spongiform encephalopathy (BSE), Gersmann-Straeussler-Scheinker Syndrom (GSS), Fmilial Prion-based neurodegeneration, including Insomnia, kuru, and Alper's syndrom; Joseph's disease; Acute disseminated encephalomyelitis; Arachnoiditis; Vascular lesions of the central nervous system; Loss of extremity neuronal function; Charcot-Marie-Tooth disease; Use characterized in that it is suffering from, or is prone to, heart failure, asthma and macular degeneration.

Images