MC2399A1 - Biologically active silicon-based compounds their therapeutic and cosmetic applications - Google Patents

Description

1

The present invention relates to biologically active silicon-based compounds, as well as the therapeutic and cosmetic applications of these compounds.

Silicon, a very widespread element in nature, is generally known in its natural inorganic forms such as silica and silicates, or as synthetic polymers, silicones. These silica compounds are very poorly soluble or insoluble in aqueous environments, which explains their low impact on living organisms. Silicones, in particular, are characterized by high inertness with respect to biological environments and consequently exhibit high biocompatibility.

However, silicon, even in trace amounts, plays an important biological role and must be considered an essential element of life. It is particularly necessary for normal growth in many species. Silicon has also been shown to be involved in the structuring of connective tissues by interacting with glycosaminoglycans and proteins. It is one of the building blocks of the protein-glycosaminoglycan complexes found in the ground substance of these tissues. Silicon also interacts with glycosaminoglycans in the development of cartilage tissue. Silicon is also known to play an important role in ossification, where it promotes the mineralization process.

In addition, silicon can be considered a constituent of collagen and is thought to play a fundamental role in the cross-linking process of collagen fibers.

Silicon is also involved in cellular metabolism and is thought to be particularly beneficial to the metabolic activity of osteoblasts.

35 Beyond the crosslinking power of silicon and its involvement in the metabolic activity of certain cells, it appears that a high silicon content in

2

tissues, along with glycosaminoglycan content, are characteristic of healthy and metabolically active tissues.

Current research tends to reinforce the idea that silicon is involved in numerous biological mechanisms. Recent work has even shown that silicon plays a major role in the elimination of aluminum by biological systems.

The applicant's work has shown that the 10 silica compounds can constitute a form of silicon assimilable by the body (as opposed to mineral silicon or silicones) provided they possess the property of existing in aqueous solution as soluble oligomers of low molecular weight. Furthermore, another characteristic necessary for the activity of these oligomers in aqueous solution is the presence of numerous Si-OH groups. It thus appears that the biological properties of these silica compounds, assimilable by the body, are observed only if they form soluble oligomers in solution, resulting from a chain of Si-O-Si siloxane bonds, rich in Si-OH groups.

Apart from the fact that the presence of highly polar Si-OH groups gives oligomers their water solubility, it is currently thought that some of the observed properties can be explained by the fact that the chemical species involved in most of the biological mechanisms mentioned above is a soluble form of silicon, silicic acid, with the formula Si(OH)4. However, given its very high propensity to polycondense to form silica, this compound exists only at very low concentrations in water.

Researchers therefore sought products similar to silicic acid, but more stable, by chemically modifying the 35 Si-OH functional groups. However, it quickly became apparent that these groups were essential for biological activity. Furthermore, it was known that a series of natural compounds, tannins and

TO S

3

Catecholamines, among others, were capable of complexing silicic acid and thus increasing its stability in solution. These complexes would constitute the transport form of silicic acid in the body, and it is in this form that the cell would import silicon. However, their stability is still too low for the development of a pharmacologically active product.

Therefore, the main objective of the invention is to provide silicon-based compounds with 10 biologically hydrolyzable bonds, particularly in contact with living tissues, and enabling the production of oligomers with biologically active Si-OH functions.

A compound that fulfills this purpose has the following general formula:

20

A B A B

\ / / \

If or X / If

^C ^C

in which A, B, C, D, and X denote different OH radicals, the bonds of A, B, C, D with Si are covalent bonds, and two or three of these bonds are biologically hydrolyzable by in vivo formation of 25 Si-OH bonds.

Radicals that are biologically hydrolyzable are either hydrogen atoms or, preferably, radicals bonded to silicon by an oxygen, nitrogen, or sulfur atom. They can therefore be esters or alkoxy or aryloxy radicals, such as phenoxy radicals, or allyloxy or vinyloxy radicals, when the silicon atom is directly bonded to an oxygen atom. These radicals can also be thioesters or aryl or alkylthioether radicals, when silicon is bonded by a sulfur atom. The radicals can also be mono- or disubstituted amines with hydrocarbon chains, substituted or not by a hydrogen atom.

4

Several functional groups, aryl or alkylamides, are formed when silicon is linked by a nitrogen atom. Finally, a very particular case is that in which the hydrolyzable radicals belong to an insoluble silica support.

Si-bound radicals that are not hydrolyzable can be hydrocarbon radicals, substituted or not by one or more functional groups, certain sterically hindered alkoxy radicals, fluorocarbon radicals, or even a fluorine atom.

In the general formula, X can be a hydrocarbon radical, substituted by one or more functional groups, and preferably linked to silicon by at least 15 hydrolyzable bonds as defined previously.

Examples of compounds according to the invention are given below:

Derivatives of salicylic alcohol (or 2-hydroxybenzyl alcohol):

20

2-oxo-benzyloxy-ethoxymethylsilane

25

Me

2-oxo-benzyloxy-dimethylsilane

30

35

l,k

5

Alpha-hydroxyvacacid derivatives:

Ethoxymethylsilyl-2-oxo-octanoate

10

Dimethylsilyl-2-oxo-octanoate

15

2,2-ethoxymethyl-4-oxo-5-methyl-1,3-dioxa-2-cyclosilane 20 or ethoxymethylsilyl-lactate:

0

-0

I

If

25

M e

Amino acid derivatives:

30

2,2-dimethyl-4-oxo-5-amino-l,3-dioxa-2-cyclosilane (or dimethylsilyl-L-serine)

6

Di-isopropyloxymethylsilyloxy-L-serlne ne

\ /(Jo.

NH-

LOOH

Di-isopropyloxymethylsilyloxy-N-acetyl-L-hydroxyproline

10

■V"

O' VMe

O

■A

15

OH

O

Dimethylsilyl-L-methionine:

20

Me'

25

O

O

HN-

-If \

Me

-Me

Caproic acid derivatives:

30 Dicaproyldimethylsilane:

0 Me Me b

35

7

Caproyldiethoxysilane:

Salicylic acid derivatives:

10 2,2-diphenyl-4-oxobenzo-1,3-dioxa-2-silane

0

15

If

O.

20 2,2-dimethyl-4-oxobenzo-l,3-dioxa-2-silane

0

25

Me

\

Me

2,2-ethoxy, n-octyl-4-oxobenzo-1,3-dioxa-2-silane

30

8

15

20

2,2-dimethyl-4-oxo-(3-octanoyl benzo)-1,3-dioxa-2-silane

Miscellaneous

10 Dimethylsilyl-2,3-5,6-ascorbate

2,2-dimethyl-5-oxo-l,3-dioxa-2-cyclosilane (or dimethylsilyl-dihydroxyacetone):

25

O

X)

Me

-Me

30 Diethyl-phosphato-ethyl-triethoxysilane

35

,0^ O *

oh

<°-\^0-

o.

/,B

9

Hereafter, the biologically active compound comprising two or three Si-OH bonds will be called silyl, and the compounds which are the subject of the invention will be considered "precursors" of silyl, referred to simply as precursors in the rest of the description.

The methods for preparing the compounds according to the invention are numerous. They use commercially available functionalized silanes as starting materials, such as chlorosilanes like 10-tetrachlorosilane SiCl4, alkoxysilanes like tetraalkoxysilane SiOR4, heterofunctional silanes like trichlorosilane C^SiH, or functionalized alkylsilanes to reduce the number of synthesis steps, such as dimethyldichlorosilane, the

15-methyltrietoxysilane, etc...

The precursors according to the invention are therefore biologically inactive compounds, capable, after topical, oral or systemic administration, of spontaneously transforming or in the presence of a specific enzymatic catalyst such as silicase to form a biologically active compound.

If we consider a single hydrolyzable bond of the precursor (knowing that two or three of the bonds are hydrolyzed in the same way), the following transformation 25 takes place on contact with a living tissue such as the skin or mucous membranes, or with a biological fluid.

I

— Si— P + H20 -* —Si— OH + P H

I

30 As previously mentioned, the compounds

Si-OH molecules in aqueous media tend to form soluble oligomers by condensation of two, three, or a few Si-OH molecules. Clearly, if this compound contains only one OH bond, such condensation resulting in dimers would eliminate the Si-OH bonds. Therefore, the precursors according to the invention must have at least two hydrolyzable bonds.

10

The P-H product obtained in the above reaction may be a non-toxic inactive compound or a compound that may promote, enhance or complement the action of silyl.

A characteristic of certain precursors is that the P-H product obtained after hydrolysis acts as a stabilizing agent, which then promotes silyl activity while also helping to limit their polycondensation. After hydrolysis, when the precursor conforms to the first type of the general formula, the stabilizing agent is released into the medium and stabilizes the silyl by forming weak bonds with it (hydrogen bridges). The stabilizing power of these agents can also be explained by their ability to reform a transient covalent bond. This results in a dynamic structure where some bonds possess a "mixed character" (hydrogen bond, covalent bond). Of course, when the precursor conforms to the second type of the general formula, the stabilizing agent can remain bound to the silyl by a covalent bond.

20 Stabilizers meeting the criterion stated above-

The above are, after hydrolysis, hydroxycarboxylic acid compounds, particularly alpha and beta hydroxy acids, glucuronides, hydroxylated or phenolic amino acids such as serine, threonine, or 25-tyrosine, compounds possessing several alcohol (or phenol) functions, and especially vicinal alcohol (or phenol) functions. Examples in this category include glycols, catechols and catecholamines (DOPA, adrenaline), polyethylene glycols, polyols such as glycerol, monosaccharides (L-threose, L-ribose, sorbitol, etc.); phenolic acids such as gallic acid, 3,4-dihydroxybenzoic acid, or caffeic acid, and esterified derivatives; diacids such as malonic acid; certain compounds possessing a particular geometry capable of stabilizing silyl complexes in aqueous media, such as tropolones (e.g., thuj aplicine).

11

In vivo, the hydrolysis reaction can occur spontaneously in the absence of a catalyst. The rate of silyl formation will then depend on several factors:

- pH: an acidic or basic environment greatly increases the reaction rate; the presence of an enzymatic catalyst will specifically increase the hydrolysis rate of certain hydrolyzable bonds.

- the chemical structure of the precursor

10 - the amount of water present, the temperature

- the presence of salts or biological molecules possessing active hydrogen.

One of the characteristics of precursors is their solubleness in nonpolar media: organic solvents, oils, silicones, etc., unlike the highly polar "silyl" form, which is soluble in aqueous solutions and insoluble in oils. Since most precursors are rapidly hydrolyzed upon contact with water to form silyls, these products offer considerable flexibility in formulation, particularly when incorporated into emulsions.

Therefore, precursors can be used in anhydrous formulations. Silyl will only be formed in situ, upon contact with the target organ. This offers 25 advantages, as lipophilic products cross certain biological barriers more easily.

Polarity modification can also be used to ensure that the active silyl retains an affinity for nonpolar media after hydrolysis. This is the case with 2,2-ethoxy, n-octyl-4-oxobenzo-l,3-dioxa-2-silane.

The lipophilic precursor forms are, in the absence of water, stable over a wide temperature range and at any concentration. They can be used pure, whereas the corresponding silyl forms 35 are only stable at high dilution within a narrower temperature range and require the addition of a stabilizer or complexing agent.

12

One of the important characteristics of these products is that it is possible to modulate the precursor's sensitivity to hydrolysis by manipulating its chemical structure. Indeed, while some precursors are hydrolyzed by contact with atmospheric moisture alone, it is perfectly possible, conversely, to obtain precursors that are stable in aqueous media under near-neutral pH conditions. These latter precursors can be useful when selective release of the active ingredient is desired, for example, during gastric hydrolysis.

If the hydrolysis of the precursor is not too rapid, it is possible to obtain a prolonged effect. This "delayed effect" applies particularly to the 15 precursors deprotected sequentially (the hydrolyzable bonds are of a different chemical nature).

Incidentally, precursor formation may help stabilize some of the compounds used as silyl P-protecting groups, which may be useful when P-H has biological activity.

Therefore, the precursors can be used in emulsion in lipids, in the form of a greasy gel, cream, ointment for topical administration, for both therapeutic and cosmetic applications, or in the form of capsules for oral administration in therapeutic treatments, or even in the form of intramuscular injections.

In general, the compounds according to invention 30 can be used in numerous applications involving the properties of the "silyl" forms, namely the therapeutic, dietary or cosmetic properties resulting from their anti-inflammatory, regenerative, anti-degenerative, normalizing activity,

35 metabolic stimulant, anti-radical and anti-glycation, and in general the activity of stimulating the body's defenses.

l.fh

13

The following examples are illustrative (but not exhaustive) of formulations used as medicines or cosmetic products to highlight the activities stated above.

5

EXAMPLE 1:

Regenerative activity - anti-inflammatory 10 Treatment of osteoarthritis

This example concerns the oral treatment of chronic and secondary osteoarthritis, by administration of Di-isopropylmethyl silyloxy-L-

15 N-acetylated hydroxyproline, i.e. Ci4H27NO6Si of M. M. =333.45. The interest is to provide very large quantities of SiOH and hydroxyproline, whose activity is potentiated by SiOH.

The tested compound contains 8.5% Si, which is equivalent to 20 to 14% SiOH.

The initial treatment consists of three 0.4g capsules of active ingredient per day, taken orally in three doses for 3 weeks, followed by two capsules per day for 1 month. The treatment continues with one capsule per day as a course of treatment.

A study was conducted on the effects of di-isopropylmethyl siloxy-L-hydroxyproline on chondroformation (incorporation of thymidine 3(H), production of collagen II and progesterone glycoproteins) and on chondroresorption (basal PGE production, interleukin 6). This study was performed on cultured human chondrocytes for periods of 4, 8, and 12 days. PGE and interleukin levels were measured using radioimmunoassay. Cell proliferation was assessed using a radiometric method.

A positive, dose-dependent effect of silyl on the synthetic activity of osteoblasts was observed in

14

through increased alkaline phosphatase activity. Furthermore, thymidine incorporation rates were found to increase by 51% after treatment.

5 However, the most remarkable effect lies in the very significant decrease in interleukin-6, a marker of inflammation, during the chondroresorption phases. This effect (dose-dependent) is highly indicative of the anti-inflammatory and regenerative activity of silyl. 10 A significant decrease in prostaglandin levels was observed concurrently.

EXAMPLE 2;

15 Regenerative Activity

Microvessel Restructuring

In this example, capsules for oral administration were formulated with Di-caproyl-dimethylsilane 20 (M.M.=288.45), corresponding to a SiOH equivalent of 16%, in order to improve venous and lymphatic microcirculation by acting on capillary tunics.

Capsules numbered 5 were manufactured with a 30% dissolution of the active ingredient in peanut oil, corresponding to a 0.03g intake of silyl per capsule. These capsules were used as a dietary supplement by individuals complaining of heavy legs. The dosage was one to two capsules per day. The tests were conducted on fifteen people over 70 years of age.

30 Twelve people reported the disappearance of pain and a reduction in evening ankle swelling. Of these twelve people, three said they regained the legs of a 20-year-old.

However, the three other people included in this trial had no results, which would correspond to a 20% failure rate.

15

EXAMPLE 3:

Anti-inflammatory, anti-edematous, analgesic and restorative activities 5 Dermo-pharmaceutical composition

The experiment was conducted on severe erythema using 2-oxo-benzyloxy-dimethylsilyl with a molecular weight of 180.28, equivalent to 25% SiOH. 10 2-oxo-benzyloxy-dimethylsilyl was diluted to 25% in

Isostearyl benzoate was subsequently incorporated at a concentration of 10% into an oily gel to restore the protective hydrolipidic film and stimulate skin regeneration through silicon. This significant silica content proved beneficial in treating erythema of varying degrees of edema and the pain resulting from skin tissue damage.

The tested gel has the following formula:

2-oxo-benzyloxy-dimethylsilyl at 25% 10.00

20 Sodium lanolate 12.00

Aluminum stearate 1.00

Vaseline oil 100.00

The trial was conducted on 10 people with severe sunburn, with the freedom to apply the gel 25 times as often as the person wished.

In 80% of cases, we obtained a cessation of pain and a reduction of edema in less than 6 hours, and a reduction of redness of more than 50% in 24 hours, which is very positive.

30 On the other hand, this greasy gel was used after cobalt therapy sessions, on mucous membranes.

We observed a superficial protection of these mucous membranes with a reduction in pain and inflammation.

35

A, 6

16

EXAMPLE 4:

Anti-inflammatory action

Treatment of tendonitis in athletes

5

A rich massage cream was developed. The massages were performed by physiotherapists, and the trials were conducted on patients with tennis elbow.

10. The compound tested was 2-oxo-benzyl-oxy

Dimethylsilane of M.M.=180.28, which is equivalent to 25% of SiOH.

We simply incorporated 8% pure product into a lano-vaseline which is an excessively greasy cream 15 allowing a long massage until almost penetration.

The results of the experiment involving twelve people with Tennis Elbow are as follows:

The patient must rest for 14 to 21 days, during which time he must massage the painful area 20 times a day using the cream.

Of the 12 patients, 4 saw their pain disappear and were able to resume their activity after 6 days, 5 after 12 days, 1 after 14 days, and 2 after 16 days.

25 With the help of this cream, it has been possible to intervene on tendinopathies of the shoulder, either subscapular, supraspinatus, or long biceps.

These tendinopathies manifested as simple painful shoulder (EDS) or acute, hyperallergic shoulder (EAH).

The experiment involved 12 patients who were treated 3 times a day.

2 patients with tendinopathy (EDS) were relieved after 5 days, 3 after 9 days, 1 patient with tendinopathy (EHA) was relieved after 7 days, 1 after 12 days, 3 after 15 days and 2 did not see their condition change.

17

EXAMPLE 5:

Normalizing action

Treatment of asthenia

5

In this example, we used Ascorbosilyl dimethylsilyl-2,3,5,6 ascorbate, with the formula C10Hi6O6Si2. We have M.M.=288.4, giving 24.56% of Si, which is equivalent to 32% of SiOH.

10 This compound has been studied in fitness, combating the effects of aging and fatigue.

The formulation was prepared for dietary use by oral administration of capsules containing 0.5g of active ingredient. The advantage is that it provides very high quantities of silyl; up to 0.19g of SiOH and 0.31g of ascorbic acid per capsule.

A 20% diluted form of ascorbosilyl in soybean oil was tested, yielding 0.04g of 20-silyl and 0.07g of ascorbic acid per dose. The recommended dosage is 1 to 3 capsules per day.

This compound allows for the oral administration of quantities that would be impossible in the case of a classic silyl obtained by complexation.

25 Taking these capsules produced very rapid results in some cases, with a return of physical fitness as early as the 8th day. In other cases, the response only occurred 3 or 4 months later, but in all cases there were changes in behavior, a return of the feeling of well-being, and a better adaptation to daily life.

EXAMPLE 6:

35 Metabolic stimulatory activity

Tanning activator i.a

18

The compound used in this example is a Dimethyl silyl-dihydroxyacetone with the formula C5H10O3Si, with M.M.=146.21, which is equivalent to 31% SiOH.

The compound was incorporated into a preparation with 5 fat-soluble but non-greasy characteristics, namely:

Fluid silicone L45 10.00g

Isopropyl palmitate 89.00g

Dimethyl silyl DHA 1.00g

The product is applied by lightly touching until 10% absorption before exposure to sunlight and UV rays.

The results were determined after UV irradiation on humans, treating only one forearm for 8 days (1 daily application), the application was made on 4 squares of 2.5 x 2.5 cm2 for durations of 10, 15, 15, 20, 25 minutes.

On the treated arm, a light to dark tan was observed depending on the exposure time.

On the untreated arm, no color change was observed for a treatment of 10 minutes, then 20 minutes, and then mild to moderate erythema was observed for longer durations.

EXAMPLE 7:

25 Metabolic stimulatory activity

Slimming composition

The compound used was dimethyl-silyl-methionine with the formula C7H15NO2SSi with M.M. = 205.34 releasing 22% 30 of SiOH after in vivo hydrolysis.

We developed a greasy gel containing 1% silyl methionine, equivalent to 0.2% SiOH. The formulation was:

Silyl methionine 1.00g

Poly oxoaluminium stearate 5.00g

35 Stearic acid 1.5 g

Oleic acid 0.5 g

Vaseline oil q.s.p. 100.00g ha

19

This gel was applied to areas with localized fat deposits, in the evening at bedtime with gentle massages until completely absorbed.

Five women aged 35 to 55 participated in this test.

5.3 results were very good: reduction of one to

Two sizes after 3 months.

One average skin improvement result was obtained without significant thinning, and on the other hand, one result was zero.

10

EXAMPLE 8:

Anti-radical activity

Use as colored cosmetics

15

The compound tested was 1'ethoxymethyl silyl-2-oxo octanoate of M.M.= 246.7, which is equivalent to 19% SiOH.

This compound was diluted in evening primrose oil, at a ratio of 45%.

20 This solution has been used at a rate of 7% in mascaras and lipsticks, which corresponds to an input of 1% in SiOH.

These cosmetics were intended to ensure regeneration and protection of sensitive mucous membranes and epidermis.

This is proven by the following test which measures the percentage of inhibition of the control oxidation rate.

The test involves producing oxygen free radicals enzymatically (by the action of xanthine oxidase on acetaldehyde) and comparing the resistance of cells (cultured in the presence or absence of ethoxymethylsilyl-2-oxo-octanoate) to these radicals. The addition of free radicals to a cell culture induces cytotoxicity. This toxicity results in cell lysis with an increase in cellular lactate dehydrogenase (LDH). The evaluation of cellular resistance to radical stress is obtained

20

by measuring LDH activity using UV spectrophotometry. If DO denotes optical density, LDH activity is measured using the following ratio:

DO control - DO test

5 x 100

DO trial

Results :

A very significant protective effect of 10 silyl was observed. The peroxidation system used produced superoxide ions and hydrogen peroxide. Analysis of the results shows that silyl induces protection against spontaneous cell lysis (LDH activity decreased by 73%). This protection persists and intensifies (LDH decrease of 77%) in the presence of induced free radical stress.

EXAMPLE 9:

20 Anti-glycation, anti-radical activity

Cataract treatment

In ophthalmology, as an anti-cataract drug, dimethylsilyl-2,3,5,6 ascorbate (or 25 ascorbosilyl) of formula CioH16°6si2 with M.M.=288.4, i.e. 24.56% of Si, which is equivalent to 32% of SiOH, has been used.

Ascorbosilyl is incorporated at a rate of 6.5% in an ophthalmic ointment composed of a mixture of petrolatum and petrolatum oil.

30 Ascorbosilyl after hydrolysis on contact with tear fluid and cornea acts progressively as an antiradical, preventing the peroxidation of cellular membrane lipids.

It also helps to restructure the 35 proteoglycans and mucopolysaccharides that make up the cornea.

21

It should be noted that the presence of ascorbic acid potentiates the antiradical action since it is a natural constituent of the eye.

The free radical scavenging activity specific to an anti-cataract drug was verified by the following test:

The test involves producing oxygen free radicals enzymatically (by the action of xanthine oxidase on acetaldehyde) and comparing the resistance of cells (cultured in the presence or absence of

10 dimethylsilyl-2,3,5,6 ascorbate) in contact with these radicals.

The addition of free radicals to a cell culture induces cytotoxicity. This toxicity results in cell lysis with an increase in lactate.

15. Cellular LDH dehydrogenase. The evaluation of cellular resistance to radical stress is obtained by measuring LDH activity using UV spectrophotometry.

Results :

20 A very sensitive protective effect of 2,3,5,6-dimethylsilyl ascorbate is observed. The activity of silyl is estimated from the changes in LDH activity compared to the analytical control. The peroxidation system used produces superoxide ions and hydrogen peroxide.

25. The analysis of the results shows that 2,3,5,6-dimethylsilyl ascorbate induces protection against spontaneous cell lysis (LDH activity decreased by 67%). This protection persists and intensifies (LDH decrease of 79%) in the presence of induced free radical stress.

30

EXAMPLE 10:

Anti-glycation activity

Treatment of arteriosclerotic diseases

35

te

22

The chosen compound was 2-2 dimethyl 4-oxo-5-amino 1,3 dioxy-cyclosilane or dimethylsilyl-L-serine of M.M.=161.23, which is equivalent to 22% SiOH.

From this derivative, 5 n*4 capsules were manufactured containing a 40% solution of dimethylsilyl-L-serine in soybean oil, such that each capsule provides an amount of 0.05g of SiOH.

Depending on the dose administered daily, this intake can range from 1 to 6, and it is possible to address 10 mild problems which can be addressed through dietary and lifestyle treatments, up to medical treatments.

The anti-glycation activity of the compound, which helps to preserve arterial tissues, has been demonstrated.

Non-enzymatic glycosylation of proteins is 15 one of the factors responsible for connective tissue sclerosis.

The chemical reactions involved in this protein degradation have been identified. Glycation (non-enzymatic glycosylation) between sugars and proteins occurs randomly at free amino protein sites and forms beta-acetomethylamine bonds (Amadori product). These bonds trigger a series of chemical reactions (Maillard reaction, 1912) that lead to a progressive increase in protein cross-linking. These irreversible bonds gradually cause the supporting tissues to lose their properties (elasticity), which explains their sclerosis.

The development of an original experimental protocol made it possible to study in vitro the specific reactivity of 30-dimethylsilyl-L-serine in the phenomenon of protein glycation.

The degree of glycosylation can be estimated by a colorimetric technique specific to glucose-protein interaction. This technique allows for the detection of 35-5-Hydroxymethylfurfural (HMF) released from the carbohydrate group after acid hydrolysis. The HMF level is

23

quantitatively determined by colorimetric reaction with 2-thiobarbituric acid (TRA).

Results :

5 The rate of protein crosslinking (albumin) is significantly decreased (-37%) when dimethylsilyl-L-serine is added at the beginning of the reaction to the protein solution.

This experiment confirms the highly sensitive antiglycation biological role of simethylsilyl-L-serine.

The product was tested in a dietary context on six men with lower limb arteriopathy who were undergoing treatment. The treatment had been ongoing for more than 12 months, and taking 15 capsules daily was therefore an additional benefit.

In 4 of these 6 people, a significant improvement in walking distance was noted.

EXAMPLE 11

20

Standardizing activity

Treatment of osteoporosis

We used diethyl-phosphato-ethyl-25 triethoxysilane with the formula C12H2906PSi, M.M. = 328.41 and Si = 8.55%.

The treatment of osteoporosis in young adults and postmenopausal osteoporosis was carried out by oral administration of diethylphosphatoethyltriethoxysilane. The dose used was 60 mg per administration (5.5 mg of silicon and 10 mg of phosphorus) and 100 mg per administration (9.17 mg of silicon and 16.67 mg of phosphorus). Administration was oral, with an initial treatment of 3 capsules of the active ingredient for 3 months, then 2 capsules daily for 6 months, followed by a 35-month break, and then chronic treatment with one capsule 5 days a week.

Z.&

24

The effects of diethylphosphatoethyltriethoxysilane are measured on bone formation (incorporation of 3(H)-thymidine, measurement of alkaline phosphatase activity in osteoblasts) and on osteoporosis (basal PGE5 production, interleukin-6 production in osteoclasts). This study is performed on cell cultures over periods of 4, 8, and 12 days. PGE5 and interleukin-6 are measured by immunological methods (ELISA). Cell proliferation is assessed by a radiometric method.

A dose-dependent positive effect of silanol on osteoblast synthetic activity was observed through an increase in alkaline phosphatase activity. Thymidine incorporation rates increased by 72% after treatment.

A significant decrease in the level of osteoclastic interleukin-6, a marker of inflammation in the stages of osteoporosis, was observed. This effect, highly indicative of the anti-inflammatory and regenerative activity of 20-silanol, is dose-dependent. Correspondingly, a significant decrease in the level of osteoclastic prostaglandins was also observed.

This molecule has an anti-osteoclastic effect; this effect is accompanied by a 25% stimulation of osteoblast activity, thus promoting bone renewal. This results in a decrease in hydroxyprolinuria and serum alkaline phosphatase levels, as well as a reduction in fractures related to the fragility of osteoporotic bone.

25

Claims (29)

DEMANDS 1. Silicon-based compound with general formula A B A B \ / / \ / If or X C If DX ^C D^ X C in which A, B, C, D, and X are different radicals of OH, the bonds with Si are 10 covalent bonds, and two or three of these bonds are biologically hydrolyzable in vivo with formation of biologically active Si OH bonds, especially in contact with living tissues. 2. Compound according to claim 1 in which said biologically hydrolyzable radicals are hydrogen atoms or radicals linked to Si by an oxygen, nitrogen or sulfur atom. 3. Compound according to claim 2, wherein at least one of said biologically hydrolyzable radicals is 20 is linked to the silicon atom by an oxygen atom and is chosen from the group consisting of esters or alkoxy, aryloxy radicals or even allyloxy or vinyloxy radicals, 4. Compound according to claim 3, wherein 25 said at least one of said radicals is an ester. 5. Compound according to claim 3, wherein said at least one of said radicals is a phenoxy radical. 6. A compound according to any one of claims 1 to 5, wherein the non-hydrolyzable radicals are selected from 30 hydrocarbon radicals, substituted or not by one or more functional groups, sterically hindered alkoxy radicals, fluorocarbon radicals, or a fluorine atom. 7. A compound according to any one of claims 1 to 6, wherein at least one of the compounds obtained after hydrolysis 26 The hydrolyzable bonds are stabilized by a compound chosen from the group consisting of carboxylic hydroxy acids such as alpha and beta hydroxy acids, glucuronides, hydroxylated or phenolic amino acids such as serine, threonine or tyrosine, compounds possessing several alcohol or phenol functions and especially vicinal alcohol or phenol functions such as glycols, catechols and catecholamines, polyethylene glycols, polyols such as glycerol, monosaccharides such as L-threose, L-ribose or sorbitol, phenolic acids such as gallic acid, 3,4-dihydroxybenzoic acid or caffeic acid, and their esterified derivatives, diacids such as malonic acid, and certain compounds possessing a particular geometry suitable for stabilizing silicon-based complexes in aqueous media such as tropolones. 8. Application of the composition according to any one of claims 1 to 7, to obtain a therapeutic, dietary or cosmetic composition having an activity 20 anti-inflammatory, regenerative, anti-degenerative, normalizing, metabolic stimulant, anti-radical or anti-glycation, or generally an activity of stimulating the defenses of the human or animal organism. 9. Therapeutic composition resulting from application according to claim 8, having an activity anti-inflammatory for the treatment of osteoarthritis, based on di-isopropyloxymethyl silyloxy-L-hydroxyproline-N-acetylated. 10. Therapeutic composition according to claim 30 9 in which di-isopropyloxymethyl silyloxy-L- N-acetylated hydroxyproline is administered in capsule form. 11. Therapeutic composition resulting from the application according to claim 8, having an activity 35 regenerative for the restructuring of microvessels, based on di-caproyl-dimethylsilane. 27 12. Therapeutic composition according to claim 11 wherein di-caproyl-dimethylsilane is administered in capsule form. 13. Therapeutic composition resulting from the application according to claim 8, having anti-inflammatory, anti-edematous, analgesic and restorative activity for the treatment of erythema, based on 2-oxo-benzyloxy-dimethylsilane. 14. Therapeutic composition according to claim 13 wherein 2-oxo-benzyloxy-dimethylsilane is used in the form of a greasy gel. 15. Therapeutic composition resulting from the application according to claim 8, having anti-inflammatory activity for the treatment of tendinitis in athletes, based on 2-oxobenzyl-oxy-dimethylsilane. 16. Therapeutic composition according to claim 15 wherein 2-oxobenzyl-oxy-dimethylsilane is used in a greasy massage cream. 17. Therapeutic composition resulting from the application according to claim 8, having anti-radical and anti-glycation activity for the treatment of catharsis, based on dimethylsilyl-2,3,5,6 ascorbate. 18. Therapeutic composition according to claim 17, wherein dimethylsilyl-2,3,5,6 ascorbate is incorporated into an ophthalmic ointment. 19. Therapeutic composition resulting from the application according to claim 8, having anti-glycation activity for the treatment of arteriopathies and arteriosclerosis, based on 2-2 dimethyl 4-oxo-5-amino 1,3 dioxy-cyclosilane (or dimethylsilyl-L-serine). 20. Therapeutic composition according to claim 19, wherein 2-2 dimethyl 4-oxo-5-amino 1,3 dioxycyclosilane (or dimethylsilyl-L-serine) is administered in capsule form. 21. Therapeutic composition resulting from the application according to claim 8, having an activity 28 normalizing agent for the treatment of osteoporosis, based on diethyl-phosphato-ethyl-triethoxysilane. 22. Therapeutic composition according to claim 21, wherein diethyl-phosphato-ethyl- 5 triethoxysilane is administered in capsule form. 23. Dietary composition resulting from the application according to claim 8, having a normalizing activity for fitness, combating aging and fatigue, based on 10 dimethylsilyl-2,3,5,6 ascorbate. 24. Dietary composition according to claim 23 wherein dimethylsilyl-2,3,5,6 ascorbate is administered in capsule form. 25. Cosmetic composition resulting from the application 15 according to claim 8, having a metabolic stimulating activity, said composition used as a tanning activator being based on 2,2-dimethyl-5-oxo-l,3-dioxa-2-cyclosilane (or dimethyl silyl dihydroxyacetone). 26. Cosmetic composition according to claim 25 20 in which the 2,2-dimethyl-5-oxo-l,3-dioxa-2-cyclosilane (or dimethyl silyl dihydroxyacetone) is applied as an ointment to parts of the body to be exposed to the sun. 27. Cosmetic composition resulting from the application 25 according to claim 8, having a metabolic stimulant activity, said composition used as a slimming composition being based on dimethyl silyl methionine. 28. Cosmetic composition according to claim 27, wherein dimethyl silyl methionine is applied 30 in the form of a greasy gel. 29. Cosmetic composition resulting from the application according to claim 8, having anti-radical activity, said composition used as mascara or lipstick being based on ethoxymethyl silyl-2-oxo- 35 octanoate. $ ©'V ci i/v\ cJP '/