FR2658185A1 - Derivatives of long-chain fatty alcohols, their applications, especially as cytotrophic (cytotropic) and cytoprotective molecules, and pharmaceutical compositions containing them - Google Patents

Abstract

The invention relates to derivatives of long-chain fatty alcohols and to methods for obtaining them. It also relates to pharmaceutical compositions containing derivatives and to their uses especially for the treatment or prevention of neurodegenerative diseases, phenomena related to skin aging, thrombosis and atherosclerosis phenomena and immunodeficiencies.

Description

DERIVATIVES OF 8 ALCOHOLS GW WITH CRAFT LONGE, THEIR APPLICATIONS, MOTAIKEIT ZM TUT CYTOTROPHIC XOLLCULES HT CYTOPROTECTIRCIS, AND CONPOSITIONS
PHARMACEUTICAL8 LE8 CONTAINING.

 The present invention relates to derivatives of fatty alcohols & long hydrocarbon chain, as well as pharmaceutical compositions comprising these derivatives, and the use thereof, especially as cytotrophic and cytoprotective drugs.

 It is generally accepted that nerve tissue in adult mammals does not regenerate after injury. This lack of regeneration can be due either to a lack of signals capable of inducing regeneration, or to irreversible damage that has led to neuronal death (A.J.

AGUAYO, in: A. BIGNAMI, F.E. BLOOM, C.L. BOLIS and A.

ADELOYE eds, CNS Plasticity and Repair, Raven Press (N.Y.) (1985) pp 31-40). However, neuronal death can be prevented by protecting the nervous tissue from the consequences of ischemia or by providing a favorable microenvironment, particularly neurotrophic or neuroprotective compounds; these compounds could also promote regeneration of nervous tissue if administered before death has occurred.

Neurotrophic factors are agents capable of promoting the survival of neurons and stimulating neuronal differentiation (JR PEREZ
POLO, in JE BOTTENSTEIN and G. SATO eds, Cell Culture in Neuroscience, Plenum Publishing Corp. (1985) pp 95-123). Activation of cellular metabolism may result in the formation of a target-oriented neurite network to innerver. The demonstration of neurotrophic factors can be done in vitro using nerve cell cultures. (G. BARBIN, I. SELAK, M. MANTHORPE, and S.

VARON t NEUROSCIENCE 12: 33-43 (1984)). Dissociated cell cultures from various regions of the central nervous system (CNS) have shown the effect of these neurotrophic factors on neuron survival and maturation.

 Moreover, the experimental lesion of the median septum in the rat leads to a significant loss of cholinergic neurons (D. M. ARMSTRONG et al., COMP.

Neurol. 264: 421-436 (1987); FH GAGE et al, BRAIN
RES. 268: 27-37 (1983)). Some diseases, such as Alzheimer's or Parkinson's disease, chorea
Huntington or amyotrophic lateral sclerosis are the consequence of the progressive disappearance of certain neurons (JT COYLE et al, SCIENCE, 219 1184-1190 (1983), JB MbRTIN, NEUROLOGY 34 1059-1072 (1984), MD YAHR and KJ BREGMANN, NEUROWGY vol., Raven Press (NY) (1985)). Some studies have suggested that this loss of neurons could be avoided by intracerebroventricular administration of neurotrophic factors such as NGF (Nerve Growth Factor) or FGF (Fibroblast Growth Factor) (LF KROMER, Science 235: 214-216). (1987), KJANDERSON et al., Nature 332-360-361 (1988), T. HAGG et al., Exp Neurol, 101 303-312 (1988)).

Neuronal death may also be related to the presence of neurotoxic compounds. Some excitatory amino acids have an excitotoxic action on neurons; when injected into the rat brain, they cause degeneration of certain areas (JT COYLE and R. SCHWARCZ, in: Handbook of
Chemical Neuroanatomy, Elsevier, Amsterdam (1983) pp 508-527). This phenomenon is close to that of the neuronal degeneration observed in the hippocampus zone in humans and is called ammonoid sclerosis (Meldrum, Clin Sci 68: 112-113 (1985)). This type of lesion can be replicated by intracerebral injections of excitotoxic compounds, such as ibotenic acid. It has been suggested that the loss of hippocampal neurons observed in Alzheimer's disease, and following cerebral ischemia, may be related to the high density of glutamate receptors present on these neurons (SM ROTHMANN et al. JW OLNEY, Ann Neurol., 105-111 (1986)). Neurotoxic amino acids can also induce lesions at a distance via glutamatergic projections and which resemble the lesions observed in epilepsy (JV NADLER et al., Nature 271: 676-677 (1978) and Huntington's chorea (JT COYLE and R. SCHWARZCZ,
Nature 263: 244-246 (1976)) Excitotoxins may also be involved in the genesis of ischemic lesions; ischemia increases the extracellular concentration of excitatory amino acids causing hyperstimulation, neuronal swelling, and cell lysis (Meldrum, Adv.

Neurol .; 44: 849-855 (1986); S.M. ROTHMANN and J.W.

OLNEY, Ann. Neurol. 19: 105-111 (1986)). Similarly during epilepsy an increased release of neurotransmitter could produce neurodegenerative lesions of the same type (Y. BENARI,
Neuroscience 14: 375-403 (1985)).

 The inventors have demonstrated that the long-chain fatty alcohol, n-hexacosanol, has neurotrophic and neuroprotective activities in vitro. This long chain fatty alcohol was isolated from the tropical plant, Hygrophile erecta, Hochr. (Acanthaceae) (Borg et al., Neuroscience Lett 213: 406-410 (1987)).

If added to a concentration of 500 nM to fetal rat neurons in culture, it increases neuritic growth by a factor of 4 to 6 as well as the number of collaterals, especially for multipolar neurons. This compound also significantly increases the biochemical differentiation of cultured neurons: it increases the level of proteins and doubles the specific activities of two neuronal enzymes, phosphate-activated glutaminase and neurospecific enolase, by 32 and 78%, respectively.

 However, the results of the in vitro study of the properties of n-hexacosanol do not make it possible to judge its possible activity in vivo, given the differences existing between in vitro and in vivo environmental conditions.

 In addition, n-hexacosanol administered peripherally significantly reduces brain neuronal degeneration after axotomy.

 It also significantly reduces the loss of neurons as a result of neurotoxin injection into the brain. This effect confirms the neurotrophic and neuroprotective properties of n-hexacosanol.

 The invention relates to long-chain fatty alcohol derivatives, derived from terpene compounds, having powerful neurotrophic and neuroprotective properties in vitro and in vivo on various nerve tissues.

 These derivatives are able to cross the blood-brain barrier and have a bioavailability much higher than other neurotrophic factors currently known.

 Advantageously, the derivatives of the invention reach specific cellular targets, which makes them therapeutic tools of primary importance.

 The invention also relates to derivatives of long-chain fatty alcohols having cytotrophic and cytoprotective properties with regard to a large variety of cells of the body.

The invention relates to fatty alcohol derivatives having the following general formula: R1-CA- (X) y'B3p'R2 in which - p is 1 or 2, - y = O or 1, - A- (X) yB is a hydrocarbon chain comprising from 8 to 50 carbon atoms, optionally substituted with one or more halogen atoms, especially fluorine, or with one or more alkyl groups of 1 to 3 carbon atoms and in which
A and B, respectively identical or different, are saturated or unsaturated aliphatic chains.

dans lequel R' représente un atome d'hydrogène ou un groupe alcoyle de 1 à 5 atomes de carbone, de préférence de 1 à 3 atomes de carbone,
un groupe de formule

le cas échéant substitué par un, ou plusieurs, atome d'halogène, notamment de fluor, ou un, ou plusieurs, groupe -CH3, et/ou -OH et/ou -OR, R étant tel que défini ci-dessous, et/ou un groupe oxy (= 0),
un groupe -OR, dans lequel R représente un atome d'hydrogène, ou un groupe

X is also a block comprising a saturated or unsaturated hydrocarbon chain engaged in a ring structure, the latter hydrocarbon chain optionally comprising a carbonyl or oxycarbonyl function; R 1 and R 2, which may be identical or different, represent
. a hydrogen atom,
. a halogen atom, especially a fluorine atom, a group

in which R 'represents a hydrogen atom or an alkyl group of 1 to 5 carbon atoms, preferably 1 to 3 carbon atoms,
a group of formula

optionally substituted with one or more halogen atoms, especially fluorine, or one or more -CH3 group, and / or -OH and / or -OR, R being as defined below, and / or an oxy group (= 0),
a group -OR, in which R represents a hydrogen atom, or a group

dans laquelle Y+ représente un ion métallique de préférence Na+, K+, Nui et R3 représente
* un atome d'hydrogène, ou un atome d'halogène, notamment de fluor,
* un nucléotide, du glucose, ou du galactose,
* un acide aminé, un peptide ou une protéine,
* un ion métallique, de préférence Na+, K+,
NH4+,
* une chaîne hydrocarbonée de formule
R1-[A-(X)y-B]p- ou de formule (A-(X)yB1pR2, comprenant de 8 à 50 atomes de carbone, le cas échéant, substituée par un ou plusieurs atomes d'halogène, notamment de fluor, ou par un ou plusieurs groupes alcoyle de 1 à 3 atomes de carbone, dans laquelle A, X, B, Rr, R2, y et p ont les significations indiquées ci-dessus, lesdits dérivés comportant au moins un groupe

ou un groupe -OR, R et R' ayant les significations indiquées ci-dessus.R 'having the meaning indicated above, or a derivative of monophosphoric acid of formula

in which Y + represents a metal ion, preferably Na +, K +, Nui and R3 represents
a hydrogen atom, or a halogen atom, especially fluorine,
a nucleotide, glucose, or galactose,
an amino acid, a peptide or a protein,
a metal ion, preferably Na +, K +,
NH4 +,
a hydrocarbon chain of formula
R1- [A- (X) yB] p- or of formula (A- (X) yB1pR2, comprising from 8 to 50 carbon atoms, where appropriate, substituted with one or more halogen atoms, in particular with fluorine, or with one or more alkyl groups of 1 to 3 carbon atoms, wherein A, X, B, R 1, R 2, y and p have the meanings indicated above, said derivatives having at least one group

or a group -OR, R and R 'having the meanings indicated above.

 When the R31 group of the abovementioned formula of the derivatives of the invention is a nucleotide or a peptide derivative, it preferably represents: uracil, cytosine, guanine, adenosine or thymine, when it is is a nucleotide, - muramylpeptides and -ipeptides, transferrin, or insulin, when it is a peptide or a protein.

 The fluorinated derivatives of the invention are particularly advantageous in particular in terms of bioavailability and chemical stability.

 The invention more particularly relates to the derivatives corresponding to the aforementioned general formula in which p = 1 (still referred to as monomers in the following).

comportant, le cas échéant, 1 à 10, et de préférence 1 à 5 double(s) liaison(s), et dans laquelle n est un nombre entier variant de 1 à 10. Les poids moléculaires des analogues saturés et insaturés de la vitamine A de l'invention sont de l'ordre de 280 à 447.A class of preferred derivatives of the invention is represented by the saturated and unsaturated analogues of vitamin A (or retinal) corresponding to the following formula

having, where appropriate, 1 to 10, and preferably 1 to 5 double bonds, and wherein n is an integer ranging from 1 to 10. The molecular weights of the saturated and unsaturated vitamin analogs A of the invention are of the order of 280 to 447.

comportant respectivement, le cas échéant, 1 à 10 et 1 à 9 double(s) liaison(s), et de préférence 1 à 5 doubles(s) liaison(s). Les poids moléculaires des homologues du squalène selon l'invention sont de l'ordre de 361 à 395.Another particularly advantageous class of derivatives of the invention is represented by the homologues of squalene (terpene compound of 30 carbon atoms) corresponding to the following formulas:

respectively comprising, where appropriate, 1 to 10 and 1 to 9 double (s) link (s), and preferably 1 to 5 double (s) link (s). The molecular weights of the homologues of squalene according to the invention are of the order of 361 to 395.

 The more or less saturated derivatives of geranylgeraniol (C25) and geraniol (C20) represent preferred derivatives of the invention.

comportant respectivement, le cas échéant, 1 à 5 et 1 à 4 double(s) liaison(s). Les poids moléculaires de ces dérivés selon l'invention sont de l'ordre de 240 à 368.Among these, we will distinguish those corresponding to the following formulas

with, where appropriate, 1 to 5 and 1 to 4 double link (s). The molecular weights of these derivatives according to the invention are of the order of 240 to 368.

Particularly preferred derivatives of the invention are such that y = 1 and X represents the group of formula:

comportant, le cas échéant, 1 à 7 double(s) liaison(s), et dans laquelle n1 et n2 sont des nombres entiers variant de 1 à 15, et R5 représente H ou OH, constituent également une classe préférée de dérivés de l'invention. Les poids moléculaires des dérivés du cholestérol selon l'invention sont de l'ordre de 445 à 643.Esters of cholesterol of formula

having, where appropriate, 1 to 7 double bonds, and wherein n1 and n2 are integers ranging from 1 to 15, and R5 is H or OH, also constitute a preferred class of derivatives of 1 to 15; 'invention. The molecular weights of the cholesterol derivatives according to the invention are of the order of 445 to 643.

 Since terpenes are by definition polymers of isoprene, a structure with 5 carbon atoms, cholesterol is also part of the terpenes in that its precursor, lanosterol is a triterpene. The presence of the cholesterol rings increases the rigidity of the derivatives of the invention, which gives them a better integration into the cell membrane.

 The invention relates more particularly to dimeric derivatives corresponding to the general formula of the derivatives of the invention in which p = 2.

 These dimeric derivatives have a size allowing them to cross on both sides of the cell membrane, thus modifying the physicochemical properties of this membrane, which gives them a particularly good activity.

 The dimers of the invention comprise 1 to 20, preferably 1 to 10, double (s) link (s).

comportant, le cas échéant, 1 à 14 double(s) liaison(s), de préférence 1 à 7 double(s) liaison(s).Among these derivatives, mention will be made especially of those of formula:

with, where appropriate, 1 to 14 double (s) link (s), preferably 1 to 7 double (s) link (s).

The molecular weights of the dimeric compounds according to the invention are of the order of 572 to 914.

 The derivatives of the present invention are obtained from terpene compounds, or a cyclic structure derived from terpenes, of synthetic or natural origin, which has undergone partial ozonization with the aid of ozone, which has the effect of effect of reducing the length of the hydrocarbon chain of the terpene compound - or an addition of one or more function (s) -OH on one or both ends of these terpene compounds, in particular according to the method of Wittig at the using a diol or an alcoholic acid (which will be more particularly developed in the detailed description which follows), either a total or partial hydrogenation, or a combination of several of the aforementioned operations.

avec un ylure de dérivé de bromure de tetrahydropyranne (bromure-THP) de formule

dans laquelle n est un nombre entier variant de 1 à 10, ce dernier composé étant lui-même obtenu par action d'un sel de bromure de tetrahydropyranne de formule Br-CH2-(CH2)n1-OTHP (THP = tetrahydropyranne) sur un triphenylphosphine de formule
#3P (# = C6H5)
L'ylure alors obtenu est mis en contact avec le rétinal en présence de butyllithium, ce qui conduit à l'obtention d'un dérivé de formule

The saturated and unsaturated derivatives of vitamin A according to the invention are obtained, in particular by coupling, by the Wittig reaction, the retinal of formula

with a ylide of tetrahydropyran bromide derivative (bromide-THP) of formula

in which n is an integer ranging from 1 to 10, the latter compound being itself obtained by the action of a tetrahydropyran bromide salt of formula Br-CH2- (CH2) n1-OTHP (THP = tetrahydropyran) on a triphenylphosphine of formula
# 3P (# = C6H5)
The ylure thus obtained is brought into contact with the retinal in the presence of butyllithium, which leads to the production of a derivative of formula

dans lequel n = 1 à 10, totalement saturé ou comportant 1 à 10 double(s) liaison(s) en fonction du temps d 'hydrogénation. The latter is then hydrogenated for a given period of time which leads to the derivative of formula

wherein n = 1 to 10, fully saturated or having 1 to 10 double bond (s) as a function of the hydrogenation time.

 The squalene derivatives according to the invention are obtained in the following manner. Since squalene, a terpenic compound of 30 carbon atoms, is too large to have good biological activity, the terminal double bonds of the latter are cleaved by partial ozonation, in particular for 2 hours. Then a hydroxyl function is introduced on one or the other, or on both ends of the derivative then obtained, in particular according to the Wittig method previously described. The derivative is subsequently hydrogenated for a given time to yield a final derivative completely saturated or having 1 to 10 double bond (s).

geranylgeraniol

The geranylgeraniol and geraniol derivatives are obtained, in particular according to a synthesis method identical to that of the above-mentioned vitamin A derivatives, namely the Wittig method for extending the chain and introducing one or two hydroxyl functions at the ends of said chain. of geranylgeraniol or geraniol, the formulas of which are as follows:

geranylgeraniol

 geraniol followed by hydrogenation to obtain more or less saturated derivatives.

et un alcool-acide de formule HO-(CH2)n-C-OH
II O dans laquelle n1 a la signification indiquée cidessus, ce qui conduit à l'obtention d'un dérivé du cholestérol dont la formule est indiquée ci-dessous

the cholesterol derivatives of the invention are obtained by forming an ester link between
The C3 hydroxyl of the formula cholesterol

and an alcohol-acid of formula HO- (CH2) nC-OH
In which n1 has the meaning indicated above, which leads to the production of a cholesterol derivative whose formula is indicated below

comportant, le cas échéant, 1 à 14 double(s) liaison(s), et dans laquelle n1 et n2 sont des nombres entiers variant de 1 à 15, et R5 a la signification indiquée ci-dessus, est obtenu selon la méthode de Wittig précédemment décrite, réalisée à partir de prégnénolone qui comporte une fonction hydroxyle, ou du type -OR5 ( ayant la signification indiquée ci-dessus), en bout de chaîne.The cholesterol derivative of the invention of formula:

having, where appropriate, 1 to 14 double bonds, and wherein n1 and n2 are integers ranging from 1 to 15, and R5 has the meaning indicated above, is obtained by the method of Wittig previously described, made from pregnenolone which has a hydroxyl function, or of the type -OR5 (having the meaning indicated above), at the end of the chain.

 The dimeric compounds of the invention are obtained either from compounds treated in a manner identical to that described above for the monomers of the invention (for example natural carotenoids of various or synthetic sources containing from 40 to 60 carbon atoms. carbon, and which are linear, or have a ring in their structure), or by coupling of two monomer units, in particular by hydrogenation on Pd / C in ethanol.

 The fatty alcohol derivatives of the invention described above being poorly soluble in aqueous medium, their use for biological studies or for therapeutic applications may present methodological difficulties. To overcome these disadvantages, water-soluble prodrugs represented by monophosphoric acid esters have been synthesized. These compounds are hydrolysed in the body to give the starting products, namely the derivatives of the invention for which R = H.

 These compounds are particularly water-soluble (more than 10% in water depending on the case), so the solutions obtained are compatible with intravenous injections. They improve the bioavailability of the derivatives of the invention, which makes it possible to potentiate the observed biological effects. Thus, the presence of the phosphate group made it possible to administer an aqueous solution of corticosteroids without loss of biological activity (R.J. W. CREMLYN and I. Khattak, Chemistry of steroid phosphates, Phosphorus 27 (1976) 237-246).

 The radical represented by R3 allows a better targeting of the derivative of the invention. It can promote the penetration of the derivative through membranes (bacterial membrane) or diffusion from the capillaries of the digestive tract, the meningeal membrane or other tissues (F. IGLESIAS-GUERRA, J.M.

NEUMANN and T. HUYNH-DINH, Synthetic 6-glutamatecosyl phospholipid as a drug transport system / Tetrahedron
Lett. 28 (1987) 3581-3584). This radical also allows the derivative to bind to a specific receptor; the derivative will therefore act specifically on cells that have such a receptor. Similar reasoning led to the synthesis of phosphate derivatives of certain steroid hormones (L.

LEBEAU, C. MIOSKOWSKI and P. OUDET, Synthesis of phospholipids linked to steroid hormone derivatives.

Chemistry and Physics of Lipids, 46 (1988) 57-62).

dans lequel R3 et y+ sont tels que définis ci-dessus,
sont obtenus par phosphorylation d'un dérivé monomère ou dimère de l'invention, pour lequel R = H, avec l'o-phenylènephosphochloridate, ou avec le bisphosphochloridate suivie d'une hydrolyse oxydative, notamment par le tétracétate de plomb.The water-soluble derivatives of the invention for which R represents the group

in which R3 and y + are as defined above,
are obtained by phosphorylation of a monomeric or dimer derivative of the invention, for which R = H, with o-phenylenephosphochloridate, or with bisphosphochloridate followed by an oxidative hydrolysis, in particular with lead tetraacetate.

The operating conditions of all the reactions described above will be more particularly developed in the following detailed description.
The derivatives of the invention promote nerve regeneration and have a neuroprotective effect; they have in particular the following properties.

 They increase neurite outgrowth in vitro and in vivo, and facilitate repair following traumatic CNS and PNS (peripheral nervous system) lesions, by promoting the extension of neurites and the formation of new cellular contacts and thus functional recovery. They attenuate the effect of ischemia, promote neuronal survival and reduce Wallerian degeneration after injury.

 They protect neurons from cell death resulting from the presence of neurotoxic compounds, such as heavy metals or neuroexcitators, such as glutamate and its analogues.

 The derivatives of the invention are cytotrophic factors, especially for skin cells and endothelial cells. They promote the repair of lesions of certain cell layers such as skin cells or vascular endothelial cells. These derivatives increase the differentiation of dermal cells, epidermis or endothelial cells; they increase the formation of prolongations and the filling of the lesion by the cells which border it.

 The derivatives of the invention have a cytoprotective effect which is exerted, in particular, on hepatic cells, cardiac striated muscle cells and renal glomerular cells. They protect these cells against chemical or ischemia-related lesions. These derivatives also protect the heart tissue against the consequences of an interruption of blood flow, especially in the coronary arteries. The derivatives of the invention therefore protect liver, kidney and cardiac muscle cells against their degeneration of chemical or ischemic origin.

 The derivatives of the invention also have a trophic effect on the cells of the renal glomerulus. They allow better synthesis and secretion of fibrinolytic factors, such as plasminogen activators. They therefore promote fibrinolysis and prevent the formation of thrombi, particularly following acute or chronic nephropathies, glomerulonephritis or intravascular coagulation.

 The derivatives of the invention have a cytotrophic effect on the cells that participate in the body's immune defenses, in particular macrophages, monocytes and lynphocytes. These derivatives promote the differentiation of lymphocytes, macrophages and monocytes; they increase the production of immunity factors, promote the acquisition of differentiated characters and strengthen the natural or induced defenses of immunity.

 The derivatives of the invention have a cytotrophic effect on mast cells and basophilic leucocytes which play a primordial role in inflammatory phenomena. These derivatives favor the acquisition of differentiated characters of these cells, modify their response to stimulation by an antigen and by IgE and decrease the consequent production of histamine. They also modify the response of smooth muscle cells to mediators of inflammation, such as histamine, leukotrienes, and prostaglandins.

 The derivatives of the invention have a cytotrophic and differentiating effect on cells that participate in the defense of the body against neoplasia. They increase the phagocytic activity of macrophages, lymphocytes and monocytes and increase the secretion of tumoricidal factors, such as TNF (tumor necrosis factor). They also have a differentiating effect on cancerous or precancerous cells, such as promyelocytes.

The derivatives of the invention also have a bacteriostatic effect. They prevent bacterial growth, especially that of gram + bacteria and mycoplasma. When the derivatives of the invention are added to a culture containing gram + bacteria, for example Streptococcus mutans,
Clostridium butyricum or Streptococcus sanguis or mycoplasmas such as Mycoplasma pneumoniae or Mycoplasma gallisepticum, we observe a slowing of their proliferation that can be measured by the evolution of the turbidity of the culture medium over time, or by a change in pH middle. It is noted that in the culture containing long-chain fatty alcohols of the invention, the increase in the optical density is markedly slowed compared to the control medium, as well as the acidification of the medium.

The important role of these compounds is supported by the fact that the inhibition of their synthesis in
Clostridium butyricum causes a significant slowdown in growth (GILBERTSON et al., J.

Lipid. Res., 19 (1978) 757-762). Furthermore, the presence of long chain fatty alcohols of the invention in the medium is likely to allow the bactericidal action of certain antibiotics. Thus, the combination of tridecanol and gentamycin results in inhibition of growth of
Streptococcus mutans (GILBERTSON et al., Antimicrob.

Agents Chemother., 26 (1984) 306-309).

Furthermore, the derivatives of the invention possess an antiviral action which is mainly exerted on enveloped viruses such as herpesvirus, VSV (Stomatitis Virus
Vesicular), the rabies virus, viruses of the HIV type (virus responsible for AIDS). The experimental model for demonstrating the anti-viral activity of the fatty alcohols according to the invention varies according to the virus in question. It will be a question of selecting the cell types sensitive to the studied virus; therefore fibroblasts, kidney cells, erythrocytes or nerve cells will be chosen.

 In all cases, an inhibition of the cytopathogenic effect of the virus is observed when fatty alcohols of the invention are added to the culture medium. This effect is measured by morphological or biochemical criteria of cell degeneration. It is noted that with the same infectious dose, the cells in culture are substantially more resistant to the virus when the medium contains long chain fatty alcohols of the invention. The anti-viral action can be exercised either directly at the replication level of the virus inside the cell, or by an inactivation mechanism which reduces the infectious properties of the virus (SNIPES et al., Anitimicrob.

Agents Chemother., 11 (1977) 98-104).

 The invention also relates to pharmaceutical compositions comprising at least one of the above-mentioned derivatives in association with a physiologically acceptable vehicle, and the use of these compositions, in particular, in the following therapeutic areas - the treatment or the prevention of neuronal degeneration. , especially during neurodegenerative diseases and neuronal loss related to chemical compounds or excitatory amino acids, such as glutamic acid, - the treatment or prevention of nervous tissue lesions in mammals, whether it is acts of traumatic lesions, chemical lesions, lesions due to a disease or a congenital deficit, - the treatment or the prevention of Alzheimer's or Parkinson's disease, Huntington's chorea and other neurodegenerative diseases, Wallerian degeneration, brain aging and genetic diseases such as Down syndrome, the treatment and prevention of brain lesions related to neurosurgery (the administration of these compositions being concomitantly with surgery).

- the healing of skin lesions, as well as the treatment and prevention of phenomena related to aging of the skin, - the repair of vascular lesions (of traumatic or chemical origin), as well as the treatment and prevention of thrombosis phenomena and atherosclerosis, - the treatment and prevention of degeneration of liver, kidney or heart tissue, in particular when due to toxic chemical or medicinal compounds for these organs, - the treatment and prevention of gastric and duodenal ulcers - the treatment of acquired deficits (such as AIDS, autoimmune diseases) or hereditary immunity, - the treatment of acute inflammatory and allergic processes, such as asthma, allergic rhinitis, anaphylactic shock or urticaria, - the treatment and prevention of neoplasia and tumors, such as hepatic or bone tumors, and the prevention of opagation of metastases from cancerous tumors, - the treatment and prevention of all pathologies related to gram + bacteria and mycoplasma, in particular pulmonary, uro-genital and oral infections, - the treatment and prevention of pathologies related to envelope, such as Herpes, rabies,
AIDS.

 Advantageously, the treatment of the above-mentioned diseases and disorders with the derivatives of the invention, as neurotrophic and neuroprotective compounds, is carried out in combination with the use of nerve tissue grafts at the level of the lesion, in particular grafts. fetal tissue or placenta.

 This combination promotes functional recovery or protects the nervous tissue by various mechanisms, such as: a trophic effect on nervous tissue; the release of neurotransmitters or hormones; or reinnervation of certain elements of the nervous tissue. It is also possible to associate with this combination of nerve transplants and derivatives of the invention, glial cell or tissue grafts capable of producing neurotrophic factors (such as neuronal growth factor (GF), or the growth factor fibroblast (FGF), platelet derivative growth factor (PDGF), insulin growth factor (IGF or somatomedin).

 The above-mentioned pharmaceutical compositions preferably comprise effective doses of derivatives of the invention which are of the order of 0.01 mg / kg to 100 mg / kg, in particular from 0.5 mg / kg to 10 mg / kg.

 Pharmaceutical compositions of the invention advantageously comprise a single dose of between 0.5 mg and 500 mg of the derivative of the invention, in combination with a pharmaceutically acceptable vehicle or excipient, especially for the parenteral or oral routes.

 The optimal concentration of these molecules varies according to the size of the lesion or the presence of side effects.

 The pharmaceutical compositions of the invention are administered parenterally, in particular intravenously, intramuscularly, intracerebrally or intraperitoneally; they are also administered orally, sublingually, vaginally or by implants or pumps.

 Parenteral preparations are prepared by sterilization through a filter with 0.22 μm pores; sterile stoppered 1 ml vials containing 100 mg of these molecules are prepared. It is also possible to use a lyophilizate which will be reconstituted before intravenous injection.

 The compositions of the invention adapted for the oral route, are advantageously in the form of pills, capsules, suspensions, powders, emulsions or capsules.

Advantageously, the above-mentioned pharmaceutical compositions, used in the field of neuroprotection, comprise at least one derivative of the invention in combination with other neurotrophic or neuroprotective factors, such as NGF
FGF, somatomedins, benzodiazepines, kappa receptor antagonists, calcium channel blockers and excitatory amino acid receptor antagonists.

 Pharmaceutical compositions which are particularly advantageous in the context of cellular grafts, in particular nerve cell transplants, comprise one or more derivatives of the invention in association with cells having the properties of those originally contained in the, or the, part (s) injured party (s) where the transplant must be performed. By way of example, such pharmaceutical compositions, according to the invention, are in the form of injectable preparations comprising a determined amount of one or more of the derivatives of the invention in association with cells originating from the septum or the hippocampus (these cells being taken from another organism than that receiving the transplant).

 In the context of bacteriostatic use, particularly advantageous pharmaceutical compositions comprise one or more derivatives of the invention in combination with one or more antibiotics.

 The set of pharmaceutical compositions of the invention is intended for the treatment and / or prevention of the pathologies described above in mammals.

 The subject of the invention is also culture media comprising at least one of the compounds of the invention in combination with products suitable for culturing cells. These culture media are more particularly intended for culturing cells such as human or animal cells from embryonic dissociated tissue of newborn animal, adult or elderly. The derivatives of the invention promote the survival and differentiation of these tissues in vitro. As examples of cells that can be cultured in the media of the invention, mention may be made of: nerve cells, macrophages, hepatocytes, renal cells, fibroblasts, endothelial cells, lymphocytes and These cells may be administered to a patient for therapeutic purposes, possibly after undergoing in vitro treatment with one or more derivatives of the invention in the above-mentioned culture media.

 In this regard, the invention also provides pharmaceutical compositions comprising cells as indicated above, in association with a pharmaceutically acceptable vehicle, derived from a cell culture according to the invention, these cells preferably being free of other constituents of these culture media.

 By way of illustration, examples of culture media of the invention are more particularly described in the detailed description which follows.

 Other features of the invention will become apparent from the following description of synthesis examples and the biological properties of the derivatives of the invention. It goes without saying that these examples are not limiting in nature.

EXXPLES OF SYNTHESIS OF DERIVATIVES OF THE INVENTION
1) Saturated and unsaturated derivatives of vitamin A
Reaction
a) Preparation of the salt of phosphonium bromide
To avoid side reactions, the primary alcohol bromides of suitable chain length Br (CH 2) n -OH are treated with 4-methoxy-3-dihydropyran to protect the primary hydroxyl.

 The phosphonium bromide salt is prepared by the addition of 0.4 moles of triphenylphosphine in a solution of 0.4 moles of methoxytetrahydropyran bromide in 100 ml of toluene.

 The solution is then heated at 60 ° C for 1 night The phosphonium bromide salt precipitates during cooling, is filtered and washed with 100 ml of toluene.

b) Wittig's reaction
To a suspension of 2 mmol of phosphonium bromide salt obtained as above, in 9 ml of anhydrous hexane, 0.8 ml (1.26 mmol) of n-butyllithium (hexane) are added dropwise. ); allowed to react at room temperature for 1 night.

 0.6 mmol of retinal dissolved in 2 ml of hexane are then added dropwise. After 1 hour of reaction, it is cooled with an ice bath and filtered to remove the triphenyl phosphate formed. After evaporation, the olefin formed with a yield of 80% is obtained.

The olefin (0.5 mmol) dissolved in 30 ml of methanol is hydrogenated in the presence of 50 mg of
Palladium on carbon (Pd / c) at 5%. Quantitatively, the desired product bound to methoxytetrahydropyran is obtained. The protecting group is removed by simple treatment with 0.1 N HCl solution.

The number of hydrogen bonds is determined by the duration of the reaction. It is also possible to protect certain double bonds which one does not wish to saturate, in particular by the method of protection with bromide
Vitamin A derivatives thus synthesized have the following analytical characteristics:

<tb> Product <SEP> Eli <SEP> Bf <SEP> solvents <SEP> of * lutlon
<tb><SEP> o
<tb><SEP> zCH2 ^ 0
<tb><SEP> CH3
## EQU1 ##
<tb><SEP> o
<tb><SEP> C <SEP> H <SEP> 2-O
<tb><SEP> N02 <SEP> 340 <SEP> 0.547 <SEP>(<SEP>"<SEP>"
<tb> jw <SEP> CH20H
<tb><SEP> n03 <SEP> 298 <SEP> 0.573 <SEP> (SEA, <SEP> EQ0, <SEP> Hexane) <SEP> (1, <SEP> 60, <SEP> 40)
<tb><SEP> e <SEP> CH20H
<tb><SEP> n "4 <SEP> 288 <SEP> 0.28 <SEP> (SEA, <SEP> Eut20, <SEP> Hexane) <SEP> (1, <SEP> 60, <SEP> 40 )
<tb><SEP> H
<tb><SEP> n 5 <SEP> 296 <SEP> 0.8 <SEP> (SEA, <SEQ> EQ0, <SEP> Hexane) <SEP> (1, <SEQ> 50, <SEP> 50)
<Tb>
TEA: triethylamine
Product fM nor expired olutlon solvents vitamin A

ainsi que les dérivés n 6 et ne 7, sont des dérivés particulièrement actifs dans le cadre de la présente invention, notamment dans le test décrit dans l'exemple 1 (effet trophique sur des neurones in vitro) du Chapitre II qui suit.<tb> IMI <SEP> CHuCH- (CH2) 2XH
<tb><SEP> n "6 <SEP> 336 <SEP> 0.54 <SEP> (Hexane. <SEP> ether) (50/50)
<tb><<SEP> (CH2) 4 <SEP> 0H
####
<Tb>
The two hydrogenated derivatives of the molecule n04 defined above, corresponding to the following formulas

as well as the derivatives No. 6 and No. 7, are particularly active derivatives in the context of the present invention, in particular in the test described in Example 1 (trophic effect on neurons in vitro) of Chapter II which follows.

2) Derivatives of squalene
Reaction: Ozonization of squalene
A solution of 4 mmol of squalene in 100 ml of CH 2 Cl 2 and 1 ml of pyridine is treated at 0 ° -70 ° C. for 2 hours. After addition of 1 ml of (CH3) 2S, the reaction mixture is allowed to react for 1 hour at -70 ° C then 1 hour at 0 ° C and is then extracted with CHCl3. After evaporation of the solvent, the residue is chromatographed on SiO 2. In particular, two products of desired biological activity are obtained: it is an alcohol with 27 carbon atoms and a diol with 24 carbon atoms.

3) Hydrogenated Derivative of Geraniol (C20)
The derivative of formula C15H31-CH2OH was prepared by hydrogenation of geraniol.

Its analytical characteristics are as follows: PM = 242,
Rf = 0.454 in elution solvent, Eut 2 O-hexane (50, 50).

 4) Dimeric compounds.

 A carotenoid containing two hydroxyl groups on both ends of the molecule, decaprenyl astaxanthin, is hydrogenated on Pd / C with ethanol as a solvent.

 5) Water-soluble derivatives of long chain alcohols: esters of monophosphoric acid.

a) monoester of monophosphoric acid
This reaction is valid for linear alcohols, such as for the derivatives and analogs of terpenes and cholesterol esters of the invention comprising a hydroxyl function, preferably located at the end of a hydrocarbon chain. For the understanding of the following description, all the derivatives mentioned above, will be designated by the simplified expression R-OH showing the hydroxyl involved in the phosphorylation reaction and wherein Rz represents the rest of these derivatives, namely more particularly a hydrocarbon chain of the R type, -CA- (X) yB] p as defined above,
A method of preparation is used to selectively obtain the monoester of monophosphoric acid. This procedure involves bis (2,2,2-trichloroethyl) phosphochloridate as reagent and the Zn / Cu pair as a deprotection agent to release the phosphate salt.

Reagent preparation
The bis (2,2,2-trichloroethyl) phosphochloridate reagent (BTEP) is prepared by dropwise addition for 15 minutes at -50 ° C. of the trichloroethanol (44.8 g, ie 29 ml or 0.3 mol). The mixture is then allowed to react at 0 ° C. for 2 hours under argon. The reaction mixture is heated at 55 ° C overnight and distilled to give 16.7 g (0.046 mol or 15.3%) of bis (2,2,2 trichloroethyl) phosphochloridate Pel = 98 ° C (0.15 mm). Hg), d415 = 1.75 g / ml.

phosphorylation
The alcohol (R 6 -OH) dissolved in 2 ml of THF (0.1 mmol) is cooled to -78 C. 750 mg of molecular sieve 4A and then 43 μl (ie 0.21 mmol) of BTEP are added.

The temperature is allowed to rise to room temperature; then the molecular sieve is removed by filtration. The filtrate is diluted with ethyl ether (10 ml). Then 5 ml of a 0.5M solution of NaHCO3 followed by an ethereal solution of iodine (38 mg, 0.3 mmol in 5 ml of ethyl ether) are added. The addition is slowly dripped with vigorous stirring. After 20 minutes of reaction, an aqueous solution of Nazca is added to destroy excess iodine. The solution was washed with saturated aqueous NaCl solution and evaporated in vacuo. Chromatography on SiO 2 with chloroform-methanol (50: 1) as eluent gave the triester phosphate in 92% yield.

 Elimination of the trichlorethylene group.

To a solution of the previously obtained triester phosphate (0.05 mmol) dissolved in 1 ml of
DMF, 65 mg of Zn / Cu and 50 μl (0.5 mmol) of acetylacetone are added. The solution is heated at 550C for 1 hour. The mixture is stirred in the presence of the Chelex resin for 1 hour; then the resin is removed by filtration. The filtrate is evaporated to dryness.

The residue is treated with formic acid (300 μl) and allowed to react for 24 hours, then evaporated to dryness and finally chromatographed on DEAE Sephadex (0.9 × 12 cm column) with pH 7.5 buffer as eluent. The phosphate is then obtained with a yield of 75%.

b) diester monophosphoric acid
This reaction proceeds by phosphorylation with o-phenylenephosphochloridate followed by oxidative hydrolysis and makes it possible to obtain the diesters of monophosphoric acid. This reaction is valid for linear alcohols, as for derivatives and analogs of terpenes and cholesterol esters of the invention, that is to say the derivatives of formula R6-OH mentioned in the previous paragraph. In this case, the group F 1 preferably represents a hydrocarbon chain of 8 to 28 carbon atoms, optionally substituted with one or more hydrogen atoms, in particular fluorine, or with one or more alkyl groups (s) ( s) from 1 to 3 carbon atoms.

1st step: nhosphorylation of alcohols
An alcohol solution containing 1 mmol of derivative of the invention (383 mg in the case of hexacosanol), represented by the expression R6-OH (R6 representing the rest of the derivative of the invention, namely a chain alkyl of 26 carbon atoms in the case of hexacosanol), and 2,6-dimethylpyridine (110 mg, 1 mmol) is treated with a solution of 100 mg (0.5 mmol) of o-phenylene phosphochloridate in THF for 24 hours at 40 ° C. After addition of a saturated solution of NaHCO 3 (10 ml) the extraction is carried out with CH 2 Cl 2 and the chromatography on SiO 2 gives 330 mg of phosphate (85%).

dermis step: hydrolysis followed by oxidation
The previously obtained product (330 mg) dissolved in 6 ml of THF is treated with a solution of 110 mg (1 mmol) of dimetylpyridine in 200 ml of water for 5 minutes and then extracted with chloroform (CHCl 3).

The CHCl 3 extract is dissolved in THF (10 ml) and then treated with 1 g of lead teracetate (Pb (OAc) 4); the mixture is adjusted to pH 10 with a 0.1N methanolic solution of potassium hydroxide (KOH). After evaporation of the solvent and washing with methanol (MeOH), the potassium salt is obtained in the form of a brown liquid which is purified by chromatography on Silo 2 with 60: 25: 5 CHCl 3 / MeOH / H 2 O eluent.

Phosphates containing two R6 radicals are obtained by using twice as much reagent, ie 2 mmol of o-phenylenephosphochloridate and allowed to react for 24 h.

ainsi obtenu possède un PM de 547 et un Rf de 0,375 dans le solvant d'élution : CHC13, Methanol, H2O (65, 25, 4).The ester of monophosphoric acid of formula

thus obtained has a MW of 547 and a Rf of 0.375 in the eluting solvent: CHCl 3, Methanol, H 2 O (65, 25, 4).

6) Substitution by fluorine atoms
It has been previously demonstrated that organofluorine compounds can potentiate the effect of biological compounds (Y. KOBAYASHI, I. KUMADOKI and T.

TAGUCHI, Synthesis of biologically active fluorine compounds. Synth. Org. Chem., 38 (1980) 1119-1129).

By already described techniques of incorporation of fluorine atoms (KOBAYASHI et al., Supra, J.T.

WELCH, advances in the preparation of biologically active organofluorine compounds. Tetrahedron, 43 (1987) 3123-3197; Biomedical Aspects of Fluorine Compounds, R. FILLER and Y. KOBAYASHI eds, KODANSHA,
Tokyo, (1982)), it is shown that the substitution of 1 to 5 fluorine atoms on fatty alcohols with 26 + 6 carbon atoms improves the bioavailability of the molecules.

 Fluorination is by an electrophilic mechanism.

The substitution can be done on a saturated CH bond (D. BARTON and D. OLLIS, in Comprehensive
Organic Chemistry, JF STODDART, ed. Pergamon Press (1979) pp504-507). The electrophilic attack is located directly at the CH bond. CH3 (CH2) -NCH 2-CH2- (CH2) m-oH + FF

n+m=23+6
La substitution peut également se faire en saturant un ou des systèmes dessaturés par des composés contenant un ou plusieurs atomes de fluor. CH3(CH2)n-CH=CH-(CH2)n-OH + FH ou F2

n + m = 23 + 6
Substitution can also be accomplished by saturating one or more desaturated systems with compounds containing one or more fluorine atoms. CH3 (CH2) n -CH = CH- (CH2) n-OH + FH or F2

n+m=23+6
R1=H ou F
R2=H ou F
Les composés fluorés contenant de 1 à 5 atomes de fluor améliorent la biodisponibilité de la molécule et augmentent leur efficacité biologique.

n + m = 23 + 6
R1 = H or F
R2 = H or F
Fluorinated compounds containing from 1 to 5 fluorine atoms improve the bioavailability of the molecule and increase their biological effectiveness.

 Difluorinated derivatives are particularly interesting in terms of biological activities (T.

MORIKAWA et al, Studies on Organic Fluorine Compounds.

Synthesis of 2,2 difluoro arachidonic acid. Chem.

Pharm. Bull, 37 (3) 813-815 (1989)). We obtain them as follows
Detailed reaction
To a mixture of Zn (33.35 atomic mass) and
THF (30 mL) was added dropwise a solution of C24 aldehyde (32 mmol) and ethyl bromodifluoroacetate (28.04 mmol) in
THF (33 ml). The mixture is refluxed for 3 hours with stirring. After addition of ether and aqueous NH4Cl, the precipitate is removed by filtration and the filtrate is extracted with ether, the extract is washed with a solution of NaCl and then chromatographed on SiO 2. The compound is then treated with a solution of 1N HCl and hydrogenated in the presence of PutO2. The ethyl ester of the C26 acid is obtained with a yield of 57 t.

This ester is then reduced by LiAlh in ethyl ether with heating under reflux.

 PM = 316 to 502.

II BIOLOGICAL TRIALS He VITRO and Il VIVO
1) Nervous regeneration
The derivatives and analogs of the long chain fatty alcohols of the invention play a role in controlling the plasticity of nervous tissue during development and in the adult. They increase neuronal survival during developmental phases that see the establishment of new neuronal connections, also in adults during learning and memory processes; As we describe in Example 1 which follows, the derivatives of the invention promote neuronal differentiation as well as neuronal survival. This property gives them the ability to increase the survival of injured neurons as a result of trauma. The derivatives and analogs of the long chain fatty alcohols of the invention promote the survival and regeneration of nerve cells as a result of trauma to the brain or spinal cord. These molecules are able to limit the extension of lesions, reduce Wallerian degeneration and promote axonal regeneration. In particular, the molecules described decrease post-ischemic necrosis, reduce edema around the lesion, increase blood perfusion of the affected nerve tissue and limit the proliferation of fibroblasts or astroblasts at the lesion level.

These properties are demonstrated using neurons maintained in primary culture under different conditions, or in vivo using various models of experimental lesion in animals (GAGE et al, Brain Res., 268: 27-37 ( 1983), WILLIAM et al.
Proc. Natl. Sci. 83: 9231-9235 (1986)). The doses used are of the order of 0.01 mg / kg, more particularly 0.1 mg / kg at 5 mg / kg. Because of the better bioavailability of the molecules we describe and their greater efficiency at the cell membrane, we improve with lower doses the previously observed effects with n-hexacosanol (BORG et al., Neurosci Lett, 213,406). -410 (1987)).

 Furthermore, the derivatives of the invention also promote the regeneration of peripheral nerves. As a result of trauma to the peripheral nerve, there may be loss of nerve continuity, followed by Wallerian degeneration.

The application of the derivatives of the present invention makes it possible in this case to reduce the importance of the lesions and to facilitate the restoration of the nerve continuity. This result is obtained thanks to the neurotrophic and regenerating properties of these derivatives.

EXAMPLE i: SURVIVAL AND REGENERATION OF NEURONS
CEREBRALS IN THE PRESENCE OF DRIVES AND ANALOGUES DE8
FATTY ALCOHOLS WITH A LONG CHAIN OF THE INVENTION

The use of brain neurons maintained in primary culture makes it possible to demonstrate the activity of neurotrophic factors (G. BARBIN,
I. SELAK, M. NANTHORPE and S. VARON; Neuroscience, 12 (1984) 33-43). Neuronal cultures are prepared from the brain of rat embryos for 13 to 18 days.

The cells are seeded at low density (10,000 to 100,000 cells per ml); they grow in petri dishes coated with a polylysine support, in the presence of a culture medium which is prepared from Eagle-Dulbecco's medium (R.

DUBELCCO and G. FREEMAN, Virology, 8 (1959); 396) supplemented with insulin, transferrin, progesterone, selenium and putrescine (BORG et al, Develop Brain Res 18: 37-49 (1985)). The tested derivatives are added at the beginning of the culture at doses ranging from 10-8 to 10-5M.

 The evolution of the culture is monitored using a phase contrast microscope. Trypan blue staining measures the number of neurons that emit extensions. It is observed that in control cultures the number of living neurons and neurons with prolongations decreases from a certain culture time. In contrast, in the cultures treated with the derivatives of the invention, the number of these neurons remains constant with time and the length of the extensions is much greater than in the controls. There are also a large number of branches from these extensions and the presence of numerous cellular contacts. In vivo, these observations correspond to the establishment of new neural circuits and the formation of intercellular or synaptic junctions.

 The increase in the survival of neurons placed under critical conditions and the improvement of their morphological maturation also results in an increased biochemical maturation.

 The presence of certain proteins specific for these neurons, such as neurofilament proteins, neurospecific enolase or glutaminase can be measured by immunocytochemical methods or enzymatic methods.

After fixation, the cultures are incubated with a specific antibody against a neurofilament or against lenolase, at different culture times. The presence of these proteins is revealed by a peroxidase method or with fluorescent antibodies.

The appearance of these proteins is earlier and more intense in the cultures containing the derivatives of the invention.

The enzymatic activity of enolase or glutaminase, which are good markers of neuronal maturation, can also be measured. (BORG et al,
Neurosci. Lett., 213: 406-410 (1987)). The enzymatic activity relative to the amount of protein makes it possible to compare the neurotrophic effect of the various derivatives of the invention. This quantitative measure shows that the effect is observed early and continuously; it also makes it possible to correlate the dose used with the observed effect. In all cases, the neurons treated with the derivatives and analogs of the long chain fatty alcohols of the invention induce an increased activity of the markers of the maturation compared to the controls.

 The derivatives of the invention have a greater effect than other neurotrophic factors already known, because of their better bioavailability and better efficiency at the cellular level.

These results show that derivatives and analogues of long-chain fatty alcohols promote the survival of brain neurons and increase their degree of maturation.

2) Neuroprotection
Another interesting application of the derivatives of the invention is related to their property of protecting neurons from lesions due to the presence of neurotoxicants, such as glutamate, ibotenic acid, AF-64, scopolamine or N-methyld aspartate. The excitatory neurotransmitter, glutamate, and excitotoxins in general, produce neurotoxic effects in relation to their depolarizing action at their receptors. Some glutamate analogues, such as ibotenic acid or quisqualate, have more potent excitatory effects and also produce neurotoxic effects. The neuroprotective properties of the derivatives and of the invention are demonstrated following a neurotoxic injection, ibotenic acid, in the nucleus basalis in the rat (Example 2) .Normally, this injection results in a decrease in the production of acetylcholine and choline acetyl transferase activity in ipsilateral neocrotex, as well as morphological lesions in this brain area.

Recall that this type of lesions found in patients suffering from Alzheimer's disease (WENK et al., Brain Res., 293: 184-186 (1984)). These lesions are substantially reduced in animals that have received intraperitoneal injections at a dose of 1 mg / kg / day of derivatives of the invention.

 The derivatives and analogues of the long chain fatty alcohols of the invention can therefore be used in the treatment of neurodegenerative diseases, such as Huntington's chorea, Alzheimer's disease or Parkinson's disease. They also improve the treatment of epilepsy and other behavioral disorders related to the limbic system. In addition, they are capable of inducing neuronal protection against neurotoxins, certain ions and oxidizing radicals. For all these applications, the therapeutic doses are of the order of 0.1 mg / kg / day to 10 mg / kg / day.

Administration is repeated, parenterally or orally.

EXAMPLE 2: VI8-A-VI8 PROTECTION FROM LESION8 DUES FROM NEUROTOXICS
The excitotoxic properties of an amino acid, ibotenic acid, are used to study the survival of the cholinergic neurons of the basalis nucleus, according to a method previously described (WENK et al.
Brain res., 293: 184-186 (1984)). After anaesthetizing male Long-Evans rats, they are placed in a stereotaxic apparatus; then 25 nmol of ibotenic acid is injected into the basalis nucleus on the left side.

 One group of rats is treated with a long-chain fatty alcohol derivative, one injection per day (1 mg / kg) intraperitoneally from two days prior to injection of ibotenic acid.

 Several types of cognitive and behavioral tests may be used during the experiment, in particular the 8-branched radial labyrinth, the Hebb-Williams maze learning, or the pool test (ALFORD et al., Exp. Brain Res., 69 (1988) 545-558)). Animals treated with ibotenic acid show a deficit of learning and memorizing abilities. There is also a deficit in spatial localization, similar to that observed in Alzheimer's disease.

For treated animals, the deficits are much smaller and the learning and memorizing abilities are maintained.

 At the end of the behavioral tests, the animals are sacrificed in order to proceed to a histological analysis of the zone of the kernel basalis. A loss of substance induced by ibotenic acid is observed which is much more restricted for the treated animals. The lesion that for controls extends in all directions from the injection site to the globus pallidus is less extensive after treatment and corresponds to a less important neurotoxin injection. Biochemical assays are also performed on the neocortex and the hippocampus. The activity of choline acetyl transferase is decreased in the frontal, temporal and parietal cortex, as well as in the amygdala two weeks after the injection of ibotenic acid. Treatment with the derivatives of the invention results in a substantial reduction of this deficit in these regions and there is a gradual recovery of choline acetyl transferase activity in the weeks following the injection.

 The derivatives of the invention make it possible to protect certain cerebral neurons against lesions induced by excitotoxic amino acids and against the functional consequences of these lesions.

3) Repair of lesions
Cellular regeneration also occurs during the repair of vascular or cutaneous lesions. Thus the vascular endothelium is composed of a monolayer of cells that frame the internal face of the cardiovascular system. This monolayer represents an area of several hundred square meters and plays a major role in vascular integrity. Endothelial cells produce many substances that participate in coagulation, fibrinolysis and inflammatory phenomena.

Alteration of these functions may lead to an increase in vascular permeability and an accumulation of proteins and lipoproteins in the interstitial tissue, or platelet adhesion to the subendothelium accompanied by secretion of platelet derived growth factors ( PDGF), or finally to the migration and proliferation of smooth muscle cells. Alteration of the vascular endothelium is therefore an important initial step in the phenomena of thrombosis and atherosclerosis (Cazenave et al.

Inter Angio 3: 27-32 (1984)). As a result of vascular endothelial injury, several phenomena appear in the in vivo repair process: first, endothelial cell migration and replication, platelet adhesion to the exposed subendothelium, and finally Smooth muscle cell proliferation that leads to plaque formation and atherosclerosis. Derivatives for protecting the vascular wall or inhibiting platelet adhesion can therefore prevent plaque formation and atherosclerosis.

 One of the applications of the invention is to use the derivatives described above to promote the repair of cutaneous or vascular lesions. Endothelial cell damage results in the formation of protein or lipoprotein deposits in the interstitial tissue, as well as the proliferation of smooth muscle cells. These phenomena constitute the initial step in the formation of thrombosis and atherosclerosis (R. Ross.

Atherosclerosis 1: 293-311 (1981)). The derivatives of the invention enhance the differentiation of dermal, epidermal and vascular endothelial cells. As shown in Example 3, these derivatives accelerate the repair of mechanical vascular endothelial cell injury. This property is demonstrated using an in vitro model of mechanical lesion of human endothelial cells in culture. The cultures are obtained from human umbilical veins and are maintained in a RPMI medium plus HEPES plus 30% human serum; the lesion is performed 3 days after confluence by the application of a cellulose disk on a confluent layer of endothelial cells (C.Klein-Soyer et al. Thrombosis Haemostasis 56: 232-235 (1986)). The rate of regeneration depends on the size of the initial lesion and the serum concentration. Moreover, the addition to the culture medium of the derivatives of the invention significantly increases the area of the initial lesion covered by the regenerating endothelium.The doses used are of the order of 0.01-1001N, more particularly 0, 1 to 10s. The corresponding doses for in vivo use are in the range of 0.01 mg / kg to 100 mg / kg, more preferably 0.1 to 10 mg / kg.

 The application of the derivatives of the present invention makes it possible to accelerate the repair of vascular or cutaneous lesions and to retard the degeneration of the cells of the skin, linked in particular to aging, exposure to U.V rays and to chemical aggression. This property is demonstrated in vitro using keratinocyte cultures. The long chain fatty alcohols of the invention increase the survival of these cells placed under unfavorable conditions or in the presence of factors that cause degeneration of these cells. They accelerate their differentiation as well as the repair of tissue lesions. The doses used are similar to those described for vascular lesions.

EXAMPLE 3: REPAIR OF LESIONS OF ENDOTUELIUX
VASCULAR BY FATTY ALCOHOLS WITH A LONG CHAIN.

 Models of mechanical lesion of a layer of endothelial cells in vitro make it possible to study the repair processes of this type of lesions (C. Klein-Soyer et al above-mentioned). Endothelial cells are isolated from human umbilical veins. They are incubated with 0.1% collagenase for 15 minutes at 37 ° C. and the effluent is collected in tubes containing culture medium (RPMI, HEPES, glutamine and 5 to 30% human serum). After centrifugation, the pellet is seeded in Petri dishes pretreated with fibronectin which serves as a support.

 The lesion is made on confluent cultures by application of a calibrated disc of cellulose polyacetate. This technique selectively detaches the endothelial cells that were in the area of application of the disc. Long chain fatty alcohols are then added to the culture medium at doses ranging from 0.01 SM to 100 gM, and preferably 0.1 to 10 WM.

 After the lesion, boxes are removed every 24 hours to measure the size of the lesion. Adhesive grids divided into squares of 0.5mm2 are used and applied to the bottom of the box, coinciding with the lesion. The area of the lesion is measured by counting the squares with an inverted microscope. The regeneration rate is linear for 48 hours, then slows down when the lesion is only 75 to 80% of the original lesion. The presence of the derivatives of the invention increases the rate of regeneration at early times and even in the absence of human serum in the culture medium. Moreover, in the absence of serum, there is a beginning of endothelial cell degeneration, which is not the case in the presence of long-chain fatty alcohols.

 In vivo damage to the vascular endothelium may result in platelet adhesion, smooth muscle cell proliferation and the formation of thrombosis or atherosclerotic plaques.

With the aid of the mechanical lesion model, it is observed that the long chain fatty alcohols of the invention protect the vascular wall and improve the regenerative capacities thereof. The physico-chemical properties of these derivatives and their good bioavailability make them therapeutic tools particularly useful in the treatment and prevention of thrombosis and atherosclerosis.

4) Cytoprotection
Some cell damage is related to the presence of toxic or is the consequence of ischemia, as in nerve tissue. These phenomena are particularly important in the liver, heart muscle and kidney. A number of molecules (xenobiotics) can alter liver cell functions either directly or after conversion of these molecules into a more toxic form. The cellular lesion can begin either by the formation of a stable complex with a protein or other intracellular compound, or by the formation of a highly reactive chemical entity or by inducing physicochemical changes in the cell or in its cell. environment (Bridges et al Ann NY

Acad. Sci. 407: 42-63 (1983)). Cell damage can be limited or prevented by certain defense systems, such as drug metabolism enzymes, binding proteins or antioxidants. Isolated hepatocytes can be used as an experimental model to study the toxicity of certain molecules. Cytotoxicity was measured by release of cytosolic enzymes, albumin secretion, morphological changes observed in light microscopy, and determination of cell viability. The cellular lesion is influenced by its environment, in particular the partial pressure of oxygen or the presence of extracellular calcium. The toxicity of some drugs is potentiated by glutathione depletion.

The use of isolated hepatocytes maintained in culture makes it possible to study hepatic cytotoxicity and also to detect compounds that are protective against cytotoxic agents. We can study in particular the maintenance of cytochromes
P450 and drug metabolism enzymes, such as glucuronyltransferase and sulfotransferase.

 Similarly, the cytotoxicity of certain molecules on glomerular or renal tubule cells can be studied using isolated mesenchial, epithelial or tubular cells. Cytotoxicity is measured by morphological changes or expression of biochemical functions specific to these cells (secretion of a plasminogen activator inhibitor, PGE2, interleukin 1) (JD Sraer et al., FEBS Lett.104: 420-424 (1979)).

 In particular, the long chain fatty alcohols of the invention increase the synthesis and secretion of Plasminogen activators in the order of 70 to 100% relative to control, in mesenchial and epithelial cells of human kidney. The maximum effect is obtained at doses ranging from 10-5 to 10-7 M.

This result makes it possible to envisage a pharmacological action in coagulation phenomena and in the formation of extracellular matrices. The molecules of the invention can also prevent the spread of metastases from cancerous tumors, and oppose the action of certain proteins.

 With respect to the heart muscle, cell damage is usually the consequence of ischemia. In particular, isolated cardiac muscle cells make it possible to follow the evolution of lesions in terms of electrophysiological changes (P. Athias et al., In Vitro 22:44 (1986)).

 The long chain fatty alcohol derivatives of the invention play a role in the protection against chemical or ischemia-related lesions that are exerted on liver, kidney or cardiac muscle cells.

 The presence of toxic compounds or ischemia causes cellular degeneration manifested by a diffusion of cytosolic enzymes (LDH), morphological changes, loss of cell viability. Cells in culture can be used to demonstrate this toxicity and possible protective agents. As we demonstrate in Example 4, the compounds of the invention increase survival and maintain the differentiation of hepatocytes maintained in culture.

The cultures are obtained by fractionation from liver of adult rats and are maintained in a Ham / F12 medium supplemented with albumin, insulin, hydrocortisone and 10% fetal calf serum. The survival of hepatocytes in vitro is limited, they tend to lose some differentiating characters and to degenerate in the presence of toxic compounds. This is particularly the case for galactosamine, paracetamol, pentobarbital (Paine and Hockin, Toxicology 25:41 (1982) or cyclophosphamide (ACOSTA and MITCHEL Bioch.Pharm.

30: 3225 (1981).

The addition of long-chain fatty alcohols to the culture medium improves hepatocyte survival in vitro, as measured by viability testing, glutathione maintenance and cytochrome P450 activity, as well as albumin secretion (Rumeur et al., Exp.Cell
RES.147: 247-254 (1983)). These derivatives of the invention also reduce the toxicity of pentobarbital or cyclophosphamide, as can be observed by morphological changes, the diffusion of cytosolic enzymes and the activity of detoxification enzymes, such as cytochromes P450, monooxygenases and the conjugating enzymes. The doses used are of the order of 0.01 to 100 microns, more particularly 0.1 to 10 microns. The corresponding doses for in vivo use are in the range of from 0.1 mg / kg to 100 mg / kg, more preferably 0.1 to 10 mg / kg.

 The application of the derivatives of the present invention makes it possible to protect liver, renal or cardiac muscle cells against degeneration due to toxic compounds or ischemia. The protective effect for renal glomerular cells is also demonstrated using mesangial, epithelial or tubular cells in vitro. The effect on cell degeneration can be measured by morphological changes and the expression of specific biochemical functions, such as the secretion of plasminogen activator inhibitor, PGE2, interleukin-1 (JD Sraer et al. The effect on the degeneration of cardiac muscle cells, especially after ischemia, by morphological changes, diffusion of cytosolic enzymes (LDH) or changes in membrane excitatory properties (P. Athias et al. aforementioned). The doses used are similar to those described for the cytoprotective effect of hepatocytes.

 The derivatives of the present invention protect intestinal and gastric cells against toxic compounds, such as excess gastric acidity. The molecules of the invention render the parietal and epithelial cells of the stomach more resistant to excess gastric acidity; they decrease the secretion of t ions and increase the secretion of mucus. This effect protects this organ against the consequences of stress, regulate intestinal motility in a stressful situation and prevent the formation of a gastric or intestinal ulcer. The derivatives of the invention also increase the trophicity of the intestinal villi, epithelial cells of the stomach and pancreatic islets of Langerhans.They make the intestinal mucosa more resistant in a situation of malnutrition and limit the functional consequences related to pancreatitis, especially on the secretion of insulin. The derivatives of the invention are advantageously added to preparations for parenteral nutrition or breast-milk substitutes. They promote the differentiation and maturation of digestive tract tissues during development or following chemical, mechanical or surgical trauma.

EXAMPLE 4: PROTECTION OF CELL 8 HEPATIC VIS-A
DEGENERATION SCREEN INDUCED BY DE8 COMPOUNDS
TOXIC.

The maintenance in culture of isolated hepatocytes makes it possible to study their metabolism and their sensitivity vis-à-vis certain toxic compounds. Hepatocytes are isolated from the liver of adult rats by perfusion with collagenase, filtration and centrifugation in L15 medium. The hepatocytes are purified by elutriation in an elutriation chamber at a flow rate of 10 to 40 ml / min which is centrifuged at 840 rpm (E. Rumeur et al above). A pure fraction containing diploid hepatocytes is obtained at a flow rate of 15 ml / min. They are sown in petri dishes covered with a layer of fibronectin, in medium
Ham F12 containing bovine albumin, insulin, 10% fetal calf serum and hydrocortisone. Some long-chain fatty alcohols are added in certain dishes at doses ranging from 0.01 WH i 10 WN, and preferably 0.1 to 10si.

Differentiation of hepatocytes can be measured by measuring albumin production by immunonephelometry and protein synthesis by incorporation of labeled leucine. Glutathione level and enzyme activity of drug metabolism such as cytochrome can also be measured
P450, glucuronyltransferases and sulfotransferases.

Cells tend to degenerate during culture and in particular lose their cytochrome P450 activity and the conjugation enzymes. On the other hand, cultures treated with the molecules we describe have a better survival rate and retain their enzymatic activities. These results show the cytotrophic effect of these molecules.

 The addition of certain drugs for 24 hours at doses of 0.1 to 1mN, such as galactosamine, paracetamol, pentobarbital or cyclophosphamide leads to degeneration of hepatocytes, which is observed by morphological and biochemical changes. The cells release cytosolic enzymes into the culture medium (such as LDH), cell viability decreases, as well as albumin secretion capacity and glutathione levels. The degeneration is substantially attenuated in cultures treated with long chain fatty alcohols, according to the invention, with improvement of the survival and maintenance of the hepatocyte differentiation characters.

 These results show the interest of the derivatives of the invention in the treatment of the toxicity induced by certain drugs and as protectors of the degeneration of liver cells.

5) Immune defenses
A lack of expression of the differentiated functions of certain cells may result in a deficit in the body's immune defenses. These rely in particular on macrophages that secrete cytokines, which participate in the regulation of immunity.

Interleukin 1 is secreted by macrophages and promotes proliferation and differentiation of lymphocytes by increasing the appearance of IL2 receptors (Hogan and Vogel.

 J.Imunol.Immunophamacol.8: 6-15 (1988)). It also promotes B-cell differentiation and antibody secretion. Macrophages also secrete a molecule called "Tumor Necrosis Factor" (TNF) that causes lysis of tumors and another called "Colony Stimulating Factor" (CSF) that can promote the production of interferon in the marrow. This CSF is itself a differentiating agent for macrophage precursors and increases the response of macrophages to certain differentiating agents such as phorbol ester.

Finally, macrophages produce interferon a and ss in response to certain stimuli. Interferon increases the phagocytic functions of macrophages and therefore their tumoricidal role.

 Immune defenses also rely on lymphocytes. These can differentiate into monocytes or granulocytes, in response to certain agents. Thus, a phorbol diester promotes differentiation of lymphocytes into monocytes (Rovera et al., Proc.Natl.Acad.Sc., 76: 2779 (1979)) and retinoids promote the differentiation of lymphocytes to granulocytes (Breitman et al.

Proc.Natl.Acad.Sci. 77: 2939 (1980)).

 Another interesting application of the present invention is to promote the differentiation of cells that participate in the body's immune defenses, such as macrophages, monocytes and lymphocytes. The degree of differentiation of these cells can be measured by their ability to secrete certain cytokines, such as IL-1 (interleukin-1), CSF or interferon, as well as their response to immune signals (Waren and Ralph.

J. Immunol, 137: 2281 (1986)). The addition of long chain fatty alcohols of the invention has a cytotrophic effect on these cells and increases the production of CSA (Colony Stimulating Activity) by monocytes in response to PMA, increases the production of interferon by macrophages, increases their phagocytic functions, as well as their receptivity to immune signals. If blood monocytes are incubated in the presence of the derivatives of the invention, an improvement in their survival is observed after 5 days, a better differentiation in quality and in number of differentiated cells (appearance of a specific surface antigen, secretion certain cytokines). Increased production of IL1 promotes activation of B and T lymphocytes, increases the number of IL2 receptors, induces granulocytosis. The doses used in vitro are of the order of 0.01 to 10 μl, more particularly 0 , 1 to 5SM. The corresponding doses for in vivo use are in the range of 0.01 mg / kg to 10 mg / kg, more particularly 0.1 to 1 mg / kg.

 The trophic action of the derivatives of the invention on lymphocytes and macrophages, allows them to be used to promote the body's immune defenses, in particular in the case of immune system deficiency (AIDS, autoimmune diseases ).

6) Anti-inflammatory and anti-allergic effect
Histamine plays a key role in the pathology of inflammation; it is also a mediator of allergic or anaphylactic phenomena. It is released by mast cells or basophilic leucocytes. The release of histamine by the mast cells could also play a role in the control of cutaneous microcirculation. Apart from this non-immunological phenomenon, it is recognized that the stimulation of basophils and mast cells by an antigen and IgE is a fundamental mechanism in acute allergic diseases such as anaphylactic shock, asthma, allergic rhinitis and certain diseases. skin, such as urticaria and atopic dermatitis (JC

Foreman Ann. Rev. Pharmacol. Toxicol. 21: 63-81 (1981)).

 IgE antibodies are secreted by B cells in response to antigen binding.

This secretion is controlled by other lymphocytes, suppressor T cells and T helper cells. IgE then binds to mast cells and basophils and causes the release of histamine plus other mediators of inflammation. Crosslinking of IgE is necessary to obtain this response and the amount of histamine released is related to the number of molecules
IgE crosslinked. Histamine release also requires the presence of extracellular calcium, as well as the activation of inositol phosphate metabolism and the intervention of cyclic nucleotides.

A number of compounds interacting either with the calcium flux or the metabolism of inositol phosphates, or with that of cyclic nucleotides, such as theophylline, modify the response of mast cells and basophils to the binding of
IgE.

 Finally, the physiological response to the secretion of histamine and other mediators of inflammation (leukotrienes, prostaglandins) involves the attachment of these molecules to their target, particularly the smooth muscles. An example of this is bronchial vasoconstriction, which results from histamine release and is involved in asthma.

 The long chain fatty alcohol derivatives of the invention exhibit a cytotrophic effect on cells that participate in the inflammatory and allergic phenomena of the body, such as mast cells and basophilic leucocytes. The inflammatory and allergic phenomena are triggered by the fixation of an antigen and IgE on these cells, which results in the release of histamine. The histamine released by mast cells from the peritoneal fluid can be measured by incubating for 30 min at 370C in a defined medium. The amount of histamine secreted increases with the concentration of calcium in this medium or in the presence of the ionophore A23187; histamine is also secreted as a result of IgE binding to the cell membrane and crosslinking of these molecules (J.C.Foreman mentioned above). If derivatives of the invention are added to the incubation medium, the amount of histamine released is significantly decreased. This suggests that they act on calcium fluxes or on the membrane movement of IgE receptors, or on the secondary mechanisms involved in the exocytosis process (metabolism of inositol phosphates, cyclic nucleotides), with consequent decrease of the secretion of histamine and thus an anti-inflammatory effect. This effect is obtained in vitro with amounts of long chain fatty alcohols of the order of 0.01 to 100 MS, more particularly 0.1 to 10 SS. The corresponding doses for in vivo use are of the order of 0.01 mg / kg to 100 mg / kg, more particularly 0.1 to 10 mg / kg.

 The derivatives of the invention therefore make it possible to attenuate the acute inflammatory and allergic processes, following the secretion of IgE and the fixation of an antigen on mast cells and basophils, as can be observed in asthmatic disease. allergic rhinitis, anaphylactic shock or urticaria.

 The derivatives of the invention protect the cartilaginous and bone tissue from the consequences of sour or chronic inflammation, as can be seen in any inflammation of the joints and bones. In particular, they slow down bone destruction and the formation of osteoarthritis. This effect is obtained thanks to a trophic effect of long-chain fatty alcohols on chondrocytes and osteoblasts, as well as a promoting action on the differentiation of these cells during development or following trauma.

7) Anti-tumor effect
Each cell can be identified by morphological, biochemical and immunological criteria representative of a given state that can change under the effect of an activation. The activation phenomena appear quickly after the stimulation: they are variations of calcium mobilization, the contents of DNA, RNA or proteins; they result in the expression of membrane antigens or the induction of enzymatic activities. In the case where the stimulation leads to the acquisition of specific characters, antigenic or functional, corresponding to a cellular state more mature than the initial state, the activating signal is a differentiating signal. These effects are observed with various cell types, such as central neurons with hexacosanol (Borg et al.

 Neurosci.Lett.213: 406-410 (1987)), but also human promyelocytes that differentiate into monocytes in the presence of phorbol diester (G.Rovera et al Proc.Natl.Acad.Sci., 76: 2779-2783 ( 1979)) or granulocytes under the action of retinoids (TRBreitman et al., Proc.Natl.Acad.Sci.

77: 2936-2940 (1980)).

 In the case of promyelocytic cells, the pathway in which the differentiation is directed can be specified with phenotypic markers, such as the expression of membrane antigens M02, specific for monocytes, or Mol, characteristic of differentiation into granulocytes or monocytes. Some inducers have the ability to differentiate cancerous or precancerous cells into differentiated cells. Other molecules such as TNF also have anti-cancer activity. This TNF is secreted by macrophages; it can cause lysis of tumors. The cytotoxic activity is exerted by TNF-activated monocytes (EACarswell et al Proc.Natl.Acad.Sc., 25: 3666 (1975)) This toxicity is selective for tumor cells and it is believed that this substance plays a vital role in defending the body against neoplasia.

Any molecule that promotes the differentiation of macrophages or monocytes and their production of TNF could therefore increase the defense capabilities of the body.

 Another application of the invention is to promote the differentiation of the cells that participate in the defense of the body against the processes. tumors, such as macrophages, lymphocytes and monocytes. When they reach their differentiated stage, these cells show phagocytic activity and the release of tumoricidal molecules, such as TNF. Promyelocytic cells can differentiate into monocytes or granulocytes under the effect of certain inducers such as phorbol esters or retinoids. The differentiation of these cells can be measured using leukemic promyelocytic cells HL60 maintained in culture, in RPMI medium containing 20% fetal calf serum. The cells are cultured at 3x105 cells per ml and subcultured twice a week (N.Mendelsohn et al., Cancer Res., 40: 1469-1474 (1980)).

 The derivatives of the invention are added to the medium at the time of cultivation and the degree of differentiation is measured 5 days after the beginning of the treatment by the morphological changes and by their capacity to reduce the nitroblue of tetrazolium, like this. is shown in Example 5. There is an increase in the number of differentiated versus control cells in the treated cultures. In the same way, the treated cells show a decrease in the number of transferrin receptors, observed by direct immunofluorescence and a larger number of membrane antigens MO1 observed by indirect immunofluorescence. The doses of long chain fatty alcohols of the invention used are on the order of 0.01 to 100 μs in culture, more particularly 0.1 to 10 μs. The corresponding doses for in vivo use are of the order of 0.1 to 10 mg / kg.

 The use of the derivatives of the invention thus makes it possible to promote the differentiation of cancer or precancerous cells, in particular the precursors of macrophages, lymphocytes and monocytes.

In particular, they increase their phagocytic and tumoricidal activity.

EXAMPLE 5: CYTOTROPIC EFFECT 8UR OF LEUCENIC PROXYELOCYTES Ho60.

 The use of leukemic promyelocytes HL60 makes it possible to study in vitro their differentiation into monocytes or granulocytes. The HL60 cells are cultured in RPMI medium containing 20% fetal calf serum; they are seeded at a density of 3 × 10 5 cells per ml and subcultured twice a week (N.Mendelsohn et al. mentioned). At the time of cultivation, long-chain fatty alcohols of the invention are added at concentrations ranging from 0.01 to 100, which are used as a differentiating signal. After 5 days of culture, the differentiation of HL60 cells into monocytes or granulocytes is studied, which can be measured by morphological changes after May Grünwald-Giemsa staining and by their ability to reduce nitroblue tetrazolium. Undifferentiated cells contain less than 3% of cells capable of reducing this compound. In the cultures treated with the derivatives of the invention, this percentage is significantly increased, whereas the cell volume decreases substantially. Alkalinization of the intracellular medium is also observed, characteristic of differentiation into monocytes or granulocytes.

 To measure the expression of transferrin receptors, a direct immunofluorescence method is used; after rinsing the cells, they were incubated with fluorescein-coupled transferrin antiretreceptor antibody for 1 hour at + 4 ° C. The cell suspension is filtered through a nylon veil, before passage to the cytofluorometer. A decrease in transferrin receptors is observed as early as 2 days of culture. The expression of phenotypic markers, such as monocyte-specific M02 membrane antigens and MO1, present on monocytes and granulocytes is then studied. Labeling is done with anti-MOI and anti-MO2 antibodies (Coultronics), followed by incubation for 1 hour at +4 ° C with the fluorescein-coupled rabbit anti-mouse antibody.From 3 days of culture, the percentage of cells expressing MO1 increases, whereas the expression of MO2, monocyte-specific appears after 4 or 5 days, when the cultures are maintained in the presence of long-chain fatty alcohols of the invention.

Propidium iodide labeling shows that cells accumulate in the GO / G1 phase of the cell cycle. During cell differentiation
HL60, there is also an increase in cAMP-dependent protein kinase activity, an increase in transglutaminase activity and a decrease in the expression of the c-myc oncogene.

 These results show that the long chain fatty alcohols of the invention used at doses ranging from 0.01 μM to 100 μ, and more particularly 0.1 to 10 μ, make it possible to induce the differentiation of promyelocytes into granulocytes or monocytes. The induced cells possess the differentiating characteristics of granulocytes and monocytes, in particular their phagocytic activity, which enables them to play a fundamental role in protecting the body against the development of cancerous tumors.

 8) Examples of culture media used in combination with the derivatives of the invention.

a) Culture of neuronal cells
Minimum Essential Medium (Middle Minimum
Essential) modified by DULBECCO (DMEM) according to DULBECCO,
R., FREEMANN G., Virology, 8, (1959) 396, supplemented by
transferrin 100 μg / ml
(final concentrations)
insulin 5 pg / ml
selenium 30 nM
putrescine 0,1 mM
progesterone 20 nM
hexacosanol 500 nM b) Culture of keratinocytes or fibroblasts
Minimum Essential Medium according to EAGLE, H.,
Science, 130, (1959), 432 supplemented with
EGF (growth factor of the epidermis) long / ml
hydrocortisone 0.4pg / ml
hexacosanol 1 μM c) Culture of endothelial or negen cells
Medium 199 according to MORGAN, JF, et al., Proc.

Soc. Exp. Biol. Med .; 73 (1950), 1: 50% Vol
Medium RPMI 1640 according to MOORE, GE et al., J.

Am. Med. Assoc., 199, (1967) 519: 50% Vol with added
HEPES 10 mM
L-glutamine 2 mM
hexacosanol 1 yM d) Hepatocyte culture
Ham medium F12 according to HAMM, RG, Proc. Nat. Acad.

Sci., 53 (1965) 288 supplemented by
BSA (bovine serum albumin) 1 g / l
insulin 10 mg / l
hexacosanol 10 yM e) Mycoplasma culture
For 200 ml of complete medium, 140 ml of PPLO medium, consisting of
. beef heart protein 50 g
. peptone 10 g
. NaCl 5g (amounts to prepare 1 1 in distilled water) - 60 ml of a preparation comprising
. 25% yeast extract 1 part
. normal horse serum 2 parts - complete with
0.4% phenol red 1.0 ml
glucose at 50 g per 100 ml 4.0 ml
penicillin (100,000 ml / ml)
10% thalium acetate 0.5 ml
hexacosanol 20 mM 0.5 ml f) Culture of lymphocytes and macrophages
Medium RPMI 1640 according to MOORE et al., J. Am.

Med. Assoc., 199 (1967) 519 supplemented by
L-alanine 8.9 mg / l
(final concentration)
L-asparagine 15.0 mg / l
L-aspartic acid 13.3 mg / l
L-glutamic acid 14.7 mg / l
glycine 7.5 mg / l
L-proline 11.5 mg / l
L-serine 10.5 mg / l
serum of veal 5% hexacosanol 1 M

Claims (9)

 1. Derivatives of fatty alcohols, characterized by the following general formula  R1- [A- (x) yB] p-R2 - p is equal to 1 or 2, - y = O or 1, - A- (X) VB yB is a hydrocarbon chain comprising from 8 to 50 carbon atoms, optionally substituted with one or more halogen atoms, especially fluorine, or with one or more alkyl groups of 1 to 3 carbon atoms, and in which AA and B, respectively identical or different, are saturated aliphatic chains or not.

 a group -OR, in which R represents a hydrogen atom, or a group  optionally substituted with one or more halogen atoms, especially fluorine, or one or more -CH3 group, and / or -OH and / or -OR, R being as defined below, and / or an oxy group (= 0),

 a group of formula  in which R 'represents a hydrogen atom or an alkyl group of 1 to 5 carbon atoms, preferably 1 to 3 carbon atoms,

 . a halogen atom, especially a fluorine atom, a group  . a hydrogen atom,  X is also a block comprising a saturated or unsaturated hydrocarbon chain engaged in a ring structure, the latter hydrocarbon chain optionally comprising a carbonyl or oxycarbonyl function; R 1 and R 2, which may be identical or different, represent  a group -OR, R and R 'having the meanings indicated above.  or

R1- [A- (X) yB] p- or of formula - [A (X) yB] p-R2, comprising from 8 to 50 carbon atoms, where appropriate, substituted with one or more halogen atoms, especially of fluorine, or with one or more alkyl groups of 1 to 3 carbon atoms, in which A, X, B, R 1, R 2, y and p have the meanings indicated above, said derivatives comprising at least one group  a hydrocarbon chain of formula NH4 +,  a metal ion, preferably Na +, K +,  an amino acid, a peptide or a protein,  a nucleotide, glucose, or galactose,  a hydrogen atom, or a halogen atom, especially fluorine,  in which Y + represents a metal ion, preferably Na +, K +, NH + 4 and R3 represents

R 'having the meaning indicated above, or a derivative of monophosphoric acid of formula  2. Derivatives according to claim 1, characterized in that p = 1.  3. Derivatives according to claim 1 or claim 2, characterized by the following formula:

 having, where appropriate, 1 to 10, and preferably 1 to 5, double bond (s) and wherein n is an integer ranging from 1 to 10.  4. Derivatives according to claim 1 or claim 2, characterized by the following formula:

 respectively comprising, where appropriate, 1 & 5 and 1 to 4 double link (s).  5. Derivatives according to claim 1, characterized in that p = 2.  6. Derivatives according to claim 5, characterized

<Tb> <tb> <SEP> o <tb> HO <tb> by <SEP> the following <SEP> <SEP> General <SEP> formula  7. A pharmaceutical composition comprising at least one derivative according to any one of claims 1 to 6 in association with a physiologically acceptable vehicle.  8. Composition according to claim 7, comprising between 0.5 mg and 500 mg of a derivative according to one of claims 1 to 10.  9. Use of a derivative according to any one of claims 1 to 6 for obtaining a medicament for the treatment or prevention of neuronal degeneration, in particular during neurodegenerative diseases and neuronal degeneration. chemical compounds or excitatory amino acids, such as glutamic acid, - the treatment or prevention of nerve tissue damage in mammals, be it traumatic lesions, chemical lesions, lesions due to disease or congenital deficiency, - the treatment of Alzheimer's disease or Parkinson's disease, Huntington's disease and other neurodegenerative diseases, Wallerian degeneration, brain aging and genetic diseases such as Down's Syndrome, - the treatment and prevention of neurosurgical brain damage (the administration of these compositions being concomitantly with surgery), - the healing of skin lesions, as well as the treatment and prevention of phenomena related to aging of the skin, - the repair of vascular lesions (of traumatic or chemical origin), as well as the treatment and prevention of thrombosis and atherosclerosis, - treatment and prevention of degeneration of liver, renal or cardiac tissue, in particular when due to chemical or medicinal compounds toxic to these organs, - treatment and prevention of gastric and duodenal ulcers, - treatment of deficits acquired or hereditary immunity, - the treatment of acute inflammatory and allergic processes, such as asthma, allergic rhinitis, anaphylactic shock or urticaria, - the treatment and prevention of neoplasia and tumors, such as hepatic or bone tumors, and the prevention of the spread of metastases from cancerous tumors, - the treatment and prevention of all pathologies related to gram + bacteria and mycoplasmas, in particular pulmonary, urogenital and oral infections, - the treatment and prevention of diseases related to enveloped viruses, such as Herpes, rabies, AIDS.