FR2742051A1 - Use of compounds having affinity for 3H-ifenprodil binding sites - Google Patents

Abstract

Use of compounds having an affinity for the binding sites of (<3>H)-ifenprodil in the manufacture of medicines for the prevention and treatment of neuropathies is new.

Description

The present invention relates to the use of compounds having an affinity for [3H] ifenprodil binding sites for the manufacture of medicaments useful in the prevention and treatment of neuropathies.

[H] ifenprodil binding sites have been described by Schoemaker et al. in European Journal of Pharmacology, 183, 1670 (1990).

In the search for compounds that can promote the regeneration of peripheral nerves, it has been observed that several compounds with a high affinity for binding sites for [H] ifenprodil induce a significant increase in the rate of regeneration of the injured sciatic nerve. in rats.

These derivatives which have an affinity for the [3H] ifenprodil binding sites are described in the literature.

dans laquelle
R représente un groupe (phényl)p-cl-8-alkylew (phényl)-C2e alcényle, (phényl)p-c2-8-alcynyle, C38-cycloalkyle ou C38- cycloalkyl-C18-alkyle, p est 0 à 2, n est 0 à 6,
A est une liaison, un atome d'oxygène ou de soufre ou un groupe NR1,
R1 est un atome d'hydrogène, un groupe C18 alkyle ou phényl Cl-4-alkyle, m est 0 à 3, et
Ar est un groupe aryle ou hétéroaryle, substitué ou non, et leurs sels.Among different series of compounds displacing the bond of t3H] ifenprodil, the following piperidine, cycloalkylamine, arylalkylamine and alkanolamine derivatives have been shown to be particularly interesting - the compounds of patent application WO 92/02502, of formula (I)

in which
R represents a (phenyl) p-C1-8-alkylw (phenyl) -C2e alkenyl, (phenyl) p-c2-8-alkynyl, C38-cycloalkyl or C38-cycloalkyl-C18-alkyl group, p is 0 to 2, n is 0 to 6,
A is a bond, an oxygen or sulfur atom or an NR1 group,
R1 is a hydrogen atom, a C18 alkyl or phenyl C1-4-alkyl group, m is 0 to 3, and
Ar is an aryl or heteroaryl group, substituted or not, and their salts.

dans laquelle
X représente un atome d'oxygène ou de soufre ou un groupe -CH2- ou -NH-,
Y représente un groupe -CH2- ou -NH-, n est égal à 1, 2 ou 3,
R1 représente un atome d'hydrogène ou un groupe alkyle, hydroxyalkyle, alcoxyalkyle, cycloalkyle, cycloalkylalkyle, phényle ou carboxyle,
R2 représente un atome d'hydrogène, un groupe alkyle, hydroxyalkyle, cycloalkyle ou cycloalkylalkyle,
R3 et R4 représentent, indépendamment l'un de l'autre, des groupes alkyle, haloalkyle, cycloalkyle, cycloalkylalkyle, alkylcycloalkyle, alkylcycloalkylalkyle, phényle, phénylalkyle, diphénylalkyle, alkylphényle, alkylphénylalkyle, halophényle, halophénylalkyle, phénoxyalkyle, halophénoxyalkyle, alcoxyphénoxyalkyle, cyanophénoxyalkyle, benzyloxyalkyle, alcoxyalkyle, alcoxyalcoxyalkyle, alcoxycarbonylalkyle, phénylthioalkyle, alkylcarbonylaminophénylalkyle, halophénylcarbonylalkyle, halobenzylcarbonylalkyle, alkylcarbonylphénoxyalkyle, alcoxycarbonylphénoxyalkyle, alkylphénoxyalkyle, alcénylalkyle, alcynylalkyle, alcynylalcoxyalkyle ou polycycloalkyle, des groupes hétérocycliques saturés ou partiellement insaturés, des groupes hétérocycloalkyle saturés ou partiellement insaturés ou des groupes hétéroarylalkyle ou hétéroaryloxyalkyle, ou bien R3 et R4 forment ensemble un groupe hétérocyclique saturé ou partiellement insaturé ou un groupe hétéroaryle, groupes pouvant eux-mêmes être substitués,
R5 représente un atome d'hydrogène, un groupe alkyle, hydroxyalkyle, cycloalkyle, cycloalkylalkyle, phénylalkyle ou phényle,
R6 représente un atome d'hydrogène, un groupe alcanoyle ou cycloalcanoyle, chacun des groupes R1-R6 pouvant être substitué par radical alkyle, cycloalkyle, cycloalkylalkyle, alcoxy, alcénylalkyle, alcoxyalkyle, hydroxyalkyle, halo, oxo, cyano, phényle ou phénylalkyle, ainsi que leurs sels pharmaceutiquement acceptables, - les composés de la demande de brevet EP 0 572 952, de formule (III)

dans laquelle
X représente un atome d'hydrogène ou de fluor, et
R représente un atome d'hydrogène ou un groupe p-fluorobenzoyle, a-hydroxy-p-fluorobenzyle, p-fluorophénoxy, bis(p-fluorophényl)méthyle ou 8-azaspiro[4,5]décane-7,9dione-8-ylméthyle, avec la condition que X ne peut être un atome d'hydrogène lorsque R est un groupe p-fluorobenzoyle, ainsi que leurs sels d'addition d'acides pharmaceutiquement acceptables.- the compounds of patent application WO 92/03131, of general formula (II)

in which
X represents an oxygen or sulfur atom or a -CH2- or -NH- group,
Y represents a -CH2- or -NH- group, n is equal to 1, 2 or 3,
R1 represents a hydrogen atom or an alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, phenyl or carboxyl group,
R2 represents a hydrogen atom, an alkyl, hydroxyalkyl, cycloalkyl or cycloalkylalkyl group,
R3 and R4 represent, independently of each other, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, phenyl, phenylalkyl, diphenylalkyl, alkylphenyl, alkylphenylalkyl, halophenyl, halophenylalkyl, phenoxyalkoxyalkenoxyalkenoxyalkyl, phenoxyalkoxychaloxyalkyl, benzyloxyalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, alkoxycarbonylalkyl, phenylthioalkyl, alkylcarbonylaminophénylalkyle, halophénylcarbonylalkyle, halobenzylcarbonylalkyle, alkylcarbonylphénoxyalkyle, alcoxycarbonylphénoxyalkyle, alkylphénoxyalkyle, alkenylalkyl, alkynylalkyl, alcynylalcoxyalkyle or polycycloalkyl, saturated heterocyclic groups or partially unsaturated, saturated heterocycloalkyl or partially unsaturated or heteroaryl groups or heteroaryloxyalkyl, or else R3 and R4 together form a saturated or partially unsaturated heterocyclic group or a heteroaryl group, which groups may themselves be substituted ues,
R5 represents a hydrogen atom, an alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, phenylalkyl or phenyl group,
R6 represents a hydrogen atom, an alkanoyl or cycloalkanoyl group, each of the groups R1-R6 possibly being substituted by an alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkenylalkyl, alkoxyalkyl, hydroxyalkyl, halo, oxo, cyano, phenyl or phenylalkyl radical, thus that their pharmaceutically acceptable salts, - the compounds of patent application EP 0 572 952, of formula (III)

in which
X represents a hydrogen or fluorine atom, and
R represents a hydrogen atom or a p-fluorobenzoyl, a-hydroxy-p-fluorobenzyl, p-fluorophenoxy, bis (p-fluorophenyl) methyl or 8-azaspiro [4,5] decane-7,9dione-8- group. ylmethyl, with the proviso that X cannot be a hydrogen atom when R is a p-fluorobenzoyl group, as well as their pharmaceutically acceptable acid addition salts.

dans laquelle
A représente un atome d'hydrogène ou d'halogène ou un groupe alcoxy, cyano, phényle, phényle substitué par un atome d'halogène, benzyle, benzyle substitué par un atome d'halogène, 2-phényléthyle substitué sur le groupe phényle par un atome d'halogène, ou un groupe 2-picolyle,
B représente un atome d'hydrogène ou un groupe alcoxy ou nitro,
D représente un atome d'hydrogène ou d'halogène ou un goupe alcoxy, ou bien
B et D représentent ensemble un groupe -CH=CH-CH=CH-,
R représente un atome d'hydrogène ou un groupe alkyle ou phényle,
G représente un atome d'hydrogène,
I représente un atome d'hydrogène ou un groupe hydroxyle, ou bien G et I représentent ensemble une simple liaison,
E représente un atome d'hydrogène ou d'halogène, un groupe alcoxy ou trifluorométhyle, et m est égal à 0, 1 ou 2, avec la condition que, lorsque A est un groupe benzyle éventuellement substitué par un atome d'halogène, soit m est égal à 0 ou 2, soit I et G sont des atomes d'hydrogène, et que m est égal à 1 lorsque A est un groupe 2-picolyle, ainsi que leurs sels d'addition à des acides, - les composés de la demande de brevet EP 0 648 744, de formule (V)

dans laquelle
R représente un atome d'hydrogène ou un groupe hydroxyle ou arylalcoxy,
X représente un atome d'hydrogène,
Y représente un atome d'hydrogène ou un groupe hydroxyle, ou bien X et Y représentent ensemble un atome d'oxygène,
Z représente un groupe arylalkyle, et m est un nombre entier de 1 à 4, ainsi que leurs énantiomères et diastéréoisomères, à l'exception du diastéréoisomère (R,R) de formule (V) dans laquelle R est un groupe phénylméthoxy, X un atome d'hydrogène, Y un groupe hydroxyle, Z un groupe phénylméthyle et m est égal à 1, et leurs sels pharmaceutiquement acceptables, - les composés de la demande de brevet EP 0 376 850 de formule (VI)

dans laquelle
R1 représente un atome d'hydrogène ou d'halogène,
R2 représente un groupe cyclohexyle ou phényle,
R3 représente un groupe C36 cycloalkyle,
R4 représente un atome d'hydrogène ou un groupe C16 alkyle ou C36 cycloalkyle,
A représente un groupe -C0-CH2-, -CH(Cl)-CH2-, -CH(OH)-CH2-, -CH2-CH2-, -CH=CH-, ou -C=-C-, ainsi que leurs sels d'addition à des acides, - les composés du brevet français FR 2699534, de formule (VII)

dans laquelle
X représente un atome d'oxygène ou un groupe de formule -CH2-, -CH20-, -OCH2- ou -CH2-CH2-,
R1 représente un ou deux atomes de chlore, et
R2 représente un atome d'hydrogène ou d'halogène ou un groupe trifluorométhyle ou C14 alkyle, ainsi que leurs énantiomères et leurs sels d'addition à des acides, - les composés du brevet US 3056836, de formule (VIII) dans laquelle
R3 représente un

- the compounds of patent application WO 93/11107, of formula (IV)

in which
A represents a hydrogen or halogen atom or an alkoxy, cyano, phenyl, phenyl group substituted by a halogen atom, benzyl, benzyl substituted by a halogen atom, 2-phenylethyl substituted on the phenyl group by a halogen atom, or a 2-picolyl group,
B represents a hydrogen atom or an alkoxy or nitro group,
D represents a hydrogen or halogen atom or an alkoxy group, or else
B and D together represent a group -CH = CH-CH = CH-,
R represents a hydrogen atom or an alkyl or phenyl group,
G represents a hydrogen atom,
I represents a hydrogen atom or a hydroxyl group, or else G and I together represent a single bond,
E represents a hydrogen or halogen atom, an alkoxy or trifluoromethyl group, and m is equal to 0, 1 or 2, with the proviso that, when A is a benzyl group optionally substituted by a halogen atom, either m is equal to 0 or 2, or I and G are hydrogen atoms, and that m is equal to 1 when A is a 2-picolyl group, as well as their addition salts with acids, - compounds of patent application EP 0 648 744, of formula (V)

in which
R represents a hydrogen atom or a hydroxyl or arylalkoxy group,
X represents a hydrogen atom,
Y represents a hydrogen atom or a hydroxyl group, or else X and Y together represent an oxygen atom,
Z represents an arylalkyl group, and m is an integer of 1 to 4, as well as their enantiomers and diastereomers, with the exception of the (R, R) diastereomer of formula (V) in which R is a phenylmethoxy group, X a hydrogen atom, Y a hydroxyl group, Z a phenylmethyl group and m is equal to 1, and their pharmaceutically acceptable salts, - the compounds of patent application EP 0 376 850 of formula (VI)

in which
R1 represents a hydrogen or halogen atom,
R2 represents a cyclohexyl or phenyl group,
R3 represents a C36 cycloalkyl group,
R4 represents a hydrogen atom or a C16 alkyl or C36 cycloalkyl group,
A represents a group -C0-CH2-, -CH (Cl) -CH2-, -CH (OH) -CH2-, -CH2-CH2-, -CH = CH-, or -C = -C-, as well as their addition salts with acids, - the compounds of French patent FR 2699534, of formula (VII)

in which
X represents an oxygen atom or a group of the formula -CH2-, -CH20-, -OCH2- or -CH2-CH2-,
R1 represents one or two chlorine atoms, and
R2 represents a hydrogen or halogen atom or a trifluoromethyl or C14 alkyl group, as well as their enantiomers and their addition salts with acids, - the compounds of US Pat. No. 3056836, of formula (VIII) in which
R3 represents a

et ses sels d'addition à des acides.<tb><SEP> O- <SEP> RJ- <SEP> N- <SEP>Rq'0<SEP> (vIII)
<tb> group <SEP> C2 ~ 6 <SEP> alkylene, <SEP> Y2
<tb>
R4 represents a C26 alkylene group optionally comprising a hydroxyl group,
Y1 and Y2 each represent a hydrogen atom or one or two hydroxyl, alkoxy, phenyloxy, benzyloxy or acetyloxy groups, at least one of the substituents Y1, Y2 and R4 containing an oxygen atom, and their salts, - the compound of US Pat. No. 2,661,372, of formula (IX)

and its addition salts with acids.

The compounds defined above were initially tested to evaluate their affinity for the binding site with respect to [3H] ifenprodil, a male Sprague-Dawley rat weighing 150 to 230 g is sacrificed and its cerebral cortex is homogenized in 20 volumes of buffer
Ice-cold 50 mM Tris-HCl (pH = 7.4 at 25 ° C), using an Ultra-Turrax (Ikawerk) or PolytronT (Kinematica) apparatus.

The homogenate is washed twice by centrifugation for 10 minutes at 45000xg, the pellet being resuspended in fresh buffer. The final pellet is taken up in 20 volumes of the same buffer.

A 100 µl aliquot of this suspension is incubated in a final volume of 1000 µl with 0.5 nM [3H] ifenprodil (specific activity: 30-35 Ci / mmol) for 30 minutes at 37 ° C. absence or presence of competitive substance.

After incubation, the membranes are recovered by filtration through Whatman GF / BTM filters pretreated with 0.05% polyethyleneimine, then washed with twice 5 ml of ice-cold buffer.

The non-specific binding is determined with 10 µM ifenprodil, the data is analyzed according to the usual methods, and the IC50 concentration is calculated, which concentration inhibits the binding of [3H] ifenprodil by 50%.

The compounds exhibit a strong affinity for the binding sites of ifenprodil, with IC50s generally less than or equal to 50 nM.

Among the most interesting compounds, mention may be made of - 4- (p-fluorobenzyl) -l- [4- (p-fluorophenyl) -4-hydroxybutyl) piperidine, - N-cycloheXyl-N-ethyl-1- ( 3-chloro-4-cyclohexylphenyl) -3-propenylamine, - 4- [2- (3,4-dichlorophenoxyethyl)] - 1-pentylpiperidine, - 4-hydroxy-a-tl - [(1-methyl-2 -phenoxyethyl) amino] ethyl] benzenemethanol, - 4-hydroxy-a- [1- [(1-methyl-3-phenylpropyl) amino] ethyl) benzenemethanol, - (+) - a- (5-chlorothien-2 -yl) -4- [2- [(4-trifluoromethyl) phenyl] ethyl] piperidine-1-ethanol, - 1- (2,3-dihydro-5-benzo [b] thienyl) -2- (4- phenylbutylamino) propanol, - a- [4 - [(4-chlorophenyl) methyl] phenyl] -4-phenyl-1,2,3,6-tetrahydropyridine-1-ethanol, - (R *, R *) - a- (4-hydroxyphenyl) -i3-methyl-4-phenylmethyl piperidine-1-propanol.

The compounds were then tested on the regeneration of the sciatic nerve after injury.

The compounds were subjected to pharmacological tests which demonstrated their neurotrophic properties in a model of local lesion of the sciatic nerve in the rat.

Freezing injury destroys the fibers of the sciatic nerve which undergo Wallerian degeneration at the site of the injury and throughout the distal stretch; it preserves the nerve sheaths and allows nerve regeneration under reproducible conditions. The regeneration process begins from the proximal side within hours of injury. The speed of regeneration of the sensitive fibers is measured by a pinch test carried out 8 days after the lesion.

Male rats of the Sprague-Dawley strain (Iffa Credo) weighing approximately 200 g are anesthetized with sodium pentobarbital at a dose of 60 mg / kg ip. The skin of the thigh is incised at the level of the femoral biceps, then the lateralis muscles and the biceps femoris are removed in order to free the sciatic nerve. The point of lesion is identified by a micro suture on the perineurium above the trifurcation of the sciatic nerve. The lesion is made over 1 mm by 6 freeze-thaw cycles using a copper cryode pre-cooled in liquid nitrogen. The wound is closed and the animals monitored daily. The animals are then divided into several groups of ten individuals.
- a batch of animals treated with the vehicle (Tween 80TM at 0.1%) administered twice a day by the intraperitoneal route,
- batches of animals treated with the test compound administered twice a day by the intraperitoneal route at a dose chosen from the following: 0.3, 1, 3 or 10 mg / kg.

Eight days after the operation, the animals are lightly anesthetized and the sciatic nerve is exposed again before subjecting it to the "pinch-test". In this test the sciatic nerve is lightly pinched with a forceps, starting at the most distal region and working your way up every 0.5mm to the point where a reflex response is obtained. The response is manifested by a contraction of the muscles of the posterior region of the animal, indicating the zone of arrival of the front of the regenerated sensory fibers. This point is marked with a micro suture, the nerve is removed and the distance between the site of the lesion and the micro suture is measured under a microscope using a graph paper.

The results of these tests show that the compounds used according to the invention possess neurotrophic activity (increase in elongation of the sciatic nerve 2 10%, compared to the control group) and can be used for the preparation of medicaments useful in the prevention. and the treatment of neurological disorders where endogenous neurotrophic factors are absent or in insufficient quantity to induce axonal regeneration and where the supply of substances capable of reproducing the effects of natural neurotrophic agents by stimulating the regeneration of damaged neurons is necessary.

The compounds can therefore be used according to the invention for the preparation of medicaments useful in the prevention and treatment of peripheral neuropathies such as traumatic (cutting or crushing of a nerve), ischemic, metabolic (diabetes, uremia), infectious neuropathies. , alcoholics, drugs and genetic neuropathies etc. and for that of drugs useful in the treatment of motor neuron damage such as spinal muscular atrophy and amyotrophic lateral sclerosis.

They can also be used for the preparation of medicaments useful for the prevention and treatment of retinopathies of various origins.

To this end, they can be used alone or in combination with other therapeutic substances such as, for example, agents for reducing intraocular pressure in the case of glaucoma or anticancer agents with a view to reducing the side effects of the latter.

To this end, they can be presented in all pharmaceutical forms suitable for enteral or parenteral administration, in association with appropriate excipients.
They can be presented for example in the form of tablets, dragees, gelatin capsules, capsules, suppositories, oral or injectable solutions or suspensions or patches.

These pharmaceutical forms are dosed to allow daily administration of 1 to 1000 mg of active substance.

Claims (2)

Claims 1. Use of compounds having affinity for [3H] ifenprodil binding sites for the manufacture of medicaments useful in the prevention and treatment of neuropathies. 2. Use of the following compounds - 4- (p-fluorobenzyl) -l- [4- (p-fluorophenyl) hydroxybutyl] piperidine, - N-cyclohexyl-N-ethyl-l- (3-chloro-4-cyclohexylphenyl) -3- propenylamine, - 4- [2- (3,4-dichlorophenoxyethyl)] - 1-pentylpiperidine, - 4-hydroxy- &alpha; - [1 - [(1-methyl-2-phenoxyethyl) amino] ethyl] benzenemethanol, - 4-hydroxy- &alpha; - [1 - [(1-methyl-3-phenylpropyl) amino] ethyl] benzenemethanol, - (+) - a- (5-chlorothien-2-yl) -4- [2-t (4-trifluoromethyl) phenyl] ethyl] piperidine-1-ethanol, - l- (2,3-dihydro-5-benzo [b] thienyl) -2- (4-phenylbutylamino) propanol, - &alpha;;-( 4 - [(4-chlorophenyl) methyl) phenyl] -4-phenyl-1,2,3,6-tetrahydropyridine-1-ethanol, - (R *, R *) -a- (4-hydroxyphenyl ) -8-methyl-4-phenylmethyl piperidin-1-propanol for the manufacture of medicaments useful in the prevention and treatment of neuropathies.