FR2855970A1 - Treatment of depression without significant side-effects, comprises administration of alverine or its metabolites, showing strong affinity for sigma-1, sigma-2 and 5-HT1a receptors - Google Patents

Abstract

Use of alverine (N-ethyl-3,3'-diphenyl-dipropylamine) (I) or its metabolites, salts or esters in the production of pharmaceutical compositions for the treatment of depression, is new. Use of alverine (N-ethyl-3,3'-diphenyl-dipropylamine) (I) or its metabolites (specifically N-ethyl-3-(hydroxyphenyl)-3'-phenyl-dipropylamine, N-ethyl-3-hydroxy-3-(hydroxyphenyl)-3'-phenyl-dipropylamine or N-ethyl-3-(hydroxyphenyl)-3-oxo-3'-phenyl-dipropylamine) or their salts or esters in the production of pharmaceutical compositions for the treatment of depression, is new. ACTIVITY : Antidepressant. Alverine citrate showed significant, dose-dependent antidepressant activity (with no side-effects) on oral administration in a forced swimming model in mice, giving average immobility times of 104.2 seconds at 10 mg/kg, 85.0 seconds at 30 mg/kg and 58.9 seconds at 100 mg/kg, compared with 148.0 seconds for vehicle-only controls and 61.9 mg/kg in mice treated with imipramine at 30 mg/kg (for comparison). MECHANISM OF ACTION : Sigma-1, sigma-2 and 5-HT1a receptor ligand.

Description

Use of Alverine and its metabolites for the treatment of

depression.

INTRODUCTION

  The subject of the invention is a new therapeutic application of Alverine or its metabolites, more specifically the treatment of depression.

  Depression is one of the most common psychological disorders. In France, the depressive rate is 14.9%, of which almost a third is not treated medically. The prevalence of reported depression has increased six-fold since 1970. The risk of developing major depression during life varies, according to studies, from 10 to 25% for women and from 5 to 12% for men. 15 Depressive syndrome combines mood disorders (feelings of sadness, abandonment, humiliation, devaluation), psychomotor inhibition (fatigue, helplessness in daily life, concentration disorders), manifest anxiety (often in the foreground) with almost constant somatic disorders (oppression, spasm, sleep disorders, appetite disorders, sexuality disorder).

  The discovery of antidepressants in the late 1950s marked a real therapeutic revolution in the world of neuropsychiatry. Antidepressants (also called thymo-analeptics) are capable, within a period of two to three weeks, of improving depressed mood and relieving mental suffering. If the primary indication for antidepressants obviously remains endogenous unipolar depression, it is necessary to know the extensions of indication which now concern other psychiatric entities such as obsessive compulsive disorders, behavioral disorders, eating disorders but also other contexts 30 nosographic such as the therapeutic management of certain pains.

  Tricyclic antidepressants (TCA) with amitriptyline (Laroxyl) and imipramine (Tofranil) were the first to be discovered, followed by irreversible and non-selective monoamine oxidase inhibitors (MAOIs) such as phenelzine and pargyline. Adverse effects, in particular orthostatic hypotension, dry mouth, drowsiness, constipation, accommodation disorders but also the proconvulsant effect and cardiotoxicity of CAW (especially in the event of overdose) and hypertensive crises of MAOIs (interactions with food tyramine, the famous cheese effect) have pushed research towards new molecules of identical therapeutic efficacy but of better acceptability.

  The notion of specificity then appeared with specific inhibitors of norepinephrine (NA) or serotonin (5-hydroxytryptamine or 5HT) reuptake.

  Phase III clinical trials have demonstrated for these new molecules an efficacy equivalent to first generation antidepressants and better tolerance, especially in the event of an overdose. However, undesirable effects remain with these molecules. They most often relate to the digestive system, with nausea, vomiting and to a lesser degree, constipation and anorexia. Insomnia is described as well as headache, hypersudative attacks and decreased libido. Withdrawal syndromes have been described, hence the rule of dose reduction when considering stopping treatment.

  Serotonin syndrome, often overlooked, is linked to certain overdoses or interactions and justifies immediate discontinuation of treatment. It can lead to hospitalization, or even exceptionally jeopardize the vital prognosis. It combines a set of digestive (diarrhea), vegetative (sweating, thermal dysregulation, hypo or hypertension), motor (myoclonias, tremors), neuropsychic (confusion, agitation or even coma) symptoms.

  The discovery of the 2 forms A and B of monoamine oxidase, differing from each other by the affinity of form A for NA and 5HT and of form B for dopamine (DA), led selective and reversible monoamine oxidase A or B inhibitors. The advantage of a selective inhibition A or B is to allow one of the activities A or B to persist, sufficient to destroy tyramine which, in patients treated with Non-selective MAOIs were at the origin of numerous undesirable effects such as hypertensive attacks.

  A distinction is thus made between moclobemide (Moclamine), befloxatone and toloxatone (Humoryl) as a selective and reversible inhibitor of monoamine oxidase A. However, there is a risk of inducing serotonergic syndromes especially when their prescription follows that of a SSRI (serotonin reuptake inhibitor).

  For the latest antidepressants on the market, their therapeutic effect results from a simultaneous inhibition of the reuptake of serotonin (5HT) and norepinephrine (NA) and they combine the resulting side effects. Thus mirtazapine, (Norset) milnacipran (IxelD) and venlafaxine (Effexor @) act both on the noradrenergic pathways and on the serotonergic pathways. However, they are also not without side effects since mirtazapine frequently results in significant weight gain. Milnacipran (Ixel) and venlafaxine (Effexor) cause an increase in diastolic blood pressure as well as nervousness and anorexia.

  Thus, the problem which currently arises is the existence of an effective treatment for depression which has the least possible side effects and zero or almost zero toxicity.

  Autoradiographic studies have shown a wide distribution of sigma 25 receptors and 5HTla receptors in the brains of many animal species, in mammals, as well as in humans (Bouchard and Quirion, 1997). It has also been shown that the limbic structures of the brain have a high density of sigma and 5HTla receptors.

  Currently, at least two subclasses of sigma receptors have been identified: sigma 1 and sigma 2 (Quirion et al, 1992), sigma 1 receptors exerting neuromodulation on several neurotransmission systems, in particular glutamatergic and cholinergic. They therefore modulate the neurotransmission systems involved in depression.

  In addition, it has been shown that many neuroleptics (for example haloperidol) have a great affinity for sigma receptors, and that certain known anti5 depressive molecules (for example sertraline, fluoxamine, maprotiline and opipramol) have a great affinity with sigma 1 receptors at the nanomolecular level.

  In addition, 5-HT1 a receptors have been shown to be involved in the pathophysiology of anxiety and depression.

  These elements make it possible to hypothesize that the sigma receptors and the 5HTla receptors present in the brain are involved in the mechanisms of pathologies of the nervous system and more particularly in the phenomena of depression.

  The Applicant has found, quite surprisingly and unexpectedly, that Alverine, an antispasmodic used for the treatment of abdominal functional manifestations in particular with meteorism, has a strong affinity with the sigma 1, sigma 2 and 5HTla receptors and also an anti -depressor in the in vivo model.

  The advantage of Alverine which is on the market since 1990 in particular under the name of Meteospasmyl, compared to other antidepressants is its very low toxicity and the good knowledge of its side effects which in any event are very limited (Vidal reference).

DESCRIPTION

  Thus, the subject of the present invention is, according to a main aspect, the use of Alverine or its metabolites, as well as esters and pharmaceutically acceptable salts for the preparation of pharmaceutical compositions intended for treating depression. By Alverine is meant N-Ethyl-3,3'-diphenyldipropylamine CH2CH2CH2

I

CH3CH2N CH2CH.

  The term “Alverine metabolites” means, inter alia, the mono or poly hydroxylated derivatives on the phenyl nuclei and the mono or poly hydroxylated or mono or poly carboxylated nuclei on the aliphatic chains. Three of the main metabolites identified by way of example after incubation of Alverine with microsomes of human liver are: Metabolite 1:

OH

  CH2CH2CH2 CH3CH2N CH2CH2CH2 (I Metabolite 2

OH

Metabolite 3

OH

  CH2CH2C = O CH3CH2N CH2CH2CH2 By pharmaceutically acceptable salts is meant the addition salts of Alverine which can be obtained by reaction of this compound with a mineral or organic acid according to a method known per se. Among the acids which can be used for this purpose are hydrochloric, hydrobromic, sulfuric, phosphoric, 4-toluene sulfonic, methane sulfonic, cyclohexyl sulfamic, oxalic, succinic, formic, fumaric, maleic, citric, aspartic, cinnamic, lactic acids. glutamic, Nacetylaspartic, N-acetylglutamiic, ascorbic, malic, benzoic, nicotinic and acetic.

  Among the esters on the hydroxy function, mention may be made of esters of aliphatic acid with 1 to 6 carbon atoms.

  Although Alverine is known for its antispasmodic activity and is used for the treatment of abdominal functional manifestations, particularly with meteorism, its action as an anti-depressant agent has never been described or suggested.

  Alverine, its metabolites, its salts, and in particular citrate salts and its esters can be administered in a pharmaceutically acceptable form by one of the various routes known for this type of active principle although the oral route is the preferred route for this type of products in this type of applications. The injectable route can also be used when necessary, and for example, the intravenous route may be used.

  Preferably, the invention relates to the use of Alverine or its metabolites for the preparation of a pharmaceutical composition which can be administered orally, in particular in the form of capsules.

  Likewise, the subject of the invention is the use of Alverine or its metabolites for the preparation of a pharmaceutical composition which can be administered intravenously.

  Those skilled in the art will also know that the routes of administration of the compounds according to this invention can change significantly (intraperitoneal, intramuscular, rectal route). In addition to oral administration, sustained release compositions can be promoted. Other routes of administration may include, but are not limited to, subcutaneous implants, as well as oral, sublingual, transdermal, topical and intranasal administration. Biodegradable and non-biodegradable delivery systems can also be used.

  The active substances of the pharmaceutical compositions according to the invention can be in any of the usual oral dosage forms comprising tablets, capsules and liquid preparations such as elixirs and suspensions containing various masking substances for coloring, flavor and stabilization.

  To make the oral dosage forms according to the invention, in particular capsules, the active substance can be mixed with various conventional materials such as starch, calcium carbonate, lactose, sucrose and dicalcium phosphate to facilitate the process. encapsulation. Magnesium stearate, as an additive, provides a useful lubricant function if necessary.

  The active substances of the pharmaceutical compositions according to the invention can be dissolved or suspended in a sterile pharmaceutically acceptable liquid, such as sterile water, a sterile organic solvent or a mixture of these two liquids for administration by the intravenous route.

  According to a particular embodiment, the subject of the invention is the use of Alverine or its metabolites for the preparation of a pharmaceutical composition which can be administered according to one of the preceding routes, dosed from 1 to 1000 mg 10 for a composition formulated in the form of capsules or tablets or 0.1 to 500 mg for a composition formulated in the form of suppositories, ointments, creams, gels or aerosol preparations, administered in human therapy in one or more daily doses for an adult of average weight 60 to 70 kg.

  In the case of use for animals, the usable daily dose is between 0.01 and 20 mg per kg.

  The processes for preparing Alverine from phenylpropyl chloride and ethylamine in an alkaline medium are described in Kilz et al., Ber. 72.2165 (1939) and its galenics is also known.

  The synthesis mechanisms of metabolites 1, 2 and 3 of Alverine are illustrated by scheme 1 and the experimental protocols for the synthesis of metabolites 1 para-OH and ortho-OH are described in patent WO92 / 02488 by WJ Horgan and illustrated by diagram 2. Diagrams 1 and 2 are presented below: c. , EH2 - NH - 117, - - THF> CI k

OH

-HN EXO rNc ULH4 Et2O

NH

  Dloyiane. HCI 'C DCC. CH2C12 Meta6olite 3 Metabolite 1 o I NaBH4 EtOH Metabolite 2 Scheme 1 0 Q u EINH2 HF o E2H.

  DCC, CH2CI2 EIaO p-OH lb 0-OH sap-OH Sb o-ON Scheme 2 The affinity of Alverine and its metabolites for sigma 1 receptors sigma 2 and 5HTla has been tested in vitro and it has been observed strong affinity with sigma 1, sigma 2 and 5HTla receptors. It can be hypothesized that the anti-depressive action of Alverine and its metabolites is linked to this interaction with the sigma 1, sigma 2 and 5-HTla receptors, located in the same region of the brain, in limbic structures, and a different mechanism from the antidepressants on the market to date.

  It seems in particular that affinities for these two types of receptors allow an improved anti-depressive action compared to products having more selective actions on one or the other of said receptors.

LEGEND OF FIGURES

  Figure 1: Histogram of presentation of the results obtained by an anti-depressive activity test of Alverine administered intraperitoneally on a batch of mice, presented in Table 1 and described in Example 1.

  FIG. 2: Histogram for presentation of the results obtained by an anti-depressive activity test of Alverine administered orally on a batch of mice, presented in Table 2 and described in Example 2.

EXAMPLES

  The examples given below illustrate the invention without however limiting it: Example 1: Test of anti-depressive activity of Alverine administered intraperitoneally on a batch of mice.

  To establish the advantages according to the invention, a study was carried out on a batch of 50 30 mice. They were divided into 5 groups of 10 mice each.

  The first group is the control group: it is only treated with an excipient.

  The second group is treated with Alverine at a dose of 3 mg / kg The third group is treated with Alverine at a dose of 10 mg / kg The fourth group is treated with Alverine at a dose of 30 mg / kg The fifth group is treated with imipramine (tricyclic anti-depressant) at a dose of 10 mg / kg The five groups of mice are then subjected to the forced swimming test, a reduction in the immobility time indicating an anti-depressant effect.

  The forced swimming test is a pre-clinical behavioral model which has good predictive validity and is widely used to determine the efficacy of anti-depressant drugs (Borsini and Meli, 1988).

  The results obtained are presented in the form of a table below, and in the form of a histogram, in FIG. 1.

  Table 1: results obtained by an anti-depressive activity test of Alverine administered intraperitoneally on a batch of mice.

  Substances Excipient (1% Citrate Citrate Citrate Imipramine methylcellulose) Alverine Alverine Alverine Doses mg / kg 3mg / kg 1Omg / kg 30mg / kg 1 Omg / kg 97 118 3 12 65 107 128 29 97 67 144 82 86 3 70 time 171 151 28 66 1 immobility 144 132 30 36 89 (sec) 136 127 90 O 3 79 88 99 15 9 128 85 65 7 38 132 99 129 16 99 93 57 7 53 Average 129.8 110.3 61.6 25.9 49.4 Error type 9.0 7.6 12.5 10. 0 11.2 P test <0.05 ns * * * Dunnett% of -15 -53 -80 -62 variation Administration is done 30 minutes before the test.

  n = 10 animals per group * indicates a significant difference for p <0.05 (Dunnett test) ns indicates a non-significant result It is observed that the higher the dose of Alverine administered, the more the immobility time of the mice decreases, indicating an anti-depressant effect proportional to the dose (Figure 1).

  In addition, it is observed that the mice of the third group treated with 10 mg / kg of Alverine exhibit a time of immobility comparable to that of the mice of the fifth group treated with 10 mg / kg of Imipramine.

  It can therefore be concluded that Alverine, injected intraperitoneally has a significant anti-depressant effect in mice and as important as Imipramine, at comparable doses.

  Example 2: Test of anti-depressive activity of Alverine administered orally on a batch of mice.

  To establish the advantages according to the invention, a study was carried out on a batch of 50 mice. They were divided into 5 groups of 10 mice each.

  The first group is the control group: it is only treated with excipients.

  The second group is treated with Alverine at a dose of 10 mg / kg The third group is treated with Alverine at a dose of 30 mg / kg The fourth group is treated with Alverine at a dose 100 mg / kg The fifth group is treated with imipramine (tricyclic antidepressant) at a dose of 30 mg / kg The five groups of mice are then subjected to the forced swimming test, a reduction in the immobility time indicating an antidepressant effect.

  The forced swimming test is a pre-clinical behavioral model that has good predictive validity and is widely used to determine the effectiveness of anti-depressant drugs (Borsini and Meli, 1988).

  The results obtained are presented in the form of a table below, and in the form of a histogram, in FIG. 2.

  Table 2: results obtained by an anti-depressive activity test of Alverine administered orally on a batch of mice.

  Substances Excipient Citrate Citrate Citrate Imipramine (Alverine Alverine Alverine solution Doses mg / kg saline) 10 mg / kg 30mg / kg 100mg / kg 30mg / kg 167 113 113 32 97 128 86 104 52 52 123 95 80 129 64 time 126 104 64 67 55 immobility 139 111 70 6 5 (sec) 159 126 105 105 75 163 108 105 75 67 147 78 105 81 70 149 115 41 5 89 179 106 63 37 45 Average 148.0 104.2 85.0 58.9 61.9 Error type 6.0 4.5 7. 8 12.8 8.1 P test <0.05 ns * * * Dunnett% of -30 -43 -60 -58 variation Administration is done 60 minutes before the test.

  n = 10 animals per group * indicates a significant difference for p <0.05 (Dunnett test) ns indicates a non-significant result 15 It is observed that the higher the dose of Alverine administered, the more the immobility time of the mice decreases, indicating an antidepressant effect proportional to the dose (Figure 2).

  In addition, it is observed that the mice of the fifth group treated with 30 mg / kg of Imipramine exhibit a lower immobility time than that of the mice of the third group treated with 30 mg / kg of Alverine but comparable to the mice of the fourth group treated with 100 mg / kg of Alverine.

  In addition, no side effects were observed in mice treated with Alverine orally, at the doses used.

  It can therefore be concluded that Alverine, administered orally has a significant anti-depressant effect in mice, although this effect is comparable to that of imipramine only at higher doses, but this without generating side effects.

Claims (6)

  1. Use of Alverine CH2CH2CH2 I   CH3CH2N CH2CH2CH2 or its metabolites, their salts and their esters, for the preparation of pharmaceutical compositions intended to treat depression.   2. Use according to claim 1, characterized in that the metabolites of 1 Alverine are preferably: OH CH2CH2CH2 I CH3CH2N CH2CH2 OH CH2H2CH OH CH3CH2N C2H2CH2 OH   CH2CH2C = O CH3CH2N C2H2CH2 3. Use according to claims 1 and 2, wherein the pharmaceutical composition is administered orally.   4. Use according to claims 1 and 2, wherein the pharmaceutical composition is administered intravenously.   5. Use according to one of claims 3 to 4, according to which the pharmaceutical composition is dosed from 0.1 to 1000 mg of Alverine.   6. Use according to one of claims 3 to 5, according to which the pharmaceutical composition is administered in human therapy in one or more daily doses for an adult of average weight 60 to 70 kg.