FR2746313A1 - Use of melatonin and melatoninergic ligands - Google Patents

Abstract

Use of melatonin (5-methoxy N-acetyl tryptamine) and melatoninergic ligands to form pharmaceutical compositions for the prevention and treatment of diabetes and diabetic complications is new.

Description

 The invention relates to the use of melatonin and melatoninergic ligands for the production of pharmaceutical compositions intended for the prevention and treatment of insulin-dependent type I diabetes, non-insulin-dependent type II diabetes, and diabetic complications.

Many analogs of melatonin (5-methoxy N-acetyl tryptamine), a hormone secreted by the pineal gland, have been described in patents. Some discuss the use of melatonin analogs for the treatment of diabetes, and cite for this purpose
Clinical Endocrinology, 1986, vol 24, pp 354364. However, this artide only relates to the decrease in the secretion of melatonin due to damage to the sympathetic nerve fibers from the upper cerebral ganglia during neurological complications of diabetes. In no way is the effect of the administration of melatonin or its analogues on diabetes studied. Only a palliative treatment of melatonin deficiency induced by neuropathies would be conceivable by those skilled in the art on reading this publication.

 On the contrary, it appears to a person skilled in the art, in view of the state of the art, that melatonin could be diabetogenic.

 Some data in the literature suggest that increased activity of the pineal gland could lead to diabetes. Indeed, it has been observed that the onset of insulin-dependent diabetes is more important during the winter months and at puberty, when the melatonin levels are higher (Diabetes Research, 1987, vol 5, pp 83-87).

 Various experiments have been carried out to study the role of melatonin on plasma glucose concentration and on insulin secretion.

 Insulin release from islets of Langerhans isolated in vitro has been measured: some authors have found no effect of melatonin (Endocrinology, 1972, vol 91, pp 809-816), while others have shown l inhibitory action of melatonin on insulin secretion (Hormone research, 1974, vol 5, pp 21-28).

 The Applicant has discovered, on the contrary, that, surprisingly, melatonin and the ligands acting on the melatoninergic system are useful in the treatment of diabetes and its complications. They could in particular potenliailser strongly the action of insulin or stimulate its release.

 Melatonin and melatoninergic ligands therefore prove to be good because, didats for the treatment of diabetes.

 Poor control of blood sugar often leads to very serious complications.

Melatonin and melatoninergic ligands help control blood sugar. They are therefore also very useful in the prevention or treatment of diabetic complications.

In particular, they are useful in the prevention or treatment of diabetic vascular complications, such as arteritis of the lower limbs, coronary artery disease,
Atherosclerosis, heart failure, high blood pressure, and arteriosclerosis, particularly cerebral arteriosclerosis.

 They are also useful in the prevention or treatment of diabetic metabolic complications such as diabetic ketoacidosis, non-ketotic hyperglycemic hyperosmolar coma and lactic acidosis.

 They are also useful in the prevention or treatment of diabetic ocular complications, such as diabetic retinopathies, damage to the optic nerve and neovascular glaucoma, damage to the anterior chamber, and damage to the lens, in particular cataracts.

 They are also useful in the prevention or treatment of diabetic renal complications, such as glomerular nephropathy, glomlopathy, urinary tract infections linked to interstitial nephropathy, papillary necrosis, renal failure.

 They are also useful in the prevention or treatment of diabetic neurological complications, such as diabetic neuropathies, in particular polyneuritis, mononeuritis, multineuritis, vegetative neuropathy and trophic disorders, such as the problem of diabetic foot.

 Finally, they are useful in the prevention or treatment of skin complications of diabetes, such as taking, flushing, diabetic dermopathy, lipid necrobiosis, diabetic bullosis, annular granuloma, bacterial skin infections and associated mycoses. diabetes.

 The invention therefore relates to the use of melatonin and melatoninergic ligands for obtaining pharmaceutical compositions intended for the prevention and treatment of insulin-dependent type I diabetes, non-insulin dependent type II diabetes, and complications. diabetics.

dans laquelle R et A sont tels que décrits dans EP 447285, e de formule (vu) :

dans laquelle R, X, A, B et p sont tels que définis dans EP 506539, e de formule (Vc):

dans laquelle R, R1, X et R2 sont tels que définis dans EP 530087 e de formule (l/d):

dans laquelle Ar', R2 et R, sont tels que définis dans EP 527687, e de formule (lie):

dans laquelle R, R1, R2 et R3 sont tels que définis dans EP 562956, e de formule (l/f):

dans laquelle Rt, R2, R3, R4, R5 et R6 sont tels que définis dans EP 591057, e ou de formule (l/g):

dans laquelle R, R1, R2, R3 et X sont tels que définis dans EP 662471, les brevets ou demandes de brevets cités ci-dessus étant incorporés par référence.More particularly, the invention relates to the use, for obtaining pharmaceutical compositions intended for the prevention and treatment of diabetes and diabetic complications, of melatoninergic ligands of formula (I) which are: - melatonin - and melatoninergic ligands e of formula (Va):

in which R and A are as described in EP 447285, e of formula (seen):

in which R, X, A, B and p are as defined in EP 506539, e of formula (Vc):

in which R, R1, X and R2 are as defined in EP 530087 e of formula (l / d):

in which Ar ', R2 and R, are as defined in EP 527687, e of formula (lie):

in which R, R1, R2 and R3 are as defined in EP 562956, e of formula (l / f):

in which Rt, R2, R3, R4, R5 and R6 are as defined in EP 591057, e or of formula (l / g):

in which R, R1, R2, R3 and X are as defined in EP 662471, the patents or patent applications cited above being incorporated by reference.

The invention also relates to the use, for obtaining pharmaceutical compounds intended for the prevention and treatment of diabetes and diabetic complications, of other melatoninergic ligands than those contained in the formulas (Va) to (I / g) as defined above For example, the invention relates to the use for obtaining pharmaceutical compositions intended for the prevention and treatment of diabetes and diabetic complications, of the compounds described in the following documents: WO 9525514, FR 2718964 , WO 9529173, WO 9517405, EP 656209, EP 655243,
US 5403851, WO 9412475, WO 9500478, US 5300481, EP 585206, US 5196435, EP 513702, EP 420064, WO 9206955, EP 483077 and EP 641565, WO 9100095, WO 9014084,
WO 8904659, EP 305194, EP 300630, WO 8807367, EP 281242, WO 8700432, US 4614807, EP 106813, FR 2455037, FR 2329274, SU 445661, US 5314908, US 5283343,
US 5206377, US 5093352, WO 8901472, GB 2192001, FR 2718445, WO 9527712, WO 9416692 and EP 578620.

 The present invention also relates to the use of melatonin and melatoninergic ligands, in combination with insulin, for obtaining pharmaceutical compositions intended for the prevention and treatment of diabetes and diabetic complications.

 More particularly, this invention relates to the use of melatoninergic ligands of formulas (IIa) to (I / g) as described above, in combination with insulin, for obtaining pharmaceutical compositions intended for the prevention and treatment diabetes and diabetic complications.

 The invention also relates to the use of melatonin and melatoninergic ligands in combination with antidiabetic active ingredients, in particular compounds of the sulfonamide family or of the biguanide family, for obtaining pharmaceutical compositions intended for the prevention and for the treatment of diabetes and diabetic complications.

 In particular, the present invention relates to the use of melatoninergic ligands of formulas (Va) to (lit) as defined above, in combination with anti-diabetic active principles, in particular the compounds of the sulfonamide family or of the biguanide family, for obtaining pharmaceutical compositions intended for the prevention and treatment of diabetes and diabetic complications.

 The invention also extends to pharmaceutical compositions containing melatonin or one or more melatoninergic ligands in combination with one or more pharmaceutically acceptable excipients, useful in the prevention and treatment of diabetes and diabetic complications.

 The invention thus extends to pharmaceutical compositions containing a melatoninergic ligand of formulas (Va) to (Vg), as defined above, in combination with one or more pharmaceutically acceptable excipients, useful in the prevention and treatment of diabetes and diabetic complications.

 The invention also relates to pharmaceutical compositions containing melatonin or one or more melatoninergic ligands, in combination with insulin, combined with one or more pharmaceutically acceptable excipients, useful in the prevention and treatment of diabetes and diabetic complications.

 In particular, the invention relates to pharmaceutical compositions containing one or more melatoninergic ligands of formulas (I / a) to (Vg) as described above, in combination with insulin, combined with one or more pharmaceutically acceptable excipients.

 The invention also relates to pharmaceutical compositions containing melatonin or one or more melatoninergic ligands, for example melatoninergic ligands of formulas (lla to (l / g) as defined above, in combination with one or more active anti-diabetic ingredients, in particular in combination with one or more compounds of the sulfonamide family or of the biguanide family, useful in the prevention and treatment of diabetes and diabetic complications, combined with one or more pharmaceutically acceptable excipients.

 Among the pharmaceutical compositions according to the invention, there may be mentioned, more particularly those which are suitable for oral, parenteral, nasal, per or transcutaneous, rectal, perlingual, ocular or respiratory administration and in particular the simple or coated tablets, sublingual tablets , sachets, packages, capsules, lollipops, tablets, suppositories, creams, ointments, dermal gels, and oral or injectable ampoules.

 The dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication, or possibly associated treatments and ranges between 0.1 mg and 1 g per 24 hours in 1 or 2 doses, more particularly between 1 to 100 mg, for example between 1 to 10 mg.

It is known that insulin resistance, especially in type II diabetes, results in a deterioration in the biological efficacy of insulin (Kahn CR et al. In
Pathogenesis of non-insulin dependent diabetes mellitus Grill V. and Effendic S. (Eds) New
York, Raven Press (1988) pp 227-239 and Reaven GM et al. Diabetes 1993, 42, pp 13241332), leading in particular to a reduction in the stimulating effect of insulin on the uptake and use of glucose in insulin-sensitive peripheral tissues (Beck-Nielsen H. In the Diabetes Annual / 4 Alberti KGGM and Knall LP (eds). North Holland, Amsterdarn,
Elsevier Science (1988), pp 565-91).

 It is also known that the regulation of blood sugar in normal physiological conciliations involves the uptake of glucose by cells of peripheral tissues, in particular skeletal muscle. Indeed, it participates more than 80% in the uptake of glucose in the tissues, as shown by euglycemic hyperinsulinemic clamp experiments in non-diabetic humans.

 In addition, skeletal muscle is considered to be the major site of insulin resistance in the patient with type I diabetes (Am. J. Physiol. 1993, vol 264, n "5, part 1, pp E756- E762), or type II diabetes (J. Clin. Invest. 1993, vol 92, n "l, pp 486-494).

 The Applicant has now discovered that melatonin and melatoninergic ligands act as a blood sugar modulator (example A), in particular through the increase in the number of Glut 4 glucose transporters on the skeletal muscle membranes (example B).

In vivo and in vitro studies have confirmed the usefulness of melatonin and its analogues.

EXAMPLE A: INSUUNE TOLERANCE TEST
Male Wistar rats of 4 weeks old, placed in cycle 12-12 (alternation of 12h of light - 12h of darkness), are anesthetized at 9h, ie 2h after the start of the light period (CT 2).

A sample is taken by the caudal artery in order to assess the basal glycemia and insuiinérnio.

An insulin load (0.025 U / 100 g) is injected into the rat and blood samples are collected at 0, 5, 15, 30, 45 and 60 minutes after the injection to determine plasma glucose concentrations.

The compounds used according to the invention tested intraperitoneally 30 minutes before the insulin load, cause a drop in blood sugar greater than that recorded in the control rats, which did not receive an injection of the compounds used according to the invention.

The compounds used according to the invention therefore reinforce the hypoglycemic action of insulin. As such, they are useful for the treatment of diabetic pathologies.

EXAMPLE B: STUDY OF THE POPULATION OF GLUCOSE CARRIERS
GLUT 4 IN SKELETON MUSCLE
Glucose transport in the cell is carried out by diffusion facilitated by a family of transporters. Among these, Glut 4, a transporter present in insulin-sensitive tissues such as skeletal muscle, allows an entry of glucose proportional to insulinemia.

The measurement of the population of Glut 4 transporters is carried out on the skeletal muscle of control rats and of pinealectomized rats, by a classic Westem Blot experiment.
Anti-Glut 4 Antibodies:
The antibody used is a polyclonal rabbit serum. This was produced by injecting synthetic glucose transporters into male New Zealand white rabbits.

Preparation of membranes:
Muscle tissue of a rat is homogenized in 7 volumes of buffer (Tris 10 nM, LESTA 1 nM, sucrose 250 nM, pH 7.4), and centrifuged (100 g, 10 min). The supernatant is collected and the pellet is resuspended in the buffer solution and centrifuged again. The supernatant collected is mixed with the first and the whole is centrifuged at 150,000 g for 75 min. The final pellet is resuspended in the buffer solution.

Westem-Blot:
The membrane preparations (protein 2G401l9) are placed in an SDS gel
PAGE (10%). After migration, the proteins are transferred to a nitrocellulose membrane.

Non-specific sites are blocked by bovine serum albumin. The nitrocellulose sheet is incubated with anti-Glut 4 antibodies (1 / 10th), washed and then incubated with protein A labeled with iodine 1251.

After autoradiography, the radioactive signals are cut off and their radioactivity is measured by a Gamma counter.

Results: Glut 4 population in the total membrane fraction of skeletal muscle. cpm / g protein

An animal without a pineal gland, the main site for melatonin production, therefore has a decrease in the number of Glut 4 transporters on the membranes of skeletal muscle cells.

This significant result suggests that melatonin has an action on the population of Glut 4 transporters in skeletal muscle and, consequently, on the regulation of glycemia.

Melatonin and melatoninergic ligands are therefore good candidates for ensuring the maintenance of plasma glucose concentration and can provide drugs of interest for the prevention and treatment of diabetes and diabetic complications.

We also know that
The two main pathways that regulate energy intake and expenditure, the nervous pathway and the hormonal pathway, are interdependent.

Thus the suprachiasmatic nuclei which are involved in the nervous control of energy metabolism via the hypothalamus exercise this control by the sympathetic and parasympathetic autonomic nervous system, which results in a modulation of hormonal secretion (insulin and glucagon by the pancreas), a release of catecholamines by the adrenals as well as a modulation of the enzymes of energy metabolism in particular in the liver and adipose tissues. (Yamamoto H, Nagai K.

et al. Biomedical Research. 1984, 5 (1), pp 55-60).

The injection of 2-deoxy-D-glucose, causing glucopenia at the central level resulting in hyperglycemia at the periphery (linked to an increase in glucagon and catecholamines and a decrease in plasma insulin) is one modes to reproduce the disruption of the control exerted by the nervous system on energy metabolism (in particular on insulinecreffon) in the pathology of diabetes (Yamamoto H., Nagai K. et al. Endocrinology 1985, 117, pp 468-473) .

Clinical data confirms that in diabetics there is a disruption of the control exerted by the nervous system on energy metabolism (increase in sympathetic activity, increase in plasma catecholamines resulting in a decrease in the release of insulin. (Christensen NJ Diabetologia 1979,
16, pp211-224).

PROTOCOL
Male WISTAR rats (250 - 300 g) maintained in the 12/12 cycle (light 8 a.m. - 8 p.m.)
temperature of 24 + 1 C receive an injection of 2-deoxy-D-glucose (250 mglkg lP).

In animals treated 5 min previously with melatonin (5 g / kg PI) in solution,
Hyperglycemia caused by 2-deoxy-D-glucose is completely inhibited during the 2
hours after the melatonin injection.

Tempe (min)
CONCLUSION:
La mélatonine et les ligands exercent donc un effet hypoglycémiant puissant et permettent donc au clinicien d'agir contre une perturbation de la régulation centrale de la glycémie. Effect of melatonin (ME) on hyperglycemia induced by 2-deoxv-D <iIucose (2-DG) Plasma glucose (mg / dl)

Tempe (min)
CONCLUSION:
Melatonin and ligands therefore exert a powerful hypoglycaemic effect and therefore allow the clinician to act against a disturbance in the central regulation of blood sugar.

Claims (10)

1. Use of melatonin and melatoninergic ligands for obtaining pharmaceutical compositions intended for the prevention and treatment of diabetes and diabetic complications. 2. Use according to claim 1 of melatonin for obtaining pharmaceutical compositions intended for the prevention and treatment of diabetes and diabetic complications. 3. Use according to claim 1 of melatoninergic ligands for obtaining pharmaceutical compositions intended for the prevention and treatment of diabetes and diabetic complications. 4. Use according to one of claims 1 to 3 of melatonin and melatoninergic ligands for obtaining pharmaceutical compositions intended for the prevention and treatment of type I diabetes. 5. Use according to one of claims 1 to 3 of melatonin and melatoninergic ligands for obtaining pharmaceutical compositions intended for the prevention and treatment of type II diabetes. 6. Use according to one of claims 1 to 3 of melatonin and melatoninergic ligands for obtaining pharmaceutical compositions intended for the prevention and treatment of diabetic complications. 7. Use of melatonin and melatoninergic ligands in combination with Insulin for obtaining pharmaceutical compositions intended for the prevention and treatment of diabetes and diabetic complications. 8. Use of melatonin and melatoninergic ligands in combination with antidiabetic active ingredients for obtaining pharmaceutical compositions of Enbes for the prevention and treatment of diabetes and diabetic complications. 9. Pharmaceutical compositions containing melatonin or one or more melatoninergic ligands in combination with insulin, combined with one or more pharmaceutically acceptable excipients. 10. Pharmaceutical compositions containing melatonin or one or more melatoninergic ligands in association with one or more active anti-diabetic ingredients, combined with one or more pharmaceutically acceptable excipients.