HK1142000B - Use of 4-cyclopropylmethoxy-n-(3,5-dichloro-1-oxidopyridin-4-yl)-5-(methoxy)pyridine-2-carboxamide for the treatment of spinal cord traumas - Google Patents

Description

Use of 4-cyclopropylmethoxy-N- (3, 5-dichloro-1-oxidopyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide for the treatment of spinal cord trauma

The present invention is directed to the use of 4-cyclopropylmethoxy-N- (3, 5-dichloro-1-oxidopyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide in the form of a hydrate, solvate, base or addition salt with an acid for the preparation of a medicament for the treatment of spinal cord trauma.

4-cyclopropylmethoxy-N- (3, 5-dichloro-1-oxidopyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide, or known as N- (3, 5-dichloro-1-oxidopyridino) -4-cyclopropylmethoxy-5-methoxypyridine-2-carboxamide, is known as part of pharmaceutical compositions for the treatment of various conditions, including in particular arthritis, rheumatoid arthritis. Such compounds in the form of hemihydrate are described, for example, in document WO 95/04045 (compounds known as FR).

There is a need to find a drug that can treat patients suffering from spinal cord trauma. Studies in animals have shown that a possible approach is to administer compounds that inhibit phosphodiesterase 4(PDE 4), such as, for example, rolipram. However, clinical studies have shown that this compound, as well as other PDE 4 inhibitors, cause emetic effects, which makes it unusable for therapy.

It has now been found that 4-cyclopropylmethoxy-N- (3, 5-dichloro-1-oxidopyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide can be used to treat spinal cord trauma while avoiding emetic effects at therapeutically acceptable doses.

The first object of the present invention therefore relates to the use of 4-cyclopropylmethoxy-N- (3, 5-dichloro-1-oxidopyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide for the preparation of a medicament for the treatment of spinal cord trauma.

According to one embodiment of the invention, 4-cyclopropylmethoxy-N- (3, 5-dichloro-1-oxidopyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide can be used in the form of a base or of an addition salt with an acid.

Salts that can be used within the scope of the invention can be prepared with pharmaceutically acceptable acids, but other useful salts of acids, such as the acid used for purification or isolation of 4-cyclopropylmethoxy-N- (3, 5-dichloro-1-oxidopyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide, are also part of the invention.

The 4-cyclopropylmethoxy-N- (3, 5-dichloro-1-oxidopyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide according to the invention can also be used in the form of a hydrate or of a solvate. By "hydrate" or "solvate" is understood the association or association of one or more molecules of 4-cyclopropylmethoxy-N- (3, 5-dichloro-1-oxidopyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide with one or more water molecules or solvents.

For the purposes of the present invention, "spinal cord trauma" is understood to be an acute or chronic condition of external origin which destroys the spinal cord tracts and/or spinal cord neurons and which occurs suddenly, for example during a fall, collision, compression or traffic accident.

A second object of the present invention relates to a pharmaceutical composition comprising 4-cyclopropylmethoxy-N- (3, 5-dichloro-1-oxidopyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide as active ingredient, and one or more pharmaceutically acceptable excipients.

The compositions used according to the invention comprise an effective dose of the active ingredient.

For example, daily dosages of the active ingredient which can be used according to the invention are from 0.001 to 10 mg/day.

According to the usual practice, the dosage suitable for each patient is determined by the physician according to the method of administration, the age, weight and response of the patient in question.

The dosage depends on the desired effect, the duration of the treatment and the route of administration used.

There may be particular circumstances where higher or lower doses are appropriate. Such dosages do not depart from the scope of the present invention.

The excipients are selected from the usual excipients known to those skilled in the art according to the pharmaceutical form and the desired method of administration.

The compositions may be administered by the oral, parenteral (including intrathecal) or rectal route.

Suitable unit administration forms include forms by the oral route, such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular or intranasal administration forms, administration forms by inhalation, topical, transdermal, subcutaneous, intramuscular, intravenous or intramembranous administration forms, rectal administration forms and implants. For topical application, the active ingredients according to the invention can be used in creams, gels, ointments or lotions.

When the composition is prepared in tablet form, the active ingredient is mixed with one or more pharmaceutical excipients such as gelatin, starch, lactose, magnesium stearate, mica, silicon dioxide, acacia, mannitol, microcrystalline cellulose, hydroxypropylmethylcellulose and the like.

The tablets may be coated with sucrose, cellulose derivatives or other materials suitable for coating. Tablets may be prepared by various techniques, such as direct compression, dry or wet granulation or hot melt.

Pharmaceutical compositions in capsule form can also be obtained by mixing the active ingredient with a diluent and transferring the mixture obtained into soft or hard capsules.

For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile injectable solutions containing pharmacologically compatible agents (e.g., propylene glycol or butylene glycol) are used.

For example, a unit dosage form of 4-cyclopropylmethoxy-N- (3, 5-dichloro-1-oxidopyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide in tablet form comprises the following ingredients:

4-cyclopropylmethoxy-N-

(3, 5-dichloro-1-epoxy-pyridine-

-4-Yl) -5- (methoxy) pyridine-2-carboxamide 1mg

Mannitol 224mg

Croscarmellose sodium 5mg

Corn starch 15mg

Hydroxypropyl methylcellulose 2mg

Magnesium stearate 3mg

The effect of 4-cyclopropylmethoxy-N- (3, 5-dichloro-1-oxidopyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide used according to the invention was evaluated in a spinal cord trauma model in mice using the equilibrium test (test de la barre).

Example 1: evaluation of the efficacy of 4-cyclopropylmethoxy-N- (3, 5-dichloro-1-oxidopyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide in the treatment of spinal cord wounds

The rod Balance test (test de Beam Balance) consists in placing the mice at the ends of horizontal rods 30cm long and 1.5cm wide raised 20cm above the ground. The time required for the mouse to reach the opposite end of the cross bar was measured. The test was terminated after 12 seconds. If the animal is dropped or the test is not completed, the maximum time is recorded.

34 weeks old 12-14g female OF1 mice (IffaCredo Lyon, France) were placed in experimental cages (32X 21X 14cm) equipped with ad-hoc food and water supplies at a controlled temperature OF 22. + -. 1 ℃.

An experiment with a rod balance test was performed to evaluate the effectiveness of 4-cyclopropylmethoxy-N- (3, 5-dichloro-1-oxidopyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide in treating spinal cord wounds.

Mice were subjected to a pre-learning phase which familiarizes them with the assessment test and allows them to reach an optimal and identical level of behavior.

The animals were then divided into 3 groups and then induced in a controlled manner in two of the 3 groups of mice before the test period began.

This trauma consists of a lesion of the spinal cord at the location of the thoracic vertebra Th 8. The damage was caused by 3 freeze-thaw cycles with sequential application of liquid nitrogen.

The functional consequences of the trauma were then measured at days 2, 7, 14 and 21 and at 28.

The following groups were built:

group 1 (without trauma) consisted of control animals not subjected to any trauma.

Group 2 (wound only) consisted of wounded animals to which one dose/day of vehicle (methylcellulose (MC) in water (0.6%) + tween 80 (0.5%)) was administered.

Group 3 (wound + 0.01mg/kg active ingredient at +4 hours) received 4-cyclopropylmethoxy-N- (3, 5-dichloro-1-oxidopyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide (0.01mg/kg) in vehicle (MC (0.6%) + tween-80 (0.5%) in water), orally 4 hours after the lesion, then daily orally within 4 weeks after the wound.

The results obtained for each group of mice are shown in table 1:

table 1: balance test results for groups 1-3

Table 1 shows that the wounded animals to which 4-cyclopropylmethoxy-N- (3, 5-dichloro-1-oxidopyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide had been therapeutically administered (group 3) reached the end of the pole more rapidly than the wounded animals to which this compound had not been administered (group 2).

In summary, these experiments show that the injured animals to which 4-cyclopropylmethoxy-N- (3, 5-dichloro-1-oxidopyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide have been administered show a better re-establishment of motor function than untreated injured animals. The results are similar when the invention is administered in prophylactic treatment (i.e. prior to trauma).

Example 2: ((4R) -4- [3- (cyclopentyloxy) -4-methoxyphenyl]Pyrrolidin-2-one) in the spinal cord Evaluation of effectiveness in wound treatment:

in spinal cord trauma therapy, experiments similar to example 1 were performed by administering ((4R) -4- [3- (cyclopentyloxy) -4-methoxyphenyl ] pyrrolidin-2-one) to 34-week-old 12-14g OF1 mice (Charles river, France).

((4R) -4- [3- (cyclopentyloxy) -4-methoxyphenyl ] pyrrolidin-2-one), also known as (R) - (-) -rolipram, is described in particular in US 4,193,926.

Mice were tested in a rod balance test according to the same operating conditions as described above.

The following groups were built:

group a (without trauma) consisted of control animals not subjected to any trauma.

Group B (wound only) consisted of wounded animals to which one dose/day of vehicle (2% PEG200) was administered.

Group C (wound + 0.03mg/kg active ingredient at +4 hours) received (R) - (-) -rolipram (0.03mg/kg) contained in a carrier (2% PEG200), through the oral route at 4 and 6 hours after the lesion, then through the oral route for every day for 4 weeks after the wound.

The results obtained for each group of mice are expressed as the percentage (%) of traumatized motor function deficits (d.f. des fontations rats) in the traumatized mice relative to the non-traumatized mice.

For this purpose, the time difference between the group of test mice to which (R) - (-) -rolipram was administered (group C) and the group of non-wounded mice (group a) was measured, expressed as a percentage of the time difference relative to the time taken between the wounded mice to which one dose/day of vehicle was administered (group B) and the non-wounded mice (group a). This ratio thus gives the percentage of motor function loss in the wounded mice relative to the non-wounded mice.

The percentage of deletion for the mice tested was calculated according to the following formula:

group (C)% missing ═ average of travel times of group C) - (average of travel times of group a) ]/[ (average of travel times of group B) - (average of travel times of group a) ]

Wherein:

group A: non-wounded animal

Group B: vector treated wounded animal

Group C: treatment of traumatized animals with (R) - (-) -rolipram

The higher the percentage expressed, the greater the loss of motor function observed. Thus, a 100% result (one hundred percent) corresponds to a group of traumatized mice in which no therapeutic effect was observed

Values greater than 100% mean that the group of mice evaluated took on average more time to complete the distance than the group of injured mice treated with vehicle.

The results obtained for each group of mice are shown in table 2:

table 2: results of the balance test for groups a-C:

these experiments show that injured animals treated with (R) - (-) -rolipram show a greater loss of motor function even at a 3-fold dose of 4-cyclopropylmethoxy-N- (3, 5-dichloro-1-oxidopyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide than animals treated with 4-cyclopropylmethoxy-N- (3, 5-dichloro-1-oxidopyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide.

By way of comparison, the values obtained for the wounded mice (group 3 of table 1) dosed with 4-cyclopropylmethoxy-N- (3, 5-dichloro-1-oxidopyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide (in the form of a percentage loss of motor function) are shown in table 3.

Table 3: comparison of results obtained for mouse 3 and group C

Group C: traumatized animals treated with (R) - (-) -rolipram

Group 3: wounded animals treated with 4-cyclopropylmethoxy-N- (3, 5-dichloro-1-oxidopyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide

Animals treated with 4-cyclopropylmethoxy-N- (3, 5-dichloro-1-oxidopyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide showed a lower rate of motor function loss than animals treated with (R) - (-) -rolipram.

Example 3: 4-Cyclopropylmethoxy-N- (3, 5-dichloro-1-epoxy-pyridin-4-yl) -5- (methoxy Yl) evaluation of emetic Effect of pyridine-2-carboxamide

The emetic capacity of 4-cyclopropylmethoxy-N- (3, 5-dichloro-1-oxidopyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide was evaluated in ferrets (furet). Two groups of ferrets were used, the first group receiving the vehicle (PEG200) and the second group receiving 4-cyclopropylmethoxy-N- (3, 5-dichloro-1-oxidopyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide dissolved in the vehicle (PEG200) by oral gavage at a dose of 0.05mg/kg and 0.1 mg/kg. The animals were observed continuously during 2 hours post-dose, then every hour until 6 hours post-dose. Clinical signs (in particular, nausea and vomiting) were recorded.

4-cyclopropylmethoxy-N- (3, 5-dichloro-1-oxidopyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide, when administered at 0.1mg/kg, did not cause nausea or vomiting in 5 treated white minks.

These results indicate that administration of a therapeutic dose of 4-cyclopropylmethoxy-N- (3, 5-dichloro-1-oxidopyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide to treat spinal cord trauma does not cause any emetic effect.

Example 4: (R) - (-) -rolipram (((4R) -4- [3- (cyclopentyloxy) -4-methoxyphenyl)]Pyridine (II) Pyrrolidine-2-one)) was evaluated for emetic effect

The emetic capacity of (R) - (-) -rolipram was evaluated in white minks. Two groups of ferrets were used, the first group received the vehicle (PEG200) and the second group received 4-cyclopropylmethoxy-N- (3, 5-dichloro-1-oxidopyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide dissolved in the vehicle (PEG200) by oral gavage at a dose of 0.05mg/kg and 0.1 mg/kg. The animals were observed continuously during 2 hours after dosing and then once an hour until 6 hours after dosing. Clinical signs were recorded.

(R) - (-) -rolipram causes emesis in treated ferrets when administered at 0.05mg/kg and 0.1 mg/kg.

The results of examples 3 and 4 show that administration of a therapeutic dose of (R) - (-) -rolipram results in emetic effects.

Thus, 4-cyclopropylmethoxy-N- (3, 5-dichloro-1-oxidopyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide may be used for the preparation of a medicament for the treatment of trauma to the nervous system, in particular spinal cord trauma, such as, for example, trauma occurring accidentally during a fall, collision or car accident, or brain trauma, while avoiding possible emetic effects.

Claims (2)

1. Use of 4-cyclopropylmethoxy-N- (3, 5-dichloro-1-oxo-pyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide in the form of a base or of an addition salt with an acid for the preparation of a medicament for the treatment of spinal cord trauma.

2. Use according to claim 1, characterized in that 4-cyclopropylmethoxy-N- (3, 5-dichloro-1-oxo-pyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide is in base form.