HK1210011B - Association of n-{[(7s)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}-3-(7,8-dimethoxy-1,2,4,5-tetrahydro-3h-3-benzazepin-3-yl)-n-methyl-3-oxo-1-propanamine and perindopril - Google Patents

Description

The present invention relates to the combination of N-{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-yl]methyl}-3-(7,8-dimethoxy-1,2,4,5-tetrahydro-3H-3-benzapine-3-yl) -N-methyl-3-oxo-1-propanamine of formula (II), - What? and its pharmaceutically acceptable acid additive salts, their hydrates and crystalline forms, and perindopril.

This combination is useful for the development of medicinal products for the treatment of heart failure, particularly heart failure with preserved systolic function.

The pharmaceutically acceptable acids include but are not limited to hydrochloric, bromic, sulphuric, phosphoric, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic, methanesulfonic, benzenesulfonic, camphoric, pamoic, 1,5-naphthaledisulfonic acids.

Selective and specific inhibitors of the If-sinusal current and in particular N-{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-yl]methyl}-3-(7,8-dimethoxy-1,2,4,5-tetrahydro-3H-zepine-3-yl) N-methyl-3-oxo-1-propanamine, and its salts of addition to a pharmaceutically acceptable acid, and in particular its chlorhydrate and fumarate, their hydrates and crystalline forms, have very interesting pharmacological and therapeutic properties, including negative troubleshooting properties (insufluency of the heart rate), which make these compounds useful in the treatment, prevention and improvement of various diseases associated with the supracardiovascular system, including cardiovascular disease and cardiovascular disease, and in the prevention of various pathological conditions, such as cardiovascular myocardial infarction and pulmonary artery disease.

The preparation and therapeutic use of N-{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-yl]methyl}-3-(7,8-dimethoxy-1,2,4,5-tetrahydro -3H-3-benzabespin-3-yl) -N-methyl-3-oxo-1-propanamine and its addition salts to a pharmaceutically acceptable acid, and in particular its chlorate and fumarate, have been described in European patent EP 2 036 892.

Perindopril is an inhibitor of the angiotensin converting enzyme. Angiotensin converting enzyme inhibitors are one of the major therapeutic classes in the treatment of hypertension, acting mainly by inhibiting angiotensin II synthesis and blocking the breakdown of bradykinin. They showed that in addition to lowering blood pressure, they improved morbidity (myocardial infarction, stroke) and cardiovascular mortality in hypertensive, diabetic, patients with pre-existing coronary disease.

The applicant found that the combination of N-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-yl]methyl}-3-(7,8-dimethoxy-1,2,4,5-tetrahydro-3H-3-benzabespin-3-yl) -N-methyl-3-oxo-1-propanamine and perindopril had interesting properties which made it possible to use it in the treatment of heart failure, in particular heart failure with preserved systolic function.

Heart failure due to systolic dysfunction of the left ventricle is no longer the only form of heart failure. Increasingly, patients who have heart failure have an ejection fraction greater than 40%. The proportion of heart failure known as diastolic (or rather with conserved systolic function ) increases with age. It currently accounts for 30 to 40 percent of heart failure hospitalizations and, after age 80, exceeds in frequency that of clinical heart failure due to systolic dysfunction.

No treatment has been shown to be effective in this disease, which kills 50% of the population within four years, as does systolic heart failure.

The applicant found that the use of the combination of N- (((7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triethyl-7-yl]methyl}-3-(7,8-dimethoxy-1,2,4,5-tetrahydro-3H-tribenzophen-3-yl) -N-methyl-3-oxo-1-propanamine and perindopril produced pharmacological effects that were higher than those observed using either N- (((7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triethyl-7-yl]methyl}-3-(7,8-dimethoxy-1,2,4-tetrahydro-3H-benzophen-3-yl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-3-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-

N{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-yl]methyl}-3-(7,8-dimethoxy-1,2,4,5-tetrahydro-3H-3-benzapine-3-yl) -N-methyl-3-oxo-1-propanamine is preferentially used as hydrochloride or fumarate or one of their hydrates or crystalline forms.

Perindopril may be used as its salts of addition to an acid or a pharmaceutically acceptable base, their hydrates and crystalline forms, in particular its tert-butylamine or arginine salts, their hydrates and crystalline forms.

The present invention relates in particular to the combination of N-{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-yl]methyl}-3-(7,8-dimethoxy-1,2,4,5-tetrahydro -3H-3-benzepine-3-yl) -N-methyl-3-oxo-1-propanamine or one of its additive salts to a pharmaceutically acceptable acid, their hydrates or crystalline forms, and perindopril or one of its additive salts to a pharmaceutically acceptable base, and in particular its tert-butylamine or arginine salts, hydrates or crystalline forms.

The effective dose varies according to the patient' s sex, age and weight, route of administration, nature of the condition and any associated treatments.

The dose of N-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-yl]methyl}-3-(7,8-dimethoxy-1,2,4,5-tetrahydro-3H-3-benzapine-3-yl) -N-methyl-3-oxo-1-propanamine (hereinafter referred to as compound A) may vary from 5 to 100 mg daily.

The daily dose of perindopril should preferably be between 1 and 10 mg inclusive. The pharmaceutical formulations that may be used are those suitable for oral, parenteral, nasal administration, single or double-blind tablets, sublingual tablets, capsules, tablets, suppositories, creams, ointments, dermal gels, etc. as well as scheduled, delayed, prolonged or delayed-release pharmaceutical formulations.

In addition to N-{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-yl]methyl}-3-(7,8-dimethoxy-1,2,4,5-tetrahydro-3H-3-benzapine-3-yl) -N-methyl-3-oxo-1-propanamine and perindopril, these pharmaceutical formulations contain one or more excipients or vehicles selected from dilutants, lubricants, binders, disintegrators, absorbers, dyes, sweeteners, etc.

Examples, but not limited to:◆ for diluents: lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycerin,◆ for lubricants: silica, talc, stearic acid and its magnesium and calcium salts, polyethylene glycol,◆ for binders: aluminium and magnesium silicate, starch, gelatin, tragahecanth, methylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone,◆ for disintegrators: agar, sodium acetic acid and its salts, effervescent algae.

The following examples illustrate the invention. - What?

: augmentation maximale de pression par seconde
: diminution maximale de pression par seconde
IC	: insuffisance cardiaque
LVEDP	: Left Ventricular End Diastolic Pressure (pression télé-diastolique du ventricule gauche)
LVEDPVR	: Left Ventricular End Diastolic Pressure Volume Relation (relation pression-volume télé-diastolique du ventricule gauche)
LVESP	: Left Ventricular End Systolic Pressure (pression télé-systolique du ventricule gauche)
LVESPVR	: Left Ventricular End Systolic Pressure Volume Relation (relation pression-volume télé-systolique du ventricule gauche)
VG	: ventricule gauche

Pharmacological tests:

Heart failure is induced in rats by the operation of a left coronary artery ligation (control animals undergo surgery but are not ligated) which causes ischemia of part of the left ventricular wall. The animals recover for 7 days and then for 12 weeks receive either 3 mg/kg of compound A or 0.4 mg/kg of perindopril or concomitant perindopril and compound A.

Twelve weeks after the operation, the animals undergoing coronary ligation were found to develop both systolic (abnormality of ejection) and diastolic (abnormality of filling) heart failure.

In these animals, compound A significantly decreased heart rate, alone or in combination with perindopril (Table 1 and Figure 1). - What?

	durée de traitement	4 semaines	372,5	349,3	388,2	352,8
		12 semaines	387,2		387,7

Co-treatment with perindopril and compound A significantly increased the left ventricular shortening fraction, i.e. improved contractility (Table 2 and Figure 2). - What?

	14,4	18,0	17,1
	114	127

As shown in Table 3 (Figure 3), the various systolic and diastolic parameters are altered by heart failure. The left ventricle contracts less (dP/dtmax and LVESPVR significantly lower in IC animals than in healthy controls), indicating systolic impairment. Diastolic function is greatly impaired: pressure inside the ventricle at the end of diastole is high (LVEDP), relaxation time (tau) is prolonged, and compliance (ventricle capacity to dilate) is low (LVEDPVR increased). - What?

	140	120	118	99	105
	9,92	6,89*	6,78	5,97	7,69
	26,4	11,1*
	1,86	9,43*
	10,24	5,66*	5,87	5,11	6,19
	3,54	12,64*
	0,84	6,93*

Treatment of animals with heart failure, either with perindopril alone or with the A compound alone, has been shown to improve systolic function, which can be observed with LVESPVR, the only load-independent parameter.

Telediastolic pressure and relaxation time are significantly improved with perindopril alone or with compound A alone and there is a tendency to further decrease when both are administered together. Left ventricular compliance (as measured by LVEDPVR), the only load-independent parameter, is very significantly improved with perindopril and compound A. Surprisingly, this effect is significantly increased when animals are given both treatments concomitantly.

The combination of compound A and perindopril significantly improves compliance to a level close to that of control animals.

The combination of perindopril and N-{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-yl]methyl}-3-(7,8-dimethoxy-1,2,4,5-tetrahydro-3H-3-benzabespin-3-yl) -N-methyl-3-oxo-1-propanamine therefore improves impaired diastolic function.

Pharmaceutical formulations: Formulation for 1000 tablets at a dose of 10 mg of compound A and 2 mg of perindopril, tert-butylamine:

Composé A, fumarate	12,48 g
2 g
Lactose monohydrate	62 g
Stéarate de Magnésium	1,3 g
Povidone	9 g
Silice colloïdale anhydre	0,3 g
Cellulose sodium glycolate	30 g
Acide stéarique	2,6 g

Other examples of pharmaceutical compositions according to the invention are given below, but not limited to: - What?

5	60	2	-
6	80	4	-
7	60	-	2,5
8	80	-	5

Claims (3)

1. Association of N-{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}-3-(7,8-dimethoxy-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl)-N-methyl-3-oxo-1-propanamine, or one of its addition salts with a pharmaceutically acceptable acid, their hydrates or crystalline forms, and perindopril, or one of its addition salts with a pharmaceutically acceptable base, their hydrates or crystalline forms.
2. Association according to claim 1, characterised in that the N-{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}-3-(7,8-dimethoxy-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl)-N-methyl-3-oxo-1-propanamine is in the form of the hydrochloride or fumarate, or one of their hydrates or crystalline forms.
3. Association according to one of claims 1 or 2, characterised in that the perindopril is in the form of the tert-butylamine or arginine salt, or one of their hydrates or crystalline forms.