WO1999055340A1

WO1999055340A1 - PHARMACEUTICAL COMPOSITIONS CONTAINING IN COMBINATION AN ARGININE-VASOPRESSIN V1a ANTAGONIST AND AN ANGIOTENSIN II AT1 RECEPTOR ANTAGONIST

Info

Publication number: WO1999055340A1
Application number: PCT/FR1999/000959
Authority: WO
Inventors: Dino Nisato
Original assignee: Sanofi-Synthelabo
Priority date: 1998-04-29
Filing date: 1999-04-22
Publication date: 1999-11-04
Also published as: FR2778103A1; AU3425999A

Abstract

The invention concerns pharmaceutical compositions containing in combination a of arginine-vasopressin V1a antagonist and an angiotensin II AT1 receptor antagonist. The use of said combination is useful for treating cardiac deficiency, high blood pressure and nephropathy.

Description

"Pharmaceutical compositions containing in association a Via antagonist, arαinine-vasopressin and an angiotensin II AT receptor antagonist" The subject of the present invention is pharmaceutical compositions containing in association a compound angiensensin AT1 receptor antagonist II, with a receptor antagonist compound of Vι _is arginine-vasopressin.

Vasopressin is a hormone known for its antidiuretic effect and its effect on the regulation of blood pressure. It stimulates several types of receptors: V- | (Vι _a , V ₁ or V ₃ ), V2. These receptors are located in the liver, smooth muscles: coronary, renal, cerebral vessels, platelets, kidney, uterus, adrenal glands, central nervous system, pituitary gland. The localization of the different receptors is described in: Jard S. et al., "Vasopressin and oxytocin receptors: an overview in Progress" in Endocrinology., Imura

H. and Shizume K. éd., Experta Medica, Amsterdam, 1988, 1183-1188, as well as in the following articles: Presse Médicale, 1987 16 (10), 481- 485, J. Lab. Clin. Med., 1989, 114 (6), 617-632 and Pharmacol. Rev., 1991, 43 (1), 73-108. In particular vasopressin exerts hormonal, cardiovascular, hepatic, renal, antidiuretic, aggregating effects and effects on the central and peripheral nervous systems, on the uterine and intestinal spheres and on the ocular and pulmonary systems.

Vasopressin receptor blockers selectively inhibit the effects of the hormone. They can intervene on the regulation of central and peripheral circulation, in particular vascular circulation: coronary, renal and gastric, as well as on the water regulation and the release of the adrenocorticotrophic hormone (ACTH), (FA Laszlo et al., Pharmacol Rev., 1991, 43, 73-108). Vasopressin itself as well as some of its peptide analogues are used in therapy and have been shown to be effective. We can cite several journals and numerous articles in the literature: Vasopressin: P. Gross et al. ed. John Libbey Eurotext, 1993, in particular p. 243-257 and p. 549-562. F.A. Laszlo and F.A. Laszlo Jr., Clinical perspectives for vasopressin antagonists, Drug News Perspect., 1993, 6 (8); W.G. North,

J. Clin. Endocrinol., 1991, 73, 1316-1320. JJ Legros et al., Prog. Neuro-Pharmacol. Biol. Psychiat., 1988, 12, 571-586; KE Andersson et al., Drugs Today, 1988, 24 (7), 509-528; DL Stump et al., Drugs, 1990, 39, 38-53; S. Caltabiano et al., Drugs Future, 1988, 3, 25-30; Y. Mura et al.,

Clin. Nephrol. 1993, 40, 60-61; Faseb J., 1994, 8 (5), A 587: 3398.

In addition, a recent review by J.D. Albright et al. (Current

Pharmaceutical Design, 1997, 3, 615-632) takes stock of arginine-vasopressin receptors and their antagonists and describes pharmacological studies and potential applications in human therapy.

Compounds having vasopressin V-i antagonist activity are described in patents or patent applications, for example: US 5,612,334, US 5,521,173, US 5,610,156, US 5,624,923, US 5,686

445,

US 5,693,635, US 5,512,563, US 5,516,774, WO 97/49707, WO

97/47624,

WO 96/22282, WO 96/22294, WO 96/41795, WO 95/29152, WO 96/35122,

WO 97/30707, WO 97/22591, WO 95/34540, WO 95/18105, EP 469 984,

EP 450 097, JP 08 143 565, JP 08 059 624, JP 08 231 512, JP 09 221

476, JP 08 081 460, JP 09 168 396, JP 09 022 175, JP 09 020 779, US 5

489 686, US 5,525,614. Among the vasopressin V antagonists described in the literature, the following compounds may be mentioned in particular: N- [3- [4 - [[4- (3,4-dihydro-2 -oxo-1- (2H) quinolinyl) -1- piperidinyl] carbonyl] phenoxy] propyl] acetamide, whose code name is

OPC-21268 described in European patent application EP 382,185. - (Z) -N- hydrochloride [4- [5- [4- (dimethylamino) piperidin-1- ylcarbonyl methylene] -4,4-difluoro-2,3,4,5-tetrahydro-1 H-1 -benzazepin-1 - ylcarbonyl] phenyl] biphenyl-2-carboxamide, whose code name is YM-

471 is described in patent application WO 95/6035;

- N- [4- (2-methyl-1, 4,5,6-tetrahydroimidazo [4,5-d] [1] benzazepin-6-ylcarbonyl) phenyl] biphenyl-2-carboxamide hydrochloride, the name of code is YM-087 is described in patent applications WO 95/03305 and EP 709,386.

- N- [2- [3- (4-methylperhydro-1, 4-diazepin-1-yl) propoxy] -4 - [(5,6,7,8- tetrahydro-4H-thieno [3,2- b] azepin-4-yl) carbonyl] phenyl] - [1, 1'-biphenyl] -2-carboxamide is described in patent application WO 97/17349.

In particular, (2S) -1 - [(2R, 3S) -5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxybenzenesulfonyl) -3-hydroxy-2,3-dihydro-1 H-indole-2- carbonyl] pyrrolidine-2-carboxamide, whose code name is SR 49059, of formula:

(I)

hereinafter referred to as compound A, was described in the literature as a potent and selective antagonist of _the receptor V of arginine vasopressin in different species, particularly human Vι _receptors, (C. Serradeil-Le Gay and al., J. Clin. Invest., 1993, 92, 224-231). It has only a weak affinity for V2 receptors. Compound A is the most potent selective antagonist of human Vι _a receptors known to date.

SR 49059 is prepared according to the method described in patent application EP 0526348 A.

According to the present invention, by angiotensin 11 A receptor antagonist is meant non-peptide compounds which exhibit a strong affinity for the angiotensin II receptors of the AT1 subtype: (Ml Steinberg et al., Cardiovascular Drug Reviews, 1993, H (3), 312-358). They are generally nitrogen heterocycles substituted by a biphenylmethyl group itself carrying an acid group. Mention may in particular be made, among nitrogen heterocycles, of imidazoles as well as other 5-membered rings such as pyrroles, pyrazoles, isoxazoles isothiazoles and triazoles. Such compounds are described in the following patents or patent applications: EP 28 834-A, EP 253 310-A, EP 324 377-A, EP 392 317-A, EP 403 159-A, EP 475 206-A, EP 503 785-A, EP 514 198-A, EP 573 271 -A, EP 646 584-A, US 4 207 324, US 4 340 598, US 4 576 958, US 4582 847, WO 91 14679, WO 91- 17148, WO 92-20662, WO 93-341, WO 94-08989, WO 94-08990, WO 96-228, WO 96-40255, WO 96-40256, WO 96-40257, WO 96-40258.

Other angiotensin II inhibitor compounds are described in patents or patent applications relating to derivatives formed on condensed heterocycles, in particular benzimidazoles and imidazopyridines: EP 245 637-A, EP 399 731 -A, EP 400 974-A, EP 392 317-A, EP 260 613-A, EP 412 848-A, EP 420 237-A , EP 426 021 -A, EP 459 136-A, EP 502 314-A, EP 503 162-A, EP 504 888, EP 546 358-A, EP 552 765-A, EP 595 151 -A, EP 598 702 -A, US 4,880,804, WO 93-190067,

WO 94-01436, WO 94-204 498, DE 4,031,635.

In addition, other angiotensin II inhibitor compounds are formed from nitrogen heterocycles with 6 members, possibly condensed. Such compounds are described in particular in the following patents or patent applications: EP 412 848-A, EP 434 249-A,, EP

443 983-A, EP 475 206-A, EP 487 252-A, EP 487 745-A, EP 500 409-A, EP 503 838-A, EP 514 198, EP 566 060-A, EP 569 013-A , EP 628 045-A, GB 2 234 748-A, US 5 187 168, US 5 385 894, WO 91 07404, WO 93-3018, WO 93-20816, WO 94-03449, WO 94-07492, WO 94 -11369, WO 94-11379, WO 95-002596.

Finally, other types of structure have been described for angiotensin II inhibitor compounds, for example in the following patents or patent applications: EP 425 921 -A, EP 488 532-A, EP 540

209-A, EP 586 513-A, EP 604 259-A, US 5 149 699, US 5 332 744, WO 94-00450, WO 94-17067.

In particular and without limitation, mention may be made of the following compounds among the angiotensin II antagonists suitable for combinations according to the invention and in the pharmaceutical compositions according to the invention; these compounds are known by their international common name or by their code name, the chemical structure associated with each code being indicated below:

Irbesartan, losartan, pomisartan, saprisartan, valsartan, telmisartan, candesartan, eprosartan, tasosartan, embusartan,

CL-329 167: 2-Butyl-6- (1-methoxy-1-methylethyl) -3 - [[2 '- (1 H-tetrazol-5-yl) [1, 1' -biphenyl] -4-yl ] methyl] -4 (3H) -quinazolinone,

CS-866: Ester 5-methyl-2-oxo-1, 3-dioxol-4-yl-methyl of 4- (1-hydroxy-1-methylethyl) -2-propyl-1- [2'- (1 H-tetrazol-5-yl) biphenyl-4-ylmethyl] imidazole-5-carboxylic,

GA-0050 = GA-0056: 2- (6 - ((2-Ethyl-5,7-dimethyl-3H-imidazo (4,5- b) pyridin-3-yl) methyl) quinolin-2-yl) benzoate sodium,

KT3-671: 2-Propyl-8-oxo-1 - [[2 ^* - (1 H-tetrazol-5-yl) [1, 1 '-biphenyl] -4- yl] methyl] - 4,5,6 , 7-tetrahydrocycloheptimidazole, L-159-282 or MK-996: N - [[4 '- [(2-Ethyl-5,7-dimethyl-3H-imidazol [4,5- b] pyridin -3-yl) methyl] [1, 1'-biphenyl] -2-yl] sulfonyl] -benzamide,

Milfasartan or tienartan or LR-B-081: Methyl 2 - (((4-butyl-2-methyl-6-oxo - ((2 '- (1 H-tetrazol-5-yl) - (1, 1' -biphenyl ) -4-yl) methyl) -1 - (6H) - pyrimidinyl) methyl) -3-thiophencarboxylate,

ME-3221 3-Methoxy-2,6-dimethyl-4 - [[2 '- (1H-tetrazol-5-yl) [1'- biphenyl] -4-yl] methoxyj-pyridine,

SC-52458 or forasartan: 5 - [(3,5-dibutyl-1 H-1,2,4-triazol-1-yl) methyl] - 2- [2- (1 H-tetrazol-5-yl) phenyl ] -pyridine, SL-910-102 6-Butyl- (2-phenylethyl) -5 - ((2 '- (1 H-tetrazol-5-yl) (1, 1'- biphenyl) -4-yl) methyl -4 (1 H) pyrimidinone,

TAK-536: 2-Ethoxy-1 acid - ((2 '- (5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl) -biphenyl-4-yl) methyl) 1 H -benzimidozole-7-carboxylic,

Ripisartan or UP-269-6: 5-Methyl-7-propyl-8 - ((2 '- (1 H-tetrazol-5-yl) biphenyl-4-yl) methyl) -1, 2,4-triazolo ( 1, 5-c) pyrimidin-2 (3H) -one,

KRH-594 = WK-1492: Dipotassium salt of 2- (5-ethyl-3- (2- (1 H-tetrazol-5-yl) biphenyl-4-yl) methyl-1,3,4- acid thiadiazoline-2-ylidene) aminocarbonyl-1-carboxyic encyclopenten,

YM-358 2,7-Diethyl-5 - [[2 '- (1 H-tetrazol-5-yl) [1, 1' -biphenyl] -4- yl] methyl] -5H-pyrazolo [1, 5- b] [1,2,4] -triazole,

606-A: Di sodium salt of 5-acetyl-2-propyl-3- [2 '- (1 H-tetrazol-5-yl) biphenyl-4-ylmethyl] -4,5,6,7 -tetrahydro-3H-imidazo [4,5-c] pyridine-4-carbo-xylic irbesartan being particularly preferred, either as such, or in polymorphic form, or in the form of one of its salts or solvates.

Several angiotensin II ATi receptor antagonist compounds are now marketed for their cardiovascular action, especially in hypertension (Arie J. Man in't Veld, J. Hypertension, 1997, 15 (suppl. 7), S27-S33 In women, SR 49059 reduces uterine contractions induced by the administration of lysine-vasopressin (T. Bossmar et al., Br. J. Obstet. Gynaecol., 1997, 104 (4), 471-477). is currently being studied in the treatment of dysmenorrhea (T. Bossmar et al., Acta Obstet. Gynecol. Scand., 1997, 76 (Suppl. 167), Pt. 5.17). Furthermore, SR 49059 inhibits the effects vasoconstrictors induced by administration of arginine-vasopressin in healthy volunteers (R. Weber et al., Hypertension, 1997, 30 (5), 1121-1127). However, on hypertensive subjects, the administration of SR 49059 did not induce any effect on blood pressure (M. Thibonnier et al., J. Hypertens., 1997, 5 (suppl. 4), S36-S37).

It has now been found that the combination of an arginine-vasopressin V antagonist with an angiotensin II AT1 receptor antagonist has a synergistic effect.

In particular, such an association can allow therapeutically to reduce the doses of each of the compounds of the association while retaining the same pharmacological response as that obtained when used alone.

The combination according to the present invention can be used in the treatment of various cardiovascular affections in particular: hypertension, cardiac failure, venous insufficiency, cardiac ischemia, dilatative cardiomyopathy, attack, prevention of mortality after infarction, arrhythmia; different conditions of the renal system such as nephropathy, diabetic nephropathy; various disorders of the central nervous system such as cerebral ischemia, dementias, in particular vascular dementia or dementia of the Alzheimer type, memory deficits, as well as in the treatment of type II diabetes, obesity and in the treatment sexual behavior disorders, including the treatment or improvement of erectile functions.

In particular, the combination according to the invention is useful in the treatment of heart failure, hypertension and nephropathy. The use of the combination according to the invention is particularly advantageous in the treatment of severe or malignant hypertensions, in particular those usually resistant to treatment with an angiotensin II receptor antagonist alone.

More specifically, the combination according to the invention can be useful for treating hypertension affecting people of African origin.

The association according to the invention comprising compound A and Pirbesartan has been studied on different animal models.

Thus, heart failure is created in pigs by increasing the heart rate by electrical training (pacing) for a long period of time. The animals are divided into several groups which each receive a different treatment in order to compare the effect of each of the compounds of the association administered alone with the effect of the 2 compounds of the association administered together. This is compared with the effects observed on groups of control animals which were not treated and were either subjected to electric training or were not subjected to electric training. The effects of the different treatments on pathology revolution are evaluated by studying the ventricular function, the contractile performance of isolated myocites as well as by neurohormonal assays.

It is found that the treatment with the combination according to the invention has a greater effect than that of each of the components administered separately, in order to restore the various parameters relating to heart failure to a level close to that observed for the control group not subjected electric training, i.e. not subject to heart failure.

Furthermore, rats of spontaneously hypertensive Okamoto strain, or SHR, are used (K. Okamoto, Jap. Cire, 1963, 27, 282-293). This strain is reputed to represent essential hypertension, with all its consequences. The animals are divided into several groups which each receive a different treatment in order to compare the effect of each of the compounds of the association administered alone with the effect of the 2 compounds of the association administered together.

These effects will also be compared with those obtained on untreated control animals.

Blood pressure and heart rate parameters are measured.

It is found that the angiotensin II antagonist alone lowers the blood pressure of SHR rats while compound A has no effect. Combination therapy potentiates the antihypertensive effect of the angiotensin II antagonist.

For use as a medicament, the combination of antagonist compound V _receptors of arginine-vasopressin antagonist compound and an AT receptor of angiotensin II according to the invention must be formulated into pharmaceutical composition. Said composition is generally formulated in dosage units.

Thus according to another of its aspects, the present invention relates to pharmaceutical compositions comprising: (2S) -1 - [(2R, 3S) -5- chloro-3- (2-chlorophenyl) -1- (3,4- dimethoxybenzene sulfonyl) -3-hydroxy-2,3-dihydro-1 r7-indole-2-carbonyl] pyrrolidine-2-carboxamide (compound A); and an angiotensin II ATi receptor antagonist in combination with at least one pharmaceutical excipient. 8

More particularly, the present invention relates to pharmaceutical compositions comprising compound A and irbesartan in combination with at least one pharmaceutical excipient.

In the pharmaceutical compositions of the present invention for oral, sublingual, inhaled, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, the active principles of the combination can be administered in unit administration forms , mixed with conventional pharmaceutical carriers, animals and humans. Suitable unit administration forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and oral administration forms, aerosols, administration forms topical, implants, forms of subcutaneous, intramuscular, intravenous, intranasal or intraocular administration and forms of rectal administration.

When a solid composition is prepared in the form of tablets, a pharmaceutical carrier can be added to the active principles of the combination, micronized or not, which can be composed of diluents such as, for example, lactose, microcrystalline cellulose, starch and formulation adjuvants such as binders (polyvinylpyrrolidone, hydroxypropylmethylcellulose, etc.), flow agents such as silica, lubricants such as magnesium stearate, stearic acid, glycerol tribehenate, sodium stearyl fumarate. Wetting agents or surfactants such as sodium lauryl sulfate can be added to the formulation.

The tablets can be produced by different techniques, direct compression, dry granulation, wet granulation, hot melting. The tablets can be naked, coated (with sucrose for example) or coated with various polymers or other suitable materials.

The tablets can have a flash, delayed or prolonged release by producing polymer matrices or by using specific polymers in the film coating.

A capsule preparation is obtained by mixing the active ingredients with dry pharmaceutical vehicles (simple mixing or dry granulation, wet granulation, hot fusion), liquids or semi-solids. The capsules can be soft or hard, coated or not, so as to have a flash, prolonged or delayed activity (for example by an enteric form).

A preparation in the form of a syrup or elixir may contain the active ingredients together with a sweetener, preferably calorie-free, methylparaben and propylparaben as an antiseptic, as well as a flavoring agent and an appropriate color.

The water-dispersible powders or granules may contain the active ingredients in admixture with dispersing agents, wetting agents or suspending agents, such as polyvinylpyrrolidone, as well as with sweeteners or flavor correctors .

Suppositories are used for rectal administration which are prepared with binders that melt at rectal temperature, for example cocoa butter or polyethylene glycols. For parenteral, intranasal or intraocular administration, aqueous suspensions, isotonic saline solutions or sterile and injectable solutions are used which contain pharmacologically compatible dispersing agents and / or solubilizing agents, for example propylene glycol or butylene glycol. Thus, to prepare an aqueous solution for intravenous injection one can use a cosolvent such as for example an alcohol such as ethanol or a glycol such as polyethylene glycol or propylene glycol, and a hydrophilic surfactant such as Tween® 80. To prepare an oily solution injectable intramuscularly, the active principles can be dissolved by a triglyceride or a glycerol ester.

For local administration, creams, ointments, gels, eye drops can be used.

For transdermal administration, it is possible to use patches in multilaminate or reservoir form in which the active ingredients can be in alcoholic solution.

For administration by inhalation, an aerosol is used containing, for example, sorbitan trioleate or oleic acid as well as trichlorofluoromethane, dichlorofluoromethane, 10

dichlorotetrafluoroethane or any other biologically compatible propellant; one can also use a system containing the active principles alone or associated with an excipient, in the form of powder. The active ingredients can also be presented in the form of a complex with a cyclodextrin, for example, α, β, γ-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin.

The active ingredients can also be formulated in the form of microcapsules or microspheres, optionally with one or more carriers or additives. Among the sustained-release forms useful in the case of chronic treatments, implants can be used. These can be prepared in the form of an oily suspension or in the form of a suspension of microspheres in an isotonic medium.

In each dosing unit the active ingredients of the combination are present in the quantities adapted to the daily doses envisaged.

In general each dosage unit is suitably adjusted according to the dosage and the type of administration intended, for example tablets, capsules and the like, sachets, ampoules, syrups and the like, drops so that such a dosage unit contains 2.5 to 1000 mg of arginine-vasopressin V _1a receptor antagonist, preferably 2.5 to 250 mg, and 0.5 to 500 mg of angiotensin II AT1 receptor antagonist, preferably from 1 to 300 mg, said dosage unit to be administered one to four times a day.

According to another of its aspects, the present invention relates to the use of the combination comprising an antagonist Vι _receptors of arginine-vasopressin, with a receptor antagonist of angiotensin II, for the preparation of medicaments for to treat all pathologies for which either arginine-vasopressin or angiotensin II are involved. According to another of its aspects, the present invention relates to the use of the combination according to the invention for the preparation of medicaments intended to treat affections of the cardiovascular system, the central nervous system, the renal sphere, as well as diabetes. type II, obesity and sexual behavior disorders, in humans and animals.

In particular, the pharmaceutical composition according to the invention is useful for the manufacture of a medicament for treating affections of the cardiovascular system, in particular failure 11

heart or hypertension, including malignant or resistant hypertension.

The compositions of the present invention may contain, in addition to the combination according to the invention, other active ingredients which may be useful in the treatment of the disorders or diseases indicated above.

Thus, according to the present invention, it is possible to prepare pharmaceutical compositions containing the combination according to the invention associated with another compound acting on the renin-angiotensin system such as a converting enzyme inhibitor or a renin inhibitor . It is also possible to combine the combination according to the invention, for example, with a peripheral vasodilator, a calcium channel blocker, a beta-blocker, an alpha-1-blocker or a diuretic. Such compositions will be useful in particular in the treatment of hypertension or heart failure. These associations will strengthen the therapeutic activities of the association according to the invention. EXAMPLE 1 Capsule

Micronized Compound A 25.00 mg

Irbesartan 75.00 mg Lactose monohydrate 252.35 mg

Modified corn starch 57.77 mg

Colloidal anhydrous silica 2.13 mg

Magnesium stearate 4.25 mg

Talc 8.50 mg For an opaque white capsule No. 0 filled to 425 mg

EXAMPLE 2 Capsule

Compound A micronized 100.00 mg

Irbesartan 150.00 mg Lactose monohydrate 113.60 mg

Modified corn starch 46.52 mg

Colloidal anhydrous silica 2.13 mg

Magnesium stearate 4.25 mg

Talc 8.50 mg For an opaque white capsule No. 0 filled to 425 mg

Claims

12

I. A pharmaceutical composition containing a combination of an antagonist compound Vι _receptors of arginine-vasopressin antagonist compound and an ATi receptors of angiotensin II.

2. Pharmaceutical composition according to claim 1 in which the active principles of the association are mixed with at least one pharmaceutical excipient.

3. Pharmaceutical composition according to claim 2, in the form of a dosage unit.

4. Pharmaceutical composition according to claim 3, containing

2.5 to 1000 mg of an antagonist Vι _receptors of arginine-vasopressin, and 0.5 to 500 mg of a receptor antagonist of angiotensin II.

5. Pharmaceutical composition according to claim 4 containing from 2.5 to 250 mg of an arginine-vasopressin V _1a receptor antagonist and from 1 to 300 mg of an angiotensin II AT 1 receptor antagonist.

6. Pharmaceutical composition according to any one of claims 1 to 5 containing the (2S) -1 - [(2R, 3S) -5-chloro-3- (2-chlorophenyl) -1 - (3,4-dimethoxy benzenesulfonyl ) -3-hydroxy-2,3-dihydro-1 H-indole-2-carbonyl] pyrrolidine-2-carboxamide.

7. Pharmaceutical composition according to claim 7 containing the (2S) -1 - [(2R, 3S) -5-chloro-3- (2-chlorophenyl) -1 - (3,4- dimethoxybenzene sulfonyl) -3-hydroxy- 2,3-dihydro-1 / - / - indole-2-carbonyl] pyrroiidine-2-carboxamide and irbesartan.

8. Pharmaceutical composition according to any one of claims 1 to 7 further containing another active principle.

9. Use of pharmaceutical compositions according to any one of claims 1 to 8 for the manufacture of a medicament for treating all pathologies for which either arginine-vasopressin or angiotensin II are involved.

10. Use according to claim 9 for the manufacture of a medicament for treating affections of the cardiovascular system, of the central nervous system, of the renal sphere, as well as type II diabetes, obesity and disorders of sexual behavior, in humans and animals.

II. Use according to claim 10 for the manufacture of a medicament for treating affections of the cardiovascular system. 13

Use according to claim 11 for the manufacture of a medicament for treating malignant or resistant hypertension.