WO1993010773A1 - Utilisation d'inhibiteurs d'endopeptidases neutres dans le traitement de l'hipertrophie ventriculaire gauche - Google Patents

Utilisation d'inhibiteurs d'endopeptidases neutres dans le traitement de l'hipertrophie ventriculaire gauche Download PDF

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Publication number
WO1993010773A1
WO1993010773A1 PCT/EP1991/002338 EP9102338W WO9310773A1 WO 1993010773 A1 WO1993010773 A1 WO 1993010773A1 EP 9102338 W EP9102338 W EP 9102338W WO 9310773 A1 WO9310773 A1 WO 9310773A1
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Prior art keywords
propionyl
isoserine
phenyl
methionine
carbonyl
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PCT/EP1991/002338
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English (en)
Inventor
Angela Monopoli
Ennio Ongini
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Schering-Plough S.P.A.
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Publication date
Application filed by Schering-Plough S.P.A. filed Critical Schering-Plough S.P.A.
Priority to PCT/EP1991/002338 priority Critical patent/WO1993010773A1/fr
Publication of WO1993010773A1 publication Critical patent/WO1993010773A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients

Definitions

  • the present invention relates to the treatment and prevention of left ventricular hypertrophy (LVH) by administration of a neutral endopeptidase (NEP) inhibitor.
  • LH left ventricular hypertrophy
  • NEP neutral endopeptidase
  • LVH characterized by an increase in cardiac mass and growth of abnormal fibrous tissue which compromise cardiac function, is a condition which often occurs in conjunction with high blood pressure associated with essential hypertension. LVH is a primary risk factor associated with heart failure and therefore increases the risk of cardiovascular morbidity and mortality.
  • LVH is detected after high blood pressure is diagnosed, although recent reports indicate that LVH may be present before high blood pressure develops, or may be aggravated by a second condition such as atherosclerosis or diabetes mellitus.
  • LVH is diagnosed by several methods, including electrocardiography, wherein enhanced voltage is detected, by chest X-rays, or preferably by echocardiography, which detects increased myocardial wall thickness and mass.
  • the existing therapy for LVH associated with essential hypertension consists of control of arterial blood pressure, for example by administering one or more of a variety of drugs: diuretics such as diazoxide or hydrochlorthiazide; hypotensives such as methyldopa or hydralazine; beta-adrenergic blockers such as propranolol or labetalol; calcium antagonists such as diltiazem or nifedepine; or angiotensin converting enzyme (ACE) inhibitors such as captopril, spirapril or cilazapril.
  • diuretics such as diazoxide or hydrochlorthiazide
  • hypotensives such as methyldopa or hydralazine
  • beta-adrenergic blockers such as propranolol or labetalol
  • calcium antagonists such as diltiazem or nifedepine
  • ACE angiotensin
  • ACE inhibitors and calcium antagonists are known to reduce the mass of the hypertrophied left ventricle, however, many other drugs routinely prescribed to treat essential hypertension, e.g. diuretics and hydralazine, either have no effect on LVH or take a long time to treat it.
  • NEP (EC 3.4.24.11; enkephalinase; atriopeptidase) is a zinc-containing metalloprotease which cleaves a variety of peptide substrates on the amino terminal side of aromatic amino acids. See Biochem. J.. 241 (1987) p. 237-247. Substrates for this enzyme include, but are not limited to, ANP, brain natriuretic peptide, met and leu enkephalin, bradykinin, neurokinin A, and substance P. It has been previously demonstrated that inhibitors of NEP potentiate the
  • hypotensive, diuretic, natriuretic and plasma ANP responses to pharmacological injection of ANP in experimental animals The potentiation of ANP and the consequent use of NEP inhibitors in general to treat volume-dependent hypertension but not angiotensin II- induced hypertension was disclosed in U.S. patent 4,749,688.
  • NEP inhibitors in particular N-[2-acetylthiomethyl-3-(2-methylphenyl)-propionyl]- methionine ethyl ester and N-[N-[(L)-[1-[(2,2-dimethyl-1,3-dioxoIan-4-yl)- methoxy]carbonyl]-2-phenylethyl]-L-phenylalanyl]- ⁇ -alanine, reduce LVH without having an effect on high blood pressure resulting from essential hypertension.
  • NEP inhibitors can be used to treat LVH when essential hypertension is not present or is not severe enough to require drug therapy, NEP inhibitors can be used in conjunction with antihypertensive drugs which do not themselves treat LVH, or NEP inhibitors can be used in combination with drugs which do treat LVH in order to provide an enhanced effect.
  • NEP inhibitors suitable for use in this invention include carboxyalkyl dipeptides disclosed in U.S. patent 4,610,816, herein incorporated by reference, having the formula
  • preferred compounds are N-[N-[(L)-[1-[(2,2-dimethyl-1 ,3- dioxolan-4-yl)-methoxy]carbonyl]-2-phenylethyl]-L-phenylalanyl]- ⁇ - alanine and N-[N-[(L)-1-carboxy-2-phenylethyI]-L-phenylalanyl]- ⁇ - alanine;
  • R 1e O-C(O)-CH(R 2e )-NH-C(R 3e R 4e )-C(O)-NH-(CHR 5 ⁇ )m e -(CH 2 ) n e -CH(R 6e )-C(O)-R 7e
  • preferred compounds are N-[1-[[ 1 (S)-benzyloxycarbonyl-3- phenylpropyl]amino]cycIopentylcarbonyl]-(S)-isoserine and N-[1-[[1 (S)- carbonyl-3-phenylpropyl]amino]-cyclopentylcarbonyl]-(S)-isoserine;
  • preferred compounds are 1,1 '-[dithiobis-[2(S)-(2-methylbenzyl)- 1-oxo-3,1-propanediyl]]-bis-(S)-isoserine and 1 ,1'-[dithiobis-[2(S)-(2- methylbenzyl)-1-oxo-3,1-propanediyI]]-bis-(S)-methionine;
  • a preferred compound is N-(3-phenyl-2-(mercaptomethyl)- propionyl)-(S)-4-(methylmercapto)methionine;
  • a preferred compound is N-[1-(acetylthiomethyl)cyclopentane- carbonyl]-(S)-methionine ethyl ester;
  • a preferred compound is 3(S)-[2-(acetylthiomethyl)-3-phenyl- propionyl]amino- ⁇ -caprolactam; glutaryl amino acids disclosed in U.S. 4,975,444, herein incorporated by reference, having the formula
  • a s completes a 4 to 7 membered carbocyclic ring which may be saturated or mono-unsaturated and which may optionally be fused to a further saturated or unsaturated 5 or 6 membered carbocyclic ring;
  • B s is (CH 2 ) m s wherein m s is an integer of from 1 to 3;
  • each of R s and R 4s is independently H, alkyl, benzyl or an alternative biolabile ester-forming group
  • R 1s is H oralkyl
  • R 2s and R 3s are each independently H, OH, alkyl or alkoxy;
  • R 5s is alkyl, alkenyl, alkynyl, arylalkynyl, cycloalkyl, cycloalkenyl, alkoxy, -NR 6s R 7s , -NR 8s COR 9s , -NR 8s SO 2 R 9s or a saturated
  • R 6s and R 7s are each independently H, alkyl, cycloalkyl (optionally substituted by hydroxy or alkoxy), aryl, arylalkyl, alkoxyalkyl or heterocyclyl; or the two groups R 6s and R 7s are taken together with the nitrogen to which they are attached to form a pyrrolidinyl, piperidino,
  • R 8s is H or alkyl
  • R 9s is alkyl, CF 3 , aryl, aryl, alkyl, arylalkoxy, heterocyclyl, alkoxy or -NR 6s R 7s wherein R 6s and R 7s are as previously defined;
  • R 10s is alkyl, aryl, heterocyclyl, or -NR 6s R 7s wherein R 6s and R 7s are as previously defined;
  • R 11 s is alkyl, cycloalkyl, aryl or heterocyclyl
  • R 12s is H or alkyl
  • a u completes a 4 to 7 membered carbocyclic ring which may be saturated or mono-unsaturated and which may optionally be fused to a further saturated or unsaturated 5 or 6 membered carbocyclic ring;
  • B u is (CH 2 )m u wherein m s is an integer of from 1 to 3;
  • each of R u and R 4u is independently H, alkyl, benzyl or an alternative biolabile ester-forming group
  • R 1u is H or alkyl
  • R 2u and R 3u are each independently H, OH, alkyl or alkoxy, or R 2u and
  • R 3u are linked together and are (CH 2 )r u wherein r u is an integer from 1 to 4;
  • Y u is an optional alkylene group of from 1 to 6 carbon atoms which may be straight or branched-chain; and R 5u is R 6u CONR 9u -, R 6u SO 2 NR 9u -, R 6u CO 2 -, R 6u CO-, R 6u SO q u -, R 7u NR 9u SO 2 -, or R 7u OCO-;
  • R 6u is a group of the formula
  • R 7u is a group of the formula
  • R 9u is H, alkyl, aryl, cycloalkyl, heterocyclyl, arylalkyl, or
  • R 8u is R 9u CONR 9u -, R 9u So 2 NR 9u - ,R 13u R 14u N-(CH 2 ) p u-, or R 9u O-, wherein each R 9u is as previously defined;
  • R 10u and R 11u are each independently H or alkyl; or R 10u is H and R 11u is alkyl which is substituted by OH, SH, SCH 3 , NH 2 , arylalkyl-OCONH-,
  • R 10u is H, n u is 0 and R 8u and R 11u are linked to form a 2-(N-COR 9u - 4-aminopyrrolidinyl) group;
  • R 12u is R 13u R 14u NCO-, R 9u OCH 2 - or heterocyclyl, wherein R 9u is as previously defined;
  • R 13u and R 14u are each independently H, alkyl, cycloalkyl, aryl, arylalkyl, alkoxyalkyl, aminoalkyl, heterocyclyl or heterocyclylalkyl; or the two groups R 13u and R 14u are taken together to form, with the nitrogen to which they are attached, a pyrrolidinyl, piperidino,
  • n u is 0 or 1;
  • p u is 0 or an integer of from 1 to 6; and q u is 0, 1 or 2;
  • NEP inhibitors suitable for use in the present invention were taken from the noted patents or applications.
  • NEP inhibitors include SQ 28603 (N-[2-
  • NEP inhibitors most preferred are N-[2- acetylthiomethyl-3-(2-methyl-phenyl)propionyl]-methionine ethyl ester, especially the S,S isomer thereof, and N-[N-[(L)-[1 -[(2,2-dimethyl-1 ,3- dioxolan-4-yl)-methoxy]carbonyI]-2-phenylethyl]-L-phenylalanyl]- ⁇ - alanine.
  • preferred antihypertensives are ACE inhibitors and calcium antagonists.
  • Preferred ACE inhibitors are spirapril, enalapril, ramipril, perindopril, indolapril, lysinopril, quinapril, pentopril, cilazapril, captopril, zofenopril, pivalopril and fosinopril.
  • Preferred calcium antagonists are diltiazem, nifedipine, verapamil, nicardipine and nimodipine
  • NEP inhibitors are diltiazem, nifedipine, verapamil, nicardipine and nimodipine
  • SHRs spontaneously hypertensive rats supplied by Charles River (Calco, Italy) are used. They are housed in individual cages for one week before starting the experiment, with free access to food and water. The animals are selected for stable baseline arterial pressure and assigned randomly to four groups of 12 each (first experiment).
  • the NEP inhibitor is administered for 4 weeks at 3,10, 30, or 100 mg/kg orally twice daily (at 9:00 a.m. and 4:00 p.m.), with carboxymethylcellulose (CMC 0.5%) used as vehicle and as a control.
  • CMC carboxymethylcellulose
  • a second experiment involves administering an NEP inhibitor at 100 mg/kg or the vehicle as a control to two groups of SHRs twice a day for 4 weeks .
  • Water intake, urine volume and sodium excretion are monitored by placing the rats in metabolic cages over a 16-hour period from the last daily administration of the drug to the first dosage of the following day.
  • SBP Systolic blood pressure
  • SHRs are anesthetized with fentanyl citrate (50 ⁇ g/kg) and droperidol (250 ⁇ g/kg; Leptofen, Farmitalia Carlo Erba, Milan, Italy) and the hearts fixed by perfusion as follows.
  • the abdominal aorta below the renal arteries is cannulated with a catheter (PE 200) filled with phosphate buffer (0.2 M, pH 7.4) and heparin (100 lU/ml), the catheter is connected to a perfusion apparatus, and perfusion is adjusted to diastolic arterial pressure measured in vivo.
  • the heart is then arrested in diastole by an intravenous injection of 1 ml of KCI (1 meq/ml) through the jugular vein, the thorax is opened and the vena cava is cut to allow drainage of blood and perfusate.
  • the coronary vasculature is then perfused with a glutaraldehyde-formaldehyde mixture diluted 1 :1 with phosphate buffer.
  • the heart is excised, the inner longitudinal diameter measured, and the right and left ventricle inclusive of the septum dissected from the atria and their weights recorded separately.
  • the left ventricle is transversely cut into 10-12 rings perpendicular to the longitudinal axis of the heart.
  • the thickness of the left ventricular free wall and septum and the transverse luminal diameter of the ventricular chamber are measured in the intermediate slice with a stereomicroscope at a calibrated magnification of 16X, having an ocular micrometer accurate to 0.01 mm. Five to ten equally spaced
  • the four middle slices of the free wall of each ventricle are radially cut to obtain 28-30 tissue blocks extending from the
  • midmyocardium and epicardium in each animal are examined at a calibrated magnification of 250X with a reticle containing 42 sampling points.
  • This reticle defines an uncompressed tissue area of 144,000 ⁇ m 2 , which is used to determine the number of lesions represented by foci of fibrosis per unit area of myocardium. The number of points overlying these foci is also counted to compute the volume fraction of fibrosis in the myocardium and the average cross sectional area of the foci profiles.
  • Baseline blood pressure ranged from 189 ⁇ 4 to 197 ⁇ 2 mmHg. 4 weeks of treatment with either Compound A or Compound B did not significantly affect arterial pressure, even at the highest dose level tested: 189 ⁇ 4 mmHg before, 195 ⁇ 4 mmHg after 4 weeks of a 30 mg/kg dose of Compound A; 196 ⁇ 4 mmHg before, 190+6 mmHg after 4 weeks of a 100 mg/kg dose of Compound B.
  • the SPIR group showed a significant reduction in systolic pressure during the treatment period: 197 ⁇ 2 mmHg before, 181 ⁇ 3 mmHg after 4 weeks of a 1 mg/kg dose of SPIR (p ⁇ 0.05). In all groups tested, heart rates were not significantly different from those observed in the vehicle controls.
  • a variety of pharmaceutical dosage forms are suitable for NEP administration, preferably for oral or parenteral administration, although mechanical delivery systems such as transdermal dosage forms are also contemplated.
  • the typical daily dosage of the NEP inhibitor for treatment or prevention of LVH is about 0.3 mg/kg to about 100 mg/kg of mammalian weight per day administered in single or divided doses.
  • the exact dose of any NEP inhibitor to be administered is determined by the attending clinician and is dependent on the potency of the compound administered, the age, weight, condition and response of the patient.
  • the NEP inhibitors of this invention can be administered in dosage ranges of about 10 to about 1000 mg NEP inhibitor per dose given 1 to 4 times a day.
  • Typical oral formulations for drugs used in this invention include tablets, capsules, syrups, elixirs and suspensions.
  • Typical injectable formulations for drugs used in this invention include solutions and suspensions.
  • NEP inhibitors are administered in combination with other antihypertensive agents, including ACE inhibitors, calcium antagonists, diuretics and beta-adrenergic blockers
  • the combinations can be administered from a single pharmaceutical composition which combines the actives in a pharmaceutically acceptable carrier, or the drugs may be administered separately. That is, a patient can undergo parallel courses of treatment with the two different actives; simultaneous administration of dosage forms is not required. Since the methods of this invention relating to the combinations comprise administering two different drugs, any suitable combination of dosage forms can be used, e.g. oral NEP inhibitor / oral antihypertensive agent or injectable NEP inhibitor / oral antihypertensive agent.
  • the present invention relates to methods of treating or preventing LVH with a combination of active ingredients, i.e. an NEP inhibitor and an antihypertensive agent, wherein said active ingredients may be administered separately
  • the invention also relates to combining separate pharmaceutical compositions in kit form. That is, a kit which combines two separate units, an NEP pharmaceutical composition and an antihypertensive composition (particularly an ACE inhibitor or a calcium antagonist composition), in one package is contemplated.
  • the kit form is particularly advantageous when the separate components must be administered in different dosage forms (e.g. oral and parenteral) or are administered at different dosage intervals.

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  • Health & Medical Sciences (AREA)
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  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

Traitement et prophylaxie de l'hypertrophie ventriculaire gauche à l'aide d'endopeptidases neutres telles que la N-[N-[(L)-[1-[(2,2-diméthyl-1,3-dioxolan-4-yl)-méthoxy]carbonyl]-2-phényléthyl]-L-phénylalanyl-β-alanine et la N-[2-mercaptométhyl-3-(2-méthylphényl-propioyl]-méthionine.
PCT/EP1991/002338 1991-12-06 1991-12-06 Utilisation d'inhibiteurs d'endopeptidases neutres dans le traitement de l'hipertrophie ventriculaire gauche WO1993010773A1 (fr)

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PCT/EP1991/002338 WO1993010773A1 (fr) 1991-12-06 1991-12-06 Utilisation d'inhibiteurs d'endopeptidases neutres dans le traitement de l'hipertrophie ventriculaire gauche

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PCT/EP1991/002338 WO1993010773A1 (fr) 1991-12-06 1991-12-06 Utilisation d'inhibiteurs d'endopeptidases neutres dans le traitement de l'hipertrophie ventriculaire gauche

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1616867A1 (fr) * 1998-11-12 2006-01-18 Seikagaku Corporation Dérivés d'acide hydroxy carboxylique
US7468390B2 (en) 2002-01-17 2008-12-23 Novartis Ag Methods of treatment and pharmaceutical composition
EP2340828A1 (fr) 2005-11-09 2011-07-06 Novartis AG Combinaisons pharmaceutiques d'un antagoniste de récepteur de l'angiotensine et inhibiteurs de nep
WO2014029848A1 (fr) 2012-08-24 2014-02-27 Novartis Ag Inhibiteurs de nep pour le traitement de maladies caractérisées par un agrandissement atrial ou une remodélisation atriale
WO2017033128A1 (fr) 2015-08-25 2017-03-02 Novartis Ag Dérivés d'acide 4-aminé-butyrique substitués par le biphényle, et leur utilisation dans la synthèse d'inhibiteurs de nep
WO2017072636A1 (fr) 2015-10-29 2017-05-04 Cadila Healthcare Limited Association pharmaceutique synergique

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991009840A1 (fr) * 1989-12-22 1991-07-11 Schering Corporation Inhibiteurs aminoacides mercaptocycloacyliques d'endopeptidase
WO1991013870A1 (fr) * 1990-03-09 1991-09-19 Schering Corporation Inhibiteurs d'endopeptidase a base d'aminolactame mercaptoacyle

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991009840A1 (fr) * 1989-12-22 1991-07-11 Schering Corporation Inhibiteurs aminoacides mercaptocycloacyliques d'endopeptidase
WO1991013870A1 (fr) * 1990-03-09 1991-09-19 Schering Corporation Inhibiteurs d'endopeptidase a base d'aminolactame mercaptoacyle

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Am. Rev. Resp. Dis., vol. 143, (4 part 2), 1991, T. KRAUSZ et al.: "Inhibition of neutral endopeptidase 24.11 attenuates pulmonary yascular remodeling and right ventricular hypertrophy in the rat", page A184, see right-hand column, abstract 2 *
J. Hypertension (Proceedings of the 5th European Meeting on Hypertension, June 1991), vol. 9, suppl. 6, 31 December 1991, A. MONOPOLI et al.: "Chronic inhibition of neutral endopeptidase reduces left ventricular hypertrophy without changing blood pressure in spontaneously hypertensive rats", pages S246-S247, see page S247, left-hand column *
J. Thorac. Cardiovasc. Surg., vol. 84, no. 4, 1982, D.F. LARSON et al.: "Concurrent left and right ventricular hypertrophy in dog models of right ventricular overload", pages 543-547, see page 543, right-hand column, lines 20-12; page 546, right-hand column, lines 21-26 *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1619189A1 (fr) * 1998-11-12 2006-01-25 Seikagaku Corporation Dérivés de cycloalkyl N-(3-acyl-2-hydroxyalkyl) amide
EP1616867A1 (fr) * 1998-11-12 2006-01-18 Seikagaku Corporation Dérivés d'acide hydroxy carboxylique
US8796331B2 (en) 2002-01-17 2014-08-05 Novartis Ag Methods of treatment and pharmaceutical composition
US7468390B2 (en) 2002-01-17 2008-12-23 Novartis Ag Methods of treatment and pharmaceutical composition
US8101659B2 (en) 2002-01-17 2012-01-24 Novartis Ag Methods of treatment and pharmaceutical composition
EP2340828A1 (fr) 2005-11-09 2011-07-06 Novartis AG Combinaisons pharmaceutiques d'un antagoniste de récepteur de l'angiotensine et inhibiteurs de nep
US8877938B2 (en) 2005-11-09 2014-11-04 Novartis Pharmaceuticals Corporation Compounds containing S-N-valeryl-N-{[2′-(1H-tetrazole-5-yl)-biphenyl-4-yl]-methyl}-valine and (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester moieties and cations
US9388134B2 (en) 2005-11-09 2016-07-12 Novartis, Ag Compounds containing S-N-valeryl-N-{[2′-(1H-tetrazole-5-yl)-biphenyl-4-yl]-methyl)-valine and (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester moieties and cations
EP3685833A1 (fr) 2005-11-09 2020-07-29 Novartis AG Composé comprenant un arb et un nepi
US11096918B2 (en) 2005-11-09 2021-08-24 Novartis Pharmaceuticals Corporation Amorphous solid form of compounds containing S—N-valeryl-N-{[2′-(1H-tetrazole-5-yl)-biphenyl-4-yl]-methyl}-valine and (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester moieties and sodium cations
US11642329B2 (en) 2005-11-09 2023-05-09 Novartis Pharmaceuticals Corporation Amorphous solid form of compounds containing S—N-valeryl-N- {[2′-( 1 H-tetrazole-5-yl)-biphenyl-4-yl]-methyl}-valine and (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester moieties and sodium cations
WO2014029848A1 (fr) 2012-08-24 2014-02-27 Novartis Ag Inhibiteurs de nep pour le traitement de maladies caractérisées par un agrandissement atrial ou une remodélisation atriale
EP3943084A1 (fr) 2012-08-24 2022-01-26 Novartis AG Inhibiteurs de nep pour le traitement de maladies caractérisées par un agrandissement atrial ou une remodélisation atriale
WO2017033128A1 (fr) 2015-08-25 2017-03-02 Novartis Ag Dérivés d'acide 4-aminé-butyrique substitués par le biphényle, et leur utilisation dans la synthèse d'inhibiteurs de nep
WO2017072636A1 (fr) 2015-10-29 2017-05-04 Cadila Healthcare Limited Association pharmaceutique synergique

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