WO2003059345A1 - Pharmaceutical compositions comprising valsartan and nep inhibitors - Google Patents

Pharmaceutical compositions comprising valsartan and nep inhibitors Download PDF

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Publication number
WO2003059345A1
WO2003059345A1 PCT/EP2003/000415 EP0300415W WO03059345A1 WO 2003059345 A1 WO2003059345 A1 WO 2003059345A1 EP 0300415 W EP0300415 W EP 0300415W WO 03059345 A1 WO03059345 A1 WO 03059345A1
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Prior art keywords
carboxy
propionyl
amino
acid
pharmaceutically acceptable
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PCT/EP2003/000415
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English (en)
French (fr)
Inventor
Randy Lee Webb
Gary Michael Ksander
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Novartis Ag
Novartis Pharma Gmbh
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Priority to JP2003559507A priority Critical patent/JP4820056B2/ja
Priority to DK03704413T priority patent/DK1467728T3/da
Priority to IL16266103A priority patent/IL162661A0/xx
Priority to MXPA04006917A priority patent/MXPA04006917A/es
Priority to CA2472399A priority patent/CA2472399C/en
Priority to KR1020047011124A priority patent/KR100984939B1/ko
Priority to BR122018015003A priority patent/BR122018015003B8/pt
Priority to AU2003206738A priority patent/AU2003206738C1/en
Priority to DE60315795T priority patent/DE60315795T2/de
Priority to NZ533968A priority patent/NZ533968A/en
Priority to BRPI0306907A priority patent/BRPI0306907B8/pt
Application filed by Novartis Ag, Novartis Pharma Gmbh filed Critical Novartis Ag
Priority to SI200331029T priority patent/SI1467728T1/sl
Priority to EP03704413A priority patent/EP1467728B1/en
Publication of WO2003059345A1 publication Critical patent/WO2003059345A1/en
Priority to IL162661A priority patent/IL162661A/en
Priority to ZA2004/05117A priority patent/ZA200405117B/en
Priority to NO20043380A priority patent/NO333191B1/no
Priority to CY20071101386T priority patent/CY1106959T1/el
Priority to FR16C0019C priority patent/FR16C0019I2/fr
Priority to BE2016C025C priority patent/BE2016C025I2/nl
Priority to NO2016009C priority patent/NO2016009I2/no
Priority to LU93074C priority patent/LU93074I2/fr
Priority to CY2016013C priority patent/CY2016013I1/el
Priority to NL300811C priority patent/NL300811I2/nl

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • 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
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
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    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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    • A61P27/00—Drugs for disorders of the senses
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    • A—HUMAN NECESSITIES
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
    • C07C215/10—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with one amino group and at least two hydroxy groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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    • C07B2200/07—Optical isomers

Definitions

  • Angiotensin II interacts with specific receptors on the surface of the target cell. It has been possible to identify receptor subtypes that are termed e.g. AT 1- and AT 2-receptors. In recent times great efforts have been made to identify substances that bind to the AT 1- receptor. Such active ingredients are often termed angiotensin II antagonists. Because of the inhibition of the AT 1 -receptor such antagonists can be used e.g. as antihypertensives or for the treatment of congestive heart failure, among other indications. Angiotensin II antagonists are therefore understood to be those active ingredients which bind to the AT 1- receptor subtype.
  • Inhibitors of the renin angiotensin system are well known drugs that lower blood pressure and exert beneficial actions in hypertension and in congestive heart failure as described, for example, in N. Eng. J. Med. 316, 23 (1987) p. 1429-1435.
  • a large number of peptide and non-peptide inhibitors of the renin angiotensin system are known, the most widely studied being the ACE inhibitors, which includes the drugs captopril, enalapril, lisinopril, benazepril and spirapril.
  • ACE inhibitors which includes the drugs captopril, enalapril, lisinopril, benazepril and spirapril.
  • ACE cleaves a variety of peptide substrates, including the vasoactive peptides bradykinin and substance P.
  • Prevention of the degradation of bradykinin by ACE inhibitors has been demonstrated, and the activity of the ACE inhibitors in some conditions has been reported in Circ. Res., 66, 1 (1990) p. 242-248 to be mediated by elevation of bradykinin levels rather than inhibition of Ang II formation. Consequently, it cannot be presumed that the effect of an ACE inhibitor is due solely to prevention of angiotensin formation and subsequent inhibition of the renin angiotensin system.
  • Neutral endopeptidase (EC 3.4.24.11; enkephalinase; atriopeptidase; NEP) is a zinc- containing metailoprotease that 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, atrial natriuretic factors (ANF, also known as ANP), brain natriuretic peptide (BNP), met and leu enkephalin, bradykinin, neurokinin A, and substance P.
  • ANPs are a family of vasodilator, diuretic and antihypertensive peptides which have been the subject of many recent reports in the literature, for example Annu. Rev. Pharm. Tox., 29, (1989) p. 23-54.
  • ANF 99-126 is a circulating peptide hormone which is released from the heart during conditions of cardiac distension. The function of ANF is to maintain salt and water homeostasis as well as to regulate blood pressure.
  • ANF is rapidly inactivated in the circulation by at least two processes: a receptor-mediated clearance reported in Am. J. Physiol., 256 (1989) p. R469-R475 and an enzymatic inactivation via NEP reported in Biochem.
  • NEP inhibitors lower blood pressure and exert ANF-like effects such as diuresis and increased cyclic guanosine 3',5'-monophosphate (cGMP) excretion in some forms of experimental hypertension.
  • cGMP cyclic guanosine 3',5'-monophosphate
  • Prolonged and uncontrolled hypertensive vascular disease ultimately leads to a variety of pathological changes in target organs such as the heart and kidney. Sustained hypertension can lead as well to an increased occurrence of stroke. Therefore, there is a strong need to evaluate the efficacy of antihypertensive therapy, an examination of additional cardiovascular endpoints, beyond those of blood pressure lowering, to get further insight into the benefits of combined treatment.
  • hypertensive vascular diseases The nature of hypertensive vascular diseases is multifactorial. Under certain circumstances, drugs with different mechanisms of action have been combined. However, just considering any combination of drugs having different mode of action does not necessarily lead to combinations with advantageous effects. Accordingly, there is a need for more efficacious combination therapy which has less deleterious side effects.
  • the present invention relates to pharmaceutical combinations comprising valsartan or pharmaceutically acceptable salts thereof and a neutral endopeptidase (NEP) inhibitor or a pharmaceutically effective salts thereof, optionally in the presence of a pharmaceutically acceptable carrier and pharmaceutical compositions comprising them.
  • NEP neutral endopeptidase
  • the present invention relates to methods of treating cardiac and renal related conditions by administration of the pharmaceutical composition comprising valsartan plus a NEP inhibitor or relates to the use of a pharmaceutical composition comprising valsartan or pharmaceutically acceptable salts thereof and a neutral endopeptidase (NEP) inhibitor or a pharmaceutically effective salts thereof.
  • NEP neutral endopeptidase
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising valsartan or pharmaceutically acceptable salts thereof and a neutral endopeptidase (NEP) inhibitor or a pharmaceutically effective salts thereof and a diuretic, especially hydrochlorothiazide.
  • NEP neutral endopeptidase
  • Valsartan is the AT 1 receptor antagonist (S) -N-(1-carboxy-2-methyl-prop-1-yl)-N- pentanoyl-N-[2;(1 H-tetrazol-5-yl)biphenyl-4-yl-methyl]amine of formula (I)
  • a NEP inhibitor useful in said combination is a compound of the formula (II)
  • R 2 is alkyl of 1 to 7 carbons, trifluoromethyl, phenyl, substituted phenyl, -(CH 2 ) 1 to 4 - phenyl, or -(CH 2 ) ⁇ to4-substituted phenyl;
  • R 3 is hydrogen, alkyl of 1 to 7 carbons, phenyl, substituted phenyl, -(CH 2 ) 1 to 4 -phenyl, or -(CH 2 ) ⁇ to4 -substituted phenyl;
  • Ri is hydroxy, alkoxy of 1 to 7 carbons, or NH 2 ; n is an integer from 1 to 15; and the term substituted phenyl refers to a substituent selected from lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, hydroxy, Cl, Br, or F.
  • Preferred selective neutral endopeptidase inhibitors of formula II include compounds wherein:
  • R 2 is benzyl
  • R 3 is hydrogen; n is an integer from 1 to 9; and
  • R-i is hydroxy
  • SQ 28,603 is the compound of formula II wherein: R 2 is benzyl; R 3 is hydrogen; n is one; and R-i is hydroxy.
  • NEP inhibitors within the scope of the present invention include compounds disclosed in U.S. Patent No. 4,610,816, herein incorporated by reference, including in particular N-[N- [1 (S)-carboxyl-3-phenylproplyl]-(S)-phenylalanyl]-(S)-isoserine and N-[N-[((1 S)-carboxy-2- phenyl)ethyl]-(S)-phenylalanyl]- ⁇ -alanine; compounds disclosed in U.S. Patent No.
  • NEP inhibitors e.g., compounds in which one or more carboxylic acid groups are esterified.
  • NEP inhibitors within the scope of the present invention also include the compounds disclosed in U.S. Patent No.
  • Patent No. 5,273,990 particularly (S)-(2- biphenyl-4-yl)-1-(1H-tetrazol-5-yl)ethylamino) methylphosphonic acid; the compounds disclosed in U.S. Patent No. 5,294,632 particularly (S)-5-(N-(2-(phosphonomethylamino)-3- (4-biphenyl)propionyl)-2-aminoethyl)tetrazole; the compounds disclosed in U.S. Patent No.
  • a diuretic is, for example, a thiazide derivative selected from the group consisting of chlorothiazide, hydrochlorothiazide, methylclothiazide, and chlorothalidon. The most preferred is hydrochlorothiazide.
  • the compounds to be combined can be present as pharmaceutically acceptable salts. If these compounds have, for example, at least one basic center, they can form acid addition salts. Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center. The compounds having at least one acid group (for example COOH) can also form salts with bases. Corresponding internal salts may furthermore be formed, if a compound comprises e.g. both a carboxy and an amino group.
  • preferred salts include the sodium salt disclosed in U.S. Patent No. 5,217,996, the triethanolamine salt and the tris(hydroxymethyl)aminomethane salt.
  • Preparation of the triethanolamine salt and the tris(hydroxymethyl)aminomethane salt may be carried out as follows:
  • Tris(hydroxymethyl) aminomethane To N-(3-carboxy-1-oxopropyl)-(4S)-p- phenylphenylmethyl)-4-amino-2R-methylbutanoic acid ethyl ester (3.2 g (7.78 mmol) is added 32 ml of ethyl acetate and 940 mg (7.78 mmol) tris(hydroxymethyl)aminomethane. The suspension is diluted with 45 ml of ethyl acetate and refluxed overnight (-20 hr). The reaction is cooled to 0°C, filtered, solid washed with ethyl acetate and dried melting at 114- 115°C.
  • the salts of N-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-2R- methylbutanoic acid ethyl ester formed with triethanolamine and tris(hydroxymethyl) aminomethane are novel and can be used as NEP inhibitors.
  • Another embodiment of the present invention are said new salts, their use as NEP inhibitors, especially for preventing and treating of conditions and disease associated with the inhibition on NEP, pharmaceutical composition comprising these salts and their combination with valsartan, especially for the treatment of conditions and diseases as disclosed for the combinations of the present invention hereinbefore or hereinafter.
  • a combination of valsartan and a NEP inhibitor achieves greater therapeutic effect than the administration of valsartan, ACE inhibitors or NEP inhibitors alone and promotes less angioedema than is seen with the administration of a vasopeptidase inhibitor alone. Greater efficacy can also be documented as a prolonged duration of action.
  • the duration of action can be monitored as either the time to return to baseline prior to the next dose or as the area under the curve (AUC) and is expressed as the product of the change in blood pressure in millimeters of mercury (change in mmHg) and the duration of the effect (minutes, hours or days).
  • lower doses of the individual drugs to be combined according to the present invention can be used to reduce the dosage, for example, that the dosages need not only often be smaller but are also applied less frequently, or can be used to diminish the incidence of side effects.
  • the combined administration of valsartan or a pharmaceutically acceptable salt thereof and a NEP inhibitor or a pharmaceutically acceptable salt thereof results in a significant response in a greater percentage of treated patients, that is, a greater responder rate results, regardless of the underlying etiology of the condition. This is in accordance with the desires and requirements of the patients to be treated.
  • combination therapy with valsartan and a NEP inhibitor results in a more effective antihypertensive therapy (whether for malignant, essential, reno-vascular, diabetic, isolated systolic, or other secondary type of hypertension) through improved efficacy as well as a greater responder rate.
  • the combination is also useful in the treatment or prevention of heart failure such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter or detrimental vascular remodeling.
  • a valsartan and NEP inhibitor therapy proves to be beneficial in the treatment and prevention of myocardial infarction and its sequelae.
  • a valsartan plus NEP inhibitor combination is also useful in treating atherosclerosis, angina (whether stable or unstable), and renal insufficiency (diabetic and non-diabetic).
  • combination therapy using valsartan and a NEP inhibitor can improve endothelial dysfunction, thereby providing benefit in diseases in which normal endothelial function is disrupted such as heart failure, angina pectoris and diabetes.
  • the combination of the present invention may be used for the treatment or prevention of secondary aldosteronism, primary and secondary pulmonary hypertension, renal failure conditions, such as diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria of primary renal disease, and also renal vascular hypertension, diabetic retinopathy, the management of other vascular disorders, such as migraine, peripheral vascular disease, Raynaud's disease, luminal hyperplasia, cognitive dysfunction (such as Alzheimer's), glaucoma and stroke.
  • renal failure conditions such as diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria of primary renal disease, and also renal vascular hypertension, diabetic retinopathy
  • other vascular disorders such as migraine, peripheral vascular disease, Raynaud's disease, luminal hyperplasia, cognitive dysfunction (such as Alzheimer's), glaucoma and stroke.
  • the structure of the active agents identified by generic or tradenames or code nos. may be taken from the actual edition of the standard compendium "The Merck Index” or from databases, e.g. Life Cycle Patents International (e.g. IMS World Publications). The corresponding content thereof is hereby incorporated by reference. Any person skilled in the art is fully enabled to identify the active agents and, based on these references, likewise enabled to manufacture and test the pharmaceutical indications and properties in standard test models, both in vitro and in vivo.
  • the subject matter of NEP inhibitors referred to in e.g. US patents, EP, , GB, JP or WO patent applications is herewith incorporated by reference, especially corresponding NEP inhibitors and pharmaceutically acceptable salts and pharmaceutical compositions thereof, that are claimed or disclosed in the working examples.
  • Drug efficacy is assessed in various animal models including the deoxycorticosterone acetate - salt rat (DOCA-salt) and the spontaneously hypertensive rat (SHR), either maintained on a normal salt diet or with salt loading (4-8% salt in rat chow or 1% NaCI as drinking water).
  • DOCA-salt deoxycorticosterone acetate - salt rat
  • SHR spontaneously hypertensive rat
  • the DOCA-salt test model utilizes either an acute or chronic study protocol.
  • An acute study procedure involves assessment of the effects of various test substances over a six-hour experimental period using rats with indwelling femoral arterial and venous catheters.
  • the Acute Study Procedure evaluates test substances for their ability to reduce blood pressure during the established phase of DOCA-salt hypertension.
  • the Chronic Study Procedure assesses the ability of test substances to prevent or delay the rise in blood pressure during the development phase of DOCA-salt hypertension. Therefore, blood pressure will be monitored in the chronic study procedure by means of a radiotransmitter.
  • the radiotransmitter is surgically implanted into the abdominal aorta of rats, prior to the initiation of DOCA-salt treatment and thus, prior to the induction of hypertension. Blood pressure is chronically monitored for periods of up 6 weeks (approximately one week prior to DOCA-salt administration and for 5 weeks thereafter).
  • Rats are anesthetized with 2-3% isoflurane in oxygen inhalant followed by Amytal sodium (amobarbital) 100 mg/kg, ip.
  • the level of anesthesia is assessed by a steady rhythmic breathing pattern.
  • a 20mm incision is made through the skin and underlying muscle to expose the left kidney.
  • the kidney is freed of surrounding tissue, exteriorized and two ligatures (3-0 silk) are tied securely around the renal artery and vein proximal to their juncture with the aorta.
  • the renal artery and vein are then severed and the kidney removed.
  • the muscle and skin wounds are closed with 4-0 silk suture and stainless steel wound clips, respectively.
  • a 15mm incision is made on the back of the neck and a 3-week-release pellet (Innovative Research of America, Sarasota, Florida) containing deoxycorticosterone acetate (100 mg/kg) is implanted subcutaneously.
  • the wound is then closed with stainless-steel clips and both wounds are treated with povidone/iodine; the rats are given a post-surgical intramuscular injection of procaine penicillin G (100,000 U) and buprenorphine (0.05 - 0.1 mg/kg) s.c.
  • the rats are immediately placed on 1% NaCI + 0.2% KCI drinking water; this treatment continues for at least 3 weeks at which time the animals have become hypertensive and available for experimentation.
  • mice Forty-eight hours prior to experimentation, animals are anesthetized with isoflurane and catheters are implanted in the femoral artery and vein for measuring arterial pressure, collection of blood, and administration of test compounds. Rats are allowed to recover for 48 hours while tethered in a Plexiglas home cage, which also serves as the experimental chamber.
  • Protocols are then set-up on the computer for measurement of blood pressure, heart rate, etc, at predetermined time points.
  • Baseline data is collected at various time points and over various time intervals.
  • baseline or pre-dose values usually consist of data collection and averaging over 3 consecutive, 24-hour time periods prior to drug administration.
  • Blood pressure, heart rate and activity are determined at various pre-selected time points before, during, and after drug administration. All measurements are performed in unrestrained and undisturbed animals.
  • the maximum study time determined by battery life, could be as long as nine months. For studies of this duration, rats are dosed orally (1-3 ml/kg vehicle), no more than twice daily or drug is administered via the drinking water or mixed with food.
  • Osmotic minipumps are selected based on drug delivery rate and time.
  • Valsartan dosages range from 1 to 10 mg/kg/day and N-(3- carboxy-1 -oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-2R-methylbutanoic acid ethyl ester range from 10 to 50 mg/kg/day.
  • SHR are utilized to study the effects of valsartan in combination with N-(3- carboxy-1 -oxopropyI)-(4S)-p-phenylphenylmethyl)-4-amino-2R-methylbutanoic acid ethyl ester.
  • the hypertensive background of the SHR is modified either by chronic salt loading in an effort to suppress the renin angiotensin system (RAS) or chronic salt depletion to activate the RAS in the SHR.
  • RAS renin angiotensin system
  • SHR spontaneously hypertensive rats
  • Taconic Farms Germantown, New York
  • a radiotelemetric device (Data Sciences International, Inc., St. Paul, Minnesota) is implanted into the lower abdominal aorta of all test animals between the ages of 14 to 16 weeks of age. All SHR are allowed to recover from the surgical implantation procedure for at least 2 weeks prior to the initiation of the experiments. Cardiovascular parameters are continuously monitored via the radiotransmitter and transmitted to a receiver where the digitized signal is then collected and stored using a computerized data acquisition system. Blood pressure (mean arterial, systolic and diastolic pressure) and heart rate are monitored in conscious, freely moving and undisturbed SHR in their home cages. The arterial blood pressure and heart rate are measured every 10 minutes for 10 seconds and recorded.
  • Data reported for each rat represent the mean values averaged over a 24 hour period and are made up of the 144-10 minute samples collected each day.
  • the baseline values for blood pressure and heart rate consist of the average of three consecutive 24 hour readings taken prior to initiating the drug treatments. All rats are individually housed in a temperature and humidity controlled room and are maintained on a 12 hour light dark cycle.
  • Typical dosages for valsartan in drinking water range from 3 to 30 mg/kg/day whereas the dosage of N-(3-carboxy-1- oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-2R-methylbutanoic acid ethyl ester is highly dependent upon the specific agent used. In most situations, a daily dose will not exceed 50 mg/kg/day when administered as the monotherapy.
  • valsartan is given in the range of 1 to 30 mg/kg/day and N-(3-carboxy-1 -oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-2R-methylbutanoic acid ethyl ester in dosages below 50 mg/kg/day.
  • the dosages are identical to those used as monotherapy.
  • the dose of valsartan ranges from 1 to 50 mg/kg/day and N-(3-carboxy-1 -oxopropyI)-(4S)-p-phenylphenylmethyl)-4-amino-2R- methylbutanoic acid ethyl ester does not exceed 100 mg/kg/day.
  • Vascular function and structure are evaluated after treatment to assess the beneficial effects of the combination.
  • SHR are studied according to the methods described by Intengan HD, Thibault G, Li JS, Schiffrin EL, Circulation 1999, 100 (22): 2267-2275.
  • the methodology for assessing vascular function in DOCA-salt rats is described in Intengan HD, Park JB, Schiffrin, EL, Hypertension, 1999, 34(4 Part 2): 907-913.
  • a pharmaceutical combination composition e.g. for the treatment or prevention of a condition or disease selected from the group consisting of hypertension, heart failure such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, angina (whether unstable or stable), renal insufficiency (diabetic and non- diabetic), heart failure, angina pectoris, diabetes, secondary aldosteronism, primary and secondary pulmonary hypertension, renal failure conditions, such as diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria of primary renal disease, and also renal vascular hypertension, diabetic retinopathy, the management of other vascular disorders, such as migraine, peripheral vascular disease, Rayn
  • components (i) and (ii) can be obtained and administered together, one after the other or separately in one combined unit dose form or in two separate unit dose forms.
  • the unit dose form may also be a fixed combination.
  • a further aspect of the present invention is a method for the treatment or prevention of a condition or disease selected from the group consisting of hypertension, heart failure such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, angina (whether unstable or stable), renal insufficiency (diabetic and non- diabetic), heart failure, angina pectoris, diabetes, secondary aldosteronism, primary and secondary pulmonary hypertension, renal failure conditions, such as diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria of primary renal disease, and also renal vascular hypertension, diabetic retinopathy, the management of other vascular disorders, such as migraine, peripheral vascular disease, Raynaud's disease, luminal hyperp
  • the corresponding active ingredient or a pharmaceutically acceptable salt thereof may also be used in form of a hydrate or include other solvents used for crystallization.
  • compositions according to the invention can be prepared in a manner known per se and are those suitable for enteral, such as oral or rectal, and parenteral administration to mammals (warm-blooded animals), including man, comprising a therapeutically effective amount of the pharmacologically active compound, alone or in combination with one or more pharmaceutically acceptable carriers, especially suitable for enteral or parenteral application.
  • Typical oral formulations include tablets, capsules, syrups, elixirs and suspensions.
  • Typical injectable formulations include solutions and suspensions.
  • the typical pharmaceutically acceptable carriers for use in the formulations described above are exemplified by: sugars such as lactose, sucrose, mannitol and sorbitol; starches such as comstarch, tapioca starch and potato starch; cellulose and derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; calcium phosphates such as dicalcium phosphate and tricalcium phosphate; sodium sulfate; calcium sulfate; polyvinylpyrrolidone; polyvinyl alcohol; stearic acid; alkaline earth metal stearates such as magnesium stearate and calcium stearate; stearic acid; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil; non-ionic, cationic and anionic surfactants; ethylene glycol polymers; betacyclodextrin; fatty alcohols; and hydrolyzed cereal solids, as well as other non-toxic
  • the invention also relates to combining separate pharmaceutical compositions in kit form. That is a kit combining two separate units: a valsartan pharmaceutical composition and a NEP inhibitor pharmaceutical composition.
  • kit form is particularly advantageous when the separate components must be administered in different dosage forms (e.g. parenteral valsartan formulation and oral NEP formulation) or are administered at different dosage intervals.
  • compositions are for enteral, such as oral, and also rectal or parenteral, administration to homeotherms, with the preparations comprising the pharmacological active compound either alone or together with customary pharmaceutical auxiliary substances.
  • the pharmaceutical preparations consist of from about 0.1 % to 90 %, preferably of from about 1 % to about 80 %, of the active compounds.
  • Pharmaceutical preparations for enteral or parenteral administration are, for example, in unit dose forms, such as coated tablets, tablets, capsules or suppositories and also ampoules. These are prepared in a manner which is known per se, for example using conventional mixing, granulation, coating, solubulizing or lyophilizing processes.
  • compositions for oral use can be obtained by combining the active compounds with solid excipients, if desired granulating a mixture which has been obtained, and, if required or necessary, processing the mixture or granulate into tablets or coated tablet cores after having added suitable auxiliary substances.
  • the dosage of the active compound can depend on a variety of factors, such as mode of administration, homeothermic species, age and/or individual condition.
  • Preferred dosages for the active ingredients of the pharmaceutical combination according to the present invention are therapeutically effective dosages, especially those which are commercially available.
  • an approximate daily dose of from about 1 mg to about 360 mg is to be estimated e.g. for a patient of approximately 75 kg in weight.
  • Valsartan is supplied in the form of suitable dosage unit form, for example, a capsule or tablet, and comprising a therapeutically effective amount, e.g. from about 20 to about 320 mg, of valsartan which may be applied to patients.
  • the application of the active ingredient may occur up to three times a day, starting e.g. with a daily dose of 20 mg or 40 mg of valsartan, increasing via 80 mg daily and further to 160 mg daily up to 320 mg daily.
  • valsartan is applied once a day or twice a day in heart failure patients with a dose of 80 mg or 160 mg, respectively, each. Corresponding doses may be taken, for example, in the morning, at mid-day or in the evening.
  • Preferred is q.d. or b.i.d. administration in heart failure.
  • preferred dosage unit forms are, for example, tablets or capsules comprising e.g. from about 20 mg to about 800 mg, preferably from about 50 mg to about 700 mg, even more preferably from about 100 mg to about 600 mg and even more preferably from about 100 mg to about 300 mg, administered once a day.
  • preferred dosage unit forms are, for example, tablets or capsules comprising e.g. from about 5 mg to about 50 mg, preferably from about 6.25 mg to about 25 mg.
  • a daily dose of 6.25 mg, 12.5 mg or 25 mg of hydrochlorothiazide is preferably administered once a day.
  • the film-coated tablet is manufactured e.g. as follows:
  • a mixture of valsartan, microcrystalline cellulose, crospovidone, part of the colloidal anhydrous silica/colloidal silicon dioxide/Aerosile 200, silicon dioxide and magnesium stearate is premixed in a diffusion mixer and then sieve through a screening mill.
  • the resulting mixture is again pre-mixed in a diffusion mixer, compacted in a roller compactor and then sieve through a screening mill.
  • the rest of the colloidal anhydrous silica/colloidal silicon dioxide/Aerosile 200 are added and the final blend is made in a diffusion mixer.
  • the whole mixture is compressed in a rotary tabletting machine and the tablets are coated with a film by using Diolack pale red in a perforated pan.
  • the film-coated tablet is manufactured e.g. as described in Formulation Example 1.
  • the tablet is manufactured e.g. as follows:
  • Valsartan and microcrystallin cellulose are spray-granulated in a fluidized bed granulator with a granulating solution consisting of povidone and sodium lauryl sulphate dissolved in purified water.
  • the granulate obtained is dried in a fluidized bed dryer.
  • the dried granulate is milled together with crospovidone and magnesium stearate.
  • the mass is then blended in a conical srew type mixer for approximately 10 minutes.
  • the empty hard gelatin capsules are filled with the blended bulk granules under controlled temperature and humidity conditions.
  • the filed capsules are dedusted, visually inspected, weightchecked and quarantined until by Quality assurance department.
  • a hard gelatin capsule comprising as active ingredient e.g. (S)-N-(1-carboxy-2-methylprop- 1-yl)-N-pentanoyl-N-[2'(1 H-tetrazol-5-yl)biphenyl-4-yl-methyl]amine, can be formulated, for example, as follows:
  • Components (1 ) and (2) are granulated with a solution of components (3) and (4) in water.
  • the components (5) and (6) are added to the dry granulate and the mixture is filled into size 1 hard gelatin capsules.

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PCT/EP2003/000415 2002-01-17 2003-01-16 Pharmaceutical compositions comprising valsartan and nep inhibitors WO2003059345A1 (en)

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CA2472399A CA2472399C (en) 2002-01-17 2003-01-16 Pharmaceutical compositions comprising valsartan and nep inhibitors
AU2003206738A AU2003206738C1 (en) 2002-01-17 2003-01-16 Pharmaceutical compositions comprising valsartan and NEP inhibitors
SI200331029T SI1467728T1 (sl) 2002-01-17 2003-01-16 Farmacevtski sestavki vkljucujoci valsartan in NEP inhibitorje
MXPA04006917A MXPA04006917A (es) 2002-01-17 2003-01-16 Composiciones farmaceuticas que comprenden inhibidores de valsartan y endopeptidasa neutra.
EP03704413A EP1467728B1 (en) 2002-01-17 2003-01-16 Pharmaceutical compositions comprising valsartan and nep inhibitors
KR1020047011124A KR100984939B1 (ko) 2002-01-17 2003-01-16 발사르탄 및 ｎｅｐ 저해제를 포함하는 제약학적 조성물
BR122018015003A BR122018015003B8 (pt) 2002-01-17 2003-01-16 kit compreendendo composições farmacêuticas de inibidor da nep e de valsartan ou seus sais
BRPI0306907A BRPI0306907B8 (pt) 2002-01-17 2003-01-16 composição farmacêutica, que compreende valsartan e inibidor de nep ou seus sais
DE60315795T DE60315795T2 (de) 2002-01-17 2003-01-16 Pharmazeutische zusammensetzung enthaltend valsartan und nep-inhibitoren
NZ533968A NZ533968A (en) 2002-01-17 2003-01-16 Pharmaceutical compositions comprising valsartan and nep inhibitors
DK03704413T DK1467728T3 (da) 2002-01-17 2003-01-16 Farmaceutiske sammensætninger indeholdende valsartan og NEP-inhibitorer
JP2003559507A JP4820056B2 (ja) 2002-01-17 2003-01-16 バルサルタンおよびｎｅｐ阻害剤を含む医薬組成物
IL16266103A IL162661A0 (en) 2002-01-17 2003-01-16 Pharmaceutical compositions comprising valsartan and nep inhibitors
IL162661A IL162661A (en) 2002-01-17 2004-06-21 Pharmaceutical compositions comprising valsartan and nep inhibitors useful for treating hypertension or heart failure
ZA2004/05117A ZA200405117B (en) 2002-01-17 2004-06-28 Pharmaceutical compositions comprising valsartan and nep inhibitors
NO20043380A NO333191B1 (no) 2002-01-17 2004-08-13 Farmasoytiske sammensetning og kit som omfatter valsartan og spesifikke NEPinhibitorer.
CY20071101386T CY1106959T1 (el) 2002-01-17 2007-10-25 Φαρμακευτικες συνθεσεις που περιλαμβανουν βαλσαρτανη και αναστολεις nep
FR16C0019C FR16C0019I2 (fr) 2002-01-17 2016-05-17 Compositions pharmaceutiques a base de valsartan et d'inhibiteurs nep
BE2016C025C BE2016C025I2 (enIt.pdf) 2002-01-17 2016-05-18
NO2016009C NO2016009I2 (no) 2002-01-17 2016-05-18 Sakubitril/valsartan, inkludert farmasøytisk akseptable salter derav
LU93074C LU93074I2 (fr) 2002-01-17 2016-05-18 Sacubitril/valsartan, y compris les sels pharmaceutiquement acceptables de celui-ci
CY2016013C CY2016013I1 (el) 2002-01-17 2016-05-18 Φαρμακευτικες συνθεσεις που περιλαμβανουν βαλσαρτανη και αναστολεις nep
NL300811C NL300811I2 (enIt.pdf) 2002-01-17 2016-05-18

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