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"Novel Salts Of 1 H 1 Benzazepine 1 Acetic Acid, Their Preparation And Pharmaceutical Composition Comprising The Same"

Abstract: Novel water soluble amino acid salts of 1H-1-benzazepine-1-acetic acid, process of preparation of such novel salts and methods of using them are provided. Also provided are pharmaceutical compositions comprising such novel salts and method of using such compositions for the prophylaxis, amelioration and/or treatment of cardiovascular and other associated disorders which comprises the administration of an effective amount of such composition to a subject in need thereof. The novel salts of the present invention are obtained in highly pure solid form, possess appreciable aqueous solubility and good bioavailability, and can be easily formulated into any pharmaceutically acceptable dosage form such as solid oral, drinkable or injectable compositions.

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Patent Information

Application #
Filing Date
07 March 2006
Publication Number
21/2016
Publication Type
INA
Invention Field
PHARMACEUTICALS
Status
Email
Parent Application

Applicants

PANACEA BIOTEC LIMITED
B-1, EXTN. A/27 MOHAN CO-OPERATIVE, INDUSTRIAL ESTATE, MATHURA ROAD, NEW DELHI 110044

Inventors

1. JAIN, RAJESH
B-1, EXTN. A/27 MOHAN CO-OPERATIVE, INDUSTRIAL ESTATE, MATHURA ROAD, NEW DELHI 110044
2. JINDAL, KOUR CHAND
B-1, EXTN. A/27 MOHAN CO-OPERATIVE, INDUSTRIAL ESTATE, MATHURA ROAD, NEW DELHI 110044
3. SINGH, JASPAL
B-1, EXTN. A/27 MOHAN CO-OPERATIVE, INDUSTRIAL ESTATE, MATHURA ROAD, NEW DELHI 110044

Specification

FIELD OF THE INVENTION The present invention relates to novel water soluble amino acid salts of 1 H-1-benzazepine-1- acetic acid. process of preparation of such novel salts and methods of using them. The present invention also provides pharmaceutical compositions comprising the same and method of using 5 such novel compositions for the prophylaxis, amelioration and/or treatment of cardiovascular and other associated disorders which comprises the administration of an effective amount of such composition to a subject in need thereof. Preferably the 1 H-1-benzazepine-1-acetic acid is an endothelin conversion enzyme (ECE) inhibitor and/or neutral endopeptidase (NEP) inhibitor having the general formula (Formula-1) as stated below: 10 15 0 Formu1a-1 Wherein: N ' c- coo- H2 n R1 is a selected from the group consisting of(C1-C6) alkoxy, (C1-C6) alkyl, phenyl-(C1-C6)-alkyl 20 and phenyloxy-(CI-C6)-alkyl wherein the phenyl group may be substituted with (C1-C6)alkyl, (CI-C6) alkoxy or halogen, and/or naphtyl-(C 1-C6)-alkyl, R2 and R3 are both independently hydrogen or halogen, ~is a biolabile ester forming group, acid, amide or a substituted aryl or alkyl amide, M is a hydrogen or a metal ion, preferably a bivalent metal ion, and 25 nis1,2or3. 30 More preferably, the 1 H-1-benzazepine-1-acetic acid used in the present invention is (3S, 2'R)- 3-{ 1-[2'-( ethoxycarbonyl)-4 · -phenylbutyl]cyclopentane-1-carbonylamino}-2, 3, 4, 5-tetrahydro- 2-oxo-lH-1-benzazepine-1-acetic acid having Formula-H. Formula-II - 2 - ,I The novel salts of the present invention possess high solubility in water and are amenable into any pharmaceutically acceptable dosage form such as solid oral, drinkable or injectable compositions. 5 BACKGROUND OF THE INVENTION Cardiovascular disorders such as coronary artery disease (CAD) and congestive heart failure (CHF) are the leading cause of mortality in the developed world. The patients with CAD have several concomitant conditions. including hypertension, diabetes and hyperlipidemia. Cardiovascular disorder such as Angina pectoris is a severe constricting pain in the chest, often I 0 radiating from the precordium to the left shoulder and down the left arm. Often angina pectoris is due to ischaemia of the heart and is usually caused by coronary disease. The symptomatic management of angina pectoris involves the use of a number of drugs, frequently as a combination of two or more of the following classes: beta-blockers, nitrates and calcium channel blockers. Most, if not all, of these patients require therapy with a lipid-lowering agent as well. Hypertension 15 is a major risk factor for cardiovascular disease. Both systolic and diastolic blood pressure has been shown to be related to cardiovascular disease leading to morbidity and mortality. Hypertension frequently coexists with hyperlipidemia and both are considered to be major risk factors for developing cardiac disease. It would therefore be advantageous for patients to have a single therapy which treats both of these conditions. Atherosclerosis is a condition characterized by 20 irregularly distributed lipid deposits in the intima of arteries, including coronary, carotid and peripheral arteries. Many individuals are at an elevated risk of suffering serious to life-threatening cardiovascular events, such as myocardial infarction (heart attack), cardiac arrest, congestive heart failure, stroke, peripheral vascular disease and/or claudication. The risk factors are numerous and widespread throughout the world population. They include cigarette smoking, diabetes, 25 hypercholesterolemia (high serum cholesterol), hypertension, angina, systemic lupus erythematosus, prior heart attacks or strokes, hemodialysis, hyperhomocysteine levels, obesity, sedentary lifestyle, receiving an organ transplant, atherosclerosis, and others. Endothelin (ET) is a peptide which is composed of 21 amino acids that is synthesized and 30 released by the vascular endothelium. Endothelin is produced by enzymatic cleavage of a TrpVal bond in the precursor peptide big endothelin (Big ET). This cleavage is caused by an endothelin converting enzyme (ECE). Endothelin exists as three isoforms, ET -1, ET -2 and ET -3 (hereinafter, unless otherwise stated, 'endothelin' shall mean any or all of the isoforms of endothelin). Endothelin acts on two pharmacologically distinct subtypes of receptors, termed - 3 - I "' ET.sub.A and ET.sub.B that are expressed on a wide variety of vascular and non-vascular target cells, eliciting, for example. contraction and proliferation of vascular smooth muscle cells and release of nitric oxide from endothelial cells. Endothelin is associated with smooth muscle contraction which is involved in the pathogenesis of, inter alia, cardiovascular, cerebrovascular, 5 respiratory and renal pathophysiology. An agent which suppresses endothelin production, such as an endothelin converting enzyme (ECE) inhibitor, or which inhibits the binding of endothelin to an endothelin receptor, such as an endothelin receptor antagonist, antagonizes various physiological effects of endothelin and produces beneficial effects in a variety of therapeutic areas. Endothelin receptor antagonists and ECE inhibitors are therefore useful in treating a 10 variety of diseases affected by endothelin. A non-exhaustive list of such diseases includes chronic heart failure, myocardial infarction, cardiogenic shock, systemic and pulmonary hypertension, ischemia-repurfusion injury, atherosclerosis, coronary and systemic vasospastic disorders, cerebral vasospasm, and subarachnoid hemorrhage and the like. 15 Neutral Endopeptidase (NEP) is a cell surface enzyme that cleaves and inactivates neuropeptides. It is well established that the natriuretic peptide system is intimately involved in the control and regulation of blood pressure and plasma volume in the body. Natriuretic peptides can also have antimitogenic actions within the cardiovascular tree. Natriuretic peptides are degraded by the metallo peptidase neutral endopeptidase enzyme (NEP). Thus NEP inhibitors 20 primarily increase the levels of vasodilatory peptides including atrial natriuretic peptide and also increase the half-life of other vasodilator peptides, thereby decreasing vascular tone and lowering blood pressure. The compound (3S, 2 · R)-3-{ 1-[2 · -( ethoxycarbonyl)-4 · -phenylbutyl] cyclopentane-1-carbonylamino} -2, 3, 4, 5-tetrahydro-2-oxo-1 H-1-benzazepine-1-acetic acid (SLV -306) also known as Daglutril and represented by Formula-II is an orally active inhibitor of 25 neutral endopeptidase (NEP) and endothelin conversion enzyme (ECE). It is a Benzazepine-Nacetic acid derivative which contains an oxo group in alpha position to the nitrogen atom and are substituted in position 3 by a 1-( carboxyalkyl) cyclopentyl-carbonylamino radical, and have NEP-inhibitory effects on the heart, as described in Waldeck et al., U.S. Pat. No. 5,677,297. The benzazepine-N-acetic acid compounds used in the present invention are known from EP 30 0733642, EP 0830863, WO 00/48601 and WO 01/03699, and can be produced by the methods described in said U.S. Pat. No. 5,677,297. The compounds of Formula-1 and Formula-11, preferably Formula-11 as stated herein, are poorly bio-available drugs due to their poor solubility in the gastric fluid. Even when they are used in the -4- I form of salts and when they are dissolved in a buffer, it precipitates in the gastric fluid. The precipitate formed is very difficult to solubilize again, leading to a low overall bioavailability. EP0733642 is related to these compounds and their physiologically acceptable salts as such and to the use of the compound in heart insufficiency. EP0830863, W000/4860 I and WOO 1/03699 are 5 related to the use of the above compounds in the improvement of gastrointestinal blood flow, in the treatment of hypertension and in the treatment and prophylaxis of cardiac damages induced by adriamycin and comparable anti-cancer drugs, respectively. PCT publication no. W02004062692 discloses a formulation with enhanced bioavailability consisting of a thermodynamically stable liquid or semisolid solution of the poorly water-soluble biologically active substance having the 10 Formula-H. Compounds of Formula-1, particularly the compound having the Formula-11 are obtained as sticky paste-like substance which are very difficult to handle and also are insoluble in aqueous medium. The monovalent metal ionic salts such as sodium and potassium salt of the compound of Formula-11, although water soluble, are obtained as solid foam which are difficult to formulate and lack reproducibility relating to its release in vivo and in turn a variable and low 15 bioavailability. Other bivalent metal ions salts such as magnesium, calcium and zinc salts of the compound of Formula-11, although can be obtained in the powder form, have a comparatively low aqueous solubility in comparison to the monovalent metal ionic salts and thus have poor bioavailability. Hence there still exists a need to develop novel salts particularly of the compounds ofFormula-11 which are easy to handle, have an appreciable aqueous solubility and bioavailability, 20 and could be formulated into any pharmaceutically acceptable dosage form such as solid oral, drinkable or injectable compositions without difficulty. The present invention provides novel salts of lH-1-benzazepine-1-acetic acid which overcomes limitations of prior art. SUMMARY OF THE INVENTION 25 It is an objective of the present invention to provide novel amino acid salts of 1H-1-benzazepinel- acetic acid. 30 It is another objective of the present invention to provide novel amino acid salts ofthe compound . ofFormula-1 as stated herein. It is also another objective of the present invention to provide novel amino acid salts of the compound ofFormula-11 as stated herein. It is another objective of the present invention to provide novel salts of 1 H-1-benzazepine-1- 35 acetic acid, the compound of Formula-1 or the compound of Formula-11 as stated herein with an - 5 - I , organic basic amino acid or a neutral amino acid ester. It is another objective of present invention to provide novel salts of I H -I-benzazepine-1-acetic acid, the compound of Fonnula-1 or the compound of Formula-11 as stated herein with an organic 5 basic amino acid preferably selected from group comprising arginine, lysine and ornithine. IO It is another objective of present invention to provide novel salts of I H-I-benzazepine-1-acetic acid, the compound of Formula-! or the compound of Formula-II as stated herein with a neutral amino acid ester preferably selected from group comprising glycine, leucine and serine. It is another objective of the present invention to provide process of preparation of such novel amino acid salts of I H-1-benzazepine-1-acetic acid, the compound of Formula-I or the compound of Formula-11 as stated herein. 15 It is another objective of the present invention to provide pharmaceutical compositions comprising such novel amino acid salts of IH-I-benzazepine-1-acetic acid, the compound of Formula-I or the compound of Formula-II as stated herein. It is a further objective of the present invention to provide a method of using such novel salts or 20 pharmaceutical compositions comprising such novel salts which comprises administering to a subject in need thereof an effective amount of such novel salt or composition thereof. The novel amino acid salts of I H-I-benzazepine-I-acetic acid, the compound of Formula-I or the compound of Formula-11 are obtained in highly pure solid form; possess appreciable aqueous 25 solubility and good bioavailability; and can be formulated into any pharmaceutically acceptable dosage form such as solid oral, drinkable or injectable compositions. DETAILED DESCRIPTION OF THE INVENTION The present invention describes novel amino acid salts of I H -I-benzazepine-1-acetic acid 30 preferably novel amino acid salts of the compound of Formula-I more preferably novel amino acid salts of the compound of Formula-II as stated herein. In an embodiment of the present invention, the novel salts of I H-1-benzazepine-1-acetic acid or the compound of Formula-1 or the compound of Formula-11 as stated herein are formed with an 35 amino acid selected from but not limited to a group comprising organic basic amino acid or a neutral amino acid ester. - 6 - In an embodiment, the organic basic amino acid is selected from but not limited to a group comprising racemic arginine. lysine and/or ornithine or their stereoselective enantiomers such as L and/or R-Lysine, L and/or R-arginine and L and/or R-ornithine and the like, or mixtures thereof. Preferably the organic basic amino acid is L-lysine, L-arginine, L-ornithine or the like, 5 or mixtures thereof. In an embodiment of the present invention, the novel amino acid salts of 1 H-1-benzazepine-1- acetic acid or the compound of Formula-1 or the compound of Formula-11 as stated herein are highly pure and can be formulated into pharmaceutical compositions without substantial loss of I 0 chiral and/or chemical purity. In a further embodiment of the present invention, the novel amino acid salts of 1H-1- benzazepine-l-acetic acid or the compound of Formula-1 or the compound of Formula-11 as stated herein have solid state properties which permit easy handling and allow preparation of a 15 pharmaceutical composition with pharmaceutically acceptable excipients and preferably by using conventional methods and equipments. 20 25 30 In an embodiment, the novel salts of the compound having Formula-I is formed with L-arginine having the formula-III and L-lysine having the formula-IV. The novel salts with L-arginine and L-lysine have the formula-V and formula-VI respectively as stated below. Formula - III NH2 HN~C-OH 2 II 0 Formula- IV - 7- 5 10 15 0 Formula- V NH2 ,--cOOH.H,N~C -OH I II N 0 Formula- VI In another embodiment of the present invention is provided the novel salts of the compound of Formula-11 as stated herein with an organic basic amino acid such as arginine, lysine, or ornithine in a racemic form represented by Formula-VII, Formula-VIII and Formula-IX 20 respectively as stated below: 25 30 35 Formula- VII 0 NH2 ,--cooH.H,N~C-OH I II N 0 Formula- VIII - 8- 5 Formula- IX 10 In another embodiment of the present invention is provided novel salts of 1H-1-benzazepine-1- acetic acid, the compound of Formula-1 or the compound of Formula-11 as stated herein with a neutral amino acid ester preferably selected from the group comprising glycine, leucine and serine represented by Formula-X, Formula-XI and Formula-XII respectively as stated below: 15 20 25 30 35 0 fCOOH. H2N - CH2 - COOR N Formula- X 0

Documents

Application Documents

# Name Date
1 590-del-2006-abstract.pdf 2011-08-21
1 590-del-2006-form-5.pdf 2011-08-21
2 590-del-2006-claims.pdf 2011-08-21
2 590-del-2006-form-3.pdf 2011-08-21
3 590-del-2006-correspondence others.pdf 2011-08-21
3 590-del-2006-form-2.pdf 2011-08-21
4 590-del-2006-description (complete).pdf 2011-08-21
4 590-del-2006-form-1.pdf 2011-08-21
5 590-del-2006-drawings.pdf 2011-08-21
6 590-del-2006-description (complete).pdf 2011-08-21
6 590-del-2006-form-1.pdf 2011-08-21
7 590-del-2006-correspondence others.pdf 2011-08-21
7 590-del-2006-form-2.pdf 2011-08-21
8 590-del-2006-claims.pdf 2011-08-21
8 590-del-2006-form-3.pdf 2011-08-21
9 590-del-2006-abstract.pdf 2011-08-21
9 590-del-2006-form-5.pdf 2011-08-21