WO2007102171A2 - Nouveaux sels de l'acide 1h-1-benzazépine-1-acétique, préparation de ceux-ci et composition pharmaceutique comprenant ceux-ci - Google Patents

Nouveaux sels de l'acide 1h-1-benzazépine-1-acétique, préparation de ceux-ci et composition pharmaceutique comprenant ceux-ci Download PDF

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Publication number
WO2007102171A2
WO2007102171A2 PCT/IN2007/000084 IN2007000084W WO2007102171A2 WO 2007102171 A2 WO2007102171 A2 WO 2007102171A2 IN 2007000084 W IN2007000084 W IN 2007000084W WO 2007102171 A2 WO2007102171 A2 WO 2007102171A2
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WIPO (PCT)
Prior art keywords
salts
benzazepine
novel
acetic acid
amino acid
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PCT/IN2007/000084
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English (en)
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WO2007102171A3 (fr
Inventor
Rajesh Jain
Kour Chand Jindal
Jaspal Singh
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Panacea Biotec Ltd
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Publication of WO2007102171A2 publication Critical patent/WO2007102171A2/fr
Publication of WO2007102171A3 publication Critical patent/WO2007102171A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines

Definitions

  • the present invention relates to 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.
  • the present invention also provides pharmaceutical compositions comprising the same and method of using 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.
  • the 1 H- 1-benzazepine-l -acetic acid is an endothelin conversion enzyme (ECE) inhibitor and/or neutral endopeptidase (NEP) inhibitor having the general formula (Formula- 1) as stated below:
  • R] is a selected from the group consisting Of (Ci-C 6 ) alkoxy, (Ci-C 6 ) alkyl, phenyl-(C r
  • R 2 and R 3 are both independently hydrogen or halogen
  • R 4 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 n is 1, 2 or 3.
  • the IH- 1-benzazepine-l -acetic acid used in the present invention is (3S, 2"R)-3- ⁇ l-[2 ⁇ -(ethoxycarbonyl)-4"-phenylbutyl]cyclopentane-l-carbonylamino ⁇ -2, 3, 4, 5-tetrahydro-2-oxo- I H- 1-benzazepine-l -acetic acid having Formula-II.
  • 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.
  • Cardiovascular disorders such as coronary artery disease (CAD) and congestive heart failure (CHF) are the leading cause of mortality in the developed world.
  • CAD coronary artery disease
  • CHF congestive heart failure
  • 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 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.
  • Atherosclerosis is a condition characterized by irregularly distributed lipid deposits in the intima of arteries, including coronary, carotid and peripheral arteries.
  • 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, 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 is a peptide which is composed of 21 amino acids that is synthesized and released by the vascular endothelium. Endothelin is produced by enzymatic cleavage of a Trp-Val 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-I , 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 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, 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.
  • ECE endothelin converting enzyme
  • Endothelin receptor antagonists and ECE inhibitors are therefore useful in treating a 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.
  • Neutral Endopeptidase 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 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.
  • NEP inhibitors 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.
  • SLV-306 S-tetrahydro ⁇ -oxo-lH-l-benzazepine-l-acetic acid
  • NEP neutral endopeptidase
  • ECE endothelin conversion enzyme
  • Benzazepine-N-acetic 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 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-I and Formula-II are poorly bio-available drugs due to their poor solubility in the gastric fluid. Even when they are used in the 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, WO00/48601 and WO01/03699 are 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. WO2004062692 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 Formula-II.
  • Compounds of Formula-I, particularly the compound having the Formula-II 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-II, 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 bioavailability.
  • Other bivalent metal ions salts such as magnesium, calcium and zinc salts of the compound of Formula-II, 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.
  • novel salts particularly of the compounds of Formula-II which are easy to handle, have an appreciable aqueous solubility and bioavailability, 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 1H-1- benzazepine-1 -acetic acid which overcomes limitations of prior art.
  • novel amino acid salts of IH- 1-benzazepine-l -acetic acid, the compound of Formula-I or the compound of Formula-II are obtained in highly pure solid form; possess appreciable aqueous solubility and good bioavailability; and can be formulated into any pharmaceutically acceptable dosage form such as solid oral, drinkable or injectable compositions.
  • the present invention describes novel amino acid salts of IH- 1-benzazepine-l -acetic acid 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.
  • the novel salts of IH- 1-benzazepine-l - acetic acid or the compound of Formula-I or the compound of Formula-II as stated herein are formed with an amino acid selected from but not limited to a group comprising organic basic amino acid or a neutral amino acid ester.
  • 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.
  • the organic basic amino acid is L-lysine, L- arginine, L-ornithine or the like, or mixtures thereof.
  • the novel amino acid salts of IH- 1 - benzazepine-1 -acetic acid or the compound of Formula-I or the compound of Formula- II as stated herein are highly pure and can be formulated into pharmaceutical compositions without substantial loss of chiral and/or chemical purity.
  • the novel amino acid salts of 1H-1- benzazepine-1 -acetic acid or the compound of Formula-I or the compound of Formula- II as stated herein have solid state properties which permit easy handling and allow preparation of a pharmaceutical composition with pharmaceutically acceptable excipients and preferably by using conventional methods and equipments.
  • novel salts of the compound having Formula-I is formed with L- arginine having the formula-HI and L-lysine having the formula-IV.
  • novel salts with L-arginirie and L-lysine have the form u Ia-V and formula-VI respectively as stated below.
  • novel salts of the compound of Formula-II 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 respectively as stated below:
  • R is selected from the group of lower alkyl containing Ci-C 6 and lower aromatic group.
  • novel salts of the present invention possess improved stability in aqueous solution in comparison to the alkali metal salts, for example, sodium and potassium salts.
  • the present invention provide process of preparation of such novel salts of IH-I -benzazepine-1 -acetic acid, the compound of Formula-I or the compound of Formula-II as stated herein.
  • the salts of the present invention can be prepared in a manner known per se by reacting (3S, 2"R)-3- ⁇ l-[2"-(ethoxycarbonyl)-4'- phenylbutyl]cyclopentane-l-carbonylamino ⁇ -2, 3, 4, 5-tetrahydro-2-oxo-lH-l- benzazepine-1 -acetic acid with a substantially equimolar amount of a compound of amino acid in an aqueous solution or in a suitable protic or aprotic organic solvent such as an aliphatic or cycloaliphatic ether, for example dioxane or a lower alcohol, such as methanol or ethanol at a temperature of from 0 0 C to the boiling temperature of the solvent.
  • the salts are recovered by standard methods such as filtration if they are insoluble in the original medium or, if they are soluble in that medium, the salt is precipitated by evaporation of the solvent or by addition of a non-
  • a process for preparation of pharmaceutical compositions comprising such novel amino acid salts(s) particularly the salts of 1 H- 1-benzazepine-l -acetic acid, the compound of Formula-I or the compound of Formula-II as stated herein along with one or more pharmaceutically acceptable excipient(s).
  • the process comprises treating the novel amino acid salt(s) of the present invention with one or more pharmaceutically acceptable excipient(s).
  • the novel amino acid salts of the present invention may be administered as an aqueous solution for parenteral use such as for an LV. (intravenous) injection or an oily suspension for intra-muscular injection or can be formulated into a drinkable aqueous or hydro-alcoholic solution.
  • the novel amino acid salts of the present invention can be formulated into suitable pharmaceutically acceptable dosage forms, such as solid, semisolid or liquid dosage forms, for e.g. tablets, mini-tablets such as such as layered or monolithic mini-tablets, capsules, suppositories, patches, topical gels or sprays, or the like.
  • suitable pharmaceutically acceptable dosage forms such as solid, semisolid or liquid dosage forms, for e.g. tablets, mini-tablets such as such as layered or monolithic mini-tablets, capsules, suppositories, patches, topical gels or sprays, or the like.
  • the solid dosage forms can be produced by known methods such as direct compression, granulation, compaction, extrusion, molding, or the like or mixtures thereof.
  • the oral composition is prepared by direct compression or compaction granulation.
  • the composition prepared by granulation technique is either by aqueous or non-aqueous technique or melt granulation technique.
  • the non-aqueous ' solvent used is selected from a group comprising dehydrated alcohol, isopropyl alcohol, methylene chloride or acetone.
  • the compositions of the present invention are in the form of granules, beads or pellets that may be further compacted, compressed, or moulded, or made into capsules.
  • the compositions of the present invention are formulated as solid oral dosage form compositions possessing good bioavailability comprising one or more alkaline substance and/or surfactants.
  • the solid oral dosage form composition preferably as capsule is formulated as SMEDDS.
  • Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise excipients such as wetting agents, emulsifying and suspending agents, or sweetening, flavoring, or perfuming agents.
  • Pharmaceutical compositions suitable for buccal or sublingual administration include lozenges comprising a compound of the present invention in a flavored base, usually sucrose, and acacia or tragacanth, and pastilles comprising the drugs in an inert base such as gelatin and glycerin or sucrose and acacia. The compositions may be coated with a functional coating.
  • the coating composition comprises a part of the active agent(s) and/or the composition comprises excipients which aid in controlling the rate of release of the active agent(s) and/or the composition comprises additionally another active agent which is different from the active agent present in the core composition.
  • the composition may be formulated as layered tablets comprising at least two layers wherein the same active agent is present in all the layers exhibiting different release profiles or one or more additional active agent(s) is present in the layers exhibiting different release profiles.
  • the coating composition employed in the present invention may be an aqueous, non-aqueous or a hydro-alcoholic system.
  • the solvents used to prepare a non-aqueous coating composition is selected from but not limited to a group comprising dehydrated alcohol, isopropyl alcohol, methylene chloride, acetone or any other solvent known to the art for such use, or mixtures thereof.
  • compositions are selected from but not limited to diluents, disintegrants, binders, fillers, bulking agents, anti-adherents, anti-oxidants, buffering agents, colorants, flavoring agents, coating agents, plasticizers, organic solvents, stabilizers, preservatives, lubricants, glidants, chelating agents, and the like known to the art used either alone or in combination thereof.
  • the filler(s) used in the present invention is selected from but not limited to a group comprising lactose, mannitol, sorbitol, starch, microcrystalline cellulose, xylitol, fructose, sucrose, dextrose, dicalcium phosphate, calcium sulphate and the like or mixtures thereof.
  • the disintegrants used in the present invention include but not limited to starch or its derivatives, partially pregelatinized maize starch, croscarmellose sodium, sodium starch glycollate, and the like used either alone or in combination thereof.
  • the lubricants used in the present invention include but not limited to talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil and the like used either alone or in combination thereof.
  • the tablets may be coated with a material such as glyceryl monostearate, glyceryl distearate, cellulose acetate phthalate, hydroxypropylcellulose phthalate, polyvinylacetate phthalate, methylmethacrylate polymer, a polymer mixture such as Eudragit®, cellulosic polymers, carbomers, zein, wax or similar material, or any other dissolvable coat, to delay absorption in the gastrointestinal tract.
  • Capsules for oral use include hard gelatin capsules in which the components are mixed with a solid diluent or soft gelatin capsules wherein the fill material exist as aqueous or hydroalcoholic or oily systems.
  • compositions according to the invention which comprises the novel salts are intended for enteral, such as oral, and also rectal and parenteral administration to a warm blooded mammal, especially human and comprise the novel salts as the pharmacological active ingredient on its own or together with a pharmaceutically acceptably carrier. Additionally other pharmaceutically active agent(s) may be used in combination with the novel salts of the present invention.
  • the amount of the novel salts of the present invention to be incorporated into the pharmaceutical composition of the present invention can vary over a wide range depending on known factors such as, for example, the disorder to be treated, the severity of the disorder, the patient's body weight, the dosage form, the chosen route of administration and the number of administration per day.
  • compositions of the present invention can be manufactured by techniques that are well-known to the art and comprise operations such as mixing, granulating, compressing, dissolving, sterilizing and the like or combinations thereof.
  • the pharmaceutical composition can be prepared by mixing the novel salts of the present invention with other drug(s) or with pharmaceutically acceptable carrier(s).
  • acidic hydrogen atom of the carboxylic group of 1 H- 1 -benzazepine-l -acetic acid can be interacted with amino group of particularly basic amino acids, preferably corresponding to formula-Ill and formula-IV, and the product and/or ionic complex or said salt thus obtained is stable in solidified form.
  • the salts are water soluble even at the pH range between about 4 to about 8 and hence are well tolerated at the gastrointestinal level. Furthermore, they do not have any unpleasant taste and/or odor.
  • the present invention provides method of using such novel amino acid salts or pharmaceutical compositions comprising such novel amino acid salts which comprises administering to a subject in need thereof an effective amount of such novel salt or composition thereof.
  • the novel salts may be used for treatment or prophylaxis of cardiovascular disorders, for the promotion of blood circulation in the mesenteric vascular system in humans and is suitable for the treatment and/or prophylaxis of gastrointestinal disorders associated with reduced gastrointestinal blood circulation due to a wide range of causes, in particular for the treatment and/or prophylaxis of abdominal angina.
  • the present invention further relates to a pharmaceutical composition for the prevention or treatment of cardiovascular diseases/disorders such as hypertension, heart failure, angina, gastrointestinal disorders, and the like, comprising the novel salts, their solvate, hydrate or a mixture thereof with pharmaceutically acceptable carrier(s)/excipient(s).
  • novel salts of the present invention can be formulated in combination with other drugs which preferably includes antihypertensives, cardiovascular drugs, diuretics, antihyperlipidemics, antidiabetics, and/or other drugs which are known to the art for the treatment of hypertension or other cardiovascular disorders or other associated disorders such as coronary artery disease, congestive heart failure, angina, atherosclerosis, hyperlipidemia, diabetes, myocardial infarction, cardiogenic shock, systemic and pulmonary hypertension, ischemia-reperfusion injury, coronary and systemic vasospastic disorders, cerebral vasospasm, and subarachnoid hemorrhage, hyperglycemia, metabolic disorders, renal disorders, neurodegenerative disorders or the like.
  • other drugs which preferably includes antihypertensives, cardiovascular drugs, diuretics, antihyperlipidemics, antidiabetics, and/or other drugs which are known to the art for the treatment of hypertension or other cardiovascular disorders or other associated disorders such as coronary artery disease, conges
  • the present invention provides use of the novel salts for the preparation of a pharmaceutical composition for the treatment/prophylaxis of cardiovascular diseases/disorders and/or for the promotion of blood circulation in the mesenteric vascular system and/or for the treatment and/or prophylaxis of gastrointestinal disorders which are associated with reduced gastrointestinal blood circulation and/or for the treatment/prophylaxis of abdominal angina.
  • the mixture of novel salts of the present invention can be in the form of an associate or a complex or inclusion compounds with the pharmaceutically acceptable excipient(s).
  • a mixture of the novel salts and povidone can be in the form of an associate of the novel salts with povidone
  • a mixture of novel salts and phospholipid can be in the form of a complex
  • a mixture of the salts with cyclodextrin can be in the form of an inclusion of the novel salts in cyclodextrin.
  • Yet another object of the present invention is to provide a pharmaceutically acceptable salt of compound, corresponding to formula-I and formula-II, which is suitable as medicament for larger mammals, especially humans, for in the treatment of heart failure and for promoting diuresis/natriuresis, especially in patients suffering from heart failure, for the improvement of gastrointestinal blood flow, in the treatment of hypertension and in the treatment and prophylaxis of cardiac damage induced by adriamycin and comparable anti-cancer drugs.
  • the said salts of the present invention can be used in medicinal forms which can be administered parenterally, especially through the IV route, orally or as suppository.
  • Yet another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising the said physiologically and pharmaceutically acceptable water soluble novel salts of compound, corresponding to formula-I or formula-II, which is suitable and useful for the prevention or treatment of heart failure and for promoting diuresis/natriuresis, especially in the patients suffering from heart failure, for the improvement of gastrointestinal blood flow, in the treatment of hypertension and in the treatment of prophylaxis of cardiac damage induced by adriamycin and comparable anti-cancer drugs. 5
  • a comparative pharmacokinetic study has been carried out to study the comparative pharmacokinetic profile of different salts of (3S, 2 * R)-3- ⁇ l-
  • mice Female Wistar rats (160-180 g) were selected for the study comprising 5 animals in each group for a period of 6 hours with sampling intervals of 0, 15, 30, 60, 90, 120, 180, 240 and 360 minutes. 17.63 mg of calcium salt of (3S, 2 ⁇ R)-3- ⁇ l-[T-
  • Table-1 Comparative pharmacokinetic profile Time Cone, of calcium salt of Cone, of L-arginine salt of
  • the result shows that the arginine salt of the compound of Formula-II showed a significantly higher drug concentration in the blood thus indicating a comparatively higher bioavailability compared to the calcium salt of the compound of Formula-II.
  • the peak blood concentration (C max ) of the arginine salt is significantly higher (35450.00 ng/ml) in comparison to the peak blood concentration (C ma ⁇ ) of the calcium salt (10163.33 ng/ml).
  • Example 1 Preparation of the L-arginine salt of (3S, 2'R)-3- ⁇ l -[2'-(Ethoxycarbonyl)- 4"-phenylbutyl]cyclopentane-l-carbonylamino ⁇ -2, 3, 4, 5-tetrahydro-2-oxo-lH-l- benzazepine-1 -acetic acid
  • Example 2 Preparation of the L-lysine salt of (3S, 2 v R)-3- ⁇ l-[T-(Ethoxycarbonyl)-4 ⁇ - phenylbutyl] cyclopentane-l-carbonylamino ⁇ -2, 3, 4, 5-tetrahydro-2-oxo-lH-l- benzazepine-1 -acetic acid
  • the L-lysine salt of (3S, 2 ⁇ )-3- ⁇ l-[2"- (Ethoxycarbonyl)-4'-phenylbutyl] cyclopentane-l-carbonylamino ⁇ , 3, 4, 5- tetrahydro-2-oxo- IH- 1-benzazepine-l -acetic acid was obtained as a white solid.
  • the morphological purity of the salt formed was confirmed by powder X-ray diffractogram of the solid ( Figure 2).
  • compositions comprising the novel salts of the present invention
  • quantity stated for unit dosage form is the equivalent dose of the compound of Formula-II.
  • the tablet/capsule compositions disclosed herein may optionally be coated by film forming polymer or enteric polymer known to the art.
  • step (i) Compound of Formula-V, Sodium carbonate, Sodium bicarbonate, Microcrystalline cellulose and Croscarmellose sodium were sifted through #40 sieve and were mixed together.
  • step (i) The blend of step (i) was granulated by using lsopropyl alcohol, iii) The wet mass of step (ii) was sifted through #24 sieve and granules obtained were dried.
  • step (ii) Hydrogenated castor oil, Purified talc and Colloidal silicon dioxide were sifted through #40 sieve and were mixed together, v) Granules of step (iii) were mixed with the mixture of step (iv).
  • the material of step (v) was compressed into tablets by using a tablet compression machine.
  • step (i) Compound of Formula-X, Magnesium carbonate, Dicalcium phosphate, Sodium starch glycolate and Magnesium stearate were sifted through #40 sieve and were mixed together, ii) The blend of step (i) was compacted and the compacts were passed through #30 sieve. iii) The granules of step (ii) were lubricated with #60 sieve passed Magnesium stearate. iv) The material of step (iii) was filled into hard gelatin capsule.
  • step (iii) The mixture in step (ii) was mixed with part of Sodium stearyl fumarate and was roller compacted to obtain compacts, iv) The compacts in step (iii) were broken into granules which were passed through
  • step (iv) The granules in step (iv) were mixed with the remaining part of Sodium stearyl fumarate. vi) The granules in step (v) were compressed to obtain tablets.
  • Example-6 Injection S. No. Ingredient Quantity/ 100 ml
  • step (iv) Specified quantity (10.0 ml) of NaOH 4.0% solution was added to the step (iv) with continuous stirring to form a homogeneous solution.
  • step (v) The solution of step (v) was mixed for about 30 minutes by continuous stirring, vii) Remaining quantity of Glycine Buffer pH 11.3 was added to make up volume to 100 ml. viii) The solution of step (vii) was mixed for about 10 minutes by continuous stirring. ix) Final pH was adjusted to 10.0 by adding NaOH 4.0% w/v solution. x) The solution of step (ix) was mixed for about 10 minutes by continuous stirring.

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Abstract

L'invention concerne de nouveaux sels d'acides aminés solubles dans l'eau de l'acide 1H-1-benzazépine-1-acétique, un procédé pour la préparation de tels nouveaux sels et des procédés d'utilisation de ceux-ci. L'invention concerne également des compositions pharmaceutiques comprenant de tels nouveaux sels et un procédé d'utilisation de telles compositions pour la prophylaxie, l'amélioration et/ou le traitement de troubles cardiovasculaires et d'autres troubles associés, lequel consiste à administrer une quantité efficace d'une telle composition à un sujet qui en a besoin. Les nouveaux sels de la présente invention sont obtenus sous une forme solide extrêmement pure, possèdent une solubilité dans l'eau appréciable et une bonne biodisponibilité et peuvent être facilement formulés en n'importe quelle forme de dosage acceptable du point de vue pharmaceutique telle que des compositions solides à usage oral, buvables ou injectables.
PCT/IN2007/000084 2006-03-07 2007-03-05 Nouveaux sels de l'acide 1h-1-benzazépine-1-acétique, préparation de ceux-ci et composition pharmaceutique comprenant ceux-ci WO2007102171A2 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009022169A1 (fr) * 2007-08-10 2009-02-19 Generics [Uk] Limited Composition de valsartan solide
EP2462922A1 (fr) * 2010-12-10 2012-06-13 Bioprojet Nouvelle forme d'administration pour inhibiteurs de l'enképhalinase

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5677297A (en) * 1995-03-23 1997-10-14 Solvay Pharmaceuticals Gmbh Benzazepine-, benzoxazepine- and benzothiazepine-n-acetic acid derivatives, process for their preparation and pharmaceutical compositions containing them
US5783573A (en) * 1996-09-18 1998-07-21 Solvay Pharmaceuticals Gmbh Pharmaceuticals which promote gastrointestinal blood circulation
US5952327A (en) * 1997-11-12 1999-09-14 Solvay Pharmaceuticals Gmbh Phosphonic acid-substituted benzazepinone-n-acetic acid derivatives process for their preparation and pharmaceutical compositions comprising them
WO2001003699A1 (fr) * 1999-07-13 2001-01-18 Solvay Pharmaceuticals Gmbh Medicaments a effet protecteur contre des substances toxiques oxydativement et en particulier contre des substances cardiotoxiques

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5677297A (en) * 1995-03-23 1997-10-14 Solvay Pharmaceuticals Gmbh Benzazepine-, benzoxazepine- and benzothiazepine-n-acetic acid derivatives, process for their preparation and pharmaceutical compositions containing them
US5783573A (en) * 1996-09-18 1998-07-21 Solvay Pharmaceuticals Gmbh Pharmaceuticals which promote gastrointestinal blood circulation
US5952327A (en) * 1997-11-12 1999-09-14 Solvay Pharmaceuticals Gmbh Phosphonic acid-substituted benzazepinone-n-acetic acid derivatives process for their preparation and pharmaceutical compositions comprising them
WO2001003699A1 (fr) * 1999-07-13 2001-01-18 Solvay Pharmaceuticals Gmbh Medicaments a effet protecteur contre des substances toxiques oxydativement et en particulier contre des substances cardiotoxiques
US20030040512A1 (en) * 1999-07-13 2003-02-27 Zsuzsanna Rozsa Pharmaceutical composition with protective action against oxidative/toxic substances, especially cardiotoxic substances

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009022169A1 (fr) * 2007-08-10 2009-02-19 Generics [Uk] Limited Composition de valsartan solide
AU2008288296B2 (en) * 2007-08-10 2014-01-16 Generics [Uk] Limited Solid valsartan composition
EP2462922A1 (fr) * 2010-12-10 2012-06-13 Bioprojet Nouvelle forme d'administration pour inhibiteurs de l'enképhalinase
WO2012076691A1 (fr) * 2010-12-10 2012-06-14 Bioprojet Nouvelle forme d'administration d'un inhibiteur de l'enképhalinase
JP2014503512A (ja) * 2010-12-10 2014-02-13 ビオプロジェ エンケファリナーゼ阻害剤の新規投与形態
EA022730B1 (ru) * 2010-12-10 2016-02-29 Биопроже Новая форма введения ингибитора энкефалиназы
AP3787A (en) * 2010-12-10 2016-08-31 Bioprojet Soc Civ New form of administration of enkephalinase inhibitor
US9439853B2 (en) 2010-12-10 2016-09-13 Bioprojet Form of administration of enkephalinase inhibitor

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