FIELD OF THE INVENTION
The present invention relates to novel nitrosated and nitrosylated derivatives of 1H-1-benzazepine-1-acetic acid, and their pharmaceutically acceptable salts, esters, amides, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof; process of preparation of such novel derivatives 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. Preferably the IH-l-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:
Formula-1
(Formula- Removed)Where in:
RI is selected from the group consisting of (C1-C6) alkoxy, (C1-C6) alkyl which may be substituted by a (C1-C6) alkoxy, phenyl-( C1-C6)-alkyl and phenyloxy-( C1-C6)-alkyl wherein the phenyl group may be substituted with (C1-C6) alkyl, (C1-C6) alkoxy or halogen, and/or naphthyl-( C1-C6)-alkyl,
R2 and R^ are both independently hydrogen or halogen,
R4 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.
More preferably, the IH-l-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-IH-l-benzazepine-l-acetic acid having Formula-II

(Formula- Removed)
FormuIa-II
The novel derivatives of the present invention have the general formula indicated as Formula-Ill

Formula-Ill

Wherein R is
Formula-IV

(Formula- Removed)
Formula-V
(Formula- Removed)
Formula-VI

Formula-VII

(Formula- Removed)
Formula-VII



Formula-XII
Formula-XIV
FormuIa-XVI

Formula-XVIII
Where X is O, S or N
Y is nitric oxide releasing moiety selected from -ONC^, -NO, -ONO, -SNOj, -SONCh and like
The novel derivatives of the present invention preferably possess appreciable aqueous solubility and/or absorption and/or permeability and/or lower incidence of side effects, and can be easily formulated as oral, parenteral or topical compositions.
BACKGROUND OF THE INVENTION
Nitric oxide is an inorganic free radical, which is a remarkably versatile biological messenger. Endogenous NO is synthesized from the amino acid L-arginine by three isoforms of the enzyme NO synthase (NOS). In the healthy cardiovascular system, NO synthesized by NO synthase found in endothelial cells (eNOS) in the endothelium was originally described as a potent vasodilator but it is now also recognized to protect against thrombosis and atherogenesis through inhibition of monocyte and platelet adhesion, platelet aggregation and smooth muscle cell
proliferation. Dysfunction in NO synthesis has been implicated as a major contributory factor in development of a wide range of cardiovascular diseases including hypertension, coronary artery disease and heart failure. The detrimental effects of reduced NO synthesis, as a result of enzyme dysfunction or endothelial damage, are often exacerbated in cardiovascular disease by increased generation of oxygen free radicals which rapidly inactivate NO forming cytotoxic peroxynitrite and, ultimately, inactive nitrate. Delivery of supplementary NO to areas of the vasculature where the protective effects of endogenous NO have been lost is an attractive therapeutic option. NO stimulates the guanylate cyclase enzyme in vascular smooth muscle cells resulting in increased levels of cyclic GMP. This leads to dephosphorylation of myosin light chain, which results in relaxation of smooth muscles (Murad 1986). NO is known to be involved in a number of bio-regulatory processes like, vasodilatation, platelet deaggregation, vascular smooth muscle proliferation, and the like. 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 radiating from the precordium to the left shoulder and down the left arm. Hypertension is a major risk factor for cardiovascular disease. Atherosclerosis is a condition characterized by irregularly distributed lipid deposits in the intima of arteries, including coronary, carotid and peripheral arteries. It has been demonstrated in animal model that in cardiovascular disorders such as atherosclerosis, the cholesterol content of membranes associated with vascular smooth muscle and macrophage foam cells becomes elevated, resulting in the formation of discrete domains which serve as nucleating sites for the formation of extracellular crystals. Preventing crystal formation is an important goal as cholesterol in this state is practically inert and does not respond well to pharmacologic interventions that promote lesion regression. In addition, the normal production of NO by the endothelium is critical for maintaining vascular function. During atherosclerosis, however, endothelial dysfunction effects a significant reduction in NO production, resulting in increased monocyte and LDL infiltration, loss of smooth muscle cell function and abnormal proliferation, increased oxidative stress, and increased platelet aggregation. Pharmacologic interventions that restore endothelial function and NO metabolism have demonstrated benefit in the treatment of various cardiovascular disorders, including coronary artery disease. 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. There is a
need for a safe and convenient pharmaceutical formulation that would effectively reduce the risk
of incurring a cardiovascular event in individuals who have these risk factors.
Endothelin (ET) 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-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 £TA and ETe 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. 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 (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 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-{l-[2'-(Ethoxycarbonyl)-4'-phenylbutyl] cyclopentane-l-carbonylamino}-2, 3, 4, 5-tetrahydro-2-oxo-lH-l-benzazepine-l-acetic acid (SLV-306) also known as Daglutril and represented by Formula-I is an orally active inhibitor of neutral endopeptidase (NEP) and endothelin conversion enzyme (ECE). It is a Benzazepine-N-
acetic acid derivative which contains an oxo group at alpha position to the nitrogen atom and are substituted in position 3 by a l-(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-1 and Formula-11, preferably Formula-II as stated herein, 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. EP 0733642 is related to these compounds and their physiologically acceptable salts as such and to the use of the compound in heart insufficiency. EP 0830863, WOOO/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. WO2005018561 relates to novel nitrosated and/or nitrosylated cardiovascular compounds or pharmaceutically acceptable salts thereof, and novel compositions comprising at least one nitrosated and/or nitrosylated cardiovascular compound, and, optionally, at least one nitric oxide donor and/or at least one therapeutic agent. PCT publication No. WO2005107384 relates to methods for treating blood disorders or for treating the symptoms and/or complications associated with blood disorders by administering a therapeutically effective amount of at least one nitric oxide donor compound and optionally at least one antioxidant, or a pharmaceutically acceptable salt thereof, and/or at least one therapeutic agent. PCT publication No. WO200560603 relates to novel pyruvate compounds comprising at least one nitric oxide releasing group and pharmaceutically acceptable salts thereof, and novel compositions comprising at least one pyruvate compound comprising at least one nitric oxide releasing group and optionally at least one nitric oxide donor and/or at least one therapeutic agent. PCT publication No. WO200523183 relates to novel nitrosated and/or nitrosylated diuretic compounds or pharmaceutically acceptable salts thereof, and novel compositions comprising at least one nitrosated and/or nitrosylated diuretic compound, and, optionally, at least one nitric oxide donor and/or at least one therapeutic agent.
The compounds administered for the treatment of cardiovascular diseases and diseases resulting from oxidative/or endothelial dysfunction often result in toxic, chronic and/or debilitating side effects. None of the prior arts describes specifically nitrosated and/or nitrosylated derivatives particularly derivatives of the compound of formula-1 or formula-II as described herein which have a substantially improved aqueous solubility and/or absorption and/or permeability and/or bioavailability and/or improved efficacy and/or low toxicity and which can easily be formulated into desired pharmaceutical compositions that are effective and safe. Hence, there still exists a need for developing novel nitrosated and/or nitrosylated derivatives with such aforementioned desirable properties, which the present invention provides.
SUMMARY OF THE INVENTION
It is an objective of the present invention to provide novel nitrosated and nitrosylated derivatives of IH-l-benzazepine-l-acetic acid of Formula-1 as stated herein, and their pharmaceutically acceptable salts, esters, amides, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof.
It is an objective of the present invention to provide novel nitrosated and nitrosylated derivatives of (3S, 2'R)-3-{l-[2'-(ethoxycarbonyl)-4'-phenylbutyl]cyclopentane-l-carbonylamino}-2, 3, 4, 5-tetrahydro-2-oxo-lH-l-benzazepine-l-acetic acid of formula-I as stated herein and pharmaceutically acceptable salts, esters, amides, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof, wherein the nitrosated and nitrosylated derivatives are substituted with at least one NO and/or NO2 groups.
It is also another objective of the present invention to provide novel nitrosated and nitrosylated derivatives of the compound of Formula-II as stated herein.
It is also an objective of the present invention to provide process for the preparation of novel nitrosated and nitrosylated derivatives of IH-l-benzazepine-l-acetic acid, the compound of Formula-I or the compound of Formula-II as stated herein.
It is another objective of the present invention to provide pharmaceutical compositions comprising such novel nitrosated and nitrosylated derivatives of IH-l-benzazepine-l-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 derivatives or their pharmaceutically acceptable salts, esters, amides, polymorphs, solvates,
hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof or pharmaceutical compositions comprising such novel derivatives or their pharmaceutically acceptable salts, esters, amides, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof which comprises administering to a subject in need thereof an effective amount
of such novel derivatives or composition thereof.
The novel derivatives of IH-l-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/or absorption and/or permeability and can be easily formulated as oral, parenteral or topical composition.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides novel nitrosated and nitrosylated derivatives of 1H-1-benzazepine-1-acetic acid of Formula-I as stated herein, and their pharmaceutically acceptable salts, esters, amides, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof.
In an embodiment, the present invention provides novel nitrosated and nitrosylated derivatives of (3S, 2'R)-3-{l-[2'-(ethoxycarbonyl)-4'-phenylbutyl] cyclopentane-l-carbonylamino}-2, 3, 4, 5-tetrahydro-2-oxo-lH-l-benzazepine-l -acetic acid of Formula-I as stated herein and pharmaceutically acceptable salts, esters, amides, polymorphs, solvates, hydrates, analogues, enantiomers. tautomeric forms or mixtures thereof, wherein the nitrosated and nitrosylated derivatives are substituted with at least one NO and/or NO2 groups.
In an embodiment, the present invention provides novel derivatives of the compound of Formula-II as stated herein.

Formula-II

In another embodiment, the novel nitrosated and nitrosylated derivatives of the present invention are able to release nitric oxide and act as Neutral Endopeptidase (NEP) inhibitor as well as
elevate endogenous level of endothelium derived relaxing factor, and stimulate endogenous synthesis of nitric oxide.
In the embodiment of the present invention, the novel nitrosated and nitrosylated derivatives are shown as the Formula-Ill

Wherein R is

Formula-Ill
Formula-
Formula-V
Formula-VI

Formula-VII



Formula-VIII
FormuIa-IX
ormula-XI
Formula-XII
Formula-XIII
Formula-XIV
Formula-XV
Formula-XVI

Formula-XVIII
Where X is O, S or N
Y is nitric oxide releasing moiety selected from -ONO2, -NO, -ONO, -SNO2, -SONO2and like
n = Ci - Cg
In an embodiment of the present invention, the novel nitrosated and nitrosylated derivatives of (3S, 2'R)-3-{l-[2'-(ethoxycarbonyl)-4'-phenylbutyl]cyclopentane-l-carbonylamino}-2,3,4,5-tetrahydro-2-oxo-lH-l-benzazepine-l -acetic acid act as potent NEP inhibitor. In another embodiment, the compounds of the present invention act as potent nitric oxide releasing NEP inhibitor.
In an embodiment of the present invention, processes are provided for preparing nitrosated and nitrosylated derivatives preferably as prodrugs of (3S, 2'R)-3-{l-[2'-(ethoxycarbonyl)-4'-phenylbutyl]cyclopentane-l-carbonylamino}-2, 3, 4, 5-tetrahydro-2-oxo-lH-l-benzazepine-l-acetic acid of Formula-11 as described herein.
In yet another embodiment of the present invention, the process of preparation of the novel nitrosated and nitrosylated derivatives of IH-l-benzazepine-l-acetic acid or the compound of Formula-I or the compound of Formula-II as stated herein are provided as synthetic schemes. The examples of synthetic schemes for the preparation of nitrosated and nitrosylated derivatives of (3S, 2'R)-3-{l-[2'-(etho\ycarbonyl)-4'-phenylbutyl]cyclopentane-l-carbonylamino}-2, 3, 4,
5-tetrahydro-2-oxo-IH-l-benzazepine-l-acetic acid serves to illustrate embodiments of the present invention. However, they do not intend to limit the scope of invention.


(Formula- Removed)
Where n= 1-8, and
Wherein Formula-IV is R'COO (CH2)4 - Y, Formula-IV" is R'COO (CH2)3 - Y, Formula-IV is R'COO (CH2)2 - Y, and
Where X = is a halogen atom selected from F, Cl, Br, I, and Y = is a nitroxy moiety
Scheme 1

In the reaction sequences stated above, the compounds of this invention are prepared by the general reactions described in art. In all the above reaction schemes, the compounds formed are the nitrosated and nitrosylated derivatives of (3S, 2'R)-3-{l-[2'-(ethoxycarbonyl)-4'-phenylbutyl]cyclopentane-l-carbonylamino}-2, 3, 4, 5-tetrahydro-2-oxo-lH-l-benzazepine-l-acetic acid. In the reaction scheme 1, n=l-8 carbon atoms, X= halogen and Y is nitroxy moiety which gives the compound of Formula-IV.
In scheme-2, X denotes hydroxyl group in V-A and V-B and Y denotes the halogen in V-B, which is coupled with (3S, 2'R)-3-{l-[2'-(ethoxycarbonyl)-4'-phenylbutyl]cyclopentane-l-carbonylamino}-2, 3, 4, 5-tetrahydro-2-oxo-lH-l-benzazepine-l -acetic acid to provide the required halogen derivative V-C which is further nitrated to give nitroxy derivative of (3S, 2'R)-3-{l-[2'-(ethoxycarbonyl)-4'-phenylbutyI]cyclopentane-l-carbonylamino}-2, 3, 4, 5-tetrahydro-2-oxo-IH-l-benzazepine-l-acetic acid having the Formula-V.
In the reaction scheme-3, the compound VI-A wherein X is hydroxyl group, is coupled with (3S, 2'R)-3-{l-[2'-(ethoxycarbonyl)-4'-phenylbutyl]cyclopentane-l-carbonylamino}-2, 3, 4, 5-
tetrahydro-2-oxo-lH-l-benzazepine-l-acetic acid to give the compound VI-B which further forms halogen derivative VI-C wherein X' is halogen atom which on further nitration gives nitroxy derivative of (3S, 2'R)-3-{l-[2'-(ethoxycarbonyl)-4'-phenylbutyl]cyclopentane-l-carbonylamino}-2, 3, 4, 5-tetrahydro-2-oxo-lH-l-benzazepine-l-acetic acid having Formula-VI.
In reaction scheme 4, the compound VI-A' wherein X is hydroxyl group and Y is halogen, is coupled with (3S, 2'R)-3-{l-[2'-(ethoxycarbonyl)-4'-phenylbutyl]cyclopentane-l-carbonylamino}-2, 3, 4, 5-tetrahydro-2-oxo-lH-l-benzazepine-l-acetic acid to give the compound VI-B' which on further nitration gives compound of Formula-VI.
The reaction scheme 5 involves the compound VII-A wherein X is hydroxyl, is treated with (CH3)3Si-Cl to give compound VII-B which is coupled with (3S, 2'R)-3-{l-[2'-(ethoxycarbonyl)-4'-phenylbutyl]cyclopentane-l-carbonylamino}-2, 3, 4, 5-tetrahydro-2-oxo-IH-l-benzazepine-l-acetic acid to give compound VII-C which is made to react with halogen to yield halogen derivative VII-D which upon nitration gives compound of Formula-VII.
In the reaction scheme 6, X is the hydroxyl group and Y is nitroxy moiety attached to corresponding C-atom coupled with stated (3S, 2'R)-3-{l-[2'-(ethoxycarbonyl)-4'-phenylbutyl]cyclopentane-l-carbonylamino}-2, 3, 4. 5-tetrahydro-2-oxo-lH-l-benzazepine-l-acetic acid to yield the compound of Formula-VIII.
The reaction scheme 7 involves the formation of compound IX-B from IX-A wherein X and X' are halogens. Compound IX-B is then coupled with stated (3S, 2'R)-3-{l-[2'-(ethoxycarbonyl)-4'-phenylbutyl]cyclopentane-l-carbonylamino}-2, 3, 4, 5-tetrahydro-2-oxo-lH-l-benzazepine-l-acetic acid to yield the compound IX-C which further produces the compound of Formula-IX wherein Y is a nitric oxide releasing moiety.
The reaction scheme 8 includes compound X-B wherein X is again a halogen atom and leads to the formation of required nitric oxide releasing derivative of R'-COOH denoted as compound of Formula-X. The reaction scheme 9 includes compound XI-B in which X is O, S or N and X1 is a halogen atom, which leads to the formation of compound of Formula-XI where Y is a nitric oxide releasing moiety. The reaction scheme 10 includes XII-C having the required nitric oxide releasing moiety Y and leads to formation of compound of Formula-XII via coupling with R'-COOH. The reaction scheme 11 that leads to the coupled product of Formula-XIII includes Y as the nitric oxide releasing moiety.
In an embodiment, the novel nitrosated and nitrosylated derivatives of the present invention may be administered as an aqueous solution for parenteral use such as for an I.V. (intravenous) injection or an oily suspension for intra-muscular injection or can be formulated into a drinkable
aqueous or hydro-alcoholic solution.
In an embodiment, the novel nitrosated and nitrosylated derivatives of the present invention can be formulated into suitable pharmaceutically acceptable dosage forms, such as solid, semi-solid or liquid dosage forms, for e.g. tablets, capsules, suppositories, patches, topical gels or sprays, drinkable solutions, injectables, or the like. The solid dosage forms can be produced by known methods such as direct compression, granulation, compaction, extrusion, molding, or the like. In an embodiment, 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. In a preferred embodiment, 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. In another preferred embodiment, 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. By the term 'functional coating' it is herein implied that 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. For semi-solid or liquid preparations, in additional to a solid excipients, liquid and/or semi-solid excipients known to the art are used.
The pharmaceutical excipients that can be used for preparation of such 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. In an embodiment, 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.
The pharmaceutical compositions according to the invention, which comprises the novel nitrosated and nitrosylated derivatives are intended for enteral, such as oral, and also rectal and parenteral administration to a warm blooded mammal, especially human and comprise the novel nitrosated and nitrosylated derivatives 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 derivatives of the present invention. The amount of the novel nitrosated and nitrosylated derivatives 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. However, selection of optimum amount is simple and
routine for a person skilled in the art. Typically the amount of such novel nitrosated and nitrosylated derivatives would be equivalent to about 10 mg to about 1000 mg of the free acid form of the IH-l-benzazepine-l-acetic acid or compound of Formula-I or compound of Formula-H. The pharmaceutical 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. According to the present invention, the pharmaceutical composition can be prepared by mixing the novel nitrosated and nitrosylated derivatives of the present invention with pharmaceutically acceptable carrier(s) or with other pharmacologically active ingredient(s).
In an embodiment, the present invention provides method of using such novel nitrosated and nitrosylated derivatives or pharmaceutical compositions comprising such novel derivatives 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. In a further embodiment of the present invention, the novel nitrosated and nitrosylated derivatives may be used 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 which are 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 hypertension, heart failure, gastrointestinal disorders, and the like, comprising the novel salts, their solvate, hydrate or a mixture thereof with Povidone, phospholipid or cyclodextrin and a pharmaceutically acceptable carrier. The novel nitrosated and nitrosylated derivatives 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 or the like.
According to the present invention, the mixture of novel nitrosated and nitrosylated derivatives of the present invention can be in the form of an associate or a complex or inclusion compounds with the pharmaceutically acceptable excipients. For example, a mixture of the novel derivatives and povidone can be in the form of an associate of the novel derivatives with povidone, a mixture of novels derivatives and phospholipid can be in the form of a complex, and a mixture of
the derivatives with cyclodextrin can be in the form of an inclusion of the novel derivatives in cyclodextrin.
Yet another object of the present invention is to provide a pharmaceutically acceptable nitrosated and nitrosylated derivatives of compound, corresponding to Formula-I and Formula-II, which is suitable as medicaments 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. For this purpose the said derivatives of the present invention can be used in medicinal forms, which can be administered parenterally, especially through the I.V. route, orally, or as suppository. Yet another object of the present invention is to provide a pharmaceutical composition comprising the said physiologically and pharmaceutically acceptable water soluble novel nitrosated and nitrosylated derivatives 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.
The following examples are only intended to further illustrate the invention, in more details, and therefore these examples are not deemed to restrict the scope of invention in any way. The compound of chemical formula (3S, 2'R)-3-{l-[2'-(ethoxycarbonyl)-4'-phenylbutyl] cyclopentane-l-carbonylamino}-2, 3, 4, 5-tetrahydro-2-oxo-lH-l-benzazepine-l-acetic acid is referred to as R'COOH herein.
(Formula- Removed)
Example 1: (i) Preparation of (3S, 2'R)-3-{l-[2'-(ethoxycarbonyl)-4'-
phenylbutyl]cyclopentane-l-carbonylamino}-2, 3, 4, 5-tetrahydro-2-oxo-lH-l-benzazepine-l-acetic acid-4-iodobutyl ester (IV-B').
4.0 g, 7.48 mmol of R'COOH was dissolved in 20 ml benzene followed by addition of 1.33 ml, 8.98 mmol of 1,8-diazabicyclo [5.4.0] undec-7-ene and stirred at room temperature for 15-20 minutes. 1.19 ml, 8.98 mmol of 1,4-diiodobutane IV-A as the starting material was added to the
vigorously stirred reaction mixture. The reaction mixture was refluxed for 3 hrs and then cooled to room temperature, diluted with 15 ml water and the organic phase was separated. The organic phase was dried over NaaSCU and filtered. The solvent was removed in vacuo and the residue was purified by column chromatography (90/10 Hexane/ethyl acetate) to give compound of Formula IV-B as oil (2.0g, 37%). (MASS (FAB) 717.5 (M+1))
(ii) Preparation of (3S, 2'R)-3-{l-[2'-(ethoxycarbonyl)-4'-phenylbutyl]cyclopentane-l-carbonylamino}-2, 3, 4, 5-tetrahydro-2-oxo-lH-l-benzazepine-l-acetic acid-4-nitroxybutyl ester (Formula-IV ').
1.5 g, 2.09 mmol of (IV-B) was mixed in 15 ml of acetonitrile followed by addition of 0.42 ml, 2.5 mmol of silver nitrate at room temperature. The resulting mixture was stirred at room temperature for 15 hrs. The resulting reaction mixture was filtered through a bed of celite, which was washed with addition 10 ml acetonitrile. The filtrate was removed in vacuo and the resulting residue was purified by column chromatography on silica gel (90/10 Hexane/ethyl acetate) to give Formula-IV as colorless oil (1.0 g, 73%). (MASS (FAB) 652.8 (M+l))
I.R. (KBr):3418,2956, 1731, 1633, 1494, 1458, 1393, 1280, 1243, 1190, 1046, 862, cm-1
'HNMR (CDC13) : 5 1.3 (m, 6H), 1.4 (m, 2H), 1.5-1.6 (m, 2H), 1.7 (m, 7H), 1.8-1.9 (m, 4H), 2.0
(m, 2H), 2.4 (m, 1H), 2.5 (m, 4H), 3.4 (m, 1H), 4.1 (m, 4H), 4.3 (d, 1H), 4.5 (m,lH), 4.7-4.8 (d,lH), 6.7 (d,lH), 7.1 (q,3H), 7.2 (t,lH), 7.3-7.4 (m,5H).
I3CNMR (CDC13) : 5 14.26, 23.32, 24.31, 25.05, 28.01, 29.7, 31.93, 33.38, 33.98, 35.93, 36.08, 37.91, 41.5, 42.8, 49.55, 50.26, 54.55, 60.41, 64.78, 122.77, 125.8, 127.3, 128.3, 128.4, 129.7, 135.7, 140.2, 141.5, 168.5, 171.6, 175.3, 176.4
(Formula- Removed)
Example 2: (i) Preparation of (3S, 2'R)-3-{l-[2'-(ethoxycarbonyl)-4'-phenylbutyl]
cyclopentane-l-carbonylamino}-2, 3, 4, 5-tetrahydro-2-oxo-lH-l-benzazepine-l-acetic acid-3-iodopropylester (IV-B").
Process of preparation is same as mentioned in Example 1, step (i). 1,3-diidopropane IV-A" was used as the starting material. Yield of (IV-B") is (0.84 g, 32%). MASS (FAB) 703.8 (M+1)
(ii) Preparation of (3S, 2'R)-3-{l-[2'-(ethoxycarbonyl)-4'-phenylbutyl]cyclopentane-l-carbonylamino}-2, 3, 4, 5-tetrahydro-2-oxo-lH-l-benzazepine-l-acetic acid-3-nitooxypropyl ester (Formula-IV").
Process of preparation is same as mentioned in Example 1, step (ii). Yield of Formula-IV" is 0.25 g, 68%. MASS (FAB) 638.7 (M+1).
I.R.(KBr):3419, 2954, 1728, 1633, 1493, 1457, 1394, 1280, 1188, 1028, 862, cm'1
'HNMR (CDC13) : 5 1.2-1.3(t, 3H), 1.4(m, 2H), 1.52-1.59(m, 2H), 81.7(m, 3H), 1.82-1.99(m, 5H), 2.02 (m, 3H), 2.3(m,lH), 2.5(m, 2H) 2.6(q, 2H), 3.2(m, 1H), 4.1(m,2H), 4.2(m, 2H), 4.3(d, 1H), 4.5(m, 3H), 4.7(d, 1H), 6.6(d, 1H), 7.09-7.15(m, 3H), 7.17-7.2(t, 1H), 7.2-7.3(m, 5H)
I3CNMR (CDC13) : 5 14.19, 23.2, 24.2, 26.2, 27.9, 29.6, 33.3, 33.8, 35.8, 35.9, 37.8, 41.4, 42.7, 49.4, 50.3, 53.4, 54.4, 60.3, 61.2, 69.4, 122.6, 125.7, 127.3, 127.9, 128.2, 128.3,129.7,135.5, 140.1, 141.4, 168.4, 171.6, 175.2,176.3.
(Formula- Removed)
Example 3: (i) Preparation of (3S, 2'R)-3-{l-[2'-(ethoxycarbonyl)-4'-phenylbutyl]
cyclopentane-l-carbonylamino}-2, 3, 4, 5-tetrahydro-2-oxo-lH-l-benzazepine-l-acetic acid-2-bromoethyl ester (IV-B"').
Process of preparation is same as mentioned in Example 1, step (i). 1,2-dibromoethane (IV-A'") was used as the starting material. Yield of (IV-B'") is 1.5 g, 41%. MASS (FAB) 641.5 (M+1).
(ii) Preparation of (3S, 2'R)-3-{l-[2'-(ethoxycarbonyl)-4'-phenylbutyl]cyclopentane-l-carbonylamino}-2, 3. 4, 5-tetrahydro-2-oxo-lH-l-benzazepine-l-acetic acid-2-nitroethyl ester (Formula-IV").
Process of preparation is same as mentioned in Example 1, step (ii). Yield of Formula-IV" is 0.8 g, 55%. MASS (FAB) 624.8 (M+l).
I.R.(KBr) : 3420, 2954, 1755, 1727, 1645, 1603, 1494, 1457, 1394, 1281, 1186, 1027, 856, 701, cm"1
'HNMR (CDCI3) : 5 1.3 (t,3H), 1.4(m, 2H), 1.55(m, 2H), 1.6-1.7(m, 3H), 1.84-2.0(m, 6H), 2.3(m, 1H), 2.5-2.6(m, 4H), 3.3(m,lH), 3.75(t, 2H), 4.1(m,2H), 4.3(d, 1H), 4.39(t, 2H), 4.5(m, 1H), 4.7(d, 1H), 6.6(d, 1H), 7.1 l-7.16(m, 3H), 7.2(t, 1H), 7.23-7.32(m, 5H)
13CNMR (CDC13) : 8 14.2, 23.2, 24.2, 25.5, 27.9, 33.3, 33.8, 35.9, 37.8,41.4, 42.7, 49.4, 50.2, 54.5, 60.4. 60.9, 67.9. 70.04, 122.6, 125.7, 127.4, 128.01, 128.2, 128.4, 129.7, 135.5, 140.0, 141.4, 168.2, 171.7, 175.3, 176.4
Example 4: (i) Preparation of 3-hydroxybenzyl bromide (V-B)
2.0 g, 16.12 mmol of 3-hydroxybenzyl alcohol V-A was dissolved in 20 ml dry dichloromethane at room temperature followed by addition of 0.758 ml, 8.09 mmol phosphorous tribromide. The resulting suspension was vigorously stirred for 15 minutes at room temperature followed by 2.3 hours at reflux temperature. The solution was cooled to room temperature, diluted with 25 ml DM water and the organic phase was separated. The organic layer was dried over Na2SC>4 and filtered. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (85/15 hexane/ ethyl acetate) to yield 3-hydroxybenzyl bromide V-B as a light brown crystalline solid (2.0 g, 66.4%).
(ii) Preparation of (3S, 2'R)-3-{l-[2'-(ethoxycarbonyl)-4'-phenylbutyl]cyclopentane-l-carbonylamino}-2, 3, 4, 5-tetrahydro-2-oxo-lH-l-benzazepine-l-acetic acid-3-(bromomethyl) phenyl ester (V-C)
4.28g, 8.02 mmol of R'COOH was dissolved in 40 ml ethyl acetate followed by addition of 2.478g, 12.03 mmol of N, N-dicyclohexylcarbodimide and the mixture is stirred for 25-30 minutes at room temperature. 1.5g, 8.02 mmol of V-B was added to the resulting suspension alongwith N, N-dimethylaminopyridine in catalytic amount and the reaction mixture was stirred for 3-4 hours at 25-30°C. The resulting mixture was filtered through celite, which was washed with additional 10 ml ethyl-acetate. The filtrate was removed in vacuo and the residue was purified by column chromatography on silica gel (85/15 hexane/ethyl acetate) to furnish V-C as clear oil (3.0g, 53.2%).
(iii) Preparation of (3S, 2'R)-3-{l-[2'-(ethoxycarbonyl)-4'-phenylbutyl]cyclopentane-l-carbonylamino}-2, 3, 4, 5-tetrahydro-2-oxo-lH-l-benzazepine-l-acetic acid-3-(nitroxymethyl) phenyl ester (Formula-V).
l.Og, 1.42 mmol of V-C was dissolved in 10 ml acetonitrile followed by addition of 0.479g, 2.8 mmol of silver nitrate. The resulting suspension was stirred at room temperature for 1 hour followed by reflux for 3-4 hrs. The reaction mixture was cooled to room temperature and filtered through a bed of celite, which was washed with additional 5.0 ml of acetonitrile. The solvent was
removed via vacuo and the residue was purified by column chromatography to give Formula-V (0.8g, 82%). MASS (FAB) 686.5 (M+1).
'HNMR (CDC13) : 61.3(i, 3H), 1.4(m, 211), 1.6(m, 5H), 1.8-2.0(m, 6H), 2.3(m, 1H), 2.5(m,4H), 3.3(m,lH), 4.1(m,2H), 4.5(m,2 H), 5.1(d,lH(, 5.4(s, 2H), 6.6(d, 1H), 7.1-7.2(m, 5H), 7.2-7.3 (m, 6H), 7.35(m, 1H), 7.4(t, 1H)
13CNMR (CDC13) : 514.29, 23.31, 24.3, 25.04, 28.0, 33.3, 33.9, 35.9, 36.0, 37.8, 41.5, 42.7, 49.5, 50.2, 54.5, 60.4, 64.7, 122.7, 125.8, 127.3, 127.9, 128.2, 128.4, 129.7, 135.7, 140.2, 141.5, 168.5, 171.6, 175.3, 176.4.
Example 5:(i) Preparation of (3S, 2'R)-3-{l-[2'-(ethoxycarbonyl)-4'-phenylbutyl]
cyclopentane-l-carbonylamino}-2, 3, 4, 5 -tetrahydro-2-oxo-lH-l-benzazepine-l -acetic acid-2,2-dimethyl-1-propanol ester (VI-B)
4.0 g, 7.48 mmol of R'COOH was dissolved in 20 ml ethyl acetate followed by addition of 2.3 g, 11.1 mmol of N, N-dicyclohexylcarbodimide and the mixture was stirred at room temperature for 30 minutes. 0.769 g, 1.48 mmol of 2,2-Dimethyl-l,3-propandiol VI-A and 0.11 g, 0.74 mmol of N, N-dimethylaminopyridine was simultaneously to the vigorously stirred reaction mixture. The reaction mixture was stirred at room temperature for 4-5 hours and the reaction mass was filtered and washed with 15 ml ethylacetate. The solvent was recovered completely from the filtrate via vacuum. The residue so obtained was purified by column chromatography (90/10 hexane/ethyl acetate) to give VI-B as colourless oil (3.0 g, 65%).
(ii) Preparation of (3S, 2'R)-3-{l-[2'-(ethoxycarbonyl)-4'-phenylbutyl]cyclopentane-l-carbonylamino}-2, 3, 4, 5-tetrahydro-2-oxo-lH-l-benzazepine-l -acetic acid-2,2-dimethyl-l-bromopropyl ester (VI-C)
1.0 g, 1.6 mmol of VI-B was dissolved in 10 ml dichloromethane followed by addition of 0.152 ml, 1.6 mmol phosphorus tribromide. The reaction mixture was refluxed for 4.5 hours followed by cooling the reaction mixture to room temperature and then washing with 10 ml DM water. The organic layer was washed with brine and the organic layer was dried over Na2SO4 followed by filtration and recovery of dichloromethane completely to give VI-C as oil (0.8 g, 70%).
(iii) Preparation of (3S, 2'R)-3-{l-[2'-(ethoxycarbonyl)-4'-phenylbutyl]cyclopentane-l-carbonylamino}-2, 3, 4, 5-tetrahydro-2-oxo-lH-l-benzazepine-l -acetic acid-2,2-dimethylpropyl nitroxy ester (Formula- VI)
0.5 g, 0.71 mmol of (VI-C) was dissolved in 10 ml acetonitrile followed by addition of 0.235 g, 1.4 mmol silver nitrate and the mixture was stirred for 20 min at room temperature. The reaction mixture was heated to 90-95°C and maintained via reflux for 5-6 hrs. The reaction mass was filtered through a bed of celite and the bed of celite was washed with 10 ml acetonitrile. The filtrate was removed in vacuo and the resulting residue was purified by column chromatography on silica gel (90/10 Hexane/ ethylacetate) to give Formula- VI as oil (0.25 g, 0.51 % yield). MASS (FAB) 663.8 (M+1)
I.R.(KBr) : 3418,3329,2929, 1729, 1650, 1627, 1603, 1493, 1457, 1393, 1178, 1027cm'1
'HNMR (CDC13) : 5 0.89(s, 6H), 1.2-1.3(t, 3H), 1.4(m, 2H), 1.5-1.7(m, 5H), 1.8-2.0 (m, 6H), 2.3(m, 1H), 2.5(m, 4H), 3.3(m, 2H), 3.5(m, 1H), 3.9(q, 2H), 4.1(m, 2H), 4.3(d, 1H), 4.5(m, 4.7(d,lH), 6.65(d, 1H), 7.0-7.1(m, 3H), 7.1-(d,lH), 7.2-7.3(m, 5H).
Example 6: (i) Preparation of (3S, 2'R)-3-{l-[2'-(ethoxycarbonyl)-4'-phenylbutyl]
cyclopentane-l-carbonylamino}-2, 3, 4, 5 -tetrahydro-2-oxo-lH-l-benzazepine-l -acetic acid-2,2-dimethyl-1-chloropropyl ester (VI-B')
5.0 g, 9.36 mmol of R'COOH was dissolved in 50 ml diethyl ether followed by addition of 2.89 g, 14.0 mmol N,N-dicyclohexylcarbodimide and the mixture was stirred at room temperature for 30 minutes. 1.146 g, 9.36 mmol of 2,2-Dimethyl-3-chloropropanol VI-A' and N,N-dimethylamino pyridine in catalytic amount was added simultaneously to the vigorously stirred reaction mixture. The reaction mixture was stirred at room temperature for 2-3 hours and the reaction mass was filtered and washed with 25 ml diethyl ether. The ether layer was washed with 20 ml water three times and finally with 20 ml brine solution. The organic layer was dried over Na2SC>4 and then recovered under vacuum to give VI-B' as a yellowish oil (4.0g, 67% yield).
(ii) Preparation of (3S, 2'R)-3-{l-[2'-(ethoxycarbonyl)-4'-phenylbutyl]cyclopentane-l-carbonylamino}-2, 3, 4, 5-tetrahydro-2-oxo-lH-l-benzazepine-l -acetic acid-2,2-dimethylpropyl nitroxy ester (Formula- VI).
3.0 g, 4.8 mmol of VI-B' was dissolved 20 ml in acetonitrile followed by addition of 0.801 g, 9.6 mmol silver nitrate and the mixture was stirred for 20-30 min at room temperature. The reaction mixture was heated to 90-95°C and maintained under reflux for 3-4 hours. The reaction mass was filtered through a bed of celite and the celite bed was washed with 10 ml acetonitrile. The solvent was recovered and the residue so obtained was purified by column chromatography on
silica gel (90/10 Hexane/ ethylacetate) to give Formula-VI as a semisolid (2.2g, 75.5% yield). MASS (FAB) 663.8 (M+1)
I.R.(KBr): 3418,3329,2929, 1729, 1650, 1627, 1603, 1493, 1457, 1393, 1178, 1027cm'1
'HNMR (CDC13) : 5 0.89(s, 6H), 1.2-1.3(1, 3H), 1.4(m, 2H), 1.5-1.7(m, 5H), 1.8-2.0 (m, 6H), 2.3(m, 1H), 2.5(m. 4H), 3.3(m, 2H). 3.5(m, 1H), 3.9(q, 2H), 4.1 (m, 2H), 4.3(d, 1H), 4.5(m, 1H), 4.7(d,lH), 6.65(d, 1H), 7.0-7. l(m, 3H), 7.1-(d,lH), 7.2-7.3(m, 5H).
13CNMR (CDC13) : 614.26, 21.55, 23.3, 24.3, 24.9, 25.6, 28.04, 33.3, 33.9, 34.8, 35.9, 37.9, 41.52, 42.76, 49.12, 49.57, 51.22, 54.54, 60.4, 69.9, 122.69, 125.83, 127.33, 127.99, 129.78, 135.67, 140.3, 141.5, 168.49, 171.67, 175.29, 176.41.
Example 7: (i) Preparation of (3-trimethylsilyloxybenzyl) aniline (VII-B). 2.0g, 16.2 mmol of 3-aminobenzylalcohol V1I-A was dissolved in 25 ml dry dichloromethane at room temperature followed by addition of 4.5 ml, 32.4 mmol triethylamine. The resulting suspension was vigorously stirred for 10 min at room temperature. The reaction mixture was cooled to 0°-5°C and 3.89 ml, 32.4 mmol of trimethylsilylchloride was added slowly. The resulting suspension was stirred for 25-30 minutes at 5-10°C and then warmed to room temperature. The reaction mixture was diluted with 15 ml DM water and the organic phase was separated. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (98/2 hexane/ethyl acetate) to give VII-B as a light brown oil (2.2 g, 71%). MASS (FAB) 196.4 (M+l)
(ii) Preparation of N-(3-trimethylsilyloxybenzyl) - (3S, 2'R)-3-{l-[2'-(ethoxycarbonyl)-4'-phenylbutyl]cyclopentane-l-carbonylamino}-2, 3, 4, 5-tetrahydro-2-oxo-lH-l-benzazepine-l-acetamide (VII-C)
5.48 g, 10.2 mmol of R'COOH was dissolved in 100 ml diethyl ether followed by addition of 3.15 g, 15.3 mmol of N,N-dichlorohexylcarbodimide. The mixture was stirred for 25-30 min at room temperature. 2.0g, 10.2 mmol of VII-B was added to the final solution alongwith N,N-dimethylaminopyridine in catalytic amount and the reaction mixture was stirred for 15 hrs at 20-25°C. The resulting mixture was filtered through celite, which was washed with additional 20 ml diethyl ether. The filtrate was removed in vacuo and the residue was purified by column chromatography on silica gel (90/10 hexane/ethyl acetate) to give VII-C as colorless oil (3.5 g, 48%).
(iii) Preparation of N-(3-Bromomethylphenyl)-(3S, 2'R)-3-{l-[2'-(ethoxycarbonyl)-4'-phenylbutyl]cyclopentane-l-carbonylamino}-2, 3, 4, 5-tetrahydro-2-oxo-lH-l-benzazepine-l-acetamide (VII-D)
3.0 g, 4.2 mmol of VII-C was dissolved in 20 ml dry dichloromethane at room temperature followed by addition of 1.138 g, 4.2 mmol phosphorous tribromide. The resulting solution was vigorously stirred for 25-30 minutes at room temperature and then refluxed for 2-3 hrs. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (90/10 hexane/ethyl acetate) to give VII-D as colorless oil (2.0 g, 67%).
(iv) Preparation of N-(3-Nitrooxymethylphenyl)-(3S, 2'R)-3-{l-[2'-(ethoxycarbonyl)-4'-phenylbutyl]cyclopentane-l-carbonylamino}-2, 3, 4, 5-tetrahydro-2-oxo-lH-l-benzazepine-l-acetamide (Formula-VII)
0.72g, 2.84 mmol of VII-D was dissolved in 15 ml acetonitrile followed by addition of 0.72 g, 4.26 mmol of silver nitrate. The resulting suspension was stirred at room temperature for 1 hour and then refluxed for 15 hours. The reaction mixture was cooled to room temperature and filtered through a bed of celite, which was washed with additional 10 ml acetonitrile. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (90-10 hexane/ethyl acetate) to give Formula-VII as a yellowish solid (1.6 g, 84%). MASS (FAB) 685.7 (M+1).
'HNMR (CDC13) : 51.2(t, 3H) l.4(m, 2H), 1.5-1.7(m, 5H), 1.8-2.l(m, 6H), 2.3(m,lH), 2.5(m, 4H), 3.3(m, 1H), 4.1(m, 2H), 4.4(d, 1H), 4.5(m, 1H), 4.7(d, 1H), 5.1(s, 2H), 6.5(d, 1H), 6.6(d,
1H). 7.0(d. 1H), 7.1(m, 4H), 7.2-7.3(m, 8H)
13CNMR (CDC13) : 514.21, 23.29, 24.2, 27.1, 29.11, 29.69, 33.3, 33.9, 34.7, 35.9, 37.8, 41.5, 42.7, 49.4, 50.5, 53.5, 54.5, 119.6, 120.1, 122.7, 123.9, 125.8, 127.3, 128.04, 128.30, 128.37, 128.42, 129, 129.7,134.5, 135.6, 138.2, 140.2, 141.01, 141.4, 166.6, 168.4, 172.3, 176.3
The examples relating to compositions comprising a nitrosated or nitrosylated derivative as the active agent which is present in a quantity equivalent to free acid form of the compound are provided below.
Example 8: Tablet
S. No. Ingredient Quantity/tablet (mg)
1. 1 H-l-benzazepine-1-acetic acid derivative (Formula-IV) 300.0
2. Sodium carbonate 270.0
3. Sodium bicarbonate 30.0
4. Microcrystalline cellulose 310.0
5. Croscarmellose sodium 20.0
6. Isopropyl alcohol q.s. (lost in processing)
7. Hydrogenated castor oil 7.5
8. Purified talc 7.5
9. Colloidal silicon dioxide 7.5
Procedure:
i) IH-l-benzazepine-l -acetic acid derivative (Formula-IV), Sodium carbonate, Sodium bicarbonate, Microcrystalline cellulose and Croscarmellose sodium were sifted through #40 sieve and were mixed together.
ii) The blend of step (i) was granulated by using Isopropyl alcohol.
iii) The wet mass of step (ii) was sifted through #24 sieve and granules obtained were dried.
iv) 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 mixture of step (iv) and compressed into tablets.
Example 9: Capsule
S. No. Ingredient Quantity/capsule (mg)
1. 1H-1 -benzazepine-1 -acetic acid derivative (Formula-V) 150.00
2. Magnesium carbonate 150.00
3. Dicalcium phosphate 131.25
4. Sodium starch glycolate 30.00
5. Magnesium stearate 10.00
Procedure:
i) 1H-1-benzazepine-1-acetic acid derivative (Formula-V), 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.
Example 10: Injection
S. No. Ingredient Quantity/100 ml
1. Polyethylene glycol 30.0ml
2. Propylene glycol 20.0 ml
3. Glycine Buffer pH 11.3 35.0ml
4. 1 H-l-benzazepine-1 -acetic acid derivative (Formula-VII) 2.5 g
5. Sodium hydroxide (NaOH) solution 4.0% w/v 10.0ml
Procedure:
i) Specified quantity (30.0 ml) of Polyethylene glycol was taken into a vessel.
ii) Propylene glycol (20.0 ml) was added to step (i) with continuous stirring.
iii) About 30.0 ml of the Glycine Buffer pH 11.3 was added to the step (ii) with stirring.
iv) Weighed amount of IH-1 -benzazepine-1 -acetic acid derivative (Formula-VII) (2.5 g) was
passed through #60 sieve and was added to the step (iii) with stirring, v) Specified quantity (10.0 ml) of NaOH 4.0% solution was added to the step (iv) with
continuous stirring to form a homogeneous solution.
vi) 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.
Example 11: Modified release Tablet
S. No. Ingredient Quantity (ing)
1. 1 H-l-benzazepine-1-acetic acid derivative (Formula-IV") 300.00
2. Valsartan 40.00
3. Lactose 120.00
4. Sodium starch glycol late 30.00
5. Hydroxypropyl methylcellulose 67.00
6. Isopropyl alcohol q.s. (lost in processing)
7. Croscarmellose sodium 3.00
8. Colloidal silicon dioxide 2.00
9. Magnesium stearate 2.00
Procedure:
i) IH-l-benzazepine-l-acetic acid derivative (Formula-IV"), Valsartan, Lactose and
Sodium starch glycollate were sifted through #30 sieve and were mixed together, ii) Hydroxypropyl methylcellulose was dissolved in Isopropyl alcohol to obtain a
homogeneous dispersion.
iii) The blend of step (i) was granulated with the dispersion of step (ii). iv) The granules of step (iii) were dried and were sifted through #24 sieve, v) Croscarmellose sodium, Colloidal silicon dioxide and Magnesium stearate were sifted
through #40 sieve, vi) The material of step (v) was mixed with the material of step (iv) and compressed into
tablets.
Example 12: Oral Liquid
S. No. Ingredient Quantity (mg/100 ml)
1. Derivative having Formula-IV" 150.0
2. Citric acid monohydrate 1.5
3. Hydroxyethyl cellulose 20.0
4. Sorbitol solution (70% w/v) 50.0
5. Saccharin sodium 0.5
6. Sodium benzoate 1.0
7. Raspberry flavor q.s.
8. Purified water q.s. to 100 ml
Procedure:
i) Derivative having Formula-IV" and Hydroxyethyl cellulose were sifted through #40
sieve and were blended together, ii) Citric acid monohydrate, Saccharin sodium, Sodium benzoate, Raspberry flavor and
Sorbitol solution were dispersed together in Purified water, iii) The material of step (i) was added with continuous stirring to the material of step (ii) and
a homogeneous suspension was obtained.
Example 13: Oral Suspension
S. No. Ingredient Quantity (mg/100 ml)
1. Derivative having Formula-VI 40.0
2. Citric acid monohydrate 1.5
3. Hydroxyethyl cellulose 20.0
4. Sorbitol solution (70% w/v) 50.0
5. Saccharin sodium 0.5
6. Sodium benzoate 1.0
7. Raspberry flavor q.s.
8. Purified water q.s. to 100 ml
Procedure:
i) Derivative having Formula-VI and Hydroxyethyl cellulose were sifted through #40 sieve
and were blended together, ii) Citric acid monohydrate, Saccharin sodium, Sodium benzoate, Raspberry flavor and
Sorbitol solution were dispersed together in Purified water, iii) The material of step (i) was added with continuous stirring to the material of step (ii) and a
homogeneous suspension was obtained.

We claim:
1. Novel nitrosated and nitrosylated derivatives of 1 H-l-benzazepine-1-acetic acid and their pharmaceutically acceptable salts, esters, amides, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof, wherein the 1H-1-benzazepine-1-acetic acid is an endothelin conversion enzyme (ECE) inhibitor and/or neutral endopeptidase (NEP) inhibitor has the following formula (Formula I):


(Formula Removed)
Wherein:
Rl is selected from the group consisting of (C1-C6) alkoxy, (C1-C6) alkyl which may be substituted by a (C1-C6) alkoxy, phenyl-(Cl-C6)-alkyl and phenyloxy-(Cl-C6)-alkyl wherein the phenyl group may be substituted with (C1-C6) alkyl, (C1-C6) alkoxy or halogen, and/or naphthyl-(Cl-C6)-alkyl, R2 and R3 are both independently hydrogen or halogen,

R4 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 derivatives of 1 H-l-benzazepine-1-acetic acid as claimed in claim 1, wherein the IH-l-benzazepine-l-acetic acid is (3S, 2'R)-3-{l-[2'-(ethoxycarbonyl)-4'-phenylbutyl]cyclopentane-l-carbonylamino}-2, 3, 4, 5-tetrahydro-2-oxo-l H-l-benzazepine-1-acetic acid has the following formula (Formula II):
(Formula Removed)
Formula II
The derivatives according to claim 1 or 2, wherein the derivatives are substituted with at least one NO and/or NC>2 groups.
4. The derivatives according to claims 1 to 3, wherein the derivatives have the following formula (Formula III):
COR
(Formula Removed)
Formula III

Wherein R is as follows:
Formula-IV





Formula-VI

Formula-VII

(Formula Removed)
Formula-VIII

Formula-XI

(Formula Removed)
Formula-XII
(Formula Removed)
FormuIa-XIH
Formula-XIV
Formula-XV
Formula-XVI
Formula-XVIII
Where X is O, S or N
Y is nitric oxide releasing moiety selected from -ONO2, -NO, -ONO, -SNO2, -SONO2
5. A process for the preparation of novel derivative herein referred to as compound of
Formula-IV as claimed in claim 4, comprising the following steps:
i) Reacting R'COOH in presence of benzene with 1,8-diazabicyclo [5.4.0] undec-7-ene and stirring,
ii) Adding haloalkane to the mixture of step (i) and refluxing and then cooling, diluting with water, separation of organic phase, drying the organic phase, and purifying the residue to give compound of formula IV-B, and
iii) Treating compound of formula IV-B of step (ii) in acetonitrile and silver nitrate at room temperature, followed by filtration and purification to give the compound of Formula-IV.
6. A process for the preparation of novel derivative herein referred to as compound of
Formula-V as claimed in claim 4, comprising the following steps:
i) Treating 3-hydroxybenzyl alcohol V-A with dry dichloromethane followed by addition of phosphorous tribromide, stirring the suspension followed by refluxing, cooling, drying and purifying the residue to obtain compound of formula V-B,
ii) Reacting R'COOH in ethyl acetate followed by addition of N, N-dicyclohexylcarbodimide, compound of formula V-B in step (i), N, N-dimethylaminopyridine, filtering the mixture, removing the filtrate and purifying the residue to obtain compound of formula V-C, and
iii) Treating the compound of formula V-C in step (ii) in acetonitrile followed by addition of silver nitrate, stirring, cooling and filtering the mixture and removing the solvent followed by purification to give compound of Formula-V.
7. A process for the preparation of novel derivative herein referred to as compound of
Formula-VI as claimed in claim 4, comprising the following steps:
i) Treating R'COOH in ethyl acetate followed by addition of N, N-dicyclohexylcarbodimide, 2,2-Dimethyl-l,3-propandiol VI-A and N, N-dimethylaminopyridine, stirring the reaction mixture, filtration, recovering of the solvent to obtain the residue followed by purification to obtain compound of formula VI-B,
ii) Reacting compound of formula VI-B of step (i) in dichloromethane followed by addition of phosphorus tribromide, refluxing the reaction mixture, cooling, washing, drying to give compound of formula VI-C, and
iii) Reacting compound of formula VI-C in step (ii) in acetonitrile followed by addition of silver nitrate, refluxing, removal of the filtrate to obtain the residue followed by purification to give compound of Formula-VI.
8. A process for the preparation of novel derivative herein referred to as compound of
Formula-VI as claimed in claim 4, comprising the following steps:
i) Treating R'COOH in diethyl ether followed by addition of N,N-dicyclohexylcarbodimide, 2,2-Dimethyl-3-chloropropanol VI-A' and N,N-dimethylamino pyridine in catalytic amount, stirring, filtering and drying the organic layer to give compound of formula VI-B', and
ii) Treating VI-B' in step (i) in acetonitrile followed by addition of silver nitrate, stirring, refluxing to obtain the residue followed by purification to give compound of Formula-VI.
9. A process for the preparation of novel derivative herein referred to as compound of
Formula-VII as claimed in claim 4, comprising the following steps:
i) Treating 3-aminobenzylalcohol VII-A in dry dichloromethane at room temperature followed by addition of triethylamine and trimethylsilylchloride, stirring, removal of

the solvent to obtain the residue followed by purification to give compound of formula VII-B,
ii) Reacting R'COOH in diethyl ether followed by addition of N,N-dichlorohexylcarbodimide, compound of formula VII-B in step (i) alongwith N,N-dimethylaminopyridine, stirring, removal of the filtrate to obtain the residue followed by purification to give compound of formula VII-C,
iii) Reacting compound of formula VII-C in step (ii) in dry dichloromethane followed by addition of phosphorous tribromide, stirring, removal of solvent to obtain residue followed by purification to give compound of formula VII-D, and
iv) Treating compound of formula of VII-D in step (iii) in acetonitrile followed by addition of silver nitrate, stirring, refluxing, filtering followed by removal of solvent to obtain residue and purification of residue to give compound of Formula-VII.
10. A pharmaceutical composition comprising the novel derivatives according to claim 1,
alongwith pharmaceutically acceptable excipient(s).
11. A pharmaceutical composition comprising the novel derivatives according to claim 1,
which additionally comprises other pharmacologically active ingredient(s).
12. A pharmaceutical composition as claimed in claim 10, wherein the pharmaceutically
acceptable carrier(s)/excipient(s) are selected from a group comprising 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, either alone or in
combination thereof.
13. A process for the preparation of pharmaceutical composition according to claim 11
comprising the novel derivatives according to claim 1, alongwith pharmaceutically
acceptable excipient(s), optionally with other pharmacologically active ingredients which
comprises treating the derivatives alongwith pharmaceutically acceptable excipient(s)
optionally with other pharmacologically active ingredients and formulating into a suitable
dosage form.
14. The novel derivatives and process for the preparation of novel derivatives substantially as
herein described and illustrated by the examples.
15. The pharmaceutical composition and process for the preparation of a pharmaceutical composition substantially as herein described and illustrated by the examples.