Specification
FIELD OF THE INVENTION
The present invention relates to novel water soluble amino acid salts of 1 H-1-benzazepine-1-
acetic acid. process of preparation of such novel salts and methods of using them. The present
invention also provides pharmaceutical compositions comprising the same and method of using
5 such novel compositions for the prophylaxis, amelioration and/or treatment of cardiovascular and
other associated disorders which comprises the administration of an effective amount of such
composition to a subject in need thereof. Preferably the 1 H-1-benzazepine-1-acetic acid is an
endothelin conversion enzyme (ECE) inhibitor and/or neutral endopeptidase (NEP) inhibitor
having the general formula (Formula-1) as stated below:
10
15 0
Formu1a-1
Wherein:
N ' c- coo-
H2
n
R1 is a selected from the group consisting of(C1-C6) alkoxy, (C1-C6) alkyl, phenyl-(C1-C6)-alkyl
20 and phenyloxy-(CI-C6)-alkyl wherein the phenyl group may be substituted with (C1-C6)alkyl,
(CI-C6) alkoxy or halogen, and/or naphtyl-(C 1-C6)-alkyl,
R2 and R3 are both independently hydrogen or halogen,
~is a biolabile ester forming group, acid, amide or a substituted aryl or alkyl amide,
M is a hydrogen or a metal ion, preferably a bivalent metal ion, and
25 nis1,2or3.
30
More preferably, the 1 H-1-benzazepine-1-acetic acid used in the present invention is (3S, 2'R)-
3-{ 1-[2'-( ethoxycarbonyl)-4 · -phenylbutyl]cyclopentane-1-carbonylamino}-2, 3, 4, 5-tetrahydro-
2-oxo-lH-1-benzazepine-1-acetic acid having Formula-H.
Formula-II
- 2 -
,I
The novel salts of the present invention possess high solubility in water and are amenable into
any pharmaceutically acceptable dosage form such as solid oral, drinkable or injectable
compositions.
5 BACKGROUND OF THE INVENTION
Cardiovascular disorders such as coronary artery disease (CAD) and congestive heart failure
(CHF) are the leading cause of mortality in the developed world. The patients with CAD have
several concomitant conditions. including hypertension, diabetes and hyperlipidemia.
Cardiovascular disorder such as Angina pectoris is a severe constricting pain in the chest, often
I 0 radiating from the precordium to the left shoulder and down the left arm. Often angina pectoris is
due to ischaemia of the heart and is usually caused by coronary disease. The symptomatic
management of angina pectoris involves the use of a number of drugs, frequently as a combination
of two or more of the following classes: beta-blockers, nitrates and calcium channel blockers.
Most, if not all, of these patients require therapy with a lipid-lowering agent as well. Hypertension
15 is a major risk factor for cardiovascular disease. Both systolic and diastolic blood pressure has been
shown to be related to cardiovascular disease leading to morbidity and mortality. Hypertension
frequently coexists with hyperlipidemia and both are considered to be major risk factors for
developing cardiac disease. It would therefore be advantageous for patients to have a single
therapy which treats both of these conditions. Atherosclerosis is a condition characterized by
20 irregularly distributed lipid deposits in the intima of arteries, including coronary, carotid and
peripheral arteries. Many individuals are at an elevated risk of suffering serious to life-threatening
cardiovascular events, such as myocardial infarction (heart attack), cardiac arrest, congestive heart
failure, stroke, peripheral vascular disease and/or claudication. The risk factors are numerous and
widespread throughout the world population. They include cigarette smoking, diabetes,
25 hypercholesterolemia (high serum cholesterol), hypertension, angina, systemic lupus
erythematosus, prior heart attacks or strokes, hemodialysis, hyperhomocysteine levels, obesity,
sedentary lifestyle, receiving an organ transplant, atherosclerosis, and others.
Endothelin (ET) is a peptide which is composed of 21 amino acids that is synthesized and
30 released by the vascular endothelium. Endothelin is produced by enzymatic cleavage of a TrpVal
bond in the precursor peptide big endothelin (Big ET). This cleavage is caused by an
endothelin converting enzyme (ECE). Endothelin exists as three isoforms, ET -1, ET -2 and ET -3
(hereinafter, unless otherwise stated, 'endothelin' shall mean any or all of the isoforms of
endothelin). Endothelin acts on two pharmacologically distinct subtypes of receptors, termed
- 3 -
I "'
ET.sub.A and ET.sub.B that are expressed on a wide variety of vascular and non-vascular target
cells, eliciting, for example. contraction and proliferation of vascular smooth muscle cells and
release of nitric oxide from endothelial cells. Endothelin is associated with smooth muscle
contraction which is involved in the pathogenesis of, inter alia, cardiovascular, cerebrovascular,
5 respiratory and renal pathophysiology. An agent which suppresses endothelin production, such
as an endothelin converting enzyme (ECE) inhibitor, or which inhibits the binding of endothelin
to an endothelin receptor, such as an endothelin receptor antagonist, antagonizes various
physiological effects of endothelin and produces beneficial effects in a variety of therapeutic
areas. Endothelin receptor antagonists and ECE inhibitors are therefore useful in treating a
10 variety of diseases affected by endothelin. A non-exhaustive list of such diseases includes
chronic heart failure, myocardial infarction, cardiogenic shock, systemic and pulmonary
hypertension, ischemia-repurfusion injury, atherosclerosis, coronary and systemic vasospastic
disorders, cerebral vasospasm, and subarachnoid hemorrhage and the like.
15 Neutral Endopeptidase (NEP) is a cell surface enzyme that cleaves and inactivates
neuropeptides. It is well established that the natriuretic peptide system is intimately involved in
the control and regulation of blood pressure and plasma volume in the body. Natriuretic peptides
can also have antimitogenic actions within the cardiovascular tree. Natriuretic peptides are
degraded by the metallo peptidase neutral endopeptidase enzyme (NEP). Thus NEP inhibitors
20 primarily increase the levels of vasodilatory peptides including atrial natriuretic peptide and also
increase the half-life of other vasodilator peptides, thereby decreasing vascular tone and lowering
blood pressure. The compound (3S, 2 · R)-3-{ 1-[2 · -( ethoxycarbonyl)-4 · -phenylbutyl]
cyclopentane-1-carbonylamino} -2, 3, 4, 5-tetrahydro-2-oxo-1 H-1-benzazepine-1-acetic acid
(SLV -306) also known as Daglutril and represented by Formula-II is an orally active inhibitor of
25 neutral endopeptidase (NEP) and endothelin conversion enzyme (ECE). It is a Benzazepine-Nacetic
acid derivative which contains an oxo group in alpha position to the nitrogen atom and are
substituted in position 3 by a 1-( carboxyalkyl) cyclopentyl-carbonylamino radical, and have
NEP-inhibitory effects on the heart, as described in Waldeck et al., U.S. Pat. No. 5,677,297. The
benzazepine-N-acetic acid compounds used in the present invention are known from EP
30 0733642, EP 0830863, WO 00/48601 and WO 01/03699, and can be produced by the methods
described in said U.S. Pat. No. 5,677,297.
The compounds of Formula-1 and Formula-11, preferably Formula-11 as stated herein, are poorly
bio-available drugs due to their poor solubility in the gastric fluid. Even when they are used in the
-4-
I
form of salts and when they are dissolved in a buffer, it precipitates in the gastric fluid. The
precipitate formed is very difficult to solubilize again, leading to a low overall bioavailability.
EP0733642 is related to these compounds and their physiologically acceptable salts as such and to
the use of the compound in heart insufficiency. EP0830863, W000/4860 I and WOO 1/03699 are
5 related to the use of the above compounds in the improvement of gastrointestinal blood flow, in the
treatment of hypertension and in the treatment and prophylaxis of cardiac damages induced by
adriamycin and comparable anti-cancer drugs, respectively. PCT publication no. W02004062692
discloses a formulation with enhanced bioavailability consisting of a thermodynamically stable
liquid or semisolid solution of the poorly water-soluble biologically active substance having the
10 Formula-H. Compounds of Formula-1, particularly the compound having the Formula-11 are
obtained as sticky paste-like substance which are very difficult to handle and also are insoluble in
aqueous medium. The monovalent metal ionic salts such as sodium and potassium salt of the
compound of Formula-11, although water soluble, are obtained as solid foam which are difficult to
formulate and lack reproducibility relating to its release in vivo and in turn a variable and low
15 bioavailability. Other bivalent metal ions salts such as magnesium, calcium and zinc salts of the
compound of Formula-11, although can be obtained in the powder form, have a comparatively low
aqueous solubility in comparison to the monovalent metal ionic salts and thus have poor
bioavailability. Hence there still exists a need to develop novel salts particularly of the compounds
ofFormula-11 which are easy to handle, have an appreciable aqueous solubility and bioavailability,
20 and could be formulated into any pharmaceutically acceptable dosage form such as solid oral,
drinkable or injectable compositions without difficulty. The present invention provides novel salts
of lH-1-benzazepine-1-acetic acid which overcomes limitations of prior art.
SUMMARY OF THE INVENTION
25 It is an objective of the present invention to provide novel amino acid salts of 1H-1-benzazepinel-
acetic acid.
30
It is another objective of the present invention to provide novel amino acid salts ofthe compound
. ofFormula-1 as stated herein.
It is also another objective of the present invention to provide novel amino acid salts of the
compound ofFormula-11 as stated herein.
It is another objective of the present invention to provide novel salts of 1 H-1-benzazepine-1-
35 acetic acid, the compound of Formula-1 or the compound of Formula-11 as stated herein with an
- 5 -
I ,
organic basic amino acid or a neutral amino acid ester.
It is another objective of present invention to provide novel salts of I H -I-benzazepine-1-acetic
acid, the compound of Fonnula-1 or the compound of Formula-11 as stated herein with an organic
5 basic amino acid preferably selected from group comprising arginine, lysine and ornithine.
IO
It is another objective of present invention to provide novel salts of I H-I-benzazepine-1-acetic
acid, the compound of Formula-! or the compound of Formula-II as stated herein with a neutral
amino acid ester preferably selected from group comprising glycine, leucine and serine.
It is another objective of the present invention to provide process of preparation of such novel
amino acid salts of I H-1-benzazepine-1-acetic acid, the compound of Formula-I or the
compound of Formula-11 as stated herein.
15 It is another objective of the present invention to provide pharmaceutical compositions
comprising such novel amino acid salts of IH-I-benzazepine-1-acetic acid, the compound of
Formula-I or the compound of Formula-II as stated herein.
It is a further objective of the present invention to provide a method of using such novel salts or
20 pharmaceutical compositions comprising such novel salts which comprises administering to a
subject in need thereof an effective amount of such novel salt or composition thereof.
The novel amino acid salts of I H-I-benzazepine-I-acetic acid, the compound of Formula-I or the
compound of Formula-11 are obtained in highly pure solid form; possess appreciable aqueous
25 solubility and good bioavailability; and can be formulated into any pharmaceutically acceptable
dosage form such as solid oral, drinkable or injectable compositions.
DETAILED DESCRIPTION OF THE INVENTION
The present invention describes novel amino acid salts of I H -I-benzazepine-1-acetic acid
30 preferably novel amino acid salts of the compound of Formula-I more preferably novel amino
acid salts of the compound of Formula-II as stated herein.
In an embodiment of the present invention, the novel salts of I H-1-benzazepine-1-acetic acid or
the compound of Formula-1 or the compound of Formula-11 as stated herein are formed with an
35 amino acid selected from but not limited to a group comprising organic basic amino acid or a
neutral amino acid ester.
- 6 -
In an embodiment, the organic basic amino acid is selected from but not limited to a group
comprising racemic arginine. lysine and/or ornithine or their stereoselective enantiomers such as
L and/or R-Lysine, L and/or R-arginine and L and/or R-ornithine and the like, or mixtures
thereof. Preferably the organic basic amino acid is L-lysine, L-arginine, L-ornithine or the like,
5 or mixtures thereof.
In an embodiment of the present invention, the novel amino acid salts of 1 H-1-benzazepine-1-
acetic acid or the compound of Formula-1 or the compound of Formula-11 as stated herein are
highly pure and can be formulated into pharmaceutical compositions without substantial loss of
I 0 chiral and/or chemical purity.
In a further embodiment of the present invention, the novel amino acid salts of 1H-1-
benzazepine-l-acetic acid or the compound of Formula-1 or the compound of Formula-11 as
stated herein have solid state properties which permit easy handling and allow preparation of a
15 pharmaceutical composition with pharmaceutically acceptable excipients and preferably by using
conventional methods and equipments.
20
25
30
In an embodiment, the novel salts of the compound having Formula-I is formed with L-arginine
having the formula-III and L-lysine having the formula-IV. The novel salts with L-arginine and
L-lysine have the formula-V and formula-VI respectively as stated below.
Formula - III
NH2 HN~C-OH 2 II
0
Formula- IV
- 7-
5
10
15
0
Formula- V
NH2 ,--cOOH.H,N~C -OH
I II
N 0
Formula- VI
In another embodiment of the present invention is provided the novel salts of the compound of
Formula-11 as stated herein with an organic basic amino acid such as arginine, lysine, or
ornithine in a racemic form represented by Formula-VII, Formula-VIII and Formula-IX
20 respectively as stated below:
25
30
35
Formula- VII
0
NH2 ,--cooH.H,N~C-OH
I II
N 0
Formula- VIII
- 8-
5
Formula- IX
10 In another embodiment of the present invention is provided novel salts of 1H-1-benzazepine-1-
acetic acid, the compound of Formula-1 or the compound of Formula-11 as stated herein with a
neutral amino acid ester preferably selected from the group comprising glycine, leucine and
serine represented by Formula-X, Formula-XI and Formula-XII respectively as stated below:
15
20
25
30
35
0
fCOOH. H2N - CH2 - COOR
N
Formula- X
0
Documents
Application Documents
| # |
Name |
Date |
| 1 |
590-del-2006-abstract.pdf |
2011-08-21 |
| 1 |
590-del-2006-form-5.pdf |
2011-08-21 |
| 2 |
590-del-2006-claims.pdf |
2011-08-21 |
| 2 |
590-del-2006-form-3.pdf |
2011-08-21 |
| 3 |
590-del-2006-correspondence others.pdf |
2011-08-21 |
| 3 |
590-del-2006-form-2.pdf |
2011-08-21 |
| 4 |
590-del-2006-description (complete).pdf |
2011-08-21 |
| 4 |
590-del-2006-form-1.pdf |
2011-08-21 |
| 5 |
590-del-2006-drawings.pdf |
2011-08-21 |
| 6 |
590-del-2006-description (complete).pdf |
2011-08-21 |
| 6 |
590-del-2006-form-1.pdf |
2011-08-21 |
| 7 |
590-del-2006-correspondence others.pdf |
2011-08-21 |
| 7 |
590-del-2006-form-2.pdf |
2011-08-21 |
| 8 |
590-del-2006-claims.pdf |
2011-08-21 |
| 8 |
590-del-2006-form-3.pdf |
2011-08-21 |
| 9 |
590-del-2006-abstract.pdf |
2011-08-21 |
| 9 |
590-del-2006-form-5.pdf |
2011-08-21 |