Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-06-08
2001-10-09
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S364400
Reexamination Certificate
active
06300359
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a new monoargininyl salt form of the endothelin receptor antagonist, (E)-3-[1-n-Butyl-5-[2-(2-carboxyphenyl)methoxy-4-chlorophenyl]-1H-pyrazol-4-yl]-2-[(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl]-prop-2-enoic acid.
BACKGROUND OF THE INVENTION
The compound, (E)-3-[1-n-Butyl-5-[2-(2-carboxyphenyl)methoxy-4-chlorophenyl]-1H-pyrazol-4-yl]-2-[(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl]-prop-2-enoic acid is included within the large generic class of compounds disclosed and claimed in the co-pending PCT application PCT/US 9612581. The compounds are described as existing in either the free acid form or as “pharmaceutically acceptable salts”. Example 2 of PCT/US 9612581 gives the method of producing the diacid, (E)-3-[1-n-Butyl-5-[2-(2-carboxyphenyl)methoxy-4-chlorophenyl]-1H-pyrazol-4-yl]-2-[(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl]-prop-2-enoic acid. The activity of the compound as an endothelin receptor antagonist is described in PCT/US 9612581.
SUMMARY OF THE INVENTION
The invention comprises the monoargininyl salt of (E)-3-[1-n-Butyl-5-[2-(2-carboxyphenyl)methoxy-4-chlorophenyl]-1H-pyrazol-4-yl]-2-[(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl]-prop-2-enoic acid) which surprisingly has been found to have increased bioavailability as compared to the disodium salt or dissolution-enhancing formulations of the diacid i.e., where the surfactant Tween 80 has been incorporated either alone and in combination with the buffering agent N-methylglucamine.
The invention further constitutes pharmaceutical compositions of the monargininyl salt of (E)-3-[1-n-Butyl-5-[2-(2-carboxyphenyl)methoxy-4-chlorophenyl]-1H-pyrazol-4-yl]-2-[(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl]-prop-2-enoic acid) and its use as an endothelin receptor antagonist which is useful in the prevention or treatment of a variety of cardiovascular and renal diseases including but not limited to: hypertension, acute and chronic renal failure, cyclosporine induced nephrotoxicity, benign prostatic hypertrophy, pulmonary hypertension, migraine, stroke, subarachnoid hemorrhage, cerebrovascular vasospasm, myocardial ischemia, angina, congestive heart failure, unstable angina, coronary vasospasm and myocardial salvage, the sequelae of diabetes including but not limited to: atherosclerosis, diabetic nephropathy, diabetic retinopathy, retinopathy, diabetic macrovascular disease; and as an adjunct in angioplasty for prevention of restenosis.
This invention further constitutes a method for antagonizing endothelin receptors in an animal, including humans, which comprises administering to an animal in need thereof an effective amount of a compound of Formula (I).
DETAILED DESCRIPTION OF THE INVENTION
The compound of this invention is represented by structural Formula (I):
The aqueous solubility of the diacid of the compound of Formula (I) is very limited under acidic conditions. The solubility is less than 0.1 ug/mL at pH<5.34. For compounds possessing a pH-dependent solubility profile of this type, it is not uncommon to find a dissolution-rate limiting component to the oral bioavailability. For the diacid of Formula (I), this contention is supported by the finding that the oral bioavailability in dogs, following the intraduodenal dosing of a non-aqueous solution of a compound of Formula (I) diacid, was approximately 15% which is close to the theoretical maximum value of 18% (the enterohepatic extraction ratio is 0.82). In contrast, the oral bioavailability in dogs, following the oral dosing of a simple capsule formulation of the diacid of Formula (I), was only 3.9%. In an attempt to overcome any dissolution-rate limitation and hence enhance the oral bioavailability, alternate salt forms were studied.
It has now unexpectedly been found that the newly prepared monoargininyl salt of Formula (I) has increased bioavailability as compared to the disodium salt or dissolution-enhancing formulations of the diacid i.e., where the surfactant Tween 80 has been incorporated either alone and in combination with the buffering agent N-methylglucamine. The mean percent oral bioavailability was 13.3% which is comparable to the intraduodenal dosing of a non-aqueous solution of the disodium form. Comparative data for the bioavailability studies is found in Table 1.
TABLE 1
Bioavailability Studies Conducted in Dogs Using Formulation
Approaches and SaIt Formd of Formula (I)
Form
Formulation
Mean % Oral
Dosed
Dosed
Bioavailability ± SD
Disodium Salt
Non-Aqueous Solution
a
14.5
b
Diacid
Capsule
c
3.9 ± 0.5
Diacid
Capsule with 0.5% Tween 80
d
2.3 ± 3.7
Diacid
Capsule with 0.5% Tween 80 &
6.3 ± 5.3
2 MEq NMG
d
Disodium Salt
Capsule
c
6.2 ± 4. 1
Monoargininyl
Capsule
c
13.8 ± 7.6
Salt
a
Solution contained 99% PEG 400 and 1% DMSO and was dosed intraduodenally.
b
Dosed in only 2 animals.
c
Formulations also contain microcrystalline cellulose as a diluent.
d
Formulations also contained some microcrystalline cellulose, lactose, and starch.
As shown in Table 2, the monoarginine salt was minimally hygroscopic absorbing only 2.3% moisture over a relative humidity range of 0 to 90%. It was slightly more hygroscopic than the diacid form and considerably less hygroscopic than the amorphous disodium salt form. Accelerated stability studies, performed on the monoarginine salt, show that it is chemically stable for at least three weeks when stored at 50° C.
TABLE 2
Hygroscopicity Studies for the Diacid and the Disodium and
Monoargininyl Salt Forms of Formula (I)
% Relative
% Moisture Uptake at 250Ca
Humidity
Diacid
Disodium
Monoarginine
0
0
0
0
10
0.077
1.849
0.261
20
0.088
2.838
0.382
30
0.126
3.821
0.526
40
0.184
5.013
0.689
50
0.245
6.773
0.827
60
0.316
10.188
0.982
70
0.395
15.919
1.092
80
0.509
22.472
1.434
90
0.518
33.671
2.334
a
Measured on a dynamic vapor sorption analyzer as percentage weight gain in the sample.
Pharmaceutical compositions having endothelin receptor antagonist activity which comprises a pharmaceutical carrier containing and active but non-toxic quantity of the monoargininyl salt of a compound of Formula (I) are also objects of this invention.
In order to use the monoargininyl salt of a compound of the Formula (I) for the treatment of humans and other mammals it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
The monoargininyl salt of Formula (I) may be administered in a standard manner for the treatment of the indicated diseases, for example orally, parenterally, sub-lingually, transdermally, rectally, via inhalation, via ocular administration, or via buccal administration.
The monoargininyl salt of Formula (I) when given orally can be formulated as a syrup, tablet, capsule and lozenge. A syrup formulation will generally consist of a suspension or solution of the compound in a liquid carrier for example, ethanol, peanut oil, olive oil, glycerine or water with a flavoring or coloring agent. Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, agar, pectin, acacia, cellulose, mannitol, stearic acid, starch, lactose and sucrose. Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell. Where the composition is in the form of a soft gelatin shell capsule any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils and are incorporated in a soft gelatin capsule shell.
Typical parenteral compositions consist of a solution or suspension of the compound in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example pol
Flisak Joseph Robert
Kearney Albert Stephen
Palepu Nagesh
Perng Cherng-Yih
Hall Linda E.
Jones Dwayne C.
Kinzig Charles M.
SmithKline Beecham Corporation
Venetianer Stephen A.
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