Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
1996-05-28
2001-01-30
Carr, Deborah (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S562000, C560S013000, C562S430000
Reexamination Certificate
active
06180665
ABSTRACT:
This application was filed under 35 U.S.C. §371 based on PCT/EP94/03750, which was filed on Nov. 9, 1994 which claims priority from U.K. application serial no. 9324931.6 which was filed on Dec. 4, 1993 and is now abandoned.
The present invention relates to a crystalline, polymorphic form of (S,S,S)-N-(1-[2-carboxy-3-(N
2
-mesyllysylamino)propyl]-1-cyclopentylcarbonyl)tyrosine which has the formula:
hereafter referred to as the “&agr;-form” of a compound of the formula (I).
More particularly, the invention relates to the &agr;-form of a compound of the formula (I) and to processes for the preparation of, to intermediates used in the preparation of, to compositions containing and to uses of, the &agr;-form.
An amorphous form (hereafter referred to as the “&bgr;-form”) of a compound of the formula (I) has been disclosed in European Patent Publication No. EP-A-0358398 as Example 181. The compound is a potent inhibitor of the zinc dependent neutral endopeptidase E.C.3.4.24.11 and is therefore able to potentiate the biological effects of atrial natriuretic factor. It is therefore a natriuretic, antihypertensive and diuretic agent that is useful for the treatment of various cardiovascular disorders. The compound is also a potent inhibitor of angiotensin converting enzyme, a further enzyme that is involved in the control of blood pressure. The compound therefore has a dual pharmacological action through being capable of inhibiting two key enzymes involved in the control of blood pressure. It is therefore likely to be useful in the treatment of various forms of hypertension and associated cardiovascular disorders such as congestive heart failure and glaucoma.
The &bgr;-form can be obtained by methods such as freeze drying of a solution of the compound of the formula (I), by rapid evaporation of the solvent from such a solution or by precipitation from such a solution by addition of a poor solvent. The &bgr;-form does not melt sharply but normally “softens” at about 160° C.
The &bgr;-form has, however, been found to have certain properties which do not make it particularly suitable for pharmaceutical formulation. In particular it is hygroscopic in nature, it has a low bulk density and poor flow properties. Processing experiments carried out using the &bgr;-form have revealed problems in manufacturing tablets from compositions containing this form.
The problem addressed by the present invention is the provision of a form of the compound of the formula (I) which can be efficiently processed to provide a stable and effective formulation of the drug.
This problem has been solved by the surprising finding that an &agr;-form of a compound of the formula (I) can be prepared which is non-hygroscopic, crystalline and, when compared to the &bgr;-form, which has a higher bulk density and better flow properties. The &agr;-form is particularly suitable for use in pharmaceutical formulation of the drug.
The present invention therefore provides a crystalline, polymorphic &agr;-form of a compound of the formula (I) which has an infra-red spectrum as a mull in nujol which shows absorption bands at &ngr;=3407, 3386, 3223, 3153, 1699, 1652, 1626, 1594, 1516, 1457 (nujol), 1377 (nujol), 1344, 1334, 1317, 1267, 1241, 1228, 1210, 1164, 1151, 1137, 1118, 1109, 1093, 1074, 1045, 1019, 1003, 981, 965, 911, 897, 862, 818, 800, 778, 762, 721 and 655 cm
−1
.
The &agr;-form is further characterised by its powder X-ray diffraction pattern obtained using copper radiation filtered with a graphite monochromator (&lgr;=0.15405 nm) which shows main peaks at 7.5, 8.9, 9.9, 11.6, 15.6, 17.2, 17.5, 18.0, 20.2, 22.1 and 23.3 degrees 2&thgr;.
The &agr;-form is yet further characterised by differential scanning calorimetry in which it shows a sharp endotherm in the range 248-259° C. and decomposes at above 260° C. when subjected to a scanning rate of 20° C. per minute.
The &agr;-form typically melts sharply in the range 242-252° C., although lower melting point ranges have been recorded.
Other forms (hereafter referred to as the “&ggr;-” and “&dgr;-forms”) of a compound of the formula (I) have also been obtained which also form part of the present invention since they can be used as intermediates in the preparation of the &agr;-form.
The invention thus further provides a polymorphic &ggr;-form of a compound of the formula (I) which has an infra-red spectrum as a mull in nujol which shows absorption bands at &ngr;=3377, 3240, 1665, 1639, 1594, 1527, 1518, 1494, 1457 (nujol), 1443, 1377 (nujol), 1344, 1321, 1304, 1254, 1195, 1178, 1162, 1143, 1111, 1098, 1046, 1031, 1012, 972, 962, 945, 932, 907, 879, 849, 815, 806, 780, 753, 729 and 658 cm
−1
.
The &ggr;-form is further characterised by its powder X-ray diffraction pattern obtained using copper radiation filtered with a graphite monochromator (&lgr;=0.15405 nm) which shows main peaks at 9.0, 9.6, 10.6, 11.6, 12.7, 13.3, 14.6, 16.2, 17.9, 18.8, 20.2 and 21.8 degrees 2&thgr;.
The &ggr;-form is yet further characterised by differential scanning calorimetry in which it shows a sharp endotherm in the range 176-186° C., an exotherm at about 207° C. and a weak endotherm at about 213° C. and decomposes at above 250° C. when subjected to a scanning rate of 20° C. per minute.
The &ggr;-form typically melts sharply in the range 170-185° C.
The invention thus also provides a hydrated 6-form of a compound of the formula (I) which has a water content of from 1 to 7%, preferably of from 2 to 4%, by weight, as determined by Karl Fischer analysis, and which has an infra-red spectrum as a mull in nujol which shows absorption bands at &ngr;=3667, 3425, 3380, 3287, 3137, 3098, 1709, 1673, 1637, 1619, 1596, 1568, 1556, 1516, 1458 (nujol), 1448, 1419, 1390, 1378 (nujol), 1356, 1338, 1300, 1270, 1249, 1229, 1198, 1174, 1141, 1108, 1091, 1075, 1064, 1045, 1033, 1019, 1001, 985, 962, 941, 909, 889, 877, 841, 822, 807, 763, 744, 732, 721 and 655 cm
−1
.
The &dgr;-form is further characterised by its powder X-ray diffraction pattern obtained using copper radiation filtered with a graphite monochromator (&lgr;=0.15405 nm) which shows main peaks at 10.5, 10.8, 12.3, 14.5, 17.2, 17.6, 17.9, 18.9, 20.4, 21.5, 22.4, 23.0, 23.1, 24.7, 27.1, 27.8 and 28.9 degrees 2&thgr;.
The &dgr;-form is yet further characterised by differential scanning calorimetry in which it shows sharp endotherms at about 162° C. and at about 166-168° C. and decomposes at above 200° C. when subjected to a scanning rate of 20° C. per minute.
The &dgr;-form typically melts sharply in the range 165-175° C.
Although the &ggr;- and &dgr;-forms of a compound of the formula (I) display the same pharmacological activities as the &agr;- and &bgr;-forms, they are not as suitable as the &agr;-form for the purpose of pharmaceutical formulation.
REFERENCES:
patent: 0358398 (1990-03-01), None
patent: 9406756 (1994-03-01), None
Protective Groups in Organic Synthesis, 2nd ed., Green and Wuts, John Willey and Sons, Inc., NY, 1991.
Dunn Peter James
Hughes Michael Leslie
Benson Gregg. C.
Carr Deborah
Davis Brian J.
Olson A. Dean
Pfizer Inc.
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