Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-07-02
2004-02-17
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S343000, C546S279100
Reexamination Certificate
active
06693120
ABSTRACT:
The invention relates to processes for preparing constant-weight thrombin inhibitors, specifically the spray drying of such inhibitors. The invention additionally relates to novel salts of thrombin inhibitors, to drugs comprising the latter and to the use of these salts for producing medicines with antithrombotic effect.
The invention specifically relates to novel salts of the general formula I, the preparation and use thereof, where formula I has the following meaning:
where n is 0, 1, 2, and tautomers thereof.
The R configuration of cyclohexylalanine and the S configuration of dehydroproline are preferred.
The preparation of the thrombin inhibitor I as acetate is described in WO 96/25426 (Example 93, page 128). On isolation of the active substance on an RP column operated with acetic acid buffer (see PCT application page 65, lines 25/26), the product is obtained in the form of the acetic acid salt, irrespective of its previous history. The acetic acid salt is hygroscopic and forms a number of byproducts during storage.
Defined compounds of the formula I are obtained by titrating acidic solutions of the active substance with aqueous ammonia. During this, the betaine of the active substance precipitates and can be obtained in pure form by filtration or centrifugation and drying. The hydrochlorides of the general formula I are obtained by adding stoichiometric amounts of HCl to the betaine. Suitable solvents are water, C
1
-C
6
-alcohols, C
1
-C
6
-ethers, C
1
-C
6
-esters, toluene, xylenes, DMF, DMSO, THF. The product is isolated by filtration or centrifugation and drying.
The active substance is prone to irreversible adsorption of organic solvents. organic solvent residues are disadvantageous for pharmaceutical preparations. Isolation from water would be an attractive process. This does not result in constant-weight products because the active substance is highly hygroscopic. The extent of the hygroscopicity depends on the relative humidity.
To determine the hygroscopicity, samples of the dry active substance are stored in desiccators in which a constant humidity has been set by saturated salt solutions, at constant temperature. The weight change is determined by weighing at intervals of a few days. The weight gain is determined by the following formula:
weight
gain
=
(
weight
after
adsorption
)
-
dry
weight
dry
weight
×
100
By way of example the weight gain is shown for the example of vacuum-ried active substance with n=1 in Table 1 below:
TABLE 1
days
45% R.H.
65% R.H.
75% R.H.
86% R.H.
93% R.H.
0
0
0
0
0
0
3
0.28
3.50
7.60
15.51
19.73
6
0.31
3.86
9.31
20.23
20.34
9
0.26
3.59
7.98
16.66
18.97
14
0.23
3.54
7.84
16.61
19.11
21
0.26
3.45
7.86
16.14
18.78
The setting up of a process chain in which the active substance is at constant humidity from production to storage to pharmaceutical processing is extremely complicated.
It is an object of the present invention to prepare an easily handled, constant-weight active substance. It has been found, surprisingly, that on spray drying of active substance I, in contrast to all other drying techniques in vacuo, a constant residual moisture content can be set, and it thus has a constant weight during further processing.
The resulting amorphous form is moreover of pharmacological interest because of the effect of the crystallinity on the bioavailability.
The aqueous solution of the active substance to be dried is atomized by means of a two-component nozzle. A gas flowing cocurrently, preferably nitrogen, dries the dispersed drops to amorphous solid particles. These solid particles are normally removed in a cyclone. The off-gas is filtered and passed to a scrubbing tower.
The concentration of the solution to be dried is in the range from 5 to 40% by weight, preferably in the range from 15 to 25% by weight.
The gas inlet temperature is in the range from 80 to 150° C., preferably in the range from 110 to 130° C.
The gas outlet temperature is in the range from 30 to 70° C., preferably in the range from 50 to 60° C.
The pressure of the atomizing gas is in the range from 1.1 to 10 bar, preferably in the range from 2 to 5 bar.
The products prepared in this way are compact, and pharmaceutical processing thereof is easy.
A product prepared in this way can be handled in the open air without a rapid change in its weight.
The spray-dried products of the general formula I show a weight gain of less than 1% after several days even with a relative humidity of 75% after spray drying.
The vacuum-dried and freeze-dried products of the general formula I show a weight gain of more than 6% at 75% relative humidity.
In addition, comparison of the storage stability of the salts I according to the invention with fumarate and acetate salts surprisingly reveals that the active substances according to the invention are more stable on storage than are the corresponding salts of organic acids.
TABLE 2
Storage at 70° C., 1 bar in an open vessel. Data are
active substance content based on initial active
substance content in the open vessel in HPLC % areas
Betaine
Betaine ×
Betaine ×
Betaine ×
Betaine ×
Days
(n = 0)
HCl
2HCl
acetate
fumarate
0
100
100
100
100
100
7
92.5
98.5
99.7
92.6
87.9
14
88.6
97.5
99.7
87.1
87.1
TABLE 3
HPLC content of the active substance in % areas
active substance formula I n = 1
spray dried
vacuum dried (60° C./12 h)
active
98.5%
97.8%
substance
byproducts
no additional
additional byproducts
byproducts
with contents of more than
over 0.1%
0.1%
The compounds of the formula I are thrombin inhibitors and can be employed for the following indications:
diseases whose pathomechanism is based directly or indirectly on the proteolytic effect of thrombin,
diseases whose pathomechanism is based on the thrombin-dependent activation of receptors and signal transduction,
diseases associated with stimulation [for example by PAI-1, PDGF (platelet derived growth factor), P-selectin, ICAM-1, tissue factor] or inhibition (for example NO synthesis in smooth muscle cells) of the expression of genes in body cells,
diseases based on the mitogenic effect of thrombin,
diseases based on a thrombin-dependent change in the contractility and permeability of epithelial cells (for example vascular endothelial cells).
thrombin-dependent thromboembolic events such as deep vein thrombosis, pulmonary embolism, myocardial or cerebral infarction, atrial fibrillation, bypass occlusion,
disseminated intravascular coagulation (DIC),
reocclusion and for reducing the reperfusion time on comedication with thrombolytics such as streptokinase, urokinase, prourokinase, t-PA, APSAC, plasminogen activators from the salivary glands of animals, and the recombinant and mutated forms of all these substances,
the occurrence of early reocclusion and late restenosis after PTCA,
thrombin-dependent proliferation of smooth muscle cells,
accumulation of active thrombin in the CNS (for example in Alzheimer's disease),
tumor growth, and to prevent the adhesion and metastasis of tumor cells.
The novel compounds can be used in particular for the therapy and prophylaxis of thrombin-dependent thromboembolic events such as deep vein thrombosis, pulmonary embolisms, myocardial or cerebral infarctions and unstable angina, also for the therapy of disseminated intravascular coagulation (DIC). They are further suitable for combination therapy with thrombolytics such as streptokinase, urokinase, prourokinase, t-PA, APSAC and other plasminogen activators for reducing the reperfusion time and extending the reocclusion time.
Further preferred areas of use are the prevention of thrombin-dependent early reocclusion and late restenosis after percutaneous transluminal coronary angioplasty, the prevention of thrombin-induced proliferation of smooth muscle cells, the prevention of the accumulation of active thrombin in the CNS (for example in Alzheimer's disease), the control of tumors and the prevention of mechanisms which lead to adhesion and meta
Ascherl Hermann
Harms Guido
Krei Georg Arnold
Schaefer Bernd
Abbott & GmbH & Co. KG
Coppins Janet L
Rotman Alan L.
Wood Phillips Katz Clark & Mortimer
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