U.S. patent application number 10/918017 was filed with the patent office on 2005-10-20 for 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl-1- h-benzimidazol-5-carbonyl)pyridin-2-ylamino]propionic acid ethylester methansulfonate and its use as medicament.
This patent application is currently assigned to Boehringer Ingelheim International GmbH. Invention is credited to Schmid, Rolf, Sieger, Peter, Sobotta, Rainer.
Application Number | 20050234104 10/918017 |
Document ID | / |
Family ID | 34202202 |
Filed Date | 2005-10-20 |
United States Patent
Application |
20050234104 |
Kind Code |
A1 |
Schmid, Rolf ; et
al. |
October 20, 2005 |
3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl-1-
H-benzimidazol-5-carbonyl)pyridin-2-ylamino]propionic acid
ethylester methansulfonate and its use as medicament
Abstract
Ethyl
3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-me-
thyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate
methanesulfonate in the crystalline modifications I and II and as
the hemihydrate and the use thereof as a pharmaceutical
composition.
Inventors: |
Schmid, Rolf; (Baltringen,
DE) ; Sieger, Peter; (Mittelbiberach, DE) ;
Sobotta, Rainer; (Ingelheim am Rhein, DE) |
Correspondence
Address: |
MICHAEL P. MORRIS
BOEHRINGER INGELHEIM CORPORATION
900 RIDGEBURY ROAD
P. O. BOX 368
RIDGEFIELD
CT
06877-0368
US
|
Assignee: |
Boehringer Ingelheim International
GmbH
Ingelheim
DE
|
Family ID: |
34202202 |
Appl. No.: |
10/918017 |
Filed: |
August 13, 2004 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
60503316 |
Sep 16, 2003 |
|
|
|
Current U.S.
Class: |
514/338 ;
546/273.7 |
Current CPC
Class: |
A61P 7/02 20180101; A61P
7/00 20180101; A61P 9/00 20180101; A61P 9/10 20180101; C07D 401/12
20130101; A61P 43/00 20180101; A61P 25/00 20180101 |
Class at
Publication: |
514/338 ;
546/273.7 |
International
Class: |
C07D 043/02; A61K
031/4439 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 29, 2003 |
DE |
103 39 862.7 |
Claims
We claim:
1. The compound ethyl
3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylam-
ino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propio-
nate methanesulfonate in crystalline form, wherein the compound has
a melting point of T.sub.mp=180.degree. C..+-.3.degree. C.
determined by DSC, evaluation by peak maximum, at a heating rate of
10.degree. C./min.
2. The compound ethyl
3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylam-
ino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propio-
nate methanesulfonate in crystalline form, wherein the compound has
a melting point of T.sub.mp=190.degree. C..+-.3.degree. C.
(hemihydrate), determined by DSC, evaluation by peak maximum, at a
heating rate of 10.degree. C./min.
3. The compound ethyl
3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylam-
ino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propio-
nate methanesulfonate in crystalline form, wherein the compound has
a melting point of T.sub.mp=120.degree. C..+-.5.degree. C.
(hemihydrate), determined by DSC, evaluation by peak maximum, at a
heating rate of 10.degree. C./min).
4. A pharmaceutical composition comprising: (a) ethyl
3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl--
1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate
methanesulfonate according to claim 1; and (b) one or more inert
carriers and/or diluents.
5. A pharmaceutical composition comprising: (a) ethyl
3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl--
1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate
methanesulfonate according to claim 2; and (b) one or more inert
carriers and/or diluents.
6. A pharmaceutical composition comprising: (a) ethyl
3-[(2-{[4-(hexyloxycarbonylaminoinminomethyl)phenylamino]methyl}-1-methyl-
-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate
methanesulfonate according to claim 3; and (b) one or more inert
carriers and/or diluents.
7. A method for the post-operative prophylaxis of deep vein
thrombosis or the prevention of stroke in a patient in need
thereof, the method comprising administering to the patient an
effective amount of the compound of claim 1.
8. A method for the post-operative prophylaxis of deep vein
thrombosis or the prevention of stroke in a patient in need
thereof, the method comprising administering to the patient an
effective amount of the compound of claim 2.
9. A method for the post-operative prophylaxis of deep vein
thrombosis or the prevention of stroke in a patient in need
thereof, the method comprising administering to the patient an
effective amount of the compound of claim 3.
10. A process for preparing a polymorph of ethyl
3-[(2-{[4-(hexyloxycarbon-
ylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbony-
l)pyridin-2-ylamino]propionate methanesulfonate in crystalline
form, the process comprising: (a) slowly adding a solution of a
slight deficiency of methanesulfonic acid in acetone to a solution
of ethyl
3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]-methyl}-1-methyl-
-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate base in
acetone at a temperature of approximately 30.degree. C. to
36.degree. C.; (b) stirring the mixture of step (a) for about 1
hour at a temperature of approximately 26.degree. C. to 33.degree.
C.; (c) cooling the mixture of step (b) to about 17.degree. C. to
23.degree. C. and stirring the mixture for a further 40 to 80
minutes at this temperature to precipitate crystals of ethyl
3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino-
]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate
methanesulfonate; (d) suction filtering the precipitated crystals
of ethyl
3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-m-
ethyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate
methanesulfonate; and (e) drying the precipitated crystals of ethyl
3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl--
1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate
methanesulfonate thus obtained in vacuo for at least 4 hours at a
maximum of 50.degree. C. to obtain the polymorph of ethyl
3-[(2-{[4-(hexyloxycarbonylaminoiminomet-
hyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-yla-
mino]propionate methanesulfonate in crystalline form.
11. A process for preparing a polymorph of ethyl
3-[(2-{[4-(hexyloxycarbon-
ylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbony-
l)pyridin-2-ylamino]propionate methanesulfonate in crystalline
form, the process comprising: (a) slowly adding a solution of a
slight deficiency of methanesulfonic acid in acetone to a solution
of ethyl
3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]-methyl}-1-methyl-
-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate base in
acetone at a temperature of approximately 40.degree. C. to
46.degree. C.; (b) optionally inoculating the mixture of step (a)
with BIBR 1048 polymorph II crystals; (c) stirring the mixture of
the previous step for about 1 hour at a temperature of
approximately 40.degree. C. to 46.degree. C.; (d) cooling the
mixture of step (c) to approximately 17.degree. C. to 23.degree. C.
and stirring the mixture for a further 40 to 80 minutes at this
temperature to precipitate crystals of ethyl
3-[(2-{[4-(hexyloxycarb-
onylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbo-
nyl)pyridin-2-ylamino]propionate methanesulfonate; (e) suction
filtering the precipitated crystals of ethyl
3-[(2-{[4-(hexyloxycarbonylaminoiminom-
ethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-y-
lamino]propionate methanesulfonate; and (f) drying the precipitated
crystals of ethyl
3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino-
]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate
methanesulfonate in vacuo for at least 4 hours at a maximum of
50.degree. C. to obtain the polymorph of ethyl
3-[(2-{[4-(hexyloxycarbonylaminoimino-
methyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2--
ylamino]propionate methanesulfonate in crystalline form.
12. A process for preparing a polymorph of ethyl
3-[(2-{[4-(hexyloxycarbon-
ylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbony-
l)pyridin-2-ylamino]propionate methanesulfonate in crystalline
form, the process comprising: (a) heating with stirring a
suspension of ethyl
3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl--
1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate
methanesulfonate polymorph I in acetone to 45.degree. C. to
50.degree. C. for approximately 4 hours; (b) optionally (i)
inoculating the mixture of step (a) with ethyl
3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]me-
thyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate
methanesulfonate (polymorph II) crystals, or (ii) inoculating the
mixture of step (a) with ethyl
3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenyl-
amino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propi-
onate methanesulfonate (polymorph II) crystals and additionally
adding a small amount of ethyl
3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenyla-
mino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propio-
nate base; (c) cooling the mixture of the previous step to
approximately 15.degree. C. to precipitate crystals of ethyl
3-[(2-{[4-(hexyloxycarbony-
laminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl-
)pyridin-2-ylamino]propionate methanesulfonate (polymorph II); (d)
suction filtering the precipitated crystals of ethyl
3-[(2-{[4-(hexyloxycarbonyla-
minoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)p-
yridin-2-ylamino]propionate methanesulfonate (polymorph II); and
(e) drying the precipitated crystals of ethyl
3-[(2-{[4-(hexyloxycarbonylamin-
oiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyri-
din-2-ylamino]propionate methanesulfonate (polymorph II) thus
obtained in vacuo for at least 4 hours at a maximum of 50.degree.
C.
13. A process for preparing a polymorph of ethyl
3-[(2-{[4-(hexyloxycarbon-
ylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbony-
l)pyridin-2-ylamino]propionate methanesulfonate in crystalline
form, the process comprising: (a) ethyl
3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl-
)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamin-
o]propionate methanesulfonate (polymorph I) is placed in acetone;
(b) optionally (i) inoculating the mixture of step (a) with a small
amount of crystals of ethyl
3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino-
]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate
methanesulfonate (polymorph II), or (ii) inoculating the mixture of
step (a) with crystals of ethyl
3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)ph-
enylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]p-
ropionate methanesulfonate (polymorph II) and additionally a small
amount of ethyl
3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}--
1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate
base is added; (c) heating the mixture of the previous step to
40.degree. C. to 46.degree. C. for at least one hour with stirring;
(d) cooling the mixture of step (c) to approximately 17.degree. C.
to 23.degree. C. and stirring for a further 40 to 80 minutes at
this temperature; (e) separating the precipitated crystals of ethyl
3-[(2-{[4-(hexyloxycarbonyl-
aminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-
pyridin-2-ylamino]propionate methanesulfonate (polymorph II); and
(f) drying the precipitated crystals of ethyl
3-[(2-{[4-(hexyloxycarbonylamin-
oiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyri-
din-2-ylamino]propionate methanesulfonate (polymorph II) thus
obtained in vacuo for at least 4 hours at a maximum of 50.degree.
C.
14. A process for preparing a polymorph of ethyl
3-[(2-{[4-(hexyloxycarbon-
ylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbony-
l)pyridin-2-ylamino]propionate methanesulfonate hemihydrate in
crystalline form, the process comprising: (a) slowly adding a
solution of one equivalent of methanesulfonic acid in ethyl acetate
to a solution of ethyl
3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]-methyl}-1--
methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate
base in a mixture of 90% aqueous ethanol and ethyl acetate in a
ratio by volume of approximately 2:5 at a temperature of
approximately 35.degree. C. to 40.degree. C.; (b) optionally adding
further ethyl acetate for dilution as the product begins to
crystallize out; (c) stirring the mixture of the previous step for
about another 30 minutes at approximately 35.degree. C. to
40.degree. C.; (d) stirring the mixture of step (c) for a further
30 minutes at ambient room temperature; (e) suction filtering the
precipitate of ethyl
3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylam-
ino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propion-
ate methanesulfonate hemihydrate; and (f) dried at approximately
40.degree. C. in the circulating air drying cupboard.
15. The product of the process of claim 10.
16. The product of the process of claim 11.
17. The product of the process of claim 12.
18. The product of the process of claim 14.
19. The product of the process of claim 15.
Description
RELATED APPLICATIONS
[0001] This application claims benefit of U.S. Ser. No. 60/503,316,
filed Sep. 16, 2003, and claims priority to German Application No.
DE 103 39 862.7, filed Aug. 29, 2003, each of which is hereby
incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to the compound ethyl
3-[(2-{[4-(hexyloxycarbonylaminoimino-methyl)phenylamino]methyl}-1-methyl-
-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate
methanesulfonate of formula A and the use thereof as a
pharmaceutical composition. 1
[0003] The base of the compound of formula A is already known from
WO 98/37075, in which compounds with a thrombin-inhibiting effect
and a thrombin time-prolonging activity are disclosed, under the
name
1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]-aminomethyl]benzimi-
dazol-5-ylcarboxylic
acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide. The compound of
formula I is a double prodrug of the compound of formula B 2
[0004] i.e., the compound of formula A (BIBR 1048 MS) is only
converted into the actual effective compound, namely the compound
of formula B, in the body. The main fields of application of the
compound of chemical formula A are the post-operative prophylaxis
of deep vein thrombosis and the prevention of stroke.
[0005] The abovementioned pharmacologically beneficial properties
of the disubstituted bicyclic heterocycles disclosed in the prior
art are the main prerequisite for effective use of the compounds as
pharmaceutical compositions. An active substance must, however,
also meet other requirements in order to be capable of being used
as pharmaceutical compositions. These parameters are to a large
extent connected with the physicochemical nature of the active
substance.
[0006] Without being restricted thereto, examples of these
parameters are the stability of effect of the starting substance
under different ambient conditions, stability in the course of the
preparation of the pharmaceutical formulation, and stability in the
final compositions of the pharmaceutical preparation. The
pharmaceutical active substance used to prepare the pharmaceutical
compositions should therefore have high stability, which should
also be guaranteed even under different environmental conditions.
This is absolutely essential to prevent the use of pharmaceutical
compositions which contain, in addition to the active substance
itself, breakdown products thereof, for example. In such cases the
content of active substance found in the pharmaceutical
formulations might be less than specified.
[0007] The absorption of moisture reduces the content of
pharmaceutically active substance as a result of the increased
weight caused by the uptake of water. Pharmaceutical compositions
with a tendency to absorb moisture have to be protected from
moisture during storage, e.g., by the addition of suitable drying
agents or by storing the drug in an environment where it is
protected from moisture. In addition, the uptake of moisture may
reduce the content of pharmaceutically active substance during
manufacture if the pharmaceutical substance is exposed to the
environment without being protected from moisture in any way.
Preferably, therefore, a pharmaceutically active substance should
be only slightly hygroscopic.
[0008] As the crystal modification of an active substance is
important to the reproducible active substance content of a
preparation, there is a need to clarify as far as possible any
existing polymorphism of an active substance present in crystalline
form. If there are different polymorphic modifications of an active
substance, care must be taken to ensure that the crystalline
modification of the substance does not change in the pharmaceutical
preparation later produced from it. Otherwise, this could have a
harmful effect on the reproducible potency of the drug. Against
this background, active substances characterized by only slight
polymorphism are preferred.
[0009] Another criterion which may be of exceptional importance
under certain circumstances, depending on the choice of formulation
or the choice of manufacturing process, is the solubility of the
active substance. If, for example, pharmaceutical solutions are
prepared (e.g., for infusions), it is essential that the active
substance should be sufficiently soluble in physiologically
acceptable solvents. It is also very important for drugs which are
to be taken orally that the active substance should be sufficiently
soluble.
[0010] The problem of the present invention is to provide a
pharmaceutically active substance which not only is characterized
by high pharmacological potency but also satisfies the
abovementioned physicochemical requirements as far as possible.
BRIEF DESCRIPTION OF THE FIGURES
[0011] FIG. 1 shows the X-ray powder diffractograms of the three
crystalline forms of ethyl
3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)ph-
enylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]p-
ropionate methanesulfonate.
[0012] FIG. 2 shows the thermoanalysis and measurement of the
melting point (DSC) for the three crystalline forms of ethyl
3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]-methyl}-1-methyl-
-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate
methanesulfonate.
DETAILED DESCRIPTION OF THE INVENTION
[0013] The problem outlined above is solved by the ethyl
3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl--
1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate
methanesulfonate salt of formula A.
[0014] In fact, it has been found, surprisingly, that crystalline
modification I of this salt can be prepared by the process
described in Example 1 and crystalline modification II of this salt
can be prepared by the processes described in Examples 2 to 4,
selectively and uniformly in each case.
[0015] Moreover, under certain conditions of synthesis as
described, for example, in Example 5, a hydrate form may be
obtained, the water content of which indicates a hemihydrate.
[0016] For use of the pharmaceutical composition, it is essential
that the active substance contained therein is in a uniform
crystalline modification to ensure reliable bioavailability.
[0017] The methanesulfonate according to the invention is
characterized in all three crystalline modifications by good
crystallinity and low amorphization during grinding and
compression. Moreover, it is non-hygroscopic in all three
crystalline modifications and dissolves very easily in
physiologically acceptable acid aqueous media.
[0018] The crystalline forms of the methanesulfonate of the
compound ethyl
3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl--
1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate according
to the invention are characterized by a melting point of
T.sub.mp=180.degree. C..+-.3.degree. C. (form I),
T.sub.mp=190.degree. C..+-.3.degree. C. (form II), or
T.sub.mp=120.degree. C..+-.5.degree. C. (hemihydrate) (determined
by DSC=Differential Scanning Calorimetry; evaluation by peak
maximum; heating rate: 10.degree. C./min). The values shown were
determined using a DSC 821 e made by Messrs. Mettler Toledo.
[0019] In a first aspect, the present invention therefore relates
to the three above mentioned polymorphic forms of the salt ethyl
3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl--
1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate
methanesulfonate, preferably in crystalline form, characterized by
melting points of T.sub.mp=180.degree. C..+-.3.degree. C.,
T.sub.mp=190.degree. C..+-.3.degree. C. or T.sub.mp=120.degree.
C..+-.5.degree. C. (determined by DSC; evaluation by peak maximum;
heating rate: 10.degree. C./min). Polymorph
[0020] I with a melting point of T.sub.mp=180.degree.
C..+-.3.degree. C. is preferred.
[0021] The invention also relates to the methods of selectively
producing the three polymorphic forms as well as the modifications
which may be obtained by these methods. According to the invention,
BIBR 1048 MS polymorph I is obtained by:
[0022] (a) slowly adding a solution of a slight deficiency (for
example, 0.98 equivalents) of methanesulfonic acid in acetone to a
solution of BIBR 1048 base in acetone at a temperature of
approximately 30.degree. C. to 36.degree. C.;
[0023] (b) stirring the mixture for about 1 hour at a temperature
of approximately 26.degree. C. to 33.degree. C.;
[0024] (c) cooling the mixture to approximately 17.degree. C. to
23.degree. C. and stirring for a further 40 to 80 minutes at this
temperature;
[0025] (d) suction filtering the precipitated crystals of BIBR 1048
MS form I; and
[0026] (e) drying the product thus obtained in vacuo for at least 4
hours at a maximum temperature of 50.degree. C.
[0027] According to the invention, BIBR 1048 MS polymorph II is
obtained by:
[0028] (a) slowly adding a solution of a slight deficiency (for
example, 0.98 equivalents) of methanesulfonic acid in acetone to a
solution of BIBR 1048 base in acetone at a temperature of
approximately 40.degree. C. to 46.degree. C.;
[0029] (b) optionally inoculating the mixture with BIBR 1048
polymorph II crystals;
[0030] (c) stirring the mixture for about 1 hour at a temperature
of approximately 40.degree. C. to 46.degree. C.;
[0031] (d) cooling the mixture to approximately 17.degree. C. to
23.degree. C. and stirring for a further 40 to 80 minutes at this
temperature;
[0032] (e) suction filtering the precipitated crystals of BIBR 1048
MS form II; and
[0033] (f) drying the product thus obtained in vacuo for at least 4
hours at a maximum temperature of 50.degree. C.; or by
[0034] (a) heating a suspension of BIBR 1048 MS polymorph I in
acetone to 45.degree. C. to 50.degree. C. for approximately 4 hours
with stirring;
[0035] (b) optionally (i) inoculating the mixture with BIBR 1048
polymorph II crystals, or (ii) inoculating the mixture with BIBR
1048 polymorph II crystals and additionally adding a small amount
of BIBR 1048 base;
[0036] (c) cooling the mixture to approximately 15.degree. C.;
[0037] (d) suction filtering the precipitated crystals of BIBR 1048
MS form II; and
[0038] (e) drying the product thus obtained in vacuo for at least 4
hours at a maximum temperature of 50.degree. C.; or by
[0039] (a) placing BIBR 1048 MS polymorph I in acetone;
[0040] (b) optionally (i) inoculating the mixture with a small
amount of BIBR 1048 polymorph II, or (ii) inoculating the mixture
with BIBR 1048 polymorph II crystals and additionally adding a
small amount of BIBR 1048 base;
[0041] (c) heating the mixture thus obtained to 40.degree. C. to
46.degree. C. for at least one hour with stirring;
[0042] (d) cooling the mixture to approximately 17.degree. C. to
23.degree. C. and stirring for a further 40 to 80 minutes at this
temperature;
[0043] (e) separating off the precipitated crystals of BIBR 1048 MS
form II; and
[0044] (f) drying the product thus obtained in vacuo for at least 4
hours at a maximum temperature of 50.degree. C.
[0045] According to the invention, BIBR 1048 MS hemihydrate is
obtained by:
[0046] (a) slowly adding a solution of one equivalent of
methanesulfonic acid in ethyl acetate to a solution of BIBR 1048
base in a mixture of 90% aqueous ethanol and ethyl acetate in a
ratio by volume of approximately 2:5 at a temperature of
approximately 35.degree. C. to 40.degree. C.;
[0047] (b) optionally adding more ethyl acetate as a diluent at the
start of the crystallization of the product;
[0048] (c) stirring the mixture for approximately another 30
minutes at approximately 35.degree. C. to 40.degree. C.;
[0049] (d) stirring the mixture for a further 30 minutes at ambient
room temperature;
[0050] (e) suction filtering the precipitate of BIBR 1048 MS
hemihydrate; and
[0051] (f) drying the precipitate at approximately 40.degree. C. in
a circulating air drying cupboard.
[0052] The crystalline forms of ethyl
3-[(2-{[4-(hexyloxycarbonylaminoimin-
omethyl)phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin--
2-ylamino]propionate methanesulfonate according to the invention
were investigated in more detail by X-ray powder diffraction. The
diagrams obtained are shown in FIG. 1. Tables 1 to 3 that follow
list the data obtained in this analysis.
1TABLE 1 X-ray powder reflections and intensities (standardized) of
ethyl 3-[(2- {[4-(hexyloxycarbonylaminoiminometh-
yl)phenylamino]methyl}-
1-methyl-1H-benzimidazole-5-carbonyl)pyridi- n-2-ylamino]propionate
methanesulfonate (form I) 2.THETA. [.degree.] d.sub.hkl value
[.ANG.] intensity [%] 4.4 20.1 100 8.94 9.90 5 9.23 9.57 4 9.55
9.26 4 10.55 8.38 2 10.95 8.08 11 12.73 6.95 1 13.46 6.57 7 13.95
6.34 3 14.26 6.21 2 15.17 5.84 1 15.93 5.56 1 16.46 5.38 1 17.66
5.02 8 18.07 4.91 13 18.60 4.77 2 19.89 4.46 6 20.28 4.38 2 20.54
4.32 2 21.12 4.20 4 22.06 4.03 8 22.85 3.89 6 24.12 3.69 1 25.10
3.54 3 25.99 3.43 1 26.52 3.36 2 26.83 3.32 2 27.16 3.28 1 27.64
3.22 2 28.09 3.17 2 29.08 3.07 1 29.26 3.05 1 29.94 2.98 1 31.88
2.80 1 34.37 2.61 1 36.21 2.48 1 38.26 2.35 1 39.47 2.28 1 39.98
2.25 1
[0053]
2TABLE 2 X-ray powder reflections and intensities (standardized) of
ethyl 3-[(2- {[4-(hexyloxycarbonylaminoiminometh-
yl)phenylamino]methyl}-1-
methyl-1H-benzimidazole-5-carbonyl)pyridi- n-2-ylamino]propionate
methanesulfonate (form II) 2.THETA. [.degree.] d.sub.hkl value
[.ANG.] intensity [%] 4.3 20.4 100 8.72 10.1 3 9.68 9.13 1 11.15
7.93 1 12.42 7.12 2 13.59 6.51 1 13.95 6.34 1 15.11 5.86 1 15.97
5.55 1 16.52 5.36 1 17.45 5.08 1 17.86 4.96 2 18.45 4.81 1 19.22
4.61 2 19.89 4.46 2 21.46 4.14 2 21.98 4.04 1 22.48 3.95 1 23.75
3.74 1 25.29 3.52 1 28.17 3.17 1 28.59 3.12 1
[0054]
3TABLE 3 X-ray powder reflections and intensities (standardized) of
ethyl 3-[(2- {[4-(hexyloxycarbonylaminoiminometh-
yl)phenylamino]methyl}-
1-methyl-1H-benzimidazole-5-carbonyl)pyridi- n-2-ylamino]propionate
methanesulfonate (hemihydrate) 2.THETA. [.degree.] d.sub.hkl value
[.ANG.] intensity [%] 3.9 22.8 100 4.4 20.1 10 5.64 15.7 2 7.57
11.8 16 8.25 10.7 17 8.77 10.1 12 9.34 9.46 7 10.69 8.27 13 11.33
7.80 3 11.66 7.58 1 11.96 7.39 1 13.04 6.78 3 14.54 6.09 11 15.16
5.84 1 16.56 5.35 13 17.27 5.13 6 17.78 4.98 12 18.75 4.73 1 19.41
4.57 3 19.95 4.45 24 20.38 4.35 4 20.84 4.26 4 21.21 4.19 12 22.22
4.00 6 22.46 3.96 5 23.05 3.85 3 23.40 3.80 4 23.85 3.73 12 24.44
3.64 7 25.30 3.52 1 25.63 3.47 1 26.22 3.40 2 26.52 3.36 3 27.06
3.29 1 27.45 3.25 2 29.27 3.05 3 30.78 2.90 2 32.32 2.77 2 32.59
2.75 2 34.31 2.61 1 34.91 2.57 1 36.04 2.49 1 37.00 2.43 1 37.84
2.38 1 38.13 2.36 1
[0055] In the preceding Tables 1 to 3, the value "2.THETA.
[.degree.]" denotes the angle of diffraction in degrees and the
value "d.sub.hki[.ANG.]" denotes the specified distances in .ANG.
between the lattice planes.
[0056] The X-ray powder diagrams were recorded, within the scope of
the present invention, using a Bruker D8 Advanced diffractometer
fitted with a location-sensitive detector (OED) and a Cu anode as
the X-ray source (Cu.sub..alpha.1 radiation, .lambda.=1.5406 .ANG.,
40 kV, 40 mA). The hydrate of the compound ethyl
3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl- )phenyl
-amino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylam-
ino]propionate methanesulfonate according to the invention occurs
in the form of the hemihydrate under standard conditions, from
which water escapes at a temperature of about 120.degree. C.,
parallel to the melting of this form.
[0057] FIG. 2 shows the thermoanalysis of the three forms.
EXPERIMENTAL SECTION
Example 1
Ethyl
3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-me-
thyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate
methanesulfonate form I (BEBR 1048 MS polymorph I)
[0058] 52.6 kg of ethyl
3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenyl-
amino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propi-
onate base (which has preferably been purified beforehand by
recrystallization from ethyl acetate) is placed in an agitator
apparatus which has been rendered inert and then 293 kg of acetone
is added. The contents of the apparatus are heated to 40.degree. C.
to 46.degree. C. with stirring. After a clear solution has formed,
the contents of the apparatus is filtered into a second agitator
apparatus through a lens filter and then cooled to 30.degree. C. to
36.degree. C. 33 kg of acetone precooled to 0.degree. C. to
5.degree. C., 7.9 kg of 99.5% methanesulfonic acid, and for rinsing
another 9 kg of acetone are placed in the suspended container of
the second apparatus. The contents of the suspended container are
added in metered amounts to the solution of ethyl
3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl--
1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate base at
26.degree. C. to 36.degree. C. within 15 to 40 minutes. Then the
mixture is stirred for 40 to 60 minutes at 26.degree. C. to
33.degree. C. It is then cooled to 17.degree. C. to 23.degree. C.
and stirred for a further 40 to 80 minutes. The crystal suspension
is filtered through a filter dryer and washed with a total of 270 L
of acetone. The product is dried in vacuo at a maximum of
50.degree. C. for at least 4 hours. Yield: 54.5-59.4 kg; 90%-98% of
theory based on ethyl 3-[(2-{[4-(hexyloxycarbony-
laminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl-
)pyridin-2-ylamino]propionate base.
Example 2
BIBR 1048 MS Polymorph II by Conversion from BIBR 1048 MS Polymorph
I
[0059] 4 g of BIBR 1048 MS polymorph 1 and 35 mL of acetone are
placed in a glass flask with stirrer and reflux condenser. The
suspension is heated to 45.degree. C. to 50.degree. C. with
stirring and kept at this temperature for 4 hours. It is then
cooled to 15.degree. C. and the crystals are suction filtered
through a Buchner funnel, washed with 20 mL of acetone, and dried
in vacuo at 45.degree. C.
[0060] This synthesis may also be carried out by inoculating with
BIBR 1048 MS polymorph II. If the speed of conversion is low, it
may be accelerated by the addition of a small amount of BIBR 1048
base (for example, on an industrial scale, about 50 g of BIBR 1048
base to roughly 90 kg of BIBR 1048 MS polymorph I) in addition to
the inoculation with BIBR 1048 MS polymorph II.
Example 3
Ethyl
3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-me-
thyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate
methanesulfonate form II (BIBR 1048 MS polymorph II)
[0061] 52.6 kg of ethyl
3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenyl-
amino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propi-
onate base (which has preferably been purified beforehand by
recrystallization from ethyl acetate) is placed in an agitator
apparatus which has been rendered inert and then 293 kg of acetone
is added. The contents of the apparatus are heated to 40.degree. C.
to 46.degree. C. with stirring. After a clear solution has formed,
the contents of the apparatus are filtered into a second agitator
apparatus through a lens filter. 33 kg of acetone precooled to
0.degree. C. to 5.degree. C., 7.9 kg of 99.5% methanesulfonic acid,
and for rinsing another 9 kg of acetone are placed in the suspended
container of the second apparatus. The contents of the suspended
container are added in metered amounts to the solution of ethyl
3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino-
]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate
base at 40.degree. C. to 46.degree. C. within 15 to 40 minutes and
inoculated with 10 g of BIBR 1048 MS polymorph II (prepared
according to Examples 2, for example). Then the mixture is stirred
for 40 to 60 minutes at 40.degree. C. to 46.degree. C. It is then
cooled to 17.degree. C. to 23.degree. C. and stirred for a further
40 to 80 minutes. The crystal suspension is filtered through a
filter dryer and washed with a total of 270 L of acetone. The
product is dried in vacuo at a maximum of 50.degree. C. for at
least 4 hours. Yield: 54.5-59.4 kg; 90%-98% of theory based on
ethyl 3-[(2-{[4 (hexyloxycarbonylaminoiminomethyl)phenyla-
mino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propio-
nate base
[0062] This synthesis may also be carried out without inoculation
with BIBR 1048 MS polymorph II. However, the method using
inoculation is preferred.
Example 4
BIBR 1048 MS Polymorph II by Conversion from BIBR 1048 MS Polymorph
I
[0063] 30.7 kg of BIBR 1048 MS polymorph I is placed in an agitator
apparatus which has been rendered inert and then 199 kg of acetone
is added. The contents of the apparatus are inoculated with 10 g of
BIBR 1048 MS polymorph II (e.g., prepared according to Example 2),
heated to 40.degree. C. to 46.degree. C. with stirring, and kept at
this temperature for at least 1 hour. Then the mixture is cooled to
17.degree. C. to 23.degree. C. and stirred for at least a further
40 to 80 minutes. The crystal suspension is separated off using a
horizontal centrifuge and washed with a total of 45 kg of acetone.
The product is dried in a vacuum drying cupboard at a maximum
temperature of 50.degree. C. for at least 4 hours. Yield: 27.7-30.1
kg; 90%-98% of theory).
[0064] This synthesis may also be carried out without inoculation
with BIBR 1048 MS polymorph II. However, the method using
inoculation is preferred. If the speed of conversion is low, a
small amount of BIBR 1048 base (for example, about 50 g of BIBR
1048 base to roughly 90 kg of BIBR 1048 MS polymorph I) may be
added, in addition to the inoculation with BIBR 1048 MS polymorph
II.
Example 5
Ethyl
3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-me-
thyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate
methanesulfonate hemihydrate
[0065] A solution of 1.53 g (15.93 mmol) of methanesulfonic acid in
15 mL of ethyl acetate was added dropwise to a solution of 10.0 g
(15.93 mmol) of ethyl
3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}--
1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate
base (prepared as described in WO 98/37075) in 16.5 mL of 90%
aqueous ethanol and 40 mL of ethyl acetate, with stirring, at
35.degree. C. to 40.degree. C. After a few minutes, the product
began to crystallize out and was diluted with 30 mL of ethyl
acetate. It was stirred for another 30 minutes at 35.degree. C. to
40.degree. C. and for a further 30 minutes at ambient (room)
temperature, then the precipitate was suction filtered, washed with
approximately 20 mL of ethyl acetate, and dried at 40.degree. C. in
the circulating air drying cupboard.
[0066] Yield: 99% of theory.
* * * * *