U.S. patent application number 13/856458 was filed with the patent office on 2013-10-31 for salts and crystall forms of 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q- uinolin-1-yl)-phenyl]-propionitrile.
This patent application is currently assigned to NOVARTIS AG. The applicant listed for this patent is Markus Banziger, Sudhakar Devidasrao Garad, Frank Stowasser. Invention is credited to Markus Banziger, Sudhakar Devidasrao Garad, Frank Stowasser.
Application Number | 20130289064 13/856458 |
Document ID | / |
Family ID | 39345299 |
Filed Date | 2013-10-31 |
United States Patent
Application |
20130289064 |
Kind Code |
A1 |
Stowasser; Frank ; et
al. |
October 31, 2013 |
Salts and crystall forms of
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]-propionitrile
Abstract
The invention relates to particular crystalline forms of
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]-propionitrile, its hydrates and solvates, its
salts and hydrates and solvates of its salts, certain processes for
their preparation, pharmaceutical compositions containing these
crystalline forms, and their use in diagnostic methods or,
preferably, for the therapeutic treatment of warm-blooded animals,
especially humans, and their use as an intermediate or for the
preparation of pharmaceutical preparations for use in diagnostic
methods or, preferably, for the therapeutic treatment of
warm-blooded animals, especially humans.
Inventors: |
Stowasser; Frank; (Murg,
DE) ; Banziger; Markus; (Bubendorf, CH) ;
Garad; Sudhakar Devidasrao; (Malden, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Stowasser; Frank
Banziger; Markus
Garad; Sudhakar Devidasrao |
Murg
Bubendorf
Malden |
MA |
DE
CH
US |
|
|
Assignee: |
NOVARTIS AG
Basel
CH
|
Family ID: |
39345299 |
Appl. No.: |
13/856458 |
Filed: |
April 4, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12514976 |
Mar 16, 2010 |
8436177 |
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PCT/US07/84893 |
Nov 16, 2007 |
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13856458 |
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60866483 |
Nov 20, 2006 |
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Current U.S.
Class: |
514/293 ;
546/82 |
Current CPC
Class: |
A61P 17/00 20180101;
A61P 17/06 20180101; A61P 15/00 20180101; A61P 25/00 20180101; A61P
35/00 20180101; C07D 471/04 20130101; A61P 13/08 20180101; A61P
35/02 20180101; C07C 309/30 20130101; A61P 43/00 20180101 |
Class at
Publication: |
514/293 ;
546/82 |
International
Class: |
C07D 471/04 20060101
C07D471/04; C07C 309/30 20060101 C07C309/30 |
Claims
1. A crystalline form of the compound of formula I ##STR00012## or
of a hydrate or solvate of the compound of formula I, or of a salt
of the compound of formula I, or of a hydrate or solvate of a salt
of the compound of formula I.
2. Compound I according to claim 1 in crystalline form A.
3. A compound according to claim 2 which shows on X-ray diffraction
a peak at an angle of diffraction 2Theta of
8.4.degree.+/-0.3.degree..
4. Compound I according to claim 1 in crystalline form B.
5. A compound according to claim 3 which shows on X-ray diffraction
a peak at an angle of diffraction 2Theta of
6.9.degree.+/-0.3.degree..
6. Compound I according to claim 1 in crystalline form C.
7. A compound according to claim 6 which shows on X-ray diffraction
a peak at an angle of diffraction 2Theta of
14.7.degree.+/-0.3.degree..
8. Compound I according to claim 1 in crystalline form D.
9. A compound according to claim 8 which shows on X-ray diffraction
a peak at an angle of diffraction 2Theta of
23.9.degree.+/-0.3.degree..
10. A monohydrate of compound 1 according to claim 1 in crystalline
form H.sub.A.
11. A compound according to claim 10 which shows on X-ray
diffraction a peak at an angle of diffraction 2Theta of
17.6.degree.+/-0.3.degree..
12. A monotosylate salt of compound I according to claim 1 in
crystalline form.
13. A monotosylate salt of compound I according to claim 12 in
crystalline form A.
14. A compound according to claim 12 or 13 which shows on X-ray
diffraction a peak at an angle of diffraction 2Theta of
5.7.degree.+/-0.3.degree..
15. A compound according to claim 12, 13 or 14 which shows on X-ray
diffraction peaks at an angle of diffraction 2Theta of
5.4.degree.+/-0.3.degree.; 5.7.degree.+/-0.3.degree. and
17.2.degree.+/-0.3.degree..
16. A compound according to claim 12 or 13 which shows an X-ray
diffraction diagram essentially as outlined in FIG. 6.
17. A monotosylate salt of compound I according to claim 12 in
crystalline form B.
18. A compound according to claim 12 or 17 which shows on X-ray
diffraction a peak at an angle of diffraction 2Theta of
5.8.degree.+/-0.3.degree..
19. A compound according to claim 12, 17 or 18 which shows on X-ray
diffraction peaks at an angle of diffraction 2Theta of
5.8.degree.+/-0.3.degree.; 17.8.degree.+/-0.3.degree. and
18.7.degree.+/-0.3.degree..
20. A monohydrate of the monotosylate salt of compound I according
to claim 1 in crystalline form H.sub.A.
21. A compound according to claim 20 which shows on X-ray
diffraction a peak at an angle of diffraction 2Theta of
6.5.degree.+/-0.3.degree..
22. A dihydrate of the monotosylate salt of compound I according to
claim 1 in crystalline form H.sub.B.
23. A compound according to claim 22 which shows on X-ray
diffraction a peak at an angle of diffraction 2Theta of
6.9.degree.+/-0.3.degree..
24. A diformic acid solvate of the monotosylate salt of compound I
according to claim 1 in crystalline form S.sub.A.
25. A compound according to claim 24 which shows on X-ray
diffraction a peak at an angle of diffraction 2Theta of
5.8.degree.+/-0.3.degree..
26. A ditosylate salt of compound I according to claim 1 in
crystalline form.
27. A ditosylate salt of compound I according to claim 26 in
crystalline form A.
28. A compound according to claim 26 or 27 which shows on X-ray
diffraction a peak at an angle of diffraction 2Theta of
22.4.degree.+/-0.3.degree..
29. A trihydrate of the ditosylate salt of compound I according to
claim 1 in crystalline form H.sub.A.
30. A compound according to claim 29 which shows on X-ray
diffraction a peak at an angle of diffraction 2Theta of
4.7.degree.+/-0.3.degree..
31. An amorphous monotosylate salt of compound I according to claim
1.
32. A monohydrate of the diformic acid solvate of the monotosylate
salt of compound I according to claim 1 in crystalline form
S.sub.C.
33. A compound according to claim 32 which shows on X-ray
diffraction a peak at an angle of diffraction 2Theta of
5.6.degree.+/-0.3.degree..
34. A diacetic acid solvate of the monotosylate salt of compound I
according to claim 1 in crystalline form S.sub.B.
35. A compound according to claim 34 which shows on X-ray
diffraction a peak at an angle of diffraction 2Theta of
5.7.degree.+/-0.3.degree..
36. The solid form of the compound of formula I or of a hydrate or
solvate of the compound of formula I, or of a salt of the compound
of formula I, or of a hydrate or solvate of a salt of the compound
of formula I according to any one of the claims 1 to 35, which is
present in essentially pure form.
37. A pharmaceutical composition comprising a solid form of the
compound of formula I, its hydrates or solvates, its salts and
hydrates or solvates of its salts according to any one of the
claims 1 to 35, and optionally at least one pharmaceutically
acceptable carrier.
38. The use of a solid form of the compound of formula I, its
hydrates or solvates, its salts and hydrates or solvates of its
salts according to any one of the claims 1 to 35 for the
preparation of a medicament for the treatment of treatment of a
proliferative disease selected from a benign or malignant tumor,
carcinoma of the brain, kidney, liver, adrenal gland, bladder,
breast, stomach, gastric tumors, ovaries, colon, rectum, prostate,
pancreas, lung, vagina or thyroid, sarcoma, glioblastomas, multiple
myeloma or gastrointestinal cancer, especially colon carcinoma or
colorectal adenoma or a tumor of the neck and head, an epidermal
hyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, a
neoplasia of epithelial character, lymphomas, a mammary carcinoma
or a leukemia. Other diseases include Cowden syndrome,
Lhermitte-Dudos disease and Bannayan-Zonana syndrome, or diseases
in which the PI3k/PKB pathway is aberrantly activated.
39. Method of treating a disease selected from a benign or
malignant tumor, carcinoma of the brain, kidney, liver, adrenal
gland, bladder, breast, stomach, gastric tumors, ovaries, colon,
rectum, prostate, pancreas, lung, vagina or thyroid, sarcoma,
glioblastomas, multiple myeloma or gastrointestinal cancer,
especially colon carcinoma or colorectal adenoma or a tumor of the
neck and head, an epidermal hyperproliferation, psoriasis, prostate
hyperplasia, a neoplasia, a neoplasia of epithelial character,
lymphomas, a mammary carcinoma or a leukemia. Other diseases
include Cowden syndrome, Lhermitte-Dudos disease and
Bannayan-Zonana syndrome, or diseases in which the PI3K/PKB pathway
is aberrantly activated in a warm-blooded animal in need thereof
comprising administering to the animal a crystalline form of the
compound of formula I, its hydrates or solvates, its salts or
hydrates or solvates of its salts according to any one of the
claims 1 to 35 in a quantity which is therapeutically effective
against the respective disease.
Description
[0001] The invention relates to particular solid, preferably
crystalline or amorphous, especially crystalline, forms of
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]-propionitrile (compound I, see below), its
hydrates and solvates, its salts and hydrates and solvates of its
salts, certain processes for their preparation, pharmaceutical
compositions containing these solid forms, and their use in
diagnostic methods or, preferably, for the therapeutic treatment of
warm-blooded animals, especially humans, and their use as an
intermediate or for the preparation of pharmaceutical preparations
for use in diagnostic methods or, preferably, for the therapeutic
treatment of warm-blooded animals, especially humans.
BACKGROUND TO THE INVENTION
[0002]
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4-
,5-c]quinolin-1-yl)-phenyl]-propionitrile, its inhibition of the
activity of the lipid kinases, such as the PI3-kinase and/or
members of the PI3-kinase-related protein kinase family (also
called PIKK and include DNA-PK, ATM, ATR, hSMG-1 and mTOR), such as
the DNA protein-kinase; its preparation; and its use, especially as
an anti-tumour agent, are described in WO2006/122806. The compound
is exemplified therein in free form (see for instance Example 7)
and as 4-toluenesulfonic acid salt in a stoichiometric ratio of
1:1. The synthesis of
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]-propionitrile is also described in the
experimental part as Example 1.
[0003] It has now been surprisingly found that under certain
conditions new particular crystalline forms of
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]-propionitrile, its hydrates and solvates, its
salts and hydrates or solvates of its salts may be found, which are
described hereinafter, and which have advantageous utilities and
properties. They exhibit new physical properties which which may
have substantial differences in certain pharmaceutical properties
and which can be utilized in drug substance and drug product
development; e.g. for the dissolution of drug substances and/or
facilitated routes of manufacturing/purification.
DETAILED DESCRIPTION OF THE INVENTION
[0004] The invention is described in more detail in the following
with the help of drawings and other aids.
[0005] The invention relates especially to essentially pure crystal
forms of
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5--
c]quinolin-1-yl)-phenyl]-propionitrile of formula I (compound
I),
##STR00001##
of a hydrate or solvate of the compound of formula I, or of a salt
of the compound of formula I, or of a hydrate or solvate of a salt
of the compound of formula I.
DESCRIPTION OF THE DRAWINGS
[0006] In the X-ray diagrams discussed below, the angle of
diffraction 2Theta is plotted on the horizontal axis (x-axis) and
the intensity (counts) on the vertical (y-axis).
[0007] FIG. 3 Form A of
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]-propionitrile
[0008] The strongest line in the X-ray diffraction diagram is
observed at an angle of diffraction 2Theta of 8.4.degree. having a
relative intensity of 100%. Two further lines were observed having
a relative intensity of more than 10% at 7.9.degree. and
10.5.degree.. More broadly, this form is characterized by
diffractions peaks at angles of diffraction 2Theta of 7.9.degree.,
8.4.degree., 10.5.degree., 10.9.degree., 13.3.degree.,
17.9.degree., 22.0.degree.. X-ray powder data measured with Scintag
instrument with Cu K alpha radiation source; Step 0.020.degree.,
Range 2.00-40.00 (Deg.), Const. Scan Rate 0.50 Deg/min (all 2Theta
values+/-0.3).
[0009] FIG. 2 Form B of
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]-propionitrile
[0010] The strongest line in the X-ray diffraction diagram is
observed at an angle of diffraction 2Theta of 6.9.degree. having a
relative intensity of 100%. Two further lines were observed having
a relative intensity of more than 10% at 14.2.degree. and
17.7.degree.. More broadly, this form is characterized by
diffractions peaks at angles of diffraction 2Theta of 6.9.degree.,
8.7.degree., 10.1.degree., 14.2.degree., 17.7.degree.,
20.5.degree., 21.1.degree., X-ray powder data measured with Scintag
instrument with Cu K alpha radiation source; Step 0.020.degree.,
Range 2.00-40.00 (Deg.), Const. Scan Rate 0.50 Deg/min (all 2Theta
values+/-0.3).
[0011] FIG. 3 Simulated X-ray powder pattern of form C of
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]-propionitrile
[0012] The strongest line in the X-ray diffraction diagram is
observed at an angle of diffraction 2Theta of 14.7.degree. having a
relative intensity of 100%. Two further lines were observed having
a relative intensity of more than 10% at 11.4.degree. and
18.6.degree.. More broadly, this form is characterized by
diffractions peaks at angles of diffraction 2Theta of 6.6.degree.,
11.4.degree., 14.7.degree., 15.6.degree., 18.3.degree.,
18.6.degree., 19.8.degree., 22.7.degree., 24.5.degree. (all 2Theta
values+/-0.3).
[0013] FIG. 4 Form D of
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]-propionitrile
[0014] The strongest line in the X-ray diffraction diagram is
observed at an angle of diffraction 2Theta of 23.9.degree. having a
relative intensity of 100%. Two further lines were observed having
a relative intensity of more than 10% at 20.6.degree. and
22.1.degree.. More broadly, this form is characterized by
diffractions peaks at angles of diffraction 2Theta of 8.5.degree.,
19.9.degree., 20.2.degree., 20.6.degree., 22.1.degree.,
23.9.degree., 26.1.degree., 27.2.degree.. X-ray powder data
measured with STOE Stadi P Combi instrument with Cu K alpha1
radiation source; Slit 4 mm/2 mm: transmission between kapton foil;
Monochrom.: Curved Germanium (111), Radiation 1.54060 .ANG.,
Generator: 50 kV, 30 mA, Detector: Linear PSD/Moving/Fixed Omega;
Range 1: 2Theta (begin, end, step)=2.000, 39.980, 0.020; 390.00
s/step (all 2Theta values+/-0.3).
[0015] FIG. 5 Form H.sub.A of
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]-propionitrile monohydrate
[0016] The strongest line in the X-ray diffraction diagram is
observed at an angle of diffraction 2Theta of 17.6.degree. having a
relative intensity of 100%. Two further lines were observed having
a relative intensity of more than 10% at 18.8.degree. and
22.5.degree.. More broadly, this form is characterized by
diffractions peaks at angles of diffraction 2Theta of 5.6.degree.,
6.9.degree., 8.5.degree., 9.2.degree., 13.8.degree., 17.6.degree.,
18.8.degree., 22.5.degree., 24.0.degree.. X-ray powder data
measured with Bruker D8 Discover GADDS in reflection geometry (all
2Theta values+/-0.3).
[0017] FIG. 6 Form A of
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]-propionitrile monotosylate
[0018] The strongest line in the X-ray diffraction diagram is
observed at an angle of diffraction 2Theta of 5.7.degree. having a
relative intensity of 100%. Two further lines were observed having
a relative intensity of more than 10% at 5.4.degree. and
17.2.degree.. More broadly, this form is characterized by
diffractions peaks at angles of diffraction 2Theta of 5.4.degree.,
5.7.degree., 16.4.degree., 17.2.degree., 18.3.degree.,
19.0.degree., 22.0.degree., 23.1.degree., 23.4.degree.,
27.5.degree.. X-ray powder data measured with Scintag instrument
with Cu K alpha radiation source; Step 0.020.degree., Range
2.00-40.00 (Deg.), Const. Scan Rate 0.50 Deg/min (all 2Theta
values+/-0.3).
[0019] FIG. 7 Form B of
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]-propionitrile monotosylate
[0020] The strongest line in the X-ray diffraction diagram is
observed at an angle of diffraction 2Theta of 5.8.degree. having a
relative intensity of 100%. Two further lines were observed having
a relative intensity of more than 10% at 17.8.degree. and
18.7.degree.. More broadly, this form is characterized by
diffractions peaks at angles of diffraction 2Theta of 5.8.degree.,
16.4.degree., 17.2.degree., 17.8.degree., 18.4.degree.,
18.7.degree., 22.1.degree., 22.7.degree., 23.7.degree.. X-ray
powder data measured with STOE Stadi P Combi instrument with Cu K
alpha1 radiation source; Slit 4 mm/2 mm; transmission between
kapton foil; Monochrom.: Curved Germanium (111), Radiation 1.54060
.ANG., Generator: 50 kV, 30 mA, Detector: Linear PSD/Moving/Fixed
Omega; Range 1: 2Theta (begin, end, step)=2.000, 39.980, 0.020;
390.00 s/step (all 2Theta values+/-0.3).
[0021] FIG. 8 Simulated X-ray powder pattern of form H.sub.A of
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]-propionitrile monotosylate monohydrate
(calculated from the corresponding single crystal structure)
Crystallographic Data of Compound I Monotosylate Monohydrate:
TABLE-US-00001 [0022] Crystal system Monoclinic Space group
P2.sub.1/C a, .ANG. 9.790 (3) b, .ANG. 12.431 (3) c, .ANG. 27.209
(8) .alpha., .beta., .gamma. 90, 92.560 (16), 90 V, .ANG..sup.3
3308.0 (16) D.sub.calc, g cm.sup.-3 1.325 Z 4
[0023] The strongest line in the X-ray diffraction diagram is
observed at an angle of diffraction 2Theta of 6.5.degree. having a
relative intensity of 100%. Four further lines were observed having
a relative intensity of more than 50% at 7.8.degree., 19.6.degree.,
23.1.degree. and 26.2.degree.. More broadly, this form is
characterized by diffractions peaks at angles of diffraction 2Theta
of 6.5.degree., 7.8.degree., 9.0.degree., 11.4.degree.,
14.9.degree., 19.3.degree., 19.6.degree., 23.1.degree.,
26.2.degree. (all 2Theta values+/-0.3).
[0024] FIG. 9 Simulated X-ray powder pattern of form H.sub.8 of
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]-propionitrile monotosylate dihydrate
(calculated from the corresponding single crystal structure)
Crystallographic Data of Compound I Monotosylate Dihydrate:
TABLE-US-00002 [0025] Crystal system Triclinic Space group P-1 a,
.ANG. 7.1921 (2) b, .ANG. 13.8439 (3) c, .ANG. 17.5667 (4) .alpha.,
.beta., .gamma. 111.203 (1), 90.980 (1), 96.388 (1) V, .ANG..sup.3
1617.33 (7) D.sub.calc, g cm.sup.-3 1.318 Z 2
[0026] The strongest line in the X-ray diffraction diagram is
observed at an angle of diffraction 2Theta of 6.9.degree. having a
relative intensity of 100%. Two further lines were observed having
a relative intensity of more than 10% at 19.5.degree. and
26.6.degree.. More broadly, this form is characterized by
diffractions peaks at angles of diffraction 2Theta of 6.9.degree.,
10.2.degree., 13.4.degree., 13.8.degree., 16.4.degree.,
16.9.degree., 19.5.degree., 21.1.degree., 26.6.degree. (all 2Theta
values+/-0.3).
[0027] FIG. 10 Simulated X-ray powder pattern of form S.sub.A of
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]-propionitrile monotosylate diformic acid
solvate (calculated from the corresponding single crystal
structure)
Crystallographic Data of Compound I Monotosylate Formic Acid
Solvate:
TABLE-US-00003 [0028] Crystal system Monoclinic Space group
P2.sub.1/n a, .ANG. 9.4104 (3) b, .ANG. 12.5101 (5) c, .ANG.
30.3995 (11) .alpha., .beta., .gamma. 90, 92.183 (2), 90 V,
.ANG..sup.3 3576.2 (2) D.sub.calc, g cm.sup.-3 1.547 Z 4
[0029] The strongest line in the X-ray diffraction diagram is
observed at an angle of diffraction 2Theta of 5.8.degree. having a
relative intensity of 100%. Two further lines were observed having
a relative intensity of more than 10% at 7.6.degree. and
20.9.degree.. More broadly, this form is characterized by
diffractions peaks at angles of diffraction 2Theta of 5.8.degree.,
7.9.degree., 11.7.degree., 13.1.degree., 13.6.degree.,
14.5.degree., 17.3.degree., 20.9.degree., 22.6.degree.,
24.5.degree. (all 2Theta values+/-0.3).
[0030] FIG. 11 Form A of
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]-propionitrile ditosylate
Crystallographic Data of Compound I Ditosylate:
TABLE-US-00004 [0031] Crystal system Monoclinic Space group
P2.sub.1/n a, .ANG. 10.3246 (2) b, .ANG. 12.0935 (3) c, .ANG.
31.5031 (7) .alpha., .beta., .gamma. 90, 99.416 (1), 90 V,
.ANG..sup.3 3880.50 (15) D.sub.calc, g cm.sup.-3 1.159 Z 4
[0032] The strongest line in the X-ray diffraction diagram is
observed at an angle of diffraction 2Theta of 22.4.degree. having a
relative intensity of 100%. Two further lines were observed having
a relative intensity of more than 10% at 21.5.degree. and
25.0.degree.. More broadly, this form is characterized by
diffractions peaks at angles of diffraction 2Theta of 5.6.degree.,
7.7.degree., 15.8.degree., 16.8.degree., 18.6.degree.,
19.1.degree., 21.5.degree., 22.4.degree., 25.0.degree.. X-ray
powder data measured with Bruker D8 Advance instrument with Cu K
alpha radiation source; Step 0.017.degree., Cnt. time 0.3 s., Range
2.00-40.00 (Deg.), variable divergence slit 12 mm, VANTEC PSD
detector (all 2Theta values+/-0.3).
[0033] FIG. 12 Simulated X-ray powder pattern of form H.sub.4 of
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]-propionitrile ditosylate trihydrate
(calculated from the corresponding single crystal structure)
Crystallographic Data of Compound I Ditosylate Trihydrate:
TABLE-US-00005 [0034] Crystal system Monoclinic Space group
P2.sub.1/n a, .ANG. 9.120 (3) b, .ANG. 12.646 (4) c, .ANG. 37.827
(12) .alpha., .beta., .gamma. 90, 95.565 (16), 90 V, .ANG..sup.3
4342 (2) D.sub.calc, g cm.sup.-3 1.328 Z 4
[0035] The strongest line in the X-ray diffraction diagram is
observed at an angle of diffraction 2Theta of 4.7.degree. having a
relative intensity of 100%, Two further lines were observed having
a relative intensity of more than 10% at 9.4.degree. and
12.6.degree.. More broadly, this form is characterized by
diffractions peaks at angles of diffraction 2Theta of 4.7.degree.,
7.4.degree., 8.4.degree., 9.4.degree., 12.6.degree., 13.7.degree.,
14.7.degree., 18.3.degree., 20.8.degree., 24.1.degree. (all 2Theta
values+/-0.3).
[0036] FIG. 13 Amorphous form of
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]-propionitrile monotosylate
[0037] X-ray powder data measured with Bruker D8 Advance instrument
with Cu K alpha radiation source; Step 0.017.degree., Cnt. time 0.3
s., Range 2.00-40.00 (Deg.), variable divergence slit 12 mm, VANTEC
PSD detector.
[0038] FIG. 14 Raman spectra of amorphous form of
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]-propionitrile monotosylate
[0039] Raman spectrum of the sample measured by dispersive Raman
spectrometer with 1064 nm laser excitation source (Bruker RFS 100).
The significant bands in the spectra are expressed in reciprocal
wave numbers (cm.sup.-1).
[0040] FIG. 15 FT-IR spectra of amorphous form of
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]-propionitrile monotosylate
[0041] The infrared absorption spectrum for the sample obtained
using Fourier Transform Infrared Microscope (Bruker Vertex 70). The
significant bands in the spectra are expressed in reciprocal wave
numbers (cm.sup.-1).
[0042] FIG. 16 Simulated X-ray powder pattern of form S.sub.C of
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]-propionitrile monotosylate diformic acid
solvate monohydrate (calculated from the corresponding single
crystal structure)
Crystallographic Data of Compound I Monotosylate Formic Acid
Solvate Monohydrate:
TABLE-US-00006 [0043] Crystal system Monoclinic Space group
P2.sub.1/n a, .ANG. 9.304 (3) b, .ANG. 12.421 (4) c, .ANG. 31.500
(10) .alpha., .beta., .gamma. 90, 91.571 (18), 90 V, .ANG..sup.3
3639 (2) D.sub.calc, g cm.sup.-3 1.372 Z 4
[0044] The strongest line in the X-ray diffraction diagram is
observed at an angle of diffraction 2Theta of 5.6.degree. having a
relative intensity of 100%. Two further lines were observed having
a relative intensity of more than 10% at 20.7.degree. and
22.2.degree.. More broadly, this form is characterized by
diffractions peaks at angles of diffraction 2Theta of 5.6.degree.,
7.6.degree., 12.9.degree., 13.3.degree., 14.3.degree.,
20.7.degree., 22.2.degree., 24.5.degree., 25.2.degree.,
26.2.degree., 29.3 (all 2Theta values+/-0.3).
[0045] FIG. 17 Simulated X-ray powder pattern of form S.sub.B of
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]-propionitrile monotosylate diacetic acid
solvate (calculated from the corresponding single crystal
structure)
CRYSTALLOGRAPHIC DATA OF COMPOUND I MONOTOSYLATE ACETIC ACID
SOLVATE
TABLE-US-00007 [0046] Crystal system Monoclinic Space group
P2.sub.1/n a, .ANG. 9.590 (2) b, .ANG. 12.372 (3) c, .ANG. 31.220
(8) .alpha., .beta., .gamma. 90, 91.487 (11), 90 V, .ANG..sup.3
3702.9 (15) D.sub.calc, g cm.sup.-3 1.367 Z 4
[0047] The strongest line in the X-ray diffraction diagram is
observed at an angle of diffraction 2Theta of 57.degree. having a
relative intensity of 100%. Two further lines were observed having
a relative intensity of more than 10% at 7.7.degree. and
22.3.degree.. More broadly, this form is characterized by
diffractions peaks at angles of diffraction 2Theta of 5.7.degree.,
7.7.degree., 12.7.degree., 13.4.degree., 14.3.degree.,
14.6.degree., 20.1.degree., 20.5.degree., 20.7.degree.,
22.3.degree., 23.7.degree., 24.0.degree., 24.2.degree.,
24.9.degree., 26.0.degree. (all 2Theta values+/-0.3).
[0048] The term "essentially pure" is understood in the context of
the present invention to mean especially that at least 90,
preferably at least 95, and most preferably at least 99 per cent by
weight of the crystals of the compound of formula I, its hydrates
or solvates, its salts or hydrates or solvates of its salts are
present in the specified crystal form according to the
invention.
[0049] The term "solid form" according to the present invention
includes crystalline forms and amorphous forms. Preferred solid
forms are crystalline forms
[0050] In the context with stating that a crystal form of the
compound of formula I, its hydrates or solvates, its salts or its
hydrates or solvates of its salts exhibits an X-ray diffraction
diagram essentially as outlined in one of the Figures, the term
"essentially" means that at least the major lines of the diagram
depicted in said Figure, i.e. those having a relative line
intensity of more than 20%, especially more than 30%, as compared
to the most intense line in the diagram, have to be present.
[0051] In one preferred embodiment, the crystal form of the
compound of formula I, its hydrates or solvates, its salts or its
hydrates or solvates of its salts exhibits an X-ray diffraction
diagram essentially as outlined in one of the Figures.
[0052] Of particularly high preference are solid, preferably
crystalline, form of the compound of formula I, its hydrates and
solvates, its salts and hydrates or solvates of its salts
obtainable as described in the Examples.
[0053] One of the advantages of having access to different crystal
forms of the compound of formula I, its hydrates or solvates, its
salts or hydrates or solvates of its salts is the fact that
distinct crystal forms are prone to incorporate distinct impurities
upon crystallization, i.e. an impurity incorporated in crystal form
AA is not necessarily also incorporated in the crystal form BB or
in the crystal form CC. With other words, preparing consecutively
distinct crystal forms of the same material increases the purity of
the finally obtained substance. Furthermore, distinct crystal forms
display different physical properties such as melting points,
hygroscopicities, solubilities, flow properties or thermodynamic
stabilities, and, hence, distinct crystal forms allow the choice of
the most suitable form for a certain use or aspect, e.g. the use as
an intermediate in the process of drug manufacture or in distinct
administration forms like tablets, capsules, ointments or
solutions.
[0054] The solid, preferably crystalline, forms of the compound of
formula I, its hydrates or solvates, its salts and hydrates or
solvates of its salts possess valuable pharmacological properties
and may, for example, be used in the treatment of conditions which
are mediated by the activation of the PI3 kinase enzymes, such as
proliferative, inflammatory or allergic conditions, or disorders
commonly occurring in connection with transplantation.
[0055] The solid, amorphous or crystalline, preferably crystalline,
forms of the compound of formula I, its hydrates or solvates, its
salts and hydrates or solvates of its salts may preferably used in
the treatment of a proliferative disease selected from a benign or
malignant tumor, carcinoma of the brain, kidney, liver, adrenal
gland, bladder, breast, stomach, gastric tumors, ovaries, colon,
rectum, prostate, pancreas, lung, vagina or thyroid, sarcoma,
glioblastomas, multiple myeloma or gastrointestinal cancer,
especially colon carcinoma or colorectal adenoma or a tumor of the
neck and head, an epidermal hyperproliferation, psoriasis, prostate
hyperplasia, a neoplasia, a neoplasia of epithelial character,
lymphomas, a mammary carcinoma or a leukemia. Other diseases
include Cowden syndrome, Lhermitte-Dudos disease and
Bannayan-Zonana syndrome, or diseases in which the PI3K/PKB pathway
is aberrantly activated.
[0056] The present invention relates especially to form A of
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]-propionitrile monotosylate in the treatment
of one of the said diseases mentioned herein or in the preparation
of a pharmacological agent for the treatment thereof.
[0057] The invention relates also to a method for the treatment of
warm-blooded animals suffering from said diseases, wherein a
quantity of the solid, preferably crystalline, form of the compound
of formula I, its hydrates or solvates, its salts or hydrates or
solvates of its salts which is effective against the disease
concerned, especially a quantity with antiproliferative efficacy,
is administered to warm-blooded animals in need of such treatment.
The invention relates moreover to the use of solid, preferably
crystalline, forms of the compound of formula I, its hydrates or
solvates, its salts and hydrates or solvates of its salts for the
preparation of pharmaceutical compositions for use in treating the
human or animal body, especially for the treatment of proliferative
disease, such as benign or malignant tumor, carcinoma of the brain,
kidney, liver, adrenal gland, bladder, breast, stomach, gastric
tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina or
thyroid, sarcoma, glioblastomas, multiple myeloma or
gastrointestinal cancer, especially colon carcinoma or colorectal
adenoma or a tumor of the neck and head, an epidermal
hyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, a
neoplasia of epithelial character, lymphomas, a mammary carcinoma
or a leukemia.
[0058] The solid, preferably crystalline, forms of the compound of
formula I, its hydrates or solvates, its salts or hydrates or
solvates of its salts described herein can be utilized to prepare
stable pharmaceutical dosage forms. Hence, the invention relates
also to pharmaceutical preparations which contain an amount,
especially an therapeutically effective amount for prevention or
treatment of one of the diseases mentioned herein, of the solid,
preferably crystalline, form of the compound of formula I, its
hydrates or solvates, its salts or hydrates or solvates of its
salts, together with pharmaceutically acceptable carriers which are
suitable for topical, enteral, for example oral or rectal, or
parenteral administration and may be inorganic or organic and solid
or liquid.
[0059] The present pharmaceutical preparations which, if so
desired, may contain further pharmacologically active substances,
are prepared in a manner known per se, for example by means of
conventional mixing, granulating, coating, dissolving or
lyophilising processes, and contain from about 1% to 100%,
especially from about 1% to about 20%, of the active substance or
substances.
[0060] The present invention relates also to a process for the
preparation of a pharmaceutical composition which comprises mixing
a solid, preferably crystalline, form of the compound of formula I,
its hydrates or solvates, its salts or hydrates or solvates of its
salts of the invention together with at least one pharmaceutically
acceptable carrier or diluent.
[0061] The term "pharmaceutical composition" is intended to
encompass a product comprising the active ingredient(s),
pharmaceutically acceptable excipients that make up the carrier, as
well as any product which results, directly or indirectly, from
combination, complexation or aggregation of any two or more of the
ingredients, or from dissociation of one or more of the
ingredients, or from other types of reactions or interactions of
one or more of the ingredients. Accordingly, the pharmaceutical
compositions of the present invention encompass any composition
made by admixing the active ingredient, optionally additional
active ingredient(s) and pharmaceutically acceptable
excipients.
[0062] The term "excipient" means a component of a pharmaceutical
product that is not the active ingredient, such as filler, diluent
and carrier. The excipients that are useful in preparing a
pharmaceutical composition are preferably generally safe, non-toxic
and neither biologically nor otherwise undesirable, and are
acceptable for veterinary use, as well as human pharmaceutical use.
"A pharmaceutically acceptable excipient", as used in the
specification and claims, includes both one and more than one such
excipient.
[0063] "Therapeutically effective amount" means the amount of a
compound that, when administered for treating or preventing a
disease, is sufficient to effect such treatment or prevention for
the disease. The "therapeutically effective amount" will vary
depending on the compound, the disease and its severity and the
age, weight, etc., of the patient to be treated.
[0064] The present invention relates also to a process for the
preparation of solid, preferably crystalline, forms of the compound
of formula I, its hydrates or solvates, its salts and hydrates or
solvates of its salts. The precise conditions under which crystals
are formed may now be empirically determined and a number of
methods are suitable in practice, including the crystallization
conditions as described in Examples 3 to 17.
[0065] Crystallization-inducing conditions normally involve the use
of an appropriate crystallization-inducing solvent, such as
t-butylmethylether (TBME), methanol, ethanol, isopropanol or water
or mixtures thereof. Conveniently, the amorphous compound is
dissolved in the solvent at a temperature of normally at least
10.degree. C. The solution may be produced by dissolving in a
solvent any one or more of amorphous forms of the compound, and
solvates thereof, such as hydrates, methanolates, ethanolates,
isopropanolates, or formiates. Crystals may then be formed by
conversion from solution, crystallization taking place at a
temperature of between about 0.degree. C. and the boiling point of
the solvent. The dissolution and crystallization may be carried out
in various conventional ways. For instance, amorphous compound may
be dissolved in a solvent or a mixture of solvents in which it is
readily soluble at elevated temperatures but in which it is only
sparingly soluble at lower temperatures. Dissolution at elevated
temperature is followed by cooling during which the desired
crystals crystallize out of solution. A cooling and reheating step
may be carried out several times, e.g. at least once, at least
twice, at least 3.times., at least 5.times.. The cooling and
reheating temperatures are e.g. at least 5.degree. C., at least
10.degree. C. or at least 15.degree. C. The low temperature of the
cooling/heating cycles may e.g. be less than 15.degree. C., less
than 10.degree. C., less than 5.degree. C. or less than 0.degree.
C., whereas the high temperature may e.g. be at least 15.degree.
C., at least 20.degree. C., at least 25.degree. C. or at least
30.degree. C.
[0066] Mixed solvents comprising a good solvent in which the
compound is readily soluble, preferably, in amounts of at least 1%
by weight at 30.degree. C., and a poor solvent in which it is more
sparingly soluble, preferably in amounts of not more than about
0.01% by weight at 30.degree. C., may also be employed provided
that crystallization from the mixture at a reduced temperature, of
normally at least about, 0.degree. C., is possible using the
selected solvent mixture.
[0067] Alternatively, the difference in solubility of the crystals
in different solvents may be used. For example, the amorphous
compound may be dissolved in a good solvent in which it is highly
soluble such as one in which it is soluble in amounts of at least
1% by weight at about 30.degree. C. and the solution subsequently
mixed with a poor solvent in which it is more sparingly soluble,
such as one in which it is soluble in amounts of not more than
about 0.01% by weight at about 30.degree. C. Thus, the solution of
the compound in the good solvent may be added to the poor solvent,
while maintaining normally a temperature in excess of about
0.degree. C., or the poor solvent may be added to the solution of
the compound in the good solvent, again while normally maintaining
a temperature in excess of about 0.degree. C. Examples of good
solvents may include lower alcohols, such as methanol, ethanol and
isopropanol, formic acid acetic acid or acetone. An example of a
poor solvent is e.g. water. Preferably, crystallization is effected
at a temperature in the range of about 0.degree. C. to about
40.degree. C.
[0068] In an alternative embodiment of the process of the
invention, solid amorphous compound is suspended at a temperature
of normally at least about 0.degree. C. in a solvent in which it is
incompletely soluble, preferably only sparingly soluble, at that
temperature. A suspension results in which particles of solid are
dispersed, and remain incompletely dissolved in the solvent.
Preferably the solids are maintained in a state of suspension by
agitation e.g. by shaking or stirring. The suspension is kept at a
temperature of normally about 0.degree. C. or higher in order to
effect a transformation of the starting solids into crystals. The
amorphous solid compound suspended in a suitable solvent may be a
solvate, e.g. hydrate, methanolate, ethanolate, acetate or
formiate. The amorphous powder may be derived by drying a
solvate.
[0069] It is preferred to add "seeds" of crystalline material to
the solution in order to induce crystallization.
[0070] In accordance with a preferred embodiment of the present
invention, the crystalline forms of formula I, its hydrates or
solvates, its salts and hydrates or solvates of its salts have a
high crystallinity. A crystal form is defined herein as having a
"high crystallinity" or being "crystallographically pure" when it
contains at most about 0.5% (w/w), e.g. at most about 0.1% (w/w) of
other form. Thus e.g. "crystallographically pure Form AA" contains
about 0.5% (w/w) or less, e.g. about 0.1% (w/w) or less of Form BB
and/or another crystalline form. With respect to the content of
amorphous form a "crystallographically pure" form contains less
than about 5% of amorphous form or an amount below the limit of
detection (i.e. no detectable amount) of amorphous form.
[0071] The following Examples illustrate the invention without
limiting the scope thereof. Temperatures are given in degrees
Celsius (.degree. C.).
EXAMPLES
Example 1
2-Methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]qu-
inolin-1-yl)-phenyl]-propionitrile
##STR00002##
[0073] In a suitable lab glass reactor are pieced 45.0 g of
starting
2[4-(8-bromo-3-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phen-
yl]2-methyl-propionitrile together with 2.25 g of
bistriphenylphosphine palladium dichloride in 445 ml
N,N-dimethylformamide. This mixture is heated to 95.degree. C. and
then a solution of 22.2 g of 3-quinoline boronic acid in a mixture
of 225 ml DMF, 300 ml H.sub.2O and 60 g of KHCO.sub.3 is added.
This mixture is heated for 2 h at 95.degree. C. Then 1080 ml
H.sub.2O are added. The product
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]propionitrile precipitates. The mixture is
cooled within 1.5 h to 0-5.degree. C. After stirring at that
temperature for 2 h the crude product is filtered and washed with
300 ml H.sub.2O. This product is dried in vacuo at 60.degree. C.
for 18 h, to yield crude product.
[0074] 40 g of this crude product is dissolved in 200 ml formic
acid at 60.degree. C. 8 g of active charcoal and Smopex 234 are
added. The mixture is stirred at 60.degree. C. for 1 h, the
charcoal is filtered, the residue washed with 80 ml formic acid and
then 175 ml formic acid are distilled off in vacuo. Then 320 ml
methanol are added and the mixture is heated at reflux for 3 h. The
purified product precipitates from the reaction mixture. The
mixture is cooled to 0-5.degree. C. within 1 h, then stirred 2 h at
that temperature is finally filtered and washed with 80 ml cold
methanol. This recrystallisation procedure is repeated again.
Finally the twice recrystallised material is dried in vacuo at
60.degree. C. to yield purified
2-Methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]propionitrile.
Example 1a
5-Bromo-2-(2-nitro-vinylamino)-benzoic acid
##STR00003##
[0076] A suspension of 25 g (16 mmol) of 2-amino-5-bromo-benzoic
acid (Fluka, Buchs, Switzerland) in H.sub.2O--HCl (37%) (10:1) is
stirred for 8 h and then filtered (solution A). 8.17 g (255 mmol)
of nitromethane (Fluke, Buchs, Switzerland) are added over 10 min
to an ice-bath cooled mixture of 35 g of ice and 15.3 g (382 mmol)
of NaOH. After stirring for 1 h at 0.degree. C. and 1 h at rt, the
solution is added at 0.degree. C. to 28 g of ice and 42 ml of HCl
(37%) (solution B). Solutions A and B are combined and the reaction
mixture is stirred for 18 h at rt. The yellow precipitate is
filtered off, washed with H.sub.2O and dried in vacuo at 40.degree.
C. to give the title compound. ES-MS: 287, 289 (M+H).sup.+, Br
pattern; .sup.1H NMR (DMSO-d.sub.6): .delta. 13.7-14.6/br s (1H),
12.94/d (1H), 8.07/d (1H), 8.03/dd (1H), 7.83/dd (1H), 7.71/d (1H),
6.76/d (1H).
Example 1b
6-Bromo-3-nitro-quinolin-4-ol
##STR00004##
[0078] 29 g (101 mmol) of 5-bromo-2-(2-nitro-vinylamino)-benzoic
acid (Example 1a) and 11.9 g (121 mmol) of potassium acetate in 129
ml (152 mmol) of acetic anhydride are stirred for 1.5 h at
120.degree. C. The precipitate is filtered off and washed with
acetic acid until the filtrate is colorless, then is washed with
H.sub.2O and dried in vacuo to give the title compound. ES-MS: 269,
271 (M+H).sup.+, Br pattern; analytical HPLC: t.sub.ret=2.70 min
(Grad 1).
Example 1c
6-Bromo-4-chloro-3-nitro-quinoline
##STR00005##
[0080] 20 g (74.3 mmol) of 6-bromo-3-nitro-quinolin-4-ol (Example
1b) in 150 ml (1.63 mol) of POCl.sub.3 are stirred for 45 min at
120.degree. C. The mixture is cooled to it and poured slowly into
ice-water. The precipitate is filtered off, washed with ice-cold
water, and dissolved in CH.sub.2Cl.sub.2. The organic phase is
washed with cold brine, and the aqueous phase is discarded. After
drying over MgSO.sub.4, the organic solvent is evaporated to
dryness to provide the title compound. .sup.1H NMR (CDCl.sub.3):
.delta. 9.20/s (1H), 8.54/d (1H), 8.04/d (1H), 7.96/dd (1H);
analytical HPLC: t.sub.ret=4.32 min (Grad 1).
Example 1d
2-Methyl-2-(4-nitro-phenyl)-propionitrile
##STR00006##
[0082] To 15 g (92.5 mmol) of (4-nitro-phenyl)-acetonitrile (Fluke,
Buchs, Switzerland), 1.64 mg (5.09 mmol) of tetrabutylammonium
bromide (Fluka, Buchs, Switzerland) and 43.3 g (305 mmol) of
iodomethane in 125 mL of CH.sub.2Cl.sub.2 are added 10 g (250 mmol)
of NaOH in 125 ml of water. The reaction mixture is stirred for 20
h at RT. After this time, the organic layer is separated, dried
over MgSO.sub.4, and evaporated to dryness. The residue is
dissolved in diethylether and treated with black charcoal for 30
min, filtered over Celite and evaporated in vacuo to give the title
compound as a pale yellow solid. Analytical HPLC: t.sub.ret=3.60
minutes (Grad 1).
Example 1e
(2-(4-Amino-phenyl)-2-methyl-propionitrile
##STR00007##
[0084] 16 g (84.1 mmol) of
2-methyl-2-(4-nitro-phenyl)-propionitrile (Example 1d) and 4.16 g
of Raney-Ni are shacked in 160 ml of THF-MeOH (1:1) under 1.1 bar
of H.sub.2 for 12 h at rt. After completion of the reaction, the
catalyst is filtered-off and the filtrate is evaporated to dryness.
The residue is purified by flash chromatography on silica gel
(hexane-EtOAc 3:1 to 1:2) to provide the title compound as an oil.
ES-MS: 161 (M+H).sup.+; analytical HPLC: t.sub.ret=2.13 minutes
(Grad 1).
Example 1f
2-[4-(6-Bromo-3-nitro-quinolin-4-ylamino)-phenyl]-2-methyl-propionitrile
##STR00008##
[0086] 18 g (62.6 mmol) of 6-bromo-4-chloro-3-nitro-quinoline
(Example 1c) and 11 g (68.9 mmol) of
(2-(4-amino-phenyl)-2-methyl-propionitrile (Example 1e) are
dissolved in 350 ml of acetic acid and stirred for 2 h. After this
time, water is added and the yellow precipitate is filtered off and
washed with H.sub.2O. The solid is dissolved in EtOAc-THF (1:1),
washed with sat. aqueous NaHCO.sub.3 and dried over MgSO.sub.4. The
organic phase is evaporated to dryness to give the title compound
as a yellow solid. ES-MS: 411, 413 (M+H).sup.+, Br pattern;
analytical HPLC: t.sub.ret=3.69 min (Grad 1).
Example 1q
2-[4-(3-Amino-6-bromo-quinolin-4-ylamino)-phenyl]-2-methyl-propionitrile
##STR00009##
[0088] 24 g (58.4 mmol) of
2-[4-(6-bromo-3-nitro-quinolin-4-ylamino)-phenyl}-2-methyl-propionitrile
(Example 1e) is shacked in 300 ml of MeOH-THF (1:1) under 1.1 bar
of H.sub.2 in the presence of 8.35 g of Raney-Ni for 1 h. After
completion of the reaction, the catalyst is filtered off and the
filtrate is evaporated to dryness to give the title compound as a
yellow foam. ES-MS: 381, 383 (M+H).sup.+, Br pattern; analytical
HPLC: t.sub.ret=3.21 min (Grad 1).
Example 1h
2-[4-(8-Bromo-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-2-met-
hyl-propionitrile
##STR00010##
[0090] A solution of 5 g (13.1 mmol) of
2-[4-(3-amino-8-bromo-quinolin-4-ylamino)-phenyl]-2-methyl-propionitrile
(Example 1g) and 1.59 g (15.7 mmol) of triethylamine in 120 ml
CH.sub.2Cl.sub.2 is added over 40 min to a solution of 2.85 g (14.4
mmol) of trichloromethyl chloroformate (Fluka, Buchs, Switzerland)
in 80 ml of CH.sub.2Cl.sub.2 at 0.degree. C. with an ice-bath. The
reaction mixture is stirred for 20 min at this temperature then is
quenched with sat, aqueous NaHCO.sub.3, stirred for 5 min and
extracted with CH.sub.2Cl.sub.2. The organic layer is dried over
Na.sub.2SO.sub.4, filtered and evaporated in vacuo to give crude
title compound as a brownish solid. ES-MS: 407, 409 (M+H).sup.+, Br
pattern; analytical HPLC: t.sub.ret=3.05 min (Grad 1).
Example 1i
2-[4-(8-Bromo-3-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phen-
yl]-2-methyl-propionitrile
##STR00011##
[0092] To a solution of 3.45 g (8.47 mmol) of
2-[4-(8-bromo-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl}-2-me-
thyl-propionitrile (Example 1h), 1.8 g (12.7 mmol) of iodomethane
(Fluke, Buchs, Switzerland) and 273 mg (0.847 mmol) of
tetrabutylammonium bromide (Fluka, Buchs, Switzerland) in 170 ml of
CH.sub.2Cl.sub.2 is added a solution of 508 mg (12.7 mmol) of NaOH
(Fluka, Buchs, Switzerland) in 85 ml of H.sub.2O. The reaction
mixture is stirred for 2 days and 900 mg (6.35 mmol) of iodomethane
and 254 mg (6.35 mmol) of NaOH in 5 ml of H.sub.2O are added. The
reaction mixture is stirred for 1 day at it. After this time, the
reaction is quenched with H.sub.2O and extracted with
CH.sub.2Cl.sub.2 (2.times.). The organic layer is washed with
brine, dried over Na.sub.2SO.sub.4, filtered and evaporated in
vacuo to give the title compound as a beige solid. ES-MS: 421, 423
(M+H).sup.+, Br pattern; analytical HPLC: t.sub.ret=3.15 min (Grad
1).
Example 2
2-Methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]qu-
inolin-1-yl)-phenyl]propionitrile p-toluenesulfonate salt
[0093] 26.5 g of
2-Methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]propionitrile are placed together with 55 ml
formic acid into a glass reactor. This mixture is heated to
60.degree. C. to get a clear solution. This solution is
clearfiltered and washed with 36 ml formic acid. Then formic acid
is distilled off until the volume of the residual solution is 55
ml. Then a solution of 11.3 g of p-toluenesulfonic acid in 228 ml
acetone is added at 50.degree. C., followed by further addition of
822 ml acetone within 30 minutes. The salt precipitates from the
reaction mixture. The mixture is cooled to 0.degree. C. within 2 h,
stirred at that temperature for 3 h, is then filtered and washed
with 84 ml acetone. The product is dried at 60.degree. C. in vacuo
for 18 h to yield 29.8 g (82.4%) of the
2-Methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]propionitrile p-toluenesulfonate salt
(crystalline form A).
[0094] The crystalline forms of the present invention are
synthesized in accordance with the following examples which are
illustrative without limiting the scope of the present
invention.
Example 3
Preparation of form A of
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]-propionitrile
[0095] Form A of compound I can be manufactured in the following
way: 241 g of free base are dissolved 2.4 l acetic acid at
50.degree. C. The solution is clearfiltered, washed with 250 ml
acetic acid and then at 50.degree. C. 7.2 l of water are added. The
free base starts precipitating. The mixture is cooled within 1 h to
25.degree. C., is then filtered and washed with 10 l H.sub.2O. The
free base is then dried in vacua at 50.degree. C. over night to
yield 204 g of free base.
Example 4
Preparation of form B of
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]-propionitrile
[0096] 0.47 g of free base (compound I) are placed into a reactor
together with 2 ml of formic acid. The mixture is heated to
60.degree. C. to get a clear solution. Then 5.2 ml of methanol are
added. The mixture is heated at 65.degree. C. for 2 h. Compound I
starts to precipitate (the formic acid is esterified to the
corresponding methylester under these conditions). The mixture is
cooled to room temperature and is stirred at room temperature for
further 2 hours. Then the precipitate is filtered, washed with 2 ml
methanol and dried in vacuo at 60.degree. C. for 17 h to yield form
B of compound I.
Example 5
Preparation of form C of
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]-propionitrile
[0097] Compound I changes its polymorphic form after equilibration
in different solvents (slurry experiment with approx. 20 mg sample
and 0.5 ml solvent at 25.degree. C. for 24 hours equilibration time
(with agitation)). In methanol, methanol/water, DMF, ethanol,
ethylacetate and THF the new form C can be observed.
[0098] Compound I (0.94 g) is added to 14 ml ethanol and heated to
62.degree. C. Then 3 ml of formic acid are added to get a clear
solution. The mixture is stirred 2 h at 62.degree. C., whereby the
free base starts precipitating. The mixture is cooled to room
temperature, is stirred at room temperature for 2.5 hours and is
then filtered off. The filter cake is then washed with 5 ml ice
cold ethanol and then dried in vacuo at 60.degree. C. over night,
to obtain form C of compound I.
[0099] Alternatively compound I is dissolved in formic acid at
60.degree. C., clearfiltered and then methanol is added. After
stirring for 2 hours at 65.degree. C., the mixture is cooled to
room temperature, the salt is filtered and washed with ice cold
methanol to yield form C of compound I.
Example 6
Preparation of form D of
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]-propionitrile
[0100] Compound I changes its polymorphic form after equilibration
in different solvents (slurry experiment with approx. 20 mg sample
and 0.5 ml solvent at 25.degree. C. for 24 hours equilibration time
(with agitation)). In isopropanol as solvent the new form D can be
observed.
Example 7
Preparation of form H.sub.A of
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]-propionitrile monohydrate
[0101] This compound is obtained after crystallization by slow
solvent evaporation from DMF solution at room temperature.
Example 8
Preparation of form A of
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]-propionitrile monotosylate
[0102]
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4-
,5-c]quinolin-1-yl)-phenyl]-propionitrile (compound of formula I)
is dissolved in formic acid at 56.degree. C. and the resulting
solution is clear filtered. The filtrate is then concentrated and a
solution of p-toluenesulfonic acid (1.05 eq) in acetone is added
within 30 minutes. After 25% and 50% of the addition volume, the
mixture is seeded to initiate crystallization. A further amount of
acetone is added and the suspension is cooled down to 0.degree. C.
The crystallized product (form A of compound I monotosylate) is
collected by centrifugation and dried at 60.degree. C. under
vacuum.
Example 9
Preparation of form B of
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]-propionitrile monotosylate
[0103] A phase transformation of form A prepared according to
Example 8 to another crystalline form, further on named form B, can
be observed at temperatures above 70.degree. C. (this can also be
detected in the corresponding DSC. The transformation is reversible
as found by DSC experiments. Form A and Form B have an
enantiotropic relationship.
Example 10
Preparation of form H.sub.A of
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]-propionitrile monotosylate monohydrate
[0104] A saturated solution of compound I ditosylate in
ethanol/acetone (1:1) can be used in a slow solvent evaporation
experiment at 25.degree. C. The formation of single crystals of
compound 1 monotosylate monohydrate (form H.sub.A) has been
observed and the single crystal structure could be calculated.
Example 11
Preparation of form H.sub.B of
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]-propionitrile monotosylate dihydrate
[0105] By equilibration experiment of compound I ditosylate in
water (after 3 days time) at 25.degree. C. the formation of single
crystals was observed. The crystal structure could be determined
and was calculated to be compound 1 monotosylate dihydrate (form
H.sub.B).
Example 12
Preparation of form S.sub.A of
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]-propionitrile monotosylate diformic acid
solvate
[0106] The single crystal structure of compound I monotosylate
diformic acid solvate was determined by X-ray diffraction
(modification S.sub.A). Suitable single crystals were obtained by
equilibration of compound I monotosylate in acetone/formic acid
(1:1 (v/v)) solvent mixture at 50.degree. C. after cooling down to
room temperature. The stoichiometry of this salt could be
determined to be 1:1.7 (compound I p-toluenesulfonate salt/formic
acid). The stoichiometry has been calculated to be 1:1.7 but as one
solvate molecule is disordered it seems to be that a stoichiometry
of 1:2 is probable. Due to the possibility for formic acid to leave
the structure stoichiometric ratios below 1:2 are observed.
Example 13
Preparation of form A of
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]-propionitrile ditosylate
[0107] When a solution of compound I in formic acid is treated with
an acetone solution of p-toluene sulfonic acid (1.25 eq) the
ditosylate salt of compound I can be isolated as a second crop from
crystallization from the mother liquor after filtering off the
monotosylate salt.
[0108] The compound I ditosylate salt has initial loss on drying of
0.4% (up to 140.degree. C.). DSC data showed a melting at approx.
262.degree. C. with a melting enthalpy of approx. 93 J/g.
Example 14
Preparation of form H.sub.A of
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]-propionitrile ditosylate trihydrate
[0109] From a saturated solution of compound I ditosylate salt in
dichlormethane/methanol (1:1 (v/v)) mixture the compound I
ditosylate trihydrate form (modification H.sub.A) could be observed
and single crystals were found.
Example 15
Preparation of amorphous
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]-propionitrile monotosylate
[0110] Amorphous material has been produced by spray drying of
compound I monotosylate. The glass transition, Tg, has been
observed by DSC at approx. 128.degree. C. After recrystallization
at approx. 175.degree. C. the substance melted at approx.
279.degree. C. with an melting enthalpy of approx. 65 J/g.
Example 16
Preparation of form S.sub.C of
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl)-2,3-dihydro-imidazo[4,5-c]-
quinolin-1-yl)-phenyl]-propionitrile monotosylate diformic acid
solvate monohydrate
[0111] The single crystal structure of compound I monotosylate
diformic acid solvate monohydrate was determined by X-ray
diffraction (modification S.sub.C). Suitable single crystals were
obtained by equilibration of compound I monotosylate in
methylisobutylketone/formic acid (1:1 (v/v)) solvent mixture at
50.degree. C. after cooling down to room temperature.
Example 17
Preparation of form S.sub.B of
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]-propionitrile monotosylate diacetic acid
solvate
[0112] The single crystal structure of compound I monotosylate
diacetic acid solvate was determined by X-ray diffraction
(modification S.sub.C). Suitable single crystals were obtained by
equilibration of compound I monotosylate in
methylisobutylketone/acetic acid (1:1 (v/v)) solvent mixture at
50.degree. C. after cooling down to room temperature.
* * * * *