NZ616198B2 - Substituted 2,3-dihydroimidazo[1,2-c]quinazoline salts - Google Patents
Substituted 2,3-dihydroimidazo[1,2-c]quinazoline salts Download PDFInfo
- Publication number
- NZ616198B2 NZ616198B2 NZ616198A NZ61619812A NZ616198B2 NZ 616198 B2 NZ616198 B2 NZ 616198B2 NZ 616198 A NZ616198 A NZ 616198A NZ 61619812 A NZ61619812 A NZ 61619812A NZ 616198 B2 NZ616198 B2 NZ 616198B2
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- NZ
- New Zealand
- Prior art keywords
- mixture
- formula
- dihydrochloride salt
- compound
- cancer
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- NTTQCLSBWRKUIJ-UHFFFAOYSA-N 2,3-dihydroimidazo[1,2-c]quinazoline Chemical class C1=CC=C2C3=NCCN3C=NC2=C1 NTTQCLSBWRKUIJ-UHFFFAOYSA-N 0.000 title 1
- 239000011780 sodium chloride Substances 0.000 claims abstract description 120
- 150000003839 salts Chemical class 0.000 claims abstract description 119
- 239000000203 mixture Substances 0.000 claims abstract description 107
- 201000011510 cancer Diseases 0.000 claims abstract description 28
- 239000003814 drug Substances 0.000 claims abstract description 24
- 201000010099 disease Diseases 0.000 claims abstract description 22
- 238000002360 preparation method Methods 0.000 claims abstract description 17
- 230000000069 prophylaxis Effects 0.000 claims abstract description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 14
- 239000008177 pharmaceutical agent Substances 0.000 claims abstract description 13
- 210000003494 Hepatocytes Anatomy 0.000 claims abstract description 11
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 10
- 206010025650 Malignant melanoma Diseases 0.000 claims abstract description 10
- 201000009030 carcinoma Diseases 0.000 claims abstract description 10
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- 208000008443 Pancreatic Carcinoma Diseases 0.000 claims abstract description 9
- 201000001441 melanoma Diseases 0.000 claims abstract description 9
- 201000002528 pancreatic cancer Diseases 0.000 claims abstract description 9
- 239000012453 solvate Substances 0.000 claims abstract description 7
- 208000002154 Non-Small-Cell Lung Carcinoma Diseases 0.000 claims abstract description 6
- 230000033115 angiogenesis Effects 0.000 claims abstract description 5
- 230000003463 hyperproliferative Effects 0.000 claims abstract description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 4
- 201000011231 colorectal cancer Diseases 0.000 claims abstract description 4
- 201000005202 lung cancer Diseases 0.000 claims abstract description 4
- -1 2-amino-N-[7-methoxy(3-morpholinylpropoxy)-2,3-dihydroimidazo[1,2- c]quinazolinyl]pyrimidinecarboxamide dihydrochloride salt Chemical compound 0.000 claims description 104
- 150000001875 compounds Chemical class 0.000 claims description 80
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- 239000007787 solid Substances 0.000 claims description 37
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- 239000001632 sodium acetate Substances 0.000 description 1
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- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 229940001607 sodium bisulfite Drugs 0.000 description 1
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- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate dihydrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229960000999 sodium citrate dihydrate Drugs 0.000 description 1
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- PHPHRWZFQRLJIA-UZUGEDCSSA-M sodium;(2S,3R,4S,5S,6R)-6-(hydroxymethyl)oxane-2,3,4,5-tetrol;chloride Chemical compound [Na+].[Cl-].OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O PHPHRWZFQRLJIA-UZUGEDCSSA-M 0.000 description 1
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- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000009168 stem cell therapy Methods 0.000 description 1
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- 239000008227 sterile water for injection Substances 0.000 description 1
- 239000008229 sterile water for irrigation Substances 0.000 description 1
- 239000003351 stiffener Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- AHBGXTDRMVNFER-FCHARDOESA-L strontium-89(2+);dichloride Chemical compound [Cl-].[Cl-].[89Sr+2] AHBGXTDRMVNFER-FCHARDOESA-L 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
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- 239000007885 tablet disintegrant Substances 0.000 description 1
- 229950010924 talaporfin Drugs 0.000 description 1
- FQZYTYWMLGAPFJ-OQKDUQJOSA-N tamoxifen citrate Chemical compound [H+].[H+].[H+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 FQZYTYWMLGAPFJ-OQKDUQJOSA-N 0.000 description 1
- 229960002613 tamsulosin Drugs 0.000 description 1
- 101700082413 tant Proteins 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
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- 201000003120 testicular cancer Diseases 0.000 description 1
- 229960000874 thyrotropin Drugs 0.000 description 1
- 230000001748 thyrotropin Effects 0.000 description 1
- 229960005324 tiludronic acid Drugs 0.000 description 1
- 210000001519 tissues Anatomy 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 231100000730 tolerability Toxicity 0.000 description 1
- 230000000699 topical Effects 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- VXKHXGOKWPXYNA-PGBVPBMZSA-N triptorelin Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 VXKHXGOKWPXYNA-PGBVPBMZSA-N 0.000 description 1
- 229960000294 triptorelin pamoate Drugs 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- 235000019263 trisodium citrate Nutrition 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
Disclosed are 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo- [1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride salts of formula (II) : or a tautomer, solvate or hydrate thereof; methods of preparing said dihydrochloride salt; said dihydrochloride salt for the treatment and/or prophylaxis of a disease; the use of said dihydrochloride salt for the preparation of a medicament for the treatment and/or prophylaxis of a disease, in particular of a hyper- proliferative and/or angiogenesis disorder, more particularly for the treatment or prophylaxis of a cancer, particularly lung cancer, in particular non-small cell lung carcinoma, colorectal cancer, melanoma, pancreatic cancer, hepatocyte carcinoma, pancreatic cancer, hepatocyte carcinoma or breast cancer; a pharmaceutical composition comprising said dihydrochloride salt; and a pharmaceutical combination comprising said dihydrochloride salt in combination with one or more further pharmaceutical agents. tment and/or prophylaxis of a disease; the use of said dihydrochloride salt for the preparation of a medicament for the treatment and/or prophylaxis of a disease, in particular of a hyper- proliferative and/or angiogenesis disorder, more particularly for the treatment or prophylaxis of a cancer, particularly lung cancer, in particular non-small cell lung carcinoma, colorectal cancer, melanoma, pancreatic cancer, hepatocyte carcinoma, pancreatic cancer, hepatocyte carcinoma or breast cancer; a pharmaceutical composition comprising said dihydrochloride salt; and a pharmaceutical combination comprising said dihydrochloride salt in combination with one or more further pharmaceutical agents.
Description
TUTED 2,3-DIHYDROIMIDAZO[1,2-C]QU|NAZOL|NE SALTS
The present invention relates :
- to 2-amino-N-[7-methoxy(3-morpholinylpropoxy)-2,3-dihydroimidazo-
]quinazolinyl]pyrimidinecarboxamide dihydrochloride salt of
formula (II) :
N N
K [‘3
N O
O NAN)?”\ \ NJ\NH2
.2HCI
(ll),
or a tautomer, solvate or hydrate thereof,
(which is hereinafter referred to as “the salt of the present invention” or the
“dihydrochloride salt”) ;
- to s of preparing said salt of the present invention ;
- to said salt of the t invention for the treatment and/or laxis of a
disease;
- to the use of said salt of the t invention for the preparation of a
medicament for the treatment and/or prophylaxis of a disease, in particular
of a hyper-proliferative and/or angiogenesis disorder, more particularly for
the treatment or prophylaxis of a cancer, particularly lung cancer, in
particular non-small cell lung carcinoma, ctal cancer, melanoma,
pancreatic cancer, hepatocyte carcinoma, or breast cancer ;
- to a pharmaceutical composition comprising said salt of the present
invention ; and
- to a pharmaceutical combination comprising said salt of the present invention
in combination with one or more further pharmaceutical agents.
Background to the Invention
The nd of formula (I) :
3$519 0
(I),
(which is hereinafter referred to as the “compound of a (|)” or the “free
base”), is a etary cancer agent with a novel mechanism of action,
inhibiting Class I phosphatidylinositol-B-kinases (PI3Ks). This class of kinases is
an attractive target since PI3Ks play a central role in the transduction of
cellular signals from surface receptors for survival and proliferation. The
compound of formula (I) exhibits a broad spectrum of activity against tumours
of multiple histologic types, both in vitro and in viva.
Said compound of formula (I) may be synthesised according to the methods
given in international patent application 2003/010377, hed as WO
04/029055 A1 on April 08, 2004, (which is incorporated herein by reference in
its entirety), on pp. 26 et seq.
Moreover, said compound of formula (I) is published in ational patent
application PCT/U52007/024985, published as A1 on June 12,
2008, (which is incorporated herein by reference in its entirety), as the
nd of Example 13 : 2-amino-N-[7-methoxy(3-morpholinylpropoxy)-
2,3-dihydroimidazo[1,2-c]quinazolinyl]pyrimidinecarboxamide. Further,
said compound of formula (I) is, in , described on pp. 9 et
seq., and may be synthesized according to the methods given therein on pp. 42
et seq. ical test data for said compound of formula (I) is given therein on
pp. 101 to 107.
Said compound of formula (I) may exist in one or more tautomeric forms :
tautomers, sometimes ed to as proton-shift tautomers, are two or more
compounds that are related by the migration of a hydrogen atom accompanied
by the migration of one or more single bonds and one or more adjacent double
bonds.
The compound of formula (I) may for e exist in tautomeric form (Ia),
tautomeric form (lb), or tautomeric form (Ic), or may exist as a mixture of any
of these forms, as depicted below. It is intended that all such tautomeric
forms are included within the scope of the present invention.
KN “IE? ('0)
Said compound of formula (I) may exist as a solvate : a e for the purpose
of this invention is a complex of a solvent and a compound of formula (I) in the
solid state. Exemplary solvates e, but are not limited to, complexes of a
compound of the invention with ethanol or methanol.
Said compound of formula (I) may exist as a hydrate : Hydrates are a specific
form of e wherein the solvent is water.
Technical problem to be solved :
In general, for a given pharmaceutically active compound, ceutically
acceptable forms of said given pharmaceutically active compound are d,
with the view to increasing the ceutical effectiveness of said
pharmaceutically active compound, e.g. improving physical chemical
characteristics, such as chemical stability, physical stability, solubility in vivo,
improving absorption of the pharmaceutically active compound in vivo, etc. In
addition, a drug substance would ideally come in a stable crystal form that can
be produced in a reliable way. Amorphous or crystal forms of low order (e.g.
mesomorphic forms) are less attractive as they carry the risk of a later form
change and changes of physical properties.
However, said compound of a (I) (which is a free base) could only be
prepared in a mesomorphic form that is stable in solid form, but unstable at
70°C in acidic aqueous on and carries the above mentioned risk of a later
form change.
The formation of a crystalline salt form of the free base (I) might solve the
above mention problem once the properties of this form are advantageous with
respect to the properties of the free base (|). In our efforts to prepare
lline salt forms of (I) we experienced that preparing crystalline salt
forms of (|) is not as easy as one might expect for a compound carrying basic
centers.
Furthermore, the nd of formula (I) exhibits very low solubility in water
and most organic solvents. With two very basic centres (Table |, vide infra),
solubility is strongly improved in acidic media. Consequently, purification of
and final processing of the compound of formula (I) is a challenging task.
The following structure shows the compound of formula (I), on which
calculated pKa values have been given in parentheses.
COMPOUND of FORMULA (I)
Table I : pKa values of the compound of formula (I) :
funct. group / pKa values experimental calculated
pKa (Imidazolinoamindine) - ‘ 10,1
pKa oline) - ‘ 7,43 — 7,5
pKa (Aminopyrimidine) - 1,99 - 2,11
More ularly, with regard to the unique chemical structure of the
compound of formula (I), vide supra, the physical properties of the compound
of formula (I) are not only nging with regard to the chemical s, the
handling of the drug substance and the production of drug product, but
additionally offer significant challenges for the development of a stable and
reliable HPLC method as well.
It would be ble to have a pharmaceutically acceptable and lline
form of the compound of formula (I) which allows its reliable purification,
e.g., by crystallization, in view of the ult, specific technical problems and
very low aqueous solubility, and which is easy to handle (e.g., which is a free-
g solid).
Solution to the technical problem :
Various attempts were made to prepare crystalline salts of the compound of
formula (I). The formation of crystalline salt forms proved to be difficult, as in
general no solution was achieved and in several cases gum-like, sticky
materials were formed.
Unexpectedly, and this represents a basis of the present invention, it has been
discovered that the ochloride salt of the compound of formula (I), of the
present ion (no specific disclosure of which is known to the Applicant’s
knowledge in the prior art), possesses technically advantageous properties, as
seen inter alia in the Experimental Section and Conclusion Section of this text.
The present invention thus relates :
to 2-amino-N-[7-methoxy(3-morpholinylpropoxy)-2,3-dihydroimidazo-
[1,2-c]quinazolinyl]pyrimidinecarboxamide dihydrochloride salt of
formula (II) :
N O
O\ \NXNHZ
.2HCI
(ll),
or a tautomer, solvate or e thereof,
(which is hereinafter referred to as “the salt of the present invention” or the
“dihydrochloride salt”) ;
- to s of preparing said salt of the present invention ;
- to the salt of the present invention, when prepared by such methods ;
- to said salt of the present invention for the treatment and/or prophylaxis of a
disease;
- to the use of said salt of the present ion for the preparation of a
medicament for the treatment and/or prophylaxis of a disease, in particular
of a hyper-proliferative and/or angiogenesis disorder, more particularly for
the ent or prophylaxis of a cancer, in particular non-small cell lung
carcinoma, colorectal cancer, melanoma, pancreatic cancer, hepatocyte
carcinoma or breast cancer ;
- to a pharmaceutical composition comprising said salt of the present
invention ; and
- to a pharmaceutical combination comprising said salt of the present invention
in combination with one or more further pharmaceutical agents.
Methods of preparing the salt of the present ion
The present ion also relates to a method of preparing the
dihydrochloride salt of formula (II) of the present invention, which involves the
addition of hydrochloric acid to the compound of a (I), or, inversely, the
addition of the nd of formula (I) to hydrochloric acid.
In accordance with an embodiment of the present invention, said method of
preparing the dihydrochloride salt of formula (II) of the present invention
comprises adding hydrochloric acid to a compound of formula (I) :
preferably in suspension,
thereby forming said dihydrochloride salt of formula (II) :
3d}0
.2HCI
(II).
In accordance with an embodiment of the present invention, said method of
preparing the dihydrochloride salt of a (II) of the present invention
comprises :
a) adding hydrochloric acid, such as aqueous hydrochloric acid solution
(32%) for e, to a suspension of said compound of a (I) in a
medium, such as water for example, at a temperature of between the
freezing point of the mixture and the boiling point of the mixture, such
as at a temperature of 20 °C (+-2°), until a pH of 3 to 4 is reached ;
b) stirring the resulting mixture at a temperature of between the freezing
point of the e and the boiling point of the mixture, such as at
room temperature for example, for a period of time, such as for more
than 10 minutes for example ; and, optionally
c) filtering off the resulting solid and washing the filtercake, such as with
water for example, then ing the pH of the filtrate to pH 1.8 to 2.0
using hydrochloric acid, such as s hydrochloric acid solution (32%)
for example ; and, optionally,
d) stirring the mixture for a period of time, such as 10 minutes for
example, at a temperature between the freezing point and the boiling
point of the mixture, such as at room ature for example, adding
ethanol, followed by r stirring for a period of time, such as for 10
s for example ; and, ally,
e) adding seed crystals, optionally followed by adding ethanol over a
period of time such as within 5 hours for example ; and, optionally,
f) ing off the resulting dihydrochloride of formula (II), optionally
washing with a water-ethanol mixture and optionally drying, such as in
vacuo for example,
thus providing the dihydrochloride salt of formula (II) of the present invention.
In accordance with an embodiment of the present invention, said method of
preparing the dihydrochloride salt of formula (II) of the present invention
comprises :
a) adding said hydrochloric acid to said compound of formula (I) in
acetone/water or ethanol/water for example ; and, then, optionally,
b) heating at a temperature between the boiling point and the freezing
point of the mixture, such as at 40 to 60 °C for example, such as at 50
°C for example, for a period of time preferably of 0,2 to 2 hours for
e, such as for 0,5 hours for example ; then, optionally,
c) heating further at a temperature between the boiling point and the
freezing point of the mixture, such as at 30 to 40 °C for example, such
as at 35°C for example, for a period of time such as 1 to 4 hours for
example, with al stirring of said sion at a temperature of
between the boiling point and the freezing point of the mixture, such as
to 45 °C for example, such as at 35°C for example, for a period of
time preferably 12 to 72 hours for example, such as for 72 hours for
example, ally followed by stirring said suspension at a
temperature of between the freezing point of the mixture and the
boiling point of the mixture, such as at room temperature for example,
for a period of time of 0 to 4 hours, such as 2 hours for example ; and,
optionally,
d) filtering, optional washing and drying,
thus providing the dihydrochloride salt of formula (II) of the present invention.
In accordance with an embodiment of the present invention, said method of
ing the dihydrochloride salt of formula (II) of the present invention is as
said hydrochloric acid is concentrated aqueous hydrochloric acid solution (1,33
g, 36% HCl) and is added to said compound of formula (I) in an acetone / water
mixture (50 mL, 8:2 v/v), followed by g at a temperature of 50 °C, for a
period of time of 0,5 hours, then followed by further g, at a
temperature of 35 °C, for a period of time of 72 hours, then with stirring of
said suspension at a temperature of room temperature, for a period of time of
2 hours, followed by tion, washing with an acetone/water mixture, and
drying in a vacuum oven (40 °C, 100 mbar, 16 h), thus providing said
dihydrochloride salt of formula (II) of the present invention.
The present invention also relates to the dihydrochloride salt of a (II) of
the present invention, when prepared by the above described methods.
EXPERIMENTAL SECTION
The following terms and abbreviations are used in the following text :
“compound of formula (I)” or “free base” means 2-amino-N-[7-methoxy(3-
morpholinylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolinyl]pyrimidine
carboxamide of formula (I) :
3d?0
(I),
which is the compound of Example 13 of A1 as indicated vide
supra.
“DS” means “drug substance”, i.e., the und of formula (I)” or “free
base”
“dihydrochloride salt of formula (II)” or “salt of a (II)” means 2-amino-N-
[7-methoxy(3-morpholinylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-
5-yl]pyrimidinecarboxamide dihydrochloride, which is the dihydrochloride
salt of formula (II) :
2012/055600
91cc? 0
.2HCI
(H);
“NMP” means N-Methylpyrrolidinone (solvent) :
“XRPD” means “X-ray powder diffraction” : the apparatus used for
measurements mentioned is the following :
STOE Powder Diffraction System:
Diffractometer : Transmission
Monochromator : Curved Germanium (111)
Generator : 45 kV, 35 mA
Wavelength : 1.540598 Cu
Detector : Linear PSD
Scan Mode : Transmission / Moving PSD / Fixed omega
Scan Type : 2Theta: Omega
Room conditions : 25 °C, 40 — 60 %rF
“IC” means “Ion Chromatography” :
Machine: Merck |on tograph with ssor System
Detection : Conductivity detector, Fa. Metrohm
“TGA” means “Thermogravimetric is” :
Machine : Thermogravimetric Analyzer TGA 7 or TGA 850e
Producer : Perkin Elmer or Mettler-Toledo
g rate : 10 Kmin'1 or 5 K/min
Flushing gas (Spiilgas) : nitrogen 20-30 ml/min
Crucible l) : open platinum crucible er Platin-Tiegel)
Sample preparation : none
“DSC” means “Differential Scanning Calorimetry” :
Machine : Differential ng meter DSC 7 or Pyris-1 or DSC 821e
Producer : Perkin-Elmer or Mettler-Toledo
Heating rate : 2 and 20 K/min or 5 K/min
Flushing gas (Spiilgas) : nitrogen
Crucible (Tiegel) : non-gas tight aluminium crucible
Sample preparation : none
,,DVS“ means ,,Dynamic Vapour Sorption“ :
Machine : Dynamic Vapour Sorption Analyzer IGA Sorp from the firm Hiden
Analytical.
The operating temperature was 25°C. Sample preparation : none.
“Pred.” or “predom.” means “predominantly”.
Overall CD (subjective) judgement with regard to overall chemical
developability.
Exam le 1 : dih drochloride salt of formula II
To a suspension of the compound of formula I (3 g) in an acetone / water
mixture (50 mL, 8:2 v/v) was added a concentrated aqueous hydrochloric acid
solution (1,33 g, 36% HCl) resulting in no visible changes. The resulting
mixture was stirred at 50 °C for 0,5 h, followed by 35 °C for 3 days, then room
temperature for 2 h. The resulting solid al was isolated by filtration,
washed with an acetone/ water mixture (8:2 v/v) and dried in a vacuum oven
(40 °C, 100 mbar, 16 h) to give the desired material (3,2 g, 93% yield). Note:
the solids had actable filtration characteristics.
characterization:
HPLC, wt% DS 72,8 wt%, y significantly improved with
~97,8% area%, sum of regard to Batch A
impurities ~2,2%
--—DSC broad peaks (60°,
--—XRPD crystalline ences prob. due to solvent
roscopy Microcrystalline,
XRPD results are consistent with the solids formed being crystalline.
IC results are tent with formation of the dihydrochloride.
TGA results are consistent with the solids containing 13-14% solvent and/or
water.
Analytical HPLC wt% DS is consistent with dihydrochloride solids containing 13-
14% solvent and/or water. The HPLC area integration shows 2,2% impurity.
stability as solid:
The dihydrochloride of formula (II) (100 mg from Example 4) was stored at
90°C for 1 week, then analyzed by HPLC.
HPLC, area% DS ~ 98,2%; sum of Stable
impurities ~1,8%
s solubility:
The dihydrochloride of formula (II) (500 mg from Example 4) was stirred at 25
°C for 20 h in water (5 mL). The resulting suspension was filtered over a
membrane , the pH of the resulting solution was measured and the
solubility was determined by HPLC. Solid material retained on the filter was
ed by XRPD and TGA.
H . .
XRPD (solid residue)-_crystalline Almost identical; slight widening of
TGA (solid residue) 13,9% up to 200°C;
2012/055600
Additional solubility data:
The dihydrochloride of formula (II) was stirred in 20 mL of different solvents
for 20h at 25°C. In all hydrous solvents approx. 2g of the dihydrochloride of
formula (II) have been solved completely.
t Solubility
Acetone 0.3 mg/100ml practically insoluble
Acetonitrile 1.1 mg/100ml practically insoluble
Ethanol 24.8 mg/100ml very slightly soluble
PEG400 301 mg/100ml slightly soluble
0,1M HCl 2 8800 mg/100ml soluble
Buffer pH 4.5 2 8900 mg/100ml soluble
Buffer pH 7.0 2 8700 ml soluble
Water 2 9400 ml soluble
stability in solution:
Hydrolytic stability
The different aqueous solutions (0.05 % of free base of formula (I) ; after
addition of 50 % 2-Propanol, r solution filtered with 0.5um membrane
filter]) were stored at 25°C and 70°C for 24 h and one week.
Conditions Appearance Organic Organic
impurities, impurities,
sum of all single
[Area %] [Area %]
Water:
Initial
24 h, 25°C
24h, 70°C
1 week, 25°C
1 week, 70°C
Buffer pH 7:
Initial
solution
24 h, 25°C slightly colored turbid 3.22 0.20
solution
24 h, 70°C slightly d solution 56.06 23.25
1 week, 25°C slightly colored turbid 4.85 0.82
solution
1 week, 70°C slightly colored solution 97.65 39.01
0,1M HCI :
Initial slightly colored on 5.87 1.13
24 h, 25°C slightly colored on 8.75 1.90
24h, 70°C slightly colored solution 92.49 22.82
1 week, 25°C slightly colored solution 24.27 7.15
1 week, 70°C ly colored solution 100.00 25.48
slightly colored solution 30.72 6.51
24 h, 25°C slightly d solution 45.40 10.02
24h, 70°C slightly colored solution 99.88 23.94
1week, 25°C slightly colored solution 86.64 22.03
1week, 70°C slightly colored solution 99.90 32.63
IR and Raman spectroscopy
Apparatus and measuring conditions
FI'-IR / FT-Raman-Spectrometer Bruker IFS 66v / Bruker RFS 100
Spectral resolution 2 cm'1 / 2 cm'1
Number of interferograms 32 / 64
Wave number range 4000 — 500 cm'1 / 3500 — 100 cm'1
Laser power - / 350mW
Sample preparation KBr pellet / solid in test tube
ment of the characteristic bands
Table: Assignment of the characteristic active vibrations to the um with
v E stretching vibrations; 8 E bending vibrations; o.o.p. 2 out of plane.” ;
ed Structure IR Band position [cm'1] Raman Band position [cm'1]
v N-H 3336 -
v =C-H 3176 3090
v C-H 2942 2990 — 2963
v NH+ 2687 — 2474 -
v Amide | 1669 1664
v C=C, v C=N, 6 N-H, Amide || 1618 — 1477 1619 — 1476
v C-O 1285 1291
6 =C-H o.o.p. 812 -
v E stretching vibrations; 8 E bending vibrations; o.o.p. 2 out of plane
The IR spectrum is given in Figure 1.
The Raman spectrum is given in Figure 2.
UVNIS spectroscopy
Apparatus and measuring conditions
UV/VIS spectrometer Varian Cary 4
e Quartz, 1 cm
Wave number range 200-800 nm
Sample preparation 4.67 mg / 500 mL water
Bands 309 nm
The UV/vis spectrum is given in Figure 3.
NMR oscopy
1H-NMR-spectroscopy
Equipment and experimental parameters:
NMR spectrometer Bruker, model Avance
Working frequency 500.13 MHZ
t Dimethylsulfoxide (DMSO'dé)
Internal reference compound Tetramethylsilane (TMS)
Concentration 3.08 mg/mL solution
Diameter of sample tube 5 mm
Temperature . 25°C
Technique Fourier transform mode
Spectral width 20.65ppm
Digital resolution 0.079 HZ/Pt
Pulse length 4.5 usec, 30° Pulse flip angle
Acquisition time 6.34sec
Relaxation time 0.5sec
No. of free induction decays 32
Structural Formula for the ment of NMR signals
HCI HCI 2
flakif:
3° (9N\N
27 /\8025 6a N
OW 70 13 14\
32 23 NAZI—'2
Chemical shift, signal multiplicity, relative number of nuclei :
H-atoms(a) Chemical shift Multiplicity and no. of nuclei
8 (ppm) ng constants H/molecule
H-26 2.32 M 2
H-29; H-33 3.11; 3.48 M; M 2; 2
H-30; H-32 3.83; 3.98 M; M 2; 2
H-27 3.29 M 2
-OCH3 4.00 S 3
H-25 4.37 T 2
H-2; H-3 4.47; 4.19 T; T 2; 2
H-9 7.39 D 1
NHz 7.54 S 2
H-10 8.21 D 1
H-16; H-20 8.97 S 1; 1
HCl 11.1; 12.6 b5; b5 1; 1
H-12 13.4 b5 1
a) Numbering refers to the structural formula for the assignment of NMR-
signals.
b) S = Singlet bS = broad Singlet D = Doublet
T = Triplet M = Multiplet
The 1H-NMR Spectrum of the dihydrochloride of formula (II) is given in Figure 4.
1 3C-NMR—spectroscopx
Equipment and experimental parameters
NMR spectrometer Bruker, model Avance
Working frequency 125.76 MHZ
t Dimethylsulfoxide-d6 (DMSO)
Internal reference compound Tetramethylsilane (TMS)
Concentration 37.2 mg/mL solution
Diameter of sample tube 5 mm
Temperature approx. 27°C
Technique Fourier orm mode
Spectral width 240.95 ppm
Digital resolution 0.4624 HZ/Pt
Pulse length 11.0 usec, 90° Pulse flip angle
Acquisition time 1.08 sec
tion time 4 sec
No. of free induction decays 256
2012/055600
Chemical shift, signal multiplicity, rel. no. of nuclei :
C-atoms(a) Chemical shift Multiplicity and no. of nuclei
8 (ppm) coupling constants (b) C/molecule
C-26 22.73 T 1
C-2; C-3 44.96; 45.65 T;T 1,1
C-29; C-33 50.84 T 1;1
C-27 53.01 T 1
OCH3 61.24 Q 1
C-30; C-32 63.03 T 1;1
C-25 66.81 T 1
C-10a 100.79 s 1
C-9 112.17 D 1
C-15 118.16 s 1
C-10 123.86 D 1
C-6a 132.43 s 1
C-7 133.95 s 1
C-5 148.58 s 1
C-11 156.29 s 1
C-8 156.89 s 1
C-16; C-20 160.20 D 1;1
C-18 164.61 s 1
C=O 175.65 s 1
a) Numbering refers to the structural formula for the assignment of NMR-signals.
b) S = Single (C) D = Doublet (CH) T = Triplet (CH2) Q = Quadruplet (CH3)
The 13C-NMR Spectra of the dihydrochloride of formula (II) are given in Figures 5
and 6.
Mass Spectrometry
Instrumental Parameters
Mass spectrometer Waters ZQ
Ionization mode ESI (Electrospray-lonization)
Solvent CH3CN/H20
Interpretation of the Spectrum
Mass value 1m/z! Rel. Intensit %
241.2 (M + 2H)+2
The Mass Spectrum of the ochloride of a (II) is given in Figure 7. Refer to
the spectrum for relative peak intensities.
Elemental Analysis
Elemental analysis was conducted by Bayer Industry Services, Leverkusen, Germany.
Results
Element ed Calculated ated Difference
[%] [%] including 7.0 %
water
C 47.5 49.9 46.4 1.1
H 5.7 5.5 5.9 0.2
N 19.1 20.3 18.8 0.3
O 18.1 11.6 17.0 1.1
Cl 11.9 12.8 11.9 0.0
Sum 102.3 100.1 100.0
The elemental is is consistent with a dihydrochloride salt of a II with 7%
water.
Example 2 : Further method of preparation of the dihydrochloride salt of
formula II
To a suspension of 366 g of compound of formula (I) in 1015 g water, 183 g of
an aqueous hydrochloric acid solution (32%) were added while maintaining the
temperature at 20 °C (+-2°) until a pH of 3 to 4 was reached. The resulting
mixture was stirred at room temperature for more than 10 min. filtered and
the filtercake washed with additional 82 g of water. The filtrate was adjusted
to pH 1.8 to 2.0 using aqueous hloric acid solution (32%). The e
was stirred for 10 min. at room temperature, 146g of ethanol (100%) were
added and stirred for another 10 min.. 1 g of seed crystals were added,
followed by 1592 g ethanol within 5 h. The resulting substance was removed by
filtration, washed with a water-ethanol mixture and dried in vacuo to give 410
g (97%) of the dihydrochloride of formula (II) of a purity >99% according to
HPLC.
Com arative Exam le 1 : monoh drochloride of com ound of formula I
To a suspension of the compound of formula (I) (0,5 g, 1.04 mmol) in an
acetone / water mixture (9 mL, 8:2 v/v) was added a concentrated
hydrochloric acid solution (89 uL, 1.07 mmol, 1.0 equiv, 36% HCl). A visible
change in the e was observed, but a clear solution was not obtained.
The mixture was heated with stirring at 50 °C for 0,5 h, followed by 35 °C for
3 days, then room temperature for 2 h.. The remaining suspended solids were
removed by filtration, washed e/water, (8:2 v/v), and dried (40 °C, 100
mbar, 16 h) to give the desired t (0,5 g).
characterization:
HPLC, wt% DS ~ 85,8 wt%, ~98,4% Quality significantly ed with
area%, sum of regard to Batch A
impurities ~1,6%
IC, wt% salt former 6,0 wt% ~1 :1 -salt
XRPD Predominantly
amorphous
Results indicate that a crystalline monohydrochloride was not formed. Though
the purity of the base was improved by the experiment, no further studies
were performed, as the material was predominantly amorphous.
Com arative Exam le 2: Bis h dro en sulfate salt of the com ound of
To a suspension of the compound of formula (I) (0,5 g, 0.103 mmol) in an
e / water mixture (9 mL, 9:1 v/v) was added a concentrated sulfuric
acid on (213 mg, 96 % H2504, 2 equiv.). A visible change in the mixture
was observed, but a clear solution was not obtained. The mixture was heated
with stirring at 50 °C for 0,5 h, followed by 35 °C for 3 days, then room
ature for 2 h. The remaining suspended solids were isolated by
filtration, washed (acetone/water, 9:1 v/v), and dried (40 °C, 100 mbar, 16 h)
to give approximately 30 mg of the desired product.
Com arative Exam le 3 : citric acid salt of the com ound of formula I
To a suspension of the compound of formula (I) (3,0 g, 6.24 mmol) in an
ethanol / water mixture (50 mL, 1:2 v/v) was added citric acid (2,4 g, 10.2
mmol, 1.6 equiv). The mixture was heated with stirring to 35 °C, 25 ml water
and 100 ml ethanol were added and ng was continued at 35 °C for 2 h.
The resulting clear solution was cooled to room temperature and stirring was
ued for 3 days. The resulting solids were isolated by filtration, washed
with 10 ml ethanol, and dried (40 °C, 100 mbar, 24 h) to give the desired
product (3,8 g, 90% yield). Note: filtration of this material was very slow.
characterization:
HPLC, wt% DS 64,1 wt%, 98,1 area%,
sum of impurities 1,9%
WO 36553
DSC Broad peaks melts with decomposition
--—XRPD Crystalline significant amounts of free base
--—Microscopy Microcrystalline;
All results indicate that a uniform, real salt was not formed but rather a
mixture of the a citric salt, free base and/or citric acid.
stability as solid:
The citric acid salt of compound of a (I) (100 mg from Comparative
Example 3) was stored at 90 °C for 1 week.
HPLC, area% DS 96,3 % Slightly unstable; Sum of impurities
ly higher (3,7% vs. 1,9%)
aqueous solubility:
The citric acid salt of the compound of formula (I) (500 mg from ative
Example 3) was stirred at 25°C for 20 h in water (5 mL). The resulting
suspension was filtered over a membrane filter, the pH of the solution was
measured and solubility was determined by HPLC. The solid material retained
on the filter was analyzed by XRPD and TGA.
XRPD (solid residue) Broad signals Significant change; less crystalline
TGA (solid residue) 4,4% at 30° to120°C;
27% at 120° to 250°C
Com arative Exam le 4 : succinic acid salt of the com ound of formula I
To a suspension of the compound of a (I) (3,0 g, 6,24 mmol) in an
acetone / water mixture (50 mL, 8:2 v/v) was added succinic acid (1,48 g, 12,5
mmol, 2 equiv) to form a white sion. The mixture was heated with
stirring at 50 °C for 0,5 h, ed by 35 °C for 3 days, then room
temperature for 2 h. The appearance of the e did not change
significantly over this period. The resulting solids were removed by filtration,
washed with few mls of an acetone / water mixture (8:2 v/v), and dried (40
°C, 100 mbar, 16 h) to give the desired product (3,4 g, 91%).
characterization:
HPLC, wt% DS 75,6 wt%,
~97,6% area%, sum of
impurities ~2,4%
IC, wt% salt former 15,1 wt% < 1:1-salt
TGA 3,2% up to 50°C; Similar to free base
17,6% @140 - 220°C
Broad peaks Similar to free base
XRPD predom. crystalline significant amounts of free base
detectable
The characterization suggests that a uniform, stochiometric salt was not
formed but rather a mixture of a succinate and the free base.
stability as solid:
The succinic acid salt of the compound of formula (I) (100 mg from
Comparative Example 4) was stored at 90°C for 1 week.
HPLC, wt% DS 48,4 wt% brownish solid after 1 w 90°C
HPLC, area% DS ~ 97,6% (sum of not stable
impurities ~2,4%)
aqueous solubility:
The succinic acid salt of the compound of a (I) (500 mg from
Comparative Example 4) was stirred in water (5 mL) at 25°C for 20 h. The
resulting suspension was filtered over a membrane filter, the pH of the
on was measured, and the solubility was determined by HPLC. The solid
material retained on the filter was analyzed by XRPD and TGA.
XRPD (solid residue) hous; free base detectablePartly crystalline Significant change; partly
TGA (solid residue) -_5,5% at 30° to120°C;
Com arative Exam le 5 : maleic acid salt of the com ound of formula I
To a suspension of the compound of formula (I) (3,0 g, 6,24 mmol) in an
acetone / water mixture (50 mL, 8:2 v/v) was added maleic acid (1,45 g, 12,5
mmol, 2,0 equiv) to form an almost clear solution that became a suspension
after 5 min. The mixture was heated with ng at 50 °C for 0,5 h, ed
by 35 °C for 3 days, then room temperature for 2 h.. The resulting solids were
isolated by filtration, washed with an e / water mixture (8:2 v/v), and
dried (40 °C, 100 mbar, 16 h) to give the desired product (4,0 g, 90%). Note:
filtration of this material proceeded well.
characterization:
HPLC, wt% DS 62,7 wt%,
~95,2% area%, sum of
impurities ~4,8%
IC, wt% salt former 30,7 wt% alt
TGA 5,8% till 50°C; 3,7% @
80-150°C; 20,7% @
160-210°C
-XRPD crystalline differences prob. due to solvent
integration; no free base detectable
Results indicate that a crystalline dimaleate was formed. The purity of the
base was not improved by the formation of the salt in this case.
stability as solid:
The maleic acid salt of the compound of formula (I) (100 mg from Comparative
Example 5) was stored at 90°C for 1 week.
HPLC, area% DS ~ 96,9% (sum of Stable
impurities ~3,1%)
aqueous solubility:
The maleic acid salt of the compound of formula (I) (500 mg from Comparative
Example 5) was stirred in water (5 mL) at 25°C for 20 h. The resulting
suspension was filtered over a membrane filter, the pH of the solution was
measured, and the solubility was determined by HPLC. The solid material
retained on the filter was analyzed by XRPD and TGA.
H . .
XRPD (solid residue)-_crystalline Almost identical; slight widening of
TGA (solid e) 8% at 30°-90°C; 2,5% at
50°C; 14% above
150°C
Comparative Example 6 : methanesulphonic acid salt of the compound of
formula I
To a suspension of the compound of formula (I) (3,0 g, 6,24 mmol) in an
acetone / water mixture (50 mL, 9:1 v/v) was added methanesulphonic acid
(1,2 g, 12,5 mmol, 2 equiv) to form a sticky material. The e was heated
with stirring at 50 °C for 0,5 h, followed by 35 °C for 3 days. The ance
of the mixture did not change icantly over this period. Additional
acetone (50 mL) was added to the mixture and stirring was continued at room
temperature for an additional 5 days, yielding a filterable suspension along
with sticky material. The suspension was d by filtration, washed with
acetone and dried (40 °C, 100 mbar, 16 h) to give the desired product (3,5 g,
83,3 %).
characterization:
analytical method Comments
HPLC, wt% DS 62,9 wt%,
~96,1% area%, sum of
impurities ~3,9%
IC, wt% salt former 26,4 wt% ~ 1:2-salt
TGA 6,3% @ 30-100°C; 22%
Microscopy Microcryst. ,
agglomerates
All results indicate that a crystalline dimesylate salt can be formed. Obviously,
optimal crystallization conditions have not been found and/or the dimesylate
is very sensitive to its ion conditions as the material was amorphous in
part. The polymorphic form produced so far seems to be able to take up
solvents/water.
stability as solid:
The esulphonic acid salt of the nd of formula (I) (100 mg from
Comparative Example 6) was stored at 90°C for 1 week.
aqueous solubility:
The methanesulphonic acid salt of the compound of formula (I) (500 mg from
itive Example 6) was stirred at 25°C for 20 h in water (5 mL). The
sample was almost tely dissolved, The resulting mixture was filtered
over a membrane filter, the pH of the solution was measured, and the
solubility was determined by HPLC. However, not enough solid material was
left after filtration for further analysis.
WO 36553 2012/055600
CONCLUSIONS
From a physicochemical point of view, the dihydrochloride salt of formula (II)
(Example 4) of the present invention provides surprising technical results as
seen in the Examples and Comparative Examples, supra, as summarised in
Table 5, infra :
Table 5
Suc-
Maleic_ Me-
Citric_ _ _ _
cmic Hydro- Compound
ac1d_ sulfomc.
acid acid chloric_ of formula
Property (Comp acid Criteria
(Comp. (Comp acrd (I)
. Ex. (Comp.
Ex. 3) . EX. (Ex. 1) (free base)
) Ex. 6)
iometry ~ 1 : 1 ~ 1 : 1 ~ 1 :2 ~ 1 :2 1 :2 Based on HPLC/IC
yield, final
chem. process 0 — O — O —
processing
purity + + O O + 0 area% HPLC
disintegration
salt stability 0 — + n.d. + + n.a.
with/in water
crystallinity O — + O + + O XRPD
1w @ 95% r.h.; aqu.
hydrates ~ 4 H20
solub.
16h @ 25 °C
aqu. solubility ~ 8,5. ~ 5,5 > 8,1 > 8,3 > 8,8 —
(mg/100ml)
therm. stab. 24h @ 70°C; 1 w @
n.d. n.d. n.d. n.d. n.d. 0
solution 25°C
therm. stab.
+ — — + + + + + 1 w @ 9ODC
solid
Overall CD 0 — — 0 — — + O
very disadvantageous
disadvantageous
O : indifferent
+ : advantageous
++ : very advantageous
n.a.: not applicable
n.f.: not found
n.d.: not determined; no clear solution after filtration, probably due to formation of
micelles.
First, as seen from ative Example 1, unexpectedly, results indicate that
a crystalline monohydrochloride of the compound of a (I) was not
formed : it was predominantly amorphous. In contrast, as seen from e
1, the dihydrochloride salt of formula (II) can form a crystalline, stable
ochloride salt. The crystalline ochloride salt is stable against
reversion in water to the free base.
Further, the dihydrochloride salt of the present invention has a superior
stability in water compared to the other salts mentioned. This means that the
salt does not revert in water to the free base under the conditions tested, i.e.
precipitation of the free base does not occur.
Crystallinity of the dihydrochloride salt of the present invention was superior
vs. the monohydrochloride salt (which was found predominantly amorphous in
XRPD»
ly, as seen from Comparative e 5, (characterisation table), from
the XRPD results, the comments are that there are differences in the maleate
salt of the compound of formula (I) of Comparative Example 5: as is
mentioned, these differences are probably due to solvent integration. Further,
it can be seen from ative Example 5 that the purity of the base was not
improved by the formation of the maleate salt. In contrast, as seen in Example
WO 36553
1 (the dihydrochloride salt of the present invention), it can be seen that the
purity of the free base was improved by the ion of the dihydrochloride
salt.
Further, the quality of the drug substance is improved upon dihydrochloride
salt formation.
Moreover, an additional technically advantageous property of the
dihydrochloride salt (II) of the present invention is that the crystalline salt
form ideally would furthermore help to improve the cation process and
the final processing : it is stable as a solid and in solution, and fits into the
galenic strategy (e.g. the salt of the present invention dissolves more rapidly
than the compound of formula (I) (the free base), which represents a clear
cal age.
Overall therefore, as seen from Table 5, vide supra, the dihydrochloride is
surprisingly advantageous in terms of purity, salt stability, crystallinity, and
aqueous solubility.
Moreover, very importantly, as seen in the P|3Ka and PI3KB biochemical
assays: both the free base and the dihydrochloride salt showed similar
activities in both P|3Ka and PI3KB biochemical assays. Slightly better potency
with the dihydrochloride salt form might be due to improved solubility. This is
clearly very ageous.
Pharmaceutical ations of the salt of the present invention
As mentioned above, the salt of the present invention may be in the form of a
pharmaceutical formulation which is ready for use to be administered
simultaneously, concurrently, separately or sequentially. The components may
be administered independnently of one another by the oral, intravenous,
l, local lations, intraperitoneal or nasal route.
Said compositions can be utilized to achieve the desired pharmacological
effect by administration to a patient in need thereof. A patient, for the
purpose of this invention, is a , including a human, in need of
treatment for the particular condition or disease. Therefore, the present
invention includes the salt of the present invention which is in the form of a
pharmaceutical formulation composition that is comprised of a
ceutically acceptable carrier and a pharmaceutically effective amount
of a said salt. A pharmaceutically acceptable carrier is preferably a carrier
that is relatively non-toxic and innocuous to a patient at concentrations
consistent with effective activity of the active ingredient so that any side
effects ascribable to the carrier do not vitiate the beneficial effects of
component, and/or combination. A pharmaceutically effective amount of a
combination is preferably that amount which produces a result or exerts an
influence on the particular condition being treated. The salts of the present
invention can be administered with pharmaceutically-acceptable carriers well
known in the art using any effective tional dosage unit forms, ing
ate, slow and timed release preparations, orally, parenterally,
topically, nasally, ophthalmically, optically, sublingually, rectally, lly,
and the like.
For oral administration, the salts can be formulated into solid or liquid
preparations such as capsules, pills, tablets, troches, lozenges, melts,
powders, ons, suspensions, or emulsions, and may be prepared according
to s known to the art for the manufacture of pharmaceutical
compositions. The solid unit dosage forms can be a capsule that can be of the
ordinary hard- or soft-shelled gelatin type containing, for example,
tants, lubricants, and inert fillers such as e, sucrose, calcium
phosphate, and corn starch.
In another embodiment, the salt of this invention may be tableted with
tional tablet bases such as lactose, sucrose and cornstarch in
combination with binders such as acacia, corn starch or gelatin, disintegrating
agents intended to assist the break-up and dissolution of the tablet following
administration such as potato starch, alginic acid, corn starch, and guar gum,
gum tragacanth, acacia, ants intended to improve the flow of tablet
granulation and to prevent the adhesion of tablet material to the surfaces of
the tablet dies and punches, for example talc, stearic acid, or magnesium,
calcium or zinc stearate, dyes, coloring agents, and flavoring agents such as
peppermint, oil of green, or cherry flavoring, intended to enhance the
aesthetic qualities of the tablets and make them more acceptable to the
patient. Suitable excipients for use in oral liquid dosage forms include
dicalcium phosphate and diluents such as water and alcohols, for e,
ethanol, benzyl alcohol, and polyethylene ls, either with or without the
addition of a pharmaceutically acceptable surfactant, suspending agent or
emulsifying agent. s other materials may be present as coatings or to
otherwise modify the physical form of the dosage unit. For instance tablets,
pills or es may be coated with shellac, sugar or both.
Dispersible powders and granules are suitable for the preparation of an
aqueous suspension. They provide the active ient in admixture with a
dispersing or wetting agent, a suspending agent and one or more preservatives.
Suitable dispersing or wetting agents and ding agents are exemplified by
those already mentioned above. Additional excipients, for example those
sweetening, flavoring and ng agents described above, may also be
The ceutical compositions of this invention may also be in the form of
oil-in-water emulsions. The oily phase may be a vegetable oil such as liquid
paraffin or a mixture of vegetable oils. Suitable emulsifying agents may be (1)
naturally ing gums such as gum acacia and gum tragacanth, (2) naturally
ing phosphatides such as soy bean and lecithin, (3) esters or partial
esters derived form fatty acids and hexitol anhydrides, for e, sorbitan
monooleate, (4) condensation products of said partial esters with ethylene
oxide, for example, polyoxyethylene sorbitan monooleate. The emulsions may
also contain sweetening and flavoring agents.
Oily suspensions may be formulated by suspending the active ingredient in a
vegetable oil such as, for example, arachis oil, olive oil, sesame oil or coconut
oil, or in a mineral oil such as liquid paraffin. The oily suspensions may n
a thickening agent such as, for example, beeswax, hard paraffin, or cetyl
alcohol. The suspensions may also contain one or more preservatives, for
example, ethyl or n-propyl oxybenzoate; one or more coloring agents;
one or more flavoring agents; and one or more sweetening agents such as
sucrose or sacchari n .
Syrups and elixirs may be formulated with sweetening agents such as, for
example, glycerol, propylene , sorbitol or sucrose. Such formulations
may also contain a demulcent, and preservative, such as methyl and propyl
parabens and ing and coloring agents.
The salt of this ion may also be administered parenterally, that is,
subcutaneously, intravenously, intraocularly, intrasynovially, uscularly,
or interperitoneally, as injectable dosages of the compound in preferably a
physiologically acceptable diluent with a pharmaceutical carrier which can be
a sterile liquid or mixture of liquids such as water, saline, aqueous se
and related sugar solutions, an alcohol such as ethanol, panol, or
hexadecyl l, glycols such as propylene glycol or polyethylene glycol,
glycerol ketals such as 2,2-dimethyl-1,1-dioxolanemethanol, ethers such as
poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acid ester or, a fatty acid
glyceride, or an acetylated fatty acid glyceride, with or without the addition of
a pharmaceutically acceptable surfactant such as a soap or a detergent,
suspending agent such as pectin, carbomers, methycellulose,
hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agent
and other pharmaceutical adjuvants.
Illustrative of oils which can be used in the parenteral formulations of this
invention are those of petroleum, animal, vegetable, or synthetic origin, for
example, peanut oil, soybean oil, sesame oil, seed oil, corn oil, olive oil,
petrolatum and mineral oil. le fatty acids include oleic acid, c
acid, isostearic acid and myristic acid. Suitable fatty acid esters are, for
example, ethyl oleate and isopropyl myristate. Suitable soaps include fatty
acid alkali metal, ammonium, and triethanolamine salts and suitable
detergents include cationic detergents, for example dimethyl l
ammonium halides, alkyl pyridinium s, and mine acetates; anionic
detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether,
and yceride sulfates, and sulfosuccinates; nic detergents, for
example, fatty amine oxides, fatty acid alkanolamides, and poly(oxyethyleneoxypropylene
)s or ethylene oxide or propylene oxide copolymers; and
amphoteric detergents, for example, alkyl-beta-aminopropionates, and 2-
alkylimidazoline quarternary ammonium salts, as well as mixtures.
The parenteral compositions of this invention will typically contain from about
0.5% to about 25% by weight of the active ingredient in solution. Preservatives
and buffers may also be used advantageously. In order to ze or
eliminate irritation at the site of injection, such compositions may contain a
non-ionic tant having a hydrophile-lipophile balance (HLB) preferably of
from about 12 to about 17. The quantity of surfactant in such formulation
preferably ranges from about 5% to about 15% by weight. The surfactant can be
a single component having the above HLB or can be a mixture of two or more
components having the desired HLB.
Illustrative of surfactants used in parenteral formulations are the class of
polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and
the high molecular weight adducts of ethylene oxide with a hydrophobic base,
formed by the condensation of propylene oxide with propylene glycol.
The pharmaceutical compositions may be in the form of sterile injectable
aqueous sions. Such suspensions may be formulated according to known
methods using le dispersing or wetting agents and suspending agents
such as, for example, sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethyl-cellulose, sodium alginate, nylpyrrolidone, gum
tragacanth and gum acacia; sing or wetting agents which may be a
naturally occurring atide such as lecithin, a condensation product of an
alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a
condensation product of ethylene oxide with a long chain aliphatic alcohol, for
example, heptadeca-ethyleneoxycetanol, a condensation product of ethylene
oxide with a partial ester derived form a fatty acid and a hexitol such as
polyoxyethylene sorbitol monooleate, or a condensation product of an
ne oxide with a partial ester d from a fatty acid and a hexitol
anhydride, for example yethylene sorbitan monooleate.
The sterile injectable preparation may also be a sterile able solution or
suspension in a non-toxic parenterally acceptable t or solvent. Diluents
and solvents that may be employed are, for example, water, Ringer’s on,
ic sodium chloride solutions and isotonic glucose solutions. In addition,
sterile fixed oils are conventionally employed as solvents or suspending media.
For this purpose, any bland, fixed oil may be employed including synthetic
mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in
the preparation of injectables.
A composition of the invention may also be administered in the form of
suppositories for rectal administration of the drug. These compositions can be
prepared by mixing the drug with a suitable non-irritation excipient which is
solid at ordinary temperatures but liquid at the rectal ature and will
therefore melt in the rectum to release the drug. Such materials are, for
example, cocoa butter and polyethylene glycol.
Another formulation employed in the methods of the present invention
employs transdermal ry devices (“patches”). Such transdermal patches
may be used to provide continuous or discontinuous infusion of the compounds
of the t invention in lled amounts. The construction and use of
transdermal patches for the delivery of ceutical agents is well known in
the art (see, e.g., US Patent No. 5,023,252, issued June 11, 1991, incorporated
herein by reference). Such patches may be ucted for continuous,
pulsatile, or on demand delivery of pharmaceutical agents.
Controlled release formulations for parenteral administration include
liposomal, polymeric microsphere and polymeric gel ations that are
known in the art.
It may be ble or necessary to introduce the pharmaceutical composition
to the patient via a mechanical delivery device. The construction and use of
mechanical delivery devices for the delivery of ceutical agents is well
known in the art. Direct techniques for, for example, stering a drug
directly to the brain usually involve placement of a drug delivery catheter into
the patient’s ventricular system to bypass the blood-brain barrier. One such
implantable delivery system, used for the transport of agents to specific
anatomical regions of the body, is described in US Patent No. 5,011,472, issued
April 30, 1991.
The compositions of the invention can also contain other conventional
pharmaceutically acceptable compounding ingredients, generally ed to
as carriers or diluents, as necessary or desired. Conventional procedures for
preparing such itions in appropriate dosage forms can be utilized.
Such ingredients and procedures include those described in the ing
references, each of which is incorporated herein by reference: Powell, M.F. et
al, "Compendium of Excipients for Parenteral ations" PDA Journal of
Pharmaceutical Science & Technology 1998, 52(5), 238-311; Strickley, R.G
"Parenteral Formulations of Small Molecule Therapeutics Marketed in the
United States (1999)-Part-1" PDA Journal of Pharmaceutical Science &
Technology 1999, 53(6), 324-349; and Nema, S. et al, "Excipients and Their Use
in Injectable Products" PDA Journal of Pharmaceutical Science & Technology
1997, 51(4), 1.
Commonly used pharmaceutical ingredients that can be used as appropriate to
formulate the composition for its intended route of administration include:
acidifying agents (examples include but are not d to acetic acid, citric
acid, fumaric acid, hydrochloric acid, nitric acid);
alkalinizing agents (examples include but are not limited to ammonia solution,
ammonium carbonate, diethanolamine, monoethanolamine, potassium
hydroxide, sodium borate, sodium carbonate, sodium hydroxide,
triethanolamine, trolamine);
adsorbents (examples include but are not d to powdered ose and
activated al);
aerosol propellants les include but are not limited to carbon dioxide,
CClez, FzClC-CCle and CClF3)
air displacement agents (examples include but are not limited to nitrogen and
argon);
antifungal preservatives (examples include but are not limited to benzoic
acid, butylparaben, ethylparaben, methylparaben, paraben, sodium
benzoate);
crobial preservatives (examples include but are not limited to
benzalkonium chloride, benzethonium chloride, benzyl alcohol,
cetylpyridinium chloride, butanol, phenol, phenylethyl alcohol,
phenylmercuric nitrate and thimerosal);
idants (examples include but are not limited to ascorbic acid, yl
palmitate, butylated hydroxyanisole, butylated hydroxytoluene,
hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate,
sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite);
binding materials (examples include but are not limited to block polymers,
natural and synthetic rubber, polyacrylates, polyurethanes, silicones,
polysiloxanes and styrene-butadiene copolymers);
buffering agents (examples include but are not limited to potassium
metaphosphate, dipotassium phosphate, sodium acetate, sodium citrate
anhydrous and sodium citrate dihydrate)
carrying agents (examples include but are not limited to acacia syrup,
aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup,
syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium
de ion and bacteriostatic water for injection)
ing agents (examples include but are not d to edetate disodium
and edetic acid)
colorants (examples include but are not limited to FD&C Red No. 3, FD&C Red
No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange
No. 5, D&C Red No. 8, caramel and ferric oxide red);
clarifying agents (examples e but are not limited to bentonite);
emulsifying agents (examples include but are not limited to acacia,
cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan
monooleate, polyoxyethylene 50 monostearate);
encapsulating agents les include but are not limited to gelatin and
cellulose acetate phthalate)
ants (examples include but are not limited to anise oil, on oil,
cocoa, menthol, orange oil, peppermint oil and vanillin);
ants (examples include but are not limited to glycerol, propylene
glycol and sorbitol);
levigating agents (examples include but are not limited to mineral oil and
glycerin);
oils (examples include but are not limited to arachis oil, mineral oil, olive oil,
peanut oil, sesame oil and vegetable oil);
ointment bases les include but are not limited to lanolin, hilic
ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum,
white ointment, yellow ointment, and rose water ointment);
WO 36553
penetration enhancers dermal delivery) (examples include but are not
limited to monohydroxy or polyhydroxy alcohols, mono-or lent alcohols,
saturated or unsaturated fatty alcohols, ted or unsaturated fatty esters,
saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl
derivatives, cephalin, terpenes, amides, ethers, ketones and ureas)
plasticizers (examples include but are not d to diethyl phthalate and
glycerol);
solvents (examples include but are not limited to ethanol, corn oil, cottonseed
oil, glycerol, isopropanol, mineral oil, oleic acid, peanut oil, purified water,
water for injection, sterile water for injection and sterile water for irrigation);
stiffening agents (examples include but are not d to cetyl alcohol, cetyl
esters wax, microcrystalline wax, paraffin, stearyl l, white wax and
yellow wax);
suppository bases (examples include but are not limited to cocoa butter and
polyethylene glycols (mixtures));
surfactants (examples include but are not limited to benzalkonium chloride,
nol 10, oxtoxynol 9, polysorbate 80, sodium lauryl sulfate and sorbitan
almitate);
ding agents (examples include but are not limited to agar, bentonite,
carbomers, carboxymethylcellulose sodium, hydroxyethyl cellulose,
hydroxypropyl cellulose, hydroxypropyl methylcellulose, kaolin,
methylcellulose, tragacanth and veegum);
WO 36553
sweetening agents (examples include but are not limited to aspartame,
se, glycerol, mannitol, propylene , saccharin sodium, sorbitol and
sucrose);
tablet anti-adherents (examples include but are not limited to magnesium
stearate and talc);
tablet binders (examples include but are not limited to acacia, alginic acid,
carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin,
liquid glucose, methylcellulose, non-crosslinked nyl pyrrolidone, and
pregelatinized starch);
tablet and capsule diluents (examples include but are not limited to dibasic
calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose,
powdered cellulose, itated calcium carbonate, sodium carbonate,
sodium phosphate, sorbitol and starch);
tablet coating agents (examples include but are not limited to liquid glucose,
hydroxyethyl ose, hydroxypropyl cellulose, hydroxypropyl
methylcellulose, methylcellulose, ethylcellulose, cellulose acetate phthalate
and shellac);
tablet direct compression excipients (examples include but are not limited to
c calcium ate);
tablet disintegrants (examples include but are not d to alginic acid,
carboxymethylcellulose calcium, microcrystalline cellulose, illin
potassium, cross-linked polyvinylpyrrolidone, sodium alginate, sodium starch
glycollate and starch);
2012/055600
tablet glidants (examples include but are not limited to colloidal silica, corn
starch and talc);
tablet lubricants (examples include but are not limited to calcium stearate,
magnesium stearate, mineral oil, c acid and zinc stearate);
tablet/capsule opaquants (examples include but are not limited to titanium
dioxide);
tablet polishing agents (examples include but are not limited to carnuba wax
and white wax);
thickening agents (examples include but are not limited to beeswax, cetyl
l and in);
tonicity agents (examples include but are not limited to dextrose and sodium
chloride);
viscosity increasing agents (examples e but are not limited to alginic
acid, bentonite, carbomers, carboxymethylcellulose sodium, methylcellulose,
polyvinyl pyrrolidone, sodium alginate and tragacanth); and
wetting agents les e but are not limited to heptadecaethylene
oxycetanol, lecithins, sorbitol monooleate, polyoxyethylene sorbitol
monooleate, and polyoxyethylene stearate).
Pharmaceutical compositions ing to the present invention can be
illustrated as follows:
Sterile IV Solution: A 5 mg/mL on of the desired compound of this
invention can be made using sterile, injectable water, and the pH is adjusted
if necessary. The solution is d for administration to 1 — 2 mg/mL with
sterile 5% dextrose and is administered as an IV infusion over about 60
minutes.
Lyophilized powder for IV administration: A e preparation can be
prepared with (i) 100 - 1000 mg of the desired compound of this invention as a
lypholized powder, (ii) 32- 327 mg/mL sodium citrate, and (iii) 300 — 3000 mg
Dextran 40. The formulation is reconstituted with sterile, injectable saline or
dextrose 5% to a concentration of 10 to 20 mg/mL, which is further diluted
with saline or dextrose 5% to 0.2 — 0.4 mg/mL, and is administered either IV
bolus or by IV infusion over 15 — 60 minutes.
Intramuscular suspension: The following solution or sion can be
prepared, for intramuscular injection:
50 mg/mL of the desired, water-insoluble compound of this invention
mg/mL sodium ymethylcellulose
4 mg/mL TWEEN 80
9 mg/mL sodium chloride
9 mg/mL benzyl alcohol
Hard Shell Capsules: A large number of unit capsules are prepared by filling
standard two-piece hard galantine capsules each with 100 mg of powdered
active ingredient, 150 mg of e, 50 mg of cellulose and 6 mg of
magnesium stearate.
Soft Gelatin Capsules: A mixture of active ingredient in a ible oil such
as soybean oil, seed oil or olive oil is prepared and injected by means of
a positive displacement pump into molten gelatin to form soft gelatin capsules
ning 100 mg of the active ingredient. The capsules are washed and
dried. The active ingredient can be dissolved in a mixture of hylene
glycol, glycerin and sorbitol to prepare a water miscible medicine mix.
Tablets: A large number of tablets are prepared by conventional procedures
so that the dosage unit is 100 mg of active ient, 0.2 mg. of dal
silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline
cellulose, 11 mg. of starch, and 98.8 mg of lactose. Appropriate aqueous and
non-aqueous coatings may be d to increase palatability, improve
elegance and ity or delay absorption.
Immediate Release Tablets/Capsules: These are solid oral dosage forms made
by conventional and novel processes. These units are taken orally without
water for immediate dissolution and delivery of the medication. The active
ingredient is mixed in a liquid ning ingredient such as sugar, gelatin,
pectin and sweeteners. These s are solidified into solid tablets or caplets
by freeze drying and solid state extraction techniques. The drug compounds
may be compressed with viscoelastic and thermoelastic sugars and polymers or
effervescent components to produce porous matrices intended for immediate
release, without the need of water.
Method of treating cancer
Within the context of the present invention, the term “cancer” includes, but is
not limited to, s of the , lung, brain, reproductive organs,
digestive tract, urinary tract, liver, eye, skin, head and neck, thyroid,
parathyroid and their distant metastases. Those disorders also include multiple
myeloma, lymphomas, sarcomas, and leukemias.
Examples of breast cancer include, but are not limited to invasive ductal
carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular
carcinoma in situ.
Examples of cancers of the respiratory tract include, but are not limited to
small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma
and pleuropulmonary blastoma.
Examples of brain s include, but are not limited to brain stem and
hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma,
moma, as well as neuroectodermal and pineal tumor.
Tumors of the male reproductive organs include, but are not limited to
prostate and testicular cancer. Tumors of the female reproductive organs
include, but are not limited to endometrial, cervical, n, l, and
vulvar cancer, as well as sarcoma of the uterus.
Tumors of the digestive tract include, but are not limited to anal, colon,
colorectal, esophageal, gallbladder, gastric, atic, rectal, small-
ine, and salivary gland cancers.
Tumors of the urinary tract include, but are not limited to r, penile,
kidney, renal pelvis, ureter, urethral and human papillary renal cancers.
Eye cancers include, but are not limited to intraocular melanoma and
retinoblastoma.
Examples of liver cancers include, but are not limited to hepatocellular
carcinoma (liver cell carcinomas with or without fibrolamellar variant),
cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed
hepatocellular cholangiocarcinoma.
Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi’s
sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma
skin cancer.
Head-and-neck cancers include, but are not limited to laryngeal,
hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oral cavity
cancer and squamous cell.
Lymphomas include, but are not limited to AIDS-related lymphoma, non-
Hodgkin’s lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma,
Hodgkin’s disease, and lymphoma of the central nervous system.
Sarcomas include, but are not limited to sarcoma of the soft tissue,
osteosarcoma, malignant fibrous cytoma, lymphosarcoma, and
rhabdomyosarcoma.
Leukemias e, but are not limited to acute myeloid leukemia, acute
lymphoblastic ia, chronic lymphocytic leukemia, chronic myelogenous
leukemia, and hairy cell leukemia.
The present ion describes a method for using the salt of the present
invention, to treat cancer, as described infra, particularly mammalian NSCLC,
CRC, ma, pancreatic , hepatocyte or breast cancer. The salt of
the t invention can be utilized to t, block, reduce, decrease, etc.,
cell proliferation and/or cell division, and/or produce apoptosis, in the
treatment or prophylaxis of cancer, in particular NSCLC, CRC, melanoma,
pancreatic , hepatocyte oma or breast cancer. This method
comprises administering to a mammal in need thereof, including a human, an
amount of a combination of this invention, or a pharmaceutically acceptable
salt, isomer, polymorph, lite, hydrate, solvate or ester thereof; etc.
which is effective for the treatment or prophylaxis of cancer, in particular
NSCLC, CRC, melanoma, pancreatic cancer, hepatocyte carcinoma or breast
cancer.
The term “treating” or “treatment” as stated throughout this document is
used tionally, e.g., the management or care of a subject for the
purpose of combating, alleviating, reducing, relieving, improving the condition
of, etc., of a disease or disorder, such as a carcinoma.
Dose and administration
Based upon standard tory ques known to evaluate compounds
useful for the treatment or prophylaxis of cancer, in particular NSCLC, CRC,
melanoma, pancreatic cancer, hepatocyte carcinoma or breast cancer, by
rd toxicity tests and by standard pharmacological assays for the
determination of treatment of the conditions identified above in mammals,
and by comparison of these results with the results of known medicaments that
are used to treat these conditions, the effective dosage of the salt of this
invention can y be ined for treatment of the indication. The
amount of the active ingredient to be administered in the treatment of the
ion can vary widely according to many considerations, including, but not
limited to the particular combination and dosage unit employed, the mode of
administration, the period of treatment, the age and sex of the patient
treated, and the nature and extent of the condition treated.
The total amount of the active ingredient to be administered will generally
range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and
preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day.
Clinically useful dosing les will range from one to three times a day
dosing to once every four weeks dosing. In addition, "drug holidays" in which a
patient is not dosed with a drug for a certain period of time, may be beneficial
WO 36553
to the overall balance n pharmacological effect and tolerability. A unit
dosage may n from about 0.5 mg to about 1,500 mg of active ingredient,
and can be administered one or more times per day or less than once a day.
The average daily dosage for administration by injection, including
intravenous, intramuscular, subcutaneous and parenteral injections, and use of
infusion ques will preferably be from 0.01 to 200 mg/kg of total body
weight. The average daily rectal dosage regimen will preferably be from 0.01
to 200 mg/kg of total body . The average daily vaginal dosage regimen
will preferably be from 0.01 to 200 mg/kg of total body weight. The e
daily topical dosage regimen will preferably be from 0.1 to 200 mg
administered between one to four times daily. The transdermal concentration
will preferably be that required to maintain a daily dose of from 0.01 to 200
mg/kg. The average daily inhalation dosage regimen will preferably be from
0.01 to 100 mg/kg of total body weight.
Tthe specific initial and continuing dosage regimen for each patient will vary
ing to the nature and severity of the ion as determined by the
attending diagnostician, the activity of the specific combination employed, the
age and general condition of the patient, time of administration, route of
administration, rate of excretion of the drug, drug salts, and the like. The
desired mode of treatment and number of doses of a combination of the
present invention or a pharmaceutically acceptable salt or ester or
composition thereof can be ascertained by those skilled in the art using
conventional treatment tests .
Therapies using the salt of the present invention : one or more further
pharmaceutical agents.
The salt of the present ion can be administered as the sole
ceutical agent or in combination with one or more further
pharmaceutical agents where the resulting combination of the salt of the
present invention and the further pharmaceutical agent causes no
unacceptable adverse effects. For example, the salt of the present ion
can be ed with a component C, i.e. one or more further pharmaceutical
a g e n t s, s u c h a s k n o w n a n t i-angiogenesis, yper-proliferative,
antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic, anti-
hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviral agents, and
the like, as well as with admixtures and salts thereof.
Component C, can be one or more pharmaceutical agents such as aldesleukin,
alendronic acid, alfaferone, alitretinoin, allopurinol, m, aloxi,
altretamine, aminoglutethimide, amifostine, amrubicin, amsacrine,
anastrozole, anzmet, aranesp, arglabin, arsenic de, aromasin, 5-
azacytidine, azathioprine, ECG or tice BCG, bestatin, betamethasone acetate,
betamethasone sodium phosphate, bexarotene, cin sulfate,
broxuridine, bortezomib, busulfan, calcitonin, campath, capecitabine,
carboplatin, casodex, cefesone, celmoleukin, cerubidine, chlorambucil,
tin, cladribine, cladribine, clodronic acid, cyclophosphamide, cytarabine,
dacarbazine, dactinomycin, DaunoXome, decadron, on phosphate,
delestrogen, denileukin diftitox, depo-medrol, deslorelin, dexomethasone,
dexrazoxane, diethylstilbestrol, diflucan, docetaxel, doxifluridine,
doxorubicin, dronabinol, DW-166HC, eligard, elitek, ellence, emend,
epirubicin, epoetin alfa, , eptaplatin, ergamisol, estrace, estradiol,
ustine phosphate sodium, ethinyl estradiol, ethyol, etidronic acid,
etopophos, etoposide, fadrozole, farston, filgrastim, finasteride, stim,
floxuridine, azole, fludarabine, 5-fluorodeoxyuridine monophosphate, 5-
fluorouracil (5-FU), fluoxymesterone, flutamide, formestane, bine,
fotemustine, fulvestrant, gammagard, gemcitabine, gemtuzumab, gleevec,
gliadel, goserelin, granisetron HCl, histrelin, hycamtin, hydrocortone, eyrthrohydroxynonyladenine
, hydroxyurea, ibritumomab tiuxetan, idarubicin,
ifosfamide, interferon alpha, interferon-alpha 2, interferon alfa-2A, eron
alfa-ZB, interferon alfa-n1, interferon alfa-n3, interferon beta, interferon
gamma-1a, interleukin-2, intron A, , irinotecan, , lentinan sulphate,
letrozole, leucovorin, leuprolide, leuprolide acetate, lenalidomide, levamisole,
levofolinic acid calcium salt, levothroid, levoxyl, ine, lonidamine,
marinol, mechlorethamine, lamin, medroxyprogesterone acetate,
megestrol acetate, melphalan, menest, 6-mercaptopurine, Mesna,
methotrexate, metvix, miltefosine, minocycline, mitomycin C, ne,
mitoxantrone, Modrenal, Myocet, nedaplatin, neulasta, neumega, neupogen,
nilutamide, nolvadex, NSC-631570, OCT-43, octreotide, etron HCl,
orapred, oxaliplatin, paclitaxel (when component B is not itself paclitaxel),
pediapred, pegaspargase, Pegasys, pentostatin, picibanil, pilocarpine HCl,
pirarubicin, plicamycin, porfimer sodium, prednimustine, prednisolone,
prednisone, in, procarbazine, procrit, raltitrexed, RDEA 119, rebif,
rhenium-186 nate, rituximab, roferon-A, romurtide, salagen,
sandostatin, sargramostim, semustine, sizofiran, sobuzoxane, solu-medrol,
sparfosic acid, stem-cell therapy, streptozocin, strontium-89 chloride,
synthroid, tamoxifen, tamsulosin, rmin, tastolactone, taxotere,
teceleukin, temozolomide, side, testosterone propionate, testred,
thioguanine, thiotepa, thyrotropin, tiludronic acid, topotecan, toremifene,
tositumomab, trastuzumab, lfan, tretinoin, trexall, trimethylmelamine,
trimetrexate, relin acetate, triptorelin pamoate, UFT, uridine,
icin, vesnarinone, vinblastine, vincristine, ine, vinorelbine,
virulizin, zinecard, zinostatin stimalamer, zofran, ABI-007, acolbifene,
actimmune, affinitak, aminopterin, arzoxifene, asoprisnil, atamestane,
ntan, BAY 6 (sorafenib), avastin, CCI-779, CDC-501, celebrex,
cetuximab, crisnatol, cyproterone e, decitabine, DN-101, doxorubicin-
MTC, dSLIM, dutasteride, edotecarin, eflornithine, exatecan, fenretinide,
histamine dihydrochloride, histrelin hydrogel implant, holmium-166 DOTMP,
onic acid, interferon gamma, intron-PEG, ixabepilone, keyhole limpet
hemocyanin, L-651582, lanreotide, lasofoxifene, libra, lonafarnib,
miproxifene, minodronate, MS-209, liposomal MTP-PE, MX-6, nafarelin,
nemorubicin, neovastat, exed, oblimersen, onco-TCS, osidem, axel
polyglutamate, pamidronate disodium, PN-401, QS-21, quazepam, R-1549,
raloxifene, ranpirnase, 13-cis -retinoic acid, satraplatin, seocalcitol, T-138067,
tarceva, taxoprexin, thalidomide, thymosin alpha 1, urine, tipifarnib,
tirapazamine, TLK-286, toremifene, ID-107R, valspodar, vapreotide,
vatalanib, verteporfin, vinflunine, Z-100, zoledronic acid or salts thereof.
In an embodiment of the present invention, component C can be one or more
of the following : 131I-chTNT, abarelix, abiraterone, aclarubicin, aldesleukin,
alemtuzumab, alitretinoin, altretamine, aminoglutethimide, amrubicin,
amsacrine, anastrozole, arglabin, arsenic trioxide, asparaginase, azacitidine,
basiliximab, BAY 6, BAY 4, BAY 86-9766 (RDEA 119), belotecan,
bendamustine, bevacizumab, bexarotene, bicalutamide, bisantrene,
bleomycin, bortezomib, lin, busulfan, cabazitaxel, calcium folinate,
calcium levofolinate, tabine, carboplatin, carmofur, tine,
catumaxomab, celecoxib, celmoleukin, cetuximab, chlorambucil,
chlormadinone, chlormethine, cisplatin, cladribine, clodronic acid,
clofarabine, crisantaspase, cyclophosphamide, cyproterone, cytarabine,
dacarbazine, dactinomycin, darbepoetin alfa, nib, daunorubicin,
decitabine, degarelix, denileukin diftitox, denosumab, deslorelin, dibrospidium
chloride, docetaxel, doxifluridine, doxorubicin, doxorubicin + estrone,
eculizumab, edrecolomab, elliptinium acetate, eltrombopag, endostatin,
enocitabine, epirubicin, epitiostanol, epoetin alfa, epoetin beta, atin,
eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus,
exemestane, fadrozole, filgrastim, fludarabine, uracil, flutamide,
formestane, fotemustine, fulvestrant, gallium nitrate, ganirelix, gefitinib,
gemcitabine, gemtuzumab, glutoxim, goserelin, histamine dihydrochloride,
histrelin, ycarbamide, |-125 seeds, onic acid, ibritumomab
tiuxetan, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, interferon
alfa, eron beta, interferon gamma, ipilimumab, irinotecan, ixabepilone,
lanreotide, lapatinib, lenalidomide, astim, lentinan, letrozole,
leuprorelin, levamisole, lisuride, lobaplatin, ine, mine,
masoprocol, medroxyprogesterone, megestrol, melphalan, mepitiostane,
mercaptopurine, methotrexate, methoxsalen, Methyl aminolevulinate,
testosterone, mifamurtide, miltefosine, atin, mitobronitol,
mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, nedaplatin,
nelarabine, nilotinib, nilutamide, nimotuzumab, nimustine, nitracrine,
ofatumumab, omeprazole, oprelvekin, oxaliplatin, p53 gene y,
paclitaxel, palifermin, palladium-103 seed, pamidronic acid, mumab,
pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta),
pegfilgrastim, peginterferon b, pemetrexed, pentazocine, pentostatin,
ycin, perfosfamide, picibanil, pirarubicin, plerixafor, plicamycin,
poliglusam, polyestradiol phosphate, polysaccharide-K, porfimer sodium,
pralatrexate, prednimustine, procarbazine, quinagolide, raloxifene,
raltitrexed, ranimustine, razoxane, regorafenib, risedronic acid, rituximab,
romidepsin, romiplostim, sargramostim, sipuleucel-T, sizofiran, sobuzoxane,
sodium glycididazole, sorafenib, ozocin, sunitinib, talaporfin,
tamibarotene, tamoxifen, tasonermin, teceleukin, tegafur, tegafur + gimeracil
+ oteracil, rfin, temozolomide, temsirolimus, teniposide, testosterone,
tetrofosmin, thalidomide, thiotepa, thymalfasin, tioguanine, tocilizumab,
topotecan, fene, tositumomab, trabectedin, trastuzumab, lfan,
tretinoin, trilostane, triptorelin, famide, tryptophan, ubenimex,
valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine,
vindesine, nine, vinorelbine, vorinostat, vorozole, yttrium-90 glass
microspheres, zinostatin, atin stimalamer, zoledronic acid, zorubicin.
Alternatively, said component C can be one or more r pharmaceutical
agents selected from gemcitabine, paclitaxel (when component B is not itself
paclitaxel), tin, carboplatin, sodium butyrate, 5-FU, doxirubicin,
tamoxifen, etoposide, mazab, gefitinib, intron A, rapamycin, 17-AAG,
U0126, insulin, an insulin derivative, a PPAR ligand, a ylurea drug, an a-
glucosidase inhibitor, a biguanide, a PTP-1B inhibitor, a DPP-IV inhibitor, a 11-
beta-HSD inhibitor, GLP-1, a GLP-1 tive, GIP, a GIP derivative, PACAP, a
PACAP derivative, secretin or a secretin derivative.
Alternatively, said component C can be one or more pharmaceutical agents
selected from: a taxane, such as Docetaxel, Paclitaxel, or Taxol; an
epothilone, such as Ixabepilone, Patupilone, or Sagopilone; Mitoxantrone;
Predinisolone; Dexamethasone; Estramustin; Vinblastin; Vincristin;
2012/055600
Doxorubicin; Adriamycin; |darubicin; Daunorubicin; Bleomycin; Etoposide;
Cyclophosphamide; |fosfamide; Procarbazine; Melphalan; 5-Fluorouracil;
Capecitabine; Fludarabine; Cytarabine; Ara-C; 2-Chloro-2'-deoxyadenosine;
Thioguanine; an anti-androgen, such as Flutamide, Cyproterone acetate, or
Bicalutamide; Bortezomib; a platinum derivative, such as Cisplatin, or
Carboplatin; mbucil; Methotrexate; and Rituximab.
Optional anti-hyper-proliferative agents which can be added as component C
to the combination of the salt of the present ion include but are not
limited to compounds listed on the cancer chemotherapy drug regimens in the
11th Edition of the Merck Index, (1996), which is hereby incorporated by
reference, such as asparaginase, bleomycin, carboplatin, carmustine,
chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine,
dacarbazine, omycin, daunorubicin, doxorubicin (adriamycine),
epirubicin, etoposide, rouracil, hexamethylmelamine, hydroxyurea,
ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-
topurine, mesna, rexate, mitomycin C, mitoxantrone,
prednisolone, prednisone, procarbazine, raloxifen, streptozocin, tamoxifen,
thioguanine, topotecan, vinblastine, vincristine, and vindesine.
Other anti-hyper-proliferative agents suitable for use as component C with the
combination of the salt of the present invention include but are not limited to
those compounds acknowledged to be used in the treatment of neoplastic
es in Goodman and Gilman's The Pharmacological Basis of Therapeutics
(Ninth Edition), editor ff et al., publ. by McGraw-Hill, pages 287,
(1996), which is hereby incorporated by reference, such as aminoglutethimide,
L-asparaginase, oprine, 5-azacytidine cladribine, busulfan,
diethylstilbestrol, 2',2'-difluorodeoxycytidine, docetaxel, erythrohydroxynonyl
e, l estradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine mono-
phosphate, fludarabine phosphate, fluoxymesterone, flutamide,
hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone
acetate, megestrol acetate, melphalan, mitotane, paclitaxel (when component
B is not itself paclitaxel), pentostatin, N-phosphonoacetyl-L-aspartate (PALA),
plicamycin, semustine, side, terone propionate, thiotepa,
trimethylmelamine, uridine, and lbine.
Other anti-hyper-proliferative agents suitable for use as component C with the
combination of the salt of the present invention include but are not limited to
other anti-cancer agents such as epothilone and its derivatives, irinotecan,
raloxifen and topotecan.
Generally, the use of cytotoxic and/or cytostatic agents as component C in
ation with the salt of the present invention will serve to:
(1) yield better efficacy in reducing the growth of a tumor or even
ate the tumor as compared to administration of either agent alone,
(2) provide for the administration of lesser amounts of the administered
chemotherapeutic agents,
(3) provide for a chemotherapeutic treatment that is well tolerated in the
patient with fewer deleterious pharmacological complications than observed
with single agent chemotherapies and certain other combined therapies,
(4) provide for treating a broader spectrum of different cancer types in
mammals, especially ,
(5) provide for a higher response rate among treated patients,
(6) provide for a longer survival time among treated patients compared to
rd chemotherapy treatments,
(7) provide a longer time for tumor progression, and/or
(8) yield efficacy and bility results at least as good as those of the
agents used alone, compared to known instances where other cancer agent
salts produce antagonistic effects.
BIOLOGICAL SECTION
PI3Koc and PI3KB Radioactive Lipid Kinase Assay
The pl lOoc biochemical assay is a radioactive assay measuring the incorporation of 33P
into the pl lOoc substrate, phosphatidylinsoitol (PI). This assay is a modification of an
assay developed at RCK (Fuchikami el al., 2002). A His-tagged N—terminal truncated
(AN 1-108) pl lOoc and the same ted pl 108 (AN 1-108) ns lacking the p85-
binding domain was expressed in Sf9 cells and purified to >50% purity. For the
generation of ICso curves, the reaction was performed in a 384-well format using
MaXiSorp plates under the following conditions. Plates were coated with 2 ug/well of a
1:1 molar ratio of phosphatidylinositol (PI: Avanti #840042C) and phosphatidylserine
(PS: Avanti #840032C) diluted in form. The organic solvent was allowed to
evaporate by g plates in the fume hood overnight. Plates were then sealed with
mylar plate sealers and stored up to a month at 4 0C until needed. 7.5 ng of truncated
purified pl lOoc protein was added to each well, containing 9 uL of reaction buffer (50
mM MOPSO pH7.0, 100 mM NaCl, 4 mM MgClz, 0.1%(w/v) BSA) except for ve
control wells which received reaction buffer only. One microliter of each test compound
in DMSO was transferred from stock dilutions to generate an eight-point dose response
(00, 0.003, 0.01 0.03, 0.1, 0.3, 1.0, 3.0 and 10 uM f1nal BAY compound concentration).
Reactions were started by the addition of 5 uL of a 40 uM ATP solution containing 20
uCi/ml [7-33P]-ATP and were allowed to proceed for two hours at room temperature with
gentle miXing. Reactions were terminated by the addition of SuL of a 25 mM EDTA
stock solution. Plates were washed with a ll plate washer in buffer without
detergent and 25 uL of UltimaGold scintillation cocktail was added to each well. The
ctivity incorporated into the immobilized PI substrate was determined with a
BetaPlate Liquid Scintillation Counter. Inhibition was calculated using the following
0/0 tion = m ' Bcpm)/(Pcpm' Bcpm) X 100.
Tcpm = 33P-cpm in presence of test compound
Bcpm = 33P-cpm in background control (no enzyme)
Pcpm = 33P-cpm in pl 10 enzyme control (no tor)
The ICso values for the free base and the dihydrochloride salt in the pllOoc and pl 10B
biochemical assays are summarized in Table A. The two compounds showed similar ties in
both PI3Koc and PI3KB mical assays. Slightly better potency with the dihydrochloride salt
form might be due to ed solubility.
Table A. Activity of the free base and the dihydrochloride salt in PBKOL and PI3KB assays
4-96E-10 3-72E-09
Dihydrochloride salt 1.23E-10 1.00E-09
Proliferation assays
Cell proliferation is determined using the Cell Titer-Glo luminescent cell viability kit from
Promega (Cat. #G7573) after 72 hours eXposure to the drugs. Briefly, cells were plated at
00 well of 384-well plates in 25 uL growth medium. For each cell line assayed,
cells were plated into a separate plate for determination of luminescence at the t = 0 hours and
t = 72 hour time points. Following overnight incubation at 37 °C, scence values for the
t = 0 samples were determined by adding 25 uL of Cell Titer-Glo solution per well,
transferring the plates to an orbital shaker for 10 minutes at room temperature, and then
reading the plates on a Wallac Victor2 1420 Multilabel HTS Counter using the luminometry
window (maximum light detection is measured at 428 nM). Dose plates for t = 72 hour time
points were treated with compounds diluted into growth medium in a final volume of 30 uL.
Cells were then incubated for 72 hours at 37 °C. Luminescence values for the t = 72 hour
samples were determined by adding 30 uL of Promega CellTiter-Glo solution, placing the
cells on a shaker for 10 s at room temperature, and then reading the luminescence using
a Victor luminometer. For data processing, t = 0 values are subtracted from those determined
2012/055600
for the t = 72 hour time points, for both the treated and untreated samples. Percent differences
in luminescence between drug treated and controls are used to determine percent inhibition of
growth.
In a panel of 16 tumor cell lines covering 6 cancer indications, both the free base and the
dihydrochloride salt showed potent anti-proliferative activities and the difference in the ICso
values was less than 3-fold in all the tumor cell lines tested. These data clearly indicated that
the ochloride salt retains the antitumor activity of the free base.
Table B. Anti-proliferative activity of the free base and the dihydrochloride in tumor cell
line proliferation assays
free base IC5O dihydrochloride
Cell Line Tissue O50 Ratio
(nM) salt IC50 (nM)
KPL4 _—\
BT474 _o
T47D _I\J
BT20 pa
MCF7 N\l pa
MDA-MB-468 pa
SK—Br—3 _—\
LNCaP O) _—\
PC3 _—\ xoomo
Co|0205 A00 _O A
HT29 A _l\J \l
HCT116 01O) \lN
A549 pa‘1 AA
H460 AO) O) _o \l
U87MG 0001 00 _A o
0 _O 01
Reference:
Fuchikami K, Togame H, Sagara A, Satoh T, Gantner F, Bacon KB, Reinemer P. J Biomol
Screen. 7(5):44l-50 (2002). A versatile high-throughput screen for inhibitors of lipid kinase
activity: development of an immobilized phospholipid plate assay for oinositide 3-kinase
gamma.
Claims (57)
1. 2-amino-N-[7-methoxy(3-morpholinylpropoxy)-2,3-dihydroimidazo[1,2- c]quinazolinyl]pyrimidinecarboxamide dihydrochloride salt of formula 5 (II) : N N N O O N N N N NH . 2 HCl (II), or a solvate, hydrate or tautomer thereof.
2. The dihydrochloride salt of a (II) according to claim 1, which is in crystalline form.
3. A method of preparing the dihydrochloride salt according to claim 1 or 2, said method comprising adding hydrochloric acid to a compound of formula (I): N N N O O N N N N NH (I), thereby forming said dihydrochloride salt of formula (II) : N N N O O N N N N NH . 2 HCl (II).
4. The method according to claim 3, wherein hydrochloric acid is added to a compound of formula (I) in suspension. 10 5. The method ing to claim 3 or 4, said method comprising: a) adding hloric acid to a suspension of said compound of formula (I) in a medium at a temperature of between the ng point of the e and the boiling point of the mixture until a pH of 3 to 4 is 15 reached; b) stirring the resulting mixture at a temperature of between the freezing point of the mixture and the boiling point of the mixture for a period of time; and, optionally c) filtering off the resulting solid and washing the filtercake, then 20 adjusting the pH of the te to pH 1.8 to 2.0 using hydrochloric acid; and, optionally, d) stirring the mixture for a period of time, at a temperature between the freezing point and the boiling point of the mixture, adding ethanol, followed by further stirring for a period of time; and, optionally, e) adding seed crystals, optionally followed by adding ethanol over a period of time; and, optionally, f) filtering off the resulting dihydrochloride of formula (II), ally washing with a water-ethanol mixture and optionally drying,
5 thus providing the dihydrochloride salt according to claim 1 or 2.
6. The method according to claim 5, wherein the hydrochloric acid in step (a) is aqueous hloric acid solution (32%). 10
7. The method according to claim 5 or 6, wherein the medium in step (a) is water.
8. The method according to any one of claims 5 to 7, wherein the ature in step (a) is 20 °C (+-2°).
9. The method according to any one of claims 5 to 8, wherein the temperature in step (b) is room temperature.
10. The method ing to any one of claims 5 to 9, wherein the period of 20 time in step (b) is more than 10 minutes.
11. The method ing to any one of claims 5 to 10, wherein in step (c) the filtercake is washed with water. 25
12. The method according to any one of claims 5 to 11, wherein the hydrochloric acid in step (c) is aqueous hydrochloric acid solution (32%).
13. The method according to any one of claims 5 to 12, wherein the period of time in step (d) for initial stirring is more than 10 minutes.
14. The method according to any one of claims 5 to 13, wherein the temperature in step (d) is room temperature.
15. The method according to any one of claims 5 to 14, wherein the period of 5 time in step (d) for further stirring is more than 10 minutes.
16. The method according to any one of claims 5 to 15, wherein in step (e) ethanol is added within 5 hours. 10
17. The method according to any one of claims 5 to 16, wherein in step (f) drying is med in vacuo.
18. The method according to claim 3, said method comprising: 15 a) adding said hydrochloric acid to said compound of formula (I); and, then, optionally, b) heating at a temperature between the boiling point and the freezing point of the mixture, for a period of time; then, optionally, c) g further at a temperature between the boiling point and the 20 freezing point of the mixture, for a period of time, with optional stirring of said suspension at a temperature of n the boiling point and the ng point of the mixture, for a period of time, optionally followed by further stirring of said suspension at a temperature of n the freezing point of the e and the boiling point of the 25 mixture, for a period of time; and, optionally, d) filtering, optional washing and drying, thus providing the dihydrochloride salt according to claim 1 or 2.
19. The method according to claim 18, wherein in step (a) said hydrochloric acid is added to said compound of formula (I) in acetone/water or ethanol/water. 5
20. The method according to claim 18 or 19, n in step (b) the mixture is heated to between 40 and 60 °C.
21. The method according to any one of claims 18 to 20, wherein in step (b) the mixture is heated to 50 °C.
22. The method according to any one of claims 18 to 21, wherein in step (b) the mixture is heated for 0.2 to 2 hours.
23. The method ing to any one of claims 18 to 22, wherein in step (b) 15 the mixture is heated for 0.5 hours.
24. The method according to any one of claims 18 to 23, wherein in step (c) the mixture is heated to between 30 and 40 °C. 20 25. The method according to any one of claims 18 to 24, n in step (c) the mixture is heated to 35 °C.
26. The method according to any one of claims 18 to 25, wherein in step (c) the mixture is heated for such as 1 to 4 hours.
26. The method according to any one of claims 18 to 25, wherein in step (c) stirring of said suspension takes place at a temperature of between 10 and 45
27. The method according to any one of claims 18 to 26, wherein in step (c) stirring of said suspension takes place at a temperature of 35 °C.
28. The method ing to any one of claims 18 to 27, wherein in step (c) 5 stirring of said suspension takes place for 12 to 72 hours.
29. The method according to any one of claims 18 to 28, wherein in step (c) stirring of said sion takes place for 72 hours. 10
30. The method according to any one of claims 18 to 29, wherein in step (c) further stirring of said suspension takes place at room temperature.
31. The method according to any one of claims 18 to 30, wherein in step (c) further stirring of said suspension takes place for 0 to 4 hours.
32. The method according to any one of claims 18 to 31, wherein in step (c) further stirring of said suspension takes place for 2 hours.
33. The method according to claim 3 or any one of claims 18 to 32, wherein 20 said hydrochloric acid is trated aqueous hydrochloric acid solution (36% HCl) and is added to said compound of formula (I) in an e / water mixture (8:2 v/v), followed by heating at a temperature of 50 °C, for a period of time of 0.5 hours, then followed by further heating, at a temperature of 35 °C, for a period of time of 72 hours, then with stirring of said suspension at a 25 temperature of room ature, for a period of time of 2 hours, followed by filtration, washing with an e/water mixture, and drying in a vacuum oven, thus providing said dihydrochloride salt according to claim 1 or 2.
34. The method according to claim 33, wherein drying in a vacuum oven takes 30 place at 40 °C, 100 mbar, 16 h.
35. Use of a compound of formula (I): N N N O O N N N N NH 5 (I), for the preparation of the dihydrochloride salt of formula (II) : N N N O O N N N N NH . 2 HCl (II). 10
36. The dihydrochloride salt according to claim 1 or 2, for the treatment and/or laxis of a disease.
37. Use of the dihydrochloride salt according to claim 1 or 2 for the preparation of a medicament for the treatment and/or prophylaxis of a 15 e.
38. Use according to claim 37, wherein the disease is a hyper-proliferative and/or angiogenesis disorder.
39. Use according to claim 37 or 38, wherein the disease is a .
40. Use according to any one of claims 37 to 39, n the disease is lung cancer, colorectal cancer, melanoma, pancreatic cancer, hepatocyte 5 carcinoma, or breast cancer.
41. Use according to any one of claims 37 to 40, wherein the disease is nonsmall cell lung carcinoma. 10
42. Use according to claim 39, wherein said cancer is a lymphoma.
43. Use according to claim 39, wherein said lymphoma is selected from AIDS- related lymphoma, non-Hodgkin’s ma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin’s disease, and lymphoma of the central nervous 15 system.
44. Use according to claim 39 or 43, wherein said ma is non-Hodgkin’s lymphoma. 20
45. A pharmaceutical composition comprising the dihydrochloride salt according to claim 1 or 2.
46. A pharmaceutical composition sing the dihydrochloride salt according to claim 1 or 2, and a further pharmaceutical agent.
47. A pharmaceutical combination comprising the ochloride salt according to claim 1 or 2, and one or more further pharmaceutical .
48. The pharmaceutical combination according to claim 45, wherein said 30 further pharmaceutical agent is selected from : 131I-chTNT, abarelix, abiraterone, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, aminoglutethimide, amrubicin, amsacrine, ozole, arglabin, arsenic trioxide, asparaginase, azacitidine, ximab, BAY 80-6946, BAY 4, BAY 86-9766 (RDEA 119), belotecan, bendamustine, bevacizumab, bexarotene, 5 tamide, bisantrene, bleomycin, omib, buserelin, busulfan, cabazitaxel, calcium folinate, calcium levofolinate, capecitabine, carboplatin, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, cetuximab, chlorambucil, chlormadinone, chlormethine, cisplatin, bine, clodronic acid, clofarabine, crisantaspase, hosphamide, cyproterone, cytarabine, 10 dacarbazine, dactinomycin, darbepoetin alfa, dasatinib, daunorubicin, bine, lix, denileukin ox, denosumab, deslorelin, dibrospidium chloride, docetaxel, doxifluridine, doxorubicin, doxorubicin + estrone, eculizumab, edrecolomab, elliptinium acetate, eltrombopag, endostatin, enocitabine, epirubicin, epitiostanol, epoetin alfa, epoetin beta, eptaplatin, 15 in, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, fadrozole, filgrastim, abine, fluorouracil, flutamide, tane, fotemustine, fulvestrant, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, glutoxim, goserelin, histamine dihydrochloride, histrelin, hydroxycarbamide, I-125 seeds, ibandronic acid, ibritumomab 20 tiuxetan, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, interferon alfa, interferon beta, interferon gamma, ipilimumab, irinotecan, ixabepilone, lanreotide, lapatinib, lenalidomide, lenograstim, lentinan, letrozole, leuprorelin, levamisole, lisuride, lobaplatin, lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, lan, mepitiostane, 25 mercaptopurine, rexate, salen, Methyl aminolevulinate, methyltestosterone, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, nedaplatin, nelarabine, nilotinib, nilutamide, zumab, nimustine, nitracrine, ofatumumab, omeprazole, oprelvekin, oxaliplatin, p53 gene therapy, 30 paclitaxel, palifermin, palladium-103 seed, pamidronic acid, panitumumab, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pegfilgrastim, peginterferon alfa-2b, pemetrexed, pentazocine, pentostatin, peplomycin, perfosfamide, picibanil, pirarubicin, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polysaccharide-K, porfimer sodium, pralatrexate, mustine, bazine, quinagolide, fene, raltitrexed, ranimustine, razoxane, regorafenib, risedronic acid, rituximab, 5 romidepsin, romiplostim, sargramostim, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sorafenib, streptozocin, sunitinib, rfin, tamibarotene, tamoxifen, tasonermin, teceleukin, tegafur, tegafur + gimeracil + oteracil, rfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, tioguanine, tocilizumab, 10 topotecan, toremifene, tositumomab, trabectedin, trastuzumab, treosulfan, tretinoin, trilostane, relin, trofosfamide, tryptophan, ubenimex, valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, ine, nine, vinorelbine, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, cin.
49. A compound of formula (II), when prepared by the method of any one of claims 3 to 34.
50. A compound according to claim 1, substantially as herein bed or 20 exemplified.
51. A method according to claim 3, substantially as herein described or exemplified. 25
52. A use according to claim 35, substantially as herein described or exemplified.
53. A use according to claim 37, substantially as herein described or exemplified.
54. A pharmaceutical ition ing to claim 45, substantially as herein described or exemplified.
55. A pharmaceutical composition according to claim 46, substantially as 5 herein described or exemplified.
56. A pharmaceutical composition according to claim 47, substantially as herein described or exemplified. 10
57. A compound according to claim 49, substantially as herein described or exemplified.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP11161111.7 | 2011-04-05 | ||
EP11161111A EP2508525A1 (en) | 2011-04-05 | 2011-04-05 | Substituted 2,3-dihydroimidazo[1,2-c]quinazoline salts |
PCT/EP2012/055600 WO2012136553A1 (en) | 2011-04-05 | 2012-03-29 | Substituted 2,3-dihydroimidazo[1,2-c]quinazoline salts |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ616198A NZ616198A (en) | 2015-09-25 |
NZ616198B2 true NZ616198B2 (en) | 2016-01-06 |
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