NZ614130B2 - Processes for preparing quinoline compounds and pharmaceutical compositions containing such compounds - Google Patents
Processes for preparing quinoline compounds and pharmaceutical compositions containing such compounds Download PDFInfo
- Publication number
- NZ614130B2 NZ614130B2 NZ614130A NZ61413012A NZ614130B2 NZ 614130 B2 NZ614130 B2 NZ 614130B2 NZ 614130 A NZ614130 A NZ 614130A NZ 61413012 A NZ61413012 A NZ 61413012A NZ 614130 B2 NZ614130 B2 NZ 614130B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- compound
- dimethoxy
- ppm
- quinolineol
- another embodiment
- Prior art date
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- 238000000034 method Methods 0.000 title description 36
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- 238000005755 formation reaction Methods 0.000 claims abstract description 16
- YCIOUNSWHDKEBM-UHFFFAOYSA-N 6,7-dimethoxy-1H-quinolin-2-one Chemical compound C1=CC(=O)NC2=C1C=C(OC)C(OC)=C2 YCIOUNSWHDKEBM-UHFFFAOYSA-N 0.000 claims description 84
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 48
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- 102000016844 Immunoglobulin-like domains Human genes 0.000 description 1
- 108050006430 Immunoglobulin-like domains Proteins 0.000 description 1
- 101710030888 KDR Proteins 0.000 description 1
- 101710028765 KITLG Proteins 0.000 description 1
- ANYSGBYRTLOUPO-UHFFFAOYSA-N Lithium tetramethylpiperidide Chemical compound [Li]N1C(C)(C)CCCC1(C)C ANYSGBYRTLOUPO-UHFFFAOYSA-N 0.000 description 1
- 210000004072 Lung Anatomy 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N Malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N Mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 1
- 206010027476 Metastasis Diseases 0.000 description 1
- 206010028549 Myeloid leukaemia Diseases 0.000 description 1
- 210000003739 Neck Anatomy 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 206010053643 Neurodegenerative disease Diseases 0.000 description 1
- 108091007929 PDGF receptors Proteins 0.000 description 1
- 208000003154 Papilloma Diseases 0.000 description 1
- 102000011653 Platelet-Derived Growth Factor Receptors Human genes 0.000 description 1
- 229960000502 Poloxamer Drugs 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N Potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 229940107700 Pyruvic Acid Drugs 0.000 description 1
- 238000001069 Raman spectroscopy Methods 0.000 description 1
- 102000004278 Receptor protein-tyrosine kinases Human genes 0.000 description 1
- 108090000873 Receptor protein-tyrosine kinases Proteins 0.000 description 1
- 208000000587 Small Cell Lung Carcinoma Diseases 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 108009000491 Small cell lung cancer Proteins 0.000 description 1
- 206010041823 Squamous cell carcinoma Diseases 0.000 description 1
- 108010039445 Stem Cell Factor Proteins 0.000 description 1
- 108010053096 Vascular Endothelial Growth Factor Receptor-1 Proteins 0.000 description 1
- CQODGVQBRIGKLJ-UHFFFAOYSA-L [Na+].[Na+].[O-]OOO[O-] Chemical compound [Na+].[Na+].[O-]OOO[O-] CQODGVQBRIGKLJ-UHFFFAOYSA-L 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000003213 activating Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 239000003570 air Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229920002892 amber Polymers 0.000 description 1
- 230000003042 antagnostic Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000001772 anti-angiogenic Effects 0.000 description 1
- 230000001028 anti-proliferant Effects 0.000 description 1
- 102000004965 antibodies Human genes 0.000 description 1
- 108090001123 antibodies Proteins 0.000 description 1
- 238000003782 apoptosis assay Methods 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000035578 autophosphorylation Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000035514 bioavailability Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 230000003197 catalytic Effects 0.000 description 1
- 230000004709 cell invasion Effects 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 201000003963 colon carcinoma Diseases 0.000 description 1
- 201000011231 colorectal cancer Diseases 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000005712 crystallization Effects 0.000 description 1
- FDKLLWKMYAMLIF-UHFFFAOYSA-N cyclopropane-1,1-dicarboxylic acid Chemical compound OC(=O)C1(C(O)=O)CC1 FDKLLWKMYAMLIF-UHFFFAOYSA-N 0.000 description 1
- 230000001419 dependent Effects 0.000 description 1
- 230000003831 deregulation Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 239000006274 endogenous ligand Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 108010003374 fms-Like Tyrosine Kinase 3 Proteins 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 230000002496 gastric Effects 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 210000004602 germ cell Anatomy 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 201000011066 hemangioma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 200000000018 inflammatory disease Diseases 0.000 description 1
- 230000003834 intracellular Effects 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000012035 limiting reagent Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 201000008806 mesenchymal cell neoplasm Diseases 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 230000000771 oncological Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000001575 pathological Effects 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- 239000001184 potassium carbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000003389 potentiating Effects 0.000 description 1
- 230000005522 programmed cell death Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 235000011044 succinic acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000001131 transforming Effects 0.000 description 1
- 102000027575 transmembrane receptors Human genes 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
Abstract
Disclosed herein are pharmaceutical compositions of the compound N-(4-{[6,7-bis(methoxyquinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide and the (L)-malate salt thereof, wherein the formation of 6,7-dimethoxy-quinoline-4-ol in the pharmaceutical formulation is minimized to 50 ppm or less over time. 50 ppm or less over time.
Description
PROCESSES FOR PREPARING QUINOLINE COMPOUNDS AND
PHARMACEUTICAL COMPOSITIONS CONTAINING SUCH COMPOUNDS
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of priority to U.S. Provisional Application No.
61/441,520, filed February 10, 2011, and 61/441,527, filed February 10, 2011, which are
incorporated herein by reference
FIELD OF THE INVENTION
Disclosed are processes for preparing compounds useful for modulating protein
kinase enzymatic activity. More specifically, disclosed are processes for preparing
quinolines that are useful for modulating cellular activities such as proliferation,
differentiation, programmed cell death, migration, and chemo-invasion. Pharmaceutical
compositions containing such compounds are provided
BACKGROUND OF THE INVENTION
Traditionally, dramatic improvements in the treatment of cancer are associated
with identification of therapeutic agents acting through novel mechanisms. One mechanism
that can be exploited in cancer treatment is the modulation of protein kinase activity because
signal transduction through protein kinase activation is responsible for many of the
characteristics of tumor cells. Protein kinase signal transduction is of particular relevance in,
for example, renal, gastric, head and neck, lung, breast, prostate, and colorectal cancers;
hepatocellular carcinoma; as well as in the growth and proliferation of brain tumor cells.
Protein kinases can be categorized as receptor type or non-receptor type.
Receptor-type tyrosine kinases are comprised of a large number of transmembrane receptors
with diverse biological activity. For a detailed discussion of the receptor-type tyrosine
kinases, see Plowman et al., DN&P 7(6): 334-339, 1994. Since protein kinases and their
ligands play critical roles in various cellular activities, deregulation of protein kinase
enzymatic activity can lead to altered cellular properties, such as uncontrolled cell growth
associated with cancer. In addition to oncological indications, altered kinase signaling is
implicated in numerous other pathological diseases, including, for example, immunological
disorders, cardiovascular diseases, inflammatory diseases, and degenerative diseases.
Therefore, protein kinases are attractive targets for small molecule drug discovery.
Particularly attractive targets for small-molecule modulation with respect to antiangiogenic
and antiproliferative activity include receptor type tyrosine kinases c-Met, KDR, c-Kit, Axl,
flt-3, and flt-4.
The kinase c-Met is the prototypic member of a subfamily of heterodimeric
receptor tyrosine kinases (RTKs) which include Met, Ron, and Sea. The endogenous ligand
for c-Met is the hepatocyte growth factor (HGF), a potent inducer of angiogenesis. Binding
of HGF to c-Met induces activation of the receptor via autophosphorylation, resulting in an
increase of receptor dependent signaling, which promotes cell growth and invasion. Anti-
HGF antibodies or HGF antagonists have been shown to inhibit tumor metastasis in vivo
(See: Maulik et al Cytokine & Growth Factor Reviews 2002 13, 41-59). c-Met
overexpression has been demonstrated on a wide variety of tumor types including breast,
colon, renal, lung, squamous cell myeloid leukemia, hemangiomas, melanomas,
astrocytomas, and glioblastomas. Additionally, activating mutations in the kinase domain of
c-Met have been identified in hereditary and sporadic renal papilloma and squamous cell
carcinoma. (See, e.g., Maulik et al., Cytokine & growth Factor reviews 2002 13, 41-59;
Longati et al., Curr Drug Targets 2001, 2, 41-55; Funakoshi et al., Clinica Chimica Acta 2003
1-23).
Inhibition of epidermal growth factor (EGF), vascular endothelial growth factor
(VEGF), and ephrin signal transduction will prevent cell proliferation and angiogenesis, two
key cellular processes needed for tumor growth and survival (Matter A., Drug Disc. Technol.
2001 6, 1005-1024). Kinase KDR (refers to kinase insert domain receptor tyrosine kinase)
and flt-4 (fms-like tyrosine kinase-4) are both VEGF receptors. Inhibition of EGF, VEGF,
and ephrin signal transduction will prevent cell proliferation and angiogenesis, two key
cellular processes needed for tumor growth and survival (Matter A. Drug Disc. Technol.
2001 6, 1005-1024). EGF and VEGF receptors are desirable targets for small molecule
inhibition. All members of the VEGF family stimulate cellular responses by binding to
tyrosine kinase receptors (the VEGFRs) on the cell surface, causing them to dimerize and
become activated through transphosphorylation. The VEGF receptors have an extracellular
portion with immunoglobulin-like domains, a single transmembrane spanning region, and an
intracellular portion containing a split tyrosine-kinase domain. VEGF binds to VEGFR-1 and
VEGFR-2. VEGFR-2 is known to mediate almost all of the known cellular responses to
VEGF.
Kinase c-Kit (also called stem cell factor receptor or steel factor receptor) is a type
3 receptor tyrosine kinase (RTK) belonging to the platelet-derived growth factor receptor
subfamily. Overexpression of c-Kit and c-Kit ligand has been described in variety of human
diseases, including human gastrointestinal stromal tumors, mastocytosis, germ cell tumors,
acute myeloid leukemia (AML), NK lymphoma, small-cell lung cancer, neuroblastomas,
gynecological tumors, and colon carcinoma. Moreover, elevated expression of c-Kit may
also relate to the development of neoplasia associated with neurofibromatosis type 1 (NF-1),
mesenchymal tumors GISTs, and mast cell disease, as well as other disorders associated with
activated c-Kit.
Kinase Flt-3 (fms-like tyrosine kinase-3) is constitutively activated via mutation,
either in the juxtamembrane region or in the activation loop of the kinase domain, in a large
proportion of patients with AML (Reilly, Leuk. Lymphoma, 2003, 44: 1-7).
Small-molecule compounds that specifically inhibit, regulate, and/or modulate the
signal transduction of kinases, such as c-Met, VEGFR2, KDR, c-Kit, Axl, flt-3, and flt-4
described above, are particularly desirable as a means to treat or prevent disease states
associated with abnormal cell proliferation and angiogenesis. One such small-molecule is
compound IA, which has the chemical structure:
WO2005/030140 describes the synthesis of compound IA (Table 2, Compound 12, Example
48) and also discloses the therapeutic activity of this molecule to inhibit, regulate, and/or
modulate the signal transduction of kinases (Assays, Table 4, entry 289), the entire contents
of which is incorporated herein by reference.
Although therapeutic efficacy is the primary concern for a therapeutic agent, the
pharmaceutical composition can be equally important to its development. Generally, the drug
developer endeavors to discover a pharmaceutical composition that possesses desirable
properties, such as satisfactory water-solubility (including rate of dissolution), storage
stability, hygroscopicity, and reproducibility, all of which can impact the processability,
manufacture, and/or bioavailability of the drug.
Accordingly, there is a need for the discovery of new processes for making
quinolines such as compound IA that minimize the formation of undesirable process
contaminants or byproducts. There is also a need for new pharmaceutical compositions
containing quinolines such as compound IA that are essentially free of process byproducts.
[0011A] In this specification where reference has been made to patent specifications,
other external documents, or other sources of information, this is generally for the purpose of
providing a context for discussing the features of the invention. Unless specifically stated
otherwise, reference to such external documents is not to be construed as an admission that
such documents, or such sources of information, in any jurisdiction, are prior art, or form part
of the common general knowledge in the art.
[0001B] In the description in this specification reference may be made to subject matter
that is not within the scope of the claims of the current application. That subject matter
should be readily identifiable by a person skilled in the art and may assist in putting into
practice the invention as defined in the claims of this application.
SUMMARY OF THE INVENTION
One or more of these needs are met; and/or the public is at least provided with a
useful choice, by the present disclosure, which is directed to compositions containing
quinolines or pharmaceutically acceptable salts thereof.
[0012A] The invention provides a pharmaceutical composition selected from the group
consisting of Table 2A, 3, 4, 5, and 6
Table 2A
Ingredient % w/w
Compound IB (10 % drug load as
Compound IA) 12.67
Microcrystalline Cellulose 51.52
Lactose 25.76
Hydroxypropyl cellulose 3.0
Croscarmellose Sodium 6.0
Colloidal Silicon Dioxide 0.3
Magnesium Stearate 0.75
Total 100
Table 3
Ingredient mg/unit dose
Compound IB (10 % drug 25
load as Compound IA)
Silicified Microcrystalline 196.75
Cellulose
Ingredient mg/unit dose
Croscarmellose sodium 12.5
Sodium starch glycolate 12.5
Fumed Silica 0.75
Stearic acid 2.5
Total Fill Weight 250
Table 4
Ingredient mg/unit dose
Compound IB (50 % drug 100
load as Compound IA)
Silicified Microcrystalline 75.40
Cellulose
Croscarmellose sodium 10.00
Sodium Starch Glycolate 10.00
Fumed silica 0.6
Stearic Acid 4.0
Total Fill Weight 200
Table 5
mg/unit dose
Ingredient 50mg
Compound IB (10 % drug 63.35
load as Compound IA)
Microcrystalline Cellulose 95.39
Croscarmellose sodium 9.05
Sodium starch glycolate 9.05
Fumed Silica 0.54
Stearic acid 3.62
Total Fill Weight 181.00
Table 6
mg/unit dose
Ingredient 60mg
Compound IB 73.95
Microcrystalline Cellulose 114.36
Croscarmellose sodium 10.85
Sodium starch glycolate 10.85
Fumed Silica 0.65
Stearic acid 4.34
Total Fill Weight 217.00
wherein Compound IA has the structure:
compound IB has the structure:
and wherein the formation of 6,7-dimethoxy-quinolineol in the pharmaceutical
formulation is minimized to 50 ppm or less over time.
[0012B] The invention also provides a pharmaceutical composition comprising
Compound IB; microcrystalline cellulose; croscarmellose sodium; sodium starch glycolate;
fumed silica; and stearic acid; wherein Compound IB has the structure:
and wherein the formation of 6,7-dimethoxy-quinolineol in the pharmaceutical
formulation is minimized to 50 ppm or less over time.
BRIEF DESCRIPTION OF THE INVENTION
Described are processes for preparing a compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
X is H, Br, Cl, or F;
X is H, Br, Cl, or F;
n1 is 1-2; and
n2 is 1-2.
Intermediates useful in preparing the above compounds are also disclosed.
The compounds of formula I are useful as protein kinase modulators, and they
inhibit various protein kinases including Ret and c-Met.
Also described is a process for preparing compound IB:
from compound IA:
comprising:
(a) heating and agitating a mixture comprising compound IA and L-malic acid,
methylethyl ketone, and water;
(b) cooling the mixture;
(c) vacuum distilling the mixture successively; and
(d) isolating the compound of IB by filtration.
Also described is a process for preparing compound IB:
from compound IA:
comprising:
(a) heating and agitating a mixture comprising compound IA and L-malic acid,
methylethyl ketone, and water;
(b) cooling the mixture;
(c) seeding the mixture with compound IB;
(d) vacuum distilling the mixture; and
(e) isolating compound IB by filtration.
Also described is a compound I, IA, or IB admixed with less than 100 ppm 6,7-
dimethoxy-quinolineol, the structure of which is .
Also described are pharmaceutical compositions containing the compound of
formula I, compound IA, or compound IB for oral administration.
Also described is a pharmaceutical tablet composition according to Table 1.
Table 1
Ingredient % w/w
Ingredient % w/w
Compound I 31.68
Microcrystalline Cellulose 38.85
(MCC) (Avicel PH102)
Lactose anhydrous 60 M 19.42
Hydroxypropyl Cellulose, EXF 3.00
Croscarmellose Sodium 3.00
Total Intra-granular 95.95
Silicon dioxide, Colloidal PWD 0.30
Croscarmellose Sodium 3.00
Magnesium Stearate 0.75
Total 100.00
Also described is a pharmaceutical tablet composition according to Table 2.
Table 2
Ingredient (% w/w)
Compound I 25.0-33.3
Microcrystalline Cellulose, NF q.s
Hydroxypropyl Cellulose, NF 3
Poloxamer, NF 0-3
Croscarmellose Sodium, NF 6.0
Colloidal Silicon Dioxide, NF 0.5
Magnesium Stearate, NF 0.5-1.0
Total 100
Also described is a pharmaceutical tablet composition according to Table 2A.
Table 2A
Ingredient % w/w
Compound IB (10 % drug load as
Compound IA) 12.67
Microcrystalline cellulose 51.52
Lactose 25.76
Hydroxypropyl cellulose 3.0
Croscarmellose Sodium 6.0
Colloidal Silicon Dioxide 0.3
Magnesium Stearate 0.75
Total 100
Also described is a pharmaceutical capsule composition according to Table 3.
Table 3
Ingredient mg/unit dose
Compound IB (10 % drug 25
load as Compound IA)
Silicified Microcrystalline 196.75
Cellulose
Croscarmellose sodium 12.5
Sodium starch glycolate 12.5
Fumed Silica 0.75
Stearic acid 2.5
Total Fill Weight 250
Also described is a pharmaceutical capsule composition according to Table 4.
Table 4
Ingredient mg/unit dose
Compound IB (50 % drug 100
load as Compound IA)
Silicified Microcrystalline 75.40
Cellulose
Croscarmellose sodium 10.00
Sodium Starch Glycolate 10.00
Fumed silica 0.6
Stearic Acid 4.0
Total Fill Weight 200
Also described is a pharmaceutical capsule composition according to Table 5,
wherein the IB weight equivalents are provided.
Table 5
mg/unit dose
Ingredient 50mg
Compound IB 63.35
Microcrystalline Cellulose 95.39
Croscarmellose sodium 9.05
Sodium starch glycolate 9.05
Fumed Silica 0.54
Stearic acid 3.62
181.00
Total Fill Weight
Also described is a pharmaceutical capsule composition according to Table 6,
wherein the IB weight equivalents are provided.
Table 6
mg/unit dose
Ingredient 60mg
Compound IB 73.95
Microcrystalline Cellulose 114.36
Croscarmellose sodium 10.85
Sodium starch glycolate 10.85
Fumed Silica 0.65
Stearic acid 4.34
217.00
Total Fill Weight
Also described is a pharmaceutical composition comprising compound I, IA, or IB
admixed with less than 100 ppm 6,7-dimethoxy-quinolineol, the structure of which is
, and a pharmaceutically acceptable carrier.
There are many different aspects and embodiments of the disclosure described
herein, and each aspect and each embodiment is non-limiting in regard to the scope of the
disclosure. The terms “aspects” and “embodiments” are meant to be non-limiting regardless
of where the terms “aspect” or “embodiment” appears in this specification. The transitional
term “comprising,” as used herein, which is synonymous with “including,” “containing,” or
“characterized by,” is inclusive or open-ended and does not exclude additional, unrecited
elements.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
As used herein, the following words and phrases are generally intended to have
the meanings as set forth below, except to the extent that the context in which they are used
indicates otherwise or they are expressly defined to mean something different.
The word “can” is used in a non-limiting sense and in contradistinction to the
word “must.” Thus, for example, in many aspects of the invention a certain element is
described as “can” having a specified identity, which is meant to convey that the subject
element is permitted to have that identity according to the invention but is not required to
have it.
If a group “R” is depicted as “floating” on a ring system, then unless otherwise
defined, the substituent(s) “R” can reside on any atom of the ring system, assuming
replacement of a depicted, implied, or expressly defined hydrogen from one of the ring
atoms, so long as a stable structure is formed.
When there are more than one such depicted “floating” groups, such as where
there are two groups; then, unless otherwise defined, the “floating” groups can reside on any
atoms of the ring system, again assuming each replaces a depicted, implied, or expressly
defined hydrogen on the ring.
“Pharmaceutically acceptable salts” include acid addition salts.
“Pharmaceutically acceptable acid addition salt” refers to those salts that retain the
biological effectiveness of the free bases and that are not biologically or otherwise
undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, and the like, or mixtures thereof, as well as organic
acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid,
oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,
benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-
toluenesulfonic acid, salicylic acid, and the like, or mixtures thereof.
“Essentially free” as used in the phrase “essentially free of process byproducts or
contaminants,” means that a compound or composition as disclosed here in is admixed with
200 parts per million (ppm) or less of such byproducts or contaminants.
The disclosure is further illustrated by the following examples, which are not to be
construed as limiting the disclosure in scope or spirit to the specific procedures described in
them. Unless specified otherwise, the starting materials and various intermediates may be
obtained from commercial sources, prepared from commercially available organic
compounds, or prepared using well-known synthetic processes.
Processes
Part 1: Processes for Making Compounds of Formula I
Described is a process of preparing a compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
X is H, Br, Cl, or F;
X is H, Br, Cl, or F;
n1 is 1-2; and
n2 is 1-2;
the process comprising:
contacting the compound of formula g(1) with reactant z(1) to yield the compound of formula
The reaction is advantageously carried out under suitable reaction conditions.
Non-limiting examples of suitable reaction conditions include using basic conditions. Non-
limiting examples of basic conditions that can be used in Aspect (1) include the use of
inorganic bases, such as aqueous KOH, NaOH, K CO , Na CO , K PO , Na PO , K HPO ,
2 3 2 3 3 4 3 4 2 4
Na HPO , and the like, or mixtures thereof. Other non-limiting examples of suitable reaction
conditions include using suitable solvents. Non-limiting examples of suitable solvents that
can be used include water miscible solvents, such as THF, acetone, ethanol, and the like, or
mixtures thereof. Other non-limiting examples of suitable reaction conditions include using
suitable temperatures. Suitable temperatures that may be used for the reaction include a
temperature at a range from about 10 °C to about 30 °C, or alternatively, at a range from
about 15 °C to about 28 °C, or alternatively, at a range from about 20 °C to about 25 °C. The
product formed by the reaction is in the free base form, and this free base form may be
converted into a pharmaceutically acceptable salt thereof by processes known in the art. For
example, the compound of formula I can be converted to the L-malate salt by the addition of
L-malic acid and a suitable solvent.
Utilities of the compound of formula I are further described in
A2, which is incorporated herein by reference.
Embodiments of Part (1)
In another embodiment of Part (1), X is Cl or F.
In another embodiment of Part (1), X is Cl or F.
In another embodiment of Part (1), X is F.
In another embodiment of Part (1), X is F.
In another embodiment of Part (1), X is H.
In another embodiment of Part (1), X is H.
In another embodiment of Part (1), n1 is 1.
In another embodiment of Part (1), n2 is 1.
In another embodiment of Part (1), n1 is 2.
In another embodiment of Part (1), n2 is 2.
All compounds of formula I for Part (1) disclosed above include any of the
disclosed alternative embodiments in Part (1) for each of X , X , n1 or n2, in combination
with any other of the disclosed alternative embodiments in Part (1) for each of X , X , n1, or
n2, as well as a pharmaceutically acceptable salt of any such combination.
Embodiments of Part (2)
In another embodiment of Part (1), n1 and n2 are each 1.
In another embodiment of Part (1), n1 and n2 are each 2.
In another embodiment of Part (1), n1 is 1; and n2 is 2.
In another embodiment of Part (1), n1 is 2 and n2 is 1.
In another embodiment of Part (1), X is H; and X is F.
In another embodiment of Part (1), X is F; and X is H.
In another embodiment of Part (1), X and X are each H.
In another embodiment of Part (1), X and X are each F.
In another embodiment of Part (1), X is Cl; and X is H.
In another embodiment of Part (1), X is H; and X is Cl.
In another embodiment of Part (1), X and X are each Cl.
In another embodiment of Part (1), X is Cl; and X is F.
In another embodiment of Part (1), X is F; and X is Cl.
Embodiments of) Part (3)
In an embodiment of Part (1), the compound of formula g(1) can be made by
reacting a compound of formula f(1) with reactant y(1) to yield the compound of g(1):
wherein LG represents a leaving group, and each of X , and n2 are as defined in Part (1), or
as in any of the embodiments of Part 1. A non-limiting example of a leaving group includes
a halo group such as Cl, Br, or F. Various compounds of reactant y(1) are commercially
available, such as 2-fluoroaminophenol and 4-aminophenol. Also, the skilled artisan
would be able to make any variation of reactant y(1) using commercially available starting
materials and by using known techniques to modify these commercially available starting
materials to yield various compounds within the scope of reactant y(1).
The reaction in this embodiment is advantageously carried out under suitable
reaction conditions. Non-limiting examples of suitable reaction conditions include using
suitable solvents such as polar solvents. Non-limiting examples of polar solvents that can be
used include tetrahydrofuran (THF), dimethylacetamide (DMA), dimethylsulfoxide (DMSO),
dimethylformamide (DMF), ethyl acetate, N-methyl pyrrolidone (NMP), propylene
carbonate, and the like, or mixtures thereof. In another embodiment, the polar solvent is
dimethylacetamide (DMA). In another embodiment, the polar solvent is dimethylsulfoxide
(DMSO). In another embodiment, the polar solvent is dimethylformamide (DMF). In
another embodiment, the polar solvent is ethyl acetate. In another embodiment, the polar
solvent is N-methyl pyrrolidone (NMP). In another embodiment, the polar solvent is
propylene carbonate. In another embodiment, the solvent is a mixture of solvents, such as a
mixture comprising THF and DMA.
The reactants f(1) and y(1) can be added together at a temperature ranging from
about 10 °C to about 30 °C, or alternatively, from about 15 °C to about 28 °C, or
alternatively, from about 20 °C to about 25 °C. The mixture is then heated to a temperature
ranging from about 80 °C to about 125 °C, or alternatively, from about 95 °C to about 110
°C, or alternatively, from about 100 °C to about 105 °C, and the selected temperature is
maintained until the reaction is complete.
Other non-limiting examples of suitable reaction conditions in this step of Part (1)
include the use of a suitable base, such as a metal hydroxide or a non-nucleophilic base.
Examples of metal hydroxides include sodium hydroxide or potassium hydroxide. Non-
limiting examples of non-nucleophilic bases that can be used include lithium
diisopropylamide, lithium tetramethylpiperidide, and alkali metal alkoxides such as sodium
tert-butoxide, potassium tert-butoxide, sodium-pentoxide, and the like, or mixtures thereof.
Preferably, the base is sodium tert-butoxide or sodium tert-pentoxide. In one embodiment,
the base is sodium tert-pentoxide. Typically the sodium tert-pentoxide is commercially
available as 35 weight percent solution of base in tetrahydrofuran, or as a 95 weight percent
solid reagent. Preferably, the sodium tert-pentoxide is a 95 weight percent solid.
Typically, approximately 1.1 to 3.0 molar equivalents of base are used relative the
moles of f(1) that are used. More preferably, 1.3 to 2.5 molar equivalents of base are used
relative the moles of f(1) that are used. More preferably, 1.5 to 2.2 molar equivalents of base
are used relative the moles of f(1) that are used. More preferably, 1.7 to 2.1 molar
equivalents of base are used relative the moles of f(1) that are used.
Typically, the amount of molar equivalents of amino phenol that are used exceeds
the molar equivalents of base that are used. In one embodiment, 1.1 to 2 molar equivalents of
amino phenol are used relative to the molar equivalents of base that are used.
Once the reaction is substantially complete, the reaction mixture can be cooled to
a temperature ranging from about 10 °C to about 25 °C. Precooled water can be charged at a
rate to maintain a temperature that ranges from about 5 °C to about 35 °C. Alternatively, the
precooled water can be charged at a rate to maintain a temperature that ranges from about 10
°C to about 25 °C. As a non-limiting example, the precooled water can be at a temperature
ranging from about 0 °C to about 10 °C. As another non-limiting example, the precooled
water can be at a temperature ranging from about 2 °C to about 7 °C. The precipitate can be
collected by filtration under standard conditions and purified by standard purification
techniques.
Embodiments of Part (4)
In an embodiment of Part (1), the compound of formula f(1) can be made by
converting a compound of formula e(1) to the compound of formula f(1):
wherein LG represents a leaving group. Non-limiting examples of leaving groups that can be
used include halo groups (e.g., Cl, Br, or F) that can be added by halogenating agents. Non-
limiting examples of halogenating agents that can be used include chlorinating agents, such
as SOCl , SO Cl , COCl , PCl , POCl , and the like.
2 2 2 2 5 3
The reaction is advantageously carried out under suitable reaction conditions.
Non-limiting examples of suitable reaction conditions in Part 4 include the use of suitable
solvents. Non-limiting example of suitable solvents that can be used during the halogenation
of the compound of formula e(1) include a polar, aprotic solvent, such as CH CN, DMF, and
the like, or mixtures thereof. In other embodiments, the chlorination can be carried out using
POCl in acetonitrile, COCl in DMF, or SOCl in DMF. The addition of the chlorination
3 2 2
agent is advantageously carried out at a temperature ranging from about 60 °C to about 90
°C. In another embodiment, the addition of the chlorination agent can be carried out at a
temperature ranging from about 70 °C to about 85 °C. In another embodiment, the addition
of the chlorination agent can be carried out at a temperature ranging from about 74 °C to
about 80 °C. The product can then be collected by filtration and purified using standard
techniques.
Embodiments of Part (5)
In an embodiment of Part (1), reactant z(1) can be made by reacting reactant z(1a)
with a chlorinating agent to yield reactant z(1):
chorinating agent
reactant z(1)
reactant z(1a)
wherein X is Br, Cl, or F; and n1 is 1-2. Compounds of reactant z(1a) can be made
according to the process described in Example 25 of A2, and the skilled
artisan would be able to make any necessary substitutions using commercially available
starting materials to come up with various compounds within the scope of reactant z(1a).
Example 25 in A2 is incorporated herein by reference.
The reaction is advantageously carried out under suitable reaction conditions.
Non-limiting examples of suitable reaction conditions include using a chlorinating agent such
as POCl , oxalyl chloride, and the like. In another embodiment, oxalyl chloride is used as a
chlorinating agent. Non-limiting examples of suitable reaction conditions include carrying
out the reaction at a temperature in the range from about 0 °C to about 25 °C, or alternatively
at a temperature in the range from about 5 °C to about 20 °C. Other non-limiting examples of
suitable reaction conditions include carrying out the reaction in a suitable solvent. Non-
limiting examples of suitable solvents that can be used include polar aprotic solvents, such as
halogenated hydrocarbons (e.g., dichloromethane and chloroform), ethers (e.g., Et O),
dioxane, tetrahydrofuran (THF) containing catalytic DMF, and the like, or mixtures thereof.
The resulting solution containing reactant z(1) can be used, without further processing, to
make the compound of formula I.
Other Embodiments of Part (1)
In another embodiment of Part (1), the compound of formula I is a compound of
formula IA-1:
IA-1
or a pharmaceutically acceptable salt thereof, wherein:
X is H, Cl, Br, or F; and X is H, Cl, Br, or F. Compound IA can be in the free base
form or it can converted to a pharmaceutically acceptable salt thereof. Accordingly,
compound IA can be converted to its L-malate salt by the addition of L-malic acid and a
suitable solvent.
In another embodiment of Part (4), the compound of formula e(1) is compound
e(2):
H CO
H CO N
e(2)
and the compound of formula f(1) is compound f(2):
H CO
H CO N
f (2)
In another embodiment of Part (3), the compound of formula f(1) is compound
f(2):
H CO
H CO
f (2)
reactant y(1) is reactant (y)(2):
reactant (y)(2)
wherein X is hydrogen or fluoro; and
the compound of formula g(1) is of formula g(2):
H CO
H CO
g(2)
In a further embodiment, the reaction employs a non-nucleophilic base. In a
further embodiment, the non-nucelophilic base is an alkali metal alkoxide; and the reaction is
carried out in a polar solvent. In a further embodiment, the alkali metal alkoxide is sodium
tert-butoxide, and the polar solvent is DMA.
In another embodiment of Part (3), the compound of formula f(1) is compound
f(2):
H CO
H CO
f (2)
reactant y(1) is reactant (y)(3):
reactant (y)(3)
wherein X is hydrogen or fluoro; and
the compound of formula g(1) is compound g(3):
H CO
H CO
g(3)
In another embodiment of Part (1) of this disclosure, the compound of formula
g(1) is compound g(3):
H CO
H CO
g(3)
reactant z(1) is reactant (z)(2):
reactant z(2)
; and
the compound of formula I is compound IA:
In a further embodiment, the reaction is carried out in the presence of an inorganic
base. In a further embodiment, the inorganic base is K CO , and the solvent employed in this
reaction is a combination of THF and H O.
In another embodiment of Part (1) of this disclosure, X and X for each of
formula g(1) and reactant z(1) are each selected from Cl or F. In another embodiment, X
and X for each of formula g(2), and reactant z(1) are both F.
The compound of formula f(2),or a pharmaceutically acceptable salt thereof, can
be made by converting the compound of formula e(2) to a compound of formula f(2) with a
chlorinating agent in a suitable solvent:
H CO
H CO
chorinating
agent
H CO
H CO
e(2)
f (2)
The compound of formula f(2) can be in its free base form or converted to a pharmaceutically
acceptable salt thereof. The reaction conditions that can be used in this aspect include any of
the reaction conditions disclosed in Part (5).
Aspect 2: Processes for Making Compounds of Formula g(2)
Part (2) of the disclosure relates to a process of preparing compound g(2):
H CO
H CO N
g(2)
or a pharmaceutically acceptable salt thereof; the process comprising reacting compound f(2)
with reactant y(3) under basic conditions (e.g., using 2,6-lutidine) in an appropriate solvent to
yield compound g(3):
reactant y(3)
H CO
H CO
H CO
f (2)
H CO N
g(3)
The reaction conditions that can be used in this aspect include any of the reaction conditions
disclosed in Part (3).
Alternative reaction conditions that can be used in this aspect include any of the
reaction conditions disclosed in Parts (3) and (4).
Aspect 3: Processes for Making Compounds of IB
Described is a process for preparing compound IB:
from compound IA:
comprising:
(a) heating and agitating a mixture comprising compound IA and L-malic acid,
methylethyl ketone, and water;
(b) cooling the mixture;
(c) vacuum distilling the mixture successively; and
(d) isolating the compound of IB by filtration.
In one embodiment of this aspect, compound IA is admixed with a sufficient
amount of L-malic acid in a methylethyl ketone (MEK)/water (1:1) mixture. Alternatively,
L-malic acid is added as a solution in water to a mixture of compound IA in methyl ethyl
ketone. Generally the amount of L-malic is greater than 1 molar equivalent relative to
compound IA. The mixture of compound IA and L-malic acid in MEK/water is heated at
about 40-70 °C, and preferably at about 50-60 °C, and more preferably at about 55-60 °C
with agitation, such as by stirring or the like, for about 1 to about 5 hours. At the end of the
heating, the mixture is optionally clarified by filtering to give a clear solution. The resulting
clear solution is then vacuum distilled from 1 to about 5 times at 150 to 200 mm Hg and a
maximum jacket temperature of 55 °C to provide the desired crystalline compound of IB.
In one embodiment, L-malic acid is charged as a solution in water to compound
IA. Generally the amount of L-malic is greater than 1 molar equivalent relative to compound
IA. The mixture of compound IA and L-malic acid in MEK/water is heated at about 40-70
°C, and preferably at about 50-60 °C, and more preferably at about 55-60 °C with agitation,
such as by stirring or the like, for about 1 to about 5 hours. At the end of the heating, the
mixture is optionally clarified by filtering to give a clear solution which is at a temperature of
about 30-40 °C, and more preferably at a temperature of about 33-37 °C. This clear solution
is optionally seeded to facilitate crystallization. After seeding, the resulting mixture is
vacuum distilled as provided above.
In one embodiment, compound IB is in the N-1 form. In another embodiment,
compound IB is in the N-2 form. In another embodiment, compound IB is a mixture of the
N-1 form and the N-2 form. Processes for preparing the N-1 and N-2 forms of compound IB
are disclosed in (PCT/US2010021194), the entire contents of which are
incorporated herein by reference.
In another embodiment, the disclosure relates to compound IA or IB admixed with
100 ppm or less of 6,7-dimethoxy-quinolineol. In one embodiment, the compound is
admixed with 50 ppm or less of 6,7-dimethoxy-quinolineol. In another embodiment, the
compound is admixed with 25 ppm or less of 6,7-dimethoxy-quinolineol. In another
embodiment, the compound is admixed with 10 ppm or less of 6,7-dimethoxy-quinolineol.
In another embodiment, the compound is admixed with 5 ppm or less of 6,7-dimethoxy-
quinolineol. In another embodiment, the compound is admixed with 2.5 ppm or less of
6,7-dimethoxy-quinolineol.
In another embodiment, the disclosure relates to compound IA admixed with 100
ppm or less of 6,7-dimethoxy-quinolineol. In one embodiment, the compound is admixed
with 50 ppm or less of 6,7-dimethoxy-quinolineol. In another embodiment, the compound
is admixed with 25 ppm or less of 6,7-dimethoxy-quinolineol. In another embodiment, the
compound is admixed with 10 ppm or less of 6,7-dimethoxy-quinolineol. In another
embodiment, the compound is admixed with 5 ppm or less of 6,7-dimethoxy-quinolineol.
In another embodiment, the compound is admixed with 2.5 ppm or less of 6,7-dimethoxy-
quinolineol.
In another embodiment, the disclosure relates to compound IB admixed with 100
ppm or less of 6,7-dimethoxy-quinolineol. In one embodiment, the compound is admixed
with 50 ppm or less of 6,7-dimethoxy-quinolineol. In another embodiment, the compound
is admixed with 25 ppm or less of 6,7-dimethoxy-quinolineol. In another embodiment, the
compound is admixed with 10 ppm or less of 6,7-dimethoxy-quinolineol. In another
embodiment, the compound is admixed with 5 ppm or less of 6,7-dimethoxy-quinolineol.
In another embodiment, the compound is admixed with 2.5 ppm or less of 6,7-dimethoxy-
quinolineol.
In another embodiment, the disclosure relates to compound IB in the N-1 form
admixed with 100 ppm or less of 6,7-dimethoxy-quinolineol. In one embodiment, the
compound is admixed with 50 ppm or less of 6,7-dimethoxy-quinolineol. In another
embodiment, the compound is admixed with 25 ppm or less of 6,7-dimethoxy-quinolineol.
In another embodiment, the compound is admixed with 10 ppm or less of 6,7-dimethoxy-
quinolineol. In another embodiment, the compound is admixed with 5 ppm or less of 6,7-
dimethoxy-quinolineol. In another embodiment, the compound is admixed with 2.5 ppm
or less of 6,7-dimethoxy-quinolineol.
In another embodiment, the disclosure relates to compound IB in the N-2 form
admixed with 100 ppm or less of 6,7-dimethoxy-quinolineol. In one embodiment, the
compound is admixed with 50 ppm or less of 6,7-dimethoxy-quinolineol. In another
embodiment, the compound is admixed with 25 ppm or less of 6,7-dimethoxy-quinolineol.
In another embodiment, the compound is admixed with 10 ppm or less of 6,7-dimethoxy-
quinolineol. In another embodiment, the compound is admixed with 5 ppm or less of 6,7-
dimethoxy-quinolineol. In another embodiment, the compound is admixed with 2.5 ppm
or less of 6,7-dimethoxy-quinolineol.
In another embodiment, the disclosure relates to compound IB as a mixture of the
N-1 form and the N-2 form admixed with 100 ppm or less of 6,7-dimethoxy-quinolineol.
In one embodiment, the compound is admixed with 50 ppm or less of 6,7-dimethoxy-
quinolineol. In another embodiment, the compound is admixed with 25 ppm or less of
6,7-dimethoxy-quinolineol. In another embodiment, the compound is admixed with 10
ppm or less of 6,7-dimethoxy-quinolineol. In another embodiment, the compound is
admixed with 5 ppm or less of 6,7-dimethoxy-quinolineol. In another embodiment, the
compound is admixed with 2.5 ppm or less of 6,7-dimethoxy-quinolineol.
Pharmaceutical Compositions
In another embodiment, the disclosure relates to a pharmaceutical composition
comprising Compound I, IA, or IB. Various carriers used in formulating pharmaceutically
acceptable compositions and known techniques for their bulk preparation and subsequent
production into unit dosage forms are employed to make the pharmaceutical compositions
disclosed herein and are described in Remington: The Science and Practice of Pharmacy, 21st
edition, 2005, ed. D. B. Troy, Lippincott Williams & Wilkins, Philadelphia, and
Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999,
Marcel Dekker, New York. The amount of carriers and excipients used in a composition can
be varied proportionally according to the amount of active ingredient used (that is,
Compound I, IA or IB).
In one embodiment, the pharmaceutical composition is a tablet.
In another embodiment, the pharmaceutical composition is a capsule.
In another embodiment, the pharmaceutical composition comprises Compound
In another embodiment, the pharmaceutical composition comprises Compound IB.
In another embodiment, the pharmaceutical composition comprises Compound IB.
as the N-1 polymorph.
In another embodiment, the pharmaceutical composition comprises Compound IB
as the N-2 polymorph.
In another embodiment, the pharmaceutical composition comprises Compound IB
as a mixture of the N-1 form and the N-2 form.
In another embodiment, the disclosure relates to a pharmaceutical composition
comprising Compound IA or IB; one or more fillers; one or more disintergrants; one or more
glidants; and one or more lubricants.
In this embodiment, the filler comprises microcrystalline cellulose.
In this embodiment, the disintegrant comprises croscarmellose sodium.
In this embodiment, the disintegrant comprises croscarmellose sodium and sodium
starch glycolate.
In this embodiment, the glidant comprises fumed silica.
In this embodiment, the lubricant comprises stearic acid.
In another embodiment, the disclosure relates to a pharmaceutical composition
comprising Compound IA or IB; microcrystalline cellulose; lactose; hydroxypropyl cellulose;
croscarmellose sodium; colloidal silicon dioxide; and magnesium stearate.
In another embodiment, the disclosure relates to a pharmaceutical composition
comprising Compound IA or IB; microcrystalline cellulose; hydroxypropyl cellulose; a
surfactant; croscarmellose sodium; colloidal silicon dioxide; and magnesium stearate.
In another embodiment, the disclosure relates to a pharmaceutical composition
comprising Compound IA or IB; microcrystalline cellulose; croscarmellose sodium; fumed
silica; and stearic acid.
In another embodiment, the disclosure relates to a pharmaceutical composition
comprising Compound IA or IB; microcrystalline cellulose; anhydrous lactose;
hydroxypropyl cellulose; croscarmellose sodium; silicon dioxide; and magnesium stearate.
In another embodiment, the disclosure relates to a pharmaceutical composition
comprising Compound IA or IB; microcrystalline cellulose; anhydrous lactose;
hydroxypropyl cellulose; a surfactant; croscarmellose sodium; silicon dioxide; and
magnesium stearate.
Also described is a pharmaceutical composition according to Tables 1, 2, 2A, 3,
4, 5, and 6 as provided above. The compositions are prepared according to methods available
to the skilled artisan. For example, the Tablet formulations are prepared by combining,
blending, and compacting the components of the tablet compositions. The capsule
compositions are prepared by combining and blending the components and then placing the
blend in a gelatin capsule.
For example, the 25 mg capsules (Table 3, 10 percent drug load formulation) are
prepared as follows. The drug substance is delumped through a mill. The delumped drug
substance is then co-screened with an equal volume Prosolv HD90. The excipients, except for
stearic acid, are screened and charged to a blender along with the co-screened drug substance.
The mixture is blended in a V-Blender. This process is repeated to manufacture a second
sublot of unlubricated blend. The two sublots are then combined together in a V-blender and
lubricated with stearic acid which has been co-screened with an equal volume of unlubricated
blend. The final blend is then encapsulated into opaque, size 1 gelatin capsules using an
automated capsule filling machine. The capsules are then weight sorted through an automatic
weight sorter.
The 100-mg capsules (Table 4, 50% drug load formulation) are manufactured in
two equal sublots of 5 kg of blend which are combined prior to lubricant blend The drug
substance is delumped through a mill. The excipients, except for stearic acid, are screened
and charged to the mixer along with the delumped drug substance. The mixture is blended
with a high shear mixer. The process is repeated to manufacture a second sublot of
unlubricated blend. The final blend is then encapsulated into Swedish oraopaque, size 1
gelatin capsules using an automated capsule filling machine. The capsuare then weight sorted
through an automatic weight sorter.
The 50 and 60 mg capsules (Tables 5 and 6) are prepared in a similar fashion as
the 25 and 100 mg capsules.
Also described is a pharmaceutical composition comprising a compound of
Formula IA or IB and a pharmaceutically acceptable carrier admixed with less than 100 ppm
of 6,7-dimethoxy-quinolineol. 6,7-dimethoxy-quinolineol, the structure of which is
, can be used as reagent e(1) to make chloride f(1) and is a byproduct that
may form during the synthesis of Compound IA or IB. Minimizing the concentration of
contaminants or byproducts such as 6,7-dimethoxy-quinolineol in pharmaceutical
compositions destined for human administration is desirable.
In one embodiment, the pharmaceutical composition as defined in any of the
previous embodiments (for example, the pharmaceutical composition of Tables 1, 2, 2A, 3, 4,
, and6) is admixed with 100 ppm 6,7-dimethoxy-quinolineol.
In another embodiment, the pharmaceutical composition as defined in any of the
previous embodiments is admixed with 50 ppm 6,7-dimethoxy-quinolineol.
In another embodiment, the pharmaceutical composition as defined in any of the
previous embodiments is admixed with 25 ppm 6,7-dimethoxy-quinolineol.
In another embodiment, the pharmaceutical composition as defined in any of the
previous embodiments is admixed with 15 ppm 6,7-dimethoxy-quinolineol.
In another embodiment, the pharmaceutical composition as defined in any of the
previous embodiments is admixed with 10 ppm 6,7-dimethoxy-quinolineol.
In another embodiment, the pharmaceutical composition as defined in any of the
previous embodiments is admixed with 5 ppm 6,7-dimethoxy-quinolineol.
In another embodiment, the pharmaceutical composition as defined in any of the
previous embodiments is admixed with 2.5 ppm 6,7-dimethoxy-quinolineol.
In another embodiment, the disclosure relates to a pharmaceutical composition
comprising Compound IA or IB; one or more fillers; one or more disintergrants; one or more
glidants; and one or more lubricants admixed with 100 ppm or less 6,7-dimethoxy-quinoline-
4-ol.
In this embodiment, the filler comprises microcrystalline cellulose.
In this embodiment, the disintegrant comprises croscarmellose sodium.
In this embodiment, the disintegrant comprises croscarmellose sodium and sodium
starch glycolate.
In this embodiment, the glidant comprises fumed silica.
In this embodiment, the lubricant comprises stearic acid.
In another embodiment, the disclosure relates to a pharmaceutical composition
comprising Compound IA or IB; microcrystalline cellulose; croscarmellose sodium; fumed
silica; and stearic acid; admixed with 100 ppm or less of 6,7-dimethoxy-quinolineol. In
one embodiment of this embodiment, the composition is admixed with 50 ppm or less of 6,7-
dimethoxy-quinolineol. In another embodiment of this embodiment, the composition is
admixed with 25 ppm or less of 6,7-dimethoxy-quinolineol. In another embodiment of
this embodiment, the composition is admixed with 10 ppm or less of 6,7-dimethoxy-
quinolineol. In another embodiment of this embodiment, the composition is admixed with
ppm or less of 6,7-dimethoxy-quinolineol. In another embodiment of this embodiment,
the composition is admixed with 2.5 ppm or less of 6,7-dimethoxy-quinolineol.
In another embodiment, the disclosure relates to a pharmaceutical composition
comprising Compound IA or IB; microcrystalline cellulose; anhydrous lactose;
hydroxypropyl cellulose; a surfactant; croscarmellose sodium; silicon dioxide; and
magnesium stearate; admixed with 100 ppm or less of 6,7-dimethoxy-quinolineol. In one
embodiment of this embodiment, the composition is admixed with 50 ppm or less of 6,7-
dimethoxy-quinolineol. In another embodiment of this embodiment, the composition is
admixed with 25 ppm or less of 6,7-dimethoxy-quinolineol. In another embodiment of
this embodiment, the composition is admixed with 10 ppm or less of 6,7-dimethoxy-
quinolineol. In another embodiment of this embodiment, the composition is admixed with
ppm or less of 6,7-dimethoxy-quinolineol. In another embodiment of this embodiment,
the composition is admixed with 2.5 ppm or less of 6,7-dimethoxy-quinolineol.
In another embodiment, the disclosure relates to a pharmaceutical composition
comprising Compound IA or IB; microcrystalline cellulose; croscarmellose sodium; fumed
silica; and stearic acid; ; admixed with 100 ppm or less of 6,7-dimethoxy-quinolineol. In
one embodiment of this embodiment, the composition is admixed with 50 ppm or less of 6,7-
dimethoxy-quinolineol. In another embodiment of this embodiment, the composition is
admixed with 25 ppm or less of 6,7-dimethoxy-quinolineol. In another embodiment of
this embodiment, the composition is admixed with 10 ppm or less of 6,7-dimethoxy-
quinolineol. In another embodiment of this embodiment, the composition is admixed with
ppm or less of 6,7-dimethoxy-quinolineol. In another embodiment of this embodiment,
the composition is admixed with 2.5 ppm or less of 6,7-dimethoxy-quinolineol.
EXAMPLES
The invention is illustrated further by the following examples in Scheme 1 and the
description thereof, which are not to be construed as limiting the invention in scope or spirit
to the specific procedures described in them. Those having skill in the art will recognize that
the starting materials may be varied and additional steps employed to produce compounds
encompassed by the invention, as demonstrated by the following examples. Those skilled in
the art will also recognize that it may be necessary to utilize different solvents or reagents to
achieve some of the above transformations. Unless otherwise specified, all reagents and
solvents are of standard commercial grade and are used without further purification. The
appropriate atmosphere to run the reaction under, for example, air, nitrogen, hydrogen, argon,
and the like, will be apparent to those skilled in the art.
Preparation of N-(4-{[6,7-bis(methyloxy)quinolinyl]oxy}phenyl)-N ’-(4-
fluorophenyl)cyclopropane-1,1-dicarboxamide and the (L)-malate salt thereof.
A synthetic route that can be used for the preparation of N-(4-{[6,7-
bis(methyloxy)quinolinyl]oxy}phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-
dicarboxamide and the (L)-malate salt thereof is depicted in Figure 1:
Figure 1
Preparation of 4-Chloro-6,7-dimethoxy-quinoline
A reactor was charged sequentially with 6,7-dimethoxy-quinolineol (47.0 kg)
and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 °C, and
phosphorus oxychloride (POCl , 130.6 kg) was added. After the addition of POCl , the
temperature of the reaction mixture was raised to approximately 77 °C. The reaction was
deemed complete (approximately 13 hours) when less than 3% of the starting material
remained (in-process high-performance liquid chromatography [HPLC] analysis). The
reaction mixture was cooled to approximately 2 – 7 °C and then quenched into a chilled
solution of dichloromethane (DCM, 482.8 kg), 26 % NH OH (251.3 kg), and water (900 L).
The resulting mixture was warmed to approximately 20 – 25 °C, and phases were separated.
The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg) and
the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed
with brine (282.9 kg) and mixed with water (120 L). The phases were separated and the
organic phase was concentrated by vacuum distillation with the removal of solvent
(approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor
containing organic phase and concentrated by vacuum distillation with the removal of solvent
(approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then
charged and the temperature of the mixture was adjusted to -20 to -25 C and held for 2.5
hours resulting in solid precipitate which was then filtered and washed with n-heptane (92.0
kg), and dried on a filter at approximately 25 °C under nitrogen to afford the title compound.
(35.6 kg).
Preparation of 4-(6,7-dimethoxy-quinolineyloxy)-phenylamine
4-Aminophenol (24.4 kg) dissolved in N,N-dimethylacetamide (DMA, 184.3 kg)
was charged to a reactor containing 4-chloro-6,7-dimethoxyquinoline (35.3 kg), sodium t-
butoxide (21.4 kg) and DMA (167.2 kg) at 20-25 °C. This mixture was then heated to 100-
105 °C for approximately 13 hours. After the reaction was deemed complete as determined
using in-process HPLC analysis (<2% starting material remaining), the reactor contents were
cooled at 15 to 20 °C and water (pre-cooled, 2 to 7 °C, 587 L) charged at a rate to maintain
to 30 C temperature . The resulting solid precipitate was filtered, washed with a mixture
of water (47 L) and DMA (89.1 kg) and finally with water (214 L). The filter cake was then
dried at approximately 25 °C on filter to yield crude 4-(6,7-dimethoxy-quinolineyloxy)-
phenylamine (59.4 kg wet, 41.6 kg dry calculated based on LOD). Crude 4-(6,7-dimethoxy-
quinolineyloxy)-phenylamine was refluxed (approximately 75 °C) in a mixture of
tetrahydrofuran (THF, 211.4 kg) and DMA (108.8 kg) for approximately 1hour and then
cooled to 0-5 °C and aged for approximately 1 h after which time the solid was filtered,
washed with THF (147.6 kg) and dried on a filter under vacuum at approximately 25 °C to
yield 4-(6,7-dimethoxy-quinolineyloxy)-phenylamine (34.0 kg).
Alternative Preparation of 4-(6,7-dimethoxy-quinolineyloxy)-phenylamine
4-chloro-6,7-dimethoxyquinoline (34.8 kg) and 4-aminophenol (30.8 kg) and
sodium tert pentoxide (1.8 equivalents) 88.7 kg, 35 wt percent in THF) were charged to a
reactor, followed by N,N-dimethylacetamide (DMA, 293.3 kg). This mixture was then
heated to 105-115 °C for approximately 9 hours. After the reaction was deemed complete as
determined using in-process HPLC analysis (<2% starting material remaining), the reactor
contents were cooled at 15 to 25 °C and water (315 kg) was added over a two hour period
while maintaining the temperature between 20 and 30 °C. The reaction mixture was then
agitated for an additional hour at 20 to 5 °C. The crude product was collected by filtration
and washed with a mixture of 88 kg water and 82.1 kg DMA, followed by 175 kg water. The
product was dried on a filter drier for 53 hours. The LOD showed less than 1% w/w.
In an alternative procedure, 1.6 equivalents of sodium tert-pentoxide were used
and the reaction temperature was increased from 110-120 °C. In addition , the cool down
temperature was increased to 35-40 °C and the starting temperature of the water addition was
adjusted to 35-40 °C, with an allowed exotherm to 45 °C.
Preparation of 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid
Triethylamine (19.5 kg) was added to a cooled (approximately 5 C) solution of
cyclopropane-1,1-dicarboxylic acid (24.7 kg) in THF (89.6 kg) at a rate such that the batch
temperature did not exceed 5 °C. The solution was stirred for approximately 1.3 hours, and
then thionyl chloride (23.1 kg) was added, keeping the batch temperature below 10 °C.
When the addition was complete, the solution was stirred for approximately 4 h keeping
temperature below 10 °C. A solution of 4–fluoroaniline (18.0 kg) in THF (33.1 kg) was then
added at a rate such that the batch temperature did not exceed 10 °C. The mixture was stirred
for approximately 10 hours after which the reaction was deemed complete. The reaction
mixture was then diluted with isopropyl acetate (218.1 kg). This solution was washed
sequentially with aqueous sodium hydroxide (10.4 kg, 50 % dissolved in 119 L of water)
further diluted with water (415 L), then with water (100 L) and finally with aqueous sodium
chloride (20.0 kg dissolved in 100 L of water). The organic solution was concentrated by
vacuum distillation (100 L residual volume) below 40 °C followed by the addition of n-
heptane (171.4 kg), which resulted in the precipitation of solid. The solid was recovered by
filtration and washed with n-Heptane (102.4 kg) resulting in wet crude, 1-(4-fluoro-
phenylcarbamoyl)-cyclopropanecarboxylic acid (29.0 kg). The crude, 1-(4-fluoro-
phenylcarbamoyl)-cyclopropanecarboxylic acid was dissolved in methanol (139.7 kg) at
approximately 25 ºC followed by the addition of water (320 L) resulting in slurry which was
recovered by filtration, washed sequentially with water (20 L) and n-heptane (103.1 kg) and
then dried on the filter at approximately 25 °C under nitrogen to afford the title compound
(25.4 kg).
Preparation of 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride
Oxalyl chloride (12.6 kg) was added to a solution of 1-(4-fluoro-
phenylcarbamoyl)-cyclopropanecarboxylic acid (22.8 kg) in a mixture of THF (96.1 kg) and
N, N-dimethylformamide (DMF; 0.23 kg) at a rate such that the batch temperature did not
exceed 25 °C. This solution was used in the next step without further processing.
Alternative Preparation of 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarbonyl
chloride
A reactor was charged with 1-(4-fluoro-phenylcarbamoyl)-
cyclopropanecarboxylic acid (35 kg), 344 g DMF, and 175kg THF. The reaction mixture
was adjusted to 12-17 °C and then to the reaction mixture was charged 19.9 kg of oxalyl
chloride over a period of 1 hour. The reaction mixture was left stirring at 12-17 °C for 3 to 8
hours. This solution was used in the next step without further processing.
Preparation of cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinoline
yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide (Compound IA)
The solution from the previous step containing 1–(4–fluoro–phenylcarbamoyl)–
cyclopropanecarbonyl chloride was added to a mixture of compound 4-(6,7-dimethoxy-
quinolineyloxy)-phenylamine (23.5 kg) and potassium carbonate (31.9 kg) in THF (245.7
kg) and water (116 L) at a rate such that the batch temperature did not exceed 30 °C. When
the reaction was complete (in approximately 20 minutes), water (653 L) was added. The
mixture was stirred at 20-25 °C for approximately 10 hours, which resulted in the
precipitation of the product. The product was recovered by filtration, washed with a
pre-made solution of THF (68.6 kg) and water (256 L), and dried first on a filter under
nitrogen at approximately 25 °C and then at approximately 45 °C under vacuum to afford the
title compound (41.0 kg, 38.1 kg, calculated based on LOD).
Alternative Preparation of cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy-
quinolineyloxy)-phenyl]-amide (4-fluoro-phenyl)-amide
A reactor was charged with 4-(6,7-dimethoxy-quinolineyloxy)-phenylamine
(35.7 kg, 1 equivalent), followed by 412.9 kg THF. To the reaction mixture was charged a
solution of 48.3 K CO in 169 kg water. The acid chloride solution of described in the
Alternative Preparation of 1-(4–Fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride
above was transferred to the reactor containing 4-(6,7-dimethoxy-quinolineyloxy)-
phenylamine while maintaining the temperature between 20-30 °C over a minimum of two
hours. The reaction mixture was stirred at 20-25 °C for a minimum of three hours. The
reaction temperature was then adjusted to 30-25 °C and the mixture was agitated. The
agitation was stopped and the phases of the mixture were allowed to separate. The lower
aqueous phase was removed and discarded. To the remaining upper organic phase was added
804 kg water. The reaction was left stirring at 15-25 °C for a minimum of 16 hours.
The product precipitated. The product was filtered and washed with a mixture of
179 kg water and 157.9 THF in two portions. The crude product was dried under a vacuum
for at least two hours. The dried product was then taken up in 285.1 kg THF. The resulting
suspension was transferred to reaction vessel and agitated until the suspension became a clear
(dissolved) solution, which required heating to 30-35 °C for approximately 30 minutes. 456
kg water was then added to the solution, as well as 20 kg SDAG-1 ethanol (ethanol denatured
with methanol over two hours. The mixture was agitated at 15-25 °C for at least 16 hours.
The product was filtered and washed with a mixture of 143 kg water and 126.7 THF in two
portions. The product was dried at a maximum temperature set point of 40 °C.
In an alternative procedure, the reaction temperature during acid chloride
formation was adjusted to 10-15 °C. The recrystallization temperature was changed from
-25 °C to 45-50 °C for 1 hour and then cooled to 15-25 °C over 2 hours.
Preparation of cyclopropane –1,1–dicarboxylic acid [4 –(6,7 –dimethoxy – quinoline –4–
yloxy) –phenyl] –amide (4 –fluoro –phenyl) –amide, (L) malate salt (Compound IB)
Cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinolineyloxy)-
phenyl]-amide (4-fluoro-phenyl)-amide (1-5; 13.3 kg), L-malic acid (4.96 kg), methyl ethyl
ketone (MEK; 188.6 kg) and water (37.3 kg) were charged to a reactor and the mixture was
heated to reflux (approximately 74 °C) for approximately 2 hours. The reactor temperature
was reduced to 50 to 55 °C and the reactor contents were filtered. These sequential steps
described above were repeated two more times starting with similar amounts of 1-5 (13.3 kg),
L-Malic acid (4.96 kg), MEK (198.6 kg) and water (37.2 kg). The combined filtrate was
azeotropically dried at atmospheric pressure using MEK (1133.2 kg) (approximate residual
volume 711 L; KF < 0.5 % w/w) at approximately 74 °C. The temperature of the reactor
contents was reduced to 20 to 25 °C and held for approximately 4 hours resulting in solid
precipitate which was filtered, washed with MEK (448 kg) and dried under vacuum at 50 C
to afford the title compound (45.5 kg).
Alternative Preparation of cyclopropane –1,1–dicarboxylic acid [4 –(6,7 –dimethoxy –
quinoline –4–yloxy) –phenyl] –amide (4 –fluoro –phenyl) –amide, (L) malate salt
Cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinolineyloxy)-
phenyl]-amide (4-fluoro-phenyl)-amide (47.9 kg), L-malic acid (17.2), 658.2 kg methyl ethyl
ketone, and 129.1 kg water (37.3 kg) were charged to a reactor and the mixture was heated
50-55 °C for approximately 1-3 hours, and then at 55-60 °C for an addition al 4-5 hours. The
mixture was clarified by filtration through a 1 μm cartridge. The reactor temperature was
adjusted to 20-25 °C and vacuum distilled with a vacuum at 150-200 mm Hg with a
maximum jacket temperature of 55 °C to the volume range of 558-731 L.
The vacuum distillation was performed two more times with the charge of 380 kg
and 380.2 kg methyl ethyl ketone, respectively. After the third distillation, the volume of the
batch was adjusted to 18 v/w of Cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy-
quinolineyloxy)-phenyl]-amide (4-fluoro-phenyl)-amide by charging 159.9 kg methyl
ethyl ketone to give a total volume of 880L. An addition al vacuum distillation was carried
out by adjusting 245.7 methyl ethyl ketone. The reaction mixture was left with moderate
agitation at 20-25 °C for at least 24 hours. The product was filtered and washed with 415.1
kg methyl ethyl ketone in three portions. The product was dried under a vacuum with the
jacket temperature set point at 45 °C.
In an alternative procedure, the order of addition was changed so that a solution of
17.7 kg L-malic acid dissolved in 129.9 kg water was added to Cyclopropane-1,1-
dicarboxylic acid [4-(6,7-dimethoxy-quinolineyloxy)-phenyl]-amide (4-fluoro-phenyl)-
amide (48.7 kg) in methyl ethyl ketone (673.3 kg).
Preparation of Compound IB, Form N-1
A solution was prepared by adding tetrahydrofuran (12 mL/g-bulk-LR (limiting
reagent); 1.20 L) and N-(4-{[6,7-bis(methyloxy)-quinolinyl]oxy}phenyl)-N'-(4-
fluorophenyl)cyclopropane-1,1-dicarboxamide, (100 g; 1.00 equiv; 100.00 g) and (L)-malic
acid (1.2 equiv (molar); 32.08 g) to a 1 L reactor. Water (0.5317 mL/g-bulk-LR; 53.17 mL)
was added and the solution was heated to 60 °C and maintained at that temperature for one
hour until the solids were fully dissolved. The solution was passed through a Polish Filter.
At 60 °C, acetonitrile (12 mL/g-bulk-LR; 1.20 L) was added over a period of 8
hours. The solution was held at 60 °C for 10 hours. The solution was then cooled to 20 °C
and held for 1 hour. The solids were filtered and washed with acetonitrile (12 mL/g-bulk-LR;
1.20 L). The solids were dried at 60 °C (25 mm Hg) for 6 hours to afford compound (I),
Form N-1 (108 g; 0.85 equivalent; 108.00 g; 85.22% yield) as a white crystalline solid.
Alternate Preparation of Compound IB, Form N-1
A solution was prepared with 190 mL tetrahydrofuran (110 mL), methyl isobutyl
ketone, and 29 mL water. Next, 20 mL of this solution were transferred into an amber bottle,
and then saturated by adding N-(4-{[6,7-bis(methyloxy)-quinolinyl]oxy}phenyl)-N'-(4-
fluorophenyl)cyclopropane-1,1-dicarboxamide, (L)-malate until a thick slurry formed, and
aging for at least 2 hours with stirring at room temperature. The solids were removed by
filtration through a Buchner funnel, rendering a clear saturated solution.
Separately, a powder blend was made with known amounts of two batches of
compound IB: (1) 300 mg of batch 1, which contained approximately 41% compound IB,
Form N-1 and 59% compound IB, Form N-2 by Raman spectroscopy analysis, and (2) 200
mg of batch 2, which had a XPRD pattern similar to compound IB, Form N-2.
The compound IB, Form N-1 and compound (I), Form N-2 powder blend was
added into the saturated solution, and the slurry was aged under magnetic stirring at room
temperature for 25 days. The slurry was then sampled and filtered through a Buchner funnel
to obtain 162 mg of wet cake. The wet cake was dried in a vacuum oven at 45 C to afford
128 mg of crystalline compound IB in the N-1 form.
Preparation of Crystalline Compound IB, Form N-2
Preparation of Crystalline Compound IB, Form N-2 Seed Crystals
A solution was prepared by combining 20 ml of acetone and 300 mg of compound
IA (N-(4-{[6,7-bis(methyloxy)quinolinyl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-
1,1-dicarboxamide) in a 25ml screw capped vial. Next, 0.758ml of a 0.79M (L)-malic acid
stock solution was added to the vial with magnetic stirring. The solution was then left
stirring for 24 hours at ambient temperature. The sample was then suction filtered with
0.45µm PTFE filter cartridge and dried in vacuo at ambient temperature overnight.
Preparation of Crystalline Compound IB, Form N-2.
To a reactor were added N-(4-{[6,7-bis(methyloxy)-quinolinyl]oxy}phenyl)-
N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (48 g; 1.00 equiv; 48.00 g) and
tetrahydrofuran (16.5 mL/g-bulk-LR; 792.00 mL). The water content was adjusted to 1 wt%
water. The solution was heated to 60 °C. Once dissolved, the solution was passed through a
polish filter to provide the first solution.
In a separate reactor, (L)-malic acid (1.2 equiv (molar); 15.40 g) was dissolved
into methyl isobutyl ketone (10 mL/g-bulk-LR; 480.00 mL) and tetrahydrofuran (1 mL/g-
bulk-LR; 48.00 mL). Next, 50 mL of the (L)-malic acid solution was added to the first
solution at 50 °C. Seed crystals were added (1%, 480 mg) and the malic acid solution was
added at 50 °C dropwise via an addition funnel (1.3 ml/min over 3 hours). The slurry was
held at 50 °C for 18 hours and then was cooled to 25 °C over 30 minutes. The solids were
filtered, and washed with 20% tetrahydrofuran/methyl isobutyl ketone (10V, 480 mL). The
solids were dried under vacuum at 60 °C for 5 hours to afford compound IB (55.7 g; 0.92
equivalent; 55.70 g; 91.56% yield) as an off-white crystalline solid.
Stability Studies of Pharmaceutical Compositions
The pharmaceutical capsule compositions of Tables 3 and 4 were prepared by
mixing the ingredients according to processes known in the art.
Table 3
Ingredient mg/unit dose
Compound IB (10 % drug 25
load as Compound IA)
Microcrystalline Cellulose 196.75
Croscarmellose sodium 12.5
Sodium starch glycolate 12.5
Fumed Silica 0.75
Stearic acid 2.5
Total Fill Weight
Table 4
Ingredient mg/unit dose
Compound IB (50 % drug 100
load as Compound IA)
Silicified Microcrystalline 75.40
Cellulose
Croscarmellose sodium 10.00
Sodium Starch Glycolate 10.00
Fumed silica 0.6
Stearic Acid 4.0
Total Fill Weight
The capsule compositions were subjected to stability studies to monitor the
formation of 6,7-dimethoxy-quinolineol at various temperatures and relative humidities
over time. The results are summarized in Tables 7A and 7B and Tables 8A and 8B.
Table 7A: Stability of 25 Mg Capsules (Table 3)
Conditions Bottle A1 Bottle A2 Bottle A3 Bottle A4
PPM of 6,7-dimethoxy-quinolineol
Initial T=0 25 °C/60% RH 2 2 3 3
1 Month 25 °C/60% RH 3 4 5 NA
°C/75% RH 4 4 NA NA
40 °C/75% RH 9 9 10 NA
3 Months 25 °C/60% RH 5 5 7 NA
°C/75% RH 7 6 NA NA
40 °C/75% RH 22 23 24 NA
6 Months 25 °C/60% RH 6 6 7 7 (3M in blister)
°C/75% RH 9 9 NA NA
40 °C/75% RH 40 44 43 27 (3M in blister)
9 Months 25 °C/60% RH 7 7 9 8 (6M in blister)
°C/75% RH 13 12 NA NA
40 °C/75% RH NA NA 68 60 (6M in blister)
M=Months; NA=Not Applicable; RH= Relative Humidity; PPM= Parts per Million. A
portion of Bottle A4 was repackaged in a blister pack after being stored in bottles for 3
months.
Table 7B: Stability of 25 Mg Capsules (Table 3)
Conditions Bottle B1 Bottle B Bottle B3 Bottle B4
PPM of 6,7-dimethoxy-quinolineol
Initial T=0 25 °C/60% RH 3 1 2 2
1 Month 25 °C/60% RH <2 <2 <2 NA
°C/75% RH <2 <2 NA NA
40 °C/75% RH 2 <2 <2 NA
3 Months 25 °C/60% RH 2 <2 <2 NA
°C/75% RH 2 <2 NA NA
40 °C/75% RH 3 <2 <2 NA
6 Months 25 °C/60% RH <2 <2 <2 <2 (3M in blister)
°C/75% RH 2 <2 NA NA
40 °C/75% RH 4 <2 3 3 (3M in blister)
9 Months 25 °C/60% RH <2 <2 <2 <2 (6M in blister)
°C/75% RH 3 <2 NA NA
40 °C/75% RH NA NA 5 4 (6M in blister)
A portion of Bottle B4 was repackaged in a blister pack after being stored in bottles for 3
months.
Table 8A: Stability of 100 Mg Capsules (Table 4)
Conditions Bottle A1 Blister A2 Bottle A3
PPM of 6,7-dimethoxy-quinolineol
Initial T=0 25 °C/60% RH 4 4 6
1 Month 25 °C/60% RH 4 4 6
°C/75% RH 4 NA 6
40 °C/75% RH 6 6 9
3 Months 25 °C/60% RH 5 5 7
°C/75% RH 6 NA 7
40 °C/75% RH 10 10 12
6 Months 25 °C/60% RH 5 5
°C/75% RH 6 NA
40 °C/75% RH 11 17
M=Months; NA=Not Applicable; RH= Relative Humidity; PPM= Parts per Million.
Table 8B: Stability of 100 Mg Capsules (Table 4)
Conditions Bottle B1 Blister B2 Bottle B3
PPM of 6,7-dimethoxy-quinolineol
Initial T=0 25 °C/60% RH 1 1 2
1 Month 25 °C/60% RH <2 <2 <2
°C/75% RH <2 <2 2
40 °C/75% RH <2 <2 2
3 Months 25 °C/60% RH <2 <2 <2
°C/75% RH <2 NA <2
40 °C/75% RH <2 <2 2
6 Months 25 °C/60% RH <2 <2
°C/75% RH <2 NA
40 °C/75% RH 2 2
M=Months; NA=Not Applicable; RH= Relative Humidity; PPM= Parts per Million.
The results summarized in Tables 7A and 7B and 8A and 8B indicate that
formation of 6,7-dimethoxy-quinolineol was minimized to 50 ppm or less over time in the
capsule formulations.
The foregoing disclosure has been described in some detail by way of illustration
and example, for purposes of clarity and understanding. The invention has been described
with reference to various specific and preferred embodiments and techniques. However, it
should be understood that many variations and modifications can be made while remaining
within the spirit and scope of the invention. It will be obvious to one of skill in the art that
changes and modifications can be practiced within the scope of the appended claims.
Therefore, it is to be understood that the above description is intended to be illustrative and
not restrictive. The scope of the invention should, therefore, be determined not with
reference to the above description, but should instead be determined with reference to the
following appended claims, along with the full scope of equivalents to which such claims are
entitled. All references cited herein are incorporated by reference in their entirety.
Claims (12)
1. A pharmaceutical composition selected from the group consisting of Table 2A, 3, 4, 5, and 6 Table 2A Ingredient % w/w Compound IB (10 % drug load as Compound IA) 12.67 Microcrystalline Cellulose 51.52 Lactose 25.76 Hydroxypropyl cellulose 3.0 Croscarmellose Sodium 6.0 Colloidal Silicon Dioxide 0.3 Magnesium Stearate 0.75 Total 100 Table 3 Ingredient mg/unit dose Compound IB (10 % drug 25 load as Compound IA) Silicified Microcrystalline 196.75 Cellulose Croscarmellose sodium 12.5 Sodium starch glycolate 12.5 Fumed Silica 0.75 Stearic acid 2.5 Total Fill Weight Table 4 Ingredient mg/unit dose Compound IB (50 % drug 100 load as Compound IA) Silicified Microcrystalline 75.40 Cellulose Croscarmellose sodium 10.00 Sodium Starch Glycolate 10.00 Fumed silica 0.6 Stearic Acid 4.0 Total Fill Weight Table 5 mg/unit dose Ingredient 50mg Compound IB (10 % drug 63.35 load as Compound IA) Microcrystalline Cellulose 95.39 Croscarmellose sodium 9.05 Sodium starch glycolate 9.05 Fumed Silica 0.54 Stearic acid 3.62 Total Fill Weight 181.00 Table 6 mg/unit dose Ingredient 60mg Compound IB 73.95 Microcrystalline Cellulose 114.36 Croscarmellose sodium 10.85 Sodium starch glycolate 10.85 Fumed Silica 0.65 Stearic acid 4.34 Total Fill Weight 217.00 wherein Compound 1A has the structure: compound IB has the structure: and wherein the formation of 6,7-dimethoxy-quinolineol in the pharmaceutical formulation is minimized to 50 ppm or less over time.
2. The pharmaceutical composition of claim 1 wherein the formation of 6,7-dimethoxy- quinolineol in the pharmaceutical formulation is minimized to 25 ppm or less over time.
3. The pharmaceutical composition of claim 1 wherein the formation of 6,7-dimethoxy- quinolineol in the pharmaceutical formulation is minimized to 15 ppm or less over time.
4. The pharmaceutical composition of claim 1 wherein the formation of 6,7-dimethoxy- quinolineol in the pharmaceutical formulation is minimized to 10 ppm or less over time.
5. The pharmaceutical composition of claim 1 wherein the formation of 6,7-dimethoxy- quinolineol in the pharmaceutical formulation is minimized to 5 ppm or less over time.
6. The pharmaceutical composition of claim 1 wherein the formation of 6,7-dimethoxy- quinolineol in the pharmaceutical formulation is minimized to 2.5 ppm or less over time.
7. A pharmaceutical composition comprising Compound IB; microcrystalline cellulose; croscarmellose sodium; sodium starch glycolate; fumed silica; and stearic acid; wherein Compound IB has the structure: and wherein the formation of 6,7-dimethoxy-quinolineol in the pharmaceutical formulation is minimized to 50 ppm or less over time.
8. The pharmaceutical composition of claim 7, which is capsule composition.
9. The pharmaceutical composition of claim 7, comprising 25 mg or 100 mg of Compound IB.
10. The pharmaceutical composition of claim 7 comprising 25 mg Compound IB, wherein formation of 6,7-dimethoxy-quinolineol is limited to 50 ppm over 9 months at temperatures of 25, 30, or 40 ºC and relative humidities of 60 or 75 percent.
11. The pharmaceutical composition of claim 7 comprising 100 mg Compound IB, wherein formation of 6,7-dimethoxy-quinolineol is limited to 50 ppm over 6 months at temperatures of 25, 30, or 40 ºC and relative humidities of 60 or 75 percent.
12. A pharmaceutical composition as claimed in any one of claims 1 to 11, substantially as herein described with reference to any example thereof.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NZ712808A NZ712808B2 (en) | 2011-02-10 | 2012-02-10 | Processes for preparing quinoline compounds and pharmaceutical compositions containing such compounds |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161441520P | 2011-02-10 | 2011-02-10 | |
US201161441527P | 2011-02-10 | 2011-02-10 | |
US61/441,520 | 2011-02-10 | ||
US61/441,527 | 2011-02-10 | ||
PCT/US2012/024591 WO2012109510A1 (en) | 2011-02-10 | 2012-02-10 | Processes for preparing quinoline compounds and pharmaceutical compositions containing such compounds |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ614130A NZ614130A (en) | 2015-10-30 |
NZ614130B2 true NZ614130B2 (en) | 2016-02-02 |
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