U.S. patent application number 14/444637 was filed with the patent office on 2014-11-13 for pharmaceutical composition.
The applicant listed for this patent is SmithKline Beecham (Cork) Limited. Invention is credited to Dwayne A. Campbell, Barry Howard Carter.
Application Number | 20140335177 14/444637 |
Document ID | / |
Family ID | 37115487 |
Filed Date | 2014-11-13 |
United States Patent
Application |
20140335177 |
Kind Code |
A1 |
Carter; Barry Howard ; et
al. |
November 13, 2014 |
PHARMACEUTICAL COMPOSITION
Abstract
Oral pharmaceutical formulations containing ditosylate salts of
4-quinazolineamines are described as well as methods of using the
same in the treatment of disorders characterized by aberrant erbB
family PTK activity.
Inventors: |
Carter; Barry Howard;
(Research Triangle Park, NC) ; Campbell; Dwayne A.;
(Research Triangle Park, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SmithKline Beecham (Cork) Limited |
County Cork |
|
IR |
|
|
Family ID: |
37115487 |
Appl. No.: |
14/444637 |
Filed: |
July 28, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11911843 |
Oct 18, 2007 |
8821927 |
|
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PCT/US2006/014447 |
Apr 18, 2006 |
|
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14444637 |
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60672805 |
Apr 19, 2005 |
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Current U.S.
Class: |
424/465 ;
514/266.24 |
Current CPC
Class: |
A61P 43/00 20180101;
A61K 9/2054 20130101; A61K 9/2059 20130101; A61K 9/2866 20130101;
A61K 31/519 20130101; A61P 35/00 20180101; A61K 9/2027 20130101;
A61K 9/28 20130101; C07D 405/04 20130101; A61K 9/2013 20130101;
A61K 31/517 20130101 |
Class at
Publication: |
424/465 ;
514/266.24 |
International
Class: |
A61K 31/517 20060101
A61K031/517; A61K 9/28 20060101 A61K009/28; A61K 9/20 20060101
A61K009/20; C07D 405/04 20060101 C07D405/04 |
Claims
1. An oral pharmaceutical composition, comprising (i) an active
ingredient selected from a compound of formula (II), ##STR00027##
or salts or solvates thereof, wherein said active ingredient is
present at a concentration of 30-60 percent by weight; (ii) at
least one binder wherein said binder is present at a concentration
of 4 to 9 percent by weight; (iii) at least one disintegrant
wherein the disintegrant is present in a range of 2 to 8 percent by
weight; (iv) at least one lubricant wherein the at least one
lubricant, is present in a range of 0.6 to 1.3 percent by weight;
and (v) at least one diluent wherein the at least one diluent, is
present in a range of 35 to 50 percent by weight.
2. The oral pharmaceutical composition of claim 1 wherein at least
one diluent is microcrystalline cellulose.
3. The oral pharmaceutical composition of claim 1 wherein the at
least one diluent, is present in a range of 40 to 46 percent by
weight.
4. The oral pharmaceutical composition of claim 1 wherein at least
one lubricant is magnesium stearate.
5. The oral pharmaceutical composition of claim 1 wherein the at
least one lubricant, is present in a range of 0.8 to 1 percent by
weight.
6. The oral pharmaceutical composition of claim 1 wherein at least
one disintegrant is sodium starch glycolate.
7. The oral pharmaceutical composition of claim 1 wherein the
disintegrant is present in a range of 3.5 to 5 percent by
weight.
8. The oral pharmaceutical composition of claim 1 wherein said
active ingredient is the ditosylate salt of the compound of formula
(II).
9. The oral pharmaceutical composition of claim 8 wherein said
active ingredient is
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate
monohydrate.
10. The oral pharmaceutical composition of claim 1 wherein said
active ingredient is present in a range of 45-51 percent by
weight.
11. The oral pharmaceutical composition of claim 1 wherein said
active ingredient, binder, disintegrant, lubricant, and diluent are
comprised within a core tablet composition.
12. The oral pharmaceutical composition of claim 11 wherein said
oral composition additionally comprises a film coat.
13. The oral pharmaceutical composition of claim 12 wherein said
film coat is present in the range of 2.5 to 3.5 percent by weight
of the core tablet composition.
14. The oral pharmaceutical composition of claim 13 wherein said
film coat is present in the range of 2.8 to 3.2 percent by weight
of the core tablet composition.
15. The oral pharmaceutical composition of claim 9, wherein the at
least one binder is povidone.
16. The oral pharmaceutical composition of claim 1 wherein said
binder is present at a concentration of 5.5 to 7.5 percent by
weight.
17. An oral pharmaceutical composition comprising: (i)
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate
monohydrate; (ii) povidone; (iii) sodium starch glycolate; (iv)
microcrystalline cellulose; and (v) magnesium stearate.
18. The oral pharmaceutical composition of claim 17 wherein: (i)
said
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate monohydrate
is present in a range of 30 to 47 percent by weight; (ii) said
povidone is present in a range of 4 to 9 percent by weight; (iii)
said sodium starch glycolate is present in a range of 2 to 8
percent by weight; (iv) said microcrystalline cellulose is present
in a range of 35 to 50 percent by weight; and (v) said magnesium
stearate is present in a range of 0.6 to 1.3 percent by weight.
19. The oral pharmaceutical composition of claim 18 herein: (i)
said
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate monohydrate
is present in a range of 30 to 60 percent by weight; (ii) said
povidone is present in a range of 4 to 9 percent by weight; (iii)
said sodium starch glycolate is present in a range of 2 to 8
percent by weight; (iv) said microcrystalline cellulose is present
in a range of 35 to 50 percent by weight; and (v) said magnesium
stearate is present in a range of 0.6 to 1.3 percent by weight.
20. The oral pharmaceutical composition of claim 19 wherein: (i)
said
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate monohydrate
is present in a range of 42 to 48 percent by weight; (ii) said
povidone is present in a range of 5.5 to 7.5 percent by weight;
(iii) said sodium starch glycolate is present in a range of 3.5 to
5.5 percent by weight; (iv) said microcrystalline cellulose is
present in a range of 40 to 46 percent by weight; and (v) said
magnesium stearate, is present in a range of 0.8 to 1.2 percent by
weight.
21. The oral pharmaceutical composition of claim 20 wherein: (i)
said
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate monohydrate
is present in a range of 45 to 51 percent by weight; (ii) said
povidone is present in a range of 5.5 to 7.5 percent by weight;
(iii) said sodium starch glycolate is present in a range of 3.5 to
5.5 percent by weight; (iv) said microcrystalline cellulose is
present in a range of 40 to 46 percent by weight; and (v) said
magnesium stearate is present in a range of 0.8 to 1.2 percent by
weight.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of U.S.
application Ser. No. 11/911,843, filed Oct. 18, 2007, which is a
National Phase Application of International Application No.
PCT/US2006/014447 filed Apr. 18, 2006 which claims priority from
Provisional Application No. 60/672,805 filed Apr. 19, 2005 in the
United States.
FIELD OF THE INVENTION
[0002] The present invention relates to pharmaceutical compositions
containing, as an active ingredient, 4-quinazolinamines as well as
use of the compositions in the treatment of proliferative diseases
such as cancer. In particular, the pharmaceutical compositions
contain at least one 4-quinazolinamine active ingredient that is an
inhibitor of EGFR and/or erbB2 protein tyrosine kinase.
BACKGROUND OF THE INVENTION
[0003] Pharmaceutically active compounds may be formulated for
administration by numerous routes. Typically, the appropriate route
will depend on the disease being treated, the chemical and physical
properties of the pharmaceutically active substance as well as the
subjects to be treated. Suitable pharmaceutical formulations
include those for oral, rectal, nasal, topical (including buccal,
sub-lingual, and transdermal), vaginal or parenteral (including
intramuscular, sub-cutaneous, intravenous, and directly into the
affected tissue) administration or in a form suitable for
administration by inhalation or insufflation. Pharmaceutical
compositions for the treatment of cancer typically have been
injectible, parenteral formulations for intravenous infusion of the
pharmaceutically active compound. Generally, use of intravenous
formulation has been indicated because of the cytotoxic nature of
the anticancer formulation and/or the weakened condition of the
patient. Anti-cancer solid dosage forms have been available in
tablet form, for example Alkeran.RTM., Leukeran.RTM., Myleran.RTM.,
Purinethol.RTM., Tabloid.RTM., and recently Xeloda.RTM., but these
have been the exception rather than the norm.
[0004] Tablets offer several advantages to both the manufacturer
and to the patient. Tablets may be manufactured economically and
are conveniently shipped, stored and dispensed. The patient can
take advantage of a dosage form, which can be produced with an
accurate dosage and has ease of administration and portability.
[0005] 4-Quinazolinamines as dual inhibitors of the protein
tyrosine kinases EGFR (Epithelial Growth Factor Receptor--also
known as erbB-1) and erbB-2 have been disclosed in International
Patent Application PCT/EP99/00048 filed Jan. 8, 1999, and published
as WO 99/35146 on Jul. 15, 1999. The anhydrous and monohydrate
ditosylate forms of specific 4-quinazolinamines were disclosed in
International Patent Application PCT/US01/20706 filed Jun. 28,
2001, and published as WO 02/02552 on Jan. 10, 2002.
[0006] Of particular interest is
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate
monohydrate. This compound is now in development as GW572016 in the
treatment of various cancers, including breast, lung, bladder, head
and neck, and gastric cancers. GW572016 has poor flow
characteristics and is poorly soluble in aqueous media over the
physiologically relevant pH range. Typically, for a pharmaceutical
composition containing a drug having poor solubility in water and a
high drug load, it is difficult to maintain the high dissolution
properties and good flow characteristics needed for typical
pharmaceutical manufacturing processes. Further, due to the poorly
soluble active ingredient, high drug dissolution is required to
achieve acceptable bioavailability. The present inventors have now
identified a novel oral pharmaceutical formulation containing as an
active ingredient a 4-quinazolinamine, which is effective as an
EGFR and/or erbB2 protein tyrosine kinase inhibitor. Such a
pharmaceutical formulation produced by fluid bed granulation
provides high drug dissolution while maintaining good flow
characteristics during processing.
DISCLOSURE OF THE INVENTION
[0007] In a first aspect of the present invention, there is
provided an oral pharmaceutical composition, comprising
[0008] (i) an active ingredient selected from a compound of formula
(I),
##STR00001##
or salts or solvates thereof, wherein R.sub.1 is Cl or Br; X is CH,
N, or CF; and Het is thiazole or furan; and
[0009] (ii) a binder.
[0010] In a second aspect of the present invention, there is
provided an oral pharmaceutical composition, comprising
[0011] (i) an active ingredient selected from a compound of formula
(I),
##STR00002##
or salts or solvates thereof, wherein R.sub.1 is Cl or Br; X is CH,
N, or CF; and Het is thiazole or furan;
[0012] (ii) at least one binder; and
[0013] (iii) at least one disintegrant.
[0014] In a third aspect of the present invention, there is
provided an oral pharmaceutical composition, comprising
[0015] (i) an active ingredient selected from a compound of formula
(I),
##STR00003##
or salts or solvates thereof, wherein R.sub.1 is Cl or Br; X is CH,
N, or CF; and Het is thiazole or furan;
[0016] (ii) at least one binder;
[0017] (iii) at least one disintegrant; and
[0018] (iv) at least one lubricant.
[0019] In a fourth aspect of the present invention, there is
provided an oral pharmaceutical composition, comprising
[0020] (i) an active ingredient selected from a compound of formula
(I),
##STR00004##
or salts or solvates thereof, wherein R.sub.1 is Cl or Br; X is CH,
N, or CF; and Het is thiazole or furan;
[0021] (ii) at least one binder;
[0022] (iii) at least one disintegrant;
[0023] (iv) at least one lubricant; and
[0024] (v) at least one diluent.
[0025] In a fifth aspect of the present invention, there is
provided a method of treating a disorder in a mammal, said disorder
being characterized by aberrant activity of at least one erbB
family PTK, including: administering to said mammal an oral
pharmaceutical composition, comprising
[0026] (i) an active ingredient selected from a compound of formula
(I),
##STR00005##
or salts or solvates thereof, wherein R.sub.1 is Cl or Br; X is CH,
N, or CF; and Het is thiazole or furan; and
[0027] (ii) a binder.
[0028] In a sixth aspect of the present invention, there is
provided a method of treating a disorder in a mammal, said disorder
being characterized by aberrant activity of at least one erbB
family PTK, including: administering to said mammal an oral
pharmaceutical composition, comprising
[0029] (i) an active ingredient selected from a compound of formula
(I),
##STR00006##
or salts or solvates thereof, wherein R.sub.1 is Cl or Br; X is CH,
N, or CF; and Het is thiazole or furan;
[0030] (ii) at least one binder; and
[0031] (iii) at least one disintegrant.
[0032] In a seventh aspect of the present invention, there is
provided an oral pharmaceutical composition, comprising
[0033] (i) an active ingredient selected from a compound of formula
(I),
##STR00007##
or salts or solvates thereof, wherein R.sub.1 is Cl or Br; X is CH,
N, or CF; and Het is thiazole or furan; and
[0034] (ii) a binder,
for use in therapy. In a eighth aspect of the present invention,
there is provided an oral pharmaceutical composition,
comprising
[0035] (i) an active ingredient selected from a compound of formula
(I),
##STR00008##
or salts or solvates thereof, wherein R.sub.1 is Cl or Br; X is CH,
N, or CF; and Het is thiazole or furan;
[0036] (ii) at least one binder; and
[0037] (iii) at least one disintegrant;
for use in therapy.
[0038] In an ninth aspect of the present invention, there is
provided
an oral pharmaceutical composition, comprising
[0039] (i) an active ingredient selected from a compound of formula
(I),
##STR00009##
or salts or solvates thereof, wherein R.sub.1 is Cl or Br; X is CH,
N, or CF; and Het is thiazole or furan;
[0040] (ii) at least one binder;
[0041] (iii) at least one disintegrant;
[0042] (iv) at least one lubricant;
for use in therapy.
[0043] In a tenth aspect of the present invention, there is
provided an oral pharmaceutical composition, comprising
[0044] (i) an active ingredient selected from a compound of formula
(I),
##STR00010##
or salts or solvates thereof, wherein R.sub.1 is Cl or Br; X is CH,
N, or CF; and Het is thiazole or furan;
[0045] (ii) at least one binder;
[0046] (iii) at least one disintegrant;
[0047] (iv) at least one lubricant; and
[0048] (v) at least one diluent
for use in therapy.
DETAILED DESCRIPTION OF THE INVENTION
[0049] As used herein, the term "effective amount" means that
amount of a drug or pharmaceutical agent that will elicit the
biological or medical response of a tissue, system, animal or human
that is being sought, for instance, by a researcher or clinician.
Furthermore, the term "therapeutically effective amount" means any
amount which, as compared to a corresponding subject who has not
received such amount, results in improved treatment, healing,
prevention, or amelioration of a disease, disorder, or side effect,
or a decrease in the rate of advancement of a disease or disorder.
The term also includes within its scope amounts effective to
enhance normal physiological function.
[0050] As used herein, the term "optionally" means that the
subsequently described event(s) may or may not occur, and includes
both event(s), which occur, and events that do not occur.
[0051] As used herein, the term "solvate" refers to a complex of
variable stoichiometry formed by a solute (in this invention, a
compound of formula (I), (II), (III), (IV) or a salt thereof) and a
solvent. Such solvents for the purpose of the invention may not
interfere with the biological activity of the solute. Examples of
suitable solvents include, but are not limited to, water, methanol,
ethanol and acetic acid. Preferably the solvent used is a
pharmaceutically acceptable solvent. Examples of suitable
pharmaceutically acceptable solvents include, without limitation,
water, ethanol and acetic acid. Most preferably the solvent used is
water.
[0052] As used herein the term "core tablet" is defined as a tablet
without a film coating. Accordingly, as used herein the term
"tablet" is defined as the core tablet with a film coating.
[0053] As used herein the term "PTK" means protein tyrosine
kinase.
[0054] As used herein the term "EP" means European Pharmacopeia;
the term "USP" means United States Pharmacopeia; the term "NF"
means National Formulary, the term "JP" means Japanese
Pharmacopeia; and the term "JPE" Japanese Pharmaceutical
Excipients.
[0055] It is to be understood that the following embodiments refer
to compounds within the scope of formula (I) and formula (II),
(Ill), or (IV) as defined herein unless specifically limited by the
definition of each formula or specifically limited otherwise. It is
also understood that the embodiments of the present invention,
including uses, compositions, and processes for making, described
herein, while being described with regard to compounds of formula
(I) are applicable to compounds of formulae (II), (III), and
(IV).
[0056] Oral Pharmaceutical Composition
[0057] As recited above, the oral pharmaceutical composition of the
present invention includes an active ingredient, which is selected
from a compound of formula (I)
##STR00011##
[0058] or a salt or solvate thereof, where R.sub.1 is Cl or Br; X
is CH, N, or CF; and Het is furan or thiazole.
[0059] The side chain CH.sub.3SO.sub.2CH.sub.2CH.sub.2NHCH.sub.2 of
the compounds of formula (I) may be linked to any suitable position
of the group Het. Similarly, the phenyl group of the quinazoline
core may be linked to any suitable position of the group Het.
[0060] In one embodiment, R.sub.1 is Cl; X is CH; and Het is furan;
preferably a compound of Formula (II) or salts or solvates
thereof.
##STR00012##
[0061] The compound of formula (II) has the chemical name
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine and is designated
GW572016.
[0062] In one embodiment, the compound is the ditosylate salt of
the compound of formula II. In another embodiment, the compound is
the monohydrate form of the ditosylate salt of formula (II). In
another embodiment, the compound is the anhydrate form of the
ditosylate salt of the compound of formula (II).
[0063] In an alternative embodiment, R.sub.1 is Cl; X is CH; and
Het is thiazole; preferably a compound of formula (III) or salts or
solvates thereof.
##STR00013##
[0064] The compound of formula III is
(4-(3-Fluoro-benzyloxy)-3-chlorophenyl)-(6-(2-((2-methanesulphonyl-ethyla-
mino)-methyl)-thiazol-4-yl)quinazolin-4-yl)-amine. In one
embodiment, the compound is the ditosylate salt of the compound of
formula III.
[0065] In a further alternative embodiment, R.sub.1 is Br; X is CH;
and Het is furan; preferably, a compound of formula (IV) or salts
or solvates thereof.
##STR00014##
[0066] The compound of formula (IV) is
(4-(3-Fluoro-benzyloxy)-3-bromophenyl)-(6-(5-((2-methanesulphonyl-ethylam-
ino)-methyl)-furan-2-yl)quinazolin-4-yl)-amine. In one embodiment,
the compound is the ditosylate salt of the compound of formula
III.
[0067] The compounds of formula (I), including the compounds of
formulae (II), (Ill), and (IV), include within their scope
substantially pure anhydrate or hydrate forms, as well as mixtures
of hydrate and anhydrate forms. It is also understood, that such
compounds include crystalline or amorphous forms and mixtures of
crystalline and amorphous forms.
[0068] The active ingredient is present in a range of 5 to 85,
preferably 30 to 60 more preferably 42 to 48 percent by weight or
45-51 percent by weight of the oral pharmaceutical composition. In
one embodiment, the active ingredient is
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate monohydrate
which is present in a range of 5 to 85, preferably 30 to 60 more
preferably 42 to 48 percent by weight or 45 to 51 percent by weight
of the oral pharmaceutical composition.
[0069] Typically, the salts of the present invention are
pharmaceutically acceptable salts. Salts encompassed within the
term "pharmaceutically acceptable salts" refer to non-toxic salts
of the compounds of this invention. Salts of the compounds of the
present invention may comprise acid addition salts derived from a
nitrogen on a substituent in the compound of formula (I).
Representative salts include the following salts: acetate,
benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate,
borate, bromide, calcium edetate, camsylate, carbonate, chloride,
clavulanate, citrate, dihydrochloride, edetate, edisylate,
estolate, esylate, fumarate, gluceptate, gluconate, glutamate,
glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,
hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate,
lactobionate, laurate, malate, maleate, mandelate, mesylate,
methylbromide, methylnitrate, methylsulfate, monopotassium maleate,
mucate, napsylate, nitrate, N-methylglucamine, oxalate, pamoate
(embonate), palmitate, pantothenate, phosphate/diphosphate,
polygalacturonate, potassium, salicylate, sodium, stearate,
subacetate, succinate, tannate, tartrate, teoclate, tosylate,
triethiodide, trimethylammonium and valerate. Other salts, which
are not pharmaceutically acceptable, may be useful in the
preparation of compounds of this invention and these form a further
aspect of the invention.
[0070] The free base and HCl salts of the compounds of Formulae
(I), (II), (Ill), and (IV), may be prepared according to the
procedures of International Patent Application No. PCT/EP99/00048,
filed Jan. 8, 1999, and published as WO 99/35146 on Jul. 15, 1999,
referred to above. A schematic of such procedures is presented in
Scheme A following. The specific page references given are to WO
99/35146. The free base of the compound of formula II is used as an
example of the general scheme.
##STR00015## ##STR00016##
[0071] The ditosylate salts, including the anhydrous and hydrated
forms thereof, of the compounds of Formulae (I), (II), (Ill), and
(IV), may be prepared according to the procedures of International
Patent Application No. PCT/US01/20706, filed Jun. 28, 2001, and
published as WO 02/02552 on Jan. 10, 2002 and International; patent
Application No. PCT/US03/10747, filed Apr. 8, 2003, and published
as WO 03/086467 on Oct. 23, 2003. A further process is illustrated
in Scheme B following.
[0072] Scheme B following illustrates the preparation of the
ditosylate salt of the compound of formula (II). The preparation
proceeds in four stages: Stage 1: reaction of quinazoline (I),
which is prepared from 3H-6-iodoquinazolin-4-one (I'), with amine
(II) to give iodoquinazoline (III); Stage 2: preparation of the
corresponding aldehyde salt (V) by reaction of iodoquinazoline
(III) and boronic acid (IV) followed by treatment with
p-toluenesulfonic acid salt; Stage 3: preparation of the ditosylate
salt of GW572016 (VI) from aldehyde salt (V); and Stage 4:
recrystallization of the GW572016 ditosylate salt (VI). Scheme C
shows an alternate preparation of the ditosylate salt of the
compound of formula (II).
##STR00017## ##STR00018##
##STR00019## ##STR00020##
[0073] The oral pharmaceutical composition of the present invention
also includes at least one binder. A binder is used to impart
cohesiveness qualities to powdered materials so that tablets or
granules formed will remain together and not fall apart. Any
suitable binder that is compatible with the active ingredient and
to good flow properties and dissolution may be utilized. Exemplary
binders include, but are not limited to gelatin, starch, cellulose,
cellulose derivatives such as methyl cellulose, hydroxylpropyl
cellulose, hydroxypropylmethyl cellulose, ethyl cellulose, and
carboxymethyl cellulose, sucrose, polyvinyl pyrrolidone, natural
sugars such as glucose or beta-lactose, corn sweeteners, natural
and synthetic gums such as acacia, tragacanth or sodium alginate,
polyethylene glycol, waxes and the like.
[0074] In one embodiment, the at least one binder is polyvinyl
pyrrolidone polymer or povidone, which is available from
International Specialty Products of Wayne, N.J. as the
Plasdone.RTM. line of products including Plasdone K-29/32.RTM..
[0075] The at least one binder is present in a range of 2 to 11,
preferably 4 to 9 more preferably 5.5 to 7.5 percent by weight of
the oral pharmaceutical composition. In one embodiment, the binder
is povidone, which is present in a range of 2 to 11, preferably 4
to 9 more preferably 5.5 to 7.5 percent by weight of the oral
pharmaceutical composition.
[0076] The oral pharmaceutical composition of the present invention
also includes at least one disintegrant. A disintegrant functions
to ensure or facilitate the breakup or disintegration of the
composition after administration thereby facilitating dissolution
of the active substance. Any suitable disintegrant which is
compatible with the active ingredient and to good flow properties
and dissolution may be utilized. Exemplary disintegrants include,
but are not limited to starch, cellulose and cellulose derivatives
such as methyl cellulose, hydroxylpropyl cellulose,
hydroxypropylmethyl cellulose, ethyl cellulose, and crosslinked
sodium carboxymethyl cellulose, crosslinked polyvinyl pyrrolidone,
sodium starch glycolate, agar, bentonite, and xanthan gum.
[0077] In one embodiment, the at least one disintegrant is sodium
starch glycolate, which is available from DMV International of
Veghel, The Netherlands as Primojel.RTM.. Primojel.RTM. is a
purified sodium starch glycolate, Ph. Eur, USP/NF, JPE, produced by
cross-linking and carboxymethylation of potato starch with
subsequent purification. Sodium starch glycolate is also available
from JRS Pharma of Patterson, N.Y. as the Explotab.RTM. or
VivaStar.RTM. line of products including Explotab.RTM.,
VivaStarP.RTM., and Explotab CLV.RTM..
[0078] It is understood by those skilled in the art that the
disintegrant described above may be added into a tablet making
process at two stages. Disintegrant can be added to the granulation
mixture before granulation. This disintegrant is termed
intra-granular disintegrant in that it becomes part of the granules
formed. Disintegrant may also be added to the formed granules to
form a compression mixture before compression. This disintegrant is
termed extra-granular disintegrant in that it is not part of the
granules, but rather is in mixture with the granules.
[0079] The at least one disintegrant is present in a range of 1 to
10, preferably 2 to 8 more preferably 3.5 to 5.5 percent by weight
of the oral pharmaceutical composition. In one embodiment, the
disintegrant is sodium starch glycolate, which is present in a
range of 1 to 10, preferably 2 to 8 more preferably 3.5 to 5.5
percent by weight of the oral pharmaceutical composition. In one
embodiment, the disintegrant is extra-granular disintegrant, which
is present in a range of 1 to 10, preferably 2 to 8 more preferably
3.5 to 5.5 percent by weight of the oral pharmaceutical
composition.
[0080] The oral pharmaceutical composition of the present invention
may further comprise at least one diluent. A diluent or filler is
used to increase the bulk of the composition so that the final
product has a practical size or volume, for instance for a tablet a
practical size for proper compression. Any suitable diluent that is
compatible with the active ingredient and to good flow properties
and dissolution may be utilized. Exemplary diluents include, but
are not limited to lactose, sucrose or powdered sugar, mannitol,
sorbitol, xylitol, inositol, calcium phosphate, calcium carbonate,
calcium sulfate, dry starch, cellulose, including microcrystalline
cellulose or silicified microcrystalline cellulose and the
like.
[0081] In one embodiment, the at least one diluent is
microcrystalline cellulose, which is available from Blanver, of
Cotia, Brazil as the Tabulose.RTM. line of products including
Tabulose.RTM.101, 102, 103, 112, 250, 301, and 302; or from FMC of
Philadelphia, Pa. as the Avicel.RTM. line of products including
Avicel.RTM. PH 101, 102, 103, 105, 112, 113, 200, 301, and 302; or
from JRS Pharma of Patterson, N.Y., which is available from as the
Vivapur.RTM. line of products including Vivapur.RTM. 99, 101, 102,
103, 105, 112, 200, 301, and 302. In another embodiment, the at
least diluent is silicified microcrystalline cellulose, which is
available from JRS Pharma of Patterson, N.Y. as ProSolv.RTM. line
of products.
[0082] The at least one diluent is present in a range of 10 to 70,
preferably 35 to 50 more preferably 40 to 46 percent by weight of
the oral pharmaceutical composition. In one embodiment, the diluent
is microcrystalline cellulose, which is present in a range of 10 to
70, preferably 35 to 50 more preferably 40 to 46 percent by weight
of the oral pharmaceutical composition. In one embodiment, the
diluent is silicified microcrystalline cellulose, which is present
in a range of 10 to 70, preferably 35 to 50 more preferably 40 to
46 percent by weight of the oral pharmaceutical composition.
[0083] The oral pharmaceutical composition of the present invention
may further comprise at least one lubricant. A lubricant is used to
prevent adhesion of material to the surface of dies and punches in
tablet formation, reduce inter-particle friction, facilitate
ejection of tablets from the die cavity, and may improve the flow
characteristics of a powder or granules. Any suitable lubricant
that is compatible with the active ingredient and to good flow
properties and dissolution profile may be utilized. Exemplary
lubricants include, but are not limited to talc, magnesium
stearate, calcium stearate, zinc stearate, sodium stearyl fumarate,
stearic acid, glyceryl behenate, hydrogenated vegetable oils, and
polyethylene glycol.
[0084] In one embodiment, the at least one lubricant is magnesium
stearate, which is available from Mallincrodkt Corporation of St.
Louis, Mo.
[0085] The at least one lubricant is present in a range of 0.1 to
5, preferably 0.6 to 1.3 more preferably 0.8 to 1.2 percent by
weight of the oral pharmaceutical composition. In one embodiment,
the lubricant is magnesium stearate, which is present in a range of
0.1 to 5, preferably 0.6 to 1.3 more preferably 0.8 to 1.2 percent
by weight of the oral pharmaceutical composition.
[0086] In one embodiment, the oral pharmaceutical composition is a
core tablet composition.
[0087] In one embodiment, the core tablet composition of the
present invention includes (i) an active ingredient that is
selected from
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine,
(4-(3-Fluoro-benzyloxy)-3-chlorophenyl)-(6-(2-((2-methane
sulphonyl-ethylamino)-methyl)-thiazol-4-yl)quinazolin-4-yl)-amine
or
(4-(3-Fluoro-benzyloxy)-3-bromophenyl)-(6-(5-((2-methanesulphonyl-ethylam-
ino)-methyl)-furan-2-yl)quinazolin-4-yl)-amine or salts or solvates
thereof; (ii) at least one binder; and) at least one
disintegrant.
[0088] In one embodiment, the core tablet composition of the
present invention includes (i) an active ingredient that is
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate
monohydrate; (ii) at least one binder; (iii) at least one
disintegrant; and (iv) at least one diluent.
[0089] In one embodiment, the core tablet composition of the
present invention includes (i) an active ingredient that is
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate
monohydrate; (ii) povidone; and (iii) sodium starch glycolate.
[0090] In one embodiment, the core tablet composition of the
present invention includes (i) an active ingredient that is
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate
monohydrate; (ii) povidone; (iii) sodium starch glycolate; and (iv)
microcrystalline cellulose.
[0091] In one embodiment, the core tablet composition of the
present invention includes (i) an active ingredient that is
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate
monohydrate; (ii) povidone; (iii) sodium starch glycolate; (iv)
microcrystalline cellulose; and (v) magnesium stearate.
[0092] In one embodiment, the core tablet composition of the
present invention includes (i) an active ingredient that is
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate
monohydrate; (ii) at least one binder; (iii) at least one
disintegrant; (iv) at least one diluent; and (v) at least one
lubricant.
[0093] In one embodiment, the core tablet composition of the
present invention includes (i) an active ingredient that is
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate monohydrate
which is present in a range of 5 to 85, preferably 30 to 60, more
preferably 42 to 48 percent by weight; (ii) at least one binder,
which is present in a range of 2 to 11, preferably 4 to 9, more
preferably 5.5 to 7.5 percent by weight; (iii) at least one
disintegrant, which is present in a range of 1 to 10, preferably 2
to 8, more preferably 3.5 to 5.5 percent by weight; (iv) at least
one diluent, which is present in a range of 10 to 70, preferably 35
to 50, more preferably 40 to 46 percent by weight; and (v) at least
one lubricant, which is present in a range of 0.1 to 5, preferably
0.6 to 1.3, more preferably 0.8 to 1.2 percent by weight of the
core tablet composition.
[0094] In one embodiment, the core tablet composition of the
present invention includes (i) an active ingredient that is
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate monohydrate
which is present in a range of 5 to 85 percent by weight; (ii)
povidone, which is present in a range of 2 to 11 percent by weight;
(iii) sodium starch glycolate, which is present in a range of 1 to
10 percent by weight; (iv) microcrystalline cellulose which may be
present in a range of 10 to 70 percent by weight; and (v) magnesium
stearate, which may be present in a range of 0.1 to 5 percent by
weight of the core tablet composition.
[0095] In one embodiment, the core tablet composition of the
present invention includes (i) an active ingredient that is
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate monohydrate
which is present in a range of 30 to 60 percent by weight; (ii)
povidone, which is present in a range of 4 to 9 percent by weight;
(iii) sodium starch glycolate, which is present in a range of 2 to
8 percent by weight; (iv) microcrystalline cellulose, which may be
present in a range of 35 to 50 percent by weight; and (v) magnesium
stearate, which may be present in a range of 0.6 to 1.3 percent by
weight of the core tablet composition.
[0096] In one embodiment, the core tablet composition of the
present invention includes (i) an active ingredient that is
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate monohydrate
which is present in a range of 42 to 48 percent by weight; (ii)
povidone, which is present in a range of 5.5 to 7.5 percent by
weight; (iii) sodium starch glycolate, which is present in a range
of 3.5 to 5.5 percent by weight; (iv) microcrystalline cellulose,
which may be present in a range of 40 to 46 percent by weight; and
(v) magnesium stearate, which may be present in a range of 0.8 to
1.2 percent by weight of the core tablet composition.
[0097] In one embodiment, the core tablet composition of the
present invention includes (i) an active ingredient that is
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate
monohydrate; (ii) povidone; (iii) sodium starch glycolate; (iv)
microcrystalline cellulose; and (v) magnesium stearate.
[0098] The active ingredients disclosed herein have been shown to
be effective inhibitors of EGFR and/or erbB2 kinases as well as
having anti-tumour efficacy versus various cancer cell lines whose
cells express EGFR and/or erbB2. See for instance the
aforementioned International Patent Application No. PCT/EP99/00048,
filed Jan. 8, 1999, and published as WO 99/35146 on Jul. 15, 1999;
International Patent Application No. PCT/US01/20706, filed Jun. 28,
2001, and published as WO 02/02552 on Jan. 10, 2002; and
International Patent Application No. PCT/US03/10747, filed on Apr.
8, 2003 and published as WO 03/086467 on Oct. 23, 2003, which
applications are incorporated herein by reference to the extent
that they disclose the biological activity of the active
ingredients recited herein.
[0099] Accordingly, also provided in the present invention, is a
method for treating a disorder in a mammal characterized by
aberrant activity of at least one erbB family PTK which includes
administering an oral pharmaceutical composition as described
herein.
[0100] The aberrant PTK activity referred to herein is any erbB
family PTK activity that deviates from the normal erbB family
protein kinase activity expected in a particular mammalian subject.
Aberrant erbB family PTK activity may take the form of, for
instance, an abnormal increase in activity, or an aberration in the
timing and or control of PTK activity. Such aberrant activity may
result then, for example, from overexpression or mutation of the
protein kinase leading to inappropriate or uncontrolled activation.
Furthermore, it is also understood that unwanted PTK activity may
reside in an abnormal source, such as a malignancy. That is, the
level of PTK activity does not have to be abnormal to be considered
aberrant, rather the activity derives from an abnormal source.
[0101] The oral pharmaceutical compositions of the present
invention contain compounds of formula (I) or anhydrate or hydrated
salt forms thereof that are inhibitors of one or more erbB family
PTKs and as such have utility in the treatment of disorders in
mammals which are characterized by aberrant PTK activity,
particularly humans. In one embodiment of the present invention,
the disorder treated is characterized by at least one erbB family
PTK, selected from EGFR, c-erb-B2 and c-erb-B4, exhibiting aberrant
activity. In another embodiment, the disorder treated is
characterized by at least two erbB family PTKs, selected from EGFR,
c-erb-B2 and c-erb-B4, exhibiting aberrant activity. In one
embodiment of the treatment method, the compounds of formula (I) or
anhydrate or hydrate forms thereof inhibit at least one erbB family
PTK, selected from EGFR, c-erb-B2 and c-erb-B4. In another
embodiment of the treatment method, the compounds of formula I or
anhydrate or hydrate forms thereof inhibit at least two erbB family
PTKs selected from EGFR, c-erb-B2 and c-erb-B4.
[0102] The disorders referred to may be any disorder which is
characterized by aberrant PTK activity. As recited above such
disorders include, but are not limited to, cancer and psoriasis. In
a preferred embodiment, the disorder is cancer. In a more preferred
embodiment, the cancer is non-small cell lung, bladder, prostate,
brain, head and neck, breast, ovarian, gastric, colorectal, or
pancreatic cancer.
[0103] A therapeutically effective amount of a compound of formula
(I) and anhydrate or hydrate forms thereof will depend on a number
of factors including, but not limited to, the age and weight of the
mammal, the precise disorder requiring treatment and its severity,
the nature of the formulation, and the route of administration, and
will ultimately be at the discretion of the attendant physician or
veterinarian. Typically, the compounds of formula (I) and anhydrate
or hydrate forms thereof will be given for treatment in the range
of 0.1 to 100 mg/kg body weight of recipient (mammal) per day and
more usually in the range of 1 to 50 mg/kg body weight per day.
Acceptable daily dosages, may be from about 0.1 to about 2000
mg/day, and preferably from about 10 to about 1800 mg/day.
[0104] The oral pharmaceutical compositions containing compounds of
formula (I) or anhydrate or hydrated salt forms thereof, described
above, are useful in therapy.
[0105] The oral pharmaceutical composition of the present invention
and at least one additional cancer treatment therapy may be
employed in combination concomitantly or sequentially in any
therapeutically appropriate combination with such other anti-cancer
therapies. The additional anti-cancer therapy is typically selected
from one or more of surgical, radiological, or chemotherapeutic
therapies. In one embodiment, the additional anti-cancer therapy is
at least one surgical therapy. In another embodiment, the
additional anti-cancer therapy is at least one radiological
therapy. In one embodiment, the additional anti-cancer therapy is
at least one of surgical, radiological, or chemotherapeutic
therapy. In one embodiment, the additional anti-cancer therapy is
at least one chemotherapeutic therapy including administration of
at least one anti-neoplastic agent. The administration in
combination of a compound of formula (I) or salts, solvates, or
physiologically functional derivatives thereof with other
anti-neoplastic agents may be in combination in accordance with the
invention by administration concomitantly in (1) a unitary
pharmaceutical composition including both compounds or (2) separate
pharmaceutical compositions each including one of the compounds.
Alternatively, the combination may be administered separately in a
sequential manner wherein one anti-neoplastic agent is administered
first and the other second or vice versa. Such sequential
administration may be close in time or remote in time.
[0106] Anti-neoplastic agents may induce anti-neoplastic effects in
a cell-cycle specific manner, i.e., are phase specific and act at a
specific phase of the cell cycle, or bind DNA and act in a non
cell-cycle specific manner, i.e., are non-cell cycle specific and
operate by other mechanisms.
[0107] Anti-neoplastic agents useful in combination with the
compounds or salts, solvates or physiologically functional
derivatives thereof of formula I include the following:
[0108] (1) cell cycle specific anti-neoplastic agents including,
but not limited to, diterpenoids such as paclitaxel and its analog
docetaxel; vinca alkaloids such as vinblastine, vincristine,
vindesine, and vinorelbine; epipodophyllotoxins such as etoposide
and teniposide; gemcitabine; fluoropyrimidines such as
5-fluorouracil and fluorodeoxyuridine; antimetabolites such as
allopurinol, fludurabine, methotrexate, cladrabine, cytarabine,
mercaptopurine and thioguanine; and camptothecins such as 9-amino
camptothecin, irinotecan, topotecan, CPT-11 and the various optical
forms of
7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20-camptothecin;
[0109] (2) cytotoxic chemotherapeutic agents including, but not
limited to, alkylating agents such as melphalan, chlorambucil,
cyclophosphamide, mechlorethamine, hexamethylmelamine, busulfan,
carmustine, lomustine, and dacarbazine; anti-tumour antibiotics
such as doxorubicin, daunomycin, epirubicin, idarubicin,
mitomycin-C, dacttinomycin and mithramycin; and platinum
coordination complexes such as cisplatin, carboplatin, and
oxaliplatin; and
[0110] (3) other chemotherapeutic agents including, but not limited
to, anti-estrogens such as tamoxifen, toremifene, raloxifene,
droloxifene and iodoxyfene; progestrogens such as megestrol
acetate; aromatase inhibitors such as anastrozole, letrazole,
vorazole, and exemestane; antiandrogens such as flutamide,
nilutamide, bicalutamide, and cyproterone acetate; LHRH agonists
and antagagonists such as goserelin acetate and luprolide,
testosterone 5.alpha.-dihydroreductase inhibitors such as
finasteride; metalloproteinase inhibitors such as marimastat;
antiprogestogens; urokinase plasminogen activator receptor function
inhibitors; growth factor function inhibitors such as inhibitors of
the functions of hepatocyte growth factor; erb-B2, erb-B4,
epidermal growth factor receptor (EGFR), platelet derived growth
factor receptor (PDGFR), insulin growth factor receptor (IGF-R1),
vascular endothelial growth factor receptor (VEGFR, and TIE-2
(other than those VEGFR and TIE-2 inhibitors described in the
present invention); and other tyrosine kinase inhibitors such as
inhibitors of CDK2 and CDK4 inhibitors.
[0111] Additional description of these and additional anti-cancer
therapies can be found in published US Application 2004/0053946A1
published Mar. 18, 2004 which is incorporated by reference herein
to the extent that it teaches anti-cancer therapies.
[0112] In one embodiment, the oral pharmaceutical composition of
the present invention is a tablet that is prepared using a fluid
bed granulation process.
[0113] Accordingly, in one aspect of the present invention, there
is provided a process for preparing a tablet, comprising:
(a) admixing and fluidizing the active ingredient and at least one
diluent to form a fluidized mixture; (b) granulating said mixture
utilizing a granulating solution of at least one binder to form
active granules; (c) blending the active granules with a
disintegrant; (d) adding a lubricant to the active
granule/disintegrant mixture and blending to form a compression
blend; and (e) forming tablets from the compression blend.
[0114] In another aspect of the present invention, there is
provided a process for preparing a tablet, comprising:
(a) admixing and fluidizing the active ingredient and at least one
diluent to form a fluidized mixture; (b) granulating said mixture
utilizing an aqueous solution of at least one binder to form active
granules; (c) blending the active granules with a disintegrant; (d)
adding a lubricant to the active granule/disintegrant mixture and
blending to form a compression blend; and (e) forming tablets from
the compression blend.
[0115] In another aspect of the present invention, there is
provided a process for preparing a tablet, comprising:
(a) admixing and fluidizing the active ingredient and at least one
diluent to form a fluidized mixture; (b) granulating said mixture
utilizing a granulating solution of at least one binder to form
active granules; (c) blending the active granules with a
disintegrant and at least one lubricant to form a compression
blend; (d) forming tablets from the compression blend; and (e) film
coating the tablets.
[0116] In another aspect of the present invention, there is
provided a process for preparing a tablet, comprising:
(a) admixing and fluidizing the active ingredient and at least one
diluent to form a fluidized mixture; (b) granulating said mixture
utilizing an aqueous solution of at least one binder to form active
granules; (c) blending the active granules with a disintegrant and
at least one lubricant to form a compression blend; (d) forming
tablets from the compression blend; and (e) film coating the
tablets.
[0117] In another aspect of the present invention, there is
provided a process for preparing a tablet, comprising:
(a) admixing and fluidizing the active ingredient, at least one
diluent, and at least one binder to form a fluidized mixture; (b)
granulating said mixture utilizing a granulating solution to form
active granules; (c) blending the active granules with a
disintegrant and at least one lubricant to form a compression
blend; (d) forming tablets from the compression blend; and (e) film
coating the tablets.
[0118] In another aspect of the present invention, there is
provided a process for preparing a tablet, comprising:
(a) admixing and fluidizing the active ingredient, at least one
diluent, and at least one binder to form a fluidized mixture; (b)
granulating said mixture utilizing a granulating solution to form
active granules; (c) blending the active granules with a
disintegrant and at least one lubricant to form a compression
blend; (d) forming tablets from the compression blend; and (e) film
coating the tablets.
[0119] As recited above, the tablet forming process of the present
invention includes a step (a) admixing the active ingredient and at
least one diluent to form a granulation mixture. The admixing is
done, for instance, in a fluid bed granulator by placing the active
ingredient and diluent in the bowl of a GLATT.RTM. GPCG30 fluid bed
granulator available from Glatt Air Technologies of Ramsey, N.J. or
a GLATT.RTM. WSTCD 160/200 fluid bed granulator available from the
Glatt Group of Companies of Binzen, Germany. The diluent may
optionally be sieved prior to admixing with the active. If sieved,
the diluent is sieved using a US Mesh sized 16, 20, or 24,
preferably a 20 sieve. The admixed active and diluent are then
fluidized in the GLATT.RTM. GPCG30 or GLATT.RTM. WSTCD 160/200 to
form a fluidized mixture using standard process parameters known in
the art.
[0120] Suitable active ingredients and diluents are as described
above for the oral pharmaceutical composition.
[0121] In an alternative embodiment, step (a) includes admixing the
active ingredient, at least one diluent, and at least binder to
form a granulation mixture. The admixing is performed as recited
above. Suitable active ingredients, diluents, and binders are as
described above for the oral pharmaceutical composition.
[0122] Accordingly, in one embodiment, the fluidized mixture of the
present invention includes (i) an active ingredient that is
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate
monohydrate; and (ii) at least one diluent.
[0123] In one embodiment, the fluidized mixture of the present
invention includes (i) an active ingredient that is
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate monohydrate
which is present in a range of 35 to 67, preferably 45 to 57
percent by weight; and (ii) at least one diluent which is present
in a range of 33 to 65, preferably 43 to 55 percent by weight of
the fluidized mixture.
[0124] In another embodiment, the fluidized mixture of the present
invention includes (i) an active ingredient that is
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate
monohydrate; and (ii) microcrystalline cellulose.
[0125] In a further embodiment, the fluidized mixture of the
present invention includes (i) an active ingredient that is
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate monohydrate
which is present in a range of 35 to 67, preferably 45 to 57
percent by weight; and (ii) microcrystalline cellulose which is
present in a range of 33 to 65, preferably 43 to 55 percent by
weight of the fluidized mixture.
[0126] After preparation, the fluidized mixture is granulated in
step (b) using a granulating solution. The granulating solution may
be an aqueous, non-aqueous or a aqueous/non-aqueous solution. The
solution may or may not include the at least one binder. That is,
the granulating solution may be an aqueous, non-aqueous, or an
aqueous/non-aqueous solution of the at least one binder or in
another embodiment, the at least one binder is included in the
fluidized mixture and the granulating solution is water, a
non-aqueous liquid, or an aqueous/non-aqueous liquid. The aqueous
solution is of course water or a water solution with the at least
one binder. The non-aqueous solution includes, but is not limited
to, alcohols such as ethanol, or isopropanol; other organics such
as acetone; or mixtures of alcohols or other organics such as an
acetone/ethanol mixture, or acetone/isopropanol mixture; and the
like with or without the at least one binder. The
aqueous/non-aqueous solution is, but is not limited to,
water/ethanol, water/acetone, or water/isopropanol mixtures with or
without the at least one binder.
[0127] In one embodiment, the aqueous solution is a 5 to 25,
preferably 10 to 25, more preferably a 15 to 25 percent solution of
at least one binder in purified water
[0128] (USP). Preferably, the aqueous solution is a 5 to 25,
preferably 10 to 25, more preferably 15 to 25 percent solution of
povidone in purified water (USP). The aqueous solution is prepared
for instance in a suitable tank with a propeller type mixer such as
a Lighting Mixer with suitable bowl. The aqueous mixture is sprayed
onto the fluidized mixture after formation of the fluidized mixture
at a rate adequate to insure proper granule formation. As is known
in the art, the specific combination of batch size, inlet air
temperature, inlet air dewpoint, and inlet air volume will
determine acceptable binder solution spray rates. An additional
amount of water may be added as needed to provide proper
granulation wetness. At the end of granulation the inlet air
temperature, may be raised to facilitate the drying process until
an acceptable moisture content (such as Loss On Drying--LOD) is
reached. The dried granules may be passed through, for instance, a
cone mill, such as a Comil.RTM. available from Quadro Engineering
Incorporated of Waterloo, Ontario, using an appropriate combination
of screen size and impeller speed to produce the desired active
granule product.
[0129] Accordingly, in one embodiment, the active granules of the
present invention includes (i) an active ingredient that is
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate
monohydrate; (ii) at least one diluent; and (iii) at least one
binder.
[0130] In one embodiment, the active granules of the present
invention includes (i) an active ingredient that is
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate
monohydrate; (ii) microcrystalline cellulose; and (iii)
povidone.
[0131] In one embodiment, the active granules of the present
invention includes (i) an active ingredient that is
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate monohydrate
which is present in a range of 5 to 85, preferably 30 to 60, more
preferably 45 to 51 percent by weight; (ii) at least one diluent,
which is present in a range of 4 to 93, preferably 31 to 66, more
preferably 41 to 49 percent by weight; and (iii) at least one
binder, which is present in a range of 2 to 11, preferably 4 to 9,
more preferably 6 to 8 percent by weight of the active
granules.
[0132] In one embodiment, the active granules of the present
invention includes (i) an active ingredient that is
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate monohydrate
which is present in a range of 5 to 85 percent by weight; (ii)
microcrystalline cellulose, which is present in a range of 4 to 93
percent by weight; and (iii) povidone, which is present in a range
of 2 to 11 percent by weight of the active granules.
[0133] In one embodiment, the active granules of the present
invention includes (i) an active ingredient that is
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate monohydrate
which is present in a range of 30 to 60 percent by weight; (ii)
microcrystalline cellulose, which is present in a range of 31 to 66
percent by weight; and (iii) povidone, which is present in a range
of 4 to 9 percent by weight of the active granules.
[0134] In one embodiment, the active granules of the present
invention includes (i) an active ingredient that is
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate monohydrate
which is present in a range of 45 to 51 percent by weight; (ii)
microcrystalline cellulose, which is present in a range of 41 to 49
percent by weight; and (iii) povidone which is present in a range
of 6 to 8 percent by weight of the active granules.
[0135] After preparation the active granules are blended in step
(c) with at least one disintegrant and at least one lubricant to
form a compression blend. The active granules may be first blended
with the at least one disintegrant and then the active
granules/disintegrant mixture blended with at least one lubricant
to form a compression blend. Alternatively, the active granules,
the at least one disintegrant, and the at least one lubricant are
blended together to form the compression mixture.
[0136] The ingredients are blended, using for instance a V-Blender
available from Granulair Technologies of Lausanne, Switzerland or
BULS cube blender available from Matcon, Incorporated of Sewell,
N.J., at low rpm until blend uniformity is achieved. As is
recognized in the art, the time needed to achieve such uniformity
will vary according to the amount and character of the ingredients
and specific process equipment.
[0137] The components of the compression blend, i.e., the active
granules, disintegrant, and lubricant are as described above.
[0138] In one embodiment, the compression blend of the present
invention includes (i) active granules; (ii) at least one
disintegrant; and (iii) at least one lubricant.
[0139] In one embodiment, the compression blend of the present
invention includes (i) active granules which are present in a range
of 85 to 99, preferably 87 to 91, more preferably 93 to 96 percent
by weight; (ii) at least one disintegrant, which is present in a
range of 1 to 10, preferably 2 to 8, more preferably 3.5 to 5.5
percent by weight; and (iii) at least one lubricant which is
present in a range of 0.1 to 5, preferably 0.6 to 1.3, more
preferably 0.8 to 1.2 percent by weight of the compression
blend.
[0140] In one embodiment, the compression blend of the present
invention includes (i) active granules; (ii) sodium starch
glycolate; and (iii) magnesium stearate.
[0141] In one embodiment, the compression blend of the present
invention includes (i) active granules which are present in a range
of 85 to 99 percent by weight; (ii) sodium starch glycolate, which
is present in a range of 1 to 10 percent by weight; and (iii)
magnesium stearate, which is present in a range of 0.1 to 5 percent
by weight of the compression blend.
[0142] In one embodiment, the compression blend of the present
invention includes (i) active granules which are present in a range
of 87 to 91 percent by weight; (ii) sodium starch glycolate, which
is present in a range of 2 to 8 percent by weight; and (iii)
magnesium stearate, which is present in a range of 0.6 to 1.3
percent by weight of the compression blend.
[0143] In one embodiment, the compression blend of the present
invention includes (i) active granules which are present in a range
of 93 to 96 percent by weight; (ii) sodium starch glycolate, which
is present in a range of 3.5 to 5.5 percent by weight; and (iii)
magnesium stearate, which may be present in a range of 0.8 to 1.2
percent by weight of the compression blend.
[0144] Core tablets are formed from the compression blend (step
(d)) by compressing the blend into tablet form. Any suitable means
for tablet compression may be used, including, but not limited to,
a single punch machine, rotary tablet machines and instrumented
tablet machines. In one embodiment, the tableting is done by a
rotary tablet machine, for instance a Hata model HT-AP18SSU rotary
tablet press available from Elizabeth-Hata International of North
Huntingdon,
[0145] Pennsylvania or William Fette GmbH of Schwarzenbek, Germany.
The Hata press is fitted with a 19.05.times.10.41 mm standard
concave tooling. In-process controls for uniformity of weight,
average weight, hardness, friability, and disintegration time are
applied during the compression run and adjustments to the tablet
press are made if necessary. The composition of the core tablets
are as described above.
[0146] The tablets may optionally be film coated (step (e)) by any
suitable means. In one embodiment, the tablets are film coated
using a coater such as a Compulab Accella Coata available from
Thomas Engineering, Inc. of Hoffman Estates, Ill. or the Glatt
Group of Companies of Binzen, Germany. Coating of the tablets will
enhance patient acceptance and control dust. In one embodiment, the
tablets are coated with 12 percent by weight aqueous suspension of
Orange Opadry.RTM. YS-1-13065A aqueous suspension available from
Colorcon, Incorporated of Westpoint, Pa.
[0147] In one embodiment, the tablets of the present invention are
immediate release tablets containing 250 mg of
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine.
[0148] In another embodiment, the tablets of the present invention
have an average dissolution of 80 percent or greater, preferably 85
percent or greater, more preferably 90 percent or greater drug
dissolution after 45 minutes when evaluated using a USP Type II
apparatus at 55 rpm paddle speed in 900 ml of 0.1N HCl containing
2% w/w Tween 80.RTM. at 37.degree. C.
[0149] In one embodiment, a tablet of the present invention
includes (i) an active ingredient that is
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate
monohydrate; (ii) at least one binder; (iii) at least one
disintegrant; and (iv) a film coat.
[0150] In one embodiment, a tablet of the present invention
includes (i) an active ingredient that is
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate
monohydrate; (ii) at least one binder; (iii) at least one
disintegrant; (iv) at least one diluent; and (v) a film coat.
[0151] In one embodiment, a tablet of the present invention
includes (i) an active ingredient that is
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate
monohydrate; (ii) at least one binder; (iii) at least one
disintegrant; (iv) at least one diluent; (v) a lubricant; and (vi)
a film coat.
[0152] In one embodiment, a tablet of the present invention
includes (i) an active ingredient that is
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate
monohydrate; (ii) povidone; (iii) sodium starch glycolate; and (iv)
a film coat.
[0153] In one embodiment, a tablet of the present invention
includes (i) an active ingredient that is
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate
monohydrate; (ii) povidone; (iii) sodium starch glycolate; (iv)
microcrystalline cellulose; and (v) a film coat.
[0154] In one embodiment, a tablet of the present invention
includes (i) an active ingredient that is
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate
monohydrate; (ii) povidone; (iii) sodium starch glycolate; (iv)
microcrystalline cellulose; (v) magnesium stearate, and (vi) a film
coat.
[0155] In one embodiment, a tablet of the present invention
includes (i) an active ingredient that is
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate monohydrate
which is present in a range of 5 to 85, preferably 30 to 60, more
preferably 45 to 51 percent by weight; (ii) at least one binder,
which is present in a range of 2 to 11, preferably 4 to 9, more
preferably 5.5 to 7.5 percent by weight; (iii) at least one
disintegrant, which is present in a range of 1 to 10, preferably 2
to 8, more preferably 3.5 to 5.5 percent by weight; (iv) at least
one diluent, which is present in a range of 10 to 70, preferably 35
to 50, more preferably 40 to 46 percent by weight; (v) at least one
lubricant, which is present in a range of 0.1 to 5, preferably 0.6
to 1.3, more preferably 0.8 to 1.2 percent by weight, and (vi) a
film coat which is present in the range of 2.0 to 4, preferably 2.5
to 3.5, more preferably 2.8 to 3.2 percent by weight of the core
tablet composition.
[0156] In one embodiment, a tablet composition of the present
invention includes (i) an active ingredient that is
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate
monohydrate; (ii) povidone; (iii) sodium starch glycolate; (iv)
microcrystalline cellulose; (v) magnesium stearate; and (vi) a film
coat.
[0157] In one embodiment, a tablet composition of the present
invention includes (i) an active ingredient that is
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate monohydrate
which is present in a range of 5 to 85 percent by weight; (ii)
povidone, which is present in a range of 2 to 11 percent by weight;
(iii) sodium starch glycolate, which is present in a range of 1 to
10 percent by weight; (iv) microcrystalline cellulose, which may be
present in a range of 10 to 70 percent by weight; (v) magnesium
stearate, which may be present in a range of 0.1 to 5 percent by
weight; and (vi) a film coat which is present in a range of 2.0 to
4.0 percent by weight of the core tablet composition.
[0158] In one embodiment, a tablet composition of the present
invention includes (i) an active ingredient that is
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate monohydrate
which is present in a range of 30 to 47 percent by weight; (ii)
povidone, which is present in a range of 4 to 9 percent by weight;
(iii) sodium starch glycolate, which is present in a range of 2 to
8 percent by weight; (iv) microcrystalline cellulose, which may be
present in a range of 35 to 50 percent by weight; (v) magnesium
stearate, which may be present in a range of 0.6 to 1.3 percent by
weight; and (vi) a film coat which is present in a range of 2.5 to
3.5 percent by weight of the core tablet composition.
[0159] In another embodiment, a tablet composition of the present
invention includes (i) an active ingredient that is
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate monohydrate
which is present in a range of 30 to 60 percent by weight; (ii)
povidone, which is present in a range of 4 to 9 percent by weight;
(iii) sodium starch glycolate, which is present in a range of 2 to
8 percent by weight; (iv) microcrystalline cellulose, which may be
present in a range of 35 to 50 percent by weight; (v) magnesium
stearate, which may be present in a range of 0.6 to 1.3 percent by
weight; and (vi) a film coat which is present in a range of 2.5 to
3.5 percent by weight of the core tablet composition.
[0160] In one embodiment, a tablet composition of the present
invention includes (i) an active ingredient that is
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate monohydrate
which is present in a range of 42 to 48 percent by weight; (ii)
povidone, which is present in a range of 5.5 to 7.5 percent by
weight; (iii) sodium starch glycolate, which is present in a range
of 3.5 to 5.5 percent by weight; (iv) microcrystalline cellulose,
which may be present in a range of 40 to 46 percent by weight; (v)
magnesium stearate, which may be present in a range of 0.8 to 1.2
percent by weight; and (vi) a film coat which is present in a range
of 2.8 to 3.2 percent by weight of the core tablet composition.
[0161] In one embodiment, a tablet composition of the present
invention includes (i) an active ingredient that is
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate monohydrate
which is present in a range of 45 to 51 percent by weight; (ii)
povidone, which is present in a range of 5.5 to 7.5 percent by
weight; (iii) sodium starch glycolate, which is present in a range
of 3.5 to 5.5 percent by weight; (iv) microcrystalline cellulose,
which may be present in a range of 40 to 46 percent by weight; (v)
magnesium stearate, which may be present in a range of 0.8 to 1.2
percent by weight; and (vi) a film coat which is present in a range
of 2.8 to 3.2 percent by weight of the core tablet composition.
[0162] In addition to tablets, the composition according to the
present invention may also be administered in the form of capsules,
caplets, gelcaps, pills, and any other oral dosage forms known in
the pharmaceutical art.
[0163] In one embodiment, the present invention includes a method
of producing a ditosylate salt of a compound of Formula (I):
##STR00021##
or salts or solvates thereof, wherein R.sub.1 is Cl or Br; X is CH,
N, or CF; and Het is thiazole or furan; wherein the method
comprises the steps of: (a) Reacting a compound of Formula
(IV):
##STR00022##
[0164] wherein X is CH, N, or CF
with amine to give a compound of formula (V)
##STR00023##
[0165] wherein X is CH, N, or CF
(b) reacting the compound of formula (V) with boronic acid of
formula (VI):
##STR00024##
[0166] where Het is thiazole or furan
followed by treatment with p-toluenesulfonic acid salt to form a
compound of Formula (VII):
##STR00025##
[0167] where Het is thiazole or furan.
(c) preparing the ditosylate salt of a compound of formula (VII) to
form a compound of formula (VIII):
##STR00026##
[0168] wherein X is CH, N, or CF and Het is thiazole or furan;
and
(d) recrystallizing the compound of formula (VIII) prepared
according to step (c) in the presence of tetrahydrofurman
(THF).
[0169] In another embodiment, the invention encompasses a method of
producing a ditosylate salt of a compound of Formula (I) where said
method comprises the step of recrystallizing the compound of
formula (VIII) is performed in the presence of at least 20 volumes
of THF. In particular embodiments, the method comprises the step of
recrystallizing the compound of formula (VIII) in the presence of
at least 25 volumes of THF, at least 27 volumes of THF, or at least
30 volumes of THF.
[0170] The invention additionally provides methods of producing a
ditosylate salt of a compound of formula (I) as described above
wherein the compound is a compound of formula (II) or formula
(III).
[0171] In a further embodiment, the invention encompasses a method
of producing a ditosylate salt of an N-phenyl-4-quinazolinamine
derivative where said method comprises the step of recrystallizing
the N-phenyl-4-quinazolinamine derivative in the presence of at
least 20 volumes of THF. In particular embodiments, the method
comprises the step of recrystallizing the compound of formula
(VIII) in the presence of at least 25 volumes of THF, at least 27
volumes of THF, or at least 30 volumes of THF. In one aspect, the
N-phenyl-4-quinazolinamine derivative is
N-(3-chloro-4-fluorophenyl)-7-(methyloxy)-6-{[3-(4-morpholinyl)propyl]-
oxyl-4-quinazolinamine.
[0172] The following examples are intended for illustration only
and are not intended to limit the scope of the invention in any
way. The physical data given for the compounds exemplified is
consistent with the assigned structure of those compounds.
EXAMPLES
[0173] As used herein the symbols and conventions used in these
processes, schemes and examples are consistent with those used in
the contemporary scientific literature, for example, the Journal of
the American Chemical Society or the Journal of Biological
Chemistry. Standard single-letter or three-letter abbreviations are
generally used to designate amino acid residues, which are assumed
to be in the L-configuration unless otherwise noted. Unless
otherwise noted, all starting materials were obtained from
commercial suppliers and used without further purification.
Specifically, the following abbreviations may be used in the
examples and throughout the specification:
TABLE-US-00001 g (grams); mg (milligrams); L (liters); mL
(milliliters); .mu.L (microliters); psi (pounds per square inch);
mm (millimeters); kN: (kiloNewton); cfm (cubic feet per minute) kP
(kilopond); M (molar); mM (millimolar); N (Normal) Kg (kilogram);
i.v. (intravenous); mol (moles); mmol (millimoles); RT (room
temperature); min (minutes); h (hours); RSD (relative standard
deviation) rpm (revolutions per minute); mp (melting point); TLC
(thin layer chromatography); T.sub.r (retention time); RP (reverse
phase); THF (tetrahydrofuran); DMSO (dimethylsulfoxide); EtOAc
(ethyl acetate); DME (1,2-dimethoxyethane); DCM (dichloromethane);
DCE (dichloroethane); DMF (N,N-dimethylformamide); HOAc (acetic
acid); POCl.sub.3 (phosphorus oxychloride); NBu.sub.3
(tri-n-butylamine); MeOH (methanol); IMS (industrial methylated
spirit); DIPEA (diisopropylethyleneamine); PTSA (p-toluene sulfonic
acid); TMSE (2-(trimethylsilyl)ethyl); TMS (trimethylsilyl); TIPS
(triisopropylsilyl); TBS (t-butyldimethylsilyl);
[0174] Unless otherwise indicated, all temperatures are expressed
in .degree. C. (degrees Centigrade). All reactions conducted under
an inert atmosphere at room temperature unless otherwise noted.
Example 1
Preparation of
N-(3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methane
sulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine Tablets,
250 mg
[0175] Table 1 contains a description of the components used in the
preparation of a granulation mixture and Table 2 contains a
description of the components used in the preparation of a
compression blend for one embodiment of
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine Tablets, 250 mg for a
batch size of 20,000 tablets.
TABLE-US-00002 TABLE 1 Amount Amount Component (mg/tab)*
(kg/batch)** Function Granulation Mixture Active.sup.1 405 8.100
Active Microcrystalline Cellulose 387 7.740 Diluent NF, PhEur, JP
Glidant Povidone USP, PhEur, JP.sup.2 58.5 1.170 Binder Purified
Water.sup.3 qs qs Granulating liquid Total dry granules 850.5 17.01
.sup.1N-{3-Chloro-4-[(3-fluorobenzyl)
oxy]phenyl}-6-[5-({[2-(methanesulphonyl)
ethyl]amino}methyl)-2-furyl]-4-quinazolinamine. Prepared according
to the procedure of Scheme B. The actual amount of drug substance
may be adjusted based on the purity of the specific lot of drug
substance included in the batch. The amount of diluent
(microcrystalline cellulose) is then adjusted to maintain a core
tablet weight of 900 mg. .sup.2Plasdone K29/32 .sup.3Removed during
drying process. *Based on theoretical drug substance factor of 1.62
= 1.00 **Quantities for a 20,000 tablet granulation.
TABLE-US-00003 TABLE 2 Amount Amount Component (mg/tab) (kg/batch)*
Function Compression Blend Granules.sup.1 850.5 102.06 Active
Granules Sodium Starch Glycolate.sup.2 40.5 4.86 Disintegrant
Magnesium Stearate 9 1.08 Lubricant Total Weight 900.0 108.0
Coating Opadry.RTM./Orange YS-1- 27.0 3.24 Film Coat 13065-A
Purified Water.sup.3 qs qs Total Tablet Weight 927.0 111.24
.sup.1Granules prepared from Granular Mix of Table 1 .sup.2Primojel
NF, Pharm Eur, JPE .sup.3Removed during drying process *120000
Tablets
[0176] For this example all ingredients were weighed to amounts
which were consistent with the weight percents recited in Tables 1
and 2.
(i) Formation of Active Granules (Batch Size--120,000 Tablets)
[0177]
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulpho-
nyl)ethyl]amino}methyl)-2-furyl]-4-quinazolin amine ditosylate
monohydrate and microcrystalline cellulose NF, PH. Eur., JP were
added to the bowl of a Glatt 30 granulator. A 10% solution of
povidone in water was prepared using a Lightnin' mixer with a
suitable tank. The
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolin amine ditosylate
monohydrate and microcrystalline cellulose were fluidized in the
Glat 30 bowl and spraying of the 10% povidone solution began
immediately at approximately 220 g/minute with an inlet air
temperature of 54.degree. C. The inlet air dewpoint was maintained
between 10 to 15.degree. C. After the povidone solution was applied
purified water was added as needed to obtain a proper granulation
wetness. At the end of granulation the inlet air temperature was
raised to 60.degree. C. and drying was continued until an LOD of
approximately 2.5% was reached. The dried active granules were
passed through a Comil Model 197S cone mill fitted with a 0.075
inch round holed screen at approximately 1720 RPM (28.6 Hz).
[0178] Sieve analysis was performed and tapped density profiles
established. Sieve analysis was performed using a Retsch sieve
shaker, Model AS200 Digit. Approximately 20 g of active dried
granules was placed on the top of a nest of tared sieves of 20, 30,
40, 60, 100, and 200 mesh. Shaking was done for 5 minutes at an
amplitude setting of 60 with the pulse on. This sieve analysis
revealed little batch to batch variation in particle size of the
active granules. The granules were also characterized for Bulk
Density (BD) and Tapped Density (TD). BD and TD of the granules was
measured by adding a weighed amount of granules into a 100 ml
graduated cylinder and measuring the volume initially and after 25,
50, 200, 500, and 1250 taps respectively.
[0179] BD and TD showed minimal variation between batches.
(ii) Tablet Formation
[0180] A compression blend was formed by combining the prepared
active granules and sodium starch glycolate in a bin which was
transferred to a tumble blender where the ingredients were blended
for 15 minutes @ 12 RPM. The bin was then removed from the tumble
blender and magnesium stearate added to the blend of active
granules and sodium starch glycolate. The bin was sealed and
transferred back to the tumble blender and blended for 3 minutes @
12 RPM to obtain the compression mix. Tablets were compressed from
the compression blend using a Hata model HT-AP18SSU rotary tablet
press fitted with 19.05.times.10.41 mm standard concave tooling.
The tablet press was adjusted to provide tablets with the following
specifications.
TABLE-US-00004 Weight of 10 tablets 9.00 g Weight Range of 10
tablets 8.80-9.20 g Individual Tablet Weight 900.0 mg Individual
Weight Range 855.0-945.0 mg Target Average Tablet Hardness 18 kp
Individual Hardness Range 9-27 kp Individual Thickness Range
5.00-8.00 mm Compression Speed Range 15-45 RPM
[0181] Uncoated tablets were characterized for weight, hardness,
disintegration and dissolution. Tablets were weighed and hardness
determined using, for example, a Dr. Schleuniger.RTM. Pharmatron
Testlink Instrument available from Dr Schleuniger.RTM. Pharmatron
of Solothurn, Switzerland. Disintegration was determined in 1 L of
water at 37.degree. C. and drug dissolution was evaluated using a
USP Type II apparatus at 55 rpm paddle speed in 900 ml of 0.1N
HCl/2% w/w Tween 80 at 37.degree. C. Results for three groups of
tablets follow:
[0182] Average Weight: [0183] #1=900.2.+-.1.23 mg; n=120 [0184]
#2=902.6.+-.1.28 mg; n=90 [0185] #3=901.8.+-.0.99; n=60
[0186] Average Hardness: [0187] #1=18.6 kp [0188] #2=19.1 kp [0189]
#3=18.6 kp
[0190] Disintegration: [0191] #1=2 min 2 seconds [0192] #2=1 minute
59 seconds [0193] #3=1 minute 57 seconds
[0194] The produced tablets were coated in a Thomas Engineering
Inc., Compu-Lab coater using 12% w/w Orange
Opadry.RTM./NS-1-13065-A aqueous suspension at a pan speed of 6-8
rpm. Two spray nozzles (orifice opening--1.2 mm) were used to
deliver coating solution at a total rate of 90-120 g/min. The
airflow was maintained at 500 to 700 cfm with the outlet air
temperature ranging from 50 to 63.degree. C. The gun to bed
distance was kept at 8.5 to 9 inches. Sufficient film coating was
applied to achieve a 3 percent by weight gain assuming 100% coating
efficiency.
[0195] Coated tablets were characterized for drug dissolution using
a USP Type II apparatus at 55 rpm paddle speed in 900 ml of 0.1N
HCl/2% w/w Tween 80 at 37.degree. C. The results follow:
[0196] % Dissolution (45 min): [0197] Range=81-95% [0198] Average=
[0199] #1=87 [0200] #2=93 [0201] #3=94 Table 3 recites the tablet
composition.
TABLE-US-00005 [0201] TABLE 3 Amount Reference to Component
(mg/tab).sup.2 Standard Function Active.sup.1 405 Active
Microcrystalline 387 NF Diluent Cellulose Povidone 58.5 EP, JP, USP
Binder Purified Water.sup.3 qs EP, JPE, NF Granulating liquid
Sodium Starch Glycolate 40.5 EP, JP, USP Disintegrant Magnesium
Stearate 9.0 EP, JPE, NF Lubricant Opadry.RTM. YS-1-13065-A 27
EP.sup.6, JPE, NF Film coat Purified Water.sup.3 qs EP, JP, USP
Film coat solvent Total tablet weight 927
.sup.1N-{3-Chloro-4-[(3-fluorobenzyl)
oxy]phenyl}-6-[5-({[2-(methanesulphonyl)
ethyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate
monohydrate, equivalent to 250 mg
.sup.1N-{3-Chloro-4-[(3-fluorobenzyl)
oxy]phenyl}-6-[5-({[2-(methanesulphonyl)
ethyl]amino}methyl)-2-furyl]-4-quinazolinamine. .sup.2Theoretical
core tablet weight is 900 mg. .sup.3Removed during drying.
Example 2
Preparation of
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolin amine ditosylate
monohydrate
[0202]
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulpho-
nyl)ethyl]amino}methyl)-2-furyl]-4-quinazolin amine ditosylate
monohydrate is prepared according to the procedure of Scheme C as
follows:
[0203] Stage 1--
[0204] A stirred suspension of 3H-6-iodoquinazolin-4-one in toluene
(5 vols) is treated with tri-n-butylamine (1.2 equiv.), and then
heated to 70-80.degree. C. Phosphorous oxychloride (1.1 equiv.) is
added and the reaction mixture is then heated to reflux and stirred
at this temperature for at least 2 hours. The reaction mixture is
then cooled to 55.degree. C. and toluene (5 vol) added followed by
3-chloro-4-{[(3-fluorophenyl)methyl]oxy}aniline (1.03 equiv.). The
reaction mixture is then warmed to 70-90.degree. C. and stirred for
at least 2 hours. The resultant slurry is transferred to a second
vessel. The temperature is adjusted to 70-75.degree. C. and 8 molar
aqueous sodium hydroxide solution (2 vols) added over 1 hour,
followed by water (6 vol.) maintaining the contents at
70-85.degree. C. The mixture is stirred at 70-85.degree. C. for ca.
1 hour and then cooled to 20-25.degree. C. The suspension is
stirred for ca. 2 hours and the product collected by filtration,
and washed successively with water, 0.1 molar aqueous sodium
hydroxide, water, and IMS, then dried in vacuo.
[0205] Stage 2--
[0206] A mixture of
N-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-iodo-4-quinazolinami-
ne (1 wt), (5-formyl-2-furanyl)boronic acid (0.374 wt, 1.35 eq) and
10% Palladium on charcoal (0.028 wt 50% water wet) is slurried in
ethanol (industrial methylated spirits, 15 vols) to give a grey
suspension. The resultant slurry is stirred for 5 minutes and then
treated with N,N-di-isopropylethylamine (0.396 vols, 1.15 eq.). The
reaction slurry is heated to 70.degree. C. for typically 3 hours
when the reaction is complete (by HPLC analysis). The mixture is a
thick green slurry at this point which is treated with THF (15
vols) to dissolve the product that has precipitated, leaving only
the Pd/C catalyst out of solution. The mixture is then filtered hot
through GFA filter to remove the catalyst. The vessel is rinsed
with IMS (1 vol) and the wash used to rinse catalyst bed. A
solution of p-toluenesulfonic acid monohydrate (1.50 wt, 4.0 eq.)
in water (1.5 vols) is added to the filtered solution over 5
minutes at 65.degree. C. The reaction solution is cooled to
60.degree. C., with crystallization observed at 60-65.degree. C.
The resultant slurry is then stirred for at least 1 hour at
60.degree. C. and then cooled to 20-25.degree. C. and then held at
this temperature for a further 1 hour. The product is isolated by
filtration and the cake washed with IMS (3 vols). The product may
be stored as a wet cake or dried.
[0207] Stage 3--
[0208]
5-{4-[(3-Chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]-6-quin-
azolinyl}-2-furancarbaldehyde 4-methylbenzenesulfonate (1 wt) and
2-(methylsulfonyl)ethylamine hydrochloride (0.4 wt, 1.60 equiv.)
are suspended in THF (10 vols). Sequentially, acetic acid (0.354
vol., 4.00 equiv.) and di-isopropylethylamine (DIPEA, 1.08 vols,
4.00 equiv.) are added. The resulting solution is stirred at
30.degree.-35.degree. C. for ca. 1 hour then cooled to ca.
22.degree. C. Sodium tri-acetoxyborohydride (0.66 wt, 2.00 equiv.)
is then added. The resulting mixture is stirred at ca. 22.degree.
C. for 2-4 hours then sampled for HPLC analysis. The reaction is
quenched by addition of aqueous sodium hydroxide (25% w/w, 3 vols.)
followed by water (2 vols.). The aqueous phase is then separated,
extracted with THF (2 vols) and the combined THF extracts are then
washed twice with 25% w/v aqueous ammonium chloride solution
(2.times.5 vols). A solution of p-toluenesulfonic acid monohydrate
(p-TSA, 0.74 wt, 2.5 equiv.) in water (1 vol) is prepared, warmed
to ca. 60.degree. C., and
N-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[5-({[2-(methylsulfo-
nyl)ethyl]amino}methyl)-2-furanyl]-4-quinazolinamine
4-methylbenzenesulfonate hydrate seeds are added. The THF solution
of the free base is added to the p-TSA solution over at least 1 hr,
maintaining the batch temperature at 60.+-.3.degree. C. The
resulting suspension is stirred at ca. 60.degree. C. for 1-2 hours,
cooled to 20-25.degree. C. over an hour and aged at this
temperature for ca. 1 hr. The solid is collected by filtration,
washed with 95:5 THF:Water (3.times.2 vols) and dried in vacuum at
ca. 35.degree. C. to give
N-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[5-({[2-(methylsulfo-
nyl)ethyl]amino}methyl)-2-furanyl]-4-quinazolinamine
4-methylbenzenesulfonate hydrate as a bright yellow crystalline
solid.
[0209] Stage 4--
[0210] A slurry of
N-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[5-({[2-(methylsulfo-
nyl)ethyl]amino}methyl)-2-furanyl]-4-quinazolinamine
4-methylbenzenesulfonate hydrate (1.00 rel. wt) in aqueous
tetrahydrofuran (80:20 THF:Water, 17 vols.) is heated to
63-64.degree. C. and held for at least 30 min until a solution
forms. The solution is clarified while hot and a line wash applied
(80:20 THF:Water, 0.5 vol.). THF (15.5 vols) is added over ca. 1
hour whilst maintaining the temperature at 60-63.degree. C. and the
solution seeded with GW572016F (0.002 rel. wt). The batch is
maintained at 60-63.degree. C. for at least 30 minutes to allow
crystallization to become established. The batch is cooled to ca.
5.degree. C. over ca. 2 hours and the product isolated by
filtration. It is washed twice with aqueous THF (90:10 THF:Water,
2.times.2 vols.) followed once with aqueous THF (19:1 THF:Water,
1.times.2 vols.). The batch is dried under vacuum up to 45.degree.
C. to give
N-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[5-({[2-(methyl-
sulfonyl)ethyl]amino}methyl)-2-furanyl]-4-quinazolinamine
4-methylbenzenesulfonate hydrate as a bright yellow crystalline
solid.
Example 3
Preparation of
N-(3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methane
sulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine Tablets,
250 mg
[0211] Table 4 contains a description of the components used in the
preparation of a granulation mixture and Table 5 contains a
description of the components used in the preparation of a
compression blend for one embodiment of
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolinamine Tablets, 250 mg for a
batch size of 120,000 tablets.
TABLE-US-00006 TABLE 4 Amount Amount Component (mg/tab)*
(kg/batch)** Function Granulation Mixture Active.sup.2 405 48.6
Active Microcrystalline Cellulose 387 46.44 Diluent NF, PhEur, JP
Glidant Povidone USP, PhEur, JP 58.5 7.02 Binder Purified
Water.sup.2 qs qs Granulating liquid Total dry granules 850.5
102.06 .sup.1N-{3-Chloro-4-[(3-fluorobenzyl)
oxy]phenyl}-6-[5-({[2-(methanesulphonyl)
ethyl]amino}methyl)-2-furyl]-4-quinazolinamine. Prepared according
to the procedure of Scheme B. The actual amount of drug substance
may be adjusted based on the purity of the specific lot of drug
substance included in the batch. The amount of diluent
(microcrystalline cellulose) is then adjusted to maintain a core
tablet weight of 900 mg. .sup.2Removed during drying process.
*Based on theoretical drug substance factor of 1.62 = 1.00
**Quantities for a 120,000 tablet granulation.
TABLE-US-00007 TABLE 5 Amount Amount Component (mg/tab) (kg/batch)*
Function Compression Blend Granules.sup.1 850.5 306.18 Active
Granules Sodium Starch Glycolate 40.5 14.58 Disintegrant Magnesium
Stearate 9 3.24 Lubricant Total Weight 900.0 324.0 Coating
Opadry.RTM./Orange YS-1- 27.0 9.72 Film Coat 13065-A Purified
Water.sup.2 qs qs Total Tablet Weight 927.0 333.72 .sup.1Granules
prepared from Granular Mix of Table 4 .sup.2Removed during drying
process *360,000 Tablets
[0212] For this example all ingredients were weighed to amounts
which were consistent with the weight percents recited in Tables 4
and 5.
(i) Formation of Active Granules (Batch Size--120,000 Tablets)
[0213]
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulpho-
nyl)ethyl]amino}methyl)-2-furyl]-4-quinazolin amine ditosylate
monohydrate and microcrystalline cellulose NF, PH. Eur., JP were
added to the bowl of a Glatt WSTCD 160/200 granulator. A 20%
solution of povidone in water was prepared using a Lightnin' mixer
with a suitable tank. The
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)et-
hyl]amino}methyl)-2-furyl]-4-quinazolin amine ditosylate
monohydrate and microcrystalline cellulose were fluidized in the
Glatt WSTCD 160/200 bowl and spraying of the 20% povidone solution
began immediately at approximately 2000 g/minute with an inlet air
temperature of 58.degree. C. The inlet air humidity was maintained
below 10 g/kg. After the povidone solution was applied purified
water was added as needed to obtain a proper granulation wetness.
At the end of granulation the inlet air temperature was raised to
60.degree. C. and drying was continued until an LOD of
approximately 2.5% was reached. The dried active granules were
passed through a Comil Model 196S cone mill fitted with a 0.075
inch round holed screen at approximately 1000 RPM.
[0214] Sieve analysis was performed and tapped density profiles
established. Sieve analysis was performed using a Retsch sieve
shaker, Model AS200 Digit. Approximately 20 g of active dried
granules was placed on the top of a nest of tared sieves of 20, 30,
40, 60, 100, and 200 mesh. Shaking was done for 5 minutes at an
amplitude setting of 60 with the pulse on. This sieve analysis
revealed little batch to batch variation in particle size of the
active granules. The granules were also characterized for Bulk
Density (BD) and Tapped Density (TD). BD and TD of the granules was
measured by adding a weighed amount of granules into a 100 ml
graduated cylinder and measuring the volume initially and after 25,
50, 100, 200, 300, 500, and 1250 taps respectively.
(ii) Tablet Formation
[0215] A compression blend was formed by combining the prepared
active granules and sodium starch glycolate in a bin which was
transferred to a Bin blender where the ingredients were blended for
15 minutes @ 17 RPM. The bin was then removed from the tumble
blender and magnesium stearate added to the blend of active
granules and sodium starch glycolate. The bin was sealed and
transferred back to the tumble blender and blended for 3 minutes @
17 RPM to obtain the compression mix. Tablets were compressed from
the compression blend using a Fette model 2090 rotary tablet press
fitted with 19.05.times.10.41 mm standard concave tooling. The
tablet press was adjusted to provide tablets with the following
specifications.
TABLE-US-00008 Weight of 10 tablets 9.00 g Weight Range of 10
tablets 8.80-9.20 g Individual Tablet Weight 900.0 mg Individual
Weight Range 855.0-945.0 mg Target Average Tablet Hardness 18 kp
Individual Hardness Range 9-27 kp Individual Thickness Range
5.00-8.00 mm Compression Speed Range 40,000-100,000 tpm
[0216] Uncoated tablets were characterized for weight, hardness,
disintegration and dissolution. Tablets were weighed and hardness
determined using, for example, a Dr. Schleuniger.RTM. Pharmatron
Testlink Instrument available from Dr Schleuniger.RTM. Pharmatron
of Solothurn, Switzerland. Disintegration was determined in 900 mL
of water at 37.degree. C. and drug dissolution was evaluated using
a USP Type II apparatus at 55 rpm paddle speed in 900 ml of 0.1 N
HCl containing 2% w/w Tween 80 at 37.degree. C.
[0217] The produced tablets were coated in a GLATT.RTM. 1500 coater
using 12% w/w Orange Opadry.RTM./NS-1-13065-A aqueous suspension at
a pan speed of 5-7 rpm. Five spray nozzles (orifice opening--1.2
mm) were used to deliver coating solution at a total rate of
450-550 g/min. The airflow was maintained at 3800-4200 cmh with the
outlet air temperature ranging from 50 to 70.degree. C. The gun to
bed distance was kept at 18-30 cm. Sufficient film coating was
applied to achieve a 3 percent by weight gain assuming 100% coating
efficiency.
[0218] Coated tablets were characterized for drug dissolution using
a USP Type II apparatus at 55 rpm paddle speed in 900 ml of 0.1N
HCl containing 2% w/w Tween 80 at 37.degree. C.=
Table 6 recites the tablet composition.
TABLE-US-00009 TABLE 6 Amount Reference to Component (mg/tab).sup.2
Standard Function Active.sup.1 405 Active Microcrystalline 387 EP,
JPE, NF Diluent Cellulose Povidone 58.5 EP, JP, USP Binder Purified
Water.sup.3 qs EP, JP, USP Granulating liquid Sodium Starch
Glycolate 40.5 EP, JPE, USP Disintegrant Magnesium Stearate 9.0 EP,
JPE, NF Lubricant Opadry.RTM. YS-1-13065-A 27 N/A Film coat
Purified Water.sup.3 qs EP, JP, USP Film coat solvent Total tablet
weight 927 .sup.1N-{3-Chloro-4-[(3-fluorobenzyl)
oxy]phenyl}-6-[5-({[2-(methanesulphonyl)
ethyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate
monohydrate, equivalent to 250 mg
.sup.1N-{3-Chloro-4-[(3-fluorobenzyl)
oxy]phenyl}-6-[5-({[2-(methanesulphonyl)
ethyl]amino}methyl)-2-furyl]-4-quinazolinamine. .sup.2Theoretical
core tablet weight is 900 mg. .sup.3Removed during drying.
* * * * *