Salts, prodrugs and formulations of 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-D] pyrimidine-5-ca

专利摘要:

公开号:NL2000337A1
申请号:NL2000337
申请日:2006-11-27
公开日:2007-06-12
发明作者:Tracy Lee Boyden；Feng Guo；Susan Deborah Lagreca；Douglas Alan Lorenz；Ravi Mysore Shanker；Franzanne Vreeland
申请人:Pfizer Prod Inc；
IPC主号:

专利说明:

SALTS. PRE-MEDICINAL PRODUCTS AND FORMULATIONS OF 1-Γ5- / 4-AMINO-7-ISOPROPYL-7H-PYRROOLr.3.3-DlPYRIMIDINE-S-CARBONYLV2-
METHOXYPHENYL1-3- (2,4-DICHLORPHENYU-UREA
The present invention relates to new crystalline and non-crystalline forms and formulations of 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl ] -3- (2,4-dichlorophenyl) urea. These forms and formulations are useful in the treatment of hyperprolyferative diseases, such as cancer, in mammals, preferably humans. The present invention also relates to methods for the preparation of these forms and formulations in the treatment of hyperprolyferative diseases in mammals, in particular humans.
1 - [5 - (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea is a kinase inhibitor , more particularly a dual TIE-2 and Trk inhibitor and is described in international patent publication WO 04/056830 published July 8, 2004. 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea is a hydrophobic molecule with extremely low water solubility and low oral bioavailability when dosed in a conventional manner. One aspect of the present invention is the discovery of formulations that permit oral administration such that high bioavailability is achieved. More specifically, one aspect of the invention relates to solid amorphous dispersions, preferably spray-dried dispersions of 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) - 2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea.
Solid amorphous dispersions, including spray-dried dispersions, are known in the art. Curatolo et al., EP 0 901 886 A2 disclose solid pharmaceutical dispersions with improved bioavailability using spray-dried dispersions of a sparingly soluble drug and hydroxypropyl methylcellulose acetate succinate. Nakamichi et al., U.S. Patent No. 5,456,923 describe an extrusion process for producing solid dispersions of sparingly soluble drugs and a variety of polymeric metals, such as hydroxypropyl methylcellulose acetate succinate. Babcock et al., U.S. Patent 2004/0156905, published August 12, 2004, relates to pharmaceutical compositions of a drug in a semi-ordered state. Beyerinck et al., U.S. Patent Publication 2005/0031692, published on February 10, 2005, relates to further embodiments of solid amorphous dispersions including spray-drying processes. Other spray-drying cases include international patent publication 03/063832, which was published on August 7, 2003.
As mentioned above, the active agent is 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4- dichlorophenyl urea, a kinase inhibitor that has a double inhibitory activity against TIE-2 and Trk. Receptor tyrosine kinases are large enzymes present in the cell membrane and an extracellular binding domain for growth factors such as the epidermal growth factor, a transmembrane domain and an intracellular part that possesses as a kinase on a phosphorylate-specific tyrosine residue in proteins and therefore affect cell proliferation. The above tyrosine kinases can be classified as growth factor receptor (e.g., TIE-2, TrkA, EGFR, PDGFR, FGFR, and erbB2) or non-receptor (e.g., c-src and bcr-abl) kinases. It is known that these kinases are often incorrectly expressed in conventional human cancers, such as breast cancer, gastrointestinal cancer, such as colon, rectal, or stomach cancer, leukemia and cancer of the ovaries, bronchi or pancreas. It is believed in the scientific world that inhibitors of receptor tyrosine kinases, such as, for example, the compounds of the present invention, are useful as selective inhibitors of mammalian cancer cell growth.
Tie-2 (TEK) is a member of a family of endothelial cell-specific receptor tyrosine kinases involved in critical angiogenic processes such as vascular branching, sprouting, remodeling, maturation and stability. Tie-2 is the first mammalian receptor tyrosine kinase for which both one or more agonist ligands (e.g., Angiopoietinel ("Angl"), which stimulate receptor autophosphorylation and signal transduction) and one or more antagonist ligands (e.g., Angiopoietin2 ("Ang2")) have been identified. Knockout and transgenic manipulation of the Tie-2 expression and its ligands indicate that close spatial and temporal control of Tie-2 signal delivery is essential for proper development of new vasculature. The current model suggests that stimulation of Tie-2 kinase through the Angl ligand is directly involved in the branching, sprouting and outgrowth of new vessels and the recruitment and interaction of peri-endothelial supporting cells that are important for maintenance maintaining vascular integrity and inducing a latent condition. The absence of Angl stimulation of Tie-2 or the inhibition of Tie-2 autophosphorylation by Ang2 produced in large quantities at vascular regression sites can cause a loss in vascular structure and matrix contacts resulting in endothelial cell death, in the particularly in the absence of growth / survival stimuli.
Trks are transmembrane proteins that contain an extracellular ligand binding domain, a transmembrane sequence and a cytoplasmic tyrosine kinase domain. The Trks include a family of structurally related proteins with preferential binding specificities for individual neurotrophins. TrkA, sometimes referred to as Trk, is a high affinity receptor for NGF, but it can also mediate biological re-punching on NT-3 under certain conditions (Kaplan et al., Science, 252: 554-558, 1991; Klein et al., Cell, 65, 189-197, 1991; Cordon-Cardo et al., Cell, 66: 173-183, 1991). TrkB binds and mediates functions of BDNF, NT-3 and NT4 / 5 (Klein et al., Cell, 66: 395-403, 1991; Squinto et al., Cell, 65: 885-893, 1991; Klein et al. , Neuron, 8: 947-956, 1992). TrkC is relatively specific for NT-3 (Lamballe et al., Cell 66: 967-979, 1991).
The Trk family of receptor tyrosine kinases is often expressed in lung, breast, pancreas and prostate cancer. See, Endocrinol., 141: 118, 2000; Cancer Res., 59: 2395, 1999; Clin. Cancer Res., 5: 2205, 1999; and Oncogene, 19: 3032, 2000. The tyrosine kinase activity of Trk probably promotes the unregulated activation of cell proliferation processes. Recent pre-clinical data suggests that Trk inhibitors suppress the growth of breast, pancreatic, and prostate tumor xeno implants. Furthermore, it is thought that Trk inhibition can be tolerated in cancer patients. Furthermore, it is believed by those skilled in the art that inhibitors of either TrkA or TrkB kinases are useful against some of the most common cancers, such as brain, melanoma, squamous cell, bladder, stomach, pancreas, breast , head, neck, esophagus, prostate, colorectal, lung, kidney, renal, fallopian tube, gynecological and tyroid cancer. Additional therapeutic uses of Trk inhibitors are thought to include pain, neuropathy and obesity.
The present invention relates to novel crystalline and non-crystalline forms and formulations of 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl ] -3- (2,4-dichlorophenyl) * urea. 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea has the formula
One specific preferred embodiment of the present invention relates to pharmaceutical compositions comprising a solid amorphous dispersion (more preferably a spray-dried dispersion, SDD) of a form of 1- [5- (4-amino-7-isopropyl-7H-) pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea and a concentration-promoting polymer.
As used herein, the terms "crystalline and non-crystalline forms", "forms" or a reference to the compound per se (unless otherwise specified) include an acceptable crystalline and non-crystalline free base, solvate, hydrate, isomorphic , polymorph, salt or precursor of 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4- dichlorophenyl) urea. The most preferred form of 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea for formulation in the solid amorphous dispersions, more preferably the SDD, is the free base.
The term "pharmaceutically acceptable salt (s)", as used herein, unless otherwise indicated, includes acid salts of 1- [5- (4-amino-7-isopropyl-7H-pyrrole [2,3-d ] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichloro-phenyl) -urea. 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea is capable of to form a wide variety of salts with various inorganic and organic acids. The acids that can be used to prepare pharmaceutically acceptable acid addition salts of 1 - [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] - 3- (2,4-dichlorophenyl) urea are those that form non-toxic acid addition salts, or salts that form pharmacologically acceptable anions such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate , salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenate or p-toluenate r-methylene bis (2-hydroxy-3-naphthoate)] salts.
1- [5- (4-amino-7-isopropyl-7 H -pyridol [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea can also be used as tautomers exist. The invention relates to the use of all these tautomers and mixtures thereof.
The present invention also encompasses pharmaceutical compositions containing them and methods for the treatment of proliferative disorders or abnormal cell growth by administering prodrugs of 1- [5- (4-amino-7-isopropyl-7H-pynOol [2,3-d ] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichloro-phenyl) -urea. Precursors include compounds in which an amino acid residue or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues are covalently linked via an amide or ester bond with a free amino, hydroxy or carboxylic acid group of 1 - [5- (4-amino) -7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea. The amino acid residues include, but are not limited to, the 20 naturally occurring amino acids commonly indicated by three letter symbols and also include 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, beta-alanine, gamma-amino butyric acid , citruline, homocysteine, homoserine, ornithine and methionine sulfone. Additional types of precursors are also included. For example, free carboxyl groups can be derivatized as amides or as alkyl esters. Free hydroxy groups can be derivatized using groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates and phosphoryloxymethyloxycarbonyls, as described in Advanced Drug Delivery Reviews, 1996, 19, 115. Carbamate precursors of hydroxy and amino groups are also included and also carbonate precursors, sulfonate esters and sulfate esters of hydroxy groups. Derivatization of hydroxy groups such as (acyloxy) methyl and (acyloxy) ethyl ethers where the acyl group can be an alkyl ester, optionally substituted with groups including but not limited to ether, amine and carboxylic acid functionalities or where the acyl group is an amino acid ester as described above. also included. Precursors of this type are in J. Med. Chem., 1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides and phosphonamides. All of these precursors may contain groups that include, but are not limited to, ether, amide, and carboxylic acid functionalities.
The term active agent or "inhibitor" as used herein refers to one or more of the aforementioned forms of 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d ] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea which are pharmaceutically acceptable.
Another specifically preferred embodiment of the invention relates to a pharmaceutical composition comprising a solid amorphous dispersion of 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl). -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea and a concentration-increasing polymer, said active agent comprising between 10 and 40% by weight of said solid amorphous dispersion, more preferably 15 to 30%, most preferably comprises 25%.
Another embodiment of the present invention is directed to a solid amorphous dispersion, more preferably SDD, compositions wherein the concentration promoting polymer has at least one hydrophobic moiety and at least one hydrophilic moiety.
Another embodiment of the present invention is directed to a solid amorphous dispersion, more preferably SDD, compositions wherein the concentration-increasing polymer is a cellulosic polymer, more preferably a cellulosic polymer selected from the group consisting of ionizable, cellulose polymers, non-ionizable cellulose polymers and vinyl polymers and copolymers with substituents selected from the group consisting of hydroxyl, alkylacyloxy and cyclicamido.
More specific embodiments of the present invention relate to compositions wherein the concentration-increasing polymer is a cellulosic polymer, more preferably a cellulosic polymer selected from the group consisting of hydroxypropyl methylcellulose acetate, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxyethylmethylcellulose, hydroxyethylcellulose acetate, hydroxyethylethylcellulose cellulose hydroxycellulose cellulose hydroxyate cellulose cellulose acetate , cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, methyl / cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl cellulose acetate phthalate, cellulose acetate terephthalate, cellulose acetate isophthalate and carboxymethylethyl cellulose.
A more specific embodiment of the invention is directed to solid amorphous dispersions comprising the concentration-increasing polymer carboxymethyl ethyl cellulose. Another embodiment of the invention is directed to the concentration-increasing polymer polyoxyethylene-polyoxypropylene copolymer.
One specifically preferred embodiment of the solid amorphous dispersion of the invention is directed to the concentration-increasing polymer hydroxypropyl methylcellulose acetate succinate (HPMCAS). An even more preferred embodiment of the solid amorphous dispersions of the invention is directed to the concentration-increasing polymer hydroxypropyl methylcellulose acetate succinate (HPMCAS) wherein the quality of succinate used is highly granular. Other preferred embodiments include the very fine analytical quality of succinate (HPMCAS-HF).
Even more preferred embodiments of the solid amorphous dispersions with the concentration-increasing polymer hydroxypropyl methylcellulose acetate succinate (HPMCAS), more preferably SDD, include those solid amorphous dispersions wherein the active agent is 10 to 40% by weight, more preferably 15 to 30% by weight , even more preferably 25% by weight of the total solid amorphous dispersion, more preferably SDD, formulation.
Preferred embodiments of the solid amorphous dispersions with the concentration-increasing polymer hydroxypropyl methylcellulose acetate succinate (HPMCAS), more preferably SDD, include those solid amorphous dispersions wherein said 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2, 3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea in the dispersion is substantially amorphous and said dispersion is substantially homogeneous.
Preferred embodiments of the solid amorphous dispersions with the concentration-increasing polymer hydroxypropyl methylcellulose acetate succinate (HPMCAS), more preferably SDD, include those solid amorphous dispersions wherein said dispersion has a single glass transition temperature. Preferably wherein the transition temperature is from 110 to 120 ° C, more preferably 116 ° C.
Even more preferred embodiments include pharmaceutical compositions of the solid amorphous dispersions with the concentration-increasing polymer hydroxypropyl methyl cellulose acetate succinate (HPMCAS), more preferably those solid amorphous dispersions wherein the active agent comprises 25 wt% of the total solid amorphous dispersion formulation, and more preferably the composition weighing no more than 1 gram per unit dose. Other most preferred embodiments of the aforementioned pharmaceutical compositions of the solid amorphous dispersions with the concentration-increasing polymer hydroxypropyl methylcellulose acetate succinate (HPMCAS) solid amorphous dispersions include those in which the active agent weighs 5, 25, 50, 100, 250 or 500 mg per unit dose.
Another specifically preferred embodiment is directed to a concentration-increasing polymeric composition wherein said pharmaceutical composition has a solid amorphous dispersion of 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5 -carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea and a concentration-promoting polymer, the concentration-increasing polymer being present in the solid amorphous dispersion in an amount sufficient to allow the composition to promote concentration provided from the aforementioned 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea in an application environment as compared to a control composition consisting essentially of an equivalent amount of the 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl ] -3- (2,4-dichlorophenyl) urea alone, more preferably wherein the concentration-promoting polymer is hydroxypropyl methylcellulose is acetate acetate succinate.
As used herein, an "application environment" may be the in vivo environment of the gastrointestinal tract or blood plasma of a mammal, in particular a human, or the in vitro environment of a test solution such as, for example, phosphate buffered saline (PBS) or the so-called Model Fasted Duodenal (MFD) solution.
The compositions of the present invention improve the aqueous concentration of 1 - [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- ( 2,4-dichlorophenyl) urea compared to compositions that are free of concentration-increasing polymer, by providing an aqueous
Cmax concentration of 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea to at least about 10 times that of control compositions that are free of the concentration-enhancing polymer. In fact, compositions of the present invention often exhibit a 5 to 500-fold improvement, more preferably a 15 to 100-fold, more preferably, a 20 to 50-fold improvement in concentration compared to that of a control crystalline composition. More preferably, the aforementioned Cmax improvement is determined by a PBS or MFD solution test.
The compositions of the present invention improve the aqueous concentration of 1 - [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- ( 2,4-dichlorophenyl) urea compared to compositions that are free of the concentration-increasing polymer by providing an aqueous Cmax concentration of 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2, 3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea of between 10 and 500 pg / ml, more preferably between 50 and 100 pg / ml. More preferably, said Cmax increase is determined by a PBS or MFD solution test. Most preferably, the increased Cmax is determined according to the MFD dissolution test performed on a saturated solution.
In another embodiment of the invention, the composition in the application environment provides an area below the concentration versus time curve for each period of at least 90 minutes between the introduction time in the application environment and about 270 minutes after the introduction to the application environment, that is at least least 10-fold, more preferably 50-fold that of the control composition. More preferably, said AUC90 enhancement is determined by a PBS or MFD solution test.
In another embodiment of the invention, the composition in the application environment provides an area below the concentration versus time curve for a period of at least 90 minutes between the introduction time in the application environment and about 270 minutes after the introduction to the application environment that is between 500 and 10,000 pg x min / ml, more preferably between 1000 and 7000 pg x min / ml. More preferably, the aforementioned AUC90 increase is determined by means of
iU
of a PBS or MFD dissolution test. Most preferably, the Cmax increase is determined according to the MFD dissolution test on a saturated solution.
Another specific preferred embodiment of the invention is directed to a concentration-increasing polymeric composition wherein the composition, when administered at least once during a 24 hour period in an oral dosage form of between 5 mg and 500 mg, more preferably 50, 100 or 200 mg of active agent to a human, has a Cmax plasma level as determined in a fasted rat at a dose of 100 mg of active agent per kg, between 20,000 nanograms base / ml to 1000 nanograms base / ml, more preferably 15,000 nanogram base / ml and 3000 nanogram base / ml, more preferably 10,000 nanogram base / ml and 5000 nanogram base / ml over the aforementioned 24-hour period.
The concentration-increasing polymer-containing composition as used herein refers to a pharmaceutical composition comprising a concentration-increasing polymer and an active agent and optionally additional pharmaceutically acceptable excipients.
Another specific preferred embodiment of the present invention is directed to a concentration-increasing polymeric composition wherein the composition, when administered, at least once during a 24-hour period in an oral dosage form of between 5 and 500 mg, more preferably 50, 100 or 200 mg of active agent to a human has a Cm8x plasma level as determined in a fasted dog at a dose of 30 mg of active agent per kg, between 15,000 nanograms base / ml to 1000 nanograms base / ml, more preferably 10,000 nanograms base / ml and 1000 nanograms base / ml, more preferably 5000 nanograms base / ml and 1110 nanograms base / ml over the aforementioned 24-hour period.
Another specific preferred embodiment of the invention is directed to a concentration-increasing polymer-containing composition wherein said composition when administered at least once during a 24-hour period in an oral dosage form of between 5 mg and 500 mg, more preferably 50, 100 or 200 mg of active agent to a human, an AUCo-24 plasma level as determined in a fast dog at a dose of 30 mg of active agent per kg, between 100,000 nanograms base x hour / ml and 8000 nanograms base x hour / ml , more preferably between 80,000 nanograms base x hour / ml and 10,000 nanograms base x hour / ml, more preferably between 50,000 nanograms base x hour / ml and 10,000 nanograms base x hour / ml.
Another specific preferred embodiment of the invention is directed to a concentration-increasing polymer-containing composition, wherein the composition when administered at least once during a 24-hour period in an oral dosage form of between 5 and 500 mg, more preferably 50, 100 or 200 mg of active agent to a human a Tmax plasma level as determined in a fasted rat at a dose of 100 mg of active agent per kg, between 3 hours and 30 minutes, more preferably between 2.5 hours and 1 hour, more preferably less than 2 hours.
Another specific preferred embodiment of the invention is directed to a concentration-increasing polymer-containing composition wherein the composition, when administered at least once during a 24-hour period in an oral dosage form of between 5 and 500 mg, more preferably 50 , 100 or 200 mg of active agent to a human has a Tmax plasma level as determined in a fast dog at a dose of 30 mg of active agent per kg, between 3 hours and 30 minutes, more preferably between 2.5 hours and 1 hour, more preferably less than 2 hours.
In another embodiment of the invention, the solid amorphous dispersion is mixed with an additional concentration-increasing polymer.
In another embodiment of the invention, the concentration-increasing polymer comprises a mixture of polymers.
In another embodiment of the invention, the concentration-increasing polymer has at least one hydrophobic portion and at least one hydrophilic portion.
In another embodiment of the invention, the concentration-increasing polymer is selected from the group consisting of ionizable cellulose polymers, non-ionizable cellulose polymers and vinyl copolymers and copolymers with substituents selected from the group consisting of hydroxyl, alkylacyloxy and cyclicamido.
In another embodiment of the invention, the concentration-enhancing polymer is selected from the group consisting of hydroxypropylmethylcelluloseacetaat, hydroxypropyl methylcellulose, hydroxypropyl-12 cellulose, methyl cellulose, hydroxyethylmethylcellulose, hydroxyethylcelluloseacetaat, hydroxyethyl ethylcellulose, hydroxypropyl methylcellulose acetate succinate, cellulose-acetaatflalaat, hydroxypropylmethylcellulose phthalate, methylcelluloseacetaatftalaat, cellulose acetate trimellitate, hydroxypropylcelluloseacetaatflalaat, cellulose acetate terephthalate, cellulose acetate isophthalate and carboxymethyl ethyl cellulose.
In another embodiment of the invention, the solid amorphous dispersion is formulated in a tablet.
In another embodiment of the invention, the solid amorphous dispersion comprises a disintegrant such as sodium starch glycolate, sodium alginate, carboxymethylcellulose sodium, methylcellulose, and croscarmellose sodium.
In another embodiment of the invention, the solid amorphous dispersion comprises a binder such as methyl cellulose, microcrystalline cellulose, starch and gums such as guar gum and tragacanth.
In another embodiment of the invention, the solid amorphous dispersion comprises a lubricant such as magnesium stearate and calcium stearate.
In another embodiment of the invention, the solid amorphous dispersion is formulated in a capsule.
Another specific embodiment of the present invention relates to a method for forming the solid amorphous dispersion by solvent processing. According to this embodiment, a solution is prepared which comprises the active agent and a concentration-increasing polymer dissolved in a common solvent. The solvent is then rapidly removed from the solution to form a solid amorphous dispersion of the active agent and the concentration-increasing polymer.
Another embodiment of the present invention is directed to a method for preparing pharmaceutical compositions by melt extrusion. The active agent and a concentration-increasing polymer are fed to an extruder. The active agent and polymer are extruded through the extruder and are rapidly solidified to form a solid amorphous dispersion comprising the active agent and the concentration-increasing polymer.
Another embodiment of the present invention is directed to a process for preparing pharmaceutical compositions by melt coagulation.
A molten mixture comprising the active agent and a concentration-increasing polymer is formed. The mixture is then cooled to form a solid amorphous dispersion comprising the active agent and the concentration-increasing polymer.
Other embodiments of the present invention relate to salts and polymorphs of the 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] - 3- (2,4-dichlorophenyl) urea.
Specific embodiments include the phosphate, mesylate, besylate, tosylate and hydrogen chloride salts of 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] - 3- (2,4-dichlorophenyl) urea.
Still other embodiments of the present invention relate to pharmaceutical compositions of the salts and polymorphs of 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2 -methoxyphenyl] -3- (2,4-dichlorophenyl) urea.
Still other embodiments of the present invention relate to capsules or tablets comprising pharmaceutically acceptable compositions of these forms and spray-dried dispersions. The compositions can be dosed in a variety of dosage units, including both immediate release and controlled release dosage units, the latter including both delayed and sustained release tablets or capsules. The composition may comprise blends of polymers and may further comprise other excipients which can be used for the bioavailability of 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2 -methoxyphenyl] -3- (2,4-dichlorophenyl) urea.
The present invention also relates to a method for the treatment of abnormal cell growth in a mammal including human, which comprises administering to the mammal in need of such treatment an amount of a salt, polymorph or spray-dried dispersion of 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea which is active in the treatment of abnormal cell growth.
The present invention also relates to a method for administering the compositions described above.
The term "abnormal cell growth," as used herein, means, unless otherwise indicated, cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibitor). This includes the abnormal growth of: (1) tumor cells (tumors) that proliferate by expressing a mutated tyrosine kinase or an overexpression of a tyrosine kinase receptor; (2) benign and malignant cells from other proliferative diseases in which abnormal tyrosine kinase activation occurs; and (4) one or more tumors that proliferate through receptor tyrosine kinases.
The term "treatment", as used herein, means, unless otherwise indicated, reversing, alleviating, inhibiting the progression or prevention of the condition or disease to which such a term applies, or one or more symptoms of this disease or condition. The term "treatment," as used herein, means, unless otherwise indicated, the act of treating as defined immediately above.
In one embodiment of the method, abnormal cell growth is cancer, including but not limited to mesothelioma, hepatobilliary cancers (hepatic and bile duct), a primary or secondary central nervous system tumor, a primary or secondary brain tumor (including tumors of the pituitary gland, astrocytomas, meningiomas, and medulloblastomas), lung cancer (NSCLC and SCLC), bone cancer, pancreatic cancer, skin cancer, cancer of the head and neck, cutaneous or intraocular melanoma, fallopian cancer, colon cancer, rectal cancer, liver cancer, cancer of the anal area, gastric cancer, gastrointestinal (stomach, colorectal and duodenal), breast cancer, uterine cancer, carcinomas of the fallopian tubes, carcinomas of the endometrium, carcinomas of the cervix, carcinomas of the vagina, carcinomas of the vulva, Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland kidney, soft tissue sarcomas, gastrointestinal stromal tumor (GIST), pancreatic endocrine tumors (such as feochromocytoma, insulinoma, vasoactive intestinal peptide tumor, island cell tumor and glucagonoma), carcinoid tumors, urethra cancer, penis cancer, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocitic lymphomas, bladder cancer, kidney or ureter cancer, renal cell carcinomas, renal pelvis carcinomas, central nervous system neoplasm, primary central nervous system lymphoma, non-Hodgkins lymphoma , spinal astumors, brainstem glioma, pituitary adenomas, adrenocortical cancer, gall bladder cancer, mutiple myeloma, cholangiocarcinomas, fibrosarcomas, neuroblastomas, retinoblastomas, tumors of the blood vessels (including malignant and benign tumors such as hemangiomas, hemangi sarcoma, hemangi sarcoma and hemangi capillary sombia) one or more of the aforementioned cancers.
Another more specific embodiment of the present invention is directed to a cancer selected from lung cancer (NSCLC and SCLC), cancer of the head or neck, ovarian cancer, colon cancer, rectal cancer, cancer of the anal area, stomach cancer, breast cancer, cancer of the kidney or ureter, renal cell carcinomas, renal pelvis carcinomas, central nervous system neoplasm, primary central nervous system lymphomas, non-Hodgkins lymphomas, spinal astumors or a combination of one or more of the aforementioned cancers.
In another more specific embodiment of the present invention, the cancer is selected from lung cancer (NSCLC and SCLC), breast cancer, ovarian cancer, colon cancer, rectal cancer, cancer of the anal area or a combination of one or more of the aforementioned cancers.
In another embodiment of the present invention, said abnormal cell growth is benign proliferative disease, including, but not limited to, psoriasis, benign prostatic hypertrophy, restinosis, synovial proliferation disorder, retinopathy or other neovascular disorders of the eye, pulmonary hypertension, or mobilization of TIE -2 positive stem cells from bone marrow for use in reconstituting normal cells of each tissue.
The invention also relates to a method for the treatment of abnormal cell growth in a mammal in need of such treatment, which comprises administering to the mammal an amount of 1- [5- (4-amino-7-isopropyl-7H)] -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea (including any of the aforementioned forms and formulations including any of the aforementioned hydrates, solvates and polymorphs or pharmaceutically acceptable salts thereof), in combination with one or more (preferably one to three) anticancer agents selected from the group consisting of traditional anticancer agents (such as, for example, DNA binding agents, mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, topoisomerase inhibitors and microtubulin inhibitors), statins, radiation, angiogenesis inhibitors, signal transduction inhibitors, cell cycle inhibitors, telomerase inhibitors, biological response mo agents (such as antibodies, immunotherapy and peptide mimics), anti-hormones, anti-androgens, gene inhibiting agents, gene activating agents and antivascular agents in which the amounts of 1 - [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine -5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea together with the amounts of the anti-cancer agent combination is effective in the treatment of abnormal cell growth.
The present invention also relates to a method for the treatment of a hyperproliferative disorder in a mammal in need of such treatment, which comprises administering to said mammal an amount of 1- [5- (4-amino-7-isopropyl)] -7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea (including all forms and formulations thereof and any of the above hydrates, solvates and polyforms thereof or pharmaceutically acceptable salts thereof), in combination with an anticancer agent selected from the group consisting of traditional anticancer agents (such as DNA binding agents, mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, topoisomerase inhibitors and microtubulin inhibitors), statins, radiation, angiogenesis inhibitors , signal transduction inhibitors, cell cycle inhibitors, telomerase inhibitors, biological response modifiers (such as antibodies immunotherapy and peptide mimetics), hormones, anti-hormones, anti-androgens, gene inhibiting agents, gene activating agents and antivascular agents where the amounts of 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine- 5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea together with the amounts of the anti-cancer agent combination is effective in the treatment of the aforementioned hyperproliferative disorder.
The present invention also relates to a pharmaceutical composition for the treatment of abnormal cell growth in a mammal, including human, which contains an amount of 1- [5- (4-amino-7-isopropyl-7H-pyrrole [2,3-) d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea, as defined above, includes (including hydrates, solvates and polymorphs of said compound or pharmaceutically acceptable salts thereof), which are active is in the treatment of abnormal cell growth, and a pharmaceutically acceptable carrier. In one embodiment of this composition, abnormal cell growth is cancer, including, but not limited to, mesothelioma, hepatobilliary cancer (hepatic and glass bladder), a primary and secondary central nervous system tumor, a primary or secondary brain tumor (including pituitary tumors, astrocytomas, meningiomas, and medulloblastomas ), lung cancer (NSCLC and SCLC), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, liver cancer, cancer of the anal area, stomach cancer, gastrointestinal cancer (of the stomach , colorectal and duodenal), breast cancer, uterine cancer, carcinomas of the fallopian tubes, carcinomas of the endometrium, carcinomas of the cervix, carcinomas of the vagina, carcinomas of the vulva, Hodgkin's disease, cancer of the esophagus, cancer of the small intestine , cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the ad renal gland, soft tissue sarcomas, gastrointestinal stromal tumor (GIST), pancreatic endocrine tumors (such as feochromocytoma, insulinoma, vasoactive intestinal peptide tumor, island cell tumor and glucagonoma), carcinoid tumors, urethra cancer, penis cancer, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocitic lymphomas, bladder cancer, kidney or ureteral cancer, renal cell carcinomas, renal pelvis carcinomas, central nervous system neoplasm, primary central nervous system lymphomas, non-Hodgkins lymphomas, spinal astumors, brainstem gliomas, pituitary adenomas, adrenocortical cancer, gall bladder cancer, mutiple myelomas, cholangiocarcinomas, fibrosarcomas, neuroblastomas, retinoblastomas, tumors of the blood vessels (including malignant and benign tumors such as hemangiomas, hemangiosi capang hemangi hemangi hemangi hemangi hemangi. combination of one or more of the aforementioned cancers.
The invention also relates to a pharmaceutical composition for the treatment of abnormal cell growth in a mammal, including humans, which contains an amount of 1- [5- (4-amino-7'-isopropyl-7 H -pyrrole [2,3-d]) pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea, as defined above (including hydrates, solvates and polymorphs of said compound or pharmaceutically acceptable salts thereof), in combination with one or more (preferably one to three) anticancer agents selected from the group consisting of traditional anticancer agents (such as DNA binding agents, mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, topoisomerase inhibitors and microtubulin inhibitors), statins, radiation, angiogenesis inhibitors, signal transduction inhibitors, cell cycle inhibitors , telomerase inhibitors, biological response modifiers, hormones, anti-hormones, anti-androgens, gene inhibitors, gene activating agents and n comprises antivascular agents and a pharmaceutically acceptable carrier, wherein the amounts of the active agent and the combination of anti-cancer agents when taken as a whole is therapeutically effective for the treatment of said abnormal cell growth.
In one embodiment of the present invention, the anticancer agent used in conjunction with 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea and pharmaceutical compositions described herein are an anti-angiogenesis agent.
A more specific embodiment of the present invention includes combinations of 1 - [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- ( 2,4-dichlorophenyl) urea with anti-angiogenesis agents selected from VEGF inhibitors, VEGFR inhibitors, TIE-2 inhibitors, PDGFR inhibitors, angiopoietin inhibitors, ΡΚ £ β inhibitors, COX-2 (cyclooxygenase II) inhibitors, integrins (alpha v / beta-3), MMP-2 (matrix metalloproteinase 2) inhibitors and MMP-9 (matrix metalloproteinase 9) inhibitors.
Preferred VEGF inhibitors include, for example, Avastine (bevacizumab), an anti-VEGF monoclonal antibody from Genentech, Ine. or South San Francisco, California.
Additional VEGF inhibitors include CP-547,632 (Pfizer Inc., NY, USA), AG 13736 (Pfizer Inc.), Vandetanib (Zactima), sorafenib (Bayer / Onyx), AEE788 (Novartis), AZD-2171, VEGF Trap (Regeneron / Aventis), vatalanib (also known as PTK-787, ZK-222584: Novartis & Schering AG, as described in U.S. Patent 6,258,812), Macugen (pegaptanib octan sodium, NX-1838, EYE-001, Pfizer Inc./Gilead / Eyetech), IM862 (Cytran Inc, or Kirkland, Washington, USA);
Neovastat (Aetema); and Angiozyme (a synthetic ribozyme that cleaves mRNA to produce VEGF1) and combinations thereof. VEGF inhibitors that are useful in the practice of the present invention are described in U.S. Patent Nos. 6,534,524 and 6,235,764, both of which are incorporated by reference in their entirety.
Particularly preferred VEGF inhibitors include CP-547,632, AG-13736, AG-28262, Vatalanib, sorafenib, Macugen, and combinations thereof.
Additional VEGF inhibitors are, for example, in U.S. Patent 6,492,383, issued December 10, 2002, U.S. Patent 6,235,764, issued May 22, 2001, U.S. Patent 6,177,401, issued January 23, 2001, U.S. Patent 6,395,734, issued on May 28, 2002, U.S. Patent 6,534,524 (describes AG13736), issued March 18, 2003, U.S. Patent 5,834,504, issued November 10, 1998, U.S. Patent 6,316,429, issued November 13, 2001, U.S. Patent 5,883,113, issued March 16, 1999, U.S. Patent No. 5,886,020, issued March 23, 1999, U.S. Patent No. 5,792,783, issued August 11, 1998, U.S. Patent No. 6,653,308, issued November 25, 2003, WO 99/10349 (published on 4 March 1999), WO 97/32856 (published on September 12, 1997), WO 97/22596 (published on June 26, 1997), WO 98/54093 (published on December 3, 1998), WO 98/02438 (published on January 22, 1998), WO 99/16755 (published on April 8, 1999) and WO 98/02437 (published on January 22, 1998), all of which are incorporated by reference in their entirety.
PDGFr inhibitors include, but are not limited to, those described in international patent publication number WO 01/40217, published on June 7, 2001 and international patent publication number WO 2004/020431, published on March 11, 2004, the contents of which are entirely for all purposes is recording.
Preferred PDGFr inhibitors include Pfizer's CP-673.451 and CP-868.596 and their pharmaceutically acceptable salts.
TIE-2 inhibitors include GlaxoSmithKline's benzimidazoles and pyridines including GW-697465A, as described in international patent publications WO 02/044156, published June 6, 2002, WO 03/066601, published August 14, 2003, WO 03/074515 published on September 12, 2003, WO
03/022852, published March 20, 2003 and WO 01/37835, published May 31, 2001. Other TIE-2 inhibitors include Regeneron's biological agents, such as those described in international patent publication WO 09/611269, published April 18, 1996, Amgen's AMG 388 and Abbott's pyrrolopyrimidines, such as A-422885 and BSF-466895, described in international patent publications WO 09/955335, WO 09/917770, WO 00/075139, WO 00/027822, WO 00/017203 and WO 00/017202.
In another more specific embodiment of the present invention, the anticancer agent is used in conjunction with 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl. ] -3- (2,4-dichlorophenyl) urea and pharmaceutical compositions described herein where the anti-angiogenetic agent is a protein kinase Cβ, such as enzastaurin, midostaurin, perifosine, staurosporin derivative (such as R0318425, R0317549, R0318830 or R0318220 (Roche)), teprenone (Selbex) and UCN-01 (Kyowa Hakko).
Examples of suitable COX-II inhibitors that can be used together with 1 - [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3 - (2,4-dichlorophenyl) urea and pharmaceutical compositions described therein include CELEBREX (celecoxib), parecoxib, deracoxib, ABT-963, COX-189 (Lumiracoxib), BMS 347070, RS 57067, NS-398, Bextra ( valdecoxib), Vioxx (rofecoxib), SD-8381, 4-methyl-2- (3,4-dimethylphenyl) -1- (4-sulfamoylphenyl) -1H-pyrrole, 2- (4-ethoxyphenyl) -4-methyl- 1- (4-sulfamoylphenyl) -1H-pyrrole, T-614, JTE-522, S-2474, SVT-2016, CT-3, SC-58125 and Arcoxia (etoricoxib). Additional COX-II inhibitors are described in U.S. Pat. Nos. 10 / 801,446 and 10 / 801,429, the contents of which are incorporated in their entirety for all purposes.
In one specific embodiment of particular interest, the anti-tumor agent is celecoxib, as described in U.S. Patent No. 5,466,823, the contents of which are incorporated herein in their entirety by reference for all purposes.
In another embodiment, the anti-tumor agent is deracoxib as described in U.S. Patent No. 5,521,207, the contents of which are incorporated herein by reference in their entirety for all purposes.
Other useful anti-angiogenic inhibitors used together with 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- ( 2,4-dichlorophenyl) urea and pharmaceutical compositions described herein include aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) that do not selectively inhibit the enzymes that make prostaglandins (cyclooxygenase I and II), resulting in lower levels of prostaglandins . Such agents include, but are not limited to, Aposyn (exisulind), Salsalate (Amigesic), Diflunisal (Dolobid), Ibuprofen (Motrin), Ketoprofen (Orudis), Nabumetone (Relafen), Piroxicam (Feldene), Naproxen (Aleve, Naprosyn) , Diclofenac (Voltaren), Indomethacin (Indocin), Sulindac (Clinoril), Tolmetin (Tolectin), Etodolac (Lodine), Ketorolac (Toradol), Oxaprozin (Daypro) and combinations thereof.
Preferred non-selective cyclooxygenase inhibitors include ibuprofen (Motrin), nuprin, naproxen (Aleve), indomethacin (Indocin), nabumetone (Relafen) and combinations thereof.
MMP inhibitors include ABT-510 (Abbott), ABT 518 (Abbott), Apratastat (Amgen), AZD 8955 (AstraZeneca), Neovostat (AE-941), COL 3 (CollaGenex Pharmaceuticals), doxycycline hyclate, MPC 2130 (Myriad) and PCK 3145 (Procyon).
Other anti-angiogenic compounds include acitretin, agiostatin, aplidine, cilengtide, COL-3, combretastatin A-4, endostatin, fenretinide, halofuginone, Panzem (2-methoxyestradiol), PF03446962 (ALK-1 inhibitor), rebimastat, removab, Revlimid, squalamine, thalidomide, ukrain, Vitaxin (alpha-v / beta-3 integrin) and zoledronic acid.
In another embodiment, the anti-cancer agent is a so-called signal transduction inhibitor. Such inhibitors include small molecules, antibodies, and antisense molecules. Signal transduction inhibitors include kinase inhibitors, such as tyrosine kinase inhibitors, serine / threonine kinase inhibitors. Such inhibitors can be antibodies or inhibitors with small molecules. More specific signal transduction inhibitors include famesyl protein transferase inhibitors, EGF inhibitor, ErbB-1 (EGFR), ErbB-2, pan erb, IGR1R inhibitors, MEK, c-Kit inhibitors, FLT-3 inhibitors, K-Ras inhibitors, PI3 kinase inhibitors, JAK inhibitors, STAT inhibitors, Raf kinase inhibitors, Akt inhibitors, mTOR inhibitor, P70S6 kinase inhibitors and WNT pathway inhibitors and so-called multi-targeted kinase inhibitors.
In another embodiment, the anti-cancer signal transduction inhibitor is a famesyl protein transferase inhibitor. Famesyl protein transferase inhibitors include the compound described and claimed in U.S. Patent No. 6,194,438, issued February 27, 2002; U.S. Patent 6,258,824, issued July 10, 2001; U.S. Patent 6,586,447, issued July 1, 2003; U.S. Patent No. 6,071,935, issued June 6, 2000; and U.S. Patent 6,150,377, issued November 21, 2000. Other famesyl protein transferase inhibitors include AZD-3409 (AstraZeneca), BMS-214662 (Bristol-Myers Squibb), Lonafamib (Sarasar) and RPR-115135 (Sanofi-Aventis). Each of the aforementioned patent applications and provisional patent applications is incorporated herein by reference in its entirety.
In another embodiment, the anti-cancer signal transduction inhibitor is a GARF inhibitor. Preferred GARF inhibitors (glycinamide ribonucleotide formyl transferase inhibitors) include Pfizer's AG-2037 (pelitrexol) and its pharmaceutically acceptable salts. GARF inhibitors useful in the practice of the present invention are described in U.S. Patent No. 5,608,082, which is incorporated in its entirety for all purposes.
In another embodiment, the anti-cancer signal transduction inhibitor used together with 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3 - (2,4-dichlorophenyl) urea and pharmaceutical compositions described herein ErbB-1 (EGFr) inhibitors such as Iressa (gefitinib, Astra Zeneca), Tarceva (erlotinib or OSI-774, OSI Pharmaceuticals Inc.), Erbitux ( cetuximab, Imblone Pharmaceuticals, Inc.), Matuzumab (Merck AG), Nimotuzumab, Panitumumab (Abgenix / Amgen), Vandetanib, hR3 (York Medical and Center for Molecular Immunology), TP-38 (IVAX), EGFR fusion protein, EGF vaccine , anti-EGFr immunoliposomes (Hermes Biosciences Inc.) and combinations thereof.
Preferred EGFr inhibitors include Iressa (gefitinib), Erbitux, Tarceva and combinations thereof.
In another embodiment, the anti-cancer signal transduction inhibitor is selected from pan erb receptor inhibitors of ErbB2 receptor inhibitors, such as CP-724.714, PF-299804, CI-1033 (canertinib, Pfizer, Ine.), Herceptin (trastuzumab, Genentech Inc.), Omnitarg (2C4, pertuzumab, Genentech Inc.), TAK-165 (Takeda), W-572016 (lapatinib, GlaxoSmithKline), Pelitinib (EKB-569 Wyeth), BMS-599626, PKI-166 (Novartis), dHER2 (HER2 Vaccine) , Corixa and GlaxoSmithKline), Osidem (IDM-1), APC8024 (HER2 Vaccine, Dendreon), anti-HER2 / neu bi-specific antibody (Decof Cancer Center), B7.her2.IgG3 (Agensys), AS HER2 (Research Institute for Rad Biology & Medicine), trifunctional bispecific antibodies (University of Munich) and mAB AR-209 (Aronex Pharmaceuticals Inc.) and mAB 2B-1 (Chiron) and combinations thereof.
Preferred selective anti-tumor agents include Herceptin, TAK-165, CP-724.714, ABX-EGF, HER3 and combinations thereof.
Preferred pan erb receptor inhibitors include GW572016, PF-299804, Pelitinib and Omnitarg and combinations thereof.
Additional erbB2 inhibitors include those described in WO 98/02434 (published January 22, 1998), WO 99/35146 (published July 15, 1999), WO 99/35132 (published July 15, 1999), WO 98/02437 (published on January 22, 1998), WO 97/13760 (published April 17, 1997), WO 95/19970 (published July 27, 1995), U.S. Patent No. 5,587,458 (issued December 24, 1996) and U.S. Patent No. 5,877,305 (issued on March 2, 1999), each of these patents is incorporated by reference in its entirety. ErbB2 receptor inhibitors useful in the present invention are also described in U.S. Patent Nos. 6,465,449 and 6,284,764 and International Application No. WO 2001/98277, each of these patent publications being incorporated by reference in its entirety.
Several other compounds, such as styrene derivatives, have also been found to possess tyrosine kinase inhibitory properties and some of the tyrosine kinase inhibitors have been identified as erbB2 receptor inhibitors. Other erbB2 inhibitors are described in European patent publications EP-566,226 A1 (published on October 20, 1993), EP-602,851 A1 (published on June 22, 1994), EP-635,507 A1 (published on January 25, 1995), EP-635,498 A1 (published January 25, 1995) and EP 520,722 A1 (published December 30, 1992). These publications refer to certain bicyclic derivatives, in particular quinazoline derivatives that have anti-cancer properties that result from their tyrosine kinase inhibitory properties. Also, patent application WO 92/20642 (published November 26, 1992) refers to certain bis-mono and bicyclic aryl and heteroaryl compounds as tyrosine kinase inhibitors useful in the inhibition of abnormal cell proliferation. Patent applications WO 96/16960 (published on June 6, 1996), WO 96/09294 (published on March 6, 1996), WO 97/30034 (published on August 21, 1997), WO 98/02434 (published on January 22, 1998), WO 98/02437 (published January 22, 1998) and WO 98/02438 (published January 22, 1998) also refer to substituted bicyclic heteroaromatic derivatives such as tyrosine kinase inhibitors that are useful for the same purpose. Other patent publications referring to anti-cancer compounds are patent applications WO 00/44728) (published on August 3, 2000), EP-1,029,853 A1 (published on August 23, 2000) and WO 01/98277 (published on December 12, 2001), all of which are a reference. are included in their entirety in the description.
In another embodiment, the anti-cancer signal transduction inhibitor is an IGF IR inhibitor. Specific IGF IR antibodies (such as CP-751871) that can be used in the present invention include those described in International Patent Application No. WO 2002/053596, which is incorporated in its entirety in the specification.
In another embodiment, the anti-cancer signal transduction inhibitor is an MEK inhibitor. MEK inhibitors include Pfizer's MEK1 / 2 inhibitor PD325901, Array biopharm's MEK inhibitor ARRY-142886 and combinations thereof.
In another embodiment, the anticancer signal transduction inhibitor is an mTOR inhibitor, mTOR inhibitors include everolimus (RAD001, Novartis), zotarolimus, temsirolimus (CCI-779, Wyeth), AP 23573 (Ariad), AP23675, Ap23841, TAFA 93, rapamimin (sirololin ) and combinations thereof.
In another embodiment, the anticancer signal transduction inhibitor is an Aurora 2 inhibitor, such as, for example, VX-680 and derivatives thereof (Vertex), R 763 and derivatives thereof (Rigel) and ZM 447439 and AZD 1152 (AstraZeneca) or a checkpoint kinase 1/2 inhibitor, such as for example XL844 (Exilixis).
In another embodiment, the anti-cancer signal transduction inhibitor is an Akt inhibitor (protein kinase B), such as API-2, perifosine and RX-0201.
Preferred multitargeted kinase inhibitors include Sutent ((sunitinib, SU-11248), described in U.S. Patent No. 6,573,293 (Pfizer, Inc., NY, USA) and imatinib mesylate (Gleevec).
Furthermore, other targeted anti-cancer agents include the raf inhibitor sorafenib (BAY-43-9006, Bayer / Onyx), GV-1002, ISIS-2503, LE-AON and GI-4000.
The invention also relates to the use of the compounds of the present invention together with cell cycle inhibitors, such as the CDK2 inhibitors ABT-751 (Abbott), AZD-5438 (AstraZeneca), Alvocidib (flavopiridol, Aventis), BMS-387,032 (SNS 032 Bristol Myers), EM-1421 (Erimos), indisulam (Esai), seliciclib (Cyclacel), BIO 112 (One Bio), UCN-01 (Kyowa Hakko) and AT7519 (Astex Therapeutics) and Pflizer's multitargeted CDK inhibitors PD0332991 and AG24322.
The invention also relates to the use of the compounds of the present invention together with telonjerase inhibitors, such as transgenic B lymphocyte immunotherapy (Cosmo Bioscience), GRN 163L (Geron), GV1001 (Pharmexa), RO 254020 (and derivatives thereof) and diazafilonic acid .
Biological response modifiers (such as antibodies, immunotherapeutics and peptide mimetics) are agents that modulate defense mechanisms of living organisms or biological responses, such as, for example, survival, growth or differentiation of tissue cells to stimulate them to anti-tumor activity.
Immunological agents including interferons and numerous other immune enhancing agents used in combination therapy with 1- [5- (4-amino-7-isopropyl-7H-pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] - 3- (2,4-dichlorophenyl) urea, which may optionally be used with one or more other agents, include, but are not limited to, interferon alpha, interferon alfa-2a, interferon, alpha-2b, interferon beta, inteferon gamma -la, interferon gamma-lb (Actimunne) or interferon gamma-nl, PEG Intron A and combinations thereof. Other agents include interleukin 2 agonists (such as, for example, aldesleukin, BAY-50-4798, Ceplene (histamine dihydrochloride), EMD-273063, MVA-HPV-IL2, HVA-Muc-1-IL2, interleukin 2, teceleukin and Virulizin), Ampligen , Canvaxin, CeaVac (CEA), denileukin, filgrastim, Gastrimmune (G17DT), gemtuzumab ozogamicin, Glutoxim (BAM-002), GMK vaccine (Progenies), Hsp 90 inhibitors (such as HspE7 from Stressgen, AG-858, KOS-953 , MVJ-1-1 and STA-4783), imiquimod, krestin (polysaccharide K), lentinan, Melacin (Corixa), melVax (mitumomab), molgramostim, Oncophage (HSPPC-96), OncoVAX (including OncoVAX-CL and OncoVAX- Pr), oregovomab, sargramostim, sizofiran, tasonermin, TheraCys, Thymalfasin, pemtumomab (Y-muHMFH1), picibanil, Provenge (Dendreon), ubenimex, WF-10 (Immunokine), Z-100 (Ancer-20 from Zeriaide, Lalid, Lalid) (REVIMID, Celegene), thalomid (Thalidomide) and combinations thereof.
Anti-cancer agents capable of promoting anti-tumor immune responses, such as, for example, CTLA4 (cytotoxic lymphocyte antigen 4) antibodies and other agents that can block CTLA4, can also be used, such as, for example, MDX-010 (Medarex) and CTLA4 compounds described in U.S. Pat. U.S. Patent 6,682,736. Additional specific CTLA4 antibodies that can be used in the present invention include those described in U.S. Provisional Application 60 / 113,647 (filed December 23, 1998), U.S. Patent No. 6,682,736, both of which are incorporated by reference in their entirety in the specification.
In another embodiment of the present invention, it is associated with 1 - [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3 - (2,4-dichlorophenyl) urea and the pharmaceutical compositions described herein used anti-cancer agent a CD20 antagonist. Specific CD20 antibody antagonists that can be used in the present invention include rituximab (Rituxan), Zevalin (Ibritumomab tiuxetan), Bexxar (131-1-tositumomab), Belimumab (LymphoStat-B), HuMax-CD20 (HuMax, Genmab), R 1594 (Roche Genetics), TRU-015 (Trubion Pharmaceuticals) and Ocrelizumab (PRO 70769).
In another embodiment of the present invention, in association with 1 - [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3 - (2,4-dichlorophenyl) urea and the pharmaceutical compositions described herein used anti-cancer agent a CD40 antagonist. Specific CD40 antibody antagonists that can be used in the present invention include CP-870893, CE-35593 and those described in International Patent Application No. WO 2003/040170 which is incorporated by reference in its entirety in the description. Other CD40 antagonists include ISF-154 (Ad-CD154, Tragen), toralizumab, CHIR 12.12 (Chiron), SGN 40 (Seattle Genetics) and ABI-793 (Novartis).
In another embodiment of the present invention, in association with 1 - [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3 - (2,4-dichlorophenyl) urea and the anticancer agent used herein as a pharmaceutical composition and a hepatocyte growth factor receptor antagonist (IGFr or c-MET).
Immuno-suppressants that can be used in combination with 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2, 4-dichlorophenyl urea include apratuzumab, alemtuzumab, daclizumab, lenograstim and pentostatin (Nipent or Coforin).
The invention also relates to the use of 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-inethoxyphenyl] -3- (2, 4-dichlorophenyl urea together with hormonal, anti-hormonal, anti-androgenic therapeutic agents such as anti-estrogens, which include, but are not limited to, fulvestrant, toremifene, raloxifene, lasofoxifene, letrozole (Femara, Novartis), anti-androgens , such as bicalutamide, finasteride, flutamide, mifepristone, nilutamide, Casodex® (4-cyano-3- (4-fluorophenylsulfonyl) -2-hydroxy-2-methyl-3'- (trifluoromethyl) propionanilide, bicalutamide) and combinations thereof.
The invention also includes the use of the compounds of the present invention in conjunction with hormonal therapy, including, but not limited to, exemestane (Aromasin, Pfizer Ine.), Abarelix (Praecis), Trelstar, anastrozole (Arimidex, AstraZeneca), Atamestane ( Biomed-777), Atrasentan (Xinlay), Bosentan, Casodex (AstraZeneca), doxercalciferol, fadrozole, formestane, gosrelin (Zoladex, AstraZeneca), Histrelin (histrelinacetate), letrozole, leuprorelu (Lupron / Leotton, Abbott, Leopon / Leotton, Leopon, Leopon, Leopon / Leotton tamoxifen citrate (tamoxifen, Nolvadex, AstraZeneca) and combinations thereof.
The invention also includes the use of the compounds of the present invention in conjunction with gene inhibiting agents or gene activating agents, such as histone deacetylase (HDAC) inhibitors, such as suberoalanilide hydroxamic acid (SAHA, Merck Inc./Aton Pharmaceuticals), depsipeptide (FR901228 or FK228), G2M 777, MS-275, pivaloyloxymethyl butyrate and PXD-101.
The invention also includes the use of compounds of the present invention in conjunction with gene therapeutic agents, such as Advexin (ING 201), TNFerade (GeneVee, a compound expressing TNFalfa in response to radiotherapy), RB94 (Baylor College of Medicine).
The invention also includes the use of the compounds of the present invention in conjunction with ribonucleases such as Onconase (ranpimase).
The invention also includes the use of the compounds of the present invention in conjunction with antisense oligonucleotides, such as bcl-2 antisense inhibitor Genasense (Oblimersen, Genta).
The invention also includes the use of the compounds of the present invention in conjunction with proteosomics such as PS-341 (MLN-341) and Velcade (bortezomib).
The invention also includes the use of the compounds of the present invention in conjunction with antivascular agents such as Combretastatin A4P (Oxigene).
The invention also includes the use of the compounds of the present invention in conjunction with traditional cytotoxic agents, including DNA binding agents, mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, topoisomerase inhibitors, and microtubulin inhibitors.
Topoisomerase I inhibitors useful in the combination embodiments of the present invention include 9-aminocamptothecin, belotecan, BN-80915 (Roche), camptothecin, diflomotecan, endotecarin, exatecan (Daiichi), gimatecan, 10-hydroxycamptothecin, irinotecan HCl (Camptosar) , lurtotecan, Orathecin (rubitecan, Supergen), SN-38, topotecan and combinations thereof.
Camptothecin derivatives are of particular interest in the combination embodiments of the invention and include 10-hydroxycamptothecin, 9-aminocamptothecin, irinotecan, SN-38, edotecarin, topotecan and combinations thereof.
A particularly preferred topoisomerase I inhibitor is irinotecan HCl (Camptosar).
Topoisomerase II inhibitors useful in the combination embodiments of the present invention include aclarubicin, adiamycin, amonafide, amrubicin, annamycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, etoposide, idarubicin, galarubicin, hydroxycarbaroxantrone, nemorubarboxantrone, nemorubarboxantrone, anticubarboxantrone, anticubicone pixantrone, procarbazine, rebeccamycin, sobuzoxane, tefluposide, valrubicin and Zinecard (dexrazoxane).
Particularly preferred topoisomerase II inhibitors include epirubicin (Ellence), doxorubicin, daunorubicin, idarubicin and etoposide.
Alkylating agents used in combination therapy with 1- [5- (4-amino-7-isopropyl-7H-pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea may be used, optionally by one or more agents, include, but are not limited to, nitrogen-inostated N-oxide, cyclophosphamide, AMD-473, altretamine, AP-5280, apaziquone, brittle metallic, bendamustine, busulfan, carboquone, carmostine, chlorambucil, dacarbazine, estramustine, photemustine, glufosfamide, ifosfamide, KW-2170, lomustine, mafosfamide, mechlorethamine, melphalan, mitobronitol, mitolactol, mitomycin C, mitoxatrone, nimustine, ranimustine, temozolomine platinum-coated, thioteplatinum-capped, platinum-platinum, (carboplatin), eptaplatin, lobaplatin, nedaplatin, Eloxatin (oxaliplatin, Sanofi), streptozocin or satrplatin and combinations thereof.
Particularly preferred alkylating agents include Eloxatin (oxaliplatin).
Antimetabolites used in combination therapy with 1- [5- (4-amino-7-isopropyl-7H-pyranol [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea may optionally be used with one or more other agents include, but are not limited to, dihydrofolate reductase inhibitors (such as methotrexate and NeuTrexin (trimetresate glucuronate)), purine antagonists (such as 6-mercaptopurine riboside, mercaptopurine, 6-thioguanine, cladribine, clofarabine (Clolar), fludarabine, nelarabine and raltitrexed), pyrimidine antagonists (such as, for example, 5-fluoracil (5-FU), Alimta (premetrexed disodium, LY231514, MTA), capecitabine (Xeloda), cytosine arabinoside, Gemzine (Gemzine) lilly (gemzine), Gemabine , Tegafur (UFT Orzel or Uforal and including TS-1 combination of tegafur, gimestat and otostat), doxifluridine, carmofur, cytarabine (including ocphosphate, phosphate stearate, sustained-release and lipsomal forms), enocitabine, 5-azacitidine (Vidaza ), decitabine and ethynylcytidine) and and other antimetabolites, such as eflomithine, hydroxyurea, leucovorin, nolatrexed (Thymitaq), triapine, trimetrexate or, for example, one of the preferred antimetabolites described in European patent application 239362, such as N- (5- [N- (3,4-dihydro-2-methyl) -4-oxo-quinazolin-6-ylmethyl) -N-methylamino] -2-thenoyl) -L-glutamic acid and combinations thereof.
In another embodiment, the anti-cancer agent is a poly (ADP-ribose) polymerase-1 (PARP-1) inhibitor, such as AG-014699, ABT-472, INO-100, KU-0687 and GPI18180.
Microtubulin inhibitors that can be used in combination therapy with 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2, 4-dichlorophenyl) urea, optionally by one or more other agents, include, but are not limited to, ABI-007, Albendazole, Batabulin, CPH-82, EPO 906 (Novartis), discodermolide (XAA 296), Vinfunine and ZD -6126 (AstraZeneca).
Antibiotics used in combination therapy with 1- [5- (4-amino-7-isopropyl-7H-pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea, optionally used with one or more other agents include, but are not limited to, intercalating antibiotics such as actinomycin D, bleomycin, mitomycin C, neocarzinostatin (Zinostatin), peplomycin and combinations thereof.
Plant-derived antitumor substances (also known as spindle inhibitors) which in combination therapy with 1- [5- (4-amino-7-isopropyl-7H-pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea can optionally be used with one or more other agents include, but are not limited to, mitotic inhibitors, for example vinblastine, vincristine, vindesine, vinorelbine (Navelbine), doxetaxel (Taxotere), Ortataxel, paclitaxel (including Taxoprexin, a DNA / paclitaxel conjugate) and combinations thereof.
Platinum-coordinated compounds include, but are not limited to, cisplatin, carboplatin, nedaplatin, oxaliplatin (Eloxatin), Satraplatin (JM-216), and combinations thereof.
Particularly preferred cytotoxic agents include Camptosar, capecitabine (Xeloda), oxaliplatin (Eloxatin), Taxotere, and combinations thereof.
Other anti-tumor agents include alitretinoin, 1-asparaginase, AVE-8062 (Aventis), calcitriol (vitamin D derivative), Canphosphamide (Telcyta, TLK-286), Cotara (1311 chTNR 1 / b), DMXAA (Antisoma), exisulind, ibandronic acid, Miltefosine, NBI-3001 (IL-4), pegaspargase, RSR13 (efaproxiral), Targretin (bexarotene), tazarotne (vitamin A derivative), Tesmilifine (DPPE), Theratope, tretinoin, Trizone (tirapazamine), Xcyafin gadote (mxxtrin gadote), Xcyafin gadium Xyotax (polyglutamate paclitaxel) and combinations thereof.
In another embodiment of the present invention, statins may be taken together with 1 - [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea can be used. Statins (HMG-CoA reductase inhibitors) can be selected from the group consisting of Atorvastatin (Lipitor, Pfizer Ine.), Provastatin (Pravachol, Bristol-Myers Squibb), Lovastatin (Mevacorm Merck Ine.), Simvastatin (Zocor, Merck Ine. ), Fluvastatin (Lescol, Novartis), Cerivastatin (Baycol, Bayer), Rosuvastatin (Crestor, AstraZeneca), Lovostatin and Niacin (Advicor, Kos Pharmaceuticals), derivatives and combinations thereof.
In a preferred embodiment, the statin is selected from the group consisting of Atovorstatin and Lovastatin, derivatives and combinations thereof.
Other agents useful as anti-tumor agents include Caduet, Lipitor and torcetrapib.
Another embodiment of the present invention of particular interest relates to a method for the treatment of breast cancer in a person in need of such treatment, which comprises administering to this person an amount of 1- [5- (4-amino) -7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5 * carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea (including hydrates, solvates and polymorphs or pharmaceutically acceptable salts thereof ), in combination with one or more (preferably one to three) anti-cancer agents selected from the group consisting of trastuzumab (Herceptin), docetaxel (Taxotere), paclitaxel, capecitabine (Xeloda), gemcitabine (Gemzar), vinorelbine (Navelbine), exemestane (Aromasin), letrozole (Femara) and anastrozole (Arimidex).
Another embodiment of the present invention of particular interest relates to a method for the treatment of colorectal cancer in a person in need of such treatment, which method comprises administering to this person an amount of 1- [5- (4- amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea (including hydrates, solvates and polymorphs or pharmaceutically acceptable salts of these) in combination with one or more (preferably one to three) anti-cancer agents selected from the group consisting of capecitabine (Xeloda), irinotecan HCl (Camptosar), bevacizumab (Avastin), cetuximab (Erbitux), oxaliplatin (Eloxatin), premetrexed disodium (Alimta), vatalanib (PTK-787), Sutent (Sunitinib), AG-13736 (axitinib), SU-14843, PF-0337210, PD-325901, PF-2341066, Tarceva, Iressa, Pelitinib, Lapatinib, Mapatumumab, Gleevec , BMS 184476, CC1 779, ISIS 2503, ONYX 015 and Flavopyridol, the the active agent together with the amounts of the anti-cancer agent combination is effective in the treatment of colorecal cancer.
Another embodiment of the present invention of particular interest relates to a method for the treatment of renal cell carcinomas in a patient in need of such treatment, which comprises administering to the patient an amount of 1- [5- (4- amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea (including hydrates, solvates and polymorphs or pharmaceutically acceptable salts of these) in combination with one or more (preferably one to three) anticancer agents selected from the group consisting of capecitabine (Xeloda), interferon alfa, interleukin-2, bevacizumab (Avastin), gemcitabine (Gemzar), thalidomide, cetuximab (Erbitux) , vatalanib (PTK-787), Sutent, AG-13736, SU-11248, Tarceva, Iressa, Lapatinib and Gleevec, wherein the amounts of active agent together with the amounts of the combination anti-cancer agents are effective in the treatment of renal cell carcinomas.
Another embodiment of the present invention of particular interest relates to a method for the treatment of melanomas in a patient in need of such treatment, which comprises administering to said patient an amount of 1- [5- (4-amino) -7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea (including hydrates, solvates and polymorphs or pharmaceutically acceptable salts thereof ) in combination with one or more (preferably one to three) anticancer agents selected from the group consisting of interferon alfa, interleukin-2, temozolomide, docetaxel (Taxotere), paclitaxel, DTIC, PD-325.901, Axitinib, bevacizumab (Avastin), thalidomide, sorafanib, vatalanib (PTK-787), Sutent, CpG-7909, AG-13736, Iressa, Lapatinib and Gleevec, wherein the amounts of active agent together with the amounts of the combination anticancer agents are effective in the treatment of melanomas.
Another embodiment of the present invention of particular interest relates to a method for the treatment of lung cancer in a patient in need of such treatment which comprises administering to said patient an amount of 1- [5- (4-amino) 7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea (including hydrates, solvates and polymorphs or pharmaceutically acceptable salts thereof) , in combination with one or more (preferably one to three) anti-cancer agents selected from the group consisting of capecitabine (Xeloda), bevacizumab (Avastin), gemcitabine (Gemzar), docetaxel (Taxotere), paclitaxel, premetrexed sodium (Alimta), Tarceva , Iressa and Paraplatin (carboplatin), wherein the amounts of active agent together with the amounts of the combination of anticancer agents are effective in the treatment of lung cancer.
In one preferred embodiment, irradiation can be used in conjunction with 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2 , 4-dichlorophenyl) urea and pharmaceutical compositions described herein. Irradiation can be administered in a variety of ways. For example, irradiation can be electromagnetic or particulate in kind. Electromagnetic irradiation useful in the practice of the present invention includes, but is not limited to, X-rays and gamma rays. In a preferred embodiment super-voltage X-rays (X-rays> 4 MeV) can be used in the practice of the present invention. Particulate irradiation useful in the practice of the present invention includes, but is not limited to, electron beams, proton beams, neutron beams, alpha particles, and negative pi mesons. The irradiation can be delivered using a conventional radiological treatment device and methods and by intraoperative and stereotactic methods. Additional discussion regarding radiation treatments available for use in the practice of the present invention can be found in Steven A. Leibel et al., Textbook of Radiation Oncology (1998) (publ. WB Saunders Company) and in particular in Chapters 13 and 14 are found. Irradiation can also be carried out by methods such as targeted release, for example by means of radioactive "seeds" or by systemic release of targeted radioactive conjugates. J. Padawer et al., Combined Treatment with Radioestradiol lucanthone in Mouse C3HBA Mammary Adenocarcinoma and With Estradiol lucanthone in an Estrogen Bioassay, Int. J. Radial. Oncol. Biol. Phys. 7: 347: 357 (1981). Other radiation delivery methods can be used in the practice of the present invention.
The amount of irradiation delivered to the desired treatment volume can be variable. In a preferred embodiment, irradiation can be administered in an amount effective to stop or regress cancer in combination with 1 - [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine 5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea (including all forms and formulations thereof and pharmaceutical compositions thereof).
In a more preferred embodiment, irradiation is administered in an amount of at least about 1 Gray (Gy) fractions at least once every day up to a treatment volume, even more preferably irradiation is administered in an amount of at least about 2 Gray (Gy) fractions at least once a day to a treatment volume, even more preferably, radiation is administered in an amount of at least about 2 Gray (Gy) fractions at least once a day to a treatment volume for five consecutive days per week.
In a more preferred embodiment, irradiation is administered in 3 Gy fractions every other day, three times a week, to a treatment volume.
In another even more preferred embodiment, a total amount of at least about 20 Gy, even more preferably at least about 30 Gy, most preferably at least about 60 Gy is administered to a host in need thereof.
In one or more preferred embodiments of the present invention, 14 Gy irradiation is administered.
In another more preferred embodiment of the present invention, 10 Gy irradiation is administered.
In another more preferred embodiment of the present invention, 7 Gy irradiation is administered.
In the most preferred embodiment, radiation is administered to the entire brain of a host, the host being treated for metastatic cancer.
Furthermore, the invention provides a compound of the present invention alone or in combination with one or more auxiliary care products, for example a product selected from the group consisting of Filgrastim (Neupogen), ondansetron (Zofran), Fragmin, Procrit, Aloxi, Emend or combinations thereof.
Figures
Figure 1: Phosphate salt form A x-ray powder diffraction pattern.
Figure 2: Phosphate salt form A differential scanning calorimeter chart.
Figure 3: Phosphate salt form B x-ray powder diffraction pattern.
Figure 4: Mesylate salt form A x-ray powder diffraction pattern.
Figure 5: Mesylate salt form A differential scanning calorimeter chart.
Figure 6: Mesylate acid form B x-ray powder diffraction pattern.
Figure 7: Mesylate salt form B differential scanning calorimeter graph.
Figure 8: Mesylate salt form C x-ray powder diffraction pattern.
Figure 9: Mesylate salt form C differential scanning calorimeter chart.
Figure 10: Besylate salt form A x-ray powder diffraction pattern.
Figure 11: Besylate salt form A differential scanning calorimeter chart.
Figure 12: Tosylate salt form A x-ray powder diffraction pattern.
Figure 13: Tosylate salt form A differential scanning calorimeter chart.
Figure 14: Hydrochloride salt form A X-ray powder diffraction pattern.
1 -f 5- (4-AMINO-7-ISOPROP YL-7H-P YRROOLr2.3-DlPYRIMIDINE-5-C ARBONYLV2-METHOXYPHEN YL1-3- (2,4-DICHLORPHENYL VUREUM
1- [5- (4-amino-7-isopropyl-7H-pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea can be produced using the methods described in international patent publication WO 04/056830, published July 8, 2004. Alternatively, 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine -5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea according to the examples described below are produced.
As indicated above, the present invention relates to novel crystalline and non-crystalline forms and formulations of 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl ) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea.
One form of the active agent of the present invention includes salts of 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea. 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea is basic from nature and is thus capable of forming a wide variety of different salts with different inorganic and organic acids. Although such salts should be pharmaceutically acceptable for administration to mammals, particularly humans, it is often desirable in practice to initially have 1- [5- (4-amino-7-isopropyl-7H-pyrrole [2,3]). -d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea from the reaction mixture as a pharmaceutically unacceptable salt, and then simply convert the latter back to the free base compound by by treatment with an alkaline reagent and subsequently converting the latter free base into a pharmaceutically acceptable acid addition salt. The acid addition salt of 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) - urea according to the invention is easily prepared by treating the basic compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. After careful evaporation of the solvent, the desired solid salt is easily obtained. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding to the solution a suitable mineral or organic acid. Specific preparations of salts are described below.
Other forms of 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea include one or more acceptable crystalline and non-crystalline solvates, hydrates, isomorphs, polymorphs or precursors of the free base or the above-mentioned salts of 1- [5- (4-amino-7-isopropyl-7H-pyrrole [2,3]) -d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea.
The most preferred form of 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea for formulation in the solid amorphous dispersion, preferably the SDD, is its free base.
1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea is an inhibitor / antagonist of various enzymes / receptors. This compound is active against a variety of kinase targets involved in angiogenesis / vasculogenesis, oncogenic and protooncogenic signal transduction and cell cycle control. As such, 1- [5- (4-aimno-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea useful in the prevention and treatment of a variety of human hyperproliferative disorders, such as benign and malignant tumors of the liver, kidney, bladder, breast, stomach, fallopian tubes, colorectal, prostate, pancreas, lung, vulva, thyroid, hepatic carcinomas, sarcomas, gliobastomas, head and neck and other hyperplastic diseases such as benign prostatic hyperplasia (e.g. BPH). Furthermore, it is expected that 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) - urea has an activity against a series of leukemias and lymphoid malignancies.
1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea is also useful in the treatment of further conditions involving aberrant ligand / receptor expression, interaction, activation or signal events related to various protein kinases. Such disorders include those of the neuronal, glial, astrocytal, hypothalamic, and other glandular macrophagal, epithelial, stromal, and blastocoal natureins, which involve aberrant function, expression, activation, or signal delivery of a protein kinase. In addition, 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea can be a have therapeutic applicability in inflammatory, angiogenic and immunological disorders involving both identified and unidentified kinases that are mediated by 1- [5- (4-amino-7-isopropyl-7H-pyrrole [2,3-d] pyrimidine-5- carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea.
The present invention relates to solid amorphous dispersion compositions of 1 - [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2 , 4-dichlorophenyl) urea and at least one concentration-increasing polymer. More specifically, the solid amorphous dispersion compositions of the present invention provide increases in aqueous concentration in an environment of application and in bioavailability compared to other conventional compositions. The compositions, active agent, suitable polymers and any excipients are discussed in more detail below.
SPREAD-DRIED DISPERSION COMPOSITIONS OF 1-Γ5-ί4-ΑΜΙΝΟ-7-ISOPROPYL-7H-PYRROOLr2.3-DlPYRIMIDlNE-5-CARBONYLV2-METHOX-YFENYLL-3- (2,4-DICHLORRORUM ENERGY-ENERGY CONCEPT-CONFIGURATION POLICY)
The solid amorphous dispersion compositions, preferably a spray-dried dispersion of the present invention include dispersions of the active agent and at least one concentration-increasing polymer. The active agent in the dispersion can be crystalline or amorphous. Preferably, at least a major portion of the active agent in the composition is amorphous. By amorphous is simply meant that the active agent is in a non-crystalline state. As used herein, the term "a major portion" means that at least 60 percent of the active agent in the composition is in the amorphous state, rather than in the crystalline form. Preferably, the active agent in the dispersion is substantially amorphous. As the term is used herein, "substantially amorphous" means that the amount of active agent in the crystalline form is not more than about 25 percent. More preferably, the active agent in the dispersion is "substantially completely amorphous," meaning that the amount of active agent in the crystalline form does not exceed about 10 percent. Amounts of crystalline 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea can be measured by powder X-ray diffraction, Scanning Electron Microscope (SEM) analysis, differential scanning calorimetry (DSC) or any other standard quantitative determination.
The SDD composition can be from about 1 to about 80% by weight 1- [5- (4-amino-7-isopropyl-7H-pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3 - (2,4-dichlorophenyl) urea, depending on the dose of active agent and the effectiveness of the concentration-increasing polymer. An increase in aqueous 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d) pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) - urea concentrations and relative bioavailability are usually optimal at low inhibition levels, usually less than about 25 to 40% by weight. However, due to the practical limit of dosage form size, higher inhibitor levels are often preferred and in many cases work well.
The amorphous inhibitor may exist within the solid amorphous dispersion as a pure phase, as a solid solution of the inhibitor homogeneously distributed by the polymer or any combination of these states or those states immediately in between. Preferably, the dispersion is in the form of a "solid solution", which means that the amorphous inhibitor is homogeneously distributed by the concentration-increasing polymer and that the mixture present in relatively pure amorphous domains within the solid amorphous dispersion is relatively small, in the order of magnitude of less than 20% by weight and preferably in an amount of less than 10% by weight of the total amount of inhibitor. Such solid solutions can also be seen as substantially homogeneous. Solid solutions of amorphous inhibitor and polymer are generally more physically stable and have improved concentration-enhancing properties and also an improved bioavailability, compared to dispersions that are not a solid solution.
Although the dispersion may have some inhibitor-rich domains, it is preferred that the dispersion itself have a single glass transition temperature (Tg), which shows that the dispersion is substantially homogeneous. This is in contrast to a simple physical mixture of pure amorphous 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea particles and pure amorphous polymer particles that generally exhibit two separate Tgs, one from the inhibitor and the other from the polymer. Tg, as the term is used herein, is the characteristic temperature at which a glassy material undergoes a relatively rapid (e.g., 10 to 100 seconds) physical change from a glass state to a rubber state after gradual heating. The Tg of an amorphous material such as, for example, a polymer, a drug or a dispersion can be measured using various techniques, including a dynamic mechanical analyzer (DMA), a dilatometer, a dielectric analyzer and by means of a differential scanning calorimeter (DSC). The exact values measured by any technique can vary slightly, but are usually within 10 ° to 30 ° C of each other. Regardless of the technique used, when an amorphous dispersion exhibits a single Tg, this indicates that the dispersion is substantially homogeneous. Dispersions of the present invention that are substantially homogeneous are generally more physically stable and have improved concentration-enhancing properties and further improved bioavailability over non-homogeneous dispersions.
The compositions comprising the active agent and the concentration increasing polymer provide an increased concentration of the dissolved inhibitor in in vitro dissolution assays. It has been determined that an increased drug concentration in an in vitro dissolution test in a Model Fasted Duodenal (MFD) solution or phosphate buffered saline (PBS) is a good indicator of in vivo performance and bioavailability. A suitable PBS solution is an aqueous solution comprising 20 mM sodium phosphate (Na 2 HPO 4, 47 mM potassium phosphate (KH 2 PO 4), 87 mM sodium chloride (NaCl) and 0.2 in M potassium chloride (KCl), which at pH 6.5 using sodium hydroxide (NaOH) A suitable MFD solution is the same PBS solution in which further 7.3 mM sodium taurocholic acid and 1.4 mM 1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine are furthermore present. a composition according to the present invention is subjected to a dissolution test by adding it to an MFD or a PBS solution and by stirring to promote dissolution.In general, the amount of composition added to the solution is in such a test an amount that, if all the drug is dissolved in the composition, would produce an inhibitor concentration that is at least about 5-fold and preferably between 20- to 50-fold equilibrium solubility of the active agent only lies in the test solution. For demonstrating even higher levels of dissolved inhibitor concentration, the addition of even larger amounts of the composition is desirable.
In one aspect, the compositions of the present invention provide a maximum drug concentration (MDC) that is at least about 20 times the equilibrium concentration of a control composition which comprises an equivalent amount of inhibitor but is free of the polymer. In other words, if the equilibrium concentration provided by the control composition is 1 pg / ml, then a composition of the present invention provides an MDC of at least about 20 pg / ml. The control composition is usually the undispersed inhibitor alone (e.g., usually the crystalline inhibitor only in its most thermodynamically stable crystalline form) or the inhibitor plus a weight of inert diluent equivalent to the weight of polymer in the test composition. It is to be understood that the control composition is free of solubilizing agents or other components that could substantially affect the solubility of the inhibitor and that the inhibitor is in solid form in the control composition. Preferably, the MDC of the inhibitor is achieved using the composition of the invention at least about 25 times, more preferably at least about 20 times, the equilibrium concentration of the control composition. Surprisingly, the present invention can achieve extremely high increases in aqueous concentration.
Alternatively, the compositions of the present invention provide an aqueous environment of application with a concentration versus time region below the curve (AUC) for each period of at least 90 minutes between the introduction time in the environment of application and about 270 minutes after introduction into the environment of the application, which is at least 10 times that of a control composition comprising an equilibrium amount of undispersed inhibitor. Preferably, the compositions according to the invention provide in an aqueous environment of application a concentration versus time AUC for each period of at least 90 minutes between the introduction time in the environment of the application and about 270 minutes after introduction into the environment of the application, which is at least about 20-fold, more preferably at least about 50-fold and even more preferably at least about 60-fold that of a control composition as described above. Such large increases in aqueous concentration versus time AUC values are surprising given the extremely low solubility in water and hydrophobicity of free base crystalline 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine -5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea.
As described above, the term "application environment" can be either the in vivo environment of the gastrointestinal tract of a mammal, in particular human, or the in vitro environment of a test solution, such as, for example, phosphate buffered saline (PBS) or Model Fasted Duodenal (MFD) solution.
A conventional in vitro test for evaluating the increased drug concentration in an aqueous solution can be performed by (1) adding with stirring a sufficient amount of the control composition, usually the inhibitor alone, to the in vitro test medium, usually MFD or a PBS solution for achieving an equilibrium concentration of the inhibitor; (2) addition while stirring a sufficient amount of test composition (e.g., the inhibitor and the polymer) in an equivalent test medium such that if the entire amount of inhibitor is dissolved, the theoretical inhibitor concentration equals the inhibitor equilibrium concentration by a factor of at least 5 and preferably by a factor of at least 20; and (3) comparison of the measured MDC and / or aqueous concentration versus time AUC of the test composition in the test medium with the equilibrium concentration and / or the aqueous concentration versus time AUC of the control composition. In conducting such a dissolution test, the amount of test composition or control composition used in an amount is such that, if the entire amount of inhibitor is dissolved, the inhibitor concentration is at least the 10-fold and preferably at least the 50-fold of that of the equilibrium concentration.
The dissolved inhibitor concentration is usually measured as a function of time by taking samples from the test medium and plotting the inhibitor concentration in the test medium versus time, such that the MDC can be determined. The MDC is considered to be the maximum value of dissolved inhibitor determined during the duration of the test. The aqueous concentration of the inhibitor versus time AUC is calculated by integrating the concentrations versus time curve over a time period of 90 minutes between the introduction time of the composition in the aqueous environment of the application (time = zero) and 270 minutes after introduction into the environment of the application (time = 270 minutes). Usually, when the composition reaches its MDC quickly, less than about 30 minutes, the time interval used for calculating the AUC is from time = zero to time = 90. However, if the AUC is over one of the 90 minute time periods, described above, of a composition satisfies the criterion of the present invention then forms when the composition forms part of the present invention.
A portion of 0.36 mg of free base active agent and 1.44 mg of active agent in spray-dried dispersion in 1.8 ml MFD tested according to the conditions described above yielded an MDC of 3 pg / ml and an AUC of 100 pg x respectively min / ml and 80 pg / ml and an AUC of 5,900 pg x min / ml.
To avoid large inhibitor particles that would give a false determination, the test solution is filtered or centrifuged. Dissolved inhibitor is considered to be the material that either passes through a 0.45 µm syringe filter or the material that remains in the supernatant after centrifugation. Filtration can be performed using a 13 mm 0.45 µm polyvinylidine difluoride syringe filter marketed by Scientific Resources under the TITAN® brand. Centrifugation is usually performed in a polypropylene microcentrifuge tube by centrifugation at 13,000 g for 60 seconds. Other comparable filtration or centrifugation methods can be used and useful results are thereby obtained. For example, using other types of microfilters may yield values that are slightly higher or lower (± 10-40 percent) than those obtained using the filter specified above, but will still allow identification of preferred dispersions. It is recognized that this definition of "dissolved inhibitor" includes not only monomerically sulfated inhibitor molecules, but also a wide range of species, such as polymer / inhibitor combinations that have sub-micron dimensions such as inhibitor aggregates, aggregates of polymer and inhibitor mixtures, micelles, polymeric micelles, colloidal particles or nanocrystals, polymer / inhibitor complexes and other species containing such inhibitor that are present in the filtrate or in the supernatant in the specified dissolution test.
In another case, the compositions of the present invention, when orally administered to a human or other mammal, provide an AUC inhibitor concentration in the blood (referred to as plasma AUC in the description) which is at least 4-fold that observed when a control composition comprises an equivalent amount of non-dispersed drug is metered. It is noted that such compositions can also be considered as compositions that have a relative bioavailability of about 4. Preferably, the compositions of the present invention, when administered orally to a human or other mammal, provide an AUC inhibitor concentration in the blood that is at least about 6-fold, more preferably at least about 10-fold and even more more preferably at least about 20 times that observed when a control composition comprising an equivalent amount of a non-dispersed drug is dosed. It is to be understood that when dosed in vivo, the dosage vehicle does not contain any solubilizing agent or other components that could substantially affect the solubility of the inhibitor and that the inhibitor in the control composition is in solid form. An example of a dosing vehicle could be a suspension solution of water containing 0.5% by weight of hydroxypropyl cellulose (such as, for example, METHOCEL) and 0.16% by weight of the polyoxyethylene sorbitan monooleate surfactant (such as, for example, TWEEN 80). Thus, the compositions of the present invention can be evaluated in in vitro or in vivo tests or in both.
A spray-dried dispersion prepared according to the methods of the invention has the plasma pharmacokinetic properties described in Table 1 below.
Table 1
The relative bioavailability of inhibitor in the dispersions of the present invention can be tested in vivo in animals or in humans using conventional methods of making such an assay. An in vivo test, such as, for example, a crossover study, can be used to determine whether an inhibitor and concentration-increasing polymer composition provides increased relative bioavailability compared to an inhibitor composition, but without polymer, as described above. In an in vivo crossover study, a "test composition" of inhibitor and polymer is administered to half of a group of test patients, after a suitable wash-out period (e.g., one week), a "control composition" is administered to the same patients which equivalent amount of inhibitor as the test composition (but without polymer). The other half of the group received the control composition first, followed by the test composition. The relative bioavailability is measured as the blood concentration (serum or plasma) versus the time under the curve (AUC) determined for the test group divided by the AUC in the blood provided by the control composition. Preferably, this test control ratio is determined for each patient and then the ratios are averaged over all patients in the study. In vivo assays of AUC can be made by plotting the serum or plasma drug concentration along the vertical axis (y-axis) against time along the horizontal axis (x-axis). Those skilled in the art should understand that such in vivo tests are usually conducted under fasting conditions.
Thus, as noted above, one embodiment of the present invention is one in which the relative bioavailability of the test composition is at least about 4 with respect to a control composition consisting of inhibitor, but without polymer as described above (i.e., the vivo AUC provided by the test composition is at least about 4 times that of the in vivo AUC provided by the control composition). A preferred embodiment of the invention is one in which the relative bioavailability of the test composition is at least about 6 and even more preferably at least about 10 relative to a control composition consisting of the inhibitor, but without polymer, as described above. The determination of AUCs is a well-known procedure and is described, for example, in Welling, "Pharmacokinetics Processes and Mathematics", ACS Monograph 185 (1986).
CONCENTRATION-INCREASING POLYMERS
Concentration-increasing polymers suitable for use in the compositions of the invention should be inert in the sense that they do not chemically react with 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d ] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea in an unfavorable manner, are pharmaceutically acceptable and at least have some solubility in aqueous solution at physiologically relevant pHs (e.g. 1-8) to have. The polymer can be neutral or ionizable and should have a water solubility of at least 0.1 mg / ml within at least a portion of the pH range of 1-8.
The polymer is a "concentration-increasing polymer", which means that it meets at least one and more preferably both of the following conditions. The first condition is that the concentration-increasing polymer should have the MDC of 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- ( 2,4-dichlorophenyl) urea in the environment of application increases relative to a control composition consisting of an equivalent amount of 1- [5- (4-amino-7-isopropyl-7H-pyrrole [2,3-d] pyrimidine -5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea, but no polymer. That is, once the composition has been introduced into an environment of application, the polymer increases the aqueous concentration of 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5. carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea relative to the control composition. Preferably, the polymer increases the MDC of 1- [5- (4-amino-7-isopropyl-7H-pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4 -dichlorophenyl) -urea in an aqueous solution with at least 5-fold relative to a control composition, preferably with at least 15-fold and even more preferably with at least 50-fold. Such large increases may be necessary in order for 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4 -dichlorophenyl) urea to achieve effective blood levels via oral dosing. The second condition is that the concentration-increasing polymer the AUC of 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- ( 2,4-dichlorophenyl) urea in the environment of application increases relative to a control composition consisting of the active compound, but with no polymer present as described above. That is, in the environment of application, the composition provides 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3 - (2,4-dichlorophenyl) urea and the concentration-increasing polymer comprises an area below the concentration versus time curve AUC for each 90-minute period between the introduction time in the environment of application and about 270 minutes after the introduction to the environment of application that is at least 10 times that of a control composition that comprises an equivalent amount of the active agent, but not a polymer. Preferably, the AUC provided by the composition is at least 50 times that of the control composition.
Concentration-increasing polymers suitable for use in the present invention can be of cellulose or non-cellulose nature. The polymers can be neutral or ionizable in an aqueous solution. Among these, ionizable and cellulosic polymers are preferred, with ionizable cellulosic polymers being even more preferred.
A preferred class of polymers includes polymers that are "amphiphilic" in nature, meaning that the polymer has hydrophobic and hydrophilic moieties. The hydrophobic moiety can include groups such as aliphatic or aromatic hydrocarbon groups. The hydrophilic moiety may comprise either ionizable or non-ionizable groups capable of hydrogen bonding, such as, for example, hydroxyl groups, carboxylic acids, esters, amines or amides.
Amphiphilic and / or ionizable polymers are preferred because such polymers tend to have relatively strong interactions with 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl). -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea and can promote the formation of various types of polymer / drug combinations in the environment of application as described above. In addition, the rejection of these charges from the ionized groups of such polymers serves to limit the dimensions of the polymer / drug combinations to the nanometer or submicron scale. For example, without wishing to be bound by any particular theory, these polymer / drug combinations may comprise hydrophobic clusters of the active agent surrounded by the polymer with the polymeric hydrophobic regions facing toward the interior toward the active agent and the hydrophilic regions of the polymer that face outwards in the direction of the aqueous environment. Alternatively, the ionized functional groups of the polymer may enter into association, e.g. via ion pairs or hydrogen bonds with ionic or polar groups of the active agent. In the case of ionizable polymers, the hydrophilic regions of the polymer would comprise the ionized functional groups. Such polymer / drug combinations in solution may resemble charged polymeric micelle-like structures. In any case, regardless of the mechanisms of action, the inventors have observed that such amphiphilic polymers, in particular ionizable cellulosic polymers, have the MDC and / or AUC of 1- [5- (4-amino-7-isopropyl-7H-pyrrole). [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea in an aqueous solution compared to the control compositions free of these polymers were found to improve.
Surprisingly, these amphiphilic polymers can achieve the obtained maximum concentration of 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2 , 4-dichlorophenyl) urea significantly increased when dosed to an environment of application. In addition, amphiphilic polymers interact with 1- [5- (4-amino-7-isopropyl-7H-pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-) dichlorophenyl urea for preventing the precipitation or crystallization of the active compound from the solution despite the fact that its concentration is considerably above the equilibrium concentration. In particular when the preferred compositions are solid amorphous dispersions of 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2 (4-dichlorophenyl) urea and the concentration-increasing polymer, the compositions provide a drug concentration that is considerably higher, particularly when the dispersions are substantially homogeneous. The maximum drug concentration can be 5-fold and often more than 50-fold the equilibrium concentration of the crystalline 1- [5- (4-amino-7-isopropyl-7H-pyrrole [2,3-d] pyrimidine-5- carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea. These increased concentrations of 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) - urea in turn lead to markedly increased relative bioavailability of the active compound.
One class of polymers suitable for use in the present invention includes neutral non-cellulosic polymers. Examples of polymers include: vinyl polymers and copolymers with substituents of hydroxyl, alkylacyloxy or cyclic amido; polyvinyl alcohols that have at least a portion of their repeating units in the non-hydrolyzed (vinyl acetate) form; polyvinyl alcohol polyvinyl acetate copolymers; polyvinylpyrrolidone; polyoxyethylene-polyoxypropylene copolymers, also known as poloxamers; and polyethylene polyvinyl alcohol copolymers.
Another class of polymers suitable for use in the present invention includes ionizable non-cellulosic polymers. Examples of polymers include: carboxylic acid-functionalized vinyl polymers, such as the carboxylic acid-functional polymethacrylates and carboxylic acid-functionalized polyacrylate, such as the EUDRAGITS produced by Rohm Tech Inc., of Maiden, Massachusetts; amine functionalized polyacrylates and polymethacrylates; proteins and carboxylic acid functionalized starches such as starch glycolate.
Non-cellulose polymers that are amphiphilic are copolymers of a relatively hydrophilic and a relatively hydrophobic monomer. Examples include acrylate and methacrylate copolymers and polyoxyethylene-polyoxypropylene copolymers. Examples of commercially available grades of these copolymers include the EUDRAGITS which are copolymers of methacrylates and acrylates and the PLURONICS marketed by BASF, which are polyoxyethylene-polyoxypropylene copolymers.
A preferred class of polymers includes ionizable and neutral cellulosic polymers with at least one ester and / or ether bonded substituent wherein the polymer has a degree of substitution of at least 0.1 for each substituent.
It should be noted that in the polymer nomenclature used herein, ether-linked substituents are mentioned prior to "cellulose" as the remainder attached to the ether group; for example "ethylbenzoic acid cellulose" has ethoxybenzoic acid substituents. Analogously, ester-linked substituents are named after "cellulose" as the carboxylate; for example, "cellulose phthalate" has one carboxylic acid of each phthalate moiety esterified with the polymer and the other carboxylic acid in unreacted form.
It should be noted that a polymer called "cellulose acetate phthalate" (CAP) refers to one or more of the family of cellulose polymers that have acetate and phthalate groups bound via ester bonds to a significant fraction of the cellulose polymer hydroxyl groups. In general, the degree of substitution of each substituent group can vary from 0.1 to 2.9 as far as the other criteria of the polymer are met. "Substitution rate" refers to the average number of the three hydroxyl groups per repeating saccharide unit on the cellulose chain that is substituted. For example, if all hydroxyl groups on the cellulose chain are substituted with phthalate, the phthalate substitution degree is 3. Also included within each polymeric family type are cellulose polymers that have additional substituents added in relatively small amounts, the performance of the polymer not being substantially altered.
Amphiphilic cellulosic materials include polymers in which the parent cellulose polymer is substituted on one or all of the 3 hydroxyl groups present on each repeating saccharide moiety with at least one relatively hydrophobic substituent.
Hydrophobic substituents can be essentially any substituent which, when substituted to a sufficiently high level or degree of substitution, can render the cellulose polymer substantially insoluble in water. Examples of hydrophobic substituents include ether-linked alkyl groups such as methyl, ethyl, propyl, butyl, etc .; or ester-linked alkyl groups such as acetate, propionate, butyrate, etc .; and aryl groups such as phenyl, benzoate or phenylate bound to ether and / or ester. Hydrophilic regions of the polymer can be either the parts that are relatively unsubstituted since the unsubstituted hydroxyl groups themselves are relatively hydrophilic, as well as the regions that are substituted with hydrophilic substituents. Hydrophilic substituents include non-ionizable groups bonded via ether or ester such as the hydroxyalkyl substituents hydroxyethyl, hydroxypropyl and the alkyl ether groups such as ethoxyethoxy or methoxyethoxy. Particularly preferred hydrophilic substituents are those which are ionizable groups bonded via ether or ester such as carboxylic acids, thiocarboxylic acids, substituted phenoxy groups, amines, phosphates or sulfonates.
One class of cellulose polymers include neutral polymers, which means that the polymers are substantially non-ionizable in aqueous solution. These polymers contain non-ionizable substituents that are bonded either via ether or via ester. Examples of ether-linked non-ionizable substituents include alkyl groups such as methyl, ethyl, propyl, butyl, etc .; hydroxyalkyl groups such as hydroxymethyl, hydroxyethyl, hydroxypropyl, etc .; and aryl groups such as phenyl. Examples of ester-bound non-ionizable substituents include: alkyl groups, such as acetate, propionate, butyrate, etc .; and aryl groups such as phenylate. However, when aryl groups are included, the polymer may need a sufficient amount of a hydrophilic substituent such that the polymer has at least some water solubility at any physiologically relevant pH of 1 to 8.
Examples of non-ionizable polymers that can be used as the polymer include: hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, hydroxyethylmethylcellulose, hydroxyethylcellulose acetate and hydroxyethyl ethylcellulose.
A preferred set of neutral cellulosic polymers are those that are amphiphilic. Examples of such polymers include hydroxypropyl methyl cellulose and hydroxypropyl cellulose acetate wherein repeating cellulose units that have relatively high numbers of methyl or acetate substituents relative to the unsubstituted hydroxyl or hydroxypropyl substituents form hydrophobic regions relative to other repeating units on the polymer.
A preferred class of cellulose polymers includes polymers that are at least partially ionizable at physiologically relevant pH and include at least one ionizable substituent bonded either via ether or via ester.
Examples of ether-linked ionizable substituents include: carboxylic acids such as, for example, acetic acid, propionic acid, benzoic acid, salicylic acid, alkoxybenzoic acids such as, for example, ethoxybenzoic acid or propoxybenzoic acid, the various isomers of alkoxyphthalic acid such as ethoxyphthalic acid and ethoxyisophthalic acid; the various isomers of alkoxynicotinic acid such as, for example, ethoxynicotinic acid and the various isomers of picolinic acid such as ethoxypicinic acid, etc .; thiocarboxylic acids such as thioacetic acid; substituted phenoxy groups, such as, for example, hydroxyphenoxy, etc .; amines such as, for example, aminoethoxy, diethylaminoethoxy, trimethylaminoethoxy, etc .; phosphates, such as phosphate ethoxy; and sulfonates, such as, for example, sulfonate ethoxy. Examples of ester-linked ionizable substituents include: carboxylic acids, such as, for example, succinate, citrate, phthalate, terephthalate, isophthalate, trimellite and the various isomers of pyridine dicarboxylic acid, etc .; thiocarboxylic acids, such as thiosuccinate; substituted phenoxy groups, such as amino salicylic acid; amines, such as natural or synthetic amino acids, such as, for example, alanine or phenylalanine; phosphates, such as, for example, acetyl phosphate; and sulfonates, such as, for example, acetyl sulfonate. For aromatically substituted polymers that must have the required water solubility, it is also desirable that sufficient hydrophilic groups such as, for example, hydroxypropyl or carboxylic acid functional groups are linked to the polymer to make the polymer water-soluble at least at pH values where one or more ionizable groups are ionized. In some cases, the aromatic group may itself be ionizable, such as, for example, phthalate or trimellate substituents. Exemplary cellulosic polymers that are at least partially ionized comprise at physiologically relevant pH's: hydroxypropyl methylcellulose acetate succinate, hydroxypropylmethylcellulose succinate, hydroxypropylcelluloseacetaatsuccinaat, hydroxyethylmethylcellulosesuccinaat, hydroxyethylcelluloseacetaatsuccinaat, hydroxypropylmethylcellulose phthalate, hydroxyethylmethylcelluloseacetaatsuccinaat, hydroxyethylmethylcelluloseacetaatftalaat cellulose, carboxyethyl cellulose, carboxy-methyl cellulose, carboxymethyl ethyl cellulose, cellulose acetate phthalate, methyl cellulose acetaatfialaat, ethylcelluloseacetaatftalaat, hydroxypropylcelluloseacetaatfialaat, hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate succinate, hydroxypropyl methyl cellulose acetate succinate phthalate, hydroxypropyl methylcellulose succinate phthalate, cellulose propionate flalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetate trimellate acetate methyl cellulose cellulose acetate cellulose cellulose l litaat, hydroxypropylcelluloseacetaattrimellitaat, hydroxy-propylmethylcelluloseacetaattrimellitaat, hydroxypropylcelluloseacetaatrimellitaat-succinate, cellulosepropionaattrimellitaat, cellulosebutyraattrimellitaat, cellulose-acetaattereftalaat, celluloseacetaatisoftalaat, celluloseacetaatpyridinedicarboxylaat, salicylzuurcelluloseacetaat, hydroxypropylsalicylzuurcelluloseacetaat, ethylbenzoë acid cellulose acetate, hydroxypropylethylbenzoëzuurcelluloseacetaat, ethylftaal acid cellulose acetate, ethyl nicotinic acid cellulose acetate, and ethyl picolinic acid cellulose acetate.
Examples of ionizable cellulose polymers that meet the definition of amphiphilic with hydrophilic and hydrophobic regions include polymers such as, for example, cellulose acetate fialate and cellulose acetate trimellitate where the repeating cellulose units that have one or more acetate substituents are hydrophobic to those having no acetate substituents or one or have more ionized phthalate or trimellate substituents.
A particularly desirable subgroup of cellulose ionizable polymers are those that have both a carboxylic acid functional aromatic substituent and an alkylate substituent and are therefore amphiphilic. Examples of such polymers include celluloseacetaatfialaat, methylcelluloseacetaatftalaat, ethyl cellulose acetate phthalate, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcelluloseacetaatflalaat, hydroxypropylcelluloseacetaat-phthalate, cellulosepropionaatfitalaat, hydroxypropylcellulosebutyraatftalaat, celluloseacetaatrimellitaat, methylcelluloseacetaattrimellitaat, ethyl cellulose acetate trimellitate, hydroxypropylcelluloseacetaattrimellitaat, hydroxypropylmethylcelluluose-acetate trimellitate, hydroxypropcelluloseacetaattrimellitaatsuccinaat, cellulose-propionaattrimellitaat, cellulosebutyraattrimellitaat , cellulose acetate terephthalate, cellulose acetate isoflalate, cellulose acetate pyridine dicarboxylate, salicylic acid cellulose acetate, hydroxypropylsalicylic acid cellulose acetate, ethylbenzoic acid cellulose acetate, hydroxypropyl ethylbenzoic acid cellulose acetate, ethyl flalacetate, cellulose cellulose acetate hylpicolinic acid cellulose acetate.
Another particularly desirable subgroup of cellulose ionizable polymers are those that are amphiphilic and have a non-aromatic carboxylate substituent. Examples of such polymers include hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose succinate, hydroxypropylcellulose acetate succinate, hydroxyethyl methylcellulose acetate succinate, hydroxyethyl methylcellulose succinate, hydroxyethylcellulose acetate succinate and carboxymethyl ethylcellulose.
Although, as enumerated above, a wide range of polymers can be used to form dispersions of 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) - 2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea, the inventors have found that relatively hydrophobic polymers have shown the best performance as demonstrated by the high MDC and AUC values.
In particular cellulose polymers which are water-insoluble in their non-ionized state but which are at least slightly water-soluble in their ionized state perform particularly well. A particular subclass of such polymers are the so-called "entheric polymers" which include, for example, certain qualities of hydroxypropyl methylcellulose phthalate and cellulose acetate trimellitate. Dispersions formed from these polymers generally exhibit very large increases in the order of magnitude from 5-fold to above 500-fold in the maximum drug concentration achieved in dissolution tests as compared to those for crystalline drug control. In addition, non-entheric qualities of these polymers as well as closely related cellulose polymers are expected to perform well due to the similarities in physical properties with 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea.
Thus, especially preferred polymers are hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), methylcellulose acetate phthalate, hydroxypropylcellulose acetate phthalate acetate cellulose acetate cellulose acetate cellulose acetate. The most preferred ionizable cellulose polymers are hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, and carboxymethyl ethyl cellulose.
Hydroxypropyl methyl cellulose acetate succinate (HPMCAS) is available in various analytical qualities and substituent profiles. Typical commercial profiles for HPMCAS are described in the following table. In addition to L, M and H qualities, this cellulose is also provided as "G" quality, which refers to a granule or pellet formulation or of an "F" grade, which relates to a fine or powder formulation.
One particularly effective polymer to form dispersions of the present invention is carboxymethyl cellulose (CMEC). Dispersions prepared from 1 - [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) - urea and CMEC usually have high glass transition temperatures at high relative humidity levels due to the high glass transition temperature of CMEC. As discussed below, such high Tgs result in solid amorphous dispersions with excellent physical stability. In addition, due to the fact that all substituents on CMEC are linked to the cellulose skeleton via ether bonds, CMEC has excellent chemical stability. In addition, commercial qualities of CMEC, such as those made available by Freund Industrial Company, Limited (Tokyo, Japan), are amphiphilic, leading to high degrees of concentration increase. Finally, 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea has a high solubility in CMEC, which allows the formation of physically stable dispersions with high drug quantities.
Another preferred class of polymers consists of neutralized acid polymers. By "neutralized acid polymer" is meant any acid polymer for which a significant fraction of the "acid residues" or "acid substituents" is neutralized; that is, they exist in their de-protonated form. By "acid polymer" is meant any polymer that has a significant number of acid residues. In general, a significant number of acid residues would be greater than or equal to about 0.1 mille-equivalent acid residues per 30 grams of polymer. "Acidic residues" include one or more functional groups that are acidic such that upon contact with or upon dissolution in water, a hydrogen cation can be donated to water at least in part and thus the hydrogen ion concentration is increased. This definition includes any functional group or "substituent," as it is called when the functional group is covalently bonded to a polymer that has a pKa of less than about 10. Examples of classes of functional groups included in the above description include carboxylic acids, thiocarboxylic acids, phosphates, phenolic groups, and sulfonates. Such functional groups can form the primary structure of the polymer as for polyacrylic acid, but are more generally covalently bonded to the backbone of the related polymer and are thus called "substituents."
The "neutralization degree" a, of a polymer substituted with monoprotic acids (such as carboxylic acids) is defined as the fraction of the acid residues on the polymer that are neutralized; that is, deprotonated by means of a base. Usually, for an acid polymer to be considered a "neutralized acid polymer", α should be at least about 0.001 (or 0.1 percent), preferably about 0.01 (1 percent) and more preferably at least about 0 , 1 (10 percent). Such small degrees of neutralization may be acceptable because the effective pH of the polymer often changes dramatically with small increases in the degree of neutralization. Nevertheless, higher degrees of neutralization are even more preferred. Thus, α is preferably at least 0.5 (which means that at least 50 percent of the acid residues are neutralized) and is more preferably at least 0.9 (which means that at least 90 percent of the acid residues are neutralized) ).
Neutralized acid polymers are described in more detail in copending U.S. Patent Application Serial No. 10 / 175,566 entitled "Pharmaceutical Compositions of Drugs and Neutralized Acidic Polymers" filed June 17, 1992 and published as U.S. Patent No. 2003-0054038, the relevant description of which is incorporated by reference.
When the neutralized form of the acid polymer comprises a polyvalent cationic species such as Ca 2+, Mg 2+, Al 3+, Fe 2+, Fe 3+ or a diamine such as ethylenediamine, the cationic species may interact with two or more neutralized acid residues on more than one polymer chain, which results in an ionic cross-linking between the polymer chains. An acidic polymer can be considered "ionically crosslinked" if the number of milli equivalents of polyvalent cationic species per gram of polymer is at least 5 percent, preferably at least 10 percent, of the number of milli equivalents of acid residues (of the polymer) per gram of polymer. Alternatively, an acidic polymer may be considered "ionically crosslinked" if sufficient polyvalent cationic species are present such that the neutralized acidic polymer has a higher Tg than the same polymer that essentially does not contain a polyvalent cationic species. Drug mobility in dispersions formed from such ionically crosslinked polymers is particularly low compared to dispersions formed from the acid form of the same polymers. Such ionically crosslinked polymers can be formed by neutralizing the acidic polymer using any base where the cationic counter ion of the base is divalent. Thus, calcium hydroxide, magnesium acetate or ethylenediamine can be added to an acidic polymer such as, for example, cellulose acetate phthalate or hydroxypropyl methylcellulose acetate succinate to form a neutralized, ionically crosslinked, acidic cellulose polymer. Low drug mobility in such polymers can be indicated by high Tg values or, more usually, a decrease in the size of the heat capacity increase in the vicinity of the Tg or, in some cases, the absence of any apparent Tg when the dispersion is subjected to differential thermal analysis. Thus, when the polymer is essentially completely neutralized, no Tg can be observed when the neutralized polymer is subjected to differential thermal analysis. Such ionically cross-linked polymers can provide improved physical stability for the drug in the dispersion as compared to non-ionically cross-linked neutralized acid polymers. Although specific polymers have been discussed as being suitable for use in the compositions of the present invention, blends of such polymers may also be suitable. The term "polymer" is intended to include blends of polymers in addition to a single species of polymer.
In order to achieve the best performance, in particular after storage for long periods prior to use, it is preferable that the active agent remains as amorphous as possible. The inventors have found that this can best be achieved by applying two separate methods. In the first method, the glass transition temperature Tg of the amorphous is 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- ( 2,4-dichlorophenyl) urea material substantially above the storage temperature of the composition. In particular, it is preferable that the Tg of the amorphous state of 1 - [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea is at least 40 ° C and is preferably at least 60 ° C. For those aspects of the invention wherein the composition has a solid, substantially wholly amorphous dispersion of 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2- methoxyphenyl] -3- (2,4-dichlorophenyl) urea in the concentration-increasing polymer and in which the compound itself has a relatively low Tg (about 70 ° C or lower), it is preferable that the concentration-increasing polymer has a Tg of at least at least 40 ° C, preferably at least 70 ° C and even more preferably greater than 100 ° C. Examples of high Tg polymers include HPMCAS, HPMCP, CAP, CAT, CMEC and other celluloses that have alkylate or aromatic substituents or both alkylate and aromatic substituents.
In a second method, the concentration-increasing polymer is selected such that the amorphous 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea is highly soluble in the concentration-increasing polymer. In general, the concentration-increasing polymer and 1 - [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2, 4-dichlorophenyl) urea concentration chosen such that the solubility of 1 - [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea is substantially equal to or greater than the concentration of the active compound in the concentration-increasing polymer. It is often preferred that the 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4- dichlorophenyl) urea composition is chosen such that both methods - high Tg and high solubility - are met.
In addition, the above preferred polymers, i.e., amphiphilic cellulose polymers, tend to exhibit higher concentration-enhancing properties compared to the other polymers of the invention. For 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea, the amphiphilic celluloses with the best concentration-enhancing properties generally those that have ionizable substituents as well as hydrophobic substituents such as methoxy, ethoxy and acetate. In vivo tests of compositions with these polymers often have higher MDC and AUC values than compositions with other polymers of the invention.
PREPARATION OF COMPOSITIONS
Dispersions of the active agent and concentration-increasing polymer can be prepared according to one or more of the known methods resulting in at least one major portion (at least 60 percent) of the amorphous state inhibitor. Examples of mechanical processes include milling and extruding; melting processes include high temperature fusion, solvent-modified fusion, and melt / gelling processes; and solvent processes include solvent-free precipitation, spray drying, and spray coating. See, for example, U.S. Patent No. 5,456,923, U.S. Patent No. 5,939,099 and U.S. Patent No. 4,801,460 which describe the formation of dispersions via extrusion processes; U.S. Patent No. 5,340,591 and U.S. Patent No. 4,673,564 which describe the preparation of dispersions by grinding processes; and U.S. Patent No. 5,684,040, U.S. Patent No. 4,894,235 and U.S. Patent No. 5,707,646 which describe the formation of dispersions via melt / gelling processes, the descriptions of which are incorporated herein by reference. Although the dispersions of the present invention can be prepared by using one or more of these processes, the dispersions generally have maximum bioavailability and stability when the inhibitor is dispersed in the polymer such that it is substantially amorphous and substantially homogeneous throughout the polymer. is divided.
In general, as the degree of homogeneity of the dispersion increases, the increase in the aqueous concentration of the active agent and the relative bioavailability also increase. Given the extremely low solubility in water and bioavailability of the free base of 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] - 3- (2,4-dichlorophenyl) urea, it is preferred that the dispersions are as homogeneous as possible to achieve therapeutically effective levels of the inhibitor. Thus, most preferred dispersions are those with a single glass transition temperature, indicating a high degree of homogeneity. Dispersions with more than one Tg, indicative of at least partial amorphous phase separation, may also function well, particularly when no amorphous phase is composed solely of amorphous drug, but contains a significant amount of the concentration-increasing polymer.
In one embodiment, the solid amorphous dispersion of inhibitor and concentration-increasing polymer can be prepared via a melt / gelling or melt / extrusion process. In such processes, a molten mixture comprising the inhibitor and concentration-increasing polymer is rapidly cooled such that the molten mixture solidifies to give a solid amorphous dispersion. By the term "molten mixture" it is meant that the mixture comprising the inhibitor and concentration-increasing polymer is heated sufficiently to cause it to become sufficiently fluid so that the drug disperses substantially in its entirety in one or more of the concentration-increasing polymers and other auxiliaries. In general, this requires the mixture to be heated to about 10 ° C or more above the lower melting point of the lowest melting component in the composition and the melting point of the drug. The inhibitor may exist as a pure phase in the molten state, as a solution of the inhibitor homogeneously distributed by the molten mixture or any combination of these states or those states that are immediately between them. The molten mixture is preferably substantially homogeneous so that the inhibitor is dispersed through the molten mixture as homogeneously as possible. When the temperature of the molten mixture is lower than the melting point of both the inhibitor and the concentration-increasing polymer, the molten auxiliaries, concentration-increasing polymer and inhibitor are preferably sufficiently soluble in each other such that a substantial portion of the inhibitor disperses in the polymer or the excipients. It is often preferred that the mixture be heated above the lower of the melting point of the concentration-increasing polymer and the inhibitor.
In general, the process temperature can vary from 50 ° C to about 200 ° C or higher, depending on the melting point of the polymer that is a function of the selected quality of the polymer. However, the process temperature should not be so high that an unacceptably high level of decomposition of the drug or polymer occurs. In some cases, the molten mixture must be formed under an inert atmosphere to prevent the decomposition of the drug and / or polymer at the process temperature. When relatively high temperatures are used, it is often preferred that the time the mixture is at the elevated temperature to minimize decomposition is kept as short as possible.
The molten mixture may also comprise an auxiliary substance that lowers the melting temperature of the composition (the drug and / or the polymer), thereby allowing low temperature processing. When these auxiliaries have a low volatility and remain appreciably in the mixture after solidification, they may generally comprise up to 30% by weight of the molten mixture. For example, a plasticizer can be added to the composition to reduce the melting temperature of the polymer. Examples of plasticizers include water, triethyl citrate, triacetin, and dibutyl sebacate. Volatile agents that solubilize or swell the polymer, such as, for example, acetone, water, methanol and ethyl acetate, may also be added in low amounts to lower the melting point of the composition. When such volatile auxiliaries are added, at least a portion to at most substantially all of these excipients can evaporate during this process from or after the conversion of the molten mixture into a solid mixture. In such cases, the operation can be considered as a combination of process operation using a solvent and melt / gel or melt extrusion. Removal of such volatile excipients from the molten mixture can be accomplished by breaking down or spraying the molten mixture into small droplets and contacting the droplets with the liquid such that the droplets both cool and wholly or partially the volatile excipient lose. Examples of other auxiliaries that can be added to the composition to reduce the process temperature include low molecular weight polymers or oligomers, such as, for example, polyethylene glycol, polyvinylpyrrolidone and poloxamers; fats and oils, including mono-, di- and triglycerides; natural and synthetic waxes, such as camauba wax, beeswax, microcrystalline wax, castor wax and paraffin wax; long chain alcohols such as cetyl alcohol and stearyl alcohol; and long chain fatty acids, such as, for example, stearic acid. As mentioned above, when the excipient that is added is volatile, it can still be removed from the mixture in the molten state or after solidification to form the solid amorphous dispersion.
Almost any process can be used to prepare the molten mixture. One method involves melting the concentration-increasing polymer in a vessel and then adding the active agent to the molten polymer. Another method involves melting the inhibitor in a vessel and then adding the concentration-increasing polymer. In yet another method, a solid mixture of the inhibitor and the concentration-increasing polymer can be added to a vessel and the mixture heated to prepare the molten mixture.
Once the mixture is formed, it can be mixed to ensure that the inhibitor is homogeneously distributed throughout the molten mixture. Such a mixing operation can be performed using mechanical means, such as, for example, overhead mixers, magnetically driven mixers and stir bars, planetary mixers and homogenizers. Optionally, when the molten mixture is formed in a vessel, the contents of the vessel can be pumped out of the vessel and through a mixer on-line or a static mixer and returned to the vessel. The amount of shear forces used to mix the molten mixture should be sufficiently high to ensure that a uniform distribution of the drug in the molten mixture is achieved. The molten mixture can be mixed for a few minutes to a few hours, the mixing time depending on the viscosity of the mixture and the solubility of the drug and one or more optional auxiliaries in the concentration increasing polymer.
An alternative method for the preparation of the molten mixture is the use of two vessels, the melting of the inhibitor in the first vessel and the concentration-increasing polymer in a second vessel. The two melts are then pumped through an on-line static mixer or extruder to produce the molten mixture which is then rapidly solidified.
Alternatively, the molten mixture can be produced using an extruder, such as, for example, a single-screw or double-screw extruder, both of which are known in the art. In such devices, a solid feed of the composition is fed into the extruder with the combination of heat and shear forces producing a uniformly melted and mixed mixture which is then rapidly solidified to form the solid amorphous dispersion. The solid feed can be prepared by methods known in the art for obtaining solid mixtures with a high homogeneity. In another way, the extruder can be provided with two feed members, which creates the possibility of supplying the inhibitor in the extruder via one feed member and the polymer through the other. Other auxiliaries for the reduction of the process temperature as described above can be included in the solid feed or, in the case of liquid auxiliaries, such as for example water, injected into the extruder using methods known from the prior art.
The extruder should be designed such that it produces a molten mixture with the drug evenly distributed throughout the composition. The various zones in the extruder must be heated to suitable temperatures such that the desired extrudate temperature as well as the desired degree of mixing or shear is achieved using procedures known in the art.
When the active agent has a high solubility in the concentration-increasing polymer, a lower amount of mechanical energy will be required to form the dispersion. In such cases, when the melting point of the undispersed inhibitor is greater than the melting point of the undispersed concentration-increasing polymer, the process temperature may be lower than the melting temperature of the undispersed inhibitor, but higher than the melting point of the polymer, since the inhibitor will dissolve in the molten polymer. When the melting point of the undispersed inhibitor is lower than the melting point of the undispersed concentration-increasing polymer, the process temperature may be above the melting point of the undispersed inhibitor, but below the melting point of the undispersed concentration-increasing polymer polymer as the molten inhibitor will dissolve in the polymer or be absorbed in the polymer.
When the inhibitor has low solubility in the polymer, a higher amount of mechanical energy may be required to form the dispersion. Here it may be necessary for the process temperature to be higher than the melting point of the inhibitor and the polymer. As mentioned above, a liquid or low-melting auxiliary may be added in a different manner which promotes the melting or mutual solubility of the concentration-increasing polymer and the inhibitor. A large amount of mechanical energy may also be required to mix the inhibitor and the polymer to form a dispersion. Typically, the lowest process temperature and an extruder design that produces the lowest amount of mechanical energy (e.g., shear) that produces a satisfactory dispersion (substantially amorphous and substantially homogeneous) is chosen to minimize exposure of the inhibitor to harsh conditions.
Once the molten mixture of inhibitor and concentration-increasing polymer has been formed, the mixture must be rapidly solidified to give the solid amorphous dispersion. By "rapidly solidified" it is meant that the molten mixture is solidified sufficiently quickly such that a substantial phase separation of the drug and polymer does not occur. Usually, this means that the mixture must be set to solidify in less than about 10 minutes, preferably less than about 5 minutes, even more preferably in less than about 1 minute. If the mixture is not solidified rapidly, phase separation may occur, resulting in the formation of inhibitor-rich phases and polymer-rich phases. Over time, the active agent can crystallize in the inhibitor-rich phase. Such compositions are therefore not substantially amorphous or appreciably homogeneous and tend not to perform as well as the compositions that are rapidly solidified and are substantially amorphous and substantially homogeneous. The solidification can often take place mainly by cooling the molten mixture to at least about 10 ° C and preferably at least about 30 ° C below its melting point. As mentioned above, solidification can be further accelerated by evaporation of all or part of one or more volatile adjuvants or solvents. In order to accelerate rapid cooling and evaporation of volatile adjuvants, the molten mixture is often formed into a large surface shape, such as, for example, a rod or fiber or drops. For example, the molten mixture can be pressed through one or more small holes to form long thin fibers or rods, or it can be introduced into an apparatus, such as, for example, an atomizer or a rotating disk, which forms the molten mixture in drops of 1 µm to 1 cm diameter. The drops are then contacted with a relatively cool liquid, such as air or nitrogen, to accelerate cooling and evaporation.
A useful tool for evaluating and selecting conditions to form substantially homogeneous, substantially amorphous dispersions via a melt / gelling or extrusion process is the differential scanning calorimeter (DSC). Although the speed at which samples are heated and cooled in a DSC is limited, it offers the possibility of an accurate check of the thermal history of a sample. For example, the inhibitor and the concentration-increasing polymer can be dry blended and then placed in the DSC sample pan. The DSC can then be programmed to heat the sample at the desired rate, keep the sample at the desired temperature for a desired time, and then allow the sample to cool rapidly to ambient or lower temperatures. The sample can then be re-analyzed on the DSC to verify whether the sample has been converted to a substantially homogeneous, substantially amorphous dispersion (for example, the sample has a single Tg). Using this procedure, the temperature and time required to achieve a substantially homogeneous, substantially amorphous dispersion of the active agent and a given concentration-increasing polymer can be determined.
The preferred method for forming substantially amorphous and substantially homogeneous dispersions is by "working with a solvent" consisting of a solution of the inhibitor and one or more polymers in a conventional solvent.
"Conventional" herein means that the solvent that can be a mixture of compounds will simultaneously dissolve the drug and one or more polymers. After both the inhibitor and the polymer have dissolved, the solvent is rapidly removed by evaporation or by mixing with a non-solvent. Examples of processes are spray drying, spray coating (pan coating, fluidized bed coating, etc.) and precipitation by rapid mixing of the polymer and the drug solution with CO2, water or some non-solvent. Preferably, the removal of the solvent results in a solid dispersion that is substantially homogeneous. As previously described, in such substantially homogeneous dispersions, the inhibitor is dispersed as homogeneously as possible by the polymer and may be considered as a solid inhibitor solution dispersed in one or more polymers. When the resulting dispersion consists of a solid solution of inhibitor in polymer, the dispersion can be thermodynamically stable, meaning that the concentration of inhibitor in the polymer is at the equilibrium value or below, or it can be considered as a super-saturated solid solution where the inhibitor concentration in the dispersion polymer or polymers is above its equilibrium value.
The solvent can be removed via the spray drying process. The term spray drying is used conventionally and generally refers to processes that involve breaking down liquid mixtures into small droplets (spraying) and quickly removing the solvent from the mixture in a container (spray drying apparatus) where there is a strong driving force for the evaporation of the solvent from the drops. The strong driving force for solvent evaporation is generally provided by maintaining the partial pressure of the solvent in the spray-drying apparatus far below the vapor pressure of the solvent at the temperature of the drying drops. This is accomplished by either (1) maintaining the pressure in the spray-drying apparatus on a partial vacuum (e.g., 0.01 to 0.50 atm); (2) mixing the liquid drops with a warm drying gas; or (3) both. In addition, at least a portion of the heat required for evaporating the solvent can be provided by heating the spray solution.
Solvents suitable for spray drying can be any organic compound in which the inhibitor and the polymer are soluble in each other. Preferably, the solvent is also volatile with a boiling point of 150 ° C or lower. In addition, the solvent should have relatively low toxicity and be removed from the dispersion to a level acceptable according to The International Committee on Harmonization (ICH) guidelines. Removal of the solvent to this level may require a process step, such as, for example, drying on a tray after spray drying or after the spray coating process. Preferred solvents include alcohols such as methanol, ethanol, n-propanol, iso-propanol and butanol; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; esters such as, for example, ethyl acetate and propyl acetate; and various other solvents such as acetonitrile, methylene chloride, toluene and 1,1,1-trichloroethane. Lower volatility solvents such as, for example, dimethylacetamide or dimethyl sulfoxide can also be used. Mixtures of solvents such as 50 percent methanol and 50 percent acetone can also be used and also mixtures with water can be used as long as the polymer and the inhibitor are sufficiently soluble to make the spray drying process feasible. Generally, due to the hydrophobic nature of the inhibitor, non-aqueous solvents are preferred, which means that the solvent comprises less than about 10 weight percent water and preferably less than 1 weight percent water.
In general, the temperature and flow rate of the drying gas are selected such that the polymer / drug solution drops are sufficiently dry by the time they reach the wall of the device and are substantially in a solid state and such that they form a fine powder and not stick the wall of the device. The actual duration for reaching this level of drought depends on the size of the drops. Droplet dimensions are generally in the range of 1 µm to 500 µm in diameter, with 5 µm to 100 µm being more common. The large surface-to-volume ratio of the droplets and the large driving force for evaporation of the solvent lead to actual drying times of a few seconds or less and more usually less than 0.1 seconds. This rapid drying is often critical for the particles that maintain a uniform, homogeneous dispersion rather than separating into a drug-rich and polymer-rich phase. As above, to achieve large increases in concentration and bioavailability, it is often necessary to obtain as homogeneous a dispersion as possible. Clotting times should be shorter than 100 seconds, preferably shorter than a few seconds and even more preferably shorter than 1 second. In general, to achieve this rapid solidification of the inhibitor / polymer solution, it is preferable that the size of the droplets formed during the spray drying process is less than about 100 µm in diameter. The resulting solid particles thus formed are generally less than about 100 µm in diameter.
After solidification, the solid powder usually remains in the spray-drying chamber for about 5 to 60 seconds, further the solvent is evaporated from the solid powder. The final solvent content of the solid dispersion as it exits the dryer should be low as this reduces the mobility of inhibitor molecules in the dispersion, thereby increasing their stability. In general, the solvent content of the dispersion as it leaves the spray chamber should be less than 10% by weight and preferably less than 2% by weight. In some cases, it may be preferable to spray a solvent or a solution of a polymer or other excipient into the spray-drying chamber to form granules, provided that the dispersion is not adversely affected.
Spray drying processes and spray drying equipment are generally in Perry's Chemical Engineers' Handbook, Sixth Edition (R. H. Perry, D. W. Green, J. O. Maloney, eds.) McGraw Hill Book Co., 1984, biz. 2054 to 2057. More details about spray drying processes and equipment are described by Marshall "Atomization and Spray-Drying", 50 Chem. Scary. Prog. Monogr. series 2 (1954).
The amount of the concentration-increasing polymer with respect to the amount of inhibitor present in the dispersions of the present invention depends on the inhibitor and polymer and can vary within wide limits from an inhibitor-to-polymer weight ratio of 0.01 to about 4 (e.g. 1% by weight inhibitor to 80% by weight inhibitor). However, in most cases, it is preferable that the inhibitor-to-polymer ratio is greater than about 0.05 (4.8% by weight inhibitor) and less than about 2.5 (71% by weight inhibitor). Often, the increase in inhibitor concentration or the relative bioavailability observed increases as the inhibitor-to-polymer ratio decreases from a value of about 1 (50% by weight inhibitor) to a value of about 0.11 (10% by weight inhibitor) ). In some cases it was found that the bioavailability of dispersions with an inhibitor-to-polymer ratio of about 0.33 (25% by weight inhibitor) have a higher bioavailability when administered orally, than dispersions with an inhibitor-to-polymer ratio of 0.11 (10% by weight inhibitor).
In addition, the amount of concentration-promoting polymer that can be used in a dosage form is often limited by the total mass requirements of the dosage form. For example, when oral administration to a human is desired, at low inhibitor-to-polymer ratios, the total mass of drug and polymer can be unacceptably large for the delivery of the desired dosage in a single tablet or capsules. Thus, it is often necessary to use inhibitor-to-polymer ratios that are smaller than the optimum in specific dosage forms to provide a sufficient inhibitor dosage in a dosage form that is small enough to be easily delivered to an environment of use.
EXCIPIENTS AND DOSAGE FORMS
Although the key ingredients present in the compositions of the present invention are simply the inhibitor 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl ] -3- (2,4-dichlorophenyl) urea and the concentration-increasing polymer (s), the inclusion of other excipients in the composition may be useful. These excipients can be used with the inhibitor / polymer composition to formulate the composition into tablets, capsules, suspensions, suspension powders, creams, transdermal patches, depots and the like. The inhibitor and polymer composition can be added to other dosage form ingredients in virtually any manner that does not substantially alter the inhibitor. The excipients can be physically mixed with the dispersion and / or incorporated within the dispersion.
One very useful class of excipients is the class of surfactants. Suitable surfactants include fatty acid and alkyl sulfonates; commercially available surfactants such as benzalkonium chloride (HYAMINE® 1622, available from Lonza, Ine., Fairlawn, New Jersey), dioctyl sodium sulfosuccinate, DOCUSATE SODIUM® (available from Mallinckrodt Spec. Chem., St. Louis, Missouri); polyoxyethylene sorbitan fatty acid esters (TWEEN®, available from ICI Americas Inc., Wilmington, Delaware; LIPOSORB® P-20, marketed by Lipochem Inc., Patterson New Jersey; CAPMUL® POE-O, marketed by Abitec Corp. (Janesville, Wisconsin) and natural surfactants such as sodium taurocholic acid, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, lecithin and other phospholipids and mono- and diglycerides. Such materials can advantageously be used to increase the rate of solubilization by facilitating wetting, thereby increasing the maximum dissolved concentration, and also to inhibit crystallization or precipitation of the drug by interacting with it. dissolved drug by mechanisms such as complexation, formation of inclusion complexes, formation of micelles or surface adsorption of a solid drug, crystalline or amorphous. These surfactants can comprise at most about 5% by weight of the composition.
The addition of pH modifiers, such as acids, bases or buffers, may also be beneficial by delaying dissolution of the composition (e.g., acids such as citric acid or succinic acid if the concentration-increasing polymer is anionic), or otherwise increase the rate of dissolution of the composition (e.g., bases such as sodium acetate or amines when the polymer is anionic).
Conventional matrix materials, complexing agents, solubilizing agents, fillers, disintegrating agents or binders can also be added as part of the composition itself or added by granulation through wet, mechanical or other means. These materials can make up at most 90% by weight of the composition.
Examples of matrix materials, fillers or diluents include lactose, mannitol, xylitol, microcrystalline cellulose, calcium diphosphate, and starch.
Examples of disintegrating agents include sodium etch glycolate, sodium alginate, carboxymethylcellulose sodium, methylcellulose and croscarmellose sodium.
Examples of binders include methyl cellulose, microcrystalline cellulose, starch and gums such as guar gum and tragagant.
Examples of lubricants include magnesium stearate and calcium stearate.
Other conventional excipients can be used in the compositions of the invention, including those known in the art. In general, adjuvants such as pigments, lubricants, flavorings, etc., can be used for conventional purposes and in conventional amounts without adversely affecting the properties of the compositions. These excipients can be used to formulate the composition into tablets, capsules, suspensions, powders for suspension, creams, transdermal patches and the like.
The compositions of the invention can be delivered via a wide variety of routes, including, but not limited to, oral, nasal, rectal, and via the lung. In general, the oral route is preferred.
Compositions of the present invention can also be used in a wide variety of dosage forms for the administration of anti-cancer compounds. Examples of dosage forms are powders or granules that can be taken orally, either in dry form or in reconstructed form by adding water or other liquids to form a paste, suspension, slurry or solution; tablets, capsules, multi-particles and pills. Various additives can be mixed, milled or granulated with the compositions of the invention to form a material suitable for the dosage forms mentioned above.
The compositions of the present invention can be formulated in various forms such that they are delivered as a suspension of particles in a liquid carrier. Such suspensions may be formulated in the form of a liquid or paste at the time of production, or may be formulated in the form of a dry powder with a liquid, usually water, which is added at a later time but prior to the oral administration. Such powders that are formulated into a suspension are often referred to as sachets or oral powder for formulating (OPC) formulations. Such dosage forms can be formulated and reconstituted using a known procedure. The simplest approach is to formulate the dosage form in the form of a dry powder that is reconstituted by simply adding and stirring water. Alternatively, the dosage form may be formulated as a liquid and a dry powder that are combined and stirred to form an oral suspension. In yet another embodiment, the dosage form can be formulated as two powders that are reconstituted by first adding water to the one powder to form a solution to which the second powder is added with stirring to form a suspension.
In general, it is preferred that the dispersion of the active agent is formulated for storage for a long period of time in the dry state as this promotes the chemical and physical stability of the inhibitor. Various adjuvants and additives are combined with the compositions of the invention to form the dosage form. For example, it may be desirable to add some or all of the following components: preservatives such as sulfites (as an antioxidant), benzalkonium chloride, methylparaben, propylparaben, benzyl alcohol or sodium benzoate; suspending or thickening agents such as xanthan gum, starch, guar gum, sodium alginate, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, polyacrylic acid, silica gel, aluminum silicate, magnesium silicate or titanium dioxide; non-stick agents or fillers such as silica or lactose; flavorings such as natural or artificial flavorings; sweeteners such as sugars, such as, for example, sucrose, lactose or sorbitol, and artificial sweeteners such as aspartam or saccharin; wetting agents or surfactants such as different grades of polysorbate, docusate sodium or sodium lauryl sulfate; solubilizing agents such as ethanol propylene glycol or polyethylene glycol; colorants such as FD and C Red No. 3 or FD and C Blue No. 1; and pH modifiers or buffers such as carboxylic acids (including citric acid, ascorbic acid, lactic acid, and succinic acid), various salts of carboxylic acids, amino acids such as glycine or analine, various phosphate, sulfate, and carbonate salts such as trisodium phosphate, sodium bicarbonate or potassium bisulfate, and bases such as, for example, amethoglucose or triethanolamine .
A preferred additive for such formulations is an additional concentration-increasing polymer that can act as a thickener or suspending agent as well as to increase the concentration of the inhibitor in the environment of application and which can also act to prevent or delay precipitation or crystallization of the inhibitor from the solution. . Such preferred additives are hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxypropyl methyl cellulose. In particular, the salts of carboxylic acid functional polymers such as cellulose acetate flalate, hydroxypropyl methyl cellulose acetate succinate and carboxymethyl cellulose are useful in this regard. Such polymers can be added in salt forms or the salt form can be formed in situ during reconstitution by adding a base such as trisodium phosphate and the acid form of such polymers.
In some cases, the total dosage form or the particles, granules or beads that make up the dosage form may have superior performance if coated with an entheric polymer to prevent or delay dissolution until the dosage form leaves the stomach. Examples of entheric coating materials include hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, carboxylic acid functionalized polymethacrylates and carboxylic acid functionalized polyacrylate.
Compositions of the present invention can be administered in a controlled release dosage form. In such a dosage form, the inhibitor and polymer composition is incorporated into a degradable polymer matrix device. By a degradable matrix is meant water degradable or water swellable or water soluble, in the sense of being either degradable or swellable or soluble in pure water or where the presence of an acid or base is required to ionize the polymer matrix to a sufficient extent to cause erosion or dissolution. When brought into contact with the aqueous environment of application, the degradable polymeric matrix absorbs water and forms an aqueous swollen gel or "matrix" that traps the dispersion of inhibitor and polymer. The aqueous swollen matrix gradually erodes, swells, disintegrates or dissolves in the environment of application, thereby controlling the release of the dispersion in the environment of application. Examples of such dosage forms are described with more details in the pending U.S. patent application serial number 09 / 495,059 filed January 31, 2000 claiming the priority of the provisional patent application serial number 60 / 119,400 filed February 10, 1999, the relevant description of which is included in the description as reference.
Alternatively, the compositions of the present invention can be administered via or incorporated into a non-degradable matrix device.
Alternatively, the compositions of the invention may be delivered using a coated osmotically controlled release dosage form. This dosage form has two components: (a) the core containing an osmotic agent and the dispersion of the active agent and the concentration-increasing polymer, and (b) a non-dissolving and non-eroding coating around the core, the coating supplying regulates water to the core starting from an aqueous environment of application, so that drug delivery is effected by expelling part or all of the core to the environment of application. The osmotic agent included in the core of this device can be an aqueous, swellable, hydrophilic polymer, osmogen or osmagent. The coating is preferably of a polymer, water-permeable and has at least one delivery port. Examples of such dosage forms are more fully described in the pending U.S. patent application serial number 09 / 495,061 filed on January 31, 2000, claiming the priority right of provisional patent application serial number 60 / 119,406 filed on February 10, 1999, the relevant description of which in the description is included as a reference.
Alternatively, the compositions may be delivered via a coated hydrogel-controlled release form with at least two components: (a) a core comprising the dispersion of the present invention and a hydrogel and (b) a coating through which the dispersion flows when dosage form exposed to an application environment. Examples of such dosage forms are more fully described in European Patent EP-0,378,404, the relevant description of which is incorporated herein by reference.
Alternatively, the medicament mixture of the invention can be delivered via a coated hydrogel-controlled release dosage form having at least three components: (a) a composition containing the dispersion, (b) a water-swellable composition wherein the water-swellable composition in a separate region is within a core formed by the drug-promoting composition and the water-swellable composition, and (c) a coating around the core that is water permeable, water-insoluble, and has at least one delivery port therethrough. Examples of such dosage forms are more fully described in the pending U.S. patent application serial number 09 / 745,095, filed December 20, 2000 which claims the priority of the provisional application serial number 60 / 171,968, filed December 23, 1999, the relevant description of which in the description is included as a reference.
Alternatively, the compositions may be administered as multiparticles. Multiparticles generally relate to dosage forms comprising a plurality of particles having dimensions ranging from about 10 µm to about 2 mm, more usually about 100 µm to 1 mm in diameter. Such multiparticles may, for example, be packaged in a capsule, such as, for example, a gelatin capsule or a capsule formed of a water-soluble polymer such as HPMCAS, HPMC or starch, or may be metered into a liquid as a suspension or slurry.
Such multiparticles can be produced using a known method, such as wet and dry granulation processes, extrusion / spheronization, cylinder compacting or spray coating seed seeds. For example, in wet and dry granulation processes, the composition of the inhibitor and concentration-increasing polymer as described above is prepared. . This composition is then granulated to form multiparticles of the desired size. Other excipients such as, for example, a binder (e.g., microcrystalline cellulose) can be mixed with the composition to assist during processing and forming the multiparticulates. In the case of the wet granulation, a binder such as microcrystalline cellulose can be incorporated into the granulating fluid to assist in the formation of a suitable multi-particle formulation.
In any case, the resulting particles may themselves form the multiparticulate dosage form or may be coated by various film-forming materials, such as entheric polymers or water-swellable or water-soluble polymers, or may be combined with other excipients or carriers for assist with the administration to patients.
METHODS OF TREATMENT AND TESTING
One aspect of the present invention is directed to a method for the treatment of hyperproliferative diseases, such as cancers in a mammal (including a human) by administration to a mammal in need of such an anti-hyperproliferative effective amount of a composition. of the present invention.
The crystalline and non-crystalline forms and formulations of 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2 4-dichlorophenyl urea are selective inhibitors of the tyrosine kinases, Tie-2, TrkA and related family member TrkB. The potency of these forms and formulations of the present invention with the tyrosine kinases can be determined by applying the following tests. has 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea an IC50 of 144 ng / ml, using a fully activated recombinant GST-TIE2 construct. Determination of inhibition of the inactive (non-phosphorylated) TIE2 kinase by 1- [5- (4-amino-7-isopropyl-7H-pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea resulted in a Ki value of 11.8 ng / ml. In a cell-based assay, 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4) inhibits -dichlorophenyl) urea the TIE-2 kinase activity of a recombinant human erbB-TIE2 chimeric receptor (erbB extracellular domain with TIE2 intracellular domain) that was overexpressed in C6 rat glioma cells (IC50 equal to 2.4 ng / ml) see Schindler et al al., 2000; Noble, et al., 2004.
The in vitro activity of the active agent in the inhibition of the Tie-2 receptor can be determined by the following procedure.
Inhibition of the Tie-2 tyrosine kinase activity is measured in 96-well Maxisorp plates (Nunc) coated with poly-Glu-Tyr (PGT 4: 1, Sigma) by adding 100 ml per well of a 25 pg / ml solution of PGT in PBS. Plates are incubated overnight at 37 ° C and transferred to 4 ° C for use. Prior to testing the compound, suitable dilutions of compounds are made in 96-well polypropylene plates. The active agents can then be diluted to 60-fold of the desired final concentrations in DMSO and then to 4-fold of the desired final concentration in phosphorylation buffer DTT (PB-DTT), a buffer composed of 50 mm HEPES, pH 7.4, 125 mm NaCl, 24 mm MgCl and 2 mm freshly added dithiothreitol (DTT; Sigma) are diluted. The plates coated with PGT are removed from the 4 ° C environment and are washed 5 times with TBST, a wash buffer composed of 1 x tris-buffered saline prepared from a powder (Sigma) containing 0.1 percent polyoxyethylene sorbitan monolaurate (Tween-20, Sigma). Twenty five μΐ of each form or formulation of the active agent dilution per well can then be added to the washed PGT coated plate. Plates can then receive 50 μΐ / well of a 200 mm ATP (Sigma) solution, freshly diluted in PB-DTT from a frozen 50 mm stock solution. Control wells can receive 50 μΐ / well of PB-DTT without ATP. Reactions are then initiated by the addition of 25 μΐ purified GST-TIE-2 fusion protein in PB-DTT. GST-Tie2 could be previously isolated from insect cells infected with GST-Tie-2 baculoviruses and used at concentrations determined such that OD450 signals of about 1.0 in the presence of ATP and absence of chemical inhibitors are provided. Reactions may then be continued for 15 minutes at ambient temperatures with shaking and terminated by washing 5 times with TBST. To detect phosphotyrosine, the wash buffer must be removed and each well receives 75 μΐ of an ant roots peroxidase-conjugated phosphotyrosine monoclonal antibody (HRP-PY20; Signal Transduction Labs), diluted 1: 2000 in block buffer, a buffer composed of washing buffer and 5 percent bovine serum albumin (BSA; Sigma). Plates are incubated for 30 minutes with shaking at ambient temperature and washed 5 times with wash buffer. The bound HRP-PY20 antibody can be detected by the addition of 70 μΐ / well TMP micro-well substrate (KPL) and color development is terminated by the addition of an equal volume of 0.9 m H 2 SO 4. The background signal from wells without ATP can be subtracted from all wells stimulated by ATP and the IC 50 values can be calculated.
The cell assay uses NIH / 3T3 fibroblasts that express a chimeric receptor composed of the extracellular region of human EGFR and the intracellular region of human Tie-2. To measure cellular activity, fifteen thousand cells are inoculated into 96-well U-bottom plates (Falcon) in Dulbecco's modified essential medium (DMEM) containing 2 mm L-glutamine, 0.1 U / ml penicillin, 0.1 pg / ml contains streptomycin and 10 percent fetal calf serum (FCS; all Gibco supplements). Cells are allowed to attach for six hours at 37 ° C, 5 percent CO2, during which time the medium is replaced with 190 μΐ / well depletion medium (fresh medium containing 0.1 percent FCS). The cell plates are put back in the incubator until the following day. Prior to testing the compound, suitable dilutions of compounds are made in 96-well polypropylene plates. The initial dilution series begins with the addition of 15 μΐ of a 4 mm compound stock solution in DMSO to 45 μΐ DMSO; the resulting concentration of 1 mm is diluted in a 1: 4 series in DMSO to obtain concentrations of 1000, 250, 62.5, 15.63, 3.91, 0.98, 0.25 and 0 μτη. In a separate 96-well plate, 20 μΐ of each dilution of the compound are then added to 80 μΐ depletion medium to obtain concentrations of the compound of 200, 50, 12.5, 3.13, 0.78, 0.20, 0.049 and 0 µm in a final DMSO concentration of 20 percent. To dose cells, 10 μΐ of the various dilutions of the compound are added to the plates containing cells, the final concentrations of the compound being obtained from 10, 2.5, 0.63, 0.16, 0.039, 0.01, 0.002 and 0 µm in 1 percent DMSO. Cell plates are allowed to incubate with compounds for 60 minutes at 37 ° C, 5 percent CO2. To activate the chimeric receptors, recombinant EGF (Sigma) is added to a final concentration of 200 ng / ml and plates are incubated for an additional 10 minutes at 37 ° C, 5 percent CO2. The medium is removed and the cells are fixed on ice for 5 minutes using 100 μΐ / well of cold methanol containing 200 μm NaVO4. The fixative is removed and the plates are allowed to dry at ambient temperature. Phosphotyrosine levels are measured in a time-dependent immunoassay with DELFIA Eu-N * -labelled anti-phosphotyrosine antibody (PT66) from Perkin Elmer ™. The antibody is diluted to a final concentration of 0.5 µg / ml in DELFIA test buffer (Perkin Elmer ™) and 100 µl / well is added for 60 minutes at ambient temperature with shaking. The antibody solution is diluted and the plates are washed six times using a 300 μΐ / well DELFIA wash buffer (Perkin Elmer ™). After the final wash, 100 μΐ / well of DELFIA Enhancement Solution (Perkin Elmer ™) is added to each well. The DELFIA Enhancement Solution (Perkin Elmer ™) acts as a means for dissociating the Europium ions that form highly fluorescent chelates. After incubating at ambient temperatures for S minutes with shaking, the plates are read on a Victor2 Multilabel HTS counter (Perkin Elmer ™). The background signal of so-called stimulated wells is subtracted from the EGF-stimulated wells and IC 50 values are calculated.
The in vitro activity of the crystalline and non-crystalline forms and formulations of 1 - [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea in inhibiting the TrkA receptor can be determined by the following procedure.
The ability of the forms and formulations of the active agent of the present invention to inhibit the tyrosine kinase activity of TrkA can be measured using a recombinant enzyme in a test where the ability of phosphorylation inhibitors of the exogenous substrate is measured, polyGIuTyr (PGT, Sigma ™, 4: 1). The kinase domain of the human NGF / TrkA receptor is expressed in Sf9 insect cells as a glutathione S-transferase (GST) fusion protein using the baculovirus expression system. The protein is purified from the lysates of these cells using glutathione agarose affinity columns. The enzyme test is performed in 96-well plates coated with the PGT substrate (1.0 pg PGT per well). The final concentration of ATP in the plates is 40 µm. Test forms and formulations of the active agent are first diluted in dimethyl sulfoxide (DMSO) and are then diluted in a series in a 96-well plate. When added to the PGT plates, the final concentration of DMSO in the test is 0.06 percent. The recombinant enzyme is diluted in phosphorylation buffer (50 mm HEPES, pH 7.4, 0.14 m NaCl, 2.2 mm MgCh, 2.5 mm MnCh, 0.1 mm DTT, 0.2 mm Na3 VO4). The reaction is initiated by the addition of the recombinant enzyme to ATP and to the test compounds. After a 30-minute incubation at room temperature with shaking, the reaction is stopped with 0.5 m EDTA, pH 8.0 and then aspirated. The plates are washed with wash buffer (1 x imidazole wash buffer). The amount of phosphorylated PGT is quantified by incubation with an HRP-conjugated (HRP is anterior root peroxidase) PY-54 antibody (Transduction Labs), developed with ABTS substrate and the reaction mixture is quantified on a Wallac Victor2 plate reader at 405 nm. Inhibition of kinase enzymatic activity by the test compound is detected as a reduced absorption and the concentration of the compound required to inhibit the signal by 50 percent is reported as the IC 50 value of the active agent form or formulation.
For measuring the ability of crystalline and non-crystalline forms and formulations of 1 - [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2- methoxyphenyl] -3- (2,4-dichlorophenyl) urea to inhibit TrkA tyrosine kinase activity for the full-length protein existing in a cellular context, the porcine aorta endothelial cells (PAE) transfected with the human TrkA can be used. Cells are plated and allowed to attach to 96-well dishes in the same medium (Ham's F12) with 10 percent FBS (fetal bovine serum). Test forms or formulations of the active agent dissolved in DMSO are diluted in sets in 96-well test blocks with serum free media containing 0.1 percent fatty acid-free bovine serum albumin (BSA). The cells are then washed, re-fed with serum-free media with and without test compounds, and allowed to incubate for 2 hours. At the end of the 2-hour incubation period, NGF (150 ng / ml final concentration) is added to the media during a 10-minute incubation. The cells are washed and lysed in trisysis buffer (50 mm tris, pH 7.4, 150 mm NaCl, 1 percent NP-40, 10 percent glycerol, 2 mm NasVQi, 0.5 mm EDTA, complete protease inhibitor cocktail tablets without EDTA). TBS is used as a diluent solution for mixing the cell lysates. The degree of phosphorylation of TrkA is measured using an ELISA test. The black, 96-well Maxisorb plates are coated with goat rabbit antibody (Pierce). The Trk (C-14) sc-11 antibody (Santa Cruz) in an amount of 0.4 pg / well is attached to the plates for 2 hours in SuperBlock Blocking Buffer in TBS (Pierce). Any unbound antibody is washed out of the plates prior to the addition of the cell lysate. After a 2-hour incubation of the lysates with the Trk (C-14) sc-11 antibody, the TrkA-associated phosphotyrosine is quantified by development with the HRP-conjugated PY54 antibody and SuperSignal ELISA Femtos substrate (Pierce). The ability of the active agent forms and formulations to inhibit the NGF-stimulated auto-phosphorylation reaction by 50 percent relative to the NGF-stimulated controls is reported as the IC 50 value.
The in vitro activity of the crystalline and non-crystalline forms and formulations of 1 - [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea in inhibiting the TrkB receptor can be determined by the following procedure.
The ability of the compounds of the present invention to inhibit tyrosine kinase activity of TrkB can be measured using a recombinant enzyme in a test where the ability of compounds to inhibit phosphorylation of the exogenous substrate, polyGlyTyr (PGT, Sigma ™, 4: 1) ) is measured. The kinase domain of the human BDNF / TrkB receptor is expressed in Sf9 insect cells as a glutathione S-transferase (GST) fusion protein using the baculovirus expression system. The protein is purified from the lysates of these cells using glutathione agarose affinity columns. The enzyme test is performed in 96-well plates coated with the PGT substrate (1.0 pg PGT per well). The ATP is diluted in phosphorylation buffer (50 mm FIEPES, pH 7.4, 0.14 m NaCl, 0.56 mm MnCl 2, 0.1 mm DTT, 0.2 mm Na 3 VC> 4). The final concentration of ATP in the plates is 300 µm. Test compounds are first diluted in dimethyl sulfoxide (DMSO) and are then diluted in a series in a 96-well plate. When added to the PGT plates, the final concentration of DMSO in the test is 0.06 percent. The recombinant enzyme is diluted in phosphorylation buffer without MnCh. The reaction is initiated by the addition of the recombinant enzyme to the ATP and to the test compounds. After a 2.5 hour incubation at 30 ° C with shaking, the reaction is stopped using 0.5 m EDTA, pH 8.0 and the mixture is then aspirated. The plates are washed with wash buffer (1 x imidazole wash buffer). The amount of phosphorylated PGT is quantified by incubation with an HRP-conjugated anti-phosphotyrosine antibody developed with ABTS substrate and the reaction is quantified on a Wallac Victor2 plate reader at 405 nm. Inhibition of kinase enzymatic activity by the test compound is detected as a reduced absorption and the concentration of the compound required to inhibit the signal by 50 percent is reported as the IC 50 value for the test compound.
For testing the ability of the compounds to inhibit TrkB tyrosine kinase activity for the full-length protein existing in a cellular context, the porcine aorta endothelial (PAE) cells transfected with the human TrkB can be used. Cells are placed on plates and allowed to attach to 96-well dishes in the same media (Ham's F12) with 10 percent FBS (fetal bovine serum). Test compounds dissolved in DMSO are diluted in series in 96-well test blocks with serum-free media containing 0.1 percent fatty acid-free bovine serum albumin (BSA). The cells are then washed, re-fed with serum-free media with and without test compounds and allowed to incubate for 2 hours. At the end of the 2-hour incubation, BDNF (100 ng / ml final concentration) is added to the media during a 10-minute incubation. The cells are washed and lysed in trisysis buffer (50 mm tris, pH 7.4, 150 mm NaCl, 1 percent NP-40, 10 percent glycerol, 2 mm NasVC ^, 0.5 mm EDTA, complete protease inhibitor cocktail tablets without EDTA). TBS is used as a diluent solution to mix the cell lysates. The degree of phosphorylation of TrkB is measured using an ELISA test. The black, 96-well Maxisorb plates are specially coated with goat anti-rabbit antibody (Pierce). The Trk (C-14) sc-11 antibody (Santa Cruz) at a concentration of 0.4 pg / well is attached to the plates for 2 hours in SuperBlock Blocking Buffer in TBS (Pierce). Any unbound antibody is washed from the plates prior to the addition of the cell lysate. After a 2 hour incubation period of the lysates with the Trk (C-14) sc-11 antibody, the TrkB associated phosphotyrosine is quantified by development with an HRP-conjugated antiphosphotyrosine antibody and SuperSignal ELISA Femtos substrate (Pierce). The ability of the compounds to inhibit the BDNP-stimulated auto-phosphorylation reaction by 50 percent relative to the BDNF-stimulated controls is reported as the IC 50 value of the test compound.
Administration of the compound of the present invention (referred to herein as the "active compound") can be performed using any method that allows the delivery of the compounds at the site of action.
These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical and rectal administration.
A preferred administration is the oral administration of a spray-dried dispersion or a pharmaceutical composition of a spray-dried dispersion.
The amount of the active compound that will be administered will depend on the patient being treated, the severity of the condition or disease, the rate of administration and the judgment of the treating physician. However, an effective dosage is within the range of about 0.001 to about 100 mg per kg of body weight per day, preferably about 1 to 35 mg / kg / day, in single or divided doses. For a person weighing 70 kg, this amounts to about 0.05 to about 7 g / day, preferably about 0.2 to 2.5 g / day. In certain cases, dosage levels below the lower limit of the above range may be more than adequate, while in other cases even larger doses may be used without causing a potentially harmful side effect, provided that such lower doses are first divided into a few small doses for administration during day.
The active compound may be used as sole therapy or may contain one or more other anti-tumor substances, for example those selected from, for example, mitotic inhibitors, for example vinblastine; alkylating agents, for example cisplatin, carboplatin and cyclophosphamide; antimetabolites, for example 5-fluorouracil, cytosine arabinoside and hydroxyurea or for example one of the preferred antimetabolites described European patent application 239,362 such as N- (5- [N- (3,4-dihydro-2-methyl-4-oxo-quinazolin-6-ylmethyl) -N -methylamino] -2-thenoyl) -L-glutamic acid; growth factor inhibitor; cell cycle inhibitors; intercalating antibiotics, for example adiamycin and bleomycin; enzymes, for example interferon; and anti-hormones, for example anti-estrogens such as Nolvadex ™ (tamoxifen) or, for example, anti-androgens such as Casodex ™ (4'-cyano-3- (4-fluorophenylsulfonyl) -2-hydroxy-2-methyl-3'-trifluoromethyl) propionanilide ). Such simultaneous treatment can be achieved via simultaneous, sequential or separate dosing of the individual components of the treatment.
The pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained or sustained-release formulations, solution and suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository. The pharmaceutical composition may exist in unit dosage forms suitable for single administration of precise dosages. The pharmaceutical composition will contain a conventional pharmaceutical carrier or excipient and a compound of the invention as an active ingredient. In addition, these other medicinal or pharmaceutical agents may include carriers, adjuvants, etc.
Examples of parenteral dosage forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example aqueous propylene glycol or dextrose solutions. Such dosage forms may suitably be buffered if desired.
Suitable pharmaceutical carriers include inert diluents or fillers, water, and various organic solvents. The pharmaceutical compositions may optionally contain additional ingredients, such as, for example, flavorings, binders, excipients, and so on. Thus, for oral administration, tablets containing various excipients, such as, for example, citric acid, can be used together with various disintegrating agents, such as starch, alginic acid and certain complex silicates, and with binders such as, for example, sucrose, gelatin and acacia. Furthermore, lubricants such as, for example, magnesium stearate, sodium lauryl sulfate and talc are often used for tableting purposes. Solid compositions of a similar type can also be used in soft and hard-filled gelatin capsules. Preferred materials for this include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous solutions or elixirs are desired for oral administration, the active component can thereby be combined with various sweeteners or flavors, colorants or dyes and optionally emulsifiers or suspending agents together with diluents such as water, ethanol, glycol, glycerol or combinations thereof.
Methods for the preparation of various pharmaceutical compositions with a specific amount of active compound are known or will be apparent to those skilled in the art. For example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easter, PA., 15th Edition (1975).
The examples and compositions provided below further illustrate and illustrate the compounds of the present invention and the method for preparing such compounds. It is to be understood that the scope of the present invention is not limited in any way by the scope of the examples and preparations below.
Detailed analytical and preparative PHLC chromatography method referred to in the preparations and examples below are set forth below:
Analytical HPLC method 1,2 and 3: Gilson HPLC equipped with a diode array detector and a MetaChem Polaris 5 µm C18-A 20 x 2.0 mm column; peak detection usually reported in total intensity chromatogram and 210 nm wavelength; solvent A: water with 2 percent acetonitrile and 0.01 percent formic acid; solvent B: acetonitrile with 0.05 percent formic acid; flow rate 1 ml / minute.
Method 1 gradient: 5 to 20 percent solvent B in 1 minute, increasing to 100 percent solvent B after 2.25 minutes, stays at 100 percent B to 2.5 minutes and back to 5 percent B after 3.75 minutes.
Method 2 gradient: 5 to 20 percent solvent B in 1.25 minutes, increasing to 50 percent after 2.5 minutes and to 100 percent B after 3.25 minutes, stays at 100 percent B for 4.5 minutes and back to 5 percent B after 4.5 minutes.
Method 3 gradient: stays with 0 percent solvent B to 1.0 minute, increases to 20 percent after 2.0 minutes, to 100 percent B after 3.5 minutes, back to 0 percent B after 3.75 minutes.
Analytical HPLC method 4: Hewlett Packard-1050 equipped with a diode array detector and a 150 x 4 mm Hewlett Packard ODS hypersil column; peak detection reported at 254 and 300 nm wavelength; solvent A: water with ammonium acetate / acetic acid buffer (0.2 m), solvent B: acetonitrile; flow rate at 3 ml / minute.
Method 4 gradient: 0 to 100 percent B in 10 minutes, stays at 100 percent B for 1.5 minutes.
Preparative HPLC method: Shimadzu HPLC equipped with a diode array detector and a Waters Symmetry or Extera C8 column, 19 x 50 mm or 30 x 50 mm; peak detection usually reported at 210 nm wavelength; solvent A: water with 2 percent acetonitrile and 0.1 percent formic acid; solvent B: acetonitrile with 0.1 percent formic acid; flow rate between 18 and 40 ml / minute.
General preparative HPLC gradient methods are usually a linear 0 to 5 percent B to 100 percent B over a time period of 10 to 25 minutes. Special gradient method with a narrower gradient range, specially made using methods familiar to those skilled in the art, are used for some compounds.
Example 1 1- [4- (4-Amino-7-isopropyl-7H-pyrrole-2,3-diprimidine-5-carbonyl] -2-methoxyphenyl-3 - ('2,4-dichlorophenyl) urea phosphate
A mixture of 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea (37.5 g, 73 mmol) and ethyl acetate / ethanol / dichloromethane (10/9/20, 3.9 L) in a 5 liter flask heated on a steam bath. Additional dichloromethane (500 ml) was added during heating until the starting material had completely dissolved. The solution was cooled for 10 to 15 minutes and phosphoric acid (7.52 g, 1.685 density, 85 wt%, 76.7 mmol) was added. Solid started to precipitate within one minute and the suspension was stirred at room temperature overnight. The reaction mixture was concentrated to 1.5 liters and filtered to give the title compound as a white solid (polymorph A). Melting point 202 ° C (DSC); hygroscopicity 0.8 percent (by weight) at a relative humidity at ambient temperature (RH) of 90 percent; characteristic x-ray powder diffraction peaks (2-theta, [ercent relative intensity]): 4.594 [44.6], 6.222 [100]; combustion analysis (theoretical / experimental) of monophosphate salt: carbon (47.15 / 47.16), hydrogen (4.12 / 3.79), nitrogen (13.75 / 13.55), chlorine (11.60 / 11, 74), phosphorus (5.07 / 5.07).
Example 2
1-f5- (4-Amino-7-isopropyl-7H-pyrromer2.3-dlpvrimidine-5-carbonylV2-methoxylphenyl-3- (2,4-dichlorophenyl urea) (form B1
A suspension of 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea (500 mg, 0.97 mmol) and ethanol (50 ml) was heated on a steam bath. A mixture of ethanol / dichloromethane (9 / 1.5, 105 ml) was added until the starting material had completely dissolved. The solution was cooled to room temperature and methanesulfonic acid (98 mg, 1.02 mmol) was added dropwise. The mixture was stirred at room temperature for 3 days, concentrated in vacuo, without heating, and the precipitate was filtered and stirred in ethyl acetate at 40 ° C for 12 hours. The solid was filtered off and dried to give the title compound as a white solid (polymorph B). M.p. 195 ° C (DSC); hygroscopicity 7.9 percent (by weight) at a relative humidity at ambient temperature (RH) of 90 percent; characteristic x-ray powder diphtheria peaks (2-theta, [ercent relative intensity]): 4.594 [44.6], 6.222 [100]; combustion analysis (theoretical / experimental) of monosylate salt: carbon (49.27 / 49.08), hydrogen (4.30 / 4.04), nitrogen (13.97 / 13.49), chlorine (11.63 / 11, 37), sulfur (5.26 / 5.24).
Example 3 1-15- (4-Amino-7-isopropyl-7H-pyrrolidi-2,3-dl-pyrimidine-5-carbonyl-2-methoxylphenyl-3- (2,4-dichlorophenyl-urea ♦ mesvessel (polyphorphous Al
A suspension of 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea (100 mg, 0.19 mmol) in tetrahydrofuran (6.5 ml) was heated on a steam bath until the starting material had completely dissolved. The solution was cooled to room temperature and methanesulfonic acid (0.166 mg, 0.20 mmol) was added. The mixture was manually filtered at room temperature for 24 hours to obtain the title compound as a white solid (polymorph A). M.p. 212 ° C (DSC); hygroscopicity 1.6 percent (by weight) at a relative humidity at ambient temperature (RH) of 90 percent; characteristic x-ray powder diffaction peaks (2-theta, [ercent relative intensity]): 6.554 [100]; combustion analysis (theoretical / experimental) of the monomesylate salt: carbon (49.27 / 49.36), hydrogen (4.30 / 4.02), nitrogen (13.79 / 13.68), chlorine (11.63 / 11) , 58), sulfur (5.26 / 5.49).
Example 4 1- [5- (4-Amino-7-isopropyl-7H-Diprroli] -2,3-diprimidin-5-carbonyl-2-methoxyphenyl] -3- (2,4-dichlorophenvurea ♦ mesylate 1- [5- (4-amino-7-isopropyl) -7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea mesylate was added to ethyl acetate to form a slurry and was added at 40 ° The product was filtered off to give the title compound as a crystalline white solid of 724 mg (720 mg, m.p. 212 ° C. Analytically calculated for C 24 H 60 O 3 Cl 2, CH 4 SO 3 C 49.27, H 4.30, N 13.79, found: C 49.20, H 4.09, N 13.79, C 49.55, H 3.95, N 13.57.
Example 5 1-15- (4-Amino-7-isopropyl-7H-pyrrolido-2,3-dl-pyrimidine-5-carbonyl-2-methoxy-phenyl-3- (2,4-dichlorophen-urea-mesylate 1- [5- (4-amino-7 isopropyl 7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea mesylate was added to tetrahydrofuran and heated at 40 ° C. The product was filtered off to give the title compound in the form of 638 mg of a white solid (640 mg, m.p. 196-198 ° C. Analytically calculated for C 24 H 26 O 3 Cl 2 * CH 4 SO 3 C 49.27, H 4.30 , N 13.79, found: C 49.44, H 4.12, N 13.63, C 49.13, H 4.04, N 13.58.
Example 6
1-15- (4-Amino-7-isopropyl-7H-pyrrole-2,3-dl-pyrimidine-5-carbonyl-2-methoxy-phenyl-phenyl-dichlorophen-phenolic support) (form B1
A suspension of 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea (500 mg; 974 mm) in ethanol (50 ml) was heated on a steam bath. A mixture of ethanol / dichloromethane (9 / 1.5.105 ml) was added until the starting material had completely dissolved. The solution was cooled to room temperature and methanesulfonic acid (0.098 g, 1.432 density, 99.5% by weight, 1.0 mm) was added dropwise. The mixture was stirred at room temperature for 3 days. The resulting slurry was concentrated in vacuo without heating and the precipitate was filtered off and stirred in ethyl acetate at 40 ° C for 12 hours. The solid was filtered to give the title compound as a white solid (polymorph B).
Example 7 1- (5-Amino-7-isopropyl-7H-pyrrole [2,3-diprimidin-5-carbonyl-2-methoxy] phenyl] -3- (2,4-dichlorophenyl urea; mesorate (polymorph A)
A suspension of 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea (0.1 g) in tetrahydrofuran (6.5 ml) was heated on a steam bath until the starting material had completely dissolved. The solution was cooled to room temperature and methanesulfonic acid (0.020 g, 1.402 density, 0.20 mm) was added. The mixture was stirred at room temperature for 7 days and filtered to give the title compound as a white solid (polymorph A).
Example 8 1- [5- (4-Amino-7-isopropyl-7H-pyrrolidi-2,3-d] pyrimidine-5-carbonyl) -2-methoxy-phenyl] -3- (2,4-dichlorophenyl urea) comprises 1- [5- (4- amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea (1.88 g, 3.66 mmol) was dissolved in dichloromethane / ethanol (5 / 0.7, 57 ml.) Benzenesulfonic acid (0.59 g) in dichloromethane (10 ml) was added to the reaction mixture and stirred at room temperature for 1 hour. The filtrate was suspended in ethyl acetate for 6 days, the solid was filtered and dried to give the title compound (750 mg, 31 percent), m.p. 250 ° C (DSC), hygroscopicity 2.0 percent (by weight) at a relative humidity at ambient temperature (RH) of 90 percent, characteristic X-ray powder diffraction peaks (2-theta, [ercent relative intensity]): 4.594 [44.6], 6.222 [100], combustion analysis (theoretis ch (experimental) of monobesylate salt: carbon (53.66 / 53.38), hydrogen (4.20 / 3.94), nitrogen (12.51 / 12.16), chlorine (10.56 / 10.49) sulfur (4.77 / 4.60).
Example 9 1- [5- (4-Amino-7-isopropyl-7H-pyrrole-2,3-dl] pyrimidine-5-carbonyl-2-methoxy-phenyl-3- (2,4-dichlorophenyl-urea) toss plate 1- [5- (4-amino-7) -isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea (850 mg, 1.66 mmol), p-toluenesulfonic acid ( 303 mg, 1.74 mmol), dichloromethane (5.0 ml) and ethyl acetate (20 ml) were stirred at room temperature for 30 minutes.The mixture was partially concentrated in vacuo and stirred for an additional 2 hours.The reaction mixture was filtered off and the white solid was stirred in ethyl acetate for 5 days, the slurry was filtered and dried to give the title compound as a white solid (0.82 g, 72 percent) Melting point 280-282 ° C Analytical calculated for C 24 H 26 O 3 Cl 2 • CH 4 SO 3 C 54.31, H 4.41, N 12.26, found: C 54.07, H 4.10, N 12.10, C 54.04, H 4.13, N 12, 05. Melting point 255 ° C (DSC), hygroscopicity 1.1 percent (by weight) at a relative v humidity at ambient temperature (RH) of 90 percent; characteristic x-ray powder diffraction peaks (2-theta, [ercent relative intensity]): 4.594 [44.6], 6.222 [100]; combustion analysis (theoretical / experimental) of monotosylate salt: carbon (54.31 / 53.89), hydrogen (4.41 / 4.19), nitrogen (12.26 / 12.08), chlorine (10.34 / 10, 46), sulfur (4.68 / 4.58).
Example 10 1- [5- (4-Amino-7-isopropyl-7H-pvnOolf] -2,3-diprimidine-5-carbonylV2-methoxyphenyl] -1-3- (2,4-dichlorophenOurea
Step 1: 4-chloro-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine 4-Chloro-7 H-pyrrole [2,3-d] pyrimidine (7.5 kg; 1 equivalent) was dissolved in 2 methyl pyrrolidinone (30.8 liters, 4 volumes). Cesium carbonate (31.8 kg, 2 equivalents), dimethylformamide (3.7 l, 0.5 volumes) and 2-iodopropane (16.7 kg, 2 equivalents) were then added to the reactor while maintaining the temperature between 20 and 30 ° C. The reaction was maintained for 5 hours at 2-25 ° C. Ethyl acetate (60 l, 7 volumes) was added and the resulting slurry was filtered through Celite to remove undissolved material. The organic layer was extracted three times with brine (60 L, 4 volumes each) and was then decolorized with Darco KBB (1.5 kg, 20 wt%). Water (60 l, 4 volumes) was added to the altate, the ethyl acetate was removed by distillation and the resulting slurry was granulated in water, isolated and dried under vacuum.
Step 2: 5-bromo-4-chloro-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine
The filtrate (4-chloro-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine (7.0 kg; 1 equivalent)) was dissolved in acetone (35.5 volumes). In a separate vessel, N-bromosuccinimide (6.4 kg, 1 equivalent) was dissolved in acetone (70 l, 10 volumes) and was then transferred after about 90 minutes to the solution of 4-chloro-7-isopropyl-7H-pyrrole [2,3-d] pyrimidine while maintaining the temperature within the range of 15-25 ° C. The reaction mixture was kept at 15-25 ° C for another 30 minutes and then the volume of the reaction mixture was reduced to 35 1 (5 volumes) by vacuum distillation. A solution of sodium thiosulfate pentahydrate (23.3 kg, about 2.75 equivalents) in water (35 l, 5 volumes) was added to produce a biphasic system. The phases were mixed for 30 minutes and then separated. The reaction mixture was then cooled to about 10 ° C and water (35 L, 6.7 volumes) was added to crystallize 5-bromo-4-chloro-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine , which was isolated by filtration and washed with water and then dried.
Step 3: 4-chloro-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidin-5-yl (4-methoxy-3-nitrophenyl) methanone 1 equivalent (7.1 kg) 5-bromo-4- chloro-7-isopropyl-7H-pyrrole [2,3-d] pyrimidine was first dissolved in 35 1 (5 volumes) of toluene. This solution was then cooled to -20 ° C. 1.05 equivalent of n-butyllithium (10.8 L, 2.5 m in hexanes) was then added slowly over a period of 1 hour to minimize a possible exotherm. After completion of the n-butyllithium addition, the reaction mixture was cooled to a temperature within the range of -70 ° C and -80 ° C. 1.2 equivalent of 4-methoxy-3-nitrobenzoyl chloride (7.5 kg) was added in 5 volumes of toluene and this solution was slowly added to the cooled solution of initiated 5-bromo-4-chloro-7-isopropyl-7H-pyrrole [2] 3-d] pyrimidine added. Further addition (for 15 minutes) was maintained so that the temperature in the reactor was maintained below -70 ° C. The reaction was allowed to continue at -78 ° C for 8 hours after which a light yellow slurry was formed. The reaction mixture was allowed to slowly transform to ambient temperature. Water (35.5 volumes) was added to quench the reaction and the product was obtained by filtration.
Step 4: 4-Amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidin-5-yl) (4-methoxy-3-nitrophenyl) methanone
The filtrate (4-chloro-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidin-5-yl) (4-methoxy-3-nitrophenyl) methanone; 4.9 kg) was mixed with 15 1 (3 volumes) of concentrated ammonium hydroxide and 15 1 (3 volumes) of tetrahydrofuran. The reaction mixture was then sealed in a pressure reactor and was heated between 50 ° C and 60 ° C for approximately 24 hours. The maximum pressure was approximately 30 psi. The reaction was then quenched with 50 L (10 volumes) of water and the product was obtained by filtration.
Step 5: 3-amino-4-methoxyphenyl) (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidin-5-yl) methanone
The product (4-amino-7-isopropyl-7H-pyrrole [2,3-d] pyrimidin-5-yl) (4-methoxy-3-nitrophenyl) methanone; 3.9 kg) was mixed with 5 percent palladium on carbon (390 g, 10 wt%) dissolved in 40 1 (10 volumes) tetrahydrofuran. The reaction mixture was then warmed to a temperature between 40 ° C and 50 ° C and a pressure of 45 psig. The reaction continued for approximately 36 to 48 hours. After completion of the hydrogenation, the mixture was filtered and 3-amino-4-methoxyphenyl) (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidin-5-yl) methanone was isolated by displacing tetrahydrofuran with toluene under vacuum.
Step 6: 1 - [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea .
1 equivalent of the product (3-amino-4-methoxyphenyl) (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidin-5-yl) methanone; 3.1 kg) was mixed in with 3.1 1 (1 volume) pyridine and 12.4 1 (4 volumes) ethyl acetate. The reaction mixture was cooled to the temperature between 5 ° C and 10 ° C. 1.01 equivalent (1.84 kg) of 2,4-dichloro-1-isocyanate benzene (solid) was then added in portions to control the exotherm.
Upon completion of the addition, the HPLC test possibly showed some starting material that was left over. Additional 0.1 (184 g) equivalents of 2,4-dichloro-1-isocyanate benzene was added. The product was then obtained by filtration.
The product (1 - [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea ) was dissolved in 35 1 (10 volumes) of pyridine and then filtered. The solution was then placed in 70 1 (20 volumes) of filtered water and 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea precipitated and the solid was isolated by filtration and washed with 7 L (2 volumes) of filtered water.
Alternatively, 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea mixed in a combination of 7.5 1 (5 volumes) ethanol and 3.5 1 (1 volume) acetone. The slurry was stirred at a temperature within the range between 25 ° C and 30 ° C for approximately 48 hours. The product was then obtained by filtration washed with 7 1 (2 volumes) of ethanol. Isolated solid was dried in a vacuum oven between 50 ° C and 60 ° C.
3.2 kg of the product was obtained.
Example 11 1- [5- (4-amino-7-isopropyl-7H-dihydro-2,3,3-drimrimidine-5-carbonyl] -2-methoxyphenyl] -3- (2,4-dichlorophenyl) -urea
Step 1: 4-chloro-7H-pyrrole [2,3-d] pyrimidine 30.5 kg Ν, Ν-diisopropylethylamine (Hunig's base; 1.1 equivalent) and 29 kg of 7H-pyrrole [2,3-d] pyrimidine -4-ol (1 equivalent) was added to 145 l of toluene (5 l / kg) and 65.8 kg of phosphoryl trichloride (2.0 equivalents) at a rate such that the temperature did not exceed 30 ° C. The reaction mixture was heated to 115 ° C for a minimum of 3 hours and was then cooled to 25 ° C and transferred to a solution of 435 l (15 l / kg): 29 l (1 l / kg) of water tetrahydrofuran (THF). During the transfer, the reaction temperature did not exceed 50 ° C. 50% NaOH (36 kg, 4.2 equivalents) was then added at a rate such that the temperature did not exceed 40 ° C and the reaction mixture was stirred for 1 hour. The reaction mixture was concentrated to 145 l (5 l / kg) and the resulting 4-chloro-7 H -pyrrole [2,3-d] pyrimidine was granulated for 2 hours, filtered and with water in 116 l (4 l / kg) crops.
Step 2: 5-bromo-4-chloro-7-isopropyl-7H-pyrrole [2,3-d] 29.5 kg of 4-chloro-7H-pyrrole [2,3-d] pyrimidine (1 equivalent) was added to 30 1 DMF (1 1 / kg) and 450 1 2-methyltetrahydrofuran (2-MeTHF; 15 1 / kg), 2-iodopropane (49 kg, 1.5 equivalent) and cesium carbonate (94 kg, 1.5 equivalent) . The reaction mixture was heated to 80 ° C for 3 hours. Ethyl acetate (148 l, 5 l / kg) was then added and cesium carbonate was filtered from the reaction mixture and rinsed with ethyl acetate (236 l, 8 l / kg). The mother liquor was washed with 1 N HCl (295 1, 10 1 / kg) and brine (295 1, 10 1 / kg) and then concentrated to remove the ethyl acetate. The solution was then added to a slurry of N-bromosuccinimide (NBS; 34 kg, 1.0 equivalent) in 2-MeTHF (295 1, 10 1 / kg) at a rate such that the temperature did not exceed 30 ° C. The reaction mixture was stirred for 1 hour and was quenched with saturated sodium thiosulfate (295 1, 10 1 / kg). After separation of the organic material from the aqueous layer, water (295 L, 10 L / kg) was added and the 2-Me THF was concentrated. The resulting 5-bromo-4-chloro-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine was granulated in water, filtered and dried.
Step 3: 4-chloro-7-isopropyl-7H-pyrrole [2,3-d] pyrimidin-5-yl) (4-methoxy-3-nitrophenyl) methanone 5-bromo-4-chloro-7-isopropyl-7H -pyrrole [2,3-d] pyrimidine CE-265,894 (1 equivalent) was added to toluene (10 l / kg) and the reaction mixture was cooled to 0 ° C or -20 ° C and 2.5 m n-butyl lithium ( n-BuLi (1.1 equivalent)) was added at a rate such that the temperature did not exceed 5 ° C or -18 ° C. The reaction mixture was stirred for 1 hour and was quenched with N, 4-dimethoxy-N-methyl-3-nitrobenzamide (Weinreb amide; 1 equivalent) in toluene (10 l / kg) at a rate such that the temperature reached 10 ° C or -10 ° C. (N, 4-dimethoxy-N-methyl-3-nitrobenzamide was prepared by slowly adding 32 kg of triethylamine (TEA; 2.0 equivalents) to 34 kg of 4-methoxy-3-nitrobenzoyl chloride (1 equivalent), 340 1 of methylene chloride (10 l / kg) and 30.7 kg of N-methoxymethylamine · HCl (2.0 equivalents) such that the temperature did not exceed 30 ° C. The reaction mixture was stirred for 3 hours and was subsequently washed with water at 340 l, 10 l / kg), a saturated sodium bicarbonate solution (340 l, 10 l / kg), a saturated ammonium chloride solution (340 l, 10 l / kg) and brine (340 l, 10 l / kg). The product was crystallized from IPE, filtered, washed with IPE (170 L, 5 L / kg) and dried. The reaction mixture was stirred at 5 ° C-15 ° C for 1 hour and quenched with water (10 l / kg). The slurry was granulated, filtered, washed with water (5 l / kg) and dried. Alternatively, 2 m isoproyl magnesium chloride (iPrMgCl; 1.4 equivalents) was added to 5-bromo-4-chloro-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine CE-265,894 (1 equivalent) in toluene (10 1 / kg) at a speed such that the temperature did not exceed 30 ° C. The reactor was stirred for 3 hours and upon completion of anion was quenched with Weinreb amide N, 4-dimethoxy-N-methyl-3-nitrobenzamide PF-419.852 (1 equivalent) in toluene (10 l / kg) with a speed such that the temperature did not exceed 30 ° C. The reaction mixture was stirred for 3 hours and quenched with water (10 l / kg). The slurry was granulated, filtered and washed with water (5 l / kg) and then dried.
Step 4: (4-amino-7-isopropyl-7H-pyrrole [2,3-d] pyrimidin-5-yl) (4-methoxy-3-nitrophenyl) methanone 8.7 kg of 4-chloro-7-isopropyl- 7 H -pyrrole [2,3-d] pyrimidin-5-yl) (4-methoxy-3-nitrophenyl) methanone (1 equivalent) was added to 26-44 1 28 percent ammonium hydroxide (3-5 1 / kg) and 26 -44 l of THF (26-44 l, 3-5 l / kg). The reaction mixture was heated to 50 ° C-60 ° C and then 87 l of water (10 l / kg) was added and the product (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5 -yl) (4-methoxy-3-nitrophenyl) methanone was granulated, filtered, washed with water and dried.
Step 5: (3-amino-4-methoxyphenyl) (4-amino-7-isopropyl-7H-pyrrole [2,3-d] pyrimidin-5-yl) methanone 6.9 kg (4-amino-7-isopropyl) -7H-pyrrole [2,3-d] pyrimidin-5-yl) (4-methoxy-3-nitrophenyl) methanone PF-2,373,207 (6.9 kg, 1 equivalent) and 69 kg of 10 percent palladium on carbon ( Pd / C; 10 wt%) was added to 138 L of THF (20 l / kg). The reaction mixture was heated to 40 ° C for 2 hours and then to 60 ° C. The catalyst was filtered and rinsed with 21 liters of THF (3 liters / kg). The THF was displaced with 69 liters of toluene (10 liters / kg) and the product was granulated, filtered, washed with toluene and then dried.
Step 6: 1 - [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea 4.8 kg of (3-amino-4-methylphenyl) (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidin-5-yl) methanone (1 equivalent) was added to 48 l of pyridine ( 10 1 / kg). The reaction mixture was stirred and 2.8 kg of 2,4-dichloro-1-isocyanate benzene (1 equivalent) was added in seven portions such that the temperature did not exceed 25 ° C. The product, 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea was quenched with water (96 l, 20 l / kg) and the slurry was stirred for 8 hours. The material was filtered off and the polymorph was reacted with an amount of water of 40 ° C (48 l, 10 l / kg). The material was filtered again and then taken up again in THF (48 1.111 / kg). The material was filtered off, washed with THF (241.5 liters / kg) and dried. The final amount of material that was isolated was 3.9 kg (total process yield was 3.5%).
Example 12
Step 1: 4-chloro-7H-pyrrole [2,3-d] pyrimidine 18.5 kg of 7H-pyrrole [2,3-d] pyrimidine-4-ol (1 equivalent) and 42 kg of POCl 3 (2.0 equivalents) ) were added to 3 liters of toluene (5 liters / kg). N, N-diisopropylethylamine (Hunig's base; 19.4 kg, 1.1 equivalent) was then added at a rate such that the temperature did not exceed 30 ° C. The reaction mixture was heated under reflux (~ 115 ° C) for a minimum duration of 3 hours and was then cooled to 25 ° C and transferred to a solution of 278 l (15 l / kg): 19 l (1 l / kg) water: tetrahydrofuran (THF). During the transfer, the reaction temperature did not exceed 50 ° C. 50 percent NaOH (26 kg, 4.2 equivalents or up to pH 7) was added at a rate such that the temperature did not exceed 40 ° C and the reaction mixture was stirred for 1 hour. The solution was then concentrated and 4-chloro-7H-pyrrole (2,3-d] pyrimidine was granulated for 2 hours, filtered and washed with water (74 l, 4 l / kg). The material was resuspended in water ( 185 (1.11 / kg).
Step 2: 5-bromo-4-chloro-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine 15 kg of 4-chloro-7 H-pyrrole [2,3-d] pyrimidine (1 equivalent) was added to 30 l of dimethylformamide (DMF; 2 l / kg), 150 l of 2-methyltetrahydrofuran (2-MeTHF; 10 l / kg), 25 kg of 2-iodopropane (1.5 equivalents) and 48 kg of cesium carbonate (1.5 equivalents). The reaction mixture was heated to reflux (80 ° C) for 3 hours before 300 L of ethyl acetate (20 L / kg) was added and cesium carbonate was filtered off from the reaction mixture and rinsed with ethyl acetate (120 L, 8 L / kg). The mother liquor was washed with 1 N HCl (150 L, 10 L / kg) and brine (150 L, 10 L / kg) and then concentrated to remove the ethyl acetate. The solution was further displaced in 2-MeTHF (75 L, 5 L / kg) and was then added to a slurry of N-bromosuccinimide (NBS; 12 kg, 1.2 equivalents) in 2-MeTHF (150 L, 10 L / kg) at a speed such that the temperature did not exceed 30 ° C. The reaction mixture was stirred for 1 hour before a further amount of 12.2 kg of NBS (0.7 equivalents) was added. The reaction mixture was quenched with saturated sodium thiosulfate (150 L, 10 L / kg) and then 150 L of water (10 L / kg) was added. After separation of the organic phase from the aqueous phase, water (150 L, 10 L / kg) was added and the 2-MeTHF was evaporated. The material was diluted with ethyl acetate (150 L, 10 L / kg), the layers were separated and then the material was treated with darco. The product, 5-bromo-4-chloro-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine was again concentrated and displaced in heptanes (75 l, 5 l / kg), filtered and dried.
Step 3: 4-chloro-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidin-5-yl) (4-methoxy-3-nitrophenyl) methanone
16.8 kg of 5-bromo-4-chloro-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine (1 equivalent) was added to 135 1 of THF (8 1 / kg). 171 1 2 M
isopropyl magnesium chloride (iPrMgCl; 1.4 equivalents) was added at a rate such that the temperature did not exceed 35 ° C. The reaction mixture was stirred for 3 hours and then quenched with N, 4-dimethoxy-N-methyl-3-nitrobenzamide (Weinreb amide; 15 kg, 1 equivalent) in toluene (168 1, 10 1 / kg) at a rate such that the temperature did not exceed 30 ° C. [N, 4-dimethoxy-N-methyl-3-nitrobenzamide was synthesized by 25 kg of 4-methoxy-3-nitrobenzoic acid (1.0 equivalent) and 22.6 kg of Ν, Ν'-carbonyldiimidazole (CD1; 1.2 equivalents) ) to 250 l of dichloromethane (10 l / kg). The reaction mixture was maintained at 20 ° C-30 ° C for a minimum of 3 hours and then N-methoxymethylamine hydrochloride (17 kg, 1.5 equivalents) was added. The reaction mixture was cooled to 15 ° C and triethylamine (TEA; 16.4 kg, 1.4 equivalents) was added at a rate such that the temperature did not exceed 25 ° C. The reaction mixture was stirred for a minimum of 3 hours and was quenched with water (250 l, 10 l / kg). The product obtained, N, 4-dimethoxy-N-methyl-3-nitrobenzamide, was washed with 1 N HCl (250 l, 10 l / kg) and then with sodium bicarbonate (250 l, 10 l / kg). The material was displaced in IPE (250 L, 10 L / kg) and concentrated to 100 L (4 L / kg). N, 4-dimethoxy-N-methyl-3-nitrobenzamide was granulated for a minimum of 3 hours, filtered and dried. The reaction mixture was stirred for 4 hours and quenched with water (168 l, 10 l / kg). The reaction mixture was adjusted to pH 507 with concentrated HCl (2.95 kg, 1.34 equivalents) and concentrated until the distillation stopped. (4-chloro-7-isopropyl-7H-pyrrole [2,3-d] pyrimidin-5-yl) (4-methoxy-3-nitrophenyl) methanol was granulated, filtered, with IPO (4, 0, 22 l / kg) washed and dried.
Step 4: (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidin-5-yl) (4-methoxy-3-nitrophenyl) methanone: 15.9 kg (4-chloro-7- isopropyl 7 H -pyrrole [2,3-d] pyrimidin-5-yl) (4-methoxy-3-nitrophenyl) methanone (1 equivalent) was added to 48 1 28 percent ammonium hydroxide (3 1 / kg) and 80 1 THF (5 l / kg). The reaction mixture was heated to 50 ° C-55 ° C and then 159 l of water (10 l / kg) was added and (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidin-5-yl (4-methoxy-3-nitrophenyl) methanone was granulated, filtered, washed with water (80 l, 5 l / kg) and dried. A new slurry was prepared in THF (32-48 L, 2-3 L / kg) to remove contaminants.
Step 5: (3-amino-4-methoxyphenyl) (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidin-5-yl) methanone: 4.5 kg (4-amino-7- isopropyl 7 H -pyrrole [2,3-d] pyrimidin-5-yl) (4-methoxy-3-nitrophenyl) methanone (1 equivalent) and 0.45 kg 10 percent palladium on carbon (Pd / C; 10 wt. %) was added to 90 1 of THF (20 1 / kg). The reaction mixture was heated to 40 ° C for 2 hours and then it was heated to 60 ° C. The catalyst was filtered off and rinsed with THF (90 l, 20 l / kg). The THF was displaced with toluene (45 l, 10 l / kg) and (3-amino-4-methoxyphenyl) (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidin-5-yl) methanone was granulated, filtered with toluene (23 l, 5 l / kg) and dried.
Step 6: 1 - [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea : 4.7 kg (3-amino-4-methoxyphenyl) (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidin-5-yl) methanone (1 equivalent) was added to 47 ml of dry pyridine (10 l / kg). The reaction mixture was stirred and 2.7 kg of 2,4-dichloro-1-isocyanate benzene (1 equivalent) was added in seven portions such that the temperature remained at approximately 28 ° C ° C. The reaction mixture was stirred at 28 ° C for 1 hour and was quenched with water (94 l, 20 l / kg). The sludge was stirred for 8 hours. The material was filtered and dried and then THF was resuspended (47 1, 10 1 / kg, stirring for 2 hours, concentrating to 14 1, 3 1 / kg at 40 ° C, stirring for 2 hours), 1- [5 - (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea was filtered at 10 ° C with THF (24 l, 5 l / kg) washed and dried. The final amount of material that was isolated was 6.2 kg.
Example 13 1- (5- (4-amino-7-iso-Dyl-7H-pyrrol-2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl-3- (2,4-dichlorophenyl) urea
The following process was used to prepare a spray-dried dispersion containing 25% by weight of dust and 75% by weight of HPMCAS-HG. First, an amount of 25,600 g of spray solution containing 2% by weight of 1- [5- (4-amino-7-isopropyl-7H-pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3 - (2,4-dichlorophenyl) urea, 6 wt% HPMCAS-HG polymer and 92 wt% tetrahydrofuran (technical grade), prepared as follows. The 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea and tetrahydrofuran were combined in a vessel and mixed for at least 1 hour and allowed 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea in solution. HPMCAS-HG was then added directly to this mixture and the mixture was stirred for a minimum of 2 hours. The resulting mixture is slightly cloudy after the entire amount of polymer has been added; this is due to the granular form of HPMCAS that contains some undissolved material (about 700 μτη size, <0.1 wt% polymer). This mixture was then passed through an on-line filter between the spray dissolving vessel and the spray nozzle to prevent clogging of the underpressure opening of the nozzle to form the spray solution.
The spray-dried dispersion was then formed using the following procedure. The spray solution was pumped using a high pressure pump (a Bran Luebbe, model N-P31) to a spray dryer (a Niro type CP portable spray dryer with a liquid feed process vessel) ("PSD-1") provided with a pressurized nozzle (Schlick 3.0 ). The PSD-1 was equipped with 9-inch and 4-inch room extensions. The spray dryer was also provided with a DPH dosing device for introducing the drying gas into the spray drying chamber. The DPH gas dosing device minimizes hot surfaces in which the SDD particles could possibly be exposed, thereby minimizing SDD adhesion and also minimizing melting during spray drying. The DPH cooling water was used to further minimize the risk of accumulation due to thermal sticking at the gas supply port. The spray solution was pumped to the spray dryer at a rate of about 150 g / minute at a pressure of about 750 psi. Drying gas (e.g. nitrogen) was introduced into the spray dryer through the DPH cover at a supply temperature of about 120 ± 10 ° C. The evaporated solvent and wet drying gas left the spray dryer at a temperature of 60 ± 5 ° C.
The spray-dried dispersion formed by using this method was collected in a cyclone mounted on the drain from the drying chamber and had a bulk specific volume of 5.7 cm / g with an average particle diameter of 17 µm. Continuous beating (at least every 10 minutes) of the drying chamber was performed to minimize the accumulation of dry powder in the spray dryer.
The dispersion formed using the above procedure was post-dried using a Gruenberg convection tray carrier with a powder depth of about 1 cm in operation at 40 ° C for a minimum of 8 hours. After drying, the dispersion was equilibrated with ambient air and humidity (e.g., 20 ° C / 50 percent relative humidity).
Representative properties of the dispersion after secondary drying were as follows:
Table 1. Physical Properties of 25 Nos. 1-5- (4-Amino-7-isopropyl-7H-pyrrole-2,3-dlvvrimidine-5-carbonyl-2-methoxylphenyl-3- (2,4-dichlorophenyl) urea: HPMCAS-HG spray-dried dispersion
In the table above, DV 10 means that the volume% of the particles had a diameter smaller than D 10; DV 50 means that the volume% of the particles had a diameter smaller than D50 and DV90 means that the volume% of the particles had a diameter smaller than D90.
TIE-2 METABOLITES
Administration of the active agent to a dog and a rat resulted in the identification of certain metabolites indicated in the table below. The present invention relates to each of these individual metabolites.

CuHiaN / fc HRMS32 & 37
GmHhCWNtQ,
HRMS 699.07
CuHgCUNaO
1.3-018 (2,4-dichlorophenyl) urea HRMS 350.03
CjSHaAWA HRM8 499.35 C & aO & Oz HRMS 497.11
CaHtiCbN *) »HRMS 497.11
Method for collecting powder X-ray diffraction for 1-fS - ^ - amino - - isopropyl-7H-Dvrrooir2.3-dlpyrimidine-5-carbonylV2-methoxylphenyl-1,3- (2,4-dichlorophenyl-urea salts
Powder X-ray diffraction patterns were collected using a Bruker D5000 diffractometer (Madison Wisconsin) equipped with a copper radiation source, fixed gaps (1.0 mm, 1.0 mm and 0.6 mm) and a Kevex solid state detector. Data was collected in the theta-theta goniometer configuration from a flat plate sample holder at a Copper wavelength 1,5αι = 1.54056 and Ka2 = 1.54439 of 3.0 to 40.0 degrees two-theta using a 0.040 step stage degrees and a pedaling time of 1 second. The results are summarized in the following table.
Table 1: List of powder X-ray diffraction reflections for the phosphate salt form A
Reflections with the highest relative intensity at 5.3, 9.0, 12.8, 15.9 and 23.2 degrees two-theta for the phosphate salt form A. Uppercase (u) indicates unique reflections of form A.
Table 2: List of powder x-ray diffraction reflections for the phosphate salt form B
Reflections with the highest relative intensity at 4.5, 9.7, 13.5, 18.0 and 28.8 degrees two-theta for the phosphate salt form B. Upper script (u) indicates unique reflections of form B.
Table 3: Lists of powder X-ray diffraction reflections for the blade A salt
Reflections with the highest relative intensity at 6.6, 10.0, 12.5, 15.4 and 16.0 degrees two-theta for the mesylate salt form A. Upper script (u) indicates unique reflections of form A.
Table 4: Lists of powder-jet radius diffraction reflections for the knife-plate salt form B
Reflections with the highest relative intensity at 4.6, 6.2, 12.5, 14.2 and 23.2 degrees two-theta for the mesylate salt form B. Upper script (u) indicates unique reflections of form B.
Table 5: List of powder X-ray diffraction reflections for the knife plate salt Form C

Reflections with the greatest relative intensity at 7.1, 8.0, 10.5, 16.0 and 21.5 degrees two-theta for the mesylate salt form B. Upper script (u) indicates unique reflections of form C.
Table 6; List of powder-to-beam diffraction reflections for the B-A salt
Reflections with the highest relative intensity at 7.7, 15.4, 23.7, 24.1 and 27.9 degrees two-theta for the besylate salt form A.
Table 7: List of powder X-ray diffraction reflections for the tos bar salt form A
Reflections with the greatest relative intensity at 7.4, 11.9, 14.8, 22.8, 23.2 and 24.1 degrees two-theta for the tosylate salt form A.
Method for collecting differential scannin calorimetry data for 1-15- (4-amino-7-isopropyl-7H-pyrrole-2,3-dlpvrimidine-5-carbonyl-2-methoxylphenyl-3- (2,4-dichlorophenyl-urea salts)
Thermal phase transition data was collected using a TA Instrument (New Castle Delaware) differential scanning calorimeter Q1000.
Temperature axis and cell constant calibration was accomplished using indium (approximately 5 mg, 99.99 percent purity, peak maximum at 156.6 ° C, fusion heat of 28.4 J / g). Corrugated aluminum sample pans with a hole in the lid were filled with one or two milligrams of sample and then scanned from room temperature to 300 ° C at a rate of 5 ° C / minute. Calibration and sample analysis used empty aluminum sample pans as reference and a dry nitrogen purge gas, flow rate of 50 ml / minute. Initial temperatures were determined by the baseline tangent - peak tangent method.
Table 8: Differential scanning calorimetry analysis

权利要求:
Claims (15)
[1]
A pharmaceutical composition comprising a solid amorphous dispersion of 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2 , 4-dichlorophenyl) urea and a concentration-increasing polymer.
[2]
A pharmaceutical composition comprising a solid amorphous dispersion of 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2 , 4-dichlorophenyl) urea and a concentration-increasing polymer, wherein the 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2- methoxyphenyl] -3- (2,4-dichlorophenyl) urea comprises between 10 and 40% by weight of the solid amorphous dispersion.
[3]
Pharmaceutical composition according to one or more of the preceding claims, wherein the 1 - [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) - 2-methoxyphenyl] - 3- (2,4-dichlorophenyl) urea is substantially amorphous and the dispersion is substantially homogeneous.
[4]
Pharmaceutical composition according to one or more of the preceding claims, wherein said dispersion has a single glass transition temperature.
[5]
A pharmaceutical composition comprising a solid amorphous dispersion of 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2 , 4-dichlorophenyl) urea and a concentration-increasing polymer, wherein the concentration-increasing polymer is present in the solid amorphous dispersion in such an amount that the composition provides a concentration increase of the 1- [5- (4-amino-7-) isopropyl 7H-pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea in an environment of application relative to a control composition consisting essentially of an equivalent amount of the 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea alone and wherein the concentration-increasing polymer is hydroxypropyl methylcellulose acetate succinate.
[6]
Pharmaceutical composition according to one or more of the preceding claims, in which the concentration-increasing polymer composition, when administered at least once over a period of 24 hours in an oral dosage form of between 5 and 500 mg 1- [5- (4-amino) 7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea to a human, has a Cmax plasma level as determined in a fasting rat at a dose of 100 mg 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- ( 2,4-dichlorophenyl urea per kg, between 20,000 ng of base / ml to 1000 ng of base / ml within the 24-hour period.
[7]
Pharmaceutical composition according to one or more of the preceding claims, in which the concentration-increasing polymer composition when at least once during a 24-hour period in an oral dosage form of between 5 mg and 500 mg 1- [5- (4-amino-7) -isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea is administered to a human, has an AUC0-24 plasma level as determined in a fastened rat at a dose of 100 mg 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea per kg, between 150,000 ng of base x hour / ml and 5000 ng of base x hour / ml.
[8]
Pharmaceutical composition according to one or more of the preceding claims, wherein said concentration-increasing polymer composition when it is at least once during a 24-hour period in an oral dosage form of between 5 mg and 500 mg 1- [5- (4-amino-7) -isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) urea is administered to a human, has a Tmax plasma level as determined in a fasting rat at a dose of 100 mg 1- [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2 (4-dichlorophenyl) * urea per kg, for a period of less than 3 hours and 30 minutes.
[9]
Pharmaceutical composition according to one or more of the preceding claims, in which the solid amorphous dispersion is mixed with a further amount of concentration-increasing polymer.
[10]
Pharmaceutical composition according to one or more of the preceding claims, in which the concentration-increasing polymer comprises a mixture of polymers.
[11]
Pharmaceutical composition according to one or more of the preceding claims, in which the concentration-increasing polymer has at least one hydrophobic part and at least one hydrophilic part.
[12]
Pharmaceutical composition according to one or more of the preceding claims, in which the concentration-increasing polymer is selected from the group consisting of ionizable cellulosic polymers, non-ionizable cellulosic polymers and vinyl polymers and copolymers with substituents selected from the group consisting of hydroxyl, alkylacyloxy and cyclic amide.
[13]
Pharmaceutical composition according to one or more of the preceding claims, wherein the concentration-increasing polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, hydroxyethylmethylcellulose, hydroxyethylcellulose acetate, hydroxyethylethylcellulose, hydroxypropylmethylcellulose acetate succinate, cellulose propyl cellulose phthalate, cellulose phthalate cellulose phthalate, cellulose propylate cellulose, cellulose propylate, cellulose phthalate, cellulose phthalate, cellulose phthalate, cellulose phthalate, cellulose phthalate, cellulose phthalate, cellulose phthalate, cellulose phthalate, cellulose phthalate, cellulose phthalate, cellulose phthalate, and cellulose phthalate. cellulose acetate isophthalate and carboxymethyl ethylcellulose.
[14]
Pharmaceutical composition according to one or more of the preceding claims, in which the solid amorphous dispersion is formulated in a tablet.
[15]
A method for the treatment of a hyperproliferative disorder in a mammal, which administers to the mammal a therapeutically effective amount of 1 - [5- (4-amino-7-isopropyl-7 H -pyrrole [2,3-d] pyrimidine-5-carbonyl) -2-methoxyphenyl] -3- (2,4-dichlorophenyl) -urea in combination with one to three anti-tumor agents, selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors and anti-androgens.

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法律状态:
2007-08-01| AD1A| A request for search or an international type search has been filed|

优先权:

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申请号 | 申请日 | 专利标题

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US74907005P| true| 2005-12-09|2005-12-09|

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US74907005|2005-12-09|

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