Maleate salts of (e)-n-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide, and crystalline forms thereof

Abstract

To provide stable, crystalline, water-soluble forms of substituted 3-cyanoquinoline compounds that selectively inhibit kinase activity and then inhibit cell proliferation and tumorigenesis.SOLUTION: The present invention relates to maleate salt forms of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide, methods of preparing crystalline maleate salt forms, associated compounds, and pharmaceutical compositions containing the maleate salt forms. The maleate salts are useful in treating cancers, particularly those affected by kinases of the epidermal growth factor receptor family.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to the maleate salt of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide, its crystalline forms, methods for preparing the salt, related compounds, pharmaceutical compositions containing the maleate salt, and methods of use thereof. The maleate salt of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide is useful in the treatment of cancer. [Background technology]

[0002] Compounds derived from 3-cyanoquinoline have been shown to have antitumor activity, which may make them useful as chemotherapeutic agents in the treatment of various cancers, including, but not limited to, pancreatic cancer, melanoma, lymphoma, parotid tumors, Barrett's esophagus, esophageal carcinoma, head and neck tumors, ovarian cancer, breast cancer, epidermoid tumors, cancers of major organs such as kidney, bladder, larynx, stomach, and lung, colon polyps, and colorectal cancer, and prostate cancer. Examples of compounds derived from 3-cyanoquinoline are disclosed in U.S. Patent Nos. 6,002,008, 6,432,979, and 6,288,082 and have been shown to have antitumor activity. One limitation of certain 3-cyanoquinoline compounds is that they are not water-soluble in their free base form. Summary of the Invention [Problem to be solved by the invention]

[0003] The crystalline form of a particular drug, as its salt, hydrate, and / or any polymorph, is often an important determinant of a drug's ease of preparation, stability, water solubility, storage stability, ease of formulation, and in vivo pharmacology. When certain aspects, such as ease of preparation, stability, water solubility, and / or superior pharmacokinetics, are deemed important, one crystalline form may be preferred over another. The crystalline form of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide salt, which has higher aqueous solubility than the free base yet is stable, fulfills the unmet need for a stable, crystalline, water-soluble form of a substituted 3-cyanoquinoline compound that selectively inhibits kinase activity and subsequently inhibits cell proliferation and tumorigenesis. [Means for solving the problem]

[0004] The present invention provides crystalline forms of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate, isolated and characterized as an anhydrous form, a monohydrate form, and a mixture of the anhydrous and monohydrate forms (referred to as the partially hydrated form). The present invention also relates to methods of using the maleate and its crystalline forms, and to pharmaceutical formulations containing them.

[0005] The present invention provides an isolated crystalline form of anhydrous (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate (Form I), characterized by an onset temperature of melting and decomposition in the range of about 196-204°C by differential scanning calorimetry (DSC).

[0006] The present invention also provides an isolated crystalline form of anhydrous (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate (Form I), which has an X-ray diffraction pattern with the following 2θ angles (±0.20°): 6.16 , 7.38, 8.75, 10.20, 12.24, 12.61, 14.65, 15.75, 17.33, 18.64, 19.99, 20.66, 21.32, 22.30, 23.18, 24.10, 24.69, 25.49, 26.09, 26.54, 27.52, 28.62, and 29.43. In another embodiment, the isolated crystalline form of anhydrous (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate exhibits an X-ray diffraction pattern in which all X-ray diffraction peaks are at approximately the 2θ angles disclosed above.

[0007] The present invention provides an isolated crystalline form of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate monohydrate (Form II), which exhibits a water loss at about 50° C. and is characterized by a water content of about 2.5 to 2.7% by weight, based on the weight of the compound as the monohydrate.

[0008] The present invention also provides an isolated crystalline form of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate monohydrate (Form II), wherein the maleate is characterized by XRD peaks at the following 2θ angles (±0.20°): 6.53, 8.43, 10.16, 12.19, 12.47, 13.01, 15.17, 16.76, 17.95, 19.86, 21.11, 21.88, 23.22, 23.78, 25.69, 26.17, 27.06, 27.58, 28.26, 28.73, and 29.77 in an X-ray diffraction pattern. In another embodiment, the isolated crystalline form of (E)—N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate monohydrate exhibits an X-ray diffraction pattern in which all X-ray diffraction peaks are at approximately the 2θ angles disclosed above.

[0009] The present invention also provides an isolated crystalline form of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate monohydrate (Form II), characterized by DSC, which exhibits an onset temperature in the range of 196-204°C, with melting and decomposition occurring at a transition temperature of about 203.8°C.

[0010] The present invention provides an isolated crystalline form of partially hydrated (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate (Form III), characterized by a water content of about 0.8 to about 2.4% by weight, including about 1.5% to about 2.3% by weight, based on the weight of the compound.

[0011] The present invention provides a method for preparing the maleate salt by combining (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide (free base) with maleic acid and dissolving the mixture in a water-alcohol solution at elevated temperature. The resulting solution is cooled, and the cooled solution contains (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate.

[0012] The present invention also provides a process for preparing (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate in the form of a crystalline monohydrate (Form II), comprising mixing anhydrous (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate (Form I) with an organic solvent and an amount of water, and filtering the crystalline monohydrate that precipitates from the mixture.

[0013] The present invention also provides a process for preparing (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate in the form of a crystalline monohydrate (Form II), comprising the steps of mixing anhydrous (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate (Form I) with an organic solvent, adding a solution comprising an amount of water to the organic solvent, and filtering the crystalline monohydrate that precipitates from the mixture.

[0014] The present invention also provides a process for preparing (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate in the form of a crystalline monohydrate (Form II), comprising mixing anhydrous (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate (Form I) with an organic solvent and an amount of water, and filtering the crystalline monohydrate that precipitates from the mixture.

[0015] The present invention also provides a process for preparing (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate in the form of a crystalline monohydrate (Form II), comprising mixing anhydrous (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate (Form I) with an organic solvent containing an amount of water, and filtering the crystalline monohydrate that precipitates from the mixture.

[0016] The present invention also provides a process for preparing (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate in the form of a crystalline monohydrate (Form II), comprising mixing anhydrous (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate (Form I) with an organic solvent containing an amount of water over a period of several days, and filtering the crystalline monohydrate that precipitates from the mixture.

[0017] The present invention also provides a method for preparing (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate in anhydrous form (Form I), comprising drying (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate in monohydrate (Form II) under vacuum at a temperature above 30° C. for about 12 to about 48 hours.

[0018] The present invention also provides pharmaceutical formulations comprising (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate and one or more related compounds having the following structure:

[0019] [ka]

[0020] The present invention also provides a pharmaceutical composition for inhibiting HER-2 kinase activity, comprising a therapeutically effective amount of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate and a pharmaceutically acceptable carrier. The pharmaceutical composition may also contain one or more related compounds described above. The maleate may be in the anhydrous form, the monohydrate form, or a combination of these forms.

[0021] The present invention also provides a method for preventing, treating, or inhibiting cancer by administering a therapeutically effective amount of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate to a subject. The subject may be a mammal, more specifically a human. The maleate may be administered in anhydrous, monohydrate, or partially hydrated form. One or more of the related compounds described above may also be administered during this method. [Brief explanation of the drawings]

[0022] [Figure 1] 1 is an XRD scan of two crystalline forms of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate, anhydrous form I and monohydrate form II. [Figure 2] FIG. 1 is a dynamic vapor sorption (DSV) isotherm plot of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate, Forms I and II. [Figure 3] 1 is a differential scanning calorimetry (DSC) plot of Forms I and II. [Figure 4] 1 is a thermogravimetric analysis (TGA) plot of Forms I and II. [Figure 5] 1 is an XRD scan of Forms I, II, and III (partially hydrated form) after exposure of Form I to 75% relative humidity at ambient temperature for 22 days. [Figure 6] 1 is an XRD scan of two batches of Form I. [Figure 7] XRD scans of Form II before and after exposure to 50-60% relative humidity at an ambient temperature of 20-25°C for 24 hours. [Figure 8] XRD scans of Form I before and after exposure to 50-60% relative humidity at an ambient temperature of 20-25°C for 24 hours. DETAILED DESCRIPTION OF THE INVENTION

[0023] (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide is an irreversible inhibitor of Her-2 (also known as ErbB-2 or neu) kinase, a member of the epidermal growth factor receptor (EGFR) family. Members of the EGFR family have been implicated in tumorigenesis and have been associated with poor prognosis for certain tumor types in humans. The structure of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide in its free base form is shown below.

[0024] [ka]

[0025] The compound (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide in its free base form is described in U.S. Patent No. 6,288,082. This compound is classified as a BCS Class IV compound (low water solubility and It is classified as a low-permeability (low-permeability and low-permeability) compound. The free base has low solubility in water, with an aqueous solubility of approximately 1 μg / mL at approximately pH 7. Because the compound is ionized, aqueous solubility increases with decreasing pH. The compound is water-soluble at gastrointestinal pH, and degradation is not rate-limiting. Forms of this compound with improved physicochemical properties are sought.

[0026] The present invention provides water-soluble acid addition salt forms of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide. The free base compound can form salts with a variety of pharmaceutically suitable acids, including, but not limited to, acetic acid, fumaric acid, maleic acid, methanesulfonic acid, succinic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid. The physicochemical properties of each acid addition salt form were evaluated to screen for the optimal pharmaceutical salt form, as shown in Table 1.

[0027] [Table 1]

[0028] Of the nine salts, the maleate salt exhibited favorable physicochemical properties. It was crystalline and had low hygroscopicity. The mesylate salt was hygroscopic and had low crystallineity. The tosylate salt was even less attractive, primarily due to its high molecular weight and safety concerns. Although the acetic acid "salt" appeared crystalline, NMR revealed that the product prepared from acetic acid was not in fact a salt. The fact that the product prepared from acetic acid produced an alkaline pH and was insoluble in water confirmed that the product retained much of the properties of the free base.

[0029] As shown in Table 2, (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate is crystalline and has higher solubility in water compared to the free base.

[0030] [Table 2]

[0031] A comparison of systemic exposure (SE) data for (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide was performed on data extracted from multiple preclinical studies in rats. Analysis of these data showed that administration of the compound as the maleate salt increased the AUC (area under the concentration) by 2-fold compared to the free base when administered over the dose range of 5 to 45 mg / kg in rats. The systemic availability of the compound as the free base was relatively low (20%), and the presence of a significant amount of drug in the feces may be due to poor absorption. The increased solubility of the maleate salt is believed to enhance absorption of the compound in rats. Table 3 shows the mean plasma AUC and C of the compound observed in rats. max Show the data.

[0032] [Table 3]

[0033] As shown in Table 4, the maleate salt consistently and reproducibly exhibited beneficial physicochemical properties.

[0034] [Table 4]

[0035] In addition to exhibiting poor aqueous solubility, the free base form of the compound (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide interacts with gastric emetic receptors in mammals, causing diarrhea. However, the maleate salt of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide unexpectedly alleviates this problem and minimizes emetic receptor interaction in mammals.

[0036] The maleate salt is prepared by combining (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide (free base) with maleic acid and dissolving the mixture in a water-alcohol solution at elevated temperatures. The resulting solution is cooled, and the cooled solution contains (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate. According to one embodiment, (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate is prepared by combining maleic acid and the free base in a solution of water and n-propanol, as depicted in Scheme 1.

[0037] [ka]

[0038] The reaction of the free base with maleic acid occurs at elevated temperatures of about 40°C to about 60°C, preferably about 40°C to about 50°C. The water:n-propanol ratio can vary, for example, from about 1:10 to about 1:5, with the optimum water:n-propanol ratio being about 1:9. The water-alcohol solution can contain about 5% to about 20% water by volume and about 80% to about 95% alcohol by volume. The alcohol can be n-propanol. In one embodiment, the water-alcohol solution contains about 10% water by volume and about 90% n-propanol by volume. The volume of the solvent solution can be about 8 to about 25 volumes, including about 10 to about 12 volumes. About 1.0 to 1.2 equivalents of maleic acid per equivalent of free base, preferably about 1.03 equivalents of maleic acid per equivalent of free base, is used.

[0039] The resulting maleate solution can be clarified by filtration prior to cooling. The cooling step can be continued until the solution reaches a temperature of about 45°C or less, including a temperature of about 39°C or less, more preferably about 30°C or less. In one embodiment, after cooling to about room temperature, preferably about 23°C to about 25°C, the solution is filtered. Typically, the maleate salt begins to crystallize out of solution when the temperature reaches 37°C or less. The solution is allowed to stand at room temperature for at least 12 hours, preferably about 12 to about 15 hours, and then filtered and washed to recover the crystalline maleate salt product. The resulting filter cake can be washed with the same or a different aqueous-alcoholic solution to obtain the product. The product can be dried to obtain crystalline (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate. At this point, the recovered and isolated maleate product is typically in the form of a maleate monohydrate.

[0040] The product can be dried under vacuum with heating to produce the anhydrous form of the maleate salt (Form I) in a yield of about 70 to about 95%, preferably about 80 to about 95%. This product is usually better than about 98% pure, and often better than about 99% pure. Typically, the drying step is carried out for about 12 to about 48 hours to ensure complete conversion of the anhydrous form of the maleate salt to the monohydrate form of maleic acid (Form II). Shorter drying times generally result in a mixture of the two crystalline forms. The drying step is often carried out at temperatures above room temperature. In one embodiment, the maleate salt is dried at a temperature above about 30°C, preferably about 40°C to about 60°C, and in another embodiment at about 50°C.

[0041] The maleate salt is soluble in many polar solvents known to those skilled in the art, although dimethyl sulfoxide (DMSO) is often used when a small volume of solvent is desired. The DMSO solution can be heated to about 45°C to about 60°C to further enhance solubility. Once the anhydrous maleate salt has dissolved, typically quickly, water can be added, causing crystallization and filtration to obtain the crystalline monohydrate form. The anhydrous salt can be dissolved in a solvent, such as DMSO, and to this solution can be added an aqueous solution of water and an organic solvent, such as tetrahydrofuran (THF), isopropanol (IPA), n-propanol, acetone, ethanol, methanol, and acetonitrile. In one embodiment, the organic solvent used is IPA; in another embodiment, n-propanol; and in a third embodiment, a mixture of these two organic solvents is used. The water content of the aqueous solution can be as little as 5% but can be about 7.5% or more, and in one embodiment, about 10% to about 15%. The resulting solution is then allowed to stand for up to about 24 hours, and in one embodiment, from about 12 to about 24 hours, to allow crystallization to occur. The mixture is filtered to obtain the crystalline monohydrate form of the maleate salt. For purposes of the present invention, the term "organic solvent and water" refers to a solution of an organic solvent, such as tetrahydrofuran (THF), DMSO, methanol, ethanol, isopropyl alcohol, or acetonitrile, and water, wherein the organic solvent comprises more than 50% by volume of the solution.

[0042] The maleate salt of (£)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide of the present invention has been isolated in three different crystalline forms: an anhydrous form (Form I), a monohydrate form (Form II), and a partially hydrated form (Form III) containing a mixture of Forms I and II.

[0043] According to one embodiment, the anhydrous form of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate (Form I) is obtained as a crystalline solid by drying the reaction product of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and maleic acid. Drying includes air drying, heating, and vacuum drying. In another embodiment, the anhydrate form of (£)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate (Form I) is obtained as a crystalline solid by drying the monohydrate form of (£)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate (Form II).

[0044] The isolated crystalline form of anhydrous (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate (Form I) is characterized by differential scanning calorimetry (DSC) as exhibiting an onset temperature for melting and decomposition in the range of approximately 196-204°C.

[0045] The maleic anhydride salt (Form I) is characterized by X-ray diffraction (XRD) peaks at the following 2θ angles (±0.20°) in the X-ray diffraction pattern: 6.16, 7.38, 8.75, 10.20, 12.24, 12.61, 14.65, 15.75, 17.33, 18.64, 19.99, 20.66, 21.32, 22.30, 23.18, 24.10, 24.69, 25.49, 26.09, 26.54, 27.52, 28.62, and 29.43. In another embodiment, the isolated crystalline form of anhydrous (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate (Form I) exhibits an X-ray diffraction pattern in which all X-ray diffraction peaks are at approximately the 2θ angles disclosed above.

[0046] According to one embodiment, (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate is prepared in a crystalline monohydrate form (Form II) by mixing anhydrous (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate (Form I) with an organic solvent and an amount of water and filtering the crystalline monohydrate that precipitates from the mixture.

[0047] According to another embodiment, the crystalline monohydrate form (Form II) of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate is prepared by mixing anhydrous (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate (Form I) with an organic solvent, adding a solution containing an amount of water to the organic solvent, and filtering the crystalline monohydrate that precipitates from the mixture.

[0048] In another embodiment, the crystalline monohydrate form (Form II) of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate is prepared by mixing anhydrous (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate (Form I) with an organic solvent containing an amount of water over a period of several days and filtering the crystalline monohydrate that precipitates from the mixture. Suitably, the period of several days is about 1 to 20 days.

[0049] An isolated crystalline form of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate monohydrate (Form II) exhibits a water loss at about 50°C as determined by DSC and is characterized by a water content of about 2.5 to 2.7 wt.%, based on the weight of the compound as the monohydrate, as determined by thermogravimetric analysis (TGA). The water content of the monohydrate form of the maleate salt was also determined by Karl Fischer titration.

[0050] Monohydrate (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate (Form II) is characterized by X-ray diffraction (XRD) peaks at the following 2θ angles (±0.20°): 6.53, 8.43, 10.16, 12.19, 12.47, 13.01, 15.17, 16.76, 17.95, 19.86, 21.11, 21.88, 23.22, 23.78, 25.69, 26.17, 27.06, 27.58, 28.26, 28.73, and 29.77. In another embodiment, the isolated crystalline form of (E)—N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate monohydrate exhibits an X-ray diffraction pattern in which all X-ray diffraction peaks are at approximately the 2θ angles disclosed above.

[0051] As used herein, the term isolated means that more than 50% of the crystalline (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate present is one of Forms I and II. In one embodiment, at least 70% of the crystalline (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate present is one of Forms I and II. In a second embodiment, at least 80% of the maleate present is one of Forms I and II. In a third embodiment, at least 90% of the maleate present is one of Forms I and II.

[0052] The two crystalline forms of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate exhibit distinct and distinct XRD patterns and peaks. The XRD pattern of each maleate salt form is unique to that salt form. The XRD patterns of Forms I and II were determined using techniques and equipment known to those skilled in the art of analytical chemistry and X-ray crystallography. The XRD patterns were generated using powder samples and consist of a series of diffraction peaks that can be expressed in terms of 2θ angles, d-spacing, and / or relative peak intensities. The XRD patterns are shown in Figures 1, 5, 6, 7, and 8. The collection parameters for the X-ray data shown in Figures 1, 7, and 8 were as follows: The X-ray data for Figures 5 and 6 were collected using a Rigaku MiniFlex benchtop X-ray diffractometer with a voltage of 30 kV, current of 15 mA, scan range of 3–40°, and scan time of 2.00° / min on a Bruker D8 Advance instrument with a scan width of 0.01° and a total scan time of 30 min, using a Vantec-1 detector and Ni filter.

[0053] The 2θ diffraction angles and corresponding d-spacing values ​​describe the positions of peaks found in the XRD pattern. The d-spacing values ​​are calculated using the Bragg equation based on the observed 2θ angles and copper Kα wavelength. Variations in these numbers may occur due to the use of different diffraction instruments and sample preparation methods. However, more variation can be expected in relative peak intensities. Therefore, identification of various forms should be based on the observed 2θ angles and d-spacings, with less emphasis on intensity. Those skilled in the art will understand that the XRD patterns of Forms I and II obtained as described herein may contain additional peaks. Furthermore, those skilled in the art will recognize that whether all peaks are observed for a given form may depend greatly on the concentration level of that form. Figure 1 illustrates XRD scans of two crystalline forms of the maleate salt, Forms I and II. The crystalline anhydrous maleate form, Form I, is shown below, and the crystalline monohydrate form of the maleate salt, Form II, is shown below.

[0054] The relative stability and hygroscopicity of the two crystalline forms of the maleate salt were studied in detail by dynamic vapor sorption (DVS). The anhydrous form of the maleate salt readily absorbs water and converts to the crystalline monohydrate form of the maleate salt. As summarized in Figure 2, upon drying or a decrease in relative humidity, the crystalline monohydrate form of the maleate salt converts to the anhydrous form of the maleate salt. Figure 2 is a dynamic vapor sorption isotherm plot showing that (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate Form I gains moisture at relative humidity (RH) above 40%, particularly at RH above 60%. Figure 2 also shows that Form II loses moisture at RH below 20%, particularly at RH below 10%. DVS was performed under the following conditions: The RH was set to 0%, 30%, 52.5%, 75%, and 90%, and the samples were exposed to each RH for 3 hours for two complete cycles.

[0055] The two crystalline forms of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate exhibit distinct DSC traces. DSC plots for both Form I and Form II of the maleate are summarized in Figure 3. Form I of the maleate exhibits a single endothermic peak, suggesting a transition temperature of 202.49 °C. Form II of the maleate exhibits two endothermic peaks, a broad endotherm with an onset temperature of 55 °C corresponding to water loss, and a second endotherm suggesting a transition temperature of 202.81 °C. The transition temperatures are observed in the range of approximately 196 to 204 °C, where melting and decomposition occur. DSC data, transition temperatures, and heat flow were collected using a TA Instrument Model Q1000 with the following parameters: 50 mL / min (N2) gas purge, scan range 40 to 240 °C, scan rate 10 °C / min. Pure crystalline solids have a characteristic transition temperature, the temperature at which the substance changes state, in this case, the solid transitions to a liquid. The transition between solid and liquid is very sharp in small samples of pure substances, so the transition temperature can be measured to within 0.1 °C. Because it is difficult to heat solids above the transition temperature and pure solids tend to transition over a very small temperature range, transition temperatures are often used to aid in compound identification. Measuring the transition temperature of a solid can also provide information about the purity of the substance. Pure crystalline solids transition over a very narrow temperature range, while mixtures transition over a wide temperature range. Mixtures also tend to transition at temperatures lower than the transition temperature of the pure solid.

[0056] TGA data for the monohydrate and anhydrous forms of the maleate salt are summarized in Figure 4. Form II of the maleate salt is characterized by a water content of approximately 2.5 to 2.7 wt.%, based on the weight of the compound as the monohydrate, as determined by TGA. TGA data were collected using a TA Instrument Model Q. A heating rate of 10 °C / min was used between 30 and 220 °C, and the TGA chamber was under a nitrogen flow of 40 mL / min.

[0057] As observed from XRD, a third crystalline form of the maleate salt has been observed and is designated as a partial hydrate (Form III). The partial hydrate is a mixture of Forms I and II of the maleate salt. Partially hydrated (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate (Form III) is characterized by a water content of about 0.8 to about 2.4% by weight, including about 1.5% to about 2.3% by weight, based on the weight of the compound.

[0058] Figure 5 contains XRD scans of the anhydrous form I, monohydrate form II, and partially hydrate form III of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate after exposing the anhydrous forms of the maleate salt to 75% relative humidity at an ambient temperature of 20-25°C for 22 days.

[0059] Figure 6 shows XRD scans of two batches of crystalline (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate in Form I. The anhydrous form of the maleate absorbs water over a 24-hour period at ambient temperatures of 20-25°C and is partially converted to the monohydrate form of the maleate. The monohydrate form of the maleate is relatively stable over a 24-hour period at ambient temperatures of 20-25°C. Figure 7 illustrates XRD scans of Form II crystalline (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate before and after exposure to 50-60% relative humidity at an ambient temperature of 20-25°C for 24 hours. Exposing the monohydrate form of the maleate to elevated temperatures (>50°C) or heating under reduced pressure promotes water loss and complete conversion back to the anhydrous form of the maleate.

[0060] The anhydrous form, Form I, readily converts to the monohydrate form, Form II. As shown in Figure 8, Form I absorbs water over time at temperatures between 20 and 25°C and relative humidity (RH) between 50 and 60%, and can partially convert to the monohydrate. Figure 8 shows XRD scans of crystalline (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate of Form I before (bottom scan) and after (top scan) exposure to 50 and 60% RH at room temperature between 20 and 25°C for 24 hours. Hydrate peaks appear in the top scan, suggesting that the crystals absorb water under these conditions.

[0061] The stability of both forms of the maleate salt of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide was evaluated in sealed and open containers at 40°C and 75% RH. Under these conditions, both Form I and Form II remained stable for 6 months. In open containers, the anhydrous form of the maleate salt rapidly absorbed 1 mole of water to form the monohydrate form of the maleate salt. Samples in sealed containers remained dry. HPLC purity analysis indicated no significant increase in degradation products in both open and sealed containers for up to 6 months. The data are summarized in Table 5.

[0062] [Table 5]

[0063] To determine which crystalline form of the maleate salt was obtained, reactive crystallization of the free base with maleic acid was carried out in various solvents. Table 6 illustrates the results of the crystallization process in a mixture of n-propanol and water under various operating conditions. In all experiments, the wet cake contained the monohydrate form of the maleate salt, which converted to the anhydrous form of the maleate salt after drying.

[0064] [Table 6]

[0065] Table 7 shows the results of reactive crystallization of the free base with maleic acid in various solvents; all experiments yielded the anhydrous form of the maleate salt.

[0066] [Table 7]

[0067] One solvent that clearly dissolves (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate is dimethyl sulfoxide (DMSO). Cooling, nonsolvent, and evaporative crystallization were performed in mixtures of DMSO with isopropanol or t-butyl methyl ether (tBME). This procedure resulted in decomposition of the solute in many instances. As summarized in Tables 8 and 9, nonsolvent and evaporative crystallization did not yield any new crystalline forms.

[0068] [Table 8]

[0069] [Table 9]

[0070] According to one embodiment, one method of converting anhydrous Form I to monohydrate Form II is by dissolving it in a solution of water and an organic solvent, such as THF, isopropanol (IPA), n-propanol, acetone, ethanol, methanol, and acetonitrile, where the water is present in an amount of about 5% to about 20% by volume, but typically about 10% to about 15% by volume. The solution can be heated to increase the solubility of the maleate salt; in one embodiment, the solution is heated to about 45° C. or higher, and in another embodiment, the solution is heated to about 60° C. The solution is then allowed to stand for several hours to allow crystallization, after which the crystals are filtered to obtain monohydrate Form II (see Table 6). In one embodiment, the solution is allowed to stand for about 12 to about 24 hours, and then filtered.

[0071] According to another embodiment, Form I is converted to Form II by reslurrying Form I in an organic solvent containing water and exposing the solution to room temperature for several days, as shown in the stability studies summarized in Table 10. As is evident from Figure 8, anhydrous Form I readily absorbs moisture, so this conversion occurs even in anhydrous solvents that have absorbed up to 1% water. In one embodiment, the reslurry is allowed to stand for about 14 days.

[0072] [Table 10]

[0073] The present invention also relates to the free base or maleate salt of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide, or compounds related to the method of the present invention. One or more of these related compounds may be found in the cooling solution during the process of the present invention. Because these compounds may not be separated from the maleate salt, pharmaceutical formulations prepared with the maleate salt may contain one or more of these compounds.

[0074] Formulations of the maleate salt were prepared and stored in a stability chamber at 40°C / 75% RH for six months and in an oven at 56°C for one month. Samples were periodically withdrawn for testing. Samples were dissolved in 50 / 50 volume / volume acetonitrile / water at a concentration of approximately 0.5 mg / mL. The solutions were assayed directly using an LC / MS method to identify degradation products and impurities (referred to herein as related compounds) at six months. The structures of related compounds detected by LC / MS are listed in Table 11. In particular, the amount of degradation products associated with (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate is reduced by the production method of the present invention.

[0075] [Table 11]

[0076] The names of these related compounds are as follows: 2-({4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}amino)-2-oxoacetic acid; N 1 -{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-ethanediamide; 6-amino-4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-7-ethoxy-3-quinolinecarbonitrile; 4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-7-ethoxy-6-(2-hydroxy-5-oxopyrrolidinyl)-3-quinolinecarbonitrile; N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-3,4-bis(dimethylamino)butanamide; N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-1-methyl-2,3-dioxo-4-piperidinecarboxamide; N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}acetamide; (E)-4-({4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}amino)-N,N,N-trimethyl-4-oxo-2-buten-1-aminium N 1 -{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-N 2 ,N 2 -dimethylethanediamide; 4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinylformamide; and 4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-7-ethoxy-6-[(1-methyl-2-pyrrolidinylidene)amino]-3-quinolinecarbonitrile.

[0077] The crystalline form of the maleate salt of the present invention is useful for preventing, treating, or suppressing inflammation or cancer by administering a therapeutically effective amount of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate to a subject. The subject may be a mammal, more specifically a human. The maleate salt may be administered in anhydrous, monohydrate, or partially hydrated form. One or more related compounds described above may also be administered during this method.

[0078] The crystalline maleate form of the present invention is useful for preparing a pharmaceutical composition for inhibiting HER-2 kinase activity, which is related to the treatment of cancer. The formulation contains a therapeutically effective amount of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate and a pharmaceutically acceptable carrier. The pharmaceutical composition can be administered in anhydrous, monohydrate, or partially hydrated form. One or more of the related compounds described above can also be administered during this method.

[0079] The pharmaceutical compositions and formulations of the present invention may be useful in treating one or more of breast cancer, ovarian cancer, epidermoid tumors, colon cancer, prostate cancer, kidney cancer, bladder cancer, laryngeal cancer, esophageal cancer, gastric cancer, and lung cancer. According to one embodiment, the maleate salt is particularly useful in treating breast cancer and / or ovarian cancer.

[0080] Pharmaceutical compositions and formulations containing the maleate salt form of the present invention can be administered orally or by intralesional, intraperitoneal, intramuscular, or intravenous injection; infusion; liposome-mediated delivery; topical, nasal, anal, vaginal, sublingual, urethral, ​​transdermal, intrathecal, intraocular, or intraaural delivery. One mode of administering the compounds of the present invention is in unit dose form. Suitable unit dose forms include tablets, capsules, and powders in sachets or vials. The crystalline compounds of the present invention can be administered orally. Such compounds can be administered one to six times daily, more typically one to four times daily. Effective amounts will be known to those skilled in the art. The effective amount may also depend on the form of the compound, the mode of administration, and the severity of the condition being treated. Those skilled in the art can routinely perform experimental activity tests to determine the biological activity of the compound in bioassays and thereby determine the dosage to be administered. However, generally, satisfactory results can be obtained with the compounds of the present invention when administered daily in the range of about 0.5 mg to about 1000 mg per kg of body weight, with the effective dosage usually being from about 1 mg / kg to about 300 mg / kg per day.

[0081] The crystalline form of the maleate salt of the present invention can be formulated with conventional excipients such as fillers, disintegrants, binders, lubricants, flavoring agents, color additives, and carriers. The carrier can be a diluent, an aerosol, a topical carrier, an aqueous solution, a non-aqueous solution, or a solid. The carrier can be a polymer or toothpaste. Carriers of the present invention include any standard pharmaceutically acceptable carrier, such as phosphate buffer solution, acetate buffer solution, water, emulsions (e.g., oil / water emulsions, or triglyceride emulsions), various wetting agents, tablets, coated tablets, and capsules.

[0082] When administered orally or topically, the crystalline form of the maleate salt of the present invention can be provided to a subject in a variety of carriers. Typically, such carriers contain excipients such as starch, milk, sugar, certain clays, gelatin, stearic acid, talc, vegetable oils, gums, or glycols. The specific carrier is typically selected based on the desired delivery method; for example, phosphate buffer solution (PBS) can be used for intravenous or systemic delivery, and vegetable oils, creams, ointments, salves, or gels can be used for topical delivery.

[0083] The crystalline forms of the maleate salt of the present invention can be delivered with suitable diluents, preservatives, solubilizers, emulsifiers, adjuvants, and / or carriers that are useful in treating, inhibiting, or preventing neoplasia. Such compositions may be liquid or lyophilized or otherwise dried formulations containing diluents (e.g., Tris-HCl, acetate, phosphate) of various pH and ionic strength buffer contents, additives such as albumin or gelatin to prevent absorption to surfaces, surfactants (e.g., TWEEN™ 20, TWEEN™ 80, PLURONIC™ F68, bile salts), solubilizers (e.g., glycerol, polyethyleneglycerol), antioxidants (e.g., ascorbic acid, sodium metabisulfate), preservatives (e.g., thimerosal, benzyl alcohol, parabens), bulking agents or tonicity adjusters (e.g., lactose, mannitol), covalently linked polymers such as polyethylene glycol, complexes with metal ions, or incorporation of the compound into or on particulate preparations of hydrogels or liposomes, microemulsions, micelles, unilamellar or multilamellar vesicles, erythrocyte ghosts, or spheroblasts. Such compositions will influence the physical state, solubility, stability, rate of in vivo release, and rate of in vivo clearance of the compound or composition. The choice of composition will depend on the physical and chemical properties of the compound.

[0084] The crystalline form of the maleate salt of the present invention can also be delivered locally via a capsule that allows for sustained release of the compound over a period of time. Controlled or sustained release compositions include formulation in lipophilic depots (e.g., fatty acids, waxes, oils).

[0085] The crystalline form of the maleate salt of the present invention can also be administered with other active compounds, such as chemotherapeutic agents or antibiotics, or in conjunction with radiation therapy, to benefit patients suffering from cancer.These active compounds can be administered simultaneously or sequentially with the compound of the present invention.The compound of the present invention can also be formulated to contain other active compounds in the same dosage form, for example, both can be contained in one pill, tablet, or capsule.Some possible types of active compounds that can be used in combination with the compound of the present invention are mitotic inhibitors such as taxol and vinblastine, alkylating agents such as cisplatin and cyclophosphamide, antimetabolites such as 5-fluorouracil and hydroxyurea, DNA intercalators such as adriamycin and bleomycin, topoisomerase inhibitors such as etoposide and camptothecin, antiangiogenic agents such as angiostatin, and antiestrogens such as tamoxifen.

[0086] The present invention will be described in more detail in conjunction with the following specific examples, which should not be construed as limiting the scope of the present invention. Those skilled in the art will be able to rearrange, combine, modify, or delete steps of the illustrated processes depending on process parameters and equipment. [Example]

[0087] Example 1 Preparation of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate, Form II Rinse crude (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide free base (0.100 kg, 0.159 mol) with a 10% solution of USP purified water in n-propanol (0.082 kg, 0.10 L), followed by a water:n-propanol solution (0.74 kg, 0.90 L). Add maleic acid (0.0191 kg, 0.164 mol) and rinse the mixture with 10% water:n-propanol (0.082 kg, 0.10 L). Rapidly heat the mixture to 50-60 °C and hold for a minimum of 15 min until a solution is obtained. Clarify the hot solution through a 0.2 mm filter cartridge preheated to 50-60°C and collect the filtrate in a 2 L multi-neck flask preheated to 45-55°C. Rinse the filter cartridge with 10% water:n-propanol (0.082 kg, 0.10 L) preheated to 45-55°C. Cool the solution to 40°C over at least 1 hour and hold at that temperature for 12 hours, then cool to room temperature (25°C) over a minimum of 4 hours and hold at that temperature for at least 2 hours. Filter the mixture through a 12.5 cm diameter Buchner funnel for 5 minutes, then rinse and wash with prefiltered 10% water:n-propanol solution (2 x 0.12 kg, 2 x 0.15 L). Dam the cake and maintain suction until dripping essentially stops, approximately 1 hour.

[0088] Example 2 Preparation of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate, Form I The product of Example 1 (Form II) is dried (50° C., 10 mmHg, 24 hours) to give 94.4 g (88% yield) of crystalline anhydrous (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate (Form I) (88% yield) with a strength of 80.8% (free base), 17.4% (maleic acid), 1.06% total impurities, and a maximum single impurity of 0.38%.

Claims

[Claim 1] A pharmaceutical formulation as described in the specification.

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