CN101238118A

CN101238118A - Salts and polymorphs of a VEGF-R inhibitor

Info

Publication number: CN101238118A
Application number: CNA2006800287683A
Authority: CN
Inventors: 李毅; 刘佳; A·西斯特拉; B·J·埃尔德; 洪玉峰; P·K·伊斯比斯特; G·J·帕尔莫; J·S·萨尔斯伯里; L·G·尤利塞斯
Original assignee: SmithKline Beecham Ltd
Current assignee: SmithKline Beecham Ltd; Pfizer Inc
Priority date: 2005-08-08
Filing date: 2006-07-27
Publication date: 2008-08-06
Also published as: ZA200800655B

Abstract

The invention relates to salts and free base forms of N,2-dimethyl-6-[7-(2- morpholinoethoxy)quinolin-4-yloxy]benzofuran-3-carboxamide. The invention further relates to pharmaceutical compositions of these salts and free base forms and methods of treating disorders such as cancer using such compositions.

Description

The salt of VEGF-R inhibitor and polymorphic

The application requires the right of priority of Application No. of submitting on August 8th, 2,005 60/706,332 and the Application No. of submitting on December 14th, 2,005 60/750,189, and both all introduce by reference at this.

Technical field

The present invention is about N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] salt form and the polymorphic of cumarone-3-methane amide, it is applicable to the mammiferous abnormal cell growth of treatment, such as cancer.The present invention is also about comprising this salt and polymorphous composition, and about using said composition to treat Mammals, the method for especially human unusual cell growth.

Background technology

Be shown in structural formula with free alkali form 1In compound N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] cumarone-3-methane amide

It is the potent selective depressant of a kind of vascular endothelial growth factor receptor 2 (VEGF-R2).Acceptor autophosphorylation effect that the Tyrosine kinase activity of its potent inhibition VEGF-R2 and selective exclusion VEGF stimulate and endotheliocyte survival.In vivo research has shown that this compound produces the remarkable restraining effect of vascular permeability, tumor-blood-vessel growth and human xenotransplantation tumor growth.This compound has been described among the disclosed openly U.S. Patent application US2005-0137395 on June 23rd, 2005, and this application disclosure way of reference in full is incorporated herein.Make compound 1The method of free alkali form also be described in the application title submitted on December 5th, 2005 in the U.S. Provisional Application 60/742,847 of " METHODS OF PREPARING A VEGF-R INHIBITOR ".

Make salt and polymorphic forms have improved characteristics, such as crystallinity, dissolution characteristics and/or the reduction water absorbability of improvement, it is favourable keeping chemistry and enantiomerism stabilising characteristic simultaneously.

Summary of the invention

In one embodiment, the invention provides a kind of N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] two maleic acid salts of cumarone-3-methane amide.In the particular aspects of this embodiment, this salt is anhydrous.In another aspect, this salt is crystalline.In another aspect, this salt is crystal anhydrous salt.In another aspect, this salt is the pure basically polymorphic of two maleic acid salt form I.In another aspect, to comprise diffraction angle (2 θ) be 18.6 ± 0.1 peak to the powder x-ray diffraction figure of this salt.In another aspect, to comprise diffraction angle (2 θ) be 4.0 ± 0.1,18.1 ± 0.1 and 18.6 ± 0.1 peak to the powder x-ray diffraction figure of this salt.In another aspect, to comprise diffraction angle (2 θ) be the peak of 4.0 ± 0.1,8.1 ± 0.1,18.1 ± 0.1,18.6 ± 0.1,2 .6 ± 0.1 and 26.2 ± 0.1 to the powder x-ray diffraction figure of this salt.In another aspect, the powder x-ray diffraction figure of this salt comprises identical with the diffraction angle shown in Figure 1 basically peak of diffraction angle (2 θ).In another aspect, the solid state NMR spectrum of this salt comprises 148.0 ± 0.1ppm's ¹³The C chemical shift, in another aspect, the solid state NMR spectrum of this salt comprises 14 8.0 ± 0.1 and 162.5 ± 0.1ppm ¹³The C chemical shift.In another aspect, the solid state NMR spectrum of this salt comprises 148.0 ± 0.1,118.0 ± 0.1, and 124.2 ± 0.1,143.9 ± 0.1 and 162.5 ± 0.1ppm ¹³The C chemical shift.In another aspect, to comprise the position identical with position shown in Figure 2 basically for the solid state NMR spectrum of this salt ¹³The C chemical shift.In another aspect, the Raman of this salt (Raman) spectrum comprises 1589 ± 1,1402 ± 1 and 755 ± 1cm ^-1Raman shift.In another aspect, the Raman spectrum of this salt comprises identical with the position shown in Figure 4 basically Raman shift in position.

In another embodiment, the invention provides a kind of N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] two maleic acid salts of cumarone-3-methane amide, wherein this salt is solvate.In a specific implementations, this salt is hydrate.In another aspect, this salt is crystalline hydrate salt.In another aspect, this salt is the pure basically polymorphic of two maleic acid salt form III.In another aspect, to comprise diffraction angle (2 θ) be 12.7 ± 0.1 peak to the powder x-ray diffraction figure of this salt.In another aspect, to comprise diffraction angle (2 θ) be 6.4 ± 0.1,12.7 ± 0.1 and 17.3 ± 0.1 peak to the powder x-ray diffraction figure of this salt.In another aspect, to comprise diffraction angle (2 θ) be 6.4 ± 0.1,12.7 ± 0.1,17.3 ± 0.1,21.3 ± 0.1 and 25.9 ± 0.1 peak to the powder x-ray diffraction figure of this salt.In another aspect, the powder x-ray diffraction figure of this salt comprises identical with the diffraction angle shown in Figure 6 basically peak of diffraction angle (2 θ).In another aspect, the solid state NMR spectrum of this salt comprises 132.8 ± 0.1ppm's ¹³The C chemical shift.In another aspect, the solid state NMR spectrum of this salt comprises 99.2 ± 0.1,125.8 ± 0. and 132.8 ± 0.1ppm ¹³The C chemical shift.In another aspect, the solid state NMR spectrum of this salt comprises 99.2 ± 0.1,125.8 ± 0.1,132.8 ± 0.1, and 142.2 ± 0.1 and 166.1 ± 0.1ppm ¹³The C chemical shift.In another aspect, to comprise the position identical with position shown in Figure 7 basically for the solid state NMR spectrum of this salt ¹³The C chemical shift.In another aspect, the Raman spectrum of this salt comprises 761 ± 1,1405 ± 1 and 1595 ± 1cm ^-1Raman shift.In another aspect, the Raman spectrum of this salt comprises identical with the position shown in Figure 9 basically Raman shift in position.

In another embodiment, the invention provides a kind of N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] the two maleic acid salts of crystallization of cumarone-3-methane amide, wherein this salt be two maleic acid salt form I and the mixture of couple maleic acid salt form III.Preferably, this mixture is two maleic acid salt form I and the pure basically mixture of two maleic acid salt form III, and the pure basically mixture of wherein two maleic acid salt form I and III comprises and is less than 10 weight %, preferable 5 weight %, preferable 3 weight %, preferable any other physical form that is less than two maleic acid salts of 1 weight % of being less than of being less than.

In another embodiment, the invention provides a kind of N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] amorphous form of two maleic acid salts of cumarone-3-methane amide.For example, the powder x-ray diffraction figure of this amorphous form can comprise identical with the diffraction angle shown in Figure 34 basically peak of diffraction angle (2 θ).

In another embodiment, the invention provides a kind of free alkali N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] crystallized form of cumarone-3-methane amide.In a specific embodiment, free alkali N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] cumarone-3-methane amide crystallized form is anhydrous.In another embodiment, free alkali N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base) cumarone-3-methane amide crystallized form is hydrate.

In another embodiment, this crystallized form is the polymorphic of free alkali form 1.In detail, to comprise diffraction angle (2 θ) be 19.9 ± 0.1 and 22.0 ± 0.1 peak to the powder x-ray diffraction figure of this crystallized form.More specifically, it is 13.5 ± 0.1,19.1 ± 0.1 that the powder x-ray diffraction figure of this crystallized form comprises diffraction angle (2 θ), 19.9 ± 0.1,22.0 ± 0.1 and 24.1 ± 0.1 peak.More specifically, the powder x-ray diffraction figure of this crystallized form comprises identical with the diffraction angle shown in Figure 11 basically peak of diffraction angle (2 θ).

In another embodiment, this crystallized form is the polymorphic of free alkali form 2.Especially, to comprise diffraction angle (2 θ) be 10.6 ± 0.1 and 15.3 ± 0.1 peak to the powder x-ray diffraction figure of this crystallized form.More specifically, to comprise diffraction angle (2 θ) be 10.6 ± 0.1,14.0 ± 0.1,15.3 ± 0.1 and 16.9 ± 0.1 peak to the powder x-ray diffraction figure of this crystallized form.More specifically, the powder x-ray diffraction figure of this crystallized form comprises identical with the diffraction angle shown in Figure 12 basically peak of diffraction angle (2 θ).

In another embodiment, this crystallized form is the polymorphic of free alkali form 3.Especially, to comprise diffraction angle (2 θ) be 12.5 ± 0.1 and 21.6 ± 0.1 peak to the powder x-ray diffraction figure of this crystallized form.More specifically, to comprise diffraction angle (2 θ) be 12.5 ± 0.1,21.2 ± 0.1,21.64 ± 0.1 and 24.0 ± 0.1 peak to the powder x-ray diffraction figure of this crystallized form.More specifically, the powder x-ray diffraction figure of this crystallized form comprises identical with the diffraction angle shown in Figure 13 basically peak of diffraction angle (2 θ).

In another embodiment, this crystallized form is the polymorphic of free alkali form 4.Especially, to comprise diffraction angle (2 θ) be 6.5 ± 0.1 and 16.0 ± 0.1 peak to the powder x-ray diffraction figure of this crystallized form.More specifically, to comprise diffraction angle (2 θ) be 5.6 ± 0.1,6.5 ± 0.1,16.0 ± 0.1 and 19.5 ± 0.1 peak to the powder x-ray diffraction figure of this crystallized form.More specifically, the powder x-ray diffraction figure of this crystallized form comprises identical with the diffraction angle shown in Figure 14 basically peak of diffraction angle (2 θ).

In another embodiment, this crystallized form is the polymorphic of free alkali form 5.Especially, to comprise diffraction angle (2 θ) be 22.6 ± 0.1 and 23.4 ± 0.1 peak to the powder x-ray diffraction figure of this crystallized form.More specifically, to comprise diffraction angle (2 θ) be 12.1 ± 0.1,18.4 ± 0.1,21.0 ± 0.1,22.6 ± 0.1 and 23.4 ± 0.1 peak to the powder x-ray diffraction figure of this crystallized form.More specifically, the powder x-ray diffraction figure of this crystallized form comprises identical with the diffraction angle shown in Figure 15 basically peak of diffraction angle (2 θ).

In another embodiment, this crystallized form is the polymorphic of free alkali form 6.Especially, to comprise diffraction angle (2 θ) be 8.4 ± 0.1 and 14.7 ± 0.1 peak to the powder x-ray diffraction figure of this crystallized form.More specifically, it is 8.4 ± 0.1,14.7 ± 0.1 that the powder x-ray diffraction figure of this crystallized form comprises diffraction angle (2 θ), 17.5 ± 0.1 and 19.6 ± 0.1 peak.More specifically, the powder x-ray diffraction figure of this crystallized form comprises identical with the diffraction angle shown in Figure 16 basically peak of diffraction angle (2 θ).

In another embodiment, the present invention system is about a kind of free alkali N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] crystallized form of cumarone-3-methane amide, wherein the Raman spectrum of this crystallized form comprise basically with Figure 17-22 in any one shown in the identical Raman shift of Raman shift.

In another embodiment, the present invention is about a kind of free alkali N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] amorphous form of cumarone-3-methane amide.For example, the powder x-ray diffraction figure of this amorphous form can comprise identical with the diffraction angle shown in Figure 35 basically peak of diffraction angle (2 θ).

The present invention is in addition about a kind of N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] two hydrobromates of cumarone-3-methane amide.In one embodiment, this salt is anhydrous crystalline forms.In another embodiment, this salt is the pure basically polymorphic of two-HBr form I.In another embodiment, the powder x-ray diffraction figure of this crystallized form comprises identical with the diffraction angle shown in Figure 29 basically peak of diffraction angle (2 θ).In another embodiment, this salt is the crystalline hydrate form.In another embodiment, this salt is the pure basically polymorphic of two-HBr form II.In another embodiment, the powder x-ray diffraction figure of this crystallized form comprises identical with the diffraction angle shown in Figure 30 basically peak of diffraction angle (2 θ).

The present invention provides a kind of pharmaceutical composition in addition, and it comprises the formula of the arbitrary form in crystallization as herein described or the amorphous form 1Two maleic acid salts of compound, two hydrobromate or free alkali form.The present invention provides a kind of capsule that comprises arbitrary pharmaceutical composition of the present invention in addition.In the particular aspects of this embodiment, this capsule comprises the normal N of 0.1-50mg free alkali, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] two maleic acid salts of cumarone-3-methane amide.In another aspect, this capsule comprises the normal N of 0.5-25mg free alkali, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] two maleic acid salts of cumarone-3-methane amide.In another embodiment, this capsule comprises 0.1-50mg free alkali N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] cumarone-3-methane amide.Other-aspect in, this capsule comprises 0.5-25mg free alkali N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] cumarone-3-methane amide.In another aspect, this capsule comprises the normal N of 0.1-50mg free alkali, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] two hydrobromates of cumarone-3-methane amide.In another aspect, this capsule comprises the normal N of 0.5-25mg free alkali, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] two hydrobromates of cumarone-3-methane amide.

In another embodiment, the invention provides the method for cancer of a kind of treatment Mammals (comprising the mankind), this method comprises to Mammals throws and of the present invention arbitrary pharmaceutical composition as described herein for the treatment of significant quantity.

In another embodiment, the invention provides the mammiferous method for cancer of a kind of treatment, this method comprises to Mammals (comprising the mankind) throws and of the present invention arbitrary capsule as described herein.

In the particular aspects of arbitrary preceding method embodiment, this method further comprises throws and one or more anti-tumor agents, angiogenesis inhibitor medicament, signal transduction inhibitor or antiproliferative medicament.

The present invention is also about a kind of method for the treatment of the abnormal cell growth of Mammals (comprising the mankind), and it comprises to this Mammals throws and the formula as defined above of effectively treating the amount of abnormal cell growth 1Compound or its pharmacy acceptable salt or solvate.In one of this method embodiment, abnormal cell growth is a cancer, it comprises, but be not limited to, lung cancer, osteocarcinoma, carcinoma of the pancreas, skin carcinoma, the cancer of head or neck, skin or intraocular melanoma, uterus carcinoma, ovarian cancer, the rectum cancer, the anal region cancer, cancer of the stomach, colorectal carcinoma, mammary cancer, uterus carcinoma, carcinoma of fallopian tube, carcinoma of endometrium, cervical cancer, carcinoma of vagina, the vaginal orifice cancer, Hodgkin's disease (Hodgkin ' s Disease), esophagus cancer, carcinoma of small intestine, the endocrine system cancer, thyroid carcinoma, parathyroid carcinoma, adrenal carcinoma, soft tissue sarcoma, urethral carcinoma, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or carcinoma of ureter, renal cell carcinoma, carcinoma of renal pelvis, central nervous system (CNS) anything superfluous or useless, primary CNS lymphoma, the vertebra tumour, the brain stem neurospongioma, the combination of Pituitaryadenoma or one or more aforementioned cancer.In another embodiment of this method, this abnormal cell growth is optimum proliferative disease, and it includes, but not limited to psoriasis, benign prostatauxe or restenosis.

The present invention is also about a kind of method for the treatment of mammiferous abnormal cell growth, and it comprises to this Mammals throws and the formula of effectively treating the amount of abnormal cell growth ₁Compound or its pharmacy acceptable salt or solvate, with be selected from by mitotic inhibitor, alkylating agent, metabolic antagonist, embed the combination of the anti-tumor agents in microbiotic, growth factor receptor inhibitors, cell cycle inhibitor, enzyme, topoisomerase enzyme inhibitor, biological response modifier, antibody, cytotoxin, hormone antagonist and the androgen antagonist.

Also about a kind of pharmaceutical composition for the treatment of the abnormal cell growth of Mammals (comprising the mankind), it comprises the formula as hereinbefore defined of the amount of effective treatment abnormal cell growth in the present invention 1Compound or its pharmacy acceptable salt or solvate and pharmaceutically acceptable carrier.In one of said composition embodiment, this abnormal cell growth is a cancer, it includes but not limited to lung cancer, osteocarcinoma, carcinoma of the pancreas, skin carcinoma, head or neck cancer, skin or intraocular melanoma, uterus carcinoma, ovarian cancer, the rectum cancer, the anal region cancer, cancer of the stomach, colorectal carcinoma, mammary cancer, uterus carcinoma, carcinoma of fallopian tube, carcinoma of endometrium, cervical cancer, carcinoma of vagina, the vaginal orifice cancer, Hodgkin's disease, esophagus cancer, carcinoma of small intestine, the endocrine system cancer, thyroid carcinoma, parathyroid carcinoma, adrenal carcinoma, soft tissue sarcoma, urethral carcinoma, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or carcinoma of ureter, renal cell carcinoma, carcinoma of renal pelvis, central nervous system (CNS) anything superfluous or useless, primary CNS lymphoma, the vertebra tumour, the brain stem neurospongioma, the combination of Pituitaryadenoma or one or more aforementioned cancer.In another embodiment of this pharmaceutical composition, this abnormal cell growth is optimum proliferative disease, and it includes but not limited to psoriasis, benign prostatauxe or restenosis.

Also about a kind of pharmaceutical composition for the treatment of the abnormal cell growth of Mammals (comprising the mankind), it comprises the formula as hereinbefore defined of the amount of effective treatment abnormal cell growth in the present invention 1Compound or its pharmacy acceptable salt or solvate are with the combination that is selected from by the anti-tumor agents in mitotic inhibitor, alkylating agent, metabolic antagonist, embedding microbiotic, growth factor receptor inhibitors, cell cycle inhibitor, enzyme, topoisomerase enzyme inhibitor, biological response modifier, hormone antagonist and the androgen antagonist.

The present invention is also about a kind of method for the treatment of the vasculogenesis associated conditions of Mammals (comprising the mankind), and it comprises to this Mammals throws and 1 compound of formula as hereinbefore defined or its pharmacy acceptable salt or the solvate of effectively treating the amount of this illness.These illnesss comprise: cancerous tumour, such as melanoma; Eye disorders reaches the retina neovascularity that is caused by proliferating diabetic retinopathy and generates such as relevant macular degeneration of age, plan ocular tissue slurry bacterium syndromes; Rheumatoid arthritis: bone-loss disorders such as osteoporosis, osteitis deformans (Paget ' s disease), pernicious body fluid hypercalcemia, is transferred to hypercalcemia that the tumour of bone causes and by glucocorticoid treatment inductive osteoporosis; Coronary restenosis: and the certain micro-organisms infection, comprise and be selected from the relevant infection of microbial pathogen of adenovirus, Hantaan virus (hantavirus), the thin spirobacteria (Borrelia burgdorferi) of Bai Shi, yersinia's genus (Yersiniaspp.), Whooping cough Bo Deshi bacillus (Bordetella pertussis) and A group B streptococcus B (group A Streptococcus).

Also about a kind of method (and pharmaceutical composition) for the treatment of mammiferous abnormal cell growth, it comprises throws and a certain amount of formula in the present invention 1Compound or its pharmacy acceptable salt or solvate, and a certain amount of one or more is selected from the material of angiogenesis inhibitor medicament, signal transduction inhibitor and antiproliferative medicament, mammiferous this abnormal cell growth of the common effectively treatment of this amount.

Such as the angiogenesis inhibitor medicament of MMP-2 (matrix metalloproteinase 2) inhibitor, MMP-9 (matrix metalloproteinase 9) inhibitor and COX-II (cyclo-oxygenase II) inhibitor can with formula 1Compound or its pharmacy acceptable salt or solvate combination are used for method as herein described and pharmaceutical composition.Effectively the embodiment of COX-II inhibitor comprises CELEBREX ^TM(A Laikao former times, alecoxib), valdecoxib (valdecoxib) and rofecoxib (rofecoxib).Effectively the example of matrix metallo-proteinase inhibitor is described in WO 96/33172 (on October 24th, 1996 is open), WO 96/27583 (on March 7th, 1996 is open), european patent application No. 97304971.1 (application on July 8th, 1997), european patent application No. 99308617.2 (application on October 29th, 1999), WO 98/07697 (on February 26th, 1998 is open), WO 98/03516 (on January 29th, 1998 is open), WO 98/34918 (on August 13rd, 1998 is open), WO 98/34915 (on August 13rd, 1998 is open), WO 98/33768 (on August 6th, 1998 is open), WO 98/30566 (on July 16th, 1998 is open), european patent application 606.046 (on July 1st, 1994 is open), european patent application 931,788 (on July 28th, 1999 is open), WO 90/05719 (May 331 nineteen ninety is open), WO 99/52910 (on October 21st, 1999 is open), WO99/52889 (on October 21st, 1999 is open), WO 99/29667 (on June 17th, 1999 is open), PCT international application PCT/IB98/01113 number (application on July 21st, 1998), european patent application No. 99302232.1 (application on March 25th, 1999), UK Patent Application No. 9912961.1 (application on June 3rd, 1999), U.S. Provisional Application the 60/148th, No. 464 (application on August 12nd, 1999), United States Patent (USP) 5,863,949 (on January 26th, 1999 was given), United States Patent (USP) 5,861,510 (on January 19th, 1999 was given) and european patent applications 780, in 386 (on June 25th, 1997 is open), the mode that these applications are all quoted in full is incorporated herein.More preferably MMP-2 and MMP-9 inhibitor are to have minimum or do not have the active inhibitor that suppresses MMP-1.The inhibitor that suppresses MMP-2 and/or MMP-9 with respect to other matrix metalloproteinases (meaning is MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12 and MMP-13) selectivity more preferably.

Some specific embodiment that is applicable to the MMP inhibitor that makes up with compound of the present invention is the compound of being stated in AG-3340, RO 32-3555, RS 13-0830 and following the listing:

3-[[4-(4-fluoro-phenoxy group)-benzenesulfonyl]-(1-hydroxyl carbamyl-cyclopentyl)-amino]-propionic acid; outside the 3--3-[4-(4-fluoro-phenoxy group)-benzenesulfonyl amino]-8-oxa--dicyclo [3.2.1] octane-3-formic acid oxyamide; (2R; 3R) 1-[4-(2-chloro-4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidines-2-formic acid oxyamide; 4-[4-(4-fluoro-phenoxy group)-benzenesulfonyl amino]-tetrahydrochysene-pyrans-4-formic acid oxyamide; 3-[[4-(4-fluoro-phenoxy group)-benzenesulfonyl]-(1-hydroxyl carbamyl-cyclobutyl)-amino]-propionic acid; 4-[4-(4-chloro-phenoxy group)-benzenesulfonyl amino]-tetrahydrochysene-pyrans-4-formic acid oxyamide; 3-[4-(4-chloro-phenoxy group)-benzenesulfonyl amino]-tetrahydrochysene-pyrans-3-formic acid oxyamide; (2R; 3R) 1-[4-(4-fluoro-2-methyl-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidines-2-formic acid oxyamide; 3-[[4-(4-fluoro-phenoxy group)-benzenesulfonyl)-(1-hydroxyl carbamyl-1-methyl-ethyl)-amino]-propionic acid; 3-[[4-(4-fluoro-phenoxy group)-benzenesulfonyl]-(4-hydroxyl carbamyl-tetrahydrochysene-pyrans-4-yl)-amido]-propionic acid; outside the 3--3-[4-(4-chloro-phenoxy group)-benzenesulfonyl amino]-]-8-oxa--dicyclo [3.2.1] octane-3-formic acid oxyamide; in the 3--3-[4-(4-fluoro-phenoxy group)-benzenesulfonyl amino]-8-oxa--dicyclo [3.2.1] octane-3-formic acid oxyamide and 3-[4-(4-fluoro-phenoxy group)-benzenesulfonyl amino]-tetrahydrochysene-furans-3-formic acid oxyamide, and the pharmacy acceptable salt of this compound; solvate and prodrug.

Formula 1 compound and pharmacy acceptable salt thereof and solvate also can be used in combination with following signal transduction inhibitor: for example, the medicament that can suppress EGFR (EGF-R ELISA) reaction, such as EGFR antibody, EGF antibody and as the molecule of EGFR inhibitor: VEGF (vascular endothelial growth factor) inhibitor: and the erbB2 acceptor inhibitor, such as organic molecule or the antibody in conjunction with the erbB2 acceptor, for example HERCEPTIN ^TM(Genentech, Inc.of SouthSan Francisco, Californ a, USA).

For example, the EGFR inhibitor is described in WO 95/19490 (July 27 nineteen ninety-five is open), in WO 98/14451 (on April 9th, 1998 is open), WO9 8/02434 (on January 22nd, 1998 is open) and the United States Patent (USP) 5,747,498 (on May 5th, 1998 was given).The EGFR inhibitor comprises but is not limited to monoclonal antibody C225 and anti-EGFR 22Mab (ImCloneSystems Incorporated of New York, New York, USA), compound ZD-1839 (AstraZeneca), BIBX-1382 (Boehringer Ingelheim), MDX-447 (Medarex Inc.of Annandale, New Jersey, USA) and OLX-103 (Merck﹠amp; Co.of Whitehouse Station, New Jersey, USA), VRCTC-310 (VentechResearch) and EGF fusion toxin (Seragen Inc.of Hopkinton, Massachusettes).

Such as the VBGF inhibitor of SU-5416 and SU-6668 (Pfizer Inc.) also can with formula 1Compound or its pharmacy acceptable salt or solvate combination.For example, the VEGF inhibitor is described in WO 99/24440 (on May 20th, 1999 is open), PCT International Application PCT/IB99/00797 (application on May 3rd, 1999), WO 95/21613 (August 17 nineteen ninety-five is open), WO 99/61422 (on December 2nd, 1999 is open), United States Patent (USP) 5,834,504 (on November 10th, 1998 was given), WO 98/50356 (on November 12nd, 1998 is open), United States Patent (USP) 5,883,113 (on March 16th, 1999 was given), United States Patent (USP) 5,886,020 (on March 23rd, 1999 was given), United States Patent (USP) 5,792,783 (on August 11st, 1998 was given), WO 99/10349 (on March 4th, 1999 is open), WO 97/32856 (on September 12nd, 1997 is open), WO 97/22596 (on June 26th, 1997 is open), WO 98/54093 (on December 3rd, 1998 is open), WO 98/02438 (on January 22nd, 1998 is open), among WO 99/16755 (on April 8th, 1999 is open) and the WO 98/02437 (on January 22nd, 1998 is open), the mode that this application is all quoted in full is incorporated herein.Other examples of some specific VEGF inhibitor are: IM862 (Cytran Inc.ofKirkland, Washington, USA), anti-VEGF monoclonal antibody (Genentech, Inc.of South San Francisco, California) and the lucky enzyme (angiozyme) of amine, its be from Ribozyme (Boulder, Colorado) and Chiron (Emeryville, synthetic rna enzyme California).

Such as GW-282974 (Glaxo Wellcome plc) and monoclonal antibody AR-209 (Aronex Pharmaceuticals Inc.of The Woodlands, Texas, USA) and the erbB2 acceptor inhibitor of 2B-1 (Chiron) can with formula 1Compound or its pharmacy acceptable salt or solvate combination dispensing.This erbB2 inhibitor comprises and is described in WO98/02434 (on January 22nd, 1998 open), WO 99/35146 (on July 15th, 1999 is open), WO 99/35132 (on July 15th, 1999 is open), WO 98/02437 (on January 22nd, 1998 is open), WO 97/13760 (on April 17th, 1997 is open), WO 95/19970 (July 27 nineteen ninety-five is open), United States Patent (USP) 5,587,458 (on December 24th, 1996 was given) and United States Patent (USP)s 5,877, inhibitor in 305 (on March 2nd, 1999 was given), the mode that this application is quoted separately in full is incorporated herein.Be applicable to that erbB2 acceptor inhibitor of the present invention also is described in the U.S. Provisional Application the 60/117th of application on January 2nd 7,1999, the U.S. Provisional Application the 60/117th of No. 341 and on January 27th, 1999 application, in No. 346, the mode that two applications are all quoted in full is incorporated herein.

Other antiproliferative medicaments that can be used for combined method of the present invention comprise the inhibitor of enzyme farnesyl (farnesyl) protein transferase and the inhibitor of acceptor Tyrosine kinases PDGFr, it comprises in the following U.S. Patent application institute's compound of disclosing and advocating: 09/221946 (application on December 28th, 1998), 09/454058 (application on December 2nd, 1999), 09/501163 (application on February 9th, 2000), 09/539930 (application on March 31st, 2000), 09/202796 (application on May 22nd, 1997), 09/384339 (application on August 26th, 1999) and 09/383755 (application on August 26th, 1999); And the compound that discloses and advocate in the following U.S. Provisional Patent Application: 60/168207 (application on November 30th, 1999), 60/170119 (application on December 10th, 1999), 60/177718 (application on January 21st, 2000), 60/168217 (application on November 30th, 1999) and 60/200834 (application on May 1st, 2000).The mode that aforementioned patent applications and temporary patent application are quoted separately in full is incorporated herein.

Formula 1Compound or its pharmacy acceptable salt or solvate also can use with other medicaments that are applicable to treatment abnormal cell growth or cancer, this medicament includes but not limited to: can strengthen the medicament of anti tumor immune response, such as CTLA4 (cytotoxic lymphocyte antigen 4) antibody and can block other medicaments of CTLA4; And the antiproliferative medicament, such as other farnesyl protein transferase inhibitors, the farnesyl protein transferase inhibitor described in the reference quoted of " background technology " paragraph for example above.Can be used for specific CTLA4 antibody of the present invention and comprise the antibody that is described in the U.S. Provisional Application 60/113,647 (application on December 23rd, 1998), the mode that this application is quoted in full is incorporated herein.

Except as otherwise noted, otherwise term as used herein " treatment " meaning reverses, alleviates, suppresses the process or it is produced of one or more symptom of illness that this term is suitable for or symptom or this illness or symptom prevents.Except as otherwise noted, otherwise term as used herein " treatment handle " refer to as the treatment behavior that has above just defined it " treatment ".

As used herein, comprise about the term " pure basically " of specific polymorphic or amorphous form meaning polymorphic amorphous form and to be less than 10 weight %, preferably be less than 5 weight %, preferably be less than 3 weight %, preferably be less than any other physical form of this compound of 1 weight %.

As used herein, consider typical peaks position and Strength Changes about term " substantially the same " meaning of X-ray diffraction peak position.For example, it will be understood by a person skilled in the art that peak position (2 θ) should show variation between some device, general many to 0.1 °.In addition, it will be understood by a person skilled in the art that relative peak intensity is answered between display unit to change and owing to degree of crystallinity, preferred directed, the prepared sample surfaces and the variation of other factors well known by persons skilled in the art, and only should be considered as qualitative measure.Similarly, as used herein, be intended to also contain the associated change of this analytical technology well known by persons skilled in the art about " substantially the same " of solid state NMR spectrum and Raman spectrum, for example, solid state NMR is measured ¹³The C chemical shift generally has the variation of 0.1ppm, and Raman shift generally has 1cm ^-1Variation.

The simple declaration of accompanying drawing

Fig. 1 shows N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] the powder x-ray diffraction figure of two maleic acid salts (polymorphic forms I) of cumarone-3-methane amide.

Fig. 2 shows N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] the solid state NMR spectrum of two maleic acid salts (polymorphic forms I) of cumarone-3-methane amide.

Fig. 3 shows N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] two maleic acid salts (polymorphic forms I) dsies (DSC) thermogram of cumarone-3-methane amide.

Fig. 4 shows N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] Raman spectrogram of two maleic acid salts (polymorphic forms I) of cumarone-3-methane amide.

Fig. 5 shows N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] the dynamic steam adsorption curve of two maleic acid salts (polymorphic forms I) of cumarone-3-methane amide.

Fig. 6 shows N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] the powder x-ray diffraction figure of two maleic acid salts (polymorphic forms III) of cumarone-3-methane amide.

Fig. 7 shows N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] the solid state NMR spectrum of two maleic acid salts (polymorphic forms III) of cumarone-3-methane amide.

Fig. 8 shows N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] two maleic acid salts (polymorphic forms III) dsies (DSC) thermogram of cumarone-3-methane amide.

Fig. 9 shows N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] cumarone-3-methane amide-the Raman spectrogram of two maleic acid salts (polymorphic forms III).

Figure 10 shows N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] the dynamic steam adsorption curve of two maleic acid salts (polymorphic forms III) of cumarone-3-methane amide.

Figure 11 shows free alkali N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base) the powder x-ray diffraction figure of cumarone-3-methane amide (polymorphic forms 1).

Figure 12 shows free alkali N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] the powder x-ray diffraction figure of cumarone-3-methane amide (polymorphic forms 2).

Figure 13 shows free alkali N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] the powder x-ray diffraction figure of cumarone-3-methane amide (polymorphic forms 3).

Figure 14 shows free alkali N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] the powder x-ray diffraction figure of cumarone-3-methane amide (polymorphic forms 4).

Figure 15 shows free alkali N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] the powder x-ray diffraction figure of cumarone-3-methane amide (polymorphic forms 5).

Figure 16 shows free alkali N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base) the powder x-ray diffraction figure of cumarone-3-methane amide (polymorphic forms 6).

Figure 17 shows free alkali N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] Raman spectrogram of cumarone-3-methane amide (polymorphic forms 1).

Figure 18 shows free alkali N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinoline-4, basic oxygen base] Raman spectrogram of cumarone-3-methane amide (polymorphic forms 2).

Figure 19 shows free alkali N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] Raman spectrogram of cumarone-3-methane amide (polymorphic forms 3).

Figure 20 shows free alkali N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] Raman spectrogram of cumarone-3-methane amide (polymorphic forms 4).

Figure 21 shows free alkali N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] Raman spectrogram of cumarone-3-methane amide (polymorphic forms 5).

Figure 22 shows free alkali N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] Raman spectrogram of cumarone-3-methane amide (polymorphic forms 6).

Figure 23 shows free alkali N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] cumarone-3-methane amide (polymorphic forms 1) dsc (DSC) thermogram.

Figure 24 shows free alkali N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] cumarone-3-methane amide (polymorphic forms 2) dsc (DSC) thermogram.

Figure 25 shows free alkali N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] cumarone-3-methane amide (polymorphic forms 3) dsc (DSC) thermogram.

Figure 26 shows free alkali N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] cumarone-3-methane amide (polymorphic forms 4) dsc (DSC) thermogram.

Figure 27 shows free alkali N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] cumarone-3-methane amide (polymorphic forms 5) dsc (DSC) thermogram.

Figure 28 shows free alkali N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] cumarone-3-methane amide (polymorphic forms 6) dsc (DSC) thermogram.

Figure 29 shows N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] the powder x-ray diffraction figure of two HBr salt (polymorphic forms I) of cumarone-3-methane amide.

Figure 30 shows N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] the powder x-ray diffraction figure of two HBr salt (polymorphic forms II) of cumarone-3-methane amide.

Figure 31 shows N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] two HBr salt (form I) dsies (DSC) thermogram of cumarone-3-methane amide.

Figure 32 shows N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] two HBr salt (form II) dsies (DSC) thermogram of cumarone-3-methane amide.

Figure 33 shows N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] thermogravimetric analysis (TGA) curve of two HBr salt (form II) of cumarone-3-methane amide.

Figure 34 shows N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] the powder x-ray diffraction figure of two maleic acid salts (amorphous form) of cumarone-3-methane amide.

Fig. 35 shows free alkali N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] the powder x-ray diffraction figure of cumarone-3-methane amide (amorphous form).

Embodiment

Now produced compound N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] several unique physical form of cumarone-3-methane amide.Free alkali compound N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] cumarone-3-methane amide can disclose that method prepares described in US2005-0137395 number according to laid-open U.S. Patents application on June 23 in 2005, and the whole disclosures of this application are incorporated herein by reference.Make free alkali compound N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] the other method of cumarone-3-methane amide be described in application on December 5th, 2005 title in the U.S. Provisional Patent Application of " Methods of Preparing a VEGF-R Inhibitor ", this application also is incorporated herein in the mode of quoting.

N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] salt of cumarone-3-methane amide is by the use solvent medium or handle this free alkali compound such as an amount of selected inorganic or organic acid in the suitable organic solvent of methyl alcohol, acetonitrile, ethanol or ethyl acetate and prepare.After careful evaporating solvent, obtain the solid salt of wanting immediately.The acid salt of wanting also can be by adding suitable inorganic or organic acid from this solution precipitation to the solution of free alkali in organic solvent.With N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] free alkali of cumarone-3-methane amide or salt is dissolved in the appropriate solvent such as methyl alcohol, ethanol or its mixture, then drying obtains solid amorphous form, can prepare the amorphous form of free alkali and salt thus.

The two maleic acid salts of crystallization

For example, under high temperature (for example about 85 ℃) with N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] cumarone-3-methane amide is dissolved in such as CH ₂Cl ₂, in THF, acetonitrile, ethyl acetate, methyl alcohol or any appropriate solvent of alcoholic acid, then be added on the maleic acid in the appropriate solvent, can make two maleic acid salts of this free alkali compound thus with well-crystallized.Then, can reach purifying by recrystallize or furnishing slurries in appropriate solvent or solvent mixture (such as acetonitrile and alcohol mixture).Preparation N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] two maleic acid salt additive methods of cumarone-3-methane amide are included under the high temperature (for example about 68 ℃) in any appropriate solvent that this free alkali compound is dissolved in such as ethyl acetate, then add the solid maleic acid.After with per hour about 20 ℃ speed cooling solution, two maleic acid salt formation throw outs of gained crystallized form and can filter collection.

N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] two kinds of polymorphic forms of two maleic acid salts of cumarone-3-methane amide through identification and characterize, and are expressed as two maleic acid salt form I and two maleic acid salt form III as shown in Fig. 1-10.

Can be when making two maleic acid salt, as discussed previouslyly make two maleic acid salt form I.Also two maleic acid salt form III can be suspended in the appropriate solvent such as acetonitrile, then stir down with two maleic acid salt form I inoculations and at high temperature (for example 50 ℃), and obtain two maleic acid salt form I, thus two maleic acid salt form III are converted into two maleic acid salt form I.Powder x-ray diffraction (PXRD) figure of two maleic acid salt form I is shown among Fig. 1, and corresponding tabulation data is shown in the table 1.

Table 1:N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] the PXRD data form of two maleic acid salt form I of cumarone-3-methane amide.

2θ(°)	The D value	Intensity (counting)
2θ(°)	The D value	Intensity (counting)	4.0	21.9	12.1
8.2	10.8	21.0	4.0	21.9	12.1
8.2	10.8	21.0	10.7	8.2	9.8
14.2	6.2	7.6	10.7	8.2	9.8
14.2	6.2	7.6	14.8	6.0	19.5
16.3	5.4	20.9	14.8	6.0	19.5
16.3	5.4	20.9	18.1	4.9	12.9
18.7	4.8	13.5	18.1	4.9	12.9
18.7	4.8	13.5	20.2	4.4	17.0
21.5	4.1	33.2	20.2	4.4	17.0
21.5	4.1	33.2	23.8	3.7	13.7
24.8	3.6	11.1	23.8	3.7	13.7
24.8	3.6	11.1	26.2	3.4	26.9
27.2	3.3	7.6	26.2	3.4	26.9
27.2	3.3	7.6	28.7	3.1	7.1

The solid state NMR spectrum of two maleic acid salt form I is shown among Fig. 2, and corresponding tabulation carbon geochemistry displacement data is shown in the table 2.

Table 2:N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] the carbon geochemistry displacement of two maleic acid salt polymorphic forms I of cumarone-3-methane amide.

Peak number ^a	¹³The C chemical shift ^b[ppm]	Intensity ^c[arbitrary unit]
Peak number ^a	¹³The C chemical shift ^b[ppm]	Intensity ^c[arbitrary unit]	1	173.4	2.1
2	171.5	6.1	1	173.4	2.1
2	171.5	6.1	3	169.0	6.9
4	167.3	7.9	3	169.0	6.9
4	167.3	7.9	5	165.0	8.3
6	163.1	9.9	5	165.0	8.3
6	163.1	9.9	7	162.5	5.6
8	154.6	9.7	7	162.5	5.6
8	154.6	9.7	9	150.7	9.8
10	148.0	3.6	9	150.7	9.8
10	148.0	3.6	11	143.9	6.3
12	140.0	3.7	11	143.9	6.3
12	140.0	3.7	13	137.5	3.1
14	136.0	3.8	13	137.5	3.1
14	136.0	3.8	15	124.7	5.5
16	124.2	12.0	15	124.7	5.5
16	124.2	12.0	17	122.9	5.0
18	118.0	5.5	17	122.9	5.0
18	118.0	5.5	19	116.5	7.1
20	112.1	6.3	19	116.5	7.1
20	112.1	6.3	21	106.3	7.9
22	102.9	4.4	21	106.3	7.9
22	102.9	4.4	23	64.6	7.8
24	62.6	5.6	23	64.6	7.8
24	62.6	5.6	25	56.1	5.3
26	55.5	5.1	25	56.1	5.3
26	55.5	5.1	27	48.6	4.5
28	27.8	5.9	27	48.6	4.5
28	27.8	5.9	29	16.9	8.0

^aPeak number is listed all peaks that successively decreased by chemical shift.

^bSolid phase diamantane external sample with reference to 29.5ppm.

^cBeing defined as peak height intensity can change according to the actual setting of CPMAS experiment parameter.CPMAS intensity needn't be for quantitatively.

The DSC thermogram of two maleic acid salt form I is shown among Fig. 3, and the Raman spectrogram of two maleic acid salt form I is shown among Fig. 4, and the dynamic steam adsorption curve of two maleic acid salt form I is shown among Fig. 5.

N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] two maleic acid salt polymorphic forms III of cumarone-3-methane amide are hydrate, and can make by following steps, for example two maleic acid salt form I are dissolved in the solvent such as water, thereafter the two maleic acid salt form III of hydration follow precipitable come out, two maleic acid salt form III also can be by being dissolved in two maleic acid salt form I in the appropriate solvent such as acetonitrile, then prepares to the conversion of form III to obtain form I with two maleic acid salt form III inoculations.Powder x-ray diffraction (PXRD) figure of two maleic acid salt form III is shown among Fig. 6, and corresponding tabulated data is shown in the table 3.

Table 3:N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] the PXRD data form of two maleic acid salt polymorphic forms III of cumarone-3-methane amide.

2θ(°)	The D value	Intensity (counting)
2θ(°)	The D value	Intensity (counting)	6.4	13.7	9.8
8.3	10.6	5.1	6.4	13.7	9.8
8.3	10.6	5.1	9.0	9.8	5.0
9.6	9.2	8.0	9.0	9.8	5.0
9.6	9.2	8.0	11.9	7.4	6.0
12.7	7.0	15.5	11.9	7.4	6.0
12.7	7.0	15.5	14.4	6.2	10.0
14.9	6.0	12.3	14.4	6.2	10.0
14.9	6.0	12.3	16.3	5.4	8.1
17.4	5.1	11.3	16.3	5.4	8.1
17.4	5.1	11.3	20.1	4.4	10.6
21.3	42	30.3	20.1	4.4	10.6
21.3	42	30.3	24.3	3.7	9.3
25.1	3.6	7.4	24.3	3.7	9.3
25.1	3.6	7.4	25.9	3.4	16.9
27.9	3.2	11.0	25.9	3.4	16.9

The solid state NMR spectrum of two maleic acid salt form III is shown among Fig. 7, and corresponding tabulation carbon geochemistry displacement data is shown in the table 4.

Table 4:N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] the carbon geochemistry displacement of two maleic acid salt polymorphic forms III of cumarone-3-methane amide.

Peak number ^a	¹³The C chemical shift ^b [ppm]	Intensity ^c[arbitrary unit]
Peak number ^a	¹³The C chemical shift ^b [ppm]	Intensity ^c[arbitrary unit]	1	172.5	6.8
2	168.8	6.5	1	172.5	6.8
2	168.8	6.5	3	168.1	6.7
4	166.1	4.8	3	168.1	6.7
4	166.1	4.8	5	165.4	5.0
6	163.6	12.0	5	165.4	5.0
6	163.6	12.0	7	154.4	6.5
8	150.9	7.3	7	154.4	6.5
8	150.9	7.3	9	149.2	2.8
10	142.2	4.5	9	149.2	2.8
10	142.2	4.5	11	137.7	4.2
12	137.0	5.6	11	137.7	4.2
12	137.0	5.6	13	132.8	2.7
14	125.8	3.1	13	132.8	2.7
14	125.8	3.1	15	124.0	6.2
16	123.3	4.6	15	124.0	6.2
16	123.3	4.6	17	122.6	4.6
18	119.0	3.6	17	122.6	4.6
18	119.0	3.6	19	116.1	5.7
20	111.4	4.5	19	116.1	5.7
20	111.4	4.5	21	106.4	3.7
22	103.3	3.7	21	106.4	3.7
22	103.3	3.7	23	99.2	3.9
24	65.9	3.0	23	99.2	3.9
24	65.9	3.0	25	64.5	3.8
26	62.1	3.7	25	64.5	3.8
26	62.1	3.7	27	55.0	3.4
28	54.5	3.9	27	55.0	3.4
28	54.5	3.9	29	49.9	3.2
30	26.5	5.4	29	49.9	3.2
30	26.5	5.4	31	14.8	6.1

^bSolid phase diamantane external sample with reference to 29.5ppm.

^cBe defined as peak height.Intensity can change according to the reality setting of CPMAS experiment parameter.CPMAS intensity needn't be for quantitatively.

The DSC thermogram of two maleic acid salt form III is shown among Fig. 8, and the Raman spectrum of two maleic acid salt form III is shown among Fig. 9 admittedly, and the dynamic steam adsorption curve of two maleic acid salt form III is shown among Figure 10.

N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] solid-state stability of polymorphic forms of two maleic acid salts of cumarone-3-methane amide is shown in the following table 5.

N under the 5:40 ℃/75%RH of table, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] solid-state stability of two maleic acid salts (form I and III) of cumarone-3-methane amide.

Sample	T(0)	T (1 week)		T (4 week)		T (6 week)
Sample	T(0)	T (1 week)		T (4 week)		T (6 week)			Open	Close	Open	Close	Open	Close
Two maleic acid salt form I	99.9％	99.9％	99.9％	99.9％	99.9％	99.9％	99.9％		Open	Close	Open	Close	Open	Close
Two maleic acid salt form I	99.9％	99.9％	99.9％	99.9％	99.9％	99.9％	99.9％	Form I	Form I	Form I	Form I	Form I	Form I	Form I
Two maleic acid salt form III	99.9％	-	-	-	-	-	99.9％	Form I	Form I	Form I	Form I	Form I	Form I	Form I
Two maleic acid salt form III	99.9％	-	-	-	-	-	99.9％	Form III		Form III		Form III		-form III

N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] the polymorphic forms I and the water-soluble of II of two maleic acid salts of cumarone-3-methane amide be shown in the following table 6.

Table 6:N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] two maleic acid salts water-soluble of cumarone-3-methane amide.

Salt form	Solvability, mg/mL
Salt form	Solvability, mg/mL	Two maleic acid salt form I	At least 150 (pH3.6)
Two maleic acid salt form III	At least 30 (pH3.8)	Two maleic acid salt form I	At least 150 (pH3.6)

The two maleic acid salts of amorphous

Shown in embodiment 11, N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base) amorphous form of two maleic acid salts of cumarone-3-methane amide also can be by being dissolved in two maleic acid salts in the appropriate solvent such as methyl alcohol, and then dry (for example under about 40 ℃) obtain solid amorphous form and make.The powder x-ray diffraction figure of the two maleic acid salt forms of amorphous is shown among Figure 34.

The two HBr salt of crystallization

For example, under high temperature (for example about 75 ℃) with N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] cumarone-3-methane amide is dissolved in such as CH ₂Cl ₂, in THF, acetonitrile, ethyl acetate, methyl alcohol or any appropriate solvent of alcoholic acid, then add such as the Hydrogen bromide in the appropriate solvent of acetonitrile, can make two hydrobromates (two HBr) of this free alkali compound thus with well-crystallized.Then, can obtain the solid crystal material by solution being cooled to room temperature with per hour about 20 ℃ speed.Shown in embodiment 9 and 10, can obtain at least two kinds of different crystallized forms of two HBr salt.The polymorphic forms of a kind of pair of HBr salt be have 263 ℃ initial melt temperature (seeing Figure 31) anhydrous form and be expressed as two HBr form I.Second kind of polymorphic forms is solvate and is expressed as two HBr form II.The powder x-ray diffraction figure of two HBr form I is shown among Figure 29, and the DSC thermogram of two HBr form I is shown among Figure 31.The powder x-ray diffraction figure of two HBr form II is shown among Figure 30, and the DSC thermogram of two HBr form II is shown among Figure 32 and the pyrolysis weight distribution curve of two HBr form II is shown among Figure 33.Two HBr form II are the solvate form thereof with desolvation temperature (seeing Figure 32) of 63 ℃.The initial fusing point of two HBr form II is 248 ℃ (seeing Figure 32).Two HBr form II thermogravimetric analysiss (TGA) are presented at that weight loss is 4.5% (seeing Figure 33) when being heated to 100 ℃.Two HBr form II are carried out the Karl-Fisher titration to measure its water content.The result shows that water content is 4.1%.Therefore, two HBr form II are through being accredited as hydrate forms.

N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] solid-state stability of polymorphic forms of two HBr salt of cumarone-3-methane amide is shown in the following table 7.

N under the 7:40 ℃/75%RH of table, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] solid-state stability of two HBr salt (form I and II) of cumarone-3-methane amide.

Sample	T(0)	T (1 week)		T (4 week)		T (6 week)
Sample	T(0)	T (1 week)		T (4 week)		T (6 week)			Open	Close	Open	Close	Open	Close
Two maleic acid salt form I	-	-	-	-	-	-	-		Open	Close	Open	Close	Open	Close
Two maleic acid salt form I	-	-	-	-	-	-	-	Form 1	Form I and II	Form	1	Form II	Form I and II	Form II	Form II
Two maleic acid salt form II	98.53％	98.61％	98.70％	98.62％	98.66％	98.49％	98.61％	Form 1	Form I and II	Form	1	Form II	Form I and II	Form II	Form II
Two maleic acid salt form II	98.53％	98.61％	98.70％	98.62％	98.66％	98.49％	98.61％	Form II	Form II	Form II	Form II	Form II	Form II	Form II

N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] the water-soluble of two kinds of polymorphic forms of two HBr salt of cumarone-3-methane amide be shown in the following table 8.

Table 8:N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] two HBr salt water-soluble of cumarone-3-methane amide.

Salt form	Solvability
Salt form	Solvability	Two HBr form I	＞30mg/ml(pH3.4)
Two HBr form II	＞30mg/ml(pH3.4)	Two HBr form I	＞30mg/ml(pH3.4)

Crystalline free base

Free alkali compound N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] crystallized form of cumarone-3-methane amide also can be as described in the embodiment 3-8 and prepare.Free alkali N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] 6 kinds of different crystallized forms of cumarone-3-methane amide as shown in Figure 11-28 through identification and characterize.Free alkali N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] these 6 kinds of crystallized forms of cumarone-3-methane amide are expressed as free alkali polymorphic forms 1 to 6.Free alkali

polymorphic forms

1 and 4 is a hydrate, and

free alkali form

2,3,5 and 6 is anhydrous.

The amorphous free alkali

Shown in embodiment 12, N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] amorphous form of cumarone-3-methane amide free alkali also can be by being dissolved in this free alkali in the appropriate solvent such as ethanol/carbinol mixture, and then dry (for example under about 40 ℃) obtain solid amorphous form and make.The powder x-ray diffraction figure of amorphous free alkali form is shown among Figure 35.

The present invention is also about comprising N as described herein, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] pharmaceutical composition of the various physical form of cumarone-3-methane amide.For example, pharmaceutical composition of the present invention can be following form: be suitable for oral administration and form, as tablet, capsule, pill, powder, extended release preparation, solution, suspension; Be suitable for the form of parenteral injection, as sterile solution, suspension or emulsion; Be suitable for local the throwing and form, as ointment or emulsifiable paste; Or be suitable for per rectum throwing and form, as suppository.This pharmaceutical composition can be the unit dosage that is suitable for single throwing and exact dosage desired.This pharmaceutical composition can comprise common medical carrier or vehicle and as active ingredient according to compound of the present invention.In addition, it also can comprise other medicinal or medicaments, carrier, adjuvant etc.

Exemplary parenteral throwing and form comprise solution or the suspension such as the active compound in the aseptic aqueous solution of the propylene glycol or the dextrose aqueous solution.In case of necessity, this formulation can be suitably through buffering.

Suitably pharmaceutical carrier comprises inert diluent or weighting agent, water and various organic solvent.In case of necessity, this pharmaceutical composition can contain other composition, such as seasonings, tamanori, vehicle and analogue thereof.Therefore, contain such as the tablet of the various vehicle of citric acid can be used from oral administration such as the various disintegrating agents of starch, alginic acid and some complex silicate and such as the tamanori one of sucrose, gelatin and gum arabic.In addition, often be applicable to the purpose of compressing tablet such as Magnesium Stearate, Sodium Lauryl Sulphate BP/USP and steatitic lubricant.The solids composition of similar type also can be used in soft and the hard-filled gelatin capsule.This preferable material is comprised lactose and high molecular weight polyethylene glycol.When needs oral administration and waterborne suspension or vina, can be with wherein active compound and various sweeting agent or seasonings, pigment or dye well (in case of necessity) emulsifying agent or suspension agent and such as the thinner combination of water, ethanol, propylene glycol, glycerine or its combination.

Those skilled in the art are known or should be appreciated that preparation contains the method for the various pharmaceutical compositions of specified quantitative active compound.For example, see Remington ' s Pharmaceutical Sciences, Mack Publishing Company, Easter, Pa., the 15th edition (1975).

Embodiment

Embodiment provided below and preparation method further specify and the particular aspects of view similar.Should be appreciated that category of the present invention also is subject to the category of the following example never in any form.

Method and material

Dsc (DSC): use the Q1000 thermal-analysis instrumentation to come

execution graph

3,8, the dsc measurement shown in the 23-28,31 and 32.In having the hermetic aluminum pan of pin hole, example weight is in 1 to 2mg scope.With sample balance to 30 ℃, then isothermal kept 3 minutes and then rose to 200 or 300 ℃ with 10 ℃/min scanning speed oblique line.Drying nitrogen is used as rinsing gas.

Powder x-ray diffraction (PXRD): collect Fig. 1,6,11-16,29,30,34 and 35 PXRD data according to following experimental arrangement.Sample (2mg) is placed on the microslide of zero background.Then, sample is placed the Discover D8 (Bruker AXS Instruments) that is equipped with the GADDS detector.This system uses to be maintained at provides the CU of 1.5406 dusts α the copper X-ray source of 1 emission under 40kV and the 40mA.Use 0.02 ° the step scan and the step time in 60.1 seconds to collect data from 4-40 ° of 2 θ.Diffraction peak is generally measured under the sensitivity of ± 0.1 degree (2 θ).

Collect the solid state NMR data shown in Fig. 2 and 7 according to following experimental arrangement.With about 50mg individual samples close packing in the 4mm ZrO turner that is used for each analytic sample.Under 295 K and ambient pressure, collect spectrum with the Bruker-Biospin 4mm BL three resonance CPMAS probes that are positioned in the heavy caliber Bruker-Biospin Avance DSX 500MHz NMR spectrograph.With magic angle location sample and under 15.0kHz, rotate.It is minimum that fast rotational speed is reduced to the intensity of spinning side band.Regulate the scanning number to obtain suitable S/N.

¹³C spectroscopic analysis: use ¹H- ¹³C cross polarization evil spirit angle rotation (Cross-PolarizationMagic Angle Spinning (CPMAS)) is collected one dimension under the condition around ¹³C spectrum.In order to optimize signal sensitivity, cross polarization is adjusted to 2.0ms and decoupling magnetic field is set at 80kHz duration of contact.Circulation delay with 45 seconds obtains 512 scanning.The diamantane external sample of using the upfield signal sets to equal 29.5ppm is come with reference to spectrum.Chemical shift is generally measured under the sensitivity of ± 0.1ppm.

Use following experimental arrangement collect Fig. 4,9 and 17-22 shown in Raman spectrum data.Sample (2-5mg) is transferred on the glass microscope slide and with it is transferred on the Raman microprobe (Kaiser Optical Instruments), and in sample adjusted focus.Use the single accumulation that exposed for 10 seconds from 0-3500cm ^-1Wave number obtain Raman shift.Raman spectrum data is generally at ± 1cm ^-1Sensitivity measure down.

Use following experimental arrangement to measure solid-state stability as shown in table 5 and 7.Utilize preliminary HPLC method research compound 1The stability of salt form.The HPLC condition is listed in hereinafter.

Damping fluid: 25 mM ammonium phosphate damping fluids (pH 2.5)

Organic modifiers: acetonitrile

Wavelength: 210nm

Post: Waters Symmetry C18,4.6 * 150mm, 5 μ m;

Flow rate: 1.0mL/min

Volume injected: 10 μ L

Working time: 40 minutes

Column temperature: envrionment temperature

Gradient:

Time	Damping fluid %	ACN(％)
Time	Damping fluid %	ACN(％)	0	90	10
10	85	15	0	90	10
10	85	15	30	50	50
36	90	10	30	50	50
36	90	10	40	90	10

Embodiment 1a: the preparation of two maleic acid salt form I

With 0.02g N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] cumarone-3-methane amide and 4mL ethyl acetate pack in the 8ml scintillation vial.This bottle stirred and be heated to 68 ℃, and this temperature was kept 5 minutes.Solid state maleic acid (11.3mg, 2.1 equivalents) is added in the bottle.Solution becomes oyster white, becomes the solution of slight haze simultaneously.After 10 minutes, white solid begins precipitation.After precipitation, with 20 ℃/hour speed solution is cooled to room temperature immediately.Place cryostat (or 2 ℃ of refrigerators) to go through 2 hours in bottle.Collect solid and make it dry down overnight by vacuum filtration in vacuum (30 inches Hg, 60 ℃).This method makes 0.025g, and productive rate is 85%.

Maleic acid also can the solution form but not solid as implied above add.

Embodiment 1b: the preparation of two maleic acid salt form I

Under 25 ℃, with N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] the two maleic acid salts of cumarone-3-methane amide, form III (0.015g) is suspended in the suspension that obtains about 7.5mg/mL in the acetonitrile (2mL).The crystal seed of a small amount of form I is added in the suspension.Suspension is stirred the conversion that obtained from form III to form I in 2 days down at 50 ℃.

Embodiment 2a: the preparation of two maleic acid salt form III

Under 25 ℃, with N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] the two maleic acid salts of cumarone-3-methane amide, form I (0.26g) is dissolved in the solution that obtains about 93mg/mL in the water (2.8mL).After dissolving fully, via 0.22 μ m pore size strainer filtering solution.Under 5 ℃, place turner after last 12 hour filtered solution, obtain the N of precipitated form, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] the two maleic acid salt form III of cumarone-3-methane amide.

Embodiment 2b: the preparation of two maleic acid salt form III

Under 25 ℃, with N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] the two maleic acid salts of cumarone-3-methane amide, form I (0.015g) is suspended in the suspension that obtains about 7.5mg/mL in the acetonitrile (2ml).The crystal seed of a small amount of form III is added in the suspension.Suspension is stirred at ambient temperature the conversion that obtained from form I to form III in 3 days

Embodiment 3: the preparation of free alkali form 1

At room temperature, with 4-(2-chloroethyl) morpholine (10.7g, 57.4mmol) and Cs ₂CO ₃(46.3g, 143.5mmol) solution stirring in DMF (100mL) is 1 hour.In solution, add 6-[(7-hydroxyquinoline-4-yl) the oxygen base]-N, 2-dimethyl-1-cumarone-3-methane amide (10g, solution 28.7mmol).Mixture heating up to 120 ℃ is gone through 15hr.Solution is cooled to room temperature and extracts with EtOAc.(use 5-10%MeOH/CH by silica gel column chromatography ₂Cl ₂) come purifying through spissated resistates, obtain the free alkali N of 2.6g solid state, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] cumarone-3-methane amide.Powder x-ray diffraction as shown in figure 11 characterizes, and this solid free base is form 1 through differentiating.Should notice that form 1 also can be by at room temperature going through 24 hours with in

form

3,5 or 6 any one furnishing slurries and preparing in water.

Embodiment 4: the preparation of free alkali form 2

At room temperature, with 4-(2-chloroethyl) morpholine (2.1g, 11.5mmol) and Cs ₂CO ₃(7.5g is 23mmol) in CH ₃Solution stirring among the CN (100mL) 45 minutes.In solution, add 6-[(7-hydroxyquinoline-4-yl) the oxygen base]-N, and 2-dimethyl-1-cumarone-3-methane amide (2g, 5.75mmol).Mixture heating up is gone through 3hr to refluxing.Remove inorganic salt and concentrated solution by filtering.(use 1-10%MeOH/CH by silica gel column chromatography ₂Cl ₂) come the purifying resistates, obtain the free alkali N of 1.8g solid state, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] cumarone-3-methane amide.Then, with this compound dissolution stirred overnight in hot Virahol and at room temperature.By filtering the N that collects 1.13g polymorphic forms 2,2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] cumarone-3-methane amide.Should notice that form 2 is anhydrous and must prepares to prevent to form hydrate (for example embodiment 6 described forms 4) under anhydrous condition.

Embodiment 5: the preparation of free alkali form 3

Under vacuum, heat form 1 (0.1g) was gone through 1 hour in 110 ℃ of baking ovens, came preparation form 3 thus.

Embodiment 6: the preparation of free alkali form 4

With 3.0mL Virahol processing form 1 (0.1g) and be heated to 70 ℃ and obtain solution, come preparation form 4 thus.After dissolving fully, solution is cooled to envrionment temperature.Filtering throw out is differentiated and is form 4 in solution.

Embodiment 7: the preparation of free alkali form 5

Form suspension with 5.0mL acetonitrile treatment form 1 (1g), come preparation form 5 thus.Then, suspension is down stirred 1hr and obtains from form 1 to form 5 conversion at 80 ℃.

Embodiment 8: the preparation of free alkali form 6

Under vacuum, heat form 4 (0.1g) is gone through 1hr in 110 ℃ of baking ovens, obtains form 6 thus.

Embodiment 9: the preparation of two HBr form I

Be prepared as follows two HBr form I.With 0.1g N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] cumarone-3-methane amide and 10mL acetonitrile pack in the 20mL scintillation vial.This bottle stirred and be heated to 72 ℃, and this temperature was kept 5 minutes.HBr solution (0.152mL, 3M in acetonitrile, 2.1 equivalents) is added under the liquid level.After adding acid, it is muddy that solution becomes immediately, but become clarification after the several seconds.Temperature is kept constant to be gone through 5 minutes.Then, with 20 ℃/hour speed solution is cooled to room temperature.Then, bottle is placed cryostat (or 2 ℃ of refrigerators) went through 2 hours.Collect solid and make it dry down overnight by vacuum filtration in vacuum (30 inches Hg, 60 ℃).Then, at room temperature go through 2hr with solid furnishing slurries in acetone (25mg/mL), and then dry overnight in 60 ℃ of vacuum drying ovens.

Embodiment 10: the preparation of two HBr form II

Under 40 ℃ and 75%RH, place open container to go through for 4 weeks form I, thus by the two HBr form II of two HBr form I preparations.

Embodiment 11: the preparation of the two maleic acid salts of amorphous

Will about 4mg N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] cumarone-3-methane amide-two maleic acid salts are dissolved in the 1mL methyl alcohol.Place 40 ℃ of vacuum drying ovens and drying to go through 30 minutes solution and obtain amorphous form.

Embodiment 12: the preparation of amorphous free alkali

Will about 4mg free alkali N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] cumarone-3-methane amide is dissolved in 2mL methyl alcohol: in the alcohol mixture (50: 50).Place 40 ℃ of vacuum drying ovens and drying to go through 30 minutes solution and obtain amorphous form.

Claims

1.N, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] and two maleic acid salts of cumarone-3-methane amide.

2. salt as claimed in claim 1, wherein this salt is crystalline.

3. salt as claimed in claim 1, wherein this salt is crystal anhydrous salt.

4. salt as claimed in claim 3, wherein this salt is the pure basically polymorphic of two maleic acid salt form I.

5. salt as claimed in claim 3, wherein to comprise diffraction angle (2 θ) be 18.6 ± 0.1 peak to the powder x-ray diffraction figure of this salt.

6. salt as claimed in claim 5, wherein to comprise diffraction angle (2 θ) be 4.0 ± 0.1,8.0 ± 0.1,18.1 ± 0.1,18.6 ± 0.1,21.6 ± 0.1 and 26.2 ± 0.1 peak to the powder x-ray diffraction figure of this salt.

7. salt as claimed in claim 3, wherein the solid state NMR spectrum of this salt comprises 148.0 ± 0.1ppm's ¹³The C chemical shift.

8. salt as claimed in claim 7, wherein the solid state NMR spectrum of this salt comprises 148.0 ± 0.1,118.0 ± 0.1,124.2 ± 0.1,143.9 ± 0.1 and 162.5 ± 0.1ppm ¹³The C chemical shift.

9. salt as claimed in claim 1, wherein this salt is the mixture of two maleic acid salt form I and two maleic acid salt form III.

10. pharmaceutical composition, it comprises as each salt in the claim 1 to 9.

11. capsule, it comprises the pharmaceutical composition as claim 10.

12. as the capsule of claim 11, it comprises the normal N of 0.1 to 50mg free alkali, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base) two maleic acid salts of cumarone-3-methane amide.

13. as the capsule of claim 12, it comprises the normal N of 0.5 to 25mg free alkali, 2-dimethyl-6-[7-(2-morpholino oxyethyl group) quinolyl-4 oxygen base] two maleic acid salts of cumarone-3-methane amide.

14. the method for treatment mammalian cancer, comprise with as the treatment significant quantity of arbitrary pharmaceutical composition of claim 10 to and Mammals.