Salts and polymorphic modifications of the inhibitor vegf-r

FIELD: medicine.

SUBSTANCE: invention refers to salt N,2-dimetyl-6-[7-(2-morpholinoethoxy)chinoline-4-iloxy]benzofuran-3-carboxamide, particularly bismaleate N,2-dimetyl-6-[7-(2-morpholinoethoxy)chinoline-4-iloxy]benzofuran-3-carboxamide with antitumor activity.

EFFECT: cancer treatment availability.

11 cl, 35 dwg, 9 tbl, 12 ex

 

This application sets the priority of U.S. patent No. 60/706332, filed August 8, 2005, application for U.S. patent No. 60/750189, filed December 14, 2005, both of which are included in the present description by reference.

BACKGROUND of INVENTION

This invention relates to forms salts and polymorphic modifications of N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide, which is applicable for the treatment of abnormal cell growth, such as cancer, in mammals. This invention also relates to compositions including such salts and polymorphic modifications, and to methods of using such compositions for the treatment of abnormal cell growth in mammals, especially for humans.

The compound N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide represented by the structural formula1in free base form, is

potent selective inhibitor of receptor 2 factor vascular endothelial growth (VEGF-R2). It strongly inhibits the tyrosine kinase activity of the receptor VEGF-R2 and selectively blocks stimulated VEGF receptor autophosphorylation, as well as the life expectancy of endothelial cells. Researchin vivoshowed that this compound significantly inhibits Accelero permeability of tumor angiogenesis and growth of tumors xenografted person. This compound was described in published patent application U.S. 2005-0137395, published on 23 June 2005, the description of which is included here as a reference. Methods for obtaining compounds1in free base form is also described in the provisional application U.S. 60/742847, entitled “Methods of Preparing a VEGF-R Inhibitor”, filed December 5, 2005

The advantage is the presence of salts and polymorphic forms having such superior characteristics as improved crystallinity and solubility and/or reduced hygroscopicity, while maintaining stability and chemical properties of enantiomers.

The INVENTION

In one embodiment of the invention, the present invention provides salt bimaleate N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide. In certain aspects of this variant embodiment of the invention, the salt is anhydrous. In the following aspect, the salt is crystalline. In the following aspect the salt is an anhydrous crystalline salt. In the following aspect the salt is essentially pure polymorph of bimaleate, form I. In the following aspect, salt has a powder x-ray diffraction, having a peak at diffraction angle (2θ), amounting to 18.6±0,1. In the following aspect, salt has a powder diffraction the x-ray is ogramme, having peaks at angles of diffraction (2θ), components 4,0±0,1; 18,1±0,1 and 18.6±0,1. In the following aspect, salt has a powder x-ray diffraction having peaks at angles of diffraction (2θ), components 4,0±0,1; 8,1±0,1; 18,1±0,1; 18,6±0,1; 21,6±0,1 and 26.2±0,1. In the following aspect, salt has a powder x-ray diffraction having peaks at diffraction angles (2θ)essentially the same as shown in Fig. 1. In the following aspect, salt is an NMR spectrum of the solid, where the chemical shift13C is 148,0±0,1 ppm In the following aspect, salt is an NMR spectrum of the solid, where the chemical shifts13C are 148,0±0.1 and are 162.5±0,1 ppm In the following aspect, salt is an NMR spectrum of the solid, where the chemical shifts13C are 148,0±0,1; 118,0±0,1; 124,2±0,1; 143,9±0,1 and are 162.5±0,1 ppm In the following aspect, salt is an NMR spectrum of the solid, where the chemical shifts13C are essentially as shown in Fig. 2. In the following aspect, g is the Raman spectrum with offset frequencies in 1589±1, 1402±1 and 755±1 cm-1. In the following aspect, g is the Raman spectrum with offset frequencies that are in the regulations essentially similar to those shown in Fig. 4.

The following variant of the invention is a salt of bimaleate N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-CT is oksamida, where salt is a MES. In a separate embodiment of the invention the salt is a hydrate. The following aspect of a variant embodiment of the invention the salt is hydrated. In the following aspect, the salt is essentially pure polymorphs of bimaleate, form III. In the following aspect, salt has a powder x-ray diffraction, having a peak at diffraction angle (2θ)of 12,7±0,1. In the following aspect, salt has a powder x-ray diffraction having peaks at angles of diffraction (2θ), components of 6.4±0,1; 12,7±0,1 and 17.3±0,1. The following aspect of the salt has a powder x-ray diffraction having peaks at angles of diffraction (2θ), components 6,4±0,1; 12,7±0,1; 17,3±0,1; 21,3±0,1 and 25.9±0,1. The following aspect of the salt has a powder x-ray diffraction having peaks at diffraction angles (2θ)essentially similar to those shown in Fig. 6. In the following aspect, salt is an NMR spectrum of the solid, where the chemical shift13C is to 132.8±0,1 ppm In the following aspect, salt is an NMR spectrum of the solid, where the chemical shifts13C be 99.2±0,1; for 125.8±0,1; and to 132.8±0,1 ppm, In another aspect, in NMR of solids, salt chemical shifts13C are 99,2±0,1, 125,8±0,1, 132,8±0,1, 142,2±0,1 and 166,1±0,1 ppm, In another aspect, the salt is an NMR spectrum of the solid, where the chemical shifts13-1. In the following aspect Sol has a spectrum of Raman scattering with displacement of vibrational frequencies in the provisions are essentially similar to those shown in Fig. 9.

In the following embodiment of the invention, the invention provides a crystalline salt of bimaleate N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide, where salt is a mixture of bimaleate forms I and bimaleate form III. Preferably, when the composition is an essentially pure mixture of bimaleate forms I and bimaleate form III, where essentially pure mixture of bimaleate forms I and III includes at least 10%, preferably less than 5%, preferably less than 3%, preferably less than 1% by weight of any other physical forms of salt bimaleate.

In the following embodiment, the invention provides an amorphous form of the salt of bimaleate N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide. For example, the amorphous form can be powder x-ray diffraction having peaks at diffraction angles (2θ)essentially the same angles shown in Fig. 34.

the following embodiment, the invention provides a crystalline form of the free base N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide. In a particular embodiment of the invention, the crystalline form of the free base N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide is anhydrous. In yet another embodiment of the invention, the crystalline form of the free base N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide is a hydrate.

In the following embodiment of the invention, the crystalline form is polymorpha free base form 1. In particular, the crystalline form has a powder x-ray diffraction having peaks at angles of diffraction (2θ), components 19,9±0,1 and 22.0±0,1. More specifically, the crystalline form has a powder x-ray having peaks at angles of diffraction (2θ), components 13,5±0,1; 19,1±0,1; 19,9±0,1; 22,0±0,1 and 24.1±0,1. More specifically, the crystalline form has a powder x-ray having peaks at diffraction angles (2θ)essentially the same angles shown in Fig. 11.

In yet another embodiment of the invention, the crystalline form is polymorpha free base form 2. In particular, the crystalline form has a powder diffract the traditional x-ray, having peaks at angles of diffraction (2θ), which is 10.6±0,1 and 15.3±0,1. More specifically, the crystalline form has a powder x-ray diffraction having peaks at angles of diffraction (2θ), components 10,6±0,1; 14,0±0,1; 15,3±0,1 and 16.9±0,1. Most specifically, the crystalline form has a powder x-ray diffraction having peaks at diffraction angles (2θ)essentially the same angles shown in Fig. 12.

In yet another embodiment of the invention, the crystalline form is polymorpha free base form 3. In particular, the crystalline form has a powder x-ray diffraction having peaks at angles of diffraction (2θ), components of 12.5±0,1 and 21.6±0,1. More specifically, the crystalline form has a powder x-ray diffraction having peaks at angles of diffraction (2θ), components 12,5±0,1; 21,2±0,1; 21,6±0,1 and 24.0±0,1. Most specifically, the crystalline form has a powder x-ray diffraction having peaks at diffraction angles (2θ)essentially the same angles shown in Fig. 13.

In yet another embodiment of the invention, the crystalline form is polymorpha free base form 4. In particular, the crystalline form has a powder x-ray diffraction having peaks at angles of diffraction (2θ), components 6,5±0,1 and 16.0±0,1. the school, more specifically, the crystalline form has a powder x-ray having peaks at angles of diffraction (2θ), components 5,6±0,1, 6,5±0,1, 16,0±0,1 and 19.5±0,1. Most specifically, the crystalline form has a powder x-ray diffraction having peaks at diffraction angles (2θ)essentially the same angles shown in Fig. 14.

In yet another embodiment of the invention, the crystalline form is polymorpha free base form 5. In particular, the crystalline form has a powder x-ray diffraction having peaks at angles of diffraction (2θ), which was 22.6±0,1 and 23.4±0,1. More specifically, the crystalline form has a powder x-ray diffraction having peaks at angles of diffraction (2θ), components 12,1±0,1; 18,4±0,1; 21,0±0,1; 22,6±0,1 and 23.4±0,1. Most specifically, the crystalline form has a powder x-ray having peaks at diffraction angles (2θ)essentially the same angles shown in Fig. 15.

In yet another embodiment of the invention, the crystalline form is polymorpha free base form 6. In particular, the crystalline form has a powder x-ray diffraction having peaks at angles of diffraction (2θ), components of 8.4±0,1 and 14.7±0,1. More specifically, the crystalline form has a powder x-ray diffraction having peaks at glah diffraction (2θ), components 8,4±0,1; 14,7±0,1; 17,5±0,1 and 19,6±0,1. Most specifically, the crystalline form has a powder x-ray diffraction having peaks at diffraction angles (2θ)essentially the same angles shown in Fig. 16.

In the following embodiment, the present invention relates to crystalline free base form of N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide, where the crystalline form has a spectrum of Raman scattering with offset vibrational frequencies, essentially similar to those shown in any of figures 17 to 22.

In the following embodiment of the invention the present invention relates to amorphous free base form of N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide. For example, the amorphous form can be powder x-ray diffraction having peaks at diffraction angles (2θ)essentially the same angles shown in Fig. 35.

The present invention also relates to bishydroperoxyde salt of N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide. In one embodiment of the invention, salt is an anhydrous crystalline form. In the following embodiment of the invention, the salt is essentially pure polymorpha bis-HBr form I. the following variant of the invention, the crystalline form has a powder x-ray diffraction, having peaks at diffraction angles (2θ)essentially the same angles shown in Fig. 29. In the following embodiment of the invention the salt is in the form of crystalline. In the following embodiment of the invention the salt is essentially pure polymorph bis-HBr form II. In the following embodiment of the invention, crystalline form has a powder x-ray diffraction having peaks at diffraction angles (2θ)essentially the same angles shown in Fig. 30.

In the present invention, in addition, offer a pharmaceutical composition comprising a salt of bimaleate, salt bishydroperoxyde or form of the free base of the compounds of formula1in any of these forms, crystalline or amorphous. In the present invention, in addition, offer a capsule containing any of the pharmaceutical compositions of the present invention. In certain aspects of this variant of the invention, the capsule contains a salt of bimaleate N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide, equivalent to 0.1-50 mg of free base. In the following aspect, the capsule contains a salt of bimaleate N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide, equivalent to 0.5-25 mg free base. In the following the corresponding aspect capsule contains 0.1 to 50 mg of the free base N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide. In the following aspect capsule contains 0.5 to 25 mg of the free base N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide. In the following aspect capsule contains the number of bishydroperoxyde salt of N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide, equivalent to 0.1-50 mg of free base. In the following aspect, the capsule contains a number of bishydroperoxyde salt of N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide, equivalent to 0.5-25 mg free base.

In yet another embodiment, the invention provides a method of treating cancer in mammals, including humans, the method comprises the administration to a mammal a therapeutically effective amount of any of the pharmaceutical compositions of the present invention, are described here.

In yet another embodiment of the invention, the invention provides a method of treating cancer in a mammal, the method includes the introduction of mammals, including humans, any of the capsules of the present invention, are described here.

In a separate aspect of any of the methods in the previous variants of the invention, the method further includes introducing one or more antitumor agents, agents that prevent angiogenesis, inhibitors of signal transduction, or is hentov, preventing proliferation.

The invention also relates to a method of treating abnormal cell growth in mammals, including humans, comprising the introduction of a given mammal the compounds of formula1defined above, or its pharmaceutically acceptable salt or MES in amounts effective for the treatment of abnormal cell growth. In one embodiment of this method according to the invention, the abnormal cell growth is cancer, including, but without limitation, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, cervical carcinoma, carcinoma of the vagina, carcinoma of the female genital organs, Hodgkin's disease, esophageal cancer, cancer of the small intestine, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, carcinoma renal cell carcinoma renal pelvis, neoplasm Central nervous system (CNS), primary do the Thomas CNS, spinal axis tumors, glioma, brain stem, pituitary adenoma, or a combination of one or more of the above cancers. In yet another embodiment of the above method according to the invention, the specified abnormal cell growth is a benign proliferative disease, including, but not limited to, psoriasis, benign hypertrophy of the prostate gland or restenosis.

This invention also relates to a method of treating abnormal cell growth in a mammal, which includes the introduction of the specified mammal amount of the compounds of formula1or its pharmaceutically acceptable salt or MES, which is effective in treating abnormal cell growth in combination with an antitumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, including antibiotics, inhibitors of growth factor inhibitors, cell cycle, enzymes, topoisomerase inhibitors, modifiers biologic response, antibodies, cytotoxic agent, antihormones, anti-androgens.

This invention also relates to pharmaceutical compositions for the treatment of abnormal cell growth in mammals, including humans, contains effective in the treatment of p is tological cell growth amount of the compounds of formula 1defined above, or its pharmaceutically acceptable salt or MES, and a pharmaceutically acceptable carrier. In one embodiment, the specified composition specified abnormal growth of cells is a cancer including, but without limitation, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, cervical carcinoma, carcinoma of the vagina, carcinoma of the female genital organs, Hodgkin's disease, esophageal cancer, cancer of the small intestine, cancer the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, carcinoma cells of the ureter, carcinoma of the renal pelvis ureter, neoplasma Central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, glioma, brain stem, pituitary adenoma, or a combination of one or more of the above cancers. In yet another embodiment, the specified pharmaceutical compositions specified the first abnormal cell growth is a benign proliferative disease, including, but not limited to, psoriasis, benign hypertrophy of the prostate gland or restenosis.

The invention also relates to pharmaceutical compositions intended for the treatment of abnormal cell growth in mammals, including humans, which contains a number of compounds of the formula1defined above, or its pharmaceutically acceptable salt or MES, is effective in treating abnormal cell growth in combination with an antitumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, including antibiotics, inhibitors of growth factor inhibitors, cell cycle, enzymes, topoisomerase inhibitors, modifiers biologic response, antihormones and anti-androgens.

This invention also relates to a method of treatment of disorders associated with angiogenesis in a mammal, including man, comprising the introduction of a given mammal the compounds of formula1defined above, or its pharmaceutically acceptable salt or MES, in an amount effective to treat such violations. Such disorders include cancers, such as melanoma; eye disorders such as age-related macular degeneration installed syndrome glaznov is histoplasmosis, and retinal revascularization due to proliferative diabetic retinopathy; rheumatoid arthritis; disorders associated with bone loss such as osteoporosis, Paget's disease, malignant development of humoral hypercalcemia, hypercalcemia, due to metastasis of tumors in the bone, and osteoporosis, treatment-induced glucocorticoid hormone; coronary restenosis; and some microbial infections, including infections associated with microbial pathogens selected from adenovirus, Hantavirus,Borrelia burgdorferi,Yersinia spp., Bordetella pertussis and A group of streptococci.

This invention also relates to a method and to a pharmaceutical composition intended for the treatment of abnormal cell growth in a mammal, comprising introducing the compound of the formula1or its pharmaceutically acceptable salt or MES, and one or more substances selected from agents that targets angiogenesis, inhibitors of signal transduction and agents, preventing proliferation, in amounts effective when used together for the treatment of this pathological cell growth in mammals.

In the methods and pharmaceutical compositions described herein, agents that targets angiogenesis, such as inhibitors of MMP-2 (matrix-metalloprotein the basics 2), inhibitors of MMP-9 (matrix-metalloproteinase 9) inhibitors, COX-II (cyclooxygenase II) can be used together with the compound of the formula1or its pharmaceutically acceptable salt or MES. Examples of applicable inhibitors of COX-II include CELEBREX™ (elecoxib), valdecoxib and rofecoksib. Examples of suitable inhibitors of matrix-metalloproteinases described in applications WO 96/33172 (published October 24, 1996), WO 96/27583 (published March 7, 1996), European patent application No. 973049711 (filed July 8, 1997), European patent application No. 993086172 (filed October 29, 1999), WO 98/07697 (published 26 February 1998), WO 98/03516 (published January 29, 1998), WO 98/34918 (published August 13, 1998), WO 98/34915 (published August 13, 1998), WO 98/33768 (published August 6, 1998), WO 98/30566 (published July 16, 1998), the publication of the European patent 606046 (published 13 July 1994), the publication of the European patent 931788 (published on July 28, 1999), WO 90/05719 (published may 31, 1990), WO 99/52910 (published October 21, 1999), WO 99/52889 (published October 21, 1999), WO 99/29667 (published June 17, 1999), PCT International application number PCT/IB98/01113 (filed July 21, 1998), European patent application patent No. 99302232.1 (filed March 25, 1999), application great Britain patent number 9912961.1 (filed June 3, 1999), the provisional application U.S. No. 60/148464 (submitted 12 is of ugust 1999), U.S. patent 5863949 (issued January 26, 1999), U.S. patent 5861510 (issued January 19, 1999), the publication of the European patent 780386 (published June 25, 1997), all of which is included in its entirety in the present description by reference. Preferred inhibitors of MMP-2 and MMP-9 are those that have low inhibitory activity against MMP-1 or do not possess such activity. The preferred inhibitors are those inhibitors that selectively inhibit matrix metalloproteinases MMP-2 and/or MMP-9 relative to the other matrix-metalloproteinases (i.e. MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12 and MMP-13).

Some specific examples of MMP inhibitors, applicable in combination with the compounds of the present invention are AG-3340, RO 32-3555, RS 13-0830, and compounds listed in the following list:

3-[[4-(4-pertenece)benzazolyl]-(1-hydroxycarbonylmethyl)amino]propionic acid; hydroxyamide 3-Exo-3-[4-(4-pertenece)benzosulfimide]-8-oxabicyclo[3.2.1]octane-3-carboxylic acid; hydroxyamide (2R, 3R) 1-[4-(2-chloro-4-forbindelse)benzazolyl]-3-hydroxy-3-methylpiperidin-2-carboxylic acid; hydroxyamide 4-[4-(4-fervency)benzosulfimide]-tetrahydropyran-4-carboxylic acid; 3-[[4-(4-pertenece)benzazolyl]-(1-hydroxycarbonylmethyl)amino]propionate the acid; hydroxyamide 4-[4-(4-chlorphenoxy)benzosulfimide]tetrahydropyran-4-carboxylic acid; hydroxyamide 3-[4-(4-chlorphenoxy)benzosulfimide]tetrahydropyran-3-carboxylic acid; hydroxyamide (2R, 3R) 1-[4-(4-fluoro-2-methylbenzoate)benzazolyl]-3-hydroxy-3-methylpiperidin-2-carboxylic acid; 3-[[4-(4-pertenece)benzazolyl]-(1-hydroxycarbamoyl-1-methylethyl)amino]propionic acid; 3-[[4-(4-pertenece)benzazolyl]-(4-hydroxycarbonylmethyl-4-yl)amino]propionic acid; hydroxyamide 3-Exo-3-[4-(4-chlorphenoxy)benzosulfimide]-8-oxabicyclo[3.2.1]octane-3-carboxylic acid; hydroxyamide 3-endo-3-[4-(4-pertenece)benzosulfimide]-8-oxabicyclo[3.2.1]octane-3-carboxylic acid and hydroxamic 3-[4-(4 fervency)benzosulfimide]tetrahydrofuran-3-carboxylic acid; and pharmaceutically acceptable salts, solvate, and prodrugs of these compounds.

The compounds of formula1and their pharmaceutically acceptable salt and solvate may also be used in combination with inhibitors of signal transduction, such as agents that can inhibit the response of EGFR (factor receptor epidermal growth), such as EGFR antibodies, EGF antibodies, and molecules that are EGFR inhibitors; VEGF inhibitors (factor vascular endothelial growth); and inhibitors of the receptor erB2, such as organic molecules or antibodies that bind to the erbB2 receptor, for example, HERCEPTIN™ (Genentech, Inc. of South San Francisco, California, USA).

The EGFR inhibitors are described, e.g. in WO 95/19970 (published July 27, 1995), WO 98/14451 (published April 9, 1998), WO 98/02434 (published January 22, 1998) and in U.S. patent 5747498 (issued may 5, 1998). Inhibiting EGFR agents include, but without limitation, monoclonal antibodies C225 and anti-EGFR 22Mab (ImClone Systems Incorporated of New York, New York, USA), the compounds ZD-1839 (straZeneca), BIBX-1382 (Boehringer Ingelheim), MDX-447 (Medarex Inc. of Annandale, New Jersey, USA), and OLX-103 (Merck & Co. of Whitehouse Station, New Jersey, USA), VRCTC-310 (Ventech Research) and toxin merge EGF (Seragen Inc. of Hopkinton, Massachusetts).

The VEGF inhibitors, for example SU-5416 and SU-6668 (Pfizer Inc.), can also be combined with the compound of the formula1or its pharmaceutically acceptable salt or MES. For example, VEGF inhibitors are described in the application WO 99/24440 (published may 20, 1999), PCT international application PCT/IB99/00797 (filed may 3, 1999), in the application WO 95/21613 (published August 17, 1995), WO 99/61422 (published December 2, 1999), in U.S. patent 5834504 (issued November 10, 1998), WO 98/50356 (published November 12, 1998), the U.S. patent 5883113 (issued March 16, 1999), U.S. patent 5886020 (issued March 23, 1999), U.S. patent 5792783 (issued August 11, 1998), WO 99/10349 (published March 4, 1999), WO 97/32856 (published September 12, 1997), WO 97/22596 (published June 26, 1997), WO 98/4093 (published 3 December 1998), WO 98/02438 (published January 22, 1998), WO 99/16755 (published 8 April 1999) and WO 98/02437 (published January 22, 1998), all of which are included in the present description fully by reference. Other examples of some specific VEGF inhibitors are IM862 (Cytran Inc. of Kirkland, Washington, USA); anti-VEGF monoclonal antibody from Genentech, Inc. of South San Francisco, California; and synthetic ribozyme, angiozyme, from Ribozyme (Boulder, Colorado) and Chiron (Emeryville, California).

Inhibitors of ErbB2 receptor, such as GW-282974 (Glaxo Wellcome plc) monoclonal antibodies AR-209 (Aronex Pharmaceuticals Inc. of The Woodlands, Texas, USA) and 2B-1 (Chiron), can be introduced in combination with the compound of the formula1or its pharmaceutically acceptable salt or MES. Such erbB2 inhibitors include inhibitors described in WO 98/02434 (published January 22, 1998), WO 99/35146 (published July 15, 1999), WO 99/35132 (published July 15, 1999), WO 98/02437 (published January 22, 1998), WO 97/13760 (published April 17, 1997), WO 95/19970 (published July 27, 1995), in U.S. patent 5587458 (issued December 24, 1996) and U.S. patent 5877305 (issued March 2, 1999), each of which is fully incorporated in the present description as a reference. Inhibitors of ErbB2 receptor, applicable in the present invention, also described in the provisional application U.S. No. 60/117341, filed January 27, 1999, and provisional application U.S. No. 60/117346, filed January 27, 1999, of which the s both applications included in this description fully by reference.

Other agents that prevent proliferation, which can be used in the combined method of the present invention include inhibitors of the enzyme farnesyltransferase and inhibitors of tyrosine kinase receptor-Derived, including the compounds described and claimed in the following patents, U.S.: 09/221946 (filed December 28, 1998); 09/454058 (filed December 2, 1999); 09/501163 (filed February 9, 2000); 09/539930 (filed March 31, 2000); 09/202796 (filed may 22, 1997); 09/384339 (filed August 26, 1999) and 09/383755 (submitted 26 August 1999); and compounds described and claimed in the following provisional patent applications U.S.: 60/168207 (filed November 30, 1999); 60/170119 (filed December 10, 1999); 60/177718 (filed January 21, 2000); 60/168217 (filed November 30, 1999) and 60/200834 (filed may 1, 2000). Each of the above patent applications and provisional patent applications included in the present description fully by reference.

The connection formulas1or its pharmaceutically acceptable salt or MES can also be used with other agents useful for the treatment of abnormal cell growth or cancer, including, but without limitation, agents, can enhance antitumor immune responses, such as CTLA4 (cytotoxic lymphocyte antigen 4) antibodies, and other agents, which can block CTLA4 and agents, preventing proliferation, such as other inhibitors farnesyltransferase, for example inhibitors farnesyltransferase previously described in the references cited in the section “Background of the invention”, above. Specific CTLA4 antibodies that can be used in the present invention include the antibodies described in the provisional application U.S. 60/113647 (filed December 23, 1998), which is fully incorporated into the present description by reference.

The term “treatment”used herein means, unless otherwise specified, the return to a former condition, weakening braking progress or the prevention of disorder or condition to which use this term, or one or more symptoms of such disorders or conditions. The term “treatment”, as used herein, unless otherwise specified, refers to the treatment as immediately defined above.

The term “essentially pure (unalloyed)”used here is specific to a particular polymorphic or amorphous form, means that polymorphic amorphous form comprises less than 10% by weight, preferably less than 5%, preferably less than 3%, preferably less than 1% of any other physical forms of connection.

The term “essentially identical” used here is related to the position of the peaks of x-ray diffraction, means that take into account the position of the typical peak and variability of intensity. For example, the person skilled in the art will understand that the position of the peak (2θ) shows some vnutripuzarnoe variability, usually in the amount of 0.1°. Moreover, the person skilled in the art will understand that the relative intensity of the peaks will show vnutripuzarnoe variability and change, determined by the degree of crystallinity, preferred orientation, pre-treatment of the sample surface and other factors known to the person skilled in the art, but which should be considered only as qualitative criteria. Similarly, the term “essentially identical” used here is related to the NMR spectrum of a solid body and to the spectrum of Raman scattering, is also intended to encompass the variability associated with the analysis technique, which is known to specialists in this field. For example, the chemical shifts13C, measured by NMR of solids, as a rule, will change by 0.1 ppm, whereas the displacement in the CR spectrum is usually measured in cm-1.

BRIEF DESCRIPTION of DRAWINGS

In Fig. 1 shows powder x-ray diffraction salt of bimaleate N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide polymorphic form I.

In Fig. 2 shows the spectrum of the Mr solid salt of bimaleate N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide polymorphic form I.

In Fig. 3 shows a thermogram obtained by differential scanning calorimetry (DSC) salt of bimaleate N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide polymorphic form I.

In Fig. 4 shows the Raman spectrum of the salt of bimaleate N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide polymorphic form I.

In Fig. 5 shows the dynamic profile of sorption pair of salt bimaleate N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide polymorphic form I.

In Fig. 6 shows a powder x-ray diffraction salt of bimaleate N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide polymorphic form III.

In Fig. 7 shows an NMR spectrum of solids salt of bimaleate N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide polymorphic form III.

In Fig. 8 shows a thermogram obtained by differential scanning calorimetry (DSC) salt of bimaleate N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide polymorphic form III.

In Fig. 9 shows the Raman spectrum of the salt of bimaleate N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide polymorphic form III.

In Fig. 10 shows the spectrum of combination the th scattering salt of bimaleate N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide polymorphic form III.

In Fig. 11 shows a powder x-ray diffraction free base N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide polymorphic form 1.

In Fig. 12 shows a powder x-ray diffraction free base N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide polymorphic form 2.

In Fig. 13 shows the powder diffraction x-ray free base N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide polymorphic forms of 3.

In Fig. 14 shows a powder x-ray diffraction free base N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide polymorphic forms of 4.

In Fig. 15 shows a powder x-ray diffraction free base N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide polymorphic form 5.

In Fig. 16 shows the powder diffraction x-ray free base N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide polymorphic form 6.

In Fig. 17 shows the Raman spectrum of the free base N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide polymorphic form 1.

In Fig. 18 shows the spectrum of Raman scattering of the free base N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide polymorphic form 2.

In Fig. 19 shows the Raman spectrum of the free base N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide polymorphic forms of 3.

In Fig. 20 shows the Raman spectrum of the free base N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide polymorphic forms of 4.

In Fig. 21 shows the Raman spectrum of the free base N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide polymorphic form 5.

In Fig. 22 shows the Raman spectrum of the free base N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide polymorphic form 6.

In Fig. 23 shows a thermogram obtained by differential scanning calorimetry (DSC), the free base N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide polymorphic form 1.

In Fig. 24 shows a thermogram obtained by differential scanning calorimetry (DSC), the free base N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide polymorphic form 2.

In Fig. 25 shows a thermogram obtained by differential scanning calorimetry (DSC), the free base N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-ylox is]benzofuran-3-carboxamide polymorphic forms of 3.

In Fig. 26 shows a thermogram obtained by differential scanning calorimetry (DSC), the free base N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide polymorphic forms of 4.

In Fig. 27 shows a thermogram obtained by differential scanning calorimetry (DSC), the free base N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide polymorphic form 5.

In Fig. 28 shows a thermogram obtained by differential scanning calorimetry (DSC), the free base N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide polymorphic form 6.

In Fig. 29 shows the powder x-ray diffraction bis-HBr salt of N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide polymorphic form I.

In Fig. 30 shows a powder x-ray diffraction bis-HBr salt of N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide polymorphic form II.

In Fig. 31 shows a thermogram obtained by differential scanning calorimetry (DSC) bis-HBr salt of N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide, polymorphic form I.

In Fig. 32 shows a thermogram obtained by differential ska is yuusei calorimetry (DSC) bis-HBr salt of N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide, polymorphic form II.

In Fig. 33 shows the profile obtained by thermogravimetric analysis (TGA) bis-HBr salt of N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide, form II.

In Fig. 34 shows a powder x-ray diffraction salt of bimaleate N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide in amorphous form.

In Fig. 35 shows a powder x-ray diffraction free base N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide in amorphous form.

DETAILED description of the INVENTION

Received several original physical forms of compound N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide. Compound free base N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide can be obtained by methods described in the published patent application U.S. No. US 2005-0137395, published on 23 June 2005, a full description of which is incorporated into this description by reference. Additional methods for obtaining compounds of the free base N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide described in the provisional application for U.S. patent entitled “Methods of Preparing a VEGF-R Inhibitor,” filed December 5, 2005, which is also included in n the present description by reference.

Salt of N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide is obtained by treating compound free base corresponding number of selected mineral or organic acid in an aqueous solvent medium or in an acceptable organic solvent, such as methanol, acetonitrile, ethanol or ethyl acetate. After careful evaporation of the solvent was obtained the desired solid salt. The desired acid salt may be precipitated from a solution of the free base in an organic solvent by adding to a solution of the appropriate mineral or organic acid. The amorphous form of the free base and salts of N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide can be obtained by dissolving the free base or salt in an appropriate solvent, such as methanol, ethanol or mixtures thereof, followed by drying to obtain a solid amorphous form.

Crystalline salt of bimaleate

Salt bimaleate N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide can be obtained with a high degree of crystallinity, for example, by dissolving the compound free base in any suitable solvent such as CH2Cl2, THF, acetonitrile, ethyl acetate, methanol or ethanol, at povyshen the th temperature (for example, approximately, 85°C) followed by the addition of maleic acid in a suitable solvent. Can then be cleared by recrystallization or suspendirovanie in appropriate solvents or mixtures of solvents such as a mixture of acetonitrile and ethanol. Other methods of obtaining salt of bimaleate N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide include dissolving compound free base in any suitable solvent, such as ethyl acetate at an elevated temperature (e.g., about 68°C) followed by addition of solid maleic acid. After cooling the solution with a speed of approximately 20°C per hour, the obtained salt of bimaleate in crystalline form precipitates and can be collected by filtration.

Two polymorphic forms of salt bimaleate N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide identified and characterized, as shown in Fig. 1-10, and is designated as form I of bimaleate and form III of bimaleate.

Form I of bimaleate can be obtained, as described previously in obtaining salts of bimaleate. Form III of bimaleate can also be converted into a form I of bimaleate suspendirovanie of bimaleate form III in a suitable solvent, such as acetonitrile, with a subsequent payment satrak is bimaleate forms I and stirring at elevated temperature (for example, 50°C) to obtain bimaleate form I. x-ray Powder diffraction (PXRD) of bimaleate form I shown in Fig. 1; the corresponding data are summarized in table 1.

Table 1
PXRD data for the form I salt of bimaleate N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide
2θ(°)The value of DIntensity (counts)
4,0of 21.912,1
8,210,821,0
10,78,29,8
14,26,27,6
14,86,019,5
16,3of 5.420,9
18,1a 4.912,9
18,74,813,5
20,2,4 of 17.0
a 21.54,133,2
23,83,713,7
24,83,611,1
26,23,426,9
27,23,37,6
28,73,17,1

An NMR spectrum of solids for bimaleate form I shown in Fig. 2. Data on the chemical shifts of carbon are summarized in table 2.

Table 2
The chemical shifts of carbon polymorphic Form I salt of bimaleate N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide
Peak numberandChemical shifts13Withb(ppm)The intensity of thewith(arbitrary units)
1173,42,1
2which is 171,5 6,1
3169,06,9
4167,37,9
5165,08,3
6to 163.19,9
7162,55,6
8154, 6mmthe 9.7
9to 150.79,8
10148,03,6
11143,96,3
12140,03,7
13137,53,1
14136,0the 3.8
15of 124.75,5
16124,2 to 12.0
17122,95,0
18118,05,5
19116,57,1
20112,16,3
21106,37,9
22102,94,4
2364,67,8
2462,65,6
2556,15,3
2655,55,1
2748,64,5
2827,85,9
2916,98,0
a) In the section "non peak" list all peaks, following the UYa sequential descending order of magnitude of chemical shift.
b) as the standard of comparison used an external sample of solid adamantane when to 29.5 ppm
c) Defined as the height of the peaks. Intensity can vary depending on the actual job of the experimental parameters CPMAS. Intensity when CPMAS not be expressed quantitatively.

The DSC thermogram of bimaleate form I shown in Fig. 3, the Raman spectrum of bimaleate form I shown in Fig. 4, and the dynamic profile of sorption pair of bimaleate form I shown in Fig. 5.

Polymorphic Form III of salt bimaleate N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide is a hydrate and can be obtained, for example, by dissolving bimaleate form I in a solvent such as water, after which it can be precipitated hydrated bimaleate form III. Bimaleate form III can also be obtained by dissolving bimaleate form I in a suitable solvent, such as acetonitrile, followed by the introduction of the seed of bimaleate form III for the conversion of form I to form III. Powder x-ray diffraction (PXRD) of bimaleate form III is shown in Fig. 6; the corresponding data are summarized in table 3.

Table 3
PXRD data for the polymorphic Form III of salt bimaleate N,2-dimethyl-6-[-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide
2θ (°)The value of DIntensity (counts)
6,413,79,8
8,310,65,1
9,09,85,0
9,69,28,0
11,97,46,0
a 12.77,015,5
14.4V6,210,0
14,96,012,3
16,3of 5.48,1
17,45,111,3
20,14,410,6
21,34230,3
24,33,7 9,3
25,13,67,4
25,93,416,9
27,93,211,0

An NMR spectrum of solids of bimaleate form III is shown in Fig. 7, the corresponding data chemical shifts of carbon, are summarized in the table shown in table 4.

116,1
Table 4
The chemical shifts of carbon salt of bimaleate N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide polymorphic Form III
Peak numberandxhimicheskie shifts13Withb(ppm)The intensity of thewith(arbitrary units)
1172,56,8
2168, 8mm6,5
3168,16,7
4166,14,8
5165,45,0
6163,6to 12.0
7154,46,5
8150,97,3
9149,22,8
10142,24,5
11137,74,2
12137,05,6
13132,82,7
14for 125.83,1
15124,06,2
16123,34,6
17122,64,6
18119,03,6
19the 5.7
20byr111.44,5
21106,43,7
22103,33,7
2399,2a 3.9
2465,93,0
2564,5the 3.8
2662,13,7
2755,03,4
2854,5a 3.9
29to 49.93,2
3026,5of 5.4
3114,86,1
a) In the section "non peak" lists all the peaks in the sequential order of descending values of chemical shifts. b) as the standard of comparison used an external sample of solid adamantane when to 29.5 ppm
c) Defined as the height of the peaks. Intensity can vary depending on the actual job of the experimental parameters CPMAS. Intensity CPMAS not be expressed quantitatively.

DSC thermogram of bimaleate form III is shown in Fig. 8, the Raman spectrum of bimaleate form III is shown in Fig. 9, and a dynamic profile of sorption pair of bimaleate form III is shown in Fig. 10.

The stability of the solid state polymorphic forms of salt bimaleate N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide shown in table 5 below.

Table 5
The stability of the solid state polymorphic forms of salt bimaleate N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide, Forms I and III at 40°C/75%RH (relative humidity)
SamplesT (0)T (1 week)T (4 weeks)T (6 weeks)
Rev. Closed.Rev.Closed.Rev.Closed.
Bimaleate form I99,9%99,9%99,9%99,9%99,9%99,8%99,9%
Form IForm IForm IForm IForm IForm IForm I
Bimaleate form III99,9%-----99,9%
Form IIIForm IIIForm III-Form III

The solubility of polymorphic forms I and III salt of bimaleate N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-carboxamide shown in table 6, below.

Table 6
The water solubility of salts of bimaleate N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide
Form saltsSolubility mg/ml
Bimaleate Form IAt least 150 (pH 3,6)
Bimaleate Form IIIAt least 30 (pH 3.8)

Amorphous bimaleate

As shown in example 11, the amorphous form of the salt of bimaleate N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide can also be obtained by dissolving salts of bimaleate in an appropriate solvent, such as methanol, followed by drying (for example, at approximately 40°C) to obtain a solid amorphous form. Powder diffraction x-ray amorphous form of bimaleate shown in Fig. 34.

Crystalline salt of bis-HBr

Biggerarray salt (bis-HBr) N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide can be obtained with a satisfactory degree of crystallinity, for example, by dissolving the compound free base in any suitable solvent such as CH Cl2, THF, acetonitrile, ethyl acetate, methanol or ethanol, at elevated temperature (for example, approximately 75°C) followed by addition of Hydrobromic acid in an acceptable solvent such as acetonitrile. A solid crystalline substance can then be obtained by cooling the solution to room temperature with a speed of approximately 20°C per hour. As shown in examples 9 and 10, can be obtained, at least two different crystalline forms of the bis-HBr salt. One polymorphic form bis-HBr salt is an anhydrous form with initial melting point component 263°C (see Fig. 31) and referred to as bis-HBr form I. the Second polymorphic form is a MES, and it is denoted as bis-HBr form II. Powder x-ray diffraction bis-HBr form I shown in Fig. 29, while the DSC thermogram bis-HBr form I shown in Fig. 31. Powder x-ray diffraction bis-HBr form II is shown in Fig. 30, the DSC thermogram bis-HBr form II is shown in Fig. 32, and thermogravimetric profile bis-HBr form II is shown in Fig. 33. Bis-HBr form II is a form of MES with temperature desolvatation, part 63°C (see Fig. 32). The starting point melting bis-HBr form II is 248°C (see Fig. 32). Thermogravimetric analysis (TGA) bis-HBr form II shows the weight loss of 4.5% when heated to 00°C (see Fig. 33). Titration bis-HBr form II according to Karl-Fischer was carried out to determine the content of water in it. The result showed the water content amounting to 4.1%. Therefore, bis-HBr form II identified as a hydrated form.

The stability of the solid state polymorphic forms bis-HBr salt of N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide shown in table 7 below.

Table 7
The stability of the solid state polymorphic forms bis-HBr salt of N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide, forms I and II at 40°C/75%RH
SamplesT (0)T (1 week)T (4 weeks)T (6 weeks)
Rev.Closed.Rev.Closed.Rev.Closed.
bis-HBr form I----- --
Form 1Form I and IIForm 1Form IIForm I and IIForm IIForm II
Bis-HBr form II98,53%98,61%98,70%98,62%98,66%is 98.49%98,61%
Form IIForm IIForm IIForm IIForm IIForm IIForm II

The solubility in water of the two polymorphic forms of the bis-HBr salt of N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide shown in table 8 below.

Table 8
Solubility in water bis-HBr salt of N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide
Forms salts Solubility
Bis-HBr form I>30 mg/ml (pH 3,4)
Bis-HBr form II>30 mg/ml (pH 3,4)

The crystalline free base

Crystalline forms of compound free base N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide can also be obtained as described in examples 3-8. Was identified and characterized six different crystalline forms of the free base N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide, as shown in Fig. 11-28. These six crystalline forms of the free base N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide designated as polymorphic forms of the free base 1-6. Polymorphic forms 1 and 4 of the free base are hydrates, whereas the forms of the free base of 2, 3, 5 and 6 do not contain water.

Amorphous free base

As shown in example 12, the amorphous form of the free base N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide can also be obtained by dissolving the free base in a suitable solvent such as a mixture of ethanol/methanol, followed by drying (for example, when closer is Ino, 40°C)to obtain the solid amorphous form. Powder diffraction x-ray amorphous form of the free base shown in Fig. 35.

The present invention also relates to pharmaceutical compositions containing the described various physical forms of N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide. The pharmaceutical compositions of the present invention can be, for example, in a form suitable for oral administration such as tablet, capsule, pill, powder, drugs extended release, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration in the form of ointment or cream or for rectal administration in the form of a suppository. The pharmaceutical composition may be in unit dosage forms suitable for pressionado single dosing. The pharmaceutical composition includes a standard pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. Additionally, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, and so on.

Model forms for parenteral administration include solutions or suspensions of the active compounds in sterile aqueous solutions, the example aqueous propylene glycol, or in solutions of dextrose. Such dosage forms, if necessary, can be properly buffered.

Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents. Pharmaceutical compositions optionally can contain additional ingredients such as flavorings, binders, fillers and the like. Thus, for oral administration, tablets containing various excipients such as citric acid, can be used with various dezinfeciruyuhimi agents such as starch, alginic acid and certain mixed silicates, and with binding agents such as sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulphate and talc, are often used for tabletting. Solid compositions of a similar type can also be used in soft and hard gelatin capsules. Preferred substances instead include lactose or milk sugar and high molecular weight polyethylene glycol. When oral administration is required aqueous suspensions or elixirs, the active compound can be combined with various sweetening or flavouring agents, colouring matter or dyes and, if necessary, Algerie agents or suspendresume agents, together with diluents, such as water, ethanol, propylene glycol, glycerin, or combinations thereof.

Methods of obtaining various pharmaceutical compositions with a specific number of active compounds are known, or will be obvious to a person skilled in the art. For examples seeRemington's Pharmaceutical Sciences,Mack Publishing Company, Easter, Pa., 15thEdition (1975).

Examples

The examples and preparations below, further illustrate and exemplify certain aspects of the embodiments of the invention. It should be understood that the scope of the present invention is in no way limited to the following examples.

Methods and Materials

Differential Scanning calorimetry (DSC)Measurement method the DSC shown in Fig. 3, 8, 23-28, 31, and 32 were carried out using instrumentation for thermal analysis Q1000. The mass of the sample size from 1 to 2 mg were sealed aluminum crucible with a hole of small diameter. Samples of equilibrium brought to 30°C with subsequent keeping isothermal for 3 minutes, and then linearly quickly brought up to 200 or 300°C at a scan rate of 10°C/min as the purge gas used dry nitrogen.

Powder x-ray diffraction(PXRD): PXRD data for Fig. 1, 6, 11-16, 29, 30, 34 and 35 were collected at the following proto the Olu. A sample (2 mg) were placed on a glass slide with zero background. Then the sample was placed in the discovery D8 (Bruker AXS Instruments)equipped with a GADDS detector. In the system used a copper x-ray source, which was constantly in the mode of 40 kV and 40 mA, to produce radiation Cuα1 with wavelength 1,5406 angstroms. Data were collected in the 2θ values comprising from 4 to 40° with a step scan of 0.02° and step components 60,1 seconds. The diffraction peaks are usually measured with a resolution of ±0.1° (2θ).

These NMR of solids, shown in Fig. 2 and 7, received in accordance with the following Protocol. Approximately 50 mg of the corresponding pattern for each of the analyzed samples were tightly Packed in a 4 mm ZrO the spinner. The spectrum was obtained at 295 K and the pressure of the external environment by the method of triple resonance with cross-polarization and rotation under magic angle in NMR spectrometer (Bruker-Biospin Avance DSX with a frequency of 500 MHz, the sensor Bruker-Biospin, with a gap of 4 mm, the Samples were placed under a magical angle and rotated with a speed of 15.0 kHz. High speed to minimize the intensity of the side bands of rotation. The number of scans was regulated in such a way as to obtain an adequate value of the ratio S/N (signal/noise).

Spectroscopy13C: one-dimensional range13C received in the environmental conditions, the COI is lsua 1H13C rotation under magic angle with cross-polarization (CPMAS). To optimize the sensitivity of the signal, the time of contact with the cross-polarization was set to 2.0 MS, specifying field isolation 80 kHz. It took 512 scans with a delay between pulses constituting 45 seconds. The spectrum was compared with an external standard of adamantane in the high field signal to 29.5 ppm, Typically the chemical shifts were measured with a resolution of ±0.1 ppm

Data on the spectra of Raman scattering, shown in Fig. 4, 9, 17-22, was obtained using the following Protocol. Samples (2 to 5 mg) were transferred to a glass slide was placed in a Raman mikonand (Kaiser Optical Instruments) and focused the beam on the sample. Offset frequency Raman scattering was recorded in the wavelength interval from 0 to 3500 cm-1accumulating the signal delay of 10 seconds. Spectral data for CU usually received with a resolution of ±1 cm-1.

The stability of the solid state, are shown in tables 5 and 7, were measured using the following method. Previously developed HPLC method (HPLC) to study the stability of the salt forms of the compounds1. Conditions of use of the HPLC below.

Buffer: 25 mm ammonizirovanny buffer (pH 2,5)

Organic modifier: Acetonitrile

Wavelength: 210 nm

Column: Waters Symmetry C18, a 4.6×150 mm, 5 μm;

Speed during the Iya: 1.0 ml/min

Injection volume: 10 ál

Experience time: 40 min

The column temperature: ambient temperature

Gradient:

Time% BufferAcetonitrile (%)
09010
108515
305050
369010
409010

Example 1a: getting bimaleate form I

In 8 ml of scintillation tube uploaded 0.02 g of N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide and 4 ml of ethyl acetate. The tube was which and was heated to 68°C, and the temperature was kept for 5 minutes. In a test tube was added maleic acid in the form of a solid (11.3 mg, 2.1 EQ.). The solution became milky, turning into a slightly turbid solution. After 10 minutes, started the precipitation of white solids. After precipitation, the solution was cooled to room temperature with skorosti°C/hour. The tube was placed in a cold bath (or the refrigerator at 2°C) for 2 hours. The solid substance was collected by filtration under vacuum and dried under vacuum (30 inches Hg, 60°C) during the night. This way we obtain a 0.025 g, yield 85%.

Instead of solids, described above, can also be added maleic acid in the form of a solution.

Example 1 b: Getting bimaleate form I

Bimaleate N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide form III (0.015 g) suspended in acetonitrile (2 ml) at 25°C to obtain a suspension of about 7.5 mg/ml of a number of seed shape I was added to the suspension. A suspension of 2 days was stirred at 50°C for the transformation of form III into form I.

Example 2a: Getting bimaleate form III

Bimaleate N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide, form I (0.26 g) at 25°C was dissolved in water (2.8 ml)to obtain a solution composition, approximately 93 mg/ml After complete dissolution, the solution was filtered through filters with a pore size of 0.22 μm. The filtered solution was placed at 5°C on a rotator. After 12 hours there was obtained a residue of bimaleate N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide, form III.

Example 2b: Getting bimaleate form III

Bimaleate N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-and the oxy]benzofuran-3-carboxamide form I (0.015 g) at 25°C suspended in acetonitrile (2 ml), to obtain a suspension of the composition, about 7.5 mg/ml of the suspension was added a certain amount of seed crystal form III. The suspension was stirred for 3 days at ambient temperature for the conversion of form I to form III.

Example 3: to obtain the free base Form 1

A solution of 4-(2-chloroethyl)of the research (10.7 g, 57,4 mmol) and CS2CO3(46,3 g, 143,5 mmol) in DMF (DMF) (100 ml) for 1 hour and stirred at room temperature. To the solution was added a solution of 6-[(7-hydroxyquinolin-4-yl)oxy]-N,2-dimethyl-1-benzofuran-3-carboxamide (10 g, 28.7 mmol). The mixture was heated to 120°C for 15 hours. The solution was cooled to room temperature and was extracted with EtOAc. The concentrated residue was purified column chromatography on silica gel using 5-10% mixture

MeOH/CH2Cl2to obtain 2.6 g of the free base N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide in the form of solids. The solid free base was identified as form 1, as shown by powder x-ray diffraction in Fig. 11. Note that the form 1 can also be obtained 24-hour suspendirovanie in the water of any of the forms 3, 5 or 6 at room temperature.

Example 4: to obtain the free base form 2

A solution of 4-(2-chloroethyl)of the research (2.1 g, 11.5 mmol) and CS2CO3(7.5 g, 23 mmol) in

C 3CN (100 ml) was stirred 45 minutes at room temperature. To the solution was added 6-[(7-hydroxyquinolin-4-yl)oxy]-N,2-dimethyl-1-benzofuran-3-carboxamide (2 g, of 5.75 mmol). The mixture was heated to a temperature of education phlegmy for 3 hours. Inorganic salt was removed by filtration, and the solution was concentrated. The residue was purified column chromatography on silica gel (using 1-10% mix

MeOH/CH2Cl2to obtain 1.8 g of the free base N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide in the form of solids. Then the compound was dissolved in hot isopropanol and stirred at room temperature overnight. 1.13 g of N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide in the form of polymorph form 2 was collected by filtration. Note that form 2 is anhydrous and must be obtained in the absence of water, to prevent the formation of hydrate (such as form 4, described in example 6).

Example 5: to obtain the free base form 3

Form 3 was obtained by warming of the Form 1 (0.1 g) in a vacuum oven at 110°C for 1 hour.

Example 6: to obtain the free base Form 4

The form 4 was obtained by processing Form 1 (0.1 g) 3,0 two ml of isopropyl alcohol and heated to 70°C to obtain a solution. After complete dissolution, the solution of which was ladli to the temperature of the external environment. The precipitated precipitate is filtered from the solution, identified as Form 4.

Example 7: to obtain the free base Form 5

Form 5 was obtained by processing of the Form 1 (1 g) in 5.0 ml of acetonitrile with formation of a suspension. Then the suspension was stirred at 80°C for 1 hour for the conversion of Form 1 to Form 5.

Example 8: to obtain the free base form 6

Form 6 was obtained by warming of the Form 4 (0.1 g) in an oven at 110°C in vacuum for 1 hour.

Example 9: Getting bis-HBr Form I

bis-HBr Form I was obtained as follows. A 20 ml scintillation tube was loaded with 0.1 g of N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide and 10 ml of acetonitrile. The tube was which and was heated to 72°C, and the temperature was maintained for 5 minutes. A solution of HBr (0,152 ml, 3 M in acetonitrile, 2.1 EQ.) added podpoverkhnostnogo. Adding acid to the solution became turbid, but after a few seconds thoughtful. The temperature was maintained constant for 5 minutes. Then the solution was cooled at a rate of 20°C/h to room temperature. Then the test tube for 2 hours was placed in a cold bath (or in the refrigerator at 2°C). The solid was collected by vacuum filtration and dried under vacuum (30 inches Hg, 60°C) during the night. Then the solid is suspended in acetone (25 mg/ml) at room temperature for 2 the aces, and then in a vacuum oven at 60°C was dried over night.

Example 10: obtain the bis-HBr form II

bis-HBr salt Form II was obtained from bis-HBr form I, when I open the container at 40°C and 75% RH for 4 weeks.

Example 11: Obtain the amorphous bimaleate

Approximately 4 mg of salt bimaleate N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide was dissolved in 1 ml of methanol. The solution was placed in a vacuum oven at 40°C and dried for 30 minutes to obtain amorphous form.

Example 12: obtain the amorphous free base

Approximately 4 mg of the free base N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide was dissolved in 2 ml (50:50) mixture of methanol/ethanol. To obtain the amorphous form of the solution was placed in a vacuum oven at 40°C and dried for 30 minutes.

1. Salt bimaleate N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy] benzofuran-3-carboxamide.

2. Salt according to claim 1, where the salt is a crystalline substance.

3. Salt according to claim 1, where the salt is an anhydrous crystalline salt, where salt has a powder x-ray diffraction, having a peak at diffraction angle (2θ), amounting to 18.6±0,1.

4. Salt according to claim 3, where salt has a powder x-ray diffraction having peaks at angles of diffraction (2θ), components 4,0±0,1; 8,1±0,1; 18,1�0,1; 18,6±0,1; 21,6±0,1 and 26.2±0,1.

5. Salt according to claim 3, where salt has an NMR spectrum of the solid, with the chemical shift13When 148,0±0,1 ppm

6. Salt according to claim 5, where salt has an NMR spectrum of the solid, with chemical shifts,13With 148,0±0,1; 118,0±0,1; 124,2±0,1; 143,9±0,1 and are 162.5±0,1 ppm

7. Pharmaceutical composition having antitumor activity, containing salt according to any one of claims 1 to 6.

8. A capsule containing a pharmaceutical composition according to claim 7.

9. Capsule of claim 8, containing a salt of bimaleate N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide, which is the equivalent of 0.1-50 mg of free base.

10. The capsule according to claim 9, containing a salt of bimaleate N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinoline-4-yloxy]benzofuran-3-carboxamide, which is the equivalent of 0.5-25 mg free base.

11. A method of treating cancer in a mammal, comprising administration to the mammal of any version therapeutically effective amount of the pharmaceutical composition according to claim 7.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention refers to compounds of general formula (I) in the state of base salt or acid-addition salt, to method of their preparation and to the pharmaceutical composition thereof In the said formula R1 is (C1-C6)alkyl; (C3-C7)cycloalkyl unsubstituted or substituted once or more than once; (C3-C7)cycloalkylmethyl unsubstituted or substituted once or more than once; phenyl unsubstituted or substituted ; benzyl unsubstituted or substituted once or twice ; thienyl unsubstituted or substituted ; R2 is atom hydrogen or (C1-C3)alkyl; R3 is (C1-C5)alkyl; R4, R5, R6, R7, each R8 and R9 independently represents the atom of hydrogen, atom of halogen, (C1-C7)alkyl, (C1-C5)alkoxy or trifluoromethyl radical; n is 0, 1 or 2; Alk is (C1-C4)alkyl.

EFFECT: new compounds possess useful biological activity.

5 cl, 5 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to the aminopyridin compound of general formula (I) or its salt wherein X1, X2, X3, Z, Y1, Y2 are carbon or nitrogen atom, R, R1, R5, R6 are hydrogen atom, alkyl group, further see formula of the invention, and R7 is hydrogen or halogen atom, nitro or cyano group, -CpH2(p-1)(Ra1)(Ra2)-O-Ra3, -C(=O)-Rd1, 5-or 6-membered saturated heterocycle group, aromatic heterocycle group, -N(Rh1)(Rh2), further see formula of the invention. The invention refers also to the pharmaceutic composition thereof intended for treatment or prevention of allergic diseases, autoimmune diseases caused by malignant tumour, to the Syk inhibitor containing the compound of formula I and to the therapeutic and/or preventive agent.

EFFECT: compounds which not only possess high Syk inhibition activity but are selective Syk inhibitors are obtained and described.

24 cl, 24 ex, 2 tbl

Cynnamide compound // 2361872

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (I) , where Ar1 is an imidazolyl group, which can be substituted with 1-3 substitutes; Ar2 is a pyridinyl group, pyrimidinyl group or phenyl group, which can be substituted with 1-2 substitutes; X1 is (1) -C≡C- or (2) double bond etc., which can be substituted, R1 and R2 are, for example, C1-6-alkyl group or C3-8-cycloalkyl group, which can be substituted; or to a pharmacologically acceptable salt of the said compound and pharmaceutical drugs for lowering production of Aβ42, containing formula (I) compound as an active ingredient.

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

FIELD: chemistry, medicine.

SUBSTANCE: invention refers to the triheterocylic compounds of formula (Ia) and their pharmaceutically acceptable salts used as growth inhibitors of the cancer or tumor cells, to the preparation method and pharmaceutical compositions thereof, to the treatment method used aforesaid compounds as well as to the intermediates of formula (II) the to the method of its preparation. In general formulas (Ia) and

, Q1 is -N(R1)-; Q2 is -C(R3)-; Q3 is -C(R5)-; Q4 is -C(R9)-; R1 is -Ym(Ra), where -Ra is -H, -OH, -C(O)R14, -O-C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OS(O)2ONa-; R2 is -H; R3, R4 and R5 independently are -Ym(Rb), where Rb is -H, halogen, -C1-C8 alkyl, -O-(C1-C8 alkyl) or -OR14, -at condition that if value m of radical Ym(Rb) is equal 0, then R5 is not H; R6 is -H; R7 is -Ym-(RC), where -RC is -O-(C1-C8 alkyl) or -NH(phenyl), R8 is -Ym(Rd), where - Rd is -H, -OH, R9, R10, R11, R12 and R13 independently are -Ym(Re), where Re is -H, halogen, 5-6-membered heterocycle containing 2 heteroatoms selected from N or O, -OR14, or -O-C(O)OR14; every R14 independently is -H, -C1-C8 alkyl, -phenyl, 5-6-membered heterocycle containing one heteroatom being S; every Y independently is -C1-C8 alkylene-; every m independently is equal 0 or 1.

EFFECT: claimed compounds can find application for treatment of different cancer species.

41 cl, 4 tbl, 4 dwg, 8 ex

FIELD: chemistry; medicine.

SUBSTANCE: compounds of claimed invention possess properties of positive allosteric modulator mGluR5. In general formula I , W represents 6-member heterocycloalkyl ring with 1-2 heteroatoms, selected from N, O; R1 and R2 independently represent hydrogen, C1-C6-alkyl; P and Q each independently is selected from: , R3, R4, R5, R6 and R7 independently represent hydrogen; halogen; -CN; nitro; C1-C6-alkyl; C3-C6-cycloalkyl; halogen-C1-C6-alkyl; 5-6-member heteroaryl with 1-2 atoms N as heteroatoms; 6-member heterocycle with 2 heteroatoms representing N, O; phenyl, optionally substituted with halogen; naphtyl; -OR8; where optionally two substituents together with located between them atoms form 9-10-member bicyclic aryl or heteroaryl ring with 1-2 heteroatoms, selected from N, S; R8 represents hydrogen, C1-C6-alkyl; D, E, F, G and H independently represent -C(R3)=, -O-, -N=, -N(R3)- or -S-; A represents ethinyl, -C(=O)NR8- or group of formula . B represents -C(=O)-C0-C2-alkyl-, -C(=O)-C2-C6-alkenyl-. Invention also relates to pharmaceutical composition based on invention compounds.

EFFECT: novel compounds possess useful biological proprties.

20 cl, 3 dwg, 75 ex

FIELD: chemistry.

SUBSTANCE: invention can be applied in medicine and concerns inhibitors of MaR-kinase p38 of formula where W represents N or O, when Y represents C, and W represents C, when Y represents N; U represents CH or N; V represents C-E or N; X represents O, S, SO, SO2, NH, C=O,-C=NOR1 or CHOR1; B represents H or NH2; R1, E and A stands for H or various alkyl, heteroalkyl, aromatic and heteroaromatic substitutes.

EFFECT: production of new biologically active compounds.

48 cl, 138 ex, 54 dwg

FIELD: pharmacology.

SUBSTANCE: claimed invention relates to novel 2,4-pyridindiamine compounds of formula (1). In structural formula (I) L1 is direct bond; L2 is direct bond; R2 is phenyl group, three times substituted with three groups R8; R4 is X represents N; Y is selected from group consisting of O, NH, S, SO and SO2; Z is selected from group consisting of O, NH; on condition that if Y is selected from group consisting of NH, S, SO and SO2, Z is not the same as Y; R5 is selected from group consisting from R6, halogen; each R6 is independently selected from group consisting of hydrogen, halogen; R8 is selected from group consisting from Ra, Rb, Ra substituted with one or several similar or different groups Ra or Rb, -ORa, -O-CHRaRb; each R35 independently on others is selected from group consisting of hydrogen and R35, or in alternative case, two groups R35, bound to one and the same carbon atom are taken together with formation of oxogroup (=O), and the remaining two groups R35 each independently on each other are selected from group consisting from hydrogen and R8; each Ra is independently selected from group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl; each Rb is suitable group which is independently selected from group consisting of -ORd, halogen, -CF3, -C(O)NRcRc, and -OC(O)ORd; each Rc is independently protective group or Ra; each Rd is independently protective group or Ra; each index m is independently integer number from 1 to 3.

EFFECT: novel compounds can be used for treatment or prevention of autoimmune diseases, for instance such as rheumatoid arthritis and/or related to it symptoms, systemic lupus erythematosus and/or related to it symptoms, as well as and/or related to it symptoms.

41 cl, 14 dwg, 1 ex

FIELD: chemistry.

SUBSTANCE: described is novel compound of formula (I)

or its pharmaceutically acceptable salt, values of radicals are given in invention formula Compound has ability to inhibit receptor mGluR5, which intends it for prevention and/or treatment of receptor mGluR5- associated disturbances. Also described is pharmaceutical composition, method of inhibiting activation of receptors mGluR5, using compound of formula (I). Described is method of obtaining compound of formula 1a or 1b structure.

EFFECT: increasing output of suitable product.

18 cl, 825 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: new compounds of formula (I) and its pharmaceutically acceptable salts. Offered compounds possess properties of bacterial gyrase and Topo-IV activity inhibitor. In general formula (I) , W is chosen from CH or CF; X represents CH; Z represents O or NH; R1 represents phenyl or 5-6-merous heteroaryl ring containing 1-3 nitrogen atoms where R1 is substituted with 0-3 groups independently chosen from -(T)y-Ar, R', oxo, C(O)R', OR', N(R')2, SR', CN or C(O)N(R')2; R2 is chosen from C1-3alkyl and C3-7-cycloalkyl; and ring A represents 5-6-merous heteroaryl ring containing 1-3 heteroatoms, independently chosen of nitrogen, oxygen or sulphur provided the specified ring has hydrogen bond acceptor in position adjacent to that of joining to B ring where ring A is substituted with 0-3 groups independently chosen from R', oxo, CO2R', OR', N(R')2, halogen, CN, C(O)N(R')2, NR'C(O)R', or NR'SO2R', and where two substitutes in adjacent positions of ring A, together can form 6-merous saturated heterocyclic or heteroaryl ring containing 1-2 nitrogen atoms.

EFFECT: pharmaceutical compositions with properties of bacterial gyrase and Topo-IV activity inhibitor containing disclosed compound as active component, method of gyrase and/or Toro IV-activity inhibition, method of bacteria number reduction.

25 cl, 3 tbl, 4 dwg, 29 ex

FIELD: medicine.

SUBSTANCE: formula bond

or it pharmaceutically comprehensible salt where value of radicals are specified in the invention formula is described. The bonds are effective as inhibitors of protein kinases FLT-3 or KIT. A way of inhibition of activity kinases FLT-3 or KIT in the biological sample in vitro and application of bonds for manufacture of a medical product, suitable for treatment or simplification of gravity of disease or a condition, the chosen acute myelogenetic leukosis, acute progranulocytic leukemia or acute lymphocytic leukosis or cancer of ovaries are described also.

EFFECT: rising of efficiency of a composition and the method of treatment.

11 cl, 86 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new a compound of formula I or formula II, or to its pharmaceutically acceptable salts, I II, where X is S; R1 is H or C1-C6alkyl; R2 is NR5R6; R3 is aryl, substituted with a halogen; R4 is H; R5 is H; R6 is H; R7 is CH2NR8R9 where R8 is H, C1-C10alkyl, C3-C8cycloalkyl, aryl, aryl(C1-C6alkyl), aryl(C2-C6alkenyl), heterocycle(C1-C6alkyl), heterocycle(C2-C6alkenyl), hydroxyl(C1-C6alkyl), hydroxyl(C2-C6alkyl), C1-C6alkoxycarbonyl, aryl(C1-C6alkoxy)carbonyl, carbamoyl(C1-C6alkyl); where the above mentioned aryl is an aromatic ring and is not substituted or substituted with one to three substituting groups, each of which, independently from the others, is chosen from: methylenedioxy, hydroxy, C1-C6-alkoxy, halogen, C1-C6alkyl, trifluoromethyl, trifluoromethoxy, NO2, NH2, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH-acyl, N(C1-C6alkyl)-acyl, hydroxy(C1-C6alkyl), dihydroxy(C1-C6alkyl), CN, C(=O)O(C1-C6alkyl), phenyl, phenyl(C1-C6alkyl), phenyl(C1-C6alkenyl), phenoxy and phenyl(C1-C6alkoxy), R9 is H, C1-C10alkyl, heterocycle(C1-C6alkyl) or heterocycle(C2-C6alkenyl); where the above mentioned heterocycle represents a 5-member saturated monocyclic ring system, consisting of carbon atoms, as well as heteroatoms, chosen from a group comprising N, O, and S, which can be unsubstituted or have one to three substituting groups, independently chosen from a list which includes NO2, aryl(C1-C6alkyl), arylsulphonyl; or R8 and R9 together with nitrogen, to which they are bonded, form a heterocycle, which represents a 5 - 7-member saturated monocyclic ring system, consisting of carbon atoms, as well as one to three heteroatoms, chosen from a group comprising N, O and S, which can be unsubstituted or have one to three substituting groups, independently chosen from a list which includes C1-C6alkoxy, hydroxy, C1-C6alkyl, C2-C6-alkenyl, C(=O)O(C1-C6alkyl), C(=O)NH2, C(=O)NH(C1-C6alkyl), C(=O)N(C1-C6-alkyl)2, hydroxy(C1-C6alkyl), dihydroxy(C2-C6alkyl), aryl, aryl(C1-C6alkyl), aryl(C2-C6alkenyl), aryl(C1-C6alkoxy) and pyrimidin-2-yl; and m equals 0. The invention also relates to a pharmaceutical composition, as well as to use of formula I or formula II compounds.

EFFECT: obtaining new biologically active compounds, with inhibitory properties towards casein kinase 1ε.

32 cl, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to N-substituted aniline and diphenylamine analogues, chosen from 3,4-bisdifluoromethoxy-(3-carboxyphenyl)-N-(5-(2-chloropyridinylmethyl))-aniline, 3,4-bisdifluoromethoxy - N-(3-carboxyphenyl) - N-(3-(2-chloropyridylmethyl))-aniline, 3,4 - bisdifluoromethoxy - N-(3-carboxyphenyl) - N-(4-(3,5-dimethylisoxazolylmethyl)) aniline, 3 - cyclopentyloxy - 4-methoxy - N-(3-aminocarbonylphenyl) - N-(3-pyridylmethyl) aniline and other compounds given in paragraph 1 of the formula of invention and to their pharmaceutically acceptable salts as inhibitors of PDE4 enzyme.

EFFECT: compounds can be used for treating and preventing diseases caused by activity of the PDE4 enzyme.

15 cl, 8 dwg, 58 ex

FIELD: chemistry.

SUBSTANCE: in formula (1) compound, cysteinprotease is cathepsin K, cathepsin S, cathepsin L or cathepsin B. In formula (I) R is , AA1 is a bond, AA2 is a bond, R7 and R8 each independently represents hydrogen, C1-8 alkyl, CycA or C1-8 alkyl, substituted CycA, R9 is hydrogen, values of the rest of the radicals are given in the formula of invention. The invention also relates to a pharmaceutical composition, containing a formula (I) compound as an active ingredient, to a cysteinprotease inhibitor, method of inhibiting cysteinprotease, use of formula (I) compound in obtaining cysteinprotease inhibitor.

EFFECT: compound has inhibitory activity towards cysteinprotease.

10 cl, 16 tbl, 8 dwg, 224 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to the new compounds of formula (I): whereat R1 is -SO2NR102R103, -NR101SO2R104 or -COOR105 whereat R101 is hydrogen atom, R102 and R103 each independently represents hydrogen atom or C1-4 alkyl, R104 is C1-4 alkyl and R105 is hydrogen atom or C1-4 alkyl ; X is bond, -CH2- or -O-; Y is -CH2-; ring A and ring B, which are same or different, each independently is benzene, pyridine, pyrazol or piperidine which can have the following substituents: C1-4 alkyl or halogen; ring D is piperidine; R2 is whereat the arrow shows the position of the bond with the ring D; R51 is (1) hydrogen atom a, (2) C1-6alkyl, which can have the following substituents: (a) hydroxy, (b) methoxy, (c) cyano, (d) carboxy, (e) halogen, (f) methyl sulphonylamino, (g) C3-8cycloalkyl or phenyl, which can have the following substituents: methyl, halogen, hydroxy or methoxy, (h) thienyl, pyrazolyl, tetrahydropyranyl, thiazolyl, isooxalyl, imidazolyl, tetraazolyl, pyridyl, pyrimidinyl which can have the following substituents: methyl, trifluoromethyl or hydroxy, (3) C2-10alkenyl, (4) C2-10alkynyl, (5) phenyl which can have the following substituents: C1-4alkyl or halogen, or (6) pyridine or tetrahydropyran; R52 is (1) hydrogen atom a, (2) C1-6alkyl which can have the following substituents: (a) hydroxy, (b) methoxy, (c) carboxy, (d) C3-8cycloalkyl, (e) phenyl or (f) oxo, (3) C3-8cycloalkyl or phenyl which can have the following substituents: C1-4alkyl, hydroxy, cyano, oxo, carbamoyl, N-methyl aminocarbonyl, carboxy, halogen, methoxy, trifluoromethoxy, methythio, methylsulphonyl, acetylamino, dimethylamino, acetyl, tetraazolyl, trifluoromethyl or methylsulphonylamino (4) C3-10cycloalkenyl, (5) adamantyl, (6) thienyl, pyrazolyl, tetrahydropyranyl, isoxaazolyl, isothiazolyl, thiadiazolyl, piperidinyl, pyridyl, pyrimidinyl, pyridazinyl, quinolyl, indolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, dioxaindanyl, benzodioxaindanyl which can have the following substituents: C1-4alkyl, hydroxy, oxo, halogen, azido or trifluoromethyl or (7) benzyloxy groups; and R53 is hydrogen atom or C1-6alkyl; to its salts or its solvates. The invention refers also to the regulator CCR5, to the agent of prevention and/or treatment of HIV infection, immunological or inflammatory diseases, to the pharmaceutical composition, to the medicinal preparation, to the method of disease treatment or prevention as well as to the application of compound as in claim 1.

EFFECT: obtaining of new bioactive compounds possessing anti CCR5 receptor activity.

23 cl, 41 ex

FIELD: chemistry.

SUBSTANCE: invention refers to the new compounds of general formula (II) , whereat values R1, R2, X, R11, R12, R18, R19, m, n are displayed in claim 1 of the formula.

EFFECT: compounds display agonistic and antagonistic activity which allows to propose their usage in pharmaceutical compositions for treatment of diseases and distresses connected with histamine H3 receptor.

38 cl, 80 ex

Cynnamide compound // 2361872

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (I) , where Ar1 is an imidazolyl group, which can be substituted with 1-3 substitutes; Ar2 is a pyridinyl group, pyrimidinyl group or phenyl group, which can be substituted with 1-2 substitutes; X1 is (1) -C≡C- or (2) double bond etc., which can be substituted, R1 and R2 are, for example, C1-6-alkyl group or C3-8-cycloalkyl group, which can be substituted; or to a pharmacologically acceptable salt of the said compound and pharmaceutical drugs for lowering production of Aβ42, containing formula (I) compound as an active ingredient.

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to new coumarin derivatives and their carboxamides, with general formula (I) , where R3 is chosen from a group consisting of H, carboxyl, alkyloxycarbonyl, 5'-(phenyloxadiazol-2')-yl, 5'-(pyridyl-4"-oxadiazol-2')-yl, , CONHR9, where R9 is chosen from a group consisting of fatty acids C2-C8, benzoxamido, isonicotinamido, unsubstituted, or mono-, or polysubstituted phenyl, in which the substitute can be hydroxy, C1-C8-alkoxy, CF3, carboxyl, alkyloxycarbonyl, OCH2CO2H, NO2, halogen, SO3H, SO2NHR11, where R11 is chosen from a group consisting of hydrogen, amidino, 2"-thizolyl, 3"-(511-methylisooxazolyl), 2"-pyrimidinyl, 2"-(4",6"-dimethylpyrimidinyl), 4"-(5",6"-dimethoxypyrimidinyl); R4 is chosen from a group consisting of hydrogen, CONHR10, where R10 is chosen from a group consisting of C2-C8 fatty acids, unsubstituted phenyl; R5 is chosen from a group consisting of H, C1-C4 alkyl; R6 is chosen from a group consisting of H, C1-C12-alkyl, halogen, NO2, CONHR13, where R13 is substituted phenyl; R7 is chosen from a group consisting of H, hydroxyl, C1-C4alkyl or alkoxyl, carboxyalkyleneoxyl, OCH2CONHR14, where R14 is chosen from a group consisting of unsubstituted, mono-, or polysubstituted phenyl, in which the substitute can be hydroxyl, OCH3, CF3, CO2H, CO2C2H5, NO2; R8 is chosen from a group consisting of H, C1-C4-alkyl or alkoxyl, NO2; under the condition that, when R3, R5 and R6 are H, and R7 is OH, R4 and R7 are not groups, chosen from H, C1-C6-alkyl or C1-C6-alkoxy. The invention also relates to pharmaceutical compositions based on formula I compounds and their use as medicinal preparations for protecting kidneys, for curing hypertonia, cardio-cerebrovascular diseases, non-achrestic diabetes, tumours, precancerous diseases and oedema.

EFFECT: enhanced effectiveness of the composition and treatment method.

17 cl, 6 tbl, 51 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new pyrimidine derivatives with general formula (I), their tautomeric or stereoisomeric form, in free form, in form of pharmaceutically acceptable salt or C1-6alkyl ester which are effective antagonists of CRTH2 (G-protein-associated chemoattractant receptor, ex prone on Th2 cells) and can be used for preventing and treating diseases related to CRTH2 activity, particularly in treatment of allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, diseases related to eosinophil. In formula (I) R1 is hydrogen, or in which n is an integer from 0 to 6; -Q1- is -NH-, -N(C1-6alkyl)- or -O; Y is hydrogen, C1-6alkyl, C3-6cycloalkyl, optionally substituted with C1-6alkyl, C3-6cycloalkyl, condensed with a benzene ring, phenyl, naphthyl or 5-6-member heteroaryl, possibly condensed with a benzene ring, and containing at least one heteroatom, chosen from a group consisting of oxygen and nitrogen, where the said phenyl, naphthyl or heteroaryl are optionally substituted on the displaceable position with one or several substitutes, chosen from a group consisting of cyano, halogen, nitro, guanidine, pyrroyl, sulfamoyl, phenyloxy, phenyl, di(C1-6)alkylamino, C1-6alkanoylamino, C1-6alkyl, optionally mono-, di- or tri-substituted with halogen, C1-6alkoxy, optionally mono-, di- or tri-substituted with halogen and C1-6alkylthio, optionally mono-, di- or tri-substituted with halogen; or phenyl, condensed with 1,3-dioxolane; R2 is hydrogen or C1-6alkyl; R3 is a halogen, C1-6alkoxy, optionally mono-, di- or tri-substituted with halogen, or , R3a and R3b are independently C3-8cycloalkyl or C1-6alkyl, this C1-6alkyl is optionally substituted with hydroxyl, carboxy, C3-6cycloalkylcarbamoyl, C5-6heterocyclocarbonyl containing a heteroatom in form of nitrogen, or C1-6alkoxy, q is an integer from 1 to 3; R3c is hydrogen, hydroxyl or carboxy; Xa is -O-; R4 is hydrogen, halogen, di(C1-6alkyl) amino or C1-6alkyl, optionally substituted C1-6alkoxy or mono- , di- or tri-substituted with halogen; R5 is hydrogen or C1-6alkyl; and R6 is carboxy, carboxamide, nitrile or tetrazolyl.

EFFECT: wider field of use of compounds.

32 cl, 9 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention is related to the compound of general formula 1 or its tautomer or pharmaceutically acceptable salt, where W selected from N and CR4; X is selected from CH(R8), O, S, N(R8), C(=O), C(=O)O, C(=O)N(R8), OC(=O), N(R8)C(=O), C(R8)-CH and C(=R8); G1 - bicyclic or tricyclic condensed derivative of azepin, selected from general formulas 2-9 , or derivative of aniline of common formula 10 , where A1, A4, A7 and A10 are independently selected from CH2, C=O, O and NR10; A2, A3, A9, A11, A13, A14, A15, A19 and A20 are independently selected from CH and N; or A5 stands for covalent connection, and A6 represents S; or A5 stands for N=CH, and A6 represents covalent connection; A8 , A12 , A18 and A21 are independently selected from CH=CH, NH, NCH3 and S; A16 and A17 both represent CH2, or one from A16 and A17 represents CH2, and the one another is selected from C=O, CH(OH), CF2, O, SOc and NR10; Y is selected from CH=CH or S; R1 and R2 are independently selected from H, F, Cl, Br, alkyl, CF3 and group O-alkyl; R3 is selected from H and alkyl; R4-R7 are independently selected from H, F, Cl, Br, alkyl, CF3, OH and group O-alkyl; R8 is selected from H, (CH2)bR9 and (C=O)(CH2)bR9; R9 is selected from H, alkyl, possibly substituted aryl, possibly substituted heteroaryl, OH, groups O-alkyl, OC(=O)alkyl, NH2, NHalkyl, N(alkyl)2, CHO, CO2H, CO2alkyl, CONH2, CONHalkyl, CON(alkyl)2 and CN; R10 is selected from H, alkyl, group COalkyl and (CH2)dOH; R11 is selected from alkyl, (CH2)dAr, (CH2)dOH, (CH2)dNH2, group (CH2)aCOOalkyl, (CH2)dCOOH and (CH2)dOAr; R12 and R13 are independently selected from H, alkyl, F, CI, Br, CH(OCH3)2, CHF2, CF3, groups COOalkyl, CONHalkyl, (CH2)dNHCH2Ar, CON(alkyl)2, CHO, COOH, (CH2)dOH, (CH2)dNH2, N(alkyl)2, CONH(CH2)dAr and Ar; Ar is selected from possibly substituted heterocycles or possibly substituted phenyl; a is selected from 1, 2 and 3; b is selected from 1, 2, 3 and 4; c is selected from 0, 1 and 2; and d is selected from 0, 1, 2 and 3. Besides, the invention is related to pharmaceutical compound and to method for activation of vasopressin receptors of type 2.

EFFECT: compounds according to invention represent agonists of receptor of vasopressin V2, which stipulates for their application (another object of invention) for preparation of medicine for treatment of condition selected from polyuria, including polyuria, which is due to central diabetes insipidus, nocturnal enuresis of nocturnal polyurea, for control of enuresis, to postpone bladder emptying and for treatment of disorders related to bleeds.

21 cl, 228 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new nitroxide compounds with formula I: where one of A, B and D represents N-O and others represent CR6; R1 represents alkyl, containing 1 to 4 carbon atoms, which is branched or straight and which is unsubstituted or substituted once or several times with a halogen; R2 represents alkyl, containing 1 to 12 carbon atoms, which is branched or straight and which is unsubstituted or substituted once or several times with a halogen; cycloalkylalkylk, containing 3 to 10 carbon atoms, which is unsubstituted or substituted once or several times with oxo, aryl, containing 6 to 14 carbon atoms, which is unsubstituted or substituted once or several times with OCF3; or a heterocyclic group, which is saturated, partially saturated or unsaturated, with 5 to 10 atoms in the ring, where at least 1 atom in the ring is an atom of N, O, or S; R3 represents cycloalkyl, containing 3 to 10 carbon atoms, which is unsubstituted once or several times with oxo, aryl, containing from 6 to 14 carbon atoms or which is unsubstituted or substituted once or several times with OCF3; or heteroaryl, with 5 to 10 atoms in the ring, in which at least 1 atom in the ring is a heteroatom; R represents H or alkyl, containing 1 to 4 carbon atoms. The invention also relates to pharmaceutically used salts of these compounds, pharmaceutical compositions containing these compounds, method of inhibiting PDE4 enzyme and to methods treatment using these compounds.

EFFECT: new compounds with useful biological properties.

62 cl, 6 ex

FIELD: medicine.

SUBSTANCE: compounds of the present invention have inhibiting effect on tyrosineprotein kinase. In formula I (I) (Ia), Z means radical of formula Ia; each several R1, R2, R3 independently of each other means hydrogen, C1-C7alkyl, halogen-C1-C7alkyl, C1-C7alkoxy, halogen-C1-C7alkoxy, halogen, 5 or 6-membered rich heterocyclil containing 1 or 2 heteroatoms selected from group comprising N and O and at least one of R1, R2 and R3 is piperidil, piperedil-C1-C7alkyl, C1-C7alkylpiperazinyl or C1-C7-alkylpiperazinyl-C1-C7alkyl; R4 means amino or C1-C7alkylamino.

EFFECT: improved effectiveness.

8 cl, 17 tbl, 168 ex

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