Claims for Patent: 10,383,876
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Summary for Patent: 10,383,876
Title: | Substituted 2,3-dihydroimidazo[1,2-c]quinazoline salts |
Abstract: | The present invention relates:--to 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo-[1,2-- c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride salt of formula (II): or a tautomer, solvate or hydrate thereof;--to methods of preparing said dihydrochloride salt;--to said dihydrochloride salt for the treatment and/or prophylaxis of a disease;--to the use of said dihydrochloride salt for the preparation of a medicament for the treatment and/or prophylaxis of a disease, in particular of a hyper-proliferative and/or angiogenesis disorder, more particularly for the treatment or prophylaxis of a cancer, particularly lung cancer, in particular non-small cell lung carcinoma, colorectal cancer, melanoma, pancreatic cancer, hepatocyte carcinoma, pancreatic cancer, hepatocyte carcinoma or breast cancer;--to a pharmaceutical composition comprising said dihydrochloride salt; and--to a pharmaceutical combination comprising said dihydrochloride salt in combination with one or more further pharmaceutical agents. ##STR00001## |
Inventor(s): | Peters; Jan-Georg (Solingen, DE), Militzer; Hans-Christian (Odenthal, DE), Muller; Hartwig (Velbert, DE) |
Assignee: | BAYER INTELLECTUAL PROPERTY GMBH (Monheim, DE) |
Application Number: | 14/009,599 |
Patent Claims: | 1. 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,- 2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride salt, having the following
formula (II): ##STR00013## or a solvate, hydrate or tautomer thereof.
2. The dihydrochloride salt of formula (II) according to claim 1, which is in crystalline form. 3. A method of preparing the dihydrochloride salt according to claim 1, said method comprising adding hydrochloric acid to a compound of formula (I): ##STR00014## to form said dihydrochloride salt of formula (II): ##STR00015## 4. The method according to claim 3, said method comprising: a) adding hydrochloric acid to a suspension of said compound of formula (I) at a temperature of between the freezing point of the mixture and the boiling point of the mixture until a pH of 3 to 4 is reached; b) stirring the resulting mixture at a temperature of between the freezing point of the mixture and the boiling point of the mixture; and, optionally c) filtering off the resulting solid and washing the filtercake then adjusting the pH of the filtrate to pH 1.8 to 2.0 using hydrochloric acid; and, optionally, d) stirring the mixture at a temperature between the freezing point and the boiling point of the mixture, adding ethanol, followed by further stirring; and, optionally, e) adding seed crystals, optionally followed by adding ethanol; and, optionally, f) filtering off the resulting dihydrochloride of formula (II), optionally washing with a water-ethanol mixture and optionally drying, to provide the dihydrochloride salt according to claim 1. 5. The method according to claim 3, said method comprising: a) adding said hydrochloric acid to said compound of formula (I) in acetone/water or ethanol/water; and, then, optionally, b) heating at a first temperature between the boiling point and the freezing point of the mixture, for a first period of time; then, optionally, c) heating further at a second temperature between the boiling point and the freezing point of the mixture, for a second period of time, with optional stirring of said suspension at a third temperature of between the boiling point and the freezing point of the mixture, for a third period of time, optionally followed by stirring said suspension at a fourth temperature of between the freezing point of the mixture and the boiling point of the mixture, for a fourth period of time; and, optionally, d) filtering, optional washing and drying, wherein said first temperature is higher than said second temperature, and said first period of time is shorter than said second period of time, and wherein said third temperature is higher than said fourth temperature, and said third period of time is longer than said fourth period of time, to provide the dihydrochloride salt of formula (II). 6. The method according to claim 3, wherein said hydrochloric acid is concentrated aqueous hydrochloric acid solution (36% HCl) and is added to said compound of formula (I) in an acetone/water mixture (8:2 v/v), followed by heating at a temperature of 50.degree. C., for a period of time of 0.5 hours, then followed by further heating, at a temperature of 35.degree. C., for a period of time of 72 hours, then with stirring of said suspension at a temperature of room temperature, for a period of time of 2 hours, followed by filtration, washing with an acetone/water mixture, and drying in a vacuum oven, thus providing said dihydrochloride salt of formula (II). 7. A method for the treatment of lung cancer, colorectal cancer, or breast cancer comprising administering to a patient in need thereof a therapeutically effective amount of the dihydrochloride salt according to claim 1, or a solvate, hydrate or tautomer thereof. 8. A pharmaceutical composition comprising the dihydrochloride salt according to claim 1, or a solvate, hydrate or tautomer thereof, and one or more pharmaceutically acceptable excipients. 9. A pharmaceutical composition comprising the dihydrochloride salt according to claim 1, or a solvate, hydrate or tautomer thereof, as a first pharmaceutical agent, and a second pharmaceutical agent. 10. The pharmaceutical composition according to claim 9, wherein said second pharmaceutical agent is selected from the group consisting of: 131I-chTNT, abarelix, abiraterone, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, aminoglutethimide, amrubicin, amsacrine, anastrozole, arglabin, arsenic trioxide, asparaginase, azacitidine, basiliximab, BAY 80-6946, BAY 1000394, BAY 86-9766 (RDEA 119), belotecan, bendamustine, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, buserelin, busulfan, cabazitaxel, calcium folinate, calcium levofolinate, capecitabine, carboplatin, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, cetuximab, chlorambucil, chlormadinone, chlormethine, cisplatin, cladribine, clodronic acid, clofarabine, crisantaspase, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, deslorelin, dibrospidium chloride, docetaxel, doxifluridine, doxorubicin, doxorubicin+estrone, eculizumab, edrecolomab, elliptinium acetate, eltrombopag, endostatin, enocitabine, epirubicin, epitiostanol, epoetin alfa, epoetin beta, eptaplatin, eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, fadrozole, filgrastim, fludarabine, fluorouracil, flutamide, formestane, fotemustine, fulvestrant, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, glutoxim, goserelin, histamine dihydrochloride, histrelin, hydroxycarbamide, I-125 seeds, ibandronic acid, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, interferon alfa, interferon beta, interferon gamma, ipilimumab, irinotecan, ixabepilone, lanreotide, lapatinib, lenalidomide, lenograstim, lentinan, letrozole, leuprorelin, levamisole, lisuride, lobaplatin, lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melphalan, mepitiostane, mercaptopurine, methotrexate, methoxsalen, Methyl aminolevulinate, methyltestosterone, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, nedaplatin, nelarabine, nilotinib, nilutamide, nimotuzumab, nimustine, nitracrine, ofatumumab, omeprazole, oprelvekin, oxaliplatin, p53 gene therapy, paclitaxel, palifermin, palladium-103 seed, pamidronic acid, panitumumab, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pegfilgrastim, peginterferon alfa-2b, pemetrexed, pentazocine, pentostatin, peplomycin, perfosfamide, picibanil, pirarubicin, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polysaccharide-K, porfimer sodium, pralatrexate, prednimustine, procarbazine, quinagolide, raloxifene, raltitrexed, ranimustine, razoxane, regorafenib, risedronic acid, rituximab, romidepsin, romiplostim, sargramostim, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sorafenib, streptozocin, sunitinib, talaporfin, tamibarotene, tamoxifen, tasonermin, teceleukin, tegafur, tegafur+gimeracil+oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, tioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trastuzumab, treosulfan, tretinoin, trilostane, triptorelin, trofosfamide, tryptophan, ubenimex, valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, and zorubicin. 11. The method according to claim 3, wherein the compound of formula (I) is in suspension. 12. The method according to claim 7, wherein the lung cancer is non-small cell lung carcinoma. 13. A method for the treatment of a lung cancer, colorectal cancer, or breast cancer mediated by PI3K.alpha. or PI3 K.beta. comprising administering to a patient in need thereof a therapeutically effective amount of the dihydrochloride salt according to claim 1, or a solvate, hydrate or tautomer thereof. 14. A method for the treatment of lung cancer, colorectal cancer, or breast cancer comprising administering to a patient in need thereof a therapeutically effective amount of the dihydrochloride salt according to claim 2. 15. The method according to claim 14, wherein the lung cancer is non-small cell lung carcinoma. 16. A method for the treatment of a lung cancer, colorectal cancer, or breast cancer mediated by PI3K.alpha. or PI3 K.beta. comprising administering to a patient in need thereof a therapeutically effective amount of the dihydrochloride salt according to claim 2. 17. The dihydrochloride salt of formula (II) according to claim 1, or a hydrate or tautomer thereof. 18. The dihydrochloride salt of formula (II) according to claim 1, or a hydrate thereof. 19. The dihydrochloride salt of formula (II) according to claim 1. 20. The method of claim 7, comprising administering the dihydrochloride salt of formula (II). 21. The pharmaceutical composition of claim 8, comprising the dihydrochloride salt of formula (II). 22. The pharmaceutical composition of claim 9, comprising the dihydrochloride salt of formula (II). 23. The method of claim 13, comprising administering the dihydrochloride salt of formula (II). |
Details for Patent 10,383,876
Applicant | Tradename | Biologic Ingredient | Dosage Form | BLA | Approval Date | Patent No. | Expiredate |
---|---|---|---|---|---|---|---|
Recordati Rare Diseases, Inc. | ELSPAR | asparaginase | For Injection | 101063 | January 10, 1978 | ⤷ Subscribe | 2031-04-05 |
Amgen Inc. | EPOGEN/PROCRIT | epoetin alfa | Injection | 103234 | June 01, 1989 | ⤷ Subscribe | 2031-04-05 |
Amgen Inc. | EPOGEN/PROCRIT | epoetin alfa | Injection | 103234 | ⤷ Subscribe | 2031-04-05 | |
Amgen Inc. | PROCRIT | epoetin alfa | Injection | 103234 | ⤷ Subscribe | 2031-04-05 | |
Iovance Biotherapeutics Manufacturing Llc | PROLEUKIN | aldesleukin | For Injection | 103293 | May 05, 1992 | ⤷ Subscribe | 2031-04-05 |
>Applicant | >Tradename | >Biologic Ingredient | >Dosage Form | >BLA | >Approval Date | >Patent No. | >Expiredate |
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