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WO 2012/136553 Al 11 October 2012 (11.10.2012) P O P C T

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WO 2012/136553 Al 11 October 2012 (11.10.2012) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2012/136553 Al 11 October 2012 (11.10.2012) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C07D 487/04 (2006.01) A61P 35/00 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 31/519 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (21) International Application Number: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, PCT/EP2012/055600 HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, (22) International Filing Date: KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, 29 March 2012 (29.03.2012) MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, (25) Filing Language: English SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, (26) Publication Language: English TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 1116 1111.7 5 April 201 1 (05.04.201 1) EP kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (71) Applicant (for all designated States except US): Bayer UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, Pharma Aktiengesellschaft [DE/DE]; Muller Strasse 178, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, 13353 Berlin (DE). DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, (72) Inventors; and SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, (75) Inventors/Applicants (for US only): PETERS, Jan, GW, ML, MR, NE, SN, TD, TG). Georg [DE/DE]; Belliniweg 6, 42719 Solingen (DE). MILITZER, Hans-Christian [DE/DE]; Waldweg 2, Declarations under Rule 4.17: 5 151 9 Odenthal (DE). MULLER, Hartwig [DE/DE]; — as to applicant's entitlement to apply for and be granted a Wiesenweg 10, 42553 Velbert (DE). patent (Rule 4.1 7(H)) (74) Common Representative: Bayer Pharma Aktiengesell¬ Published: schaft; Law and Patents, Patents and Licensing, Muller Strasse 178, 13353 Berlin (DE). — with international search report (Art. 21(3)) [Continued on next page] (54) Title: SUBSTITUTED 2,3-DfflYDROIMIDAZO[l,2-C]QUINAZOLINE SALTS 2 HCI (II) (57) 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 dihydrochlonde 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 particu - o lar 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, pan - creatic cancer, hepatocyte carcinoma or breast cancer; - to a pharmaceutical composition comprising said dihydrochloride salt; and - o to a pharmaceutical combination comprising said dihydrochloride salt in combination with one or more further pharmaceutical agents. w o 2012/136553 Al II 11 II I 1 Illlll I I III II IIIIII III II I II before the expiration of the time limit for amending the claims and to be republished in the event of receipt of amendments (Rule 48.2(h)) SUBSTITUTED 2,3-DIHYDROIMIDAZO[1 ,2-C]QUINAZOLINE SALTS 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) : . 2 HCI (II), or a tautomer, solvate or hydrate thereof, (which is hereinafter referred to as "the salt of the present invention" or the "dihydrochloride salt") ; - to methods of preparing said salt of the present invention ; - to said salt of the present invention for the treatment and /or prophylaxis of a disease; - t o the use of said salt of the present invention 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, i n particular non-small cell lung carcinoma, colorectal cancer, melanoma, pancreatic cancer, hepatocyte carcinoma, or breast cancer ; - t o a pharmaceutical composition comprising said salt of the present invention ; and - to a pharmaceutical combination comprising said salt of the present invention in combination with one or more further pharmaceutical agents. Background t o the Invention The compound of formula (I) : (which is hereinafter referred t o as the "compound of formula (I)" or the "free base"), i s a proprietary cancer agent with a novel mechanism of action, inhibiting Class I phosphatidylinositol- 3-kinases (PI3Ks). This class of kinases is an attractive target since PI3Ks play a central role i n the transduction of cellular signals from surface receptors for survival and proliferation. The compound of formula (I) exhibits a broad spectrum of activity against tumours of multiple histologic types, both in vitro and in vivo. Said compound of formula (I) may be synthesised according t o the methods given i n international patent application PCT/EP2003/010377, published as WO 04/029055 A 1 on April 08, 2004, (which is incorporated herein by reference i n its entirety), on pp. 26 et seq. Moreover, said compound of formula (I) is published i n international patent application PCT/US2007/024985, published as WO 2008/0701 50 A 1 on June 12, 2008, (which i s incorporated herein by reference i n its entirety), as the compound of Example 13 : 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)- 2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide. Further, said compound of formula (I) is, i n WO 2008/0701 50, described on pp. 9 et seq., and may be synthesized according t o the methods given therein on pp. 42 et seq. Biological test data for said compound of formula (I) is given therein on pp. 101 to 107. Said compound of formula (I) may exist i n one or more tautomeric forms : tautomers, sometimes referred t o as proton-shift tautomers, are two or more compounds that are related by the migration of a hydrogen atom accompanied by the migration of one or more single bonds and one or more adjacent double bonds. The compound of formula (I) may for example exist in tautomeric form (la), tautomeric form (lb), or tautomeric form (Ic), or may exist as a mixture of any of these forms, as depicted below. It is intended that all such tautomeric forms are included within the scope of the present invention. Said compound of formula (I) may exist as a solvate : a solvate for the purpose of this invention is a complex of a solvent and a compound of formula (I) in the solid state. Exemplary solvates include, but are not limited to, complexes of a compound of the invention with ethanol or methanol. Said compound of formula (I) may exist as a hydrate : Hydrates are a specific form of solvate wherein the solvent is water. Technical problem to be solved : In general, for a given pharmaceutically active compound, pharmaceutically acceptable forms of said given pharmaceutically active compound are desired, with the view t o increasing the pharmaceutical effectiveness of said pharmaceutically active compound, e.g. improving physical chemical characteristics, such as chemical stability, physical stability, solubility in vivo, improving absorption of the pharmaceutically active compound in vivo, etc. In addition, a drug substance would ideally come in a stable crystal form that can be produced in a reliable way. Amorphous or crystal forms of low order (e.g. mesomorphic forms) are less attractive as they carry the risk of a later form change and changes of physical properties. However, said compound of formula (I) (which is a free base) could only be prepared in a mesomorphic form that is stable in solid form, but unstable at 70 °C in acidic aqueous solution and carries the above mentioned risk of a later form change. The formation of a crystalline salt form of the free base (I) might solve the above mention problem once the properties of this form are advantageous with respect t o the properties of the free base ( I). In our efforts t o prepare crystalline salt forms of (I) we experienced that preparing crystalline salt forms of (I) is not as easy as one might expect for a compound carrying basic centers. Furthermore, the compound of formula (I) exhibits very low solubility in water and most organic solvents. With two very basic centres (Table I, vide infra), solubility is strongly improved i n acidic media. Consequently, purification of and final processing of the compound of formula (I) is a challenging task. The following structure shows the compound of formula (I), on which calculated pKa values have been given in parentheses. COMPOUND of FORMULA (I) Table I : pKa values of the compound of formula (I) : More particularly, with regard t o the unique chemical structure of the compound of formula (I), vide supra, the physical properties of the compound of formula (I) are not only challenging with regard t o the chemical process, the handling of the drug substance and the production of drug product, but additionally offer significant challenges for the development of a stable and reliable HPLC method as well.
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