CA2807859A1 - Forms of methyl {4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridino-3-yl]pyrimidino-5-yl}methyl carbamate - Google Patents
Forms of methyl {4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridino-3-yl]pyrimidino-5-yl}methyl carbamate Download PDFInfo
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- CA2807859A1 CA2807859A1 CA2807859A CA2807859A CA2807859A1 CA 2807859 A1 CA2807859 A1 CA 2807859A1 CA 2807859 A CA2807859 A CA 2807859A CA 2807859 A CA2807859 A CA 2807859A CA 2807859 A1 CA2807859 A1 CA 2807859A1
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 title claims abstract description 20
- GTCAXTIRRLKXRU-UHFFFAOYSA-N carbamic acid methyl ester Natural products COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 title claims abstract description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 68
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 63
- 239000012453 solvate Substances 0.000 claims abstract description 54
- 230000004048 modification Effects 0.000 claims abstract description 46
- 238000012986 modification Methods 0.000 claims abstract description 46
- 150000001875 compounds Chemical class 0.000 claims description 99
- 239000000203 mixture Substances 0.000 claims description 20
- 239000000843 powder Substances 0.000 claims description 18
- 238000001757 thermogravimetry curve Methods 0.000 claims description 8
- 238000002329 infrared spectrum Methods 0.000 claims description 5
- 229940093499 ethyl acetate Drugs 0.000 description 29
- 239000008194 pharmaceutical composition Substances 0.000 description 13
- 238000002360 preparation method Methods 0.000 description 12
- 239000002904 solvent Substances 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 239000000047 product Substances 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-YYWVXINBSA-N N,N-dimethylformamide-d7 Chemical compound [2H]C(=O)N(C([2H])([2H])[2H])C([2H])([2H])[2H] ZMXDDKWLCZADIW-YYWVXINBSA-N 0.000 description 2
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 2
- 102000007637 Soluble Guanylyl Cyclase Human genes 0.000 description 2
- 108010007205 Soluble Guanylyl Cyclase Proteins 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 239000004411 aluminium Substances 0.000 description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 229910003460 diamond Inorganic materials 0.000 description 2
- 239000010432 diamond Substances 0.000 description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000066 endothelium dependent relaxing factor Substances 0.000 description 2
- -1 etc. Chemical compound 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000012022 methylating agents‎ Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 101100481033 Arabidopsis thaliana TGA7 gene Proteins 0.000 description 1
- KSFOVUSSGSKXFI-GAQDCDSVSA-N CC1=C/2NC(\C=C3/N=C(/C=C4\N\C(=C/C5=N/C(=C\2)/C(C=C)=C5C)C(C=C)=C4C)C(C)=C3CCC(O)=O)=C1CCC(O)=O Chemical compound CC1=C/2NC(\C=C3/N=C(/C=C4\N\C(=C/C5=N/C(=C\2)/C(C=C)=C5C)C(C=C)=C4C)C(C)=C3CCC(O)=O)=C1CCC(O)=O KSFOVUSSGSKXFI-GAQDCDSVSA-N 0.000 description 1
- RKSDERSVTSQBAZ-RJQCTPFPSA-N C[C@H]1C2(CCC3)[C@@H]3CC1C2 Chemical compound C[C@H]1C2(CCC3)[C@@H]3CC1C2 RKSDERSVTSQBAZ-RJQCTPFPSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 238000001237 Raman spectrum Methods 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 229940043232 butyl acetate Drugs 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical class [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 description 1
- MNRGFUBMMILKAL-UHFFFAOYSA-N methyl phenylmethanesulfonate Chemical compound COS(=O)(=O)CC1=CC=CC=C1 MNRGFUBMMILKAL-UHFFFAOYSA-N 0.000 description 1
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 1
- 150000004031 phenylhydrazines Chemical class 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 229940090181 propyl acetate Drugs 0.000 description 1
- 229950003776 protoporphyrin Drugs 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000010996 solid-state NMR spectroscopy Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00Â -Â C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00Â -Â C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
This present invention relates to forms of methyl {4.6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3.4-b]pyridino-3-yl]pyrimidino-5-yl}methylcarbamate comprising its Modification I.
Modification II. mono-DMSO solvate. sesqui-DMSO solvate and 1/4-ethyl acetate solvate.
Modification II. mono-DMSO solvate. sesqui-DMSO solvate and 1/4-ethyl acetate solvate.
Description
FORMS OF METHYL {4,6-DIAMINO-2-11-(2-FLUOROBENZYL)-1H-PYRAZOL013,4-This present invention relates to forms of methyl {4,6-diamino-241-(2-fluorobenzy1)-1H-pyrazolo[3,4-b]pyridino-3-yl]pyrimidino-5-yllmethylcarbamate of formula (I):
HC
'r¨'- C1-13 H2 N\
N
WO 03/095451 discloses the compound of formula (I), and further describes that this and other compounds disclosed therein are stimulators of soluble guanylate cyclase, and may therefore be used as agents for the prophylaxis and/or treatment of cardiovascular disorders.
WO 03/095451 describes the preparation of the compound of the formula (I).
However, there are a number of disadvantages associated with the process disclosed in WO
03/095451, as discussed in WO 2011/064171. WO 2011/064171 thus discloses an alternative process for preparing a compound of the formula (I).
In the process of WO 2011/064171, a compound of the formula (VI) is provided:
HC
'r¨'- C1-13 H2 N\
N
WO 03/095451 discloses the compound of formula (I), and further describes that this and other compounds disclosed therein are stimulators of soluble guanylate cyclase, and may therefore be used as agents for the prophylaxis and/or treatment of cardiovascular disorders.
WO 03/095451 describes the preparation of the compound of the formula (I).
However, there are a number of disadvantages associated with the process disclosed in WO
03/095451, as discussed in WO 2011/064171. WO 2011/064171 thus discloses an alternative process for preparing a compound of the formula (I).
In the process of WO 2011/064171, a compound of the formula (VI) is provided:
Hs ,Me / \ NH2 N
(VI) The compound of the formula (VI) is reacted in a manner known per se, for example in accordance with one of the descriptions in WO 03/0945451 or ChemMedChem 2009, 4, 853-865, with a methylating agent Me-X to give a crude product which contains high amounts of the compound of the formula (I).
Hs /I
-Me H3C, 0 n' Me / \ NH2 Me-X
N
N ;/--1`1' base N
=
(VI) (I) (crude product) The methylating agent Me-X used is methyl iodide, dimethyl sulphate, methyl toluenesulphonate, etc., and methyl iodide or dimethyl sulphate is preferred.
The purification of the crude product of the formula (I) for use as pharmaceutically active compound is carried out via the compound methyl {4,6-diamino-241-(2-fluorobenzy1)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}methylcarbamate sulphinyldimethane (1:1), i.e. a compound of the formula (II) as isolated intermediate or generated in a mixture.
CA 02807859 2013-02,-21 H3C, ' - NE12 I I
N S, H3Cõ CH3 I N
N N
=
For the purification, initially, a mixture is formed which contains high amounts of the compound of the formula (II) as intermediate.
H3C, H3C, H2N 0 c H2N
I I
H3CCH3 )r-c¨NH2 0 I I
N'1\11 (I) (crude product) (II) To this end, the crude product of the formula (I) is dissolved in DMSO
(dimethylsulfoxide, sulphinyldimethane or (methylsulfinyOmethane which are different names for the same compound). To form a solution, the mixture is heated to 40-120 C, preferably 50-100 C. To form a pharmaceutically acceptable product of the formula (I), the solution has to be filtered, and the filtration is carried out hot, the temperatures are 40-120 C, preferably 50-100 C.
After the filtration, a pharmaceutically acceptable solvent, preferably the same solvent as above, is added to the hot filtrate. This results in a crystallization of the product of the formula (II).
Prior to the isolation of the solid which contains high amounts of the compound of the formula (II), to bring the precipitation to completion, the mixture is cooled to a temperature range of 0-35 C, preferably to an ambient temperature of, for example, 20-30 C.
(VI) The compound of the formula (VI) is reacted in a manner known per se, for example in accordance with one of the descriptions in WO 03/0945451 or ChemMedChem 2009, 4, 853-865, with a methylating agent Me-X to give a crude product which contains high amounts of the compound of the formula (I).
Hs /I
-Me H3C, 0 n' Me / \ NH2 Me-X
N
N ;/--1`1' base N
=
(VI) (I) (crude product) The methylating agent Me-X used is methyl iodide, dimethyl sulphate, methyl toluenesulphonate, etc., and methyl iodide or dimethyl sulphate is preferred.
The purification of the crude product of the formula (I) for use as pharmaceutically active compound is carried out via the compound methyl {4,6-diamino-241-(2-fluorobenzy1)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}methylcarbamate sulphinyldimethane (1:1), i.e. a compound of the formula (II) as isolated intermediate or generated in a mixture.
CA 02807859 2013-02,-21 H3C, ' - NE12 I I
N S, H3Cõ CH3 I N
N N
=
For the purification, initially, a mixture is formed which contains high amounts of the compound of the formula (II) as intermediate.
H3C, H3C, H2N 0 c H2N
I I
H3CCH3 )r-c¨NH2 0 I I
N'1\11 (I) (crude product) (II) To this end, the crude product of the formula (I) is dissolved in DMSO
(dimethylsulfoxide, sulphinyldimethane or (methylsulfinyOmethane which are different names for the same compound). To form a solution, the mixture is heated to 40-120 C, preferably 50-100 C. To form a pharmaceutically acceptable product of the formula (I), the solution has to be filtered, and the filtration is carried out hot, the temperatures are 40-120 C, preferably 50-100 C.
After the filtration, a pharmaceutically acceptable solvent, preferably the same solvent as above, is added to the hot filtrate. This results in a crystallization of the product of the formula (II).
Prior to the isolation of the solid which contains high amounts of the compound of the formula (II), to bring the precipitation to completion, the mixture is cooled to a temperature range of 0-35 C, preferably to an ambient temperature of, for example, 20-30 C.
For pharmaceutical use, the DMSO has to be removed from the product of the formula (II) or the mixture comprising high amounts of the compound of the formula (II).
H3C, C H3C, N
boiling in a solvent N
N "
(I) (pure product) To this end, the product of the formula (II) or the isolated mixture comprising high amounts of the product of the formula (II) is boiled in a pharmaceutically acceptable solvent from the class of the ketones, ethers, esters or alcohols. Examples of such solvents which may be mentioned are:
methanol, ethanol, isopropanol, 1-butanol, 2-butanol, ethyl acetate, isopropyl acetate or propyl acetate, butyl acetate, tert-butyl methyl ether, diisopropyl ether, acetone, methyl ethyl ketone, methyl isobutyl ketone, etc. Preference is given to ethanol, isopropanol, ethyl acetate, isopropyl acetate, butyl acetate, methyl ethyl ketone, methyl isobutyl ketone. It is also possible to use mixtures of these solvents. Particular preference is given to ethyl acetate or a mixture of ethyl acetate with ethanol.
Boiling takes place at reflux of the solvent in question or, if appropriate, at slightly elevated pressure. The temperature is 50-150 C, preferably 80-120 C. The solid obtained is then filtered.
The present invention relates to new forms of methyl {4,6-diamino-241-(2-fluorobenzy1)-1H-pyrazolo[3,4-b]pyridino-3-yl]pyrimidino-5-yl}metinylcarbamate of formula (I).
Surprisingly it has been found that the compound of formula (I) crystallizes in two modifications with melting points at 268 C (Modification I) and 250 C (Modification II). In this context modifications and polymorphs have the same meaning. In addition, three pseudo-polymorphs, a mono-DMSO
solvate, a sesqui-DMSO solvate, a 1/4-ethyl acetate solvate and the amorphous form have been found. The amorphous form can exist at room temperature, but crystallizes very quickly. All together ¨modifications or polymorphs, pseudo-polymorphs and amorphous forms ¨ are different forms of the compound of formula (I) according to the present invention.
H3C, C H3C, N
boiling in a solvent N
N "
(I) (pure product) To this end, the product of the formula (II) or the isolated mixture comprising high amounts of the product of the formula (II) is boiled in a pharmaceutically acceptable solvent from the class of the ketones, ethers, esters or alcohols. Examples of such solvents which may be mentioned are:
methanol, ethanol, isopropanol, 1-butanol, 2-butanol, ethyl acetate, isopropyl acetate or propyl acetate, butyl acetate, tert-butyl methyl ether, diisopropyl ether, acetone, methyl ethyl ketone, methyl isobutyl ketone, etc. Preference is given to ethanol, isopropanol, ethyl acetate, isopropyl acetate, butyl acetate, methyl ethyl ketone, methyl isobutyl ketone. It is also possible to use mixtures of these solvents. Particular preference is given to ethyl acetate or a mixture of ethyl acetate with ethanol.
Boiling takes place at reflux of the solvent in question or, if appropriate, at slightly elevated pressure. The temperature is 50-150 C, preferably 80-120 C. The solid obtained is then filtered.
The present invention relates to new forms of methyl {4,6-diamino-241-(2-fluorobenzy1)-1H-pyrazolo[3,4-b]pyridino-3-yl]pyrimidino-5-yl}metinylcarbamate of formula (I).
Surprisingly it has been found that the compound of formula (I) crystallizes in two modifications with melting points at 268 C (Modification I) and 250 C (Modification II). In this context modifications and polymorphs have the same meaning. In addition, three pseudo-polymorphs, a mono-DMSO
solvate, a sesqui-DMSO solvate, a 1/4-ethyl acetate solvate and the amorphous form have been found. The amorphous form can exist at room temperature, but crystallizes very quickly. All together ¨modifications or polymorphs, pseudo-polymorphs and amorphous forms ¨ are different forms of the compound of formula (I) according to the present invention.
Aspects of some embodiments of the present invention which may be beneficial in the present pharmaceutical field may include stability (e.g. pressure stability, chemical stability, storage stability), compatibility over other ingredients, purity, solubility (thermodynamically, kinetically), crystallization properties, properties regarding isolation during the chemical synthesis and bioavailability of the forms of the compound of formula (I).
The compound of the formula (I) in the Modification I is the thermodynamically stable form between 0 C and 80 C.
Two of the solvates occur during synthesis, the mono-DMSO solvate and the 1/4-ethyl acetate solvate of the compound of the formula (I). The compound of the formula (I) in the Modification II can form from the solvates after solvent release, e.g. during drying at 80 C.
Embodiments of the present invention are not only each single form the compound of the formula (I) which are Modification I, Modification II, mono-DMSO solvate, sesqui-DMSO
solvate and 1/4-ethyl acetate solvate of the compound of the formula (I) but also mixtures comprising two, three, four or five forms of the aforementioned.
A pharmaceutical composition according to the present invention comprises preferably only one of the forms selected from the group comprising Modification I, Modification II, mono-DMSO solvate, sesqui-DMSO solvate and 1/4-ethyl acetate solvate of the compound of the formula (I) mainly and no significant fractions of another form of the compound of the formula (I), for example of another modification or pseudopolymorph of the compound of the formula (I). More preferably the pharmaceutical composition contains more than 90 percent by weight, most preferably more than 95 percent by weight, and up to 100 percent, of the compound of the formula (I) in one of the aforementioned forms related to the total amount of all forms of the compound of the formula (I) present in the composition.
Preference is given to a pharmaceutical composition comprising the compound of the formula (I) in the Modification I mainly and no significant fractions of another form of the compound of the formula (I), for example of another modification or pseudopolymorph of the compound of the formula (I). The pharmaceutical composition preferably contains more than 90 percent by weight, more preferably more than 95 percent by weight, and up to 100 percent of the compound of the formula (I) in the Modification I related to the total amount of all forms of the compound of the formula (I) present in the composition.
Further preference is given to a pharmaceutical composition comprising the compound of the formula (I) in the Modification II mainly and no significant fractions of another form of the compound of the =
The compound of the formula (I) in the Modification I is the thermodynamically stable form between 0 C and 80 C.
Two of the solvates occur during synthesis, the mono-DMSO solvate and the 1/4-ethyl acetate solvate of the compound of the formula (I). The compound of the formula (I) in the Modification II can form from the solvates after solvent release, e.g. during drying at 80 C.
Embodiments of the present invention are not only each single form the compound of the formula (I) which are Modification I, Modification II, mono-DMSO solvate, sesqui-DMSO
solvate and 1/4-ethyl acetate solvate of the compound of the formula (I) but also mixtures comprising two, three, four or five forms of the aforementioned.
A pharmaceutical composition according to the present invention comprises preferably only one of the forms selected from the group comprising Modification I, Modification II, mono-DMSO solvate, sesqui-DMSO solvate and 1/4-ethyl acetate solvate of the compound of the formula (I) mainly and no significant fractions of another form of the compound of the formula (I), for example of another modification or pseudopolymorph of the compound of the formula (I). More preferably the pharmaceutical composition contains more than 90 percent by weight, most preferably more than 95 percent by weight, and up to 100 percent, of the compound of the formula (I) in one of the aforementioned forms related to the total amount of all forms of the compound of the formula (I) present in the composition.
Preference is given to a pharmaceutical composition comprising the compound of the formula (I) in the Modification I mainly and no significant fractions of another form of the compound of the formula (I), for example of another modification or pseudopolymorph of the compound of the formula (I). The pharmaceutical composition preferably contains more than 90 percent by weight, more preferably more than 95 percent by weight, and up to 100 percent of the compound of the formula (I) in the Modification I related to the total amount of all forms of the compound of the formula (I) present in the composition.
Further preference is given to a pharmaceutical composition comprising the compound of the formula (I) in the Modification II mainly and no significant fractions of another form of the compound of the =
formula (I), for example of another modification or pseudopolymorph of the compound of the formula (I). The pharmaceutical composition preferably contains more than 90 percent by weight, more preferably more than 95 percent by weight, and up to 100 percent of the compound of the formula (I) in the Modification II related to the total amount of all forms of the compound of the formula (I) present in the composition.
Further preference is given to a pharmaceutical composition comprising the mono-DMSO solvate of the compound of the formula (I) mainly and no significant fractions of another form of the compound of the formula (I), for example of another modification or pseudopolymorph of the compound of the formula (I). The pharmaceutical composition preferably contains more than 90 percent by weight, more preferably more than 95 percent by weight, and up to 100 percent of the mono-DMSO solvate of the compound of the formula (I) related to the total amount of all forms of the compound of the formula (I) present in the composition.
Further preference is given to a pharmaceutical composition comprising the sesqui-DMSO solvate of the compound of the formula (I) mainly and no significant fractions of another form of the compound of the formula (I), for example of another modification or pseudopolymorph of the compound of the formula (I). The pharmaceutical composition preferably contains more than 90 percent by weight, more preferably more than 95 percent by weight, and up to 100 percent of the sesqui-DMSO solvate of the compound of the formula (I) related to the total amount of all forms of the compound of the formula (I) present in the composition.
Further preference is given to a pharmaceutical composition comprising the 1/4-ethyl acetate solvate of the compound of the formula (I) mainly and no significant fractions of another form of the compound of the formula (I), for example of another modification or pseudopolymorph of the compound of the formula (I). The pharmaceutical composition preferably contains more than 90 percent by weight, more preferably more than 95 percent by weight, and up to 100 percent of the 1/4-ethyl acetate solvate of the compound of the formula (I) related to the total amount of all forms of the compound of the formula (I) present in the composition.
The forms of the compound of the formula (I) of the present invention are used alone or together as a mixture in high purity in pharmaceutical formulations. As mixtures a combination of the compound of formula (I) in the Modification I and the compound of formula (I) in the Modification II, a combination of the compound of formula (I) in the Modification I and the mono-DMSO solvate of the compound of formula (I), a combination of the compound of formula (I) in the Modification I and the sesqui-DMSO solvate of the compound of formula (I), a combination of the compound of formula (I) in the Modification I and the 1/4-ethyl acetate solvate of the compound of formula (I), a combination of the compound of formula (I) in the Modification I and the mono-DMSO solvate of CA 02807859 2013-02:21 the compound of formula (I) and the 1/4-ethyl acetate solvate of the compound of formula (I), or a combination of the compound of formula (I) in the Modification I and the sesqui-DMSO solvate of the compound of formula (I) and the 1/4-ethyl acetate solvate of the compound of formula (I) optionally with no other form of the compound of the formula (I) are preferred.
The different forms of the compound of formula (I) can be distinguished by X-ray powder diffraction, differential scanning calorimetry (DSC), IR-, Raman-, NIR-, FIR- and 13C-solid-state-NMR-spectroscopy:
Figure 1: X-Ray powder diffractogram of the modification I
Figure 2: DSC- and TGA-Thermogram of modification I
Figure 3: IR-Spectrum (ATR) of modification I
Figure 4: X-Ray powder diffractogram of the 1/4-ethyl acetate solvate Figure 5: DSC- and TGA-Thermogram of the 1/4-ethyl acetate solvate Figure 6: IR-Spectrum (ATR) of the 1/4-ethyl acetate solvate Figure 7: X-Ray powder diffractogram of the mono-DMSO solvate Figure 8: DSC- and TGA-Thermogram of the mono-DMSO solvate Figure 9: 1R-Spectrum (ATR) of the mono-DMSO solvate Figure 10: X-Ray powder diffractogram of the sesqui-DMSO solvate Figure 11: DSC- and TGA-Thermogram of the sesqui-DMSO solvate Figure 12: IR-Spectrum (ATR) of the sesqui-DMSO solvate Figure 13: X-Ray powder diffractogram of modification II
Figure 14: DSC- and TGA-Thermogram of modification II
Figure 15: IR-Spectrum (ATR) of modification II
Figure 16: X-Ray powder diffractogram of the amorphous form Figure 17: DSC- and TGA-Thermogram of the amorphous form Figure 18: LR-Spectrum of the amorphous form The compound of formula (I) in the Modification I can be characterized unambiguously by a X-Ray powder diffractogram comprising peak maxima of the 2 Theta angle of 6.7, 9.1, 14.3, 14.4, 17.8, 19.8, 20.2, 24.8, 25.6, 27.3.
The compound of formula (I) in the Modification II can be characterized unambiguously by a X-Ray powder diffractogram comprising peak maxima of the 2 Theta angle of 11.2, 12.6, 12.7, 13.9, 15.2, 17.3, 22.5, 22.8, 25.0, 25.5.
The mono-DMSO solvate of the compound of formula (I) can be characterized unambiguously by a X-Ray powder diffractogram comprising peak maxima of the 2 Theta angle of 9.0, 10.8, 11.1, 11.2, 13.0, 15.5, 15.9, 16.0, 20.7, 25.6.
The sesqui-DMSO solvate of the compound of formula (I) can be characterized unambiguously by a X-Ray powder diffractogram comprising peak maxima of the 2 Theta angle of 8.3, 8.4, 13.7, 13.9, 15.7, 17.2, 18.4, 19.6, 21.4, 24.9.
The 1/4-Ethylacetate solvate of the compound of formula (I) can be characterized unambiguously by a X-Ray powder diffractogram comprising peak maxima of the 2 Theta angle of 6.7, 8.3, 8.7, 12.9, 14.2, 17.8, 19.3, 24.0, 25.1, 26.7.
The compound of formula (I) in the Modification I can be characterized unambiguously by an IR-spectrogram comprising peak maxima of the 2 Theta angle of 3454, 3360, 3273, 3103, 1688, 1622, 1559, 1284, 1193, 989, 777.
The compound of formula (I) in the Modification II can be characterized unambiguously by an IR-spectrogram comprising peak maxima of the 2 Theta angle of 3498, 3382, 3269, 3104, 1704, 1622, 1586, 1563, 1326, 1288, 1106.
The mono-DMSO solvate of the compound of formula (I) can be characterized unambiguously by an 1R-spectrogram fractogram comprising peak maxima of the 2 Theta angle of 3401, 3361, 3295, 3168, 1702, 1626, 1560, 1333, 1286, 1042, 751.
The sesqui-DMSO solvate of the compound of formula (I) can be characterized unambiguously by an IR-spectrogram comprising peak maxima of the 2 Theta angle of 3407, 3361, 3300, 3190, 1698, 1629, 1558, 1293, 1043, 770, 757.
The 1/4-Ethylacetate solvate of the compound of formula (I) can be characterized unambiguously by an IR-spectrogram comprising peak maxima of the 2 Theta angle of 3363, 3275, 1732, 1702, 1619, 1560, 1457, 1246, 899, 810, 771.
The compounds according to the invention may bring about vessel relaxation and inhibition of thrombocyte aggregation and lead to a lowering of blood pressure and to an increase in coronary blood flow. These effects are due to direct stimulation of soluble guanylate cyclase and an increase in intracellular cGMP. Moreover, the compounds according to the invention may intensify the action of substances that raise the cGMP level, for example EDRF (endothelium-derived relaxing factor), NO donors, protoporphyrin IX, arachidonic acid or phenylhydrazine derivatives.
The weight data in the tests and examples which follow are, unless stated otherwise, percentages by weight; parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid/liquid solutions are based on each case on the volume.
CA 02807859 2013-02.-21 , Working examples DSC thermograms were recorded using Differential Scanning Calorimeters (model DSC7, Pyris-1 or Diamond) from Perkin-Elmer. The measurements were performed with a heating rate of 20 Kminl using non-gastight aluminium pans. Flow gas was nitrogen. There was no sample preparation.
TGA thermograms were recorded using thermobalances (model TGA7 and Pyris 1) from Perkin-Elmer.. The measurements were performed with a heating rate of 10 Kmin-1 using open platinum pans. Flow gas was nitrogen. There was no sample preparation.
X-Ray diffraction patterns were recorded at room temperature using XRD
¨diffractometers X'Pert PRO (PANalytical) and STOE STADI-P (radiation Cu K alpha 1, wavelength 1.5406 A). There was no sample preparation.
Raman spectra were recorded at room temperature using FT-Raman-spectrophotometers (model RFS
100 and MultiRam) from Bruker. Resolution was 2 cm-'. Measurements were perfomed in glass vials or aluminium discs. There was no sample preparation.
1R-ATR-spectra were recorded at room temperature using a FT-IR-spectrophotometer one with universal diamond ATR device from Perkin-Elmer. Resolution was 4 cm-1. There was no sample preparation.
Example 1 Preparation of purified methyl 4,6-diamino-2-[1-(2-fluorobenzy1)-1H-pyrazolo[3,4-b]pyridin-3-y11-5-pyrimidinyhmethyl)carbamate (I) in its modification I
The entire amount of the product of the formula (II) prepared in the Example 6 of WO 2011/064171 was stirred in 135 ml of ethyl acetate at reflux (about 78 C) for 1 h and cooled to about 25 C. The solid was filtered off with suction, washed with a total of 36 ml of ethyl acetate and dried under reduced pressure. The weight was 7.6 g or 93.8% of theory.
The content of the product was markedly above 98% by weight (HPLC). As solvent, ethyl acetate was present in an amount of about 0.2%. The DMSO content was below 0.1%.
Further preference is given to a pharmaceutical composition comprising the mono-DMSO solvate of the compound of the formula (I) mainly and no significant fractions of another form of the compound of the formula (I), for example of another modification or pseudopolymorph of the compound of the formula (I). The pharmaceutical composition preferably contains more than 90 percent by weight, more preferably more than 95 percent by weight, and up to 100 percent of the mono-DMSO solvate of the compound of the formula (I) related to the total amount of all forms of the compound of the formula (I) present in the composition.
Further preference is given to a pharmaceutical composition comprising the sesqui-DMSO solvate of the compound of the formula (I) mainly and no significant fractions of another form of the compound of the formula (I), for example of another modification or pseudopolymorph of the compound of the formula (I). The pharmaceutical composition preferably contains more than 90 percent by weight, more preferably more than 95 percent by weight, and up to 100 percent of the sesqui-DMSO solvate of the compound of the formula (I) related to the total amount of all forms of the compound of the formula (I) present in the composition.
Further preference is given to a pharmaceutical composition comprising the 1/4-ethyl acetate solvate of the compound of the formula (I) mainly and no significant fractions of another form of the compound of the formula (I), for example of another modification or pseudopolymorph of the compound of the formula (I). The pharmaceutical composition preferably contains more than 90 percent by weight, more preferably more than 95 percent by weight, and up to 100 percent of the 1/4-ethyl acetate solvate of the compound of the formula (I) related to the total amount of all forms of the compound of the formula (I) present in the composition.
The forms of the compound of the formula (I) of the present invention are used alone or together as a mixture in high purity in pharmaceutical formulations. As mixtures a combination of the compound of formula (I) in the Modification I and the compound of formula (I) in the Modification II, a combination of the compound of formula (I) in the Modification I and the mono-DMSO solvate of the compound of formula (I), a combination of the compound of formula (I) in the Modification I and the sesqui-DMSO solvate of the compound of formula (I), a combination of the compound of formula (I) in the Modification I and the 1/4-ethyl acetate solvate of the compound of formula (I), a combination of the compound of formula (I) in the Modification I and the mono-DMSO solvate of CA 02807859 2013-02:21 the compound of formula (I) and the 1/4-ethyl acetate solvate of the compound of formula (I), or a combination of the compound of formula (I) in the Modification I and the sesqui-DMSO solvate of the compound of formula (I) and the 1/4-ethyl acetate solvate of the compound of formula (I) optionally with no other form of the compound of the formula (I) are preferred.
The different forms of the compound of formula (I) can be distinguished by X-ray powder diffraction, differential scanning calorimetry (DSC), IR-, Raman-, NIR-, FIR- and 13C-solid-state-NMR-spectroscopy:
Figure 1: X-Ray powder diffractogram of the modification I
Figure 2: DSC- and TGA-Thermogram of modification I
Figure 3: IR-Spectrum (ATR) of modification I
Figure 4: X-Ray powder diffractogram of the 1/4-ethyl acetate solvate Figure 5: DSC- and TGA-Thermogram of the 1/4-ethyl acetate solvate Figure 6: IR-Spectrum (ATR) of the 1/4-ethyl acetate solvate Figure 7: X-Ray powder diffractogram of the mono-DMSO solvate Figure 8: DSC- and TGA-Thermogram of the mono-DMSO solvate Figure 9: 1R-Spectrum (ATR) of the mono-DMSO solvate Figure 10: X-Ray powder diffractogram of the sesqui-DMSO solvate Figure 11: DSC- and TGA-Thermogram of the sesqui-DMSO solvate Figure 12: IR-Spectrum (ATR) of the sesqui-DMSO solvate Figure 13: X-Ray powder diffractogram of modification II
Figure 14: DSC- and TGA-Thermogram of modification II
Figure 15: IR-Spectrum (ATR) of modification II
Figure 16: X-Ray powder diffractogram of the amorphous form Figure 17: DSC- and TGA-Thermogram of the amorphous form Figure 18: LR-Spectrum of the amorphous form The compound of formula (I) in the Modification I can be characterized unambiguously by a X-Ray powder diffractogram comprising peak maxima of the 2 Theta angle of 6.7, 9.1, 14.3, 14.4, 17.8, 19.8, 20.2, 24.8, 25.6, 27.3.
The compound of formula (I) in the Modification II can be characterized unambiguously by a X-Ray powder diffractogram comprising peak maxima of the 2 Theta angle of 11.2, 12.6, 12.7, 13.9, 15.2, 17.3, 22.5, 22.8, 25.0, 25.5.
The mono-DMSO solvate of the compound of formula (I) can be characterized unambiguously by a X-Ray powder diffractogram comprising peak maxima of the 2 Theta angle of 9.0, 10.8, 11.1, 11.2, 13.0, 15.5, 15.9, 16.0, 20.7, 25.6.
The sesqui-DMSO solvate of the compound of formula (I) can be characterized unambiguously by a X-Ray powder diffractogram comprising peak maxima of the 2 Theta angle of 8.3, 8.4, 13.7, 13.9, 15.7, 17.2, 18.4, 19.6, 21.4, 24.9.
The 1/4-Ethylacetate solvate of the compound of formula (I) can be characterized unambiguously by a X-Ray powder diffractogram comprising peak maxima of the 2 Theta angle of 6.7, 8.3, 8.7, 12.9, 14.2, 17.8, 19.3, 24.0, 25.1, 26.7.
The compound of formula (I) in the Modification I can be characterized unambiguously by an IR-spectrogram comprising peak maxima of the 2 Theta angle of 3454, 3360, 3273, 3103, 1688, 1622, 1559, 1284, 1193, 989, 777.
The compound of formula (I) in the Modification II can be characterized unambiguously by an IR-spectrogram comprising peak maxima of the 2 Theta angle of 3498, 3382, 3269, 3104, 1704, 1622, 1586, 1563, 1326, 1288, 1106.
The mono-DMSO solvate of the compound of formula (I) can be characterized unambiguously by an 1R-spectrogram fractogram comprising peak maxima of the 2 Theta angle of 3401, 3361, 3295, 3168, 1702, 1626, 1560, 1333, 1286, 1042, 751.
The sesqui-DMSO solvate of the compound of formula (I) can be characterized unambiguously by an IR-spectrogram comprising peak maxima of the 2 Theta angle of 3407, 3361, 3300, 3190, 1698, 1629, 1558, 1293, 1043, 770, 757.
The 1/4-Ethylacetate solvate of the compound of formula (I) can be characterized unambiguously by an IR-spectrogram comprising peak maxima of the 2 Theta angle of 3363, 3275, 1732, 1702, 1619, 1560, 1457, 1246, 899, 810, 771.
The compounds according to the invention may bring about vessel relaxation and inhibition of thrombocyte aggregation and lead to a lowering of blood pressure and to an increase in coronary blood flow. These effects are due to direct stimulation of soluble guanylate cyclase and an increase in intracellular cGMP. Moreover, the compounds according to the invention may intensify the action of substances that raise the cGMP level, for example EDRF (endothelium-derived relaxing factor), NO donors, protoporphyrin IX, arachidonic acid or phenylhydrazine derivatives.
The weight data in the tests and examples which follow are, unless stated otherwise, percentages by weight; parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid/liquid solutions are based on each case on the volume.
CA 02807859 2013-02.-21 , Working examples DSC thermograms were recorded using Differential Scanning Calorimeters (model DSC7, Pyris-1 or Diamond) from Perkin-Elmer. The measurements were performed with a heating rate of 20 Kminl using non-gastight aluminium pans. Flow gas was nitrogen. There was no sample preparation.
TGA thermograms were recorded using thermobalances (model TGA7 and Pyris 1) from Perkin-Elmer.. The measurements were performed with a heating rate of 10 Kmin-1 using open platinum pans. Flow gas was nitrogen. There was no sample preparation.
X-Ray diffraction patterns were recorded at room temperature using XRD
¨diffractometers X'Pert PRO (PANalytical) and STOE STADI-P (radiation Cu K alpha 1, wavelength 1.5406 A). There was no sample preparation.
Raman spectra were recorded at room temperature using FT-Raman-spectrophotometers (model RFS
100 and MultiRam) from Bruker. Resolution was 2 cm-'. Measurements were perfomed in glass vials or aluminium discs. There was no sample preparation.
1R-ATR-spectra were recorded at room temperature using a FT-IR-spectrophotometer one with universal diamond ATR device from Perkin-Elmer. Resolution was 4 cm-1. There was no sample preparation.
Example 1 Preparation of purified methyl 4,6-diamino-2-[1-(2-fluorobenzy1)-1H-pyrazolo[3,4-b]pyridin-3-y11-5-pyrimidinyhmethyl)carbamate (I) in its modification I
The entire amount of the product of the formula (II) prepared in the Example 6 of WO 2011/064171 was stirred in 135 ml of ethyl acetate at reflux (about 78 C) for 1 h and cooled to about 25 C. The solid was filtered off with suction, washed with a total of 36 ml of ethyl acetate and dried under reduced pressure. The weight was 7.6 g or 93.8% of theory.
The content of the product was markedly above 98% by weight (HPLC). As solvent, ethyl acetate was present in an amount of about 0.2%. The DMSO content was below 0.1%.
Example 2 Preparation and analytical characterization of methyl {4,6-diamino-2-[1-(2-fluorobenzy1)-1H-pyrazolo[3,4-13]pyridin-3-yll pyrimidin-5-yl}methylcarbamate sulphinyldimethane (compound according to formula (I) as mono-DMSO solvate) 14.8 g of a crude product of the formula (I) were dissolved in 28.9 g of DMSO
and 11.85 g of ethyl acetate at about 94 C. 1.5 g of activated carbon Norit A-Supra and a further 11.85 g of ethyl acetate were then added, the mixture was stirred at reflux (88-90 C) for 1 h and the hot mixture was then filtered to remove the activated carbon. The solid, some of which had already precipitated, was re-dissolved by warming to about 78 C, and the solution was then allowed to cool slowly. The precipitated solid was filtered off with suction at RT, washed three times with in each case 50 ml of ethyl acetate and dried in a drying cabinet at 30 C for 18 h. This gave 9.2 g or 52.5% of theory of a slightly yellowish crystal powder of the compound of the formula (II).
HPLC: 99.90 area% (without taking the DMSO into account) DMSO (GC): 14.7% by weight 1H-NMR (400 MHz in DMF-d7):
d = 2.59 (s, about 6H, 2 CH3 at DMSO), 3.13 (s, 3H, N-CH3), 3.58 + 3.67 (two s, 3H, hindered rotation at 0-CH3), 5.91 (s ,2H, -CH2-), 6.53 (s, 4H, 2 -NH2), 7.05-7.40 (m, 5H, 4 aromatic H at the o-fluorobenzyl substituent and 1H at the pyrido ring meta to the pyrido nitrogen), 8.60 (dd, 11, at the pyrido ring ortho to the pyrido nitrogen), 9.12 (dd, 1H, at the pyrido ring para to the pyrido nitrogen).
Elemental analysis:
found C: 52.2% calculated C: 52.79%
H: 4.9% H: 5.03%
N: 22.7% N: 22.39%
and 11.85 g of ethyl acetate at about 94 C. 1.5 g of activated carbon Norit A-Supra and a further 11.85 g of ethyl acetate were then added, the mixture was stirred at reflux (88-90 C) for 1 h and the hot mixture was then filtered to remove the activated carbon. The solid, some of which had already precipitated, was re-dissolved by warming to about 78 C, and the solution was then allowed to cool slowly. The precipitated solid was filtered off with suction at RT, washed three times with in each case 50 ml of ethyl acetate and dried in a drying cabinet at 30 C for 18 h. This gave 9.2 g or 52.5% of theory of a slightly yellowish crystal powder of the compound of the formula (II).
HPLC: 99.90 area% (without taking the DMSO into account) DMSO (GC): 14.7% by weight 1H-NMR (400 MHz in DMF-d7):
d = 2.59 (s, about 6H, 2 CH3 at DMSO), 3.13 (s, 3H, N-CH3), 3.58 + 3.67 (two s, 3H, hindered rotation at 0-CH3), 5.91 (s ,2H, -CH2-), 6.53 (s, 4H, 2 -NH2), 7.05-7.40 (m, 5H, 4 aromatic H at the o-fluorobenzyl substituent and 1H at the pyrido ring meta to the pyrido nitrogen), 8.60 (dd, 11, at the pyrido ring ortho to the pyrido nitrogen), 9.12 (dd, 1H, at the pyrido ring para to the pyrido nitrogen).
Elemental analysis:
found C: 52.2% calculated C: 52.79%
H: 4.9% H: 5.03%
N: 22.7% N: 22.39%
Example 3 Preparation of methyl {4,6-diamino-2-11-(2-fluorobenzy1)-1H-pyrazolo13,4-131pyridin-3-ylipyrimidin-5-y1}methylcarbamate of formula (I) in its Modification II
0.5 g of the compound according to formula (I) as mono DMSO sovlate was tempered for 2 days at 80 C.
Example 4 Preparation of methyl {4,6-diamino-241-(2-fluorobenzy1)-1H-pyrazolo13,4-b]pyridin-3-yl]pyrimidin-5-yl}methylcarbamate of formula (I) as sesqui-DMSO solvate 160 mg of the compound according to formula (I) in its amorphous form were suspended in 2 ml Ethylacetat:DMSO (1:1). The suspension was stirred in a sealed container for three weeks at room temperature. The residue was filtered and dried at room temperature.
Example 5 Preparation of methyl {4,6-diamino-241-(2-fluorobenzy1)-1H-pyrazolo[3,4-131pyridin-3-yllpyrimidin-5-ylImethylcarbamate of formula (I) in its amorphous form.
0.5 g of the compound according to formula (I) in its Modification (I) were ground in a swing mill for 30 mm with a vibration of 30 swings per second.
Example 6 Preparation of methyl {4,6-diamino-241-(2-fluorobenzy1)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}methylcarbamate of formula (I) as Y4 ethyl acetate solvate 9.6 g of compound according to formula (I) was stirred in 135 ml of ethyl acetate at reflux (about 78 C) for 1 h and cooled to about 25 C. The solid was filtered off with suction, washed with a total of 36 ml of ethyl acetate and dried under reduced pressure. The weight was 7.6 g or 93.8% of theory. The content of the product was markedly above 98% by weight (HPLC). As solvent, ethyl acetate was present in an amount of about 0.2%. The DMSO content was below 0.1%.
In this reaction, an ethyl acetate containing solid polymorph (1/4-ethyl acetate-solvate) may be formed and isolated.
0.5 g of the compound according to formula (I) as mono DMSO sovlate was tempered for 2 days at 80 C.
Example 4 Preparation of methyl {4,6-diamino-241-(2-fluorobenzy1)-1H-pyrazolo13,4-b]pyridin-3-yl]pyrimidin-5-yl}methylcarbamate of formula (I) as sesqui-DMSO solvate 160 mg of the compound according to formula (I) in its amorphous form were suspended in 2 ml Ethylacetat:DMSO (1:1). The suspension was stirred in a sealed container for three weeks at room temperature. The residue was filtered and dried at room temperature.
Example 5 Preparation of methyl {4,6-diamino-241-(2-fluorobenzy1)-1H-pyrazolo[3,4-131pyridin-3-yllpyrimidin-5-ylImethylcarbamate of formula (I) in its amorphous form.
0.5 g of the compound according to formula (I) in its Modification (I) were ground in a swing mill for 30 mm with a vibration of 30 swings per second.
Example 6 Preparation of methyl {4,6-diamino-241-(2-fluorobenzy1)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}methylcarbamate of formula (I) as Y4 ethyl acetate solvate 9.6 g of compound according to formula (I) was stirred in 135 ml of ethyl acetate at reflux (about 78 C) for 1 h and cooled to about 25 C. The solid was filtered off with suction, washed with a total of 36 ml of ethyl acetate and dried under reduced pressure. The weight was 7.6 g or 93.8% of theory. The content of the product was markedly above 98% by weight (HPLC). As solvent, ethyl acetate was present in an amount of about 0.2%. The DMSO content was below 0.1%.
In this reaction, an ethyl acetate containing solid polymorph (1/4-ethyl acetate-solvate) may be formed and isolated.
Tab. 1: lR bands of the different crystalline forms IR Bands [cm-1]
Mono-DMS0- Sesqui-DMS0- 1/4-Ethylacetate-Mod. I Mod. II
Solvate Solvate Solvate IR Bands [cm-1] [cont.]
Mono-DMS0- Sesqui-DMS0- 1/4-Ethylacetate-Mod. I Mod. II
Solvate Solvate Solvate Tab. 2: 10 Major Peaks of 1R bands of the different crystalline forms IR Major Bands [emi]
Mono-DMS0- Sesqui-DMS0- 1/4-Ethylacetate-Mod. I Mod. H
Solvate Solvate Solvate Tab. 3: X-Ray powder diffractogram of the different crystalline forms Reflexes [ Position 2Th.]
Mono-DMS0- Sesqui-DMS0- 1/4-Ethylacetate-Mod. I Mod. II
Solvate Solvate Solvate 6.7 7.6 5.5 6.2 6.7 9.1 8.3 6.2 6.7 7.2 13.7 10.3 6.7 7.3 8.3 13.8 11.2 7.5 8.3 8.7 14.3 12.6 8.4 8.4 9.1 14.4 12.7 9.0 9.0 10.9 17.8 13.9 10.3 10.1 12.9 18.4 14.3 10.8 11.1 13.3 18.7 15.2 11.1 12.4 13.7 18.9 16.6 11.2 12.8 13.8 19.8 17.3 12.4 13.7 14.2 20.2 17.6 12.8 13.9 14.5 21.0 18.2 13.0 14.3 15.4 21.2 20.0 13.4 15.1 16.4 23.3 20.3 13.7 15.7 17.5 23.7 21.8 13.9 16.1 17.8 24.3 22.5 14.2 16.8 18.6 24.8 22.8 14.3 17.2 18.8 25.6 24.9 15.1 17.2 19.3 26.1 25.0 15.5 17.7 19.8 27.3 25.5 15.7 18.4 20.2 27.9 26.2 15.9 18.8 20.3 29.1 26.8 16.0 19.1 20.5 29.4 27.5 16.5 19.1 21.0 30.5 28.1 16.8 19.6 22.8 31.0 28.8 17.2 20.7 23.2 31.3 29.4 17.7 21.1 23.6 33.2 30.0 18.4 21.4 24.0 34.0 30.5 18.7 21.9 24.4 34.2 32.3 19.1 22.3 24.7 34.9 34.0 19.6 22.6 25.1 Reflexes [ Position 2T11.] [cont.]
Mono-DMS0- Sesqui-DMS0- Vi-Ethylacetate-Mod. I Mod. II
Solvate Solvate Solvate 36.1 34.4 20.2 22.8 25.6 37.5 35.0 20.7 23.4 26.3 35.7 21.1 23.8 26.7 36.5 21.4 24.6 27.1 21.8 24.9 27.4 22.2 25.4 27.6 22.4 25.6 28.2 22.6 25.9 28.6 23.0 26.7 29.1 23.5 26.8 29.7 23.9 27.3 30.0 24.3 27.9 30.7 24.6 28.4 31.3 24.8 28.8 31.8 25.6 29.4 32.7 26.0 29.6 33.1 26.3 30.5 33.5 26.7 31.5 35.2 27.2 31.7 35.9 28.8 32.1 37.6 29.3 32.5 29.8 33.1 30.5 34.0 30.8 35.0 31.4 35.9 32.0 37.2 32.3 34.0 34.9 35.7 36.4 Tab. 4: 10 Major Reflexes of X-Ray powder diffractogram of the different crystalline forms Major Reflexes [ Position '2Th.]
Mono-DMS0- Sesqui-DMS0- 1/4-Ethylacetate-Mod. I Mod. II
Solvate Solvate Solvate 6.7 11.2 9.0 8.3 6.7 9.1 12.6 10.8 8.4 8.3 14.3 12.7 11.1 13.7 8.7 14.4 13.9 11.2 13.9 12.9 17.8 15.2 13.0 15.7 14.2 19.8 17.3 15.5 17.2 17.8 20.2 22.5 15.9 18.4 19.3 24.8 22.8 16.0 19.6 24.0 25.6 25.0 20.7 21.4 25.1 27.3 25.5 25.6 24.9 26.7
Mono-DMS0- Sesqui-DMS0- 1/4-Ethylacetate-Mod. I Mod. II
Solvate Solvate Solvate IR Bands [cm-1] [cont.]
Mono-DMS0- Sesqui-DMS0- 1/4-Ethylacetate-Mod. I Mod. II
Solvate Solvate Solvate Tab. 2: 10 Major Peaks of 1R bands of the different crystalline forms IR Major Bands [emi]
Mono-DMS0- Sesqui-DMS0- 1/4-Ethylacetate-Mod. I Mod. H
Solvate Solvate Solvate Tab. 3: X-Ray powder diffractogram of the different crystalline forms Reflexes [ Position 2Th.]
Mono-DMS0- Sesqui-DMS0- 1/4-Ethylacetate-Mod. I Mod. II
Solvate Solvate Solvate 6.7 7.6 5.5 6.2 6.7 9.1 8.3 6.2 6.7 7.2 13.7 10.3 6.7 7.3 8.3 13.8 11.2 7.5 8.3 8.7 14.3 12.6 8.4 8.4 9.1 14.4 12.7 9.0 9.0 10.9 17.8 13.9 10.3 10.1 12.9 18.4 14.3 10.8 11.1 13.3 18.7 15.2 11.1 12.4 13.7 18.9 16.6 11.2 12.8 13.8 19.8 17.3 12.4 13.7 14.2 20.2 17.6 12.8 13.9 14.5 21.0 18.2 13.0 14.3 15.4 21.2 20.0 13.4 15.1 16.4 23.3 20.3 13.7 15.7 17.5 23.7 21.8 13.9 16.1 17.8 24.3 22.5 14.2 16.8 18.6 24.8 22.8 14.3 17.2 18.8 25.6 24.9 15.1 17.2 19.3 26.1 25.0 15.5 17.7 19.8 27.3 25.5 15.7 18.4 20.2 27.9 26.2 15.9 18.8 20.3 29.1 26.8 16.0 19.1 20.5 29.4 27.5 16.5 19.1 21.0 30.5 28.1 16.8 19.6 22.8 31.0 28.8 17.2 20.7 23.2 31.3 29.4 17.7 21.1 23.6 33.2 30.0 18.4 21.4 24.0 34.0 30.5 18.7 21.9 24.4 34.2 32.3 19.1 22.3 24.7 34.9 34.0 19.6 22.6 25.1 Reflexes [ Position 2T11.] [cont.]
Mono-DMS0- Sesqui-DMS0- Vi-Ethylacetate-Mod. I Mod. II
Solvate Solvate Solvate 36.1 34.4 20.2 22.8 25.6 37.5 35.0 20.7 23.4 26.3 35.7 21.1 23.8 26.7 36.5 21.4 24.6 27.1 21.8 24.9 27.4 22.2 25.4 27.6 22.4 25.6 28.2 22.6 25.9 28.6 23.0 26.7 29.1 23.5 26.8 29.7 23.9 27.3 30.0 24.3 27.9 30.7 24.6 28.4 31.3 24.8 28.8 31.8 25.6 29.4 32.7 26.0 29.6 33.1 26.3 30.5 33.5 26.7 31.5 35.2 27.2 31.7 35.9 28.8 32.1 37.6 29.3 32.5 29.8 33.1 30.5 34.0 30.8 35.0 31.4 35.9 32.0 37.2 32.3 34.0 34.9 35.7 36.4 Tab. 4: 10 Major Reflexes of X-Ray powder diffractogram of the different crystalline forms Major Reflexes [ Position '2Th.]
Mono-DMS0- Sesqui-DMS0- 1/4-Ethylacetate-Mod. I Mod. II
Solvate Solvate Solvate 6.7 11.2 9.0 8.3 6.7 9.1 12.6 10.8 8.4 8.3 14.3 12.7 11.1 13.7 8.7 14.4 13.9 11.2 13.9 12.9 17.8 15.2 13.0 15.7 14.2 19.8 17.3 15.5 17.2 17.8 20.2 22.5 15.9 18.4 19.3 24.8 22.8 16.0 19.6 24.0 25.6 25.0 20.7 21.4 25.1 27.3 25.5 25.6 24.9 26.7
Claims (13)
1. A the compound of the formula (I) in the form of Modification I, Modification II, as mono-DMSO solvate, as sesqui-DMSO
solvate, as 1/4-ethyl acetate solvate, in the amorphous form or a mixture thereof.
solvate, as 1/4-ethyl acetate solvate, in the amorphous form or a mixture thereof.
2. The compound of claim 1 characterized by one or more of the following: X-Ray powder diffractogram substantially as shown in Figures 1, 4, 7, 10, 13, 16;
DSC- and TGA-Thermogram substantially as shown in Figures 2, 5, 8, 11, 14, 17; IR-Spectrum (ATR) substantially as shown in Figures 3, 6, 9, 12, 15, 18.
DSC- and TGA-Thermogram substantially as shown in Figures 2, 5, 8, 11, 14, 17; IR-Spectrum (ATR) substantially as shown in Figures 3, 6, 9, 12, 15, 18.
3. The compound of claim 1 which is methyl {4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridino-3-yl]pyrimidino-5-yl}methyl carbamate in the Modification I.
4. The compound of claim 3 characterized by a X-Ray powder diffractogram comprising peak maxima of the 2 Theta angle of 6.7, 9.1, 14.3, 14.4, 17.8, 19.8, 20.2, 24.8, 25.6, 27.3.
5. The compound of claim 1 which is methyl {4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridino-3-yl]pyrimidino-5-yl}methylcarbamate in the Modification II.
6. The compound of claim 5 characterized by a X-Ray powder diffractogram comprising peak maxima of the 2 Theta angle of 11.2, 12.6, 12.7, 13.9, 15.2, 17.3, 22.5, 22.8, 25.0, 25.5.
7. The compound of claim 1 which is the mono-DMSO solvate of methyl {4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridino-3-yl]pyrimidino-5-yl}methylcarbamate.
8. The compound of claim 7 characterized by a X-Ray powder diffractogram comprising peak maxima of the 2 Theta angle of 9.0, 10.8, 11.1, 11.2, 13.0, 15.5, 15.9, 16.0, 20.7, 25.6.
9. The compound of claim 1 which is the sesqui-DMSO solvate of methyl {4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridino-3-yl]pyrimidino-5-yl}methylcarbamate.
10. The compound of claim 9 characterized by a X-Ray powder diffractogram comprising peak maxima of the 2 Theta angle of 8.3, 8.4, 13.7, 13.9, 15.7, 17.2, 18.4, 19.6, 21.4, 24.9.
11. The compound of claim 1 which is the 1/4-ethyl acetate solvate of methyl {4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridino-3-yl]pyrimidino-5-yl} methylcarbamate.
12. The compound of claim 10 characterized by a X-Ray powder diffractogram comprising peak maxima of the 2 Theta angle of 6.7, 8.3, 8.7, 12.9, 14.2, 17.8, 19.3, 24.0, 25.1, 26.7.
13. The compound of claim 1 which is methyl {4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridino-3-yl]pyrimidino-5-yl}methylcarbamate in the amorphous form.
Priority Applications (29)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA2807859A CA2807859A1 (en) | 2013-02-21 | 2013-02-21 | Forms of methyl {4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridino-3-yl]pyrimidino-5-yl}methyl carbamate |
| BR112015019571A BR112015019571A2 (en) | 2013-02-21 | 2014-02-18 | methyl {4,6-diamino-2- [1- (2-fluorobenzyl) -1h-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl} methylcarbamate forms |
| EA201500852A EA201500852A1 (en) | 2013-02-21 | 2014-02-18 | The forms of methyl {4,6-diamine-2- [1- (2-fluoro-benzyl) -1H-pyrazolo [3,4-b] pyridine-3-il] pyrimidino-5-il} methyl methyl carbamide |
| US14/769,334 US20150376184A1 (en) | 2013-02-21 | 2014-02-18 | Forms of methyl methyl carbamate |
| PCT/EP2014/053096 WO2014128109A1 (en) | 2013-02-21 | 2014-02-18 | Forms of methyl {4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridino-3-yl]pyrimidino-5-yl}methyl carbamate |
| AP2015008670A AP2015008670A0 (en) | 2013-02-21 | 2014-02-18 | Forms of methyl {4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-B]pyridino-3-yl]pyrimidino-5-yl} methyl carbamate |
| KR1020157022555A KR20150119871A (en) | 2013-02-21 | 2014-02-18 | Forms of methyl {4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridino-3-yl]pyrimidino-5-yl}methyl carbamate |
| EP20185169.8A EP3760629A1 (en) | 2013-02-21 | 2014-02-18 | Forms of methyl {4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridino-3-yl]pyrimidino-5-yl}methyl carbamate |
| PE2015001788A PE20151590A1 (en) | 2013-02-21 | 2014-02-18 | FORMS OF METHYL {4,6-DIAMINE-2- [1- (2-FLUOROBENZYL) -1H-PYRAZOLO [3,4-B] PYRIDINE-3-IL] PYRIMIDINE-5-IL} METHYL CARBAMATE |
| CA2901636A CA2901636A1 (en) | 2013-02-21 | 2014-02-18 | Forms of methyl {4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridino-3-yl]pyrimidino-5-yl}methyl carbamate |
| EP14705337.5A EP2958914B1 (en) | 2013-02-21 | 2014-02-18 | Forms of methyl {4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridino-3-yl]pyrimidino-5-yl}methyl carbamate |
| AU2014220801A AU2014220801A1 (en) | 2013-02-21 | 2014-02-18 | Forms of methyl {4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridino-3-yl]pyrimidino-5-yl}methyl carbamate |
| MX2015010725A MX2015010725A (en) | 2013-02-21 | 2014-02-18 | Forms of methyl {4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3, 4-b]pyridino-3-yl]pyrimidino-5-yl}methyl carbamate. |
| SG11201506211RA SG11201506211RA (en) | 2013-02-21 | 2014-02-18 | Forms of methyl {4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridino-3-yl]pyrimidino-5-yl}methyl carbamate |
| JP2015558419A JP6386478B2 (en) | 2013-02-21 | 2014-02-18 | Form of methyl {4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-B] pyridino-3-yl] pyrimidino-5-yl} methylcarbamate |
| CN201480009667.6A CN105102457A (en) | 2013-02-21 | 2014-02-18 | Forms of methyl {4, 6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3, 4-b]pyridino-3-yl]pyrimidino-5-yl}methyl carbamate |
| IL240397A IL240397A0 (en) | 2013-02-21 | 2015-08-06 | Forms of methyl {4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridino-3-yl]pyrimidino-5-yl}methyl carbamate |
| NI201500110A NI201500110A (en) | 2013-02-21 | 2015-08-17 | FORMS OF METHYL {4,6-DIAMINE-2- [1- (2-FLUOROBENZYL) -1h-PIRAZOLO [4,3-B] PYRIDINE-3-IL] PYRIMIDINE-5-IL} METHYL CARBAMATE |
| CL2015002304A CL2015002304A1 (en) | 2013-02-21 | 2015-08-17 | Forms of methyl {4,6-diamino-2- [1- (2-fluorobenzyl) -1h-pyrazolo [3,4-b] pyridino-3-yl] pyrimidino-5-yl} methyl carbamate |
| DO2015000199A DOP2015000199A (en) | 2013-02-21 | 2015-08-18 | FORMS OF THE METHYL {4,6-DIAMINO-2- [1- (2-FLUOROBENCIL) -1H-PIRAZOLO [3,4-B] PIRIDINO-3-IL] PIRIMIDINO-5-IL} METHYL CARBAMATE |
| CR20150422A CR20150422A (en) | 2013-02-21 | 2015-08-18 | METHOD FORMS {4,6-DIAMINO-2- [1- (2-FLUOROBENCIL) -1H-PIRAZOLO [3,4-B] PIRIDINO -3-IL] PIRIMIDINO-5-IL} CARBAMATO DE METTILO |
| PH12015501839A PH12015501839A1 (en) | 2013-02-21 | 2015-08-20 | Forms of methyl {4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridino-3-yl]pyrimidino-5-yl}methyl carbamate |
| CUP2015000092A CU20150092A7 (en) | 2013-02-21 | 2015-08-20 | FORMS OF THE METHYL {4,6-DIAMINO-2- [1- (2-FLUOROBENCIL) -1H-PIRAZOLO [3,4-B] PIRIDINO-3-IL] PIRIMIDINO-5-IL} METHYL CARBAMATE |
| TN2015000361A TN2015000361A1 (en) | 2013-02-21 | 2015-08-21 | Forms of methyl {4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridino-3-yl]pyrimidino-5-yl}methyl carbamate |
| HK16105474.6A HK1217488A1 (en) | 2013-02-21 | 2016-05-13 | Forms of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3,4- b]pyridino-3-yl]pyrimidino-5-ylmethyl carbamate 4,6--2-[1-(2-)-1h-[3,4-b]-3-]-5- |
| US15/672,921 US10087183B2 (en) | 2013-02-21 | 2017-08-09 | Forms of methyl {4,6-diamino-2-[1 (2-fluorobenzyl)-1h-pyrazolo[3-4-b]pyridino-3-yl]pyrimidino-5-yl}methyl carbamate |
| US16/119,671 US10662188B2 (en) | 2013-02-21 | 2018-08-31 | Forms of methyl {4,6-diamino-2-[1 (2-fluorobenzyl)-1H-pyrazolo[3-4-b]pyridino-3-yl]pyrimidino-5-yl} methyl carbamate |
| US16/848,249 US11203593B2 (en) | 2013-02-21 | 2020-04-14 | Forms of methyl {4,6-diamino-2-[1(2-fluorobenzyl)-1H-pyrazolo[3-4-b]pyridino-3-yl]pyrimidino-5-yl}methyl carbamate |
| US17/526,129 US20220073515A1 (en) | 2013-02-21 | 2021-11-15 | Forms of methyl {4,6-diamino-2-[1 (2-fluorobenzyl)-1h-pyrazolo[3-4-b]pyridino-3-yl]pyrimidino-5-yl}methyl carbamate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA2807859A CA2807859A1 (en) | 2013-02-21 | 2013-02-21 | Forms of methyl {4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridino-3-yl]pyrimidino-5-yl}methyl carbamate |
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| CA2807859A1 true CA2807859A1 (en) | 2014-08-21 |
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| CA2807859A Pending CA2807859A1 (en) | 2013-02-21 | 2013-02-21 | Forms of methyl {4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridino-3-yl]pyrimidino-5-yl}methyl carbamate |
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| Country | Link |
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| CA (1) | CA2807859A1 (en) |
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