NZ629885B - Solid forms of 2-(tert-butylamino)-4-((1r,3r,4r)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide, compositions thereof and methods of their use - Google Patents
Solid forms of 2-(tert-butylamino)-4-((1r,3r,4r)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide, compositions thereof and methods of their useInfo
- Publication number
- NZ629885B NZ629885B NZ629885A NZ62988514A NZ629885B NZ 629885 B NZ629885 B NZ 629885B NZ 629885 A NZ629885 A NZ 629885A NZ 62988514 A NZ62988514 A NZ 62988514A NZ 629885 B NZ629885 B NZ 629885B
- Authority
- NZ
- New Zealand
- Prior art keywords
- crystal form
- approximately
- compound
- ray powder
- powder diffraction
- Prior art date
Links
- 239000007787 solid Substances 0.000 title claims description 234
- 239000000203 mixture Substances 0.000 title claims description 64
- QBBRJRLJWXRSHQ-CKYFFXLPSA-N 2-(tert-butylamino)-4-[[(1R,3R,4R)-3-hydroxy-4-methylcyclohexyl]amino]pyrimidine-5-carboxamide Chemical compound C1[C@@H](O)[C@H](C)CC[C@H]1NC1=NC(NC(C)(C)C)=NC=C1C(N)=O QBBRJRLJWXRSHQ-CKYFFXLPSA-N 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 259
- 201000010099 disease Diseases 0.000 claims abstract description 51
- 210000004185 Liver Anatomy 0.000 claims abstract description 20
- 230000003176 fibrotic Effects 0.000 claims abstract description 14
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 14
- 206010025135 Lupus erythematosus Diseases 0.000 claims abstract description 10
- 206010012601 Diabetes mellitus Diseases 0.000 claims abstract description 8
- 208000001145 Metabolic Syndrome Diseases 0.000 claims abstract description 7
- 206010052779 Transplant rejections Diseases 0.000 claims abstract description 7
- 206010063209 Chronic allograft nephropathy Diseases 0.000 claims abstract description 6
- 208000006897 Interstitial Lung Disease Diseases 0.000 claims abstract description 6
- 206010039710 Scleroderma Diseases 0.000 claims abstract description 6
- 206010042953 Systemic sclerosis Diseases 0.000 claims abstract description 6
- 201000009594 systemic scleroderma Diseases 0.000 claims abstract description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 111
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 106
- -1 chloro, iodo Chemical group 0.000 claims description 105
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 86
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 75
- 239000002904 solvent Substances 0.000 claims description 69
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 61
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 57
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 57
- 238000010928 TGA analysis Methods 0.000 claims description 51
- 238000002411 thermogravimetry Methods 0.000 claims description 51
- 238000001757 thermogravimetry curve Methods 0.000 claims description 51
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 43
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 42
- 125000000217 alkyl group Chemical group 0.000 claims description 37
- LRHPLDYGYMQRHN-UHFFFAOYSA-N n-butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 34
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 34
- 235000019439 ethyl acetate Nutrition 0.000 claims description 28
- 125000000623 heterocyclic group Chemical group 0.000 claims description 23
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 21
- 238000001816 cooling Methods 0.000 claims description 20
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 18
- 125000001424 substituent group Chemical group 0.000 claims description 18
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 17
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 17
- 108091000081 Phosphotransferases Proteins 0.000 claims description 16
- 125000002950 monocyclic group Chemical group 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 12
- HXJUTPCZVOIRIF-UHFFFAOYSA-N Sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 125000003367 polycyclic group Chemical group 0.000 claims description 10
- QRXWMOHMRWLFEY-UHFFFAOYSA-N Isoniazid Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 claims description 9
- 125000004442 acylamino group Chemical group 0.000 claims description 9
- 150000001299 aldehydes Chemical class 0.000 claims description 9
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000005262 alkoxyamine group Chemical group 0.000 claims description 9
- 150000001409 amidines Chemical class 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 150000002081 enamines Chemical class 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 9
- JOYRKODLDBILNP-UHFFFAOYSA-N ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims description 9
- ZRALSGWEFCBTJO-UHFFFAOYSA-N guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 9
- AVXURJPOCDRRFD-UHFFFAOYSA-N hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 9
- 150000003949 imides Chemical class 0.000 claims description 9
- 150000002466 imines Chemical class 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 9
- 150000002576 ketones Chemical class 0.000 claims description 9
- 150000002923 oximes Chemical class 0.000 claims description 9
- 230000037361 pathway Effects 0.000 claims description 9
- XYFCBTPGUUZFHI-UHFFFAOYSA-N phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 9
- NJRWNWYFPOFDFN-UHFFFAOYSA-L phosphonate(2-) Chemical compound [O-][P]([O-])=O NJRWNWYFPOFDFN-UHFFFAOYSA-L 0.000 claims description 9
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 9
- 150000003457 sulfones Chemical class 0.000 claims description 9
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 claims description 9
- 150000003568 thioethers Chemical class 0.000 claims description 9
- 150000001204 N-oxides Chemical class 0.000 claims description 8
- FDDDEECHVMSUSB-UHFFFAOYSA-N Sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 claims description 8
- IQPQWNKOIGAROB-UHFFFAOYSA-N [N-]=C=O Chemical compound [N-]=C=O IQPQWNKOIGAROB-UHFFFAOYSA-N 0.000 claims description 8
- ZBKFYXZXZJPWNQ-UHFFFAOYSA-N [N-]=C=S Chemical compound [N-]=C=S ZBKFYXZXZJPWNQ-UHFFFAOYSA-N 0.000 claims description 8
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide Chemical compound [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 claims description 8
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 8
- 239000004202 carbamide Substances 0.000 claims description 8
- YSWRZALBDSJANW-UHFFFAOYSA-L cyanate;thiocyanate Chemical compound [O-]C#N.[S-]C#N YSWRZALBDSJANW-UHFFFAOYSA-L 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- ZHXTWWCDMUWMDI-UHFFFAOYSA-N dihydroxyboron Chemical compound O[B]O ZHXTWWCDMUWMDI-UHFFFAOYSA-N 0.000 claims description 8
- 150000007857 hydrazones Chemical class 0.000 claims description 8
- 125000002883 imidazolyl group Chemical group 0.000 claims description 8
- 125000002757 morpholinyl group Chemical group 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 8
- 229960001663 sulfanilamide Drugs 0.000 claims description 8
- 150000003573 thiols Chemical class 0.000 claims description 8
- ASZLNPRMVCGYCI-UHFFFAOYSA-N 1$l^{2}-azolidine Chemical group C1CC[N]C1 ASZLNPRMVCGYCI-UHFFFAOYSA-N 0.000 claims description 7
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 7
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 7
- 125000001246 bromo group Chemical group Br* 0.000 claims description 7
- 125000001153 fluoro group Chemical group F* 0.000 claims description 7
- 125000002541 furyl group Chemical group 0.000 claims description 7
- 125000001041 indolyl group Chemical group 0.000 claims description 7
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 7
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 7
- 125000001624 naphthyl group Chemical group 0.000 claims description 7
- 125000002971 oxazolyl group Chemical group 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 125000004193 piperazinyl group Chemical group 0.000 claims description 7
- 125000005936 piperidyl group Chemical group 0.000 claims description 7
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 7
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 7
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 7
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 7
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 7
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 7
- 125000000335 thiazolyl group Chemical group 0.000 claims description 7
- 125000001544 thienyl group Chemical group 0.000 claims description 7
- 125000001425 triazolyl group Chemical group 0.000 claims description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- 150000003973 alkyl amines Chemical class 0.000 claims description 6
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
- 239000011521 glass Substances 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 6
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 5
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 5
- 125000004104 aryloxy group Chemical group 0.000 claims description 5
- 125000005844 heterocyclyloxy group Chemical group 0.000 claims description 5
- 125000004305 thiazinyl group Chemical group S1NC(=CC=C1)* 0.000 claims description 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- YBRBMKDOPFTVDT-UHFFFAOYSA-N Tert-Butylamine Chemical group CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims description 3
- JIAARYAFYJHUJI-UHFFFAOYSA-L Zinc chloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- 101700082297 nhr-2 Proteins 0.000 claims 6
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 4
- 125000005418 aryl aryl group Chemical group 0.000 claims 4
- 102000030951 Phosphotransferases Human genes 0.000 claims 3
- 239000002841 Lewis acid Substances 0.000 claims 2
- SECXISVLQFMRJM-UHFFFAOYSA-N NMP Substances CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims 2
- 150000007517 lewis acids Chemical class 0.000 claims 2
- 239000003960 organic solvent Substances 0.000 claims 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 2
- UKXXPXZWRSUDBA-UHFFFAOYSA-N ClC1(NC=CC(=N1)Cl)C(=O)N Chemical compound ClC1(NC=CC(=N1)Cl)C(=O)N UKXXPXZWRSUDBA-UHFFFAOYSA-N 0.000 claims 1
- 108010087301 Mitogen-Activated Protein Kinase 8 Proteins 0.000 claims 1
- 108010087313 Mitogen-Activated Protein Kinase 9 Proteins 0.000 claims 1
- 238000010899 nucleation Methods 0.000 claims 1
- 239000001184 potassium carbonate Substances 0.000 claims 1
- 229910000027 potassium carbonate Inorganic materials 0.000 claims 1
- 239000001187 sodium carbonate Substances 0.000 claims 1
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- 238000001938 differential scanning calorimetry curve Methods 0.000 description 38
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 20
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L MgCl2 Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 20
- 238000005481 NMR spectroscopy Methods 0.000 description 18
- 102000001253 Protein Kinases Human genes 0.000 description 18
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- 238000004458 analytical method Methods 0.000 description 16
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- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 13
- 238000000034 method Methods 0.000 description 12
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- BZLVMXJERCGZMT-UHFFFAOYSA-N MeOtBu Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- 230000036231 pharmacokinetics Effects 0.000 description 11
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- 229910001629 magnesium chloride Inorganic materials 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
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- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 8
- ZKHQWZAMYRWXGA-KQYNXXCUSA-N Adenosine triphosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-N 0.000 description 8
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- KCXVZYZYPLLWCC-UHFFFAOYSA-N edta Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 8
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- 239000010414 supernatant solution Substances 0.000 description 1
- 238000004441 surface measurement Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000037141 t1/2,z Effects 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005944 tetrahydroimidazopyridyl group Chemical group 0.000 description 1
- 125000005888 tetrahydroindolyl group Chemical group 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M thiocyanate group Chemical group [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- 230000000699 topical Effects 0.000 description 1
- 102000003995 transcription factors Human genes 0.000 description 1
- 108090000464 transcription factors Proteins 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 235000013337 tricalcium citrate Nutrition 0.000 description 1
- 239000011778 trisodium citrate Substances 0.000 description 1
- 201000006704 ulcerative colitis Diseases 0.000 description 1
- 238000002562 urinalysis Methods 0.000 description 1
- 238000002460 vibrational spectroscopy Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000035513 volume of distribution Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 239000012130 whole-cell lysate Substances 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 238000003963 x-ray microscopy Methods 0.000 description 1
Classifications
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
Abstract
Provided are crystalline and amorphous forms of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide (formula 1). Further provided are intermediates useful in the preparation of the compounds. The compounds are JNK 1 and JNK2 inhibitors. The compounds may be useful in the treatment or prevention of interstitial pulmonary fibrosis, systemic sclerosis, scleroderma, chronic allograft nephropathy, antibody mediated rejection, lupus, liver fibrotic disorders, diabetes or metabolic syndromes leading to liver fibrotic disorders. useful in the treatment or prevention of interstitial pulmonary fibrosis, systemic sclerosis, scleroderma, chronic allograft nephropathy, antibody mediated rejection, lupus, liver fibrotic disorders, diabetes or metabolic syndromes leading to liver fibrotic disorders.
Description
SOLID FORMS OF 2-(TERT-BUTYLAMINO)((1R,3R,4R)HYDROXY
METHYLCYCLOHEXYLAMINO)-PYRIMIDINECARBOXAMIDE, COMPOSITIONS
THEREOF AND METHODS OF THEIR USE
We, Signal Pharmaceuticals, LLC, a company of the United States of America, of 10300
Campus Point Drive, Suite 100, San Diego, CA 92121, UNITED STATES OF AMERICA
do hereby declare the invention, for which we pray that a patent may be granted to us, and the
method by which it is to be performed, to be particularly described in and by the following
statement:-
SOLID FORMS OF 2-(TERT-BUTYLAMINO)((1R,3R,4R)HYDROXY
METHYLCYCLOHEXYLAMINO)-PYRIMIDINECARBOXAMIDE, COMPOSITIONS
THEREOF AND METHODS OF THEIR USE
FIELD
[0001] Provided herein are solid forms of 2-(tert-butylamino)((1R,3R,4R)hydroxy4-methylcyclohexylamino)-pyrimidinecarboxamide, compositions thereof, and methods of
their use for the treatment of a disease, disorder, or condition.
BACKGROUND
[0002] The identification and selection of a solid form of a pharmaceutical compound are
complex, given that a change in solid form may affect a variety of physical and chemical
properties, which may provide benefits or drawbacks in processing, formulation, stability,
bioavailability, storage, handling (e.g., shipping), among other important pharmaceutical
characteristics. Useful pharmaceutical solids include crystalline solids and amorphous solids,
depending on the product and its mode of administration. Amorphous solids are characterized
by a lack of long-range structural order, whereas crystalline solids are characterized by structural
periodicity. The desired class of pharmaceutical solid depends upon the specific application;
amorphous solids are sometimes selected on the basis of, e.g., an enhanced dissolution profile,
while crystalline solids may be desirable for properties such as, e.g., physical or chemical
stability (see, e.g., S. R. Vippagunta et al., Adv. Drug. Deliv. Rev., (2001) 48:3-26; L. Yu, Adv.
Drug. Deliv. Rev., (2001) 48:27-42).
[0003] Whether crystalline or amorphous, solid forms of a pharmaceutical compound
include single-component and multiple-component solids. Single-component solids consist
essentially of the pharmaceutical compound or active ingredient in the absence of other
compounds. Variety among single-component crystalline materials may potentially arise from
the phenomenon of polymorphism, wherein multiple three-dimensional arrangements exist for a
particular pharmaceutical compound (see, e.g., S. R. Byrn et al., Solid State Chemistry of Drugs,
(1999) SSCI, West Lafayette). The importance of discovering polymorphs was underscored by
the case of RitonavirTM, an HIV protease inhibitor that was formulated as soft gelatin capsules.
About two years after the product was launched, the unanticipated precipitation of a new, less
soluble polymorph in the formulation necessitated the withdrawal of the product from the market
until a more consistent formulation could be developed (see S. R. Chemburkar et al., Org.
Process Res. Dev., (2000) 4:413-417).
[0004] Notably, it is not possible to predict a priori if crystalline forms of a compound
even exist, let alone how to successfully prepare them (see, e.g., Braga and Grepioni, 2005,
“Making crystals from crystals: a green route to crystal engineering and polymorphism,” Chem.
Commun.:3635-3645 (with respect to crystal engineering, if instructions are not very precise
and/or if other external factors affect the process, the result can be unpredictable); Jones et al.,
2006, Pharmaceutical Cocrystals: An Emerging Approach to Physical Property Enhancement,”
MRS Bulletin 31:875-879 (At present it is not generally possible to computationally predict the
number of observable polymorphs of even the simplest molecules); Price, 2004, “The
computational prediction of pharmaceutical crystal structures and polymorphism,” Advanced
Drug Delivery Reviews 56:301-319 (“Price”); and Bernstein, 2004, “Crystal Structure Prediction
and Polymorphism,” ACA Transactions 39:14-23 (a great deal still needs to be learned and done
before one can state with any degree of confidence the ability to predict a crystal structure, much
less polymorphic forms)).
[0005] The compound chemically named 2-(tert-butylamino)((1R,3R,4R)hydroxy4-methylcyclohexylamino)-pyrimidinecarboxamide (alternatively named 2-[(1,1-
dimethylethyl)amino][[(1R,3R,4R)hydroxymethylcyclohexyl]amino]
pyrimidinecarboxamide) and tautomers thereof (collectively referred to herein as
“Compound 1”) are disclosed in U.S. Patent Application Publication No. 2013/0029987,
published on January 31, 2013, and International Pub. No. WO2012/145569, the entireties of
each of which are incorporated by reference herein.
[0006] The variety of possible solid forms creates potential diversity in physical and
chemical properties for a given pharmaceutical compound. The discovery and selection of solid
forms are of great importance in the development of an effective, stable and marketable
pharmaceutical product.
[0007] The connection between abnormal protein phosphorylation and the cause or
consequence of diseases has been known for over 20 years. Accordingly, protein kinases have
become a very important group of drug targets. (See Cohen, Nature, 1:309-315 (2002),
Gaestel et al. Curr.Med.Chem.14: 2214-223 (2007); Grimminger et al. Nat. Rev. Drug Disc.
9(12):956-970 (2010)). Various protein kinase inhibitors have been used clinically in the
treatment of a wide variety of diseases, such as cancer and chronic inflammatory diseases,
including rheumatoid arthritis and psoriasis. (See Cohen, Eur. J. Biochem., 268:5001-5010
(2001); Protein Kinase Inhibitors for the Treatment of Disease: The Promise and the Problems,
Handbook of Experimental Pharmacology, Springer Berlin Heidelberg, 167 (2005)).
[0008] JNK is a ubiquitously expressed serine/threonine kinase belonging, together with
ERK (extracellular-regulated kinase) and p38, to the family of mitogen-activated protein kinases
(MAPKs). (Kyriakis JM, Sci. STKE (48):pe1 (2000); Whitmarsh AJ, et al. Sci. STKE (1):pe1
(1999); Schramek H, News Physiol. Sci.17:62-7 (2002); Ichijo H, Oncogene 18(45):6087-93
(1999)). MAPKs are important mediators of signal transduction from the cell surface to the
nucleus, using phosphorylation cascades to generate a coordinated response by a cell to an
external stimulus by phosphorylation of selected intracellular proteins, including transcription
factors. Additionally, JNK also phosphorylates non-nuclear proteins, for example, IRS-1, and
Bcl-2 family members. (Davis RJ, Trends Biochem. Sci. 9(11):470-473 (1994); Seger R et al.,
FASEB J.; 9(9):726-35 (1995); Fanger GR et al., Curr. Opin. Genet. Dev.; 7(1):67-74 (1997)).
[0009] The elucidation of the intricacy of protein kinase pathways and the complexity of
the relationship and interaction among and between the various protein kinases and kinase
pathways highlights the importance of developing pharmaceutical agents capable of acting as
protein kinase modulators, regulators or inhibitors that have beneficial activity on multiple
kinases or multiple kinase pathways. Accordingly, there remains a need for new kinase
modulators, for example, JNK modulators, and in particular solid forms of those kinase
modulators.
[0010] Citation or identification of any reference in Section 2 of this application is not to
be construed as an admission that the reference is prior art to the present application.
[0018] FIG. 4 depicts a thermogravimetrical analysis (TGA) thermogram of Form A.
[0019] FIG. 5 depicts a differential scanning calorimetry (DSC) thermogram of Form A.
[0020] FIG. 6 depicts a dynamic vapor sorption (DVS) isotherm plot of Form A.
[0021] FIG. 7 depicts a 1
H nuclear magnetic resonance (NMR) spectrum of Form A.
[0022] FIG. 8 depicts an overlay of XRPD patterns of Form A before and after DVS (top
and bottom).
[0023] FIG. 9 depicts an XRPD pattern of Form A after compression of 2000-psi for
1 minute.
[0024] FIG. 10 depicts an XRPD pattern of Form B.
[0025] FIG. 11 depicts a TGA thermogram of Form B.
[0026] FIG. 12 depicts a DSC thermogram of Form B.
[0027] FIG. 13 depicts a 1
H NMR spectrum of Form B.
[0028] FIG. 14 depicts an XRPD pattern of Form C.
[0029] FIG. 15 depicts a TGA thermogram of Form C.
[0030] FIG. 16 depicts a DSC thermogram of Form C.
[0031] FIG. 17 depicts a 1
H NMR spectrum of Form C.
[0032] FIG. 18 depicts an XRPD pattern of Form D.
[0033] FIG. 19 depicts a TGA thermogram of Form D.
[0034] FIG. 20 depicts a DSC thermogram of Form D.
[0035] FIG. 21 depicts a 1
H NMR spectrum of Form D.
[0036] FIG. 22 depicts an XRPD pattern of Form E.
[0037] FIG. 23 depicts a TGA thermogram of Form E.
[0038] FIG. 24 depicts a DSC thermogram of Form E.
[0039] FIG. 25 depicts a 1
H NMR spectrum of Form E.
[0040] FIG. 26 depicts an XRPD pattern of Form F.
[0041] FIG. 27 depicts a TGA thermogram of Form F.
[0042] FIG. 28 depicts a DSC thermogram of Form F.
[0043] FIG. 29 depicts a 1
H NMR spectrum of Form F.
[0044] FIG. 30 depicts an XRPD pattern of Form G.
[0045] FIG. 31 depicts a TGA thermogram of Form G.
[0046] FIG. 32 depicts a DSC thermogram of Form G.
[0047] FIG. 33 depicts a 1
H NMR spectrum of Form G.
[0048] FIG. 34 depicts an XRPD pattern of Form H.
[0049] FIG. 35 depicts a TGA thermogram of Form H.
[0050] FIG. 36 depicts a DSC thermogram of Form H.
[0051] FIG. 37 depicts an overlay of XRPD patterns of Form A, Form B, Form C,
Form D, Form E, Form F, Form G and Form H.
[0052] FIG. 38 depicts an XRPD pattern of Form I.
[0053] FIG. 39 depicts a DSC thermogram of Form I.
[0054] FIG. 40 depicts a 1
H NMR spectrum of Form I.
[0055] FIG. 41 depicts an XRPD pattern of the amorphous solid.
[0056] FIG. 42 depicts a DSC thermogram of the amorphous solid.
[0057] FIG. 43 depicts a 1
H NMR spectrum of the amorphous solid.
[0058] FIG. 44 depicts a Liquid Chromatography with Mass Spectroscopy of the
amorphous solid.
[0059] FIG. 45 depicts a form map of Forms A and H of Compound 1 in %water in
DMSO vs temperature.
DETAILED DESCRIPTION
DEFINITIONS
[0060] As used herein, and in the specification and the accompanying claims, the
indefinite articles “a” and “an” and the definite article “the” include plural as well as single
referents, unless the context clearly indicates otherwise.
[0061] As used herein, and unless otherwise specified, the terms “about” and
“approximately,” when used in connection with doses, amounts, or weight percents of
ingredients of a composition or a dosage form, mean a dose, amount, or weight percent that is
recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to
that obtained from the specified dose, amount, or weight percent. In certain embodiments, the
terms “about” and “approximately,” when used in this context, contemplate a dose, amount, or
weight percent within 30%, within 20%, within 15%, within 10%, or within 5%, of the specified
dose, amount, or weight percent.
[0062] As used herein, and unless otherwise specified, the terms “about” and
“approximately,” when used in connection with a numeric value or range of values which is
provided to characterize a particular solid form, e.g., a specific temperature or temperature range,
such as, for example, that describes a melting, dehydration, desolvation, or glass transition
temperature; a mass change, such as, for example, a mass change as a function of temperature or
humidity; a solvent or water content, in terms of, for example, mass or a percentage; or a peak
position, such as, for example, in analysis by, for example, IR or Raman spectroscopy or XRPD;
indicate that the value or range of values may deviate to an extent deemed reasonable to one of
ordinary skill in the art while still describing the solid form. Techniques for characterizing
crystal forms and amorphous solids include, but are not limited to, thermal gravimetric analysis
(TGA), differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD),
single-crystal X-ray diffractometry, vibrational spectroscopy, e.g., infrared (IR) and Raman
spectroscopy, solid-state and solution nuclear magnetic resonance (NMR) spectroscopy, optical
microscopy, hot stage optical microscopy, scanning electron microscopy (SEM), electron
crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis,
solubility studies, and dissolution studies. In certain embodiments, the terms “about” and
“approximately,” when used in this context, indicate that the numeric value or range of values
may vary within 30%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or
0.25% of the recited value or range of values. For example, in some embodiments, the value of
an XRPD peak position may vary by up to ±0.2º 2θ (or ±0.2 degree 2θ) while still describing the
particular XRPD peak.
[0063] As used herein, and unless otherwise specified, a crystalline that is “pure,” i.e.,
substantially free of other crystalline or amorphous solids, contains less than about 10% by
weight of one or more other crystalline or amorphous solids, less than about 5% by weight of one
or more other crystalline or amorphous solids, less than about 3% by weight of one or more other
crystalline or amorphous solids, or less than about 1% by weight of one or more other crystalline
or amorphous solids.
[0064] As used herein, and unless otherwise specified, a solid form that is “substantially
physically pure” is substantially free from other solid forms. In certain embodiments, a crystal
form that is substantially physically pure contains less than about 10%, 9%, 8%, 7%, 6%, 5%,
4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.01% of one or more other solid
forms on a weight basis. The detection of other solid forms can be accomplished by any method
apparent to a person of ordinary skill in the art, including, but not limited to, diffraction analysis,
thermal analysis, elemental combustion analysis and/or spectroscopic analysis.
[0065] As used herein, and unless otherwise specified, a solid form that is “substantially
chemically pure” is substantially free from other chemical compounds (i.e., chemical impurities).
In certain embodiments, a solid form that is substantially chemically pure contains less than
about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or
0.01% of one or more other chemical compounds on a weight basis. The detection of other
chemical compounds can be accomplished by any method apparent to a person of ordinary skill
in the art, including, but not limited to, methods of chemical analysis, such as, e.g., mass
spectrometry analysis, spectroscopic analysis, thermal analysis, elemental combustion analysis
and/or chromatographic analysis.
[0066] As used herein, and unless otherwise indicated, a chemical compound, solid form,
or composition that is “substantially free” of another chemical compound, solid form, or
composition means that the compound, solid form, or composition contains, in certain
embodiments, less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%,
0.2% 0.1%, 0.05%, or 0.01% by weight of the other compound, solid form, or composition.
[0067] Unless otherwise specified, the terms “solvate” and “solvated,” as used herein,
refer to a solid form of a substance which contains solvent. The terms “hydrate” and “hydrated”
refer to a solvate wherein the solvent is water. “Polymorphs of solvates” refer to the existence of
more than one solid form for a particular solvate composition. Similarly, “polymorphs of
hydrates” refer to the existence of more than one solid form for a particular hydrate composition.
The term “desolvated solvate,” as used herein, refers to a solid form of a substance which can be
made by removing the solvent from a solvate. The terms “solvate” and “solvated,” as used
herein, can also refer to a solvate of a salt, cocrystal, or molecular complex. The terms “hydrate”
and “hydrated,” as used herein, can also refer to a hydrate of a salt, cocrystal, or molecular
complex.
[0068] An “alkyl” group is a saturated, partially saturated, or unsaturated straight chain
or branced non-cyclic hydrocarbon having from 1 to 10 carbon atoms, typically from 1 to 8
carbons or, in some embodiments, from 1 to 6, 1 to 4, or 2 to 6 or 2 to 4 carbon atoms.
Representative alkyl groups include –methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl;
while saturated branched alkyls include –isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl,
-neopentyl, -tert-pentyl, methylphenyl, methylphenyl, methylphenyl, -2,3-dimethylbutyl
and the like. Examples of unsaturated alkly groups include, but are not limited to, vinyl, allyl,
-CH=CH(CH3), -CH=C(CH3)2, - C(CH3)=CH2, - C(CH3)=CH(CH3), -C(CH2CH3)=CH2, -C≡CH,
-C≡C(CH3), -C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3) and -CH2C≡C(CH2CH3), among
others. An alkyl group can be substituted or unsubstituted. When the alkyl groups described
herein are said to be “substituted,” they may be substituted with any substituent or substituents as
those found in the exemplary compounds and embodiments disclosed herein, as well as halogen
(chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino;
carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine;
aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone;
sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxyl amine; alkoxyamine;
aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate;
cyanate; thiocyanate; B(OH)2, or O(alkyl)aminocarbonyl.
[0069] A “cycloalkyl” group is a saturated, or partially saturated cyclic alkyl group of
from 3 to 10 carbon atoms having a single cyclic ring or multiple condensed or bridged rings
which can be optionally substituted with from 1 to 3 alkyl groups. In some embodiments, the
cycloalkyl group has 3 to 8 ring members, whereas in other embodiments the number of ring
carbon atoms ranges from 3 to 5, 3 to 6, or 3 to 7. Such cycloalkyl groups include, by way of
example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and the
like, or multiple or bridged ring structures such as 1-bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl,
bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl and the like. Examples of unsaturared
cycloalkyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl,
pentadienyl, hexadienyl, among others. A cycloalkyl group can be substituted or unsubstituted.
Such substituted cycloalkyl groups include, by way of example, cyclohexanol and the like.
[0070] An “aryl” group is an aromatic carbocyclic group of from 6 to 14 carbon atoms
having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). In
some embodiments, aryl groups contain 6-14 carbons, and in others from 6 to 12 or even 6 to
carbon atoms in the ring portions of the groups. Particular aryls include phenyl, biphenyl,
naphthyl and the like. An aryl group can be substituted or unsubstituted. The phrase “aryl
groups” also includes groups containing fused rings, such as fused aromatic-aliphatic ring
systems (e.g., indanyl, tetrahydronaphthyl, and the like).
[0071] A “heteroaryl” group is an aryl ring system having one to four heteroatoms as ring
atoms in a heteroaromatic ring system, wherein the remainder of the atoms are carbon atoms. In
some embodiments, heteroaryl groups contain 3 to 6 ring atoms, and in others from 6 to 9 or
even 6 to 10 atoms in the ring portions of the groups. Suitable heteroatoms include oxygen,
sulfur and nitrogen. In certain embodiments, the heteroaryl ring system is monocyclic or
bicyclic. Non-limiting examples include but are not limited to, groups such as pyrrolyl,
pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl
(e.g., benzo[d]isoxazolyl), thiazolyl, pyrolyl, pyridazinyl, pyrimidyl, pyrazinyl, thiophenyl,
benzothiophenyl, furanyl, benzofuranyl, indolyl (e.g., indolylonyl or isoindolinonyl),
azaindolyl (pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl), indazolyl, benzimidazolyl
(e.g., 1H-benzo[d]imidazolyl), imidazopyridyl (e.g., azabenzimidazolyl or 1H-imidazo[4,5-
b]pyridyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl),
benzoxazolyl (e.g., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, isoxazolopyridyl,
thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl
(e.g., 3,4-dihydroisoquinolin-1(2H)-onyl), tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl
groups.
[0072] A “heterocyclyl” is an aromatic (also referred to as heteroaryl) or non-aromatic
cycloalkyl in which one to four of the ring carbon atoms are independently replaced with a
heteroatom from the group consisting of O, S and N. In some embodiments, heterocyclyl groups
include 3 to10 ring members, whereas other such groups have 3 to 5, 3 to 6, or 3 to 8 ring
members. Heterocyclyls can also be bonded to other groups at any ring atom (i.e., at any carbon
atom or heteroatom of the heterocyclic ring). A heterocycloalkyl group can be substituted or
unsubstituted. Heterocyclyl groups encompass unsaturated, partially saturated and saturated ring
systems, such as, for example, imidazolyl, imidazolinyl and imidazolidinyl (e.g., imidazolidin
one or imidazolidin-2,4-dionyl) groups. The phrase heterocyclyl includes fused ring species,
including those comprising fused aromatic and non-aromatic groups, such as, for example, 1-and
2-aminotetraline, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl
(e.g., 1H-benzo[d]imidazolyl), 2,3-dihydrobenzo[l,4]dioxinyl, and benzo[l,3]dioxolyl. The
phrase also includes bridged polycyclic ring systems containing a heteroatom such as, but not
limited to, quinuclidyl. Representative examples of a heterocyclyl group include, but are not
limited to, aziridinyl, azetidinyl, azepanyl, oxetanyl, pyrrolidyl, imidazolidinyl
(e.g., imidazolidinonyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl,
tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl,
imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,
benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl,
oxadiazolyl, piperidyl, piperazinyl (e.g., piperazinonyl), morpholinyl, thiomorpholinyl,
tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dioxyl,
dithianyl, pyranyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl,
dihydrodithiinyl, dihydrodithionyl, 1,4-dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidyl,
indolyl (e.g., indolylonyl or isoindolinonyl), indolinyl, isoindolyl, isoindolinyl, azaindolyl
(pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl), indazolyl, indolizinyl, benzotriazolyl
(e.g. 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (e.g., 1H-benzo[d]imidazolyl or
1H-benzo[d]imidazol-2(3H)-onyl), benzofuranyl, benzothiophenyl, benzothiazolyl,
benzoxadiazolyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl, benzothiazinyl, benzoxazolyl
(i.e., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, benzo[l,3]dioxolyl, pyrazolopyridyl
(for example, 1H-pyrazolo[3,4-b]pyridyl, 1H-pyrazolo[4,3-b]pyridyl), imidazopyridyl
(e.g., azabenzimidazolyl or 1H-imidazo[4,5-b]pyridyl), triazolopyridyl, isoxazolopyridyl,
purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl (e.g., 3,4-dihydroisoquinolin1(2H)-onyl), quinolizinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl,
pteridinyl, thianaphthalenyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl,
dihydrobenzodioxinyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl,
tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl,
tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, tetrahydropyrimidin-2(1H)-one and
tetrahydroquinolinyl groups. Representative non-aromatic heterocyclyl groups do not include
fused ring species that comprise a fused aromatic group. Examples of non-aromatic heterocyclyl
groups include aziridinyl, azetidinyl, azepanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin
onyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl,
tetrahydrofuranyl, piperidyl, piperazinyl (e.g., piperazinonyl), morpholinyl, thiomorpholinyl,
tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dithianyl,
1,4-dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidyl, or tetrahydropyrimidin-2(1H)-one.
Representative substituted heterocyclyl groups may be mono-substituted or substituted more than
once, such as, but not limited to, pyridyl or morpholinyl groups, which are 2-, 3-, 4-, 5-, or
6-substituted, or disubstituted with various substituents such as those listed below.
[0073] A “cycloalkylalkyl” group is a radical of the formula: -alkyl-cycloalkyl, wherein
alkyl and cycloalkyl are as defined above. Substituted cycloalkylalkyl groups may be substituted
at the alkyl, the cycloalkyl, or both the alkyl and the cycloalkyl portions of the group.
Representative cycloalkylalkyl groups include but are not limited to methylcyclopropyl,
methylcyclobutyl, methylcyclopentyl, methylcyclohexyl, ethylcyclopropyl, ethylcyclobutyl,
ethylcyclopentyl, ethylcyclohexyl, propylcyclopentyl, propylcyclohexyl and the like.
[0074] An “aralkyl” group is a radical of the formula: -alkyl-aryl, wherein alkyl and aryl
are defined above. Substituted aralkyl groups may be substituted at the alkyl, the aryl, or both
the alkyl and the aryl portions of the group. Representative aralkyl groups include but are not
limited to benzyl and phenethyl groups and fused (cycloalkylaryl)alkyl groups such as
4-ethyl-indanyl.
[0075] An “heterocyclylalkyl” group is a radical of the formula: -alkyl-heterocyclyl,
wherein alkyl and heterocyclyl are defined above. Substituted heterocyclylalkyl groups may be
substituted at the alkyl, the heterocyclyl, or both the alkyl and the heterocyclyl portions of the
group. Representative heterocylylalkyl groups include but are not limited to 4-ethylmorpholinyl, 4-propylmorpholinyl, furanyl methyl, furanyl methyl, pyridinyl methyl,
tetrahydrofuranyl ethyl, and indolyl propyl. When the groups described herein, with the
exception of alkyl group, are said to be “substituted,” they may be substituted with any
appropriate substituent or substituents. Illustrative examples of substituents are those found in
the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo,
bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amine; alkylamine; carboxy; nitro;
cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino;
phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester;
urea; urethane; oxime; hydroxyl amine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine;
hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (═O);
B(OH)2, O(alkyl)aminocarbonyl; cycloalkyl, which may be monocyclic or fused or non-fused
polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocyclyl, which
may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidyl, piperidyl, piperazinyl,
morpholinyl, or thiazinyl); monocyclic or fused or non-fused polycyclic aryl or heteroaryl
(e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl,
thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl,
pyridazinyl, pyrimidyl, benzimidazolyl, benzothiophenyl, or benzofuranyl) aryloxy; aralkyloxy;
heterocyclyloxy; and heterocyclyl alkoxy.
[0076] A “halogen” is chloro, iodo, bromo, or fluoro.
[0077] A “hydroxyalkyl” group is an alkyl group as described above substituted with one
or more hydroxy groups.
[0078] An “alkoxy” group is -O-(alkyl), wherein alkyl is defined above.
[0079] An “alkoxyalkyl” group is -(alkyl)-O-(alkyl), wherein alkyl is defined above.
[0080] An “amine” group is a radical of the formula: -NH2.
[0081] A “hydroxyl amine” group is a radical of the formula: -N(R#
)OH or -NHOH,
wherein R# is a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,
heterocyclyl or heterocyclylalkyl group as defined herein.
[0082] An “alkoxyamine” group is a radical of the formula: -N(R#
)O-alkyl or
-NHO-alkyl, wherein R# is as defined above.
[0083] An “aralkoxyamine” group is a radical of the formula: -N(R#
)O-aryl or
-NHO-aryl, wherein R# is as defined above.
[0084] An “alkylamine” group is a radical of the formula: -NH-alkyl or -N(alkyl)2,
wherein each alkyl is independently as defined above.
[0085] An “aminocarbonyl” group is a radical of the formula: -C(=O)N(R#
)2,
-C(=O)NH(R#
) or -C(=O)NH2, wherein each R#
is as defined above.
[0086] An “acylamino” group is a radical of the formula: -NHC(=O)(R#
) or -N(alkyl)C(=O)(R#
),
wherein each alkyl and R#
are independently as defined above.
[0087] An “O(alkyl)aminocarbonyl” group is a radical of the formula:
-O(alkyl)C(=O)N(R#
)2, -O(alkyl)C(=O)NH(R#
) or -O(alkyl)C(=O)NH2, wherein each R#
is
independently as defined above.
[0088] An “N-oxide” group is a radical of the formula: -N+
-O-
.
[0089] A “carboxy” group is a radical of the formula: -C(=O)OH.
[0090] A “ketone” group is a radical of the formula: -C(=O)(R#
), wherein R#
is as
defined above.
[0091] An “aldehyde” group is a radical of the formula: -CH(=O).
[0092] An “ester” group is a radical of the formula: -C(=O)O(R#
) or -OC(=O)(R#
),
wherein R#
is as defined above.
[0093] A “urea” group is a radical of the formula: -N(alkyl)C(=O)N(R#
)2,
N(alkyl)C(=O)NH(R#
), –N(alkyl)C(=O)NH2, -NHC(=O)N(R#
)2, -NHC(=O)NH(R#
), or
-NHC(=O)NH2
#
, wherein each alkyl and R#
are independently as defined above.
[0094] An ”imine” group is a radical of the formula: -N=C(R#
)2 or –C(R#
)=N(R#
),
wherein each R#
is independently as defined above.
[0095] An “imide” group is a radical of the formula: -C(=O)N(R#)C(=O)(R#
) or
-N((C=O)(R#
))2, wherein each R#
is independently as defined above.
[0096] A “urethane” group is a radical of the formula: -OC(=O)N(R#
)2, -OC(=O)NH(R#
),
-N(R#
)C(=O)O(R#
), or -NHC(=O)O(R#
), wherein each R#
is independently as defined above.
[0097] An “amidine” group is a radical of the formula: -C(=N(R#
))N(R#
)2,
-C(=N(R#
))NH(R#
), -C(=N(R#
))NH2, -C(=NH)N(R#
)2, -C(=NH)NH(R#
), -C(=NH)NH2,
-N=C(R#
)N(R#
)2, -N=C(R#
)NH(R#
), -N=C(R#
)NH2, -N(R#
)C(R#
)=N(R#
), -NHC(R#
)=N(R#
),
-N(R#
)C(R#
)=NH, or -NHC(R#
)=NH, wherein each R#
is independently as defined above.
[0098] A “guanidine” group is a radical of the formula: -N(R#
)C(=N(R#
))N(R#
)2,
-NHC(=N(R#
))N(R#
)2, -N(R#
)C(=NH)N(R#
)2, -N(R#
)C(=N(R#
))NH(R#
), -N(R#
)C(=N(R#
))NH2,
-NHC(=NH)N(R#
)2, -NHC(=N(R#
))NH(R#
), -NHC(=N(R#
))NH2, -NHC(=NH)NH(R#
),
-NHC(=NH)NH2, -N=C(N(R#
)2)2, -N=C(NH(R#
))2, or -N=C(NH2)2, wherein each R#
is
independently as defined above.
[0099] A “enamine” group is a radical of the formula: -N(R#
)C(R#
)=C(R#
)2,
-NHC(R#
)=C(R#
)2, -C(N(R#
)2)=C(R#
)2, -C(NH(R#
))=C(R#
)2, -C(NH2)=C(R#
)2,
-C(R#
)=C(R#
)(N(R#
)2), -C(R#
)=C(R#
)(NH(R#
)) or -C(R#
)=C(R#
)(NH2), wherein each R#
is
independently as defined above.
[00100] An “oxime” group is a radical of the formula: -C(=NO(R#
))(R#
), -C(=NOH)(R#
),
-CH(=NO(R#
)), or -CH(=NOH), wherein each R#
is independently as defined above.
[00101] A “hydrazide” group is a radical of the formula: -C(=O)N(R#
)N(R#
)2,
-C(=O)NHN(R#
)2, -C(=O)N(R#
)NH(R#
), -C(=O)N(R#
)NH2, -C(=O)NHNH(R#
)2, or
-C(=O)NHNH2, wherein each R#
is independently as defined above.
[00102] A “hydrazine” group is a radical of the formula: -N(R#
)N(R#
)2, -NHN(R#
)2,
-N(R#
)NH(R#
), -N(R#
)NH2, -NHNH(R#
)2, or -NHNH2, wherein each R# is independently as
defined above.
[00103] A “hydrazone” group is a radical of the formula: -C(=N-N(R#
)2)(R#
)2,
-C(=N-NH(R#
))(R#
)2, -C(=N-NH2)(R#
)2, -N(R#
)(N=C(R#
)2), or -NH(N=C(R#
)2), wherein each
R# is independently as defined above.
[00104] An “azide” group is a radical of the formula: -N3.
[00105] An “isocyanate” group is a radical of the formula: -N=C=O.
[00106] An “isothiocyanate” group is a radical of the formula: -N=C=S.
[00107] A “cyanate” group is a radical of the formula: -OCN.
[00108] A “thiocyanate” group is a radical of the formula: -SCN.
[00109] A “thioether” group is a radical of the formula; -S(R#
), wherein R# is as defined
above.
[00110] A “thiocarbonyl” group is a radical of the formula: -C(=S)(R#
), wherein R# is as
defined above.
[00111] A “sulfinyl” group is a radical of the formula: -S(=O)(R#
), wherein R# is as
defined above.
[00112] A “sulfone” group is a radical of the formula: -S(=O)2(R#
), wherein R# is as
defined above.
[00113] A “sulfonylamino” group is a radical of the formula: -NHSO2(R#
) or
-N(alkyl)SO2(R#
), wherein each alkyl and R# are defined above.
[00114] A “sulfonamide” group is a radical of the formula: -S(=O)2N(R#
)2, or
-S(=O)2NH(R#
), or -S(=O)2NH2, wherein each R# is independently as defined above.
[00115] A “phosphonate” group is a radical of the formula: -P(=O)(O(R#
))2,
-P(=O)(OH)2,-OP(=O)(O(R#
))(R#
), or -OP(=O)(OH)(R#
), wherein each R# is independently as
defined above.
[00116] A “phosphine” group is a radical of the formula: -P(R#
)2, wherein each R# is
independently as defined above.
[00117] “Tautomers” refers to isomeric forms of a compound that are in equilibrium with
each other. The concentrations of the isomeric forms will depend on the environment the
compound is found in and may be different depending upon, for example, whether the compound
is a solid or is in an organic or aqueous solution. For example, in aqueous solution, pyrazoles
may exhibit the following isomeric forms, which are referred to as tautomers of each other:
N
HN
H
N
N
.
[00118] As readily understood by one skilled in the art, a wide variety of functional
groups and other structures may exhibit tautomerism and all tautomers of Compound 1 are
within the scope of the present invention.
[00119] Unless otherwise specified, the term “composition” as used herein is intended to
encompass a product comprising the specified ingredient(s) (and in the specified amount(s), if
indicated), as well as any product which results, directly or indirectly, from combination of the
specified ingredient(s) in the specified amount(s). By “pharmaceutically acceptable,” it is meant
a diluent, excipient, or carrier in a formulation must be compatible with the other ingredient(s) of
the formulation and not deleterious to the recipient thereof.
[00120] The term “solid form” refers to a physical form which is not predominantly in a
liquid or a gaseous state. As used herein and unless otherwise specified, the term “solid form,”
when used herein to refer to Compound 1, refers to a physical form comprising Compound 1
which is not predominantly in a liquid or a gaseous state. A solid form may be a crystalline form
or a mixture thereof. In certain embodiments, a solid form may be a liquid crystal. In certain
embodiments, the term “solid forms comprising Compound 1” includes crystal forms comprising
Compound 1. In certain embodiments, the solid form of Compound 1 is Form A, Form B, Form
C, Form D, Form E, Form F, Form G, Form H, Form I, the amorphous solid, or a mixture
thereof.
[00121] As used herein and unless otherwise specified, the term “crystalline” when used
to describe a compound, substance, modification, material, component or product, unless
otherwise specified, means that the compound, substance, modification, material, component or
product is substantially crystalline as determined by X-ray diffraction. See, e.g., Remington: The
Science and Practice of Pharmacy, 21st edition, Lippincott, Williams and Wilkins, Baltimore,
MD (2005); The United States Pharmacopeia, 23rd ed., 1843-1844 (1995).
[00122] The term “crystal form” or “crystalline form” refers to a solid form that is
crystalline. In certain embodiments, a crystal form of a substance may be substantially free of
amorphous solids and/or other crystal forms. In certain embodiments, a crystal form of a
substance may contain less than about 1%, less than about 2%, less than about 3%, less than
about 4%, less than about 5%, less than about 6%, less than about 7%, less than about 8%, less
than about 9%, less than about 10%, less than about 15%, less than about 20%, less than about
%, less than about 30%, less than about 35%, less than about 40%, less than about 45%, or
less than about 50% by weight of one or more amorphous solids and/or other crystal forms. In
certain embodiments, a crystal form of a substance may be physically and/or chemically pure. In
certain embodiments, a crystal form of a substance may be about 99%, about 98%, about 97%,
about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, or about 90% physically
and/or chemically pure.
[00123] Unless otherwise specified, the term “amorphous” or “amorphous solid” means
that the substance, component, or product in question is not substantially crystalline as
determined by X-ray diffraction. In particular, the term “amorphous solid” describes a
disordered solid form, i.e., a solid form lacking long range crystalline order. In certain
embodiments, an amorphous solid of a substance may be substantially free of other amorphous
solids and/or crystal forms. In certain embodiments, an amorphous solid of a substance may
contain less than about 1%, less than about 2%, less than about 3%, less than about 4%, less than
about 5%, less than about 10%, less than about 15%, less than about 20%, less than about 25%,
less than about 30%, less than about 35%, less than about 40%, less than about 45%, or less than
about 50% by weight of one or more other amorphous solids and/or crystal forms on a weight
basis. In certain embodiments, an amorphous solid of a substance may be physically and/or
chemically pure. In certain embodiments, an amorphous solid of a substance be about 99%,
about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%,
or about 90% physically and/or chemically pure.
[00124] “JNK” means a protein or an isoform thereof expressed by a JNK1, JNK2, or
JNK3 gene (Gupta, S., Barrett, T., Whitmarsh, A.J., Cavanagh, J., Sluss, H.K., Derijard, B. and
Davis, R.J. The EMBO J. 15:2760-2770 (1996)).
[00125] “Treating” as used herein, means an alleviation, in whole or in part, of a disorder,
disease or condition, or one or more of the symptoms associated with a disorder, disease, or
condition, or slowing or halting of further progression or worsening of those symptoms, or
alleviating or eradicating the cause(s) of the disorder, disease, or condition itself. In one
embodiment, the disorder is a condition treatable or preventable by inhibition of a JNK pathway,
as described herein. In another embodiment, the disorder is selected from interstitial pulmonary
fibrosis, systemic sclerosis, scleroderma, chronic allograft nephropathy, antibody mediated
rejection, or lupus. In yet another embodiment, the disorder is a liver fibrotic disorder, or
diabetes and/or metabolic syndrome leading to liver fibrotic disorders, as described herein. In
some embodiments, the disorder is a liver fibrotic disorder, such as non-alcoholic steatohepatitis,
steatosis (i.e. fatty liver), cirrhosis, primary sclerosing cholangitis, primary biliary cirrhosis,
hepatitis, hepatocellular carcinoma, or liver fibrosis coincident with chronic or repeated alcohol
ingestion (alcoholic hepatitis), with infection (e.g., viral infection such as HCV), with liver
transplant, or with drug induced liver injury (e.g., acetaminophen toxicity). In some
embodiments, “treating” means an alleviation, in whole or in part, of a disorder, disease or
condition, or symptoms associated with diabetes or metabolic syndrome leading to liver fibrotic
disorders, such as non-alcoholic steatohepatitis, steatosis (i.e. fatty liver), hepatitis or cirrhosis, or
a slowing, or halting of further progression or worsening of those symptoms. In one
embodiment, the symptom is jaundice.
[00126] “Preventing” as used herein, means a method of delaying and/or precluding the
onset, recurrence or spread, in whole or in part, of a disorder, disease or condition; barring a
subject from acquiring a disorder, disease, or condition; or reducing a subject’s risk of acquiring
a disorder, disease, or condition. In one embodiment, the disorder is a condition treatable or
preventable by inhibition of a JNK pathway, as described herein. In another embodiment, the
disorder is selected from interstitial pulmonary fibrosis, systemic sclerosis, scleroderma, chronic
allograft nephropathy, antibody mediated rejection, or lupus. In one embodiment, the disorder is
a liver fibrotic disorder, or diabetes or metabolic syndrome leading to liver fibrotic disorders, as
described herein, or symptoms thereof.
[00127] The term “effective amount” in connection with a solid form of Compound 1
means an amount capable of treating or preventing a disorder, disease or condition, or symptoms
thereof, disclosed herein.
[00128] “Patient” or “subject” is defined herein to include animals, such as mammals,
including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats,
(1R,2R,5R)aminomethylcyclohexanol sidechain to yield compound (vi). Subsequent
treatment with t-BuNH2 in DMSO at about 68 °C or with t-BuNH2 in the presence of
ZnCl2 in ACN provides introduction of the t-BuNH2 sidechain to yield Compound 1.
Recrystallization of Compound 1 in a mixture of IPA and water at about 70 °C provides
Compound 1 with improved purity.
SOLID FORMS OF COMPOUND 1
[00160] In certain embodiments, provided herein are solid forms of Compound 1. In
certain embodiments, the solid form is crystalline. In certain embodiments, the solid form is a
single-component solid form. In certain embodiments, the solid form is a solvate.
[00161] While not intending to be bound by any particular theory, certain solid forms are
characterized by physical properties, e.g., stability, solubility and dissolution rate, appropriate for
pharmaceutical and therapeutic dosage forms. Moreover, while not wishing to be bound by any
particular theory, certain solid forms are characterized by physical properties (e.g., density,
compressibility, hardness, morphology, cleavage, stickiness, solubility, water uptake, electrical
properties, thermal behavior, solid-state reactivity, physical stability, and chemical stability)
affecting particular processes (e.g., yield, filtration, washing, drying, milling, mixing, tableting,
flowability, dissolution, formulation, and lyophilization) which make certain solid forms suitable
for the manufacture of a solid dosage form. Such properties can be determined using particular
analytical chemical techniques, including solid-state analytical techniques (e.g., X-ray
diffraction, microscopy, spectroscopy and thermal analysis), as described herein and known in
the art.
[00162] The solid forms provided herein (e.g., Form A, Form B, Form C, Form D, Form
E, Form F, Form G, Form H, Form I, and the amorphous solid of Compound 1) may be
characterized using a number of methods known to a person skilled in the art, including, but not
limited to, single crystal X-ray diffraction, X-ray powder diffraction (XRPD), microscopy (e.g.,
scanning electron microscopy (SEM)), thermal analysis (e.g., differential scanning calorimetry
(DSC), dynamic vapor sorption (DVS), thermal gravimetric analysis (TGA), and hot-stage
microscopy), spectroscopy (e.g., infrared, Raman, and solid-state nuclear magnetic resonance),
ultra-high performance liquid chromatography (UHPLC), and proton nuclear magnetic resonance
(
1
H NMR) spectrum. The particle size and size distribution of the solid form provided herein
may be determined by conventional methods, such as laser light scattering technique.
[00163] The purity of the solid forms provided herein may be determined by standard
analytical methods, such as thin layer chromatography (TLC), gel electrophoresis, gas
chromatography, ultra-high performance liquid chromatography (UHPLC), and mass
spectrometry (MS).
[00164] It should be understood that the numerical values of the peaks of an X-ray powder
diffraction pattern may vary slightly from one machine to another or from one sample to another,
and so the values quoted are not to be construed as absolute, but with an allowable variability,
such as ±0.2º 2θ (see United State Pharmacopoeia, page 2228 (2003)).
[00165] In certain embodiments, provided herein are methods for making a solid form of
Compound 1, comprising 1) obtaining a slurry of Form A in a solvent; 2) stirring the slurry for a
period of time (e.g., about 24 h) at a certain temperature (e.g., about 25 °C or about 50 °C); and
3) collecting solids from the slurry by filtration and optionally drying. In certain embodiments,
provided herein are methods for making a solid form of Compound 1, comprising 1) obtaining a
slurry of Form A in a solvent; 2) stirring the slurry for about 24 h at about 25 °C or about 50 °C;
and 3) collecting solids from the slurry by filtration through 0.45 µm PTFE syring filters and
optionally air drying. In certain embodiments, the methods for making a solid form of
Compound 1 are equilibration experiments, such as slurry experiments.
[00166] In certain embodiments, provided herein are methods for making a solid form of
Compound 1, comprising 1) dissolving Form A in a solvent to yield a solution; 2) filtering the
solution if Form A does not dissolve completely; and 3) evaporating the solution under certain
air pressure (e.g., about 1 atm) at a certain temperature (e.g., about 25 °C or about 50 °C) to yield
a solid. In certain embodiments, provided herein are methods for making a solid form of
Compound 1, comprising 1) dissolving Form A in a solvent to yield a solution; 2) filtering the
solution through 0.45 µm PTFE syring filters if Form A does not dissolve completely; and 3)
evaporating the solution under about 1 atm air pressure at about 25 °C or about 50 °C under
nitrogen to yield a solid. In certain embodiments, the methods for making a solid form of
Compound 1 are evaporation experiments.
[00167] In certain embodiments, provided herein are methods for making a solid form of
Compound 1, comprising 1) obtaining a saturated solution of Form A in a solvent at a first
temperature (e.g., about 60 °C); 2) stirring the solution at the first temperature for a period of
time (e.g., 10 minutes); 3) filtering the solution; 4) cooling the solution slowly to a second
temperature (e.g., about -5 °C to about 15 °C); and 5) isolating solids from the solution and
optionally drying. In certain embodiments, provided herein are methods for making a solid form
of Compound 1, comprising 1) obtaining a saturated solution of Form A in a solvent at about
60 °C; 2) stirring the solution at about 60 °C for 10 minutes; 3) filtering the solution through
0.45 µm PTFE syring filters; 4) cooling the solution slowly to about 5 °C; and 5) isolating solids
from the solution and optionally air-drying. In certain embodiments, the methods for making a
solid form of Compound 1 are cooling recrystallization experiments.
[00168] In certain embodiments, provided herein are methods for making a solid form of
Compound 1, comprising 1) obtaining a saturated solution of Form A in a solvent at a first
temperature (e.g., about 60 °C); 2) adding an anti-solvent into the saturated solution at the first
temperature; 3) cooling down to a second temperature (e.g., about -5 °C to about 15 °C); and 4)
collecting a solid if there is precipitation, and evaporating the solvent to collect a solid if there is
no precipitation; and 5) optionally drying. In certain embodiments, provided herein are methods
for making a solid form of Compound 1, comprising 1) obtaining a saturated solution of Form A
in a solvent at about 60 °C; 2) adding an anti-solvent into the saturated solution at about 60 °C;
3) cooling down to about 5 °C; and 4) collecting a solid if there is precipitation, and evaporating
the solvent to collect a solid if there is no precipitation; and 5) optionally air drying. In certain
embodiments, the ratio by volume of solvent and anti-solvent is about 1:9. In certain
embodiments, the methods for making a solid form of Compound 1 are anti-solvent
recrystallization experiments.
[00169] In certain embodiments, the solvent is acetone, DCM, EtOAc, EtOH, EtOH/H2O
(about 1:1), H2O, heptane, IPA, ACN, ACN/H2O (about 1:1), MEK, MeOH, MTBE, n-BuOH,
THF, THF/H2O (about 1:1), toluene or sulfolane.
[00170] In certain embodiments, the anti-solvent is ACN, heptane, MTBE, or water.
Form A
[00171] In certain embodiments, provided herein is Form A.
[00172] In one embodiment, Form A is a solid form of Compound 1. In one embodiment,
Form A is a non-stoichiometric channel hydrate solid form of Compound 1. In another
embodiment, Form A is crystalline.
[00173] In certain embodiments, Form A provided herein is obtained by equilibration
experiments, evaporation experiments and anti-solvent recrystallization experiments (see Table
1, Table 2 and Table 3). In certain embodiments, Form A is obtained from certain solvent
systems including MTBE, heptane, water, EtOH/H2O (about 1:1), MeOH with water as antisolvent, EtOH with water as anti-solvent, EtOH with MTBE as anti-solvent, and IPA with
heptane as anti-solvent.
[00174] In one embodiment, a method of preparing Form A comprises the steps of
1) mixing Form H with a solvent (e.g., DMSO) mixture containing water (e.g., at least
about 70% by volume of water); 2) stirring at a temperature (e.g., from about 20 °C to
about 25 °C, such as about 22 °C) for a period of time (e.g., from about 1 hour to about 6
hours, such as about 3 hours); and 3) collecting solids and optionally drying.
[00175] In one embodiment, a method of preparing Form A comprises the steps of
1) mixing Form H with a solvent (e.g., DMSO) mixture containing water (e.g., at least
about 50% by volume of water); 2) heating to a temperature (e.g., from between about 60
°C to about 100 °C, such as about 60 °C or about 70 °C) for a period of time (e.g., from
about 1 hour to about 6 hours, such as about 3 hours); 3) cooling to a second temperature
(e.g., from between about 10 °C to about 40 °C, such as about 25 °C); and 4) collecting
solids and optionally drying.
[00176] In one embodiment, a method of preparing Form A comprises the steps of
1) mixing Form H with a solvent (e.g., DMSO) mixture containing water (e.g., at least
about 70% by volume of water); 2) heating the resulting mixture to a first temperature
(e.g., from between about 60 °C to about 100 °C, such as about 60 °C or about 70 °C) for a
period of time (e.g., from about 1 hour to about 6 hours, such as 3 hours); 3) cooling the
mixture to a second temperature (e.g., from between about 10 °C to about 40 °C, such as
about 25 °C); and 4) collecting solids and optionally drying.
[00177] In another embodiment, a method of preparing Form A comprises the steps
of 1) mixing Form H with a solvent (e.g., DMSO) mixture containing at least about 70%
by volume of water; 2) heating the resulting mixture to a temperature (e.g., from between
about 60 °C to about 100 °C, such as about 60 °C or about 70 °C) for from about 1 hour to
about 6 hours, such as about 3 hours; 3) cooling the mixture to a temperature (e.g., from
between about 10 °C to about 40 °C, such as about 25 °C); and 4) collecting solids and
optionally drying.
[00178] In certain embodiments, a solid form provided herein, e.g., Form A, is
substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one
embodiment, Form A has an X-ray powder diffraction pattern substantially as shown in FIG. 1.
In one embodiment, Form A has one or more characteristic X-ray powder diffraction peaks at
approximately 9.74, 10.55, 11.86, 12.98, 13.61, 15.90, 16.41, 17.20, 17.85, 18.04, 18.54, 19.29,
19.56, 19.84, 20.19, 21.37, 21.83, 22.90, 23.46, 23.84, 24.36, 24.88, 25.29, 26.14, 26.92, 27.83,
28.30, 28.69, 29.21, 30.50, 31.63, 32.11, 32.63, 33.17, 34.32, 34.74, 36.00, 36.56, 36.95, 37.26,
37.61, 38.40, 39.07, 39.34 or 39.64º 2θ as depicted in FIG. 1. In a specific embodiment, Form A
has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at
approximately 10.55, 13.61, 17.20, 17.85, 18.04, 19.84, 22.90 or 24.36º 2θ. In another
embodiment, Form A has one, two, three or four characteristic X-ray powder diffraction peaks at
approximately 10.55, 13.61, 17.20 or 19.84º 2θ. In another embodiment, Form A has one, two,
three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen,
seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four,
twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two,
thirty-three, thirty-four, thirty-five, thirty-six, thirty-seven, thirty-eight, thirty-nine, forty, fortyone, forty-two, forty-three, forty-four or forty-five characteristic X-ray powder diffraction peaks
as set forth in Table 8.
[00179] Table 7 presents a summary of the crystallographic data from a single-crystal
structure determination. In one embodiment, Form A has a crystal packing pattern substantially
as shown in FIG. 2. In one embodiment, Form A is a solid form crystallizing in the space group
P2(1)2(1)2(1). In one embodiment, Form A is a non-stoichiometric channel hydrate.
[00180] In one embodiment, Form A has a SEM image substantially as shown in FIG. 3.
[00181] In one embodiment, provided herein is Form A having a TGA thermograph
corresponding substantially to the representative TGA thermogram as depicted in FIG. 4. In
certain embodiments, the crystalline form exhibits a TGA thermogram comprising a total mass
loss of approximately 0.45% of the total mass of the sample between approximately 30 °C and
approximately 150 °C when heated from approximately 20 °C to approximately 300 °C. Thus, in
certain embodiments, the crystalline form loses from about 0.1% to about 5%, for example,
about 0.45% or about 3.3%, of its total mass when heated from about ambient temperature to
about 300 °C.
[00182] In one embodiment, provided herein is Form A having a DSC thermogram
substantially as depicted in FIG. 5 comprising an endothermic event with an onset temperature of
about 223 °C when heated from approximately 25 °C to approximately 300 °C.
[00183] In one embodiment, provided herein is Form A having a DVS isotherm plot
substantially as depicted in FIG. 6.
[00184] In one embodiment, provided herein is Form A having a 1
H NMR spectrum
substantially as depicted in FIG. 7.
[00185] In still another embodiment, Form A is substantially pure. In certain
embodiments, the substantially pure Form A is substantially free of other solid forms, e.g.,
amorphous solid. In certain embodiments, the purity of the substantially pure Form A is no less
than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less
than about 98.5%, no less than about 99%, no less than about 99.5%, or no less than about
99.8%.
Form B
[00186] In certain embodiments, provided herein is Form B.
[00187] In one embodiment, Form B is a solid form of Compound 1. In another
embodiment, Form B is crystalline. In one embodiment, Form B is a solvated form of
Compound 1. In one embodiment, Form B is an acetone solvated form of Compound 1. In one
embodiment, Form B is an acetone hemi-solvated form of Compound 1.
[00188] In certain embodiments, Form B provided herein is obtained by equilibration
experiments, evaporation experiments and anti-solvent recrystallization experiments (see Table
1, Table 2 and Table 3). In certain embodiments, Form B is obtained from certain solvent
systems including acetone, MEK, DCM, THF, THF/H2O (about 1:1), and IPA with heptane as
anti-solvent.
[00189] In certain embodiments, a solid form provided herein, e.g., Form B, is
substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one
embodiment, Form B has an X-ray powder diffraction pattern substantially as shown in FIG. 10.
In one embodiment, Form B has one or more characteristic X-ray powder diffraction peaks at
approximately 9.80, 10.30, 12.23, 14.62, 16.70, 17.29, 18.23, 18.59, 19.61, 20.19, 20.66, 20.94,
21.74, 23.03, 23.84, 24.32, 24.58, 25.88, 26.27, 26.86, 27.52, 28.35, 28.62, 29.63, 30.55, 30.87,
31.44, 32.12, 33.71, 33.95, 34.96, 35.94, 36.14, 36.56, 37.22 or 38.76º 2θ as depicted in FIG. 10.
In a specific embodiment, Form B has one, two, three, four, five, six, seven or eight
characteristic X-ray powder diffraction peaks at approximately 9.80, 10.30, 14.62, 17.29, 18.23,
.66, 21.74 or 30.55º 2θ. In another embodiment, Form B has one, two, three or four
characteristic X-ray powder diffraction peaks at approximately 9.80, 17.29, 18.23 or 21.74º 2θ.
In another embodiment, Form B has one, two, three, four, five, six, seven, eight, nine, ten,
eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twentyone, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight,
twenty-nine, thirty, thirty-one, thirty-two, thirty-three, thirty-four, thirty-five or thirty-six
characteristic X-ray powder diffraction peaks as set forth in Table 9.
[00190] In one embodiment, provided herein is a crystalline form of Compound 1 having a
TGA thermograph corresponding substantially to the representative TGA thermogram as
depicted in FIG. 11. In certain embodiments, the crystalline form exhibits a TGA thermogram
comprising a total mass loss of approximately 8.5% of the total mass of the sample between
approximately 75 °C and approximately 175 °C when heated from approximately 25 °C to
approximately 300 °C. Thus, in certain embodiments, the crystalline form loses about 8.5% of its
total mass when heated from about ambient temperature to about 300 °C. In certain
embodiments, the crystalline form contains 0.5 molar equivalents of solvent in the crystal lattice
corresponding to approximately 0.5 mole of acetone per mole of Compound 1. The theoretical
acetone content of an acetone hemi-solvate of Compound 1 is 8.3 % by weight, matching the
TGA weight loss observed. In certain embodiments, the crystalline form is an acetone hemisolvate of Compound 1.
[00191] In one embodiment, provided herein is a crystalline form of Compound 1 having a
DSC thermogram as depicted in FIG. 12 comprising an endothermic event with a maximum at
about 147 °C when heated from approximately 25 °C to approximately 300 °C.
[00192] In one embodiment, provided herein is a crystalline form of Compound 1 having a
DSC thermogram as depicted in FIG. 12 comprising an endothermic event with an onset
temperature of about 223 °C when heated from approximately 25 °C to approximately 300 °C.
[00193] In one embodiment, provided herein is Form B having a 1
H NMR spectrum
substantially as depicted in FIG. 13.
[00194] In still another embodiment, Form B is substantially pure. In certain
embodiments, the substantially pure Form B is substantially free of other solid forms, e.g.,
amorphous solid. In certain embodiments, the purity of the substantially pure Form B is no less
than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less
than about 98.5%, no less than about 99%, no less than about 99.5%, or no less than about
99.8%.
Form C
[00195] In certain embodiments, provided herein is Form C.
[00196] In one embodiment, Form C is a solid form of Compound 1. In another
embodiment, Form C is crystalline. In one embodiment, Form C is a solvated form of
Compound 1. In one embodiment, Form C is an ethanol solvated form of Compound 1. In one
embodiment, Form C is an ethanol hemi-solvated form of Compound 1.
[00197] In certain embodiments, Form C provided herein is obtained by equilibration
experiments, evaporation experiments, cooling recrystallization experiments and anti-solvent
recrystallization experiments (see Table 1, Table 2 and Table 3). In certain embodiments, Form
C is obtained from certain solvent systems including ACN, ACN/H2O (about 1:1) , EtOH,
EtOH/H2O (about 1:1), IPA, MEK, EtOH with MTBE as anti-solvent, EtOH with heptane as
anti-solvent, EtOH with ACN as anti-solvent and IPA with heptane as anti-solvent.
[00198] In certain embodiments, a solid form provided herein, e.g., Form C, is
substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one
embodiment, Form C has an X-ray powder diffraction pattern substantially as shown in FIG. 14.
In one embodiment, Form C has one or more characteristic X-ray powder diffraction peaks at
approximately 9.83, 10.21, 12.16, 14.66, 15.52, 16.50, 17.26, 17.61, 17.91, 18.18, 18.65, 19.67,
19.99, 20.46, 21.86, 23.32, 23.78, 24.44, 25.65, 25.81, 26.28, 26.72, 27.46, 28.04, 28.30, 28.60,
29.56, 30.47, 30.70, 31.29, 31.77, 32.16, 32.94, 33.55, 34.00, 34.85, 35.14, 35.57, 35.90, 36.62,
37.76 or 38.93º 2θ as depicted in FIG. 14. In a specific embodiment, Form C has one, two, three,
four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately
9.83, 10.21, 12.16, 17.26, 17.61, 18.18, 20.46 or 21.86º 2θ. In another embodiment, Form C has
one, two, three or four characteristic X-ray powder diffraction peaks at approximately 9.83,
.21, 17.26 or 21.86º 2θ. In another embodiment, Form C has one, two, three, four, five, six,
seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen,
nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six,
twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-three, thirty-four,
thirty-five, thirty-six, thirty-seven, thirty-eight, thirty-nine, forty, forty-one or forty-two
characteristic X-ray powder diffraction peaks as set forth in Table 10.
[00199] In one embodiment, provided herein is a crystalline form of Compound 1 having a
TGA thermograph corresponding substantially to the representative TGA thermogram as
depicted in FIG. 15. In certain embodiments, the crystalline form exhibits a TGA thermogram
comprising a total mass loss of approximately 7.3% of the total mass of the sample between
approximately 75 °C and approximately 175 °C when heated from approximately 25 °C to
approximately 300 °C. Thus, in certain embodiments, the crystalline form loses about 7.3% of its
total mass when heated from about ambient temperature to about 300 °C. In certain
embodiments, the crystalline form contains 0.5 molar equivalents of solvent in the crystal lattice
corresponding to approximately 0.5 mole of ethanol per mole of Compound 1. The theoretical
ethanol content of an ethanol hemi-solvate of Compound 1 is 6.7% by weight, matching the
TGA weight loss observed. In certain embodiments, the crystalline form is an ethanol hemisolvate of Compound 1.
[00200] In one embodiment, provided herein is a crystalline form of Compound 1 having a
DSC thermogram as depicted in FIG. 16 comprising an endothermic event with a maximum at
about 143 °C when heated from approximately 25 °C to approximately 300 °C.
[00201] In one embodiment, provided herein is a crystalline form of Compound 1 having a
DSC thermogram as depicted in FIG. 16 comprising an endothermic event with an onset
temperature of about 224 °C when heated from approximately 25 °C to approximately 300 °C.
[00202] In one embodiment, provided herein is Form C having a 1
H NMR spectrum
substantially as depicted in FIG. 17.
[00203] In still another embodiment, Form C is substantially pure. In certain
embodiments, the substantially pure Form C is substantially free of other solid forms, e.g.,
amorphous solid. In certain embodiments, the purity of the substantially pure Form C is no less
than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less
than about 98.5%, no less than about 99%, no less than about 99.5%, or no less than about
99.8%.
Form D
[00204] In certain embodiments, provided herein is Form D.
[00205] In one embodiment, Form D is a solid form of Compound 1. In another
embodiment, Form D is crystalline. In one embodiment, Form D is a solvated form of
Compound 1. In one embodiment, Form D is a methanol solvated form of Compound 1. In one
embodiment, Form D is a methanol hemi-solvated form of Compound 1.
[00206] In certain embodiments, Form D provided herein is obtained by equilibration
experiments, evaporation experiments, cooling recrystallization experiments and anti-solvent
recrystallization experiments (see Table 1, Table 2 and Table 3). In certain embodiments, Form
D is obtained from certain solvent systems including MeOH and MeOH with MTBE as antisolvent.
[00207] In certain embodiments, a solid form provided herein, e.g., Form D, is
substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one
embodiment, Form D has an X-ray powder diffraction pattern substantially as shown in FIG. 18.
In one embodiment, Form D has one or more characteristic X-ray powder diffraction peaks at
approximately 10.37, 12.85, 13.41, 15.68, 16.25, 17.02, 17.54, 17.73, 18.34, 19.52, 19.93, 20.78,
21.09, 21.54, 22.47, 23.11, 23.55, 23.92, 24.51, 24.99, 25.81, 26.47, 26.88, 27.33, 27.83, 28.19,
28.64, 30.08, 30.82, 31.20, 31.60, 32.02, 32.50, 33.58, 34.25, 35.39, 35.87, 36.55, 36.81, 37.06,
37.77 or 38.60º 2θ as depicted in FIG. 18. In a specific embodiment, Form D has one, two,
three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at
approximately 10.37, 13.41, 17.54, 17.73, 19.52, 21.54, 22.47 or 23.92º 2θ. In another
embodiment, Form D has one, two, three or four characteristic X-ray powder diffraction peaks at
approximately 10.37, 13.41, 19.52 or 22.47º 2θ. In another embodiment, Form D has one, two,
three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen,
seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four,
twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two,
thirty-three, thirty-four, thirty-five, thirty-six, thirty-seven, thirty-eight, thirty-nine, forty, fortyone, forty-two characteristic X-ray powder diffraction peaks as set forth in Table 11.
[00208] In one embodiment, provided herein is a crystalline form of Compound 1 having a
TGA thermograph corresponding substantially to the representative TGA thermogram as
depicted in FIG. 19. In certain embodiments, the crystalline form exhibits a TGA thermogram
comprising a total mass loss of approximately 4% of the total mass of the sample between
approximately 100 °C and approximately 160 °C when heated from approximately 25 °C to
approximately 300 °C. Thus, in certain embodiments, the crystalline form loses about 4% of its
total mass when heated from about ambient temperature to about 300 °C. In certain
embodiments, the crystalline form contains 0.5 molar equivalents of solvent in the crystal lattice
corresponding to approximately 0.5 mole of methanol per mole of Compound 1. The theoretical
methanol content of a methanol hemi-solvate of Compound 1 is 4.7% by weight, matching the
TGA weight loss observed. In certain embodiments, the crystalline form is a methanol hemisolvate of Compound 1.
[00209] In one embodiment, provided herein is a crystalline form of Compound 1 having a
DSC thermogram as depicted in FIG. 20 comprising an endothermic event with a maximum at
about 170 °C when heated from approximately 25 °C to approximately 300 °C.
[00210] In one embodiment, provided herein is a crystalline form of Compound 1 having a
DSC thermogram as depicted in FIG. 20 comprising an endothermic event with an onset
temperature of about 223 °C when heated from approximately 25 °C to approximately 300 °C.
[00211] In one embodiment, provided herein is Form D having a 1
H NMR spectrum
substantially as depicted in FIG. 21.
[00212] In still another embodiment, Form D is substantially pure. In certain
embodiments, the substantially pure Form D is substantially free of other solid forms, e.g.,
amorphous solid. In certain embodiments, the purity of the substantially pure Form D is no less
than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less
than about 98.5%, no less than about 99%, no less than about 99.5%, or no less than about
99.8%.
Form E
[00213] In certain embodiments, provided herein is Form E.
[00214] In one embodiment, Form E is a solid form of Compound 1. In another
embodiment, Form E is crystalline. In one embodiment, Form E is a solvated form of
Compound 1. In one embodiment, Form E is an n-butanol solvated form of Compound 1. In
one embodiment, Form E is an n-butanol hemi-solvated form of Compound 1.
[00215] In certain embodiments, Form E provided herein is obtained by equilibration
experiments and evaporation experiments (see Table 1 and Table 2). In certain embodiments,
Form E is obtained from certain solvent systems including n-butanol.
[00216] In certain embodiments, a solid form provided herein, e.g., Form E, is
substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one
embodiment, Form E has an X-ray powder diffraction pattern substantially as shown in FIG. 22.
In one embodiment, Form E has one or more characteristic X-ray powder diffraction peaks at
approximately 8.70, 9.92, 10.36, 11.97, 14.50, 15.51, 16.39, 17.29, 18.37, 19.55, 20.10, 21.81,
23.21, 23.45, 24.17, 24.61, 25.44, 25.83, 26.23, 26.45, 26.61, 27.64, 28.48, 29.19, 29.97, 30.39,
.81, 31.36, 31.66, 32.62, 33.67, 34.75, 35.24, 35.96, 36.48, 37.20, 37.62, 38.93 or 39.20 º 2θ as
depicted in FIG. 22. In a specific embodiment, Form E has one, two, three, four, five, six, seven
or eight characteristic X-ray powder diffraction peaks at approximately 9.92, 10.36, 11.97, 14.50,
17.29, 18.37, 20.10 or 21.81º 2θ. In another embodiment, Form E has one, two, three or four
characteristic X-ray powder diffraction peaks at approximately 9.92, 17.29, 18.37 or 21.81º 2θ.
In another embodiment, Form E has one, two, three, four, five, six, seven, eight, nine, ten,
eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twentyone, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight,
twenty-nine, thirty, thirty-one, thirty-two, thirty-three, thirty-four, thirty-five, thirty-six, thirtyseven, thirty-eight or thirty-nine characteristic X-ray powder diffraction peaks as set forth in
Table 12.
[00217] In one embodiment, provided herein is a crystalline form of Compound 1 having a
TGA thermograph corresponding substantially to the representative TGA thermogram as
depicted in FIG. 23. In certain embodiments, the crystalline form exhibits a TGA thermogram
comprising a total mass loss of approximately 10.3% of the total mass of the sample between
approximately 75 °C and approximately 175 °C when heated from approximately 25 °C to
approximately 300 °C. Thus, in certain embodiments, the crystalline form loses about 10.3% of
its total mass when heated from about ambient temperature to about 300 °C. In certain
embodiments, the crystalline form contains 0.5 molar equivalents of solvent in the crystal lattice
corresponding to approximately 0.5 mole of n-butanol per mole of Compound 1. The theoretical
n-butanol content of an n-butanol hemi-solvate of Compound 1 is 10.3% by weight, matching the
TGA weight loss observed. In certain embodiments, the crystalline form is an n-butanol hemisolvate of Compound 1.
[00218] In one embodiment, provided herein is a crystalline form of Compound 1 having a
DSC thermogram as depicted in FIG. 24 comprising an endothermic event with a maximum at
about 124 °C when heated from approximately 25 °C to approximately 300 °C.
[00219] In one embodiment, provided herein is a crystalline form of Compound 1 having a
DSC thermogram as depicted in FIG. 24 comprising an endothermic event with an onset
temperature of about 224 °C when heated from approximately 25 °C to approximately 300 °C.
[00220] In one embodiment, provided herein is Form E having a 1
H NMR spectrum
substantially as depicted in FIG. 25.
[00221] In still another embodiment, Form E is substantially pure. In certain
embodiments, the substantially pure Form E is substantially free of other solid forms, e.g.,
amorphous solid. In certain embodiments, the purity of the substantially pure Form E is no less
than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less
than about 98.5%, no less than about 99%, no less than about 99.5%, or no less than about
99.8%.
Form F
[00222] In certain embodiments, provided herein is Form F.
[00223] In one embodiment, Form F is a solid form of Compound 1. In another
embodiment, Form F is crystalline. In one embodiment, Form F is a solvated form of Compound
1. In one embodiment, Form F is a toluene solvated form of Compound 1. In one embodiment,
Form F is a 0.3 molar toluene solvated form of Compound 1.
[00224] In certain embodiments, Form F provided herein is obtained by equilibration
experiments (see Table 1). In certain embodiments, Form F is obtained from certain solvent
systems including toluene.
[00225] In certain embodiments, a solid form provided herein, e.g., Form F, is
substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one
embodiment, Form F has an X-ray powder diffraction pattern substantially as shown in FIG. 26.
In one embodiment, Form F has one or more characteristic X-ray powder diffraction peaks at
approximately 8.07, 9.21, 10.58, 10.88, 12.06, 14.56, 14.87, 16.28, 17.45, 17.79, 18.53, 19.65,
.05, 20.85, 21.10, 23.72, 24.41, 25.11, 25.98, 26.61, 27.94, 29.25, 30.40, 32.00, 34.06, 35.72,
36.58 or 37.59º 2θ as depicted in FIG. 26. In a specific embodiment, Form F has one, two, three,
four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately
8.07, 9.21, 12.06, 17.45, 17.79, 18.53, 20.85 or 21.10º 2θ. In another embodiment, Form F has
one, two, three or four characteristic X-ray powder diffraction peaks at approximately 17.45,
18.53, 20.85 or 21.10º 2θ. In another embodiment, Form F has one, two, three, four, five, six,
seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen,
nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six,
twenty-seven or twenty-eight characteristic X-ray powder diffraction peaks as set forth in Table
13.
[00226] In one embodiment, provided herein is a crystalline form of Compound 1 having a
TGA thermograph corresponding substantially to the representative TGA thermogram as
depicted in FIG. 27. In certain embodiments, the crystalline form exhibits a TGA thermogram
comprising a total mass loss of approximately 6.9% of the total mass of the sample between
approximately 75 °C and approximately 175 °C when heated from approximately 25 °C to
approximately 300 °C. Thus, in certain embodiments, the crystalline form loses about 6.9% of its
total mass when heated from about ambient temperature to about 300 °C.
[00227] In one embodiment, provided herein is a crystalline form of Compound 1 having a
DSC thermogram as depicted in FIG. 28 comprising an endothermic event with a maximum at
about 113 °C when heated from approximately 25 °C to approximately 300 °C.
[00228] In one embodiment, provided herein is a crystalline form of Compound 1 having a
DSC thermogram as depicted in FIG. 28 comprising an endothermic event with an onset
temperature of about 223 °C when heated from approximately 25 °C to approximately 300 °C.
[00229] In one embodiment, provided herein is Form F having a 1
H NMR spectrum
substantially as depicted in FIG. 29. In one embodiment, the 1
H NMR spectrum of Form F
shows Form F contains about 0.3 molar equivalents of toluene. In certain embodiments, Form F
is a 0.3 molar equivalents toluene solvate of Compound 1.
[00230] In still another embodiment, Form F is substantially pure. In certain
embodiments, the substantially pure Form F is substantially free of other solid forms, e.g.,
amorphous solid. In certain embodiments, the purity of the substantially pure Form F is no less
than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less
than about 98.5%, no less than about 99%, no less than about 99.5%, or no less than about
99.8%.
Form G
[00231] In certain embodiments, provided herein is Form G.
[00232] In one embodiment, Form G is a solid form of Compound 1. In another
embodiment, Form G is crystalline. In one embodiment, Form G is a solvated form of
Compound 1. In one embodiment, Form G is an EtOAc solvated form of Compound 1. In one
embodiment, Form G is an EtOAc hemi-solvated form of Compound 1.
[00233] In certain embodiments, Form G provided herein is obtained by equilibration
experiments, evaporation experiments and anti-solvent recrystallization experiments (see Table
1, Table 2 and Table 3). In certain embodiments, Form G is obtained from certain solvent
systems including EtOAc.
[00234] In certain embodiments, a solid form provided herein, e.g., Form G, is
substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one
embodiment, Form G has an X-ray powder diffraction pattern substantially as shown in FIG. 30.
In one embodiment, Form G has one or more characteristic X-ray powder diffraction peaks at
approximately 8.63, 9.51, 10.34, 12.14, 14.43, 16.44, 16.94, 17.33, 17.90, 18.58, 19.10, 20.09,
.41, 20.80, 21.28, 22.66, 23.62, 24.33, 25.55, 25.65, 26.42, 26.89, 27.00, 27.78, 28.83, 29.86,
31.22, 31.77, 32.67, 33.90, 34.28, 35.04, 35.44, 36.24, 36.57, 37.59, 38.00 or 38.76º 2θ as
depicted in FIG. 30. In a specific embodiment, Form G has one, two, three, four, five, six, seven
or eight characteristic X-ray powder diffraction peaks at approximately 9.51, 10.34, 16.94, 17.33,
17.90, 21.28, 28.83 or 31.22º 2θ. In another embodiment, Form G has one, two, three or four
characteristic X-ray powder diffraction peaks at approximately 9.51, 10.34, 17.90 or 21.28º 2θ.
In another embodiment, Form G has one, two, three, four, five, six, seven, eight, nine, ten,
eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twentyone, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight,
twenty-nine, thirty, thirty-one, thirty-two, thirty-three, thirty-four, thirty-five, thirty-six, thirtyseven or thirty-eight characteristic X-ray powder diffraction peaks as set forth in Table 14.
[00235] In one embodiment, provided herein is a crystalline form of Compound 1 having a
TGA thermograph corresponding substantially to the representative TGA thermogram as
depicted in FIG. 31. In certain embodiments, the crystalline form exhibits a TGA thermogram
comprising a total mass loss of approximately 11.9% of the total mass of the sample between
approximately 75 °C and approximately 175 °C when heated from approximately 25 °C to
approximately 300 °C. Thus, in certain embodiments, the crystalline form loses about 11.9% of
its total mass when heated from about ambient temperature to about 300 °C. In certain
embodiments, the crystalline form contains 0.5 molar equivalents of solvent in the crystal lattice
corresponding to approximately 0.5 mole of EtOAc per mole of Compound 1. The theoretical
EtOAc content of an EtOAc hemi-solvate of Compound 1 is 12.1% by weight, matching the
TGA weight loss observed. In certain embodiments, the crystalline form is an EtOAc hemisolvate of Compound 1.
[00236] In one embodiment, provided herein is a crystalline form of Compound 1 having a
DSC thermogram as depicted in FIG. 32 comprising an endothermic event with a maximum at
about 116 °C when heated from approximately 25 °C to approximately 300 °C.
[00237] In one embodiment, provided herein is a crystalline form of Compound 1 having a
DSC thermogram as depicted in FIG. 32comprising an endothermic event with an onset
temperature of about 223 °C when heated from approximately 25 °C to approximately 300 °C.
[00238] In one embodiment, provided herein is Form G having a 1
H NMR spectrum
substantially as depicted in FIG. 33. In one embodiment, the 1
H NMR spectrum of Form G
shows Form G contains about 0.5 molar equivalents of EtOAc. In certain embodiments, Form G
is an EtOAc hemi-solvate of Compound 1.
[00239] In still another embodiment, Form G is substantially pure. In certain
embodiments, the substantially pure Form G is substantially free of other solid forms, e.g.,
amorphous solid. In certain embodiments, the purity of the substantially pure Form G is no less
than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less
than about 98.5%, no less than about 99%, no less than about 99.5%, or no less than about
99.8%.
Form H
[00240] In certain embodiments, provided herein is Form H.
[00241] In one embodiment, Form H is a solid form of Compound 1. In another
embodiment, Form H is crystalline. In one embodiment, Form H is a solvated form of
Compound 1. In one embodiment, Form H is a DMSO solvated form of Compound 1. In one
embodiment, Form H is a DMSO hemi-solvated form of Compound 1.
[00242] In certain embodiments, Form H provided herein is obtained by equilibration
experiments, evaporation experiments, cooling recrystallization experiments and anti-solvent
recrystallization experiments. In certain embodiments, Form H is obtained from certain solvent
systems including DMSO.
[00243] In certain embodiments, provided herein are methods of preparing Form H
comprising the steps of 1) mixing 2-chloro((1R,3R,4R)hydroxy
methylcyclohexylamino)pyrimidinecarboxamide with tert-butylamine and DMSO; 2)
heating to a temperature (e.g., from between about 55 to about 80 °C, such as about 68 °C)
for a period of time (e.g., from about 40 hours to about 80 hours, such as about 60 hours);
3) cooling to ambient temperature; 4) adding water; and 5) collecting solids and optionally
drying. In one embodiment, the temperature is from between about 55 to about 80 °C,
such as about 68 °C. In one embodiment, the period of time is from about 40 hours to
about 80 hours, such as about 60 hours. In another embodiment, water is added over from
about 1 hour to about 4 hours, such as about 2 hours.
[00244] In certain embodiments, a solid form provided herein, e.g., Form H, is
substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one
embodiment, Form H has an X-ray powder diffraction pattern substantially as shown in FIG. 34.
In one embodiment, Form H has one or more characteristic X-ray powder diffraction peaks at
approximately 8.69, 9.74, 10.23, 12.17, 14.64, 15.38, 16.33, 17.22, 18.04, 18.55, 20.10, 20.62,
21.76, 23.10, 24.18, 25.65, 26.18, 26.78, 27.27, 27.83, 28.43, 29.50, 30.00, 30.54, 31.03, 32.07,
32.65, 33.41, 33.74, 34.86, 35.25, 35.77, 36.22, 36.62, 37.08, 37.59 or 38.78º 2θ as depicted in
FIG. 34. In a specific embodiment, Form H has one, two, three, four, five, six, seven or eight
characteristic X-ray powder diffraction peaks at approximately 9.74, 10.23, 14.64, 17.22, 18.04,
18.55, 21.76 or 24.18º 2θ. In another embodiment, Form H has one, two, three or four
characteristic X-ray powder diffraction peaks at approximately 9.74, 17.22, 18.04 or 21.76º 2θ.
In another embodiment, Form H has one, two, three, four, five, six, seven, eight, nine, ten,
eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twentyone, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight,
twenty-nine, thirty, thirty-one, thirty-two, thirty-three, thirty-four, thirty-five, thirty-six or thirtyseven characteristic X-ray powder diffraction peaks as set forth in Table 15.
[00245] In one embodiment, provided herein is a crystalline form of Compound 1 having a
TGA thermograph corresponding substantially to the representative TGA thermogram as
depicted in FIG. 35. In certain embodiments, the crystalline form exhibits a TGA thermogram
comprising a total mass loss of approximately 11.2% of the total mass of the sample between
approximately 75 °C and approximately 175 °C when heated from approximately 25 °C to
approximately 300 °C. Thus, in certain embodiments, the crystalline form loses about 11.2% of
its total mass when heated from about ambient temperature to about 300 °C. In certain
embodiments, the crystalline form contains 0.5 molar equivalents of solvent in the crystal lattice
corresponding to approximately 0.5 mole of DMSO per mole of Compound 1. The theoretical
DMSO content of a DMSO hemi-solvate of Compound 1 is 10.8% by weight, matching the TGA
weight loss observed. In certain embodiments, the crystalline form is a DMSO hemi-solvate of
Compound 1.
[00246] In one embodiment, provided herein is a crystalline form of Compound 1 having a
DSC thermogram as depicted in FIG. 36 comprising an endothermic event with a maximum at
about 160 °C when heated from approximately 25 °C to approximately 300 °C.
[00247] In one embodiment, provided herein is a crystalline form of Compound 1 having a
DSC thermogram as depicted in FIG. 36 comprising an endothermic event with an onset
temperature of about 222 °C when heated from approximately 25 °C to approximately 300 °C.
[00248] In still another embodiment, Form H is substantially pure. In certain
embodiments, the substantially pure Form H is substantially free of other solid forms, e.g.,
amorphous solid. In certain embodiments, the purity of the substantially pure Form H is no less
than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less
than about 98.5%, no less than about 99%, no less than about 99.5%, or no less than about
99.8%.
Form I
[00249] In certain embodiments, provided herein is Form I.
[00250] In one embodiment, Form I is a solid form of Compound 1. In another
embodiment, Form I is crystalline. In one embodiment, Form I is a solvated form of Compound
1. In one embodiment, Form I is a sulfolane solvated form of Compound 1. In one embodiment,
Form I is a 0.75 molar sulfolane solvated form of Compound 1.
[00251] In certain embodiments, Form I provided herein is obtained by cooling
recrystallization experiments and anti-solvent recrystallization experiments. In certain
embodiments, Form I is obtained from certain solvent systems including sulfolane and water. In
certain embodiments, Form I is obtained from a solvent mixture of sulfolane and water (e.g.,
about 1:1).
[00252] In certain embodiments, a solid form provided herein, e.g., Form I, is substantially
crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment,
Form I has an X-ray powder diffraction pattern substantially as shown in FIG. 38. In one
embodiment, Form I has one or more characteristic X-ray powder diffraction peaks at
approximately 7.94, 10.50, 10.80, 11.86, 13.54, 13.92, 14.79, 16.00, 17.26, 18.27, 18.82, 19.48,
19.78, 20.65, 21.31, 21.78, 22.83, 23.53, 24.12, 24.75, 25.66, 26.29, 27.71, 28.18, 28.73, 29.17,
.01, 30.52, 31.18, 31.60, 31.85, 32.36, 32.93, 33.59, 34.20, 34.76, 35.42, 36.56 or 37.67º 2θ as
depicted in FIG. 38. In a specific embodiment, Form I has one, two, three, four, five, six, seven
or eight characteristic X-ray powder diffraction peaks at approximately 7.94, 10.50, 11.86, 16.00,
17.26, 18.27, 20.65 or 24.12º 2θ. In another embodiment, Form I has one, two, three or four
characteristic X-ray powder diffraction peaks at approximately 7.94, 16.00, 18.27 or 20.65º 2θ.
In another embodiment, Form I has one, two, three, four, five, six, seven, eight, nine, ten, eleven,
twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one,
twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight,
twenty-nine, thirty, thirty-one, thirty-two, thirty-three, thirty-four, thirty-five, thirty-six, thirtyseven, thirty-eight or thirty-nine characteristic X-ray powder diffraction peaks as set forth in
Table 16.
[00253] In one embodiment, provided herein is a crystalline form of Compound 1 having a
DSC thermogram as depicted in FIG. 39 comprising an endothermic event with a maximum at
about 118 °C when heated from approximately 25 °C to approximately 300 °C.
[00254] In one embodiment, provided herein is a crystalline form of Compound 1 having a
DSC thermogram as depicted in FIG. 39 comprising an endothermic event with an onset
temperature of about 213 °C when heated from approximately 25 °C to approximately 300 °C.
[00255] In still another embodiment, Form I is substantially pure. In certain
embodiments, the substantially pure Form I is substantially free of other solid forms, e.g.,
amorphous solid. In certain embodiments, the purity of the substantially pure Form I is no less
than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less
than about 98.5%, no less than about 99%, no less than about 99.5%, or no less than about
99.8%.
Amorphous Solid
[00256] In certain embodiments, provided herein is an amorphous solid of Compound 1.
[00257] In certain embodiments, the amorphous solid provided herein is obtained by heat
treatment of Form A. In certain embodiments, the heat treatment process comprises: (1)
equilibrating the temperature of Form A at a particular temperature (e.g., about 25 °C); (2)
heating to a first temperature (e.g., about 235 °C) at a first speed (e.g., about 10 °C per minute);
(3) holding isothermally for a first period of time (e.g., about 2 minutes); (4) cooling to a second
temperature (e.g., about -10 °C) at a second speed (e.g., about 30 °C per minute); (5) modulating
the temperature at a third speed (e.g., about 0.64 °C every 40 seconds); (6) holding isothermally
for a second period of time (e.g., about 5 minutes); (7) heating to a third temperature (e.g., about
213 °C) at a fourth speed (e.g., about 3 °C per minute); and (8) collecting the resulted solid.
[00258] In one embodiment, the amorphous solid has an X-ray powder diffraction
spectrum substantially as shown in FIG. 41.
[00259] In one embodiment, provided herein is an amorphous solid of Compound 1
having a DSC thermogram as depicted in FIG. 42 comprising a glass transition temperature of
106.6 °C when heated from approximately 25 °C to approximately 300 °C.
[00260] In still another embodiment, the amorphous solid of Compound 1 is substantially
pure. In certain embodiments, the substantially pure amorphous solid of Compound 1 is
substantially free of other solid forms, e.g., Form A, Form B, Form C, Form D, Form E, Form F,
Form G, Form H, and Form I. In certain embodiments, the purity of the substantially pure
amorphous solid is no less than about 95%, no less than about 96%, no less than about 97%, no
less than about 98%, no less than about 98.5%, no less than about 99%, no less than about
99.5%, or no less than about 99.8%.
METHODS OF USE
[00261] Solid forms of Compound 1 have utility as pharmaceuticals to treat, prevent
or improve conditions in animals or humans. Further, the solid forms of Compound 1 are
active against protein kinases, particularly JNK1 and/or JNK2. Accordingly, provided
herein are many uses of the solid forms of Compound 1, including the treatment or
prevention of those diseases set forth below. The methods provided herein comprise the
administration of an effective amount of one or more solid form(s) of Compound 1 to a
subject in need thereof.
[00262] In one aspect provided herein are methods of inhibiting a kinase in a cell
expressing said kinase, comprising contacting said cell with an effective amount of a solid
form of Compound 1. In one embodiment the kinase is JNK1, JNK2, or mutants or
isoforms thereof, or a combination thereof. For example, the solid form of Compound A
is Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, the
amorphous solid or a mixture thereof.
[00263] In another aspect provided herein are methods for treating or preventing
one ore more disorders selected from interstitial pulmonary fibrosis, systemic sclerosis,
scleroderma, chronic allograft nephropathy, antibody mediated rejection, or lupus,
comprising administering to a subject in need thereof an effective amount of a solid form
of Compound 1. In some such embodiments, the lupus is lupus erythematosus (such as
discoid lupus erythematosus, or cutaneous lupus erythematosus) or systemic lupus.
[00264] In another aspect provided herein are methods for treating or preventing
liver fibrotic disorders, such as non-alcoholic steatohepatitis, steatosis (i.e. fatty liver),
cirrhosis, primary sclerosing cholangitis, primary biliary cirrhosis, hepatitis, hepatocellular
carcinoma, and liver fibrosis coincident with chronic or repeated alcohol ingestion
(alcoholic hepatitis), with infection (e.g., viral infection such as HCV), with liver
transplant, or with drug induced liver injury (e.g., acetaminophen toxicity), comprising
administering to a subject in need thereof an effective amount of a solid form of
Compound 1. In some such aspects, provided herein are methods for treating or
preventing diabetes or metabolic syndrome leading to liver fibrotic disorders, such as nonalcoholic steatohepatitis, steatosis (i.e. fatty liver), cirrhosis, primary sclerosing
cholangitis, primary biliary cirrhosis, and hepatitis, comprising administering to a subject
in need thereof an effective amount of a solid form of Compound 1.
[00265] In another aspect provided herein are methods for treating or preventing
conditions treatable or preventable by inhibition of JNK1 and/or JNK2, the method
comprising administering to a subject in need thereof an effective amount of a solid form
of Compound 1. Examples of such conditions include rheumatoid arthritis; rheumatoid
spondylitis; osteoarthritis; asthma, bronchitis; allergic rhinitis; chronic obstructive
pulmonary disease; cystic fibrosis; inflammatory bowel disease; irritable bowel syndrome;
mucous colitis; ulcerative colitis; Crohn's disease; Huntington's disease; hepatitis;
pancreatitis; nephritis; multiple sclerosis; lupus erythematosus; Type II diabetes; obesity;
atherosclerosis; restenosis following angioplasty; left ventricular hypertrophy; myocardial
infarction; stroke; ischemic damages of heart, lung, gut, kidney, liver, pancreas, spleen and
brain; acute or chronic organ transplant rejection; preservation of the organ for
transplantation; organ failure or loss of limb (e.g., including, but not limited to, that
resulting from ischemia-reperfusion injury, trauma, gross bodily injury, car accident, crush
injury or transplant failure); graft versus host disease; endotoxin shock; multiple organ
failure; psoriasis; burn from exposure to fire, chemicals or radiation; eczema; dermatitis;
skin graft; ischemia; ischemic conditions associated with surgery or traumatic injury (e.g.,
vehicle accident, gunshot wound or limb crush); epilepsy; Alzheimer's disease; Parkinson's
disease; immunological response to bacterial or viral infection; cachexia; angiogenic and
proliferative diseases; solid tumor; and cancers of a variety of tissues such as colon,
rectum, prostate, liver, lung, bronchus, pancreas, brain, head, neck, stomach, skin, kidney,
cervix, blood, larynx, esophagus, mouth, pharynx, urinary bladder, ovary or uterine.
PHARMACEUTICAL COMPOSITIONS AND ROUTES OF ADMINISTRATION
[00266] The solid forms of Compound 1 can be administered to a subject orally,
topically or parenterally in the conventional form of preparations, such as capsules,
microcapsules, tablets, granules, powder, troches, pills, suppositories, injections,
suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions and
emulsions. Suitable formulations can be prepared by methods commonly employed using
conventional, organic or inorganic additives, such as an excipient (e.g., sucrose, starch,
mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium
carbonate), a binder (e.g., cellulose, methylcellulose, hydroxymethylcellulose,
polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethyleneglycol,
sucrose or starch), a disintegrator (e.g., starch, carboxymethylcellulose,
hydroxypropylstarch, low substituted hydroxypropylcellulose, sodium bicarbonate,
calcium phosphate or calcium citrate), a lubricant (e.g., magnesium stearate, light
anhydrous silicic acid, talc or sodium lauryl sulfate), a flavoring agent (e.g., citric acid,
menthol, glycine or orange powder), a preservative (e.g, sodium benzoate, sodium
bisulfite, methylparaben or propylparaben), a stabilizer (e.g., citric acid, sodium citrate or
acetic acid), a suspending agent (e.g., methylcellulose, polyvinyl pyrroliclone or aluminum
stearate), a dispersing agent (e.g., hydroxypropylmethylcellulose), a diluent (e.g., water),
and base wax (e.g., cocoa butter, white petrolatum or polyethylene glycol). The effective
amount of the solid forms of Compound 1 in the pharmaceutical composition may be at a
level that will exercise the desired effect; for example, about 0.005 mg/kg of a subject’s
body weight to about 10 mg/kg of a subject’s body weight in unit dosage for both oral and
parenteral administration.
[00267] The dose of a solid form of Compound 1 to be administered to a subject is
rather widely variable and can be subject to the judgment of a healthcare practitioner. In
general, the solid forms of Compound 1 can be administered one to four times a day in a
dose of about 0.005 mg/kg of a subject’s body weight to about 10 mg/kg of a subject’s
body weight in a subject, but the above dosage may be properly varied depending on the
age, body weight and medical condition of the subject and the type of administration. In
one embodiment, the dose is about 0.01 mg/kg of a subject’s body weight to about
mg/kg of a subject’s body weight, about 0.05 mg/kg of a subject’s body weight to about
1 mg/kg of a subject’s body weight, about 0.1 mg/kg of a subject’s body weight to about
0.75 mg/kg of a subject’s body weight or about 0.25 mg/kg of a subject’s body weight to
about 0.5 mg/kg of a subject’s body weight. In one embodiment, one dose is given per
day. In any given case, the amount of the solid form of Compound 1 administered will
depend on such factors as the solubility of the active component, the formulation used and
the route of administration. In one embodiment, application of a topical concentration
provides intracellular exposures or concentrations of about 0.01 – 10 M.
[00268] In another embodiment, provided herein are methods for the treatment or
prevention of a disease or disorder comprising the administration of about 0.375 mg/day to
about 750 mg/day, about 0.75 mg/day to about 375 mg/day, about 3.75 mg/day to about
75 mg/day, about 7.5 mg/day to about 55 mg/day or about 18 mg/day to about 37 mg/day
of a solid form of Compound 1 to a subject in need thereof.
[00269] In another embodiment, provided herein are methods for the treatment or
prevention of a disease or disorder comprising the administration of about 1 mg/day to
about 1200 mg/day, about 10 mg/day to about 1200 mg/day, about 100 mg/day to about
1200 mg/day, about 400 mg/day to about 1200 mg/day, about 600 mg/day to about
1200 mg/day, about 400 mg/day to about 800 mg/day, about 60 mg/day to about
720 mg/day, about 240 mg/day to about 720 mg/day or about 600 mg/day to about
800 mg/day of a solid form of Compound 1 to a subject in need thereof. In a particular
embodiment, the methods disclosed herein comprise the administration of 400 mg/day,
600 mg/day or 800 mg/day of a solid form of Compound 1 to a subject in need thereof.
[00270] In another embodiment, provided herein are methods for the treatment or
prevention of a disease or disorder comprising the administration of about 10 mg/day to
about 720 mg/day, about 10 mg/day to about 480 mg/day, about 60 mg/day to about
720 mg/day or about 240 mg/day to about 720 mg/day of a solid form of Compound 1 to a
subject in need thereof.
[00271] In another embodiment, provided herein are unit dosage formulations that
comprise between about 10 mg and 100 mg, about 1 mg and 200 mg, about 35 mg and
about 1400 mg, about 125 mg and about 1000 mg, about 250 mg and about 1000 mg, or
about 500 mg and about 1000 mg of a solid form of Compound 1.
[00272] In a particular embodiment, provided herein are unit dosage formulations
comprising about 100 mg or 400 mg of a solid form of Compound 1.
[00273] In another embodiment, provided herein are unit dosage formulations that
comprise about 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 50 mg, 60 mg, 70 mg,
100 mg, 120 mg, 125 mg, 140 mg, 175 mg, 200 mg, 240 mg, 250 mg, 280 mg, 350 mg,
480 mg, 500 mg, 560 mg, 700 mg, 720 mg, 750 mg, 1000 mg or 1400 mg of a solid form
of Compound 1.
[00274] In another embodiment, provided herein are unit dosage formulations that
comprise about 10 mg, 30 mg or 100 mg of a solid form of Compound 1.
[00275] A solid form of Compound 1 can be administered once, twice, three, four or
more times daily. In a particular embodiment, doses of 600 mg or less are administered as
a once daily dose and doses of more than 600 mg are administered twice daily in an
amount equal to one half of the total daily dose. In one embodiment, a solid form of
Compound 1 can be administered once daily for 14 days.
[00276] A solid form of Compound 1 can be administered orally for reasons of
convenience. In one embodiment, when administered orally, a solid form of Compound 1
is administered with a meal and water. In another embodiment, the solid form of
Compound 1 is dispersed in water or juice (e.g., apple juice or orange juice) and
administered orally as a suspension.
[00277] The solid form of Compound 1 can also be administered intradermally,
intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously,
intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally,
rectally, mucosally, by inhalation, or topically to the ears, nose, eyes, or skin. The mode
of administration is left to the discretion of the health-care practitioner, and can depend inpart upon the site of the medical condition.
[00278] In one embodiment, provided herein are capsules containing a solid form of
Compound 1 without an additional carrier, excipient or vehicle.
[00279] In another embodiment, provided herein are compositions comprising an
effective amount of a solid form of Compound 1 and a pharmaceutically acceptable carrier
or vehicle, wherein a pharmaceutically acceptable carrier or vehicle can comprise an
excipient, diluent, or a mixture thereof. In one embodiment, the composition is a
pharmaceutical composition.
[00280] The compositions can be in the form of tablets, chewable tablets, capsules,
solutions, parenteral solutions, troches, suppositories and suspensions and the like.
Compositions can be formulated to contain a daily dose, or a convenient fraction of a daily
dose, in a dosage unit, which may be a single tablet or capsule or convenient volume of a
liquid. In one embodiment, the solutions are prepared from water-soluble salts, such as the
hydrochloride salt. In general, all of the compositions are prepared according to known
methods in pharmaceutical chemistry. Capsules can be prepared by mixing a solid form of
Compound 1 with a suitable carrier or diluent and filling the proper amount of the mixture
in capsules. The usual carriers and diluents include, but are not limited to, inert powdered
substances such as starch of many different kinds, powdered cellulose, especially
crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose,
grain flours and similar edible powders.
[00281] Tablets can be prepared by direct compression, by wet granulation, or by
dry granulation. Their formulations usually incorporate diluents, binders, lubricants and
disintegrators as well as the compound. Typical diluents include, for example, various
types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts
such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also
useful. Typical tablet binders are substances such as starch, gelatin and sugars such as
lactose, fructose, glucose and the like. Natural and synthetic gums are also convenient,
including acacia, alginates, methylcellulose, polyvinylpyrrolidine and the like.
Polyethylene glycol, ethylcellulose and waxes can also serve as binders.
[00282] A lubricant might be necessary in a tablet formulation to prevent the tablet
and punches from sticking in the dye. The lubricant can be chosen from such slippery
solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable
oils. Tablet disintegrators are substances that swell when wetted to break up the tablet and
release the compound. They include starches, clays, celluloses, algins and gums. More
particularly, corn and potato starches, methylcellulose, agar, bentonite, wood cellulose,
powdered natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp and
carboxymethyl cellulose, for example, can be used as well as sodium lauryl sulfate.
Tablets can be coated with sugar as a flavor and sealant, or with film-forming protecting
agents to modify the dissolution properties of the tablet. The compositions can also be
formulated as chewable tablets, for example, by using substances such as mannitol in the
formulation.
[00283] When it is desired to administer a solid form of Compound 1 as a
suppository, typical bases can be used. Cocoa butter is a traditional suppository base,
which can be modified by addition of waxes to raise its melting point slightly. Watermiscible suppository bases comprising, particularly, polyethylene glycols of various
molecular weights are in wide use.
[00284] In certain embodiments, the pharmaceutical compositions provided herein
comprise Form A, including substantially pure Form A.
[00285] In certain embodiments, the pharmaceutical compositions provided herein
comprise Form B, including substantially pure Form B.
[00286] In certain embodiments, the pharmaceutical compositions provided herein
comprise Form C, including substantially pure Form C.
[00287] In certain embodiments, the pharmaceutical compositions provided herein
comprise Form D, including substantially pure Form D.
[00288] In certain embodiments, the pharmaceutical compositions provided herein
comprise Form E, including substantially pure Form E.
[00289] In certain embodiments, the pharmaceutical compositions provided herein
comprise Form F, including substantially pure Form F.
[00290] In certain embodiments, the pharmaceutical compositions provided herein
comprise Form G, including substantially pure Form G.
[00291] In certain embodiments, the pharmaceutical compositions provided herein
comprise Form H, including substantially pure Form H.
[00292] In certain embodiments, the pharmaceutical compositions provided herein
comprise Form I, including substantially pure Form I.
[00293] In certain embodiments, the pharmaceutical compositions provided herein
comprise the amorphous solid, including the substantially pure amorphous solid.
[00294] In certain embodiments, the pharmaceutical compositions provided herein
comprise a mixture of one or more solid form(s) of Compound 1, including Form A, Form B,
Form C, Form D, Form E, Form F, Form G, Form H, Form I and the amorphous solid.
EXAMPLES
[00295] The following Examples are presented by way of illustration, not limitation. The
following abbreviations are used in descriptions and examples:
ACN: Acetonitrile
Am: Amorphous
AmPhos: p-Dimethylamino phenylditbutylphosphine
API: Active Pharmaceutical Ingredient
Boc: tert-Butoxycarbonyl
n-BuOH: n-Butanol
dba: Dibenzylidene acetone
DBU: 1,8-Diazabicyclo[5.4.0]undecene
DCM: Dichloromethane
DIPEA: N,N-Diisopropylethylamine
DMAc: N,N-Dimethylacetamide
DMF: N,N-Dimethylformide
DMSO: Dimethylsulfoxide
DSC: Differential Scanning Calorimetry
DVS: Dynamic Vapor Sorption
EDTA: Ethylenediamine tetraacetate
ESI: Electronspray ionization
EtOAc: Ethyl acetate
EtOH: Ethanol
FTIR: Fourier Transform Infra Red Spectroscopy
HPLC: High performance liquid chromatography
IPA: 2-Propanol
IPAc: Isopropyl acetate
LCMS: Liquid Chromatography with Mass Spectroscopy
MEK: Methyl ethyl ketone
MeOH: Methanol
2-MeTHF: 2-Methyl tetrahydrofuran
mp: Melting point
THF (160 L) at 25 °C. The batch was cooled to 0 °C, and water (160 L) was added. The batch
was stirred for an additional 1 h at 0 °C, warmed to 25 °C and held for 16 h. Water (288 L) was
added to the batch while keeping the batch at 25 °C, and the batch was cooled to 15 °C and
agitated for an additional 4 hs. The batch was filtered, rinsed twice with water (2X80 L), and
dried in a vacuum oven at 40 °C with nitrogen bleed for 24 h to give 2-chloro{[(1R,3R,4R)
hydroxymethylcyclohexyl]amino}pyrimidinecarboxamide as white powder (23.3 kg, 86%
yield). 1
H NMR (DMSO-d6) δ 0.93 (d, J = 5.7 Hz, 3H), 0.97- 1.29 (m, 4H), 1.63- 1.68 (m, 1H),
1.75- 1.88 (m, 1H), 2.09-2.13 (m, lH), 3.00-3.08 (m, lH), 3.80-3.95 (m, lH), 4.65 (d, J = 5.1 Hz,
lH), 7.69 (br. s., 1H), 8.20 (br. s., lH), 8.53 (s, 1H), 9.22 (d, J = 7.5 Hz, lH).
[00298] 2-(tert-Butylamino){[(1R,3R,4R)hydroxymethylcyclohexyl]amino}
pyrimidinecarboxamide (Compound 1): To a reactor was charged 2-chloro
{[(1R,3R,4R)hydroxymethylcyclohexyl]amino}pyrimidinecarboxamide (41 kg),
t-butylamine (105.3 kg) and DMSO (205 L). The batch was heated to 68 °C under 10 psig of
nitrogen pressure, held for 80 h, and cooled to 25 °C. The batch was filtered through a 0.45 µm
in-line filter to a second reactor. The batch was heated to 60 °C, and water (205 L) was charged
through a 0.45 µm in-line filter. The batch was seeded with micronized Compound 1 (820 g)
agitated at 60 °C for over an hour, and water (615 L) was charged to the batch through a 0.45 µm
in-line filter in 3 h at 60 °C. The batch was agitated for 1 h at 60 °C, cooled to 25 °C over 6 h,
filtered, and washed with water (410 mL), which was filtered through a 0.45 µm in-line filter.
The solids were dried in a vacuum oven at 40 °C with nitrogen bleed for over 72 h to give
2-(tert-butylamino){[(1R,3R,4R)hydroxy methylcyclohexyl]amino}pyrimidine
carboxamide as Form A and a white solid (43.5 kg, 94% yield). 1
H NMR (DMSO-d6) δ 0.95 (d,
J=6.2 Hz, 3H), 0.97- 1.28 (m, 4H), 1.37 (s, 9H), 1.60- 1.75 (m, lH), 1.83-2.00 (m, IH), 2.06-2.26
(m, lH), 2.86-3.07 (m, 1H), 3.74-4.01 (m, lH), 4.59 (d, J= 5.7 Hz, lH), 6.65 (br. s., lH), 7.03 (br.
s., lH), 7.57 (br. s., lH), 8.36 (s, lH), 8.93 (br. s., lH).
[00299] Recrystallization of 2-(tert-butylamino){[(1R,3R,4R)hydroxy
methylcyclohexyl]amino}pyrimidinecarboxamide (Compound 1): To a reactor was
charged 2-(tert-buty1amino){[(1R,3R,4R)hydroxymethylcyclohexyl]amino}pyrimidine5-carboxamide (30 g), 2-propanol (203 mL) and water (67.5 mL). The batch was heated to
°C and filtered through a 0.45 µm in-line filter at 35 °C into a second reactor. The first
SOLID FORMS
ANALYTICAL METHODS
[00306] A polymorph screen of Compound 1 was performed to investigate whether
different solid forms could be generated under various conditions, such as different solvents,
temperature and humidity changes.
[00307] The solvents used in the polymorph screen were either HPLC or reagent grade,
including n-BuOH, acetone, ACN, ACN/water, DCM, DMSO, EtOAc, EtOH, EtOH/water,
heptane, heptanes, IPA, MEK, MeOH, MTBE, THF, THF/water, toluene and water.
[00308] All of solid samples generated in the polymorph screen were analyzed by XRPD.
XRPD analysis was conducted on a PANalytical Empyrean or a Thermo ARL X’TRA X-ray
powder diffractometer using Cu K radiation at 1.54 Å.
[00309] The PANalytical Empyrean instrument was equipped with a fine focus X-ray
tube. The voltage and amperage of the X-ray generator were set at 45 kV and 40 mA,
respectively. The divergence slits were set at 1/16° and 1/8°, and the receiving slits was set at
1/16°. Diffracted radiation was measured using a Pixel 2D detector. A theta-two theta
continuous scan was set at step size 0.013 or 0.026 from 3 to 40 2 with sample spinning rate
at 4. A sintered alumina standard was used to check the peak positions.
[00310] The Thermo ARL X’TRA instrument was equipped with a fine focus X-ray tube.
The voltage and amperage of the X-ray generator were set at 45 kV and 40 mA, respectively.
The divergence slits were set at 4 mm and 2 mm and the measuring slits were set at 0.5 mm and
0.2 mm. Diffracted radiation was measured using a Peltier-cooled Si (Li) solid-state detector. A
theta-two theta continuous scan at 2.40/min (0.5 sec/0.02 step) from 1.5 to 40 2 was used.
A sintered alumina standard was used to check the peak positions.
[00311] DSC analyses were performed on a TA Discovery Differential Scanning
Calorimeter. Indium was used as the calibration standard. Approximately 2-5 mg of sample was
placed into a DSC pan. The sample was heated under nitrogen at a rate of 10 C/min, up to a
final temperature of 300 C. Melting points were reported as the extrapolated onset
temperatures.
[00312] TGA analyses were performed on a TA Discovery Thermogravimetric Analyzer.
Calcium oxalate was used for a performance check. Approximately 2-10 mg of accurately
weighed sample was placed on a pan and loaded into the TGA furnace. The sample was heated
under nitrogen at a rate of 10 C/min, up to a final temperature of 300 C.
[00313] Morphology analysis of the samples was carried out on an Even Mini SEM.
Small amounts of samples were dispersed on a sample holder, and then coating with gold and
viewed with 500x magnification.
[00314] Hygroscopicity was determined on a Surface Measurement Systems DVS.
Typically a sample size of 5-20 mg was loaded into the DVS instrument sample pan and the
sample was analyzed on a DVS automated sorption analyzer at room temperature. The relative
humidity was increased from 0 % to 90 %RH at 10 %RH step, then at 95 % RH. The relative
humidity was then decreased in a similar manner to accomplish a full adsorption/desorption
cycle.
[00315] 1
H NMR spectra were obtained on a Bruker 300 MHz NMR spectrometer.
Samples were dissolved in DMSO-d6 and analyzed with 32 scans.
EQUILIBRATION/SLURRY AND EVAPORATION EXPERIMENTS
[00316] Equilibration (also referred to as slurry experiments) and evaporation experiments
were carried out by adding an excess of Compound 1 to upto 2 mL of a test solvent. The
resulting mixture was agitated for at least 24 h at room temperature and 50 C separately. Upon
reaching equilibrium, the saturated supernatant solution was removed, filtered using 0.45 µm
PTFE filters and allowed to evaporate in an open vial under nitrogen at room temperature and
50 C, respectively. The solid resulting from the equilibration was isolated and air-dried before
analysis.
[00317] Equilibration experiments were performed at room temperature and 50 C using
Form A as starting material. The results are summarized in Table 1. The solids isolated from
MTBE, heptanes and water were confirmed to be Form A by XRPD patterns. All other solvents
afforded new forms. The solids isolated from acetone, DCM, THF and THF/water were
designated as Form B. The solid isolated from EtOH/water, EtOH, ACN, ACN/water and IPA
were designated as Form C. The solids isolated from MeOH were designated as Form D. The
solids isolated from n-BuOH were designated as Form E. The solids isolated from toluene were
designated as Form F. The solids isolated from EtOAc were designated as Form G. The solids
isolated from DMSO were designated as Form H. All forms besides Form A were found to
solvate during further characterization.
[00318] Table 1. Equilibration Experiments of Form A at Room Temperature and 50 °C
Form by XRPD Solvent
RT 50 °C
Acetone B A+B
ACN C C
ACN/H2O (1:1) C C
n-BuOH E -
EtOH C -
EtOH/ H2O (1:1) C -
MeOH D -
IPA C -
EtOAc G -
MEK C B
DCM B -
MTBE A A
Heptane A A
Toluene F F
THF B -
THF/H2O (1:1) B -
H2O A A
- : not performed
[00319] Evaporation experiments were performed at room temperature and 50 C. The
results are summarized in Table 2. The solvents that showed enough solubility for Form A
afforded similar solvate forms as observed during the equilibration experiments.
[00320] Table 2. Evaporation Experiments of Form A at Room Temperature and 50 °C.
Form by XRPD Solvent
RT 50 °C
Acetone - -
ACN - -
ACN/H2O (1:1) C C
Form by XRPD Solvent
RT 50 °C
n-BuOH - E
EtOH C C
EtOH/H2O (1:1) C A
MeOH D D
IPA C C
EtOAc G G
MEK - -
DCM - -
MTBE - -
Heptane - -
Toluene - -
THF B B
THF/ H2O (1:1) B B
H2O - -
- : Not analyzable
ANTI-SOLVENT RECRYSTALLIZATION AND COOLING RECRYSTALLIZATION
EXPERIMENTS
[00321] For cooling recrystallization, each of the selected solvents (MeOH, EtOH,
EtOH/water) was saturated with Compound 1 at 60 °C. The solution was stirred at 60 °C for
minutes, filtered using a 0.45 µm PTFE syringe filter, and then cooled to room temperature
naturally and then placed into a refrigerator. The solid resulting from the recrystallization was
isolated and air-dried before analysis.
[00322] For anti-solvent recrystallization, the selected solvents (MeOH, EtOH, IPA, and
EtOAc) were saturated with Compound 1 at 60 °C. Once the solid was completely dissolved, a
portion of the solution was filtered into a pre-heated vial and a selected anti-solvent (water,
MTBE, or heptane) was added at 60 °C. The mixture was cooling to room temperature naturally
and then placed into a refrigerator. The solid resulting from the recrystallization was isolated
and air-dried before analysis.
[00323] MeOH, EtOH, EtOH/water, IPA, and EtOAc were used as single or primary
solvents. Water, MTBE, and heptanes were used as anti-solvent. The results are summarized in
Table 3. Only crystallizations using water as anti-solvents generated Form A. All other solvents
or solvent combinations afforded similar solvate forms as observed during equilibration
experiment.
[00324] Table 3. Summary of Recrystallization Experiments.
Primary solvent Anti-Solvent Solvent ratio Form by XRPD
MeOH n/a n/a D
EtOH n/a n/a C
EtOH/H2
O (1:1) n/a n/a C
MeOH water 1:9 A
MeOH MTBE 1:9 D
EtOH water 1:9 A
EtOH MTBE 1:9 A+C
EtOH heptane 1:9 C
EtOH ACN 1:9 C
IPA heptane 1:9 A+B+C
EtOAc MTBE 1:9 G
EtOAc heptane 1:9 G
n/a: not applicable.
[00325] Additional experiments were performed using DMSO as the primary solvent. The
solids isolated were found to be a new form and designated as Form H.
CONVERSION EXPERIMENTS
[00326] Further form conversion experiments were performed to determine
interconversion among solid forms. The results are summarized in Table 4. The solvated forms
were isothermally held at 150 °C for 5 min and the resulted solids were consistent with Form A.
All aqueous slurries also afforded Form A.
[00327] Table 4. Converstion Experiments of Compound 1
Starting Solid Form (s) Solvent/Condition Temperature/Condition XRPD Result
Form B Heating Isothermal hold at 150 °C
for 5 min Form A
Form C Heating Isothermal hold at 150 °C
for 5 min Form A
Form D Heating Isothermal hold at 150 °C
for 5 min Form A
Form E Heating Isothermal hold at 150 °C
for 5 min Form A
Form F Heating Isothermal hold at 150 °C
for 5 min Form A
Form G Heating Isothermal hold at 150 °C
for 5 min Form A
Form H Heating Isothermal hold at 150 °C
for 5 min Form A
Form B Slurry in water RT, 5 days Form A
Form C Slurry in water RT, 5 days Form A
Form D Slurry in water RT, 5 days Form A
Form E Slurry in water RT, 5 days Form A
Form F Slurry in water RT, 5 days Form A
Form G Slurry in water RT, 5 days Form A
Form H Slurry in water RT, 5 days Form A
SUMMARY OF POLYMORPHIC FORMS
[00328] A total of eight crystalline forms for Compound 1 were found during this
polymorph screen study. The stack plot of XRPD patterns for these forms are shown in FIG. 37,
and the physical characteristics are summarized in Table 5.
[00329] Table 5. Summary of Physical Characterization of Compound 1 Crystalline
Forms.
Form Description Representative
conditions
DSC onset or
peak ( °C)
TGA
loss
(wt%)
DVS or other
comments
A nonstoichiometric channel
hydrate
Rx from water-rich
solvent system
223 (onset) 0.5 1.2 wt% water
uptake at from
0 to 95 %RH;
1.0 wt% at
80 %RH
B solvate Slurry or Rx from
acetone (or DCM,
THF)
147 (small endo),
223 (onset)
8.5 n/a
C solvate Slurry or Rx from
EtOH/water (or
EtOH, ACN, IPA)
143 (small endo),
224 (onset)
7.3 n/a
D solvate Slurry or Rx from
MeOH
171 (small endo),
223 (onset)
~ 4 n/a
E solvate Slurry in n-BuOH 124 (small endo),
224 (onset)
.3 n/a
F solvate Slurry in toluene 113 (small endo),
223 (onset)
6.9 n/a
G solvate Slurry or Rx from
EtOAc
116 (small endo),
223 (onset)
11.9 n/a
H solvate Slurry in DMSO 160 (small endo),
222 (onset)
11.2 n/a
I solvate Rx from sulfolane
and water (1:1).
118 (small endo),
213 (m.p.)
n/a n/a
amorph
ous
Heat treatment Glass transition
temperature:
106.6
n/a n/a
n/a: not available.
FORM A
[00330] Form A is a non-stoichiometric channel hydrate crystalline solid form of
Compound 1. This form was mostly obtained from recrystallization or slurry experiments in
aqueous or “water-rich” solvent systems.
[00331] Form A can also be obtained by conversion from Form H. A mixture of crude
Form H (4 g) and water (40 mL) was heated to 70 °C for 3 hours. After cooling to room
temperature, the product was collected by suction filtration. The wet cake was dried in a vacuum
oven at 40 °C with a nitrogen bleed for 16 hours to give 2-(tert-butylamino)((1R,3R,4R)
hydroxymethylcyclohexylamino)pyrimidinecarboxamide as Form A and a white solid
(3.54 g, 80 %).
[00332] The effect of temperature (22 °C - 70 °C) and water compositions in DMSO
(50%-88%) on the stability of Form A and Form H of Compound 1 is mapped out in Table 6 and
FIG. 45. This information indicates that Form A is the thermodynamically stable form in the
water rich water/DMSO mixture (>70%).
[00333] Table 6. Stable forms after slurry experiments of Form H in ratio of water/DMSO
from 50 to 88% and temperatures from 22 to 70 °C
% water in DMSO (Stable Polymorph Form) Temperature 50% 60% 67% 70% 80% 86% 88%
70 °C A
60 °C A A A A
40 °C H A/H A A
22 °C A/H H H A A A A
[00334] Form A was favored at 60 °C from 1:1 (50% water) to 1:4 DMSO:Water (80%
water) and remained as Form A at 22 °C in 70-88% water in DMSO. 70% water in DMSO was
at the edge of the Form conversion between Form A and Form H. Therefore, the final solvent
composition was selected as 80% water in DMSO. These results indicated that for a synthesis of
Compound 1 employing 5X vol. of DMSO, the addition of 20 X vol of water at 60 °C to the
reaction mixture after reaction completion would afford Compound 1 as Form A.
[00335] Form A has a crystalline XRPD pattern as shown in FIG. 1. The crystal habit is
cube-like or rod-like as shown in FIG. 2. TGA and DSC thermograms of Form A are shown in
FIG. 4 and FIG. 5, respectively. The DSC thermogram showed only one major event with an
onset temperature of 223 °C, corresponding to melt/decomposition. TGA weight loss of 0.45%
was observed up to 150 °C. The 1
H NMR spectrum of Form A was consistent with Compound 1
structure (see FIG. 7).
[00336] The moisture sorption/desorption behavior of Form A was determined by DVS.
The results are summarized in FIG. 6. A total mass change of 2.3 % was observed between
0 and 95 %RH, with a steep change of 1.3 % between 0 and 10 %RH. After undergoing the
adsorption/desorption cycles, the XRPD diffractogram of the sample showed no change (see
FIG. 8). Steep change between 0 and 10 %RH was observed for several samples, but the amount
of water uptake varied among samples. The total water uptake between 0 and 95 %RH ranged
from approximately 0.5 % to 2 % for all Form A samples analyzed.
[00337] Further characterization using single-crystal X-ray diffraction was performed for
Form A. The structure was resolved in the space group P2(1)2(1)2(1). The crystal data and
structure refinement is summarized in Table 7. The power x-ray pattern was calculated and
matched the experimental XRPD patterns observed for Form A, as shown in FIG. 1. Fractional
occupancy of water molecules was found in the crystal lattice. Inclusion of roughly 20% of
occupancy lowered the R factor from 5.2 % to 3.6 %. The drawing of cell packing along b-axis
as shown in FIG. 2 revealed channeled water molecules in the crystal lattice. These observations
suggested that Form A is a channel hydrate. The theoretical water content is 1.1 wt% for
0.2 molar equivalents of water and 2.7 wt% for 0.5 molar equivalents of water.
[00338] Table 7. Crystal data and structure refinement for Form A.
Empirical formula C16 H27 N5 O2 (w/ ca. 0.2 H2O)
Formula weight 321.43
Temperature 100(2) K
Wavelength 0.71073 Å
Crystal system Orthorhombic
Space group P2(1)2(1)2(1)
Unit cell dimensions a = 10.2905(15) Å; α= 90°
b = 10.7755(19) Å β= 90°
c = 16.557(2) Å γ= 90°
Volume 1836.0(5) Å3
Z 4
Density (calculated) 1.163 g/cm3
Absorption coefficient 0.079 mm
-1
F(000) 696
Crystal size 0.35 x 0.35 x 0.30 mm3
Theta range for data collection 3.68 to 25.43°
Index ranges -12<=h<=12, -12<=k<=12, -18<=l<=19
Reflections collected 7480
Independent reflections 3297 [R(int) = 0.0369]
Completeness to theta = 25.00° 99.5 %
Absorption correction Multi-scan
Max. and min. transmission 0.9766 and 0.9728
Refinement method Full-matrix least-squares on F2
Data / restraints / parameters 3297 / 2 / 221
Goodness-of-fit on F2 1.046
Final R indices [I>2sigma(I)] R1 = 0.0365, wR2 = 0.0868
R indices (all data) R1 = 0.0433, wR2 = 0.0910
Absolute structure parameter 0.8(12)
Largest diff. peak and hole 0.175 and -0.170 e Å-3
[00339] The stability of Form A was further characterized by compression test and form
transfer experiments. Upon application of 2000-psi pressure for about 1 minute, the material was
still Form A, with slightly broader diffraction peaks (see FIG. 9). Results from form transfer
experiments in Table 4 showed that all solvate forms convert to Form A upon desolvation by
heating or upon slurry in water. These results suggested that Form A is a most stable or
developable form of Compound 1.
[00340] FIG. 1 provides an XRPD pattern of Form A. A list of X-Ray Diffraction Peaks
for Form A is provided below in Table 8.
[00341] Table 8. X-Ray Diffraction Peaks for Form A
Two-theta angle (°) d Space (Å)
Relative
Intensity (%)
9.74 9.0811 3.7
.55 8.3820 56.2
11.86 7.4633 26.2
12.98 6.8187 6.9
13.61 6.5079 100.0
.90 5.5750 6.4
16.41 5.4031 2.9
17.20 5.1550 43.0
17.85 4.9706 31.9
18.04 4.9180 42.6
18.54 4.7868 7.8
19.29 4.6003 5.3
19.56 4.5386 15.2
19.84 4.4744 83.5
.19 4.3989 1.8
21.37 4.1572 15.1
21.83 4.0715 10.8
22.90 3.8842 29.7
23.46 3.7920 8.5
23.84 3.7320 3.6
24.36 3.6537 30.0
24.88 3.5782 4.6
.29 3.5222 2.3
26.14 3.4093 2.7
26.92 3.3120 2.1
27.83 3.2055 6.8
28.30 3.1538 8.8
28.69 3.1115 1.5
29.21 3.0574 5.6
.50 2.9314 1.2
31.63 2.8286 2.1
32.11 2.7878 1.5
32.63 2.7444 2.7
33.17 2.7008 0.6
34.32 2.6129 1.1
34.74 2.5826 3.1
36.00 2.4950 1.7
36.56 2.4582 2.7
36.95 2.4330 1.8
37.26 2.4131 1.5
Two-theta angle (°) d Space (Å)
Relative
Intensity (%)
37.61 2.3918 3.3
38.40 2.3442 1.5
39.07 2.3056 2.7
39.34 2.2905 1.5
39.64 2.2739 1.0
[00342] FIG. 3 is an SEM image of Form A.
[00343] The intrinsic solubility of Form A at 25 °C after 24 h was 0.038 mg/mL and 0.289
mg/mL at pH 4.5. Although Form A is a channel hydrate, it has a relatively slow water uptake at
room temperature. However, Form A may potentially absorb up to 3% water after storage at 40
°C/75%RH for 7 months. The water uptake may strongly depend on the humidity of the storage
conditions and therefore, it is recommended to protect Compound 1 from moisture during
storage.
FORM B
[00344] Form B was obtained from recrystallization or slurry experiments of Form A in
acetone, CH2Cl2 or THF. Form B had a crystalline XRPD pattern as shown in FIG. 10. TGA
and DSC thermograms of Form B obtained from acetone are shown in FIG. 11 and FIG. 12,
respectively. The TGA weight loss of 8.5 wt% corresponded to small broad DSC peak around
147 °C and can be attributed to loss of solvent in Form B. The major DSC peak with onset
temperature of 223 °C corresponded to the melt/decomposition of Form A. The 1
H-NMR
spectrum was obtained for the Form B sample and showed approximately 0.5 molar equivalents
of acetone (see FIG. 13). The theoretical acetone content of a hemi-solvate of Compound 1 is
8.3 wt%, matching the TGA weight loss observed. These observations suggested that Form B is
an acetone hemi-solvate of Compound 1. Form transfer experiment showed that heating Form B
above the desolvation temperature resulted in Form A. Slurry of Form B in water also resulted
in Form A.
[00345] A list of X-Ray Diffraction Peaks for Form B is provided below in Table 9.
[00346] Table 9. X-Ray Diffraction Peaks for Form B
Two-theta angle (°) d Space (Å)
Relative
Intensity (%)
9.80 9.0251 100.0
.30 8.5867 16.4
12.23 7.2379 5.6
14.62 6.0604 10.9
16.70 5.3091 2.0
17.29 5.1285 96.6
18.23 4.8654 25.4
18.59 4.7722 5.3
19.61 4.5268 0.6
.19 4.3976 2.9
.66 4.2992 11.4
.94 4.2425 2.2
21.74 4.0873 96.5
23.03 3.8620 1.4
23.84 3.7327 1.5
24.32 3.6599 2.0
24.58 3.6223 6.0
.88 3.4425 7.1
26.27 3.3924 6.9
26.86 3.3192 8.3
27.52 3.2411 2.4
28.35 3.1478 4.1
28.62 3.1190 1.2
29.63 3.0155 5.6
.55 2.9265 9.9
.87 2.8965 2.2
31.44 2.8459 1.7
32.12 2.7871 0.6
33.71 2.6592 1.2
33.95 2.6407 0.8
34.96 2.5667 1.5
.94 2.4987 2.1
36.14 2.4855 1.3
36.56 2.4579 1.8
37.22 2.4156 0.6
38.76 2.3230 1.4
[00347] FIG. 13 provides a 1
H NMR (DMSO-d6) of Form B with δ 0.94 (d, J = 6.4 Hz,
3H), 0.96 - 1.04 (m, 1H), 1.04 - 1.28 (m, 3H), 1.36 (s, 9H), 1.60 - 1.74 (m, 1H), 1.83 - 1.98 (m,
1H), 2.09 (s, 3H, acetone), 2.10 - 2.19 (m, 1H), 2.89 - 3.04 (m, 1H), 3.76 - 3.99 (m, 1H), 4.57 (d,
J = 5.5 Hz, 1H), 6.64 (br. s., 1H), 6.94 (br. s., 1H), 7.51 (br. s., 1H), 8.34 (s, 1H), 8.93 (br. s.,
1H).
FORM C
[00348] Form C was obtained from recrystallization or slurry experiments of Form A in
EtOH/water, EtOH, ACN or IPA. Form C had a crystalline XRPD pattern as shown in FIG. 14.
TGA and DSC thermograms of Form C obtained from EtOH/water are shown in FIG. 15 and
FIG. 16, respectively. The TGA weight loss of 7.3 wt% corresponded to small broad DSC peak
around 143 °C and can be attributed to loss of solvent in Form C. The major DSC peak with
onset temperature of 224 °C corresponded to the melt/decomposition of Form A. The 1
H-NMR
spectrum was obtained for the Form C sample and showed approximately 0.5 molar equivalents
of EtOH (see FIG. 17). The theoretical EtOH content of a hemi-solvate of Compound 1 is
6.7 wt%, matching the TGA weight loss observed. These observations suggested that Form C is
an ethanol hemi-solvate of Compound 1. Form transfer experiment showed that heating Form C
above the desolvation temperature resulted in Form A. Slurry of Form C in water also resulted
in Form A.
[00349] A list of X-Ray Diffraction Peaks for Form C is provided below in Table 10.
[00350] Table 10. X-Ray Diffraction Peaks for Form C
Two-theta angle (°) d Space (Å)
Relative
Intensity (%)
9.83 8.9960 77.7
.21 8.6630 23.0
12.16 7.2807 13.3
14.66 6.0419 9.6
.52 5.7080 0.8
16.50 5.3712 1.4
17.26 5.1376 62.2
17.61 5.0354 19.6
17.91 4.9534 8.9
18.18 4.8799 18.5
18.65 4.7591 12.5
19.67 4.5133 1.4
19.99 4.4414 2.9
.46 4.3399 14.2
21.86 4.0664 100.0
Two-theta angle (°) d Space (Å)
Relative
Intensity (%)
23.32 3.8151 2.9
23.78 3.7416 3.9
24.44 3.6421 8.4
.65 3.4730 9.8
.81 3.4520 5.8
26.28 3.3914 8.4
26.72 3.3360 7.9
27.46 3.2481 2.6
28.04 3.1820 1.5
28.30 3.1536 2.6
28.60 3.1210 8.3
29.56 3.0216 5.5
.47 2.9342 3.7
.70 2.9127 6.8
31.29 2.8586 2.3
31.77 2.8170 0.8
32.16 2.7830 0.5
32.94 2.7194 0.4
33.55 2.6708 0.9
34.00 2.6367 1.1
34.85 2.5744 0.6
.14 2.5541 0.5
.57 2.5238 1.9
.90 2.5013 1.9
36.62 2.4542 2.2
37.76 2.3828 0.7
38.93 2.3136 1.1
[00351] FIG. 17 provides a 1
H NMR (DMSO-d6) of Form C with δ 0.94 (d, J = 6.4 Hz,
3H), 1.00 - 1.27 (m, 5.6 H) {include 1.02 (t, J = 7.0 Hz, 1.6H, ethanol)}, 1.36 (s, 9H), 1.67 (dd,
J = 3.3, 13.1 Hz, 1H), 1.81 - 2.00 (m, 1H), 2.10 - 2.24 (m, 1H), 2.87 - 3.05 (m, 1H), 3.32 (s, 4H),
3.44 (qd, J = 5.1, 7.0 Hz, 1H, ethanol), 3.74 - 3.99 (m, 1H), 4.35 (t, J = 5.1 Hz, 1H), 4.57 (d,
J = 5.7 Hz, 1H), 6.45 - 6.77 (m, 1H), 6.92 (br. s., 1H), 7.51 (br. s., 1H), 8.34 (s, 1H), 8.92 (br. s.,
1H).
FORM D
[00352] Form D was obtained from recrystallization or slurry experiments of Form A in
MeOH. Form D had a crystalline XRPD pattern as shown in FIG. 18. TGA and DSC
thermograms of Form D are shown in FIG. 19 and FIG. 20, respectively. The TGA weight loss
of approximately 4 wt% corresponded to small DSC peak around 170 °C and can be attributed to
loss of solvent in Form D. The major DSC peak with onset temperature of 223 °C corresponded
to the melt/decomposition of Form A. The 1
H-NMR spectrum was obtained for the Form D
sample and showed approximately 0.5 molar equivalents of MeOH (see FIG. 21). The
theoretical MeOH content of a hemi-solvate of Compound 1 is 4.7 wt%, similar to the TGA
weight loss observed. These observations suggested that Form D is most likely a methanol
hemi-solvate of Compound 1. Form transfer experiment showed that heating Form D above the
desolvation temperature resulted in Form A. Slurry of Form D in water also resulted in Form A.
[00353] A list of X-Ray Diffraction Peaks for Form D is provided below in Table 11.
[00354] Table 11. X-Ray Diffraction Peaks for Form D
Two-theta angle (°) d Space (Å)
Relative
Intensity (%)
.37 8.5278 100.0
12.85 6.8897 6.7
13.41 6.6046 42.7
.68 5.6527 6.5
16.25 5.4562 3.4
17.02 5.2108 9.8
17.54 5.0569 22.7
17.73 5.0013 38.0
18.34 4.8371 3.9
19.52 4.5474 65.5
19.93 4.4550 3.1
.78 4.2750 9.7
21.09 4.2119 2.6
21.54 4.1252 14.1
22.47 3.9564 42.4
23.11 3.8492 12.0
23.55 3.7780 2.7
23.92 3.7207 37.4
24.51 3.6324 4.7
24.99 3.5627 1.3
Two-theta angle (°) d Space (Å)
Relative
Intensity (%)
.81 3.4516 2.6
26.47 3.3669 4.0
26.88 3.3167 1.4
27.33 3.2634 8.3
27.83 3.2056 5.5
28.19 3.1659 1.3
28.64 3.1168 6.2
.08 2.9709 0.7
.82 2.9013 1.7
31.20 2.8667 3.2
31.60 2.8315 0.8
32.02 2.7952 2.2
32.50 2.7551 4.7
33.58 2.6692 1.6
34.25 2.6183 1.6
.39 2.5363 0.6
.87 2.5034 2.8
36.55 2.4588 1.5
36.81 2.4415 2.7
37.06 2.4261 2.1
37.77 2.3820 2.8
38.60 2.3323 1.8
[00355] FIG. 21 provides a 1
H NMR (DMSO-d6) of Form D with δ 0.94 (d, J = 6.4 Hz,
3H), 0.96 - 1.04 (m, 1H), 1.05 - 1.28 (m, 3H), 1.36 (s, 9H), 1.67 (dd, J = 3.1, 13.1 Hz, 1H), 1.84 -
1.97 (m, 1H), 2.08 - 2.20 (m, 1H), 2.86 - 3.04 (m, 1H), 3.17 (d, J = 5.3 Hz, 1.6H, methanol), 3.76
- 3.99 (m, 1H), 4.09 (q, J = 5.3 Hz, 1H), 4.57 (d, J = 5.5 Hz, 1H), 6.65 (br. s., 1H), 6.95 (br. s.,
1H), 7.47 (br. s., 1H), 8.34 (s, 1H), 8.93 (br. s., 1H).
FORM E
[00356] Form E was obtained from recrystallization or slurry experiments of Form A in
n-BuOH. Form E had a crystalline XRPD pattern as shown in FIG. 22. TGA and DSC
thermograms of Form E are shown in FIG. 23 and FIG. 24, respectively. The TGA weight loss
of 10.3 wt% corresponded to small broad DSC peak around 124 °C and can be attributed to loss
of solvent in Form E. The major DSC peak with onset temperature of 224 °C corresponded to
the melt/decomposition of Form A. The 1
H-NMR spectrum was obtained for the Form E sample
and showed approximately 0.5 molar equivalents of n-BuOH (see FIG. 25). The theoretical
n-BuOH content of a hemi-solvate of Compound 1 is 10.3 wt%, matching the TGA weight loss
observed. These observations suggested that Form E is an n-BuOH hemi-solvate of Compound
1. Form transfer experiment showed that heating Form E above the desolvation temperature
resulted in Form A. Slurry of Form E in water also resulted in Form A.
[00357] A list of X-Ray Diffraction Peaks for Form E is provided below in Table 12.
[00358] Table 12. X-Ray Diffraction Peaks for Form E
Two-theta angle (°) d Space (Å)
Relative
Intensity (%)
8.70 10.1625 3.1
9.92 8.9143 66.8
.36 8.5380 19.6
11.97 7.3945 10.4
14.50 6.1092 11.3
.51 5.7126 0.9
16.39 5.4097 6.2
17.29 5.1283 55.7
18.37 4.8287 40.5
19.55 4.5419 3.0
.10 4.4180 15.6
21.81 4.0760 100.0
23.21 3.8330 3.2
23.45 3.7936 4.6
24.17 3.6830 9.0
24.61 3.6175 1.1
.44 3.5013 6.4
.83 3.4496 6.6
26.23 3.3982 6.1
26.45 3.3701 9.5
26.61 3.3495 5.8
27.64 3.2274 2.4
28.48 3.1337 8.4
29.19 3.0593 2.9
29.97 2.9820 5.4
.39 2.9413 1.3
.81 2.9025 5.0
31.36 2.8530 2.6
31.66 2.8265 1.1
32.62 2.7454 0.6
Two-theta angle (°) d Space (Å)
Relative
Intensity (%)
33.67 2.6621 2.1
34.75 2.5819 1.2
.24 2.5467 1.9
.96 2.4975 1.7
36.48 2.4630 3.4
37.20 2.4169 0.5
37.62 2.3911 0.3
38.93 2.3136 0.6
39.20 2.2983 0.6
[00359] FIG. 25 provides a 1
H NMR (DMSO-d6) of Form E with δ 0.85 (t, J = 7.2 Hz,
1.5H, n-butanol), 0.94 (d, J = 6.4 Hz, 3H), 0.96 - 1.04 (m, 1H), 1.04 - 1.25 (m, 3H), 1.25 - 1.46
(m, 11H){ {include 1.36 (s, 9H), 1.3 - 1.46 (m, 2H, n-butanol) }, 1.67 (dd, J = 3.2, 13.0 Hz, 1H),
1.81 - 2.00 (m, 1H), 2.10 - 2.24 (m, 1H), 2.86 - 3.05 (m, 1H), 3.35 - 3.44 (m, 1H, n-butanol),
3.75 - 3.99 (m, 1H), 4.31 (t, J = 5.2 Hz, 0.5H), 4.57 (d, J = 5.7 Hz, 1H), 6.65 (br. s., 1H), 6.97
(br. s., 1H), 7.53 (br. s., 1H), 8.34 (s, 1H), 8.93 (br. s., 1H).
FORM F
[00360] Form F was obtained from recrystallization or slurry experiments of Form A in
toluene. Form F had a crystalline XRPD pattern as shown in FIG. 26. The diffuse character of
the diffraction pattern suggested low crystalline of the sample. TGA and DSC thermograms of
Form F are shown in FIG. 27 and FIG. 28, respectively. The TGA weight loss of 6.9 wt%
corresponded to small broad DSC peak around 113 °C and can be attributed to loss of solvent in
Form F. The major DSC peak with onset temperature of 223 °C corresponded to the
melt/decomposition of Form A. The 1
H-NMR spectrum obtained for the Form F sample showed
approximately 0.3 molar equivalents of toluene (see FIG. 29), matching the TGA weight loss
observed. These observations suggested that Form F is a 0.3 molar toluene solvate of Compound
1. Form transfer experiment showed that heating Form F above the desolvation temperature
resulted in Form A. Slurry of Form F in water also resulted in Form A.
[00361] A list of X-Ray Diffraction Peaks for Form F is provided below in Table 13.
[00362] Table 13. X-Ray Diffraction Peaks for Form F
Two-theta angle (°) d Space (Å)
Relative
Intensity (%)
8.07 10.9511 52.7
9.21 9.5984 41.8
.58 8.3604 19.2
.88 8.1318 17.4
12.06 7.3409 48.5
14.56 6.0822 22.0
14.87 5.9564 22.1
16.28 5.4434 21.3
17.45 5.0817 58.1
17.79 4.9851 48.4
18.53 4.7887 98.0
19.65 4.5174 35.7
.05 4.4277 17.4
.85 4.2615 100.0
21.10 4.2108 83.7
23.72 3.7519 4.5
24.41 3.6467 19.0
.11 3.5470 15.8
.98 3.4300 16.6
26.61 3.3499 5.2
27.94 3.1938 9.7
29.25 3.0532 4.4
.40 2.9405 6.1
32.00 2.7967 1.7
34.06 2.6325 2.8
.72 2.5139 3.6
36.58 2.4567 3.1
37.59 2.3928 3.2
[00363] FIG. 29 provides a 1
H NMR (DMSO-d6) of Form F with δ 0.94 (d, J = 6.4 Hz,
3H), 0.96 - 1.04 (m, 1H), 1.04 - 1.29 (m, 3H), 1.35 (s, 9H), 1.67 (dd, J = 3.3, 13.1 Hz, 1H), 1.90
(d, J = 9.3 Hz, 1H), 2.06 - 2.23 (m, 1H), 2.30 (s, 0.9H, toluene), 2.89 - 3.04 (m, 1H), 3.71 - 4.00
(m, 1H), 4.57 (d, J = 5.7 Hz, 1H), 6.64 (br. s., 1H), 6.94 (br. s., 1H), 7.08 - 7.30 (m, 1.4H,
toluene), 7.50 (br. s., 1H), 8.34 (s, 1H), 8.93 (br. s., 1H).
FORM G
[00364] Form G was obtained from recrystallization or slurry experiments of Form A in
EtOAc. Form G had a crystalline XRPD pattern as shown in FIG. 30. TGA and DSC
thermograms of Form G are shown in FIG. 31 and FIG. 32, respectively. The TGA weight loss
of 11.9 wt% corresponded to small broad DSC peak around 116 °C and can be attributed to loss
of solvent in Form G. The major DSC peak with onset temperature of 223 °C corresponded to
the melt/decomposition of Form A. The 1
H-NMR spectrum obtained for the Form G sample
showed approximately 0.5 molar equivalents of EtOAc (see FIG. 33). The theoretical EtOAc
content of a hemi-solvate of Compound 1 is 12.1 wt%, matching the TGA weight loss observed.
These observations suggested that Form G is an EtOAc hemi-solvate of Compound 1. Form
transfer experiment showed that heating Form G above the desolvation temperature resulted in
Form A. Slurry of Form G in water also resulted in Form A.
[00365] A list of X-Ray Diffraction Peaks for Form G is provided below in Table 14.
[00366] Table 14. X-Ray Diffraction Peaks for Form G
Two-theta angle (°) d Space (Å)
Relative
Intensity (%)
8.63 10.2508 0.7
9.51 9.3026 100.0
.34 8.5585 15.1
12.14 7.2888 0.5
14.43 6.1377 2.3
16.44 5.3907 1.3
16.94 5.2347 10.9
17.33 5.1185 5.0
17.90 4.9555 17.9
18.58 4.7768 4.2
19.10 4.6467 0.9
.09 4.4211 0.4
.41 4.3507 2.1
.80 4.2704 0.4
21.28 4.1747 34.8
22.66 3.9240 0.4
23.62 3.7671 0.3
24.33 3.6584 2.8
.55 3.4842 1.6
.65 3.4726 1.9
26.42 3.3739 1.1
26.89 3.3128 0.3
27.00 3.3030 0.4
27.78 3.2114 0.9
Two-theta angle (°) d Space (Å)
Relative
Intensity (%)
28.83 3.0969 9.1
29.86 2.9925 1.5
31.22 2.8651 6.8
31.77 2.8164 0.1
32.67 2.7410 0.2
33.90 2.6443 0.7
34.28 2.6156 0.2
.04 2.5606 0.5
.44 2.5326 0.2
36.24 2.4789 0.5
36.57 2.4574 0.5
37.59 2.3926 0.4
38.00 2.3681 0.3
38.76 2.3231 0.4
[00367] FIG. 33 provides a 1
H NMR (DMSO-d6) of Form G with δ 0.94 (d, J = 6.4 Hz,
3H), 0.96 - 1.04 (m, 1H), 1.04 - 1.29 (m, 5H) {include 1.17 (t, J = 9.0 Hz, EtOAc)}, 1.29 - 1.46
(m, 9H), 1.60 - 1.76 (m, 1H), 1.86 - 1.96 (m, 1H), 1.99 (s, 1.4H, EtOAc), 2.04 - 2.16 (m, 1H),
2.88 - 3.06 (m, 1H), 3.75 - 3.97 (m, 1H), 4.03 (q, J = 7.1 Hz, 1H, EtOAc), 4.57 (d, J = 5.7 Hz,
1H), 6.65 (br. s., 1H), 6.94 (br. s., 1H), 7.52 (br. s., 1H), 8.34 (s, 1H), 8.93 (br. s., 1H).
FORM H
[00368] Form H was obtained from recrystallization or slurry of Form A in DMSO.
Form H had a crystalline XRPD pattern as shown in FIG. 34. TGA and DSC thermograms of
Form H are shown in FIG. 35 and FIG. 36, respectively. The TGA thermogram showed a step
weight loss of 11.2 wt% corresponded to small broad DSC peak around 160 °C and can be
attributed to loss of solvent in Form H. The major DSC peak with onset temperature of 222 °C
corresponded to the melt/decomposition of Form A. The theoretical DMSO content of a hemisolvate of Compound 1 is 10.8 wt%, matching the TGA weight loss observed. These
observations suggested that Form H is a DMSO hemi-solvate of Compound 1. Form transfer
experiment showed that heating Form H above the desolvation temperature resulted in Form A.
Slurry of Form H in water also resulted in Form A.
[00369] A list of X-Ray Diffraction Peaks for Form H is provided below in Table 15.
[00370] Table 15. X-Ray Diffraction Peaks for Form H
Two-theta angle (°) d Space (Å)
Relative
Intensity (%)
8.69 10.1702 5.5
9.74 9.0820 55.8
.23 8.6432 16.7
12.17 7.2715 2.4
14.64 6.0510 15.1
.38 5.7625 0.7
16.33 5.4296 3.7
17.22 5.1496 52.2
18.04 4.9185 22.8
18.55 4.7842 12.7
.10 4.4170 3.0
.62 4.3067 5.6
21.76 4.0836 100.0
23.10 3.8498 3.2
24.18 3.6807 8.3
.65 3.4732 5.5
26.18 3.4044 3.9
26.78 3.3286 3.5
27.27 3.2703 1.1
27.83 3.2057 0.6
28.43 3.1396 7.2
29.50 3.0279 6.6
.00 2.9782 0.6
.54 2.9272 6.6
31.03 2.8821 2.5
32.07 2.7910 0.5
32.65 2.7425 0.4
33.41 2.6817 1.0
33.74 2.6569 1.4
34.86 2.5738 1.0
.25 2.5460 2.0
.77 2.5106 1.6
36.22 2.4803 2.0
36.62 2.4537 2.3
37.08 2.4243 0.7
37.59 2.3929 0.8
38.78 2.3220 2.3
[00371] A 1
H NMR (MeOD) of Form H provides δ as 1.03 (d, J = 6.2 Hz, 3H), 1.05 - 1.19
(m, 1H), 1.19 - 1.38 (m, 3H), 1.45 (s, 9H), 1.78 (dq, J = 3.3, 13.2 Hz, 1H), 1.90 - 2.16 (m, 1H),
2.16 - 2.40 (m, 1H), 2.65 (s, 3H, DMSO), 2.95 - 3.24 (m, 1H), 3.85 - 4.21 (m, 1H), 8.25 (s, 1H).
FORM I
[00372] Form I was obtained from recrystallization of Form A in sulfolane and water
(1:1). Form I had a crystalline XRPD pattern as shown in FIG. 38. DSC thermograms of Form I
are shown in FIG. 39. A DSC peak around 118 °C can be attributed to loss of solvent in Form I.
The major DSC peak with maxium temperature of 213 °C corresponded to the
melt/decomposition of Form A. 1
H-NMR spectrum of Form I shows approximately 0.75 molar
equivalents of sulfolane (see FIG. 40). These observations suggested that Form H is a
0.75 molar sulfolane solvate of Compound 1.
[00373] A list of X-Ray Diffraction Peaks for Form I is provided below in Table 16.
[00374] Table 16. X-Ray Diffraction Peaks for Form I
Two-theta angle (°) d Space (Å)
Relative
Intensity (%)
7.94 11.1290 72.2
.50 8.4267 21.5
.80 8.1909 16.7
11.86 7.4599 25.3
13.54 6.5394 11.7
13.92 6.3612 3.2
14.79 5.9901 2.1
16.00 5.5389 76.2
17.26 5.1378 45.0
18.27 4.8557 100.0
18.82 4.7163 4.9
19.48 4.5569 4.3
19.78 4.4881 9.1
.65 4.3022 62.9
21.31 4.1699 4.4
21.78 4.0812 1.2
22.83 3.8959 5.0
23.53 3.7808 3.3
24.12 3.6899 29.4
24.75 3.5973 7.6
Two-theta angle (°) d Space (Å)
Relative
Intensity (%)
.66 3.4715 4.7
26.29 3.3903 6.0
27.71 3.2189 17.4
28.18 3.1666 0.9
28.73 3.1072 0.7
29.17 3.0616 1.2
.01 2.9778 1.5
.52 2.9288 1.0
31.18 2.8687 0.7
31.60 2.8311 0.4
31.85 2.8099 2.1
32.36 2.7664 6.5
32.93 2.7203 0.7
33.59 2.6678 2.7
34.20 2.6219 0.9
34.76 2.5812 0.4
.42 2.5341 0.6
36.56 2.4577 0.5
37.67 2.3880 1.1
[00375] FIG. 40 provides a 1
H NMR (DMSO-d6) of Form I with δ 0.94 (d, J = 6.2 Hz,
3H), 0.96 - 1.04 (m, 1H), 1.11 (s, 3H), 1.36 (s, 9H), 1.59 - 1.74 (m, 1H), 1.83 - 1.98 (m, 1H),
2.00 - 2.20 (m, 4H), 2.80 - 3.18 (m, 4H), 3.74 - 4.02 (m, 1H), 4.57 (d, J = 5.5 Hz, 1H), 6.64 (br.
s., 1H), 7.02 (br. s., 1H), 7.60 (br. s., 1H), 8.34 (s, 1H), 8.82 - 9.06 (m, 1H).
AMORPHOUS SOLID
[00376] An amorphous solid of Compound 1 was obtained from heat treatment of Form A.
The heat treatment process comprises: (1) equilibrating the temperature of Form A at 25 °C;
(2) heating to 235 °C at the speed of 10 °C per minute; (3) holding isothermally for 2 minutes;
(4) cooling down to -10 °C at the speed of 30 °C per minute; (5) modulating 0.64 °C every
40 seconds; (6) holding isothermally for 5 minutes; (7) heating to 213 °C at the speed of 3 °C per
minute; and (8) collecting the resulted solid.
[00377] The amorphous solid had an XRPD spectrum as shown in FIG. 41. DSC
thermogram of the amorphous solid sample are shown in FIG. 42. The amorphous solid has
aglass transition temperature of approximately 106.6°C.
[00378] FIG. 43 and FIG. 44 provide 1
H-NMR spectrum and LCMS of the amorphous
solid.
BIOLOGICAL EXAMPLES
BIOCHEMICAL ASSAYS
[00379] A. Time resolved fluorescence assays
[00380] JNK1 Assay. A 384-well time resolved fluorescence assay can be used to
monitor JNK1 activity. The JNK1 assay can be run in the following assay buffer: 50 mM
HEPES, 10 mM MgCl2, 1 mM EGTA, 2 mM DTT, and 0.01% Tween 20. To initiate the
reaction 100 nM of ULightTM-labeled 4EBP1 peptide (Perkin-Elmer) and 5 μM of ATP
can be mixed with 500 pM of JNK1 (Carna Biosciences), for a total assay volume of 20
μL in each well. The assay can be incubated at room temperature for 1 h and terminated
using a mixture of 30 mM EDTA and 4 nM Eu-anti-4EBP1, by adding 20 μL of stop
solution to each well. Plates can be read on a Perkin-Elmer Envision Reader.
[00381] JNK2 Assay. A 384-well time resolved fluorescence assay can be used to
monitor JNK2 activity. The JNK2 assay can be run in the following assay buffer: 50 mM
HEPES, 10 mM MgCl2, 1 mM EGTA, 2 mM DTT, and 0.01% Tween 20. To initiate the
reaction 100 nM of ULightTM-labeled 4EBP1 peptide (Perkin-Elmer) and 5 μM of ATP
can be mixed with 500 pM of JNK2 (Carna Biosciences), for a total assay volume of 20
μL in each well. The assay can be incubated at room temperature for 1 h and terminated
using a mixture of 30 mM EDTA and 4 nM Eu-anti-4EBP1, by adding 20 μL of stop
solution to each well. Plates can be read on a Perkin-Elmer Envision Reader.
[00382] B. Z’-LYTE® Cascade Assays
[00383] JNK1 Assay. The JNK1 Z’-LYTE® Cascade kinase assay can be run in the
following buffer: 50 mM HEPES at pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA,
and 1 mM DTT. A 10 μL kinase reaction mixture can be prepared containing 1.81 - 7.25
ng JNK1, 25 ng inactive MAPKAPK2, 100 μM ATP, and 2 μM Ser/Thr 04 peptide. The
assay can be incubated at room temperature for 1 h. Next, 5 μL of a 1:512 dilution of
Development Reagent A (Invitrogen, PV3295) can be added to the reaction mixture and
incubated at room temperature for an additional h. The data can then be read on a
fluorescence plate reader and analyzed.
[00384] JNK2 assay. The JNK2 Z’-LYTE® Cascade kinase assay can be run in the
following buffer: 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA,
2 mM DTT. A 10 μL kinase reaction mixture can be prepared containing 0.38 - 1.5 ng
JNK2, 100 ng inactive MAPKAPK2, 100 μM ATP, and 2 μM Ser/Thr 04 peptide. The
assay can be incubated at room temperature for 1 h. Next, 5 μL of a 1:512 dilution of
Development Reagent A (Invitrogen, PV3295) can be added to the reaction mixture and
incubated at room temperature for an additional h. The data can then be read on a
fluorescence plate reader and analyzed.
[00385] C. Radioactive Assays
[00386] JNK1 assay. The radioactive JNK kinase assay can be carried out in a 96-
well plate format at a final volume of 100 µL. The final assay concentration can be 6.6
µM ATP (3-fold ATP Km), 2.64 to 5 µg/mL JNK1, and 100 µg/mL cJUN. JNK1 can be
diluted in the following dilution buffer (20 mM HEPES pH 7.6, 0.1 mM EDTA, 2.5 mM
MgCl2, 0.004%(w/v) Triton X100, 2 µg/ml Leupeptin, 20 mM B-glycerol phosphate, 0.1
mM Na3VO4 dithiothreitol) and then pre-mixed with cJun diluted in the substrate solution
buffer (20 mM HEPES pH 7.6, 50 mM NaCl, 0.1 mM EDTA, 2.5 mM MgCl2, 0.05%(w/v)
Triton X100). The JNK1/cJun mix (85µl) can be added to the inhibitor (5 µl) diluted in
100% DMSO to give a final DMSO assay concentration of 5%(v/v). The enzyme,
substrate and inhibitor mixture can be allowed to equilibrate at room temperature for
minutes. The reaction can be started by the addition of 10µL of 10X ATP in kinase
buffer (130 mM MgCl2, 6 mM dithiothreitol, 150 mM para-nitrophenyl phosphate, 100
µCi/ml γ-[33P]-ATP). Reactions can be allowed to proceed for 60 minutes before
precipitation of protein via trichloroacetic acid (7.2% TCA final). After a 30 minute
incubation with TCA, reaction products can be collected onto glass microfilter 96-well
plates (Millipore MAHF CIH60) using a Packard Filtermate. The precipitate can be
washed with Phosphate Buffered Saline and the amount of phosphate incorporated into
cJun can be quantified by scintillation counting using a Packard Topcount-NXT. All
assays can be conducted under conditions where phosphate incorporation can be linear
with respect to time and enzyme concentration. The IC50 values can be calculated as the
concentration of the inhibitor at which the c-Jun phosphorylation can be reduced to 50% of
the control value.
[00387] JNK2 assay. The assay can be carried out in a 96-well plate format at a
final volume of 100 µL. The final assay concentrations can be 6.6 µM ATP (3-fold ATP
Km), 0.2 to 0.53 µg/mL JNK2, and 100 µg/mL cJUN. JNK2 can be diluted in the
following dilution buffer (20 mM HEPES pH 7.6, 0.1 mM EDTA, 2.5 mM MgCl2,
0.004%(w/v) Triton X100, 2 µg/ml Leupeptin, 20 mM B-glycerol phosphate, 0.1 mM
Na3VO4 dithiothreitol) and then pre-mixed with cJun diluted in the substrate solution
buffer (20 mM HEPES pH 7.6, 50 mM NaCl, 0.1 mM EDTA, 2.5 mM MgCl2, 0.05%
(w/v) Triton X100). The JNK2/cJun mix (85 µl) can be added to the inhibitor (5 µl)
diluted in 100% DMSO to give a final DMSO assay concentration of 5%(v/v). The
enzyme, substrate and inhibitor mixture can be allowed to equilibrate at room temperature
for 15 minutes. The reaction can be started by the addition of 10µL of 10X ATP in kinase
buffer (130 mM MgCl2, 6 mM dithiothreitol, 150 mM para-nitrophenyl phosphate,
100 µCi/ml γ-[33P]-ATP). Reactions can be allowed to proceed for 60 minutes before
precipitation of protein via trichloroacetic acid (7.2% TCA final). After a 30 minute
incubation with TCA, reaction products are collected onto glass microfilter 96-well plates
(Millipore MAHF CIH60) using a Packard Filtermate. The precipitate can be washed with
Phosphate Buffered Saline and the amount of phosphate incorporated into cJun can be
quantified by scintillation counting using a Packard Topcount-NXT. All assays can be
conducted under conditions where phosphate incorporation can be linear with respect to
time and enzyme concentration. The IC50 values can be calculated as the concentration of
the inhibitor at which the c-Jun phosphorylation can be reduced to 50% of the control
value.
CELL ASSAYS
[00388] RAW264.7 Phospho-cJun Whole Cell Assay. RAW264.7 cells can be
purchased from the American Tissue Culture Collection and maintained in growth media
consisting of 90% high glucose Dulbecco's Modified Eagle Medium (Invitrogen), 10%
fetal bovine serum (Hyclone), and 2 mM L-glutamine (Invitrogen). All cells can be
cultured at 37 °C in 95% air and 5% CO2. Cells can be plated at a density of 1.0 x 105
cells
per well in a 96-well plate in 120 μL of growth media. Diaminopyrimidine Compound
stock (30 mM) can be diluted serially in DMSO, further diluted in growth media, and can
be added to each well as a 10x concentrated solution in a volume of 15 μL, mixed, and
allowed to incubate with cells. The compound vehicle (DMSO) can be maintained at a
final concentration of 0.2% in all wells. After 30 minutes, the cells can be activated with
lipopolysaccharide (ALEXIS Biochemicals) at a final concentration of 25 ng/mL.
Lipopolysaccharide can be added as a 10x concentrated solution in growth media and
added in a volume of 15 μL per well. Cell plates can be cultured for 1 h, after which the
cell media can be removed. The level of c-Jun protein which can be phosphorylated at
serine 63 can be measured according to the manufacturer’s instructions for the Whole Cell
Lysate Kit-Phospho-c-Jun (Ser 63) Assay (Meso Scale Discovery) with the exception that
the concentration of NaCl in the lysis buffer can be increased to a final concentration of
350 mM. The IC50 values can be calculated as the concentration of Diaminopyrimidine
Compound at which the level of phosphorylated c-Jun protein can be reduced to 50% of
the signal window. Certain compounds of Table 1, 2 and 3 have an IC50 value ranging
from 0.01 - 30 μM in this assay.
[00389] Jurkat T-cell IL-2 Production Assay. Jurkat T cells (clone E6-1) can be
purchased from the American Tissue Culture Collection and maintained in growth media
consisting of RPMI 1640 medium containing 2 mM L-glutamine (Mediatech), with 10%
fetal bovine serum (Hyclone) and penicillin/streptomycin. All cells can be cultured at 37
°C in 95% air and 5% CO2. Cells can be plated at a density of 1 x 105
cells per well in 120
μL of media in a 96-well plate. Diaminopyrimidine Compound stock (20 mM) can be
diluted in growth media and added to each well as a 10 x concentrated solution in a
volume of 15 μL, mixed, and allowed to pre-incubate with cells for 30 min. The compound
vehicle (dimethylsulfoxide) can be maintained at a final concentration of 0.2% in all
samples. After 30 min the cells can be activated with PMA (phorbol myristate acetate;
final concentration 50 ng/mL) and PHA (phytohemagglutinin; final concentration 1
μg/mL). PMA and PHA can be added as a 10 x concentrated solution made up in growth
media and added in a volume of 15 μL per well. Cell plates can be cultured for 6 h. Cells
can be pelleted by centrifugation and the media removed and stored at -20 °C. Media
aliquots can be analyzed according the manufacturers instructions for the Human IL-2
Tissue Culture Kit (Meso Scale Discovery). The IC50 values can be calculated as the
concentration of the Diaminopyrimidine Compound at which the IL-2 production can be
reduced to 50% of the signal window. Certain compounds from Table 1, 2 and 3 have an
IC50 value ranging from 0.01 - 10 μM in this assay.
CLINICAL PROTOCOL
[00390] A Phase 1, Randomized, Two-Part Study to Evaluate the Safety,
Tolerability, and Pharmacokinetics of Single and Multiple Ascending Doses of
Compound 1 in Healthy Subjects.
[00391] The primary objective is to evaluate the safety and tolerability of single and
multiple oral doses of Compound 1 in health subjects.
[00392] The secondary objectives are to assess the pharmacokinetics (PK) of
Compound 1 following single and multiple oral doses.
[00393] Study Design.
[00394] This is a two-part study to be conducted at up to two study centers.
[00395] Part 1 is a randomized, double-blind, placebo-controlled study to evaluate the
safety, tolerability, and PK of Compound 1 following a single oral dose in healthy subjects.
Investigators and study participants will be blinded to treatment throughout the study, while the
Sponsor will remain unblinded. The chosen study design is an escalating dose in sequential
groups.
[00396] In Part 1, approximately 56 subjects will be randomized and enrolled into seven
planned cohorts. Each cohort will consist of eight subjects; six subjects will receive Compound
1 and two subjects will receive placebo.
[00397] During the course of Part 1, each subject will participate in a screening phase, a
baseline phase, a treatment phase, and a follow-up visit. Subjects will be screened for eligibility.
Subjects who have met all inclusion criteria and none of the exclusion criteria at screening will
return to the clinical site on Day-1 for baseline assessments, and will be domiciled at the clinical
site from Day-1 to Day 4. Subjects will receive a single oral dose of investigational product (IP;
either Compound 1 or placebo) on Day 1, under fasted conditions, according to the
randomization schedule. Blood and urine samples will be collected at pre-specified times for PK
and/or clinical laboratory assessments and/or exploratory analyses. Safety will be monitored
throughout the study. Subjects will be discharged from the clinical site on Day 4 following
completion of the required study procedures and will return to the clinical site for a follow-up
visit on Day 7 (± 1-day window). In the event that a subject discontinues from the study, an
early termination (ET) visit will be performed.
[00398] After each cohort, safety data will be reviewed and PK data will be reviewed as
needed. The parameters to be reviewed prior to each dose escalation along with specific dose
escalation.
[00399] Part 2 is a randomized, double-blind, placebo-controlled study to evaluate the
safety, tolerability, and PK of Compound 1 following multiple oral doses (up to 14 days of
dosing) in healthy subjects. Investigators and study participants will be blinded to treatment
throughout the study, while the Sponsor will remain unblinded. The chosen study design is an
escalating dose in sequential groups.
[00400] Part 2 will not begin until total daily doses up to and including 240 mg have been
evaluated in Part 1. Only doses that are safe and well tolerated in Part 1 will be administered in
Part 2.
[00401] In Part 2, approximately 48 subjects will be randomized and enrolled into six
planned cohorts. Each cohort will consist of eight subjects; six subjects will receive Compound 1
and two subjects will receive placebo.
[00402] During the course of Part 2, each subject will participate in a screening phase, a
baseline phase, a treatment phase, and a follow-up visit. Subjects will be screened for eligibility.
Subjects who have met all inclusion criteria and none of the exclusion criteria at screening will
return to the clinical site on Day 1 for baseline assessments, and will be domiciled at the clinical
site from Day 1 to Day 17. The first dose of IP (either Compound 1 or placebo) will be
administered on Day 1, under fasted conditions, according to the randomization schedule. The
same total daily dose will be administered under fasted conditions on Days 2 to 14. Blood
samples will be collected at pre-specified times for PK, clinical laboratory assessments, and/or
exploratory biomarkers. Urine samples will be collected at pre-specified times for clinical
laboratory assessments. Safety will be monitored throughout the study. Subjects will be
discharged from the clinical site on Day 17 following completion of the required study
procedures and will return to the clinical site for a follow-up visit on Day 21 (± 1-day window).
In the event that a subject discontinues from the study, an ET visit will be performed.
[00403] After each cohort, safety data will be reviewed and PK data will be reviewed as
needed. The parameters will be reviewed prior to each dose escalation along with specific dose
escalation.
[00404] Study Population: Approximately 104 healthy adult subjects (males or females
of non-childbearing potential) from any race between 18 and 50 years of age, inclusive, will be
enrolled into the study, with approximately 56 subjects participating in Part 1 and approximately
48 subjects participating in Part 2.
[00405] Length of Study: The estimated duration of the study, inclusive of Parts 1 and 2,
from first-subject-first-visit to last-subject-last-visit, is approximately 8 months.
[00406] The estimated duration of the clinical phase of Part 1, from first-subject-first-visit
to last-subject-last-visit, is approximately 4 months. The estimated duration of each subject’s
participation in Part 1, from screening through follow-up, is approximately 4 weeks.
[00407] Part 2 will not begin until total daily doses up to and including 240 mg have been
evaluated in Part 1. Only doses that are safe and well tolerated in Part 1 will be administered in
Part 2. The estimated duration of the clinical phase of Part 2, from first-subject-first-visit to lastsubject-last-visit, is approximately 6 months. The estimated duration of each subject’s
participation in Part 2, from screening through follow-up, is approximately 6 weeks.
[00408] The End of Trial is defined as either the date of the last visit of the last subject to
complete the study, or the date of receipt of the last data point from the last subject that is
required for primary, secondary and/or exploratory analysis, as pre-specified in the protocol
and/or the Statistical Analysis Plan, whichever is the later date.
[00409] Study Treatments.
[00410] Part 1: Approximately 56 subjects will be randomized and enrolled into seven
planned cohorts, with eight subjects per cohort. In each cohort, six subjects will receive
Compound 1 and two subjects will receive placebo.
[00411] Doses in Part 1 will be administered as active pharmaceutical ingredient (API) in
capsules (or matching placebo) once daily (QD).
[00412] The following Compound 1 dose levels in Table 17 are planned for Part 1.
[00413] Table 17. Compound 1 Dose Levels in Part 1
Cohort Compound 1 Dose Level (Total Daily Dose)
1A 10mg
1B 30mg
1C 60mg
1D 120mg
1E 240mg
1F 480mg
1G 720mg
[00414] If gastrointestinal (GI)-related events such as intolerable nausea or vomiting
occur, total daily doses may be lowered or may be administered BID or three times daily (TID).
[00415] Investigational product will be administered at only one dose level at a time, and
administration at the next dose level will not begin until the safety and tolerability of the
preceding dose level have been evaluated and deemed acceptable by the Investigator and
Sponsor’s Medical Monitor.
[00416] Part 2: Part 2 will not begin until total daily doses up to and including 240 mg
have been evaluated in Part 1. Only doses that are safe and well tolerated in Part 1 will be
administered in Part 2.
[00417] Approximately 48 subjects will be randomized and enrolled into six planned
cohorts, with eight subjects per cohort. In each cohort, six subjects will receive Compound 1 and
two subjects will receive placebo.
[00418] The planned dosing regimen in Part 2 is Compound 1 in capsules (or matching
placebo) QD for 14 days. The following Compound 1 dose levels in Table 18 are proposed for
Part 2.
[00419] Table 18. Compound 1 Dose Levels in Part 2
Cohort Compound 1 Dose Level (Total Daily Dose) Duration
2A 10mg Daily x 14 days
2B 30mg Daily x 14 days
2C 60mg Daily x 14 days
2D 120mg Daily x 14 days
2E 240mg Daily x 14 days
2F 480mg Daily x 14 days
[00420] Proposed dose levels in Part 2 may be modified and/or eliminated based on data
obtained from Part 1. Should a change to the proposed dose escalation step(s) be required, the
maximum dose escalation step in Part 2 will be ≤ 3-fold the previous dose level. In addition, the
maximum dose administered in Part 2 will not exceed the maximum tolerated dose (MTD) in
Part 1 and will not exceed 480 mg daily for 14 days.
[00421] If GI-related events such as intolerable nausea or vomiting occur, total daily doses
may be lowered or may be administered BID or TID.
[00422] Investigational product will be administered at only one dose level at a time, and
administration at the next dose level will not begin until the safety and tolerability of the
preceding dose level have been evaluated and deemed acceptable by the Investigator and
Sponsor’s Medical Monitor. In addition, if a certain dose level is not tolerated in Part 1 then that
dose level or any higher dose level will not be administered in Part 2 except for the instance of a
GI intolerability (e.g., nausea, vomiting) that is mitigated via an alternative dose regimen (i.e.,
BID or TID).
[00423] Overview of Safety Assessments. Safety will be monitored throughout the study.
Safety evaluations will include AE reporting, PEs, vital signs, 12-lead ECGs, clinical laboratory
safety tests (including liver function tests [LFTs], total cholesterol, triglycerides, high-density
lipoprotein [HDL], and low-density lipoprotein [LDL] in addition to standard clinical chemistry,
hematology, and urinalysis tests), review of concomitant medications/procedures, FOB tests and
stool monitoring, and pregnancy tests for female subjects. All AEs will be monitored and
recorded throughout the study from the time the informed consent form (ICF) is signed until
study completion, and when made known to the Investigator within 28 days after the last dose of
IP (and those SAEs made known to the Investigator at any time thereafter that are suspected of
being related to IP). All concomitant medications and procedures will be reviewed and recorded
from the time the subject signs the ICF until study completion. A follow-up visit will be
scheduled for all subjects. If a subject is discontinued from the study for any reason, an ET visit
will be performed.
[00424] Overview of Pharmacokinetic Assessments. In both parts of the study, blood
samples will be collected at pre-specified times to determine levels of Compound 1 in plasma.
For Cohorts 1C to 1G of Part 1 (planned dose levels of 60 mg to 720 mg), urine samples will be
collected at pre-specified times for exploratory metabolite analyses. Prominent metabolites in
plasma and urine will be identified and Compound 1 in urine may be quantified as part of the
exploratory analyses.
[00425] The following PK parameters will be estimated for Compound 1, as appropriate:
maximum observed plasma concentration (Cmax); time to Cmax (Tmax); area under the plasma
concentration-time curve from time zero extrapolated to infinity (AUC∞); area under the plasma
concentration-time curve from time zero to the last quantifiable concentration (AUCt); area
under the plasma concentration-time curve from time zero to tau (τ), where τ is the dosing
interval (AUCτ); terminal-phase elimination half-life (t1/2,z); apparent total plasma clearance
when dosed orally (CL/F); apparent total volume of distribution when dosed orally, based on the
terminal phase (Vz/F); ratio of accumulation (RA) based on Day 1 and Day 14 AUCτ.
[00426] Compound 1 concentrations in urine samples collected in Part 1 may be further
quantified using a validated method if exploratory analyses indicate that Compound 1 is
abundant in urine. The following PK parameters related to urine analyses may then be
determined, as appropriate: cumulative amount of drug excreted unchanged in urine during the
collection period from predose (0-hour) to the end of collection (Ae); cumulative percentage of
the administered dose excreted unchanged in urine during the collection period from predose (0-
hour) to the end of collection (fe); renal clearance (CLr).
[00427] A number of references have been cited, the disclosures of which are incorporated
herein by reference in their entirety.
Claims (137)
1. A crystal form comprising Compound 1, or a tautomer thereof: s1 which has an X-ray powder diffraction pattern comprising peaks at approximately 10.55, 13.61 and 19.84° 2θ.
2. The crystal form of claim 1 which has an X-ray powder diffraction pattern further comprising peaks at approximately 17.20 and 17.85 and 18.04° 2θ.
3. The crystal form of claim 1 which has a differential scanning calorimetry thermogram comprising an endotherm with an onset temperature at approximately 223 °C when heated from about 25 °C to about 300 °C.
4. The crystal form of claim 1 which is a non-stoichiometric channel hydrate.
5. The crystal form of claim 1 which is substantially pure.
6. A crystal form comprising Compound 1, or a tautomer thereof: 1 which has an X-ray powder diffraction pattern comprising peaks at approximately 9.80, 17.29 and 21.74° 2θ. N N N H NH OH NH2 O N N N H NH OH NH2 O
7. The crystal form of claim 6 which has an X-ray powder diffraction pattern further comprising peaks at approximately 10.30, 18.23 and 20.66° 2θ.
8. The crystal form of claim 6 which has a thermogravimetric analysis thermogram comprising a total mass loss of approximately 8.5% of the total mass of the crystal form when heated from about 75 °C to about 175 °C.
9. The crystal form of claim 6 which has a differential scanning calorimetry thermogram comprising an endotherm with a maximum at approximately 147 °C when heated from about 25 °C to about 300 °C.
10. The crystal form of claim 9 wherein the differential scanning calorimetry thermogram further comprises an endotherm with an onset temperature at approximately 223 °C.
11. The crystal form of claim 6 which is acetone solvated.
12. The crystal form of claim 11 comprises 0.5 molar equivalents of acetone.
13. The crystal form of claim 6 which is substantially pure.
14. A crystal form comprising Compound 1, or a tautomer thereof: 1 which has an X-ray powder diffraction pattern comprising peaks at approximately 9.83, 10.21, 17.26 and 21.86° 2θ.
15. The crystal form of claim 14 which has an X-ray powder diffraction pattern further comprising peaks at approximately 17.61 and 18.18° 2θ. N N N H NH OH NH2 O
16. The crystal form of claim 14 which has a thermogravimetric analysis thermogram comprising a total mass loss of approximately 7.3% of the total mass of the crystal form when heated from about 75 °C to about 175 °C.
17. The crystal form of claim 14 which has a differential scanning calorimetry thermogram comprising an endotherm with a maximum at approximately 143 °C when heated from about 25 °C to about 300 °C.
18. The crystal form of claim 17 wherein the differential scanning calorimetry thermogram further comprises an endotherm with an onset temperature at approximately 224 °C.
19. The crystal form of claim 14 which is ethanol solvated.
20. The crystal form of claim 19 comprises 0.5 molar equivalents of ethanol.
21. The crystal form of claim 14 which is substantially pure.
22. A crystal form comprising Compound 1, or a tautomer thereof: 1 which has an X-ray powder diffraction pattern comprising peaks at approximately 10.37, 13.41, 19.52 and 22.47° 2θ.
23. The crystal form of claim 22 which has an X-ray powder diffraction pattern further comprising peaks at approximately 17.73 and 23.92 °2θ.
24. The crystal form of claim 22 which has a thermogravimetric analysis thermogram comprising a total mass loss of approximately 4% of the total mass of the crystal form when heated from about 100 °C to about 160 °C. N N N H NH OH NH2 O
25. The crystal form of claim 22 which has a differential scanning calorimetry thermogram comprising an endotherm with a maximum at approximately 170 °C when heated from about 25 °C to about 300 °C.
26. The crystal form of claim 25 wherein the differential scanning calorimetry thermogram further comprises an endotherm with an onset temperature at approximately 223 °C.
27. The crystal form of claim 22 which is methanol solvated.
28. The crystal form of claim 27 comprises 0.5 molar equivalents of methanol.
29. The crystal form of claim 22 which is substantially pure.
30. A crystal form comprising Compound 1, or a tautomer thereof: 1 which has an X-ray powder diffraction pattern comprising peaks at approximately 9.92, 17.29, 18.37 and 21.81° 2θ.
31. The crystal form of claim 30 which has an X-ray powder diffraction pattern further comprising peaks at approximately 10.36 and 20.10° 2θ.
32. The crystal form of claim 30 which has a thermogravimetric analysis thermogram comprising a total mass loss of approximately 10.3% of the total mass of the crystal form when heated from about 75 °C to about 175 °C.
33. The crystal form of claim 30 which has a differential scanning calorimetry thermogram comprising an endotherm with a maximum at approximately 124 °C when heated from about 25 °C to about 300 °C. N N N H NH OH NH2 O
34. The crystal form of claim 33 wherein the differential scanning calorimetry thermogram further comprises an endotherm with an onset temperature at approximately 224 °C.
35. The crystal form of claim 30 which is n-butanol solvated.
36. The crystal form of claim 35 comprises 0.5 molar equivalents of n-butanol.
37. The crystal form of claim 30 which is substantially pure.
38. A crystal form comprising Compound 1, or a tautomer thereof: 1 which has an X-ray powder diffraction pattern comprising peaks at approximately 18.53, 20.85 and 21.10° 2θ.
39. The crystal form of claim 38 which has an X-ray powder diffraction pattern further comprising peaks at approximately 8.07, 12.06 and 17.45° 2θ.
40. The crystal form of claim 38 which has a thermogravimetric analysis thermogram comprising a total mass loss of approximately 4% of the total mass of the crystal form when heated from about 100 °C to about 160 °C.
41. The crystal form of claim 38 which has a differential scanning calorimetry thermogram comprising an endotherm with a maximum at approximately 113 °C when heated from about 25 °C to about 300 °C.
42. The crystal form of claim 41 wherein the differential scanning calorimetry thermogram further comprises an endotherm with an onset temperature at approximately 223 °C. N N N H NH OH NH2 O
43. The crystal form of claim 38 which is toluene solvated.
44. The crystal form of claim 43 comprises 0.3 molar equivalents of toluene.
45. The crystal form of claim 38 which is substantially pure.
46. A crystal form comprising Compound 1, or a tautomer thereof: 1 which has an X-ray powder diffraction pattern comprising peaks at approximately 9.51, 17.90 and 21.28° 2θ.
47. The crystal form of claim 46 which has an X-ray powder diffraction pattern further comprising peaks at approximately 10.34, 16.94 and 28.83° 2θ.
48. The crystal form of claim 46 which has a thermogravimetric analysis thermogram comprising a total mass loss of approximately 11.9% of the total mass of the crystal form when heated from about 75 °C to about 175 °C.
49. The crystal form of claim 46 which has a differential scanning calorimetry thermogram comprising an endotherm with a maximum at approximately 116 °C when heated from about 25 °C to about 300 °C.
50. The crystal form of claim 49 wherein the differential scanning calorimetry thermogram further comprises an endotherm with an onset temperature at approximately 223 °C.
51. The crystal form of claim 46 which is ethyl acetate solvated.
52. The crystal form of claim 51 comprises 0.5 molar equivalents of ethyl acetate. N N N H NH OH NH2 O
53. The crystal form of claim 46 which is substantially pure.
54. A crystal form comprising Compound 1, or a tautomer thereof: 1 which has an X-ray powder diffraction pattern comprising peaks at approximately 9.74, 14.64, 17.22 and 21.76° 2θ.
55. The crystal form of claim 54 which has an X-ray powder diffraction pattern further comprising peaks at approximately 10.23 and 18.04° 2θ.
56. The crystal form of claim 54 which has a thermogravimetric analysis thermogram comprising a total mass loss of approximately 11.2% of the total mass of the crystal form when heated from about 75 °C to about 175 °C.
57. The crystal form of claim 54 which has a differential scanning calorimetry thermogram comprising an endotherm with a maximum at approximately 160 °C when heated from about 25 °C to about 300 °C.
58. The crystal form of claim 57 wherein the differential scanning calorimetry thermogram further comprises an endotherm with an onset temperature at approximately 222 °C.
59. The crystal form of claim 54 which is dimethyl sulfoxide solvated.
60. The crystal form of claim 59 comprises 0.5 molar equivalents of dimethyl sulfoxide.
61. The crystal form of claim 54 which is substantially pure. N N N H NH OH NH2 O
62. A crystal form comprising Compound 1, or a tautomer thereof: 1 which has an X-ray powder diffraction pattern comprising peaks at approximately 7.94, 16.00 and 18.27° 2θ.
63. The crystal form of claim 62 which has an X-ray powder diffraction pattern further comprising peaks at approximately 17.26, 20.65 and 24.12° 2θ.
64. The crystal form of claim 62 which has a differential scanning calorimetry thermogram comprising an endotherm with a maximum at approximately 118 °C when heated from about 25 °C to about 300 °C.
65. The crystal form of claim 64 wherein the differential scanning calorimetry thermogram further comprises an endotherm with an onset temperature at approximately 213 °C.
66. The crystal form of claim 62 which is sulfolane solvated.
67. The crystal form of claim 66 comprises 0.75 molar equivalents of sulfolane.
68. The crystal form of claim 62 which is substantially pure.
69. An amorphous solid comprising Compound 1, or a tautomer thereof: 1. N N N H NH OH NH2 O N N N H NH OH NH2 O
70. The solid form of claim 69 which has a differential scanning calorimetry thermogram comprising a glass transition temperature of 106.6 °C when heated from about 25 °C to about 300 °C.
71. The solid form of claim 69 which is substantially pure.
72. Use of a solid form of any one of claims 1, 6, 14, 22, 30, 38, 46, 54, 62 and 69 in the manufacture of a medicament for treating or preventing a condition treatable or preventable by inhibition of a kinase pathway.
73. The use of claim 72, wherein the kinase pathway is the JNK1 or JNK2 kinase pathway.
74. Use of a solid form of any one of claims 1, 6, 14, 22, 30, 38, 46, 54, 62 and 69 in the manufacture of a medicament for treating or preventing interstitial pulmonary fibrosis, systemic sclerosis, scleroderma, chronic allograft nephropathy, antibody mediated rejection, or lupus.
75. Use of a solid form of any one of claims 1, 6, 14, 22, 30, 38, 46, 54, 62 and 69 in the manufacture of a medicament for treating or preventing liver fibrotic disorders, diabetes, metabolic syndrome leading to liver fibrotic disorders, or a conditions treatable or preventable by inhibition of a kinase pathway.
76. A method of preparing a compound of formula (iv), (iv), the method comprising contacting a compound of formula (iii), (iii), with R1 NH2 in the presence of a base or a Lewis acid, in an organic solvent, wherein R1 is substituted or unsubstituted C1-8 alkyl, or substituted or unsubstituted saturated cycloalkyl, wherein R2 is substituted or unsubstituted C1-8 alkyl, or substituted or unsubstituted cycloalkyl; wherein when an alkyl group is substituted, it is substituted with a substituent or substituents selected from halogen; alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxyl amine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; B(OH)2, or O(alkyl)aminocarbonyl; and wherein when a group other than an alkyl group is substituted, it is substituted with a substituent or substituents selected from halogen; alkyl; hydroxyl; alkoxy; alkoxyalkyl; amine; alkylamine; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxyl amine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (═O); B(OH)2, O(alkyl)aminocarbonyl; cycloalkyl, which may be monocyclic or fused or non-fused polycyclic, or a heterocyclyl, which may be monocyclic or fused or non-fused polycyclic; N R1HN N NHR2 NH2 O N Cl N NHR2 NH2 O monocyclic or fused or non-fused polycyclic aryl or heteroaryl; aryloxy; aralkyloxy; heterocyclyloxy; or heterocyclyl alkoxy.
77. The method of claim 76, wherein halogen is chloro, iodo, bromo, or fluoro.
78. The method of claim 76 or 77, wherein the optional cycloalkyl substituent is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
79. The method of any one of claims 76 to 78, wherein heterocyclyl is pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiazinyl.
80. The method of any one of claims 76 to 79, wherein aryl or heteroaryl is phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidyl, benzimidazolyl, benzothiophenyl, or benzofuranyl.
81. The method of claim 76, wherein R2 is , or .
82. The method of claim 76, wherein R1 is , or .
83. The method of claim 76, wherein the base is t-butylamine or sodium carbonate.
84. The method of claim 76, wherein the Lewis acid is ZnCl2.
85. The method of claim 76, wherein the organic solvent is acetonitrile, EtOAc, THF, NMP, DMSO or sulfolane. OH OH OH
86. The method of claim 76, wherein the contacting is performed at about 60 °C to about 85 °C.
87. A method of preparing a compound of formula (iii), (iii), the method comprising contacting of 2,4-dichloropyrimidinecarboxamide with R2 NH2 in the presence of a base in a solvent, wherein R2 is substituted or unsubstituted cycloalkyl; wherein when a group is substituted, it is substituted with a substituent or substituents selected from halogen; alkyl; hydroxyl; alkoxy; alkoxyalkyl; amine; alkylamine; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxyl amine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (═O); B(OH)2, O(alkyl)aminocarbonyl; cycloalkyl, which may be monocyclic or fused or non-fused polycyclic, or a heterocyclyl, which may be monocyclic or fused or non-fused polycyclic; monocyclic or fused or non-fused polycyclic aryl or heteroaryl; aryloxy; aralkyloxy; heterocyclyloxy; or heterocyclyl alkoxy.
88. The method of claim 87, wherein halogen is chloro, iodo, bromo, or fluoro.
89. The method of claim 87 or 88, wherein the optional cycloalkyl substituent is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
90. The method of any one of claims 87 to 89, wherein heterocyclyl is pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiazinyl.
91. The method of any one of claims 87 to 90, wherein aryl or heteroaryl is phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidyl, benzimidazolyl, benzothiophenyl, or benzofuranyl. N Cl N NHR2 NH2 O
92. The method of claim 87, wherein R2 is or .
93. The method of claim 87, wherein the base is diisopropylethylamine, potassium carbonate or sodium bicarbonate.
94. The method of claim 87, wherein the solvent is THF, NMP or THF/water.
95. The method of claim 87, wherein the contacting is performed at about 0 °C to about 25 °C.
96. A method of purifying a compound of formula (iv), (iv), the method comprising 1) dissolving the compound of formula (iv) in a first solvent at a first temperature; 2) adding a second different solvent into the resulting solution; 3) cooling the solution to a second temperature; and 4) collecting a solid, wherein R1 is substituted or unsubstituted C1-8 alkyl, or substituted or unsubstituted cycloalkyl; and R2 is substituted or unsubstituted C1-8 alkyl, or substituted or unsubstituted cycloalkyl; wherein when an alkyl group is substituted, it is substituted with a substituent or substituents selected from halogen; alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxyl amine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; B(OH)2, or O(alkyl)aminocarbonyl; OH N R1HN N NHR2 NH2 O and wherein when a group other than an alkyl group is substituted, it is substituted with a substituent or substituents selected from halogen; alkyl; hydroxyl; alkoxy; alkoxyalkyl; amine; alkylamine; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxyl amine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (═O); B(OH)2, O(alkyl)aminocarbonyl; cycloalkyl, which may be monocyclic or fused or non-fused polycyclic, or a heterocyclyl, which may be monocyclic or fused or non-fused polycyclic; monocyclic or fused or non-fused polycyclic aryl or heteroaryl; aryloxy; aralkyloxy; heterocyclyloxy; or heterocyclyl alkoxy.
97. The method of claim 96, wherein halogen is chloro, iodo, bromo, or fluoro.
98. The method of claim 96 or 97, wherein the optional cycloalkyl substituent is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
99. The method of any one of claims 96 to 98, wherein heterocyclyl is pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiazinyl.
100. The method of any one of claims 96 to 99, wherein aryl or heteroaryl is phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidyl, benzimidazolyl, benzothiophenyl, or benzofuranyl.
101. The method of claim 96, further comprising seeding with Form A of claim 1.
102. The method of claim 96, wherein the first solvent is i) a mixture of 2-propanol and water; ii) DMSO; or iii) ethanol.
103. The method of claim 102, wherein the ratio by volume of 2-propanol and water in the mixture is about 3:1.
104. The method of claim 96, wherein the second solvent is water.
105. The method of claim 96, wherein the first temperature is about 60 °C or about 70 °C.
106. The method of claim 96, wherein the second temperature is about 0 °C or about 25 °C.
107. A compound of formula (iii), (iii), and tautomers thereof, wherein R2 is substituted saturated cycloalkyl, which is substituted with a substituent or substituents selected from halogen; alkyl; hydroxyl; alkoxy; alkoxyalkyl; amine; alkylamine; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxyl amine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (═O); B(OH)2, O(alkyl)aminocarbonyl; cycloalkyl, which may be monocyclic or fused or non-fused polycyclic, or a heterocyclyl, which may be monocyclic or fused or non-fused polycyclic; monocyclic or fused or non-fused polycyclic aryl or heteroaryl; aryloxy; aralkyloxy; heterocyclyloxy; or heterocyclyl alkoxy.
108. The compound of claim 107, wherein halogen is chloro, iodo, bromo, or fluoro.
109. The compound of claim 107 or 108, wherein the optional cycloalkyl substituent is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
110. The compound of any one of claims 107 to 109, wherein heterocyclyl is pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiazinyl.
111. The compound of any one of claims 107 to 110, wherein aryl or heteroaryl is phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidyl, benzimidazolyl, benzothiophenyl, or benzofuranyl. N Cl N NHR2 NH2 O
112. The compound of claim 107, wherein R2 is .
113. A compound of formula (iii), (iii), and tautomers thereof, wherein R2 is .
114. A compound of formula (iv), when prepared by the method of any one of claims 76 to 86.
115. A compound of formula (iii), when prepared by the method of any one of claims 87 to 95.
116. A compound of formula (iv), when prepared by the method of any one of claims 96 to 106.
117. A crystal form according to claim 1, substantially as herein described or exemplified.
118. A crystal form according to claim 6, substantially as herein described or exemplified.
119. A crystal form according to claim 14, substantially as herein described or exemplified.
120. A crystal form according to claim 22, substantially as herein described or exemplified. OH N Cl N NHR2 NH2 O
121. A crystal form according to claim 30, substantially as herein described or exemplified.
122. A crystal form according to claim 38, substantially as herein described or exemplified.
123. A crystal form according to claim 46, substantially as herein described or exemplified.
124. A crystal form according to claim 54, substantially as herein described or exemplified.
125. A crystal form according to claim 62, substantially as herein described or exemplified.
126. An amorphous solid according to claim 69, substantially as herein described or exemplified.
127. A use according to claim 72, substantially as herein described or exemplified.
128. A use according to claim 74, substantially as herein described or exemplified.
129. A use according to claim 75, substantially as herein described or exemplified.
130. A method according to claim 76, substantially as herein described or exemplified.
131. A method according to claim 87, substantially as herein described or exemplified.
132. A method according to claim 96, substantially as herein described or exemplified.
133. A compound according to claim 107, substantially as herein described or exemplified.
134. A compound according to claim 113, substantially as herein described or exemplified.
135. A compound according to claim 114, substantially as herein described or exemplified.
136. A compound according to claim 115, substantially as herein described or exemplified.
137. A compound according to claim 116, substantially as herein described or exemplified.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NZ715903A NZ715903A (en) | 2014-01-30 | 2014-09-03 | Solid forms of 2-(tert-butylamino)-4-((1r,3r,4r)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide, compositions thereof and methods of their use |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201461933636P | 2014-01-30 | 2014-01-30 | |
US61/933,636 | 2014-01-30 | ||
US201462025161P | 2014-07-16 | 2014-07-16 | |
US62/025,161 | 2014-07-16 |
Publications (2)
Publication Number | Publication Date |
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NZ629885A NZ629885A (en) | 2016-04-29 |
NZ629885B true NZ629885B (en) | 2016-08-02 |
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