TWI455932B - Acid addition salts of, processes for preparing, and uses of 4-(2,6-dichloro-benzoylamino)-1H-pyrazole-3-carboxylic acid piperidin-4-ylamide - Google Patents

Claims (46)

An acid addition salt of 4-(2,6-dichloro-benzimidino)-1H-pyrazole-3-carboxylic acid piperidin-4-ylguanamine, which is formed with methanesulfonic acid. An acid addition salt according to claim 1 of the patent application, which is a crystal and has a crystal structure as defined by the following coordinates: Table 2 Space group: Pbca has a unit crystal of 5% su at 93K and a, b & c Cell, a=8.9 b=12.4 c=38.5 α=β=γ=90 coordinates in cif format: loop__atom_site_label_atom_site_type_symbol_atom_site_fract_x_atom_site_fract_y_atom_site_fract_z_atom_site_U_iso_or_equiv_atom_site_adp_type atom site_occupancy_atom_site_symmetry_multiplicity atom site_calc_flag _atom_site_refinement_flags _atom_site_disorder_assembly _atom_site_disorder_group SIM S 0.13517(17)0.18539(13)0.03193(5)0.0286(5)Uani 1 1 d... O1M 00.1193(5)0.2208(3)-0.00409(14)0.0326(13)Uani 1 1 d ... O2M 00.1551(5)0.0681(3)0.03330(13)0.0331(13)Uani 1 1 d... O3M 00.0151(5)0.2217(4)0.05453(14)0.0368(13)Uani 1 1 d.. C4M C 0.3036(8)0.2420(6)0.0475(2)0.0355(19)Uani 1 1 d... H4M1 H 0.3855 0.2197 0.0329 0.053 Uiso 1 1 calc R.. H4M2 H 0.3212 0.2181 0.0708 0.053 Uiso 1 1 calc R .. H4M3 H 0.2959 0.3189 0.0471 0.053 Uiso 1 1 calc R.. C11 C1 0.26158(17)0.18137(12)0.34133(5)0.0325(5)Uani 1 1 d... C12 C1 0.75698(19)0.16766(13) 0.26161(5)0.0366(6)Uani 1 1 d... N1 N 0.6277(6)-0.2419(4)0.34903(16)0.0276(14) Uani 1 1 d... H1 H 0.5932-0.3064 0.3484 0.033 Uiso 1 1 calc R.. N2 N 0.7505(5)-0.2150(4)0.36663(16)0.0286(15)Uani 1 1 d... C3 C 0.7635 (7)-0.1082(5)0.36163(19)0.0265(17)Uani 1 1 d... C4 C 0.6453(7)-0.0708(5)0.34039(18)0.0211(16)Uani 1 1 d... C5 C 0.5616(7)-0.1594(5)0.3322(2)0.0277(18)Uani 1 1 d.... H5 H 0.4770-0.1623 0.3181 0.033 Uiso 1 1 calc R.. C6 C 0.8878(7)-0.0454(5 ) 0.3760(2)0.0269(17)Uani 1 1 d.... 07 0 0.9037(5)0.0506(3)0.36722(14)0.0368(13)Uani 1 1 d.... N8 N 0.9821(6)- 0.0939(4)0.39821(15)0.0267(14)Uani 1 1 d... H8 H 0.9626-0.1584 0.4048 0.032 Uiso 1 1 calc R.. C9 C 1.1147(7)-0.0417(5)0.41139(19)0.0253( 17) Uani 1 1 d... H9 H 1.1272 0.0261 0 3987 0.030 Uiso 1 1 calc R.. C10 C1 1.1019(8)-0.0148(5)0.4502(2)0.0330(18)Uani 1 1 d.... H10 AH 1.0156 0.0315 0.4540 0.040 Uiso 1 1 calc R.. H10 BH 1.0866-0.0804 0.4633 0.040 Uiso 1 1 calc R.. C11 C 1.2429(7)0.0412(5)0.4630(2)0.0349(19)Uani 1 1 d... H11A H 1.2533 0.1102 0.4515 0.042 Uani 1 1 d.. H11B H 1.2355 0.0538 0.4878 0.042 Uiso 1 1calc R.. N12 N 1.37846)-0.0279(4)0.45532(16)0.0258(14)Uani 1 1 d... H12 AH 1.4618 0.0069 0.4623 0 031 Uiso 1 1 Calc R.. H12 BH 1.3716-0.0892 0.4676 0.031 Uiso 1 1 calc R.. C13 C 1.3929(7)-0.0546(6)0.4181(2)0.0314(18)Uani 1 1 d... H13 AH 1.4790-0.1013 0.4147 0.038 Uiso 1 1 calc R.. H13 BH 1.4098 0.0107 0.4049 0.038 Uiso 1 1 calc R.. C14 C 1.2538(7)-0.1097(6)0.4049(2)0.0356(19)Uani 1 1 d... H14 AH 1.2425 -0.1785 0.4165 0.043 Uiso 1 1 calc R.. H14 BH 1.2639-0.1231 0.3802 0.043 Uiso 1 1 calc R.. N15 N 0.6215(5)0.0371(4)0.33108(16)0.0256(14)Uani 1 1 d... H15 H 0.6768 0.0852 0.3408 0.031 Uiso 1 1 calc R.. C16 C 0.5183(7)0.0697(5 )0.30805(18)0.0213(15)Uani 1 1 d...017 0 0.4336(5)0.0082(3)0.29260(13)0.0309(12)Uani 1 1 d... C18 C 0.5120(6)0.1890(5 ) 0.30170(17)0.0195(15)Uani 1 1 d... C19 C 0.3923(7)0.2486(5)0.31620(19)0.0252(16)Uani 1 1 d... C20 C 0.3785(7)0.3569(5 ) 0.30904(19)0.0267(17)Uani 1 1 d... H20 H 0.2991 0.3957 0.3185 0.032 Uiso 1 1 calc R.. C21C 0.4814(7)0.4078(5)0.28805(19)0.0270(17)Uani 1 1 d H21 H 0.4708 0.4808 0.2834 0.032 Uiso 1 1 calc R.. C22 C 0.6005(7)0.3518(5)0.27375(19)0.0294(18)Uani 1 1 d... H22 H 0.6702 0.3865 0.2597 0.035 Uiso 1 1 Calc R.. C23 C 0.6142 (7) 0.2425 (5) 0.2807 (2) 0.0286 (17) Uani 1 1 d... An acid addition salt according to item 1 of the patent application, which is a knot Crystal and has a crystal structure of Pbca (#61) belonging to an orthorhombic space group. An acid addition salt according to item 1 of the patent application, which is amorphous. An acid addition salt according to item 1 of the patent application, which is anhydrous. An acid addition salt of 4-(2,6-dichlorobenzamide)-1H-pyrazole-3-carboxylic acid piperidin-4-ylguanamine according to claim 1 of the patent application, which is anhydrous And showed an endothermic peak at 379-380 °C. An acid addition salt of 4-(2,6-dichlorobenzamide)-1H-pyrazole-3-carboxylic acid piperidin-4-ylguanamine according to claim 6 of the patent application, which is anhydrous And when DSC was performed, an endothermic peak at 379.8 ° C was shown. An acid addition salt according to item 1 of the patent application, wherein the single crystal form is accompanied by less than 0.9% by weight of other crystal forms. An acid addition salt of 4-(2,6-dichlorobenzamide)-1H-pyrazole-3-carboxylic acid piperidin-4-yl decylamine according to claim 1 of the scope of the patent application, when used The KBr disk method analysis is shown in 3233, 3002, 2829, 1679, 1632, 1560, 1430, 1198, 1037, 909, and 784 cm-1. The infrared spectrum of the characteristic peak. An acid addition salt of 4-(2,6-dichlorobenzamide)-1H-pyrazole-3-carboxylic acid piperidin-4-ylguanamine according to the first aspect of the patent application, which is a crystal And has a lattice parameter of 93K a = 8.90 (10), b = 12.44 (10), c = 38.49 (4) Å, α = β = γ = 90 °. An acid addition salt according to item 1 of the patent application, which is a salt having a solubility in water of more than 15 mg/ml. 4-(2,6-Dichlorobenzamide)-1H-pyrazole-3-carboxylic acid hydrochloride a methanesulfonate of pyridine-4-ylguanamine which is at least 50% crystalline and has a main peak and a crystal face distance (d) characterized by the presence of a diffraction angle (2 θ) as described in Table A. X-ray powder diffraction pattern: . a methanesulfonate of 4-(2,6-dichlorobenzamide)-1H-pyrazole-3-carboxylic acid piperidin-4-ylguanamine according to claim 12, which is at least 50% crystallisation, wherein the X-ray powder diffraction pattern is characterized by the presence of the main peak, crystal plane distance (d) and intensity of the diffraction angle (2 θ) described in Table C: . One preparation is as defined in item 1 of the scope of the patent application A method for the acid addition salt of 4-(2,6-dichlorobenzamide)-1H-pyrazole-3-carboxylic acid piperidin-4-ylguanamine, which comprises forming 4-(2, a solution of 6-dichloro-benzimidamide)-1H-pyrazole-3-carboxylic acid piperidin-4-ylguanamine free base in a solvent or a mixture of solvents, and a solution treated with methanesulfonic acid to form A precipitate of an acid addition salt. An acid addition salt forming 4-(2,6-dichlorobenzamide)-1H-pyrazole-3-carboxylic acid piperidin-4-ylguanamine as defined in the first paragraph of the patent application A method comprising treating a compound of formula (X) with methanesulfonic acid in an organic solvent: To remove the third-butoxycarbonyl group and form 4-(2,6-dichloro-benzylidinium)-1H-pyrazole-3-carboxylic acid piperidin-4-ylguanamine to methanesulfonic acid The addition salt, and optionally the methanesulfonic acid addition salt thus formed, is optionally isolated and the methanesulfonic acid addition salt is optionally recrystallized to produce a crystalline form. A pharmaceutical composition comprising 4-(2,6-dichlorobenzamide)-1H-pyrazole-3 as defined in claim 1 in a concentration greater than 15 mg/ml An aqueous solution of an acid addition salt of a carboxylic acid piperidin-4-ylguanamine. A pharmaceutical composition comprising 4-(2,6-dichlorobenzamide)-1H-pyrazole-3, as defined in claim 1 of the scope of the patent application, at a concentration greater than 30 mg/ml An aqueous solution of an acid addition salt of a carboxylic acid piperidin-4-ylguanamine. An aqueous solution of an acid addition salt of 4-(2,6-dichlorobenzamide)-1H-pyrazole-3-carboxylic acid piperidin-4-ylguanamine according to claim 1 of the scope of the patent application, The aqueous solution has a pH of from 2 to 12. An aqueous solution of an acid addition salt of 4-(2,6-dichlorobenzamide)-1H-pyrazole-3-carboxylic acid piperidin-4-ylguanamine according to claim 18 of the scope of the patent application, wherein The aqueous solution has a pH of 2 to 9. An aqueous solution of an acid addition salt of 4-(2,6-dichlorobenzamide)-1H-pyrazole-3-carboxylic acid piperidin-4-ylguanamine according to claim 18 of the scope of the patent application, wherein The aqueous solution has a pH of 4 to 7. According to the aqueous solution of claim 19, it is buffered. An aqueous solution according to claim 21, wherein the buffer is a buffer formed from acetic acid and sodium acetate. An aqueous solution according to claim 22, wherein the buffer is a buffer formed from acetic acid and sodium acetate, and the solution has a pH of about 4.6. An acid addition salt for preparing 4-(2,6-dichloro-benzamide)-1H-pyrazole-3-carboxylic acid piperidin-4-yl decylamine according to claim 1 of the scope of the patent application Method, the method comprising a compound of formula (XI): Reaction with a compound of formula (XII) in the presence of a non-interfering base in an organic solvent: Wherein PG is an amine-protecting group to produce a compound of formula (XIII): And thereafter removing the protecting group PG with methanesulfonic acid to produce methanesulfonate of 4-(2,6-dichloro-benzamide)-1H-pyrazole-3-carboxylic acid piperidin-4-ylguanamine Acid addition salt, and optionally recrystallized the methanesulfonic acid addition salt thus formed To produce a crystal form. The method of claim 24, wherein the protecting group PG is a third-butoxycarbonyl group. An acid addition salt for preparing 4-(2,6-dichloro-benzamide)-1H-pyrazole-3-carboxylic acid piperidin-4-yl decylamine according to claim 1 of the scope of the patent application The method comprises: (i) treating a compound of formula (XIV) with sulfinium chloride in an aprotic organic solvent Optionally, and heating; (ii) reacting the product of step (i) with a compound of formula (XII) in the presence of a non-interfering base, optionally and heating to produce a compound of formula (XIII); And (iii) removing the protecting group PG from the compound of formula (XIII) to give 4-(2,6-dichloro-benzamide)-1H-pyrazole-3-carboxylic acid piperidin-4-yl a methanesulfonic acid addition salt of guanamine; and optionally (iv) recrystallizing the salt to produce a crystalline form. The method according to claim 26, wherein in the step (i), the reaction with sulfinium chloride is carried out and heated to a range of 80 to 100 ° C temperature. According to the method of claim 26, the solvent in which the step (i) is carried out is an aromatic hydrocarbon solvent. According to the method of claim 26, wherein step (ii) is carried out and heated to a temperature of up to about 55 °C. The method of claim 26, wherein in the step (ii), the reaction is carried out in tetrahydrofuran. The method of claim 26, wherein in the step (iii), the protecting group is a remover which can be treated by treatment with methanesulfonic acid. The method according to claim 31, wherein the protecting group is a third-butoxycarbonyl group. 4-(2,6-Dichlorobenzamide)-1H-pyrazole-3-carboxylic acid piperidin-4-yl decylamine as defined in any one of claims 1 to 13 The salt is used in the manufacture of a medicament for the treatment of a disease state or condition mediated by a cyclin-dependent kinase or glycogen synthase kinase-3. 4-(2,6-Dichlorobenzamide)-1H-pyrazole-3-carboxylic acid piperidin-4-yl decylamine as defined in any one of claims 1 to 13 The salt is used in the manufacture of a medicament for reducing or reducing the incidence of a disease state or condition mediated by a cyclin-dependent kinase or glycogen synthase kinase-3. 4-(2,6-Dichlorobenzamide)-1H-pyrazole-3-carboxylic acid piperidin-4-yl decylamine as defined in any one of claims 1 to 13 The salt is used in the manufacture of medicines, which are used in the treatment of Or a disease or condition resulting from abnormal cell growth in a mammal. 4-(2,6-Dichlorobenzamide)-1H-pyrazole-3-carboxylic acid piperidin-4-yl decylamine as defined in any one of claims 1 to 13 Salts are used in the manufacture of medicines for reducing or reducing the incidence of diseases or conditions that comprise or result from abnormal cell growth in a mammal. 4-(2,6-Dichlorobenzamide)-1H-pyrazole-3-carboxylic acid piperidin-4-yl decylamine as defined in any one of claims 1 to 13 The salt is used for the manufacture of a medicament for inhibiting a cyclin-dependent kinase or hepatose synthase kinase-3. A pharmaceutical composition comprising 4-(2,6-dichlorobenzamide)-1H-pyrazole-3-carboxylic acid piperidine as defined in any one of claims 1 to 13 of the patent application. a salt of -4-ylguanamine and a pharmaceutically acceptable carrier. 4-(2,6-Dichlorobenzamide)-1H-pyrazole-3-carboxylic acid piperidine-4 as defined in any one of claims 1 to 13 of the patent application - a salt of guanamine. 4-(2,6-Dichlorobenzamide)-1H-pyrazole-3-carboxylic acid as defined in any one of claims 1 to 13 for the treatment of B cell lymphoma An acid addition salt of piperidin-4-ylguanamine. 4-(2,6-Dichlorobenzamide)-1H-pyrazole-3-carboxylic acid as defined in any one of claims 1 to 13 for the treatment of chronic lymphocytic leukemia An acid addition salt of piperidin-4-ylguanamine. A root for treating diffuse large cell B-cell lymphoma 4-(2,6-Dichlorobenzamide)-1H-pyrazole-3-carboxylic acid piperidin-4-ylguanamine as defined in any one of claims 1 to 13 Acid addition salt. 4-(2,6-Dichlorobenzamide)-1H-pyrazole-3-carboxylic acid piperidin-4-yl decylamine as defined in any one of claims 1 to 13 The use of a salt for the manufacture of a medicament for the treatment of cancer. According to the application of the scope of claim 43, wherein the cancer is cancer of the bladder, breast, colon, kidney, epidermis, liver, lung, esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate, or skin; Blood tumor of lymphoid lineage; blood tumor of myeloid lineage; thyroid follicular carcinoma; mesenchymal-derived tumor; tumor of central or peripheral nervous system; melanoma; cytoma; teratoma; Tumor; xeroderma pigmentosum; keratoctanthoma; thyroid follicular carcinoma; or Kaposi sarcoma. The use according to claim 43, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, colon cancer, prostate cancer, esophageal cancer, squamous carcinoma, and non-small cell lung cancer. The use according to claim 43, wherein the cancer is a blood tumor selected from the group consisting of a lymphoid lineage of a group consisting of leukemia, chronic lymphocytic leukemia, quilt cell lymphoma and B cell lymphoma.