JP5102785B2 - Cd80アンタゴニストの塩 - Google Patents
Cd80アンタゴニストの塩 Download PDFInfo
- Publication number
- JP5102785B2 JP5102785B2 JP2008555857A JP2008555857A JP5102785B2 JP 5102785 B2 JP5102785 B2 JP 5102785B2 JP 2008555857 A JP2008555857 A JP 2008555857A JP 2008555857 A JP2008555857 A JP 2008555857A JP 5102785 B2 JP5102785 B2 JP 5102785B2
- Authority
- JP
- Japan
- Prior art keywords
- choline salt
- ethyl
- pyrazolo
- fluoro
- difluoro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 150000003839 salts Chemical class 0.000 title description 6
- 229940123828 CD80 antagonist Drugs 0.000 title description 2
- 239000004381 Choline salt Substances 0.000 claims description 12
- 235000019417 choline salt Nutrition 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- 150000003248 quinolines Chemical class 0.000 claims description 10
- -1 4- (6-Fluoro-3-oxo-1,3-dihydro-pyrazolo [4,3-c] cinnolin-2-yl) -N- (2,2-difluoro-ethyl) -benzamide choline salt Chemical class 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 239000006071 cream Substances 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 13
- 239000007787 solid Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 239000000725 suspension Substances 0.000 description 7
- 239000003814 drug Substances 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000006188 syrup Substances 0.000 description 4
- 235000020357 syrup Nutrition 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 125000004778 2,2-difluoroethyl group Chemical group [H]C([H])(*)C([H])(F)F 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- MHFKFNJSUZVGGZ-UHFFFAOYSA-N n-(2,2-difluoroethyl)-4-(6-fluoro-3-oxo-1h-pyrazolo[4,3-c]cinnolin-2-yl)benzamide Chemical compound C1=CC(C(=O)NCC(F)F)=CC=C1N1C(=O)C(N=NC=2C3=CC=CC=2F)=C3N1 MHFKFNJSUZVGGZ-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 235000010356 sorbitol Nutrition 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- 240000007472 Leucaena leucocephala Species 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 102100027222 T-lymphocyte activation antigen CD80 Human genes 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229960001231 choline Drugs 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- IHFGSLVPSBXQIN-UHFFFAOYSA-N 1-n,1-n'-difluoroethane-1,1-diamine Chemical compound FNC(C)NF IHFGSLVPSBXQIN-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- HMBHAQMOBKLWRX-UHFFFAOYSA-N 2,3-dihydro-1,4-benzodioxine-3-carboxylic acid Chemical compound C1=CC=C2OC(C(=O)O)COC2=C1 HMBHAQMOBKLWRX-UHFFFAOYSA-N 0.000 description 1
- VUEGFRGKVXRNGW-UHFFFAOYSA-M 2-[4-(2,2-difluoroethylcarbamoyl)phenyl]-6-fluoropyrazolo[4,3-c]cinnolin-3-olate;2-hydroxyethyl(trimethyl)azanium Chemical compound C[N+](C)(C)CCO.N1=C(C2=CC=CC(F)=C2N=N2)C2=C([O-])N1C1=CC=C(C(=O)NCC(F)F)C=C1 VUEGFRGKVXRNGW-UHFFFAOYSA-M 0.000 description 1
- 235000019489 Almond oil Nutrition 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- TVTVQGLLEHEPBD-UHFFFAOYSA-N C1=CC2=C3C(=NN=C2C(=C1)F)C(=O)NN3 Chemical compound C1=CC2=C3C(=NN=C2C(=C1)F)C(=O)NN3 TVTVQGLLEHEPBD-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- OQMUTEILBLNZDX-UHFFFAOYSA-N N-(2,2-Difluoroethyl)benzamide Chemical compound FC(F)CNC(=O)C1=CC=CC=C1 OQMUTEILBLNZDX-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000008168 almond oil Substances 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 229940075419 choline hydroxide Drugs 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000008157 edible vegetable oil Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- 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
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Physical Education & Sports Medicine (AREA)
- Rheumatology (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Pain & Pain Management (AREA)
- Diabetes (AREA)
- Transplantation (AREA)
- Dermatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicinal Preparation (AREA)
Description
この発明は、化合物(A)のコリン塩が望ましい良好な水溶性を有していることを見出したことに基づいている。
本発明によれば、上記の式(A)の4-(6-フルオロ-3-オキソ-1,3-ジヒドロ-ピラゾロ[4,3-c]シンノリン-2-イル)-N-(2,2-ジフルオロ-エチル)-ベンズアミドのコリン塩が提供される。
上記のコリン塩の注射可能な水性溶液、および上記のコリン塩を含み局所に適用できる水をベースとする液状またはクリーム状の組成物は、本発明のもう一つの目的である。
経口投与用の錠剤およびカプセル剤は、1回投与用の形態であってよく、結合剤、例えばシロップ、アカシア、ゼラチン、ソルビトール、トラガントもしくはポリビニルピロリドン;充填剤、例えばラクトース、砂糖、トウモロコシ澱粉、燐酸カルシウム、ソルビトールもしくはグリシン; 打錠用の滑沢剤、例えばステアリン酸マグネシウム、タルク、ポリエチレングリコールもしくはシリカ;崩壊剤、例えばバレイショ澱粉、またはラウリル硫酸ナトリウムのような許容される湿潤剤のような、通常の賦形剤を含んでいてもよい。錠剤は、通常の製薬業界で周知の方法に従ってコーティングされていてもよい。
次のようにして、4-(6-フルオロ-3-オキソ-1,3-ジヒドロ-ピラゾロ[4,3-c]シンノリン-2-イル)-N-(2,2-ジフルオロ-エチル)-ベンズアミドを製造し、そのコリン(すなわち、(2-ヒドロキシ-エチル)-トリメチル-アンモニウム)塩を製造した。
磁石撹拌器、還流濃縮器およびガスバブラーを備えた丸底フラスコに、WO 2004/081011の実施例5のようにして製造された、4-(6-フルオロ-3-オキソ-1,3-ジヒドロ-ピラゾロ[4,3-c]シンノリン-2-イル)-安息香酸(12.9 g)を入れた。塩化チオニル(65 ml)をゆっくり加えた。窒素雰囲気を適用し、混合物を加熱還流した。加熱するとガスの発生が見られ、そのガスをスクラバー中にトラップした。
LC-MS: 目的物の一つのピーク。この物質のQC 分析は、91.6%の純度を示した。
磁石撹拌器を備えた丸底フラスコに、N-(2,2-ジフルオロ-エチル)-4-(6-フルオロ-3-オキソ-1,3-ジヒドロ-ピラゾロ[4,3-c]シンノリン-2-イル)-ベンズアミド(2.50 g)を入れた。固形物をメタノール(25 ml)中に懸濁し、コリン水酸化物(782 mg、1.74 ml 45重量% メタノール中) を滴下した。この滴下により、澄明な暗褐色の溶液が生成した。
LC-MS: 単離された固形物; 一つの主ピーク [M+H]+ 388、純度 95%。
固形の塩は、褐色の粗い粉末(2.26 g、4.61 mmol、71%)であった。
融点:172-180℃(分解)。
N-(2,2-ジフルオロ-エチル)-4-(6-フルオロ-3-オキソ-1,3-ジヒドロ-ピラゾロ[4,3-c]シンノリン-2-イル)-ベンズアミドの塩になっていない形態(遊離の酸)、および一連のその他の塩の溶解性も、同じ分析で試験した。
試験化合物10 mgをバイアル中に秤取し、溶媒1 ml を加えた。澄明な溶液の形成により証明されるように、サンプルが直ちに溶解したら、試験物質をさらに加え、バイアルを15分間超音波処理した。懸濁液の形成により証明されるように、試験化合物がもはや溶解しなくなるまで、この手順を繰り返した。次いで、懸濁液を含むバイアルを15分間超音波処理し、25 ℃/60% 相対湿度で24時間シェイカー上に置いた。シェイカーから外し、サンプルを遠心分離し、上澄液をHPLCで分析した。結果を表1に示す。
Claims (4)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0603522.4 | 2006-02-22 | ||
GBGB0603522.4A GB0603522D0 (en) | 2006-02-22 | 2006-02-22 | Kinase inhibition |
PCT/GB2007/000550 WO2007096588A1 (en) | 2006-02-22 | 2007-02-19 | Salt of cd 80 antagonist |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2009527538A JP2009527538A (ja) | 2009-07-30 |
JP5102785B2 true JP5102785B2 (ja) | 2012-12-19 |
Family
ID=36178528
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2008555857A Expired - Fee Related JP5102785B2 (ja) | 2006-02-22 | 2007-02-19 | Cd80アンタゴニストの塩 |
Country Status (20)
Country | Link |
---|---|
US (3) | US20090221590A1 (ja) |
EP (1) | EP1991548B1 (ja) |
JP (1) | JP5102785B2 (ja) |
KR (1) | KR101433738B1 (ja) |
CN (1) | CN101384595B (ja) |
AU (1) | AU2007217170B2 (ja) |
BR (1) | BRPI0708114B8 (ja) |
CA (1) | CA2643668C (ja) |
DK (1) | DK1991548T3 (ja) |
EA (1) | EA014101B1 (ja) |
ES (1) | ES2449569T3 (ja) |
GB (1) | GB0603522D0 (ja) |
HK (1) | HK1125376A1 (ja) |
IL (1) | IL192954A (ja) |
NZ (1) | NZ570055A (ja) |
PL (1) | PL1991548T3 (ja) |
PT (1) | PT1991548E (ja) |
UA (1) | UA91904C2 (ja) |
WO (1) | WO2007096588A1 (ja) |
ZA (1) | ZA200806508B (ja) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EA009680B1 (ru) | 2003-03-14 | 2008-02-28 | Эвидекс Лимитед | Иммуномодулирующие гетероциклические соединения |
JP4763697B2 (ja) | 2004-08-09 | 2011-08-31 | メディジーン リミテッド | Cd80抑制剤としての免疫調整性オキソピラゾロシンノリン類 |
AU2009309575B2 (en) | 2008-10-31 | 2015-02-26 | C-A-I-R Biosciences Gmbh | Choline and tromethamine salt of Licofelone |
RU2557237C2 (ru) | 2010-02-10 | 2015-07-20 | Киссеи Фармасьютикал Ко., Лтд. | Соль конденсированного гетероциклического производного и его кристаллы |
UA109287C2 (uk) * | 2010-11-02 | 2015-08-10 | Солі органічного аміну похідних амінобензойної кислоти і спосіб їх одержання | |
EP4119128A1 (en) | 2021-07-13 | 2023-01-18 | Dr. Falk Pharma Gmbh | Pharmaceutical composition for the oral administration of poorly soluble drugs comprising an amorphous solid dispersion |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2670350A (en) * | 1952-08-08 | 1954-02-23 | Nepera Chemical Co Inc | Method of preparing choline salt of theophylline |
US3576637A (en) * | 1967-04-20 | 1971-04-27 | Konishiroku Photo Ind | Lith-type of emulsion containing pyrozolone |
US3778150A (en) * | 1971-10-27 | 1973-12-11 | K Aston | Printing of photographic colour negatives |
JPS523818A (en) * | 1975-06-26 | 1977-01-12 | Hoffmann La Roche | Salt of penicillanic acid |
US4591589A (en) * | 1985-01-16 | 1986-05-27 | Roussel Uclaf | 2-aryl pyrazolo[4,3-c]cinnolin-3-ones |
DE3903993A1 (de) * | 1989-02-10 | 1990-08-16 | Basf Ag | Diarylsubstituierte heterocyclische verbindungen, ihre herstellung und arzneimittel daraus |
IT1290448B1 (it) * | 1997-04-01 | 1998-12-03 | Schiena Michele Giuseppe Di | Nimesulide sale di colina,metodo di preparazione e composizioni farmaceutiche che lo contengono |
EA009680B1 (ru) | 2003-03-14 | 2008-02-28 | Эвидекс Лимитед | Иммуномодулирующие гетероциклические соединения |
TW200526638A (en) * | 2003-10-22 | 2005-08-16 | Smithkline Beecham Corp | 2-(3,4-dimethylphenyl)-4-{[2-hydroxy-3'-(1H-tetrazol-5-yl)biphenyl-3-yl]-hydrazono}-5-methyl-2,4-dihydropyrazol-3-one choline |
GB0325644D0 (en) * | 2003-11-04 | 2003-12-10 | Avidex Ltd | Immuno ihibitory pyrazolone compounds |
GB0411770D0 (en) * | 2004-05-26 | 2004-06-30 | Avidex Ltd | Immuno inhibitory heterocyclic compouds |
JP4763697B2 (ja) * | 2004-08-09 | 2011-08-31 | メディジーン リミテッド | Cd80抑制剤としての免疫調整性オキソピラゾロシンノリン類 |
WO2006083687A1 (en) * | 2005-01-28 | 2006-08-10 | Cardiome Pharma Corp. | Crystal salt of xanthine oxidase inhibitors |
-
2006
- 2006-02-22 GB GBGB0603522.4A patent/GB0603522D0/en not_active Ceased
-
2007
- 2007-02-19 JP JP2008555857A patent/JP5102785B2/ja not_active Expired - Fee Related
- 2007-02-19 EP EP07712727.2A patent/EP1991548B1/en active Active
- 2007-02-19 DK DK07712727.2T patent/DK1991548T3/en active
- 2007-02-19 US US12/279,898 patent/US20090221590A1/en not_active Abandoned
- 2007-02-19 NZ NZ570055A patent/NZ570055A/en unknown
- 2007-02-19 UA UAA200811363A patent/UA91904C2/ru unknown
- 2007-02-19 AU AU2007217170A patent/AU2007217170B2/en active Active
- 2007-02-19 EA EA200801875A patent/EA014101B1/ru unknown
- 2007-02-19 PL PL07712727T patent/PL1991548T3/pl unknown
- 2007-02-19 CN CN2007800051162A patent/CN101384595B/zh active Active
- 2007-02-19 KR KR1020087019729A patent/KR101433738B1/ko active IP Right Grant
- 2007-02-19 CA CA2643668A patent/CA2643668C/en active Active
- 2007-02-19 BR BRPI0708114A patent/BRPI0708114B8/pt active IP Right Grant
- 2007-02-19 PT PT77127272T patent/PT1991548E/pt unknown
- 2007-02-19 ES ES07712727.2T patent/ES2449569T3/es active Active
- 2007-02-19 WO PCT/GB2007/000550 patent/WO2007096588A1/en active Application Filing
-
2008
- 2008-07-22 IL IL192954A patent/IL192954A/en active IP Right Grant
- 2008-07-25 ZA ZA200806508A patent/ZA200806508B/xx unknown
-
2009
- 2009-05-07 HK HK09104229.6A patent/HK1125376A1/xx unknown
-
2011
- 2011-09-15 US US13/233,634 patent/US20120004237A1/en not_active Abandoned
-
2017
- 2017-11-20 US US15/817,323 patent/US20180265514A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
CN101384595A (zh) | 2009-03-11 |
GB0603522D0 (en) | 2006-04-05 |
US20090221590A1 (en) | 2009-09-03 |
BRPI0708114A2 (pt) | 2011-05-17 |
BRPI0708114B1 (pt) | 2020-02-04 |
WO2007096588A1 (en) | 2007-08-30 |
US20120004237A1 (en) | 2012-01-05 |
KR101433738B1 (ko) | 2014-08-25 |
EA014101B1 (ru) | 2010-08-30 |
CA2643668A1 (en) | 2007-08-30 |
UA91904C2 (en) | 2010-09-10 |
US20180265514A1 (en) | 2018-09-20 |
IL192954A (en) | 2015-01-29 |
BRPI0708114B8 (pt) | 2021-05-25 |
EA200801875A1 (ru) | 2008-12-30 |
IL192954A0 (en) | 2009-02-11 |
ZA200806508B (en) | 2009-06-24 |
HK1125376A1 (en) | 2009-08-07 |
DK1991548T3 (en) | 2014-03-10 |
NZ570055A (en) | 2011-08-26 |
PL1991548T3 (pl) | 2014-05-30 |
CN101384595B (zh) | 2011-02-09 |
AU2007217170B2 (en) | 2012-02-02 |
KR20080103523A (ko) | 2008-11-27 |
PT1991548E (pt) | 2014-03-10 |
EP1991548B1 (en) | 2013-12-11 |
JP2009527538A (ja) | 2009-07-30 |
AU2007217170A1 (en) | 2007-08-30 |
CA2643668C (en) | 2014-05-13 |
ES2449569T3 (es) | 2014-03-20 |
EP1991548A1 (en) | 2008-11-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20180265514A1 (en) | Salt of cd80 antagonist | |
JP2021073214A (ja) | γ−ヒドロキシ酪酸(GHB)のプロドラッグ、その組成物および使用 | |
JP4669836B2 (ja) | ピペリジニル−およびピペラジニル−アルキルカルバメート誘導体、その製造法および治療用途 | |
EP2855478A1 (en) | Solid forms of an antiviral compound | |
JP2007524707A (ja) | アリール及びヘテロアリールピペリジンカルボン酸誘導体、その製造並びにfaah酵素阻害剤としてのその使用 | |
JP2001523712A (ja) | Pde−ivのベンゼンスルホンアミド阻害剤およびそれらの治療的使用 | |
JP2000505451A (ja) | キノロン類およびこれらの治療的使用 | |
KR20170061616A (ko) | 피마살탄의 신규 염 | |
JPH06500085A (ja) | ベンズイミダゾール、その製造および使用法 | |
JP2005527518A (ja) | 新規なカルコン(chalcone)誘導体とその使用 | |
EP2841419A1 (en) | Crystalline forms of saxagliptin | |
KR20090101171A (ko) | 디히드록시안트라퀴논 카르복실산의 염 및 그들의 치료적 용도 | |
JP2567593B2 (ja) | イミダゾリジントリオン誘導体及び該化合物を有効成分として含有するアレルギ−性疾患治療剤 | |
MX2008010379A (en) | Salt of cd 80 antagonist | |
US9376382B2 (en) | N-substituted isopropyldimethyl azulene sulfonamide derivatives, and preparation method and use thereof | |
WO2010022634A1 (zh) | 新型乙二胺衍生物 | |
JPS61249970A (ja) | 新規な置換2−(n−アルキニル−n−フエニルアミノ)イミダゾリン誘導体 | |
JPS6123796B2 (ja) | ||
WO2012038905A1 (fr) | Derives de thienopyridine nicotinamide, leur preparation et leur application en therapeutique | |
EP1218334A1 (en) | Polymorphic n-[3-[[2-(3,4-dimethoxyphenyl)ethyl]amino]propyl]- 4-nitro benzamide hydrochloride | |
CA2456349A1 (en) | 1,2-dihydro-2-oxo-1,8-naphthyridine derivative | |
JPS62283965A (ja) | ベンズイミダゾール誘導体薬剤組成物 | |
WO2001027072A1 (en) | Hydrated n-[3-[[2-(3,4-dimethoxyphenyl) ethyl] amino] propyl] -4-nitro benzamide hydrochloride and its use in pharmaceutical compositions | |
IE51010B1 (en) | Derivatives of pyrrole for protecting the myocardium,having an anti-arrhythmic activity and an activity as blood platelet anti-aggregant process for preparation thereof and drugs containing same |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20100105 |
|
A711 | Notification of change in applicant |
Free format text: JAPANESE INTERMEDIATE CODE: A711 Effective date: 20111025 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20111025 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20120918 |
|
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20120928 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20151005 Year of fee payment: 3 |
|
R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 Ref document number: 5102785 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
LAPS | Cancellation because of no payment of annual fees |