WO2022164085A1 - 트리아졸로피라진 유도체의 신규한 말레산염, 조성물, 사용방법 및 이의 제조방법 - Google Patents
트리아졸로피라진 유도체의 신규한 말레산염, 조성물, 사용방법 및 이의 제조방법 Download PDFInfo
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- maleate
- salt
- maleic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
Definitions
- a maleic acid salt of a triazolopyrazine derivative represented by the following Chemical Formula 1 (ABN 401).
- the present invention also provides a method of binding hepatocyte growth factor to a salt of the compound represented by formula (I) by administering to a patient or subject one or more of the maleate or dimaleate forms described above.
- the disease is a dysproliferative disease.
- Dose Level (mg/kg) 5 5 20 Route IV PO PO Mean SD Mean SD Mean SD Tmax(h) 4 n/a 4 n/a Cmax(nM) 343 13.2 1080 116 AUClast(h*nM) 7060 1030 2750 192 9760 898 AUClast/Dose (h*kg*nM/mg) 1410 207 551 38.4 488 44.9 AUC ⁇ (h*nM) 7200 1070 2810 192 10100 623 AUC ⁇ /Dose (h*kg*nM/mg) 1440 214 562 38.4 504 31.1 Vz (mg/(nM)/kg) 0.00471 0.00102 CI (mg/(h*nM)/kg) 0.000705 0.000104 Vss (mg/(nM)/kg) 0.00347 0.000359 F(%) 39.0 35.0
- the pharmaceutical composition of the present invention may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, and the like, in addition to the above components.
- the pharmaceutical composition may be provided in any suitable dosage form (eg, oral solutions, emulsions, syrups, elixirs, tablets, capsules, liquid filled capsules, softgels, sustained release and solid dosage forms, etc.).
- the maleic acid salt of the triazolopyrazine derivative provided in the present invention is represented by the following formula (2).
- DSC Differential scanning calorimetry
- DVS dynamic vapor sorption
- the maleate represented by Chemical Formula 2 did not show significant chemical degradation even after exposure to 25°C/60% RH, and was chemically stable at 40°C/75% RH for up to 15 months.
- the compound of Formula 2 has less hygroscopicity and improved chemical stability compared to the compound of Formula 1.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
pH | Composition buffer solution |
1.2 | 0.05M Gastric Buffer |
3 | 0.05M Citrate Buffer |
4 | 0.05M Citrate Buffer |
5 | 0.05M Citrate Buffer |
6 | 0.05M and 0.2M Phosphate Buffer |
7.4 | 0.05M Phosphate Buffer |
Dose Level(mg/kg) | 5 | 5 | 20 | |||
Route | IV | PO | PO | |||
Mean | SD | Mean | SD | Mean | SD | |
Tmax(h) | 2-4$ | n/a | 2-4$ | n/a | ||
Cmax(nM) | 246 | 65.2 | 676 | 15.5 | ||
AUClast(h*nM) | 8130 | 441 | 1730 | 117 | 6820 | 836 |
AUClast/Dose(h*kg*nM/mg) | 1630 | 88.2 | 347 | 23.4 | 341 | 41.8 |
AUC∞(h*nM) | 8265 | n/a | 1770 | 101 | 6930 | 769 |
AUC∞/Dose(h*kg*nM/mg) | 1655 | n/a | 355 | 20.1 | 346 | 38.5 |
Vz(mg/(nM)/kg) | 0.00259 | n/a | ||||
CI(mg/(h*nM)/kg) | 0.000606 | n/a | ||||
Vss(mg/(nM)/kg) | 0.00271 | n/a | ||||
F(%) | 21.4 | 20.9 |
Dose Level(mg/kg) | 5 | 5 | 20 | |||
Route | IV | PO | PO | |||
Mean | SD | Mean | SD | Mean | SD | |
Tmax(h) | 4 | n/a | 4 | n/a | ||
Cmax(nM) | 343 | 13.2 | 1080 | 116 | ||
AUClast(h*nM) | 7060 | 1030 | 2750 | 192 | 9760 | 898 |
AUClast/Dose(h*kg*nM/mg) | 1410 | 207 | 551 | 38.4 | 488 | 44.9 |
AUC∞(h*nM) | 7200 | 1070 | 2810 | 192 | 10100 | 623 |
AUC∞/Dose(h*kg*nM/mg) | 1440 | 214 | 562 | 38.4 | 504 | 31.1 |
Vz(mg/(nM)/kg) | 0.00471 | 0.00102 | ||||
CI(mg/(h*nM)/kg) | 0.000705 | 0.000104 | ||||
Vss(mg/(nM)/kg) | 0.00347 | 0.000359 | ||||
F(%) | 39.0 | 35.0 |
Dose Level(mg/kg) | 5 | 5 | 20 | |||
TotalDailyDoseLevel(mg/kg/day) | 10 | 10 | 40 | |||
Route | IV | PO | PO | |||
Mean | SD | Mean | SD | Mean | SD | |
Tmax1(h) | 0.5-3$ | n/a | 2-3$ | n/a | ||
Tmax2(h) | 12.5-13$ | n/a | 12.5-14$ | n/a | ||
Cmax1(nM) | 611 | 195 | 1600 | 421 | ||
Cmax2(nM) | 802 | 216 | 2120 | 553 | ||
AUC(0-12h)(h*nM) | 5320 | 1310 | 3430 | 487 | 12200 | 4560 |
AUC(0-12h)/Dose(h*kg*nM/mg) | 1060 | 262 | 685 | 97.4 | 612 | 228 |
AUC(12-24h)(h*nM) | 7340 | n/a | 3990 | 852 | 12000 | 1030 |
AUC(12-24h)/Dose(h*kg*nM/mg) | 1470 | n/a | 798 | 170 | 601 | 51.6 |
AUClast(h*nM) | 12975 | n/a | 7420 | 1340 | 24300 | 5550 |
AUClast/Dose(h*kg*nM/mg) | 1298 | n/a | 742 | 134 | 607 | 139 |
Vz(mg/(nM)/kg) | 0.00283 | n/a | n/a | n/a | ||
CI(mg/(h*nM)/kg) | 0.000860 | n/a | n/a | n/a | ||
Vss(mg/(nM)/kg) | 0.00782 | n/a | n/a | n/a | ||
F(%) | 57.2 | 46.8 |
Dose Level(mg/kg) | 5 | 5 | 20 | |||
TotalDailyDoseLevel(mg/kg/day) | 10 | 10 | 40 | |||
Route | IV | PO | PO | |||
Mean | SD | Mean | SD | Mean | SD | |
Tmax1(h) | 3-4$ | n/a | 1-3$ | n/a | ||
Tmax2(h) | 13-14$ | n/a | 12.083-16$ | n/a | ||
Cmax1(nM) | 564 | 425 | 821 | 396 | ||
Cmax2(nM) | 488 | 114 | 1000 | 472 | ||
AUC(0-12h)(h*nM) | 5360 | 2320 | 2440 | 1160 | 7900 | n/a |
AUC(0-12h)/Dose(h*kg*nM/mg) | 1070 | 465 | 487 | 232 | 395 | n/a |
AUC(12-24h)(h*nM) | 7380 | 1980 | 2450 | 421 | 6260 | 1970 |
AUC(12-24h)/Dose(h*kg*nM/mg) | 1480 | 395 | 490 | 8403 | 313 | 98.4 |
AUClast(h*nM) | 14100 | 3460 | 4880 | 1320 | 12700 | 3410 |
AUClast/Dose(h*kg*nM/mg) | 1410 | 346 | 488 | 132 | 318 | 85.2 |
Vz(mg/(nM)/kg) | 0.00265 | 0.00102 | ||||
CI(mg/(h*nM)/kg) | 0.000733 | 0.000193 | ||||
Vss(mg/(nM)/kg) | 0.00760 | 0.00283 | ||||
F(%) | 34.6 | 22.6 |
cell line | chemical formula 2 | chemical formula 1 | |
cell activity(GI50) | EBC-1 | 14.17 nM | 8.17 nM |
Claims (20)
- 제1항에 있어서, 상기 말레산염은 시차 주사 열량계(DSC) 서모그램에서 55°및 145°의 흡열 피크와 280°의 발열 피크를 갖는 것을 특징으로 하는 말레산염
- 제1항에 있어서, 상기 말레산염은 수소 자기공명스펙트럼에서 하기의 피크를 갖는 것을 특징으로 하는 말레산염3.48 - 3.58 (m, 2 H), 3.64 (br s, 3 H), 3.87 - 4.03 (m, 4 H), 4.17 - 4.28 (m, 1 H,) 4.40 (br d, J=13.43 Hz, 1H), 4.74 (br d, J=12.21 Hz, 1 H), 4.88 - 5.00 (m, 2 H), 6.16 (s, 4 H), 7.42 (d, J=8.24 Hz, 2 H), 7.66 (d, J=8.24 Hz, 2 H), 8.33 (d, J=0.61 Hz, 1 H), 8.67 (s, 1 H), 8.77 (s, 2 H), and 9.23 (s, 1 H).
- 하기의 화학식 2로 표현되는 트리아졸로피라진 유도체의 말레산염을 제조하는 방법에 관한 것으로서, 상기 제조방법은 하기의 단계로 이루어지는 것을 특징으로 하는 말레산염을 제조하는 방법;(a) 용매를 포함하는 반응기에 하기 화학식 1로 표시되는 화합물을 투입하는 단계;<화학식 1>(b) 상기 반응기 내에서 상기 화합물 및 용매를 교반하는 단계;(c) 상기 (b)에서 제조된 용액에 말레산을 화학식 1의 화합물에 대하여 1:1 내지 1:3의 당량비로 첨가하는 단계;(d) (c)에서 제조된 용액을 교반하는 단계; 및(e) (d)에서 제조된 용액을 냉각시켜 하기 화학식 2로 표시되는 말레산염의 침전물을 얻는 단계<화학식 2>
- 제8항에 있어서, 상기 말레산염은 하나 이상의 말레산 분자를 포함하여 이루어지는 것을 특징으로 하는 말레산염
- 제9항에 있어서, 상기 말레산염은 두개 이상의 말레산 분자를 포함하여 이루어지는 것을 특징으로 하는 말레산염
- 제8항에 있어서, 상기 용매는 아세토나이트릴, 아세톤 및 1,2-디메톡시에탄으로 이루어지는 군에서 선택되는 어느 하나인 것을 특징으로 하는 제조방법
- 제8항에 있어서, 상기 b 단계는 50℃에서 한 시간 이상 수행되는 것을 특징으로 하는 제조방법
- 제8항에 있어서, 상기 침전물은 25℃로 냉각된 후에 24 내지 48시간 동안 숙성되는 것을 특징으로 하는 제조방법
- 제14항에 있어서, 상기 약학적으로 허용가능한 담체는 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아 고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세결정성 셀룰로스, 폴리비닐피롤리돈, 셀룰로스, 물, 시럽, 메틸 셀룰로스, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일로 이루어지는 군에서 선택되는 것을 특징으로 하는 약학 조성물
- 제14항에 있어서, 상기 약학 조성물은 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 중에서 선택되는 하나 이상의 성분을 추가로 포함하여 이루어지는 것을 특징으로 하는 약학 조성물
- 제17항에 있어서, 상기 질병은 이상증식성 장애인 것을 특징으로 하는 대상체의 c-Met 키나제의 활성을 억제하는 방법
- 제18항에 있어서, 상기 이상증식성 장애는 폐암, 위암, 췌장암, 결장암, 난소암, 신장세포암, 전립선암 및 뇌종양으로 이루어지는 군에서 선택되는 것을 특징으로 하는 대상체의 c-Met 키나제의 활성을 억제하는 방법
- 제17항에 있어서, 상기 말레산염을 대상체에 유효량을 투여되는 것을 특징으로 하는 대상체의 c-Met 키나제의 활성을 억제하는 방법
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CN202280012104.7A CN116867786A (zh) | 2021-01-27 | 2022-01-12 | 三唑并吡嗪衍生物的新型马来酸盐、组合物、使用方法及其制备方法 |
EP22746114.2A EP4286385A1 (en) | 2021-01-27 | 2022-01-12 | Novel maleate of triazolopyrazine derivative, composition, use method, and preparation method therefor |
KR1020237016785A KR20230113739A (ko) | 2021-01-27 | 2022-01-12 | 트리아졸로피라진 유도체의 신규한 말레산염, 조성물, 사용방법 및 이의 제조방법 |
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Citations (5)
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KR20090077063A (ko) * | 2006-11-01 | 2009-07-14 | 아스트라제네카 아베 | 진통 활성을 가짐으로써 통증의 치료 또는 예방에 유용한 피라졸릴 유도체 |
KR20140022229A (ko) * | 2012-08-13 | 2014-02-24 | 한국화학연구원 | 신규한 트리아졸로 피라진 유도체 및 그의 용도 |
WO2015046653A1 (ko) * | 2013-09-30 | 2015-04-02 | 한국화학연구원 | 신규한 트리아졸로 피라진 유도체 및 그의 용도 |
KR20180092096A (ko) * | 2017-02-08 | 2018-08-17 | 에이비온 주식회사 | 트리아졸로 피라진 유도체의 신규한 다형체 및 이의 제조 방법 |
KR20180095198A (ko) * | 2017-02-17 | 2018-08-27 | 동아에스티 주식회사 | 토파시티닙의 신규 염 및 이를 포함하는 약학적 조성물 |
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2021
- 2021-05-10 US US17/315,368 patent/US11987582B2/en active Active
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2022
- 2022-01-12 KR KR1020237016785A patent/KR20230113739A/ko unknown
- 2022-01-12 WO PCT/KR2022/000536 patent/WO2022164085A1/ko active Application Filing
- 2022-01-12 EP EP22746114.2A patent/EP4286385A1/en active Pending
- 2022-01-12 CN CN202280012104.7A patent/CN116867786A/zh active Pending
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KR20090077063A (ko) * | 2006-11-01 | 2009-07-14 | 아스트라제네카 아베 | 진통 활성을 가짐으로써 통증의 치료 또는 예방에 유용한 피라졸릴 유도체 |
KR20140022229A (ko) * | 2012-08-13 | 2014-02-24 | 한국화학연구원 | 신규한 트리아졸로 피라진 유도체 및 그의 용도 |
WO2015046653A1 (ko) * | 2013-09-30 | 2015-04-02 | 한국화학연구원 | 신규한 트리아졸로 피라진 유도체 및 그의 용도 |
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KR20180095198A (ko) * | 2017-02-17 | 2018-08-27 | 동아에스티 주식회사 | 토파시티닙의 신규 염 및 이를 포함하는 약학적 조성물 |
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P. HEINRICH STAHLCAMILE G. WERMUTH: "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", 2002, WILEY-VCH, pages: 2 |
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KR20230113739A (ko) | 2023-08-01 |
US11987582B2 (en) | 2024-05-21 |
CN116867786A (zh) | 2023-10-10 |
EP4286385A1 (en) | 2023-12-06 |
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