CO-CRYSTALS OF MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR
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IPC분류정보
국가/구분
United States(US) Patent
공개
국제특허분류(IPC7판)
C07D-215/56
A61K-045/06
A61K-031/225
C07C-069/34
A61K-031/47
출원번호
US-0877914
(2015-10-07)
공개번호
US-0096807
(2016-04-07)
발명자
/ 주소
Strohmeier, Mark
Caesar, JR., John
Connelly, Patrick Raymond
Fawaz, Majed
Luss-Lusis, Eduard
McClain, Brian
Medek, Ales
Miao, Hai
Nti-Addae, Kwame Wiredu
Yin, Ping
Zhang, Yuegang
출원인 / 주소
Vertex Pharmaceuticals Incorporated
인용정보
피인용 횟수 :
0인용 특허 :
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초록▼
The present disclosure relates to co-crystals comprising N-2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl-1,4-dihydro-4-oxoquinoline-3-carboxamide (Compound 1) and a co-former and methods for their preparation. The present disclosure further relates to pharmaceutical compositions comprising the co-cryst
The present disclosure relates to co-crystals comprising N-2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl-1,4-dihydro-4-oxoquinoline-3-carboxamide (Compound 1) and a co-former and methods for their preparation. The present disclosure further relates to pharmaceutical compositions comprising the co-crystal forms, as well as methods of treatment therewith and kits.
대표청구항▼
1. A co-crystal comprising Compound 1 and only one triglyceride, wherein the triglyceride is chosen from the following structural formula: wherein R1, R2, and R3 are independently C1-29 aliphatic,and wherein Compound 1 is represented by the following structural formula: 2. The co-crystal of claim 1
1. A co-crystal comprising Compound 1 and only one triglyceride, wherein the triglyceride is chosen from the following structural formula: wherein R1, R2, and R3 are independently C1-29 aliphatic,and wherein Compound 1 is represented by the following structural formula: 2. The co-crystal of claim 1, characterized as having an X-ray powder diffraction pattern with characteristic peaks expressed in 2-theta±0.2 degrees at the following positions: 3.5, 6.9, and 10.9. 3. The co-crystal of claim 1, characterized as having an X-ray powder diffraction pattern with characteristic peaks expressed in 2-theta±0.2 degrees at the following positions: 3.5, 6.9, 9.2, 10.9, 16.9, 18.0, and 23.8. 4. The co-crystal of claim 1, characterized as having a 13C ssNMR spectrum with characteristic peaks expressed in ppm±0.1 at the following positions: 178.6, 155.0, and 119.4. 5. The co-crystal of claim 1, characterized as having a 13C ssNMR spectrum with characteristic peaks expressed in ppm±0.1 at the following positions: 178.6, 155.0, 130.5, and 119.4. 6. The co-crystal of claim 1, wherein the stoichiometry of Compound 1 to the triglyceride is 3 to 1. 7. The co-crystal of claim 1, wherein the stoichiometry of Compound 1 to the triglyceride is 6 to 1. 8. The co-crystal of claim 1, wherein Compound 1 forms a hexamer in the co-crystal and further wherein R1, R2, and R3 are independently C7-29 aliphatic. 9. The co-crystal of claim 1, wherein the co-crystal dissolves in simulated intestinal fluid in fed state (FeSSIF) to yield a concentration of Compound 1 of greater than 0.4 mg/mL and the concentration is maintained for at least 10 hours. 10. The co-crystal of claim 1, wherein the triglyceride is chosen from: glyceryl trioleate, glyceryl tristearate, glycerol tridecanoate, glycerol trihexanoate, glyceryl tritridecanoate, glycerol trioctanoate, glyceryl trimyristate, glyceryl tripalmitate, glyceryl tributyrate, glyceryl trilinoleate, glyceryl tridodecanoate, glyceryl decanoate, glyceryl tripalmitoleate, glycerol trierucate, glyceryl tripropionate, palmitodiolein, triarachidonin, glyceryl trilinolenate, trierucin, glycerol triarachidate, glyceryl tri(cis-13-docosenoate), glyceryl tripetroselinate, glyceryl tribehenate, glyceryl trielaidate, and triacetin. 11. A co-crystal comprising Compound 1 and a triglyceride, wherein the triglyceride is chosen from the following structural formula, wherein R1, R2, and R3 are independently C1-29 aliphaticand wherein Compound 1 is represented by the following structural formula: wherein the co-crystal is prepared by a process comprising:combining Compound 1 and the triglyceride to form the co-crystal. 12. A pharmaceutical composition comprising a therapeutic effective amount of Compound 1 and a pharmaceutically acceptable carrier or excipient, wherein Compound 1 is represented by the following structural formula: and further wherein at least 30% of Compound 1 is present as a co-crystal comprising Compound 1 and a triglyceride, wherein the triglyceride is chosen from the following structural formula: wherein R1, R2, and R3 are independently C1-29 aliphatic. 13. The pharmaceutical composition according to claim 12, further comprising an additional therapeutic agent selected from a mucolytic agent, a bronchodilator, an antibiotic, an anti-infective agent, an anti-inflammatory agent, a CFTR modulator other than Compound 1, or a nutritional agent, or combinations thereof. 14. The pharmaceutical composition according to claim 13, wherein the additional therapeutic agent is a CFTR modulator other than Compound 1. 15. The pharmaceutical composition according to claim 14, wherein the CFTR modulator is (3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid or (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide. 16. A method of treating or lessening the severity of a disease in a patient, wherein said disease is selected from cystic fibrosis, hereditary emphysema, COPD, or dry-eye disease, the method comprising the step of administering to the patient a therapeutic effective amount of the co-crystal of claim 1. 17. The method according to claim 16, wherein the disease is cystic fibrosis. 18. The method according to claim 16, further comprising co-administering one or more additional therapeutic agents to the subject. 19. The method according to claim 18, wherein the additional therapeutic agent is (3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid or (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide. 20. The method according to claim 19, wherein the additional therapeutic agent is administered concurrently with, prior to, or subsequent to the co-crystal. 21. A method of preparing a co-crystal comprising Compound 1 and a triglyceride, wherein Compound 1 is represented by the following structural formula: and wherein the triglyceride is chosen from the following structural formula: wherein R1, R2, and R3 are independently C1-29 aliphatic;comprising the steps of:(a) preparing a mixture comprising Compound 1 and the triglyceride; and(b) heating the mixture.
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