CN105213394A - There is the quinoline of anti-tumor activity - Google Patents
There is the quinoline of anti-tumor activity Download PDFInfo
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- CN105213394A CN105213394A CN201410249544.1A CN201410249544A CN105213394A CN 105213394 A CN105213394 A CN 105213394A CN 201410249544 A CN201410249544 A CN 201410249544A CN 105213394 A CN105213394 A CN 105213394A
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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Abstract
The invention provides a kind of quinoline with anti-tumor activity, and in the purposes for the preparation for the treatment of antitumor medicine composition.Specifically, the present invention relates to the purposes of quinoline 1-[[[4-(the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base-6-methoxy quinoline-7-base] oxygen base] methyl] cyclopropylamine in treatment medullary thyroid carcinoma.
Description
Technical field
The invention belongs to field of medicaments, the present invention relates to quinoline in the purposes for the preparation for the treatment of antitumor medicine composition.Specifically, the present invention relates to the purposes of quinoline in treatment medullary thyroid carcinoma.
Background technology
Medullary thyroid carcinoma (medullarythyroidcarcinoma, MTC) be the tumor originating from parafollicular cells of thyroid gland or parafollicular cell, account for 5% ~ 10% of thyroid malignancy, its grade malignancy, between papillary carcinoma and undifferentiated carcinoma, belongs to medium malignant tumor.Nineteen fifty-nine Hazard etc. describes this disease first, and MTC patient women, more than male, in being common in, Juvenile-onset, and having local infiltration growth and comparatively early occurs blood road lymphatic metastasis feature.
MTC is divided into genotype medullary carcinoma (hereditaryMTC) clinically and distributes type medullary carcinoma (sporadicMTC) two kinds, wherein genotype medullary carcinoma accounts for 25% ~ 30% of MTC, genotype medullary carcinoma is divided into again 3 kinds of hypotypes, i.e. Multiple Endocrine tumor 2A type (multipleendocrineneoplasiatypeIIa, MEN2A), Multiple Endocrine tumor 2B type (multipleendocrineneoplasiatypeIIb, and familial MTC (familialmedullarythyroidcarcinoma, FMTC) MEN2B).
Large quantity research has confirmed that RET gene mutation is the main molecules etiology basis of MTC morbidity, and the sporadic MTC of the heritability MTC and 70% of about 95% is caused by RET gene mutation.Have research to point out, in oncogene activation process, the characteristic of RET is very unique.RET sudden change seems only to be confined to thyroid tumor and adrenal tumor.
RET is the member in receptor tyrosine kinase protein family, and receptor tyrosine kinase plays interconnect function between extracellular environment and nucleus, and signal is transmitted to Cytoplasm from cell surface, and then to nucleus.The extracellular part of this receptor connects particular ligand, after linking ligand, is the process of polymerization and activation between receptor.Once receptor is activated, the Cascaded amplification of signal will occur, all signals can be passed by special substrate phosphorylation.Allly there is relevant RET with tumor and suddenly change and take advantage compared with normal RET function on a cellular level.
Determine that RET proto-oncogene is positioned No. 10 chromosome long arm at present, containing 21 exons, to encode a kind of transmembrane protein belonging to tyrosine kinase receptor superfamily, this albumen is divided into extracellular region, the cross-film district of being rich in cysteine and includes intracellular region three part of tyrosine kinase domain, the wherein tyrosine residue of intracellular region energy autophosphorylation after receptor and ligand binding, inducing cell hypertrophy.Total about more than 20 of the RET gene mutation site relevant with MTC of current discovery, these sudden changes can cause the change of extracellular region and intracellular region protein conformation respectively, the change of this type of conformation strengthens the conversion capability of RET, excite tyrosine kinase autophosphorylation, inducing cell overgrown is so that canceration.Cause the RET gene mutation of MTC mostly to be simple point mutation, but studies have found that in MTC the phenomenon that there is RET exon double-site mutant and cause a disease.
Excision is still the first-selection radical cure mode of MTC, to the MTC patient fallen ill, most scholar emphasizes that range of operation is minimum should comprise total thyroidectomy and central lymph node is removed, different patients again according to the size of swollen thing, pathological changes side or bilateral, mutational site do not determine whether to go expansion radical neck dissection on an equal basis.
For MTC in late period, depend merely on operation to be difficult to thoroughly remove tumor, because it is insensitive to lonizing radiation, and adjacent organs is as low to lonizing radiation toleration in thyroid cartilage, trachea, spinal cord etc., generally fluconazole ear drops weak effect, even has part research to think to accept patient's prognosis of radiotherapy poor all the better.
ZD6474 (Vandetanib, ZD6474, trade name Zactima, structural formula is as follows) obtains FDA Food and Drug Administration (FDA) approval on April 6th, 2011 and is used for the treatment of medullary thyroid carcinoma (MTC).This medicine is developed by Astrazeneca AB, it is oral micromolecule multiple receptor tyrosine kinases inhibitor, mainly acts on transfection and resets (RET) tyrosine kinase, EGF-R ELISA (EGFR) and vascular endothelial growth factor receptor-2 (VEGFR-2).
zD6474
Card is rich for Buddhist nun (COMETRIQ
tM, cabozantinib, structural formula is as follows) be the oral small molecule kinase inhibitors being used for the treatment of medullary thyroid carcinoma (MTC) that in November, 2012, FDA ratified.
card is rich for Buddhist nun
Up to the present, the effect of a lot of small molecule tyrosine kinase inhibitors (TKI) in medullary thyroid carcinoma treatment is still in further assessment.Along with understanding in depth oncomolecularbiology behavior, constantly deepen the understanding in new tomour specific site, new target therapeutic agent also will continue to bring out.There is more medicine to be developed, to reaching better therapeutic effect, improving survival rate, bringing substantial benefit to patient.
Summary of the invention
On the one hand, the invention provides a kind of method for the treatment of medullary thyroid carcinoma, comprise compounds I or its pharmaceutically acceptable salt of the bacterium giving needs treatment.Described medullary thyroid carcinoma comprises genotype medullary carcinoma and distributes type medullary carcinoma.
In some embodiments, a kind of method for the treatment of medullary thyroid carcinoma in late period is provided.
Compounds I can with its free alkali form administration, also can with the form administration of its salt, hydrate and prodrug, and this prodrug converts the free alkali form of Compound Compound I in vivo to.Such as, give compounds I within the scope of the invention with pharmaceutically acceptable salt form, produce salt according to method well known in the art by different organic acid and mineral acid.
In some embodiments, with the form administration of compounds I hydrochlorate.In some embodiments, with the form administration of compounds I one hydrochlorate.In some embodiments, with the form administration of compounds I dihydrochloride.In some embodiments, with the crystal form administration of compounds I hydrochlorate.In certain embodiments, with the crystal form administration of compounds I dihydrochloride.
The chemistry of compounds I is called 1-[[[4-(the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base-6-methoxy quinoline-7-base] oxygen base] methyl] cyclopropylamine, and it has following structural formula:
compounds I.
Compounds I or its pharmaceutically acceptable salt are by number of ways administration, and this approach includes but not limited to be selected from following approach: oral, parenteral, intraperitoneal, intravenous, intra-arterial, transdermal, Sublingual, intramuscular, rectum, thoroughly cheek, intranasal, through suctions, vagina, ophthalmic, through topical, subcutaneous, fatty in, in intraarticular, intraperitoneal and sheath.In a specific embodiment, pass through oral administration.
The amount giving compounds I or its pharmaceutically acceptable salt can be determined according to the age of the response of the order of severity of disease, disease, toxicity that any treatment is correlated with, patient and health status.In some embodiments, the daily dose giving compounds I or its pharmaceutically acceptable salt is 8 milligrams to 20 milligrams.In some embodiments, the daily dose giving compounds I or its pharmaceutically acceptable salt is 10 milligrams to 16 milligrams.In some embodiments, the daily dose giving compounds I or its pharmaceutically acceptable salt is 10 milligrams to 14 milligrams.In a specific embodiment, the daily dose giving compounds I or its pharmaceutically acceptable salt is 10 milligrams.In a specific embodiment, the daily dose giving compounds I or its pharmaceutically acceptable salt is 12 milligrams.In a specific embodiment, the daily dose giving compounds I or its pharmaceutically acceptable salt is 14 milligrams.In a specific embodiment, the daily dose giving compounds I or its pharmaceutically acceptable salt is 16 milligrams.
Compounds I or its pharmaceutically acceptable salt can once-a-day administration or repeatedly.In some embodiments, compounds I or its pharmaceutically acceptable salt is given once a day.Compounds I or its pharmaceutically acceptable salt also can single dose or multiple dose form administrations.In one embodiment, administration every day 1 time, and can optionally with single dose administration every day 1 time.In one embodiment, be administered once every day with the oral solid formulation of single dose.
Cycle of administration comprehensively can be determined according to the toleration etc. of the activity of medicine, toxicity and patient.In some embodiments, within every 3 weeks, be the cycle of a treatment, wherein continuous use 2 weeks, stops 1 week.
In one embodiment, compounds I or its pharmaceutically acceptable salt give patient's separately as unique active component.
On the other hand, the invention provides compounds I or the purposes of its pharmaceutically acceptable salt in the medicine for the preparation for the treatment of medullary thyroid carcinoma.Wherein, described medullary thyroid carcinoma comprises genotype medullary carcinoma and distributes type medullary carcinoma.
In one embodiment, compounds I or the purposes of its pharmaceutically acceptable salt in the medicine for the preparation for the treatment of medullary thyroid carcinoma in late period is provided.
Compounds I can be its free alkali form, and also can be the form of its salt, hydrate and prodrug, this prodrug converts the free alkali form of Compound Compound I in vivo to.Such as, compounds I pharmaceutically acceptable salt within the scope of the invention, can produce salt according to method well known in the art by different organic acid and mineral acid.
In some embodiments, compounds I or its pharmaceutically acceptable salt are the hydrochloride form of compounds I.In some embodiments, be the form of compounds I one hydrochlorate.In some embodiments, be the form of compounds I dihydrochloride.In some embodiments, be the crystal form of compounds I hydrochlorate.In certain embodiments, be the crystal form of compounds I dihydrochloride.
The amount of compounds I or its pharmaceutically acceptable salt can be determined according to the age of the response of the order of severity of disease, disease, toxicity that any treatment is correlated with, patient and health status.In some embodiments, the amount of compounds I or its pharmaceutically acceptable salt is 8 milligrams to 20 milligrams.In some embodiments, the amount of compounds I or its pharmaceutically acceptable salt is 10 milligrams to 16 milligrams.In some embodiments, the amount of compounds I or its pharmaceutically acceptable salt is 10 milligrams to 14 milligrams.In a specific embodiment, the amount of compounds I or its pharmaceutically acceptable salt is 10 milligrams.In a specific embodiment, the amount of compounds I or its pharmaceutically acceptable salt is 12 milligrams.In a specific embodiment, the amount of compounds I or its pharmaceutically acceptable salt is 14 milligrams.In a specific embodiment, the amount of compounds I or its pharmaceutically acceptable salt is 16 milligrams.
Again on the one hand, the invention provides a kind of pharmaceutical composition for the treatment of medullary thyroid carcinoma, its inclusion compound I or its pharmaceutically acceptable salt, and the pharmaceutically acceptable carrier of at least one.Described medullary thyroid carcinoma comprises genotype medullary carcinoma and distributes type medullary carcinoma.
In some embodiments of the present invention, a kind of pharmaceutical composition for the treatment of medullary thyroid carcinoma in late period is provided.
Compounds I can be its free alkali form, and also can be the form of salt, hydrate and prodrug, this prodrug converts the free alkali form of Compound Compound I in vivo to.Such as, compounds I pharmaceutically acceptable salt within the scope of the invention, can produce salt according to method well known in the art by different organic acid and mineral acid.
In some embodiments, compounds I or its pharmaceutically acceptable salt are the hydrochloride form of compounds I.In some embodiments, be the form of compounds I one hydrochlorate.In some embodiments, be the form of compounds I dihydrochloride.In some embodiments, be the crystal form of compounds I hydrochlorate.In certain embodiments, be the crystal form of compounds I dihydrochloride.
Compounds I or its pharmaceutically acceptable amount can be determined according to the age of the response of the order of severity of disease, disease, toxicity that any treatment is correlated with, patient and health status.In some embodiments, in this pharmaceutical composition, the amount of compounds I or its pharmaceutically acceptable salt is 8 milligrams to 20 milligrams.In some embodiments, the amount of compounds I or its pharmaceutically acceptable salt is 10 milligrams to 16 milligrams.In some embodiments, the amount of compounds I or its pharmaceutically acceptable salt is 10 milligrams to 14 milligrams.In a specific embodiment, the amount of compounds I or its pharmaceutically acceptable salt is 10 milligrams.In a specific embodiment, the amount of compounds I or its pharmaceutically acceptable salt is 12 milligrams.In a specific embodiment, the amount of compounds I or its pharmaceutically acceptable salt is 14 milligrams.In a specific embodiment, the amount of compounds I or its pharmaceutically acceptable salt is 16 milligrams.
In some embodiments of the present invention, described pharmaceutical composition is suitable for oral preparation, comprises tablet, capsule, powder, granule, drop pill, paste, powder etc., preferred tablet and capsule.Wherein tablet can be conventional tablet, dispersible tablet, effervescent tablet, slow releasing tablet, controlled release tablet or enteric coatel tablets, and capsule can be conventional capsule, slow releasing capsule, controlled release capsule or enteric coated capsule.Described oral formulations can use pharmaceutically acceptable carrier well known in the art to be obtained by conventional method.Pharmaceutically acceptable carrier comprises filler, absorbent, wetting agent, binding agent, disintegrating agent, lubricant etc.Filler comprises starch, lactose, mannitol, microcrystalline Cellulose etc.; Absorbent comprises calcium sulfate, calcium hydrogen phosphate, calcium carbonate etc.; Wetting agent comprises water, ethanol etc.; Binding agent comprises hypromellose, polyvidone, microcrystalline Cellulose etc.; Disintegrating agent comprises cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, surfactant, low-substituted hydroxypropyl cellulose etc.; Lubricant comprises magnesium stearate, Pulvis Talci, Polyethylene Glycol, sodium lauryl sulphate, micropowder silica gel, Pulvis Talci etc.Pharmaceutic adjuvant is also comprising toner, sweeting agent etc.
In one embodiment, this pharmaceutical composition is suitable for oral solid preparation.Said composition can be such as the form of tablet or capsule.In a specific embodiment, this pharmaceutical composition is capsule.In a particular of the present invention, the pharmaceutically acceptable carrier of oral solid formulation comprises mannitol, microcrystalline Cellulose, hyprolose, magnesium stearate.
In one embodiment, a kind of pharmaceutical composition being mixed with single dose form for the treatment of medullary thyroid carcinoma is provided.In one embodiment, this single dose form contains compounds I or its pharmaceutically acceptable salt of 8 milligrams to 20 milligrams, the preferably compounds I of 10 milligrams to 16 milligrams or its pharmaceutically acceptable salt, the more preferably compounds I of 10 milligrams to 14 milligrams or its pharmaceutically acceptable salt.In a specific embodiment, this pharmaceutical composition contains compounds I or its pharmaceutically acceptable salt of 10 milligrams.In a specific embodiment, this pharmaceutical composition contains compounds I or its pharmaceutically acceptable salt of 12 milligrams.In a specific embodiment, this pharmaceutical composition contains compounds I or its pharmaceutically acceptable salt of 14 milligrams.In a specific embodiment, this pharmaceutical composition contains compounds I or its pharmaceutically acceptable salt of 16 milligrams.
In some embodiments, the dosage regimen of described pharmaceutical composition is stop 1 week in continuous 2 weeks, namely within every 21 days, is a treatment cycle.In a specific embodiment, in a treatment cycle, aforementioned pharmaceutical compositions is administered once every day, successive administration 14 days, then drug withdrawal 7 days.
Herein, except as otherwise noted, the dosage provided here and scope are all the molecular weight based on compounds I free alkali form.
Herein, the crystal form of the hydrochlorate of described compounds I includes but not limited to A, B and C type crystallization disclosed in Chinese patent application CN102344438A, wherein A and Type B crystallization are the crystallization being substantially free of water of crystallization and other solvents, and the crystallization of C type is the crystallization containing two water of crystallization.In some embodiments, the crystal form of the dihydrochloride of described compounds I is the crystallization of A type.
Except as otherwise noted, be the object of the application, following term used in the specification and claims should have following implication.
" patient " refers to mammal, preferred people.In some embodiments, described patient is through standard care failure or the patient lacking standard care.
" pharmaceutically acceptable " refers to that it is for the preparation of pharmaceutical composition, this pharmaceutical composition normally safety, nontoxic and neither biologically or other side do not cater to the need, and to comprise that it uses for human medicine be acceptable.
" pharmaceutically acceptable salt " includes, but are not limited to the acid-addition salts formed with mineral acid example hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid etc.; Or the acid-addition salts formed as acetic acid, trifluoroacetic acid, propanoic acid, caproic acid, enanthic acid, Pentamethylene. propanoic acid, glycolic, acetone acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethyl sulfonic acid, 1,2-ethionic acid, 2-ethylenehydrinsulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, p-methyl benzenesulfonic acid, 3-phenylpropionic acid, trimethylace tonitric, butylacetic acid, lauryl sulphate acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid etc. with organic acid.
" treatment effective dose " means compound and is given people when being used for the treatment of disease, is enough to realize the amount to the treatment of this disease.
" treatment " means any of the compound for the treatment of effective dose and uses, and comprises:
(1) prevention can easily be suffered from described disease but still also not experience or demonstrate in the pathology of this disease or semeiologic human body this disease is occurred,
(2) this disease in the pathology of described disease or semeiologic human body (that is, the described pathology of resistance system and/or semeiologic further develop) is suppressed just to experience or demonstrating, or
(3) this disease (namely reversing described pathology and/or symptomatology) in the pathology just experiencing or demonstrating described disease or semeiologic human body is improved.
Detailed description of the invention
Embodiment 11-[[[4-(the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base-6-methoxy quinoline-7-base] oxygen base] methyl] cyclopropylamine dihydrochloride
1-[[[4-(the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base-6-methoxy quinoline-7-base] oxygen base] methyl] cyclopropylamine is prepared with reference to the method for embodiment 24 in WO2008112407, then with reference to the preparation method of the embodiment of salt form in description, title compound is prepared.
Or prepare with reference to method disclosed in Chinese patent application CN102344438A.
The capsule of embodiment 2 containing 1-[[[4-(the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base-6-methoxy quinoline-7-base] oxygen base] methyl] cyclopropylamine dihydrochloride (dihydrochloride of compounds I)
The dihydrochloride of compounds I is pulverized, crosses 80 mesh sieves; Then mix homogeneously with mannitol, hyprolose; Then add the microcrystalline Cellulose of recipe quantity, mix homogeneously, cross 0.8mm screen cloth; Finally add the magnesium stearate mix homogeneously of recipe quantity, and filled capsules.
Dihydrochloride for compounds I is the capsule of other content, can refer to above-mentioned identical ratio and formula preparation obtains.
The toleration of the dihydrochloride capsule for treating of embodiment 3 compounds I and the research of medication preliminary efficacy
(1) tolerance studies result
Include diagnosis in clear and definite, through standard care failure or the malignant tumor patient lacking standard care, adopt continuous use to stop 1 week in 2 weeks, within namely 3 weeks, (21 days) are a treatment cycle, at least maintain 2 cycles (42 days) and proceed Tolerance, carry out observation of curative effect simultaneously.
Every day 1 10mg, the untoward reaction that 3 routine patients occur comprises III degree and above fat, amylase raises 1 example, weak 1 example of II degree, and other I degree untoward reaction comprises hoarseness 2 example, diarrhoea, stomachache 1 example, hypertension 1 example etc.
Every day, 1 16mg, respectively occurred during 3 routine patient the 2nd cycle medication in the 2nd week that 1 routine III degree blood pressure raises and weak.
Other untoward reaction that this group research process occurs comprises II degree hypertension 1 example, and thyroid function reduces by 2 examples, and ALT raises 1 example; I degree triglyceride raises 2 examples, diarrhoea, stomachache 2 example, syndrome: case in hands, hoarseness 1 example etc.
During 1 12mg every day, this group observes 18 examples (wherein 5 examples go out group) patient altogether.All there is untoward reaction in various degree in medication process.The order of severity 1 ~ 2 degree, there is no 3 degree or more untoward reaction and occurs.Concrete condition comprises:
Blood fat: triglyceride raises 8 examples, T-CHOL raises 7 examples;
Liver function: total bilirubin raises 4 examples, ALT raises 4 examples, and AST raises 5 examples; Creatinine raises 1 example;
Dermal toxicity: hand-foot skin reaction 6 example, erythra 4 example;
Hormonal system: low 7 examples of first, hyperthyroidism 2 example, amylase raise 3 examples, and CK-MB raises 2 examples;
Symptom: weak 6 examples, hoarseness 4 example, diarrhoea 6 example, dizziness headache 2 example, toothache 3 example, muscular soreness 3 example; Feel sick, appetite declines 3 examples, tinnitus, heating, each 1 example of insomnia;
Other: hypertension 5 example, hematuria 5 example, albuminuria 5 example, WBC decline 3 example.
(2) medication preliminary efficacy situation
12mg dosage group is current just in totally 13 examples of medication, 11 cycles of the longest medication, the shortest medication 4 cycle.3 examples are had to be that two cycles post-evaluation PD (progression of disease) goes out group in 5 routine experimenters of drug withdrawal, 1 example is that 6 weeks after date PD go out group, 1 example is 4 cycles post-evaluation SD (stable disease) (little), 5 weeks after date SAE (serious adverse events) go out group.
(3) to the preliminary efficacy of medullary thyroid carcinoma
Medullary thyroid carcinoma (once a day 12mg): totally 6 routine experimenters, 1 example can not be evaluated, and 4 examples are SD (little), and 1 example is PD.Visible medullary thyroid carcinoma yield more than 80%.
Dosage involved in this embodiment all calculates with compounds I.
Compounds I hydrochlorate capsule adopts and within 12mg/ days, connects the therapeutic regimen that two stop, and overall tolerability is very good, and untoward reaction is 1/2 degree, does not observe other unexpected untoward reaction; Curative effect aspect, treatment medullary thyroid carcinoma has benefit.
The further effectiveness study of the dihydrochloride capsule for treating medullary thyroid carcinoma of embodiment 4 compounds I
Enter to organize qualification:
Age 18-70 year, sex man and female, do not accept healthy volunteer.
The standard that case is selected:
A) late period medullary thyroid carcinoma;
B) 18-70 year, ECOG:0-2, the > 3 months life cycle of expection;
C) calcitonin >=500pg/ml, euthyroidism;
D) HB>=100g/L, ANC (neutrophilic granulocyte absolute counting)>=1.5 × 10
9/ L; BIL/Cr in normal range, ALT/AST (aspartate transaminase)≤1.5*ULN (for hepatic metastases enzyme, ALT/AST (aspartate transaminase)≤5*ULN); TG≤3.0mmol/L, cholesterol≤7.75mmol/L;
E), under study for action and after 6 months afterwards, require that experimenter practises contraception;
F) group is entered voluntarily
Case exclusion standard:
A) targeted therapy of vascular endothelial growth inhibitor class was accepted;
B) patient of the second tumor is suffered from after diagnosing;
C) take part in other clinical trial in surrounding;
D) other X-ray therapy or chemotherapeutic treatment is received in surrounding;
e)AE>1；
F) oral drugs have impact;
G) patient of brain metastes, spinal compression, meningitis carcinomatosa or brain/pia mater encephali disease;
H) any seriously or out of control disease;
I) artery/vein thrombosis;
J) dysfunction of blood coagulation;
K) arteriovenous Cardioversion;
L) antipsychotic drugs abuse or mental disorder history;
M) immunodeficiency history;
N) along with other diseases.
Claims (10)
1. treat the method for medullary thyroid carcinoma, comprise 1-[[[4-(the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base-6-methoxy quinoline-7-base] oxygen base] methyl] cyclopropylamine or its pharmaceutically acceptable salt of the bacterium giving needs treatment.
2. method according to claim 1, wherein medullary thyroid carcinoma is medullary thyroid carcinoma in late period.
3. the method described in claim 1-2, wherein 1-[[[4-(4-fluoro-2-Methyl-1H-indole-5-base) oxygen base-6-methoxy quinoline-7-base] oxygen base] methyl] cyclopropylamine or its pharmaceutically acceptable salt are the hydrochlorate of 1-[[[4-(the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base-6-methoxy quinoline-7-base] oxygen base] methyl] cyclopropylamine.
4. the method described in claim 1-2, within every 3 weeks, be wherein the cycle of a treatment, wherein continuous use 2 weeks, stops 1 week.
5.1-[[[4-(the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base-6-methoxy quinoline-7-base] oxygen base] methyl] cyclopropylamine or the purposes of its pharmaceutically acceptable salt in the medicine for the preparation for the treatment of medullary thyroid carcinoma.
6. purposes according to claim 5, wherein said medullary thyroid carcinoma is medullary thyroid carcinoma in late period.
7. treat the pharmaceutical composition of medullary thyroid carcinoma, it comprises 1-[[[4-(4-fluoro-2-Methyl-1H-indole-5-base) oxygen base-6-methoxy quinoline-7-base] oxygen base] methyl] cyclopropylamine or its pharmaceutically acceptable salt and the pharmaceutically acceptable carrier of at least one.
8. the pharmaceutical composition of claim 7, wherein said medullary thyroid carcinoma is medullary thyroid carcinoma in late period.
9. the pharmaceutical composition described in claim 7 or 8, wherein the amount of 1-[[[4-(the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base-6-methoxy quinoline-7-base] oxygen base] methyl] cyclopropylamine or its pharmaceutically acceptable salt is 8 milligrams to 20 milligrams.
10. treat the pharmaceutical composition being mixed with single dose form of medullary thyroid carcinoma, it comprises 1-[[[4-(the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base-6-methoxy quinoline-7-base] oxygen base] methyl] cyclopropylamine or its pharmaceutically acceptable salt of 8 milligrams to 20 milligrams.
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410249544.1A CN105213394B (en) | 2014-06-06 | 2014-06-06 | Quinoline with anti-tumor activity |
| CN201580026812.6A CN106413712B (en) | 2014-06-06 | 2015-06-05 | Quinoline is used to treat the method and purposes and the pharmaceutical composition for treating thyroid cancer of thyroid cancer |
| CN201910645676.9A CN111035640B (en) | 2014-06-06 | 2015-06-05 | Methods and uses of quinoline derivatives for treating thyroid cancer |
| PCT/CN2015/080859 WO2015185011A1 (en) | 2014-06-06 | 2015-06-05 | Methods and uses of quinoline derivatives in the treatment of thyroid cancer and pharmaceutical compositions for treatment of same |
| CN201910645272.XA CN111012785B (en) | 2014-06-06 | 2015-06-05 | Methods and uses of quinoline derivatives for treating thyroid cancer |
| KR1020167034751A KR102490547B1 (en) | 2014-06-06 | 2015-06-05 | Methods and uses of quinoline derivatives in the treatment of thyroid cancer and pharmaceutical compositions for treatment of same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410249544.1A CN105213394B (en) | 2014-06-06 | 2014-06-06 | Quinoline with anti-tumor activity |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105213394A true CN105213394A (en) | 2016-01-06 |
| CN105213394B CN105213394B (en) | 2019-04-09 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201410249544.1A Active CN105213394B (en) | 2014-06-06 | 2014-06-06 | Quinoline with anti-tumor activity |
| CN201910645272.XA Active CN111012785B (en) | 2014-06-06 | 2015-06-05 | Methods and uses of quinoline derivatives for treating thyroid cancer |
| CN201580026812.6A Active CN106413712B (en) | 2014-06-06 | 2015-06-05 | Quinoline is used to treat the method and purposes and the pharmaceutical composition for treating thyroid cancer of thyroid cancer |
| CN201910645676.9A Active CN111035640B (en) | 2014-06-06 | 2015-06-05 | Methods and uses of quinoline derivatives for treating thyroid cancer |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201910645272.XA Active CN111012785B (en) | 2014-06-06 | 2015-06-05 | Methods and uses of quinoline derivatives for treating thyroid cancer |
| CN201580026812.6A Active CN106413712B (en) | 2014-06-06 | 2015-06-05 | Quinoline is used to treat the method and purposes and the pharmaceutical composition for treating thyroid cancer of thyroid cancer |
| CN201910645676.9A Active CN111035640B (en) | 2014-06-06 | 2015-06-05 | Methods and uses of quinoline derivatives for treating thyroid cancer |
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| KR (1) | KR102490547B1 (en) |
| CN (4) | CN105213394B (en) |
| WO (1) | WO2015185011A1 (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106413712A (en) * | 2014-06-06 | 2017-02-15 | 正大天晴药业集团股份有限公司 | Methods and uses of quinoline derivatives in the treatment of thyroid cancer and pharmaceutical compositions for treatment of same |
| WO2019052520A1 (en) * | 2017-09-15 | 2019-03-21 | 正大天晴药业集团股份有限公司 | Quinoline derivative for treatment of neuroendocrine tumors |
| WO2020156501A1 (en) * | 2019-01-31 | 2020-08-06 | 正大天晴药业集团股份有限公司 | Crystals of quinolone derivatives |
| CN111714498A (en) * | 2019-03-20 | 2020-09-29 | 正大天晴药业集团股份有限公司 | Quinoline derivatives for the treatment of ovarian cancer |
| WO2020233723A1 (en) * | 2019-05-23 | 2020-11-26 | 正大天晴药业集团股份有限公司 | Quinoline derivatives for treatment of head and neck cancer |
| CN112043831A (en) * | 2019-06-05 | 2020-12-08 | 正大天晴药业集团股份有限公司 | Quinolines for use in the combined treatment of breast cancer |
| CN112336726A (en) * | 2019-08-09 | 2021-02-09 | 正大天晴药业集团股份有限公司 | Combined pharmaceutical composition for treating colorectal cancer |
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| WO2017118401A1 (en) | 2016-01-08 | 2017-07-13 | 正大天晴药业集团股份有限公司 | Use of quinoline derivatives for treating oesophageal cancer and treatment method, pharmaceutical composition and kit thereof |
| CN107296811B (en) * | 2016-04-15 | 2022-12-30 | 正大天晴药业集团股份有限公司 | Quinoline derivative for treating gastric cancer |
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| CN106413712A (en) * | 2014-06-06 | 2017-02-15 | 正大天晴药业集团股份有限公司 | Methods and uses of quinoline derivatives in the treatment of thyroid cancer and pharmaceutical compositions for treatment of same |
| CN106413712B (en) * | 2014-06-06 | 2019-08-16 | 正大天晴药业集团股份有限公司 | Quinoline is used to treat the method and purposes and the pharmaceutical composition for treating thyroid cancer of thyroid cancer |
| CN111035640A (en) * | 2014-06-06 | 2020-04-21 | 正大天晴药业集团股份有限公司 | Quinoline derivatives for the treatment of thyroid cancer |
| WO2019052520A1 (en) * | 2017-09-15 | 2019-03-21 | 正大天晴药业集团股份有限公司 | Quinoline derivative for treatment of neuroendocrine tumors |
| CN111065395A (en) * | 2017-09-15 | 2020-04-24 | 正大天晴药业集团股份有限公司 | Quinoline derivatives for the treatment of neuroendocrine tumors |
| CN111065395B (en) * | 2017-09-15 | 2021-08-10 | 正大天晴药业集团股份有限公司 | Quinoline derivatives for the treatment of neuroendocrine tumors |
| WO2020156501A1 (en) * | 2019-01-31 | 2020-08-06 | 正大天晴药业集团股份有限公司 | Crystals of quinolone derivatives |
| CN111714498A (en) * | 2019-03-20 | 2020-09-29 | 正大天晴药业集团股份有限公司 | Quinoline derivatives for the treatment of ovarian cancer |
| WO2020233723A1 (en) * | 2019-05-23 | 2020-11-26 | 正大天晴药业集团股份有限公司 | Quinoline derivatives for treatment of head and neck cancer |
| CN113766917A (en) * | 2019-05-23 | 2021-12-07 | 正大天晴药业集团股份有限公司 | Quinoline derivatives for the treatment of head and neck cancer |
| CN112043831A (en) * | 2019-06-05 | 2020-12-08 | 正大天晴药业集团股份有限公司 | Quinolines for use in the combined treatment of breast cancer |
| CN112336726A (en) * | 2019-08-09 | 2021-02-09 | 正大天晴药业集团股份有限公司 | Combined pharmaceutical composition for treating colorectal cancer |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20170007789A (en) | 2017-01-20 |
| CN111035640B (en) | 2024-03-19 |
| CN111035640A (en) | 2020-04-21 |
| KR102490547B1 (en) | 2023-01-18 |
| CN111012785A (en) | 2020-04-17 |
| CN105213394B (en) | 2019-04-09 |
| CN111012785B (en) | 2024-01-30 |
| CN106413712A (en) | 2017-02-15 |
| CN106413712B (en) | 2019-08-16 |
| WO2015185011A1 (en) | 2015-12-10 |
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