CN107137403A - A kind of purposes of PI3K/MTOR inhibitor in the medicine for preparing treatment cancer of pancreas - Google Patents
A kind of purposes of PI3K/MTOR inhibitor in the medicine for preparing treatment cancer of pancreas Download PDFInfo
- Publication number
- CN107137403A CN107137403A CN201710116510.9A CN201710116510A CN107137403A CN 107137403 A CN107137403 A CN 107137403A CN 201710116510 A CN201710116510 A CN 201710116510A CN 107137403 A CN107137403 A CN 107137403A
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- CN
- China
- Prior art keywords
- pi3k
- pancreas
- compound
- mtor inhibitor
- purposes
- Prior art date
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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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- 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
Abstract
The present invention relates to a kind of purposes of PI3K/MTOR inhibitor in the medicine for preparing treatment cancer of pancreas.The PI3K/MTOR inhibitor can be used in combination with Hedgehog inhibitor.The invention further relates to include the pharmaceutical composition of above two inhibitor.
Description
Technical field
The present invention relates to a kind of purposes of PI3K/MTOR inhibitor in the medicine for preparing treatment cancer of pancreas.
Background technology
Cancer of pancreas is that a kind of grade malignancy is very high, diagnoses and treat all highly difficult malignant tumor of digestive tract, about 90% is
Duct adenocarcinoma originating from glandular tube epithelium.Chinese cancer of pancreas morbidity and mortality substantially rise within 2000~2011.Life in 5 years
Deposit rate<1%, it is one of worst malignant tumour of prognosis.The diagnosis rate of cancer of pancreas early stage is not high, and operative mortality rate is higher, and controls
More rate is very low.This sick incidence of disease male is higher than women, and the ratio between men and women is 1.5~2:1, male patient is more far beyond premenopausal women
See, the incidence of disease of postmenopausal women and male are similar.
CN103282363A discloses a class PI3K/mTOR double inhibitors, and they have very to PI3K and mTOR kinases
Strong inhibitory action, including the compound shown in lower formula (I), its chemical entitled 1- methyl -3- [5- [3- methyl -2- oxygen -
1- [3- (trifluoromethyl) phenyl] -2,3- dihydro -1H- imidazoles [4,5-c] quinoline-8-yl] pyridine -2- bases] urea, it is also pointed out this
Class compound may be applied to treatment melanoma, Papillary thyroid carcinoma, cholangiocarcinoma, colon cancer, oophoroma, lung cancer, pernicious
Lympha tumour, liver, kidney, bladder, prostate, mammary gland and cancer of pancreas and sarcoma and skin, colon, thyroid gland, lung and ovary
Primary and recurrent solid tumor or leukaemia.
CN103261198A discloses a class Hedgehog signal pathway inhibitors, including such as following formula (II) chemical combination
Thing, its chemical entitled N- (2- ethyls -5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b] pyridazine -2- bases) benzene
Base) -1- methylcyclopropyl groups formamides, and disclose Hedgehog signal paths may be with glioblastoma, basal-cell carcinoma
And cancer of pancreas is relevant.
But can the combination that above-mentioned document does not disclose specific PI3K/mTOR and Hedgehog inhibitor be used for pancreas
The treatment of cancer.
The content of the invention
The present invention is it has surprisingly been found that PI3K/mTOR inhibitor has good therapeutic effect for cancer of pancreas.In the present invention
In preferred embodiment, described PI3K/mTOR inhibitor is compound or pharmaceutically acceptable salt thereof shown in following formula (I).This
In invention, the consumption of described PI3K/MTOR inhibitor can be in 0.1-1000mg/kg, preferably 1-100mg/kg, more preferably
5-20mg/kg, described consumption is measured in the form of compound (I).
In a preferred embodiment of the present invention, described PI3K/MTOR inhibitor suppresses with Hedgehog signal paths
Agent is used in combination, the two combination, better for cancer of pancreas, particularly preferably, described Hedgehog signal paths suppress
Agent is the compound or pharmaceutically acceptable salt thereof as shown in following formula (II).In the present invention, described Hedgehog signal pathway inhibitors
Consumption can in 1-1000mg/kg, most preferably preferably 5-500mg/kg, more preferably 10-200mg/kg, 20-150mg/kg,
Described consumption is measured in the form of compound (II).In the present invention, it is two or more medicines same that finger, which is used in combination,
All bestow administration object in dosage period, but whether the two is administered simultaneously then unrestricted, can have after first having, can there is certain
Time interval.
The officinal salt of formula (I), formula (II) compound in the present invention can be selected from various inorganic acids well known in the art
Or acylate.
Formula (I) and (II) compound or their pharmaceutically acceptable salt can also be with pharmaceutically acceptable carriers one
Rise and composition forms well known in the art, such as tablet, capsule, granule, injection are made.The invention further relates to containing selected from
The composition of formula (I) and formula (II) compound or their pharmaceutically acceptable salt is preparing the medicine of the foregoing cancer of pancreas for the treatment of
Purposes in thing.
Brief description of the drawings
Fig. 1 shows compound (I), the treatment that (II) is alone or Papillary is to human pancreas cancer BXPC-3 Nude Mices
Effect.
Fig. 2 shows compound (I), (II) alone or Papillary is to the curative effects of human pancreas cancer BXPC-3 Nude Mices
(tumour photo).
Embodiment
It is used to further describe the present invention with reference to embodiments, but these embodiments are not intended to limit the scope of the invention.
Embodiment 1：Evaluate compound (I), compound (II) is alone or Papillary is to human pancreas cancer BXPC-3 nude mouses
The curative effect of transplantable tumor.
1 test medicine
Test-compound (I), compound (II) respectively refer to CN103282363A and CN103261198A disclosures
Synthesis.Compound method：Compound (I) is prepared with 70%PEG 400, and compound (II) is prepared with 30%PEG 400.
2 experimental animals
BALB/cA-nude nude mouses, 6-7 weeks, ♀, purchased from Shanghai Slac Experimental Animal Co., Ltd..The quality certification
Number：SCXK (Shanghai) 2007-0005.Feeding environment：SPF grades.
3 experimental procedures
Nude mouse subcutaneous vaccination human pancreas cancer BXPC-3 cells, treat tumour growth to 100-200mm3Afterwards, it is animal is random
It is grouped (D0).Dosage and dosage regimen are shown in Table 1.2-3 knurl volume is surveyed weekly, claims mouse weight, record data.Gross tumor volume
(V) calculation formula is：
V=1/2 × a × b2Wherein a, b represent length and width respectively.
T/C (%)=(T-T0)/(C-C0) × 100 wherein T, C are the gross tumor volume at the end of experiment；T0、C0Opened for experiment
The gross tumor volume during beginning.
4 results
Compound (II) (75mg/kg, PO, QD × 16) and compound (I) (10mg/kg, PO, QD × 16) alone to people
The growth of cancer of pancreas BxPC-3 Nude Mices has certain inhibitory action, and tumour inhibiting rate is respectively 33% and 40%；Papillary, suppression
Knurl effect is remarkably reinforced, inhibitory rate to 77%, hence it is evident that be better than two prescription curative effects).
The compound of table 1 (I), the treatment that compound (II) is alone or Papillary is to human pancreas cancer BxPC-3 Nude Mices
Effect
D0:First time administration time.P values refer to compared with the control；*P<0.05vs compounds (I)+compound (II),
Student ' s t ' are examined.Control group n=10, treatment group n=6.
5 conclusions
Compound (I) and (II) alone grown to human pancreas cancer BxPC-3 Nude Mices have certain inhibitory action,
Papillary, tumor-inhibiting action is remarkably reinforced.
Claims (8)
- Purposes of the 1.PI3K/MTOR inhibitor in the medicine for preparing treatment cancer of pancreas, it is preferably describedPI3K/MTOR inhibitor is PI3K/MTOR-2 inhibitor.
- 2. purposes according to claim 1, wherein described PI3K/MTOR inhibitor be compound shown in formula (I) or its Officinal salt,
- 3. purposes according to claim 2, wherein the consumption of described PI3K/MTOR inhibitor is 0.1-1000mg/ Kg, preferably 1-100mg/kg, more preferably 5-20mg/kg.
- 4. the purposes according to claims 1 to 3 any one, wherein described PI3K/MTOR inhibitor and Hedgehog Signal pathway inhibitor is used in combination.
- 5. purposes according to claim 4, wherein described Hedgehog signal pathway inhibitors are formula (II) shownization Compound or its officinal salt,
- 6. purposes according to claim 5, wherein described Hedgehog signal pathway inhibitors consumption is 1- 1000mg/kg, preferably 5-500mg/kg, more preferably 10-200mg/kg, most preferably 20-150mg/kg.
- 7. a kind of pharmaceutical composition, containing described in (I) compound or pharmaceutically acceptable salt thereof of formula described in claim 2 and claim 5 (II) compound or pharmaceutically acceptable salt thereof shown in, and pharmaceutically acceptable carrier.
- 8. purposes of the pharmaceutical composition in the medicine for preparing treatment cancer of pancreas described in claim 7.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610115807 | 2016-03-01 | ||
| CN2016101158079 | 2016-03-01 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107137403A true CN107137403A (en) | 2017-09-08 |
| CN107137403B CN107137403B (en) | 2021-07-02 |
Family
ID=59784087
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710116510.9A Active CN107137403B (en) | 2016-03-01 | 2017-02-28 | Application of PI3K/MTOR inhibitor in preparation of medicine for treating pancreatic cancer |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107137403B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103030637A (en) * | 2011-10-10 | 2013-04-10 | 上海恒瑞医药有限公司 | Imidazole quinoline derivative, and pharmaceutically acceptable salts thereof, preparation method thereof and application thereof on medicines |
| CN103261198A (en) * | 2010-12-22 | 2013-08-21 | 江苏恒瑞医药股份有限公司 | 2-arylimidazo[1,2-]pyridazine, 2-phenylimidazo[1,2-a]pyridine, and 2-phenylimidazo[1,2-a]pyrazine derivatives |
-
2017
- 2017-02-28 CN CN201710116510.9A patent/CN107137403B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103261198A (en) * | 2010-12-22 | 2013-08-21 | 江苏恒瑞医药股份有限公司 | 2-arylimidazo[1,2-]pyridazine, 2-phenylimidazo[1,2-a]pyridine, and 2-phenylimidazo[1,2-a]pyrazine derivatives |
| CN103030637A (en) * | 2011-10-10 | 2013-04-10 | 上海恒瑞医药有限公司 | Imidazole quinoline derivative, and pharmaceutically acceptable salts thereof, preparation method thereof and application thereof on medicines |
| WO2013053273A1 (en) * | 2011-10-10 | 2013-04-18 | 上海恒瑞医药有限公司 | Imidazo quinoline derivative and medicinal salt thereof, preparation method thereof and use in medicine thereof |
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| Publication number | Publication date |
|---|---|
| CN107137403B (en) | 2021-07-02 |
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