CN107382827A - Amino acid derivativges or its pharmaceutically acceptable salt and application - Google Patents
Amino acid derivativges or its pharmaceutically acceptable salt and application Download PDFInfo
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- CN107382827A CN107382827A CN201710243936.0A CN201710243936A CN107382827A CN 107382827 A CN107382827 A CN 107382827A CN 201710243936 A CN201710243936 A CN 201710243936A CN 107382827 A CN107382827 A CN 107382827A
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- aryl
- cycloalkyl
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- HJWLCRVIBGQPNF-UHFFFAOYSA-N C=CCc1ccccc1 Chemical compound C=CCc1ccccc1 HJWLCRVIBGQPNF-UHFFFAOYSA-N 0.000 description 1
- GZMKLOKYCGBVKL-UHFFFAOYSA-N CC(C)(C1)NC(C)(C)CC1NC(C(Cc(cc1)ccc1-c1ccccc1)NC(c1c[nH]c2c1cccc2)=O)=O Chemical compound CC(C)(C1)NC(C)(C)CC1NC(C(Cc(cc1)ccc1-c1ccccc1)NC(c1c[nH]c2c1cccc2)=O)=O GZMKLOKYCGBVKL-UHFFFAOYSA-N 0.000 description 1
- XRXDMQBBSDZXEP-UHFFFAOYSA-N CC(C)(C1)NC(C)(C)CC1NC(C(Cc(cc1)ccc1-c1ccccc1)NC(c1nc(cccc2)c2cc1)=O)=O Chemical compound CC(C)(C1)NC(C)(C)CC1NC(C(Cc(cc1)ccc1-c1ccccc1)NC(c1nc(cccc2)c2cc1)=O)=O XRXDMQBBSDZXEP-UHFFFAOYSA-N 0.000 description 1
- 0 CC[C@@](*)C1CC(C)(C)NC(C)(C)C1 Chemical compound CC[C@@](*)C1CC(C)(C)NC(C)(C)C1 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention discloses a kind of amino acid derivativges or its pharmaceutically acceptable salt and application.Wherein, amino acid derivativges or its pharmaceutically acceptable salt, there is the structure shown in below formula (I):
Description
Technical field
The present invention relates to pharmaceutical field, in particular to a kind of amino acid derivativges or its pharmaceutically acceptable salt,
And application.
Background technology
Bradykinin is a potential inflammatory peptide fragment, it be by high molecular weight kininogen in the presence of kallikrein
Caused vaso-active substance, mainly combined by autocrine-paracrine mechanism in the form of local hormone with bradykinin receptor
To play a role, including vasodilation, smooth muscle spasm, oedema, and pain and hyperalgia.Research shows that bradykinin is to be permitted
One important growth factor of more cancers, such as lung cancer, liver cancer, prostate cancer, breast cancer.It not only directly stimulates cancer cell
Growth, come irritation cancer migration and invasion and attack also by matrix metalloproteinase (MMP) organized enzyme is stimulated.And in tumour, delay and swash
Peptide is mainly by stimulating secretion VEGF to stimulate new vessels to be formed.These activities collectively promote some swollen
The growth of knurl type and invasion.
Bradykinin receptor belongs to seven transmembrane receptors of protein coupling.Clearer and more definite bradykinin receptor type has two at present
Kind:B1 and B2 acceptors.The expression of both acceptors in vivo is different.B2 acceptors are present in normal body,
Express it is more, it is sensitive to bradykinin and kallidins;And expression quantity is seldom under normal operation for B1 acceptors, but in inflammation, anoxic, swollen
It is induced under knurl and stressed condition, expression increases, and B1 acceptors also participate in tumor neovasculature formation in addition.Research show B1 by
Body and B2 acceptors play a significant role in metastases and tumour progression.Bradykinin receptor has become current oncotherapy
New target spot.In recent years, the research and development for bradykinin receptor antagonists class medicine have turned into the study hotspot in the field.
The content of the invention
It is the present invention is intended to provide a kind of as the amino acid derivativges of brad ykinin antagonists or its is pharmaceutically acceptable
Salt and application, for preparing new anti-tumor drug.
To achieve these goals, according to an aspect of the invention, there is provided a kind of amino acid derivativges or its pharmacy
Upper acceptable salt, has the structure shown in below formula (I):
Wherein, R is selected from C6-12Aryl, 5-12 unit's heteroaryls, C3-12Cycloalkyl or 3-12 members are miscellaneous alicyclic, and the hydrogen on R can
Optionally by one or more R1Substitution;
Each R1Independently selected from H, halogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Cycloalkyl, C6-12Aryl, 3-12
Miscellaneous alicyclic, the 5-12 unit's heteroaryls of member ,-CN ,-C (=O) R2,-C (=O) OR2,-C (=O) NR3R4、-NO2、-NR3R4、-NR5C
(=O) R2、-NR5C (=O) OR6、-NR5C (=O) NR3R4、-NR5S (=O)2R6、-NR5S (=O)2R3R4、-OR2、-OCN、-OC
(=O) R2,-OC (=O) NR3R4,-OC (=O) OR2,-OC (=O) NR3R4,-S (=O)mR2,-S (=O)2NR3R4, or adjacent original
R on son1Group can merge to form C3-12Cycloalkyl, C6-12The first miscellaneous alicyclic and 5-12 member hetero-aromatic rings of aryl, 3-12, and R1
On hydrogen can be optionally by R7Substitution;
R2、R3、R4、R5And R6Separately selected from H, halogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Cycloalkyl,
C6-12Aryl, miscellaneous alicyclic, the 5-12 unit's heteroaryls of 3-12 members;Or it is bound to the R on identical nitrogen-atoms2、R3、R4、R5And R6In appoint
Merge together with two nitrogen that can be combined with it of meaning, to form the first miscellaneous alicyclic or 5-12 unit's heteroaryls of 3-12, it optionally contains 1
The other hetero atom for being selected from N, O and S to 3;Or it is bound to the R in identical carbon atoms2、R3、R4、R5And R6In any two can
Merge and form C3-12Cycloalkyl, C6-12The first miscellaneous alicyclic or 5-12 unit's heteroaryls of aryl, 3-12;And R2、R3、R4、R5And R6
In each hydrogen optionally by R8Substitution, or in R2、R3、R4、R5And R6Two hydrogen atoms in middle identical carbon atoms are optionally that oxo takes
Dai Ji;
Each R7Can be independently selected from halogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Cycloalkyl, C6-12Aryl, 3-12
Miscellaneous alicyclic, the 5-12 unit's heteroaryls of member ,-CN ,-C (=O) R10,-C (=O) OR10,-C (=O) NR11R12、-NO2、-NR11R12、-
NR13C (=O) R10、-NR13C (=O) OR14、-NR13C (=O) NR11R12、-NR13S (=O)2R14、-NR13S (=O)2NR11R12、-
OR10,=O ,-OC (=O) R10,-OC (=O) NR11R12,-S (=O)mR10And-S (=O)2NR11R12, and R7On hydrogen can appoint
Choosing is by R9Substitution;
R10、R11、R12、R13、R14H, C can be separately selected from1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Cycloalkyl,
C6-12Aryl, miscellaneous alicyclic, the 5-12 unit's heteroaryls of 3-12 members, and R10、R11、R12、R13、R14In each hydrogen optionally by halogen ,-
OH ,-CN, can be by-the C of partly or completely perhalogenation1-5Alkyl;
R8、R9Can be independently selected from halogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Cycloalkyl, C6-12Aryl, 3-12
Miscellaneous alicyclic, the 5-12 unit's heteroaryls of member ,-CN ,-C (=O) (CH2)nCH3,-C (=O) O (CH2)nCH3,-C (=O) N [(CH2)nCH3]2,-C (=O) OH ,-C (=O) NH2,-C (=O) NH (CH2)nCH3、-NO2、-NH2、-NH(CH2)nCH3、-N[(CH2)nCH3]2,-NHC (=O) (CH2)nCH3,-NHS (=O)2(CH2)nCH3、-OH、-OC(CH2) nCH3 ,=O ,-OC (=O) (CH2)nCH3,-S (=O) (CH2)nCH3,-OS (=O) (CH2)nCH3And-S (=O)2N[(CH2)nCH3]2;
M is selected from 0,1 or 2;
N is selected from 0,1,2,3,4 or 5.
Further, R is selected from the group shown in logical formula (II) or logical formula (III), and the hydrogen on R can be optionally by one or more
Individual R1Substitution,
X1Selected from O, S, N-R1Or C-R1;
X2Selected from O, S, N-R1Or C-R1;
X3Selected from O, S, N-R1Or C-R1;
X4Selected from O, S, N-R1Or C-R1;
X5Selected from O, S, N-R1Or C-R1;
Y1Selected from O, S, N-R1Or C-R1;
Y2Selected from O, S, N-R1Or C-R1;
Y3Selected from O, S, N-R1Or C-R1;
Y4Selected from O, S, N-R1Or C-R1;
Each R1Independently selected from H, halogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Cycloalkyl, C6-12Aryl, 3-12
Miscellaneous alicyclic, the 5-12 unit's heteroaryls of member ,-CN ,-C (=O) R2,-C (=O) OR2,-C (=O) NR3R4、-NO2、-NR3R4、-NR5C
(=O) R2、-NR5C (=O) OR6、-NR5C (=O) NR3R4、-NR5S (=O)2R6、-NR5S (=O)2R3R4、-OR2、-OCN、-OC
(=O) R2,-OC (=O) NR3R4,-OC (=O) OR2,-OC (=O) NR3R4,-S (=O)mR2,-S (=O)2NR3R4, or adjacent original
R1 groups on son can merge to form C3-12Cycloalkyl, C6-12The first miscellaneous alicyclic and 5-12 member hetero-aromatic rings of aryl, 3-12, and R1
On hydrogen can be optionally by R7Substitution.
Further, when R is logical formula (II), and the hydrogen on R can be optionally by one or more R1Substitution;
X1Selected from O, S, N-R1Or C-R1;
X2Selected from O, S, N-R1Or C-R1;
X3Selected from O, S, N-R1Or C-R1;
X4Selected from O, S, N-R1Or C-R1;
X5Selected from O, S, N-R1Or C-R1;
Each R1Independently selected from H, halogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Cycloalkyl, C6-12Aryl, 3-12
Miscellaneous alicyclic, the 5-12 unit's heteroaryls of member ,-CN ,-C (=O) R2,-C (=O) OR2,-C (=O) NR3R4、-NO2、-NR3R4、-NR5C
(=O) R2、-NR5C (=O) OR6、-NR5C (=O) NR3R4、-NR5S (=O)2R6、-NR5S (=O)2R3R4、-OR2、-OCN、-OC
(=O) R2,-OC (=O) NR3R4,-OC (=O) OR2,-OC (=O) NR3R4,-S (=O)mR2,-S (=O)2NR3R4, or adjacent original
R1 groups on son can merge to form C3-12Cycloalkyl, C6-12The first miscellaneous alicyclic and 5-12 member hetero-aromatic rings of aryl, 3-12, and R1
On hydrogen can be optionally by R7Substitution.
Further, when R is logical formula (II), X1、X2、X3、X4With X5Respectively C-R1When,
Each R1Independently selected from H, halogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Cycloalkyl, C6-12Aryl, 3-12
Miscellaneous alicyclic, the 5-12 unit's heteroaryls of member ,-CN ,-C (=O) R2,-C (=O) OR2,-C (=O) NR3R4、-NO2、-NR3R4、-NR5C
(=O) R2、-NR5C (=O) OR6、-NR5C (=O) NR3R4、-NR5S (=O)2R6、-NR5S (=O)2R3R4、-OR2、-OCN、-OC
(=O) R2,-OC (=O) NR3R4,-OC (=O) OR2,-OC (=O) NR3R4,-S (=O)mR2,-S (=O)2NR3R4, or adjacent original
R1 groups on son can merge to form C3-12Cycloalkyl, C6-12The first miscellaneous alicyclic and 5-12 member hetero-aromatic rings of aryl, 3-12, and R1
On hydrogen can be optionally by R7Substitution.
Further, when R is logical formula (II), X2、X3、X4、X5For C-R1, X1For N-R1When,
Each R1Independently selected from H, halogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Cycloalkyl, C6-12Aryl, 3-12
Miscellaneous alicyclic, the 5-12 unit's heteroaryls of member ,-CN ,-C (=O) R2,-C (=O) OR2,-C (=O) NR3R4、-NO2、-NR3R4、-NR5C
(=O) R2、-NR5C (=O) OR6、-NR5C (=O) NR3R4、-NR5S (=O)2R6、-NR5S (=O)2R3R4、-OR2、-OCN、-OC
(=O) R2,-OC (=O) NR3R4,-OC (=O) OR2,-OC (=O) NR3R4,-S (=O)mR2,-S (=O)2NR3R4, or adjacent original
R1 groups on son can merge to form C3-12Cycloalkyl, C6-12The first miscellaneous alicyclic and 5-12 member hetero-aromatic rings of aryl, 3-12, and R1
On hydrogen can be optionally by R7Substitution.
Further, when R is logical formula (II), X1、X2、X4、X5For C-R1When, X3For N-R1When,
Each R1Independently selected from H, halogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Cycloalkyl, C6-12Aryl, 3-12
Miscellaneous alicyclic, the 5-12 unit's heteroaryls of member ,-CN ,-C (=O) R2,-C (=O) OR2,-C (=O) NR3R4、-NO2、-NR3R4、-NR5C
(=O) R2、-NR5C (=O) OR6、-NR5C (=O) NR3R4、-NR5S (=O)2R6、-NR5S (=O)2R3R4、-OR2、-OCN、-OC
(=O) R2,-OC (=O) NR3R4,-OC (=O) OR2,-OC (=O) NR3R4,-S (=O)mR2,-S (=O)2NR3R4, or adjacent original
R1 groups on son can merge to form C3-12Cycloalkyl, C6-12The first miscellaneous alicyclic and 5-12 member hetero-aromatic rings of aryl, 3-12, and R1
On hydrogen can be optionally by R7Substitution.
Further, when R is logical formula (III), and the hydrogen on R can be optionally by one or more R1Substitution;
Y1Selected from O, S, N-R1Or C-R1;
Y2Selected from O, S, N-R1Or C-R1;
Y3Selected from O, S, N-R1Or C-R1;
Y4Selected from O, S, N-R1Or C-R1;
Each R1Independently selected from H, halogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Cycloalkyl, C6-12Aryl, 3-12
Miscellaneous alicyclic, the 5-12 unit's heteroaryls of member ,-CN ,-C (=O) R2,-C (=O) OR2,-C (=O) NR3R4、-NO2、-NR3R4、-NR5C
(=O) R2、-NR5C (=O) OR6、-NR5C (=O) NR3R4、-NR5S (=O)2R6、-NR5S (=O)2R3R4、-OR2、-OCN、-OC
(=O) R2,-OC (=O) NR3R4,-OC (=O) OR2,-OC (=O) NR3R4,-S (=O)mR2,-S (=O)2NR3R4, or adjacent original
R1 groups on son can merge to form C3-12Cycloalkyl, C6-12The first miscellaneous alicyclic and 5-12 member hetero-aromatic rings of aryl, 3-12, and R1
On hydrogen can be optionally by R7Substitution.
Further, when R is logical formula (III), and the hydrogen on R can be optionally by one or more R1Substitution, Y1、Y3For C-
R1, Y2、Y4It is independently selected from N-R1、C-R1Or during O,
Each R1Independently selected from H, halogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Cycloalkyl, C6-12Aryl, 3-12
Miscellaneous alicyclic, the 5-12 unit's heteroaryls of member ,-CN ,-C (=O) R2,-C (=O) OR2,-C (=O) NR3R4、-NO2、-NR3R4、-NR5C
(=O) R2、-NR5C (=O) OR6、-NR5C (=O) NR3R4、-NR5S (=O)2R6、-NR5S (=O)2R3R4、-OR2、-OCN、-OC
(=O) R2,-OC (=O) NR3R4,-OC (=O) OR2,-OC (=O) NR3R4,-S (=O)mR2,-S (=O)2NR3R4, or adjacent original
R1 groups on son can merge to form C3-12Cycloalkyl, C6-12The first miscellaneous alicyclic and 5-12 member hetero-aromatic rings of aryl, 3-12, and R1
On hydrogen can be optionally by R7Substitution.
Further, when R is logical formula (III), Y2、Y3、Y4For C-R1, Y1For N-R1When,
Each R1Independently selected from H, halogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Cycloalkyl, C6-12Aryl, 3-12
Miscellaneous alicyclic, the 5-12 unit's heteroaryls of member ,-CN ,-C (=O) R2,-C (=O) OR2,-C (=O) NR3R4、-NO2、-NR3R4、-NR5C
(=O) R2、-NR5C (=O) OR6、-NR5C (=O) NR3R4、-NR5S (=O)2R6、-NR5S (=O)2R3R4、-OR2、-OCN、-OC
(=O) R2,-OC (=O) NR3R4,-OC (=O) OR2,-OC (=O) NR3R4,-S (=O)mR2,-S (=O)2NR3R4, or adjacent original
R1 groups on son can merge to form C3-12Cycloalkyl, C6-12The first miscellaneous alicyclic and 5-12 member hetero-aromatic rings of aryl, 3-12, and R1
On hydrogen can be optionally by R7Substitution.
Further, when R is logical formula (III), and the hydrogen on R can be optionally by one or more R1Substitution, Y3、Y4For C-
R1, Y1、Y2For N-R1When,
Each R1Independently selected from H, halogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Cycloalkyl, C6-12Aryl, 3-12
Miscellaneous alicyclic, the 5-12 unit's heteroaryls of member ,-CN ,-C (=O) R2,-C (=O) OR2,-C (=O) NR3R4、-NO2、-NR3R4、-NR5C
(=O) R2、-NR5C (=O) OR6、-NR5C (=O) NR3R4、-NR5S (=O)2R6、-NR5S (=O)2R3R4、-OR2、-OCN、-OC
(=O) R2,-OC (=O) NR3R4,-OC (=O) OR2,-OC (=O) NR3R4,-S (=O)mR2,-S (=O)2NR3R4, or adjacent original
R1 groups on son can merge to form C3-12Cycloalkyl, C6-12The first miscellaneous alicyclic and 5-12 member hetero-aromatic rings of aryl, 3-12, and R1
On hydrogen can be optionally by R7Substitution.
According to another aspect of the present invention, there is provided a kind of amino acid derivativges or its pharmaceutically acceptable salt are as slow
Application of the tachykinin receptor antagonist in anti-tumor drug is prepared.
According to another aspect of the invention, there is provided a kind of amino acid derivativges or its pharmaceutically acceptable salt are in vitro
Suppress the application in the growth and invasion and attack of tumour cell.
In accordance with a further aspect of the present invention, there is provided a kind of pharmaceutical composition.The pharmaceutical composition includes effective dose
Any of the above-described derived from amino acid thing or its pharmaceutically acceptable salt.
Further, pharmaceutical composition also includes medically acceptable carrier, and pharmaceutical composition is injection or oral
Agent, the dosage range of amino acid derivativges and its esters is in injection:0.1-50mg/kg;This in oral agents is amino acid derived
The dosage range of thing and its esters is:0.1-50mg/kg.The compound of the present invention, is the brand-new change for from the beginning designing to obtain
Compound.Compound in the present invention is a kind of bradykinin receptor antagonists, is combined by suppressing bradykinin with its acceptor to suppress
The growth and invasion and attack of tumour cell, further suppress the generation of tumour.
Embodiment
It should be noted that in the case where not conflicting, the feature in embodiment and embodiment in the application can phase
Mutually combination.The present invention is described in detail below in conjunction with embodiment.
According to of the invention a kind of typically embodiment there is provided a kind of amino acid derivativges or its is pharmaceutically acceptable
Salt, there is the structure shown in below formula (I):
Wherein, R may be selected from C6-12Aryl, 5-12 unit's heteroaryls, C3-12Cycloalkyl or 3-12 members are miscellaneous alicyclic, and the hydrogen on R
Can be optionally by one or more R1Substitution;
Each R1Can be independently selected from H, halogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Cycloalkyl, C6-12Aryl,
Miscellaneous alicyclic, the 5-12 unit's heteroaryls of 3-12 members ,-CN ,-C (=O) R2,-C (=O) OR2,-C (=O) NR3R4、-NO2、-NR3R4、-
NR5C (=O) R2、-NR5C (=O) OR6、-NR5C (=O) NR3R4、-NR5S (=O)2R6、-NR5S (=O)2R3R4、-OR2、-
OCN ,-OC (=O) R2,-OC (=O) NR3R4,-OC (=O) OR2,-OC (=O) NR3R4,-S (=O)mR2,-S (=O)2NR3R4,
Or the R on adjacent atom1Group can merge to form C3-12Cycloalkyl, C6-12The first miscellaneous alicyclic and 5-12 member heteroaryls of aryl, 3-12
Ring, and R1On hydrogen can be optionally by R7Substitution;
R2、R3、R4、R5And R6H, halogen, C can be separately selected from1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Ring
Alkyl, C6-12Aryl, miscellaneous alicyclic, the 5-12 unit's heteroaryls of 3-12 members;Or it is bound to the R on identical nitrogen-atoms2、R3、R4、R5And R6
Merge together with the nitrogen that middle any two can be combined with it, to form the first miscellaneous alicyclic or 5-12 unit's heteroaryls of 3-12, its is optional
Contain 1 to 3 other hetero atom for being selected from N, O and S;Or it is bound to the R in identical carbon atoms2、R3、R4、R5And R6In it is any
Two can merge and form C3-12Cycloalkyl, C6-12The first miscellaneous alicyclic or 5-12 unit's heteroaryls of aryl, 3-12;And R2、R3、R4、
R5And R6In each hydrogen optionally by R8Substitution, or in R2、R3、R4、R5And R6Two hydrogen atoms in middle identical carbon atoms are optionally oxygen
For substituent;
Each R7Can be independently selected from halogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Cycloalkyl, C6-12Aryl, 3-12
Miscellaneous alicyclic, the 5-12 unit's heteroaryls of member ,-CN ,-C (=O) R10,-C (=O) OR10,-C (=O) NR11R12、-NO2、-NR11R12、-
NR13C (=O) R10、-NR13C (=O) OR14、-NR13C (=O) NR11R12、-NR13S (=O)2R14、-NR13S (=O)2NR11R12、-
OR10,=O ,-OC (=O) R10,-OC (=O) NR11R12,-S (=O)mR10And-S (=O)2NR11R12, and R7On hydrogen can appoint
Choosing is by R9Substitution;
R10、R11、R12、R13、R14H, C can be separately selected from1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Cycloalkyl,
C6-12Aryl, miscellaneous alicyclic, the 5-12 unit's heteroaryls of 3-12 members, and R10、R11、R12、R13、R14In each hydrogen optionally by halogen ,-
OH ,-CN, can be by-the C of partly or completely perhalogenation1-5Alkyl;
R8、R9Halogen, C can be separately selected from1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Cycloalkyl, C6-12Aryl,
Miscellaneous alicyclic, the 5-12 unit's heteroaryls of 3-12 members ,-CN ,-C (=O) (CH2)nCH3,-C (=O) O (CH2)nCH3,-C (=O) N
[(CH2)nCH3]2,-C (=O) OH ,-C (=O) NH2,-C (=O) NH (CH2)nCH3、-NO2、-NH2、-NH(CH2)nCH3、-N
[(CH2)nCH3]2,-NHC (=O) (CH2)nCH3,-NHS (=O)2(CH2)nCH3、-OH、-OC(CH2) nCH3 ,=O ,-OC (=O)
(CH2)nCH3,-S (=O) (CH2)nCH3,-OS (=O) (CH2)nCH3And-S (=O)2N[(CH2)nCH3]2;
M may be selected from 0,1 or 2;
N is selected from 0,1,2,3,4 or 5.
The present invention provide compound be a kind of new compound from the beginning designed, may be used as antineoplastic, mitigate by
The pain of year incremental vast tumor patient.Its antitumor action is stable, and toxicity is low, is easy to human body receiving.Pharmaceutically apply
Can be N- (3- ([1,1 '-biphenyl] -4- bases) -1- oxos -1- ((2,2,6,6- tetramethyl piperidine -4- bases) amino) propyl- 2-
Base) -2- carboxamides derivatives or its pharmaceutically acceptable salt, hydrate or solvated compoundses.
The amino acid derivativges of the present invention are a kind of bradykinin receptor antagonists, can be by suppressing bradykinin and its acceptor
With reference to the effect that bradykinin receptor plays in metastases and tumour progression is suppressed, further suppress the generation of tumour.
According to a kind of typical embodiment of the present invention, R is selected from logical formula (II) or the group shown in logical formula (III), and on R
Hydrogen can be optionally by one or more R1During substitution,
X1It may be selected from O, S, N-R1Or C-R1;
X2It may be selected from O, S, N-R1Or C-R1;
X3It may be selected from O, S, N-R1Or C-R1;
X4It may be selected from O, S, N-R1Or C-R1;
X5It may be selected from O, S, N-R1Or C-R1;
Y1It may be selected from O, S, N-R1Or C-R1;
Y2It may be selected from O, S, N-R1Or C-R1;
Y3It may be selected from O, S, N-R1Or C-R1;
Y4It may be selected from O, S, N-R1Or C-R1;
Each R1Can be independently selected from H, halogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Cycloalkyl, C6-12Aryl,
Miscellaneous alicyclic, the 5-12 unit's heteroaryls of 3-12 members ,-CN ,-C (=O) R2,-C (=O) OR2,-C (=O) NR3R4、-NO2、-NR3R4、-
NR5C (=O) R2、-NR5C (=O) OR6、-NR5C(=O) NR3R4、-NR5S (=O)2R6、-NR5S (=O)2R3R4、-OR2、-
OCN ,-OC (=O) R2,-OC (=O) NR3R4,-OC (=O) OR2,-OC (=O) NR3R4,-S (=O)mR2,-S (=O)2NR3R4,
Or the R1 groups on adjacent atom can merge to form C3-12Cycloalkyl, C6-12The first miscellaneous alicyclic and 5-12 member heteroaryls of aryl, 3-12
Ring, and R1On hydrogen can be optionally by R7Substitution.
According to a kind of typical embodiment of the present invention, when R is II, and the hydrogen on R can be optionally by one or more R1
Substitution,
X1It may be selected from O, S, N-R1Or C-R1;
X2It may be selected from O, S, N-R1Or C-R1;
X3It may be selected from O, S, N-R1Or C-R1;
X4It may be selected from O, S, N-R1Or C-R1;
X5It may be selected from O, S, N-R1Or C-R1;
Each R1Can be independently selected from H, halogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Cycloalkyl, C6-12Aryl,
Miscellaneous alicyclic, the 5-12 unit's heteroaryls of 3-12 members ,-CN ,-C (=O) R2,-C (=O) OR2,-C (=O) NR3R4、-NO2、-NR3R4、-
NR5C (=O) R2、-NR5C (=O) OR6、-NR5C (=O) NR3R4、-NR5S (=O)2R6、-NR5S (=O)2R3R4、-OR2、-
OCN ,-OC (=O) R2,-OC (=O) NR3R4,-OC (=O) OR2,-OC (=O) NR3R4,-S (=O)mR2,-S (=O)2NR3R4,
Or the R1 groups on adjacent atom can merge to form C3-12Cycloalkyl, C6-12The first miscellaneous alicyclic and 5-12 member heteroaryls of aryl, 3-12
Ring, and R1On hydrogen can be optionally by R7Substitution.
According to a kind of typical embodiment of the present invention, when R is logical formula (II), X1、X2、X3、X4With X5Respectively C-R1
When,
Each R1Can be independently selected from H, halogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Cycloalkyl, C6-12Aryl,
Miscellaneous alicyclic, the 5-12 unit's heteroaryls of 3-12 members ,-CN ,-C (=O) R2,-C (=O) OR2,-C (=O) NR3R4、-NO2、-NR3R4、-
NR5C (=O) R2、-NR5C (=O) OR6、-NR5C (=O) NR3R4、-NR5S (=O)2R6、-NR5S (=O)2R3R4、-OR2、-
OCN ,-OC (=O) R2,-OC (=O) NR3R4,-OC (=O) OR2,-OC (=O) NR3R4,-S (=O)mR2,-S (=O)2NR3R4,
Or the R1 groups on adjacent atom can merge to form C3-12Cycloalkyl, C6-12The first miscellaneous alicyclic and 5-12 member heteroaryls of aryl, 3-12
Ring, and R1On hydrogen can be optionally by R7Substitution.
According to a kind of typical embodiment of the present invention, when R is logical formula (II), X2、X3、X4、X5For C-R1, X1For N-R1
When,
Each R1Can be independently selected from H, halogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Cycloalkyl, C6-12Aryl,
Miscellaneous alicyclic, the 5-12 unit's heteroaryls of 3-12 members ,-CN ,-C (=O) R2,-C (=O) OR2,-C (=O) NR3R4、-NO2、-NR3R4、-
NR5C (=O) R2、-NR5C (=O) OR6、-NR5C (=O) NR3R4、-NR5S (=O)2R6、-NR5S (=O)2R3R4、-OR2、-
OCN ,-OC (=O) R2,-OC (=O) NR3R4,-OC (=O) OR2,-OC (=O) NR3R4,-S (=O)mR2,-S (=O)2NR3R4,
Or the R1 groups on adjacent atom can merge to form C3-12Cycloalkyl, C6-12The first miscellaneous alicyclic and 5-12 member heteroaryls of aryl, 3-12
Ring, and R1On hydrogen can be optionally by R7Substitution.
According to a kind of typical embodiment of the present invention, when R is logical formula (II), X1、X2、X4、X5For C-R1When, X3For N-
R1When,
Each R1Can be independently selected from H, halogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Cycloalkyl, C6-12Aryl,
Miscellaneous alicyclic, the 5-12 unit's heteroaryls of 3-12 members ,-CN ,-C (=O) R2,-C (=O) OR2,-C (=O) NR3R4、-NO2、-NR3R4、-
NR5C (=O) R2、-NR5C (=O) OR6、-NR5C (=O) NR3R4、-NR5S (=O)2R6、-NR5S (=O)2R3R4、-OR2、-
OCN ,-OC (=O) R2,-OC (=O) NR3R4,-OC (=O) OR2,-OC (=O) NR3R4,-S (=O)mR2,-S (=O)2NR3R4,
Or the R1 groups on adjacent atom can merge to form C3-12Cycloalkyl, C6-12The first miscellaneous alicyclic and 5-12 member heteroaryls of aryl, 3-12
Ring, and R1On hydrogen can be optionally by R7Substitution.
According to a kind of typical embodiment of the present invention, when R is logical formula (III), and the hydrogen on R can optionally by one or
Multiple R1Substitution;
Y1It may be selected from O, S, N-R1Or C-R1;
Y2It may be selected from O, S, N-R1Or C-R1;
Y3It may be selected from O, S, N-R1Or C-R1;
Y4It may be selected from O, S, N-R1Or C-R1;
Each R1Can be independently selected from H, halogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Cycloalkyl, C6-12Aryl,
Miscellaneous alicyclic, the 5-12 unit's heteroaryls of 3-12 members ,-CN ,-C (=O) R2,-C (=O) OR2,-C (=O) NR3R4、-NO2、-NR3R4、-
NR5C (=O) R2、-NR5C (=O) OR6、-NR5C (=O) NR3R4、-NR5S (=O)2R6、-NR5S (=O)2R3R4、-OR2、-
OCN ,-OC (=O) R2,-OC (=O) NR3R4,-OC (=O) OR2,-OC (=O) NR3R4,-S (=O)mR2,-S (=O)2NR3R4,
Or the R1 groups on adjacent atom can merge to form C3-12Cycloalkyl, C6-12The first miscellaneous alicyclic and 5-12 member heteroaryls of aryl, 3-12
Ring, and R1On hydrogen can be optionally by R7Substitution.
According to a kind of typical embodiment of the present invention, when R is logical formula (III), and the hydrogen on R can optionally by one or
Multiple R1Substitution, Y1、Y3For C-R1, Y2、Y4It is independently selected from N-R1、C-R1Or during O,
Each R1Can be independently selected from H, halogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Cycloalkyl, C6-12Aryl,
Miscellaneous alicyclic, the 5-12 unit's heteroaryls of 3-12 members ,-CN ,-C (=O) R2,-C (=O) OR2,-C (=O) NR3R4、-NO2、-NR3R4、-
NR5C (=O) R2、-NR5C (=O) OR6、-NR5C (=O) NR3R4、-NR5S (=O)2R6、-NR5S (=O)2R3R4、-OR2、-
OCN ,-OC (=O) R2,-OC (=O) NR3R4,-OC (=O) OR2,-OC (=O) NR3R4,-S (=O)mR2,-S (=O)2NR3R4,
Or the R1 groups on adjacent atom can merge to form C3-12Cycloalkyl, C6-12The first miscellaneous alicyclic and 5-12 member heteroaryls of aryl, 3-12
Ring, and R1On hydrogen can be optionally by R7Substitution.
According to a kind of typical embodiment of the present invention, when R is logical formula (III), Y2、Y3、Y4For C-R1, Y1For N-R1
When,
Each R1Can be independently selected from H, halogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Cycloalkyl, C6-12Aryl,
Miscellaneous alicyclic, the 5-12 unit's heteroaryls of 3-12 members ,-CN ,-C (=O) R2,-C (=O) OR2,-C (=O) NR3R4、-NO2、-NR3R4、-
NR5C (=O) R2、-NR5C (=O) OR6、-NR5C (=O) NR3R4、-NR5S (=O)2R6、-NR5S (=O)2R3R4、-OR2、-
OCN ,-OC (=O) R2,-OC (=O) NR3R4,-OC (=O) OR2,-OC (=O) NR3R4,-S (=O)mR2,-S (=O)2NR3R4,
Or the R1 groups on adjacent atom can merge to form C3-12(each H can be by R for cycloalkyl7Substitution), C6-12Aryl, 3-12 member heterolipid rings
Race and 5-12 member hetero-aromatic rings, and R1On hydrogen can be optionally by R7Substitution.
According to a kind of typical embodiment of the present invention, when R is logical formula (III), and the hydrogen on R can optionally by one or
Multiple R1Substitution, Y3、Y4For C-R1, Y1、Y2For N-R1When,
Each R1Can be independently selected from H, halogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Cycloalkyl, C6-12Aryl,
Miscellaneous alicyclic, the 5-12 unit's heteroaryls of 3-12 members ,-CN ,-C (=O) R2,-C (=O) OR2,-C (=O) NR3R4、-NO2、-NR3R4、-
NR5C (=O) R2、-NR5C (=O) OR6、-NR5C (=O) NR3R4、-NR5S (=O)2R6、-NR5S (=O)2R3R4、-OR2、-
OCN ,-OC (=O) R2,-OC (=O) NR3R4,-OC (=O) OR2,-OC (=O) NR3R4,-S (=O)mR2,-S (=O)2NR3R4,
Or the R1 groups on adjacent atom can merge to form C3-12Cycloalkyl, C6-12The first miscellaneous alicyclic and 5-12 member heteroaryls of aryl, 3-12
Ring, and R1On hydrogen can be optionally by R7Substitution.
According to one kind of the invention, typically embodiment there is provided a kind of any of the above-described derived from amino acid thing or its pharmacy
Upper application of the acceptable salt in anti-tumor drug is prepared.
According to one kind of the invention, typically embodiment there is provided a kind of pharmaceutical composition.The pharmaceutical composition includes
Imitate any of the above-described the derived from amino acid thing or its pharmaceutically acceptable salt of dosage.
Preferably, pharmaceutical composition also includes pharmaceutically acceptable carrier, excipient or diluent, and pharmaceutical composition is
Injection or oral agents, the dosage range of amino acid derivativges and its esters of the present invention is in injection:0.1-50mg/
kg;The dosage range of amino acid derivativges and its esters of the present invention is in oral agents:0.1-50mg/kg.
The new compound of the present invention can be prepared by artificial synthesized method, and the new compound has antitumor work
With can extend life cycle of tumor patient, improve the life quality of tumor patient.The new compound efficacy stability of the present invention,
Toxicity is low, is easy to human body receiving, can apply to the treatment of most of cancers, the antineoplastic listed at present relatively has one
Determine advantage.
Bulk drug preferred formulation dosage range of the present invention is 0.01-50mg parts by weight.Ejection preparation of the present invention is prepared to commonly use
Auxiliary material includes:Disodium ethylene diamine tetraacetate, Tween 80, mannitol, glycerine, propane diols etc..
Preparing the conventional auxiliary material of oral solid formulation of the present invention includes:Microcrystalline cellulose, L-hydroxypropyl cellulose,
Polyvinylpyrrolidone, superfine silica gel powder, starch, dextrin, sucrose, lactose, talcum powder, magnesium stearate, sodium carboxymethyl starch, crosslinking
Polyvinylpyrrolidone, pregelatinized starch etc..
Preparing oral liquid auxiliary material of the present invention includes:Ethanol, ethyl hydroxy benzoate, methyl hydroxybenzoate, Tween-80, benzene
Sodium formate, sorbic acid, honey, sucrose, sodium hydrogensulfite, sodium thiosulfate, ascorbic acid, thiocarbamide, disodium ethylene diamine tetraacetate,
Phosphoric acid, citric acid, glycerine, lactose etc..
Above-mentioned raw materials component can match with a certain proportion of common medicinal supplementary material, and bag is can be made into according to this area conventional method
Containing any of injection, tablet, capsule etc..
The dosage range of compound is in anticancer:Injection 0.1-50mg/kg;Oral agents 0.1-50mg/ examples.
Beneficial effects of the present invention are further illustrated below in conjunction with embodiment.
Following compounds will be related in embodiments of the invention:
Compound PL-AC-1, its chemical constitution are:
Chinese is:N- (3- ([1,1 '-biphenyl] -4- bases) -1- oxos -1- ((2,2,6,6- tetramethyl piperidine -4-
Base) amino) propyl- 2- yls) -4- phenoxy benzonitrile acid amides.
English name is:
N- (3- ([1,1 '-biphenyl] -4-yl) -1-oxo-1- ((2,2,6,6-tetramethylpiperidin-4-
yl)amino)propan-2-yl)-4-phenoxybenzamide。
Compound PL-AC-2, its chemical constitution are:
Chinese is:N- (3- ([1,1 '-biphenyl] -4- bases) -1- oxos -1- ((2,2,6,6- tetramethyl piperidine -4-
Base) amino) propyl- 2- yls) -2- methoxy benzamides.
English name is:
N- (3- ([1,1 '-biphenyl] -4-yl) -1-oxo-1- ((2,2,6,6-tetramethylpiperidin-4-
yl)amino)propan-2-yl)-2-methoxybenzamide。
Compound PL-AC-3, its chemical constitution are:
Chinese is:N- (3- ([1,1 '-biphenyl] -4- bases) -1- oxos -1- ((2,2,6,6- tetramethyl piperidine -4-
Base) amino) propyl- 2- yls) Pyrazinamide.
English name is:
N- (3- ([1,1 '-biphenyl] -4-yl) -1-oxo-1- ((2,2,6,6-tetramethylpiperidin-4-
yl)amino)propan-2-yl)isonicotinamide。
Compound PL-AC-4, its chemical constitution are:
Chinese is:N- (3- ([1,1 '-biphenyl] -4- bases) -1- oxos -1- ((2,2,6,6- tetramethyl piperidine -4-
Base) amino) propyl- 2- yls) -4- (dimethylamino) benzamide.
English name is:
N- (3- ([1,1 '-biphenyl] -4-yl) -1-oxo-1- ((2,2,6,6-tetramethylpiperidin-4-
yl)amino)propan-2-yl)-4-(dimethylamino)benzamide。
Compound PL-AC-5, its chemical constitution are:
Chinese is:N- (3- ([1,1 '-biphenyl] -4- bases) -1- oxos -1- ((2,2,6,6- tetramethyl piperidine -4-
Base) amino) propyl- 2- yls) -2- cyanobenzamides.
English name is:
N- (3- ([1,1 '-biphenyl] -4-yl) -1-oxo-1- ((2,2,6,6-tetramethylpiperidin-4-
yl)amino)propan-2-yl)-2-cyanobenzamide。
Compound PL-AC-6, its chemical constitution are:
Chinese is:N- (3- ([1,1 '-biphenyl] -4- bases) -1- oxos -1- ((2,2,6,6- tetramethyl piperidine -4-
Base) amino) propyl- 2- yls) the chloro- 5- hydroxy-benzoyIamides of -2-.
English name is:
N- (3- ([1,1 '-biphenyl] -4-yl) -1-oxo-1- ((2,2,6,6-tetramethylpiperidin-4-
yl)amino)propan-2-yl)-2-chloro-5-hydroxy-benzamide。
Compound PL-AC-7, its chemical constitution are:
Chinese is:N- (3- ([1,1 '-biphenyl] -4- bases) -1- oxos -1- ((2,2,6,6- tetramethyl piperidine -4-
Base) amino) propyl- 2- yls) -1H- indoles -6- formamides.
English name is:
N- (3- ([1,1 '-biphenyl] -4-yl) -1-oxo-1- ((2,2,6,6-tetramethylpiperidin-4-
yl)amino)propan-2-yl)-1H-indole-6-carboxamide。
Compound PL-AC-8, its chemical constitution are:
Chinese is:N- (3- ([1,1 '-biphenyl] -4- bases) -1- oxos -1- ((2,2,6,6- tetramethyl piperidine -4-
Base) amino) propyl- 2- yls) -2-Hydroxylbenzamide.
English name is:
N- (3- ([1,1 '-biphenyl] -4-yl) -1-oxo-1- ((2,2,6,6-tetramethylpiperidin-4-
yl)amino)propan-2-yl)-2-hydroxybenzamide。
PL-AC-9, its chemical constitution are:
Chinese is:N- (3- ([1,1 '-biphenyl] -4- bases) -1- oxos -1- ((2,2,6,6- tetramethyl piperidine -4-
Base) amino) propyl- 2- yls) benzofuran-2-carboxamides.
English name is:
N- (3- ([1,1 '-biphenyl] -4-yl) -1-oxo-1- ((2,2,6,6-tetramethylpiperidin-4-
yl)amino)propan-2-yl)benzofuran-2-carboxamide。
Compound PL-AC-10, its chemical constitution are:
Chinese is:N- (3- ([1,1 '-biphenyl] -4- bases) -1- oxos -1- ((2,2,6,6- tetramethyl piperidine -4-
Base) amino) propyl- 2- yls) quinoline-2-formamide.
English name is:
N- (3- ([1,1 '-biphenyl] -4-yl) -1-oxo-1- ((2,2,6,6-tetramethylpiperidin-4-
yl)amino)propan-2-yl)quinoline-2-carboxarnide。
Compound PL-AC-11, its chemical constitution are:
Chinese is:N- (3- ([1,1 '-biphenyl] -4- bases) -1- oxos -1- ((2,2,6,6- tetramethyl piperidine -4-
Base) amino) propyl- 2- yls) -1,2- indole 2-carboxamides.
English name is:
N- (3- ([1,1 '-biphenyl] -4-yl) -1-oxo-1- ((2,2,6,6-tetramethylpiperidin-4-
yl)amino)propan-2-yl)-112-indole-2-carboxamide。
Compound PL-AC-12, its chemical constitution are:
Chinese is:N- (3- ([1,1 '-biphenyl] -4- bases) -1- oxos -1- ((2,2,6,6- tetramethyl piperidine -4-
Base) amino) propyl- 2- yls) -1- methyl -2H- benzos [d] indazole -3- formamides.
English name is:
N- (3- ([1,1 '-biphenyl] -4-yl) -1-oxo-1- ((2,2,6,6-tetramethylpiperidin-4-
yl)amino)propan-2-yl)-1-methyl-2H-114-indazole-3-carboxamide。
Compound PL-AC-13, its chemical constitution are:
Chinese is:N- (3- ([1,1 '-biphenyl] -4- bases) -1- oxos -1- ((2,2,6,6- tetramethyl piperidine -4-
Base) amino) propyl- 2- yls) -1H- indoles -3- formamides.
English name is:
N- (3- ([1,1 '-biphenyl] -4-yl) -1-oxo-1- ((2,2,6,6-tetramethylpiperidin-4-
yl)amino)propan-2-yl)-1H-indole-3-carboxamide。
Compound PL-AC-14, its chemical constitution are:
Chinese is:N- (3- ([1,1 '-biphenyl] -4- bases) -1- oxos -1- ((2,2,6,6- tetramethyl piperidine -4-
Base) amino) propyl- 2- yls) -1H- benzos [d] imidazoles -2- formamides.
English name is:
N- (3- ([1,1 '-biphenyl] -4-yl) -1-oxo-1- ((2,2,6,6-tetramethylpiperidin-4-
yl)amino)propan-2-yl)-1H-benzo[d]imidazole-2-carboxamide。
Compound PL-AC-15, its chemical constitution are:
Chinese is:N- (3- ([1,1 '-biphenyl] -4- bases) -1- oxos -1- ((2,2,6,6- tetramethyl piperidine -4-
Base) amino) propyl- 2- yls) -1- benzyl -1H- indole 2-carboxamides.
English name is:
N- (3- ([1,1 '-biphenyl] -4-yl) -1-oxo-1- ((2,2,6,6-tetramethylpiperidin-4-
yl)amino)propan-2-yl)-1-benzyl-1H-indole-2-carboxamide。
Compound PL-AC-16, its chemical constitution are:
Chinese is:N- (3- ([1,1 '-biphenyl] -4- bases) -1- oxos -1- ((2,2,6,6- tetramethyl piperidine -4-
Base) amino) propyl- 2- yls) -1- methyl isophthalic acid H- benzos [d] imidazoles -2- formamides.
English name is:
N- (3- ([1,1 '-biphenyl] -4-yl) -1-oxo-1- ((2,2,6,6-tetramethylpiperidin-4-
yl)amino)propan-2-yl)-1-methyl-1H-benzo[d]imidazole-2-carboxamide。
Compound PL-AC-17, its chemical constitution are:
Chinese is:N- (3- ([1,1 '-biphenyl] -4- bases) -1- oxos -1- ((2,2,6,6- tetramethyl piperidine -4-
Base) amino) propyl- 2- yls) -2- chlorobenzamides.
English name is:
N- (3- ([1,1 '-biphenyl] -4-yl) -1-oxo-1- ((2,2,6,6-tetramethylpiperidin-4-
yl)amino)propan-2-yl)-2-chlorobenzamide。
Compound PL-AC-18, its chemical constitution are:
Chinese is:N- (3- ([1,1 '-biphenyl] -4- bases) -1- oxos -1- ((2,2,6,6- tetramethyl piperidine -4-
Base) amino) propyl- 2- yls) -1- benzyl -1H- benzos [d] imidazoles -2- formamides.
English name is:
N- (3- ([1,1 '-biphenyl] -4-yl) -1-oxo-1- ((2,2,6,6-tetramethylpiperidin-4-
yl)amino)propan-2-yl)-1-benzyl-1H-benzo[d]imidazole-2-carboxamide。
Embodiment 1
The chemical synthesis process and structural characterization of embodiment compound
Synthesize universal method:
Successively by compound 1 (1.0g, 2.93mmol), compound 2 (458mg, 2.93mmol), BOP (1.42mg,
3.22mmol) being added to DIPEA (1.02ml, 5.86mmol) in dry acetonitrile (50ml), reaction solution is stirred at room temperature overnight,
Separate out a large amount of white solids.It is concentrated under reduced pressure with Rotary Evaporators, residual solid adds 50ml water and 50ml ethyl acetate, has separated
Machine layer.(50ml × 2) twice are extracted with ethyl acetate in water layer again, use saturation NaHCO after merging successively3Solution (30ml × 3), food
Salt solution (30ml × 3) washs, after anhydrous magnesium sulfate is dried, silica gel column chromatography separating purification, and methylene chloride/methanol (20: 1, v/v)
Elution, obtains product 3 (1.25g), white solid, yield 94%.
Compound 3 (749mg, 1.56mmol) is added in 25%TFA/DCM (50ml), at room temperature stirring reaction
30min, reaction finish.It is concentrated under reduced pressure, remaining syrup is dissolved with proper amount of methanol, and saturation is instilled under ice bath cooling and stirring
After HCl/EtOAc solution about 10ml, 10min, it is concentrated under reduced pressure, and constant weight is evacuated to oil pump, obtains near-white solid product 4
(658mg), yield 93%.
Successively by compound 4 (91mg, 0.2mmol), carboxylic acid (0.22mmol), HATU (114mg, 0.3mmol) and DIPEA
(0.13mL, 0.8mmol) is added in dry DMF or dichloromethane (3ml), and reaction solution is stirred at room temperature 24 hours.Add water
15ml, with dichloromethane extraction three times (20ml × 3), saturation NaHCO is used after merging organic layer3Washed with saline solution (10ml × 3)
Wash, after anhydrous sodium sulfate drying, silica gel column chromatography separating purification, methylene chloride/methanol elution, obtain target product.
Compound of Example structural characterization
PL-AC-1:N- (3- ([1,1 '-biphenyl] -4- bases) -1- oxos -1- ((2,2,6,6- tetramethyl piperidine -4- bases) ammonia
Base) propyl- 2- yls) -4- phenoxy benzonitrile acid amides,1H-NMR(CDCl3, 400MHz), δ:1.18-1.30 (s, 15H, CH3;CH2;NH),
1.64-1.84 (dd, 2H, J=65.2,16.0Hz, CH2), 3.10-3.33 (m, 2H, CH2), 4.15 (s, 1H, CH), 4.83-
4.85 (m, 1H, CH), 6.96-7.76 (m, 18H, ArH) .MS m/z (%):576.3(MH+, 100%).
PL-AC-2:N- (3- ([1,1 '-biphenyl] -4- bases) -1- oxos -1- ((2,2,6,6- tetramethyl piperidine -4- bases) ammonia
Base) propyl- 2- yls) -2- methoxy benzamides1H-NMR(CDCl3, 400MHz), δ:0.86-0.89 (s, 2H, CH2), 1.12-
1.26 (m, 13H, CH3;NH) 1.71-1.83 (dd, 2H, J=65.2,16.0Hz, CH2), 3.12-3.31 (m, 2H, CH2), 3.90
(s, 3H, CH3), 4.14-4.22 (m, 1H, CH), 4.90-4.95 (m, 1H, CH), 6.96-7.47 (m, 12H, ArH), 8.28-
8.30 (m, 1H, ArH), 8.62 (s, 1H, NH), 9.62 (s, 1H, NH) .MS m/z (%):514.3(MH+, 100%).
PL-AC-3:N- (3- ([1,1 '-biphenyl] -4- bases) -1- oxos -1- ((2,2,6,6- tetramethyl piperidine -4- bases) ammonia
Base) propyl- 2- yls) Pyrazinamide,1H-NMR(CDCl3, 400MHz), δ:1.20-1.50 (s, 15H, CH3;CH2;NH), 1.71-
1.83 (dm, 2H, J=65.2Hz, CH2), 3.06-3.09 (d, 2H, CH2), 3.99-4.06 (m, 1H, CH2), 4.64-4.72 (m,
1H, CH), 7.31-7.46 (m, 10H, ArH), 8.36-8.41 (d, 1H, NH), 8.70-8.72 (m, 2H, ArH), 9.10-9.20
(d, 1H, NH) .MS m/z (%):485.3(MH+, 100%).
PL-AC-4:N- (3- ([1,1 '-biphenyl] -4- bases) -1- oxos -1- ((2,2,6,6- tetramethyl piperidine -4- bases) ammonia
Base) propyl- 2- yls) -4- (dimethylamino) benzamide,1H-NMR(CDCl3, 400MHz), δ:1.37-1.53 (s, 15H, CH3;
CH2;NH), 1.68-1.83 (dd, 2H, J=65.2,16.0Hz, CH2) 2.96 (s, 6H, CH3) 3.06-3.09 (m, 2H, CH2),
4.04 (s, 1H, CH2) 4.59-4.67 (s, 1H, CH2), 6.67-6.70 (d, 2H), 7.30-7.64 (m, 11H, ArH), 8.10
(s, 1H, NH) 8.23-8.26 (d, 2H, ArH), 9.16 (s, 1H, NH) .MS m/z (%):527.3(MH+, 100%).
PL-AC-5:N- (3- ([1,1 '-biphenyl] -4- bases) -1- oxos -1- ((2,2,6,6- tetramethyl piperidine -4- bases) ammonia
Base) propyl- 2- yls) -2- cyanobenzamides,1H-NMR(CDCl3, 400MHz), δ:1.12-1.20 (m, 15H, CH3;CH2;NH),
1.80-1.92 (dd, 2H, J=65.2,16.0Hz, CH2), 3.55-3.75 (m, 2H, CH2), 4.27-4.31 (m, 1H, CH),
5.39-5.45 (m, 1H, CH), 7.21-7.78 (m, 12H, ArH), 8.10-8.13 (d, 2H, ArH), 8.36 (s, 1H, NH),
9.37 (s, 1H, NH) .MS m/z (%):509.3(MH+, 100%).
PL-AC-6:N- (3- ([1,1 '-biphenyl] -4- bases) -1- oxos -1- ((2,2,6,6- tetramethyl piperidine -4- bases) ammonia
Base) propyl- 2- yls) the chloro- 5- hydroxy-benzoyIamides of -2-,1H-NMR(CDCl3, 400MHz), δ:1.27-1.36 (m, 15H, CH3;
CH2;NH), 1.84-1.97 (dd, 2H, J=65.2,16.0Hz, CH2), 3.59-3.76 (m, 2H, CH2), 4.02-4.06 (m,
1H, CH), 4.59-4.67 (m, 1H, CH), 6.73-6.81 (m, 2H, ArH), 7.19-7.69 (m, 9H, ArH), 8.36 (s, 1H,
ArH), 9.37 (s, 1H, NH), 10.27 (s, 1H, NH) .MS m/z (%):534.3(MH+, 100%).
PL-AC-7:N- (3- ([1,1 '-biphenyl] -4- bases) -1- oxos -1- ((2,2,6,6- tetramethyl piperidine -4- bases)
Base) propyl- 2- yls) -1H- indoles -6- formamides,1H-NMR(CDCl3, 400MHz), δ:0.86-0.89 (s, 2H, CH2), 1.23-
1.45 (m, 13H, CH3;NH), 1.73-1.94 (dd, 2H, J=65.2,16.0Hz, CH2), 3.02-3.16 (m, 2H, CH2),
4.03-4.14 (m, 1H, CH), 5.65-4.73 (m, 1H, CH), 7.30-7.72 (m, 12H, ArH), 7.56 (s, 1H, NH),
8.19-8.22 (d, 1H, NH), 8.48-8.59 (m, 2H, ArH), 11.40 (s, 1H, NH) .MS m/z (%):523.3(MH+,
100%).
PL-AC-8:N- (3- ([1,1 '-biphenyl] -4- bases) -1- oxos -1- ((2,2,6,6- tetramethyl piperidine -4- bases) ammonia
Base) propyl- 2- yls) -2-Hydroxylbenzamide,1H-NMR(CDCl3, 400MHz), δ:0.87-0.89 (s, 2H, CH2), 1.16-
1.33 (m, 13H, CH3;NH), 1.62-1.84 (dd, 2H, J=65.2,16.0Hz, CH2), 3.10-3.37 (m, 2H, CH2),
4.13-4.22 (m, 1H, CH), 4.74-4.89 (m, 1H, CH), 5.31 (s, 1H, OH), 6.80-6.86 (m, 2H, ArH), 7.26-
7.57 (m, 13H, ArH) .MS m/z (%):500.3(MH+, 100%).
PL-AC-9:N- (3- ([1,1 '-biphenyl] -4- bases) -1- oxos -1- ((2,2,6,6- tetramethyl piperidine -4- bases) ammonia
Base) propyl- 2- yls) benzofuran-2-carboxamides,1H-NMR(CDCl3, 400MHz), δ:1.24-1.44 (m, 15H, CH3;CH2;
NH), 1.60-1.82 (dd, 2H, J=65.2,16.0Hz, CH2), 3.14-3.31 (m, 2H, CH2), 4.17-4.20 (m, 1H,
CH), 4.69-4.77 (m, 1H, CH), 7.26-7.49 (m, 14H, ArH), 8.12-8.15 (m, 1H, NH), 8.19-8.22 (d,
1H, NH) .MS m/z (%):524.3(MH+, 100%).
PL-AC-10:N- (3- ([1,1 '-biphenyl] -4- bases) -1- oxos -1- ((2,2,6,6- tetramethyl piperidine -4- bases)
Amino) propyl- 2- yls) quinoline-2-formamide,1H-NMR(CDCl3, 400MHz), δ:1.20-1.55 (m, 15H, CH3;CH2;NH),
1.70-1.93 (dd, 2H, J=65.2,16.0Hz, CH2), 3.21-3.37 (m, 2H, CH2), 4.28-4.33 (m, 1H, CH),
4.99-5.01 (m, 1H, CH), 7.29-7.51 (m, 13H, ArH), 8.14-8.17 (m, 2H, ArH), 8.33 (s, 1H, ArH),
8.12-8.15 (m, 1H, NH), 9.00 (s, 1H, NH) .MS m/z (%):535.3(MH+, 100%).
PL-AC-11:N- (3- ([1,1 '-biphenyl] -4- bases) -1- oxos -1- ((2,2,6,6- tetramethyl piperidine -4- bases)
Amino) propyl- 2- yls) -1,2- indole 2-carboxamides,1H-NMR(CDCl3, 400MHz), δ:1.06-1.29 (m, 15H, CH3;
CH2;NH), 1.62-1.76 (dd, 2H, J=65.2,16.0Hz, CH2), 3.06-3.08 (m, 2H, CH2), 4.07 (s, 1H, CH),
4.67-4.74 (m, 1H, CH), 7.00-7.61 (m, 14H, ArH), 8.09 (s, 1H, NH), 8.66-8.69 (m, 1H, NH),
11.54 (s, 1H, NH) .MS m/z (%):523.3(MH+, 100%).
PL-AC-12:N- (3- ([1,1 '-biphenyl] -4- bases) -1- oxos -1- ((2,2,6,6- tetramethyl piperidine -4- bases)
Amino) propyl- 2- yls) -1- methyl -2H- benzos [d] indazole -3- formamides,1H-NMR(CDCl3, 400MHz), δ:0.91-1.11
(m, 15H, CH3;CH2;NH), 1.49-1.64 (dd, 2H, J=65.2,16.0Hz, CH2), 3.06-3.10 (m, 2H, CH2),
3.98 (s, 1H, CH), 4.10 (s, 3H, CH3), 4.78-4.83 (m, 1H, CH), 7.24-7.48 (m, 12H, ArH), 7.58-
7.63 (m, 1H, NH), 7.89-8.03 (m, 2H, ArH), 7.92-7.97 (d, 1H, NH) .MS m/z (%):538.3(MH+,
100%).
PL-AC-13:N- (3- ([1,1 '-biphenyl] -4- bases) -1- oxos -1- ((2,2,6,6- tetramethyl piperidine -4- bases)
Amino) propyl- 2- yls) -1H- indoles -3- formamides,1H-NMR(CDCl3, 400MHz), δ:0.93-1.23 (m, 15H, CH3;CH2;
NH), 1.61-1.78 (dd, 2H, J=65.2,16.0Hz, CH2), 2.97-3.02 (m, 2H, CH2), 4.03 (s, 1H, CH),
4.68-4.75 (m, 1H, CH), 7.04-7.61 (m, 13H, ArH), 8.01-8.05 (m, 2H, ArH;NH), 8.16-8.17 (m,
1H, NH), 11.57 (s, 1H, NH) .MS m/z (%):523.3(MH+, 100%).
PL-AC-14:N- (3- ([1,1 '-biphenyl] -4- bases) -1- oxos -1- ((2,2,6,6- tetramethyl piperidine -4- bases)
Amino) propyl- 2- yls) -1H- benzos [d] imidazoles -2- formamides,1H-NMR(CDCl3, 400MHz), δ:1.27-1.37 (m, 15H,
CH3;CH2;NH), 1.65-1.83 (dd, 2H, J=65.2,16.0Hz, CH2), 3.71-3.78 (m, 2H, CH2), 4.45 (s, 1H,
CH), 4.50-4.52 (m, 1H, CH), 7.14-7.37 (m, 14H, ArH), 8.50 (s, 1H, NH), 8.67-8.69 (d, 1H, NH),
12.24 (s, 1H, NH) .MS m/z (%):538.3(MH+, 100%).
PL-AC-15:N- (3- ([1,1 '-biphenyl] -4- bases) -1- oxos -1- ((2,2,6,6- tetramethyl piperidine -4- bases)
Amino) propyl- 2- yls) -1- benzyl -1H- indole 2-carboxamides,1H-NMR(CDCl3, 400MHz), δ:1.23-1.39 (m, 15H,
CH3;CH2;NH), 1.72-1.86 (dd, 2H, J=65.2,16.0Hz, CH2), 2.91-2.96 (m, 2H, CH2), 4.10 (s, 1H,
CH), 4.63-4.68 (m, 1H, CH), 7.01-7.62 (m, 21H, ArH), 8.20-8.22 (d, 1H, NH), 8.77-8.79 (d,
1H, NH) .MS m/z (%):613.4(MH+, 100%).
PL-AC-16:N- (3- ([1,1 '-biphenyl] -4- bases) -1- oxos -1- ((2,2,6,6- tetramethyl piperidine -4- bases)
Amino) propyl- 2- yls) -1- methyl isophthalic acid H- benzos [d] imidazoles -2- formamides,1H-NMR(CDCl3, 400MHz), δ:1.40-1.43
(m, 15H, CH3;CH2;NH), 1.55-1.66 (dd, 2H, J=65.2,16.0Hz, CH2), 3.24-3.26 (m, 2H, CH2),
4.11 (s, 3H, CH3), 4.24 (s, 1H, CH), 4.82-4.85 (m, 1H, CH), 7.24-7.41 (m, 12H, ArH), 7.75-
7.77 (d, 2H, ArH), 8.22-8.24 (d, 1H, NH), 8.78 (s, 1H, NH) .MS m/z (%):538.3(MH+, 100%).
PL-AC-17:N- (3- ([1,1 '-biphenyl] -4- bases) -1- oxos -1- ((2,2,6,6- tetramethyl piperidine -4- bases)
Amino) propyl- 2- yls) -2- chlorobenzamides,1H-NMR(CDCl3, 400MHz), δ:1.17-1.33 (m, 15H, CH3;CH2;NH),
1.95-2.00 (dd, 2H, J=65.2,16.0Hz, CH2), 3.45-3.46 (m, 2H, CH2), 4.15 (s, 1H, CH), 4.52-
4.55 (m, 1H, CH), 7.22-7.75 (m, 13H, ArH), 8.05-8.06 (d, 1H, NH), 8.51 (s, 1H, NH) .MS m/z
(%):518.3(MH+, 100%).
PL-AC-18:N- (3- ([1,1 '-biphenyl] -4- bases) -1- oxos -1- ((2,2,6,6- tetramethyl piperidine -4- bases)
Amino) propyl- 2- yls) -1- benzyl -1H- benzos [d] imidazoles -2- formamides,1H-NMR(CDCl3, 400MHz), δ:1.27-1.41
(m, 2H, CH2), 1.63 (s, 13H, CH3;NH), 2.45-2.57 (m, 4H, CH2), 4.45-4.51 (m, 1H, CH), 5.98 (s,
2H, CH2), 4.52-4.55 (m, 1H, CH), 7.19-7.80 (m, 16H, ArH), 8.19-8.24 (m, 2H, ArH), 8.62-8.64
(d, 1H, NH), 10.02 (s, 1H, NH) .MS m/z (%):614.3(MH+, 100%).
Embodiment 2
Embodiment Compound ira vitro antitumor activity is tested
9 plants of human tumor cell line, culture and 10% inactivated fetal bovine serum are provided by Jilin University's school of life and health sciences,
In the RPMI-1640 culture mediums (Gibco companies) of 100U/ml penicillin and 100 μ g/ml streptomysins, in 37 DEG C, 5%CO2Culture
Case culture, passage in 2 days is once.Using mtt assay, exponential phase cell is digested with 0.25% pancreatin, 1000r/min centrifugations
5min, add 8 × 10 per hole3Individual cell, 96 orifice plates are inoculated in, add 180 μ l cell suspensions, while blank photo hole is set per hole.Will
96 orifice plates of inoculated tumour cell are put and add the μ l of medicine 20 in CO2gas incubator after culture 24h, the bodies such as blank control wells add
Long-pending nutrient solution, it is 10 concentration that medicine is divided from 64 μ g/mL-0.125 μ g/mL.Each drug concentration sets 3 multiple holes, places
Continue to cultivate 24h in incubator.10 μ l MTT solution (5mg/ml) are added per hole, continue to cultivate 4h.Supernatant is abandoned in suction, is added per hole
Enter 100 μ l dimethyl sulfoxide (DMSO)s (DMSO) solution, be placed on micro oscillator and vibrate 10min, surveyed in ELIASA with 492nm wavelength
Absorbance (A values), inhibiting rate of the medicine to tumour cell is obtained by following equation.
This experimental evidence compound inhibiting rate, the IC of compound on tumor cell is calculated using Origin softwares50Value.As a result
It is shown in Table 1.
The embodiment Compound ira vitro antitumor activity experimental result (nM) of table 1.
Embodiment 3
Embodiment compound hemolytic activity test experience is reported
People blood 2-3ml is extracted using anticoagulant tube, fully mixed, 4 DEG C standby.Inhale 2ml blood and add 2-3mlPBS, gently blow
Beat, centrifugation, 5min, 1000rpm, 3-4 times repeatedly, draw PBS after last 1 centrifugation, add PBS to 40ml (20 times of volumes),
Now blood cell count is 2 × 108cells/ml.Red cell suspension is added in flat board (U-shaped 96 orifice plate), 70 μ l/ holes are as cloudy
Property hole.Blank well only adds PBS, 140 μ l/ holes.Red cell suspension 2ml is centrifuged, discards PBS, adds 2ml pure water, is mixed,
140 μ l/ holes are as positive hole.The various concentrations polypeptide solution of dilution is added into flat board, 70 μ l/ holes.37 DEG C of incubations, 87rpm, shake
2h is swung, centrifuges 5min, 3000rpm.ELIASA surveys OD values:90 μ l supernatants are drawn after centrifugation and are transferred in flat 96 orifice plate, enzyme
Mark OD values at instrument measure 578nm.OD survey-OD the moon > 0.1 (qualified first peptide concentration is MHC).It the results are shown in Table 2
The embodiment compound hemolytic activity test experience result of table 2.
Embodiment 4
Embodiment compound single-dose is tested to ICR Mouse Acute Toxicities
Using ICR mouse, 18-22g, the raising of regular grade Animal House, feed with normal diet, freely absorb.Grope embodiment
After compound Dm and Dn determination group away from and dosage.Seven concentration of embodiment compound of dosage needed for preparation.Distinguish tail by body weight
It is injected intravenously the medicine of corresponding dosage, blank control group injecting normal saline.Observed immediately after administration and record the table of each animal
Existing and death condition, observes and records animal is likely to occur in 7 days after single-dose toxic reaction or death condition.It the results are shown in Table
3
The embodiment compound single-dose of table 3. is to ICR Mouse Acute Toxicity experimental results
PL-AC-1LD50For 18.6mg/kg;PL-AC-2LD50For 23.87mg/kg;PL-AC-3LD50For 19.61mg/kg;
PL-AC-4LD50For 19.73mg/kg, PL-AC-5LD50For 18.69mg/kg, PL-AC-6LD50For 20.51mg/kg, PL-AC-
7LD50For 17.92mg/kg, PL-AC-8LD50For 19.54mg/kg, PL-AC-8LD50For 18.73mg/kg, PL-AC-10LD50For
21.46mg/kg PL-AC-11LD50For 23.33mg/kg, PL-AC-12LD50For 20.06mg/kg, PL-AC-13LD50For
18.61mg/kg PL-AC-14LD50For 24.56mg/kg, PL-AC-15LD50For 23.64mg/kg, PL-AC-16LD50For
20.12mg/kg PL-AC-17LD50For 18.71mg/kg, PL-AC-18LD50For 21.69mg/kg.
Embodiment 5
Inhibitory action of the intravenously administrable to mice-transplanted tumor
Using ICR mouse, Heps hepatomas, EAC ascites tumors are inoculated with sterile working by transplanted tumor organon, cell
Density is no less than 2.5 × 107Ml, connect in every mouse right hind armpit subcutaneous vaccination 0.2ml, EAC knurl in every mouse peritoneal
Kind 0.2ml.(concentration is intravenously administrable after inoculation 24h:5mg/kg, 10mg/kg, 15mg/kg), it is administered 5 times altogether per 2d once,
It is discontinued after 2d, tumor-bearing mice is all put to death, weighed, knurl weight and increase in life span.It is shown in Table 4, table 5
Influence of the embodiment compound intravenously administrable of table 4. to Heps tumor-bearing mices body weight and knurl weight
* P < 0.05, * * P < 0.01 are compared with model group.
Effect of the embodiment compound intravenously administrable of table 5. to the EAC ascites tumor Bearing Mice Life Prolongation phases
* P < 0.05, * * P < 0.01 are compared with model group.
Embodiment 6
Inhibitory action of the embodiment compound gastric infusion to mice-transplanted tumor
Using ICR mouse, Heps hepatomas, EAC ascites tumors are inoculated with sterile working by transplanted tumor organon, cell
Density is no less than 2.5 × 107Ml, connect in every mouse right hind armpit subcutaneous vaccination 0.2ml, EAC knurl in every mouse peritoneal
Kind 0.2ml.(concentration is gastric infusion after inoculation 24h:5mg/kg, 10mg/kg, 15mg/kg), it is administered 5 times altogether per 2d once,
It is discontinued after 2d, tumor-bearing mice is all put to death, weighed, knurl weight and increase in life span.It is shown in Table 6,7
Influence of the embodiment compound gastric infusion of table 6. to Heps tumor-bearing mices body weight and knurl weight
* P < 0.05, * * P < 0.01 are compared with model group.
Effect of the embodiment compound gastric infusion of table 7. to the EAC ascites tumor Bearing Mice Life Prolongation phases
* P < 0.05, * * P < 0.01 are compared with model group.
Embodiment 7
Prescription and technique (5mg/ branch, the 5ml of water needle injection:5mg)
The prescription of the water needle injection of table 8.
60% water for injection of recipe quantity cumulative volume is weighed, the disodium ethylene diamine tetraacetate and lactic acid of recipe quantity is added, stirs
Mix uniformly, then add recipe quantity PL-AC-1 compounds, stirring makes it all dissolve.0.1% needle-use activated carbon is added to be heated to
50 DEG C, stirring and adsorbing 30 minutes, de- charcoal is filtered, is added with water for injection to cumulative volume.Aseptic filtration, intermediate fill after the assay was approved
Dress.The semi-finished product of filling completion are put into sterilizing cabinet.Sterilising temp is set as 105 DEG C, the time is to start to sterilize for 30 minutes.Go out
The qualified packaging of product lamp inspection after bacterium, is produced.
Embodiment 8
The prescription and technique (20mg/ branch) of freezing-dried powder injection
The prescription of the freezing-dried powder injection of table 9.
The water for injection of formula ratio 60% is measured, adds mannitol, lactose, citric acid and the disodium hydrogen phosphate of recipe quantity, is stirred
Dissolving, then add the PL-AC-2 compounds of recipe quantity, stirring and dissolving.0.05% pin is added to be stirred evenly with activated carbon, stirring and adsorbing
30 minutes, decarburization filtering.Volume is supplied with water for injection.Then aseptic filtration, visible foreign matters, qualified laggard filling work are checked
Sequence.After the completion of filling, lyophilized process (quick freezing) is carried out.After lyophilized end, start adding device under vacuum conditions, plug is pressed
Sternly, then outlet.The defrost after product all takes out.Roll lid.Pack, produce after visual inspection is qualified.
Embodiment 9
The prescription and technique (2mg/ pieces) of tablet
The prescription of the tablet of table 10.
Microcrystalline cellulose excipients 75g, lactose 100g, L-hydroxypropyl cellulose 10g, pregelatinized starch 20g, dioxy
SiClx 2g, talcum powder 2g are well mixed.Equal increments method is mixed to uniform with PL-AC-4 compounds.With 5% polyvinylpyrrolidine
The ethanol solution of ketone 50% is binder, is pelletized using fluidized-bed spray granulation technology, additional talcum powder 2g, is well mixed, tabletting, i.e.,
.
Embodiment 10
The prescription and technique (15mg/ pieces) of tablet
The prescription of the tablet of table 11.
Raw material and auxiliary material cross 100 mesh sieves respectively, by mannitol 55g, starch 50g, lactose 80g, low-substituted hydroxypropyl cellulose
10g, PVPP 8g, microcrystalline cellulose 100g, superfine silica gel powder 0.6g and talcum powder 3g are well mixed.Equal increments method with
PL-AC-6 compounds are mixed to uniform.Suitable softwood is prepared by binder of the ethanol solution of polyvinylpyrrolidone 50%.16-
24 mesh nylon screens are pelletized, and manufactured particle is in 40-65 DEG C of drying.Dry particl crosses 10 mesh nylon screen whole grains, additional talcum powder
3g, it is well mixed, tabletting, produces.
Embodiment 11
The prescription and technique (10mg/ grains) of capsule
The prescription of the capsule of table 12.
Supplementary material crosses 100 mesh sieves respectively.By pregelatinized starch 100g, dextrin 100g, mannitol 80g, talcum powder 7g and hard
Fatty acid magnesium 4g is well mixed, and equal increments method is mixed with PL-AC-9 to uniform.Using the solution of sodium carboxymethylcellulose 1% as bonding
Agent prepares suitable softwood.16-24 mesh nylon screen is pelletized, and manufactured particle is in 55-60 DEG C of drying.The eye mesh screen of dry particl 10 is whole
Grain, load capsule, produce.
Embodiment 12
The prescription and technique (2mg/ pieces) of enteric coatel tablets
The prescription of the enteric coatel tablets label of table 13.
The prescription of the enteric coating of table 14.
Raw material and auxiliary material cross 100 mesh sieves respectively in Core formulation, by mannitol 75g, lactose 100g, low-substituted hydroxypropyl fiber
Plain 10g, pregelatinized starch 60g, sodium carboxymethyl starch 5g, magnesium stearate 2g and talcum powder 2g are well mixed.Equal increments method with
PL-AC-11 compounds are mixed to uniform.Suitable softwood is prepared by binder of the ethanol solution of polyvinylpyrrolidone 50%.16-
24 mesh nylon screens are pelletized, and manufactured particle is in 40-65 DEG C of drying.Dry particl crosses 10 mesh nylon screen whole grains, additional stearic acid
Magnesium 2g and talcum powder 2g, it is well mixed, tabletting, produces label.
Auxiliary material in enteric coating prescription is weighed into the polyvinyl alcohol titanate esters of recipe quantity and cellulose acetate benzenetricarboxylic acid ester adds
In 85% ethanol, stirring, until completely dissolved, recipe quantity talcum powder is added, mixed standby.Above-mentioned obtained label is added to bag
In clothing pot, film coating, it is drying to obtain.
Embodiment 13
The prescription and technique (10mg/ branch) of oral liquid
The prescription of the oral liquid of table 15.
The water for injection for measuring recipe quantity 50% adds sucrose to make its dissolving, and the water for injection for separately measuring recipe quantity 20% will
PL-AC-13 compounds dissolve, and are well mixed with aqueous sucrose solution.The water for injection for measuring recipe quantity 10% is heated to 60 DEG C, adds
Entering ethyl hydroxy benzoate makes dissolving, stirs.With in the aqueous sucrose solution that mixes.It is well mixed.Using 0.2um miillpore filter mistakes
Bacterium is filtered out, it is filling after the assay was approved, obtain finished product.
Embodiment 14
The prescription and technique (100mg/ bags) of granule
The prescription of the granule of table 16.
Supplementary material crosses 100 mesh sieves respectively.By pregelatinized starch 135g, lactose 120g, dextrin 120g, mannitol 100g, cunning
Stone flour 10g and magnesium stearate 5g are well mixed, and equal increments method is mixed with PL-AC-15 to uniform.With polyvinylpyrrolidone
5% solution is that adhesive prepares suitable softwood.14 mesh nylon screens are pelletized, and manufactured particle is in 55-60 DEG C of drying.Dry particl 14
Eye mesh screen whole grain, fine powder is removed after 65 mesh sieves, divided dose, packaging, is produced.
The preferred embodiments of the present invention are the foregoing is only, are not intended to limit the invention, for the skill of this area
For art personnel, the present invention can have various modifications and variations.Within the spirit and principles of the invention, that is made any repaiies
Change, equivalent substitution, improvement etc., should be included in the scope of the protection.
Claims (13)
1. a kind of amino acid derivativges or its pharmaceutically acceptable salt, there is the structure shown in below formula (I):
Wherein, R is selected from C6-12Aryl, 5-12 unit's heteroaryls, C3-12Cycloalkyl or 3-12 members are miscellaneous alicyclic, and the hydrogen on R can be optional
By one or more R1Substitution;
Each R1Independently selected from H, halogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Cycloalkyl, C6-12Aryl, 3-12 members are miscellaneous
Alicyclic, 5-12 unit's heteroaryls ,-CN ,-C (=O) R2,-C (=O) OR2,-C (=O) NR3R4、-NO2、-NR3R4、-NR5C (=O)
R2、-NR5C (=O) OR6、-NR5C (=O) NR3R4、-NR5S (=O)2R6、-NR5S (=O)2R3R4、-OR2,-OCN ,-OC (=O)
R2,-OC (=O) NR3R4,-OC (=O) OR2,-OC (=O) NR3R4,-S (=O)mR2,-S (=O)2NR3R4, or on adjacent atom
R1Group can merge to form C3-12Cycloalkyl, C6-12The first miscellaneous alicyclic and 5-12 member hetero-aromatic rings of aryl, 3-12, and R1On
Hydrogen can be optionally by R7Substitution;
R2、R3、R4、R5And R6Separately selected from H, halogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Cycloalkyl, C6-12
Aryl, miscellaneous alicyclic, the 5-12 unit's heteroaryls of 3-12 members;Or it is bound to the R on identical nitrogen-atoms2、R3、R4、R5And R6In any two
Merge together with the individual nitrogen that can be combined with it, to form the first miscellaneous alicyclic or 5-12 unit's heteroaryls of 3-12, it optionally contains 1 to 3
The individual other hetero atom selected from N, O and S;Or it is bound to the R in identical carbon atoms2、R3、R4、R5And R6In any two can close
And and form C3-12Cycloalkyl, C6-12The first miscellaneous alicyclic or 5-12 unit's heteroaryls of aryl, 3-12;And R2、R3、R4、R5And R6In
Each hydrogen optionally by R8Substitution, or in R2、R3、R4、R5And R6Two hydrogen atoms in middle identical carbon atoms are optionally oxo substitution
Base;
Each R7Can be independently selected from halogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Cycloalkyl, C6-12Aryl, 3-12 members are miscellaneous
Alicyclic, 5-12 unit's heteroaryls ,-CN ,-C (=O) R10,-C (=O) OR10,-C (=O) NR11R12、-NO2、-NR11R12、-NR13C
(=O) R10、-NR13C (=O) OR14、-NR13C (=O) NR11R12、-NR13S (=O)2R14、-NR13S (=O)2NR11R12、-OR10、
=O ,-OC (=O) R10,-OC (=O) NR11R12,-S (=O)mR10And-S (=O)2NR11R12, and R7On hydrogen can optional quilt
R9Substitution;
R10、R11、R12、R13、R14H, C can be separately selected from1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Cycloalkyl, C6-12
Aryl, miscellaneous alicyclic, the 5-12 unit's heteroaryls of 3-12 members, and R10、R11、R12、R13、R14In each hydrogen optionally by halogen ,-OH ,-
CN, can be by-the C of partly or completely perhalogenation1-5Alkyl;
R8、R9Can be independently selected from halogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Cycloalkyl, C6-12Aryl, 3-12 members are miscellaneous
Alicyclic, 5-12 unit's heteroaryls ,-CN ,-C (=O) (CH2)nCH3,-C (=O) O (CH2)nCH3,-C (=O) N [(CH2)nCH3
]2,-C (=O) OH ,-C (=O) NH2,-C (=O) NH (CH2)nCH3、-NO2、-NH2、-NH(CH2)nCH3、-N[(CH2)nCH3]2、-
NHC (=O) (CH2)nCH3,-NHS (=O)2(CH2)nCH3、-OH、-OC(CH2) nCH3 ,=O ,-OC (=O) (CH2)nCH3、-S
(=O) (CH2)nCH3,-OS (=O) (CH2)nCH3And-S (=O)2N[(CH2)nCH3]2;
M is selected from 0,1 or 2;
N is selected from 0,1,2,3,4 or 5.
2. amino acid derivativges according to claim 1 or its pharmaceutically acceptable salt, it is characterised in that R is selected from logical
Group shown in formula (II) or logical formula (III), and the hydrogen on R can be optionally by one or more R1Substitution,
X1Selected from O, S, N-R1Or C-R1;
X2Selected from O, S, N-R1Or C-R1;
X3Selected from O, S, N-R1Or C-R1;
X4Selected from O, S, N-R1Or C-R1;
X5Selected from O, S, N-R1Or C-R1;
Y1Selected from O, S, N-R1Or C-R1;
Y2Selected from O, S, N-R1Or C-R1;
Y3Selected from O, S, N-R1Or C-R1;
Y4Selected from O, S, N-R1Or C-R1;
Each R1Independently selected from H, halogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Cycloalkyl, C6-12Aryl, 3-12 members are miscellaneous
Alicyclic, 5-12 unit's heteroaryls ,-CN ,-C (=O) R2,-C (=O) OR2,-C (=O) NR3R4、-NO2、-NR3R4、-NR5C (=O)
R2、-NR5C (=O) OR6、-NR5C (=O) NR3R4、-NR5S (=O)2R6、-NR5S (=O)2R3R4、-OR2,-OCN ,-OC (=O)
R2,-OC (=O) NR3R4,-OC (=O) OR2,-OC (=O) NR3R4,-S (=O)mR2,-S (=O)2NR3R4, or on adjacent atom
R1 groups can merge to form C3-12Cycloalkyl, C6-12The first miscellaneous alicyclic and 5-12 member hetero-aromatic rings of aryl, 3-12, and R1On
Hydrogen can be optionally by R7Substitution.
3. amino acid derivativges according to claim 2 or its pharmaceutically acceptable salt, it is characterised in that when R is logical
During formula (II), and the hydrogen on R can be optionally by one or more R1Substitution;
X1Selected from O, S, N-R1Or C-R1;
X2Selected from O, S, N-R1Or C-R1;
X3Selected from O, S, N-R1Or C-R1;
X4Selected from O, S, N-R1Or C-R1;
X5Selected from O, S, N-R1Or C-R1;
Each R1Independently selected from H, halogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Cycloalkyl, C6-12Aryl, 3-12 members are miscellaneous
Alicyclic, 5-12 unit's heteroaryls ,-CN ,-C (=O) R2,-C (=O) OR2,-C (=O) NR3R4、-NO2、-NR3R4、-NR5C (=O)
R2、-NR5C (=O) OR6、-NR5C (=O) NR3R4、-NR5S (=O)2R6、-NR5S (=O)2R3R4、-OR2,-OCN ,-OC (=O)
R2,-OC (=O) NR3R4,-OC (=O) OR2,-OC (=O) NR3R4,-S (=O)mR2,-S (=O)2NR3R4, or on adjacent atom
R1 groups can merge to form C3-12Cycloalkyl, C6-12The first miscellaneous alicyclic and 5-12 member hetero-aromatic rings of aryl, 3-12, and R1On
Hydrogen can be optionally by R7Substitution.
4. amino acid derivativges according to claim 3 or its pharmaceutically acceptable salt, it is characterised in that when R is logical
During formula (II), X1、X2、X3、X4With X5Respectively C-R1When,
Each R1Independently selected from H, halogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Cycloalkyl, C6-12Aryl, 3-12 members are miscellaneous
Alicyclic, 5-12 unit's heteroaryls ,-CN ,-C (=O) R2,-C (=O) OR2,-C (=O) NR3R4、-NO2、-NR3R4、-NR5C (=O)
R2、-NR5C (=O) OR6、-NR5C (=O) NR3R4、-NR5S (=O)2R6、-NR5S (=O)2R3R4、-OR2,-OCN ,-OC (=O)
R2,-OC (=O) NR3R4,-OC (=O) OR2,-OC (=O) NR3R4,-S (=O)mR2,-S (=O)2NR3R4, or on adjacent atom
R1 groups can merge to form C3-12Cycloalkyl, C6-12The first miscellaneous alicyclic and 5-12 member hetero-aromatic rings of aryl, 3-12, and R1On
Hydrogen can be optionally by R7Substitution.
5. amino acid derivativges according to claim 3 or its pharmaceutically acceptable salt, it is characterised in that when R is logical
During formula (II), X2、X3、X4、X5For C-R1, X1For N-R1When,
Each R1Independently selected from H, halogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Cycloalkyl, C6-12Aryl, 3-12 members are miscellaneous
Alicyclic, 5-12 unit's heteroaryls ,-CN ,-C (=O) R2,-C (=O) OR2,-C (=O) NR3R4、-NO2、-NR3R4、-NR5C (=O)
R2、-NR5C (=O) OR6、-NR5C (=O) NR3R4、-NR5S (=O)2R6、-NR5S (=O)2R3R4、-OR2,-OCN ,-OC (=O)
R2,-OC (=O) NR3R4,-OC (=O) OR2,-OC (=O) NR3R4,-S (=O)mR2,-S (=O)2NR3R4, or on adjacent atom
R1 groups can merge to form C3-12Cycloalkyl, C6-12The first miscellaneous alicyclic and 5-12 member hetero-aromatic rings of aryl, 3-12, and R1On
Hydrogen can be optionally by R7Substitution.
6. amino acid derivativges according to claim 3 or its pharmaceutically acceptable salt, it is characterised in that when R is logical
During formula (II), X1、X2、X4、X5For C-R1When, X3For N-R1When,
Each R1Independently selected from H, halogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Cycloalkyl, C6-12Aryl, 3-12 members are miscellaneous
Alicyclic, 5-12 unit's heteroaryls ,-CN ,-C (=O) R2,-C (=O) OR2,-C (=O) NR3R4、-NO2、-NR3R4、-NR5C (=O)
R2、-NR5C (=O) OR6、-NR5C (=O) NR3R4、-NR5S (=O)2R6、-NR5S (=O)2R3R4、-OR2,-OCN ,-OC (=O)
R2,-OC (=O) NR3R4,-OC (=O) OR2,-OC (=O) NR3R4,-S (=O)mR2,-S (=O)2NR3R4, or on adjacent atom
R1 groups can merge to form C3-12Cycloalkyl, C6-12The first miscellaneous alicyclic and 5-12 member hetero-aromatic rings of aryl, 3-12, and R1On
Hydrogen can be optionally by R7Substitution.
7. amino acid derivativges according to claim 2 or its pharmaceutically acceptable salt, it is characterised in that when R is logical
During formula (III), and the hydrogen on R can be optionally by one or more R1Substitution;
Y1Selected from O, S, N-R1Or C-R1;
Y2Selected from O, S, N-R1Or C-R1;
Y3Selected from O, S, N-R1Or C-R1;
Y4Selected from O, S, N-R1Or C-R1;
Each R1Independently selected from H, halogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Cycloalkyl, C6-12Aryl, 3-12 members are miscellaneous
Alicyclic, 5-12 unit's heteroaryls ,-CN ,-C (=O) R2,-C (=O) OR2,-C (=O) NR3R4、-NO2、-NR3R4、-NR5C (=O)
R2、-NR5C (=O) OR6、-NR5C (=O) NR3R4、-NR5S (=O)2R6、-NR5S (=O)2R3R4、-OR2,-OCN ,-OC (=O)
R2,-OC (=O) NR3R4,-OC (=O) OR2,-OC (=O) NR3R4,-S (=O)mR2,-S (=O)2NR3R4, or on adjacent atom
R1 groups can merge to form C3-12Cycloalkyl, C6-12The first miscellaneous alicyclic and 5-12 member hetero-aromatic rings of aryl, 3-12, and R1On
Hydrogen can be optionally by R7Substitution.
8. amino acid derivativges according to claim 7 or its pharmaceutically acceptable salt, it is characterised in that when R is logical
During formula (III), and the hydrogen on R can be optionally by one or more R1Substitution, Y1、Y3For C-R1, Y2、Y4It is independently selected from N-
R1、C-R1Or during O,
Each R1Independently selected from H, halogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Cycloalkyl, C6-12Aryl, 3-12 members are miscellaneous
Alicyclic, 5-12 unit's heteroaryls ,-CN ,-C (=O) R2,-C (=O) OR2,-C (=O) NR3R4、-NO2、-NR3R4、-NR5C (=O)
R2、-NR5C (=O) OR6、-NR5C (=O) NR3R4、-NR5S (=O)2R6、-NR5S (=O)2R3R4、-OR2,-OCN ,-OC (=O)
R2,-OC (-=O) NR3R4,-OC (=O) OR2,-OC (=O) NR3R4,-S (=O)mR2,-S (=O)2NR3R4, or on adjacent atom
R1 groups can merge to form C3-12Cycloalkyl, C6-12The first miscellaneous alicyclic and 5-12 member hetero-aromatic rings of aryl, 3-12, and R1On
Hydrogen can be optionally by R7Substitution.
9. amino acid derivativges according to claim 7 or its pharmaceutically acceptable salt, it is characterised in that when R is logical
During formula (III), Y2、Y3、Y4For C-R1, Y1For N-R1When,
Each R1Independently selected from H, halogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Cycloalkyl, C6-12Aryl, 3-12 members are miscellaneous
Alicyclic, 5-12 unit's heteroaryls ,-CN ,-C (=O) R2,-C (=O) OR2,-C (=O) NR3R4、-NO2、-NR3R4、-NR5C (=O)
R2、-NR5C (=O) OR6、-NR5C (=O) NR3R4、-NR5S (=O)2R6、-NR5S (=O)2R3R4、-OR2,-OCN ,-OC (=O)
R2,-OC (=O) NR3R4,-OC (=O) OR2,-OC (=O) NR3R4,-S (=O)mR2,-S (=O)2NR3R4, or on adjacent atom
R1 groups can merge to form C3-12Cycloalkyl, C6-12The first miscellaneous alicyclic and 5-12 member hetero-aromatic rings of aryl, 3-12, and R1On
Hydrogen can be optionally by R7Substitution.
10. amino acid derivativges according to claim 7 or its pharmaceutically acceptable salt, it is characterised in that when R is logical
During formula (III), and the hydrogen on R can be optionally by one or more R1Substitution, Y3、Y4For C-R1, Y1、Y2For N-R1When,
Each R1Independently selected from H, halogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-12Cycloalkyl, C6-12Aryl, 3-12 members are miscellaneous
Alicyclic, 5-12 unit's heteroaryls ,-CN ,-C (=O) R2,-C (=O) OR2,-C (=O) NR3R4、-NO2、-NR3R4、-NR5C (=
O)R2、-NR5C (=O) OR6、-NR5C (=O) NR3R4、-NR5S (=O)2R6、-NR5S (=O)2R3R4、-OR2,-OCN ,-OC (=
O)R2,-OC (=O) NR3R4,-OC (=O) OR2,-OC (=O) NR3R4,-S (=O)mR2,-S (=O)2NR3R4, or adjacent atom
On R1 groups can merge to form C3-12Cycloalkyl, C6-12The first miscellaneous alicyclic and 5-12 member hetero-aromatic rings of aryl, 3-12, and R1On
Hydrogen can be optionally by R7Substitution.
11. the amino acid derivativges or its pharmaceutically acceptable salt as any one of claim 1 to 10 swash as slow
Application of the peptide receptor antagonists in anti-tumor drug is prepared.
12. a kind of pharmaceutical composition, it is characterised in that including effective dose as any one of claim 1 to 10
Amino acid derivativges or its pharmaceutically acceptable salt.
13. pharmaceutical composition according to claim 12, it is characterised in that described pharmaceutical composition also includes pharmaceutically may be used
Carrier, excipient or the diluent of receiving, described pharmaceutical composition are injection or oral agents, as right will in the injection
The dosage range for asking the amino acid derivativges any one of 1 to 10 and its esters is:0.1-50mg/kg;The oral agents
In the dosage range of amino acid derivativges as any one of claim 1 to 10 and its esters be:0.1-50mg/kg.
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CN113620862A (en) * | 2020-05-09 | 2021-11-09 | 江苏普莱医药生物技术有限公司 | Amino acid derivative containing non-steroidal anti-inflammatory drug structure and preparation method and application thereof |
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