CN105198966B - GnRH analog-Cytotoxic molecules conjugate, preparation method and the usage - Google Patents

GnRH analog-Cytotoxic molecules conjugate, preparation method and the usage Download PDF

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Publication number
CN105198966B
CN105198966B CN201410293274.4A CN201410293274A CN105198966B CN 105198966 B CN105198966 B CN 105198966B CN 201410293274 A CN201410293274 A CN 201410293274A CN 105198966 B CN105198966 B CN 105198966B
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aph
cancer
leu
ser
pro
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CN105198966A (en
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刘克良
周宁
马永涛
王晨宏
冯思良
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Institute of Pharmacology and Toxicology of AMMS
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Institute of Pharmacology and Toxicology of AMMS
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Priority to CN201410293274.4A priority Critical patent/CN105198966B/en
Priority to PCT/CN2015/081781 priority patent/WO2015196944A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/23—Luteinising hormone-releasing hormone [LHRH]; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides

Abstract

The invention belongs to medicine, chemical field, are related to GnRH analog-Cytotoxic molecules conjugate, preparation method as shown in formula (I) and its are preparing the purposes in the drug for treating tumour.The invention further relates to the salt of GnRH analog-Cytotoxic molecules conjugate stereoisomer, solvate or its physiological-toxicity-free shown in formula (I), and the pharmaceutical composition comprising above compound.Cytotoxic molecules are coupled by the present invention by degradable linking arm and GnRH analog, obtained GnRH analog-taxol-conjugate is able to maintain and the combination of GnRH high receptor activity, there is preferable plasma stability and growth of tumour cell inhibitory activity simultaneously, there is good research significance and prospect.(X)Aaa1‑Aaa2‑Aaa3‑Ser‑Aaa5‑Aaa6(Y)‑Leu‑Aaa8‑Pro‑Aaa10‑NH2I。

Description

GnRH analog-Cytotoxic molecules conjugate, preparation method and the usage
Technical field
The invention belongs to medicine, chemical field, and in particular to GnRH analog-Cytotoxic molecules conjugate, its preparation side Method and its purposes in the drug of preparation prevention and/or treatment tumour.
Background technique
Gonadotropin-releasing hormone (GRH) (GnRH) is also known as luteinizing hormone releasing hormone (LHRH), is hypothalamus with impulse form Ten peptide hormones (Glp-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-the GlyNH of secretion2), it is to adjust reproductive system Key molecule.It is generated by the neuron of hypothalamus, hypophysis is reached by portal vein.At hypophysis position, GnRH has activated its receptor GPCR, a septuple transmembrane G-protein coupled receptor, and then promote the synthesis of LH (lutropin) and FSH (follicular stimulating hormone) And secretion.Nearest studies have shown that GnRH also has effect in other organs outside hypothalamus and hypophysis.In uterus, ovary is defeated In the tumour cell of oviduct, placenta, mammary gland, prostate, peripheral blood mononuclear cell, colon, rectum and kidney and lymthoma and GnRH receptor has been had been found that in melanoma.The receptor of GnRH is even had also discovered in digestive system.In addition, GnRH receptor is just Often tissue in be distributed it is limited, this make using GnRH receptor as the receptor of anti-tumor drug target administration and with GnRH analog work It is possibly realized for targeting group.
It is targeting group with GnRH analog, such as by a degradable linking arm: disulfide bond, ester bond, hydrazone bond, with Cytotoxic molecules are such as: adriamycin, daunorubicin, taxol, docetaxel, methotrexate (MTX), camptothecine are directly conjugated, with receptor The mode of mediation enters tumour cell, and then (acidic environment and specificity under the microenvironment of inside tumor cells specificity The high expression of enzyme), free Cytotoxic molecules are released, the final growth for inhibiting tumour.
Currently, the research about such compound obtains considerable progress, individual compound has entered clinical research rank Section, but the disadvantage not high there are still stability, be easy it is premature release Cytotoxic molecules, and then generate toxic side effect.
To solve the above-mentioned problems, it is still necessary to study new GnRH analog-Cytotoxic molecules conjugate, keeping higher Growth of tumour cell inhibitory activity, stronger receptor-binding activity while, improve the stability of conjugate.
Summary of the invention
The first aspect of the present invention be related to formula (I) compound represented, its stereoisomer, solvate or its without physiology The salt of toxicity,
(X)Aaa1-Aaa2-Aaa3-Ser-Aaa5-Aaa6(Y)-Leu-Aaa8-Pro-Aaa10-NH2
I
Wherein,
Aaa1For the Glp or Nal of L or D type；
Aaa2For the His or Cpa of L or D type；
Aaa3For the Trp or Pal of L or D type；
Aaa5For the Tyr or Aph (L-Hor) of L or D type；
Aaa6For the Lys or Aph of L or D type；
Aaa8For the Arg or ILys of L or D type；
Aaa10For the Gly or Ala of L or D type；
X is selected from H, Ac ,-a-b ,-Xaa1-Xaa2-a-b；
Y is selected from H, Cbm ,-a-b ,-Xaa1-Xaa2-a-b；
Wherein Xaa1、Xaa2It is each independently hydrophilic amino acid；
Wherein a is
, wherein m=1-6, for example, 1-3；
A passes through amido bond and peptide chain link (amino on the carboxyl and peptide chain of a forms amido bond).
B is small numerator modified taxol or Docetaxel, and decorating site is located at its 2 ' position hydroxyl.
In embodiments of the invention, C1 or C2 that the small molecule is as follows, wherein n=1-10 is (for example, 1,3,5,10), C1 or C2 connect the (carboxyl and taxol or Docetaxel of C1 with taxol or Docetaxel by ester bond 2 ' position hydroxyls at ester, 2 ' position hydroxyls of C2 and taxol or Docetaxel are by ester exchange reaction at ester).
In embodiments of the invention, the small numerator modified taxol or Docetaxel b are as shown below B1, b2, b3 or b4, wherein (for example, 1,3,5,10) n=1-10.
In embodiments of the invention, the small numerator modified taxol b is by disulfide bond (on such as b2, b4 and a Sulfydryl forms disulfide bond) or thioether bond (sulfydryl formed thioether bond) on the maleimide and a on such as b1, b3 on polypeptide chain The a of connection is coupled.
Compound, its stereoisomer, solvate or its physiological-toxicity-free of any one according to a first aspect of the present invention Salt, wherein the type of the water-soluble amino acids is well known in the art, for example, selected from Arg, Gln, Glu, Ser, Asp, Asn, Thr etc..
In embodiments of the invention ,-the Xaa1-Xaa2Such as the following peptide fragment selected from L or D type ,-Arg- Gln- ,-Gln-Arg- ,-Arg-Arg- ,-Gln-Gln- ,-Arg-Ser- ,-Arg-Asp-.
In the present invention ,-the Xaa1-Xaa2Connection type with a is amido bond.
In the present invention, the connection type of a and b is thioether bond or disulfide bond.
In the present invention ,-Xaa1-Xaa2By replacing Aaa1α amino on H or Aaa6Side-chain amino group on H and more Peptide chain is connected.
In the present invention, X is by replacing Aaa1α amino on H and Aaa1It is connected.
In the present invention, Y is by replacing Aaa6Side-chain amino group on H and Aaa6It is connected.
Compound, its stereoisomer, solvate or its physiological-toxicity-free of any one according to a first aspect of the present invention Salt, be selected from following compound:
1、(R1)Glp-His-Trp-Ser-Tyr-D-Lys(R2)-Leu-Arg-Pro-Gly-NH2；
2、(R1)Glp-His-Trp-Ser-Tyr-D-Lys(R3)-Leu-Arg-Pro-Gly-NH2；
3、(R1)Glp-His-Trp-Ser-Tyr-D-Lys(R4)-Leu-Arg-Pro-Gly-NH2；
4、(R1)Glp-His-Trp-Ser-Tyr-D-Lys(R5)-Leu-Arg-Pro-Gly-NH2；
5、(R1)Glp-His-Trp-Ser-Tyr-D-Lys(R6)-Leu-Arg-Pro-Gly-NH2；
6、(R1)Glp-His-Trp-Ser-Tyr-D-Lys(R7)-Leu-Arg-Pro-Gly-NH2；
7、(R1)Glp-His-Trp-Ser-Tyr-D-Lys(R8)-Leu-Arg-Pro-Gly-NH2；
8、(R1)Glp-His-Trp-Ser-Tyr-D-Lys(R9)-Leu-Arg-Pro-Gly-NH2；
9、(R10)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R2)-Leu-ILys-Pro-D-Ala- NH2；
10、(R10)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R3)-Leu-ILys-Pro-D- Ala-NH2；
11、(R10)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R4)-Leu-ILys-Pro-D- Ala-NH2；
12、(R10)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R5)-Leu-ILys-Pro-D- Ala-NH2；
13、(R10)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R6)-Leu-ILys-Pro-D- Ala-NH2；
14、(R10)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R7)-Leu-ILys-Pro-D- Ala-NH2；
15、(R10)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R8)-Leu-ILys-Pro-D- Ala-NH2；
16、(R10)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R9)-Leu-ILys-Pro-D- Ala-NH2；
17、(R2)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R11)-Leu-ILys-Pro-D- Ala-NH2；
18、(R3)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R11)-Leu-ILys-Pro-D- Ala-NH2；
19、(R4)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R11)-Leu-ILys-Pro-D- Ala-NH2；
20、(R5)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R11)-Leu-ILys-Pro-D- Ala-NH2；
21、(R6)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R11)-Leu-ILys-Pro-D- Ala-NH2；
22、(R7)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R11)-Leu-ILys-Pro-D- Ala-NH2；
23、(R8)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R11)-Leu-ILys-Pro-D- Ala-NH2；
24、(R9)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R11)-Leu-ILys-Pro-D- Ala-NH2；
25、(R5)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R5)-Leu-ILys-Pro-D-Ala- NH2；
26、(R6)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R6)-Leu-ILys-Pro-D-Ala- NH2；
27、(R7)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R7)-Leu-ILys-Pro-D-Ala- NH2；
28、(R8)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R8)-Leu-ILys-Pro-D-Ala- NH2；
29、(R9)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R9)-Leu-ILys-Pro-D-Ala- NH2；
30、(R1)Glp-His-Trp-Ser-Tyr-D-Lys(R12)-Leu-Arg-Pro-Gly-NH2；
31、(R1)Glp-His-Trp-Ser-Tyr-D-Lys(R13)-Leu-Arg-Pro-Gly-NH2；
32、(R1)Glp-His-Trp-Ser-Tyr-D-Lys(R14)-Leu-Arg-Pro-Gly-NH2；
33、(R1)Glp-His-Trp-Ser-Tyr-D-Lys(R15)-Leu-Arg-Pro-Gly-NH2；
34、(R1)Glp-His-Trp-Ser-Tyr-D-Lys(R16)-Leu-Arg-Pro-Gly-NH2；
35、(R1)Glp-His-Trp-Ser-Tyr-D-Lys(R17)-Leu-Arg-Pro-Gly-NH2；
36、(R1)Glp-His-Trp-Ser-Tyr-D-Lys(R18)-Leu-Arg-Pro-Gly-NH2；
37、(R1)Glp-His-Trp-Ser-Tyr-D-Lys(R19)-Leu-Arg-Pro-Gly-NH2；
38、(R10)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R12)-Leu-ILys-Pro-D- Ala-NH2；
39、(R10)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R13)-Leu-ILys-Pro-D- Ala-NH2；
40、(R10)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R14)-Leu-ILys-Pro-D- Ala-NH2；
41、(R10)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R15)-Leu-ILys-Pro-D- Ala-NH2；
42、(R10)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R16)-Leu-ILys-Pro-D- Ala-NH2；
43、(R10)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R17)-Leu-ILys-Pro-D- Ala-NH2；
44、(R10)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R18)-Leu-ILys-Pro-D- Ala-NH2；
45、(R10)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R19)-Leu-ILys-Pro-D- Ala-NH2；
46、(R12)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R11)-Leu-ILys-Pro-D- Ala-NH2；
47、(R13)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R11)-Leu-ILys-Pro-D- Ala-NH2；
48、(R14)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R11)-Leu-ILys-Pro-D- Ala-NH2；
49、(R15)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R11)-Leu-ILys-Pro-D- Ala-NH2；
50、(R16)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R11)-Leu-ILys-Pro-D- Ala-NH2；
51、(R17)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R11)-Leu-ILys-Pro-D- Ala-NH2；
52、(R18)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R11)-Leu-ILys-Pro-D- Ala-NH2；
53、(R19)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R11)-Leu-ILys-Pro-D- Ala-NH2；
54、(R15)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R15)-Leu-ILys-Pro-D- Ala-NH2；
55、(R16)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R16)-Leu-ILys-Pro-D- Ala-NH2；
56、(R17)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R17)-Leu-ILys-Pro-D- Ala-NH2；
57、(R18)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R18)-Leu-ILys-Pro-D- Ala-NH2；
58、(R19)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R19)-Leu-ILys-Pro-D- Ala-NH2；
Wherein R1-R19 corresponds to modification group and is shown in Table 1.
Table 1
In the present invention, the number of above-mentioned 1-58 is the compound number, can represent the compound.
In the present invention, as not specified, then amino acid is L-type amino acid.
Second aspect of the present invention is related to pharmaceutical composition, the chemical combination containing any one of at least one first aspect present invention Object, its stereoisomer, solvate or its physiological-toxicity-free salt and pharmaceutical acceptable carrier or excipient.
The compound, its stereoisomer, solvent that the third aspect of the present invention is related to any one of first aspect present invention close The preparation method of object or the salt of its physiological-toxicity-free comprising following steps:
The modification of (1) 6 amino acids: peptide sequence is synthesized from C-terminal to N-terminal according to synthesis in solid state Boc, Fmoc cross protection strategy To 6 amino acids, 20-50% piperidines/DMF solution removes the Fmoc protecting group on 6 amino acids side-chain amino groups, and it is single that modification is added Member (to the mercaptopropionic acid of methylbenzyl protection), DIC, HOBT are reacted ninhydrin after 4 hours and are detected, after fully reacting, continue according to The secondary condensation for completing amino acid, after the completion of peptide sequence, anhydrous HF peptide resin, the dissolution of 10-30% aqueous acetic acid, freezing is dry Thick peptide is obtained after dry, middle pressure chromatogram purification obtains sterling；
(2) N-terminal modification (including modifying N-terminal and 6 amino acids simultaneously): according to synthesis in solid state Boc, Fmoc cross protection plan Peptide sequence slightly is synthesized to 6 amino acids or N-terminal from C-terminal to N-terminal, and 20-50% piperidines/DMF solution removes 6 amino acids side chain ammonia Modification unit (to the mercaptopropionic acid of methylbenzyl protection), DIC, HOBT is added, after reacting 4 hours in Fmoc protecting group on base Ninhydrin detection, after fully reacting, continues the condensation for being sequentially completed amino acid, until all amino acid of peptide sequence and modification unit Condensation is completed, anhydrous HF peptide resin is finally used, the dissolution of 10-30% aqueous acetic acid obtains thick peptide, middle pressure color after freeze-drying Spectrum purifies to obtain sterling；
(3) peptide sequence is with the coupling of thioether bond and small numerator modified taxol: by after purification peptide sequence and small molecule Reaction is stirred at room temperature in 50% acetonitrile/water solution in the taxol of modification, and after fully reacting, middle suppress obtains for chromatogram purification Sterling；
(4) peptide sequence is with the coupling of disulfide bond and small numerator modified taxol: by after purification peptide sequence and small molecule Reaction is stirred at room temperature in DMSO in the taxol of modification, and after fully reacting, middle suppress obtains sterling for chromatogram purification.
The fourth aspect of the present invention be related to the compound of any one of first aspect present invention, its stereoisomer or its without life The salt for managing toxicity is preparing the purposes in the drug for preventing and/or treating tumour.
The invention further relates to the methods prevented and/or treat tumour, and the method includes preventing to subject in need And/or the salt of the compound of any one of first aspect present invention of therapeutically effective amount, its stereoisomer or its physiological-toxicity-free The step of.
In the present invention, the tumour includes but is not limited to rodent ulcer, cancer of bile ducts；Bladder cancer；Osteocarcinoma；Brain With CNS cancer；Breast cancer；Cervical carcinoma；Choriocarcinoma；Colon and the carcinoma of the rectum；Connective tissue cancer；The cancer of digestive system；Intrauterine The cancer of film；Cancer of the esophagus；Cancer eye；The cancer on head and neck；Gastric cancer；Neoplasm in epithelial cell；Kidney；Laryngocarcinoma；White blood Disease；Liver cancer；Lung cancer (such as cellule and non-small cell)；Lymthoma includes Huo Qijin's and non-Hodgkin's lymthoma；Melanocyte Tumor；Myeloma；Neuroblastoma；Carcinoma of mouth (for example, lip, tongue, oral cavity and pharynx)；Oophoroma；Cancer of pancreas；Prostate cancer；At Retinocytoma；Rhabdomyosarcoma；The carcinoma of the rectum；Kidney；The cancer of respiratory system；Sarcoma；Cutaneum carcinoma；Gastric cancer；Carcinoma of testis；First shape Gland cancer；Uterine cancer；The cancer of urinary system and other cancers and sarcoma.
Advantageous effect of the invention
The present inventor maintains good GnRH receptor and combines it has been investigated that compound shown in first aspect present invention Activity, and there is stronger growth of tumour cell inhibitory activity；And there is certain tumor cells selectivity, while stability It is greatly improved, advantageously reduces the toxic side effect that drug is generated due to premature release anticancer factor.In addition, The compound of the present invention maintains the GnRH receptor agonism and antagonistic activity of its ligand respectively, the tumour relied on for sex hormone (such as: prostate cancer, carcinoma of endometrium, breast cancer) may play the role of synergistic treatment.
Detailed description of the invention
The plasma stability of Fig. 1 conjugate 1 and 4
The plasma stability of Fig. 2 conjugate 9-11 and conjugate 17-19
The plasma stability of Fig. 3 conjugate 12,16,20,24 and 29
The receptor saturation experiments figure of Fig. 4 taxol (PTX)
The receptor saturation experiments figure of Fig. 5 conjugate 4
The receptor saturation experiments figure of Fig. 6 conjugate 9
The receptor saturation experiments figure of Fig. 7 conjugate 20
Specific embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will Understand, the following example is merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.It is not specified in embodiment specific Condition person carries out according to conventional conditions or manufacturer's recommended conditions.Reagents or instruments used without specified manufacturer is It can be with conventional products that are commercially available.
The abbreviation being used in the present invention has following meaning:
Ac-acetyl group
Ala- alanine
Arg- arginine
Aph-4- amino phenylalanine
Boc- tertbutyloxycarbonyl
Cbm- carbamoyl
Cpa-4- chlorophenylalanine
DIC- diisopropylcarbodiimide
DMF-N, dinethylformamide
Fmoc- fluorenylmethyloxycarbonyl
Gly- glycine
Gln- glutamine
Glp- pyroglutamic acid
HF- hydrofluoric acid
HOBt-1- hydroxybenzotriazole
L-Hor-L-4,5- dihydrooratic acid
Leu- leucine
Lys- lysine
ILys- isopropyl lysine
MBHA- phenyl aminomethyl resin
Nal- naphthylalanine
Pal-3- pyrazoleahtnine
Pro- proline
Ser- serine
Unless otherwise indicated, the term used in this application has following meanings:
In the present invention, all amino acid configurations are L-type in addition to being labeled as D- type；
Side-chain amino group refers to the amino on amino acid except α amino；
Ninhydrin refers to ninhydrin indicator:
(a) ninhydrin/ethyl alcohol (5g/100mL)；
(b) phenol/ethyl alcohol (4g/mL)；
(c) KCN/ pyridine solution (2mL × 0.01mol/L/100mL).
The invention further relates at least one formulas (I) and/or its alloisomerism containing the effective dose as active constituent The salt and customary pharmaceutical excipients of body or its physiological-toxicity-free or the pharmaceutical composition of adjuvant.Here " customary pharmaceutical excipients Or adjuvant " it include any or all solvents, decentralized medium is coated, antibacterial agent or antifungal agent, isotonic and sustained release dosage, with And similar physiology compatibility agent, be suitble to intravenous injection, intramuscular injection, subcutaneous injection or other administration modes, such as take orally to Medicine.According to the mode of administration, reactive compound can be coated to protect compound from the influence of acid or other natural conditions and Inactivation.
Term used herein " salt of physiological-toxicity-free " refer to can retain the expected physiological activity of parent compound without Generate the salt or their compositions of any unexpected toxic side effect.Such as: hydrochloride, hydrobromate, sulfate, phosphoric acid Salt, nitrate and acetate, oxalates, tartrate, succinate, malate, benzoate, embonate, sea Alginates, mesylate, naphthalene sulfonate etc..It and can according to the cation contained in salt are as follows: sylvite, lithium salts, zinc salt, mantoquita, barium Salt, bismuth salt, the inorganic salts such as calcium salt can be also the organic salts such as trialkyl ammonium salts.
Formula (I) of the present invention and its stereoisomer, solvate, physiological-toxicity-free salt or pharmaceutical composition containing it can By by it is known it is any in a manner of be administered, such as oral, muscle, subcutaneous, form of administration such as tablet, capsule, buccal tablet, chewing Piece, elixir, suspension, transdermal agent, micro-capsule embedding medium, implants, syrup etc..It can be ordinary preparation, sustained release preparation, controlled release Preparation and various particulate delivery systems.In order to which tablet is made in unit dosage forms for administration, can be widely used well known in the art each The biodegradable or physiologically acceptable carrier of kind.About the example of carrier, as salt is water base and various buffered aqueous solutions, ethyl alcohol or its Its polyalcohol, liposome, polylactic acid, vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoester etc..
Solid-phase synthesized carrier MBHA resin used in embodiment is that Tianjin Nankai synthesizes responsibility Co., Ltd product；DIC,HOBT And the natural amino acid that Boc- protection or Fmoc- are protected is the limited duty of the triumphant safe new technology in Shanghai gill biochemical corp and Chengdu Appoint Products, TFA, DIEA be ACROS Products, Boc- or Fmoc- protection unnatural amino acid except explanation in addition to by The synthesis of this laboratory provides.
Embodiment 1: the synthesis of peptide sequence
With 0.5g MBHA resin (0.54mmol) for solid phase carrier, DIC/HOBt is condensing agent, according to the amino of compound Acid sequence has been sequentially connected all amino acid and modification unit according to Boc, Fmoc cross protection strategy, above-mentioned peptide resin has been put In the reactor for entering HF cutting device, 1.0mL methyl phenyl ethers anisole is added, the system of HF cutting device is pumped by 0.5mL dithioglycol after installing Vacuum is transferred to about 10mL liquid HF, in 0 DEG C of reaction 1h with the cooling reactor of liquid nitrogen.HF is taken away with oil pump, removes reactor, is added Enter to freeze anhydrous ether and be settled out solid, then suspension is transferred in sand core funnel.It is washed with anhydrous ether cooling on a small quantity Three times, it then is rinsed with 10% acetic acid aqueous solution to resin and is no longer adhered to each other, collect cleaning solution, white wadding is obtained after freeze-drying Shape solid.
6 peptide sequences have been synthesized in this way, and specific structure is as follows:
Embodiment 2: GnRH analog-taxol-conjugate synthesis of thioether key connection
The peptide sequence and paclitaxel derivatives A for weighing equimolar amounts are stirred at room temperature anti-in 50% acetonitrile/water solution It answers, after fully reacting, middle suppress obtains sterling for chromatogram purification.
Conjugate has been synthesized in this way: 1,9,10,11,17,18,19.
Embodiment 3: GnRH analog-taxol-conjugate synthesis of disulfide bond connection
Reaction is stirred at room temperature in DMSO in the peptide sequence and paclitaxel derivatives B for weighing equimolar amounts, after fully reacting, Middle suppress obtains sterling for chromatogram purification.
Conjugate has been synthesized in this way: 4,12,16,20,24,29.
The mass spectral characteristi data of embodiment 2 and embodiment 3 are shown in Table 2.
Table 2GnRH analog-The Maldi-Tof-MS of taxol-conjugate is characterized
Embodiment 4: growth of tumour cell inhibitory activity and GnRH receptor-binding activity
Growth of tumour cell inhibitory activity measuring method: logarithmic growth phase cell (human breast cancer cell line Bcap-37 and Human colorectal cancer cells HT-29) it digests, be inoculated in 96 orifice plates, culture medium is diluted to cell suspension density about 3 × 104A/mL, Every hole 100uL inoculation, is incubated for for 24 hours in cell incubator.
Taxol and conjugate are weighed respectively, is dissolved with DMSO, are made 10-3The mother liquor of mol/L, adds culture medium to dilute step by step Culture medium at 2000nmol/L, 400nmol/L, 80nmol/L, 16nmol/L, 3.2nmol/L, 0.64nmol/L isoconcentration is molten Liquid.96 orifice plates being incubated in the incubator for 24 hours are taken out, culture medium is absorbed, the culture medium solution containing various concentration drug is added, Every 100 μ L of hole, each concentration point repeat 5 holes, are then placed in incubator and are incubated for 48h, and the culture medium for removing drug later is molten Liquid, PBS washing, then every hole are added 20% 100 μ L of MTS/PBS solution and pass through multi-function microplate reader after being incubated for 1h in incubator Absorbance of each hole of culture plate at 490nm is measured, the half-inhibitory concentration (IC of each concentration inhibiting rate and each compound is calculated50 Value).
According to the method described above, measurement result is shown in Table 3.
GnRH receptor-binding activity measuring method:
This experiment is by using intracellular calcium ion detection technique of fluorescence, to stablize 15 cell of CHO-K1/G α of expression GnRHr For study subject, in 37 DEG C/5%CO2It is cultivated in incubator, when cell confluency degree reaches 90%, carries out digestion process, will receive The cell suspension collected is inoculated into 384 microwell plates with the density of 20,000 cell per wells, is then placed in 37 DEG C/5%CO2Training It supports and continues to cultivate at least 18h in case, dyestuff is added, the configured compound solution of 10ul is then added to cell by every hole 20ul In plate, cell plates are then put into 37 DEG C/5%CO2Incubator is incubated for 1 hour, finally in equilibrium at room temperature 15min.Then lead to FLIPR detection is crossed, for each detection hole, arrives the maximum of 120s using the average fluorescent strength value of 1-20s as baseline, 21 It is relative intensity of fluorescence value that fluorescence intensity level, which subtracts baseline value,.
% excitement rate={ 1- (Δ RFUCompound-ΔRFUBackground)/(ΔRFUReference agonist–ΔRFUBackground)}×100
% inhibiting rate={ 1- (Δ RFUCompound-ΔRFUBackground)/(ΔRFUReferring to antagonist–ΔRFUBackground)}×100
Go out its EC by S curve the Fitting Calculation50Or IC50, measurement result is as shown in table 3.
Table 3
A:GnRH agonist activity, referring to Leuprorelin:EC50=0.8nmol/L；
B:GnRH antagonistic activity, referring to Degarelix:IC50=0.2nmol/L；
C: control group taxol: IC50=9.53 ± 0.63nmol/L；
D: control group taxol: IC50=10.3 ± 2.2nmol/L.
Growth of tumour cell inhibitory activity the result shows that, conjugate two kinds of cells (human breast cancer cell (MCF-7) and Human colorectal cancer cells (HT-29)) in show good growth of tumour cell inhibitory activity, individual compound even with Taxol activity is quite.
The receptor-binding activity of conjugate the results show that conjugate maintain with the higher combination activity of GnRH receptor, Illustrate that conjugate has through the receptor-mediated potentiality into tumour cell of GnRH.
Embodiment 5: conjugate plasma stability
Plasma stability measuring method: by 10 μ L of sample to be tested DMSO solution (12.5mg/mL), human plasma 2mL, whirlpool is added Rotation uniformly, is incubated in 37 DEG C of constant temperature oscillators, and different time points sample 200 μ L, and three times volumes of acetonitrile terminates reaction；High speed centrifugation (12000r/min) 10min takes supernatant to carry out HPLC analysis, by its prototype reserved of calculated by peak area.
According to the method described above, measurement result is shown in Fig. 1-3.
Plasma stability measurement result is shown: conjugate shows higher stability in blood plasma, largely sews It closes prototype after object is incubated for for 24 hours in blood plasma and is retained in 50% or more, individual conjugates such as 9,10 prototype percent retentions are up to 90% or more, plasma stability obtains great improvement.In addition, choose peptide sequence N-terminal modified conjugate (9,10, 11) compared with choosing 6 conjugates (17,18,19) modified, plasma stability does not have significant difference；With thioether bond It as linking arm, is connected compared to disulfide bond, the stability of conjugate significantly improves.
Embodiment 6: the cell selective of conjugate
Investigate the cell selective of conjugate indirectly by cell receptor saturation experiments, experimental method: with GnRH receptor sun Property MCF-7 cell be study subject, and two groups are divided into, wherein the culture of the Degarelix of one group of addition various concentration Based sols pretreatment, another group of addition blank cultures, in 37 DEG C of 5%CO2After being incubated for 1 hour in constant incubator, training is absorbed Base is supported, the drug solution of taxol or conjugate is then added, investigates it in the difference of the growth inhibitory activity of two groups of cells.
Cell receptor saturation experiments are as the result is shown (such as Fig. 4-Fig. 7): the Degarelix presaturation processing through various concentration , GnRH receptor is by different degrees of shielding, taxol (PTX) MCF-7 cell pre-saturated to GnRH receptor and without pre- The growth inhibitory activity of the MCF-7 cell of saturated process does not show difference；And for conjugate, GnRH receptor is pre-saturated The survival rate of MCF-7 cell increases.Show conjugate by the receptor-mediated approach into cell of GnRH, establishes conjugate Cell selective basis.
Although a specific embodiment of the invention has obtained detailed description, it will be understood to those of skill in the art that.Root According to all introductions having disclosed, those details can be carry out various modifications and be replaced, these change in guarantor of the invention Within the scope of shield.Full scope of the invention is given by the appended claims and any equivalents thereof.

Claims (8)

1. following compounds, its stereoisomer, solvate or its physiological-toxicity-free salt, be selected from following compound:
1、(R1)Glp-His-Trp-Ser-Tyr-D-Lys(R2)-Leu-Arg-Pro-Gly-NH2；
4、(R1)Glp-His-Trp-Ser-Tyr-D-Lys(R5)-Leu-Arg-Pro-Gly-NH2；
9、(R10)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R2)-Leu-ILys-Pro-D-Ala-NH2；
10、(R10)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R3)-Leu-ILys-Pro-D-Ala-NH2；
11、(R10)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R4)-Leu-ILys-Pro-D-Ala-NH2；
12、(R10)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R5)-Leu-ILys-Pro-D-Ala-NH2；
16、(R10)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R9)-Leu-ILys-Pro-D-Ala-NH2；
17、(R2)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R11)-Leu-ILys-Pro-D-Ala-NH2；
18、(R3)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R11)-Leu-ILys-Pro-D-Ala-NH2；
19、(R4)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R11)-Leu-ILys-Pro-D-Ala-NH2；
20、(R5)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R11)-Leu-ILys-Pro-D-Ala-NH2；
24、(R9)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R11)-Leu-ILys-Pro-D-Ala-NH2；
29、(R9)D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(R9)-Leu-ILys-Pro-D-Ala-NH2；
Wherein it is as follows to correspond to modification group by R1-R5 and R9-R11:
A, b1 and b2 respectively represents following group:
2. pharmaceutical composition, the compound containing claim 1, its stereoisomer, solvate or its physiological-toxicity-free Salt and pharmaceutical acceptable carrier or excipient.
3. the compound of claim 1, its stereoisomer, solvate or its physiological-toxicity-free salt preparation method, The following steps are included:
The modification of (1) 6 amino acids: peptide sequence is synthesized to 6 from C-terminal to N-terminal according to synthesis in solid state Boc, Fmoc cross protection strategy Amino acids, 20-50% piperidines/DMF solution remove the Fmoc protecting group on 6 amino acids side-chain amino groups, and modification unit is added Mercaptopropionic acid, DIC, HOBT to methylbenzyl protection, ninhydrin detects after reacting 4 hours, after fully reacting, continues successively complete At the condensation of amino acid, after the completion of peptide sequence, anhydrous HF peptide resin, 10-30% aqueous acetic acid dissolution, after freeze-drying Thick peptide is obtained, middle pressure chromatogram purification obtains sterling；(2) peptide sequence is with the coupling of thioether bond and small numerator modified taxol: will purify Reaction is stirred at room temperature in 50% acetonitrile/water solution in peptide sequence and small numerator modified taxol afterwards, after fully reacting, Middle suppress obtains sterling for chromatogram purification；Alternatively,
Peptide sequence is with the coupling of disulfide bond and small numerator modified taxol: by peptide sequence and small numerator modified purple after purification Reaction is stirred at room temperature in DMSO in China fir alcohol, and after fully reacting, middle suppress obtains sterling for chromatogram purification.
4. the compound of claim 1, its stereoisomer, solvate or its physiological-toxicity-free salt preparation method, The following steps are included:
(1) N-terminal and 6 amino acids are modified simultaneously: is synthesized according to synthesis in solid state Boc, Fmoc cross protection strategy from C-terminal to N-terminal Peptide sequence to 6 amino acids, 20-50% piperidines/DMF solution removes the Fmoc protecting group on 6 amino acids side-chain amino groups, is added Mercaptopropionic acid, DIC, HOBT that modification unit protects methylbenzyl, ninhydrin detects after reacting 4 hours, after fully reacting, after The continuous condensation for being sequentially completed amino acid is finally split with anhydrous HF until all amino acid of peptide sequence and modification unit complete condensation Peptide resin is solved, the dissolution of 10-30% aqueous acetic acid obtains thick peptide after freeze-drying, middle pressure chromatogram purification obtains sterling；
(2) peptide sequence is with the coupling of thioether bond and small numerator modified taxol: by after purification peptide sequence with it is small numerator modified Taxol in 50% acetonitrile/water solution, reaction is stirred at room temperature, it is middle to suppress standby chromatogram purification and obtain sterling after fully reacting； Alternatively,
Peptide sequence is with the coupling of disulfide bond and small numerator modified taxol: by peptide sequence and small numerator modified purple after purification Reaction is stirred at room temperature in DMSO in China fir alcohol, and after fully reacting, middle suppress obtains sterling for chromatogram purification.
5. the compound of claim 1, its stereoisomer, solvate or its physiological-toxicity-free salt in preparation for preventing And/or the purposes in the drug for the treatment of tumour；Wherein the tumour is selected from rodent ulcer, cancer of bile ducts；Bladder cancer；Bone Cancer；Brain and CNS cancer；Breast cancer；Cervical carcinoma；Choriocarcinoma；Colon and the carcinoma of the rectum；Connective tissue cancer；The cancer of digestive system；Son The cancer of Endometrium；Cancer of the esophagus；Cancer eye；The cancer on head and neck；Gastric cancer；Neoplasm in epithelial cell；Kidney；Laryngocarcinoma； Leukaemia；Liver cancer；Lung cancer；Lymthoma；Melanoma；Myeloma；Neuroblastoma；Carcinoma of mouth；Oophoroma；Cancer of pancreas；Forefront Gland cancer；Retinoblastoma；Rhabdomyosarcoma；The cancer of respiratory system；Sarcoma；Cutaneum carcinoma；Carcinoma of testis；Thyroid cancer；Uterus Cancer；The cancer of urinary system.
6. the purposes of claim 5, wherein the lung cancer is selected from small cell carcinoma and non-small cell carcinoma.
7. the purposes of claim 5, wherein the lymthoma is selected from Hodgkin lymphoma and non-Hodgkin lymphoma.
8. the purposes of claim 5, wherein the carcinoma of mouth is selected from lip, tongue, oral cavity and the cancer of pharynx.
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