WO2019007383A1 - 一种肽类化合物、其应用及含其的组合物 - Google Patents
一种肽类化合物、其应用及含其的组合物 Download PDFInfo
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- WO2019007383A1 WO2019007383A1 PCT/CN2018/094618 CN2018094618W WO2019007383A1 WO 2019007383 A1 WO2019007383 A1 WO 2019007383A1 CN 2018094618 W CN2018094618 W CN 2018094618W WO 2019007383 A1 WO2019007383 A1 WO 2019007383A1
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- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- LRBQNJMCXXYXIU-NRMVVENXSA-N tannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-NRMVVENXSA-N 0.000 description 1
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- HBEJJYHFTZDAHZ-QMMMGPOBSA-N tert-butyl (2s)-2-amino-4-methylpentanoate Chemical compound CC(C)C[C@H](N)C(=O)OC(C)(C)C HBEJJYHFTZDAHZ-QMMMGPOBSA-N 0.000 description 1
- RFUWRXIYTQGFGA-QRPNPIFTSA-N tert-butyl (2s)-2-amino-4-methylpentanoate;hydron;chloride Chemical compound Cl.CC(C)C[C@H](N)C(=O)OC(C)(C)C RFUWRXIYTQGFGA-QRPNPIFTSA-N 0.000 description 1
- UOUFRTFWWBCVPV-UHFFFAOYSA-N tert-butyl 4-(2,4-dioxo-1H-thieno[3,2-d]pyrimidin-3-yl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(CC1)n1c(=O)[nH]c2ccsc2c1=O UOUFRTFWWBCVPV-UHFFFAOYSA-N 0.000 description 1
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- XKXIQBVKMABYQJ-UHFFFAOYSA-M tert-butyl carbonate Chemical compound CC(C)(C)OC([O-])=O XKXIQBVKMABYQJ-UHFFFAOYSA-M 0.000 description 1
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- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
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- 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
- A61K47/51—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 the non-active ingredient being a modifying agent
- A61K47/56—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 the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—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 the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—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 the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
-
- 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
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- 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
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention relates to a peptide compound, its use and compositions containing the same.
- the Kiss-1 gene is a novel gene that inhibits human melanoma metastasis by Jeong-Hyung Lee et al. (Lee JH, et. al. Journal of the National Cancer Institute, Vol. 88(23): 1731-1737 ( 1996)).
- the Kiss-1 gene is located on human chromosome 1q32 and consists of four exons - two non-translated and two partially translated exons, which encode a precursor polypeptide of 145 amino acids.
- the precursor peptide is cleaved into a 54 amino acid length of Kisspeptin-54 (aka metastin or metastastatin) and can be further truncated to 14 [Kisspeptin-14/metastin (40-54)], 13 [Kisspeptin- 13/metastin (41-54)] or 10 [Kisspeptin-10/metastin (45-54)] amino acids; these truncations and precursors are collectively referred to as Kisspeptin (Kp) and in mammals Highly conservative (Kotani M, et. Al. Journal of Biological Chemistry, Vol. 276 (27): 34631-34636; Ohtaki T.
- the four kiss peptides all contain the same 10 amino acid residues, and the C-terminus has arginine and amidated phenylalanine (RF-amide), but the N-terminal polypeptide has different lengths.
- the C-terminal portion of the kiss peptide is involved in efficient binding of the receptor and activation of the receptor, and truncated peptides such as Kisspeptin-10 and Kisspeptin-14 are 3-10 times more active than Kisspeptin-54.
- Kiss-1 mRNA is mainly expressed in the human placenta and is also widely expressed throughout the central nervous system: the shell expression is highest, and the expression in the caudate nucleus, globus pallidus, hypothalamus, nucleus accumbens and cerebellum is higher, in the forehead, Amygdala, cingulate gyrus, hippocampus, side hippocampus, thalamus, substantia nigra, blue plaque, medulla oblongata expression, very little expression in the spinal cord.
- Kiss1R The receptor for these kiss peptides (Kiss1R) is currently known to be a member of the orphan G-protein coupled receptor retinoic acid family (referred to as GPR54 in rats and AXOR12 in humans). Kiss1R contains 398 amino acid residues and is associated with the galanin receptor family, but it does not bind to galanin. Rat GPR54 is highly conserved in mammals, 81% homologous to human receptors, and 85% homologous to mice.
- Human Kiss1R mRNA is abundantly expressed in placenta, pituitary, spinal cord and pancreas, and includes other brains (thalamic, caudate nucleus, substantia nigra, hippocampus, amygdala, cerebellum), stomach, small intestine, thymus, spleen, lung in other tissues. The testis, kidney and fetal liver have low levels of expression. Kisspeptin and its receptors are distributed in various tissues and organs in the brain and periphery, including the hypothalamus, aorta, ovary, prostate and placenta, and receptors are also expressed in the pituitary. Their role is to regulate reproductive function, affect endocrine, affect the growth and metastasis of tumor cells.
- the kiss peptide and Kiss1R (GPR54) signal transduction activates intracellular phospholipase C (PLC) after binding of the peptide to its receptor, which in turn hydrolyzes phosphatidylinositol diphosphate (PIP2) to produce inositol triphosphate (IP3).
- PLC phospholipase C
- PIP2 phosphatidylinositol diphosphate
- IP3 inositol triphosphate
- DAG diglyceride
- PLC protein kinase C
- ERK1 and ERK2 extracellular signal-regulated kinase
- MAPK mitogen-activated protein kinase
- GnRH gonadotropin-releasing hormone
- LH luteinizing hormone
- FSH follicle stimulating hormone
- GnRH analog kiss peptides act at the level of the hypothalamus to stimulate GnRH release (US7754220). The input of the kiss peptide can stimulate GnRH release at all stages.
- the Kiss1R agonist is a method for preventing or treating hormone-related diseases such as prostate cancer, breast cancer, endometriosis, uterine fibroids, premenopausal breast cancer, central precocious puberty, and sexual functional diseases.
- hormone-related diseases such as prostate cancer, breast cancer, endometriosis, uterine fibroids, premenopausal breast cancer, central precocious puberty, and sexual functional diseases.
- In vitro fertilization is used to induce ovulation, and as a new generation of contraceptives.
- Kiss peptide binding to Kiss1R has multiple functions, and inhibition of cell proliferation is an important one (Kotani M, et al., J. Biol. Chem. Vol 276:34631-34636).
- Kiss1R agonists can inhibit cell proliferative diseases selected from the group consisting of benign prostatic hyperplasia, prostate cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer, endometrial cancer, melanoma, pancreatic cancer, gastric cancer, and renal cells. Cancer, esophageal cancer, bladder cancer, brain cancer, etc.
- the Kiss1 gene was originally identified as the Kiss1 metastasis suppressor gene, which can manage tumor cell metastasis and has clinical value.
- the primary melanocyte cell line expressing the Kiss1 gene has a negative correlation with the metastatic potential of the melanoma cell line.
- C8161 cells express the Kiss1 gene and lung metastasis is inhibited by more than 95% (Nash et al., "The KISS1 metastasis suppressor: mechanistic insights and clinical utility", Front. Biosci. vol. 11, pp. 647-659 (2006).) .
- Kiss peptides can inhibit tumor cell migration by inducing an excess cell adhesion phenotype, reducing cell mobility (Lee JH and Welch DR, Int. J. Cancer. Vol.
- the metastatin derivative also has excellent biological activity (for example, cancer cell metastasis inhibitory activity, cancer cell growth inhibitory activity, etc.) (US6800611B2, US 7625869B2, US 8361968B2, US 8592379B2).
- Kiss1R agonists inhibit tumor metastasis and migration, affecting trophoblastic infiltration, wherein the disease or disease state is selected from the group consisting of: melanoma, pancreatic cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer, endometrial cancer, thyroid cancer, Cancers such as bladder cancer, esophageal squamous cell carcinoma, stomach cancer, and liver cancer.
- Kiss1R is also highly expressed in the central nervous system (CNS), a region of the hippocampus of the brain, which has been shown to reversibly enhance synaptic transmission in hippocampal dentate granule cells by a mechanism involving MAP kinase, where the mechanism appears to be Regulation of calcium-activated kinases and tyrosine kinases [Roa, J., Hypothalamic expression of KiSS-1 system and gonadotropin-releasing effects of kisspeptin in different reproductive states of the female Rat. et. al. Endocrinology 147(6): 1624 -1632, 2006].
- Kiss1R agonists enhance the emotional signals of the brain and emotions and treat sexual dysfunction caused by psychological causes.
- the kiss peptide has the function of affecting the function of the placenta.
- the treatment of the disease or disease state by Kiss1R agonist is selected from: choriocarcinoma, invasive hernia, abortion, fetal hypoplasia, abnormal glucose metabolism, abnormal lipid metabolism, etc. (WO00/ 24890; WO01/75104 2; WO 02/85399).
- the technical problem to be solved by the present invention is that the existing peptide compound has low stability and low activity against Kiss1R, and the like, therefore, the present invention provides a peptide compound, an application thereof and a composition containing the same, the compound The stability is better and the activity against Kiss1R is better.
- the present invention provides a peptide compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a tautomer thereof, a solvate thereof, a crystal form thereof or a prodrug thereof:
- Cap is
- R a is CH 3 -, q is 0 to 18 (for example, a range in which the following two values are endpoints: 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18; another, for example, 0 to 14; for example, 4 to 14); or, R a is HOOC-, and q is 1 to 18 (for example, with any two of the following values) Range of endpoints: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18; again, for example, 1 to 16);
- n is 0 to 2 (for example, 0, 1, or 2);
- PEG is independently X is independently -NHR b or -OH, and R b is independently hydrogen or a C 1-3 alkyl group (e.g., methyl, ethyl, isopropyl or n-propyl); k is independently 2 to 24 ( For example, a range in which any two of the following values are endpoints: 2, 3, 4, 5, 6, 8, 12, 16, 20, or 24; again, for example, 2-8, and also, for example, 4-8); XX0 is independently
- the X may be -NH 2 ; the k may independently be 2-8 (for example, 4-8); Can independently be OEG, PEG4, PEG5, PEG8,
- the X when m is 2, in the PEG linked to AA0 or AA1, the X may be -NH 2 ; when m is 2, in the PEG linked to AA0 or AA1, the k may be 2 to 4 ⁇ For example, 2, 3 or 4 ⁇ ; when m is 2, in the PEG connected to AA0 or AA1, the XX0 may be When m is 2, in the PEG linked to AA0 or AA1, the Can be OEG or PEG4;
- n is 0 to 3 (for example, 0, 1, 2 or 3);
- All AA0 are independently Gly, Beta-Ala, Ahx or Ac-Lys; (for example, when n is 2 or 3, at least 2 AA0 are Gly; for example, Can be a chemical bond, "Gly-Gly” or "Ac-Lys-Gly-Gly” ⁇ the left side is connected to XX0 ⁇ )
- PEG' is R c is a C 14 -C 18 linear alkyl group (for example, a C 16 linear alkyl group), and X' is "a hetero atom is one or more of N, O and S, and the number of hetero atoms is 1-3.
- Five- or six-membered heteroaryl (for example, "a heteroatom is N, a five- or six-membered heteroaryl group having one to three heteroatoms", for example ⁇ its left end is connected to R c ⁇ ) or (the left end is connected to R c ), k' is 5 to 9 (again, for example, 5 to 7);
- n' is 0 to 3 (for example, 0, 1, 2 or 3, for example 2);
- All AA0' are independently Gly, Beta-Ala, Ahx or Ac-Lys; (for example, when n' is 2 or 3, at least 2 AA0' are Gly; for example, Can be a chemical bond, "Gly-Gly” or "Ac-Lys-Gly-Gly” ⁇ left side connected to PEG' ⁇
- AA1 is an amino unsubstituted or amino group (which may be an amino group on a chiral carbon atom or a primary amino group when a plurality of amino groups are present in an amino acid) is substituted by one C 1-3 alkyl group (for example, methyl group, ethyl group, The following amino acids substituted with n-propyl or isopropyl) (the "substituted amino acids" such as N-Me-Ala, N-Me-D-Ala, N-Me-Leu, N-Me-D-Leu , N-Me-Phe or N-Me-D-Phe): D-Ala, Leu, D-Leu, Tyr, D-Tyr, Thi, (S)-Pip, Ala, ⁇ MeTyr, 1Nal, 2Nal, 4Pal, Dap(Dnp), D-2Fua, Pro(5Ph), 2Pal, 3Pal, Tyr(Me),
- AA2 is Asn, Hyp, Pro, Ala, Thz, Pro(diF), Pro(4-NH 2 ), Thi, NAsn, ACPA, D-2Fua, A6c, azaPro, Ind, (S)-Pip, (R) -Pip, Oic, azaTic, AlphaMeLeu, Cba, A6c, Aze, Cpa or D-Tic;
- XX3 is Trp, Ala, Phe(4-I) or a chemical bond
- AA5 is 2Fua, Thr or Ser
- AA6 is an amino unsubstituted or amino group (which may be an amino group on a chiral carbon atom or a primary amino group when a plurality of amino groups are present in an amino acid) is substituted by a C 1-3 alkyl group (eg, methyl group, ethyl group, The following amino acids substituted with n-propyl or isopropyl) (the "substituted amino acid" such as N-Me-Phe): Ala, 1Nal, 2Nal, Trp, ⁇ MePhe, Bta, 4Pal, HoPhe, BetaPhe, BetaHomoPhe, Bpa, Ala (dip), Bip, D-2 Fua, A6c, Tic, azaTic, azaPhe, and ⁇ eg Phe, D-Phe, Phe(4-F), Phe(pentaF), Phe(3-Cl), Phe(2-Br), Phe(4-I), Phe(4
- AA7 is an amino unsubstituted or amino group (which may be an amino group on a chiral carbon atom or a primary amino group when a plurality of amino groups are present in an amino acid) is substituted by one C 1-3 alkyl group (for example, methyl group, ethyl group, The following amino acids substituted with n-propyl or isopropyl) (the "substituted amino acid” such as N-Me-A6c or aza-N-Me-Gly): Gly, azaGly, Ala, Alg, Ava, Aib, Sar, Chg, BetaAla, ACPO, Aze, D-2Fua, A6c, azaPro, Ind, (S)-Pip, (R)-Pip, azaTic, Oic, Hyp, cycloLeu, BetaHomoAla, Cba, ACPA, Alg, morpholino cyclic Amino acid, beta-(thiazoly
- AA6-AA7 refers to the carboxyl group of AA6 (which may be a carboxyl group on a chiral carbon atom when a plurality of carboxyl groups are present in an amino acid) and the amino group of AA7 (when a plurality of amino groups are present in an amino acid, it may be a chiral carbon atom)
- the upper amino group may also be a primary amino group a group, or "the carboxyl group of AA6 is bonded to the amino group of AA7" In the group A group formed by substitution with any of the following groups: The left end of the group is attached to AA6 (for example, when AA6 is Phe and AA7 is Gly, "AA6-AA7" means );
- AA6 and AA7 are formed together.
- AA7-Leu means the carboxyl group of AA7 (which may be a carboxyl group on a chiral carbon atom when a plurality of carboxyl groups are present in an amino acid) and the amino group of Leu (when a plurality of amino groups are present in an amino acid, it may be a chiral carbon atom) Amino group, which may also be formed by a primary amino group a group, or "the carboxyl group of AA7 is bonded to the amino group of Leu" In the group A group formed by substitution with any of the following groups: The left end of the group is attached to AA7 (for example, when AA7 is Gly and AA7 is Leu, "AA7-Leu" means );
- AA9 is an amino unsubstituted or amino group (which may be an amino group on a chiral carbon atom when the amino acid has a plurality of amino groups, and may also be a primary amino group) is a C 1-3 alkyl group (for example, methyl group, ethyl group, The following amino acids substituted with n-propyl or isopropyl) (the "substituted amino acid" such as N-Me-Arg, N-Me-HoLeu or N-Me-D-HoLeu): Arg, Arg(Me) , Ala, His, HoLeu, D-HoLeu, 4Pal, Phe (4-amidino),
- AA10 is an amino unsubstituted or amino group (which may be an amino group on a chiral carbon atom or a primary amino group when a plurality of amino groups are present in an amino acid) is substituted by one C 1-3 alkyl group (for example, methyl group, ethyl group, The following amino acids substituted with n-propyl or isopropyl) (the "substituted amino acid" such as N-Me-Phe): Trp, Ala, ⁇ MePhe, 1Nal, 2Nal, 4Pal, BetaPhe, BetaHoPhe, Bpa, Ala ( Dip), NPhe, Bip, D-2Fua, A6c, Tic, and ⁇ eg Phe, D-Phe, Phe(4-F), Phe(pentaF), Phe(2-Br), Phe(4-I), or Phe(4-CF 3 ) ⁇ ; n10 is 0-5 (eg, 0, 1, 2, 3, 4
- P is -NH 2 , -OH, -NH-tBu, -NH-Et, -NH-Me, 1H-1,2,3-triazol-4-yl or 2H-tetrazol-5-yl.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- R a is CH 3 -, q is 0 to 16 (for example, a range in which the following two values are endpoints: 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16; again, for example, 0 to 14; for example, 4 to 14); or, R a is HOOC-, and q is 2 to 18 (for example, a range in which the following two values are end points: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16; again, for example, 2 to 16);
- n is 0 to 2 (for example, 0, 1, or 2);
- PEG is independently X is independently -NHR b or -OH, and R b is independently hydrogen or a C 1-3 alkyl group (e.g., methyl, ethyl, isopropyl or n-propyl); k is independently 2 to 12 ( For example, a range in which any two of the following values are endpoints: 2, 3, 4, 5, 6, 8, or 12); XX0 is independently
- the X may be -NH 2 ; the k may independently be 2 to 8 ⁇ eg 4 to 8 ⁇ ; Can independently be OEG, PEG4, PEG5, PEG8,
- the X when m is 2, in the PEG linked to AA0 or AA1, the X may be -NH 2 ; when m is 2, in the PEG linked to AA0 or AA1, the k may be 2 to 4 ⁇ For example, 2, 3 or 4 ⁇ ; when m is 2, in the PEG connected to AA0 or AA1, the XX0 may be When m is 2, in the PEG linked to AA0 or AA1, the Can be OEG or PEG4;
- n is 0 to 3 (for example, 0, 1, 2 or 3);
- All AA0 are independently Gly, Beta-Ala, Ahx or Ac-Lys; (for example, when n is 2 or 3, at least 2 AA0 are Gly; for example, Can be a chemical bond, "Gly-Gly” or "Ac-Lys-Gly-Gly” ⁇ the left side is connected to XX0 ⁇ )
- PEG' is R c is a C 14 -C 18 linear alkyl group (for example, a C 16 linear alkyl group), and X' is "a hetero atom is one or more of N, O and S, and the number of hetero atoms is 1-3.
- Five- or six-membered heteroaryl (for example, "a heteroatom is N, a five- or six-membered heteroaryl group having one to three heteroatoms", for example ⁇ its left end is connected to R c ⁇ ) or (the left end is connected to R c ), k' is 5 to 9 (again, for example, 5 to 7);
- n' is 0 to 3 (for example, 0, 1, 2 or 3, for example 2);
- All AA0' are independently Gly, Beta-Ala, Ahx or Ac-Lys; (for example, when n' is 2 or 3, at least 2 AA0' are Gly; for example, Can be a chemical bond, "Gly-Gly” or "Ac-Lys-Gly-Gly” ⁇ left side connected to PEG' ⁇
- AA1 is an amino unsubstituted or amino group (which may be an amino group on a chiral carbon atom or a primary amino group when a plurality of amino groups are present in an amino acid) is substituted by one C 1-3 alkyl group (for example, methyl group, ethyl group, The following amino acids substituted with n-propyl or isopropyl) (the "substituted amino acid" such as N-Me-Phe or N-Me-D-Phe): Tyr, D-Tyr, Thi, (S)- Pip, ⁇ MeTyr, 1Nal, 2Nal, 4Pal, Dap(Dnp), D-2Fua, Pro(5Ph), 2Pal, 3Pal, Tyr(Me), Ala(dip), A6c, ACPA, D-Tic, 3-[( 1-methylpyridinium-3-yl]alanine, and ⁇ eg Phe, D-Phe, Phe(4-F
- the * labeled carbon atom is a chiral carbon atom, which is in the R configuration or the S configuration (all R 1 can be independently located in the ortho, meta or para position of the amino acid side chain, for example, when n1 is 1 R 1 may be located at the meta or para position of the amino acid side chain; when n 1 is 2, R 1 may be located at the ortho and para position of the amino acid side chain; for example, it is );
- AA2 is Asn, Hyp, Pro, Ala, Thz, Pro(diF), Pro(4-NH 2 ), Thi, ACPA, D-2Fua, A6c, azaPro, Ind, (S)-Pip, (R)-Pip , Oic, AlphaMeLeu, Cba, A6c, Aze, Cpa or D-Tic;
- XX3 is Trp, Ala, Phe(4-I) or a chemical bond
- AA5 is 2Fua, Thr or Ser
- AA6 is an amino unsubstituted or amino group (which may be an amino group on a chiral carbon atom or a primary amino group when a plurality of amino groups are present in an amino acid) is substituted by a C 1-3 alkyl group (eg, methyl group, ethyl group, The following amino acids substituted with n-propyl or isopropyl) (the "substituted amino acid" such as N-Me-Phe): 1Nal, 2Nal, ⁇ MePhe, 4Pal, HoPhe, BetaPhe, BetaHomoPhe, Bpa, D-2Fua, A6c, Tic, azaPhe, and ⁇ eg Phe, D-Phe, Phe(4-F), Phe(pentaF), Phe(3-Cl), Phe(2-Br), Phe(4-I), Phe(4-tBu), or Phe(4-CF 3 ) ⁇ ; n6 is 0, 1
- AA7 is an amino unsubstituted or amino group (which may be an amino group on a chiral carbon atom or a primary amino group when a plurality of amino groups are present in an amino acid) is substituted by one C 1-3 alkyl group (for example, methyl group, ethyl group, The following amino acids substituted with n-propyl or isopropyl) (the "substituted amino acid” such as N-Me-A6c or aza-N-Me-Gly): Gly, azaGly, Ala, Alg, Ava, Aib, Sar, Chg, BetaAla, ACPO, Aze, D-2Fua, A6c, azaPro, Ind, (S)-Pip, (R)-Pip, Oic, Hyp, cycloLeu, BetaHomoAla, Cba, ACPA, Alg, morpholino cyclic amino acid , beta-(thiazoly-4-yl)-
- AA6-AA7 refers to the carboxyl group of AA6 (which may be a carboxyl group on a chiral carbon atom when a plurality of carboxyl groups are present in an amino acid) and the amino group of AA7 (when a plurality of amino groups are present in an amino acid, it may be a chiral carbon atom)
- the upper amino group may also be a primary amino group a group, or "the carboxyl group of AA6 is bonded to the amino group of AA7" In the group A group formed by substitution with any of the following groups: The left end of the group is attached to AA6 (for example, when AA6 is Phe and AA7 is Gly, "AA6-AA7" means );
- AA6 and AA7 are formed together.
- AA7-Leu means the carboxyl group of AA7 (which may be a carboxyl group on a chiral carbon atom when a plurality of carboxyl groups are present in an amino acid) and the amino group of Leu (when a plurality of amino groups are present in an amino acid, it may be a chiral carbon atom) Amino group, which may also be formed by a primary amino group a group, or "the carboxyl group of AA7 is bonded to the amino group of Leu" In the group A group formed by substitution with any of the following groups: The left end of the group is attached to AA7 (for example, when AA7 is Gly and AA7 is Leu, "AA7-Leu" means );
- AA9 is an amino unsubstituted or amino group (which may be an amino group on a chiral carbon atom when the amino acid has a plurality of amino groups, and may also be a primary amino group) is a C 1-3 alkyl group (for example, methyl group, ethyl group, The following amino acids substituted with n-propyl or isopropyl) (the "substituted amino acid" such as N-Me-Arg, N-Me-HoLeu or N-Me-D-HoLeu): Arg, Arg(Me) , His, HoLeu, D-HoLeu, 4Pal, Phe (4-amidino), and,
- AA10 is an amino unsubstituted or amino group (which may be an amino group on a chiral carbon atom or a primary amino group when a plurality of amino groups are present in an amino acid) is substituted by one C 1-3 alkyl group (for example, methyl group, ethyl group, The following amino acids substituted with n-propyl or isopropyl) (the "substituted amino acid" such as N-Me-Phe): Trp, ⁇ MePhe, 1Nal, 2Nal, 4Pal, BetaPhe, BetaHoPhe, Bpa, NPhe, D- 2Fua, A6c, Tic, and ⁇ eg Phe, D-Phe, Phe(4-F), Phe(pentaF), Phe(2-Br), Phe(4-I), or Phe(4-CF 3 ) ⁇ ; n10 is 0,*
- the labeled carbon atom is a chiral carbon atom which is
- P is -NH 2 , -OH, -NH-tBu, -NH-Et, -NH-Me, 1H-1,2,3-triazol-4-yl or 2H-tetrazol-5-yl.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- Cap is
- R a is CH 3 -, q is 0 to 14 (for example, a range in which the following two values are end points: 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14; further, for example, 4 to 14); or, R a is HOOC-, and q is 14 to 18 (for example, a range of endpoints of any of the following two values: 14, 15, 16, 17, and 18; Another example is 14-16);
- n is 0 to 2 (for example, 0, 1, or 2);
- PEG is independently X is independently -NHR b , and R b is independently hydrogen; k is independently 2 to 8 (for example, a range of endpoints of any of the following two values: 2, 3, 4, 5, 6, and 8, for example 4 ⁇ 8); XX0 is independently
- the X when m is 2, in the PEG linked to AA0 or AA1, the X may be -NH 2 ; when m is 2, in the PEG linked to AA0 or AA1, the k may be 2 to 4 ⁇ For example, 2, 3 or 4 ⁇ ; when m is 2, in the PEG connected to AA0 or AA1, the XX0 may be When m is 2, in the PEG linked to AA0 or AA1, the Can be OEG or PEG4;
- n is 0 to 3 (for example, 0, 1, 2 or 3);
- All AA0 are independently Gly, Beta-Ala, Ahx or Ac-Lys; (for example, when n is 2 or 3, at least 2 AA0 are Gly; for example, Can be a chemical bond, "Gly-Gly” or "Ac-Lys-Gly-Gly” ⁇ the left side is connected to XX0 ⁇ )
- PEG' is R c is a C 14 -C 18 linear alkyl group (for example, a C 16 linear alkyl group), and X' is "a hetero atom is one or more of N, O and S, and the number of hetero atoms is 1-3.
- Five- or six-membered heteroaryl (for example, "a heteroatom is N, a five- or six-membered heteroaryl group having one to three heteroatoms", for example ⁇ its left end is connected to R c ⁇ ) or (the left end is connected to R c ), k' is 5 to 9 (again, for example, 5 to 7);
- n' is 0 to 3 (for example, 0, 1, 2 or 3, for example 2);
- All AA0' are independently Gly, Beta-Ala, Ahx or Ac-Lys; (for example, when n' is 2 or 3, at least 2 AA0' are Gly; for example, Can be a chemical bond, "Gly-Gly” or "Ac-Lys-Gly-Gly” ⁇ left side connected to PEG' ⁇
- AA1 is any of the following amino acids: Tyr, D-Tyr, D-2Fua, and ⁇ eg Phe, D-Phe, Phe(4-F), D-Phe(4-F), Phe(3-Cl), D-Phe(3-Cl), Phe(4-Cl), D-Phe (4-Cl), Phe(4-I), D-Phe(4-I), Phe(4-Me), Phe(4-tBu), or D-Phe(2,4-diCl) ⁇ ; N1 is 0 to 2 (e.g., 0, 1, or 2), and all R 1 are independently C 1 -C 4 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl) Or isobutyl), C 1 -C 4 alkoxy (eg methoxy, ethoxy, n-propoxy, isopropoxy, n-but
- AA2 is Asn, Hyp, Thz, Pro(diF), Pro(4-NH 2 ), Thi, AlphaMeLeu, Cba, A6c, Aze, Cpa or A6c;
- XX3 is a Trp or a chemical bond
- AA5 is Thr or Ser
- AA6 is ⁇ eg Phe, D-Phe, Phe(4-F), Phe(pentaF), Phe(3-Cl), Phe(2-Br), Phe(4-I), Phe(4-tBu), or Phe(4-CF 3 ) ⁇ ; n6 is 0-5 (eg 0, 1, 2, 3, 4 or 5), and all R 6 are independently halogenated C 1 -C 4 alkyl (described "halo" such as fluorine, chlorine, bromine or iodine; said "C 1 -C 4 alkyl” such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or isobutyl Said "halogenated C 1 -C 4 alkyl” such as trifluoromethyl), C 1 -C 4 alkyl (eg methyl, ethyl, isopropyl or isobutyl) or halogen (eg Fluor
- AA7 is any of the following amino acids: Gly, azaGly, Alg, Aze, D-2Fua, Alg, morpholino cyclic amino acid, beta-(thiazoly-4-yl)-L-Ala, And A6c;
- AA6-AA7 refers to the carboxyl group of AA6 (which may be a carboxyl group on a chiral carbon atom when a plurality of carboxyl groups are present in an amino acid) and the amino group of AA7 (when a plurality of amino groups are present in an amino acid, it may be a chiral carbon atom)
- the upper amino group may also be a primary amino group Group
- AA7-Leu refers to the carboxyl group of AA7 (which may be a carboxyl group on a chiral carbon atom when a plurality of carboxyl groups are present in an amino acid) and the amino group of Leu (when a plurality of amino groups are present in an amino acid,
- the amino group on the chiral carbon atom may also be formed by the attachment of a primary amino group.
- AA9 is any of the following amino acids: Arg and Arg(Me);
- AA10 is Trp, or ⁇ eg Phe, D-Phe, Phe(4-F), Phe(pentaF), Phe(2-Br), Phe(4-I), or Phe(4-CF 3 ) ⁇ ; n10 is 0-5 (eg, 0, 1, 2, 3, 4 or 5), all R 10 are independently halogenated C 1 -C 4 alkyl (the "halo” such as fluorine, chlorine, bromine or iodine; "C 1 -C 4 alkyl” such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or isobutyl; said "halogenated C 1 -C 4 alkane” a group such as "trifluoromethyl” or a halogen (such as fluorine, chlorine, bromine or iodine), the carbon atom labeled * is a chiral carbon atom, which is in the R configuration or the S configuration
- P is -NH 2 .
- each group in the compound 1 can be as follows (unannotated definition as described above):
- Cap is
- R a is CH 3 -, q is 0 to 14 (for example, a range in which the following two values are end points: 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14; further, for example, 4 to 14); or, R a is HOOC-, and q is 14 to 18 (for example, a range of endpoints of any of the following two values: 14, 15, 16, 17, and 18; Another example is 14-16);
- n is 0 to 2 (for example, 0, 1, or 2);
- PEG is independently X is independently -NHR b , and R b is independently hydrogen; k is independently 2 to 8 (for example, a range of endpoints of any of the following two values: 2, 3, 4, 5, 6, and 8, for example 4 ⁇ 8); XX0 is independently
- the X when m is 2, in the PEG linked to AA0 or AA1, the X may be -NH 2 ; when m is 2, in the PEG linked to AA0 or AA1, the k may be 2 to 4 ⁇ For example, 2, 3 or 4 ⁇ ; when m is 2, in the PEG connected to AA0 or AA1, the XX0 may be When m is 2, in the PEG linked to AA0 or AA1, the Can be OEG or PEG4;
- n is 0 to 3 (for example, 0, 1, 2 or 3);
- All AA0 are independently Gly, Beta-Ala, Ahx or Ac-Lys; (for example, when n is 2 or 3, at least 2 AA0 are Gly; for example, Can be a chemical bond, "Gly-Gly” or "Ac-Lys-Gly-Gly” ⁇ the left side is connected to XX0 ⁇ )
- PEG' is R c is a C 14 -C 18 linear alkyl group (for example, a C 16 linear alkyl group), and X' is ⁇ The left end is connected to R c ⁇ or (the left end is connected to R c ), k' is 5 to 9 (again, for example, 5 to 7);
- n' is 0 to 3 (for example, 0, 1, 2 or 3, for example 2);
- All AA0' are independently Gly, Beta-Ala, Ahx or Ac-Lys; (for example, when n' is 2 or 3, at least 2 AA0' are Gly; for example, Can be a chemical bond, "Gly-Gly” or "Ac-Lys-Gly-Gly” ⁇ left side connected to PEG' ⁇
- AA1 is Tyr, D-Tyr, D-2Fua, D-Phe(4-I) or Phe(4-I);
- AA2 is Asn, Hyp, Thz, Pro(diF), Pro(4-NH 2 ), Thi, AlphaMeLeu, Cba, A6c, Aze, Cpa or A6c;
- XX3 is a Trp or a chemical bond
- AA5 is Thr or Ser
- AA6 is Phe
- AA7 is any of the following amino acids: Gly, azaGly, Alg, Aze, D-2Fua, Alg, morpholino cyclic amino acid, beta-(thiazoly-4-yl)-L-Ala, And A6c;
- AA6-AA7 refers to the carboxyl group of AA6 (which may be a carboxyl group on a chiral carbon atom when a plurality of carboxyl groups are present in an amino acid) and the amino group of AA7 (when a plurality of amino groups are present in an amino acid, it may be a chiral carbon atom)
- the upper amino group may also be a primary amino group Group
- AA7-Leu refers to the carboxyl group of AA7 (which may be a carboxyl group on a chiral carbon atom when a plurality of carboxyl groups are present in an amino acid) and the amino group of Leu (when a plurality of amino groups are present in an amino acid,
- the amino group on the chiral carbon atom may also be formed by the attachment of a primary amino group.
- AA9 is any of the following amino acids: Arg and Arg(Me);
- AA10 is Trp or Phe
- P is -NH 2 .
- each group in the compound 1 can be as follows (unannotated definition as described above):
- Cap is
- R a is CH 3 -, q is 0 to 14 (for example, a range in which the following two values are end points: 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14; further, for example, 4 to 14); or, R a is HOOC-, and q is 14 to 18 (for example, a range of endpoints of any of the following two values: 14, 15, 16, 17, and 18; Another example is 14-16);
- n is 0 to 2 (for example, 0, 1, or 2);
- PEG is independently X is independently -NHR b , and R b is independently hydrogen; k is independently 2 to 8 (for example, a range of endpoints of any of the following two values: 2, 3, 4, 5, 6, and 8, for example 4 ⁇ 8); XX0 is independently
- the X when m is 2, in the PEG linked to AA0 or AA1, the X may be -NH 2 ; when m is 2, in the PEG linked to AA0 or AA1, the k may be 2 to 4 ⁇ For example, 2, 3 or 4 ⁇ ; when m is 2, in the PEG connected to AA0 or AA1, the XX0 may be When m is 2, in the PEG linked to AA0 or AA1, the Can be OEG or PEG4;
- n is 0 to 3 (for example, 0, 1, 2 or 3);
- All AA0 are independently Gly, Beta-Ala, Ahx or Ac-Lys; (for example, when n is 2 or 3, at least 2 AA0 are Gly; for example, Can be a chemical bond, "Gly-Gly” or "Ac-Lys-Gly-Gly” ⁇ the left side is connected to XX0 ⁇ )
- PEG' is R c is a C 14 -C 18 linear alkyl group (for example, a C 16 linear alkyl group), and X' is "a hetero atom is one or more of N, O and S, and the number of hetero atoms is 1-3.
- Five- or six-membered heteroaryl (for example, "a heteroatom is N, a five- or six-membered heteroaryl group having one to three heteroatoms", for example ⁇ its left end is connected to R c ⁇ ) or (the left end is connected to R c ), k' is 5 to 9 (again, for example, 5 to 7);
- n' is 0 to 3 (for example, 0, 1, 2 or 3, for example 2);
- All AA0' are independently Gly, Beta-Ala, Ahx or Ac-Lys; (for example, when n' is 2 or 3, at least 2 AA0' are Gly; for example, Can be a chemical bond, "Gly-Gly” or "Ac-Lys-Gly-Gly” ⁇ left side connected to PEG' ⁇
- AA1 is any of the following amino acids: Tyr, D-Tyr, D-2Fua, and ⁇ eg Phe, D-Phe, Phe(4-F), D-Phe(4-F), Phe(3-Cl), D-Phe(3-Cl), Phe(4-Cl), D-Phe (4-Cl), Phe(4-I), D-Phe(4-I), Phe(4-Me), Phe(4-tBu), or D-Phe(2,4-diCl) ⁇ ; N1 is 0 to 2 (e.g., 0, 1, or 2), and all R 1 are independently C 1 -C 4 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl) Or isobutyl), C 1 -C 4 alkoxy (eg methoxy, ethoxy, n-propoxy, isopropoxy, n-but
- AA2 is Asn, Hyp, Pro(diF), Pro(4-NH 2 ) or A6c;
- XX3 is a Trp or a chemical bond
- AA5 is Thr or Ser
- AA6 is ⁇ eg Phe, D-Phe, Phe(4-F), Phe(pentaF), Phe(3-Cl), Phe(2-Br), Phe(4-I), Phe(4-tBu), or Phe(4-CF 3 ) ⁇ ; n6 is 0-5 (eg 0, 1, 2, 3, 4 or 5), and all R 6 are independently halogenated C 1 -C 4 alkyl (described "halo" such as fluorine, chlorine, bromine or iodine; said "C 1 -C 4 alkyl” such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or isobutyl Said "halogenated C 1 -C 4 alkyl” such as trifluoromethyl), C 1 -C 4 alkyl (eg methyl, ethyl, isopropyl or isobutyl) or halogen (eg Fluor
- AA7 is any of the following amino acids: Gly, azaGly, Alg, Aze, D-2 Fua and A6c;
- AA6-AA7 refers to the carboxyl group of AA6 (which may be a carboxyl group on a chiral carbon atom when a plurality of carboxyl groups are present in an amino acid) and the amino group of AA7 (when a plurality of amino groups are present in an amino acid, it may be a chiral carbon atom)
- the upper amino group may also be a primary amino group Group
- AA7-Leu refers to the carboxyl group of AA7 (which may be a carboxyl group on a chiral carbon atom when a plurality of carboxyl groups are present in an amino acid) and the amino group of Leu (when a plurality of amino groups are present in an amino acid,
- the amino group on the chiral carbon atom may also be formed by the attachment of a primary amino group.
- AA9 is any of the following amino acids: Arg and Arg(Me);
- AA10 is Trp, or ⁇ eg Phe, D-Phe, Phe(4-F), Phe(pentaF), Phe(2-Br), Phe(4-I), or Phe(4-CF 3 ) ⁇ ; n10 is 0-5 (eg, 0, 1, 2, 3, 4 or 5), all R 10 are independently halogenated C 1 -C 4 alkyl (the "halo” such as fluorine, chlorine, bromine or iodine; "C 1 -C 4 alkyl” such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or isobutyl; said "halogenated C 1 -C 4 alkane” a group such as "trifluoromethyl” or a halogen (such as fluorine, chlorine, bromine or iodine), the carbon atom labeled * is a chiral carbon atom, which is in the R configuration or the S configuration
- P is -NH 2 .
- each group in the compound 1 can be as follows (unannotated definition as described above):
- Cap is
- R a is CH 3 -, q is 0 to 14 (for example, a range in which the following two values are end points: 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14; further, for example, 4 to 14); or, R a is HOOC-, and q is 14 to 18 (for example, a range of endpoints of any of the following two values: 14, 15, 16, 17, and 18; Another example is 14-16);
- n is 0 to 2 (for example, 0, 1, or 2);
- PEG is independently X is independently -NHR b , and R b is independently hydrogen; k is independently 2 to 8 (for example, a range of endpoints of any of the following two values: 2, 3, 4, 5, 6, and 8, for example 4 ⁇ 8); XX0 is independently
- the X when m is 2, in the PEG linked to AA0 or AA1, the X may be -NH 2 ; when m is 2, in the PEG linked to AA0 or AA1, the k may be 2 to 4 ⁇ For example, 2, 3 or 4 ⁇ ; when m is 2, in the PEG connected to AA0 or AA1, the XX0 may be When m is 2, in the PEG linked to AA0 or AA1, the Can be OEG or PEG4;
- n is 0 to 3 (for example, 0, 1, 2 or 3);
- All AA0 are independently Gly, Beta-Ala, Ahx or Ac-Lys; (for example, when n is 2 or 3, at least 2 AA0 are Gly; for example, Can be a chemical bond, "Gly-Gly” or "Ac-Lys-Gly-Gly” ⁇ the left side is connected to XX0 ⁇ )
- PEG' is R c is a C 14 -C 18 linear alkyl group (for example, a C 16 linear alkyl group), and X' is ⁇ The left end is connected to R c ⁇ or (the left end is connected to R c ), k' is 5 to 9 (again, for example, 5 to 7);
- n' is 0 to 3 (for example, 0, 1, 2 or 3, for example 2);
- All AA0' are independently Gly, Beta-Ala, Ahx or Ac-Lys; (for example, when n' is 2 or 3, at least 2 AA0' are Gly; for example, Can be a chemical bond, "Gly-Gly” or "Ac-Lys-Gly-Gly” ⁇ left side connected to PEG' ⁇
- AA1 is Tyr, D-Tyr, D-2Fua or D-Phe(4-I);
- AA2 is Asn, Hyp, Pro(diF), Pro(4-NH 2 ) or A6c;
- XX3 is a Trp or a chemical bond
- AA5 is Thr or Ser
- AA6 is Phe
- AA7 is any of the following amino acids: Gly, azaGly, Alg, Aze, D-2 Fua and A6c;
- AA6-AA7 refers to the carboxyl group of AA6 (which may be a carboxyl group on a chiral carbon atom when a plurality of carboxyl groups are present in an amino acid) and the amino group of AA7 (when a plurality of amino groups are present in an amino acid, it may be a chiral carbon atom)
- the upper amino group may also be a primary amino group Group
- AA7-Leu refers to the carboxyl group of AA7 (which may be a carboxyl group on a chiral carbon atom when a plurality of carboxyl groups are present in an amino acid) and the amino group of Leu (when a plurality of amino groups are present in an amino acid,
- the amino group on the chiral carbon atom may also be formed by the attachment of a primary amino group.
- AA9 is any of the following amino acids: Arg and Arg(Me);
- AA10 is Trp or Phe
- P is -NH 2 .
- each group in the compound 1 can be as follows (unannotated definition as described above):
- Cap is
- R a is CH 3 -, q is 0 to 14 (for example, a range in which the following two values are end points: 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14; further, for example, 4 to 14); or, R a is HOOC-, and q is 14 to 18 (for example, a range of endpoints of any of the following two values: 14, 15, 16, 17, and 18; Another example is 14-16);
- n is 0 to 2 (for example, 0, 1, or 2);
- PEG is independently X is independently -NHR b , and R b is independently hydrogen; k is independently 2 to 8 (for example, a range of endpoints of any of the following two values: 2, 3, 4, 5, 6, and 8, for example 4 ⁇ 8); XX0 is independently
- the X when m is 2, in the PEG linked to AA0 or AA1, the X may be -NH 2 ; when m is 2, in the PEG linked to AA0 or AA1, the k may be 2 to 4 ⁇ For example, 2, 3 or 4 ⁇ ; when m is 2, in the PEG connected to AA0 or AA1, the XX0 may be When m is 2, in the PEG linked to AA0 or AA1, the Can be OEG or PEG4;
- n is 0 to 3 (for example, 0, 1, 2 or 3);
- All AA0 are independently Gly, Beta-Ala, Ahx or Ac-Lys; (for example, when n is 2 or 3, at least 2 AA0 are Gly; for example, Can be a chemical bond, "Gly-Gly” or "Ac-Lys-Gly-Gly” ⁇ the left side is connected to XX0 ⁇ )
- PEG' is R c is a C 14 -C 18 linear alkyl group (for example, a C 16 linear alkyl group), and X' is "a hetero atom is one or more of N, O and S, and the number of hetero atoms is 1-3.
- Five- or six-membered heteroaryl (for example, "a heteroatom is N, a five- or six-membered heteroaryl group having one to three heteroatoms", for example ⁇ its left end is connected to R c ⁇ ) or (the left end is connected to R c ), k' is 5 to 9 (again, for example, 5 to 7);
- n' is 0 to 3 (for example, 0, 1, 2 or 3, for example 2);
- All AA0' are independently Gly, Beta-Ala, Ahx or Ac-Lys; (for example, when n' is 2 or 3, at least 2 AA0' are Gly; for example, Can be a chemical bond, "Gly-Gly” or "Ac-Lys-Gly-Gly” ⁇ left side connected to PEG' ⁇
- AA1 is any of the following amino acids: Tyr, D-Tyr, D-2Fua, and ⁇ eg Phe, D-Phe, Phe(4-F), D-Phe(4-F), Phe(3-Cl), D-Phe(3-Cl), Phe(4-Cl), D-Phe (4-Cl), Phe(4-I), D-Phe(4-I), Phe(4-Me), Phe(4-tBu), or D-Phe(2,4-diCl) ⁇ ; N1 is 0 to 2 (e.g., 0, 1, or 2), and all R 1 are independently C 1 -C 4 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl) Or isobutyl), C 1 -C 4 alkoxy (eg methoxy, ethoxy, n-propoxy, isopropoxy, n-but
- AA2 is Asn, Hyp, Pro (diF) or A6c;
- XX3 is a Trp or a chemical bond
- AA5 is Thr or Ser
- AA6 is ⁇ eg Phe, D-Phe, Phe(4-F), Phe(pentaF), Phe(3-Cl), Phe(2-Br), Phe(4-I), Phe(4-tBu), or Phe(4-CF 3 ) ⁇ ; n6 is 0-5 (eg 0, 1, 2, 3, 4 or 5), and all R 6 are independently halogenated C 1 -C 4 alkyl (described "halo" such as fluorine, chlorine, bromine or iodine; said "C 1 -C 4 alkyl” such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or isobutyl Said "halogenated C 1 -C 4 alkyl” such as trifluoromethyl), C 1 -C 4 alkyl (eg methyl, ethyl, isopropyl or isobutyl) or halogen (eg Fluor
- AA7 is any of the following amino acids: Gly, azaGly, Alg, Aze, D-2 Fua and A6c;
- AA6-AA7 refers to the carboxyl group of AA6 (which may be a carboxyl group on a chiral carbon atom when a plurality of carboxyl groups are present in an amino acid) and the amino group of AA7 (when a plurality of amino groups are present in an amino acid, it may be a chiral carbon atom)
- the upper amino group may also be a primary amino group Group
- AA7-Leu refers to the carboxyl group of AA7 (which may be a carboxyl group on a chiral carbon atom when a plurality of carboxyl groups are present in an amino acid) and the amino group of Leu (when a plurality of amino groups are present in an amino acid,
- the amino group on the chiral carbon atom may also be formed by the attachment of a primary amino group.
- AA9 is any of the following amino acids: Arg and Arg(Me);
- AA10 is Trp, or ⁇ eg Phe, D-Phe, Phe(4-F), Phe(pentaF), Phe(2-Br), Phe(4-I), or Phe(4-CF 3 ) ⁇ ; n10 is 0-5 (eg, 0, 1, 2, 3, 4 or 5), all R 10 are independently halogenated C 1 -C 4 alkyl (the "halo” such as fluorine, chlorine, bromine or iodine; "C 1 -C 4 alkyl” such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or isobutyl; said "halogenated C 1 -C 4 alkane” a group such as "trifluoromethyl” or a halogen (such as fluorine, chlorine, bromine or iodine), the carbon atom labeled * is a chiral carbon atom, which is in the R configuration or the S configuration
- P is -NH 2 .
- each group in the compound 1 can be as follows (unannotated definition as described above):
- Cap is
- R a is CH 3 -, q is 0 to 14 (for example, a range in which the following two values are end points: 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14; further, for example, 4 to 14); or, R a is HOOC-, and q is 14 to 18 (for example, a range of endpoints of any of the following two values: 14, 15, 16, 17, and 18; Another example is 14-16);
- n is 0 to 2 (for example, 0, 1, or 2);
- PEG is independently X is independently -NHR b , and R b is independently hydrogen; k is independently 2 to 8 (for example, a range of endpoints of any of the following two values: 2, 3, 4, 5, 6, and 8, for example 4 ⁇ 8); XX0 is independently
- the X when m is 2, in the PEG linked to AA0 or AA1, the X may be -NH 2 ; when m is 2, in the PEG linked to AA0 or AA1, the k may be 2 to 4 ⁇ For example, 2, 3 or 4 ⁇ ; when m is 2, in the PEG connected to AA0 or AA1, the XX0 may be When m is 2, in the PEG linked to AA0 or AA1, the Can be OEG or PEG4;
- n is 0 to 3 (for example, 0, 1, 2 or 3);
- All AA0 are independently Gly, Beta-Ala, Ahx or Ac-Lys; (for example, when n is 2 or 3, at least 2 AA0 are Gly; for example, Can be a chemical bond, "Gly-Gly” or "Ac-Lys-Gly-Gly” ⁇ the left side is connected to XX0 ⁇ )
- PEG' is R c is a C 14 -C 18 linear alkyl group (for example, a C 16 linear alkyl group), and X' is ⁇ The left end is connected to R c ⁇ or (the left end is connected to R c ), k' is 5 to 9 (again, for example, 5 to 7);
- n' is 0 to 3 (for example, 0, 1, 2 or 3, for example 2);
- All AA0' are independently Gly, Beta-Ala, Ahx or Ac-Lys; (for example, when n' is 2 or 3, at least 2 AA0' are Gly; for example, Can be a chemical bond, "Gly-Gly” or "Ac-Lys-Gly-Gly” ⁇ left side connected to PEG' ⁇
- AA1 is Tyr, D-Tyr, D-2Fua or Phe(4-I);
- AA2 is Asn, Hyp, Pro (diF) or A6c;
- XX3 is a Trp or a chemical bond
- AA5 is Thr or Ser
- AA6 is Phe
- AA7 is any of the following amino acids: Gly, azaGly, Alg, Aze, D-2 Fua and A6c;
- AA6-AA7 refers to the carboxyl group of AA6 (which may be a carboxyl group on a chiral carbon atom when a plurality of carboxyl groups are present in an amino acid) and the amino group of AA7 (when a plurality of amino groups are present in an amino acid, it may be a chiral carbon atom)
- the upper amino group may also be a primary amino group Group
- AA7-Leu refers to the carboxyl group of AA7 (which may be a carboxyl group on a chiral carbon atom when a plurality of carboxyl groups are present in an amino acid) and the amino group of Leu (when a plurality of amino groups are present in an amino acid,
- the amino group on the chiral carbon atom may also be formed by the attachment of a primary amino group.
- AA9 is any of the following amino acids: Arg and Arg(Me);
- AA10 is Trp or Phe
- P is -NH 2 .
- each group in the compound 1 can be as follows (unannotated definition as described above):
- R a is CH 3 -
- q is 0 to 16 (for example, a range in which the following two values are endpoints: 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16; again, for example, 0 to 14; for example, 4 to 14).
- each group in the compound 1 can be as follows (unannotated definition as described above):
- R a is CH 3 -
- q is 0 to 14 (for example, a range in which the following two values are end points: 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14; for example, 4 to 14).
- each group in the compound 1 can be as follows (unannotated definition as described above):
- R a is HOOC-, and q is 2 to 18 (for example, a range in which the following two values are end points: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 , 15 and 16; another example, 2 to 16).
- each group in the compound 1 can be as follows (unannotated definition as described above):
- R a is HOOC-, and q is 14 to 18 (for example, a range in which the following two values are end points: 14, 15, 16, 17, and 18; and, for example, 14 to 16).
- each group in the compound 1 can be as follows (unannotated definition as described above):
- k is independently 2 to 8 (for example, a range in which the following two values are end points: 2, 3, 4, 5, 6, and 8, and for example, 4 to 8).
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA1 is an amino unsubstituted or amino group (which may be an amino group on a chiral carbon atom or a primary amino group when a plurality of amino groups are present in an amino acid) is substituted by one C 1-3 alkyl group (for example, methyl group, ethyl group, The following amino acids substituted with n-propyl or isopropyl) (the "substituted amino acid" such as N-Me-Phe or N-Me-D-Phe): Tyr, D-Tyr, Thi, (S)- Pip, ⁇ MeTyr, 1Nal, 2Nal, 4Pal, Dap(Dnp), D-2Fua, Pro(5Ph), 2Pal, 3Pal, Tyr(Me), Ala(dip), A6c, ACPA, D-Tic, 3-[( 1-methylpyridinium-3-yl]alanine, and ⁇ eg Phe, D-Phe, Phe(4-F
- the * labeled carbon atom is a chiral carbon atom, which is in the R configuration or the S configuration (all R 1 can be independently located in the ortho, meta or para position of the amino acid side chain, for example, when n1 is 1 R 1 may be located at the meta or para position of the amino acid side chain; when n 1 is 2, R 1 may be located at the ortho and para position of the amino acid side chain; for example, it is ).
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA1 is any of the following amino acids: Tyr, D-Tyr, D-2Fua, and ⁇ eg Phe, D-Phe, Phe(4-F), D-Phe(4-F), Phe(3-Cl), D-Phe(3-Cl), Phe(4-Cl), D-Phe (4-Cl), Phe(4-I), D-Phe(4-I), Phe(4-Me), Phe(4-tBu), or D-Phe(2,4-diCl) ⁇ ; N1 is 0 to 2 (e.g., 0, 1, or 2), and all R 1 are independently C 1 -C 4 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl) Or isobutyl), C 1 -C 4 alkoxy (eg methoxy, ethoxy, n-propoxy, isopropoxy, n-but
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA1 is Tyr, D-Tyr, D-2 Fua, D-Phe (4-I) or Phe (4-I).
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA1 is Tyr, D-Tyr, D-2 Fua or D-Phe (4-I).
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA1 is Tyr, D-Tyr, D-2 Fua or Phe(4-I).
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA2 is Asn, Hyp, Pro, Ala, Thz, Pro(diF), Pro(4-NH 2 ), Thi, ACPA, D-2Fua, A6c, azaPro, Ind, (S)-Pip, (R)-Pip , Oic, AlphaMeLeu, Cba, A6c, Aze, Cpa or D-Tic.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA2 is Asn, Hyp, Thz, Pro(diF), Pro(4-NH 2 ), Thi, AlphaMeLeu, Cba, A6c, Aze, Cpa or A6c.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA2 is Asn, Hyp, Pro(4-NH 2 ), AlphaMeLeu, Cba, A6c, Aze, Cpa or A6c.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA2 is Asn, Hyp, AlphaMeLeu, Cba, A6c, Aze, Cpa or A6c.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA2 is Asn, Hyp, Pro(4-NH 2 ), Pro(diF) or A6c.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA2 is Asn, Hyp, Pro (diF) or A6c.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- XX3 is a Trp or a chemical bond.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA5 is Thr or Ser.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA6 is an amino unsubstituted or amino group (which may be an amino group on a chiral carbon atom or a primary amino group when a plurality of amino groups are present in an amino acid) is substituted by a C 1-3 alkyl group (eg, methyl group, ethyl group, The following amino acids substituted with n-propyl or isopropyl) (the "substituted amino acid" such as N-Me-Phe): 1Nal, 2Nal, ⁇ MePhe, 4Pal, HoPhe, BetaPhe, BetaHomoPhe, Bpa, D-2Fua, A6c, Tic, azaPhe, and ⁇ eg Phe, D-Phe, Phe(4-F), Phe(pentaF), Phe(3-Cl), Phe(2-Br), Phe(4-I), Phe(4-tBu), or Phe(4-CF 3 ) ⁇ ; n6 is 0, 1
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA6 is ⁇ eg Phe, D-Phe, Phe(4-F), Phe(pentaF), Phe(3-Cl), Phe(2-Br), Phe(4-I), Phe(4-tBu), or Phe(4-CF 3 ) ⁇ ; n6 is 0-5 (eg 0, 1, 2, 3, 4 or 5), and all R 6 are independently halogenated C 1 -C 4 alkyl (described "halo" such as fluorine, chlorine, bromine or iodine; said "C 1 -C 4 alkyl” such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or isobutyl Said "halogenated C 1 -C 4 alkyl” such as trifluoromethyl), C 1 -C 4 alkyl (eg methyl, ethyl, isopropyl or isobutyl) or halogen (eg Fluor
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA6 is Phe.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA7 is an amino unsubstituted or amino group (which may be an amino group on a chiral carbon atom or a primary amino group when a plurality of amino groups are present in an amino acid) is substituted by one C 1-3 alkyl group (for example, methyl group, ethyl group, The following amino acids substituted with n-propyl or isopropyl) (the "substituted amino acid” such as N-Me-A6c or aza-N-Me-Gly): Gly, azaGly, Ala, Alg, Ava, Aib, Sar, Chg, BetaAla, ACPO, Aze, D-2Fua, A6c, azaPro, Ind, (S)-Pip, (R)-Pip, Oic, Hyp, cycloLeu, BetaHomoAla, Cba, ACPA, Alg, morpholino cyclic amino acid , beta-(thiazoly-4-yl)-
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA7 is an amino group in which an amino group is unsubstituted or an amino group is substituted with one C 1-3 alkyl group: Gly, azaGly, Ala, Ava, Aib, Sar, Chg, BetaAla, ACPO, Aze, Alg, D-2 Fua, A6c , azaPro, Ind, (S)-Pip, (R)-Pip, azaTic, Oic, Hyp, cycloLeu, BetaHomoAla, Cba, ACPA and
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA7 is any of the following amino acids: Gly, azaGly, Alg, Aze, D-2Fua, Alg, morpholino cyclic amino acid, beta-(thiazoly-4-yl)-L-Ala, And A6c.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA7 is any of the following amino acids: Gly, azaGly, Alg, Aze, D-2 Fua, morpholino cyclic amino acid, beta-(thiazoly-4-yl)-L-Ala, And A6c.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA7 is azaGly, Aib, A6c, Alg, cycloLeu, Ind, Cba, Aze, Gly or D-2 Fua.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA7 is azaGly, Aib, A6c, Alg, cycloLeu, Ind, Cba, Aze or Gly.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA7 is any of the following amino acids: Gly, azaGly, Alg, Aze, D-2 Fua, and A6c.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA7 is AzaGly, A6c, Alg, D-2Fua or Aze.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA6-AA7 refers to the carboxyl group of AA6 (which may be a carboxyl group on a chiral carbon atom when a plurality of carboxyl groups are present in an amino acid) and the amino group of AA7 (when a plurality of amino groups are present in an amino acid, it may be a chiral carbon atom)
- the upper amino group may also be a primary amino group a group, or "the carboxyl group of AA6 is bonded to the amino group of AA7" In the group A group formed by substitution with any of the following groups: The left end of the group is attached to AA6 (for example, when AA6 is Phe and AA7 is Gly, "AA6-AA7" means ).
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA6-AA7 refers to the carboxyl group of AA6 (which may be a carboxyl group on a chiral carbon atom when a plurality of carboxyl groups are present in an amino acid) and the amino group of AA7 (when a plurality of amino groups are present in an amino acid, it may be a chiral carbon atom)
- the upper amino group may also be a primary amino group Group.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA7-Leu refers to the carboxyl group of AA7 (which may be a carboxyl group on a chiral carbon atom when a plurality of carboxyl groups are present in an amino acid) and the amino group of Leu (when a plurality of amino groups are present in an amino acid,
- the amino group on the chiral carbon atom may also be formed by the attachment of a primary amino group.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA7-Leu refers to the carboxyl group of AA7 (which may be a carboxyl group on a chiral carbon atom when a plurality of carboxyl groups are present in an amino acid) and the amino group of Leu (when a plurality of amino groups are present in an amino acid,
- the amino group on the chiral carbon atom may also be formed by the attachment of a primary amino group.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA9 is an amino unsubstituted or amino group (which may be an amino group on a chiral carbon atom when the amino acid has a plurality of amino groups, and may also be a primary amino group) is a C 1-3 alkyl group (for example, methyl group, ethyl group, The following amino acids substituted with n-propyl or isopropyl) (the "substituted amino acid" such as N-Me-Arg, N-Me-HoLeu or N-Me-D-HoLeu): Arg, Arg(Me) , His, HoLeu, D-HoLeu, 4Pal, Phe (4-amidino), and,
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA9 is any of the following amino acids: Arg and Arg(Me).
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA10 is an amino unsubstituted or amino group (which may be an amino group on a chiral carbon atom or a primary amino group when a plurality of amino groups are present in an amino acid) is substituted by one C 1-3 alkyl group (for example, methyl group, ethyl group, The following amino acids substituted with n-propyl or isopropyl) (the "substituted amino acid" such as N-Me-Phe): Trp, ⁇ MePhe, 1Nal, 2Nal, 4Pal, BetaPhe, BetaHoPhe, Bpa, NPhe, D- 2Fua, A6c, Tic, and ⁇ eg Phe, D-Phe, Phe(4-F), Phe(pentaF), Phe(2-Br), Phe(4-I), or Phe(4-CF 3 ) ⁇ ; n10 is 0,*
- the labeled carbon atom is a chiral carbon atom which is
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA10 is Trp, or ⁇ eg Phe, D-Phe, Phe(4-F), Phe(pentaF), Phe(2-Br), Phe(4-I), or Phe(4-CF 3 ) ⁇ ; n10 is 0-5 (eg, 0, 1, 2, 3, 4 or 5), all R 10 are independently halogenated C 1 -C 4 alkyl (the "halo” such as fluorine, chlorine, bromine or iodine; "C 1 -C 4 alkyl” such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or isobutyl; said "halogenated C 1 -C 4 alkane” a group such as "trifluoromethyl” or a halogen (such as fluorine, chlorine, bromine or iodine), the carbon atom labeled * is a chiral carbon atom, which is in the R configuration or the S configuration
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA10 is Trp or Phe.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- P is -NH 2 .
- each group in the compound 1 can be as follows (unannotated definition as described above):
- R a is CH 3 - and q is 0 to 18 (for example, a range in which any two of the following values are endpoints: 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18; again, for example, 0 to 14; for example, 4 to 14); or, R a is HOOC-, and q is 1 to 18 (for example, with any of the following two) Values are in the range of endpoints: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18; again, for example, 1 to 16);
- n is 0 to 2 (for example, 0, 1, or 2);
- PEG is independently X is independently -NHR b or -OH, and R b is independently hydrogen or a C 1-3 alkyl group (e.g., methyl, ethyl, isopropyl or n-propyl); k is independently 2 to 24 ( For example, a range in which any two of the following values are endpoints: 2, 3, 4, 5, 6, 8, 12, 16, 20 or 24); XX0 is independently
- the X may be -NH 2 ; the k may independently be 2 to 12 ⁇ eg 4 to 8 ⁇ ; Can independently be OEG, PEG4, PEG5, PEG8, PEG12,
- the X when m is 2, in the PEG linked to AA0 or AA1, the X may be -NH 2 ; when m is 2, in the PEG linked to AA0 or AA1, the k may be 2 to 4 ⁇ For example, 2, 3 or 4 ⁇ ; when m is 2, in the PEG connected to AA0 or AA1, the XX0 may be When m is 2, in the PEG linked to AA0 or AA1, the Can be OEG or PEG4;
- n is 0 to 3 (for example, 0, 1, 2 or 3);
- All AA0 are independently Gly, Beta-Ala, Ahx or Ac-Lys; (for example, when n is 2 or 3, at least 2 AA0 are Gly; for example, Can be a chemical bond, "Gly-Gly” or "Ac-Lys-Gly-Gly” ⁇ the left side is connected to XX0 ⁇ )
- AA1 is an amino group (which may be an amino group on a chiral carbon atom or a primary amino group when a plurality of amino groups are present in an amino acid) is a C 1-3 alkyl group (for example, methyl, ethyl, n-propyl or Isopropyl) a substituted or unsubstituted amino acid (the "substituted amino acid” such as N-Me-Ala, N-Me-D-Ala, N-Me-Leu, N-Me-D-Leu, N-Me-Phe or N-Me-D-Phe): D-Ala, Leu, D-Leu, Tyr, D-Tyr, Thi, (S)-Pip, Ala, ⁇ MeTyr, 1Nal, 2Nal, 4Pal, Dap (Dnp), D-2Fua, Pro(5Ph), 2Pal, 3Pal, Tyr(Me), Ala(dip), A
- AA2 is Asn, Hyp, Pro, Ala, Thz, Pro(diF), Pro(4-NH 2 ), Thi, NAsn, ACPA, D-2Fua, A6c, azaPro, Ind, (S)-Pip, (R) -Pip, Oic, azaTic or D-Tic;
- XX3 is Trp, Ala, Phe(4-I) or a chemical bond
- AA5 is 2Fua, Thr or Ser
- AA6 is an amino group (which may be an amino group on a chiral carbon atom or a primary amino group when a plurality of amino groups are present in an amino acid) is a C 1-3 alkyl group (for example, methyl, ethyl, n-propyl or Isopropyl) substituted or unsubstituted amino acid (the "substituted amino acid” such as N-Me-Phe): Ala, 1Nal, 2Nal, Trp, ⁇ MePhe, Bta, 4Pal, HoPhe, BetaPhe, BetaHomoPhe, Bpa , Ala(dip), Bip, D-2Fua, A6c, Tic, azaTic, azaPhe, and ⁇ eg Phe, D-Phe, Phe(4-F), Phe(pentaF), Phe(3-Cl), Phe(2-Br), Phe(4-I), Phe(4-tBu), or P
- AA7 is an amino group (which may be an amino group on a chiral carbon atom or a primary amino group when a plurality of amino groups are present in an amino acid) is a C 1-3 alkyl group (for example, methyl, ethyl, n-propyl or Isopropyl) substituted or unsubstituted amino acid (the "substituted amino acid” such as N-Me-A6c or aza-N-Me-Gly): Gly, azaGly, Ala, Ava, Aib, Sar, Chg , BetaAla, ACPO, Aze, D-2Fua, A6c, azaPro, Ind, (S)-Pip, (R)-Pip, azaTic, Oic, Hyp, cycloLeu, BetaHomoAla, Cba, ACPA and
- AA6-AA7 refers to the carboxyl group of AA6 (which may be a carboxyl group on a chiral carbon atom when a plurality of carboxyl groups are present in an amino acid) and the amino group of AA7 (when a plurality of amino groups are present in an amino acid, it may be a chiral carbon atom)
- the upper amino group may also be a primary amino group a group, or "the carboxyl group of AA6 is bonded to the amino group of AA7" In the group A group formed by substitution with any of the following groups: The left end of the group is attached to AA6 (for example, when AA6 is Phe and AA7 is Gly, "AA6-AA7" means );
- AA6 and AA7 are formed together.
- AA9 is an amino group (which may be an amino group on a chiral carbon atom or a primary amino group when a plurality of amino groups are present in an amino acid) is a C 1-3 alkyl group (for example, methyl, ethyl, n-propyl or Isopropyl) a substituted or unsubstituted amino acid (the "substituted amino acid” such as N-Me-Arg, N-Me-HoLeu or N-Me-D-HoLeu): Arg, Arg(Me), Ala, His, HoLeu, D-HoLeu, 4Pal, Phe (4-amidino),
- AA10 is an amino group (which may be an amino group on a chiral carbon atom or a primary amino group when a plurality of amino groups are present in an amino acid) is a C 1-3 alkyl group (for example, methyl, ethyl, n-propyl or Isopropyl) substituted or unsubstituted amino acid (the "substituted amino acid” such as N-Me-Phe): Trp, Ala, ⁇ MePhe, 1Nal, 2Nal, 4Pal, BetaPhe, BetaHoPhe, Bpa, Ala (dip ), NPhe, Bip, D-2Fua, A6c, Tic, and ⁇ eg Phe, D-Phe, Phe(4-F), Phe(pentaF), Phe(2-Br), Phe(4-I), or Phe(4-CF 3 ) ⁇ ; n10 is 0-5 (eg, 0, 1, 2, 3, 4 or 5), all R 10
- P is -NH 2 , -OH, -NH-tBu, -NH-Et, -NH-Me, 1H-1,2,3-triazol-4-yl or 2H-tetrazol-5-yl.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- n 1 or 2.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- each group in the compound 1 can be as follows (unannotated definition as described above):
- n 1 to 3.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- R a is CH 3 - and q is 0 to 14 (for example, a range in which any two of the following values are endpoints: 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16); or, R a is HOOC-, q is 1 to 16 (for example, a range of endpoints with any of the following two values: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16).
- each group in the compound 1 can be as follows (unannotated definition as described above):
- n 0 to 2 (for example, 1).
- each group in the compound 1 can be as follows (unannotated definition as described above):
- X is -NH 2 .
- each group in the compound 1 can be as follows (unannotated definition as described above):
- k is independently 2 to 8 (for example, a range in which the following two values are endpoints: 2, 3, 4, 5, 6, 7, and 8; again, for example, 4 to 8).
- each group in the compound 1 can be as follows (unannotated definition as described above):
- XX0 is independently (E.g, Can be a chemical bond, "OEG”, “PEG4", “PEG8”, “OEG-OEG”, “PEG4-PEG4" or ).
- each group in the compound 1 can be as follows (unannotated definition as described above):
- n is 0 to 3 (for example, 0, 1, 2 or 3).
- each group in the compound 1 can be as follows (unannotated definition as described above):
- All AA0 are independently Gly or Ac-Lys. (For example, when n is 2 or 3, at least 2 AA0 are Gly; for another example, Can be a chemical bond, "Gly-Gly” or "Ac-Lys-Gly-Gly” ⁇ the left side is connected to XX0 ⁇ )
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA1 is Tyr, D-Tyr, or D-2 Fua.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA2 is Asn, Hyp, or Pro(diF).
- each group in the compound 1 can be as follows (unannotated definition as described above):
- XX3 is a Trp or a chemical bond.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA5 is Thr or Ser.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA6 is Phe.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA7 is Gly, azaGly, Aze, D-2Fua or A6c.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA9 is Arg or Arg(Me).
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA10 is Trp or Phe.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- P is -NH 2 .
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA1 is Dap (Dnp), D-Phe (2,4-diCl), D-Tic, 2Pal, 3Pal, D-Tyr, Ala(dip), or D-2Fua.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA2 is Thz, (S)-Pip, Oic, A6c, Thi, D-2 Fua, ACPA or Pro.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA5 is 2Fua.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA6 is Phe.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA7 is azaGly, Aib, A6c, cycloLeu, Ind, Cba, Aze or Gly (eg "AA6-AA7" means ).
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA6 and AA7 are formed together.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA10 is 2-Nal.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- P is -NH 2 .
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA1 is Dap (Dnp), D-Phe (2,4-diCl), D-Tic, 2Pal, 3Pal, Tyr, D-Tyr, Ala(dip), or D-2Fua; n1 is 1 or 2, and all R 1 are independently C 1 -C 3 alkyl (eg methyl, ethyl, n-propyl or iso) Propyl), C 1 -C 3 alkoxy (for example methoxy, ethoxy, n-propoxy or isopropoxy) or halogen (for example fluorine or chlorine).
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA2 is Thz, (S)-Pip, Oic, A6c, Thi, D-2 Fua, ACPA, Pro, Asn, Hyp, or Pro (diF).
- each group in the compound 1 can be as follows (unannotated definition as described above):
- XX3 is a Trp or a chemical bond.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA5 is 2Fua, Thr or Ser.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA6 is Phe
- AA7 is Aib, cycloLeu, Ind, Cba, Gly, azaGly, Aze, D-2Fua or A6c (eg "AA6-AA7" means );
- AA6 and AA7 are formed together.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA9 is Arg or Arg(Me).
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA10 is 2-Nal, Trp or Phe.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- P is -NH 2 .
- each group in the compound 1 can be as follows (unannotated definition as described above):
- All AA0 are independently Gly, BetaAla, Ac-Lys or Ahx.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA1 is D-Tyr, D-Phe(2,4-DiCl), D-2Fua, L-Phe(4-F), D-Phe(4-F), Thi, (S)-Pip, D-Tic , Dap (Dnp), D-Phe (4-Cl), D-Phe (3-Cl), 2-Pal, 3Pal, Ala (dip), or ACPA.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA2 is Hyp, Thi, A6c, Thz, Pro(diF), Pro, Pro(4-NH 2 ), D-2Fua, (S)-Pip, ACPA, (R)-Pip or Oic.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- XX3 is a Trp or a chemical bond.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA5 is 2Fua or Thr.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA6 is Phe.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA7 is azaGly, Aib, A6c, cycloLeu, Ind, Cba, Aze, Gly or D-2 Fua or Aze. (eg "AA6-AA7" is )
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA6 and AA7 are formed together.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA9 is Arg(Me).
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA10 is Trp or 2-Nal.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- P is OH or NH 2 .
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA1 is D-Tyr, D-Phe (2,4-DiCl), D-2 Fua, Thi, (S)-Pip or D-Phe (4-F).
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA2 is Hyp, Thi, A6c, Thz, Pro(diF), Pro(4-NH 2 ), D-2Fua, (S)-Pip, (R)-Pip or Oic.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- XX3 is a chemical bond.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA6 is Phe.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA7 is AzaGly, A6c, D-2Fua or Aze. (eg "AA6-AA7" is )
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA6 and AA7 are formed together.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA9 is Arg(Me).
- each group in the compound 1 can be as follows (unannotated definition as described above):
- AA10 is Trp or 2-Nal.
- each group in the compound 1 can be as follows (unannotated definition as described above):
- P is OH or NH 2 .
- the compound 1 can be any of the following compounds:
- the present invention also provides the use of the above compound 1, a pharmaceutically acceptable salt thereof, a tautomer thereof, a crystal form thereof, a solvate thereof or a prodrug thereof for the preparation of a medicament, which is used for the preparation of a medicament Treating and/or preventing diseases associated with kissing peptide receptors.
- the diseases associated with kissing peptide receptors are, for example, hormone-related diseases, cell proliferative diseases, or diseases associated with placental function.
- hormone-related diseases such as prostate cancer, breast cancer (such as pre-menopausal breast cancer), endometriosis, uterine fibroids, central precocious puberty, estrogen receptor-positive, sexually functional diseases ( For example, sexual dysfunction, coldness, infertility, depression, or pregnancy.
- the cell proliferative disorder such as benign prostatic hyperplasia or cancer.
- the cancer such as prostate cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer, endometrial cancer, thyroid cancer, bladder cancer, liver cancer, melanoma, pancreatic cancer, gastric cancer, renal cell carcinoma, esophageal cancer (such as esophagus) Squamous cell carcinoma), bladder cancer or brain cancer.
- the diseases associated with placental function such as choriocarcinoma, invasive hernia, abortion, fetal hypoplasia, abnormal glucose metabolism or abnormal lipid metabolism.
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising the above compound 1, a pharmaceutically acceptable salt thereof, a tautomer thereof, a crystal form thereof, a solvate thereof or a prodrug thereof, and one or A variety of pharmaceutical excipients.
- the pharmaceutical excipients may be those excipients widely used in the field of pharmaceutical production.
- the excipients are primarily used to provide a safe, stable, and functional pharmaceutical composition, and may also provide means for the subject to be dissolved at the desired rate after administration, or to promote the subject's activity after administration of the composition.
- the ingredients are effectively absorbed.
- the pharmaceutical excipient may be an inert filler or provide a function such as stabilizing the overall pH of the composition or preventing degradation of the active ingredient of the composition.
- the pharmaceutical excipient may include one or more of the following excipients: binder, suspending agent, emulsifier, diluent, filler, granulating agent, adhesive, disintegrant, lubricant, anti-adhesion Agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, reinforcing agents, adsorbents, buffers, chelating agents, preservatives, coloring agents, flavoring agents, and sweeteners.
- excipients binder, suspending agent, emulsifier, diluent, filler, granulating agent, adhesive, disintegrant, lubricant, anti-adhesion Agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, reinforcing agents, adsorbents, buffers, chelating agents, preservatives, coloring agents, flavoring agents, and sweeteners.
- compositions of the present invention can be prepared according to the disclosure using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or lyophilizing processes.
- compositions of the present invention may be formulated for administration in any form, including injection (intravenous), mucosa, oral (solid and liquid preparations), inhalation, ocular, rectal, topical or parenteral (infusion, Administration by injection, implantation, subcutaneous, intravenous, intraarterial, intramuscular).
- the pharmaceutical compositions of the invention may also be in a controlled release or delayed release dosage form (e.g., liposomes or microspheres).
- solid oral formulations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets.
- liquid preparations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions.
- topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum preparations.
- preparations for parenteral administration include, but are not limited to, solutions for injection, dry preparations which can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection.
- suitable formulations of the pharmaceutical compositions include, but are not limited to, eye drops and other ophthalmic formulations; aerosols: such as nasal sprays or inhalants; liquid dosage forms suitable for parenteral administration; suppositories and ingots Agent.
- the present invention also provides a peptide compound 3, a pharmaceutically acceptable salt thereof, a tautomer thereof, a solvate thereof, a crystal form thereof or a prodrug thereof, wherein the peptide compound 3 is as follows A structure:
- the present invention also provides the use of the above compound 3, a pharmaceutically acceptable salt thereof, a tautomer thereof, a crystal form thereof, a solvate thereof or a prodrug thereof for the preparation of a medicament, which is used for the preparation of a medicament Treating and/or preventing diseases associated with kissing peptide receptors.
- the diseases associated with kissing peptide receptors are, for example, hormone-related diseases, cell proliferative diseases, or diseases associated with placental function.
- hormone-related diseases such as prostate cancer, breast cancer (such as pre-menopausal breast cancer), endometriosis, uterine fibroids, central precocious puberty, estrogen receptor-positive, sexually functional diseases ( For example, sexual dysfunction, coldness, infertility, depression, or pregnancy.
- the cell proliferative disorder such as benign prostatic hyperplasia or cancer.
- the cancer such as prostate cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer, endometrial cancer, thyroid cancer, bladder cancer, liver cancer, melanoma, pancreatic cancer, gastric cancer, renal cell carcinoma, esophageal cancer (such as esophagus) Squamous cell carcinoma), bladder cancer or brain cancer.
- the diseases associated with placental function such as choriocarcinoma, invasive hernia, abortion, fetal hypoplasia, abnormal glucose metabolism or abnormal lipid metabolism.
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising the above compound 3, a pharmaceutically acceptable salt thereof, a tautomer thereof, a crystal form thereof, a solvate thereof or a prodrug thereof, and one or A variety of pharmaceutical excipients.
- the pharmaceutical excipients may be those excipients widely used in the field of pharmaceutical production.
- the excipients are primarily used to provide a safe, stable, and functional pharmaceutical composition, and may also provide means for the subject to be dissolved at the desired rate after administration, or to promote the subject's activity after administration of the composition.
- the ingredients are effectively absorbed.
- the pharmaceutical excipient can be an inert filler or provide a function, such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition.
- the pharmaceutical excipient may include one or more of the following excipients: binder, suspending agent, emulsifier, diluent, filler, granulating agent, adhesive, disintegrant, lubricant, anti-adhesion Agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, reinforcing agents, adsorbents, buffers, chelating agents, preservatives, coloring agents, flavoring agents, and sweeteners.
- excipients binder, suspending agent, emulsifier, diluent, filler, granulating agent, adhesive, disintegrant, lubricant, anti-adhesion Agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, reinforcing agents, adsorbents, buffers, chelating agents, preservatives, coloring agents, flavoring agents, and sweeteners.
- compositions of the present invention can be prepared according to the disclosure using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or lyophilizing processes.
- compositions of the present invention may be formulated for administration in any form, including injection (intravenous), mucosa, oral (solid and liquid preparations), inhalation, ocular, rectal, topical or parenteral (infusion, Administration by injection, implantation, subcutaneous, intravenous, intraarterial, intramuscular).
- the pharmaceutical compositions of the invention may also be in a controlled release or delayed release dosage form (e.g., liposomes or microspheres).
- solid oral formulations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets.
- liquid preparations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions.
- topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum preparations.
- preparations for parenteral administration include, but are not limited to, solutions for injection, dry preparations which can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection.
- suitable formulations of the pharmaceutical compositions include, but are not limited to, eye drops and other ophthalmic formulations; aerosols: such as nasal sprays or inhalants; liquid dosage forms suitable for parenteral administration; suppositories and ingots Agent.
- the reagents and starting materials used in the present invention are commercially available.
- AA0-AA1 means a carboxyl group in AA0 (which may be a carboxyl group on a chiral carbon atom when an amino acid has a plurality of carboxyl groups) and an amino group in AA1 (when an amino group has a plurality of amino groups, it may be a hand) Amino groups on a carbon atom, which may also be formed by the attachment of a primary amino group Group.
- PEG-PEG (in this case, the carboxyl group of the previous PEG is linked to the amino or hydroxyl group of the latter PEG), "PEG-AA0", “PEG-AA1”, “PEG'-AA0'”, “PEG'-AA1””,AA0-AA0”,”AA1-AA2",”AA2-XX3”,”AA2-Asn”,”XX3-Asn”,”Asn-AA5",”AA5-AA6",”AA6-AA7”,”AA7-Leu” and “AA9-AA10" are the same.
- AA6-AA7 means That is, the left end of Equation 1 is the N end, and the right end is the C end.
- AA10-P refers to a group in which -OH in the carboxyl group (-COOH) of AA10 is replaced by P, for example, when AA10 is Phe and P is -NH 2 , "AA10-P" is Means If the right end of the specific sequence ends with an amino acid (AA10), it is not clear which group -P is, indicating that the default P is -OH.
- the "chemical bond” in XX3 means that the groups before and after the site are linked by a chemical bond "-", and the specific chemical bond has the same meaning as above.
- the case where "m is 0" and "n is 0" is the same.
- XX3 is a chemical bond
- AA2 and Asn are linked by a chemical bond "-"
- AA2-Asn is the case of "AA2-Asn”.
- amino acid includes water-soluble organic compounds having a carboxyl (-COOH) and amino (-NH 2 ) group attached to an a-carbon atom.
- Amino acids can be represented by the formula R-CH(NH 2 )COOH; the R group is hydrogen or an organic group and determines the nature of any particular amino acid.
- R-CH(NH 2 )COOH the R group is hydrogen or an organic group and determines the nature of any particular amino acid.
- the tetrahedral arrangement of four different groups around the alpha-carbon atom renders the amino acid optically active.
- the two mirror images are referred to as the L-isomer and the D-isomer.
- L-amino acids are components of proteins such as eukaryotic proteins.
- the peptide molecules of the invention comprise L-amino acids.
- a D-amino acid is present in a peptide molecule of the invention, it is represented by a conventional one-letter amino acid code with the prefix "(D)".
- the molecule of the present invention may comprise a peptide sequence having an "arbitrary D-amino acid” at a specific position or a peptide sequence having an "arbitrary D-amino acid” at a specific position.
- the "arbitrary D-amino acid” includes any natural or non-natural (eg, chemically modified) D-amino acid at a particular position in the sequence.
- Examples of natural D-amino acids are as follows: D-alanine; D-aspartic acid; D-cysteine; D-glutamic acid; D-phenylalanine; D-glycine; D-histidine D-isoleucine; D-lysine; D-leucine; D-methionine; D-asparagine; D-valine; D-glutamine; D-arginine; D- Serine; D-threonine; D-valine; D-tryptophan; D-tyrosine.
- non-natural D-amino acids are as follows: naphthylalanine; D-pyridylalanine; D-tert-butylserine; D-ornithine; D- ⁇ -aminolysine; D-homoarginine ; D- ⁇ methyl leucine and the substitution of halogens (such as F) and protons in these other unnatural amino acids.
- the amino acid By forming a peptide bond, the amino acid combines to form a short chain (peptide) or a longer chain (polypeptide).
- Proteins and/or peptides are known to be composed of approximately 20 common amino acids in different flow ratios, the sequence of which determines the shape, properties and biological effects of the protein and/or peptide.
- Amino acid residues in such peptides or polypeptide chains are usually represented by their arrangement on the chain, and the first position (ie, position 1) is designated as the N-terminal amino acid of the chain.
- pharmaceutically acceptable salt refers to a pharmaceutically acceptable organic or inorganic salt.
- exemplary acid salts include, but are not limited to, sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, hydrogen sulfates, phosphates, acid phosphates, isoniazids Acid salt, lactate, salicylate, acid citrate, tartrate, oleate, tannic acid, pantothenate, hydrogen tartrate, ascorbate, succinate, maleate, Fumarate, gluconate, glucuronate, sugar, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, besylate, P-toluenesulfonate and pamoate (i.e., 1-1-methylene-bis(2-hydroxy-3-naphthoate)).
- Suitable base salts include, but are not limited to, aluminum salts, calcium salts, lithium salts, magnesium salts, potassium salts, sodium salts, zinc salts, barium salts, and diethanolamine salts.
- Suitable base salts include, but are not limited to, aluminum salts, calcium salts, lithium salts, magnesium salts, potassium salts, sodium salts, zinc salts, barium salts, and diethanolamine salts.
- crystalline form refers to one or more crystal structures formed by the different arrangement of molecules in the lattice space upon crystallization.
- solvate is a crystalline form which, in addition to the active molecule, contains one or more solvent molecules incorporated into the crystal structure.
- the solvate may include a stoichiometric or non-stoichiometric amount of solvent, and the solvent molecules in the solvent may be present in an ordered or non-ordered arrangement. Solvates containing non-stoichiometric amounts of solvent molecules may be obtained by the solvate losing at least a portion, but not all, of the solvent molecules.
- a solvate is a hydrate, meaning that the crystalline form of the compound can include water molecules.
- prodrug refers to a derivative of a compound comprising a biologically reactive functional group such that under biological conditions (in vitro or in vivo), the bioreactive functional group can be cleaved from the compound or otherwise reacted to provide the compound.
- the prodrug is inactive, or at least less active than the compound itself, such that the compound does not exert its activity until it is cleaved from the biologically reactive functional group.
- the bioreactive functional group can be hydrolyzed or oxidized under biological conditions to provide the compound.
- a prodrug can comprise a biohydrolyzable group
- biohydrolyzable groups include, but are not limited to, biohydrolyzable phosphates, biohydrolyzable esters, biohydrolyzable amides, biohydrolyzable carbonates, Biohydrolyzable carbamate and biohydrolyzable ureide.
- alkyl refers to a saturated monovalent hydrocarbon radical straight or branched chain of eighteen carbon atoms (e.g., C 1 -C 6 alkyl, and C 1 -C 4 alkyl, for example).
- alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-butyl, 2-butyl, 2-methyl-2 -propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2 -methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl , 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-di
- a positive progressive effect of the present invention is that the compounds of the present invention are more stable and have better activity against Kiss1R.
- the peptide compounds of the present invention are all synthesized by the Fmoc-polyamide solid phase peptide synthesis method disclosed in Lu et al (1981) J. Org. Chem. 46, 3433, the references thereof.
- the 9-fluorenylmethoxycarbonyl (Fmoc) group provides temporary N-amino protection. Repeated removal of this highly base labile protecting group was carried out using 20% piperidine in N,N-dimethylformamide.
- the side chain functional group can be protected as its butyl ether (for the case of serine, threonine and tyrosine), butyl ester (for the case of glutamic acid and aspartic acid), butoxycarboxy derivative ( For the case of lysine and histidine), a trityl derivative (for the case of asparagine and glutamine) and 4-methoxy-2,3,6-trimethylbenzenesulfonyl derivative (for the case of arginine).
- the C-terminal residue is glutamine or asparagine
- the 4,4'-dimethoxybenzhydryl group is used to protect the side chain amino functionality.
- the solid phase carrier is based on polydimethylene consisting of three monomers: dimethyl acrylamide (backbone monomer), bisacryloylethylenediamine (crosslinking agent) and acryloyl sarcosinate methyl ester (functionalizing agent). Alkyl-acrylamide polymer.
- the peptide-resin cleavable linker used is an acid labile 4-hydroxymethyl-phenoxyacetic acid derivative. Except for asparagine and glutamine, all amino acid derivatives were added as their pre-formed symmetrical anhydride derivatives, and reverse N,N-dicyclohexylcarbodiimide/1-hydroxybenzotriazole was used. The coupling method was introduced by adding asparagine and glutamine.
- Any scavenger present is removed by a simple extraction step in which the crude peptide free of scavenger is provided by freeze-drying the aqueous phase.
- Reagents for peptide synthesis are generally available from Calbiochem-Novabiochem (UK) Ltd, Nottingham NG72QJ, UK. Purification can be achieved by any one or combination of techniques such as size exclusion chromatography, ion exchange chromatography, and (primarily) reverse phase high performance liquid chromatography. Analysis of the peptide can be carried out using thin layer chromatography, reversed phase high performance liquid chromatography, amino acid analysis after acid hydrolysis, and rapid atom bombardment (FAB) mass spectrometry.
- FAB rapid atom bombardment
- the peptide compounds of the present invention can also be synthesized using a liquid phase method well known to those skilled in the chemical and biochemical arts.
- the peptide sequences of the active agents of the invention can be purified using methods known in the art, such as HPLC and chromatography.
- Step 1 (S)-2-(2-(((9-Hydrazin-9-yl)methoxy)carbonyl)amino)-3-phenylpropionyl) decylcarboxylate tert-butyl ester (Compound YA-3- A)
- Step 2 (S)-2-(2-(((hydro)-9-yl)methoxy)carbonyl)amino)-3-phenylpropionyl)hydrazine hydrochloride (Compound YA-3-B)
- Step 3 (2-(((9-Hydroxy-9-yl)methoxycarbonyl)-L-phenylalanyl-2-mercapto-1-carbonyl-L-leucine tert-butyl ester ( Compound YA-3-C)
- Step 4 (2-(((9-Hydroxy-indol-9-yl)methoxycarbonyl-L-phenylalanyl-2-mercapto-1-carbonyl-L-leucine (Compound YA-3) -D)
- Step 1 (R)-2-(2-(((hydro)-9-yl)methoxy)carbonyl)amino)-3-(furan-2-yl)propanoyl)carboxylic acid tert-butyl ester ( Compound YA-167-a)
- Step 2 Hydrochloride of (R)-2-(2-(((hydro)-9-yl)methoxy)carbonylamino)-3-(furan-2-yl)propanoyl)hydrazine ( Compound YA-167-b)
- Step 3 (5R,11S)-1-(9-hydrogen-9-yl)-5-(furan-2-ylmethyl)-11-isobutyl-3,6,9-trioxo- 2-oxa-4,7,8,10-tetraazadecane-12-acid tert-butyl ester (compound YA-167-c)
- Step 4 (5R,11S)-1-(9-hydrogen-9-yl)-5-(furan-2-ylmethyl)-11-isobutyl-3,6,9-trioxo- 2-oxa-4,7,8,10-tetradecadecane-12-acid (compound YA-167-d)
- Step 1 Tert-butyl phthalate-1,2-dicarboxylate (compound YA-184-a)
- Step 2 Pyrazolidine-1,2-dicarboxylate tert-butyl ester (compound YA-184-b)
- Step 3 Pyrazolidine-1,2-diacid mono-tert-butyl ester (compound YA-184-c)
- Step 4 (S)-2-(2-((9-Hydroxy-indol-9-yl)methoxy)carbonylamino)-3-phenylpropionyl)pyrazolidine-1-carboxylic acid tert-butyl ester ( Compound YA-184-d)
- Step 5 (S)-2-(2-(((9-Hydroxy-9-yl))methoxy)carbonyl)amino)-3-phenylpropionyl)pyrazolidine (Compound YA-184-e)
- Step 6 (S)-2-(2-((S)-2-(((9-hydro)-9-yl)methoxy)carbonyl)amino)-3-phenylpropionyl)pyrazol-1 -formamide)-4-methylpentanoic acid tert-butyl ester (compound YA-184-f)
- Step 7 (S)-2-(2-((S)-2-(((9-hydro)-9-yl)methoxy)carbonyl)amino)-3-phenylpropionyl)pyrazol-1 -carboxamido)-4-methylpentanoic acid (compound YA-184-g)
- Step 1 (R)-2-(2-((9-Hydroxy-indol-9-yl)methoxy)carbonylamino)-3-phenylpropionyl)-3-(2,4-dichlorophenyl) Propionyl)pyrazolidine-1-carboxylic acid tert-butyl ester (compound YA-200-a)
- Step 2 (R)-2-(2-(((hydro)-9-yl)methoxy)carbonylamino)-3-phenylpropanoyl)-3-(2,4-dichlorophenyl) Propionyl)pyrazolidine (compound YA-200-b)
- Step 3 (S)-2-(2-((R)-2-(((9-hydro-indol-9-yl)methoxy)carbonyl)amino)-3-(2,4-dichlorophenyl) Propionyl)pyrazol-1-ylcarboxamide)-4-oxo-4-(tritylamino)butyric acid allyl ester (compound YA-200-c)
- Step 4 (S)-2-(2-((R)-2-(((9-hydro-indol-9-yl)methoxy)carbonylamino)-3-phenylpropanoyl)-3-(2) ,4-dichlorophenyl)propionyl)pyrazol-1-ylcarboxamide)-4-oxo-4-(tritylamino)butanoic acid (compound YA-200-d)
- Step 1 tert-Butyl (S)-(2-phenyl-1-(5-(trifluoromethyl)-1hydro-imidazol-2-yl)ethyl)carbonate (Compound YA-208-a)
- Step 2 tert-Butyl (S)-(2-phenyl-1-(5-(trimethoxymethyl)-1hydro-imidazol-2-yl)ethyl)carbonate (Compound YA-208-b )
- Step 3 (S)-2-(1-Amino-2-phenylethyl)-1hydro-imidazole-5-methyl carbonate (compound YA-208-c)
- Step 4 (S)-2-(1-Amino-2-phenylethyl)-1hydro-imidazole-5-carboxylic acid (Compound YA-208-d)
- Step 5 (S)-2-(1-((((hydro)-9-yl)methoxy)carbonyl)amino)-2-phenylethyl)-1 -hydro-imidazole-5-carboxylic acid (Compound YA-208-e)
- Step 1 (9-Hydroxy-fluoren-9-yl)methyl 2-benzyl hydrazine carbonate (compound YA-241-a)
- Step 3 (S)-8-Benzyl-5-((R)-1-tert-butoxyethyl)-1-(9-hydrogen-9-yl)-3,6,9-tricarbonyl- Methyl 2-oxa-4,7,8,10-tetraazadodecane-12-carboxylate (Compound YA-241-c)
- Step 4 (S)-8-Benzyl-5-((R)-1-tert-butoxyethyl)-1-(9-hydrogen-9-yl)-3,6,9-tricarbonyl- 2-oxa-4,7,8,10-tetraazadodecane-12-carboxylic acid (compound YA-241-d)
- Step 2 3-(4-(1H-pyrazol-1-yl)phenyl)-2-(tert-butoxycarbonylamino)propanoic acid (Compound YA-242-B)
- Step 3 3-(4-(1H-pyrazol-1-yl)phenyl)-2-(((9-hydro-indol-9-yl)methoxy)methoxy))propanoic acid (compound) YA-242-C)
- reaction mixture was adjusted to pH 3-4 with 1 mol/L hydrochloric acid, and then extracted with ethyl acetate (100 mL ⁇ 3) and washed with brine (150 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporated.
- Step 1 p-Nitrophenyloxycarbonyl-L-leucine tert-butyl ester (Compound YA-247-A)
- Step 2 (2-(((9(hydro)-9-yl)methoxy)carbonyl))-L-phenylalanyl)-2-methylindole-1-carbonyl) tert-butyl ester (compound) YA-247-B)
- Step 3 (2-(((9(hydro)-9-yl)methoxy)carbonyl)-L-phenylalanyl)-2-methylindole-1-carbonyl (Compound YA-247-C )
- Step 4 (2-((((hydro)-9-yl)methoxy)carbonyl)-L-phenylalanyl)-2-methylindole-1-carbonyl)-L-leucine Tert-butyl ester (compound YA-247-D)
- Step 5 (2-((((hydro)-9-yl)methoxy)carbonyl)-L-phenylalanyl)-2-methylindole-1-carbonyl)-L-leucine (Compound YA-247-E)
- Step 2 (S)-(S)-2-((tert-Butoxycarbonyl)amino)-3-phenylpropionic acid acetic anhydride (YA-209-B)
- N-tert-butoxycarbonyl-L-phenylalanine (10 g, 37.7 mmol) and triethylamine (7.62 g, 75.5 mmol) were dissolved in tetrahydrofuran (100 mL), then ethyl chloroformate (6.11) was added dropwise at zero degrees Celsius. g, 56.6 mmol), and the reaction solution was stirred at 0 ° C for 2 hours. The reaction solution was concentrated and used directly in the next step.
- Step 3 (E)-2-Amino-2-(2-((tert-butoxycarbonyl)-L-phenylpropyl)indolyl)acetate (YA-209-C)
- Step 4 (S)-5-(1-((tert-Butoxycarbonyl)amino)-2-phenylethyl)-4H-1,2,4-triazole-3-carboxylate (YA-209 -D)
- Step 5 5-((S)-1-((2S,3R)-2-(((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(tert-butoxy) Ethyl butylamino)-2-phenylethyl)-4H-1,2,4-triazole-3-carboxylate (YA-209-E)
- Step 6 5-((S)-1-((2S,3R)-2-(((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(tert-butoxy) Butylamino)-2-phenylethyl)-4H-1,2,4-triazole-3-carboxylic acid (YA-209-F)
- Step 7 (5-((S)-1-((2S,3R)-2-(((9H- ⁇ -9-yl)methoxy)carbonyl)amino)-3-(tert-butoxy) Butylamino)-2-phenylethyl)-4H-1,2,4-triazole-3-carbonyl)-L-leucine methyl ester (YA-209-G)
- Step 8 (5-((S)-1-((2S,3R)-2-(((9H- ⁇ -9-yl)methoxy)carbonyl)amino)-3-(tert-butoxy) Butylamino)-2-phenylethyl)-4H-1,2,4-triazole-3-carbonyl)-L-leucine (YA-209-H)
- Step 1 (S)-3-(2-(((9(hydro)-9-yl)methoxy)carbonyl)amino)-3-amino-3-oxapropyl)-1hydro-indole ⁇ -1-tert-butyl carbonate (compound YA-250-a)
- Step 3 (9-Hydroxy-fluoren-9-yl)methyl)(S)-(2-1-hydro-indol-3-yl)-1-(1hydro-tetrazol-5-yl)carbonate ( Compound YA-250-c)
- Step 4 (S)-2-(1H-indol-3-yl)-1-(1H-tetrazol-5-yl)ethylamine (Compound YA-250-d)
- Step 2 2-(Aminomethylaminomethylsulfanyl)-4-methylpentanoate ethyl ester hydrobromide (YA-254-B)
- Step 3 (5S)-5-Benzyl-1-(9-hydrogen-9-yl)-11-isobutyl-3,6-dioxo-10-thio-2-oxa-4 , 7,9-triazadecane-12-carboxylic acid ethyl ester (YA-254-C)
- Step 4 2-(((S)-2-Amino-3-phenylpropionamido)methylaminothiocarbonyl)-4-methylpentanoic acid (YA-254-D)
- Step 5 (5S)-5-benzyl-1-(9-hydrogen-indol-9-yl)-11-isobutyl-3,6,-dioxo-10-thio-2-oxa- 4,7,9-triazanonane-12-carboxylic acid (YA-254-E)
- Step 1 Benzyl 2-amino-2-oxaethyl carbonate (YA-256-A)
- Step 3 ((Benzyloxycarbonylaminomethyl)carbamoyl)-L-leucine tert-butyl ester (YA-256-C)
- Step 4 (Aminomethylcarbamoyl)-L-leucine tert-butyl ester (YA-256-D)
- Step 5 (((()))((((((()))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))
- Step 1 (S)-(4-(Dimethoxyphosphino)-3-oxa-1-phenylbutyl-2-yl)carbamic acid tert-butyl ester (Compound YA-274-a)
- the dimethyl methyl phosphate (14.2 g, 114.5 mmol) was dissolved in dry tetrahydrofuran (100 mL), cooled to -78 ° C, then BuLi (2.5 N in hexane, 45.8 mL, 114.5 mmol) was added dropwise. The reaction was carried out at ° C for 1 hour. Then, a solution of Boc-L-phenylalanine methyl ester (6.4 g, 22.9 mmol) in tetrahydrofuran (50 mL) was added dropwise, and the mixture was reacted at -78 ° C for 2 hours.
- Step 2 (S,E)-5-((tert-Butoxycarbonyl)amino)-4-oxa-6-phenylhex-2-enoate (Compound YA-274-b)
- Step 3 (S)-5-((tert-Butoxycarbonyl)amino)-4-oxa-6-phenylhexanoic acid ethyl ester (Compound YA-274-c)
- Step 4 (S)-5-((tert-Butoxycarbonyl)amino)-4-oxa-6-phenylhexanoic acid (Compound YA-274-d)
- Step 5 (S)-5-((((9-Hydrazin-9-yl)methoxy)carbonyl)amino)-4-oxa-6-phenylhexanoic acid (Compound YA-274-e)
- Step 1 4-(2-(((9(hydro))-9-yl)methoxy)carbonyl)-1-benzylindenyl)-4-oxobutanoate tert-butyl ester (Compound YA-275- a)
- Step 2 4-(2-(((hydro)-9-yl)methoxy)carbonyl)-1-benzylindenyl)-4-oxobutanoic acid (Compound YA-275-b)
- Step 1 Isobutylmalonate monoethyl ester potassium salt (YA-303-A)
- Step 4 2-((Benzyloxycarbonylamino)methylcarbamoyl)-4-methylpentanoate (YA-303-D)
- Step 6 (5S)-5-benzyl-1-(9-hydrogen-9-yl)-11-isobutyl-3,6,10-trioxo-2-oxa-4,7, 9-Triazadecane-12-carboxylic acid ethyl ester (YA-303-F)
- Step 7 2-(((S)-2-Amino-3-phenylpropionamido)methylamino)-4-methylpentanoic acid (YA-303-G)
- Step 8 (5S)-5-benzyl-1-(9-hydrogen-9-yl)-11-isobutyl-3,6,10-trioxo-2-oxa-4,7, 9-triazanonane-12-carboxylic acid (YA-303-H)
- Step 2 (1-(cinnamamide-PEG5)-1,2,3-triazaindene)-4-acetic acid (YA-326-B)
- Step 1 The polypeptide is synthesized by standard Fmoc chemistry, and the basic operation is as follows. 5.0 g of commercially available Rink Amide MBHA resin (0.5 mmol/g) was swollen in DMF and treated with 20 mL of 20% piperidine/DMF for 20 minutes to remove Fmoc, which was repeated twice.
- the obtained resin was washed with DMF, and a solution of Fmoc-Phe-OH (2.9 g, 7.5 mmol), HATU (2.85 g, 7.5 mmol) and HOAt (1.04 g, 7.5 mmol) in 20 mL DMF was added, then DIPEA (2.6 mL, 15 mmol), treated at room temperature for 40 minutes, and the resin was washed with DMF to obtain Fmoc-Phe-Rink Amide MBHA resin. The resin was treated with 20 mL of 20% piperidine/DMF for 20 minutes to remove Fmoc.
- the resin was washed with DMF, DCM, methanol, methyl tert-butyl ether, and then dried to give 8.5 g of Ac-NH 2 -D-Tyr(tBu)-Asn(Trt)-Trp(Boc)-Asn ( Trt)-Thr(tBu)-Phe-Gly-Leu-Arg-Phe-Rink Amide MBHA resin.
- Step 2 The dried resin was added to 85 mL of TFA/TIS/EDT/H 2 O (94/2/2/2) solution, the mixture was stirred for 2 hours, and the resin was removed by filtration, using 20 mL of TFA/TIS/EDT/ The resin was washed with a H 2 O (94/2/2/2) solution. The filtrate was combined, and ice diethyl ether (1000 mL) was added to the filtrate. The obtained mixture was centrifuged at 3,000 rpm for 3 minutes, the supernatant was removed, and the solid was washed twice with diethyl ether and dried.
- Step 3 The obtained crude polypeptide was dissolved in DMF, followed by a linear gradient elution (10 minutes) at a flow rate of 25 mL/min, eluent A/B: 74/26-64/36, using: eluent A: An aqueous solution of 0.05% TFA, eluent B: 0.05% TFA in acetonitrile, on a preparative HPLC using Sunfire C18, 10 um, Column (19 x 250 mm). The fractions containing the product were collected and lyophilized to give 1.1 g of a white solid.
- Step 1 5.0 g of commercially available Rink Amide MBHA resin (0.5 mmol/g) was swollen in DMF and treated with 20 mL of 20% piperidine/DMF for 20 minutes to remove Fmoc, which was repeated twice.
- the obtained resin was washed with DMF, and a solution of Fmoc-Trp(Boc)-OH (4.0 g, 7.5 mmol), HATU (2.85 g, 7.5 mmol) and HOAt (1.04 g, 7.5 mmol) in 20 mL DMF was added, then DIPEA ( 2.6 mL, 15 mmol), treated at room temperature for 40 minutes, and the resin was washed with DMF to give Fmoc-Trp(Boc)-Rink Amide MBHA resin.
- the resin was treated with 20 mL of 20% piperidine/DMF for 20 minutes to remove Fmoc.
- the obtained resin was added to a solution of Fmoc-Phe-azaGly-Leu-OH (1.68 g, 3.0 mmol), DIC (945 mg, 7.5 mmol) and HOBt (1.01 g, 7.5 mmol) in 15 mL of DMF at room temperature overnight; Treatment with 20 mL of 20% piperidine/DMF for 20 minutes to remove Fmoc was repeated twice; the resin was washed with DMF to give Phe-azaGly-Leu-Arg(Me, Pbf)-Trp(Boc)-Rink Amide MBHA resin.
- amino acids such as Thr(tBu), Asn(Trt), Hyp(tBu), D-Tyr(tBu) are sequentially introduced to obtain NH 2 -D-Tyr(tBu)-Hyp(tBu)-Asn( Trt)-Thr(tBu)-Phe-azaGly-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA resin.
- Step 2 The dried resin was added to 85 mL of TFA/TIS/EDT/H 2 O (94/2/2/2) solution, the mixture was stirred for 2 hours, and the resin was removed by filtration, using 20 mL of TFA/TIS/EDT/ The resin was washed with a H 2 O (94/2/2/2) solution. The filtrate was combined, and ice diethyl ether (1000 mL) was added to the filtrate. The obtained mixture was centrifuged at 3,000 rpm for 3 minutes, the supernatant was removed, and the solid was washed twice with diethyl ether and dried.
- Step 3 The obtained precipitate was dissolved in DMF, followed by linear concentration gradient elution (17 minutes) at a flow rate of 25 mL/min.
- Eluent A/B 79/21-69/31 used:
- Eluent A An aqueous solution of 0.05% TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Phenomenex Gemini 10u, Column (21.2 x 250 mm). The fractions containing the product were collected and lyophilized to give 1.2 g of trifluoroacetic acid salt.
- the crude product YA-41 was subjected to HPLC separation and purification, and subjected to linear gradient elution (10 min) at a flow rate of 25 mL/min, eluent A/B: 70/30-62/38, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire C18, 10um, Column (19 x 250 mm). The fractions containing the product were collected and lyophilized to give 10.0 mg of a white solid.
- the crude product YA-42 was subjected to HPLC separation and purification, and subjected to linear gradient elution (10 min) at a flow rate of 25 mL/min, eluent A/B: 73/27-63/37, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire C18, 5um, Column (19 x 150 mm). The fractions containing the product were collected and lyophilized to give 68.8 mg of white solid.
- Fmoc-(D-2Fua)-OH(3equivalent) was used instead of Fmoc-D-Tyr(tBu)-OH condensation
- HBTU/HOBt/DIPEA was used as condensation conditions
- DMF was used as solvent
- the mixture was at room temperature. Reaction for 3 hours.
- the resin is dried after washing.
- the target polypeptide was cleaved from the resin by the method of the second step of Example 2 and the protection was removed.
- the cutting solution contained no EDT and was a TFA/TIS/H 2 O (94/3/3) solution, and the other operations were identical.
- the crude product YA-43 was subjected to HPLC separation and purification, and subjected to a linear gradient elution (10 min) at a flow rate of 20 mL/min, eluent A/B: 78/22-70/30, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire C18, 5um, Column (19 x 150 mm). The fractions containing the product were collected and lyophilized to give 6.2 mg of a white solid.
- the crude product YA-44 was subjected to HPLC separation and purification, and subjected to linear gradient elution (10 min) at a flow rate of 25 mL/min, eluent A/B: 73/27-67/33, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire C18, 10um, Column (19 x 250 mm). The fractions containing the product were collected and lyophilized to give 28.0 mg of a white solid.
- the crude product YA-45 was subjected to HPLC separation and purification, and subjected to linear gradient elution (10 min) at a flow rate of 25 mL/min, eluent A/B: 75/25-68/32, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire C18, 10um, Column (19 x 250 mm). The fractions containing the product were collected and lyophilized to give 10.0 mg of a white solid.
- the crude product YA-69 was subjected to HPLC separation and purification, and subjected to a linear gradient elution (10 min) at a flow rate of 25 mL/min, eluent A/B: 85/15-75/25, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC, using Sunfire C18, 10um, Column (19 x 250 mm). The fractions containing the product were collected and lyophilized to give 21.6 mg of a white solid.
- the crude product YA-70 was subjected to HPLC separation and purification, and subjected to linear gradient elution (10 min) at a flow rate of 25 mL/min, eluent A/B: 73/27-64/36, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire C18, 10um, Column (19 x 250 mm). The fractions containing the product were collected and lyophilized to give 11.0 mg of a white solid.
- the crude product YA-71 was subjected to HPLC separation and purification, and subjected to a linear gradient elution (10 min) at a flow rate of 30 mL/min, eluent A/B: 68/32-62/38, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire C18, 10um, Column (19 x 250 mm). The fractions containing the product were collected and lyophilized to give 7.6 mg of a white solid.
- the crude product YA-72 was subjected to HPLC separation and purification, and subjected to a linear gradient elution (10 min) at a flow rate of 30 mL/min, eluent A/B: 61/39-54/46, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire C18, 10um, Column (19 x 250 mm). The fractions containing the product were collected and lyophilized to give 12.4 mg of a white solid.
- the crude product YA-73 was subjected to HPLC separation and purification, and subjected to a linear gradient elution (10 min) at a flow rate of 25 mL/min, eluent A/B: 76/24-68/32, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire C18, 10um, Column (19 x 250 mm). The fractions containing the product were collected and lyophilized to give 4.7 mg of a white solid.
- the crude product YA-74 was subjected to HPLC separation and purification, and subjected to a linear gradient elution (10 min) at a flow rate of 25 mL/min, eluent A/B: 73/27-65/35, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire C18, 10um, Column (19 x 250 mm). The fractions containing the product were collected and lyophilized to give 5.1 mg of a white solid.
- the crude product YA-75 was subjected to HPLC separation and purification, and subjected to a linear gradient elution (10 min) at a flow rate of 30 mL/min, eluent A/B: 62/38-56/44, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire C18, 10um, Column (19 x 250 mm). The fractions containing the product were collected and lyophilized to give 5.9 mg of a white solid.
- the crude product YA-80 was subjected to HPLC separation and purification, and subjected to linear gradient elution (10 min) at a flow rate of 30 mL/min, eluent A/B: 67/33-59/41, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire C18, 10um, Column (19 x 250 mm). The fractions containing the product were collected and lyophilized to give 8.8 mg of a white solid.
- the crude product YA-81 was subjected to HPLC separation and purification, and subjected to linear gradient elution (10 min) at a flow rate of 30 mL/min, eluent A/B: 61/39-54/46, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire C18, 10um, Column (19 x 250 mm). The fractions containing the product were collected and lyophilized to give 11.6 mg of a white solid.
- the crude product YA-83 was subjected to HPLC separation and purification, linear gradient elution (10 min), flow rate 25 mL/min, eluent A/B: 82/18-72/28, use: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire C18, 10um, Column (19 x 250 mm). The fractions containing the product were collected and lyophilized to give 29.8 mg of a white solid.
- the crude product YA-84 was subjected to HPLC separation and purification, and subjected to a linear gradient elution (10 min) at a flow rate of 30 mL/min, eluent A/B: 67/33-61/39, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire C18, 10um, Column (19 x 250 mm). The fractions containing the product were collected and lyophilized to give 15.0 mg of a white solid.
- the crude product YA-85 was subjected to HPLC separation and purification, and subjected to linear gradient elution (10 min) at a flow rate of 30 mL/min, eluent A/B: 67.5/32.5-59/41, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire C18, 10um, Column (19 x 250 mm). The fractions containing the product were collected and lyophilized to give 6.2 mg of a white solid.
- the crude product YA-132 was subjected to HPLC separation and purification, and subjected to linear gradient elution (10 min) at a flow rate of 20 mL/min, eluent A/B: 71/29-65/35, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire C18, 5um, Column (19 x 150 mm). The fractions containing the product were collected and lyophilized to give 4.6 mg of a white solid.
- Example 2 In a similar manner to the synthesis of Example 2, Fmoc-2Fua-OH (3equivalent) was used instead of Fmoc-Thr(tBu)-OH, HBTU/HOBt/DIPEA was used as a condensation condition, and DMF was used as a solvent, and the mixture was reacted at room temperature for 3 hours. The resin is dried after washing. The target polypeptide was cleaved from the resin by the method of the second step of Example 2 and the protection was removed. The cutting solution contained no EDT and was a TFA/TIS/H 2 O (94/3/3) solution, and the other operations were identical.
- the crude product YA-143 was subjected to HPLC separation and purification, and subjected to a linear gradient elution (10 min) at a flow rate of 25 mL/min, eluent A/B: 75/25-67/33, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire C18, 10um, Column (19 x 250 mm). The fractions containing the product were collected and lyophilized to give a white solid.
- the crude product YA-145 was subjected to HPLC separation and purification, and subjected to linear gradient elution (10 min) at a flow rate of 25 mL/min, eluent A/B: 78/22-68/32, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Phenomenex Gemini C18, 10um, Column (21.2 x 250 mm). The fractions containing the product were collected and lyophilized to give 17.9 mg of a white solid.
- Step 1 The polypeptide is synthesized by standard Fmoc chemistry, and the basic operation is as follows. 1.0 g of commercially available Rink Amide MBHA resin (0.5 mmol/g) was swollen in DMF, which was treated with 10 mL of 20% piperidine/DMF for 20 minutes to remove Fmoc, and this was repeated twice.
- the obtained resin was washed with DMF, and a solution of Fmoc-Trp(Boc)-OH (0.8 g, 1.5 mmol), HATU (0.57 g, 1.5 mmol) and HOAt (0.208 g, 1.5 mmol) in 10 mL DMF was added, then DIPEA ( 0.52 mL, 3 mmol), treated at room temperature for 40 minutes, and the resin was washed with DMF to give Fmoc-Trp(Boc)-Rink Amide MBHA resin. The resin was treated with 10 mL of 20% piperidine/DMF for 20 minutes to remove Fmoc.
- Step 2 The dried resin was added to 20 mL of TFA/TIS/EDT/H 2 O (94/2/2/2) solution, the mixture was stirred for 2 hours, and the resin was removed by filtration, using 4 mL of TFA/TIS/EDT/ The resin was washed with a H 2 O (94/2/2/2) solution. The filtrate was combined, and ice diethyl ether (200 mL) was added to the filtrate, and the mixture was centrifuged at 3,000 rpm for 3 minutes, the supernatant was removed, and the solid was washed twice with diethyl ether and dried.
- Step 3 The obtained crude polypeptide was dissolved in DMF, followed by a linear gradient elution (10 min) at a flow rate of 30 mL/min, eluent A/B: 77/23-67/33, using: eluent A: An aqueous solution of 0.05% TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Xtimate C18, 10 um, Column (20 x 250 mm). The fractions containing the product were collected and lyophilized to give 7.1 mg of a white solid.
- Example 23 In a similar manner to the synthesis of Example 23, Fmoc-Aze-OH (3equivalent) was used instead of Fmoc-ACPO-OH condensation, HATU/HOAt/DIPEA was used as a condensation condition, and DMF was used as a solvent, and the mixture was reacted at room temperature for 3 hours. The resin is dried after washing. The polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 23 and deprotected.
- the crude product YA-153 was subjected to HPLC separation and purification, and subjected to linear gradient elution (10 min) at a flow rate of 30 mL/min, eluent A/B: 78/22-68/32, using: eluent A: 0.05% An aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Xtimate C18, 10um, Column (20 x 250 mm). The fractions containing the product were collected and lyophilized to give 24.4 mg of a white solid.
- the polypeptide was synthesized using standard solid phase peptide synthesis procedures and Fmoc strategy, except for the starting material Fmoc-(D-2Fua)-azaGly-Leu-OH, the basic procedure was the same as in Example 2 (synthesis of YA-3). .
- the target polypeptide was cleaved from the resin by the method of the second step of Example 2 and the protection was removed.
- the cutting solution contained no EDT and was a TFA/TIS/H 2 O (94/3/3) solution, and the other operations were identical.
- the crude product YA-167 was subjected to HPLC separation and purification, and subjected to a linear gradient elution (10 min).
- the flow rate was 25 mL/min, the eluent A/B: 78/22-68/32, using: eluent A: 0.05% TFA in water, eluent B: 0.05% TFA in acetonitrile, in preparative On HPLC, using Phenomenex Gemini C18, 10um, Column (21.2 x 250 mm). The fractions containing the product were collected and lyophilized to give 19.1 mg of a white solid.
- Example 23 Fmoc-(D-2Fua)-OH (3equivalent) was used in place of Fmoc-ACPO-OH condensation, and HATU/HOAt/DIPEA was used as a condensation condition, and DMF was used as a solvent, and the mixture was reacted at room temperature for 3 hours.
- the resin is dried after washing.
- the target polypeptide was cleaved from the resin by the method of the second step of Example 2 and the protection was removed.
- the cutting solution contained no EDT and was a TFA/TIS/H 2 O (94/3/3) solution, and the other operations were identical.
- the crude product YA-168 was subjected to HPLC separation and purification, and subjected to linear gradient elution (10 min) at a flow rate of 30 mL/min, eluent A/B: 73/27-63/37, using: eluent A: 0.05% An aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Xtimate C18, 10um, Column (20 x 250 mm). The fractions containing the product were collected and lyophilized to give 8.4 mg of a white solid.
- the crude product YA-170 was subjected to HPLC separation and purification, and subjected to a linear gradient elution (10 min) at a flow rate of 20 mL/min, eluent A/B: 71/29-65/35, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire C18, 5um, Column (19 x 150 mm). The fractions containing the product were collected and lyophilized to give 4.6 mg of a white solid.
- Eluent A/B 67/33-57/43 used: eluent A: 0.05 Aqueous solution of %TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC, using SHIMADAZU C18 10um, Column (2 x 21.2 x 250 mm). The product containing fractions were collected and lyophilized to give 12.2 mg of white solid.
- the crude product YA-175 was subjected to HPLC separation and purification, and subjected to a linear gradient elution (10 min) at a flow rate of 25 mL/min, eluent A/B: 73/27-65/35, using: eluent A: 0.05% An aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Xtimate C18, 10um, Column (20 x 250 mm). The fractions containing the product were collected and lyophilized to give 16.4 mg of a white solid.
- Fmoc-Thi-OH (3equivalent) was used instead of Fmoc-Hyp(tBu)-OH condensation, and HATU/HOAt/DIPEA was used as a condensation condition, and DMF was used as a solvent, and the mixture was reacted at room temperature for 3 hours.
- Fmoc-[D-Phe(2,4-DiCl)]-OH(3equivalent) was substituted for Fmoc-Tyr(tBu)-OH condensation, HATU/HOAt/DIPEA was the condensation condition, DMF was used as the solvent, and the mixture was reacted at room temperature for 3 hours. The resin is dried after washing.
- the polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 2 and deprotected.
- the crude product YA-178 was subjected to HPLC separation and purification.
- the fractions containing the product were collected and lyophilized to give 20.1 mg of a white solid.
- Fmoc-Pro(diF)-OH(3equivalent) was used instead of Fmoc-Hyp(tBu)-OH condensation, HATU/HOAt/DIPEA was used as a condensation condition, DMF was used as a solvent, and the mixture was reacted at room temperature for 3 hours.
- Fmoc-[D-Phe(2,4-DiCl)]-OH(3equivalent) was substituted for Fmoc-Tyr(tBu)-OH condensation, HATU/HOAt/DIPEA was the condensation condition, DMF was used as the solvent, and the mixture was reacted at room temperature for 3 hours. The resin is dried after washing.
- the polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 2 and deprotected.
- the crude product YA-180 was subjected to HPLC separation and purification. Linear gradient elution (10 min), flow rate 25 mL/min, eluent A/B: 68/32-58/42, using: eluent A: 0.05% TFA in water, eluent B: 0.05 %TFA in acetonitrile on a preparative HPLC using Sunfire C18, 10um, Column (19 x 250 mm). The fractions containing the product were collected and lyophilized to give 115.4 mg of a white solid.
- Example 2 In a similar manner to the synthesis of Example 2, Fmoc-S-Pip-OH (3equivalent) was used instead of Fmoc-Hyp(tBu)-OH condensation, and HATU/HOAt/DIPEA was used as a condensation condition, and DMF was used as a solvent, and the mixture was reacted at room temperature for 3 hours. Fmoc-(D-2Fua)-OH(3equivalent) was substituted for Fmoc-Tyr(tBu)-OH condensation, HATU/HOAt/DIPEA was the condensation condition, and DMF was used as a solvent, and the mixture was reacted at room temperature for 3 hours. The resin is dried after washing.
- the target polypeptide was cleaved from the resin by the method of the second step of Example 2 and the protection was removed.
- the cutting solution contained no EDT and was a TFA/TIS/H 2 O (94/3/3) solution, and the other operations were identical.
- the crude product YA-181 was subjected to HPLC separation and purification. Linear gradient elution (10 min), flow rate 25 mL/min, eluent A/B: 68/32-58/42, using: eluent A: 0.05% TFA in water, eluent B: 0.05 %TFA in acetonitrile on preparative HPLC using Phenomenex Gemini C18, 10um, Column (21.2 x 250 mm). The fractions containing the product were collected and lyophilized to give 20.7 mg of a white solid.
- Fmoc-S-Pip-OH (3equivalent) was used instead of Fmoc-Hyp(tBu)-OH condensation, and HATU/HOAt/DIPEA was used as a condensation condition, and DMF was used as a solvent, and the mixture was reacted at room temperature for 3 hours.
- Fmoc-[D-Phe(2,4-DiCl)]-OH(3equivalent) was substituted for Fmoc-Tyr(tBu)-OH condensation, HATU/HOAt/DIPEA was the condensation condition, DMF was used as the solvent, and the mixture was reacted at room temperature for 3 hours. The resin is dried after washing.
- the polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 2 and deprotected.
- the crude product YA-182 was subjected to HPLC separation and purification. Linear gradient elution (10 min), flow rate 25 mL/min, eluent A/B: 59/41-49/51, using: eluent A: 0.05% TFA in water, eluent B: 0.05 %TFA in acetonitrile, on preparative HPLC, using Phenomenex Gemini C18, 10um, Column (21.2 x 250 mm). The fractions containing the product were collected and lyophilized to give 20.2 mg of a white solid.
- Fmoc-Pro(diF)-OH(3equivalent) was used instead of Fmoc-Hyp(tBu)-OH condensation, HATU/HOAt/DIPEA was used as a condensation condition, DMF was used as a solvent, and the mixture was reacted at room temperature for 3 hours.
- Fmoc-(D-2Fua)-OH(3equivalent) was substituted for Fmoc-Tyr(tBu)-OH condensation, HATU/HOAt/DIPEA was the condensation condition, and DMF was used as a solvent, and the mixture was reacted at room temperature for 3 hours. The resin is dried after washing.
- the target polypeptide was cleaved from the resin by the method of the second step of Example 2 and the protection was removed.
- the cutting solution contained no EDT and was a TFA/TIS/H 2 O (94/3/3) solution, and the other operations were identical.
- the crude product YA-183 was subjected to HPLC separation and purification. Linear gradient elution (10 min), flow rate 25 mL/min, eluent A/B: 71/29-61/39, using: eluent A: 0.05% TFA in water, eluent B: 0.05 %TFA in acetonitrile on preparative HPLC using Xtimate C18, 10um, Column (20 x 250 mm). The fractions containing the product were collected and lyophilized to give 19.6 mg of a white solid.
- Step 1 0.4 g of commercially available Rink Amide MBHA resin (0.5 mmol/g) was swollen in DCM, which was treated with 12 mL of 20% piperidine/DMF for 20 minutes to remove Fmoc, and this was repeated twice.
- the obtained resin was washed with DMF, and a solution of Fmoc-Trp(Boc)-OH (320 mg, 0.6 mmol), HBTU (227 mg, 0.6 mmol) and HOBt (81 mg, 0.6 mmol) in 10 mL DMF was added, then DIPEA (155 mg, 1.2 Methyl), treated at room temperature for 40 minutes; the resin was washed with DMF to give Fmoc-Trp(Boc)-Rink Amide MBHA resin.
- the resin was treated with 12 mL of 20% piperidine/DMF for 20 minutes to remove Fmoc, and this was repeated twice; the resin was washed with DMF, and Fmoc-Arg(Me, Pbf)-OH (180 mg, 0.3 mmol), HATU (113 mg, 0.3 mmol) and HOAt (27 mg, 0.2 mmol) in 7 mL of DMF solution, then DIPEA (78 mg, 0.6 mmol) was added and treated at room temperature for 40 minutes; the resin was treated with 12 mL of 20% piperidine/DMF for 20 minutes to remove Fmoc, repeat This operation was repeated twice; the resin was washed with DMF to give NH2-Arg(Me, Pbf)-Trp(Boc)-Rink Amide MBHA resin.
- Tr(tBu), Asn(Trt), Hyp(tBu) and D-Phe(2,4-DiCl) were gradually introduced in a Trp-like manner, and the obtained resin was washed with DMF, and Ac 2 O (184 mg, 1.8 mmol) was added.
- Step 2 The dried resin was added to 10 mL of TFA/TIS/EDT/H 2 O (94/2/2/2) solution, the mixture was stirred for 2 hours, and the resin was removed by filtration, using 2 mL of TFA/TIS/EDT/ The resin was washed with a H 2 O (94/2/2/2) solution. The filtrate was combined, diethyl ether (70 mL) was added to the filtrate, and the mixture obtained was centrifuged at 3,000 rpm for 3 minutes, the supernatant was removed, and the solid was washed twice with diethyl ether and dried.
- the resulting precipitate was dissolved in DMF, followed by a linear concentration gradient elution (10 min) at a flow rate of 25 mL/min, eluent A/B: 66/34-58/42, using: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Xtimate C18, 10 um, Column (20 x 250 mm). The fractions containing the product were collected and lyophilized to give 5.9 mg of a white solid.
- Example 24 In a similar manner to the synthesis of Example 24, Fmoc-Thi-OH (3equivalent) was used instead of Fmoc-Hyp(tBu)-OH condensation, and HATU/HOAt/DIPEA was used as a condensation condition, and DMF was used as a solvent, and the mixture was reacted at room temperature for 3 hours. The resin is dried after washing. The target polypeptide was cleaved from the resin by the method of the second step of Example 2 and the protection was removed. The cutting solution contained no EDT and was a TFA/TIS/H 2 O (94/3/3) solution, and the other operations were identical. The crude product YA-191 was subjected to HPLC separation and purification.
- the crude product YA-195 was subjected to HPLC separation and purification, and subjected to a linear gradient elution (10 min) at a flow rate of 25 mL/min, eluent A/B: 68/32-58/42, using: eluent A: 0.05% An aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Xtimate C18, 10um, Column (20 x 250 mm). The fractions containing the product were collected and lyophilized to give 12.6 mg of a white solid.
- the crude product YA-196 was subjected to HPLC separation and purification, and subjected to a linear gradient elution (10 min) at a flow rate of 25 mL/min, eluent A/B: 65/35-55/45, using: eluent A: 0.05% An aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Xtimate C18, 10um, Column (20 x 250 mm). The fractions containing the product were collected and lyophilized to give 22.4 mg of a white solid.
- the crude product YA-197 was subjected to HPLC separation and purification, and subjected to a linear gradient elution (10 min) at a flow rate of 25 mL/min, eluent A/B: 71/29-61/39, using: eluent A: 0.05% An aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Xtimate C18, 10um, Column (20 x 250 mm). The fractions containing the product were collected and lyophilized to give 18.3 mg of a white solid.
- the obtained resin was washed with DMF, and a solution of Fmoc-Trp(Boc)-OH (320 mg, 0.6 mmol), HBTU (227 mg, 0.6 mmol) and HOBt (81 mg, 0.6 mmol) in 10 mL DMF was added, then DIPEA (155 mg, 1.2 Methyl), treated at room temperature for 40 minutes; the resin was washed with DMF to give Fmoc-Trp(Boc)-Rink Amide MBHA resin.
- the resin was treated with 12 mL of 20% piperidine/DMF for 20 minutes to remove Fmoc, and this was repeated twice; the resin was washed with DMF, and Fmoc-Arg(Me, Pbf)-OH (180 mg, 0.3 mmol), HATU (113 mg, 0.3 mmol) and HOAt (27 mg, 0.2 mmol) in 7 mL of DMF solution, then DIPEA (78 mg, 0.6 mmol) was added and treated at room temperature for 40 minutes; the resin was treated with 12 mL of 20% piperidine/DMF for 20 minutes to remove Fmoc, repeat This operation was repeated twice; the resin was washed with DMF to give NH2-Arg(Me, Pbf)-Trp(Boc)-Rink Amide MBHA resin.
- Amino acid such as Leu, A6c, Phe, Thr(tBu) was introduced in a Trp-like manner, and the resin was washed with DMF to obtain NH2-Thr(tBu)-Phe-A6c-Leu-Arg(Me,Pbf)-Trp(Boc). -Rink Amide MBHA resin.
- the dried resin was added to 10 mL of TFA/TIS/PhSMe/EDT (84/6/6/4) solution, the mixture was stirred for 40 minutes, and the resin was removed by filtration using 2 mL of TFA/TIS/PhSMe/EDT (84/6). /6/4) Solution wash resin.
- the filtrate was combined, and diethyl ether (70 mL) was added to the filtrate.
- the obtained mixture was centrifuged at 3,000 rpm for 1 minute, the supernatant was removed, and the solid was washed twice with diethyl ether and dried.
- the resulting precipitate was dissolved in DMF and then subjected to a linear concentration gradient elution (10 min) at a flow rate of 25 mL/min.
- eluent A/B 65/35-55/45 used: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Phenomenex Gemini 10 ⁇ , Column (21.2 mm ⁇ 250 mm). The fractions containing the product were collected and lyophilized to give 12 mg of a white solid.
- Fmoc-Pro(diF)-OH(3equivalent) was used instead of Fmoc-Hyp(tBu)-OH condensation, HATU/HOAt/DIPEA was used as a condensation condition, DMF was used as a solvent, and the mixture was reacted at room temperature for 3 hours.
- Fmoc-(D-2Fua)-OH(3equivalent) was used instead of Fmoc-Tyr(tBu)-OH condensation, HATU/HOAt/DIPEA was the condensation condition, DMF was used as the solvent, and the mixture was reacted at room temperature for 3 hours. The resin is dried after washing.
- the target polypeptide was cleaved from the resin by the method of the second step of Example 2 and the protection was removed.
- the cutting solution contained no EDT and was a TFA/TIS/H 2 O (94/3/3) solution, and the other operations were identical.
- the crude product YA-201 was subjected to HPLC separation and purification, linear gradient elution (10 min), flow rate 25 mL/min, eluent A/B: 68/32-58/42, use: eluent A: 0.05% An aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Xtimate C18, 10um, Column (20 x 250 mm). The fractions containing the product were collected and lyophilized to give 11.6 mg of a white solid.
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Abstract
本发明公开了一种肽类化合物、其应用及含其的组合物。本发明提供了一种如式(1)所示的肽类化合物、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药。该化合物稳定性较佳且对Kiss1R的活性较佳。
Description
本申请要求申请日为2017年7月5日的中国专利申请CN201710543383.0、申请日为2018年7月4日的中国专利申请CN201810725881.1的优先权。本申请引用上述中国专利申请的全文。
本发明涉及一种肽类化合物、其应用及含其的组合物。
Kiss-1基因是Jeong-Hyung Lee等人研究发现一种新型的抑制人类黑色素瘤转移的基因(Lee JH,et.al.Journal of the National Cancer Institute,Vol.88(23):1731-1737(1996))。Kiss-1基因位于人染色体1q32上,由四个外显子-两个非翻译和两个部分翻译的外显子组成,它编码一个含145个氨基酸的前体多肽。前体肽被剪切成54个氨基酸长度的Kisspeptin-54(又名metastin或转移抑制素),还可以进一步被截短至14[Kisspeptin-14/metastin(40-54)]、13[Kisspeptin-13/metastin(41-54)]或10[Kisspeptin-10/metastin(45-54)]个氨基酸;这些截短物和前体被统称为亲吻肽(Kisspeptin,简称Kp),并且在哺乳动物中高度保守(Kotani M,et.Al.Journal of Biological Chemistry,Vol.276(27):34631-34636;Ohtaki T.et al.,Nature Vol,411(6837):613-671(2001))。四种亲吻肽均含有相同的10个氨基酸残基,C端具有精氨酸和酰胺化的苯丙氨酸(RF-amide),但N端的多肽长度不同。亲吻肽C端部分与受体的高效结合及激活受体有关,截断肽如Kisspeptin-10和Kisspeptin-14的活性比Kisspeptin-54高3-10倍。Kiss-1的mRNA主要在人的胎盘表达,在整个中枢神经系统也广泛表达:壳表达最高,在尾状核、苍白球、小丘脑、伏隔核和小脑表达较高,在额上回、杏仁核、扣带回、海马、旁海马回、丘脑、黑质、蓝斑、延髓表达较低、在脊髓表达非常少。
目前已知这些亲吻肽的受体(Kiss1R)是一个孤儿G蛋白偶联受体视黄酸家族成员(在大鼠中被称为GPR54,在人中被称为AXOR12)。Kiss1R含398个氨基酸残基,甘丙肽(galanin)受体家族相关,但是其并不与甘丙肽结合。大鼠GPR54在且哺乳动物中高度保守,与人受体有81%的同源性,与小鼠有85%的同源性。人Kiss1R的mRNA在胎盘、垂体、脊髓和胰表达丰富,在其他组织包括不同的脑部(丘脑、尾状核、黑质、海马、杏仁核、小脑)、胃、小肠、胸腺、脾、肺、睾丸、肾和胎儿肝表达水平低。Kisspeptin及 其受体在脑和外周多种组织器官有分布,包括下丘脑、主动脉、卵巢、前列腺和胎盘,受体还表达于垂体中。它们的作用具有调节生殖功能、影响内分泌、影响肿瘤细胞的生长和转移等作用。
亲吻肽与Kiss1R(GPR54)的信号传导,是在多肽与其受体结合后激活细胞内的磷脂酶C(PLC),进而使二磷酸脂酰肌醇(PIP2)水解,产生三磷酸肌醇(IP3)和甘油二脂(DAG),从而促使细胞内钙离子增加、花生烯酸释放、蛋白激酶C(PKC)活化、细胞外信号调节激酶(ERK1和ERK2)及p38有丝分裂激活蛋白激酶(MAPK)磷酸化,从而产生生物学作用。Kisspeptin与Kiss1R信号传导的一个重要作用就是在青春期期间开始分泌促性腺激素释放激素(gonadotropin-releasing hormone,GnRH)。促性腺激素释放激素的释放是垂体前叶的行为,也包括释放促黄体激素(luteinizing hormone,LH)和促卵泡激素(follicle stimulating hormone,FSH)。扰乱此信号通路会引起GnRH释放不足,造成人和啮齿动物的性腺机能减退。异常释放或缺失是导致男女性生殖异常的主要原因。研究证明GnRH类似物亲吻肽在下丘脑水平发挥作用达到刺激GnRH释放(US7754220)。亲吻肽的输入可以在所有阶段刺激GnRH释放。Kiss1R激动剂是一种预防或治疗前列腺癌、乳腺癌、子宫内膜异位症、子宫肌瘤、闭经前乳腺癌、中枢性性早熟症、性功能性疾病等激素相关疾病的方法。并在体外受精用于诱导排卵,以及作为新一代的避孕药。
亲吻肽结合Kiss1R(GPR54)具有多种功能,抑制细胞增殖是重要的一种(Kotani M,et al.,J.Biol.Chem.Vol 276:34631-34636)。Kiss1R激动剂能抑制细胞增殖性疾病选自以下病症组:良性前列腺增生症、前列腺癌、乳腺癌、卵巢癌、子宫癌、宫颈癌、子宫内膜癌、黑色素瘤、胰腺癌、胃癌、肾细胞癌、食管癌、膀胱癌、脑癌等。
Kiss1基因发现初期名为Kiss1转移抑制基因,能管理肿瘤细胞转移,具有临床价值。表达Kiss1基因的原发性黑色素细胞系,其表达量与黑色素瘤细胞系的转移潜能负相关。C8161细胞表达Kiss1基因,肺转移被抑制了95%以上(Nash et al.,“The KISS1metastasis suppressor:mechanistic insights and clinical utility”,Front.Biosci.vol.11,pp.647-659(2006).)。亲吻肽能够通过诱导过量细胞粘附性表型,降低细胞移动性,抑制肿瘤细胞的转移(Lee JH and Welch DR,Int.J.Cancer.Vol.71(6):1035-1044(1997))。转移抑制素衍生物还具有卓越的生物活性(例如:癌细胞转移抑制活性、癌细胞生长抑制活性等)(US6800611B2,US 7625869B2,US 8361968B2,US 8592379B2)。Kiss1R激动剂抑制肿瘤转移和迁移、影响滋养细胞浸润,其中所述疾病或疾病状态选自:黑色素瘤、胰腺癌、乳腺癌、卵巢癌、子宫癌、宫颈癌、子宫内膜癌、甲状腺癌、膀胱癌、食管鳞状细胞癌、胃癌、肝癌等癌症。
Kiss1R(GPR54)还高度表达于中枢神经系统(CNS),脑海马区域中,已证明其通过涉及MAP激酶的机理可逆地增强海马齿状回颗粒细胞中的突触传递,其中所述机理似乎受到钙-激活激酶和酪氨酸激酶的调控[Roa,J.,Hypothalamic expression of KiSS-1system and gonadotropin-releasing effects of kisspeptin in different reproductive states of the female Rat.et.al.Endocrinology 147(6):1624-1632,2006]。研究证明注射亲吻肽能增强边缘大脑活动,产生性刺激。所以亲吻肽能够从本质上激发性欲,而且与性感、浪漫和性兴奋的感觉有关。Kiss1R激动剂能增强大脑和情绪的情欲信号,治疗心理原因造成的性功能障碍。
亲吻肽又具有影响胎盘功能的功能,Kiss1R激动剂治疗所述疾病或疾病状态选自:绒毛膜癌、侵袭性痣、流产、胎儿发育不全、糖代谢异常、脂质代谢异常等有效(WO00/24890;WO01/75104 2;WO 02/85399)。
Takeda公司在专利CN101341168B、US8592379B2、US8765909B2、US9778871B2中公布了亲吻肽类似物TAK448:
发明内容
本发明所要解决的技术问题是现有的肽类化合物稳定性低、对Kiss1R的活性低等缺陷,故而,本发明提供了一种肽类化合物、其应用及含其的组合物,该化合物的稳定性较佳且对Kiss1R的活性较佳。
本发明提供了一种如式1所示的肽类化合物、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药:
R
a为CH
3-,q为0~18(例如,以下述任两个值为端点的范围:0、1、2、3、4、5、 6、7、8、9、10、11、12、13、14、15、16、17和18;又例如0~14;再例如4~14);或者,R
a为HOOC-,q为1~18(例如,以下述任两个值为端点的范围:1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17和18;又例如1~16);
m为0~2(例如0、1或2);
PEG独立地为
X独立地为-NHR
b或-OH,R
b独立地为氢或C
1-3的烷基(例如甲基、乙基、异丙基或正丙基);k独立地为2~24(例如,以下述任两个值为端点的范围:2、3、4、5、6、8、12、16、20或24;又例如2~8,还例如4~8);XX0独立地为
(PEG的X端与羰基连接,XX0端与AA0或AA1连接;
当m为2时,与AA0或AA1连接的PEG中,所述的X可为-NH
2;当m为2时,与AA0或AA1连接的PEG中,所述的k可为2~4{例如2、3或4};当m为2时,与AA0或AA1连接的PEG中,所述的XX0可为
当m为2时,与AA0或AA1连接的PEG中,所述的
可为OEG或PEG4;
n为0~3(例如0、1、2或3);
所有的AA0独立地为Gly、Beta-Ala、Ahx或Ac-Lys;(例如,当n为2或3时,至少2个AA0为Gly;又例如,
可为化学键、“Gly-Gly”或“Ac-Lys-Gly-Gly”{其左侧与XX0连接})
但当q为0时,m和n不同时为0;(也即
不为乙酰基;例如当m为0、n为0时,q为1~18;又例如,以下述任两个值为端点的范围:1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17和18;再例如4~14);
PEG’为
R
c为C
14-C
18的直链烷基(例如C
16直链烷基),X’为“杂原子为N、O和S中的一种或多种,杂原子数为1~3个的五元或六元杂芳基”(例如“杂原子为N,杂原子数为1~3个的五元或六元杂芳基”,又例如
{其左端与R
c连接})或
(其左端与R
c连接),k’为5~9(又例如5~7);
n’为0~3(例如0、1、2或3,又例如2);
所有的AA0’独立地为Gly、Beta-Ala、Ahx或Ac-Lys;(例如,当n’为2或3时,至少2个AA0’为Gly;又例如,
可为化学键、“Gly-Gly”或“Ac-Lys-Gly-Gly”{其左侧与PEG’连接})
AA1为氨基未取代或氨基(当氨基酸存在多个氨基时,可以为手性碳原子上的氨基,还可以为伯氨基)被1个C
1-3的烷基(例如甲基、乙基、正丙基或异丙基)取代的下述氨基酸(所述的“取代的氨基酸”例如N-Me-Ala、N-Me-D-Ala、N-Me-Leu、N-Me-D-Leu、N-Me-Phe或N-Me-D-Phe):D-Ala、Leu、D-Leu、Tyr、D-Tyr、Thi、(S)-Pip、Ala、αMeTyr、1Nal、2Nal、4Pal、Dap(Dnp)、D-2Fua、Pro(5Ph)、2Pal、3Pal、Tyr(Me)、Ala(dip)、A6c、 ACPA、D-Tic、3-[(1-甲基吡啶鎓)-3-基]丙氨酸、和、
{例如Phe、D-Phe、Phe(4-F)、D-Phe(4-F)、Phe(3-Cl)、D-Phe(3-Cl)、Phe(4-Cl)、D-Phe(4-Cl)、Phe(4-I)、D-Phe(4-I)、Phe(4-Me)、Phe(4-tBu)、或、D-Phe(2,4-diCl)};n1为0~2(例如0、1或2),所有的R
1独立地为C
1~C
4烷基(例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基或异丁基)、C
1~C
4烷氧基(例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基或异丁氧基)或卤素(例如氟、氯或碘),*标记的碳原子为手性碳原子,其为R构型或S构型(所有的R
1可独立地位于氨基酸侧链的邻位、间位或对位,例如,当n1为1时,R
1可位于氨基酸侧链的间位或对位;当n1为2时,R
1可位于氨基酸侧链的邻位和对位;又例如,其为
);
AA2为Asn、Hyp、Pro、Ala、Thz、Pro(diF)、Pro(4-NH
2)、Thi、NAsn、ACPA、D-2Fua、A6c、azaPro、Ind、(S)-Pip、(R)-Pip、Oic、azaTic、AlphaMeLeu、Cba、A6c、Aze、Cpa或D-Tic;
XX3为Trp、Ala、Phe(4-I)或化学键;
AA5为2Fua、Thr或Ser;
AA6为氨基未取代或氨基(当氨基酸存在多个氨基时,可以为手性碳原子上的氨基,还可以为伯氨基)被1个C
1-3的烷基(例如甲基、乙基、正丙基或异丙基)取代的下述氨基酸(所述的“取代的氨基酸”例如N-Me-Phe):Ala、1Nal、2Nal、Trp、αMePhe、Bta、4Pal、HoPhe、BetaPhe、BetaHomoPhe、Bpa、Ala(dip)、Bip、D-2Fua、A6c、Tic、azaTic、azaPhe、和、
{例如Phe、D-Phe、Phe(4-F)、Phe(pentaF)、Phe(3-Cl)、Phe(2-Br)、Phe(4-I)、Phe(4-tBu)、或、Phe(4-CF
3)};n6为0~5(例如0、1、2、3、4或5),所有的R
6独立地为卤代的C
1~C
4烷基(所述的“卤”例如氟、氯、溴或碘;所述的“C
1~C
4烷基”例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基或异丁基;所述的“卤代的C
1~C
4烷基”例如三氟甲基)、C
1~C
4烷基(例如甲基、乙基、异丙基或异丁基)或卤素(例如氟、氯、溴或碘),*标记的碳原子为手性碳原子,其为R构型或S构型(所有的R
6可独立地位于氨基酸侧链的邻位、间位或对位,例如,当n6为1时,R
6可位于 氨基酸侧链的邻位、间位或对位;例如,其可为
);
AA7为氨基未取代或氨基(当氨基酸存在多个氨基时,可以为手性碳原子上的氨基,还可以为伯氨基)被1个C
1-3的烷基(例如甲基、乙基、正丙基或异丙基)取代的下述氨基酸(所述的“取代的氨基酸”例如N-Me-A6c或aza-N-Me-Gly):Gly、azaGly、Ala、Alg、Ava、Aib、Sar、Chg、BetaAla、ACPO、Aze、D-2Fua、A6c、azaPro、Ind、(S)-Pip、(R)-Pip、azaTic、Oic、Hyp、cycloLeu、BetaHomoAla、Cba、ACPA、Alg、morpholino cyclic amino acid、beta-(thiazoly-4-yl)-L-Ala、
当AA6为
时,“AA6-AA7”是指AA6的羧基(当氨基酸存在多个羧基时,可以为手性碳原子上的羧基)与AA7的氨基(当氨基酸存在多个氨基时,可以为手性碳原子上的氨基,还可以为伯氨基)连接形成的含
的基团、或者、“AA6的羧基与AA7的氨基连接形成的含
的基团”中的
被下述的任一基团取代后、形成的基团:
所述基团的左端与AA6相连(例如,当AA6为Phe、AA7为Gly时,“AA6-AA7”是指
);
“AA7-Leu”是指AA7的羧基(当氨基酸存在多个羧基时,可以为手性碳原子上的羧基)与Leu的氨基(当氨基酸存在多个氨基时,可以为手性碳原子上的氨基,还可以为伯氨基)连接形成的含
的基团、或者、“AA7的羧基与Leu的氨基连接形成的含
的基团”中的
被下述的任一基团取代后、形成的基团:
所述基团的左端与AA7相连(例如,当AA7为Gly、AA7为Leu时,“AA7-Leu”是指
);
AA9为氨基未取代或氨基(当氨基酸存在多个氨基时,可以为手性碳原子上的氨基,还可以为伯氨基)被1个C
1-3的烷基(例如甲基、乙基、正丙基或异丙基)取代的下述氨基酸(所述的“取代的氨基酸”例如N-Me-Arg、N-Me-HoLeu或N-Me-D-HoLeu): Arg、Arg(Me)、Ala、His、HoLeu、D-HoLeu、4Pal、Phe(4-amidino)、
AA10为氨基未取代或氨基(当氨基酸存在多个氨基时,可以为手性碳原子上的氨基,还可以为伯氨基)被1个C
1-3的烷基(例如甲基、乙基、正丙基或异丙基)取代的下述氨基酸(所述的“取代的氨基酸”例如N-Me-Phe):Trp、Ala、αMePhe、1Nal、2Nal、4Pal、BetaPhe、BetaHoPhe、Bpa、Ala(dip)、NPhe、Bip、D-2Fua、A6c、Tic、和、
{例如Phe、D-Phe、Phe(4-F)、Phe(pentaF)、Phe(2-Br)、Phe(4-I)、或、Phe(4-CF
3)};n10为0~5(例如0、1、2、3、4或5),所有的R
10独立地为卤代的C
1~C
4烷基(所述的“卤”例如氟、氯、溴或碘;所述的“C
1~C
4烷基”例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基或异丁基;所述的“卤代的C
1~C
4烷基”例如三氟甲基)或卤素(例如氟、氯、溴或碘),*标记的碳原子为手性碳原子,其为R构型或S构型(所有的R
10可独立地位于氨基酸侧链的邻位、间位或对位,例如,当n10为1时,R
10可位于氨基酸侧链的邻位或对位;例如,其可为
);
P为-NH
2、-OH、-NH-tBu、-NH-Et、-NH-Me、1H-1,2,3-三唑-4-基或2H-四唑-5-基。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
R
a为CH
3-,q为0~16(例如,以下述任两个值为端点的范围:0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15和16;又例如0~14;再例如4~14);或者,R
a为HOOC-,q为2~18(例如,以下述任两个值为端点的范围:2、3、4、5、6、7、8、9、10、11、12、13、14、15和16;又例如2~16);
m为0~2(例如0、1或2);
PEG独立地为
X独立地为-NHR
b或-OH,R
b独立地为氢或C
1-3的烷基(例如甲基、乙基、异丙基或正丙基);k独立地为2~12(例如,以下述任两个值为端点的范围:2、3、4、5、6、8或12);XX0独立地为
当m为2时,与AA0或AA1连接的PEG中,所述的X可为-NH
2;当m为2时,与AA0或AA1连接的PEG中,所述的k可为2~4{例如2、3或4};当m为2时,与AA0或AA1连接的PEG中,所述的XX0可为
当m为2时,与AA0或AA1连接的PEG中,所述的
可为OEG或PEG4;
n为0~3(例如0、1、2或3);
所有的AA0独立地为Gly、Beta-Ala、Ahx或Ac-Lys;(例如,当n为2或3时,至少2个AA0为Gly;又例如,
可为化学键、“Gly-Gly”或“Ac-Lys-Gly-Gly”{其左侧与XX0连接})
但当q为0时,m和n不同时为0;(也即
不为乙酰基;例如当m为0、n为0时,q为1~18;又例如,以下述任两个值为端点的范围:1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17和18;再例如4~14);
PEG’为
R
c为C
14-C
18的直链烷基(例如C
16直链烷基),X’为“杂原子为N、O和S中的一种或多种,杂原子数为1~3个的五元或六元杂芳基”(例如“杂原子为N,杂原子数为1~3个的五元或六元杂芳基”,又例如
{其左端与R
c连接})或
(其左端与R
c连接),k’为5~9(又例如5~7);
n’为0~3(例如0、1、2或3,又例如2);
所有的AA0’独立地为Gly、Beta-Ala、Ahx或Ac-Lys;(例如,当n’为2或3时,至少2个AA0’为Gly;又例如,
可为化学键、“Gly-Gly”或“Ac-Lys-Gly-Gly”{其左侧与PEG’连接})
AA1为氨基未取代或氨基(当氨基酸存在多个氨基时,可以为手性碳原子上的氨基,还可以为伯氨基)被1个C
1-3的烷基(例如甲基、乙基、正丙基或异丙基)取代的下述氨基酸(所述的“取代的氨基酸”例如N-Me-Phe或N-Me-D-Phe):Tyr、D-Tyr、Thi、(S)-Pip、αMeTyr、1Nal、2Nal、4Pal、Dap(Dnp)、D-2Fua、Pro(5Ph)、2Pal、3Pal、Tyr(Me)、Ala(dip)、A6c、ACPA、D-Tic、3-[(1-甲基吡啶鎓)-3-基]丙氨酸、和、
{例如Phe、D-Phe、Phe(4-F)、D-Phe(4-F)、Phe(3-Cl)、D-Phe(3-Cl)、Phe(4-Cl)、D-Phe(4-Cl)、Phe(4-I)、D-Phe(4-I)、Phe(4-Me)、Phe(4-tBu)、或、D-Phe(2,4-diCl)};n1为0~2(例如0、1或2),所有的R
1独立地为甲基、甲氧基、C
4烷氧基(例如异丁氧基)或卤素(例如氟、氯或碘),*标记的碳原子为手性碳原子,其为R构型或S构型(所有的R
1可独立地位于氨基酸侧链的邻位、间位或对位,例如,当n1为1时,R
1可位于氨基酸侧链的间位或对位;当n1为2时,R
1可位于氨基酸侧链的邻位和对位;又例如,其为
);
AA2为Asn、Hyp、Pro、Ala、Thz、Pro(diF)、Pro(4-NH
2)、Thi、ACPA、D-2Fua、A6c、azaPro、Ind、(S)-Pip、(R)-Pip、Oic、AlphaMeLeu、Cba、A6c、Aze、Cpa或D-Tic;
XX3为Trp、Ala、Phe(4-I)或化学键;
AA5为2Fua、Thr或Ser;
AA6为氨基未取代或氨基(当氨基酸存在多个氨基时,可以为手性碳原子上的氨基,还可以为伯氨基)被1个C
1-3的烷基(例如甲基、乙基、正丙基或异丙基)取代的下述氨基酸(所述的“取代的氨基酸”例如N-Me-Phe):1Nal、2Nal、αMePhe、4Pal、HoPhe、BetaPhe、BetaHomoPhe、Bpa、D-2Fua、A6c、Tic、azaPhe、和、
{例如Phe、D-Phe、Phe(4-F)、Phe(pentaF)、Phe(3-Cl)、Phe(2-Br)、Phe(4-I)、Phe(4-tBu)、或、Phe(4-CF
3)};n6为0、1或2,所有的R
6独立地为C
1~C
4烷基(例如甲基、乙基、异丙基或异丁基)或卤素(例如氟、氯、溴或碘),*标记的碳原子为手性碳原子,其为R构型或S构型(所有的R
6可独立地位于氨基酸侧链的邻位、间位或对位,例如,当n6为1时,R
6可位于氨基酸侧链的邻位、间位或对位;例如,其可为
);
AA7为氨基未取代或氨基(当氨基酸存在多个氨基时,可以为手性碳原子上的氨基,还可以为伯氨基)被1个C
1-3的烷基(例如甲基、乙基、正丙基或异丙基)取代的下述 氨基酸(所述的“取代的氨基酸”例如N-Me-A6c或aza-N-Me-Gly):Gly、azaGly、Ala、Alg、Ava、Aib、Sar、Chg、BetaAla、ACPO、Aze、D-2Fua、A6c、azaPro、Ind、(S)-Pip、(R)-Pip、Oic、Hyp、cycloLeu、BetaHomoAla、Cba、ACPA、Alg、morpholino cyclic amino acid、beta-(thiazoly-4-yl)-L-Ala、
当AA6为
时,“AA6-AA7”是指AA6的羧基(当氨基酸存在多个羧基时,可以为手性碳原子上的羧基)与AA7的氨基(当氨基酸存在多个氨基时,可以为手性碳原子上的氨基,还可以为伯氨基)连接形成的含
的基团、或者、“AA6的羧基与AA7的氨基连接形成的含
的基团”中的
被下述的任一基团取代后、形成的基团:
所述基团的左端与AA6相连(例如,当AA6为Phe、AA7为Gly时,“AA6-AA7”是指
);
“AA7-Leu”是指AA7的羧基(当氨基酸存在多个羧基时,可以为手性碳原子上的羧基)与Leu的氨基(当氨基酸存在多个氨基时,可以为手性碳原子上的氨基,还可以为伯氨基)连接形成的含
的基团、或者、“AA7的羧基与Leu的氨基连接形成的 含
的基团”中的
被下述的任一基团取代后、形成的基团:
所述基团的左端与AA7相连(例如,当AA7为Gly、AA7为Leu时,“AA7-Leu”是指
);
AA9为氨基未取代或氨基(当氨基酸存在多个氨基时,可以为手性碳原子上的氨基,还可以为伯氨基)被1个C
1-3的烷基(例如甲基、乙基、正丙基或异丙基)取代的下述氨基酸(所述的“取代的氨基酸”例如N-Me-Arg、N-Me-HoLeu或N-Me-D-HoLeu):Arg、Arg(Me)、His、HoLeu、D-HoLeu、4Pal、Phe(4-amidino)、和、
AA10为氨基未取代或氨基(当氨基酸存在多个氨基时,可以为手性碳原子上的氨基,还可以为伯氨基)被1个C
1-3的烷基(例如甲基、乙基、正丙基或异丙基)取代的下述氨基酸(所述的“取代的氨基酸”例如N-Me-Phe):Trp、αMePhe、1Nal、2Nal、4Pal、BetaPhe、BetaHoPhe、Bpa、NPhe、D-2Fua、A6c、Tic、和、
{例如Phe、D-Phe、Phe(4-F)、Phe(pentaF)、Phe(2-Br)、Phe(4-I)、或、Phe(4-CF
3)};n10为0,*标记的碳原子为手性碳原子,其为R构型或S构型(所有的R
10可独立地位于氨基酸侧链的邻位、间位或对位,例如,当n10为1时,R
10可位于氨基酸侧链的邻位或对位;例如,其可为
);
P为-NH
2、-OH、-NH-tBu、-NH-Et、-NH-Me、1H-1,2,3-三唑-4-基或2H-四唑-5-基。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
R
a为CH
3-,q为0~14(例如,以下述任两个值为端点的范围:0、1、2、3、4、5、6、7、8、9、10、11、12、13和14;再例如4~14);或者,R
a为HOOC-,q为14~18(例如,以下述任两个值为端点的范围:14、15、16、17和18;又例如14~16);
m为0~2(例如0、1或2);
当m为2时,与AA0或AA1连接的PEG中,所述的X可为-NH
2;当m为2时,与AA0或AA1连接的PEG中,所述的k可为2~4{例如2、3或4};当m为2时,与AA0或AA1连接的PEG中,所述的XX0可为
当m为2时,与AA0或AA1连接的PEG中,所述的
可为OEG或PEG4;
n为0~3(例如0、1、2或3);
所有的AA0独立地为Gly、Beta-Ala、Ahx或Ac-Lys;(例如,当n为2或3时,至少2个AA0为Gly;又例如,
可为化学键、“Gly-Gly”或“Ac-Lys-Gly-Gly”{其左侧与XX0连接})
但当q为0时,m和n不同时为0;
PEG’为
R
c为C
14-C
18的直链烷基(例如C
16直链烷基),X’为“杂原子为N、O和S中的一种或多种,杂原子数为1~3个的五元或六元杂芳基”(例如“杂原子为N,杂原子数为1~3个的五元或六元杂芳基”,又例如
{其左端与R
c连接})或
(其左端与R
c连接),k’为5~9(又例如5~7);
n’为0~3(例如0、1、2或3,又例如2);
所有的AA0’独立地为Gly、Beta-Ala、Ahx或Ac-Lys;(例如,当n’为2或3时,至少2个AA0’为Gly;又例如,
可为化学键、“Gly-Gly”或“Ac-Lys-Gly-Gly”{其左侧与PEG’连接})
AA1为下述任一氨基酸:Tyr、D-Tyr、D-2Fua、和、
{例如Phe、D-Phe、Phe(4-F)、D-Phe(4-F)、Phe(3-Cl)、D-Phe(3-Cl)、Phe(4-Cl)、D-Phe(4-Cl)、Phe(4-I)、D-Phe(4-I)、Phe(4-Me)、Phe(4-tBu)、或、D-Phe(2,4-diCl)};n1为0~2(例如0、1或2),所有的R
1独立地为C
1~C
4烷基(例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基或异丁基)、C
1~C
4烷氧基(例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基或异丁氧基)或卤素(例如氟、氯或碘),*标记的碳原子为手性碳原子,其为R构型或S构型(所有的R
1可独立地位于氨基酸侧链的邻位、间位或对位,例如, 当n1为1时,R
1可位于氨基酸侧链的间位或对位;当n1为2时,R
1可位于氨基酸侧链的邻位和对位;又例如,其为
);
AA2为Asn、Hyp、Thz、Pro(diF)、Pro(4-NH
2)、Thi、AlphaMeLeu、Cba、A6c、Aze、Cpa或A6c;
XX3为Trp或化学键;
AA5为Thr或Ser;
AA6为
{例如Phe、D-Phe、Phe(4-F)、Phe(pentaF)、Phe(3-Cl)、Phe(2-Br)、Phe(4-I)、Phe(4-tBu)、或、Phe(4-CF
3)};n6为0~5(例如0、1、2、3、4或5),所有的R
6独立地为卤代的C
1~C
4烷基(所述的“卤”例如氟、氯、溴或碘;所述的“C
1~C
4烷基”例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基或异丁基;所述的“卤代的C
1~C
4烷基”例如三氟甲基)、C
1~C
4烷基(例如甲基、乙基、异丙基或异丁基)或卤素(例如氟、氯、溴或碘),*标记的碳原子为手性碳原子,其为R构型或S构型(所有的R
6可独立地位于氨基酸侧链的邻位、间位或对位,例如,当n6为1时,R
6可位于氨基酸侧链的邻位、间位或对位;例如,其可为
);
AA7为下述任一氨基酸:Gly、azaGly、Alg、Aze、D-2Fua、Alg、morpholino cyclic amino acid、beta-(thiazoly-4-yl)-L-Ala、
和A6c;
当AA6为
时,“AA6-AA7”是指AA6的羧基(当氨基酸存在多个羧基时,可以为手性碳原子上的羧基)与AA7的氨基(当氨基酸存在多个氨基时,可以为手性碳原子上的氨基,还可以为伯氨基)连接形成的含
的基团;
当AA7为Gly时,“AA7-Leu”是指AA7的羧基(当氨基酸存在多个羧基时,可以为手性碳原子上的羧基)与Leu的氨基(当氨基酸存在多个氨基时,可以为手性碳原子 上的氨基,还可以为伯氨基)连接形成的含
的基团、或者、“AA7的羧基与Leu的氨基连接形成的含
的基团”中的
被下述的任一基团取代后、形成的基团:
所述基团的左端与AA7相连(例如,当AA7为Gly、AA7为Leu时,“AA7-Leu”是指
);
AA9为下述任一氨基酸:Arg和Arg(Me);
AA10为Trp、或
{例如Phe、D-Phe、Phe(4-F)、Phe(pentaF)、Phe(2-Br)、Phe(4-I)、或、Phe(4-CF
3)};n10为0~5(例如0、1、2、3、4或5),所有的R
10独立地为卤代的C
1~C
4烷基(所述的“卤”例如氟、氯、溴或碘;所述的“C
1~C
4烷基”例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基或异丁基;所述的“卤代的C
1~C
4烷基”例如三氟甲基)或卤素(例如氟、氯、溴或碘),*标记的碳原子为手性碳原子,其为R构型或S构型(所有的R
10可独立地位于氨基酸侧链的邻位、间位或对位,例如,当n10为1时,R
10可位于氨基酸侧链的邻位或对位;例如,其可为
);
P为-NH
2。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
R
a为CH
3-,q为0~14(例如,以下述任两个值为端点的范围:0、1、2、3、4、5、 6、7、8、9、10、11、12、13和14;再例如4~14);或者,R
a为HOOC-,q为14~18(例如,以下述任两个值为端点的范围:14、15、16、17和18;又例如14~16);
m为0~2(例如0、1或2);
当m为2时,与AA0或AA1连接的PEG中,所述的X可为-NH
2;当m为2时,与AA0或AA1连接的PEG中,所述的k可为2~4{例如2、3或4};当m为2时,与AA0或AA1连接的PEG中,所述的XX0可为
当m为2时,与AA0或AA1连接的PEG中,所述的
可为OEG或PEG4;
n为0~3(例如0、1、2或3);
所有的AA0独立地为Gly、Beta-Ala、Ahx或Ac-Lys;(例如,当n为2或3时,至少2个AA0为Gly;又例如,
可为化学键、“Gly-Gly”或“Ac-Lys-Gly-Gly”{其 左侧与XX0连接})
但当q为0时,m和n不同时为0;
n’为0~3(例如0、1、2或3,又例如2);
所有的AA0’独立地为Gly、Beta-Ala、Ahx或Ac-Lys;(例如,当n’为2或3时,至少2个AA0’为Gly;又例如,
可为化学键、“Gly-Gly”或“Ac-Lys-Gly-Gly”{其左侧与PEG’连接})
AA1为Tyr、D-Tyr、D-2Fua、D-Phe(4-I)或Phe(4-I);
AA2为Asn、Hyp、Thz、Pro(diF)、Pro(4-NH
2)、Thi、AlphaMeLeu、Cba、A6c、Aze、Cpa或A6c;
XX3为Trp或化学键;
AA5为Thr或Ser;
AA6为Phe;
AA7为下述任一氨基酸:Gly、azaGly、Alg、Aze、D-2Fua、Alg、morpholino cyclic amino acid、beta-(thiazoly-4-yl)-L-Ala、
和A6c;
当AA6为
时,“AA6-AA7”是指AA6的羧基(当氨基酸存在多个羧基时,可以为手性碳原子上的羧基)与AA7的氨基(当氨基酸存在多个氨基时,可以为手性碳原子上的氨基,还可以为伯氨基)连接形成的含
的基团;
当AA7为Gly时,“AA7-Leu”是指AA7的羧基(当氨基酸存在多个羧基时,可以为手性碳原子上的羧基)与Leu的氨基(当氨基酸存在多个氨基时,可以为手性碳原子上的氨基,还可以为伯氨基)连接形成的含
的基团、或者、“AA7的羧基与Leu的氨基连接形成的含
的基团”中的
被下述的任一基团取代后、形成的基团:
所述基团的左端与AA7相连(例如,当AA7为Gly、AA7为Leu时,“AA7-Leu”是指
);
AA9为下述任一氨基酸:Arg和Arg(Me);
AA10为Trp或Phe;
P为-NH
2。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
R
a为CH
3-,q为0~14(例如,以下述任两个值为端点的范围:0、1、2、3、4、5、6、7、8、9、10、11、12、13和14;再例如4~14);或者,R
a为HOOC-,q为14~18(例如,以下述任两个值为端点的范围:14、15、16、17和18;又例如14~16);
m为0~2(例如0、1或2);
当m为2时,与AA0或AA1连接的PEG中,所述的X可为-NH
2;当m为2时,与AA0或AA1连接的PEG中,所述的k可为2~4{例如2、3或4};当m为2时,与AA0或AA1连接的PEG中,所述的XX0可为
当m为2时,与AA0或AA1连接的PEG中,所述的
可为OEG或PEG4;
n为0~3(例如0、1、2或3);
所有的AA0独立地为Gly、Beta-Ala、Ahx或Ac-Lys;(例如,当n为2或3时,至少2个AA0为Gly;又例如,
可为化学键、“Gly-Gly”或“Ac-Lys-Gly-Gly”{其左侧与XX0连接})
但当q为0时,m和n不同时为0;
PEG’为
R
c为C
14-C
18的直链烷基(例如C
16直链烷基),X’为“杂原子为N、O和S中的一种或多种,杂原子数为1~3个的五元或六元杂芳基”(例如“杂原子为N,杂原子数为1~3个的五元或六元杂芳基”,又例如
{其 左端与R
c连接})或
(其左端与R
c连接),k’为5~9(又例如5~7);
n’为0~3(例如0、1、2或3,又例如2);
所有的AA0’独立地为Gly、Beta-Ala、Ahx或Ac-Lys;(例如,当n’为2或3时,至少2个AA0’为Gly;又例如,
可为化学键、“Gly-Gly”或“Ac-Lys-Gly-Gly”{其左侧与PEG’连接})
AA1为下述任一氨基酸:Tyr、D-Tyr、D-2Fua、和、
{例如Phe、D-Phe、Phe(4-F)、D-Phe(4-F)、Phe(3-Cl)、D-Phe(3-Cl)、Phe(4-Cl)、D-Phe(4-Cl)、Phe(4-I)、D-Phe(4-I)、Phe(4-Me)、Phe(4-tBu)、或、D-Phe(2,4-diCl)};n1为0~2(例如0、1或2),所有的R
1独立地为C
1~C
4烷基(例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基或异丁基)、C
1~C
4烷氧基(例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基或异丁氧基)或卤素(例如氟、氯或碘),*标记的碳原子为手性碳原子,其为R构型或S构型(所有的R
1可独立地位于氨基酸侧链的邻位、间位或对位,例如,当n1为1时,R
1可位于氨基酸侧链的间位或对位;当n1为2时,R
1可位于氨基酸侧链的邻位和对位;又例如,其为
);
AA2为Asn、Hyp、Pro(diF)、Pro(4-NH
2)或A6c;
XX3为Trp或化学键;
AA5为Thr或Ser;
AA6为
{例如Phe、D-Phe、Phe(4-F)、Phe(pentaF)、Phe(3-Cl)、Phe(2-Br)、Phe(4-I)、Phe(4-tBu)、或、Phe(4-CF
3)};n6为0~5(例如0、1、2、3、4或5),所有的R
6独立地为卤代的C
1~C
4烷基(所述的“卤”例如氟、氯、溴或碘;所述的“C
1~C
4烷基”例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基或异丁基;所述的“卤代的C
1~C
4 烷基”例如三氟甲基)、C
1~C
4烷基(例如甲基、乙基、异丙基或异丁基)或卤素(例如氟、氯、溴或碘),*标记的碳原子为手性碳原子,其为R构型或S构型(所有的R
6可独立地位于氨基酸侧链的邻位、间位或对位,例如,当n6为1时,R
6可位于氨基酸侧链的邻位、间位或对位;例如,其可为
);
AA7为下述任一氨基酸:Gly、azaGly、Alg、Aze、D-2Fua和A6c;
当AA6为
时,“AA6-AA7”是指AA6的羧基(当氨基酸存在多个羧基时,可以为手性碳原子上的羧基)与AA7的氨基(当氨基酸存在多个氨基时,可以为手性碳原子上的氨基,还可以为伯氨基)连接形成的含
的基团;
当AA7为Gly时,“AA7-Leu”是指AA7的羧基(当氨基酸存在多个羧基时,可以为手性碳原子上的羧基)与Leu的氨基(当氨基酸存在多个氨基时,可以为手性碳原子上的氨基,还可以为伯氨基)连接形成的含
的基团、或者、“AA7的羧基与Leu的氨基连接形成的含
的基团”中的
被下述的任一基团取代后、形成的基团:
所述基团的左端与AA7相连(例如,当AA7为Gly、AA7为Leu时,“AA7-Leu”是指
);
AA9为下述任一氨基酸:Arg和Arg(Me);
AA10为Trp、或
{例如Phe、D-Phe、Phe(4-F)、Phe(pentaF)、Phe(2-Br)、Phe(4-I)、或、Phe(4-CF
3)};n10为0~5(例如0、1、2、3、4或5),所有的R
10独立地为卤代的C
1~C
4烷基(所述的“卤”例如氟、氯、溴或碘;所述的“C
1~C
4烷基” 例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基或异丁基;所述的“卤代的C
1~C
4烷基”例如三氟甲基)或卤素(例如氟、氯、溴或碘),*标记的碳原子为手性碳原子,其为R构型或S构型(所有的R
10可独立地位于氨基酸侧链的邻位、间位或对位,例如,当n10为1时,R
10可位于氨基酸侧链的邻位或对位;例如,其可为
);
P为-NH
2。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
R
a为CH
3-,q为0~14(例如,以下述任两个值为端点的范围:0、1、2、3、4、5、6、7、8、9、10、11、12、13和14;再例如4~14);或者,R
a为HOOC-,q为14~18(例如,以下述任两个值为端点的范围:14、15、16、17和18;又例如14~16);
m为0~2(例如0、1或2);
当m为2时,与AA0或AA1连接的PEG中,所述的X可为-NH
2;当m为2时,与AA0或AA1连接的PEG中,所述的k可为2~4{例如2、3或4};当m为2时,与AA0或AA1连接的PEG中,所述的XX0可为
当m为2时,与AA0或AA1连接的PEG中,所述的
可为OEG或PEG4;
n为0~3(例如0、1、2或3);
所有的AA0独立地为Gly、Beta-Ala、Ahx或Ac-Lys;(例如,当n为2或3时,至少2个AA0为Gly;又例如,
可为化学键、“Gly-Gly”或“Ac-Lys-Gly-Gly”{其左侧与XX0连接})
但当q为0时,m和n不同时为0;
n’为0~3(例如0、1、2或3,又例如2);
所有的AA0’独立地为Gly、Beta-Ala、Ahx或Ac-Lys;(例如,当n’为2或3时,至少2个AA0’为Gly;又例如,
可为化学键、“Gly-Gly”或“Ac-Lys-Gly-Gly”{其左侧与PEG’连接})
AA1为Tyr、D-Tyr、D-2Fua或D-Phe(4-I);
AA2为Asn、Hyp、Pro(diF)、Pro(4-NH
2)或A6c;
XX3为Trp或化学键;
AA5为Thr或Ser;
AA6为Phe;
AA7为下述任一氨基酸:Gly、azaGly、Alg、Aze、D-2Fua和A6c;
当AA6为
时,“AA6-AA7”是指AA6的羧基(当氨基酸存在多个羧基时,可以为手性碳原子上的羧基)与AA7的氨基(当氨基酸存在多个氨基时,可以为手性碳原子上的氨基,还可以为伯氨基)连接形成的含
的基团;
当AA7为Gly时,“AA7-Leu”是指AA7的羧基(当氨基酸存在多个羧基时,可以为手性碳原子上的羧基)与Leu的氨基(当氨基酸存在多个氨基时,可以为手性碳原子上的氨基,还可以为伯氨基)连接形成的含
的基团、或者、“AA7的羧基与Leu的氨基连接形成的含
的基团”中的
被下述的任一基团取代后、形成的基团:
所述基团的左端与AA7相连(例如,当AA7为Gly、AA7为Leu时,“AA7-Leu”是指
);
AA9为下述任一氨基酸:Arg和Arg(Me);
AA10为Trp或Phe;
P为-NH
2。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
R
a为CH
3-,q为0~14(例如,以下述任两个值为端点的范围:0、1、2、3、4、5、6、7、8、9、10、11、12、13和14;再例如4~14);或者,R
a为HOOC-,q为14~18(例如,以下述任两个值为端点的范围:14、15、16、17和18;又例如14~16);
m为0~2(例如0、1或2);
当m为2时,与AA0或AA1连接的PEG中,所述的X可为-NH
2;当m为2时,与AA0或AA1连接的PEG中,所述的k可为2~4{例如2、3或4};当m为2时,与AA0或AA1连接的PEG中,所述的XX0可为
当m为2时,与AA0或AA1连接的PEG中,所述的
可为OEG或PEG4;
n为0~3(例如0、1、2或3);
所有的AA0独立地为Gly、Beta-Ala、Ahx或Ac-Lys;(例如,当n为2或3时,至少2个AA0为Gly;又例如,
可为化学键、“Gly-Gly”或“Ac-Lys-Gly-Gly”{其左侧与XX0连接})
但当q为0时,m和n不同时为0;
PEG’为
R
c为C
14-C
18的直链烷基(例如C
16直链烷基),X’为“杂原子为N、O和S中的一种或多种,杂原子数为1~3个的五元或六元杂芳基”(例如“杂原子为N,杂原子数为1~3个的五元或六元杂芳基”,又例如
{其左端与R
c连接})或
(其左端与R
c连接),k’为5~9(又例如5~7);
n’为0~3(例如0、1、2或3,又例如2);
所有的AA0’独立地为Gly、Beta-Ala、Ahx或Ac-Lys;(例如,当n’为2或3时,至少2个AA0’为Gly;又例如,
可为化学键、“Gly-Gly”或“Ac-Lys-Gly-Gly”{其左侧与PEG’连接})
AA1为下述任一氨基酸:Tyr、D-Tyr、D-2Fua、和、
{例如Phe、D-Phe、Phe(4-F)、D-Phe(4-F)、Phe(3-Cl)、D-Phe(3-Cl)、Phe(4-Cl)、D-Phe(4-Cl)、Phe(4-I)、D-Phe(4-I)、Phe(4-Me)、Phe(4-tBu)、或、D-Phe(2,4-diCl)};n1为0~2(例如0、1或2),所有的R
1独立地为C
1~C
4烷基(例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基或异丁基)、C
1~C
4烷氧基(例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基或异丁氧基)或卤素(例如氟、氯或碘),*标记的碳原子为手性碳原子,其为R构型或S构型(所有的R
1可独立地位于氨基酸侧链的邻位、间位或对位,例如,当n1为1时,R
1可位于氨基酸侧链的间位或对位;当n1为2时,R
1可位于氨基酸侧链 的邻位和对位;又例如,其为
);
AA2为Asn、Hyp、Pro(diF)或A6c;
XX3为Trp或化学键;
AA5为Thr或Ser;
AA6为
{例如Phe、D-Phe、Phe(4-F)、Phe(pentaF)、Phe(3-Cl)、Phe(2-Br)、Phe(4-I)、Phe(4-tBu)、或、Phe(4-CF
3)};n6为0~5(例如0、1、2、3、4或5),所有的R
6独立地为卤代的C
1~C
4烷基(所述的“卤”例如氟、氯、溴或碘;所述的“C
1~C
4烷基”例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基或异丁基;所述的“卤代的C
1~C
4烷基”例如三氟甲基)、C
1~C
4烷基(例如甲基、乙基、异丙基或异丁基)或卤素(例如氟、氯、溴或碘),*标记的碳原子为手性碳原子,其为R构型或S构型(所有的R
6可独立地位于氨基酸侧链的邻位、间位或对位,例如,当n6为1时,R
6可位于氨基酸侧链的邻位、间位或对位;例如,其可为
);
AA7为下述任一氨基酸:Gly、azaGly、Alg、Aze、D-2Fua和A6c;
当AA6为
时,“AA6-AA7”是指AA6的羧基(当氨基酸存在多个羧基时,可以为手性碳原子上的羧基)与AA7的氨基(当氨基酸存在多个氨基时,可以为手性碳原子上的氨基,还可以为伯氨基)连接形成的含
的基团;
当AA7为Gly时,“AA7-Leu”是指AA7的羧基(当氨基酸存在多个羧基时,可以为手性碳原子上的羧基)与Leu的氨基(当氨基酸存在多个氨基时,可以为手性碳原子上的氨基,还可以为伯氨基)连接形成的含
的基团、或者、“AA7的羧基与Leu的氨基连接形成的含
的基团”中的
被下述的任一基团取代后、形成的基 团:
所述基团的左端与AA7相连(例如,当AA7为Gly、AA7为Leu时,“AA7-Leu”是指
);
AA9为下述任一氨基酸:Arg和Arg(Me);
AA10为Trp、或
{例如Phe、D-Phe、Phe(4-F)、Phe(pentaF)、Phe(2-Br)、Phe(4-I)、或、Phe(4-CF
3)};n10为0~5(例如0、1、2、3、4或5),所有的R
10独立地为卤代的C
1~C
4烷基(所述的“卤”例如氟、氯、溴或碘;所述的“C
1~C
4烷基”例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基或异丁基;所述的“卤代的C
1~C
4烷基”例如三氟甲基)或卤素(例如氟、氯、溴或碘),*标记的碳原子为手性碳原子,其为R构型或S构型(所有的R
10可独立地位于氨基酸侧链的邻位、间位或对位,例如,当n10为1时,R
10可位于氨基酸侧链的邻位或对位;例如,其可为
);
P为-NH
2。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
R
a为CH
3-,q为0~14(例如,以下述任两个值为端点的范围:0、1、2、3、4、5、6、7、8、9、10、11、12、13和14;再例如4~14);或者,R
a为HOOC-,q为14~18(例如,以下述任两个值为端点的范围:14、15、16、17和18;又例如14~16);
m为0~2(例如0、1或2);
当m为2时,与AA0或AA1连接的PEG中,所述的X可为-NH
2;当m为2时,与AA0或AA1连接的PEG中,所述的k可为2~4{例如2、3或4};当m为2时,与AA0或AA1连接的PEG中,所述的XX0可为
当m为2时,与AA0或AA1连接的PEG中,所述的
可为OEG或PEG4;
n为0~3(例如0、1、2或3);
所有的AA0独立地为Gly、Beta-Ala、Ahx或Ac-Lys;(例如,当n为2或3时,至少2个AA0为Gly;又例如,
可为化学键、“Gly-Gly”或“Ac-Lys-Gly-Gly”{其左侧与XX0连接})
但当q为0时,m和n不同时为0;
n’为0~3(例如0、1、2或3,又例如2);
所有的AA0’独立地为Gly、Beta-Ala、Ahx或Ac-Lys;(例如,当n’为2或3时,至少2个AA0’为Gly;又例如,
可为化学键、“Gly-Gly”或“Ac-Lys-Gly-Gly”{其左侧与PEG’连接})
AA1为Tyr、D-Tyr、D-2Fua或Phe(4-I);
AA2为Asn、Hyp、Pro(diF)或A6c;
XX3为Trp或化学键;
AA5为Thr或Ser;
AA6为Phe;
AA7为下述任一氨基酸:Gly、azaGly、Alg、Aze、D-2Fua和A6c;
当AA6为
时,“AA6-AA7”是指AA6的羧基(当氨基酸存在多个羧基时,可以为手性碳原子上的羧基)与AA7的氨基(当氨基酸存在多个氨基时,可以为手性碳原子上的氨基,还可以为伯氨基)连接形成的含
的基团;
当AA7为Gly时,“AA7-Leu”是指AA7的羧基(当氨基酸存在多个羧基时,可以为手性碳原子上的羧基)与Leu的氨基(当氨基酸存在多个氨基时,可以为手性碳原子上的氨基,还可以为伯氨基)连接形成的含
的基团、或者、“AA7的羧基与Leu的氨基连接形成的含
的基团”中的
被下述的任一基团取代后、形成的基 团:
所述基团的左端与AA7相连(例如,当AA7为Gly、AA7为Leu时,“AA7-Leu”是指
);
AA9为下述任一氨基酸:Arg和Arg(Me);
AA10为Trp或Phe;
P为-NH
2。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
R
a为CH
3-,q为0~16(例如,以下述任两个值为端点的范围:0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15和16;又例如0~14;再例如4~14)。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
R
a为CH
3-,q为0~14(例如,以下述任两个值为端点的范围:0、1、2、3、4、5、6、7、8、9、10、11、12、13和14;再例如4~14)。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
R
a为HOOC-,q为2~18(例如,以下述任两个值为端点的范围:2、3、4、5、6、7、8、9、10、11、12、13、14、15和16;又例如2~16)。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
R
a为HOOC-,q为14~18(例如,以下述任两个值为端点的范围:14、15、16、17和18;又例如14~16)。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
k独立地为2~8(例如,以下述任两个值为端点的范围:2、3、4、5、6和8,又例如4~8)。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA1为氨基未取代或氨基(当氨基酸存在多个氨基时,可以为手性碳原子上的氨基,还可以为伯氨基)被1个C
1-3的烷基(例如甲基、乙基、正丙基或异丙基)取代的下述氨基酸(所述的“取代的氨基酸”例如N-Me-Phe或N-Me-D-Phe):Tyr、D-Tyr、Thi、(S)-Pip、αMeTyr、1Nal、2Nal、4Pal、Dap(Dnp)、D-2Fua、Pro(5Ph)、2Pal、3Pal、Tyr(Me)、Ala(dip)、A6c、ACPA、D-Tic、3-[(1-甲基吡啶鎓)-3-基]丙氨酸、和、
{例如Phe、D-Phe、Phe(4-F)、D-Phe(4-F)、Phe(3-Cl)、D-Phe(3-Cl)、Phe(4-Cl)、D-Phe(4-Cl)、Phe(4-I)、D-Phe(4-I)、Phe(4-Me)、Phe(4-tBu)、或、D-Phe(2,4-diCl)};n1为0~2(例如0、1或2),所有的R
1独立地为甲基、甲氧基、C
4烷氧基(例如异丁氧基)或卤素(例如氟、氯或碘),*标记的碳原子为手性碳原子,其为R构型或S构型(所有的R
1可独立地位于氨基酸侧链的邻位、间位或对位,例如,当n1为1时,R
1可位于氨基酸侧链的间位或对位;当n1为2时,R
1可位于氨基酸侧链的邻位和对位;又例如,其为
)。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA1为下述任一氨基酸:Tyr、D-Tyr、D-2Fua、和、
{例如Phe、D-Phe、Phe(4-F)、D-Phe(4-F)、Phe(3-Cl)、D-Phe(3-Cl)、Phe(4-Cl)、D-Phe(4-Cl)、Phe(4-I)、D-Phe(4-I)、Phe(4-Me)、Phe(4-tBu)、或、D-Phe(2,4-diCl)};n1为0~2(例如0、1或2),所有的R
1独立地为C
1~C
4烷基(例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基或异丁基)、C
1~C
4烷氧基(例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基或异丁氧基)或卤素(例如氟、氯或碘),*标记的碳原子为手性碳原子,其为R构型或S构型(所有的R
1可独立地位于氨基酸侧链的邻位、间位或对位,例如,当n1为1时,R
1可位于氨基酸侧链的间位或对位;当n1为2时,R
1可位于氨基酸侧链的邻位和对位;又例如,其为
)。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA1为Tyr、D-Tyr、D-2Fua、D-Phe(4-I)或Phe(4-I)。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA1为Tyr、D-Tyr、D-2Fua或D-Phe(4-I)。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA1为Tyr、D-Tyr、D-2Fua或Phe(4-I)。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA2为Asn、Hyp、Pro、Ala、Thz、Pro(diF)、Pro(4-NH
2)、Thi、ACPA、D-2Fua、A6c、azaPro、Ind、(S)-Pip、(R)-Pip、Oic、AlphaMeLeu、Cba、A6c、Aze、Cpa或D-Tic。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA2为Asn、Hyp、Thz、Pro(diF)、Pro(4-NH
2)、Thi、AlphaMeLeu、Cba、A6c、Aze、Cpa或A6c。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA2为Asn、Hyp、Pro(4-NH
2)、AlphaMeLeu、Cba、A6c、Aze、Cpa或A6c。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA2为Asn、Hyp、AlphaMeLeu、Cba、A6c、Aze、Cpa或A6c。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA2为Asn、Hyp、Pro(4-NH
2)、Pro(diF)或A6c。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA2为Asn、Hyp、Pro(diF)或A6c。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
XX3为Trp或化学键。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如 前任一所述):
AA5为Thr或Ser。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA6为氨基未取代或氨基(当氨基酸存在多个氨基时,可以为手性碳原子上的氨基,还可以为伯氨基)被1个C
1-3的烷基(例如甲基、乙基、正丙基或异丙基)取代的下述氨基酸(所述的“取代的氨基酸”例如N-Me-Phe):1Nal、2Nal、αMePhe、4Pal、HoPhe、BetaPhe、BetaHomoPhe、Bpa、D-2Fua、A6c、Tic、azaPhe、和、
{例如Phe、D-Phe、Phe(4-F)、Phe(pentaF)、Phe(3-Cl)、Phe(2-Br)、Phe(4-I)、Phe(4-tBu)、或、Phe(4-CF
3)};n6为0、1或2,所有的R
6独立地为C
1~C
4烷基(例如甲基、乙基、异丙基或异丁基)或卤素(例如氟、氯、溴或碘),*标记的碳原子为手性碳原子,其为R构型或S构型(所有的R
6可独立地位于氨基酸侧链的邻位、间位或对位,例如,当n6为1时,R
6可位于氨基酸侧链的邻位、间位或对位;例如,其可为
)。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA6为
{例如Phe、D-Phe、Phe(4-F)、Phe(pentaF)、Phe(3-Cl)、Phe(2-Br)、Phe(4-I)、Phe(4-tBu)、或、Phe(4-CF
3)};n6为0~5(例如0、1、2、3、4或5),所有的R
6独立地为卤代的C
1~C
4烷基(所述的“卤”例如氟、氯、溴或碘;所述的“C
1~C
4烷基”例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基或异丁基;所述的“卤代的C
1~C
4烷基”例如三氟甲基)、C
1~C
4烷基(例如甲基、乙基、异丙基或异丁基)或卤素(例如氟、氯、溴或碘),*标记的碳原子为手性碳原子,其为R构型或S构型(所有的R
6可独立地位于氨基酸侧链的邻位、间位或对位,例如,当n6为1时,R
6可位于氨基酸侧链的邻位、 间位或对位;例如,其可为
)。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA6为Phe。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA7为氨基未取代或氨基(当氨基酸存在多个氨基时,可以为手性碳原子上的氨基,还可以为伯氨基)被1个C
1-3的烷基(例如甲基、乙基、正丙基或异丙基)取代的下述氨基酸(所述的“取代的氨基酸”例如N-Me-A6c或aza-N-Me-Gly):Gly、azaGly、Ala、Alg、Ava、Aib、Sar、Chg、BetaAla、ACPO、Aze、D-2Fua、A6c、azaPro、Ind、(S)-Pip、(R)-Pip、Oic、Hyp、cycloLeu、BetaHomoAla、Cba、ACPA、Alg、morpholino cyclic amino acid、beta-(thiazoly-4-yl)-L-Ala、
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA7为氨基未取代或氨基被1个C
1-3的烷基取代的下述氨基酸:Gly、azaGly、Ala、Ava、Aib、Sar、Chg、BetaAla、ACPO、Aze、Alg、D-2Fua、A6c、azaPro、Ind、(S)-Pip、(R)-Pip、azaTic、Oic、Hyp、cycloLeu、BetaHomoAla、Cba、ACPA和
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA7为下述任一氨基酸:Gly、azaGly、Alg、Aze、D-2Fua、Alg、morpholino cyclic amino acid、beta-(thiazoly-4-yl)-L-Ala、
和A6c。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA7为下述任一氨基酸:Gly、azaGly、Alg、Aze、D-2Fua、morpholino cyclic amino acid、beta-(thiazoly-4-yl)-L-Ala、
和A6c。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA7为azaGly、Aib、A6c、Alg、cycloLeu、Ind、Cba、Aze、Gly或D-2Fua。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA7为azaGly、Aib、A6c、Alg、cycloLeu、Ind、Cba、Aze或Gly。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA7为下述任一氨基酸:Gly、azaGly、Alg、Aze、D-2Fua和A6c。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA7为AzaGly、A6c、Alg、D-2Fua或Aze。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
当AA6为
时,“AA6-AA7”是指AA6的羧基(当氨基酸存在多个羧基时,可以为手性碳原子上的羧基)与AA7的氨基(当氨基酸存在多个氨基时,可以为手性碳原子上的氨基,还可以为伯氨基)连接形成的含
的基团、或者、“AA6的羧基与AA7的氨基连接形成的含
的基团”中的
被下述的任一基团取代后、形成的基团:
所述基团的左端与AA6相连(例如,当AA6为Phe、AA7为Gly时,“AA6-AA7”是指
)。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如 前任一所述):
当AA6为
时,“AA6-AA7”是指AA6的羧基(当氨基酸存在多个羧基时,可以为手性碳原子上的羧基)与AA7的氨基(当氨基酸存在多个氨基时,可以为手性碳原子上的氨基,还可以为伯氨基)连接形成的含
的基团。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
当AA7为Gly时,“AA7-Leu”是指AA7的羧基(当氨基酸存在多个羧基时,可以为手性碳原子上的羧基)与Leu的氨基(当氨基酸存在多个氨基时,可以为手性碳原子上的氨基,还可以为伯氨基)连接形成的含
的基团、或者、“AA7的羧基与Leu的氨基连接形成的含
的基团”中的
被下述的任一基团取代后、形成的基团:
所述基团的左端与AA7相连(例如,当AA7为Gly、AA7为Leu时,“AA7-Leu”是指
)。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
当AA7为Gly时,“AA7-Leu”是指AA7的羧基(当氨基酸存在多个羧基时,可以为手性碳原子上的羧基)与Leu的氨基(当氨基酸存在多个氨基时,可以为手性碳原子 上的氨基,还可以为伯氨基)连接形成的含
的基团、或者、“AA7的羧基与Leu的氨基连接形成的含
的基团”中的
被下述的任一基团取代后、形成的基团:
所述基团的左端与AA7相连(例如,当AA7为Gly、AA7为Leu时,“AA7-Leu”是指
)。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA9为氨基未取代或氨基(当氨基酸存在多个氨基时,可以为手性碳原子上的氨基,还可以为伯氨基)被1个C
1-3的烷基(例如甲基、乙基、正丙基或异丙基)取代的下述氨基酸(所述的“取代的氨基酸”例如N-Me-Arg、N-Me-HoLeu或N-Me-D-HoLeu):Arg、Arg(Me)、His、HoLeu、D-HoLeu、4Pal、Phe(4-amidino)、和、
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA9为下述任一氨基酸:Arg和Arg(Me)。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA10为氨基未取代或氨基(当氨基酸存在多个氨基时,可以为手性碳原子上的氨基,还可以为伯氨基)被1个C
1-3的烷基(例如甲基、乙基、正丙基或异丙基)取代的下述氨基酸(所述的“取代的氨基酸”例如N-Me-Phe):Trp、αMePhe、1Nal、2Nal、4Pal、BetaPhe、BetaHoPhe、Bpa、NPhe、D-2Fua、A6c、Tic、和、
{例如Phe、D-Phe、Phe(4-F)、Phe(pentaF)、Phe(2-Br)、Phe(4-I)、或、Phe(4-CF
3)};n10为 0,*标记的碳原子为手性碳原子,其为R构型或S构型(所有的R
10可独立地位于氨基酸侧链的邻位、间位或对位,例如,当n10为1时,R
10可位于氨基酸侧链的邻位或对位;例如,其可为
)。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA10为Trp、或
{例如Phe、D-Phe、Phe(4-F)、Phe(pentaF)、Phe(2-Br)、Phe(4-I)、或、Phe(4-CF
3)};n10为0~5(例如0、1、2、3、4或5),所有的R
10独立地为卤代的C
1~C
4烷基(所述的“卤”例如氟、氯、溴或碘;所述的“C
1~C
4烷基”例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基或异丁基;所述的“卤代的C
1~C
4烷基”例如三氟甲基)或卤素(例如氟、氯、溴或碘),*标记的碳原子为手性碳原子,其为R构型或S构型(所有的R
10可独立地位于氨基酸侧链的邻位、间位或对位,例如,当n10为1时,R
10可位于氨基酸侧链的邻位或对位;例如,其可为
)。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA10为Trp或Phe。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
P为-NH
2。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
其中,R
a为CH
3-,q为0~18(例如,以下述任两个值为端点的范围:0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17和18;又例如0~14;再例如4~14);或者,R
a为HOOC-,q为1~18(例如,以下述任两个值为端点的范围:1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17和18;又例如1~16);
m为0~2(例如0、1或2);
PEG独立地为
X独立地为-NHR
b或-OH,R
b独立地为氢或C
1-3的烷基(例如甲基、乙基、异丙基或正丙基);k独立地为2~24(例如,以下述任两个值为端点的范围:2、3、4、5、6、8、12、16、20或24);XX0独立地为
当m为2时,与AA0或AA1连接的PEG中,所述的X可为-NH
2;当m为2时,与AA0或AA1连接的PEG中,所述的k可为2~4{例如2、3或4};当m为2时,与AA0或AA1连接的PEG中,所述的XX0可为
当m为2时,与AA0或AA1连接的PEG中,所述的
可为OEG或PEG4;
n为0~3(例如0、1、2或3);
所有的AA0独立地为Gly、Beta-Ala、Ahx或Ac-Lys;(例如,当n为2或3时,至少2个AA0为Gly;又例如,
可为化学键、“Gly-Gly”或“Ac-Lys-Gly-Gly”{其左侧与XX0连接})
但当q为0时,m和n不同时为0;(也即
不为乙酰基;例如当m为0、n为0时,q为1~18;又例如,以下述任两个值为端点的范围:1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17和18;再例如4~14);
AA1为氨基(当氨基酸存在多个氨基时,可以为手性碳原子上的氨基,还可以为伯氨基)被1个C
1-3的烷基(例如甲基、乙基、正丙基或异丙基)取代或未取代的下述氨基酸(所述的“取代的氨基酸”例如N-Me-Ala、N-Me-D-Ala、N-Me-Leu、N-Me-D-Leu、N-Me-Phe或N-Me-D-Phe):D-Ala、Leu、D-Leu、Tyr、D-Tyr、Thi、(S)-Pip、Ala、αMeTyr、1Nal、2Nal、4Pal、Dap(Dnp)、D-2Fua、Pro(5Ph)、2Pal、3Pal、Tyr(Me)、Ala(dip)、A6c、ACPA、D-Tic、3-[(1-甲基吡啶鎓)-3-基]丙氨酸、和、
{例如Phe、D-Phe、Phe(4-F)、D-Phe(4-F)、Phe(3-Cl)、D-Phe(3-Cl)、Phe(4-Cl)、D-Phe(4-Cl)、Phe(4-I)、Phe(4-Me)、Phe(4-tBu)、或、D-Phe(2,4-diCl)};n1为0~2(例如0、1或2),所有的R
1独立地为C
1~C
4烷基(例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基或异丁基)、C
1~C
4烷氧基(例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基或异丁氧基)或卤素(例如氟或氯),*标记的碳原子为手性碳原子,其为R构型或S构型(所有的R
1可独立地位于氨基酸侧链的邻位、间位或对位,例如,当n1为1时,R
1可位于氨基酸侧链的间位或对位;当n1为2时,R
1可位于氨基酸侧链的邻位和对位;又例如,其为
);
AA2为Asn、Hyp、Pro、Ala、Thz、Pro(diF)、Pro(4-NH
2)、Thi、NAsn、ACPA、D-2Fua、A6c、azaPro、Ind、(S)-Pip、(R)-Pip、Oic、azaTic或D-Tic;
XX3为Trp、Ala、Phe(4-I)或化学键;
AA5为2Fua、Thr或Ser;
AA6为氨基(当氨基酸存在多个氨基时,可以为手性碳原子上的氨基,还可以为伯 氨基)被1个C
1-3的烷基(例如甲基、乙基、正丙基或异丙基)取代或未取代的下述氨基酸(所述的“取代的氨基酸”例如N-Me-Phe):Ala、1Nal、2Nal、Trp、αMePhe、Bta、4Pal、HoPhe、BetaPhe、BetaHomoPhe、Bpa、Ala(dip)、Bip、D-2Fua、A6c、Tic、azaTic、azaPhe、和、
{例如Phe、D-Phe、Phe(4-F)、Phe(pentaF)、Phe(3-Cl)、Phe(2-Br)、Phe(4-I)、Phe(4-tBu)、或、Phe(4-CF
3)};n6为0~5(例如0、1、2、3、4或5),所有的R
6独立地为卤代的C
1~C
4烷基(所述的“卤”例如氟、氯、溴或碘;所述的“C
1~C
4烷基”例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基或异丁基;所述的“卤代的C
1~C
4烷基”例如三氟甲基)、C
1~C
4烷基(例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基或异丁基)或卤素(例如氟、氯、溴或碘),*标记的碳原子为手性碳原子,其为R构型或S构型(所有的R
6可独立地位于氨基酸侧链的邻位、间位或对位,例如,当n6为1时,R
6可位于氨基酸侧链的邻位、间位或对位;例如,其可为
);
AA7为氨基(当氨基酸存在多个氨基时,可以为手性碳原子上的氨基,还可以为伯氨基)被1个C
1-3的烷基(例如甲基、乙基、正丙基或异丙基)取代或未取代的下述氨基酸(所述的“取代的氨基酸”例如N-Me-A6c或aza-N-Me-Gly):Gly、azaGly、Ala、Ava、Aib、Sar、Chg、BetaAla、ACPO、Aze、D-2Fua、A6c、azaPro、Ind、(S)-Pip、(R)-Pip、azaTic、Oic、Hyp、cycloLeu、BetaHomoAla、Cba、ACPA和
当AA6为
时,“AA6-AA7”是指AA6的羧基(当氨基酸存在多个羧基时,可以为手性碳原子上的羧基)与AA7的氨基(当氨基酸存在多个氨基时,可以为手性碳原子上的氨基,还可以为伯氨基)连接形成的含
的基团、或者、 “AA6的羧基与AA7的氨基连接形成的含
的基团”中的
被下述的任一基团取代后、形成的基团:
所述基团的左端与AA6相连(例如,当AA6为Phe、AA7为Gly时,“AA6-AA7”是指
);
AA9为氨基(当氨基酸存在多个氨基时,可以为手性碳原子上的氨基,还可以为伯氨基)被1个C
1-3的烷基(例如甲基、乙基、正丙基或异丙基)取代或未取代的下述氨基酸(所述的“取代的氨基酸”例如N-Me-Arg、N-Me-HoLeu或N-Me-D-HoLeu):Arg、Arg(Me)、Ala、His、HoLeu、D-HoLeu、4Pal、Phe(4-amidino)、
AA10为氨基(当氨基酸存在多个氨基时,可以为手性碳原子上的氨基,还可以为伯氨基)被1个C
1-3的烷基(例如甲基、乙基、正丙基或异丙基)取代或未取代的下述氨基酸(所述的“取代的氨基酸”例如N-Me-Phe):Trp、Ala、αMePhe、1Nal、2Nal、4Pal、BetaPhe、BetaHoPhe、Bpa、Ala(dip)、NPhe、Bip、D-2Fua、A6c、Tic、和、
{例如Phe、D-Phe、Phe(4-F)、Phe(pentaF)、Phe(2-Br)、Phe(4-I)、或、Phe(4-CF
3)};n10为0~5(例如0、1、2、3、4或5),所有的R
10独立地为卤代的C
1~C
4烷基(所述的“卤”例如氟、氯、溴或碘;所述的“C
1~C
4烷基”例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基或异丁基;所述的“卤代的C
1~C
4烷基”例如三氟甲基)或卤素(例如氟、氯、溴或碘),*标记的碳原子为手性碳原子,其为R构型或S构型(所有的R
10可独立地位于氨基酸侧链的邻位、间位或对位,例如,当n10为1时,R
10可位于氨基酸侧链的邻位或对位;例如,其可为
);
P为-NH
2、-OH、-NH-tBu、-NH-Et、-NH-Me、1H-1,2,3-三唑-4-基或2H-四唑-5-基。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
m为1或2。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
m为0,n为0,R
a为CH
3-或HOOC-,q为1~18(例如,以下述任两个值为端点的范围:1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17和18;又例如 4~14)。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
m为0,n为1~3。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
其中,R
a为CH
3-,q为0~14(例如,以下述任两个值为端点的范围:0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15和16);或者,R
a为HOOC-,q为1~16(例如,以下述任两个值为端点的范围:1、2、3、4、5、6、7、8、9、10、11、12、13、14、15和16)。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
m为0~2(例如1)。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
X为-NH
2。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
k独立地为2~8(例如,以下述任两个值为端点的范围:2、3、4、5、6、7和8;又例如4~8)。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
n为0~3(例如0、1、2或3)。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA1为Tyr、D-Tyr、或、D-2Fua。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA2为Asn、Hyp、或、Pro(diF)。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
XX3为Trp或化学键。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA5为Thr或Ser。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA6为Phe。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA7为Gly、azaGly、Aze、D-2Fua或A6c。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA9为Arg或Arg(Me)。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA10为Trp或Phe。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如 前任一所述):
P为-NH
2。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA1为Dap(Dnp)、D-Phe(2,4-diCl)、D-Tic、2Pal、3Pal、D-Tyr、Ala(dip)、或、D-2Fua。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA2为Thz、(S)-Pip、Oic、A6c、Thi、D-2Fua、ACPA或Pro。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA5为2Fua。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA6为Phe。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA10为2-Nal。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
P为-NH
2。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA1为Dap(Dnp)、D-Phe(2,4-diCl)、D-Tic、2Pal、3Pal、
Tyr、D-Tyr、Ala(dip)、或、D-2Fua;n1为1或2,所有的R
1独立地为C
1~C
3烷基(例如甲基、乙基、正丙基或异丙基)、C
1~C
3烷氧基(例如甲氧基、乙氧基、正丙氧基或异丙氧基)或卤素(例如氟或氯)。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA2为Thz、(S)-Pip、Oic、A6c、Thi、D-2Fua、ACPA、Pro、Asn、Hyp、或、Pro(diF)。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
XX3为Trp或化学键。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA5为2Fua、Thr或Ser。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA6为Phe;
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA9为Arg或Arg(Me)。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如 前任一所述):
AA10为2-Nal、Trp或Phe。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
P为-NH
2。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
所有的AA0独立地为Gly、BetaAla、Ac-Lys或Ahx。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA1为D-Tyr、D-Phe(2,4-DiCl)、D-2Fua、L-Phe(4-F)、D-Phe(4-F)、Thi、(S)-Pip、D-Tic、Dap(Dnp)、D-Phe(4-Cl)、D-Phe(3-Cl)、2-Pal、3Pal、Ala(dip)、或、ACPA。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA2为Hyp、Thi、A6c、Thz、Pro(diF)、Pro、Pro(4-NH
2)、D-2Fua、(S)-Pip、ACPA、(R)-Pip或Oic。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
XX3为Trp或化学键。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA5为2Fua或Thr。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA6为Phe。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA9为Arg(Me)。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA10为Trp或2-Nal。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
P为OH或NH
2。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA1为D-Tyr、D-Phe(2,4-DiCl)、D-2Fua、Thi、(S)-Pip或D-Phe(4-F)。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA2为Hyp、Thi、A6c、Thz、Pro(diF)、Pro(4-NH
2)、D-2Fua、(S)-Pip、(R)-Pip或Oic。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
XX3为化学键。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA6为Phe。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA9为Arg(Me)。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
AA10为Trp或2-Nal。
在某一技术方案中,所述的化合物1中各基团的定义可如下所述(未注释的定义如前任一所述):
P为OH或NH
2。
在某一技术方案中,所述的化合物1可为下列任一化合物:
本发明还提供了上述的化合物1、其药学上可接受的盐、其互变异构体、其晶型、其溶剂合物或其前药在制备药物中的应用,所述的药物用于治疗和/或预防与亲吻肽受体相关的疾病。
所述的与亲吻肽受体相关的疾病例如与激素相关的疾病、细胞增殖性疾病、或、与胎盘功能相关的疾病。
所述的与激素相关的疾病例如前列腺癌、乳腺癌(例如闭经前乳腺癌)、子宫内膜异位症、子宫肌瘤、中枢性性早熟症、雌激素受体阳性、性功能性疾病(例如性功能障碍、性冷淡)、不育症、抑郁症、或怀孕。
所述的细胞增殖性疾病例如良性前列腺增生症或癌症。所述的癌症例如前列腺癌、乳腺癌、卵巢癌、子宫癌、宫颈癌、子宫内膜癌、甲状腺癌、膀胱癌、肝癌、黑色素瘤、胰腺癌、胃癌、肾细胞癌、食管癌(例如食管鳞状细胞癌)、膀胱癌或脑癌。
所述的与胎盘功能相关的疾病例如绒毛膜癌、侵袭性痣、流产、胎儿发育不全、糖代谢异常或脂质代谢异常。
本发明还提供了一种药物组合物,其包含上述的化合物1、其药学上可接受的盐、其互变异构体、其晶型、其溶剂合物或其前药,以及一种或多种药用辅料。
所述的药用辅料可为药物生产领域中广泛采用的那些辅料。辅料主要用于提供一个安全、稳定和功能性的药物组合物,还可以提供方法,使受试者接受给药后活性成分以所期望速率溶出,或促进受试者接受组合物给药后活性成分得到有效吸收。所述的药用辅料可以是惰性填充剂,或者提供某种功能,例如稳定该组合物的整体pH值或防止组合 物活性成分的降解。所述的药用辅料可以包括下列辅料中的一种或多种:粘合剂、助悬剂、乳化剂、稀释剂、填充剂、成粒剂、胶粘剂、崩解剂、润滑剂、抗粘着剂、助流剂、润湿剂、胶凝剂、吸收延迟剂、溶解抑制剂、增强剂、吸附剂、缓冲剂、螯合剂、防腐剂、着色剂、矫味剂和甜味剂。
本发明的药物组合物可根据公开的内容使用本领域技术人员已知的任何方法来制备。例如,常规混合、溶解、造粒、乳化、磨细、包封、包埋或冻干工艺。
本发明所述的药物组合物可以配制用于任何形式给药,包括注射(静脉内)、粘膜、口服(固体和液体制剂)、吸入、眼部、直肠、局部或胃肠外(输注、注射、植入、皮下、静脉内、动脉内、肌内)给药。本发明的药物组合物还可以是控释或延迟释放剂型(例如脂质体或微球)。固体口服制剂的实例包括但不限于粉末、胶囊、囊片、软胶囊剂和片剂。口服或粘膜给药的液体制剂实例包括但不限于悬浮液、乳液、酏剂和溶液。局部用制剂的实例包括但不限于乳剂、凝胶剂、软膏剂、乳膏剂、贴剂、糊剂、泡沫剂、洗剂、滴剂或血清制剂。胃肠外给药的制剂实例包括但不限于注射用溶液、可以溶解或悬浮在药学上可接受载体中的干制剂、注射用悬浮液和注射用乳剂。所述的药物组合物的其它合适制剂的实例包括但不限于滴眼液和其他眼科制剂;气雾剂:如鼻腔喷雾剂或吸入剂;适于胃肠外给药的液体剂型;栓剂以及锭剂。
本发明还提供了一种肽类化合物3、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药,所述的肽类化合物3为如下任一结构:
本发明还提供了上述的化合物3、其药学上可接受的盐、其互变异构体、其晶型、其溶剂合物或其前药在制备药物中的应用,所述的药物用于治疗和/或预防与亲吻肽受体相关的疾病。
所述的与亲吻肽受体相关的疾病例如与激素相关的疾病、细胞增殖性疾病、或、与胎盘功能相关的疾病。
所述的与激素相关的疾病例如前列腺癌、乳腺癌(例如闭经前乳腺癌)、子宫内膜异位症、子宫肌瘤、中枢性性早熟症、雌激素受体阳性、性功能性疾病(例如性功能障碍、 性冷淡)、不育症、抑郁症、或怀孕。
所述的细胞增殖性疾病例如良性前列腺增生症或癌症。所述的癌症例如前列腺癌、乳腺癌、卵巢癌、子宫癌、宫颈癌、子宫内膜癌、甲状腺癌、膀胱癌、肝癌、黑色素瘤、胰腺癌、胃癌、肾细胞癌、食管癌(例如食管鳞状细胞癌)、膀胱癌或脑癌。
所述的与胎盘功能相关的疾病例如绒毛膜癌、侵袭性痣、流产、胎儿发育不全、糖代谢异常或脂质代谢异常。
本发明还提供了一种药物组合物,其包含上述的化合物3、其药学上可接受的盐、其互变异构体、其晶型、其溶剂合物或其前药,以及一种或多种药用辅料。
所述的药用辅料可为药物生产领域中广泛采用的那些辅料。辅料主要用于提供一个安全、稳定和功能性的药物组合物,还可以提供方法,使受试者接受给药后活性成分以所期望速率溶出,或促进受试者接受组合物给药后活性成分得到有效吸收。所述的药用辅料可以是惰性填充剂,或者提供某种功能,例如稳定该组合物的整体pH值或防止组合物活性成分的降解。所述的药用辅料可以包括下列辅料中的一种或多种:粘合剂、助悬剂、乳化剂、稀释剂、填充剂、成粒剂、胶粘剂、崩解剂、润滑剂、抗粘着剂、助流剂、润湿剂、胶凝剂、吸收延迟剂、溶解抑制剂、增强剂、吸附剂、缓冲剂、螯合剂、防腐剂、着色剂、矫味剂和甜味剂。
本发明的药物组合物可根据公开的内容使用本领域技术人员已知的任何方法来制备。例如,常规混合、溶解、造粒、乳化、磨细、包封、包埋或冻干工艺。
本发明所述的药物组合物可以配制用于任何形式给药,包括注射(静脉内)、粘膜、口服(固体和液体制剂)、吸入、眼部、直肠、局部或胃肠外(输注、注射、植入、皮下、静脉内、动脉内、肌内)给药。本发明的药物组合物还可以是控释或延迟释放剂型(例如脂质体或微球)。固体口服制剂的实例包括但不限于粉末、胶囊、囊片、软胶囊剂和片剂。口服或粘膜给药的液体制剂实例包括但不限于悬浮液、乳液、酏剂和溶液。局部用制剂的实例包括但不限于乳剂、凝胶剂、软膏剂、乳膏剂、贴剂、糊剂、泡沫剂、洗剂、滴剂或血清制剂。胃肠外给药的制剂实例包括但不限于注射用溶液、可以溶解或悬浮在药学上可接受载体中的干制剂、注射用悬浮液和注射用乳剂。所述的药物组合物的其它合适制剂的实例包括但不限于滴眼液和其他眼科制剂;气雾剂:如鼻腔喷雾剂或吸入剂;适于胃肠外给药的液体剂型;栓剂以及锭剂。
在不违背本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
如无特别说明,本发明中所用的术语具有以下含义:
结构式中,“AA0-AA1”是指AA0中的羧基(当氨基酸存在多个羧基时,可以为手性碳原子上的羧基)与AA1中的氨基(当氨基酸存在多个氨基时,可以为手性碳原子上的氨基,还可以为伯氨基)连接形成的含
的基团。“PEG-PEG”(此时是前一个PEG的羧基与后一个PEG的氨基或羟基连接)、“PEG-AA0”、“PEG-AA1”、“PEG’-AA0’”、“PEG’-AA1”、“AA0-AA0”、“AA1-AA2”、“AA2-XX3”、“AA2-Asn”、“XX3-Asn”、“Asn-AA5”、“AA5-AA6”、“AA6-AA7”、“AA7-Leu”和“AA9-AA10”同此。例如,当AA6为Phe、AA7为Gly时,“AA6-AA7”是指
也即,式1的左端为N端,右端为C端。
结构式中,“AA10-P”是指AA10的羧基(-COOH)中的-OH被P代替所形成的基团, 例如,当AA10为Phe、P为-NH
2时,“AA10-P”是指
若具体序列的右端以氨基酸(AA10)结尾,未明确-P是哪一基团,即表示默认P为-OH。
结构式中,XX3中的“化学键”是指该位点前后的基团通过化学键“-”连接,具体化学键的含义同上。“m为0”、“n为0”的情形同此。例如,当XX3为化学键时,则AA2与Asn通过化学键“-”连接,其情形即“AA2-Asn”。
在本文中使用常规的用于表示氨基酸的单字母代码来定义本发明所述的肽分子。术语“氨基酸”包括水溶性的、具有与α-碳原子连接的羧基(-COOH)和氨基(-NH
2)基团的有机化合物。氨基酸可以用通式R-CH(NH
2)COOH表示;R基团为氢或有机基团,并且决定了任意具体氨基酸的性质。α-碳原子周围的四个不同基团的四面体排列使氨基酸具有光学活性。两种镜像形式被称为L-异构体和D-异构体。通常,仅有L-氨基酸是蛋白质(如真核蛋白质)的组成成分。
除非另作说明,本发明的肽分子包含L-氨基酸。当D-氨基酸存在于本发明的肽分子时,用带有前缀“(D)”的常规单字母氨基酸代码表示。
如所述,本发明的分子可以包含在特定位置具有“任意D-氨基酸”的肽序列或由在特定位置具有“任意D-氨基酸”的肽序列组成。所述“任意D-氨基酸”包括在序列中在特定位置的任意天然或非天然(例如化学修饰的)D-氨基酸。天然D-氨基酸的实例如下:D-丙氨酸;D-天冬氨酸;D-半胱氨酸;D-谷氨酸;D-苯丙氨酸;D-甘氨酸;D-组氨酸;D-异亮氨酸;D-赖氨酸;D-亮氨酸;D-蛋氨酸;D-天冬酰胺;D-脯氨酸;D-谷氨酰胺;D-精氨酸;D-丝氨酸;D-苏氨酸;D-缬氨酸;D-色氨酸;D-酪氨酸。非天然D-氨基酸的实例如下:萘基丙氨酸;D-吡啶基丙氨酸;D-叔丁基丝氨酸;D-鸟氨酸;D-ε氨基赖氨酸;D-高精氨酸;D-α甲基亮氨酸以及用卤素取代(如F)这些和其它非天然氨基酸中的质子。
通过形成肽键,氨基酸结合形成短链(肽)或较长的链(多肽)。已知蛋白质和/或肽由不同流动相比例的大约20种常见氨基酸组成,其序列决定了蛋白质和/或肽的形状、性质和生物学作用。这种肽或多肽链中的氨基酸残基通常用它们在链上的排列位置来表示,第一位(即位点1)指定为链N-末端的氨基酸。
表1 氨基酸缩写解释
术语“药学上可接受的盐”指药学上可接受的有机或无机盐。示例性酸盐包括但不 限于:硫酸盐、柠檬酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、异烟酸盐、乳酸盐、水杨酸盐、酸式柠檬酸盐、酒石酸盐、油酸盐、单宁酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、富马酸盐、葡糖酸盐、葡糖醛酸盐、糖酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲烷磺酸盐、乙烷磺酸盐、苯磺酸盐、对甲苯磺酸盐和双羟萘酸盐(即1-1-亚甲基-双(2-羟基-3-萘甲酸盐))。本发明中所用化合物可与各种氨基酸形成药学上可接受的盐。合适的碱盐包括但不限于铝盐、钙盐、锂盐、镁盐、钾盐、钠盐、锌盐、铋和二乙醇胺盐。药学上可接受的盐的综述见Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl and Camille G.Wermuth,ed.,Wiley-VCH,2002)。
术语“晶型”是指在结晶时,分子在晶格空间的排列不同而形成的一种或多种晶体结构。
术语“溶剂合物”是一种晶体形式,除活性分子以外,它还包含一种或多种融入晶体结构中的溶剂分子。溶剂合物可包括化学计量量或非化学计量量的溶剂,并且溶剂中的溶剂分子可能以有序或非有序排列的形式存在。含有非化学计量量溶剂分子的溶剂合物可能是溶剂合物至少丢失一部分(但并非全部)溶剂分子得到的。在一个特定实施例中,一种溶剂合物是一种水合物,意味着化合物的结晶形式可包括水分子。
术语“前药”是指包含生物反应官能团的化合物的衍生物,使得在生物条件下(体外或体内),生物反应官能团可从化合物上裂解或以其他方式发生反应以提供所述化合物。通常,前药无活性,或者至少比化合物本身活性低,使得直到将所述化合物从生物反应官能团上裂解后才能发挥其活性。生物反应官能团可在生物条件下水解或氧化以提供所述化合物。例如,前药可包含可生物水解的基团,可生物水解的基团实例包括但不限于可生物水解的磷酸盐、可生物水解的酯、可生物水解的酰胺、可生物水解的碳酸酯、可生物水解的氨基甲酸酯和可生物水解的酰脲。有关前药的综述参见,例如,J.Rautio et al.,Nature Reviews Drug Discovery(2008)7,255-270and Prodrugs:Challenges和Rewards(V.Stella et al.ed.,Springer,2007)。
术语“烷基”是指具有一个到十八个碳原子的饱和的直链或支链的一价烃基(例如C
1-C
6烷基,又例如C
1-C
4烷基)。烷基的实例包括但不仅限于甲基、乙基、1-丙基、2-丙基、1-丁基、2-甲基-1-丁基、2-丁基、2-甲基-2-丙基、1-戊基、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、1-己基、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基、3,3-二甲基-2-丁基、1-庚基、1-辛基。
本发明的积极进步效果在于:本发明的化合物的稳定性较佳且对Kiss1R的活性较佳。
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
本发明的肽类化合物全部通过Lu et al(1981)J.Org.Chem.46,3433、其参考文献中公开的Fmoc-聚酰胺式固相肽合成法来合成。用9-芴基甲氧羰基(Fmoc)基团提供临时的N-氨基保护。使用含20%哌啶的N,N-二甲基甲酰胺进行该高度碱不稳定的保护基团的重复去除。可以将侧链官能团保护成其丁基醚(对于丝氨酸、苏氨酸和酪氨酸的情况)、丁基酯(对于谷氨酸和天冬氨酸的情况)、丁基氧羧基衍生物(对于赖氨酸和组氨酸的情况)、三苯甲基衍生物(对于天冬酰胺和谷氨酰胺的情况)和4-甲氧基-2,3,6-三甲基苯磺酰衍生物(对于精氨酸的情况)。当C-末端残基为谷氨酰胺或天冬酰胺时,使用4,4′-二甲氧基二苯甲基基团保护侧链氨基官能团。固相载体基于由二甲基丙烯酰胺(主链单体)、双丙烯酰乙二胺(交联剂)和丙烯酰肌氨酸甲酯(功能化试剂)三种单体组成的聚二甲基-丙烯酰胺聚合物。所使用的肽-树脂可断裂连接剂为酸不稳定的4-羟甲基-苯氧基乙酸衍生物。除了天冬酰胺和谷氨酰胺之外,全部氨基酸衍生物均作为它们预制的对称酐衍生物加入,而使用反向N,N-二环己基碳二亚胺/1-羟基苯并三唑介导的偶联方法加入天冬酰胺和谷氨酰胺。使用茚三酮、三硝基苯磺酸或吲哚醌(isotin)检测方法来监测所有的偶联和去保护反应。合成完成时,从树脂载体切下肽,同时用含有50%清除剂混合物的95%三氟乙酸处理去除侧链的保护基团。常用的清除剂为乙二硫醇、苯酚、苯甲醚和水,准确的选择取决于所合成的肽的氨基酸组成。通过真空蒸发去除三氟乙酸,接着通过用乙醚研磨而提供粗肽。通过简单的萃取步骤来去除存在的任何清除剂,其中通过冷冻干燥水相提供不含清除剂的粗肽。用于肽合成的试剂通常可购自Calbiochem-Novabiochem(UK)Ltd,Nottingham NG72QJ,UK。纯化可以通过例如体积排阻色谱法、离子交换色谱法和(主要地)反相高效液相色谱法等技术中的任意一种或组合来实现。肽的分析可以使用薄层色谱法、反相高效液相色谱法、酸水解后的氨基酸分析以及快速原子轰击(FAB)质谱分析来进行。
同时,还可以使用化学和生物化学领域技术人员所熟知的液相法来合成本发明的肽类化合物。
在合成之后,可以使用本领域中已知的方法,如HPLC和色谱法纯化本发明的活性剂(agent)的肽序列。
制备例1 Fmoc-Phe-aza-Leu-OH(YA-3包含的特殊化合物)的制备:
(2-((((9氢-芴-9-基)甲氧基)羰基-L-苯丙氨酰基-2-肼基-1-羰基-L-亮氨酸
步骤1:(S)-2-(2-(((9氢-芴-9-基)甲氧基)羰基氨基)-3-苯丙酰基)肼基甲酸叔丁酯(化合物YA-3-A)
将(S)-2-(((9氢-芴-9-基)甲氧基)羰基氨基)-3-苯丙氨酸(10g,25.8mmol)、肼甲酸叔丁酯(3.41g,25.8mmol)、HOBt(5.23g,38.7mmol)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(7.42g,38.7mmol)溶于二氯甲烷(250mL),室温下搅拌10分钟后,加入二异丙基乙胺(6.67g,51.6mmol)。该混合物在室温下搅拌20小时后,浓缩。剩余物中加入300mL石油醚和30mL水,室温下搅拌10分钟,过滤,固体用混合液EA:PE=1:5(180mL)洗涤,滤饼干燥得标题化合物(10g,77%),为白色固体。LCMS(ESI)[M-99]
+=402.0。
步骤2:(S)-2-(2-(((9氢-芴-9-基)甲氧基)羰基氨基)-3-苯丙酰基)肼盐酸盐(化合物YA-3-B)
将化合物(S)-2-(2-(((9氢-芴-9-基)甲氧基)羰基氨基)-3-苯丙酰基)肼基甲酸叔丁酯(10g,19.94mmol)溶于乙酸乙酯(100mL),然后加入HCl/dioxane(4M,100mL).反应液室 温搅拌2小时。过滤,固体用混合液EA:PE=2:3(50mL)洗涤两次,滤饼干燥,得标题化合物(6.4g,80%),为白色固体。LCMS(ESI)[M+H]
+=402.2。
步骤3:(2-((((9氢-芴-9-基)甲氧基羰基)-L-苯丙氨酰基-2-肼基-1-羰基-L-亮氨酸叔丁酯(化合物YA-3-C)
将化合物(S)-2-(2-(((9氢-芴-9-基)甲氧基)羰基氨基)-3-苯丙酰基)肼的盐酸盐(6.4g,16mmol)和(S)-2-异氰酸酯基-4-甲基戊酸叔丁酯(4.42g,20.7mmol)溶于二氯甲烷(200mL),该反应液在0度下搅拌2小时。将反应混合物浓缩,所得粗产品用快速色谱法分离纯化(石油醚/乙酸乙酯=1/3),得标题化合物(5.5g,56%),为白色固体。LCMS(ESI)[M-55]
+=559.3。
步骤4:(2-((((9氢-芴-9-基)甲氧基羰基-L-苯丙氨酰基-2-肼基-1-羰基-L-亮氨酸(化合物YA-3-D)
将化合物(2-((((9氢-芴-9-基)甲氧基)羰基)-L-苯丙氨酰基-2-肼基-1-羰基-L-亮氨酸叔丁酯(5.5g,8.95mmol)溶于二氯甲烷(20mL),加入三氟乙酸(20mL),反应液在室温下搅拌3小时。将反应混合物浓缩,所得残余物用快速色谱法分离纯化(二氯甲烷/甲醇=4/1)得标题化合物(4.8g,96%),为白色固体。LCMS(ESI)[M+H]
+=559.2.
1H NMR(400MHz,DMSO-d
6)δ8.34(s,1H),8.23(s,1H),7.99(s,1H),7.88(d,J=7.6Hz,2H),7.75(d,J=7.6Hz,1H),7.64(q,J=11.6Hz,2H),7.42-7.25(m,9H),7.20(d,J=7.2Hz,1H),4.16-4.11(m,3H),3.02(d,J=10.0Hz,1H),2.84(d,J=10.8Hz,1H),2.51(s,2H),1.63(s,1H),1.48-1.46(m,2H),0.87-0.82(m,6H).
制备例2:(5R,11S)-1-(9氢-芴-9-基)-5-(呋喃-2-基甲基)-11-异丁基-3,6,9-三氧代-2-氧杂-4,7,8,10-四氮十二烷-12-酸(化合物YA-167-d)
步骤1:(R)-2-(2-(((9氢-芴-9-基)甲氧基)羰基氨基)-3-(呋喃-2-基)丙酰基)肼甲酸叔丁酯(化合物YA-167-a)
将(R)-2-(((9氢-芴-9-基)甲氧基)羰基氨基)-3-(呋喃-2-基)丙酸(3.02g,8mmol)和肼甲酸叔丁酯(1.06g,8mmol)溶于二氯甲烷(30mL),然后室温下加入HATU(3.96g,10.4mmol)和二异丙基乙胺(5.17g,40mmol)。反应液在室温下搅拌2小时,然后浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯=1/4),得标题化合物(2.8g,71%),为白色固体。LCMS(ESI)[M-99]
+=392.2。
步骤2:(R)-2-(2-(((9氢-芴-9-基)甲氧基)羰基氨基)-3-(呋喃-2-基)丙酰基)肼的盐酸盐(化合物YA-167-b)
将(R)-2-(2-(((9氢-芴-9-基)甲氧基)羰基氨基)-3-(呋喃-2-基)丙酰基)肼甲酸叔丁酯(2.8g,5.84mmol)和盐酸的1,4-二氧六环溶液(4M,20mL)的混合液在室温下搅拌3小时。然后浓缩,得标题化合物(2.2g,99%),为白色固体。LCMS(ESI)[M+H]
+=392.1。
步骤3:(5R,11S)-1-(9氢-芴-9-基)-5-(呋喃-2-基甲基)-11-异丁基-3,6,9-三氧代-2-氧杂-4,7,8,10-四氮十二烷-12-酸叔丁酯(化合物YA-167-c)
将化合物(R)-2-(2-(((9氢-芴-9-基)甲氧基)羰基氨基)-3-(呋喃-2-基)丙酰基)肼的盐酸盐(2.43g,12.96mmol)溶于二氯甲烷(40mL),然后0℃下加入(S)-2-异氰酸酯基-4-甲基戊酸叔丁酯(2.76g,12.96mmol)。反应液在0℃下搅拌2小时,然后浓缩。残余物用快速色谱法分离纯化(纯乙酸乙酯),得标题化合物(1.8g,30%),为白色固体。LCMS(ESI)[M-55]
+=549.1。
步骤4:(5R,11S)-1-(9氢-芴-9-基)-5-(呋喃-2-基甲基)-11-异丁基-3,6,9-三氧代-2-氧杂-4,7,8,10-四氮十二烷-12-酸(化合物YA-167-d)
将化合物(5R,11S)-1-(9氢-芴-9-基)-5-(呋喃-2-基甲基)-11-异丁基-3,6,9-三氧代-2-氧杂-4,7,8,10-四氮十二烷-12-酸叔丁酯(1.8g,2.98mmol)溶于二氯甲烷(20mL),然后加入三氟乙酸(20mL)。反应液室温搅拌2小时,然后浓缩。残余物用快速色谱法分离纯化(二氯甲烷/甲醇=20/1),得标题化合物(1g,61%),为白色固体。LCMS(ESI)[M+H]
+=549.1;
1H NMR(400MHz,DMSO-d
6)δ12.55(s,1H),9.87(s,1H),7.97(s,1H),7.89(d,J=7.6Hz,2H),7.76(d,J=8.0Hz,1H),7.68(d,J=6.8Hz,2H),7.52(s,1H),7.42(t,J=7.2Hz,2H),7.32(q,J=12.4Hz,2H),6.41(d,J=8.4Hz,1H),6.34(s,1H),6.18(s,1H),4.33-4.09(m,5H),3.06(q,J=15.2Hz,1H),2.91(q,J=15.2Hz,1H),1.68-1.61(m,1H),1.48(t,J=6.0Hz,2H),0.88-0.84(m,6H)。
制备例3:(S)-2-(2-((S)-2-(((9氢-芴-9-基)甲氧基)羰基氨基)-3-苯丙酰基)吡唑烷-1-甲酰胺基)-4-甲基戊酸(化合物YA-184-g)
步骤1:肼-1,2-二酸苄酯叔丁酯(化合物YA-184-a)
将肼二酸单叔丁酯(23.7g,17.9mmol)溶于二氯甲烷(600mL),室温下滴加溶有氯甲酸苄酯(33.6g,19.7mmol)的二氯甲烷(100mL)溶液。反应液在室温下搅拌过夜,反应液分别用饱和碳酸氢钠水溶液(300mL×2)、饱和食盐水(300mL×2)和水(300mL×2)洗涤。分出有机相,用无水硫酸钠干燥,过滤并浓缩。残余物用石油醚(100mL)洗涤两次,得标题化合物(30g,63%),为白色固体。LCMS(ESI)[M+Na]
+=289.0。
步骤2:吡唑烷-1,2-二酸苄酯叔丁酯(化合物YA-184-b)
冰水浴中,将氢化钠(60%,4.5g,112.8mmol)悬浮于N,N-二甲基甲酰胺(500mL),然后滴加肼-1,2-二酸苄酯叔丁酯(15g,56.3mmol)的N,N-二甲基甲酰胺(100mL)溶液。该混合液在冰水浴中搅拌3个小时后,滴加1,3-二溴丙烷(11.9g,1.05mmol)的N,N-二甲基甲酰胺(150mL)溶液。反应液在室温下搅拌过夜。然后反应液分别用饱和碳酸氢钠水溶液(150mL×2)、饱和食盐水(150mL×2)和水(150mL×2)洗涤。分 出有机相,用无水硫酸钠干燥,过滤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯=5/1),得标题化合物(15g,88%),为无色液体。LCMS(ESI)[M+Na]
+=329.1。
步骤3:吡唑烷-1,2-二酸单叔丁酯(化合物YA-184-c)
吡唑烷-1,2-二酸苄酯叔丁酯(5g,16.3mmol)溶于甲醇(100mL),钯碳(0.5g),反应瓶用氢气置换3次,然后在氢气球保护下室温搅拌过夜。将不溶物滤掉,滤渣用甲醇(15mL)洗涤3次。将滤液浓缩,残余物用快速色谱法分离纯化(石油醚/乙酸乙酯=2/1),得标题化合物(2.5g,89%),为无色液体。LCMS(ESI)[M+Na]
+=195.1。
步骤4:(S)-2-(2-(((9氢-芴-9-基)甲氧基)羰基氨基)-3-苯丙酰基)吡唑烷-1-羧酸叔丁酯(化合物YA-184-d)
将(S)-2-(((9氢-芴-9-基)甲氧基)羰基氨基)-3-苯丙氨酸(2.5g,6.4mmol)溶于二氯甲烷(60mL),室温下依次加入HATU(3.3g,8.7mmol)、HOAT(0.87g,6.4mmol)及三乙胺(2.42mL,17.4mmol)。该混合物在室温下搅拌0.5小时后,加入吡唑烷-1,2-二酸单叔丁酯(1g,5.8mmol),反应液在室温下搅拌过夜。然后反应液分别用饱和食盐水(50mL×2)和水(50mL)洗涤。分出的有机相,用无水硫酸钠干燥,过滤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯=1/1),得标题化合物(3.2g,92%),为白色固体。LCMS(ESI)[M+Na]
+=564.2。
步骤5:(S)-2-(2-(((9氢-芴-9-基)甲氧基)羰基氨基)-3-苯丙酰基)吡唑烷(化合物YA-184-e)
将化合物(S)-2-(2-(((9氢-芴-9-基)甲氧基)羰基氨基)-3-苯丙酰基)吡唑烷-1-羧酸叔丁酯(2.2g,4.06mmol)溶于二氯甲烷(60mL),然后加入HCl/dioxane(4M,5mL)。反应液室温搅拌过夜。然后反应液分别用饱和碳酸氢钠水溶液(20mL×2)、饱和食盐水(50mL×2)和水(50mL)洗涤。分出的有机相,用无水硫酸钠干燥,过滤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯=1/0~0/1),得标题化合物(1.2g,68%),为白 色固体。LCMS(ESI)[M+H]
+=442.1。
步骤6:(S)-2-(2-((S)-2-(((9氢-芴-9-基)甲氧基)羰基氨基)-3-苯丙酰基)吡唑烷-1-甲酰胺基)-4-甲基戊酸叔丁酯(化合物YA-184-f)
将化合物(S)-2-(2-(((9氢-芴-9-基)甲氧基)羰基氨基)-3-苯丙酰基)吡唑烷(1.2g,2.7mmol)溶于四氢呋喃(30mL),氮气保护下加入N-甲基吗啉(273mg,2.7mmol)和三光气(267mg,0.9mmol),该反应液在0度下搅拌1小时。然后滴加L-亮氨酸盐酸盐(602mg,2.7mmol)的四氢呋喃(10mL)溶液,反应液室温搅拌过夜。将反应混合物浓缩,所得残余物用快速色谱法分离纯化(石油醚/乙酸乙酯=10/1~0/1),得标题化合物(350mg,20%),为白色固体。LCMS(ESI)[M+Na]
+=677.3。
步骤7:(S)-2-(2-((S)-2-(((9氢-芴-9-基)甲氧基)羰基氨基)-3-苯丙酰基)吡唑烷-1-甲酰胺基)-4-甲基戊酸(化合物YA-184-g)
将化合物(S)-2-(2-((S)-2-(((9氢-芴-9-基)甲氧基)羰基氨基)-3-苯丙酰基)吡唑烷-1-甲酰胺基)-4-甲基戊酸叔丁酯(350mg,0.54mmol)溶于二氯甲烷(5mL),冰水浴下加入三氟乙酸(5mL),该反应液在室温下下搅拌过夜。将反应混合物浓缩,所得残余物用快速色谱法分离纯化(二氯甲烷/甲醇=1/0~10/1),得标题化合物(280mg,85%),为白色固体。LCMS(ESI)[M+H]
+=599。
制备例4:(S)-2-(2-((R)-2-(((9氢-芴-9-基)甲氧基)羰基氨基)-3-苯丙酰基)-3-(2,4-二氯苯基)丙酰基)吡唑烷-1-甲酰胺基)-4-氧代-4-(三苯甲基氨基)丁酸(化合物YA-200-d)
步骤1:(R)-2-(2-(((9氢-芴-9-基)甲氧基)羰基氨基)-3-苯丙酰基)-3-(2,4-二氯苯基)丙酰基)吡唑烷-1-羧酸叔丁酯(化合物YA-200-a)
将(R)-2-(((9氢-芴-9-基)甲氧基)羰基氨基)-3-(2,4-二氯苯基)丙酸(1g,2.2mmol)溶于N,N-二甲基甲酰胺(20mL),室温下依次加入HATU(1.25g,3.3mmol)、HOAT(0.36g,2.64mmol)及三乙胺(667mg,6.6mmol)。该混合物在室温下搅拌0.5小时后,加入吡唑烷-1,2-二酸单叔丁酯(0.45g,2.64mmol),反应液在室温下搅拌3小时。然后往反应液中加入水(30mL),析出大量固体。将固体滤出并干燥得标题化合物(1.2g,95%),为白色固体。LCMS(ESI)[M+Na]
+=632.2。
步骤2:(R)-2-(2-(((9氢-芴-9-基)甲氧基)羰基氨基)-3-苯丙酰基)-3-(2,4-二氯苯基)丙酰基)吡唑烷(化合物YA-200-b)
将化合物(R)-2-(2-(((9氢-芴-9-基)甲氧基)羰基氨基)-3-苯丙酰基)-3-(2,4-二氯苯基)丙酰基)吡唑烷-1-羧酸叔丁酯(1.2g,1.97mmol)溶于二氯甲烷(30mL),然后加入HCl/dioxane(4M,2mL)。反应液室温搅拌过夜。然后反应液分别用饱和碳酸氢钠水溶液 (20mL×2)、饱和食盐水(50mL×2)和水(50mL×2)洗涤。分出的有机相,用无水硫酸钠干燥,过滤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯=1/0~0/1),得标题化合物(1g,85%),为白色固体。LCMS(ESI)[M+H]
+=510.2。
步骤3:(S)-2-(2-((R)-2-(((9氢-芴-9-基)甲氧基)羰基氨基)-3-(2,4-二氯苯基)丙酰基)吡唑烷-1-甲酰胺基)-4-氧代-4-(三苯甲基氨基)丁酸烯丙酯(化合物YA-200-c)
将化合物(R)-2-(2-(((9氢-芴-9-基)甲氧基)羰基氨基)-3-苯丙酰基)-3-(2,4-二氯苯基)丙酰基)吡唑烷(1.5g,2.95mmol)溶于四氢呋喃(60mL),冰水浴中,氮气保护下加入N-甲基吗啉(299mg,2.95mmol)和三光气(292mg,0.98mmol),该反应液在0度下搅拌1小时。然后滴加(S)-2-氨基-4-氧代-4-(三苯甲基氨基)丁酸烯丙酯(1.22g,2.95mmol)的四氢呋喃(10mL)溶液,反应液室温搅拌过夜。将反应混合物浓缩,所得残余物用快速色谱法分离纯化(石油醚/乙酸乙酯=10/1~0/1),得标题化合物(570mg,21%),为白色固体。LCMS(ESI)[M+Na]
+=972.3。
步骤4:(S)-2-(2-((R)-2-(((9氢-芴-9-基)甲氧基)羰基氨基)-3-苯丙酰基)-3-(2,4-二氯苯基)丙酰基)吡唑烷-1-甲酰胺基)-4-氧代-4-(三苯甲基氨基)丁酸(化合物YA-200-d)
将化合物(S)-2-(2-((R)-2-(((9氢-芴-9-基)甲氧基)羰基氨基)-3-(2,4-二氯苯基)丙酰基)吡唑烷-1-甲酰胺基)-4-氧代-4-(三苯甲基氨基)丁酸烯丙酯(570mg,0.6mmol)溶于二氯甲烷(20mL),加入Pd(PPh3)4(277mg,0.24mmol)和N-甲基苯胺(64mg,0.6mmol),室温搅拌1小时。旋干溶剂,所得残余物用快速色谱法分离纯化(二氯甲烷/甲醇=1/0~10/1)得到粗品,再经反相制备得标题化合物(170mg,30%),为白色固体。LCMS(ESI)[M+Na]
+=932。
制备例5:(S)-2-(1-((((9氢-芴-9-基)甲氧基)羰基)氨基)-2-苯乙基)-1氢-咪唑-5-羧酸 (化合物YA-208-e)
步骤1:叔丁基(S)-(2-苯基-1-(5-(三氟甲基)-1氢-咪唑-2-基)乙基)碳酸酯(化合物YA-208-a)
将3,3-二溴-1,1,1-三氟甲基丙酮(0.87g,3.2mmol)和醋酸钠(0.53g,6.4mmol)加入到甲醇(5ml)中,反应液加热到90℃搅拌1h,然后冷却到室温。加入N-叔丁氧羰基-L-苯丙氨醛(0.73g,2.9mmol)的甲醇溶液(10mL)和浓氨水(2mL),室温搅拌16h。将混合液过滤,固体用水(20mL)洗得到标题化合物(0.8g,yield 80%),为白色固体。LCMS(ESI):[M+H]
+=356.1。
步骤2:叔丁基(S)-(2-苯基-1-(5-(三甲氧基甲基)-1氢-咪唑-2-基)乙基)碳酸酯(化合物YA-208-b)
将叔丁基(S)-(2-苯基-1-(5-(三氟甲基)-1氢-咪唑-2-基)乙基)碳酸酯((0.8g,2.2mmol)和甲醇钠的甲醇溶液(25%)(20mL)溶于甲醇(20mL)。混合液在100℃加热2小时,然后浓缩。残余物用乙酸乙酯(100mL)溶解,水洗,有机相用无水硫酸钠干燥,过滤,浓缩得标题化合物(0.88g,100%),为黄色油状物。LCMS(ESI)[M+H]
+=346.1。
步骤3:(S)-2-(1-氨基-2-苯乙基)-1氢-咪唑-5-碳酸甲酯(化合物YA-208-c)
将叔丁基(S)-(2-苯基-1-(5-(三甲氧基甲基)-1氢-咪唑-2-基)乙基)碳酸酯(0.8g,2.0mmol)溶于盐酸二氧六环(20mL),反应液室温搅拌2小时,然后浓缩。残余物用快速色谱法分离纯化(二氯甲烷/甲醇=95/5),得标题化合物(250mg,50%),为棕色固体。LCMS(ESI)[M+H]
+=246.1。
步骤4:(S)-2-(1-氨基-2-苯乙基)-1氢-咪唑-5-羧酸(化合物YA-208-d)
将化合物(S)-2-(1-氨基-2-苯乙基)-1氢-咪唑-5-碳酸甲酯(250mg,1.0mmol)溶于四氢呋喃(5mL)和水(5mL),然后加入强氧化钠(400mg,10.0mmol),室温搅拌120小时。将混合液pH值调到7,直接用于下一步反应。LCMS(ESI)[M+H]
+=232.1。
步骤5:(S)-2-(1-((((9氢-芴-9-基)甲氧基)羰基)氨基)-2-苯乙基)-1氢-咪唑-5-羧酸(化合物YA-208-e)
将((S)-2-(1-氨基-2-苯乙基)-1氢-咪唑-5-羧酸(231mg,1.0mmol)and 9-芴甲基-N-琥珀酰亚胺基碳酸酯(337mg,1.0mmol)溶于饱和的碳酸氢钠水溶液(20mL)和二氧六环(20mL),混合液室温搅拌3小时。将混合液用乙酸乙酯(50mL)萃取,有机相用无水硫酸钠干燥,过滤,浓缩,残余物用快速色谱法分离纯化(二氯甲烷/甲醇=80/20),得标题化合物(200mg,44%),为白色固体。LCMS(ESI):[M+H]
+=454.2;
1H NMR(400MHz,DMSO)δ12.68(s,1H),12.40(s,1H),8.09–7.75(m,3H),7.73–7.59(m,2H),7.41(t,J=7.4Hz,2H),7.39–6.96(m,8H),4.87(s,1H),4.37–3.95(m,3H),3.19(d,J=16.9Hz,1H),3.10–2.70(m,1H).
制备例6:(S)-8-苄基-5-((R)-1-叔丁氧乙基)-1-(9氢-芴-9-基)-3,6,9-三羰基-2-氧杂-4,7,8,10-四氮杂十二烷-12-甲酸(化合物YA-241-d)
步骤1:(9氢-芴-9-基)甲基2-苄基肼碳酸酯(化合物YA-241-a)
将Fmoc-肼(20g,78.7mmol)溶于乙醇(300mL),然后在室温下加入苯甲醛(8.35g,78.7mmol)。反应液加热回流搅拌6小时,然后浓缩,再溶于四氢呋喃(300mL)中。然后在室温下加入Pd(OH)
2/C(4g,含量20%),用氢气换气五次,然后在五个大气压下氢气中反应16小时。然后过滤并浓缩,残余物用快速色谱法分离纯化(石油醚/乙酸乙酯=3/2),得标题化合物(20g,74%),为白色固体。LCMS(ESI)[M+Na]
+=367.1。
步骤2:2-(1-苄基肼酰胺基)乙酸甲酯(化合物YA-241-b)
将三光气(1.82g,6.1mmol)溶于二氯甲烷(10mL),然后在零摄氏度下滴加溶于二氯甲烷(30mL)的甘胺酸甲酯盐酸盐(1.5g,12.2mmol)溶液。反应液在零摄氏度下搅拌4小时,然后加入三乙胺(4.95g,48.9mmol),再搅拌20分钟。然后再加入(9氢-芴-9-基)甲基2-苄基肼碳酸酯(5.5g,15.9mmol)和三乙胺(6.81g,61.2mmol),反应液室温下搅拌过夜。然后反应液直接浓缩,残余物用快速色谱法分离纯化(二氯甲烷/乙酸乙酯=1/3),得标题化合物(900mg,91%),为白色固体。LCMS(ESI)[M+H]
+=238.2。
步骤3:(S)-8-苄基-5-((R)-1-叔丁氧乙基)-1-(9氢-芴-9-基)-3,6,9-三羰基-2-氧杂-4,7,8,10-四氮杂十二烷-12-甲酸甲酯(化合物YA-241-c)
将Fmoc-O-叔丁基-L-苏氨酸(1.51g,3.8mmol)和2-(1-苄基肼酰胺基)乙酸甲酯(900mg,3.8mmol)溶于二氯甲烷(80mL),然后加入HATU(1.73g,4.6mmol)和二异丙基乙胺(1.47g,11.4mmol)。反应液室温搅拌过夜,然后浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯=3/1),得标题化合物(300mg,13%),为白色固体。LCMS(ESI)[M+H]
+=617.4。
步骤4:(S)-8-苄基-5-((R)-1-叔丁氧乙基)-1-(9氢-芴-9-基)-3,6,9-三羰基-2-氧杂-4,7,8,10-四氮杂十二烷-12-甲酸(化合物YA-241-d)
将(S)-8-苄基-5-((R)-1-叔丁氧乙基)-1-(9氢-芴-9-基)-3,6,9-三羰基-2-氧杂-4,7,8,10-四氮杂十二烷-12-甲酸甲酯(300mg,0.49mmol)溶于四氢呋喃(5mL)和水(5mL)的混合液中,然后室温下加入一水合氢氧化锂(123mg,2.92mmol),在室温下搅拌过夜。反应液在真空下旋干,用1mol/L盐酸把PH调到4。然后在室温下加入二氧六环(8mL),FMOC-OSU(164mg,0.49mmol)和碳酸钠(103mg,0.97mmol),然后在室温下搅拌一晚上。反应液用1mol/L的盐酸把PH调到3~4,然后用乙酸乙酯(200mL×3)萃取,饱和食盐水(100mL)洗涤。分出有机相,用无水硫酸钠干燥,过滤并浓缩。残余物用线性浓度梯度洗脱(30分钟),流速为50ml/分钟,洗脱液A/B:90/10-40/60使用:洗脱液A:0.1%TFA的水溶液,洗脱液B:乙腈,在制备型HPLC上,使用Boston ODS 120g Flash,CV 60ml-100ml/min,Pmax:200psi。收集含有产物的级分,冻干,得标题化合物(240mg,82%),为白色固体。LCMS(ESI)[M+Na]
+=625.0;
1H NMR(400MHz,DMSO-d
6)δ10.01(s,1H),7.90-7.78(m,5H),7.74-7.29(m,10H),6.85(s,1H),4.66-4.11(m,6H),3.79-3.70(m,3H),1.18(s,9H),1.06(d,J=44.4,3H).
制备例7:3-(4-(1氢-吡唑-1-基)苯基)-2-(((9氢-芴-9-基)甲氧基)羰基基氨基)丙酸(化合物YA-242-C)
步骤1:叔丁氧羰基-4-溴-L-苯丙氨酸甲酯(化合物YA-242-A)
将叔丁氧羰基-4-溴-L-苯丙氨酸(2.21g,6.4mmol)和碳酸钠(1.37g,12.9mmol)溶于N,N-二甲基甲酰胺(60mL),冷却到零度,加入碘甲烷(4.57g,32.2mmol)。反应液在零度下搅拌2小时,然后用乙酸乙酯(500mL)稀释。混合液分别用水(150mL×4)和饱和食盐水(150mL)洗涤。分出有机相,用无水硫酸钠干燥,过滤并浓缩。粗产物用快速色谱法分离纯化(石油醚/乙酸乙酯=5/1),得标题化合物(2.16g,94%),为白色固体。LCMS(ESI)[M+H]
+=380.0。
步骤2:3-(4-(1氢-吡唑-1-基)苯基)-2-(叔丁氧羰基氨基)丙酸(化合物YA-242-B)
将叔丁氧羰基-4-溴-L-苯丙氨酸甲酯(500mg,1.4mmol),吡唑(475mg,7mmol)和碳酸铯(907mg,2.8mmol)溶于乙腈(40mL),氮气保护下加入氧化亚铜(399mg,2.8mmol)。反应液在氮气保护下加热回流搅拌24小时,冷却至室温,用乙酸乙酯(100mL)稀释。混合液过滤并浓缩,粗产物用线性浓度梯度洗脱(30分钟),流速为50ml/分钟,洗脱液A/B:90/10-50/50使用:洗脱液A:0.1%TFA的水溶液,洗脱液B:乙腈,在制备型HPLC上,使用Boston ODS 120g Flash,CV 60ml-100ml/min,Pmax:200psi。收集含有产物的级分,冻干,得标题化合物(150mg,32%),为白色固体。LCMS(ESI)[M+Na]
+=354.1。
步骤3:3-(4-(1氢-吡唑-1-基)苯基)-2-(((9氢-芴-9-基)甲氧基)甲氧基氨基)丙酸(化合物YA-242-C)
将3-(4-(1氢-吡唑-1-基)苯基)-2-(叔丁氧羰基氨基)丙酸(370mg,1.1mmol)溶于二氯甲烷(8mL)和三氟乙酸(2mL)的混合液中,室温下搅拌2小时。反应液在真空下旋干,用饱和的碳酸氢钠把PH调到8。然后在室温下加入水(10mL),二氧六环(10mL),9-芴甲基-N-琥珀酰亚胺基碳酸酯(377mg,1.1mmol)和碳酸钠(237mg,2.2mmol),室温搅拌过夜。反应液用1mol/L的盐酸将PH调到3~4,然后用乙酸乙酯(100mL×3)萃取,饱和食盐水(150mL)洗涤。分出有机相,用无水硫酸钠干燥,过滤并浓缩。粗产物用快速色谱法分离纯化(石油醚/乙酸乙酯=1/1),得标题化合物(316mg,61%),为白色固体。LCMS(ESI)[M+H]
+=454.2;
1H NMR(400MHz,DMSO-d
6)δ12.77(s,1H),8.45(d,J=2.4,1H),7.87(d,J=7.6,2H),7.78-7.73(m,4H),7.64(t,J=7.4,2H),7.41-7.36(m,4H),7.32-7.25(m,2H),6.53(s,1H),4.22-4.15(m,4H),3.15-3.10(m,1),2.93-2.87(m,1H).
制备例8:(2-((((9氢-芴-9-基)甲氧基羰基)-L-苯丙氨酰基)-2-甲基肼)-1-羰基-L-亮氨酸(化合物YA-247-E)
步骤1:对硝基苯氧羰基-L-亮氨酸叔丁酯(化合物YA-247-A)
将L-亮氨酸叔丁酯(1.87g,10mmol)溶于二氯甲烷(50mL),然后室温下加入三乙胺(1.1g,11mmol)和对硝基苯基氯甲酸酯(2g,10mmol)。反应液在氮气保护下搅拌2小时,然后用乙酸乙酯(200mL)稀释。混合液分别用水(100mL)和饱和食盐水(100mL)洗涤。有机相用无水硫酸钠干燥,过滤并浓缩。粗产品用快速色谱法分离纯化(石油醚/乙酸乙酯=4/1),得标题化合物(2.1g,59%),为白色固体。LCMS(ESI)[M+H]
+=375.2.
步骤2:(2-((((9氢-芴-9-基)甲氧基)羰基))-L-苯丙氨酰基)-2-甲基肼-1-羰基)叔丁酯(化合物YA-247-B)
将N-芴甲氧羰基-L-苯丙氨酸(5.38g,13.7mmol)和2-甲基肼基羧酸叔丁酯(2g,13.7mmol)溶于二氯甲烷(100mL),然后加入HATU(5.72g,15.1mmol)和二异丙基乙胺(5.3g,41mmol)。反应液室温搅拌过夜,然后浓缩。粗产品用快速色谱法分离纯化(石油醚/乙酸乙酯=2/1),得标题化合物(5g,75%),为白色固体。LCMS(ESI)[M+H]
+=538.3.
步骤3:(2-((((9氢-芴-9-基)甲氧基)羰基)-L-苯丙氨酰基)-2-甲基肼-1-羰基(化合物YA-247-C)
将化合物(2-((((9氢-芴-9-基)甲氧基)羰基)-L-苯丙氨酰基)-2-甲基肼-1-羰基)叔丁酯(4.0g,7.77mmol)溶于二氯甲烷(100mL),然后加入三氟乙酸(25mL)。反应液室温搅拌2小时,然后浓缩。粗产品用快速色谱法分离纯化(石油醚/乙酸乙酯=1/2,得标题化合物(2.5g,77%),为白色固体。LCMS(ESI)[M+H]
+=416.2.
步骤4:(2-((((9氢-芴-9-基)甲氧基)羰基)-L-苯丙氨酰基)-2-甲基肼-1-羰基)-L-亮氨酸叔丁酯(化合物YA-247-D)
将化合物2-((((9氢-芴-9-基)甲氧基)羰基)-L-苯丙氨酰基)-2-甲基肼-1-羰基(1.0g,2.4mmol)溶于四氢呋喃(10mL),然后加入对硝基苯氧羰基-L-亮氨酸叔丁酯(2.0g,5.7mmol)并在50℃和氮气保护下搅拌3小时,然后浓缩。残余物溶于乙酸乙酯,用饱和食盐水洗涤,有机相用无水硫酸钠干燥,过滤并浓缩,得标题化合物粗品(1.0g),黄色固体,不经纯化直接用于下一步反应。LCMS(ESI)[M-55]
+=573.3.
步骤5:(2-((((9氢-芴-9-基)甲氧基)羰基)-L-苯丙氨酰基)-2-甲基肼-1-羰基)-L-亮氨酸(化合物YA-247-E)
将化合物2-((((9氢-芴-9-基)甲氧基)羰基)-L-苯丙氨酰基)-2-甲基肼-1-羰基)-L-亮氨酸叔丁酯(1.0g,6.0mmol)溶于二氯甲烷(20mL),然后加入三氟乙酸(10mL)。反应液室温搅拌3小时,然后浓缩。粗产品用快速色谱法分离纯化(石油醚/乙酸乙酯=1/5),得标题化合物(250mg,18%两步收率),为白色固体。LCMS(ESI)[M+H]
+=573.3;
1H NMR(400MHz,DMSO-d
6)δ12.64(s,1H),8.59(s,1H),7.87(m,2H),7.70-7.63(m,2H),7.43-7.38(m,2H),7.27-7.14(m,8H),4.79(s,1H),4.20(s,1H),4.15-4.09(m,3H),3.11-2.81(m,5H),1.67-1.46(m,3H),0.87(s,6H).
制备例9:(5-((S)-1-((2S,3R)-2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(叔丁氧基丁基氨基)-2-苯基乙基)-4H-1,2,4-三氮唑-3-羰基)-L-亮氨酸(化合物YA-209-H)
步骤1:2-氨基-2-腙基乙酸乙酯(YA-209-A)
将硫代草氨酸乙酯(5.27g,39.6mmol)溶于四氢呋喃(40mL),然后零摄氏度下滴加水合肼(1.89g,37.7mmol),反应液室温下搅拌1.5小时。反应液浓缩直接用于下一步。
步骤2:(S)-(S)-2-((叔丁氧羰基)氨基)-3-苯基丙酸乙酸酐(YA-209-B)
将N-叔丁氧羰基-L-苯丙氨酸(10g,37.7mmol)和三乙胺(7.62g,75.5mmol)溶于四氢呋喃(100mL),然后零摄氏度下滴加氯甲酸乙脂(6.11g,56.6mmol),反应液在零摄氏度下搅拌2小时。反应液浓缩直接用于下一步。
步骤3:(E)-2-氨基-2-(2-((叔丁氧羰基)-L-苯丙基)腙基)乙酸乙酯(YA-209-C)
将2-氨基-2-腙基乙酸乙酯(5.19g,39.6mmol)溶于四氢呋喃(50mL),然后室温下加入(S)-(S)-2-((叔丁氧羰基)氨基)-3-苯基丙酸乙酸酐(12.7g,37.7mmol),反应液室温下搅拌过夜。反应液直接过滤,用四氢呋喃(30mL)清洗白色固体,干燥得标题化合物(3.4g,24%),为白色固体。LC-MS(ESI)[M+H]
+=379.1.
步骤4:(S)-5-(1-((叔丁氧羰基)氨基)-2-苯乙基)-4H-1,2,4-三氮唑-3-甲酸乙酯(YA-209-D)
将(E)-2-氨基-2-(2-((叔丁氧羰基)-L-苯丙基)腙基)乙酸乙酯(3.4g,9mmol)溶于甲苯(40mL),反应液在150度下搅拌1小时,然后在185度搅拌5小时。反应液直接浓缩,得粗品标题化合物(3g,94%),为黄色固体。LC-MS(ESI)[M+Na]
+=383.1.
步骤5:5-((S)-1-((2S,3R)-2-((((9H-芴-9-基)甲氧基)羰)氨基)-3-(叔丁氧基)丁基氨基)-2-苯乙基)-4H-1,2,4-三氮唑-3-甲酸乙酯(YA-209-E)
将(S)-5-(1-((叔丁氧羰基)氨基)-2-苯乙基)-4H-1,2,4-三氮唑-3-甲酸乙酯(3g,8.3mmol)溶于二氯甲烷(40mL)和三氟乙酸(10mL)的混合液中,在室温下搅拌3小时。将反应液直接浓缩,再溶于二甲基甲酰胺(50mL)中。然后加入Fmoc-O-叔丁基-L-苏氨酸(4.97g,12.5 mmol),HATU(4.75g,12.5mmol)和二异丙基乙胺(5.38g,41.7mmol)。反应液室温搅拌过夜,用乙酸乙酯(800mL)稀释。混合液分别用水(300mL×4)和饱和食盐水(300mL)洗涤。分出有机相,用无水硫酸钠干燥,过滤并浓缩。残余物用线性浓度梯度洗脱(30分钟),流速为50ml/分钟,洗脱液A/B:90/10-30/70使用:洗脱液A:0.1%TFA的水溶液,洗脱液B:乙腈,在制备型HPLC上,使用Boston ODS 120g Flash,CV 60ml-100ml/min,Pmax:200psi。收集含有产物的级分,冻干,得标题化合物(2.2g,42%),为白色固体。LC-MS(ESI)[M+H]
+=640.3.
步骤6:5-((S)-1-((2S,3R)-2-((((9H-芴-9-基)甲氧基)羰)氨基)-3-(叔丁氧基)丁基氨基)-2-苯乙基)-4H-1,2,4-三氮唑-3-甲酸(YA-209-F)
将5-((S)-1-((2S,3R)-2-((((9H-芴-9-基)甲氧基)羰)氨基)-3-(叔丁氧基)丁基氨基)-2-苯乙基)-4H-1,2,4-三氮唑-3-甲酸乙酯(2g,3.1mmol)溶于四氢呋喃(30mL)和水(30mL)的混合液中,然后室温下加入一水合氢氧化锂(1.05g,25mmol),在室温下搅拌过夜。反应液在真空下旋干四氢呋喃,用0.5mol/L盐酸把PH调到4。然后在室温下加入二氧六环(50mL),Fmoc-OSu(1.05g,3.1mmol)和碳酸钠(664mg,6.3mmol),然后在室温下搅拌过夜。反应液用1mol/L的盐酸把PH调到3~4,用乙酸乙酯(200mL×3)萃取,饱和食盐水(100mL)洗涤。分出有机相,用无水硫酸钠干燥,过滤并浓缩,得粗品标题化合物(2.5g,60%),为白色固体。LC-MS(ESI)[M+H]
+=612.3.
步骤7:(5-((S)-1-((2S,3R)-2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(叔丁氧基丁基氨基)-2-苯基乙基)-4H-1,2,4-三氮唑-3-羰基)-L-亮氨酸甲酯(YA-209-G)
将5-((S)-1-((2S,3R)-2-((((9H-芴-9-基)甲氧基)羰)氨基)-3-(叔丁氧基)丁基氨基)-2-苯乙基)-4H-1,2,4-三氮唑-3-甲酸(1.9g,3.1mmol)和L-亮氨酸甲酯盐酸盐(734mg,4mmol)溶于二氯甲烷(60mL),加入HATU(1.42g,3.7mmol)和二异丙基乙胺(1.2g,9.3mmol)。反应液室温搅拌过夜,然后浓缩。残余物用快速色谱法分离纯化(二氯甲烷/甲醇20/1),得标题化合物(970mg,42%)为白色固体。LC-MS(ESI)[M+H]
+=739.4.
步骤8:(5-((S)-1-((2S,3R)-2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(叔丁氧基丁基氨基)-2-苯基乙基)-4H-1,2,4-三氮唑-3-羰基)-L-亮氨酸(YA-209-H)
将(5-((S)-1-((2S,3R)-2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(叔丁氧基丁基氨基)-2-苯基乙基)-4H-1,2,4-三氮唑-3-羰基)-L-亮氨酸甲酯(970mg,1.31mmol)溶于四氢呋喃(10mL)和水(10mL)的混合液中,然后室温下加入一水合氢氧化锂(442mg,10.5mmol),在室温下搅拌过夜。反应液在真空下旋干,0.5mol/盐酸把PH调到4。然后在室温下加入二氧六环(10mL),Fmoc-OSu(443mg,1.31mmol)和碳酸钠(229mg,2.62mmol),反应液室温下搅拌一晚上。反应液用1mol/L的盐酸把PH调到3~4,然后用乙酸乙酯(300mL×3)萃取,饱和食盐水(200mL)洗涤。分出有机相,用无水硫酸钠干燥,过滤并浓缩。粗产物用快速色谱法分离纯化(乙酸乙酯),得标题化合物(400mg,42%),为白色固体。LC-MS(ESI)[M+H]
+=725.3;
1H NMR(400MHz,DMSO-d
6)δ7.77-6.96(m,17H),5.91(s,0.5H),5.58(s,0.5H),4.73-4.35(m,2H),4.22-4.04(m,4H),3.37-3.21(m,1H),2.05(s,1H),1.82-1.71(m,2H),1.28-0.66(m,20H).
制备例10:(S)-2-(1H-吲哚-3-基)-1-(1H-四唑-5-基)乙胺(化合物YA-250-d)
步骤1:(S)-3-(2-((((9氢-芴-9-基)甲氧基)羰基)氨基)-3-氨基-3-氧杂丙基)-1氢-吲哚-1-碳酸叔丁酯(化合物YA-250-a)
将Fmoc-L-色氨酸(Boc)(10.0g,18.99mmol)溶解在DMF(50mL)中,然后加入碳酸氢铵(1.88g,23.30mmol),吡啶(0.9mL,11.3mmol和(Boc)
2O(5.39g,24.69mmol)。反应液室温搅拌16小时。将反应液倒入水(200mL)中,析出白色固体。过滤,固水洗体。将固体溶解在乙酸乙酯(200mL)中,向溶液中缓慢加入石油醚(500mL),室温搅拌30分钟。过滤,固体用石油醚洗涤,得标题化合物(9.9g,99.5%),为白色固体。LC-MS(ESI)[M-99]
+=426.1.
步骤2:(S)-3-(2-((((9氢-芴-9-基)甲氧基)羰基)氨基)-2-氰基乙基)-1氢-吲哚-1-碳酸叔丁酯(化合物YA-250-b)
将(S)-3-(2-((((9氢-芴-9-基)甲氧基)羰基)氨基)-3-氨基-3-氧杂丙基)-1氢-吲哚-1-碳酸叔丁酯(化合物YA-250-a,9.9g,18.8mmol)溶解在二氯甲烷(150mL)中,冷却到0℃,一次加入三乙胺(10.6mL,75.2mmol)和三氟乙酸酐(7.8mL,56.4mmol),反应液室温下搅 拌4小时。混合物用饱和食盐水(20mL×2)洗涤,无水硫酸钠干燥,过滤并浓缩。粗产物用快速色谱法分离纯化(石油醚/乙酸乙酯=3/1),得标题化合物(5.6g,58%),为白色固体。LC-MS(ESI)[M+18]
+=525.3。
步骤3:(9氢-芴-9-基)甲基)(S)-(2-1氢-吲哚-3-基)-1-(1氢-四唑-5-基)碳酸酯(化合物YA-250-c)
将(S)-3-(2-((((9氢-芴-9-基)甲氧基)羰基)氨基)-2-氰基乙基)-1氢-吲哚-1-碳酸叔丁酯(化合物YA-250-b,3.0g,5.91mmol),ZnBr
2(665mg,3.0mmol)和NaN
3(768mg,11.8mmol)溶解在异丙醇(80mL)和水(80mL)中,反应液在85℃下搅拌72小时。反应液浓缩除掉异丙醇,二氯甲烷(100mL×2)萃取,有机相无水硫酸钠干燥,过滤并浓缩。粗产物用快速色谱法分离纯化(二氯甲烷/甲醇=10/1),得标题化合物(1.9g,58%),为棕色固体LC-MS(ESI)[M+H]
+=451.2。
步骤4:(S)-2-(1H-吲哚-3-基)-1-(1H-四唑-5-基)乙胺(化合物YA-250-d)
将(9氢-芴-9-基)甲基)(S)-(2-1氢-吲哚-3-基)-1-(1氢-四唑-5-基)碳酸酯(900mg,2.0mmol)溶解在二氯甲烷(10mL)中,加入哌啶(2mL),室温下搅拌1小时。将反应液倒入水中,沉淀析出,过滤出固体,水洗,真空干燥得到目标化合物(420mg,92%),为棕色固体。LC-MS(ESI)[M+H]
+=229.0。
1H NMR(400MHz,DMSO-d
6)δ11.00(s,1H),7.58(d,J=7.6Hz,1H),7.41(d,J=8.0Hz,1H),7.24(s,1H),7.13(dd,J=6.8,7.6Hz,1H),7.04(dd,J=7.6,8.0Hz,1H),4.47(br,1H),3.60-3.30(m,3H),3.10-3.00(m,1H).
制备例11:(5S)-5-苄基-1-(9氢-芴-9-基)-11-异丁基-3,6,-二氧代-10-硫代-2-氧杂-4,7,9-三氮杂癸烷-12-羧酸(化合物YA-254-E)
步骤1:2-((苄氧羰基氨基)甲基氨基甲硫酰基)-4-甲基戊酸乙酯(YA-254-A)
将2-((苄氧羰基氨基)甲基氨基甲酰基)-4-甲基戊酸乙酯(YA-303-D)(1.1g,3.14mmol)和Lawesson试剂(1.40g,3.46mmol)溶于1,4-二氧六环(30mL)中,在80摄氏度下搅拌反应48小时。反应液浓缩,所得残余物用快速色谱法分离纯化(石油醚/乙酸乙酯=5/1),得到得标题化合物(1.05g,91%)。LCMS(ESI)[M+H]
+=367.1.
步骤2:2-(氨甲基氨基甲硫酰基)-4-甲基戊酸乙酯氢溴酸盐(YA-254-B)
向2-((苄氧羰基氨基)甲基氨基甲硫酰基)-4-甲基戊酸乙酯(700mg,1.91mmol)中加入33%的氢溴酸醋酸溶液(3mL)和二氯甲烷(2mL),室温下搅拌反应30分钟。反应液浓缩干燥,得到粗产物直接用作下一步反应。LC-MS(ESI)[M+H-29]
+=204.1.
步骤3:(5S)-5-苄基-1-(9氢-芴-9-基)-11-异丁基-3,6-二氧代-10-硫代-2-氧杂-4,7,9-三氮杂癸烷-12-羧酸乙酯(YA-254-C)
将2-(氨甲基氨基甲硫酰基)-4-甲基戊酸乙酯氢溴酸盐(粗产物,约1.91mmol),(S)-2-(((9氢-芴-9-基)甲氧基)羰基氨基)-3-苯丙氨酸(739mg,1.74mmol),HATU(726mg,1.74mmol),HOAT(261mg,1.91mmol)溶于二氯甲烷(20mL)中,加入N,N-二异丙基乙胺(1.23g,9.55mmol),该反应液在室温下搅拌2小时。反应混合物浓缩,粗产物用快速色谱法分离纯化(石油醚/乙酸乙酯=1/1),得标题化合物(452mg,39%),为浅黄色油状物。LC-MS(ESI)[M+H]
+=602.3.
步骤4:2-(((S)-2-氨基-3-苯丙酰胺基)甲基氨基硫代酰基)-4-甲基戊酸(YA-254-D)
将(5S)-5-苄基-1-(9氢-芴-9-基)-11-异丁基-3,6-二氧代-10-硫代-2-氧杂-4,7,9-三氮杂癸烷-12-羧酸乙酯(0.45g,0.75mmol)溶于四氢呋喃(10mL)和水(10mL)中加入一水合氢氧化锂(158mg,3.75mmol),混合液在零摄氏度下搅拌反应5小时。将反应混合物用2N盐酸酸化至pH=2~3,乙酸乙酯萃取,干燥、浓缩,所得粗产物不经纯化直接用于下一步反应。LC-MS(ESI)[M+H]
+=352.1.
步骤5:(5S)-5-苄基-1-(9氢-芴-9-基)-11-异丁基-3,6,-二氧代-10-硫代-2-氧杂-4,7,9-三氮杂癸烷-12-羧酸(YA-254-E)
将2-(((S)-2-氨基-3-苯丙酰胺基)甲基氨基硫代酰基)-4-甲基戊酸(粗产物,约0.75mmol),芴甲氧羰酰琥珀酰亚胺(304mg,0.90mmol)溶于30mL丙酮:水=1:1的混合液 中,分批加入碳酸氢钠(630mg,7.5mmol),反应液在室温下搅拌4小时。用2N盐酸酸化至pH=5~6,乙酸乙酯(50mL×2)萃取,饱和食盐水洗,无水硫酸钠干燥,过滤浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯=1/5),得标题化合物(226mg,两步总52%),为浅黄色固体。LCMS(ESI)[M+H]
+=574.3.
制备例12:((((S)-2-((((9氢-芴-9-基)甲氧基)羰基)氨基)-3-苯丙氨基)甲基)羰基脲)-L-亮氨酸(化合物YA-256-f)
步骤1:苄基2-氨基-2-氧杂乙基碳酸酯(YA-256-A)
将2-甘氨酰胺(10g,90.5mmol)和碳酸钠(10g,90.5mmol)溶于二氧六环(100mL)和水(100mL),冷却至零摄氏度,加入氯甲酸苄酯(15.43g,90.5mmol),室温下搅拌16小时。混合物浓缩,过滤。固体用水洗,干燥,得标题化合物(12g,64%),为白色固体。LC-MS(ESI)[M-55]
+=209.1.
步骤2:苄氧羰基氨基甲胺(YA-256-B)
将苄基2-氨基-2-氧杂乙基碳酸酯(6g,28.9mmol)溶解在二氯甲烷(180mL)和水(10mL)中,加入双三氟乙酰基碘苯(14.9g,34.6mmol),混合物室温下搅拌过夜。反应液冷却至零摄氏度,固体析出。过滤,固体用正庚烷(100ml)洗涤,自然晾干,得标题化合物(6.7g,79%),为白色固体。LC-MS(ESI)[M-55]
+=181.1.
步骤3:((苄氧羰基氨基甲基)氨基甲酰基)-L-亮氨酸叔丁酯(YA-256-C)
将三光气(3.38g,11.4mmol)溶于二氯甲烷(40mL),然后在零摄氏度下滴加L-亮氨酸叔丁酯盐酸盐(5.09g,22.8mmol)的二氯甲烷(30mL)溶液。反应液在零摄氏度下搅拌1小时,然后加入三乙胺(6.91g,68.4mmol),搅拌20分钟。反应液浓缩,溶于二氯甲烷(50mL)。加入苄氧羰基氨基甲胺三氟乙酸盐(6.7g,22.8mmol)和三乙胺(4.6g,45.6mmol),反应液室温下搅拌过夜。反应液浓缩,粗产物用快速色谱法分离纯化(石油醚/乙酸乙酯=2/3),得标题化合物(3.1g,35%),为白色固体。LC-MS(ESI)[M+H]
+=394.0.
步骤4:(氨基甲基氨基甲酰基)-L-亮氨酸叔丁酯(YA-256-D)
将((苄氧羰基氨基甲基)氨基甲酰基)-L-亮氨酸叔丁酯(3.3g,8.4mmol)溶于甲醇(100mL),加入Pd/C(1g,10%on C)和HCl/dioxane(4.2mL,16.8mmol,4mol/L)。反应液在氢气氛围下室温搅拌1.5小时。过滤,浓缩,得标题化合物(2.3g,90%),为白色固体。LCMS(ESI)[M+Na-29]
+=253.0。
步骤5:((((S)-2-((((9氢-芴-9-基)甲氧基)羰基)氨基)-3-苯丙氨基)甲基)羰基脲)-L-亮氨酸叔丁酯(YA-256-E)
将Fmoc-L-苯丙氨酸(3g,7.8mmol)和(氨基甲基氨基甲酰基)-L-亮氨酸叔丁酯(2.3g,7.8mmol)溶于二氯甲烷(100mL),然后加入HATU(2.96g,7.8mmol)和二异丙基乙胺(2g,15.6mmol)。反应液室温搅拌过夜,浓缩。粗产物用线性浓度梯度洗脱(30分钟),流速为50ml/分钟,洗脱液A/B:90/10-10/90使用:洗脱液A:0.1%TFA的水溶液,洗脱液B:乙腈,在制备型HPLC上,使用Boston ODS 120g Flash,CV 60ml-100ml/min,Pmax:200psi。收集含有产物的级分,冻干,得标题化合物(2.5g,51%),为白色固体。LC-MS(ESI)[M+H]
+=629.1。
步骤6:((((S)-2-((((9氢-芴-9-基)甲氧基)羰基)氨基)-3-苯丙氨基)甲基)羰基脲)-L-亮氨酸(YA-256-F)
将((((S)-2-((((9氢-芴-9-基)甲氧基)羰基)氨基)-3-苯丙氨基)甲基)羰基脲)-L-亮氨酸叔丁酯(500mg,0.8mmol)溶于二氯甲烷(15mL)和三氟乙酸(15mL),室温下搅拌2小时,浓缩。粗产物用线性浓度梯度洗脱(30分钟),流速为50ml/分钟,洗脱液A/B:90/10-30/70使用:洗脱液A:0.1%TFA的水溶液,洗脱液B:乙腈,在制备型HPLC上,使用Boston ODS120g Flash,CV 60ml-100ml/min,Pmax:200psi。收集含有产物的级分,冻干,得标题化合物(340mg,75%),为白色固体。LC-MS(ESI)[M+H]
+=573.1.
制备例13:(S)-5-((((9氢-芴-9-基)甲氧基)羰基)氨基)-4-氧杂-6-苯基己酸(化合物YA-274-f)
步骤1:(S)-(4-(二甲氧基磷酸基)-3-氧杂-1-苯基丁基-2-基)氨基甲酸叔丁酯(化合物YA-274-a)
将甲基磷酸二甲酯(14.2g,114.5mmol)溶解在干燥的四氢呋喃(100mL)中,冷却到-78℃,滴加BuLi(2.5N in hexane,45.8mL,114.5mmol),混合物在-78℃下反应1小时。然后滴加Boc-L-苯丙氨酸甲酯(6.4g,22.9mmol)的四氢呋喃(50mL)溶液,混合物在-78℃下反应2小时。向反应液中加入饱和的氯化铵溶液(150mL),用乙酸乙酯(200mL×2)萃取,分出有机相。有机相用饱和食盐水(50mL)洗涤,用无水硫酸钠干燥,过滤并浓缩。粗产物用快速色谱法分离纯化(石油醚/乙酸乙酯=5/1),得标题化合物(6.5g,76%),为白色固体。LC-MS(ESI)[M+H]
+=370.1。
步骤2:(S,E)-5-((叔丁氧羰基)氨基)-4-氧杂-6-苯基己-2-烯酸乙酯(化合物YA-274-b)
将(S)-(4-(二甲氧基磷酸基)-3-氧杂-1-苯基丁基-2-基)氨基甲酸叔丁酯(6.5g,17.5mmol)和乙醛酸乙酯(50%w/w in toluene,3.57g,17.5mmol)溶解在无水乙醇(100mL)中,然后加入碳酸钾(2.42g,17.5mmol),反应混合液在室温下搅拌4小时。过滤,滤液用乙酸(0.5mL)中和,浓缩,粗产物用快速色谱法分离纯化(石油醚/乙酸乙酯=5/1),得标题化合物(trans-isomer,4.5g,74%),为淡黄色固体。LC-MS(ESI)[M-H]
+=346.2。
1H NMR(400MHz,CDCl
3)δ7.25-7.13(m,3H),7.08(d,J=15.6Hz,1H),7.06-7.00(m,2H),6.69(d,J=15.6Hz,1H),5.09(d,J=8.0Hz,1H),4.75-4.68(m,1H),4.18(q,J=7.2Hz,2H),3.09(dd,J=6.4,14.0Hz,1H),2.91(dd,J=6.4,14.0Hz,1H),1.34(s,9H),1.25(t,J=7.2Hz,3H).
同时得到另一异构体(cis-isomer,1.5g,24%),为黄色油状物。LC-MS(ESI)[M-H]
-=346.2.
1H NMR(400MHz,CDCl
3)δ7.32-7.16(m,5H),6.43(d,J=12.0Hz,1H),6.05(d,J=12.0Hz,1H),5.16(d,J=8.0Hz,1H),4.76-4.68(m,1H),4.21(q,J=7.6Hz,2H),3.25(dd,J=6.0,10.0Hz,1H),3.01(dd,J=6.0,10.0Hz,1H),1.39(s,9H),1.28(t,J=7.6Hz,3H).
步骤3:(S)-5-((叔丁氧羰基)氨基)-4-氧杂-6-苯基己酸乙酯(化合物YA-274-c)
将(S,E)-5-((叔丁氧羰基)氨基)-4-氧杂-6-苯基己-2-烯酸乙酯(trans-isomer,990mg,2.85mmol)溶解在乙酸乙酯(25mL),然后加入Pd/C(10%Pd,100mg),在氢气氛围里室温下搅拌2小时。过滤,滤液浓缩,粗产物用快速色谱法分离纯化(石油醚/乙酸乙酯=5/1),得标题化合物(0.88g,88%),为黄色固体。LC-MS(ESI)[M-99]
+=250.1
步骤4:(S)-5-((叔丁氧羰基)氨基)-4-氧杂-6-苯基己酸(化合物YA-274-d)
将(S)-5-((叔丁氧羰基)氨基)-4-氧杂-6-苯基己酸乙酯(850mg,2.43mmol)溶解在甲醇 (7mL)和四氢呋喃(27mL)中,然后加入氢氧化锂的水溶液(0.5N,34mL,17.0mmol),室温下搅拌3小时。混合物用醋酸调节pH至4~5,乙酸乙酯萃取(100mL×2)。有机相用饱和食盐水洗涤(30mL),无水硫酸钠干燥,过滤,浓缩。得标题化合物(0.78g,100%),为淡黄色固体。830mg as pale-yellow solid。LC-MS(ESI)[M-H]
-=320.2
步骤5:(S)-5-((((9氢-芴-9-基)甲氧基)羰基)氨基)-4-氧杂-6-苯基己酸(化合物YA-274-e)
将(S)-5-((叔丁氧羰基)氨基)-4-氧杂-6-苯基己酸(830mg,2.43mmol)溶解在二氯甲烷(10mL),然后加入HCl(4N in 1,4-dioxane,10mL,40mmol),室温下搅拌4小时。混合物浓缩,然后依次加入丙酮(50mL),水(25mL),NaHCO
3(202mg,2.41mmol),9-芴甲基-N-琥珀酰亚胺基碳酸酯(811mg,2.41mmol),室温下搅拌4小时。混合物用2N HCl调节pH至2~3,旋转蒸发去除丙酮,二氯甲烷萃取(100mL×2)。有机相用无水硫酸钠干燥,过滤,浓缩。粗产物用快速色谱法分离纯化(二氯甲烷/乙酸乙酯=5/1-1/5),得标题化合物(0.65g,56%),为白色固体。LCMS(ESI)[M+H]
+=444.1.
1H NMR(400MHz,CDCl
3)δ7.75(d,J=7.6Hz,2),7.53(d,J=7.6,8.0Hz,2H),7.39(dd,J=7.2,8.0Hz,2H),7.32-7.20(m,5H),7.13(d,J=7.2Hz,2H),5.36(d,J=7.6Hz,1H),4.66-4.52(m,1H),4.40-4.31(m,2H),4.19-4.15(m,2H),3.14(dd,J=6.0,14.0Hz,1H),2.98(dd,J=6.8,14.0Hz,1H),2.74-2.67(m,2H),2.64-2.57(m,2H).
制备例14:4-(2-(((9氢-芴-9-基)甲氧基)羰基)-1-苄基肼基)-4-氧代丁酸(化合物YA-275-b)
步骤1:4-(2-(((9氢-芴-9-基)甲氧基)羰基)-1-苄基肼基)-4-氧代丁酸叔丁酯(化合物 YA-275-a)
将(9氢-芴-9-基)2-苄基肼甲酸甲酯(1g,2.9mmol),1,4-丁二酸单叔丁酯(1g,5.8mmol),HOBt(0.59g,4.35mmol)和HATU(1.65g,4.35mmol)溶于二氯甲烷(25mL),然后室温下加入N,N-二异丙基乙胺(0.75g,5.8mmol)。该反应液在室温下搅拌16小时,然后浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯=4/1),得标题化合物(1g,69%),为白色固体。LC-MS(ESI)[M-55]
+=445.0.
步骤2:4-(2-(((9氢-芴-9-基)甲氧基)羰基)-1-苄基肼基)-4-氧代丁酸(化合物YA-275-b)
将化合物4-(2-(((9氢-芴-9-基)甲氧基)羰基)-1-苄基肼基)-4-氧代丁酸叔丁酯(1g,2.0mmol)溶于二氯甲烷(15mL),冰水浴下加入三氟乙酸(15mL),该反应液在室温下搅拌3小时。将反应混合物浓缩,粗产物用快速色谱法分离纯化(石油醚/乙酸乙酯=35/65),得标题化合物(800mg,90%),为白色固体。LC-MS(ESI)[M+H]
+=445.0.
制备例15:(5S)-5-苄基-1-(9氢-芴-9-基)-11-异丁基-3,6,10-三氧代-2-氧杂-4,7,9-三氮杂癸烷-12-羧酸(化合物YA-303-h)
步骤1:异丁基丙二酸单乙酯钾盐(YA-303-A)
将2-异丁基丙二酸二乙酯(2.16g,10mmol)和氢氧化钾(560mg,10mmol)溶于乙醇(50mL)中,加入一滴水。反应液在室温下搅拌24小时。然后将反应液浓缩,得标题化合物(1.8g,96%),为白色固体。
步骤2:2-苄氧羰基氨基乙酰胺(YA-303-B)
将2-氨基乙酰胺的盐酸盐(10g,90.5mmol)和碳酸钠(9.59g,90.5mmol)溶于1,4-二氧六环/水(1/1,200mL),冷却至零度,然后滴加氯甲酸苄酯(15.43g,90.5mmol),该混合液在室温下搅拌16小时。反应液浓缩,所得残余物中加入水(20mL),将固体滤出并用水洗涤滤饼,干燥后得标题化合物(12g,64%),为白色固体。LC-MS(ESI)[M+H]
+=209.1.
步骤3:2-苄氧羰基氨基甲胺三氟乙酸盐(YA-303-C)
将2-苄氧羰基氨基乙酰胺(1g,5mmol)和双(三氟乙酰氧基)碘代苯(2.4g,5.5mmol)溶于二氯甲烷(50mL),然后加入一滴水,反应液在室温搅拌18小时。将反应液浓缩,得标题化合物(1.39g,99%),为白色固体。LC-MS(ESI)[M+H]
+=181.3.
步骤4:2-((苄氧羰基氨基)甲基氨基甲酰基)-4-甲基戊酸乙酯(YA-303-D)
将2-苄氧羰基氨基甲胺三氟乙酸盐(1.39g,5mmol),异丁基丙二酸单乙酯钾盐(1.05g,5mmol),HATU(1.9g,5mmol)和N,N-二异丙基乙胺(1.29g,10mmol)溶于二氯甲烷(50mL)中,该混合物在室温下搅拌2小时。将反应液浓缩,所得残余物用快速色谱法分离纯化(石油醚/乙酸乙酯=5/1),得标题化合物(800mg,46%),为白色固体。LC-MS(ESI)[M+H]
+=351.2.
步骤5:2-(氨甲基氨基甲酰基)-4-甲基戊酸乙酯(YA-303-E)
将2-((苄氧羰基氨基)甲基氨基甲酰基)-4-甲基戊酸乙酯(700mg,2mmol),Pd/C(70mg)和盐酸/1,4-二氧六环溶液(4M,1mL)溶于甲醇(10mL),反应体系用氢气置换3次。反应液在氢气保护下室温搅拌2小时。过滤,滤液浓缩,得标题化合物(432mg,99%),为无色油状物。LC-MS(ESI)[M+Na]
+=239.2.
步骤6:(5S)-5-苄基-1-(9氢-芴-9-基)-11-异丁基-3,6,10-三氧代-2-氧杂-4,7,9-三氮杂癸烷-12-羧酸乙酯(YA-303-F)
将2-(氨甲基氨基甲酰基)-4-甲基戊酸乙酯(432mg,2mmol),(S)-2-(((9氢-芴-9-基)甲氧基)羰基氨基)-3-苯丙氨酸(774mg,2mmol),HATU(760mg,2mmol)和N,N-二异丙基乙胺(516mg,4mmol)溶于二氯甲烷(20mL),该反应液在室温下搅拌2小时。反应混合物浓缩,粗产物用快速色谱法分离纯化(石油醚/乙酸乙酯=1/1),得标题化合物(1g,85%),为白色固体。LC-MS(ESI)[M+H]
+=586.3.
步骤7:2-(((S)-2-氨基-3-苯丙酰胺基)甲基氨基酰基)-4-甲基戊酸(YA-303-G)
将(5S)-5-苄基-1-(9氢-芴-9-基)-11-异丁基-3,6,10-三氧代-2-氧杂-4,7,9-三氮杂癸烷-12-羧酸乙酯(1g,1.7mmol)和氢氧化钠(340mg,8.5mmol)溶于四氢呋喃(50mL)和水(20mL)中,该反应液在室温下搅拌16小时。将反应混合物浓缩,所得粗产物(570mg,99%)不经纯化直接用于下一步反应。LC-MS(ESI)[M+H]
+=336.4.
步骤8:(5S)-5-苄基-1-(9氢-芴-9-基)-11-异丁基-3,6,10-三氧代-2-氧杂-4,7,9-三氮杂癸烷-12-羧酸(YA-303-H)
将2-(((S)-2-氨基-3-苯丙酰胺基)甲基氨基酰基)-4-甲基戊酸(570mg,1.7mmol),氯甲酸(9氢-芴-9-基)甲基酯(570mg,1.7mmol)和N,N-二异丙基乙胺(440mg,3.4mmol)溶于二氯甲烷(20mL)。反应液在室温下搅拌2小时后浓缩。残余物用快速色谱法分离纯化(二氯甲烷/甲醇=10/1),得标题化合物(400mg,41%),为白色固体。LC-MS(ESI)[M+H]
+=558.4.
制备例16:(5S)-5-苄基-1-(9氢-芴-9-基)-11-异丁基-3,6,-二氧代-10-硫代-2-氧杂-4,7,9- 三氮杂癸烷-12-羧酸(化合物YA-326-B)
步骤1:肉桂酰胺-PEG5-叠氮(YA-326-A)
向肉桂酸(273mg,1.36mmol),EDCI(261mg,1.36mmol),DMAP(166mg,1.36mmol)和NH
2-PEG5-N
3(347mg,1.13mmol)溶入二氯甲烷(10mL)中,室温下搅拌过夜。反应液浓缩,加入水(50mL),用乙酸乙酯(50mL×2)萃取,饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,所得粗产物直接用作下一步反应。LC-MS(ESI)[M+H]
+=489.3
步骤2:(1-(肉桂酰胺-PEG5)-1,2,3-三氮锉)-4-乙酸(YA-326-B)
向YA-326-A(1.13mmol)的N,N-二甲基甲酰胺(10mL)的溶液中加入3-丁炔酸(190mg,2.26mmol)、维生素C钠盐(448mg,2.26mmol)、五水合硫酸铜(282mg,1.13mmol)和水(1mL),室温下搅拌反应3小时。反应液倒入30mL水中,用乙酸乙酯(100mL)萃取,饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩。所得粗产物用反相柱分离纯化,洗脱液为乙腈:水=70:30,收集产物,冻干得到标题化合物(389mg,两步总收率:60%)。LC-MS(ESI)[M-H]
-=571.4
制备例17:十六烷基-1,2,3-三氮锉-1-PEG8-丙酸(化合物YA-367-A)
向PEG8-N
3(468mg,1.0mmol)的N,N-二甲基甲酰胺(10mL)溶液中加入1-十八炔(376mg,1.5mmol)、维生素C钠盐(297mg,1.5mmol)、五水合硫酸铜(240mg,1.5mmol)和水(1mL),室温下搅拌反应3小时。反应液倒入30mL水中,用乙酸乙酯(100mL)萃取,饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩。所得粗产物用反相柱分离纯化,洗脱液为乙腈:水=70:30,收集产物,冻干得到标题化合物300mg,收率:41%。LC-MS(ESI)[M+H]
+=718.4
实施例1
Ac-Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH
2(化合物YA-2)的制备
步骤1:多肽通过标准的Fmoc化学合成,基本操作如下。将5.0g商购可得的Rink Amide MBHA树脂(0.5mmol/g)溶胀于DMF中,该树脂用20mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Fmoc-Phe-OH(2.9g,7.5mmol),HATU(2.85g,7.5mmol)和HOAt(1.04g,7.5mmol)的20mL DMF溶液,然后加入DIPEA(2.6mL,15mmol),室温下处理40分钟,树脂用DMF洗涤,得到Fmoc-Phe-Rink Amide MBHA树脂。该树脂用20mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作,树脂用DMF洗涤,加入Fmoc-Arg(Pbf)-OH(5.0g,7.5mmol),DIC(945mg,7.5mmol)和HOBt(1.01g,7.5mmol)的20mL DMF溶液,室温下反应过夜。以类似的方式,依次将Leu,Gly,Phe,Ser(tBu),Asn(Trt),Trp(Boc),Asn(Trt),D-Tyr(tBu)等氨基酸引入,得到NH
2-D-Tyr(tBu)-Asn(Trt)-Trp(Boc)-Asn(Trt)-Thr(tBu)-Phe-Gly-Leu-Arg-Phe-Rink Amide MBHA树脂。用DMF洗涤,加入AcOH(44μL,7.5mmol),DIC(945mg,7.5mmol)和HOBt(1.01g,7.5mmol)的10mL DMF溶液,室温下反应过夜,引入Ac基团。树脂用DMF,DCM,甲醇,甲基叔丁基醚洗涤,然后抽干,最终得到的8.5g的Ac-NH
2-D-Tyr(tBu)-Asn(Trt)-Trp(Boc)-Asn(Trt)-Thr(tBu)-Phe-Gly-Leu-Arg-Phe-Rink Amide MBHA树脂。
步骤2:将干燥的树脂加入85mL的TFA/TIS/EDT/H
2O(94/2/2/2)溶液中,该混合物搅拌2小时,过滤除去树脂,用20mL的TFA/TIS/EDT/H
2O(94/2/2/2)溶液洗涤树脂。合并滤液,向滤液中加入冰乙醚(1000mL),得到的混合物在3000转/分钟离心3分钟,除去上层液,固体用乙醚洗涤2次,并抽干。
步骤3:得到的多肽粗品用DMF溶解,然后进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:74/26-64/36,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Sunfire C18,10um,
柱(19×250mm)。收集含有产物的级分,冻干,得到1.1g白色固体。
实施例2
Ac-(D-Tyr)-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH
2(化合物YA-3)的制备
步骤1:将5.0g商购可得的Rink Amide MBHA树脂(0.5mmol/g)溶胀于DMF中,该树脂用20mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Fmoc-Trp(Boc)-OH(4.0g,7.5mmol),HATU(2.85g,7.5mmol)和HOAt(1.04g,7.5mmol)的20mL DMF溶液,然后加入DIPEA(2.6mL,15mmol),室温下处理40分钟,树脂用DMF洗涤,得到Fmoc-Trp(Boc)-Rink Amide MBHA树脂。该树脂用20mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作,树脂用DMF洗涤,加入Fmoc-Arg(Me,Pbf)-OH(2.08g,3.0mmol),DIC(945mg,7.5mmol)和HOBt(1.01g,7.5mmol)的20mL DMF溶液,室温下反应过夜。该树脂用20mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作,树脂用DMF洗涤,得到Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。得到的树脂,加入Fmoc-Phe-azaGly-Leu-OH(1.68g,3.0mmol),DIC(945mg,7.5mmol)和HOBt(1.01g,7.5mmol)的15mL DMF溶液,室温下反应过夜;该树脂用20mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作;树脂用DMF洗涤,得到Phe-azaGly-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。以类似的方式,依次将Thr(tBu),Asn(Trt),Hyp(tBu),D-Tyr(tBu)等氨基酸引入,得到NH
2-D-Tyr(tBu)-Hyp(tBu)-Asn(Trt)-Thr(tBu)-Phe-azaGly-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。用DMF洗涤,加入AcOH(44mL,7.5mmol),DIC(945mg,7.5mmol)和HOBt(1.01g,7.5mmol)的10mL DMF溶液,室温下反应过夜,引入Ac基团。树脂用DMF,DCM,甲醇,甲基叔丁基醚洗涤,然后抽干,最终得到8.6g的Ac-D-Tyr(tBu)-Hyp(tBu)-Asn(Trt)-Thr(tBu)-Phe-azaGly-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。
步骤2:将干燥的树脂加入85mL的TFA/TIS/EDT/H
2O(94/2/2/2)溶液中,该混合物搅拌2小时,过滤除去树脂,用20mL的TFA/TIS/EDT/H
2O(94/2/2/2)溶液洗涤树脂。合并滤液,向滤液中加入冰乙醚(1000mL),得到的混合物在3000转/分钟离心3分钟,除去上层液,固体用乙醚洗涤2次,并抽干。
步骤3:得到的沉淀用DMF溶解,然后进行线性浓度梯度洗脱(17分种),流速为25mL/分钟,洗脱液A/B:79/21-69/31使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈,在制备型的HPLC上,使用Phenomenex Gemini 10u,
柱(21.2×250mm)。收集含有产物的级分,冻干,得到1.2g三氟乙酸盐,经过转盐得到1.0g醋酸盐,均为白色固体。
实施例3:
Ac-Dap(Dnp)-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH
2(化合物YA-41)的制备
类似实施例2的合成方法,用Fmoc-Dap(Dnp)-OH(3equivalent)代替Fmoc-D-Tyr(tBu)-OH缩合,HBTU/HOBt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护。粗产物YA-41进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:70/30-62/38,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Sunfire C18,10um,
柱(19×250mm)。收集含有产物的级分,冻干,得到10.0mg白色固体。
实施例4:
Ac-[D-Phe(2,4-DiCl)]-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH
2(化合物YA-42)的制备
类似实施例2的合成方法,用Fmoc-[D-Phe(2,4-DiCl)]-OH(3equivalent)代替Fmoc-D-Tyr(tBu)-OH缩合,HBTU/HOBt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护。粗产物YA-42进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:73/27-63/37,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Sunfire C18,5um,
柱(19×150mm)。收集含有产物的级分,冻干,得到68.8mg白色固体。
实施例5:
Ac-(D-2Fua)-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH
2(化合物YA-43)的制备
类似实施例2的合成方法,用Fmoc-(D-2Fua)-OH(3equivalent)代替Fmoc-D-Tyr(tBu)-OH缩合,HBTU/HOBt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并 脱除保护,切割液不含EDT,为TFA/TIS/H
2O(94/3/3)溶液,其他操作一致。粗产物YA-43进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为20mL/分钟,洗脱液A/B:78/22-70/30,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Sunfire C18,5um,
柱(19×150mm)。收集含有产物的级分,冻干,得到6.2mg白色固体。
实施例6:
Ac-Pro(5Ph)-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH
2(化合物YA-44)的制备
类似实施例2的合成方法,用Fmoc-Pro(5Phe)-OH(3equivalent)代替Fmoc-D-Tyr(tBu)-OH缩合,HBTU/HOBt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护。粗产物YA-44进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:73/27-67/33,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Sunfire C18,10um,
柱(19×250mm)。收集含有产物的级分,冻干,得到28.0mg白色固体。
实施例7:
Ac-D-Tyr-Thz-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH
2(化合物YA-45)的制备
类似实施例2的合成方法,用Fmoc-Thz-OH(3equivalent)代替Fmoc-Hyp(tBu)-OH缩合,HBTU/HOBt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护。粗产物YA-45进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:75/25-68/32,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Sunfire C18,10um,
柱(19×250mm)。收集含有产物的级分,冻干,得到10.0mg白色固体。
实施例8:
Ac-3Pal-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH
2(化合物YA-69)的制备
类似实施例2的合成方法,用Fmoc-3Pal-OH(3equivalent)代替Fmoc-D-Tyr(tBu)-OH,HBTU/HOBt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护。粗产物YA-69进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:85/15-75/25,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液, 在制备型的HPLC上,使用Sunfire C18,10um,
柱(19×250mm)。收集含有产物的级分,冻干,得到21.6mg白色固体。
实施例9:
Ac-Phe(3-Cl)-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH
2(化合物YA-70)的制备
类似实施例2的合成方法,用Fmoc-Phe(3-Cl)-OH(3equivalent)代替Fmoc-D-Tyr(tBu)-OH,HBTU/HOBt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护。粗产物YA-70进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:73/27-64/36,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Sunfire C18,10um,
柱(19×250mm)。收集含有产物的级分,冻干,得到11.0mg白色固体。
实施例10:
Ac-Phe(4-F)-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH
2(化合物YA-71)的制备
类似实施例2的合成方法,用Fmoc-Phe(4-F)-OH(3equivalent)代替Fmoc-D-Tyr(tBu)-OH,HBTU/HOBt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护。粗产物YA-71进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为30mL/分钟,洗脱液A/B:68/32-62/38,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Sunfire C18,10um,
柱(19×250mm)。收集含有产物的级分,冻干,得到7.6mg白色固体。
实施例11:
Ac-Phe(4-Cl)-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH
2(化合物YA-72)的制备
类似实施例2的合成方法,用Fmoc-Phe(4-Cl)-OH(3equivalent)代替Fmoc-D-Tyr(tBu)-OH,HBTU/HOBt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护。粗产物YA-72进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为30mL/分钟,洗脱液A/B:61/39-54/46,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Sunfire C18,10um,
柱(19×250mm)。收 集含有产物的级分,冻干,得到12.4mg白色固体。
实施例12:
Ac-Tyr(Me)-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH
2(化合物YA-73)的制备
类似实施例2的合成方法,用Fmoc-Tyr(Me)-OH(3equivalent)代替Fmoc-D-Tyr(tBu)-OH,HBTU/HOBt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护。粗产物YA-73进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:76/24-68/32,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Sunfire C18,10um,
柱(19×250mm)。收集含有产物的级分,冻干,得到4.7mg白色固体。
实施例13:
Ac-Phe(4-Me)-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH
2(化合物YA-74)的制备
类似实施例2的合成方法,用Fmoc-Phe(4-Me)-OH(3equivalent)代替Fmoc-D-Tyr(tBu)-OH,HBTU/HOBt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护。粗产物YA-74进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:73/27-65/35,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Sunfire C18,10um,
柱(19×250mm)。收集含有产物的级分,冻干,得到5.1mg白色固体。
实施例14:
Ac-Phe(4-tBu)-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH
2(化合物YA-75)的制备
类似实施例2的合成方法,用Fmoc-Phe(4-tBu)-OH(3equivalent)代替Fmoc-D-Tyr(tBu)-OH,HBTU/HOBt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护。粗产物YA-75进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为30mL/分钟,洗脱液A/B:62/38-56/44,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Sunfire C18,10um,
柱(19×250mm)。收集含有产物的级分,冻干,得到5.9mg白色固体。
实施例15:
Ac-D-Tyr-Pro(diF)-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH
2(化合物YA-80)的制备
类似实施例2的合成方法,用Fmoc-Pro(diF)-OH(3equivalent)代替Fmoc-Hyp(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护。粗产物YA-80进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为30mL/分钟,洗脱液A/B:67/33-59/41,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Sunfire C18,10um,
柱(19×250mm)。收集含有产物的级分,冻干,得到8.8mg白色固体。
实施例16:
Ac-D-Tyr-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-2Nal-NH
2(化合物YA-81)的制备
类似实施例2的合成方法,用Fmoc-2Nal-OH(3equivalent)代替Fmoc-Trp(Boc)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护。粗产物YA-81进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为30mL/分钟,洗脱液A/B:61/39-54/46,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Sunfire C18,10um,
柱(19×250mm)。收集含有产物的级分,冻干,得到11.6mg白色固体。
实施例17:
Ac-D-Tyr-Pro(4-NH
2)-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH
2(化合物YA-83)的制备
类似实施例2的合成方法,用Fmoc-Pro(4-NH
2)-OH(3equivalent)代替Fmoc-Hyp(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护。粗产物YA-83进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:82/18-72/28,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Sunfire C18,10um,
柱(19×250mm)。收集含有产物的级分,冻干,得到29.8mg白色固体。
实施例18:
Ac-D-Tyr-Thi-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH
2(化合物YA-84)的制备
类似实施例2的合成方法,用Fmoc-Thi-OH(3equivalent)代替Fmoc-Hyp(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护。粗产物YA-84进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为30mL/分钟,洗脱液A/B:67/33-61/39,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Sunfire C18,10um,
柱(19×250mm)。收集含有产物的级分,冻干,得到15.0mg白色固体。
实施例19:
Ac-D-Tyr-(S-Pip)-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH
2(化合物YA-85)的制备
类似实施例2的合成方法,用Fmoc-(S-Pip)-OH(3equivalent)代替Fmoc-Hyp(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护。粗产物YA-85进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为30mL/分钟,洗脱液A/B:67.5/32.5-59/41,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Sunfire C18,10um,
柱(19×250mm)。收集含有产物的级分,冻干,得到6.2mg白色固体。
实施例20:
Ac-Ala(dip)-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH
2(化合物YA-132)的制备
类似实施例2的合成方法,用Fmoc-Ala(dip)-OH(3equivalent)代替Fmoc-D-Tyr(tBu)-OH,HBTU/HOBt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护。粗产物YA-132进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为20mL/分钟,洗脱液A/B:71/29-65/35,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Sunfire C18,5um,
柱(19×150mm)。收集含有产物的级分,冻干,得到4.6mg白色固体。
实施例21:
Ac-D-Tyr-Hyp-Asn-2Fua-Phe-azaGly-Leu-Arg(Me)-Trp-NH
2(化合物YA-143)的制备
类似实施例2的合成方法,用Fmoc-2Fua-OH(3equivalent)代替Fmoc-Thr(tBu)-OH, HBTU/HOBt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护,切割液不含EDT,为TFA/TIS/H
2O(94/3/3)溶液,其他操作一致。粗产物YA-143进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:75/25-67/33,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Sunfire C18,10um,
柱(19×250mm)。收集含有产物的级分,冻干,得到4.2mg白色固体。
实施例22:
Ac-D-Tyr-ACPA-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH
2(化合物YA-145)的制备
类似实施例2的合成方法,用Fmoc-ACPA-OH(3equivalent)代替Fmoc-Hyp(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护。粗产物YA-145进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:78/22-68/32,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Phenomenex Gemini C18,10um,
柱(21.2×250mm)。收集含有产物的级分,冻干,得到17.9mg白色固体。
实施例23:
Ac-D-Tyr-Hyp-Asn-Thr-Phe-ACPO-Leu-Arg(Me)-Trp-NH
2(化合物YA-152)的制备
步骤1:多肽通过标准的Fmoc化学合成,基本操作如下。将1.0g商购可得的Rink Amide MBHA树脂(0.5mmol/g)溶胀于DMF中,该树脂用10mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Fmoc-Trp(Boc)-OH(0.8g,1.5mmol),HATU(0.57g,1.5mmol)和HOAt(0.208g,1.5mmol)的10mL DMF溶液,然后加入DIPEA(0.52mL,3mmol),室温下处理40分钟,树脂用DMF洗涤,得到Fmoc-Trp(Boc)-Rink Amide MBHA树脂。该树脂用10mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作,树脂用DMF洗涤,加入Fmoc-Arg(Me,Pbf)-OH(0.832g,1.2mmol),DIC(149mg,1.5mmol)和HOBt(0.202g,1.5mmol)的10mL DMF溶液,室温下反应过夜。以类似的方式,依次将Leu,ACPO,Phe,Thr(tBu),Asn(Trt),D-Tyr(tBu)等氨基酸引入,得到NH
2-D-Tyr(tBu)-Asn(Trt)-Trp(Boc)-Asn(Trt)-Thr(tBu)-Phe-ACPO-Leu-Arg-Phe-Rink Amide MBHA树脂。用DMF洗涤,加入AcOH(88μL,1.5mmol),DIC(189mg,1.5mmol)和 HOBt(0.202g,1.5mmol)的10mL DMF溶液,室温下反应过夜,引入Ac基团。树脂用DMF,DCM,甲醇,甲基叔丁基醚洗涤,然后抽干,最终得到的1.3g的Ac-NH
2-D-Tyr(tBu)-Asn(Trt)-Thr(tBu)-Phe-ACPO-Leu-Arg-Phe-Rink Amide MBHA树脂。
步骤2:将干燥的树脂加入20mL的TFA/TIS/EDT/H
2O(94/2/2/2)溶液中,该混合物搅拌2小时,过滤除去树脂,用4mL的TFA/TIS/EDT/H
2O(94/2/2/2)溶液洗涤树脂。合并滤液,向滤液中加入冰乙醚(200mL),得到的混合物在3000转/分钟离心3分钟,除去上层液,固体用乙醚洗涤2次,并抽干。
步骤3:得到的多肽粗品用DMF溶解,然后进行线性梯度洗脱(10分钟),流速为30mL/分钟,洗脱液A/B:77/23-67/33,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Xtimate C18,10um,
柱(20×250mm)。收集含有产物的级分,冻干,得到7.1mg白色固体。
实施例24:
Ac-D-Tyr-Hyp-Asn-Thr-Phe-Aze-Leu-Arg(Me)-Trp-NH
2(化合物YA-153)的制备
类似实施例23的合成方法,用Fmoc-Aze-OH(3equivalent)代替Fmoc-ACPO-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例23步骤2方法从树脂上切割下来并脱除保护。粗产物YA-153进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为30mL/分钟,洗脱液A/B:78/22-68/32,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Xtimate C18,10um,
柱(20×250mm)。收集含有产物的级分,冻干,得到24.4mg白色固体。
实施例25:
Ac-D-Tyr-(D-2Fua)-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH
2(化合物YA-165)的制备
类似实施例2的合成方法,用Fmoc-(D-2Fua)-OH(3equivalent)代替Fmoc-Hyp(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护,切割液不含EDT,为TFA/TIS/H
2O(94/3/3)溶液,其他操作一致。粗产物YA-165进行HPLC分离纯化。
实施例26:
Ac-(D-Tyr)-Hyp-Asn-Thr-(D-2Fua)-azaGly-Leu-Arg(Me)-Trp-NH
2(化合物YA-167)的制备
该多肽是用标准的固相多肽合成操作和Fmoc策略合成的,除原料Fmoc-(D-2Fua)-azaGly-Leu-OH不同,基本操作与实施例2(合成YA-3)的制备方法一样。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护,切割液不含EDT,为TFA/TIS/H
2O(94/3/3)溶液,其他操作一致。粗产物YA-167进行HPLC分离纯化,进行线性梯度洗脱(10分钟)。流速为25mL/分钟,洗脱液A/B:78/22-68/32,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Phenomenex Gemini C18,10um,
柱(21.2×250mm)。收集含有产物的级分,冻干,得到19.1mg白色固体。
实施例27:
Ac-D-Tyr-Hyp-Asn-Thr-Phe-(D-2Fua)-Leu-Arg(Me)-Trp-NH
2(化合物YA-168)的制备
类似实施例23的合成方法,用Fmoc-(D-2Fua)-OH(3equivalent)代替Fmoc-ACPO-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护,切割液不含EDT,为TFA/TIS/H
2O(94/3/3)溶液,其他操作一致。粗产物YA-168进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为30mL/分钟,洗脱液A/B:73/27-63/37,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Xtimate C18,10um,
柱(20×250mm)。收集含有产物的级分,冻干,得到8.4mg白色固体。
实施例28:
Ac-[D-Phe(4-F)]-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH
2(化合物YA-170)的制备
类似实施例2的合成方法,用Fmoc-[D-Phe(4-F)]-OH(3equivalent)代替Fmoc-D-Tyr(tBu)-OH,HBTU/HOBt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护。粗产物YA-170进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为20mL/分钟,洗脱液A/B:71/29-65/35,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Sunfire C18,5um,
柱(19×150mm)。收集含有产物的级分,冻干,得到4.6mg白色固体。
实施例29:
Ac-D-Tyr-A6c-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH
2(化合物YA-172)的制备
类似实施例2的合成方法,用Fmoc-A6c-OH(3equivalent)代替Fmoc-Hyp(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护。粗产物YA-172进行HPLC分离纯化,然后进行线性浓度梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:67/33-57/43使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈,在制备型的HPLC上,使用SHIMADAZU C18 10um,
柱(2×21.2×250mm).收集含有产物的级分,冻干,得到12.2mg白色固体。
实施例30:
Ac-D-Tyr-Hyp-Asn-Thr-Phe-A6c-Leu-Arg(Me)-Trp-NH
2(化合物YA-175)的制备
类似实施例23的合成方法,用Fmoc-A6c-OH(3equivalent)代替Fmoc-ACPO-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例23步骤2方法从树脂上切割下来并脱除保护。粗产物YA-175进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:73/27-65/35,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Xtimate C18,10um,
柱(20×250mm)。收集含有产物的级分,冻干,得到16.4mg白色固体。
实施例31:
Ac-[D-Phe(2,4-DiCl)]-Thi-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH
2(化合物YA-178)的制备
类似实施例2的合成方法,用Fmoc-Thi-OH(3equivalent)代替Fmoc-Hyp(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。Fmoc-[D-Phe(2,4-DiCl)]-OH(3equivalent)代替Fmoc-Tyr(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护。粗产物YA-178进行HPLC分离纯化。行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:59/41-49/51,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Phenomenex Gemini C18,10um,
柱(21.2×250mm)。收集含有产物的级分,冻干,得到20.1mg白色固体。
实施例32:
Ac-[D-Phe(2,4-DiCl)]-Pro(diF)-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH
2(化合物YA-180)的制备
类似实施例2的合成方法,用Fmoc-Pro(diF)-OH(3equivalent)代替Fmoc-Hyp(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。Fmoc-[D-Phe(2,4-DiCl)]-OH(3equivalent)代替Fmoc-Tyr(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护。粗产物YA-180进行HPLC分离纯化。行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:68/32-58/42,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Sunfire C18,10um,
柱(19×250mm)。收集含有产物的级分,冻干,得到115.4mg白色固体。
实施例33:
Ac-(D-2Fua)-(S-Pip)-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH
2(化合物YA-181)的制备
类似实施例2的合成方法,用Fmoc-S-Pip-OH(3equivalent)代替Fmoc-Hyp(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。Fmoc-(D-2Fua)-OH(3equivalent)代替Fmoc-Tyr(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护,切割液不含EDT,为TFA/TIS/H
2O(94/3/3)溶液,其他操作一致。粗产物YA-181进行HPLC分离纯化。行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:68/32-58/42,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Phenomenex Gemini C18,10um,
柱(21.2×250mm)。收集含有产物的级分,冻干,得到20.7mg白色固体。
实施例34:
Ac-[D-Phe(2,4-DiCl)]-(S-Pip)-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH
2(化合物YA-182)的制备
类似实施例2的合成方法,用Fmoc-S-Pip-OH(3equivalent)代替Fmoc-Hyp(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。Fmoc-[D-Phe(2,4-DiCl)]-OH(3equivalent)代替Fmoc-Tyr(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护。粗产物YA-182进行HPLC分离纯化。行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:59/41-49/51,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液, 在制备型的HPLC上,使用Phenomenex Gemini C18,10um,
柱(21.2×250mm)。收集含有产物的级分,冻干,得到20.2mg白色固体。
实施例35:
Ac-(D-2Fua)-Pro(diF)-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH
2(化合物YA-183)的制备
类似实施例2的合成方法,用Fmoc-Pro(diF)-OH(3equivalent)代替Fmoc-Hyp(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。Fmoc-(D-2Fua)-OH(3equivalent)代替Fmoc-Tyr(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护,切割液不含EDT,为TFA/TIS/H
2O(94/3/3)溶液,其他操作一致。粗产物YA-183进行HPLC分离纯化。行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:71/29-61/39,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Xtimate C18,10um,
柱(20×250mm)。收集含有产物的级分,冻干,得到19.6mg白色固体。
实施例36:
Ac-[D-Phe(2,4-DiCl)]-Hyp-Asn-Thr-Phe-azaPro-Leu-Arg(Me)-Trp-NH2(化合物YA-184)的制备
步骤1:将0.4g商购可得的Rink Amide MBHA树脂(0.5mmol/g)溶胀于DCM中,该树脂用12mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Fmoc-Trp(Boc)-OH(320mg,0.6mmol),HBTU(227mg,0.6mmol)和HOBt(81mg,0.6mmol)的10mL DMF溶液,然后加入DIPEA(155mg,1.2mmol),室温下处理40分钟;树脂用DMF洗涤,得到Fmoc-Trp(Boc)-Rink Amide MBHA树脂。该树脂用12mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作;树脂用DMF洗涤,加入Fmoc-Arg(Me,Pbf)-OH(180mg,0.3mmol),HATU(113mg,0.3mmol)和HOAt(27mg,0.2mmol)的7mL DMF溶液,然后加入DIPEA(78mg,0.6mmol),室温下处理40分钟;该树脂用12mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作;树脂用DMF洗涤,得到NH2-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。加入Fmoc-Phe-Azap-Leu(150mg,0.24mmol),DIC(60mg,0.48mmol)和HOBt(67mg,0.48mmol)的10mL DMF溶液,室温反应过夜后,加入HATU(182mg,0.48mmol),HOAt(67mg,0.48mmol)和DIPEA(62mg,0.48mmol),室温下继续反应40分钟;树脂用DMF洗涤,该树脂用12mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作;得到 NH2-Phe-Azap-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide树脂。以类似Trp的方式依次逐步引入Thr(tBu),Asn(Trt),Hyp(tBu)和D-Phe(2,4-DiCl),得到的树脂用DMF洗涤,加入Ac
2O(184mg,1.8mmol)和DIPEA(460mg,3.6mmol),室温反应30分钟,引入Ac基团,树脂用DMF,DCM,甲醇,甲基叔丁基醚洗涤,然后抽干,最终得到Ac-[D-Phe(2,4-diCl)]-Hyp(tBu)-Asn(Trt)-Thr(tBu)-Phe-Azap-Leu-Arg(Me,Pbf)Trp(Boc)-Rink Amide MBHA树脂。
步骤2:将干燥的树脂加入10mL的TFA/TIS/EDT/H
2O(94/2/2/2)溶液中,该混合物搅拌2小时,过滤除去树脂,用2mL的TFA/TIS/EDT/H
2O(94/2/2/2)溶液洗涤树脂。合并滤液,向滤液中加入乙醚(70mL),得到的混合物在3000转/分钟离心3分钟,除去上层液,固体用乙醚洗涤2次,并抽干。得到的沉淀用DMF溶解,然后进行线性浓度梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:66/34-58/42,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Xtimate C18,10um,
柱(20×250mm)。收集含有产物的级分,冻干,得到5.9mg白色固体。
实施例37:
Ac-[D-Phe(2,4-DiCl)]-Hyp-Asn-Thr-Phe-Aze-Leu-Arg(Me)-Trp-NH2(化合物YA-188)的制备
类似实施例24的合成方法,用Fmoc-[D-Phe(2,4-DiCl)]-OH(3equivalent)代替Fmoc-Tyr(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例24的方法从树脂上切割下来并脱除保护。粗产物YA-188进行HPLC分离纯化。行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:73/27-65/35,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Xtimate C18,10um,
柱(20×250mm)。收集含有产物的级分,冻干,得到11.2mg白色固体。
实施例38:
Ac-D-Tyr-Thi-Asn-Thr-Phe-Aze-Leu-Arg(Me)-Trp-NH2(化合物YA-191)的制备
类似实施例24的合成方法,用Fmoc-Thi-OH(3equivalent)代替Fmoc-Hyp(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护,切割液不含EDT,为TFA/TIS/H
2O(94/3/3)溶液,其他操作一致。粗产物YA-191进行HPLC分离纯化。行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:71/29-63/37,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上, 使用Xtimate C18,10um,
柱(20×250mm)。收集含有产物的级分,冻干,得到3.8mg白色固体。
实施例39:
Ac-D-Tyr-(S-Pip)-Asn-Thr-Phe-Aze-Leu-Arg(Me)-Trp-NH2(化合物YA-194)的制备
类似实施例24的合成方法,用Fmoc-(S-Pip)-OH(3equivalent)代替Fmoc-Hyp(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护,切割液不含EDT,为TFA/TIS/H
2O(94/3/3)溶液,其他操作一致。粗产物YA-194进行HPLC分离纯化。行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:76/24-68/32,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Xtimate C18,10um,
柱(20×250mm)。收集含有产物的级分,冻干,得到6.5mg白色固体。
实施例40:
Ac-[D-Phe(4-F)]-Hyp-Asn-Thr-Phe-A6c-Leu-Arg(Me)-Trp-NH
2(化合物YA-195)的制备
类似实施例30的合成方法,用Fmoc-[D-Phe(4-F)]-OH(3equivalent)代替Fmoc-Tyr(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护。粗产物YA-195进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:68/32-58/42,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Xtimate C18,10um,
柱(20×250mm)。收集含有产物的级分,冻干,得到12.6mg白色固体。
实施例41:
Ac-[D-Phe(2,4-DiCl)]-Hyp-Asn-Thr-Phe-A6c-Leu-Arg(Me)-Trp-NH
2(化合物YA-196)的制备
类似实施例30的合成方法,用Fmoc-[D-Phe(2,4-DiCl)]-OH(3equivalent)代替Fmoc-Tyr(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护。粗产物YA-196进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:65/35-55/45,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Xtimate C18,10um,
柱(20×250mm)。收 集含有产物的级分,冻干,得到22.4mg白色固体。
实施例42:
Ac-(D-2Fua)-Hyp-Asn-Thr-Phe-A6c-Leu-Arg(Me)-Trp-NH
2(化合物YA-197)的制备
类似实施例30的合成方法,用Fmoc-(D-2Fua)-OH(3equivalent)代替Fmoc-Tyr(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护,切割液不含EDT,为TFA/TIS/H
2O(94/3/3)溶液,其他操作一致。粗产物YA-197进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:71/29-61/39,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Xtimate C18,10um,
柱(20×250mm)。收集含有产物的级分,冻干,得到18.3mg白色固体。
实施例42’:
Ac-D-Phe(2,4-DiCl)-azaPro-Asn-Thr-Phe-A6c-Leu-Arg(Me)-Trp-NH2(化合物YA-200)的制备
将0.4g商购可得的Rink Amide MBHA树脂(0.5mmol/g)溶胀于DCM中,该树脂用12mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Fmoc-Trp(Boc)-OH(320mg,0.6mmol),HBTU(227mg,0.6mmol)和HOBt(81mg,0.6mmol)的10mL DMF溶液,然后加入DIPEA(155mg,1.2mmol),室温下处理40分钟;树脂用DMF洗涤,得到Fmoc-Trp(Boc)-Rink Amide MBHA树脂。该树脂用12mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作;树脂用DMF洗涤,加入Fmoc-Arg(Me,Pbf)-OH(180mg,0.3mmol),HATU(113mg,0.3mmol)和HOAt(27mg,0.2mmol)的7mL DMF溶液,然后加入DIPEA(78mg,0.6mmol),室温下处理40分钟;该树脂用12mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作;树脂用DMF洗涤,得到NH2-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。
以类似Trp的方式将Leu,A6c,Phe,Thr(tBu)等氨基酸引入,树脂用DMF洗涤,得到NH2-Thr(tBu)-Phe-A6c-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。加入D-Phe(2,4-DiCl)-azaPro-Asn(Trt)(219mg,0.24mmol),HATU(91mg,0.48mmol)和HOAt(67mg,0.48mmol)的7mL DMF溶液,然后加入DIPEA(62mg,0.48mmol),室温下处理40分钟;该树脂用10mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作;树脂用DMF洗涤,得到NH2-D-Phe(2,4-DiCl)-azaPro-Asn(Trt)-Thr(tBu)-Phe-A6c-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。加入Ac
2O(61mg,0.6mmol)和DIPEA (77mg,0.6mmol),室温反应30分钟,引入Ac基团,树脂用DMF,DCM,甲醇,甲基叔丁基醚洗涤,然后抽干,最终得到Ac-[D-Phe(2,4-diCl)]-azaPro-Asn(Trt)-Thr(tBu)-Phe-A6c-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。
将干燥的树脂加入10mL的TFA/TIS/PhSMe/EDT(84/6/6/4)溶液中,该混合物搅拌40分钟,过滤除去树脂,用2mL的TFA/TIS/PhSMe/EDT(84/6/6/4)溶液洗涤树脂。合并滤液,向滤液中加入乙醚(70mL),得到的混合物在3000转/分钟离心1分钟,除去上层液,固体用乙醚洗涤2次,并抽干。得到的沉淀用DMF溶解,然后进行线性浓度梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:65/35-55/45使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈,在制备型的HPLC上,使用Phenomenex Gemini 10μ,
柱(21.2mm×250mm)。收集含有产物的级分,冻干,得到12mg白色固体。
实施例43:
Ac-(D-2Fua)-Pro(diF)-Asn-Thr-Phe-A6c-Leu-Arg(Me)-Trp-NH
2(化合物YA-201)的制备
类似实施例30的合成方法,用Fmoc-Pro(diF)-OH(3equivalent)代替Fmoc-Hyp(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时;用Fmoc-(D-2Fua)-OH(3equivalent)代替Fmoc-Tyr(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护,切割液不含EDT,为TFA/TIS/H
2O(94/3/3)溶液,其他操作一致。粗产物YA-201进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:68/32-58/42,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Xtimate C18,10um,
柱(20×250mm)。收集含有产物的级分,冻干,得到11.6mg白色固体。
实施例44:
Ac-(D-Tyr)-Hyp-Asn-Thr-{(S)-2-(1-amino-2-phenylethyl)-1H-imidazole-5-carboxylic acid}-Leu-Arg(Me)-Trp-NH2(化合物YA-208)的制备
步骤1:将0.4g商购可得的Rink Amide MBHA树脂(0.5mmol/g)溶胀于DMF中,该树脂用8mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Fmoc-Trp(Boc)-OH(320mg,0.6mmol),HBTU(227mg,0.6mmol)和HOBt(81mg,0.6mmol)的10mL DMF溶液,然后加入DIPEA(155mg,1.2mmol),室温下处理40分钟;该树脂用8mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍 此操作;树脂用DMF洗涤,加入第二个氨基酸Fmoc-Arg(Me,Pbf)-OH(180mg,0.3mmol),HATU(113mg,0.3mmol),HOBt(27mg,0.2mmol)的10mL DMF溶液,然后加入DIPEA(78mg,0.6mmol),室温下处理2小时,得到Fmoc-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。以引入Trp(Boc)的方式引入Leu,得到Fmoc-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。该树脂用8mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。树脂用DMF洗涤,然后加入Fmoc-(S)-2-(1-amino-2-phenylethyl)-1H-imidazole-5-carboxylic acid(120mg,0.3mmol),HATU(113mg,0.3mmol),HOBt(27mg,0.2mmol)的10mL DMF溶液,然后加入DIPEA(78mg,0.6mmol),室温下处理2小时。该树脂用8mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作,树脂用DMF洗涤,得到{(S)-2-(1-amino-2-phenylethyl)-1H-imidazole-5-carboxylic acid}-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。以类似的方式将其他氨基酸[Fmoc-Thr(OtBu)-OH,Fmoc-Asn(Trt)-OH,Fmoc-Hyp(OtBu)-OH,Fmoc-D-Tyr(OtBu)-OH]引入得到Fmoc-(D-Tyr)-Hyp-Asn-Thr-{(S)-2-(1-amino-2-phenylethyl)-1H-imidazole-5-carboxylic acid}-Leu-Arg(Me)-Trp-Rink Amide MBHA树脂。该树脂用5mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。树脂用DMF洗涤,然后依次加入10mL DMF,乙酸(100mg,1.6mmol),DIC(76mg,0.6mmol),室温下处理60分钟,引入Ac基团。树脂用DMF,DCM,甲醇,甲基叔丁基醚洗涤,然后抽干,最终得到Ac-D-Tyr(tBu)-Hyp(tBu)-Asn(Trt)-Thr(tBu)-{(S)-2-(1-amino-2-phenylethyl)-1H-imidazole-5-carboxylic acid}-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。
步骤2:将干燥的树脂加入10mL的TFA/TIS/EDT/H
2O(94/2/2/2)溶液中,该混合物搅拌2小时,过滤除去树脂,用2mL的TFA/TIS/EDT/H
2O(94/2/2/2)溶液洗涤树脂。合并滤液,向滤液中加入乙醚(50mL),得到的混合物在3000转/分钟离心1分钟,除去上层液,固体用乙醚洗涤2次,并抽干。得到的沉淀用DMF溶解,然后进行线性浓度梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:76/24-66/34使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈,在制备型的HPLC上,使用Phenomenex Gemini 10μ,
柱(21.2×250mm)。收集含有产物的级分,冻干,得到40mg白色固体。
实施例45:
Ac-[D-Phe(4-F)]-Pro(diF)-Asn-Thr-Phe-A6c-Leu-Arg(Me)-Trp-NH
2(化合物YA-212)的制备
类似实施例30的合成方法,用Fmoc-Pro(diF)-OH(3equivalent)代替Fmoc-Hyp(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时;用Fmoc-[D-Phe(4-F)]-OH(3equivalent)代替Fmoc-Tyr(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护。粗产物YA-212进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:66/34-56/44,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Xtimate C18,10um,
柱(20×250mm)。收集含有产物的级分,冻干,得到20.2mg白色固体。
实施例46:
Ac-[D-Phe(4-F)]-Pro(diF)-Asn-Thr-Phe-Aze-Leu-Arg(Me)-Trp-NH
2(化合物YA-213)的制备
类似实施例24的合成方法,用Fmoc-Pro(diF)-OH(3equivalent)代替Fmoc-Hyp(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时;用Fmoc-[D-Phe(4-F)]-OH(3equivalent)代替Fmoc-Tyr(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护。粗产物YA-213进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:70/30-60/40使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈,在制备型的HPLC上,使用Phenomenex Gemini C18 10um,
柱(21.2×250mm).收集含有产物的级分,冻干,得到39.8mg白色固体。
实施例47:
Ac-[D-Phe(4-Cl)]-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH
2(化合物YA-214)的制备
类似实施例2的合成方法,用Fmoc-[D-Phe(4-Cl)]-OH(3equivalent)代替Fmoc-Tyr(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护。粗产物YA-214进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:72/28-62/38,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Phenomenex Gemini C18 10um,
柱(21.2×250mm).收集含有产物的级分,冻干,得到32.1mg白色固体。
实施例48:
Ac-[D-Phe(3-Cl)]-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH
2(化合物YA-215)的制备
类似实施例2的合成方法,用Fmoc-[D-Phe(3-Cl)]-OH(3equivalent)代替Fmoc-Tyr(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护。粗产物YA-215进行HPLC分离纯化,进行线性梯度洗脱(10分钟),然后进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:73/27-65/35,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Phenomenex Gemini C18 10um,
柱(21.2×250mm).收集含有产物的级分,冻干,得到28.1mg白色固体。
实施例49:
Ac-D-Tyr-Hyp-Asn-Thr-Phe-Ind-Leu-Arg(Me)-Trp-NH
2(化合物YA-221)的制备
类似实施例23的合成方法,用Fmoc-Idn-OH(3equivalent)代替Fmoc-ACPO-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护。粗产物YA-221进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:70/30-60/40,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Phenomenex Gemini C18 10um,
柱(21.2×250mm).收集含有产物的级分,冻干,得到16.5mg白色固体。
实施例50:
Ac-D-Tyr-(S-Pip)-Asn-Thr-Phe-A6c-Leu-Arg(Me)-Trp-NH
2(化合物YA-228)的制备
类似实施例30的合成方法,用Fmoc-(S-Pip)-OH(3equivalent)代替Fmoc-Hyp(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护。粗产物YA-228进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:74/26-64/36,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Sunfire C18,10um,
柱(19×250mm)。收集含有产物的级分,冻干,得到32.2mg白色固体。
实施例51:
Ac-D-Tyr-Oic-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH
2(化合物YA-230)的制备
类似实施例2的合成方法,用Fmoc-Oic-OH(3equivalent)代替Fmoc-Hyp(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护。粗产物YA-230进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:75/25-67/33,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Sunfire C18,10um,
柱(19×250mm)。收集含有产物的级分,冻干,得到20.1mg白色固体。
实施例52:
Ac-D-Tic-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH
2(化合物YA-236)的制备
类似实施例2的合成方法,用Fmoc-D-Tic-OH(3equivalent)代替Fmoc-Tyr(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护。粗产物YA-236进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:75/25-65/35,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Sunfire C18,10um,
柱(19×250mm)。收集含有产物的级分,冻干,得到16.0mg白色固体。
实施例52-1:
Ac-[D-Phe(2,4-diCl)]-(S-Pip)-Asn-Thr-azaPhe-Gly-Leu-Arg(Me)-Trp-NH2(化合物YA-241)的制备
将0.26g商购可得的Rink Amide MBHA树脂(0.5mmol/g)溶胀于DMF中,该树脂用5mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Fmoc-Trp(Boc)-OH(205mg,0.39mmol),HBTU(148mg,0.39mmol),HOBt(53mg,0.39mmol)的10mL DMF溶液,然后加入DIPEA(100mg,0.78mmol),室温下处理40分钟,树脂用DMF洗涤,得到Fmoc-Trp(Boc)-Rink Amide MBHA树脂。树脂用5mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Fmoc-Arg(Me,Pbf)-OH(100mg,0.15mmol),DIC(57mg,0.45mmol)和HOBt(60mg,0.45mmol)的10mL DMF溶液,室温下反应过夜。该树脂用20mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作,树脂用DMF洗涤,得到NH2-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。以类似的方式引入Leu。树脂用DMF洗涤,加入Fmoc-Thr(tBu)-azaPhe-Gly-OH(94mg,0.16mmol),HATU(61mg,0.16mmol)和HOAt(22mg,0.16mmol)的5mL DMF溶液,然后加入DIPEA(41mg,0.32 mmol),室温下处理40分钟;该树脂用8mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作,树脂用DMF洗涤,得到NH2-Thr(tBu)-azaPhe-Gly-Leu-Arg(Me,Pbf)-Trp(Boc)-MBHA树脂。以类似Trp的方式将Asn,S-Pip和D-Phe(2,4-diCl)引入,树脂用DMF洗涤,加入AcOH(47mg,0.78mmol),DIC(98mg,0.78mmol)和HOBt(108mg,0.78mmol)的5mL DMF溶液,室温下反应过夜,引入Ac基团。树脂用DMF,DCM,甲醇,甲基叔丁基醚洗涤,然后抽干,最终得到Ac-[D-Phe(2,4-diCl)]-(S-Pip)-Asn(Trt)-Thr(tBu)-azaPhe-Gly-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。
将干燥的树脂加入10mL的TFA/TIS/EDT/H
2O(94/2/2/2)溶液中,该混合物搅拌2小时,过滤除去树脂,用2mL的TFA/TIS/EDT/H
2O(94/2/2/2)溶液洗涤树脂。合并滤液,向滤液中加入乙醚(70mL),得到的混合物在3000转/分钟离心1分钟,除去上层液,固体用乙醚洗涤2次,并抽干。得到的沉淀用DMF溶解,然后进行线性浓度梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:67/33-57/43使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈,在制备型的HPLC上,使用Phenomenex Gemini 10μ,
柱(21.2×250mm)。收集含有产物的级分,冻干,得到45mg白色固体。
实施例52-2:
Ac-[D-Phe(2,4-diCl)]-(S-Pip)-Asn-Thr-Phe-azaGly-Leu-Phe(4-Pyrazol)-Trp-NH2(化合物YA-242)的制备
将0.26g商购可得的Rink Amide MBHA树脂(0.5mmol/g)溶胀于DMF中,该树脂用5mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Fmoc-Trp(Boc)-OH(205mg,0.39mmol),HBTU(148mg,0.39mmol),HOBt(53mg,0.39mmol)的10mL DMF溶液,然后加入DIPEA(100mg,0.78mmol),室温下处理40分钟,树脂用DMF洗涤,得到Fmoc-Trp(Boc)-Rink Amide MBHA树脂。树脂用5mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Fmoc-Phe(4-Pyrazol)-OH(54mg,0.12mmol),DIC(30mg,0.24mmol)和HOBt(33mg,0.24mmol)的5mL DMF溶液,室温下反应过夜;该树脂用8mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作,树脂用DMF洗涤,得到NH2-Phe(4-Pyrazol)-Trp(Boc)-Rink Amide MBHA树脂。加入Fmoc-Phe-azaGly-Leu-OH(67mg,0.3mmol),DIC(76mg,0.6mmol)和HOBt(83mg,0.6mmol)的5mL DMF溶液,室温下反应过夜;该树脂用8mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作;树脂用DMF洗涤,得到NH2-Phe-azaGly-Leu-Phe(4-Pyrazol)-Trp(Boc)-Rink Amide MBHA树脂。以类似Trp的方式将Thr(tBu),Asn(Trt),S-Pip和D-Phe(2,4-diCl)引入,树脂 用DMF洗涤,加入AcOH(47mg,0.78mmol),DIC(98mg,0.78mmol)和HOBt(108mg,0.78mmol)的5mL DMF溶液,室温下反应过夜,引入Ac基团。树脂用DMF,DCM,甲醇,甲基叔丁基醚洗涤,然后抽干,最终得到Ac-[D-Phe(2,4-diCl)]-(S-Pip)-Asn(Trt)-Thr(tBu)-Phe-azaGly-Leu-Phe(4-Pyrazol)-Trp(Boc)-Rink Amide MBHA树脂。
将干燥的树脂加入10mL的TFA/TIS/EDT/H
2O(94/2/2/2)溶液中,该混合物搅拌2小时,过滤除去树脂,用2mL的TFA/TIS/EDT/H
2O(94/2/2/2)溶液洗涤树脂。合并滤液,向滤液中加入乙醚(70mL),得到的混合物在3000转/分钟离心1分钟,除去上层液,固体用乙醚洗涤2次,并抽干。得到的沉淀用DMF溶解,然后进行线性浓度梯度洗脱(10分钟),流速为45mL/分钟,洗脱液A/B:50/50-43/57使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈,在制备型的HPLC上,使用Phenomenex Gemini 10μ,
柱(30mm×250mm)。收集含有产物的级分,冻干,得到80mg白色固体。
实施例53:
Ac-D-Tyr-A6c-Asn-Thr-Phe-A6c-Leu-Arg(Me)-Trp-NH
2(化合物YA-243)的制备
类似实施例30的合成方法,用Fmoc-A6c-OH(3equivalent)代替Fmoc-Hyp(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护。粗产物YA-243进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:67/33-57/43,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Phenomenex Gemini C18,10um,
柱(21.2×250mm)。收集含有产物的级分,冻干,得到30.7mg白色固体。
实施例53-1:
Ac-(D-Tyr)-Hyp-Asn-Thr-Phe-azaNMeGly-Leu-Arg(Me)-Trp-NH2(化合物YA-247)的制备
将0.26g商购可得的Rink Amide MBHA树脂(0.5mmol/g)溶胀于DMF中,该树脂用5mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Fmoc-Trp(Boc)-OH(205mg,0.39mmol),HBTU(148mg,0.39mmol),HOBt(53mg,0.39mmol)的10mL DMF溶液,然后加入DIPEA(100mg,0.78mmol),室温下处理40分钟,树脂用DMF洗涤,得到Fmoc-Trp(Boc)-Rink Amide MBHA树脂。树脂用5mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Fmoc-Arg(Me,Pbf)-OH(100mg,0.15mmol),DIC(57mg,0.45mmol)和HOBt(60 mg,0.45mmol)的10mL DMF溶液,室温下反应过夜。该树脂用20mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作,树脂用DMF洗涤,得到Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。得到的树脂,加入Fmoc-Phe-azaNMeGly-Leu-OH(110mg,0.15mmol),DIC(57mg,0.45mmol)和HOBt(60mg,0.45mmol)的15mL DMF溶液,室温下反应过夜;该树脂用20mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作;树脂用DMF洗涤得到NH2-Phe-azaNMeGly-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。以类似的方式将其他氨基酸[Fmoc-Thr(OtBu)-OH,Fmoc-Asn(Trt)-OH,Fmoc-Hyp(OtBu)-OH,Fmoc-D-Tyr(OtBu)-OH]引入得到NH
2-D-Tyr(tBu)-Hyp(tBu)-Asn(Trt)-Thr(tBu)-Phe-azaNMeGly-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。然后加入10mL DMF,乙酸(25mg,0.4mmol),DIC(49mg,0.39mmol),室温下处理40分钟,引入Ac基团。树脂用DMF,DCM,甲醇,甲基叔丁基醚洗涤,然后抽干,最终得到的Ac-D-Tyr(tBu)-Hyp(tBu)-Asn(Trt)-Thr(tBu)-Phe-azaNMeGly-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。
将干燥的树脂加入10mL的TFA/TIS/EDT/H
2O(94/2/2/2)溶液中,该混合物搅拌2小时,过滤除去树脂,用2mL的TFA/TIS/EDT/H
2O(94/2/2/2)溶液洗涤树脂。合并滤液,向滤液中加入乙醚(70mL),得到的混合物在3000转/分钟离心1分钟,除去上层液,固体用乙醚洗涤2次,并抽干。得到的沉淀用DMF溶解,然后进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:79/21-69/31,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈,在制备型的HPLC上,使用Phenomenex Gemini 10μ,
柱(21.2×250mm)。收集含有产物的级分,冻干,得到11.5mg白色固体。
实施例54:
Ac-[D-Phe(2,4-diCl)]-Pro(diF)-Asn-Thr-Phe-A6c-Leu-Arg(Me)-Trp-NH
2(化合物YA-248)的制备
类似实施例30的合成方法,用Fmoc-Pro(diF)-OH(3equivalent)代替Fmoc-Hyp(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时;用Fmoc-[D-Phe(2,4-diCl)-OH(3equivalent)代替Fmoc-Tyr(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护。粗产物YA-248进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:64/36-56/44使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈,在制备型的HPLC上,使用Sunfire C18 10um,
柱(19×250mm).收集含有产物的级分, 冻干,得到25.2mg白色固体。
实施例55:
Ac-D-Tyr-Pro(diF)-Asn-Thr-Phe-A6c-Leu-Arg(Me)-Trp-NH
2(化合物YA-251)的制备
类似实施例30的合成方法,用Fmoc-Pro(diF)-OH(3equivalent)代替Fmoc-Hyp(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护。粗产物YA-251进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:66/34-63/37使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈,在制备型的HPLC上,使用Boston C18 10um,
柱(21.2×250mm).收集含有产物的级分,冻干,得到28.3mg白色固体。
实施例56:
Ac-[D-Phe(2,4-DiCl)]-A6c-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH
2(化合物YA-260)的制备
类似实施例2的合成方法,用Fmoc-A6c-OH(3equivalent)代替Fmoc-Hyp(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。Fmoc-[D-Phe(2,4-DiCl)]-OH(3equivalent)代替Fmoc-Tyr(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护。粗产物YA-260进行HPLC分离纯化。行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:60/40-56/44使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈,在制备型的HPLC上,使用Boston C18 10um,
柱(21.2×250mm).收集含有产物的级分,冻干,得到12.8mg白色固体。
实施例57:
Ac-(D-2Fua)-A6c-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH
2(化合物YA-271)的制备
类似实施例2的合成方法,用Fmoc-A6c-OH(3equivalent)代替Fmoc-Hyp(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。Fmoc-(D-2Fua)-OH(3equivalent)代替Fmoc-Tyr(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护。粗产物YA-271进行HPLC分离纯化。行线 性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:72/28-62/38使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈,在制备型的HPLC上,使用Sunfire C1810um,
柱(19×250mm).收集含有产物的级分,冻干,得到19.4mg白色固体。
实施例58:
Ac-[D-Phe(4-F)]-Hyp-Asn-Thr-Phe-A6c-Leu-Arg(Me)-Trp-NH
2(化合物YA-195)的制备
类似实施例30的合成方法,用Fmoc-[D-Phe(4-F)]-OH(3equivalent)代替Fmoc-Tyr(tBu)-OH缩合,HATU/HOAt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例2步骤2方法从树脂上切割下来并脱除保护。粗产物YA-195进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:68/32-58/42,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Xtimate C18,10um,
柱(20×250mm)。收集含有产物的级分,冻干,得到12.6mg白色固体。
实施例59:
Ac-PEG4-(D-Tyr)-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2(化合物YA-150)的制备
步骤1:将0.26g商购可得的Rink Amide MBHA树脂(0.5mmol/g)溶胀于DMF中,按照实施例2得到NH
2--D-Tyr(tBu)-Hyp(tBu)-Asn(Trt)-Thr(tBu)-Phe-azaGly-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。树脂用DMF洗涤,加入Fmoc-PEG4-CH
2CH
2-COOH(94mg,0.19mmol),HBTU(227mg,0.6mmol),HOBt(81mg,0.6mmol)的10mL DMF溶液,然后加入DIPEA(209μL,1.2mmol),室温下处理40分钟,向其中引入PEG4。该树脂用5mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。树脂用DMF洗涤,加入AcOH(47mg,0.78mmol),DIC(98mg,0.78mmol)和HOBt(108mg,0.78mmol)的5mL DMF溶液,室温下反应过夜,引入Ac基团。树脂用DMF,DCM,甲醇和甲基叔丁基醚洗涤,然后抽干,得到Ac-PEG4-D-Tyr(tBu)-Hyp(tBu)-Asn(Trt)-Thr(tBu)-Phe-azaGly-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。
步骤2:将干燥的树脂加入10mL的TFA/TIS/H
2O(95/2.5/2.5)溶液中,该混合物搅拌2小时,过滤除去树脂,用2mL的TFA/TIS/H
2O(95/2.5/2.5)溶液洗涤树脂。合并滤液,向滤液中加入冰甲基叔丁基醚(70mL),得到的混合物在3000转/分钟离心3分钟,固体用冰乙醚洗涤两次,并抽干。得到的沉淀用DMF溶解,然后进行线性浓度梯度洗脱(10 分钟),流速为25mL/分钟,洗脱液A/B:80/20-70/30使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈,在制备型的HPLC上,使用Sunfire 10μ,
柱(19mm×250mm)。收集含有产物的级分,冻干,得到12.0mg白色固体。
实施例60:
Ac-PEG8-(D-Tyr)-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2(化合物YA-151)的制备
类似实施例59的合成方法,用Fmoc-PEG8-CH
2CH
2-COOH(1.5equivalent)代替Fmoc-PEG8-CH
2CH
2-COOH缩合,HBTU/HOBt/DIPEA为缩合条件,以DMF为溶剂,混合物室温反应40分钟。树脂洗涤后干燥。目标多肽用实施例59步骤2方法从树脂上切割下来并脱除保护。粗产物YA-151进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:80/20-70/30使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈,在制备型的HPLC上,使用Boston C18 10um,
柱(21.2×250mm).收集含有产物的级分,冻干,得到34.5mg白色固体。
实施例61:
Palm-PEG8-Gly-Gly-(D-Tyr)-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2(化合物YA-156)的制备
步骤1:将0.26g商购可得的Rink Amide MBHA树脂(0.5mmol/g)溶胀于DMF中,按照实施例2得到NH
2-Gly-Gly-D-Tyr(tBu)-Hyp(tBu)-Asn(Trt)-Thr(tBu)-Phe-azaGly-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。树脂用DMF洗涤,加入Fmoc-PEG8-CH
2CH
2-COOH(126mg,0.19mmol),HBTU(227mg,0.6mmol),HOBt(81mg,0.6mmol)的10mL DMF溶液,然后加入DIPEA(209μL,1.2mmol),室温下处理40分钟,向其中引入PEG8。该树脂用5mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Palm acid(61.5mg,0.24mmol),HBTU(227mg,0.6mmol),HOBt(81mg,0.6mmol)的10mL DMF溶液,然后加入DIPEA(209μL,1.2mmol,室温下处理40分钟,得到Palm-PEG8-Gly-Gly-D-Tyr-Asn-Trp-Asn-Ser-Tic-Gly-Leu-Arg-Phe-MBHA树脂。树脂用DMF,DCM,甲醇和甲基叔丁基醚洗涤,然后抽干,得到Ac-PEG4-D-Tyr(tBu)-Hyp(tBu)-Asn(Trt)-Thr(tBu)-Phe-azaGly-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。
步骤2:将干燥的树脂加入10mL的TFA/TIS/H
2O(95/2.5/2.5)溶液中,该混合物搅拌2小时,过滤除去树脂,用2mL的TFA/TIS/H
2O(95/2.5/2.5)溶液洗涤树脂。合并滤液, 向滤液中加入冰甲基叔丁基醚(70mL),得到的混合物在3000转/分钟离心3分钟,固体用冰乙醚洗涤两次,并抽干。得到的沉淀用DMF溶解,然后进行线性浓度梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:47/53-37/63,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Xtimate C18,10um,
柱(20×250mm)。收集含有产物的级分,冻干,得到20.4mg白色固体。
实施例62:
Ac-Lys(Palm-PEG8)-Gly-Gly-(D-Tyr)-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2(化合物YA-157)的制备
步骤1:将0.26g(0.5mmol/g)商购可得的Rink Amide MBHA树脂溶胀于DMF中,该树脂用5mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Fmoc-Trp(Boc)-OH(205mg,0.39mmol),HBTU(148mg,0.39mmol),HOBt(53mg,0.39mmol)的10mL DMF溶液,然后加入DIPEA(100mg,0.78mmol),室温下处理40分钟,向其中引入Trp(Boc),得到Fmoc-Trp(Boc)-MBHA树脂。树脂用5mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Fmoc-Arg(Me,Pbf)-OH(100mg,0.15mmol),DIC(57mg,0.45mmol)和HOBt(60mg,0.45mmol)的10mL DMF溶液,室温下反应过夜。该树脂用20mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作,得到Arg(Me,Pbf)-Trp(Boc)-MBHA树脂。得到的树脂用DMF洗涤,加入Fmoc-Phe-azaGly-Leu-OH(104mg,0.15mmol),DIC(57mg,0.45mmol)和HOBt(60mg,0.45mmol)的15mL DMF溶液,室温下反应过夜;该树脂用20mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作;得到Phe-azaGly-Leu-Arg(Me,Pbf)-Trp(Boc)-MBHA树脂。以类似的方式将其他氨基酸(Fmoc-Thr(OtBu)-OH,Fmoc-Asn(Trt)-OH,Fmoc-Hyp(OtBu)-OH,Fmoc-D-Tyr(OtBu)-OH),Fmoc-Gly-OH,Fmoc-GLy-OH,Ac-Lys(Fmoc)-OH)引入得到Ac-Lys-Gly-Gly-(D-Tyr)-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-MBHA树脂。然后加入Fmoc-PEG8-CH2CH2-COOH(172mg,0.26mmol),HBTU(148mg,0.39mmol),HOBt(53mg,0.39mmol)的10mL DMF溶液,然后加入DIPEA(100mg,0.78mmol),室温下处理40分钟,向其中引入PEG8。该树脂用5mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Palm acid(103mg,0.4mmol),HBTU(227mg,0.6mmol),HOBt(81mg,0.6mmol)的10mL DMF溶液,然后加入DIPEA(155mg,1.2mmol),室温下处理40分钟,得到Ac-Lys(Palm-PEG8)-Gly-Gly-(D-Tyr)-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-MBHA树 脂。
用DCM,甲醇,甲基叔丁基醚洗涤树脂,然后抽干,得到400mg树脂。将干燥的树脂加入10mL的TFA/TIS/EDT/H
2O(94/2/2/2)溶液中,接着摇动2小时,过滤除去树脂,用2mL的TFA/TIS/EDT/H
2O(94/2/2/2)溶液洗涤树脂。合并滤液,向滤液中加入乙醚(70mL),离心得到的沉淀,除去上层液。得到的沉淀用DMF溶解,在制备型的HPLC上,使用Phenomenex Gemini 10u,
柱(21.2×250mm)。收集含有产物的级分,冻干,得到31mg白色固体。
步骤2:将干燥的树脂加入10mL的TFA/TIS/H
2O(95/2.5/2.5)溶液中,该混合物搅拌2小时,过滤除去树脂,用2mL的TFA/TIS/H
2O(95/2.5/2.5)溶液洗涤树脂。合并滤液,向滤液中加入冰甲基叔丁基醚(70mL),得到的混合物在3000转/分钟离心3分钟,固体用冰乙醚洗涤两次,并抽干。得到的沉淀用DMF溶解,然后进行线性浓度梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:47/53-37/63,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Xtimate C18,10um,
柱(20×250mm)。收集含有产物的级分,冻干,得到20.4mg白色固体。
实施例63:
Palm-PEG8-Gly-Gly-Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH2(化合物YA-158)的制备
将0.26g商购可得的Rink Amide MBHA树脂(0.5mmol/g)溶胀于DMF中,按照实施例1步骤1方法得到NH
2-D-Tyr(tBu)-Asn(Trt)-Trp(Boc)-Asn(Trt)-Thr(tBu)-Phe-Gly-Leu-Arg-Phe-Rink Amide MBHA树脂。按照实施例61步骤1方法分别引入Gly,Gly,PEG8和Palm,得到Palm-PEG8-D-Tyr(tBu)-Asn(Trt)-Trp(Boc)-Asn(Trt)-Thr(tBu)-Phe-Gly-Leu-Arg-Phe-Rink Amide MBHA树脂。树脂洗涤后干燥。目标多肽用实施例61步骤2方法从树脂上切割下来并脱除保护。粗产物YA-158进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:48/52-38/62,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Xtimate C18,10um,
柱(20×250mm)。收集含有产物的级分,冻干,得到10.9mg白色固体。
实施例65:
Palm-PEG8-Gly-Gly-D-3Fua-Pro(diF)-Asn-Thr-Phe-A6c-Leu-Arg(Me)-Trp-NH2(化合物YA-220)的制备
按照实施例43方法得到NH
2-3Fua-Pro(diF)-Asn(Trt)-Thr(tBu)-Phe- A6c-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。按照实施例61步骤1方法分别引入Gly,Gly,PEG8和Palm,得到Palm-PEG8-Gly-Gly-3Fua-Pro(diF)-Asn(Trt)-Thr(tBu)-Phe-A6c-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。树脂洗涤后干燥。目标多肽用实施例61步骤2方法从树脂上切割下来并脱除保护。粗产物YA-220进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:45/55-25/75,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Xtimate C18,10um,
柱(20×250mm)。收集含有产物的级分,冻干,得到24.5mg白色固体。
实施例66:
Palm-PEG8-Gly-Gly-D-Tyr-Hyp-Asn-Thr-Phe-A6c-Leu-Arg(Me)-Trp-NH
2(化合物YA-264)的制备
类似实施例30的合成方法,方法得到NH
2-D-Tyr(tBu)-Hyp(tBu)-Asn(Trt)-Thr(tBu)-Phe-A6c-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。按照实施例61步骤1方法分别引入Gly,Gly,PEG8和Palm,得到Palm-PEG8-D-Tyr(tBu)-Hyp(tBu)-Asn(Trt)-Thr(tBu)-Phe-A6c-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。树脂洗涤后干燥。目标多肽用实施例61步骤2方法从树脂上切割下来并脱除保护。粗产物YA-264进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:43/57-33/67,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Xtimate C18,10um,
柱(20×250mm)。收集含有产物的级分,冻干,得到13.0mg白色固体。
实施例67:
Palm-PEG8-D-3Fua-Pro(diF)-Asn-Thr-Phe-A6c-Leu-Arg(Me)-Trp-NH2(化合物YA-267)的制备
按照实施例43方法得到NH
2-3Fua-Pro(diF)-Asn(Trt)-Thr(tBu)-Phe-A6c-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。按照实施例61步骤1方法分别引入Gly,Gly,PEG8和Palm,得到Palm-PEG8-3Fua-Pro(diF)-Asn(Trt)-Thr(tBu)-Phe-A6c-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。树脂洗涤后干燥。目标多肽用实施例61步骤2方法从树脂上切割下来并脱除保护。粗产物YA-267进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:40/60-30/70,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Phenomenex Gemini C18,10um,
柱(21.2×250mm)。收 集含有产物的级分,冻干,得到41.3mg白色固体。
实施例68:
C18diacid-OEG-OEG-D-Tyr-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2(化合物YA-273)的制备
按照实施例2步骤1方法得到NH
2-D-Tyr(tBu)-Hyp(tBu)-Asn(Trt)-Thr(tBu)-Phe-azaGly-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。按照实施例61步骤1方法分别引入OEG,OEG和C18diacid(monotBu),得到C18diacid(tBu)-OEG-OEG-D-Tyr(tBu)-Hyp(tBu)-Asn(Trt)-Thr(tBu)-Phe-A6c-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。树脂洗涤后干燥。目标多肽用实施例61步骤2方法从树脂上切割下来并脱除保护。粗产物YA-273进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:58/42-42/52使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈,在制备型的HPLC上,使用Utimate C8 10um,
柱(21.2×250mm).收集含有产物的级分,冻干,得到30.4mg白色固体。。
实施例69:
Palm-PEG8-Gly-Gly-D-Tyr-Hyp-Asn-Thr-(S)-2-{(1-amino-2-phenylethyl)-1H-imidazole-5-carboxylic acid}-Leu-Arg(Me)-Trp-NH
2(化合物YA-286)的制备
类似实施例44的合成方法,方法得到NH
2-D-Tyr(tBu)-Hyp(tBu)-Asn(Trt)-Thr(tBu)-(S)-2-{(1-amino-2-phenylethyl)-1H-imidazole-5-carboxylic acid}-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂树脂。按照实施例61步骤1方法分别引入Gly,Gly,PEG8和Palm,得到Palm-PEG8-D-Tyr(tBu)-Hyp(tBu)-Asn(Trt)-Thr(tBu)-Phe-(S)-2-{(1-amino-2-phenylethyl)-1H-imidazole-5-carboxylic acid}-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。树脂洗涤后干燥。目标多肽用实施例61步骤2方法从树脂上切割下来并脱除保护。粗产物YA-286进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:53/47-43/57使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈,在制备型的HPLC上,使用Phenomenex Gemini C18 10um,
柱(21.2×250mm).收集含有产物的级分,冻干,得到2.1mg白色固体。
实施例70:
Palm-PEG8-Gly-Gly-D-Tyr-Hyp-Asn-Thr-Phe-Aze-Leu-Arg(Me)-Trp-NH
2(化合物YA-287)的制备
类似实施例24的合成方法,方法得到NH
2-D-Tyr(tBu)-Hyp(tBu)-Asn(Trt)-Thr(tBu)-Phe-Aze-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。按照实施例61步骤1方法分别引入Gly,Gly,PEG8和Palm,得到Palm-PEG8-D-Tyr(tBu)-Hyp(tBu)-Asn(Trt)-Thr(tBu)-Phe-Aze-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。树脂洗涤后干燥。目标多肽用实施例61步骤2方法从树脂上切割下来并脱除保护。粗产物YA-287进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:47/53-37/63,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Xtimate C18,10um,
柱(20×250mm)。收集含有产物的级分,冻干,得到2.4mg白色固体。
实施例71:
Palm-PEG8-Gly-Gly-D-Tyr-Hyp-Asn-Thr-Phe-(D-2Fua)-Leu-Arg(Me)-Trp-NH
2(化合物YA-288)的制备
类似实施例27的合成方法,方法得到NH
2-D-Tyr(tBu)-Hyp(tBu)-Asn(Trt)-Thr(tBu)-Phe-(D-2Fua)-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。按照实施例61步骤1方法分别引入Gly,Gly,PEG8和Palm,得到Palm-PEG8-D-Tyr(tBu)-Hyp(tBu)-Asn(Trt)-Thr(tBu)-Phe-(D-2Fua)-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。树脂洗涤后干燥。目标多肽用实施例61步骤2方法从树脂上切割下来并脱除保护。粗产物YA-288进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:45/55-35/65,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Xtimate C18,10um,
柱(20×250mm)。收集含有产物的级分,冻干,得到13.4mg白色固体。
实施例72:
Hexanoyl-D-Tyr-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2(化合物YA-294)的制备
按照实施例2步骤1方法得到NH
2-D-Tyr(tBu)-Hyp(tBu)-Asn(Trt)-Thr(tBu)-Phe-azaGly-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。按照实施例61步骤1方法分别引入Hexanoyl基团,得到Hexanoyl-Tyr(tBu)-Hyp(tBu)-Asn(Trt)-Thr(tBu)-Phe-A6c-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。树脂洗涤后干燥。目标多肽用实施例61步骤2方法从树脂上切割下来并脱除保护。粗产物YA-294进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:70/30-60/40,使用:洗脱液A:0.05%TFA的水溶液,洗脱液 B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Phenomenex Gemini C18 10um,
柱(21.2×250mm).收集含有产物的级分,冻干,得到6.5mg白色固体。。
实施例73:
Nonanoyl-OEG-D-Tyr-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2(化合物YA-295)的制备
按照实施例2步骤1方法得到NH
2-D-Tyr(tBu)-Hyp(tBu)-Asn(Trt)-Thr(tBu)-Phe-azaGly-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。按照实施例61步骤1方法分别引入OEG,Nonanoyl基团,得到Nonanoyl-OEG-Tyr(tBu)-Hyp(tBu)-Asn(Trt)-Thr(tBu)-Phe-A6c-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。树脂洗涤后干燥。目标多肽用实施例61步骤2方法从树脂上切割下来并脱除保护。粗产物YA-295进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:63/37-53/47,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Utimate C8 10um,
柱(21.2×250mm).收集含有产物的级分,冻干,得到5.5mg白色固体。
实施例74:
Dodecanoyl-PEG4-PEG4-D-Tyr-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2(化合物YA-296)的制备
按照实施例2步骤1方法得到NH
2-D-Tyr(tBu)-Hyp(tBu)-Asn(Trt)-Thr(tBu)-Phe-azaGly-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。按照实施例61步骤1方法分别引入PEG,PEG,Dodecanoyl基团,得到Dodecanoyl-PEG4-PEG4-Tyr(tBu)-Hyp(tBu)-Asn(Trt)-Thr(tBu)-Phe-A6c-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。树脂洗涤后干燥。目标多肽用实施例61步骤2方法从树脂上切割下来并脱除保护。粗产物YA-296进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:60/40-50/50,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Phenomenex Gemini C18,10um,
柱(21.2×250mm)。收集含有产物的级分,冻干,得到14.5mg白色固体。
实施例75:
Palm-D-Tyr-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2(化合物YA-297)的制备
按照实施例2步骤1方法得到NH
2-D-Tyr(tBu)-Hyp(tBu)-Asn(Trt)- Thr(tBu)-Phe-azaGly-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。按照实施例61步骤1方法分别引入Palm基团,得到Palm-Tyr(tBu)-Hyp(tBu)-Asn(Trt)-Thr(tBu)-Phe-A6c-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。树脂洗涤后干燥。目标多肽用实施例61步骤2方法从树脂上切割下来并脱除保护。粗产物YA-297进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:34/66-24/76,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Phenomenex Gemini C18,10um,
柱(21.2×250mm)。收集含有产物的级分,冻干,得到40.0mg白色固体。。
实施例76:
Palm-PEG8-D-Tyr-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2(化合物YA-298)的制备
按照实施例2步骤1方法得到NH
2-D-Tyr(tBu)-Hyp(tBu)-Asn(Trt)-Thr(tBu)-Phe-azaGly-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。按照实施例61步骤1方法分别引入PEG8,Palmitoyl基团,得到Palm-PEG8-D-Tyr(tBu)-Hyp(tBu)-Asn(Trt)-Thr(tBu)-Phe-A6c-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。树脂洗涤后干燥。目标多肽用实施例61步骤2方法从树脂上切割下来并脱除保护。粗产物YA-298进行HPLC分离纯化,进行线性梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:46/54-36/64,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈溶液,在制备型的HPLC上,使用Xtimate C18,10um,
柱(20×250mm)。收集含有产物的级分,冻干,得到16.0mg白色固体。
实施例78:
步骤1:将0.1g商购可得的Rink Amide MBHA树脂(0.5mmol/g)溶胀于DMF中,该树脂用2mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。按照实施例2步骤1方法得到NH
2-D-Tyr(tBu)-Hyp(tBu)-Asn(Trt)-Thr(tBu)-Phe-azaGly-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。树脂用DMF洗涤,加入4-(pyridin-2-yldisulfaneyl)butanoic acid(34mg,0.15mmol),HATU(57mg,0.15mmol),HOAt(20mg,0.15mmol)的2.5mL DMF溶液,然后加入DIPEA(53μL,0.3mmol),室温下处理2小时,树脂用DMF洗涤,得到 4-(Pyridin-2-yldisulfaneyl)butanoyl-D-Tyr(tBu)-Hyp(tBu)-Asn(Trt)-Thr(tBu)-Phe-azaGly-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。向树脂中加入NH
2-PEG5-SH的盐酸盐(33mg,0.1mmol)的2..0mL DMF溶液,室温下处理36小时,树脂用DMF洗涤,得到NH
2-PEG5-S-S-butanoyl-D-Tyr(tBu)-Hyp(tBu)-Asn(Trt)-Thr(tBu)-Phe-azaGly-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。得到的树脂,加入Dodecanoic acid(30mg,0.15mmol),HATU(57mg,0.15mmol),HOAt(20mg,0.15mmol)的2.5mL DMF溶液,然后加入DIPEA(53μL,0.3mmol),室温下处理40分钟,树脂用DMF,DCM,甲醇和甲基叔丁基醚洗涤,然后抽干,得到Dodecanoyl-
-D-Tyr(tBu)-Hyp(tBu)-Asn(Trt)-Thr(tBu)-Phe-azaGly-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂.
步骤2:将干燥的树脂加入4mL的TFA/TIS/phenol/H
2O(94/2/2/2)溶液中,该混合物搅拌2小时,过滤除去树脂,用1mL的TFA/TIS/phenol/H
2O(94/2/2/2)溶液洗涤树脂。合并滤液,向滤液中加入冰甲基叔丁基醚(20mL),得到的混合物在3000转/分钟离心3分钟,固体用冰乙醚洗涤两次,并抽干。得到的沉淀用DMF溶解,然后进行线性浓度梯度洗脱(11分钟),流速为25mL/分钟,洗脱液A/B:53/47-43/57使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈,在制备型的HPLC上,使用Xtimate 10u,
柱(20mm×250mm).收集含有产物的级分,冻干,得到2.7mg白色固体。
实施例79:
Ac-(D-Tyr)-Hyp-Asn-Thr-Phe-azaG-Leu-Arg(Me)-Trp-2H-tetrazol-5-yl(化合物YA-250)的制备
将1.1g商购可得的2-CTC树脂(1.36mmol/g)溶胀于DCM(10mL)中,加入Fmoc-Arg(Me,Pbf)-OH(332mg,0.5mmol)和DIPEA(387mg,3mmol),室温下处理3小时,然后加入甲醇(1.5mL),振荡1小时,封端没有反应的树脂。过滤,树脂用DCM洗涤。得到的Fmoc-Arg(Me,Pbf)-CTC树脂用5mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入第二个氨基酸Fmoc-Phe-azaGly-Leu-OH(335mg,0.6mmol),HATU(456mg,1.2mmol),HOBt(162mg,1.2mmol)的10mL DMF溶液,然后加入DIPEA(310mg,2.4mmol),室温下处理1小时,树脂用DMF洗涤,得到Fmoc-Phe-azaGly-Leu-Arg(Me,Pbf)-CTC树脂。以类似的方式依次将其他氨基酸Fmoc-Thr(
tBu)-OH,Fmoc-Asn(Trt)-OH,Fmoc-Hyp(tBu)-OH,Fmoc-D-Tyr(tBu)-OH)引入,得 到Fmoc-D-Tyr(tBu)-Hyp(tBu)-Asn(Trt)-Thr(tBu)-Phe-azaG-Leu-Arg(Me,Pbf)-CTC树脂。该树脂用5mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。树脂用DMF洗涤,加入DIPEA(3096mg,24mmol)的10mL DMF溶液,然后加入(Ac)
2O(816mg,8mmol),室温下处理30分钟,重复一遍此操作。树脂用DMF,DCM,甲醇和甲基叔丁基醚洗涤,然后抽干,最终得到Ac-D-Tyr(tBu)-Hyp(tBu)-Asn(Trt)-Thr(tBu)-Phe-azaG-Leu-Arg(Me,Pbf)-CTC树脂。
将干燥的1346mg树脂加入10mL的HFIP/DCM(3/7)溶液中,该混合物搅拌2小时,过滤除去树脂。滤液浓缩,得到全保护的多肽Ac-D-Tyr(tBu)-Hyp(tBu)-Asn(Trt)-Thr(tBu)-Phe-azaG-Leu-Arg(Me,Pbf)-OH(63mg,0.037mmol)。将粗品肽溶于DCM(10mL),然后加入HATU(21mg,0.055mmol),DIPEA(14mg,0.11mmol)和(S)-2-(1H-indol-3-yl)-1-(2H-tetrazol-5-yl)ethanamine(化合物YA-250-d,17mg,0.074mmol),室温搅拌4小时。向反应液中加入水(5mL),水层用DCM萃取,合并的有机相水洗,无水硫酸钠干燥,浓缩,得到全保护的酰胺(100mg),不经纯化直接用于下一步反应。
将得到的酰胺粗品加入到10mL的TFA/EDT/TIS/H
2O(92/2/2/2)溶液中,该混合物搅拌2小时,向溶液中加入冰乙醚(100mL),得到的混合物在3000转/分钟离心1分钟,除去上层液,固体用乙醚洗涤2次,并抽干。得到的沉淀用DMF溶解,然后进行线性浓度梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:69/31-64/36,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈,在制备型的HPLC上,使用Phenomenex10μm,
柱(21.2mm×250mm)。收集含有产物的级分,冻干,得到化合物YA-250-A(1.8mg)白色固体和化合物YA-250-B(0.4mg)白色固体。
实施例80:
Ac-(D-Tyr)-Hyp-Asn-Thr-Phe-ψ(NHCS)Gly-Leu-Arg(Me)-Trp-NH2(化合物YA-254)的制备
将313mg商购可得的Rink Amide MBHA树脂(0.32mmol/g)溶胀于DMF中,该树脂用5mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Fmoc-Trp(Boc)-OH(158mg,0.3mmol),HATU(114mg,0.3mmol),HOAt(41mg,0.3mmol)的5mL DMF溶液,然后加入DIPEA(77mg,0.6mmol),室温下处理40分钟,向其中引入Trp(Boc),得到Fmoc-Trp(Boc)-Rink Amide MBHA树脂。树脂用5mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Fmoc-Arg(Me,Pbf)-OH(99mg,0.15mmol),HATU(57mg,0.15mmol),HOAt(21mg,0.15 mmol)的5mL DMF溶液,然后加入DIPEA(39mg,0.3mmol),室温下处理1小时,树脂用DMF洗涤,得到Fmoc-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。以类似的方式将其他氨基酸Fmoc-Phe-ψ(NHCS)Gly-Leu-OH,Fmoc-Thr(OtBu)-OH,Fmoc-Asn(Trt)-OH,Fmoc-Hyp(OtBu)-OH,Fmoc-[D-Tyr(OtBu)]-OH引入,得到Fmoc-[D-Tyr(OtBu)]-Hyp(OtBu)-Asn(Trt)-Thr(OtBu)-Phe-ψ(NHCS)Gly-Leu-Arg(Me)-Trp(Boc)-Rink Amide MBHA树脂。该树脂用5mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。树脂用DMF洗涤,加入冰醋酸(36mg,0.6mmol),HBTU(227mg,0.6mmol),HOBt(81mg,0.6mmol)的5mL DMF溶液,然后加入DIPEA(155mg,1.2mmol),室温下处理40分钟,树脂用DMF,DCM,甲醇和甲基叔丁基醚洗涤,然后抽干,得到Ac-[D-Tyr(OtBu)]-Hyp(OtBu)-Asn(Trt)-Thr(OtBu)-Phe-ψ(NHCS)Gly-Leu-Arg(Me)-Trp(Boc)-Rink Amide MBHA树脂。
将干燥的树脂加入10mL的TFA/TIS/H
2O(92/4/4)溶液中,该混合物搅拌2小时,过滤除去树脂,用1mL的TFA/TIS/H
2O(92/4/4)溶液洗涤树脂。合并滤液,向滤液中加入甲基叔丁基醚(110mL),得到的混合物在3000转/分钟离心1分钟,固体用冰乙醚洗涤两次,并抽干。得到的沉淀用DMF溶解,然后进行线性浓度梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:75/25-65/35使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈,在制备型的HPLC上,使用Xtimate 10μm,
柱(20×250mm)。收集含有产物的级分(相同分子量的两个峰中保留时间靠后的峰),冻干,得到5.0mg白色固体。
实施例81:
Ac-[D-Phe(2,4-DiCl)]-DiFluorPro-Asn-Thr-Phe-ψ(NHCS)Gly-Leu-Arg(Me)-Trp-NH2(化合物YA-255)的制备
将313mg商购可得的Rink Amide MBHA树脂(0.32mmol/g)溶胀于DMF中,该树脂用5mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Fmoc-Trp(Boc)-OH(158mg,0.3mmol),HATU(114mg,0.3mmol),HOAt(41mg,0.3mmol)的5mL DMF溶液,然后加入DIPEA(77mg,0.6mmol),室温下处理40分钟,向其中引入Trp(Boc),得到Fmoc-Trp(Boc)-Rink Amide MBHA树脂。树脂用5mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Fmoc-Arg(Me,Pbf)-OH(99mg,0.15mmol),HATU(57mg,0.15mmol),HOAt(21mg,0.15mmol)的5mL DMF溶液,然后加入DIPEA(39mg,0.3mmol),室温下处理1小时,树 脂用DMF洗涤,得到Fmoc-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。以类似的方式将其他氨基酸Fmoc-Phe-ψ(NHCS)Gly-Leu-OH,Fmoc-Thr(OtBu)-OH,Fmoc-Asn(Trt)-OH,Fmoc-DiFluorPro-OH,Fmoc-[D-Phe(2,4-DiCl)]-OH引入,得到Fmoc-[D-Phe(2,4-DiCl)]-DiFluorPro-Asn(Trt)-Thr(OtBu)-Phe-ψ(NHCS)Gly-Leu-Arg(Me)-Trp(Boc)-Rink Amide MBHA树脂。该树脂用5mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。树脂用DMF洗涤,加入冰醋酸(36mg,0.6mmol),HBTU(227mg,0.6mmol),HOBt(81mg,0.6mmol)的5mL DMF溶液,然后加入DIPEA(155mg,1.2mmol),室温下处理40分钟,树脂用DMF,DCM,甲醇和甲基叔丁基醚洗涤,然后抽干,得到Ac-[D-Phe(2,4-DiCl)]-DiFluorPro-Asn(Trt)-Thr(OtBu)-Phe-ψ(NHCS)Gly-Leu-Arg(Me)-Trp(Boc)-Rink Amide MBHA树脂。
将干燥的树脂加入10mL的TFA/TIS/H
2O(92/4/4)溶液中,该混合物搅拌2小时,过滤除去树脂,用1mL的TFA/TIS/H
2O(92/4/4)溶液洗涤树脂。合并滤液,向滤液中加入甲基叔丁基醚(110mL),得到的混合物在3000转/分钟离心1分钟,固体用冰乙醚洗涤两次,并抽干。得到的沉淀用DMF溶解,然后进行线性浓度梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:64/36-54/46使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈,在制备型的HPLC上,使用Xtimate 10μm,
柱(20×250mm)。收集含有产物的级分(相同分子量的两个峰中保留时间靠后的峰),冻干,得到3.8mg白色固体。
实施例82:
Ac-(D-Tyr)-Hyp-Asn-Thr-Phe-ψ(NH-CO-NH)Gly-Leu-Arg(Me)-Trp-NH2(化合物YA-256)的制备
将617mg商购可得的Rink Amide MBHA(0.324mmol/g)树脂溶胀于DMF中,该树脂用10mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Fmoc-Trp(Boc)-OH(316mg,0.6mmol),HATU(228mg,0.6mmol),HOBt(81mg,0.6mmol)的10mL DMF溶液,然后加入DIPEA(155mg,1.2mmol),室温下处理40分钟,树脂用DMF洗涤,得到Fmoc-Trp(Boc)-Rink Amide MBHA树脂。树脂用10mL20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。以类似的方式将其他氨基酸(Fmoc-Arg(Me,Pbf)-OH,Fmoc-Phe-ψ(NH-CO-NH)Gly-Leu-OH,Fmoc-Thr(
tBu)-OH,Fmoc-Asn(Trt)-OH,Fmoc-Hyp(
tBu)-OH,Fmoc-D-Tyr(tBu)-OH引入得到Fmoc-D-Tyr(tBu)-Hyp(tBu)-Asn(Trt)-Thr(tBu)-Phe-ψ(NH-CO-NH)Gly-Leu-Arg(Me, Pbf)-Trp(Boc)-Rink Amide MBHA树脂。该树脂用10mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。树脂用DMF洗涤,加入DIPEA(774mg,6mmol)的10mL DMF溶液,然后加入(Ac)
2O(204mg,2mmol),室温下处理30分钟,重复一遍此操作。树脂用DMF,DCM,甲醇和甲基叔丁基醚洗涤,然后抽干,得到Ac-D-Tyr(tBu)-Hyp(tBu)-Asn(Trt)-Thr(tBu)-Phe-ψ(NH-CO-NH)Gly-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。
将干燥的树脂加入10mL的TFA/TIS/EDT/H
2O(94/2/2/2)溶液中,该混合物搅拌2小时,过滤除去树脂,用4mL TFA/TIS/EDT/H
2O(94/2/2/2)溶液洗涤树脂。合并滤液,向滤液中加入甲基叔丁基醚(200mL),得到的混合物在3000转/分钟离心1分钟,固体用冰乙醚洗涤两次,并抽干。得到的沉淀用DMF溶解,然后进行线性浓度梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:75/25-69/31,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈,在制备型的HPLC上,使用Welch 10μm,
柱(20×250mm)。收集含有产物的级分,冻干,得到32.8mg白色固体。
实施例83:
Ac-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Pro-Gln-(beta-Ala)-(beta-Ala)-(D-Tyr)-Hyp-Asn-Thr-Phe-azaG-Leu-Arg(Me)-Trp-NH2(化合物YA-291)的制备
将313mg商购可得的Rink Amide MBHA树脂(0.32mmol/g)溶胀于DMF中,该树脂用5mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Fmoc-Trp(Boc)-OH(158mg,0.3mmol),HATU(114mg,0.3mmol),HOAt(41mg,0.3mmol)的5mL DMF溶液,然后加入DIPEA(77mg,0.6mmol),室温下处理40分钟,向其中引入Trp(Boc),得到Fmoc-Trp(Boc)-Rink Amide MBHA树脂。树脂用5mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Fmoc-Arg(Me,Pbf)-OH(99mg,0.15mmol),HATU(57mg,0.15mmol),HOAt(21mg,0.15mmol)的5mL DMF溶液,然后加入DIPEA(39mg,0.3mmol),室温下处理1小时,树脂用DMF洗涤,得到Fmoc-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。以类似的方式将其他氨基酸Fmoc-Phe-azaG-Leu-OH,Fmoc-Thr(OtBu)-OH,Fmoc-Asn(Trt)-OH,Fmoc-Hyp(OtBu)-OH,Fmoc-[D-Tyr(OtBu)]-OH,Fmoc-beta-Ala-OH,Fmoc-beta-Ala-OH,Fmoc-Gln(Trt)-OH,Fmoc-Pro-OH,Fmoc-Arg(Pbf)-OH,Fmoc-Arg(Pbf)-OH,Fmoc-Arg(Pbf)-OH,Fmoc-Gln(Trt)-OH,Fmoc-Arg(Pbf)-OH,Fmoc-Arg(Pbf)-OH,Fmoc-Lys(Boc)-OH,FMoc-Lys(Boc)-OH,Fmoc-Arg(Pbf)-OH,Fmoc-Gly-OH引入,得到Fmoc-Gly-Arg(Pbf)-Lys(Boc)-Lys(Boc)-Arg(Pbf)- Arg(Pbf)-GlnTrt)-Arg(Pbf)-Arg(Pbf)-Arg(Pbf)-Pro-Gln(Trt)-(beta-Ala)-(beta-Ala)-[D-Tyr(OtBul)]-Hyp(OtBu)-Asn(Trt)-Thr(OtBu)-Phe-azaG-Leu-Arg(Me)-Trp(Boc)-Rink Amide MBHA树脂。该树脂用5mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。树脂用DMF洗涤,加入冰醋酸(36mg,0.6mmol),HBTU(227mg,0.6mmol),HOBt(81mg,0.6mmol)的5mL DMF溶液,然后加入DIPEA(155mg,1.2mmol),室温下处理40分钟,树脂用DMF,DCM,甲醇和甲基叔丁基醚洗涤,然后抽干,得到Ac-Gly-Arg(Pbf)-Lys(Boc)-Lys(Boc)-Arg(Pbf)-Arg(Pbf)-GlnTrt)-Arg(Pbf)-Arg(Pbf)-Arg(Pbf)-Pro-Gln(Trt)-(beta-Ala)-(beta-Ala)-[D-Tyr(OtBul)]-Hyp(OtBu)-Asn(Trt)-Thr(OtBu)-Phe-azaG-Leu-Arg(Me)-Trp(Boc)-Rink Amide MBHA树脂。
将干燥的树脂加入10mL的TFA/TIS/H
2O(92/4/4)溶液中,该混合物搅拌2小时,过滤除去树脂,用1mL的TFA/TIS/H
2O(92/4/4)溶液洗涤树脂。合并滤液,向滤液中加入甲基叔丁基醚(110mL),得到的混合物在3000转/分钟离心1分钟,固体用冰乙醚洗涤两次,并抽干。得到的沉淀用DMF溶解,然后进行线性浓度梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:86/14-76/24使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈,在制备型的HPLC上,使用Phenomenex 10μm,
柱(21.2×250mm)。收集含有产物的级分,冻干,得到6.9mg白色固体。
实施例84:
Ac-(D-Tyr)-Hyp-Asn-Thr-[(S)-2-((2-amino-3-phenylpropyl)amino)-2-oxoacetyl]-Leu-Arg(Me)-Trp-NH
2(化合物YA-302)的制备
将0.4g商购可得的Rink Amide MBHA树脂(0.5mmol/g)溶胀于DMF中,该树脂用5mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Fmoc-Trp(Boc)-OH(0.53g,1mmol),HOBT(0.162g,1.2mmol)和DIC(0.486mL,1.2mmol)的5mL DMF溶液,室温下处理55分钟,树脂用DMF洗涤,得到Fmoc-Trp(Boc)-Rink Amide MBHA树脂。该树脂用5mL 20%哌啶/DMF处理30分钟以除去Fmoc,树脂用DMF洗涤,加入Fmoc-Arg(Me,Pbf)-OH(0.199g,0.3mmol),DIC(0.055mL,0.36mmol)和HOBt(0.048g,0.36mmol)的5mL DMF溶液,室温下反应过夜。该树脂用5mL 20%哌啶/DMF处理30分钟以除去Fmoc,树脂用DMF洗涤,得到Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。得到的树脂,加入Fmoc-Leu-OH(0.35g,1mmol),DIC(0.181mL,1.2mmol)和HOBt(0162g,1.2mmol)的5mL DMF溶液,室温下处理95分钟,树脂用DMF洗涤,该树脂用5mL 20%哌啶/DMF处理30分钟以除去Fmoc,树脂用DMF洗涤,得到NH
2-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。 得到的树脂,加入Fmoc-Thr(tBu)-[(S)-2-((2-amino-3-phenylpropyl)amino)-2-oxoacetyl]-OH(0.18g,0.3mmol),DIC(0.055mL,0.36mmol)和HOBt(0.048g,0.36mmol)的5mL DMF溶液,室温下反应过夜;该树脂用20mL 20%哌啶/DMF处理30分钟以除去Fmoc,树脂用DMF洗涤,得到NH2-Thr(tBu)-[(S)-2-((2-amino-3-phenylpropyl)amino)-2-oxoacetyl]-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。以类似的方式,依次将Asn(Trt),Hyp(tBu),D-Tyr(tBu)等氨基酸引入,树脂用DMF洗涤,得到NH
2-D-Tyr(tBu)-Hyp(tBu)-Asn(Trt)-Thr(tBu)-[(S)-2-((2-amino-3-phenylpropyl)amino)-2-oxoacetyl]--Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。加入AcOH(0.115ml,2mmol),DIC(0.309ml,2mmol)的5mL DMF溶液,室温下反应25分钟,引入Ac基团。树脂用DMF,DCM,甲醇,甲基叔丁基醚洗涤,然后抽干,最终得到Ac-D-Tyr(tBu)-Hyp(tBu)-Asn(Trt)-Thr(tBu)-[(S)-2-((2-amino-3-phenylpropyl)amino)-2-oxoacetyl]-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。
将干燥的树脂加入6mL的TFA/TIS/Phenol/H
2O(88/2/5/5)溶液中,该混合物搅拌2小时,过滤除去树脂,用2mL的TFA/TIS/Phenol/H
2O(88/2/5/5)溶液洗涤树脂。合并滤液,向滤液中加入乙醚(80mL),得到的混合物在3000转/分钟离心1分钟,除去上层液,固体用乙醚洗涤2次,并抽干。得到的沉淀用DMF溶解,然后进行线性浓度梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:75/25-65/35,使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈,在制备型的HPLC上,使用Phenomenex Gemini 10μm,
柱(21.2×250mm)。收集含有产物的级分,冻干,得到43.5mg三氟乙酸盐,为白色固体。
实施例85:
Ac-(D-Tyr)-Hyp-Asn-Thr-Phe-ψ(NHCO)Gly-Leu-Arg(Me)-Trp-NH2(化合物YA-303)的制备
将940mg商购可得的Rink Amide MBHA树脂(0.32mmol/g)溶胀于DMF中,该树脂用10mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Fmoc-Trp(Boc)-OH(474mg,0.9mmol),HATU(342mg,0.9mmol),HOAt(122mg,0.9mmol)的10mL DMF溶液,然后加入DIPEA(232mg,1.8mmol),室温下处理40分钟,向其中引入Trp(Boc),得到Fmoc-Trp(Boc)-Rink Amide MBHA树脂。树脂用10mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Fmoc-Arg(Me,Pbf)-OH(298mg,0.45mmol),HATU(171mg,0.45mmol),HOAt (61mg,0.45mmol)的10mL DMF溶液,然后加入DIPEA(116mg,0.9mmol),室温下处理1小时,树脂用DMF洗涤,得到Fmoc-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。以类似的方式将其他氨基酸Fmoc-Phe-ψ(NHCO)Gly-Leu-OH,Fmoc-Thr(OtBu)-OH,Fmoc-Asn(Trt)-OH,Fmoc-Hyp(OtBu)-OH,Fmoc-[D-Tyr(OtBu)]-OH]引入,得到Fmoc-[D-Tyr(OtBu)]-Hyp(OtBu)-Asn(Trt)-Thr(OtBu)-Phe-ψ(NHCO)Gly-Leu-Arg(Me)-Trp(Boc)-Rink Amide MBHA树脂。该树脂用10mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。树脂用DMF洗涤,加入冰醋酸(108mg,1.8mmol),HBTU(671mg,1.8mmol),HOBt(243mg,1.8mmol)的10mL DMF溶液,然后加入DIPEA(465mg,3.6mmol),室温下处理40分钟,树脂用DMF,DCM,甲醇和甲基叔丁基醚洗涤,然后抽干,得到Ac-[D-Tyr(OtBu)]-Hyp(OtBu)-Asn(Trt)-Thr(OtBu)-Phe-ψ(NHCO)Gly-Leu-Arg(Me)-Trp(Boc)-Rink Amide MBHA树脂。
将干燥的树脂加入20mL的TFA/TIS/H
2O(92/4/4)溶液中,该混合物搅拌2小时,过滤除去树脂,用2mL的TFA/TIS/H
2O(92/4/4)溶液洗涤树脂。合并滤液,向滤液中加入甲基叔丁基醚(220mL),得到的混合物在3000转/分钟离心1分钟,固体用冰乙醚洗涤两次,并抽干。得到的沉淀用DMF溶解,然后进行线性浓度梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:75/25-72/28使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈,在制备型的HPLC上,使用Phenomenex 10μm,
柱(21.2×250mm)。收集含有产物的级分,冻干,分别得到白色固体20.2mg,保留时间为13.11min。
实施例86:
Dodecanoyl-(NH-PEG5-CH
2CH
2S)-(4-thiol-butanoyl)-(D-Tyr)-Hyp-Asn-Thr-Phe-azaG-Leu-Arg(Me)-Trp-NH
2(化合物YA-324)的制备
将0.1g商购可得的Rink Amide MBHA树脂(0.5mmol/g)溶胀于DMF中,该树脂用2mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Fmoc-Trp(Boc)-OH(79mg,0.15mmol),HBTU(57mg,0.15mmol),HOBt(20mg,0.15mmol)的2.5mL DMF溶液,然后加入DIPEA(39mg,0.3mmol),室温下处理40分钟,树脂用DMF洗涤,得到Fmoc-Trp(Boc)-Rink Amide MBHA树脂。该树脂用2mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作,树脂用DMF洗涤,加入Fmoc-Arg(Me,Pbf)-OH(97.3mg,0.15mmol),HATU(57mg,0.15mmol),HOAt(20mg,0.15mmol)的2.5mL DMF溶液,然后加入DIPEA(39mg,0.3mmol),室温下处理1小 时,树脂用DMF洗涤,得到Fmoc-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。该树脂用2mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作,树脂用DMF洗涤,加入Fmoc-Phe-azaGly-Leu-OH(56mg,0.1mmol),HATU(57mg,0.15mmol),HOAt(20mg,0.15mmol)的2.5mL DMF溶液,然后加入DIPEA(39mg,0.3mmol),室温下处理1小时,树脂用DMF洗涤,得到Fmoc-Phe-azaG-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。以类似的方式,依次将Thr(OtBu),Asn(Trt),Hyp(OtBu),D-Tyr(OtBu)等氨基酸引入,得到Fmoc-[D-Tyr(OtBu)]-Hyp(OtBu)-Asn(Trt)-Thr(OtBu)-Phe-azaG-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。该树脂用2mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作,树脂用DMF洗涤,加入4-(pyridin-2-yldisulfaneyl)butanoic acid(34mg,0.15mmol),HATU(57mg,0.15mmol),HOAt(20mg,0.15mmol)的2.5mL DMF溶液,然后加入DIPEA(39mg,0.3mmol),室温下处理2小时,树脂用DMF洗涤,得到4-(pyridin-2-yldisulfaneyl)butanoyl-NH-[D-Tyr(OtBu)]-Hyp(OtBu)-Asn(Trt)-Thr(OtBu)-Phe-azaG-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。得到的树脂,加入NH
2-PEG5-CH
2CH
2SH的盐酸盐(33mg,0.1mmol)的2.0mL DMF溶液,室温下处理36小时,树脂用DMF洗涤,得到NH
2-PEG5-CH
2CH
2S-(4-thiol-butanoyl)-NH-[D-Tyr(OtBu)]-Hyp(OtBu)-Asn(Trt)-Thr(OtBu)-Phe-azaG-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。得到的树脂,加入月桂酸(30mg,0.15mmol),HATU(57mg,0.15mmol),HOAt(20mg,0.15mmol)的2.5mL DMF溶液,然后加入DIPEA(39mg,0.3mmol),室温下处理40分钟,树脂用DMF,DCM,甲醇和甲基叔丁基醚洗涤,然后抽干,得到Dodecanoyl-(NH-PEG5-CH
2CH
2S)-(4-thiol-butanoyl)-[D-Tyr(OtBu)]-Hyp(OtBu)-Asn(Trt)-Thr(OtBu)-Phe-azaG-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。
将干燥的树脂加入4mL的TFA/TIS/phenol/H
2O(94/2/2/2)溶液中,该混合物搅拌2小时,过滤除去树脂,用1mL的TFA/TIS/phenol/H
2O(94/2/2/2)溶液洗涤树脂。合并滤液,向滤液中加入甲基叔丁基醚(50mL),得到的混合物在3000转/分钟离心1分钟,固体用冰乙醚洗涤两次,并抽干。得到的沉淀用DMF溶解,然后进行线性浓度梯度洗脱(11分钟),流速为25mL/分钟,洗脱液A/B:53/47-43/57使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈,在制备型的HPLC上,使用Welch 10μm,
柱(20×250mm).收集含有产物的级分,冻干,得到2.7mg白色固体。
实施例87:
Dodecanoy-(NH-PEG5-CH
2CH
2S)-(maleimide-butanoyl-)-(D-Tyr)-Hyp-Asn-Thr-Phe-azaG-Leu-Arg(Me)-Trp-NH
2(化合物YA-325)的制备
将0.3g商购可得的Rink Amide MBHA树脂(0.5mmol/g)溶胀于DMF中,该树脂用5mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Fmoc-Trp(Boc)-OH(237mg,0.45mmol),HBTU(171mg,0.45mmol),HOBt(61mg,0.45mmol)的5mL DMF溶液,然后加入DIPEA(116mg,0.9mmol),室温下处理40分钟,树脂用DMF洗涤,得到Fmoc-Trp(Boc)-Rink Amide MBHA树脂。该树脂用5mL20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作,树脂用DMF洗涤,加入Fmoc-Arg(Me,Pbf)-OH(199mg,0.3mmol),HATU(114mg,0.3mmol),HOAt(41mg,0.3mmol)的5mL DMF溶液,然后加入DIPEA(77mg,0.6mmol),室温下处理1小时,树脂用DMF洗涤,得到Fmoc-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。该树脂用5mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作,树脂用DMF洗涤,加入Fmoc-Phe-azaG-Leu-OH(168mg,0.3mmol),HATU(114mg,0.3mmol),HOAt(41mg,0.3mmol)的5mL DMF溶液,然后加入DIPEA(77mg,0.6mmol),室温下处理1小时,树脂用DMF洗涤,得到Fmoc-Phe-azaG-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。以类似的方式,依次将Thr(OtBu),Asn(Trt),Hyp(OtBu),D-Tyr(OtBu)等氨基酸引入,得到Fmoc-[D-Tyr(OtBu)]-Hyp(OtBu)-Asn(Trt)-Thr(OtBu)-Phe-azaG-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。该树脂用5mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作,树脂用DMF洗涤,加入4-Maleimidobutyric acid(82mg,0.45mmol),HATU(171mg,0.45mmol),HOAt(61mg,0.45mmol)的5mL DMF溶液,然后加入DIPEA(116mg,0.9mmol),室温下处理40分钟,树脂用DMF洗涤,得到4-Maleimide-butanoyl-NH-[D-Tyr(OtBu)]-Hyp(OtBu)-Asn(Trt)-Thr(OtBu)-Phe-azaG-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。得到的树脂,加入NH
2-PEG5-CH
2CH
2SH的盐酸盐(99mg,0.3mmol)的5.0mL DMF溶液,室温下处理16小时,树脂用DMF洗涤,得到NH
2-PEG5-CH
2CH
2S-(4-maleimide-butanoyl)-NH-[D-Tyr(OtBu)]-Hyp(OtBu)-Asn(Trt)-Thr(OtBu)-Phe-azaG-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。得到的树脂,加入Dodecanoic acid(90mg,0.45mmol),HATU(171mg,0.45mmol),HOAt(61mg,0.45mmol)的5mL DMF溶液,然后加入DIPEA(116mg,0.9mmol),室温下处理1小时,树脂用DMF,DCM,甲醇和甲基叔丁基醚洗涤,然后抽干,得到Dodecanoyl-(NH-PEG5-CH
2CH
2S)-(4-maleimide-butanoyl)- [D-Tyr(OtBu)]-Hyp(OtBu)-Asn(Trt)-Thr(OtBu)-Phe-azaGly-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂.
将干燥的树脂加入10mL的TFA/TIS/phenol/H
2O(94/2/2/2)溶液中,该混合物搅拌2小时,过滤除去树脂,用2mL的TFA/TIS/phenol/H
2O(94/2/2/2)溶液洗涤树脂。合并滤液,向滤液中加入甲基叔丁基醚(120mL),得到的混合物在3000转/分钟离心1分钟,固体用冰乙醚洗涤两次,并抽干。得到的沉淀用DMF溶解,然后进行线性浓度梯度洗脱(11分钟),流速为25mL/分钟,洗脱液A/B:58/42-48/52使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈,在制备型的HPLC上,使用Xtimate 10μm,
柱(20mm×250mm)。收集含有产物的级分,冻干,得到11.6mg白色固体。
实施例88:
Dodecanoyl-NH-PEG5-1,2,3-Triazole-cyclic-butanoyl-(D-Tyr)-Hyp-Asn-Thr-Phe-azaG-Leu-Arg(Me)-Trp-NH2(化合物YA-326)的制备
将0.3g商购可得的Rink Amide MBHA树脂(0.5mmol/g)溶胀于DMF中,该树脂用5mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Fmoc-Trp(Boc)-OH(237mg,0.45mmol),HBTU(171mg,0.45mmol),HOBt(61mg,0.45mmol)的5mL DMF溶液,然后加入DIPEA(116mg,0.9mmol),室温下处理40分钟,树脂用DMF洗涤,得到Fmoc-Trp(Boc)-Rink Amide MBHA树脂。该树脂用5mL20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作,树脂用DMF洗涤,加入Fmoc-Arg(Me,Pbf)-OH(199mg,0.3mmol),HATU(114mg,0.3mmol),HOAt(41mg,0.3mmol)的5mL DMF溶液,然后加入DIPEA(77mg,0.6mmol),室温下处理1小时,树脂用DMF洗涤,得到Fmoc-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。该树脂用5mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作,树脂用DMF洗涤,加入Fmoc-Phe-azaG-Leu-OH(168mg,0.3mmol),HATU(114mg,0.3mmol),HOAt(41mg,0.3mmol)的5mL DMF溶液,然后加入DIPEA(77mg,0.6mmol),室温下处理1小时,树脂用DMF洗涤,得到Fmoc-Phe-azaGly-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。以类似的方式,依次将Thr(OtBu),Asn(Trt),Hyp(OtBu),D-Tyr(OtBu)等氨基酸引入,得到Fmoc-[D-Tyr(OtBu)]-Hyp(OtBu)-Asn(Trt)-Thr(OtBu)-Phe-azaG-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。该树脂用5mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作,树脂用DMF洗涤,加入Dodecanoyl-NH-PEG5-1,2,3-Triazole-cyclic-butanoyl acid(126mg,0.22mmol),HATU(171mg,0.45mmol),HOAt(61mg,0.45mmol)的5mL DMF溶液,然后加入DIPEA(116mg,0.9mmol),室温下处理2 小时,树脂用DMF,DCM,甲醇和甲基叔丁基醚洗涤,然后抽干,得到Dodecanoyl-NH-PEG5-1,2,3-Triazole-cyclic-butanoyl-[D-Tyr(OtBu)]-Hyp(OtBu)-Asn(Trt)-Thr(OtBu)-Phe-azaG-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。
将干燥的树脂加入10mL的TFA/TIS/phenol/H
2O(94/2/2/2)溶液中,该混合物搅拌2小时,过滤除去树脂,用2mL的TFA/TIS/phenol/H
2O(94/2/2/2)溶液洗涤树脂。合并滤液,向滤液中加入甲基叔丁基醚(120mL),得到的混合物在3000转/分钟离心1分钟,固体用冰乙醚洗涤两次,并抽干。得到的沉淀用DMF溶解,然后进行线性浓度梯度洗脱(11分钟),流速为25mL/分钟,洗脱液A/B:59/41-49/51使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈,在制备型的HPLC上,使用Xtimate 10μm,
柱(20×250mm).收集含有产物的级分,冻干,得到15.5mg白色固体。
实施例89:
Ac-(D-Phe(2,4-DiCl))-HoPro-Asn-Thr-Phe-ψ(NHCO)Gly-Leu-Arg(Me)-Trp-NH2(化合物YA-332)的制备
将0.2g商购可得的Rink Amide MBHA树脂(0.5mmol/g)溶胀于DMF中,该树脂用3mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Fmoc-Trp(Boc)-OH(158mg,0.3mmol),HATU(114mg,0.3mmol),HOAt(27mg,0.3mmol)的2.5mL DMF溶液,然后加入DIPEA(78mg,0.6mmol),室温下处理40分钟,树脂用DMF洗涤,得到Fmoc-Trp(Boc)-Rink Amide MBHA树脂。该树脂用3mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作,树脂用DMF洗涤,加入Fmoc-Arg(Me,Pbf)-OH(80mg,0.12mmol),DIC(19mg,0.15mmol)的2.5mL DMF溶液,室温下处理16小时,树脂用DMF洗涤,得到Fmoc-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。该树脂用3mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作,树脂用DMF洗涤,加入Fmoc-Phe-ψ(NHCO)Gly-Leu-OH(87mg,0.15mmol),HATU(114mg,0.3mmol),HOAt(27mg,0.3mmol)的2.5mL DMF溶液,然后加入DIPEA(78mg,0.6mmol),室温下处理1小时,树脂用DMF洗涤,得到Fmoc-Phe-ψ(NHCO)Gly-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。以类似的方式,依次将Thr(tBu),Asn(Trt),HoPro,D-Phe(2,4-DiCl)等氨基酸引入,得到Fmoc-[D-Phe(2,4-DiCl)]-HoPro-Asn(Trt)-Thr(tBu)-Phe-ψ(NHCO)Gly-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。该树脂用3mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作,树脂用DMF洗涤,加入AcOH(18mg,0.3mmol),DIC(38mg, 0.3mmol)和HOBt(41mg,0.3mmol)的2.5mL DMF溶液,室温下反应过夜,引入Ac基团。树脂用DMF,DCM,甲醇,甲基叔丁基醚洗涤,然后抽干,最终得到Ac-[D-Phe(2,4-DiCl)]-HoPro-Asn(Trt)-Thr(tBu)-Phe-ψ(NHCO)Gly-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。
将干燥的树脂加入4mL的TFA/TIS/phenol/H
2O(94/2/2/2)溶液中,该混合物搅拌2小时,过滤除去树脂,用1mL的TFA/TIS/phenol/H
2O(94/2/2/2)溶液洗涤树脂。合并滤液,向滤液中加入甲基叔丁基醚(50mL),得到的混合物在3000转/分钟离心1分钟,固体用冰乙醚洗涤两次,并抽干。得到的沉淀用DMF溶解,然后进行线性浓度梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:63/37-53/47使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈,在制备型的HPLC上,使用Utimate 10μm,
柱(21.2×250mm).收集含有产物的级分,冻干,得到9.0mg白色固体。
实施例90:
Ac-[3-(2-furyl)-D-Ala]-HoPro-Asn-Thr-Phe-ψ(NHCO)Gly-Leu-Arg(Me)-Trp-NH
2(化合物YA-333)的制备
将0.2g商购可得的Rink Amide MBHA树脂(0.5mmol/g)溶胀于DMF中,该树脂用3mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Fmoc-Trp(Boc)-OH(158mg,0.3mmol),HATU(114mg,0.3mmol),HOAt(27mg,0.3mmol)的2.5mL DMF溶液,然后加入DIPEA(78mg,0.6mmol),室温下处理40分钟,树脂用DMF洗涤,得到Fmoc-Trp(Boc)-Rink Amide MBHA树脂。该树脂用3mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作,树脂用DMF洗涤,加入Fmoc-Arg(Me,Pbf)-OH(80mg,0.12mmol),DIC(19mg,0.15mmol)的2.5mL DMF溶液,室温下处理16小时,树脂用DMF洗涤,得到Fmoc-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。该树脂用3mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作,树脂用DMF洗涤,加入Fmoc-Phe-ψ(NHCO)Gly-Leu-OH(87mg,0.15mmol),HATU(114mg,0.3mmol),HOAt(27mg,0.3mmol)的2.5mL DMF溶液,然后加入DIPEA(78mg,0.6mmol),室温下处理1小时,树脂用DMF洗涤,得到Fmoc-Phe-ψ(NHCO)Gly-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。以类似的方式,依次将Thr(OtBu),Asn(Trt),HoPro,3-(2-furyl)-D-alanine等氨基酸引入,得到Fmoc-[3-(2-furyl)-D-Ala]-HoPro-Asn(Trt)-Thr(OtBu)-Phe-ψ(NHCO)Gly-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。该树脂用3mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作,树脂用DMF洗涤,加入AcOH(18mg,0.3mmol),DIC(38mg, 0.3mmol)和HOBt(41mg,0.3mmol)的2.5mL DMF溶液,室温下反应过夜,引入Ac基团。树脂用DMF,DCM,甲醇,甲基叔丁基醚洗涤,然后抽干,最终得到Ac-[3-(2-furyl)-D-Ala]-HoPro-Asn(Trt)-Thr(OtBu)-Phe-ψ(NHCO)Gly-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。
将干燥的树脂加入4mL的TFA/TIS/phenol/H
2O(94/2/2/2)溶液中,该混合物搅拌2小时,过滤除去树脂,用1mL的TFA/TIS/phenol/H
2O(94/2/2/2)溶液洗涤树脂。合并滤液,向滤液中加入甲基叔丁基醚(50mL),得到的混合物在3000转/分钟离心1分钟,固体用冰乙醚洗涤两次,并抽干。得到的沉淀用DMF溶解,然后进行线性浓度梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:69/31-59/41使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈,在制备型的HPLC上,使用Ultimate C8,10μm,
柱(21.2mm×250mm).收集含有产物的级分,冻干,得到5.9mg白色固体。
实施例91:
Ac-[D-Phe(2,4-DiCl)]-DiFluoroPro-Asn-Thr-Phe-ψ(NHCO)Gly-Leu-Arg(Me)-Trp-NH
2(化合物YA-334)的制备
将0.2g商购可得的Rink Amide MBHA树脂(0.5mmol/g)溶胀于DMF中,该树脂用3mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Fmoc-Trp(Boc)-OH(158mg,0.3mmol),HATU(114mg,0.3mmol),HOAt(27mg,0.3mmol)的2.5mL DMF溶液,然后加入DIPEA(78mg,0.6mmol),室温下处理40分钟,树脂用DMF洗涤,得到Fmoc-Trp(Boc)-Rink Amide MBHA树脂。该树脂用3mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作,树脂用DMF洗涤,加入Fmoc-Arg(Me,Pbf)-OH(80mg,0.12mmol),DIC(19mg,0.15mmol)的2.5mL DMF溶液,室温下处理16小时,树脂用DMF洗涤,得到Fmoc-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。该树脂用3mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作,树脂用DMF洗涤,加入Fmoc-Phe-ψ(NHCO)Gly-Leu-OH(87mg,0.15mmol),HATU(114mg,0.3mmol),HOAt(27mg,0.3mmol)的2.5mL DMF溶液,然后加入DIPEA(78mg,0.6mmol),室温下处理1小时,树脂用DMF洗涤,得到Fmoc-Phe-ψ(NHCO)Gly-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。以类似的方式,依次将Thr(OtBu),Asn(Trt),DiFluoroPro,D-Phe(2,4-DiCl)等氨基酸引入,得到Fmoc-(D-Phe(2,4-DiCl))-DiFluoroPro-Asn(Trt)-Thr(OtBu)-Phe-ψ(NHCO)Gly-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。该树脂用3mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作,树脂用DMF洗涤,加入AcOH(18mg,0.3mmol),DIC(38mg, 0.3mmol)和HOBt(41mg,0.3mmol)的2.5mL DMF溶液,室温下反应过夜,引入Ac基团。树脂用DMF,DCM,甲醇,甲基叔丁基醚洗涤,然后抽干,最终得到Ac-[D-Phe(2,4-DiCl)]-DiFluoroPro-Asn(Trt)-Thr(OtBu)-Phe-ψ(NHCO)Gly-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。
将干燥的树脂加入4mL的TFA/TIS/phenol/H
2O(94/2/2/2)溶液中,该混合物搅拌2小时,过滤除去树脂,用1mL的TFA/TIS/phenol/H
2O(94/2/2/2)溶液洗涤树脂。合并滤液,向滤液中加入甲基叔丁基醚(50mL),得到的混合物在3000转/分钟离心1分钟,固体用冰乙醚洗涤两次,并抽干。得到的沉淀用DMF溶解,然后进行线性浓度梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:64/36-54/46使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈,在制备型的HPLC上,使用Welche C8,10μm,
柱(20.0mm×250mm).收集含有产物的级分,冻干,得到16.1mg白色固体。
实施例92:
Dodecanoyl-(NH-PEG5-)-(1,2,3-Triazole-cyclic-butanoyl)-(D-Tyr)-Hyp-Asn-Thr-Phe-ψ(NHCS)Gly-Leu-Arg(Me)-Trp-NH2(化合物YA-348)的制备
将3.13g商购可得的Rink Amide MBHA树脂(0.32mmol/g)溶胀于DMF中,该树脂用30mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Fmoc-Trp(Boc)-OH(1.58g,3.0mmol),HATU(1.14g,3.0mmol),HOAt(410mg,3.0mmol)的30mL DMF溶液,然后加入DIPEA(774mg,6.0mmol),室温下处理40分钟,向其中引入Trp(Boc),得到Fmoc-Trp(Boc)-Rink Amide MBHA树脂。树脂用30mL20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Fmoc-Arg(Me,Pbf)-OH(1.99g,3.0mmol),HATU(1.14g,3.0mmol),HOAt(410mg,3.0mmol)的30mL DMF溶液,然后加入DIPEA(774mg,6.0mmol),室温下处理1小时,树脂用DMF洗涤,得到Fmoc-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。以类似的方式将其他氨基酸Fmoc-Phe-ψ(NHCS)Gly-Leu-OH,Fmoc-Thr(OtBu)-OH,Fmoc-Asn(Trt)-OH,Fmoc-Hyp(OtBu)-OH,Fmoc-D-Tyr(OtBu)-OH]引入,得到Fmoc-[D-Tyr(OtBu)]-Hyp(OtBu)-Asn(Trt)-Thr(OtBu)-Phe-ψ(NHCS)Gly-Leu-Arg(Me)-Trp(Boc)-Rink Amide MBHA树脂。该树脂用30mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。树脂用DMF洗涤,加入Dodecanoyl-(NH-PEG5-)-(1,2,3-Triazole cyclic-butanoyl-OH(688mg,1.2mmol),HATU(456mg,1.2mmol),HOAt(163mg,1.2mmol)的30mL DMF溶液,然后加入DIPEA(310mg,2.4mmol),室温下处理40分钟,树脂用DMF,DCM, 甲醇和甲基叔丁基醚洗涤,然后抽干,得到Dodecanoyl-(NH-PEG5-)-(1,2,3-Triazolecyclic-butanoyl-[D-Tyr(OtBu)]-Hyp(OtBu)-Asn(Trt)-Thr(OtBu)-Phe-ψ(NHCS)Gly-Leu-Arg(Me)-Trp(Boc)-Rink Amide MBHA树脂。
将干燥的树脂加入40mL的TFA/TIS/H
2O(92/4/4)溶液中,该混合物搅拌2小时,过滤除去树脂,用5mL的TFA/TIS/H
2O(92/4/4)溶液洗涤树脂。合并滤液,向滤液中加入甲基叔丁基醚(450mL),得到的混合物在3000转/分钟离心1分钟,固体用冰乙醚洗涤两次,并抽干。得到的沉淀用DMF溶解,然后进行线性浓度梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:62/38-52/48使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈,在制备型的HPLC上,使用Sunfire 10u,
柱(19×250mm).。收集含有产物的级分,冻干,得到120mg白色固体。
实施例93:
Ac-(D-Tyr)-Hyp-Asn-Thr-Phe-Alg-Gly-Leu-Arg(Me)-Trp-NH2(化合物YA-350)的制备
将625mg商购可得的Rink Amide MBHA树脂(0.32mmol/g)溶胀于DMF中,该树脂用10mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Fmoc-Trp(Boc)-OH(316mg,0.6mmol),HATU(228mg,0.6mmol),HOAt(82mg,0.6mmol)的10mL DMF溶液,然后加入DIPEA(155mg,1.2mmol),室温下处理40分钟,向其中引入Trp(Boc),得到Fmoc-Trp(Boc)-Rink Amide MBHA树脂。树脂用10mL20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Fmoc-Arg(Me,Pbf)-OH(199mg,0.3mmol),HATU(114mg,0.3mmol),HOAt(41mg,0.3mmol)的10mL DMF溶液,然后加入DIPEA(77mg,0.6mmol),室温下处理1小时,树脂用DMF洗涤,得到Fmoc-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。以类似的方式将其他氨基酸Fmoc-Leu-OH,Fmoc-Alg-OH,Fmoc-Phe-OH,Fmoc-Thr(OtBu)-OH,Fmoc-Asn(Trt)-OH,Fmoc-Hyp(OtBu)-OH,Fmoc-D-Tyr(OtBu)-OH引入,得到Fmoc-[D-Tyr(OtBu)]-Hyp(OtBu)-Asn(Trt)-Thr(OtBu)-Phe-Alg-Gly-Leu-Arg(Me)-Trp(Boc)-R ink Amide MBHA树脂。该树脂用10mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。树脂用DMF洗涤,加入冰醋酸(72mg,1.2mmol),HBTU(454mg,1.2mmol),HOBt(162mg,1.2mmol)的10mL DMF溶液,然后加入DIPEA(310mg,2.4mmol),室温下处理40分钟,树脂用DMF,DCM,甲醇和甲基叔丁基醚洗涤,然后抽干,得到Ac-[D-Tyr(OtBu)]-Hyp(OtBu)-Asn(Trt)-Thr(OtBu)-Phe-Alg-Leu-Arg(Me)-Trp(Boc)-Rink Amide MBHA树脂。
将干燥的树脂加入10mL的TFA/TIS/H
2O(92/4/4)溶液中,该混合物搅拌2小时,过滤除去树脂,用1mL的TFA/TIS/H
2O(92/4/4)溶液洗涤树脂。合并滤液,向滤液中加入甲基叔丁基醚(110mL),得到的混合物在3000转/分钟离心1分钟,固体用冰乙醚洗涤两次,并抽干。得到的沉淀用DMF溶解,然后进行线性浓度梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:75/25-65/35使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈,在制备型的HPLC上,使用Sunfire 10μm,
柱(19×250mm)。收集含有产物的级分,冻干,得到32.7mg白色固体。
实施例94:
Palm-PEG8-(D-Tyr)-Hyp-Asn-Thr-Phe-Alg-Gly-Leu-Arg(Me)-Trp-NH2(化合物YA-360)的制备
将625mg商购可得的Rink Amide MBHA树脂(0.32mmol/g)溶胀于DMF中,该树脂用10mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Fmoc-Trp(Boc)-OH(316mg,0.6mmol),HATU(228mg,0.6mmol),HOAt(82mg,0.6mmol)的10mL DMF溶液,然后加入DIPEA(155mg,1.2mmol),室温下处理40分钟,向其中引入Trp(Boc),得到Fmoc-Trp(Boc)-Rink Amide MBHA树脂。树脂用10mL20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Fmoc-Arg(Me,Pbf)-OH(199mg,0.3mmol),HATU(114mg,0.3mmol),HOAt(41mg,0.3mmol)的10mL DMF溶液,然后加入DIPEA(77mg,0.6mmol),室温下处理1小时,树脂用DMF洗涤,得到Fmoc-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。以类似的方式将其他氨基酸Fmoc-Leu-OH,Fmoc-Alg-OH,Fmoc-Phe-OH,Fmoc-Thr(OtBu)-OH,Fmoc-Asn(Trt)-OH,Fmoc-Hyp(OtBu)-OH,Fmoc-D-Tyr(OtBu)-OH,PEG8引入,得到Fmoc-PEG8-[D-Tyr(OtBu)]-Hyp(OtBu)-Asn(Trt)-Thr(OtBu)-Phe-Alg-Gly-Leu-Arg(Me)-Trp(Boc)-Rink Amide MBHA树脂。该树脂用10mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。树脂用DMF洗涤,加入十六烷酸(154mg,0.6mmol),HBTU(228mg,0.6mmol),HOBt(82mg,0.6mmol)的10mL DMF溶液,然后加入DIPEA(155mg,1.2mmol),室温下处理40分钟,树脂用DMF,DCM,甲醇和甲基叔丁基醚洗涤,然后抽干,得到Palm-PEG8-[D-Tyr(OtBu)]-Hyp(OtBu)-Asn(Trt)-Thr(OtBu)-Phe-Alg-Leu-Arg(Me)-Trp(Boc)-Rink Amide MBHA树脂。
将干燥的树脂加入10mL的TFA/TIS/H
2O(92/4/4)溶液中,该混合物搅拌2小时,过滤除去树脂,用1mL的TFA/TIS/H
2O(92/4/4)溶液洗涤树脂。合并滤液,向滤液中加 入甲基叔丁基醚(110mL),得到的混合物在3000转/分钟离心1分钟,固体用冰乙醚洗涤两次,并抽干。得到的沉淀用DMF溶解,然后进行线性浓度梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:50/50-40/60使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈,在制备型的HPLC上,使用Phenomenex 10μm,
柱(21.2×250mm)。收集含有产物的级分,冻干,得到28.5mg白色固体。
实施例95:
Hexadecyl-1,2,3-Triazole-PEG8-Gly-Gly-(D-Tyr)-Hyp-Asn-Thr-Phe-azaG-Leu-Arg(Me)-Trp-NH2(化合物YA-367)的制备
将1.0g商购可得的Rink Amide MBHA树脂(0.31mmol/g)溶胀于DMF中,该树脂用10mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Fmoc-Trp(Boc)-OH(474mg,0.9mmol),HATU(342mg,0.9mmol),HOAt(113mg,0.9mmol)的10mL DMF溶液,然后加入DIPEA(232mg,1.8mmol),室温下处理40分钟,树脂用DMF洗涤,得到Fmoc-Trp(Boc)-Rink Amide MBHA树脂。该树脂用10mL20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作,树脂用DMF洗涤,加入Fmoc-Arg(Me,Pbf)-OH(239mg,0.36mmol),DIC(57mg,0.45mmol)的10mL DMF溶液,室温下处理16小时,树脂用DMF洗涤,得到Fmoc-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。该树脂用10mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作,树脂用DMF洗涤,加入Fmoc-Phe-azaG-Leu-OH(251mg,0.45mmol),HATU(171mg,0.45mmol),HOAt(57mg,0.45mmol)的10mL DMF溶液,然后加入DIPEA(116mg,0.9mmol),室温下处理1小时,树脂用DMF洗涤,得到Fmoc-Phe-azaG-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。以类似的方式将其他氨基酸依次将Fmoc-Thr(OtBu)-OH,Fmoc-Asn(Trt)-OH,Fmoc-Hyp(OtBu)-OH,Fmoc-D-Tyr(OtBu)-OH,Fmoc-Gly-OH,Fmoc-Gly-OH等氨基酸引入,得到Fmoc-Gly-Gly-[D-Tyr(OtBu)]-Hyp(OtBu)-Asn(Trt)-Thr(OtBu)-Phe-azaG-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。该树脂用10mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Hexadecyl-1,2,3-Triazole-PEG8-OH(300mg,0.418mmol),HATU(159mg,0.418mmol),HOAt(53mg,0.418mmol)的10mL DMF溶液,然后加入DIPEA(108mg,0.836mmol),室温下处理60分钟。树脂依次用DMF、甲醇、甲基叔丁基醚洗涤,然后抽干,最终得到Hexadecyl-1,2,3-Triazole-PEG8-Gly-Gly-[D-Tyr(OtBu)]-Hyp(OtBu)-Asn(Trt)-Thr(OtBu)-Phe-azaG-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。
将上述干燥的树脂加入10mL的TFA/TIS/phenol/H
2O(94/2/2/2)溶液中,该混合物搅拌2小时,过滤除去树脂,用1mL的TFA/TIS/phenol/H
2O(94/2/2/2)溶液洗涤树脂。合并滤液,向滤液中加入甲基叔丁基醚(110mL),得到的混合物在3000转/分钟离心1分钟,固体用冰乙醚洗涤两次,并抽干。得到的沉淀用DMF溶解,然后进行线性浓度梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:41/59-32/68使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈,在制备型的HPLC上,使用Phenomenex C18柱(21.2mm×250mm).收集含有产物的级分,冻干,得到70.2mg白色固体
实施例96:
Hexadecyl-S-maleimide-PEG8-Gly-Gly-(D-Tyr)-Hyp-Asn-Thr-Phe-azaG-Leu-Arg(Me)-Trp-NH2(化合物YA-368)的制备
将650mg商购可得的Rink Amide MBHA树脂(0.31mmol/g)溶胀于DMF中,该树脂用6mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Fmoc-Trp(Boc)-OH(316mg,0.6mmol),HATU(228mg,0.6mmol),HOAt(76mg,0.6mmol)的6mL DMF溶液,然后加入DIPEA(155mg,1.2mmol),室温下处理40分钟,树脂用DMF洗涤,得到Fmoc-Trp(Boc)-Rink Amide MBHA树脂。该树脂用6mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作,树脂用DMF洗涤,加入Fmoc-Arg(Me,Pbf)-OH(159mg,0.24mmol),DIC(38mg,0.3mmol)的6mL DMF溶液,室温下处理16小时,树脂用DMF洗涤,得到Fmoc-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。该树脂用6mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作,树脂用DMF洗涤,加入Fmoc-Phe-azaGly-Leu-OH(167mg,0.3mmol),HATU(114mg,0.3mmol),HOAt(38mg,0.3mmol)的6mL DMF溶液,然后加入DIPEA(75mg,0.6mmol),室温下处理1小时,树脂用DMF洗涤,得到Fmoc-Phe-azaG-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。以类似的方式,依次将Fmoc-Thr(OtBu)-OH,Fmoc-Asn(Trt)-OH,Fmoc-Hyp(OtBu)-OH,Fmoc-D-Tyr(OtBu)-OH,Fmoc-Gly-OH,Fmoc-Gly-OH等氨基酸引入,得到Fmoc-Gly-Gly-[D-Tyr(OtBu)]-Hyp(OtBu)-Asn(Trt)-Thr(OtBu)-Phe-azaG-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。该树脂用6mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Mal-PEG8-acid(125mg,0.24mmol),HATU(91mg,0.24mmol),HOAt(30mg,0.24mmol)的6mL DMF溶液,然后加入DIPEA(62mg,0.48mmol),室温下处理60分钟。得到的树脂用DMF洗涤,依次加入DMF(6ml)、DIPEA(62mg,0.48mmol)和Hexadecane-1-thiol(124mg.0.48mmol),室温下处理3小 时。树脂依次用DMF、甲醇、甲基叔丁基醚洗涤,然后抽干,最终得到Hexadecyl-S-maleimide-PEG8-Gly-Gly-[D-Tyr(OtBu)]-Hyp(OtBu)-Asn(Trt)-Thr(OtBu)-Phe-azaG-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。
将上述干燥的树脂加入10mL的TFA/TIS/phenol/H
2O(94/2/2/2)溶液中,该混合物搅拌2小时,过滤除去树脂,用1mL的TFA/TIS/phenol/H
2O(94/2/2/2)溶液洗涤树脂。合并滤液,向滤液中加入甲基叔丁基醚(110mL),得到的混合物在3000转/分钟离心1分钟,固体用冰乙醚洗涤两次,并抽干。得到的沉淀用DMF溶解,然后进行线性浓度梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:30/70-10/90使用:洗脱液A:0.05%TFA的水溶液,洗脱液B:0.05%TFA的乙腈,在制备型的HPLC上,使用Phenomenex C18柱(21.2mm×250mm).收集含有产物的级分,冻干,得到22.1mg白色固体
实施例97:
Ac-(D-Tyr)-Hyp-Asn-Thr-Phe-(α-Me-Leu)-Leu-Arg(Me)-Trp-NH2(化合物YA-370)的制备
将0.4g商购可得的Rink Amide MBHA树脂(0.432mmol/g)溶胀于DMF中,该树脂用6mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Fmoc-Trp(Boc)-OH(273mg,0.52mmol),HBTU(198mg,0.52mmol),HOBt(71mg,0.52mmol)的6mL DMF溶液,然后加入DIPEA(185μL,1.04mmol),室温下处理40分钟,树脂用DMF洗涤,得到Fmoc-Trp(Boc)-Rink Amide MBHA树脂。该树脂用6mL20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作,树脂用DMF洗涤,加入Fmoc-Arg(Me,Pbf)-OH(345mg,0.52mmol),HATU(198mg,0.52mmol),HOAt(71mg,0.52mmol)的6mL DMF溶液,然后加入DIPEA(185μL,1.04mmol),室温下处理1小时,树脂用DMF洗涤,得到Fmoc-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。该树脂用6mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作,树脂用DMF洗涤,加入Fmoc-Leu-OH(184mg,0.52mmol),HATU(198mg,0.52mmol),HOAt(71mg,0.52mmol)的6mL DMF溶液,然后加入DIPEA(185μL,1.04mmol),室温下处理1小时,树脂用DMF洗涤,得到Fmoc-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。以类似的方式,依次将α-Me-Leu,Phe,Thr(tBu),Asn(Trt),Hyp(tBu),D-Tyr(tBu)等氨基酸引入,得到Fmoc-(D-Tyr(tBu))-Hyp(tBu)-Asn(Trt)-Thr(tBu)-Phe-(α-Me-Leu)-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink-Amide MBHA树脂。树脂用6mL 20%哌啶/DMF处理20分钟以除去Fmoc,树脂用DMF洗涤,加入乙酸酐(49μL,0.52mmol),DIPEA(185μL,1.04mmol)的6mL DMF溶液,室温下处理1小时,树脂用DMF洗涤,得到 Ac-(D-Tyr(tBu))-Hyp(tBu)-Asn(Trt)-Thr(tBu)-Phe-(α-Me-Leu)-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。树脂用DMF,DCM,甲醇和甲基叔丁基醚洗涤,然后抽干。
将干燥的树脂加入15mL的TFA/TIS/phenol/H
2O(94/2/2/2)溶液中,该混合物搅拌2小时,过滤除去树脂,用3mL的TFA/TIS/phenol/H
2O(94/2/2/2)溶液洗涤树脂。合并滤液,向滤液中加入甲基叔丁基醚(150mL),得到的混合物在4000转/分钟离心1分钟,固体用冰乙醚洗涤两次,并抽干,得到沉淀160mg。得到的沉淀用DMF溶解,然后进行线性浓度梯度洗脱(10分钟),流速为25mL/分钟,洗脱液A/B:71/29-61/39使用:洗脱液A:0.1%TFA的水溶液,洗脱液B:乙腈,在制备型的HPLC上,使用XBridge Peptide BEH C18 10μm,
柱(19mm×250mm)。收集含有产物的组分,冻干,得到77.0mg白色固体。
实施例98:
Ac-(D-Tyr)-Hyp-Asn-A6c-Phe-azaGly-Leu-Arg(Me)-Trp-NH2(化合物YA-387)的制备
将0.5g商购可得的Rink Amide MBHA树脂(0.5mmol/g)溶胀于DMF中,该树脂用5mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Fmoc-Trp(Boc)-OH(316mg,0.60mmol),HBTU(230mg,0.60mmol),HOBt(81mg,0.60mmol)的8mL DMF溶液,然后加入DIPEA(160μL,0.9mmol),室温下处理40分钟,树脂用DMF洗涤,得到Fmoc-Trp(Boc)-Rink Amide MBHA树脂。该树脂用8mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作,树脂用DMF洗涤,加入Fmoc-Arg(Me,Pbf)-OH(130mg,0.30mmol),HATU(230mg,0.60mmol),HOAt(81mg,0.60mmol)的8mL DMF溶液,然后加入DIPEA(107μL,0.60mmol),室温下处理1小时,树脂用DMF洗涤,得到Fmoc-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。该树脂用8mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作,树脂用DMF洗涤,加入Fmoc-Phe-azaGly-Leu-OH(200mg,0.3mmol),HATU(114mg,0.30mmol),HOAt(41mg,0.30mmol)的5mL DMF溶液,然后加入DIPEA(106μL,0.6mmol),室温下处理1小时,树脂用DMF洗涤,得到Fmoc-Phe-azaGly-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。以类似的方式,依次将A6c,Asn(Trt),Hyp(tBu),D-Tyr(tBu)等氨基酸引入,得到Fmoc-(D-Tyr(tBu))-Hyp(tBu)-Asn(Trt)-A6c-Phe-azaGly-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。该树脂用5mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作,树脂用DMF 洗涤,加入乙酸酐(30mg,0.60mmol),HATU(230mg,0.60mmol),HOAt(81mg,0.60mmol)的8mL DMF溶液,然后加入DIPEA(107μL,0.6mmol),室温下处理2小时,树脂用DMF,DCM,甲醇和甲基叔丁基醚洗涤,然后抽干,得到Ac-NH-(D-Tyr(tBu))-Hyp(tBu)-Asn(Trt)-A6c-Phe-azaGly-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。
将干燥的树脂加入10mL的TFA/TIS/H
2O(95/2.5/2.5)溶液中,该混合物搅拌2小时,过滤除去树脂,用2mL的TFA/TIS/H
2O(95/2.5/2.5)溶液洗涤树脂。合并滤液,向滤液中加入甲基叔丁基醚(100mL),得到的混合物在3000转/分钟离心1分钟,固体用冰乙醚洗涤两次,并抽干。得到的沉淀用DMF溶解,然后进行线性浓度梯度洗脱(10分钟),流速为20mL/分钟,洗脱液A/B:70/30-65/35使用:洗脱液A:0.1%TFA的水溶液,洗脱液B:乙腈,在制备型的HPLC上,使用Welch XB-C18 10μm柱(21.2mm×250mm).收集含有产物的级分,冻干,得到46.00mg白色固体。
实施例99:
Ac-(D-Tyr)-Hyp-Asn-Aze-Phe-azaGly-Leu-Arg(Me)-Trp-NH2(化合物YA-388)的制备
将0.5g商购可得的Rink Amide MBHA树脂(0.5mmol/g)溶胀于DMF中,该树脂用5mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作。得到的树脂用DMF洗涤,加入Fmoc-Trp(Boc)-OH(316mg,0.60mmol),HBTU(230mg,0.60mmol),HOBt(81mg,0.60mmol)的8mL DMF溶液,然后加入DIPEA(160μL,0.9mmol),室温下处理40分钟,树脂用DMF洗涤,得到Fmoc-Trp(Boc)-Rink Amide MBHA树脂。该树脂用8mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作,树脂用DMF洗涤,加入Fmoc-Arg(Me,Pbf)-OH(130mg,0.30mmol),HATU(230mg,0.60mmol),HOAt(81mg,0.60mmol)的8mL DMF溶液,然后加入DIPEA(107μL,0.60mmol),室温下处理1小时,树脂用DMF洗涤,得到Fmoc-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。该树脂用8mL 20%哌啶/DMF处理20分钟以除去Fmoc,重复两遍此操作,树脂用DMF洗涤,加入Fmoc-Phe-azaGly-Leu-OH(200mg,0.3mmol),HATU(114mg,0.30mmol),HOAt(41mg,0.30mmol)的5mL DMF溶液,然后加入DIPEA(106μL,0.6mmol),室温下处理1小时,树脂用DMF洗涤,得到Fmoc-Phe-azaGly-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。以类似的方式,依次将Aze,Asn(Trt),Hyp(tBu),D-Tyr(tBu)等氨基酸引入,得到Fmoc-(D-Tyr(tBu))-Hyp(tBu)-Asn(Trt)-Aze-Phe-azaGly-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。该 树脂用20%哌啶/DMF处理除去Fmoc,重复两遍此操作,树脂用DMF洗涤,加入乙酸(30mg,0.60mmol),HATU(230mg,0.60mmol),HOAt(81mg,0.60mmol)的8mL DMF溶液,然后加入DIPEA(107μL,0.6mmol),室温下处理2小时,树脂用DMF,DCM,甲醇和甲基叔丁基醚洗涤,然后抽干,得到Ac-NH-(D-Tyr(tBu))-Hyp(tBu)-Asn(Trt)-Aze-Phe-azaGly-Leu-Arg(Me,Pbf)-Trp(Boc)-Rink Amide MBHA树脂。
将干燥的树脂加入10mL的TFA/TIS/H
2O(95/2.5/2.5)溶液中,该混合物搅拌2小时,过滤除去树脂,用2mL的TFA/TIS/H
2O(95/2.5/2.5)溶液洗涤树脂。合并滤液,向滤液中加入甲基叔丁基醚(100mL),得到的混合物在3000转/分钟离心1分钟,固体用冰乙醚洗涤两次,并抽干。得到的沉淀用DMF溶解,然后进行线性浓度梯度洗脱(10分钟),流速为20mL/分钟,洗脱液A/B:74/26-64/36使用:洗脱液A:0.1%TFA的水溶液,洗脱液B:乙腈,在制备型的HPLC上,使用Welch XB-C18 10μm柱(21.2mm×250mm)。收集含有产物的级分,冻干,得到7.00mg白色固体。
上述实施例制得的多肽,以及参照上述实施例制得的多肽见下表2,表2还记载了各多肽的纯度分析条件、保留时间、表征数据以及效果数据(其按照效果实施例1的方法测定)
表2
上表2中的HPLC纯度分析条件具体如下:
条件A:洗脱液A/B=95/5-35/65
流动相:A:水(0.01%TFA),B:ACN(0.01%TFA)
流动相比例:5%B within 0-3min,线性梯度洗脱5-65%B within 20min流速:1.2ml/min
色谱柱:Eclipse XDB-C18,4.6*150mm,5um
箱温:40℃
条件B:洗脱液A/B=95/5-35/65
流动相:A:水(0.01%TFA),B:ACN(0.01%TFA)
流动相比例:5%B within 0-3min,线性梯度洗脱5-65%B within 20min
流速:1.0ml/min
色谱柱:AGLIENT ZORBAX Eclipse XDB,C18,4.6*150mm,5um
温度:40℃
条件C:洗脱液A/B=95/5-35/65
流动相:A:水(0.01%TFA),B:ACN(0.01%TFA)
流动相比例:5%B within 0-3min,线性梯度洗脱5-65%B with 20min
流速:1.0ml/min
色谱柱:SunFire C18,4.6*150mm,3.5um
温度:40℃
条件D:洗脱液A/B=95/5-35/65
流动相:A:水(0.05%TFA),B:ACN(0.05%TFA)
流动相比例:5%B within 0-3min,线性梯度洗脱5-65%B within 20min
流速:1.2ml/min
色谱柱:Eclipse XDB-C18,4.6*150mm,5um
条件E:洗脱液A/B=85/15-25/75
流动相:A:水(0.01%TFA),B:ACN(0.01%TFA)
流动相比例:15%B within 0-3min,线性梯度洗脱15-75%B with 20min
流速:1.0ml/min
色谱柱:SunFire C18,4.6*150mm,3.5um
温度:40℃
条件F:洗脱液A/B=95/5-35/65
流动相:A:水(0.05%TFA),B:ACN(0.05%TFA)
流动相比例:5%B within 0-3min,线性梯度洗脱5-65%B within 20min
流速:1.2ml/min
色谱柱:SunFire C18,4.6*150mm,3.5um
条件G:洗脱液A/B=80/20-20/80
流动相:A:水(0.01%TFA),B:ACN(0.01%TFA)
流动相比例:20%B within 0-3min,线性梯度洗脱20-80%B with 20min
流速:1.0ml/min
色谱柱:SunFire C18,4.6*150mm,3.5um
温度:40℃
条件H:洗脱液A/B=50/50-0/100
流动相:A:水(0.05%TFA),B:ACN(0.05%TFA)
流动相比例:50%B within 0-3min,线性梯度洗脱50-100%B within 20min
流速:1.0mL/min
色谱柱:XBridge Peptide BEH C18,4.6*150mm,3.5um
柱温:40℃
条件I:洗脱液A/B=80/20-5/95
流动相:A:水(0.01%TFA),B:ACN(0.01%TFA)
流动相比例:20%B within 0-2min,线性梯度洗脱20-95%B within 25min
流速:1.0mL/min
色谱柱:SunFire C18,4.6*150mm,3.5um
柱温:40℃
条件J:洗脱液A/B=95/5-35/65
流动相:水(0.05%TFA),B:ACN(0.05%TFA)
流动相比例:5%B within 0-3min,线性梯度洗脱5-65%B within 20min
流速:1.0mL/min
色谱柱:XBridge Peptide BEH C18,4.6*150mm,3.5um
柱温:40℃
条件K:洗脱液A/B=50/50-0/100
流动相:A:A:水(0.01%TFA),B:ACN(0.01%TFA)
流动相比例:50%B within 0-3min,线性梯度洗脱50-100%B within 20min
流速:1.0ml/min
色谱柱:SunFire C18,4.6*150mm,3.5um
柱温:40℃
条件L:洗脱液A/B=80/20-5/95
流动相:A:水(0.05%TFA),B:ACN(0.05%TFA)
流动相比例:20%B within 0-2min,线性梯度洗脱20-95%B within 25min
流速:1.0ml/min
色谱柱:XBridge Peptide BEH,4.6*150mm,3.5um
柱温:40℃
条件M:洗脱液A/B=80/20-20/80
流动相:A:水(0.05%TFA),B:ACN(0.05%TFA)
流动相比例:20%B within 0-1min,线性梯度洗脱20-80%B within 20min
流速:1.0mL/min
色谱柱:XBridge Peptide BEH C18,4.6*150mm,3.5um
柱温:40℃
条件N:洗脱液A/B=70/30-0/100
流动相:A:水(0.05%TFA),B:ACN(0.05%TFA)
流动相比例:30%B within 0-3min,线性梯度洗脱30-100%B within 20min
流速:1.0mL/min
柱温:40℃
色谱柱:XBridge Peptide BEH C18,4.6*150mm,3.5um
条件O:洗脱液A/B=65/35-0/100
流动相:A:水(0.05%TFA),B:ACN(0.05%TFA)
流动相比例:35%B within 0-1min,线性梯度洗脱35-100%B within 20min
流速:1.0mL/min
柱温:40℃
色谱柱:XBridge Peptide BEH C18,4.6*150mm,3.5um
条件P:洗脱液A/B=65/25-45/55
流动相:A:水(0.05%TFA),B:ACN(0.05%TFA)
线性梯度洗脱25-45%B within 30min
流速:1.0mL/min
柱温:40℃
色谱柱:XBridge Peptide BEH C18,4.6*150mm,3.5um
条件Q:洗脱液A/B=82/18-52/48
流动相:A:水(0.05%TFA),B:ACN(0.05%TFA)
线性梯度洗脱25-45%B within 30min
流速:1.0mL/min
柱温:40℃
色谱柱:XBridge Peptide BEH C18,4.6*150mm,3.5um
效果实施例1 kiss1受体(GPR54)激动剂的kiss1受体(GPR54)结合活性测定
上述实施例中各化合物与kiss1受体(GPR54)的结合活性测试采用的是荧光能量共振转移(FRET)检测技术,检测多肽和肽类似物的EC
50值。本实验所用细胞为表达人kiss1受体(GPR54)的NFAT-bla CHO-K1细胞(k1720,invitrogen,Thermo Fisher)。具体操作如下:
第1天:细胞种板
1.显微镜(CKX41,OLYMPUS),物镜×4倍,目镜×10倍下观察。确定细胞状态良好。
2.将细胞消化,在培养皿中加入3ml的0.05%胰酶;将细胞置于37℃、5%CO
2培养箱中2分钟(Thermo Fisher)。待显微镜下细胞变圆后,加入培养基7ml。培养基配方如下:DMEM90%,Dialyzed FBS10%,NEAA0.1mM,HEPES25mM,Penicillin 100U/ml,Streptomycin 100μg/ml,pH7.3。吹打,转移到15mL的离心管中(430790,Corning)。1000rpm离心5min(5810R,Eppendorf),弃上清。
3.加入7mL培养基(DMEM+0.1%BSA),吹打成单细胞悬液,Bio-RAD计数仪计数,并将细胞调整到所需密度,312500个/ml。
4.接种至384孔板中,每孔32μL使细胞数控制在10000个/孔,空白对照加入32μl 培养基。
第2天:加药及数据分析
1.
1000×化合物板配置
1)将待测化合物用DMSO配置成50mM工作液。
2)在U形96孔板(3797,CorningS)A-H行的第2列加入40μl待测化合物工作液,3-11列加入60μl的DMSO。用排枪从第二列吸取20μl化合物溶液加至第三列,吹打混合均匀;用排枪从第三列吸取20μl化合物溶液加至第四列,吹打混合均匀;依次继续将化合物进行四倍稀释,共十个浓度。96孔板第一列和第十二列补充40μl的DMSO。
2.
中间板配置
1)取U型96孔板,每孔加入199μL培养基(DMEM+0.1%BSA),吸取1000×化合物板中稀释化合物(或DMSO)1μl加入到相应位置的96孔板中,吹打混合均匀。
2)自产阳性化合物及待测化合物的加入。从培养箱中取出细胞培养板,显微镜下观察细胞状态良好,取中间板中稀释好的化合物或DMSO加入细胞中,每孔8μl。
3)将细胞置于37℃、5%CO
2中培养4小时。
3.
底物加入检测药物与受体结合
1)将1μmol/L浓度CCF-4AM溶液和缓冲液solution B,C,D平衡至室温。LiveBLAzer
TM-FRET B/G Loading kit(K1095,Thermo Fisher)试剂盒中含有CCF-4AM以及solutionB、solutionC,solutionD同样购自invitrogen(K1157,Thermo Fisher)。
2)准备6×loading液:吸取6μl的CCF-4AM溶解的solution A,60μl的solution B,904μl solution C,30μl的solution D于EP管中,吹打震荡,混合均匀。
3)用排枪吸取8μl上述液体,加入96孔板中,室温孵育2小时。
4)PerkinElmer检测仪检测各孔的发光信号。FI模式,λex=409nm,λem1=460nm,λem2=530nm。
4.
使用GraphPad Prism5(GraphPad Software.Inc)数据处理
有效率%=(Signal-Min)/(Max-Min)×100%。Max:高浓度阳性化合物与kiss1受体结合的最大值。Min:加入0.1%DMSO与受体完全不结合的最小值。Signal:化合物相应浓度下的信号值。以化合物浓度和相应的有效率做参数曲线拟合,得到相应化合物的EC
50,如表3所示。
表3 各多肽的EC
50
多肽编号 | GPR54EC 50/nM | 多肽编号 | GPR54EC 50/nM | 多肽编号 | GPR54EC 50/nM |
YA-1 | YA-160 | 0.027 | YA-204 | 8.72 |
YA-2 | 2.11 | YA-161 | 0.075 | YA-205 | 50.35 |
YA-3 | 0.03 | YA-162 | 0.004 | YA-206 | 3.60 |
YA-41 | 0.095 | YA-163 | 1000 | YA-207 | 90.00 |
YA-42 | 0.015 | YA-164 | 1.749 | YA-208 | 1.09 |
YA-43 | 0.095 | YA-165 | 0.025 | YA-209 | 1.4 |
YA-44 | 0.015 | YA-166 | 0.86 | YA-210 | 1.47 |
YA-45 | 0.095 | YA-167 | 0.33 | YA-211 | 1.13 |
YA-68 | 0.18 | YA-168 | 0.531 | YA-212 | 0.50 |
YA-69 | 0.3 | YA-169 | 6.532 | YA-213 | 0.40 |
YA-70 | 0.245 | YA-170 | 0.007 | YA-214 | 0.083 |
YA-71 | 0.058 | YA-172 | 0.012 | YA-215 | 0.122 |
YA-72 | 5.55 | YA-174 | 2.6 | YA-216 | 0.44 |
YA-73 | 1.32 | YA-175 | 0.132 | YA-217 | 2.56 |
YA-74 | 0.921 | YA-178 | 0.011 | YA-218 | 12.2 |
YA-75 | 18.7 | YA-180 | 0.015 | YA-219 | 63.42 |
YA-80 | 0.007 | YA-181 | 0.043 | YA-220 | 0.023 |
YA-81 | 0.011 | YA-182 | 0.021 | YA-221 | 0.64 |
YA-82 | 2.792 | YA-183 | 0.029 | YA-223 | 4.4 |
YA-83 | 0.008 | YA-184 | 48 | YA-224 | 6.5 |
YA-84 | 0.007 | YA-185 | 3.627 | YA-226 | 8.00 |
YA-85 | 0.026 | YA-186 | 3.893 | YA-227 | 1.89 |
YA-132 | 0.19 | YA-187 | 1.854 | YA-228 | 0.65 |
YA-139 | 0.023 | YA-188 | 0.477 | YA-229 | 20.26 |
YA-140 | 0.040 | YA-189 | 1.696 | YA-234 | 202 |
YA-141 | 0.064 | YA-190 | 24.3 | YA-236 | 0.058 |
YA-142 | 0.064 | YA-191 | 0.521 | YA-239 | 1.00 |
YA-143 | 0.023 | YA-192 | 2.170 | YA-240 | 173 |
YA-144 | 0.201 | YA-193 | 1.365 | YA-241 | 0.93 |
YA-145 | 0.034 | YA-194 | 0.544 | YA-242 | 3.75 |
YA-146 | 544.8 | YA-195 | 0.68 | YA-243 | 0.69 |
YA-150 | 0.004 | YA-196 | 0.48 | YA-244 | 1.17 |
YA-151 | 0.045 | YA-197 | 0.57 | YA-246 | 2.86 |
YA-152 | 1000 | YA-198 | 381.8 | YA-247 | 11 |
YA-153 | 0.18 | YA-199 | 15.56 | YA-248 | 0.78 |
YA-156 | 0.045 | YA-200 | 25.43 | YA-251 | 0.65 |
YA-157 | 0.03 | YA-201 | 0.39 | YA-252 | 1000 |
YA-158 | 0.0478 | YA-202 | 9.60 | YA-253 | 97.8 |
YA-159 | 1000 | YA-203 | 1.19 | YA-260 | 0.027 |
YA-264 | 0.029 | YA-266 | 0.320 | YA-267 | 0.03 |
YA-268 | 0.02 | YA-271 | 0.025 | YA-273 | 0.05 |
YA-274 | 0.048 | YA-287 | 0.038 | YA-288 | 0.018 |
YA-294 | 0.038 | YA-295 | 0.02 | YA-296 | 0.011 |
YA-297 | 0.014 | YA-298 | 0.016 | YA-324 | 0.007 |
YA-291 | 0.31 | YA-303 | 0.01 | YA-325 | 0.017 |
YA-326 | 0.010 | YA-327 | 0.40 | YA-332 | 0.18 |
YA-333 | 0.066 | YA-334 | 0.084 | YA-336 | 2.48 |
YA-337 | 2.20 | YA-338 | 0.057 | YA-339 | 0.075 |
YA-348 | 0.019 | YA-350 | 0.17 | YA-354 | 0.26 |
YA-355 | 1.2 | YA-357 | 0.30 | YA-358 | 0.032 |
YA-360 | 0.006 | YA-366 | 0.048 | YA-367 | 0.103 |
YA-368 | 0.051 | YA-370 | 1.563 | YA-379 | 0.0150 |
YA-380 | 0.191 | YA-381 | 0.052 | YA-382 | 0.175 |
YA-383 | 0.074 | YA-384 | 0.338 | YA-387 | 0.041 |
YA-388 | 0.058 | YA-396 | 1.188 | YA-403 | 0.272 |
表3所列的部分化合物EC
50优于TAK448,显示出较强的活性,表明本发明的化合物在体外生化实验水平可以有效结合kiss1受体(GPR54),因此本发明的化合物可以成为肿瘤的有效治疗药物。
效果实施例2 部分化合物的血浆稳定性实验数据:
1. 50mM磷酸盐缓冲液的配制:
将称取的5.750g Na
2HPO
4,1.141g NaH
2PO
4·和4.095g NaCl(Shanghai Titan)溶于1000mL超纯水,并调节pH至7.4,即得含70mM NaCl的50mM磷酸盐缓冲液。配置好的磷酸缓冲液放在冰箱4℃储存,有效期为一周。
2.化合物储备液的配制:
1)5mg/mL受试化合物:称取5mg的化合物溶于1mL的DMSO。
2)20mM对照品:2.728mg的奴弗卡因溶于0.5mL的DMSO。3.878mg的苯氟雷司溶于0.5mL的DMSO(Amresco)。
3.准备实验用血浆:
将冻存的血浆(人:上海睿智化学;大鼠、小鼠:上海西普尔-必凯;犬、猴:苏州西山中科)从-80℃冰箱中取出,立即置于37℃的水浴锅中,轻微振荡使其融化,然后将解冻后的血浆倒入离心管中,3000rpm离心8min,取上清用于实验。用pH计(METTLER TOLEDO)检测血浆的pH值,只有pH值在7.4~8之间的血浆才被用于实验。将血浆放在冰浴上备用。
4.给药溶液的配制:
1)125μg/mL受试化合物溶液:将5μL的5mg/mL的受试化合物(见步骤2)加入到195μL DMSO中;、500μM对照品溶液:将20mM的对照品储备液(见步骤2)加入到195μL DMSO中。
2)0.5%BSA磷酸盐缓冲溶液:将0.05g的BSA加入到10mL磷酸盐缓冲液中(见步骤1);
3)5μg/mL受试化合物给药溶液:将40μL的125μg/mL受试化合物溶液加入到960μL 0.5%BSA磷酸盐缓冲溶液中,振荡混匀,并将给药溶液放于37℃水浴中预热5分钟。
20μM对照品给药溶液:将40μL的500μM对照品给药溶液加入到960μL 0.5%BSA磷酸盐缓冲溶液中,振荡混匀,并将给药溶液放于37℃水浴中预热5分钟。
5.将10μL的5μg/mL受试化合物和20μM对照品给药溶液分别加入到96孔板上 设置为不同时间点(0分钟、1小时、2小时和4小时)的孔中,复样数为3。
6.将500μL含5%FA的ACN(IS)加入到设置为0分钟点的孔中,然后加入90μL血浆,混匀后贴上封口膜放于4℃(复样数为3)。
7.将90μL血浆分别加到设置时间点为1小时、2小时和4小时的孔中,复样数为3,并开始计时(反应终浓度受试化合物为500ng/mL;对照品为2μM)。
8.然后在计时器显示1小时、2小时和4小时时,分别加入500μL含5%FA的ACN(IS)溶液到相应时间点的孔中终止反应,混匀后贴上封口膜放于4℃。
9.将96孔板上不同时间点的所有样品(0分钟、1小时、2小时和4小时)放在振荡器(MTS 2/4,IKA)上600rpm/min震荡10分钟,然后在离心机(Multifuge×3R,Thermo Fisher)上采用5594×g将样品离心15分钟。
10.从离心后的样品中取出150μL上清液送至LC-MS/MS进行分析(常规的多肽LC-MS/MS分析方法)。计算得到相应化合物的半衰期,如表4所示。
表4 化合物的血浆稳定性实验数据
多肽编号 | 大鼠血浆(T 1/2(h)) |
YA-3 | 10.06 |
YA-150 | 6.67 |
YA-156 | 44.38 |
YA-157 | 6.67 |
YA-162 | 6.96 |
YA-172 | 9.42 |
YA-175 | 2.05 |
YA-180 | 9.63 |
YA-182 | 5.32 |
YA-201 | 2.65 |
YA-220 | 59.02 |
YA-230 | 3.64 |
YA-264 | 13.05 |
YA-271 | 15.63 |
YA-273 | 166.40 |
YA-288 | 27.48 |
YA-296 | 2.73 |
YA-298 | 12.68 |
YA-324 | 0.29 |
YA-325 | 4.26 |
YA-326 | 4.97 |
YA-350 | 0.22 |
YA-360 | 79.86 |
虽然以上描述了本发明的具体实施方式,但是本领域的技术人员应当理解,这些仅是举例说明,在不背离本发明的原理和实质的前提下,可以对这些实施方式做出多种变更或修改。因此,本发明的保护范围由所附权利要求书限定。
Claims (35)
- 一种如式1所示的肽类化合物、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药:R a为CH 3-,q为0~18;或者,R a为HOOC-,q为1~18;m为0~2;n为0~3;所有的AA0独立地为Gly、Beta-Ala、Ahx或Ac-Lys;但当q为0时,m和n不同时为0;n’为0~3;所有的AA0’独立地为Gly、Beta-Ala、Ahx或Ac-Lys;AA1为氨基未取代或氨基被1个C 1-3的烷基取代的下述氨基酸:D-Ala、Leu、D-Leu、Tyr、D-Tyr、Thi、(S)-Pip、Ala、αMeTyr、1Nal、2Nal、4Pal、Dap(Dnp)、D-2Fua、Pro(5Ph)、 2Pal、3Pal、Tyr(Me)、Ala(dip)、A6c、ACPA、D-Tic、3-[(1-甲基吡啶鎓)-3-基]丙氨酸、和、 n1为0~2,所有的R 1独立地为C 1~C 4烷基、C 1~C 4烷氧基或卤素,*标记的碳原子为手性碳原子,其为R构型或S构型;AA2为Asn、Hyp、Pro、Ala、Thz、Pro(diF)、Pro(4-NH 2)、Thi、NAsn、ACPA、D-2Fua、A6c、azaPro、Ind、(S)-Pip、(R)-Pip、Oic、azaTic、AlphaMeLeu、Cba、A6c、Aze、Cpa或D-Tic;XX3为Trp、Ala、Phe(4-I)或化学键;AA5为2Fua、Thr或Ser;AA6为氨基未取代或氨基被1个C 1-3的烷基取代的下述氨基酸:Ala、1Nal、2Nal、Trp、αMePhe、Bta、4Pal、HoPhe、BetaPhe、BetaHomoPhe、Bpa、Ala(dip)、Bip、D-2Fua、A6c、Tic、azaTic、azaPhe、和、 n6为0~5,所有的R 6独立地为卤代的C 1~C 4烷基、C 1~C 4烷基或卤素,*标记的碳原子为手性碳原子,其为R构型或S构型;AA7为氨基未取代或氨基被1个C 1-3的烷基取代的下述氨基酸:Gly、azaGly、Ala、Alg、Ava、Aib、Sar、Chg、BetaAla、ACPO、Aze、D-2Fua、A6c、azaPro、Ind、(S)-Pip、(R)-Pip、azaTic、Oic、Hyp、cycloLeu、BetaHomoAla、Cba、ACPA、Alg、morpholino cyclic amino acid、beta-(thiazoly-4-yl)-L-Ala、当AA6为 时,“AA6-AA7”是指AA6的羧基与AA7的氨基连接形成的含 的基团、或者、“AA6的羧基与AA7的氨基连接形成的含 的基团”中的 被下述的任一基团取代后、形成的基团: 所述基团的左端与AA6相连;AA10为氨基未取代或氨基被1个C 1-3的烷基取代的下述氨基酸:Trp、Ala、αMePhe、1Nal、2Nal、4Pal、BetaPhe、BetaHoPhe、Bpa、Ala(dip)、NPhe、Bip、D-2Fua、A6c、Tic、和、 n10为0~5,所有的R 10独立地为卤代的C 1~C 4烷 基或卤素,*标记的碳原子为手性碳原子,其为R构型或S构型;P为-NH 2、-OH、-NH-tBu、-NH-Et、-NH-Me、1H-1,2,3-三唑-4-基或2H-四唑-5-基。
- 如权利要求1所述的肽类化合物1、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药,其特征在于,当R a为CH 3-时,所述的q为以下述任两个值为端点的范围:0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17和18;和/或,当R a为HOOC-时,所述的q为以下述任两个值为端点的范围:1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17和18;和/或,所述的m为0、1或2;和/或,所述的R b中的C 1-3的烷基为甲基、乙基、异丙基或正丙基;和/或,所述的k独立地为以下述任两个值为端点的范围:2、3、4、5、6、8、12、16、20或24;和/或,所述的n为0、1、2或3;和/或,当m为0、n为0时,所述的q为以下述任两个值为端点的范围:1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17和18;和/或,所述的R c中的C 14-C 18的直链烷基为C 16直链烷基;和/或,所述的X’中的“杂原子为N、O和S中的一种或多种,杂原子数为1~3个的五元或六元杂芳基”为“杂原子为N,杂原子数为1~3个的五元或六元杂芳基”;和/或,所述的k’为5~7;和/或,所述的n’为0、1、2或3;和/或,所述的AA1中,当氨基酸存在多个氨基时,所述的氨基为手性碳原子上的氨基;和/或,所述的AA1中,当氨基酸存在多个氨基时,所述的氨基为伯氨基;和/或,所述的AA1中,所述的C 1-3的烷基为甲基、乙基、正丙基或异丙基;和/或,所述的n1为0、1或2;和/或,所述的R 1中,所述的C 1~C 4烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基或异丁基;和/或,所述的R 1中,所述的C 1~C 4烷氧基为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基或异丁氧基;和/或,所述的R 1中,所述的卤素为氟、氯或碘;和/或,所有的R 1独立地位于氨基酸侧链的邻位、间位或对位;和/或,所述的AA6中,当氨基酸存在多个氨基时,所述的氨基为手性碳原子上的氨基;和/或,所述的AA6中,当氨基酸存在多个氨基时,所述的氨基为伯氨基;和/或,所述的AA6中,所述的C 1-3的烷基为甲基、乙基、正丙基或异丙基;和/或,所述的n6为0、1、2、3、4或5;和/或,当所述的R 1为卤代的C 1~C 4烷基时,所述的“卤”为氟、氯、溴或碘;和/或,当所述的R 1为卤代的C 1~C 4烷基时,所述的“C 1~C 4烷基”为甲基、乙基、正丙基、异丙基、正丁基、仲丁基或异丁基;和/或,当所述的R 6为C 1~C 4烷基时,所述的C 1~C 4烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基或异丁基;和/或,所述的R 6中,所述的卤素为氟、氯、溴或碘;和/或,所有的R 6独立地位于氨基酸侧链的邻位、间位或对位;和/或,所述的AA7中,当氨基酸存在多个氨基时,所述的氨基为手性碳原子上的氨基;和/或,所述的AA7中,当氨基酸存在多个氨基时,所述的氨基为伯氨基;和/或,所述的AA7中,所述的C 1-3的烷基为甲基、乙基、正丙基或异丙基;和/或,所述的AA9中,当氨基酸存在多个氨基时,所述的氨基为手性碳原子上的氨基;和/或,所述的AA9中,当氨基酸存在多个氨基时,所述的氨基为伯氨基;和/或,所述的AA9中,所述的C 1-3的烷基为甲基、乙基、正丙基或异丙基;和/或,所述的AA10中,当氨基酸存在多个氨基时,所述的氨基为手性碳原子上的 氨基;和/或,所述的AA10中,当氨基酸存在多个氨基时,所述的氨基为伯氨基;和/或,所述的AA10中,所述的C 1-3的烷基为甲基、乙基、正丙基或异丙基;和/或,所述的n10为0、1、2、3、4或5;和/或,当所述的R 10为卤代的C 1~C 4烷基时,所述的“卤”为氟、氯、溴或碘;和/或,当所述的R 10为卤代的C 1~C 4烷基时,所述的“C 1~C 4烷基”为甲基、乙基、正丙基、异丙基、正丁基、仲丁基或异丁基;和/或,所述的R 10中,所述的卤素为氟、氯、溴或碘;和/或,所有的R 10独立地位于氨基酸侧链的邻位、间位或对位;
- 如权利要求2所述的肽类化合物1、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药,其特征在于,当R a为CH 3-时,所述的q为0~14;和/或,当R a为HOOC-时,所述的q为1~16;和/或,所述的k独立地为2~12;和/或,当m为0、n为0时,所述的q为4~14;和/或,所述的n’为2;和/或,当n1为1时,R 1位于氨基酸侧链的间位或对位;和/或,当n1为2时,R 1位于氨基酸侧链的邻位和对位和/或,当n6为1时,R 6位于氨基酸侧链的邻位、间位或对位所述的n6为0、1、2、3、4或5;和/或,当n10为1时,R 10位于氨基酸侧链的邻位或对位。
- 如权利要求3所述的肽类化合物1、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药,其特征在于,当R a为CH 3-时,所述的q为4~14;和/或,所述的k独立地为2~8;和/或,当n为2或3时,至少2个AA0为Gly;和/或,当n’为2或3时,至少2个AA0’为Gly;和/或,所述的 为Phe、D-Phe、Phe(4-F)、D-Phe(4-F)、Phe(3-Cl)、D-Phe(3-Cl)、Phe(4-Cl)、D-Phe(4-Cl)、Phe(4-I)、D-Phe(4-I)、Phe(4-Me)、Phe(4-tBu)、或、D-Phe(2,4-diCl);
- 如权利要求1~4中至少一项所述的肽类化合物1、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药,其特征在于,R a为CH 3-,q为0~16;和/或,R a为HOOC-,q为2~18;和/或,k独立地为2~8;和/或,AA1为氨基未取代或氨基被1个C 1-3的烷基取代的下述氨基酸:Tyr、D-Tyr、Thi、(S)-Pip、αMeTyr、1Nal、2Nal、4Pal、Dap(Dnp)、D-2Fua、Pro(5Ph)、2Pal、3Pal、Tyr(Me)、Ala(dip)、A6c、ACPA、D-Tic、3-[(1-甲基吡啶鎓)-3-基]丙氨酸、和、 n1为0~2,所有的R 1独立地为甲基、甲氧基、C 4烷氧基或卤素,*标记的碳原子为手性碳原子,其为R构型或S构型;和/或,AA2为Asn、Hyp、Pro、Ala、Thz、Pro(diF)、Pro(4-NH 2)、Thi、ACPA、D-2Fua、A6c、azaPro、Ind、(S)-Pip、(R)-Pip、Oic、AlphaMeLeu、Cba、A6c、Aze、Cpa或D-Tic;和/或,XX3为Trp或化学键;和/或,AA5为Thr或Ser;和/或,AA6为氨基未取代或氨基被1个C 1-3的烷基取代的下述氨基酸:1Nal、2Nal、αMePhe、4Pal、HoPhe、BetaPhe、BetaHomoPhe、Bpa、D-2Fua、A6c、Tic、azaPhe、和、 n6为0、1或2,所有的R 6独立地为C 1~C 4烷基或卤素,*标记的碳原子为手性碳原子,其为R构型或S构型;和/或,AA7为氨基未取代或氨基被1个C 1-3的烷基取代的下述氨基酸:Gly、azaGly、Ala、Alg、Ava、Aib、Sar、Chg、BetaAla、ACPO、Aze、D-2Fua、A6c、azaPro、Ind、(S)-Pip、(R)-Pip、Oic、Hyp、cycloLeu、BetaHomoAla、Cba、ACPA、Alg、morpholino cyclic amino acid、beta-(thiazoly-4-yl)-L-Ala、和/或,当AA6为 时,“AA6-AA7”是指AA6的羧基与AA7的氨基连接形成的含 的基团、或者、“AA6的羧基与AA7的氨基连接形成的含 的基团”中的 被下述的任一基团取代后、形成的基团: 所述基团的左端与AA6相连;和/或,当AA7为Gly时,“AA7-Leu”是指AA7的羧基与Leu的氨基连接形成的含 的基团、或者、“AA7的羧基与Leu的氨基连接形成的含 的基团”中的 被下述的任一基团取代后、形成的基团: 所述基团的左端与AA7相连;和/或,AA10为氨基未取代或氨基被1个C 1-3的烷基取代的下述氨基酸:Trp、αMePhe、1Nal、2Nal、4Pal、BetaPhe、BetaHoPhe、Bpa、NPhe、D-2Fua、A6c、Tic、和、 n10为0,*标记的碳原子为手性碳原子,其为R构型或S构型;和/或,P为-NH 2。
- 如权利要求5所述的肽类化合物1、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药,其特征在于,R a为CH 3-,q为0~14;和/或,R a为HOOC-,q为14~18;和/或,k独立地为4~8;和/或,AA2为Asn、Hyp、Thz、Pro(diF)、Pro(4-NH 2)、Thi、AlphaMeLeu、Cba、A6c、Aze、Cpa或A6c;和/或,AA7为下述任一氨基酸:Gly、azaGly、Alg、Aze、D-2Fua、morpholino cyclic amino acid、beta-(thiazoly-4-yl)-L-Ala、 和A6c;和/或,当AA7为Gly时,“AA7-Leu”是指AA7的羧基与Leu的氨基连接形成的含 的基团、或者、“AA7的羧基与Leu的氨基连接形成的含 的基团”中的 被下述的任一基团取代后、形成的基团: 所述基团的左端与AA7相连;和/或,AA9为下述任一氨基酸:Arg和Arg(Me);
- 如权利要求6所述的肽类化合物1、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药,其特征在于,AA1为Tyr、D-Tyr、D-2Fua、D-Phe(4-I)或Phe(4-I);和/或,AA2为Asn、Hyp、Pro(diF)或A6c;和/或,AA6为Phe;和/或,AA7为Gly、azaGly、Alg、Aze、D-2Fua或A6c;和/或,AA9为下述任一氨基酸:Arg和Arg(Me);和/或,AA10为Trp或Phe。
- 如权利要求7所述的肽类化合物1、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药,其特征在于,AA1为Tyr、D-Tyr、D-2Fua或D-Phe(4-I)。
- R a为CH 3-,q为0~16;或者,R a为HOOC-,q为2~18;m为0~2;n为0~3;所有的AA0独立地为Gly、Beta-Ala、Ahx或Ac-Lys;但当q为0时,m和n不同时为0;n’为0~3;所有的AA0’独立地为Gly、Beta-Ala、Ahx或Ac-Lys;AA1为氨基未取代或氨基被1个C 1-3的烷基取代的下述氨基酸:Tyr、D-Tyr、Thi、(S)-Pip、αMeTyr、1Nal、2Nal、4Pal、Dap(Dnp)、D-2Fua、Pro(5Ph)、2Pal、3Pal、Tyr(Me)、Ala(dip)、A6c、ACPA、D-Tic、3-[(1-甲基吡啶鎓)-3-基]丙氨酸、和、 n1为0~2,所有的R 1独立地为甲基、甲氧基、C 4烷氧基或卤素,*标记的碳原子为手性碳原子,其为R构型或S构型;AA2为Asn、Hyp、Pro、Ala、Thz、Pro(diF)、Pro(4-NH 2)、Thi、ACPA、D-2Fua、A6c、azaPro、Ind、(S)-Pip、(R)-Pip、Oic、AlphaMeLeu、Cba、A6c、Aze、Cpa或D-Tic;XX3为Trp、Ala、Phe(4-I)或化学键;AA5为2Fua、Thr或Ser;AA6为氨基未取代或氨基被1个C 1-3的烷基取代的下述氨基酸:1Nal、2Nal、αMePhe、4Pal、HoPhe、BetaPhe、BetaHomoPhe、Bpa、D-2Fua、A6c、Tic、azaPhe、和、 n6为0、1或2,所有的R 6独立地为C 1~C 4烷基或卤素,*标记的碳原子为手性碳原子,其为R构型或S构型;AA7为氨基未取代或氨基被1个C 1-3的烷基取代的下述氨基酸:Gly、azaGly、Ala、Alg、Ava、Aib、Sar、Chg、BetaAla、ACPO、Aze、D-2Fua、A6c、azaPro、Ind、(S)-Pip、(R)-Pip、Oic、Hyp、cycloLeu、BetaHomoAla、Cba、ACPA、Alg、morpholino cyclic amino acid、beta-(thiazoly-4-yl)-L-Ala、当AA6为 时,“AA6-AA7”是指AA6的羧基与AA7的氨基连接形成的含 的基团、或者、“AA6的羧基与AA7的氨基连接形成的含 的基团”中的 被下述的任一基团取代后、形成的基团: 所述基团的左端与AA6相连;“AA7-Leu”是指AA7的羧基与Leu的氨基连接形成的含 的基团、或者、 “AA7的羧基与Leu的氨基连接形成的含 的基团”中的 被下述的任一基团取代后、形成的基团: 所述基团的左端与AA7相连;AA10为氨基未取代或氨基被1个C 1-3的烷基取代的下述氨基酸:Trp、αMePhe、1Nal、2Nal、4Pal、BetaPhe、BetaHoPhe、Bpa、NPhe、D-2Fua、A6c、Tic、和、 n10为0,*标记的碳原子为手性碳原子,其为R构型或S构型;P为-NH 2、-OH、-NH-tBu、-NH-Et、-NH-Me、1H-1,2,3-三唑-4-基或2H-四唑-5-基。
- R a为CH 3-,q为0~14;或者,R a为HOOC-,q为14~18;m为0~2;n为0~3;所有的AA0独立地为Gly、Beta-Ala、Ahx或Ac-Lys;但当q为0时,m和n不同时为0;n’为0~3;所有的AA0’独立地为Gly、Beta-Ala、Ahx或Ac-Lys;AA2为Asn、Hyp、Thz、Pro(diF)、Pro(4-NH 2)、Thi、AlphaMeLeu、Cba、A6c、Aze、Cpa或A6c;XX3为Trp或化学键;AA5为Thr或Ser;AA7为下述任一氨基酸:Gly、azaGly、Alg、Aze、D-2Fua、Alg、morpholino cyclic amino acid、beta-(thiazoly-4-yl)-L-Ala、 和A6c;当AA7为Gly时,“AA7-Leu”是指AA7的羧基与Leu的氨基连接形成的含 的基团、或者、“AA7的羧基与Leu的氨基连接形成的含 的基团”中的 被下述的任一基团取代后、形成的基团: 所述基团的左端与AA7相连;AA9为下述任一氨基酸:Arg和Arg(Me);P为-NH 2。
- R a为CH 3-,q为0~14;或者,R a为HOOC-,q为14~18;m为0~2;n为0~3;所有的AA0独立地为Gly、Beta-Ala、Ahx或Ac-Lys;但当q为0时,m和n不同时为0;n’为0~3;所有的AA0’独立地为Gly、Beta-Ala、Ahx或Ac-Lys;AA2为Asn、Hyp、Pro(diF)或A6c;XX3为Trp或化学键;AA5为Thr或Ser;AA7为下述任一氨基酸:Gly、azaGly、Alg、Aze、D-2Fua和A6c;当AA7为Gly时,“AA7-Leu”是指AA7的羧基与Leu的氨基连接形成的含 的基团、或者、“AA7的羧基与Leu的氨基连接形成的含 的基团”中的 被下述的任一基团取代后、形成的基团: 所述基团的左端与AA7相连;AA9为下述任一氨基酸:Arg和Arg(Me);P为-NH 2。
- R a为CH 3-,q为0~18;或者,R a为HOOC-,q为1~18;m为0~2;n为0~3;所有的AA0独立地为Gly、Beta-Ala、Ahx或Ac-Lys;但当q为0时,m和n不同时为0;AA1为氨基被1个C 1-3的烷基取代或未取代的下述氨基酸:D-Ala、Leu、D-Leu、Tyr、D-Tyr、Thi、(S)-Pip、Ala、αMeTyr、1Nal、2Nal、4Pal、Dap(Dnp)、D-2Fua、Pro(5Ph)、2Pal、3Pal、Tyr(Me)、Ala(dip)、A6c、ACPA、D-Tic、3-[(1-甲基吡啶鎓)-3-基]丙氨酸、和、 n1为0~2,所有的R 1独立地为C 1~C 4烷基、C 1~C 4烷氧基或卤素,*标记的碳原子为手性碳原子,其为R构型或S构型;AA2为Asn、Hyp、Pro、Ala、Thz、Pro(diF)、Pro(4-NH 2)、Thi、NAsn、ACPA、D-2Fua、A6c、azaPro、Ind、(S)-Pip、(R)-Pip、Oic、azaTic或D-Tic;XX3为Trp、Ala、Phe(4-I)或化学键;AA5为2Fua、Thr或Ser;AA6为氨基被1个C 1-3的烷基取代或未取代的下述氨基酸:Ala、1Nal、2Nal、Trp、αMePhe、Bta、4Pal、HoPhe、BetaPhe、BetaHomoPhe、Bpa、Ala(dip)、Bip、D-2Fua、A6c、Tic、azaTic、azaPhe、和、 n6为0~5,所有的R 6独立地为卤代的C 1~C 4烷基、C 1~C 4烷基或卤素,*标记的碳原子为手性碳原子,其为R构型或S构型;AA7为氨基被1个C 1-3的烷基取代或未取代的下述氨基酸:Gly、azaGly、Ala、Ava、Aib、Sar、Chg、BetaAla、ACPO、Aze、D-2Fua、A6c、azaPro、Ind、(S)-Pip、(R)-Pip、azaTic、Oic、Hyp、cycloLeu、BetaHomoAla、Cba、ACPA和当AA6为 时,“AA6-AA7”是指AA6的羧基与AA7的氨基连接形成的含 的基团、或者、“AA6的羧基与AA7的氨基连接形成的含 的基团”中的 被下述的任一基团取代后、形成的基团: 所述基团的左端与AA6相连;AA10为氨基被1个C 1-3的烷基取代或未取代的下述氨基酸:Trp、Ala、αMePhe、1Nal、2Nal、4Pal、BetaPhe、BetaHoPhe、Bpa、Ala(dip)、NPhe、Bip、D-2Fua、A6c、Tic、和、 n10为0~5,所有的R 10独立地为卤代的C 1~C 4烷基或卤素,*标记的碳原子为手性碳原子,其为R构型或S构型;P为-NH 2、-OH、-NH-tBu、-NH-Et、-NH-Me、1H-1,2,3-三唑-4-基或2H-四唑-5-基。
- 如权利要求12所述的肽类化合物1、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药,其特征在于,当R a为CH 3-时,所述的q为以下述任两个值为端点的范围:0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17和18;和/或,当R a为HOOC-时,所述的q为以下述任两个值为端点的范围:1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17和18;和/或,所述的m为0、1或2;和/或,所述的R b中的C 1-3的烷基为甲基、乙基、异丙基或正丙基;和/或,所述的k独立地为以下述任两个值为端点的范围:2、3、4、5、6、8、12、16、20或24;和/或,当m为0、n为0时,所述的q为以下述任两个值为端点的范围:1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17和18;和/或,所述的AA1中,当氨基酸存在多个氨基时,所述的氨基为手性碳原子上的氨基;和/或,所述的AA1中,当氨基酸存在多个氨基时,所述的氨基为伯氨基;和/或,所述的AA1中,所述的C 1-3的烷基为甲基、乙基、正丙基或异丙基;和/或,所述的n1为0、1或2;和/或,所述的R 1中,所述的C 1~C 4烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基或异丁基;和/或,所述的R 1中,所述的C 1~C 4烷氧基为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基或异丁氧基;和/或,所述的R 1中,所述的卤素为氟或氯;和/或,所有的R 1独立地位于氨基酸侧链的邻位、间位或对位;和/或,所述的AA6中,当氨基酸存在多个氨基时,所述的氨基为手性碳原子上的氨基;和/或,所述的AA6中,当氨基酸存在多个氨基时,所述的氨基为伯氨基;和/或,所述的AA6中,所述的C 1-3的烷基为甲基、乙基、正丙基或异丙基;和/或,所述的n6为0、1、2、3、4或5;和/或,所述的R 6中,所述的C 1~C 4烷基为甲基、乙基、正丙基、异丙基、正丁基、 仲丁基或异丁基;和/或,当所述的R 1为卤代的C 1~C 4烷基时,所述的“卤”为氟、氯、溴或碘;和/或,当所述的R 1为卤代的C 1~C 4烷基时,所述的“C 1~C 4烷基”为甲基、乙基、正丙基、异丙基、正丁基、仲丁基或异丁基;和/或,所述的R 6中,所述的卤素为氟、氯、溴或碘;和/或,所有的R 6独立地位于氨基酸侧链的邻位、间位或对位;和/或,所述的AA7中,当氨基酸存在多个氨基时,所述的氨基为手性碳原子上的氨基;和/或,所述的AA7中,当氨基酸存在多个氨基时,所述的氨基为伯氨基;和/或,所述的AA7中,所述的C 1-3的烷基为甲基、乙基、正丙基或异丙基;和/或,所述的AA9中,当氨基酸存在多个氨基时,所述的氨基为手性碳原子上的氨基;和/或,所述的AA9中,当氨基酸存在多个氨基时,所述的氨基为伯氨基;和/或,所述的AA9中,所述的C 1-3的烷基为甲基、乙基、正丙基或异丙基;和/或,所述的AA10中,当氨基酸存在多个氨基时,所述的氨基为手性碳原子上的氨基;和/或,所述的AA10中,当氨基酸存在多个氨基时,所述的氨基为伯氨基;和/或,所述的AA10中,所述的C 1-3的烷基为甲基、乙基、正丙基或异丙基;和/或,所述的n10为0、1、2、3、4或5;和/或,当所述的R 10为卤代的C 1~C 4烷基时,所述的“卤”为氟、氯、溴或碘;和/或,当所述的R 10为卤代的C 1~C 4烷基时,所述的“C 1~C 4烷基”为甲基、乙基、正丙基、异丙基、正丁基、仲丁基或异丁基;和/或,所述的R 10中,所述的卤素为氟、氯、溴或碘;和/或,所有的R 10独立地位于氨基酸侧链的邻位、间位或对位;
- 如权利要求13所述的肽类化合物1、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药,其特征在于,当R a为CH 3-时,所述的q为0~14;和/或,当R a为HOOC-时,所述的q为1~16;和/或,所述的X为-NH 2;和/或,所述的k独立地为2~12;和/或,当m为0、n为0时,所述的q为4~14;和/或,当n1为1时,R 1位于氨基酸侧链的间位或对位;和/或,当n1为2时,R 1位于氨基酸侧链的邻位和对位;和/或,所述的AA7中,所述的“取代的氨基酸”为N-Me-A6c或aza-N-Me-Gly;和/或,所述的AA9中,所述的“取代的氨基酸”为N-Me-Arg、N-Me-HoLeu或N-Me-D-HoLeu;和/或,当n10为1时,R 10位于氨基酸侧链的邻位或对位。
- 如权利要求14所述的肽类化合物1、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药,其特征在于,当R a为CH 3-时,所述的q为4~14;和/或,当n为2或3时,至少2个AA0为Gly;和/或,所述的 为Phe、D-Phe、Phe(4-F)、D-Phe(4-F)、Phe(3-Cl)、 D-Phe(3-Cl)、Phe(4-Cl)、D-Phe(4-Cl)、Phe(4-I)、Phe(4-Me)、Phe(4-tBu)、或、D-Phe(2,4-diCl);和/或,所述的AA6中,所述的“取代的氨基酸”为N-Me-Phe;
- 如权利要求12~16中至少一项所述的肽类化合物1、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药,其特征在于,m为1或2;或者,m为0,n为0,R a为CH 3-或HOOC-,q为1~18;或者,m为0,n为1~3。
- 如权利要求12~16中至少一项所述的肽类化合物1、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药,其特征在于,R a为CH 3-,q为0~14;或者,R a为HOOC-,q为1~16;和/或,所述的X为-NH 2;和/或,所述的k独立地为2~8;和/或,所有的AA0独立地为Gly或Ac-Lys;和/或,所述的AA1为Tyr、D-Tyr、或D-2Fua;和/或,所述的AA2为Asn、Hyp、或、Pro(diF);和/或,所述的XX3为Trp或化学键;和/或,所述的AA5为Thr或Ser;和/或,所述的AA6为Phe;和/或,所述的AA7为Gly、azaGly、Aze、D-2Fua或A6c;和/或,所述的AA9为Arg或Arg(Me);和/或,所述的AA10为Trp或Phe;和/或,所述的P为-NH 2。
- 如权利要求12~16中至少一项所述的肽类化合物1、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药,其特征在于,R a为CH 3-,q为0~14;或者,R a为HOOC-,q为1~16;和/或,所述的X为-NH 2;和/或,所述的k独立地为2~8;和/或,所有的AA0独立地为Gly或Ac-Lys;和/或,AA1为Dap(Dnp)、D-Phe(2,4-diCl)、D-Tic、2Pal、3Pal、D-Tyr、Ala(dip)、 或、D-2Fua;和/或,所述的AA2为Thz、(S)-Pip、Oic、A6c、Thi、D-2Fua、ACPA或Pro;和/或,所述的AA5为2Fua;和/或,所述的AA10为2-Nal;和/或,所述的P为-NH 2。
- 如权利要求12~16中至少一项所述的肽类化合物1、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药,其特征在于,R a为CH 3-,q为0~14;或者,R a为HOOC-,q为1~16;和/或,所述的X为-NH 2;和/或,所述的k独立地为2~8;和/或,所有的AA0独立地为Gly、BetaAla、Ac-Lys或Ahx;和/或,AA1为D-Tyr、D-Phe(2,4-DiCl)、D-2Fua、L-Phe(4-F)、D-Phe(4-F)、Thi、(S)-Pip、D-Tic、Dap(Dnp)、D-Phe(4-Cl)、D-Phe(3-Cl)、2-Pal、3Pal、Ala(dip)、或、ACPA;和/或,AA2为Hyp、Thi、A6c、Thz、Pro(diF)、Pro、Pro(4-NH 2)、D-2Fua、(S)-Pip、ACPA、(R)-Pip或Oic;和/或,XX3为Trp或化学键;和/或,AA5为2Fua或Thr;和/或,AA9为Arg(Me);和/或,AA10为Trp或2-Nal;和/或,P为OH或NH 2。
- 如权利要求12~16中至少一项所述的肽类化合物1、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药,其特征在于,R a为CH 3-,q为0~14;或者,R a为HOOC-,q为1~16;和/或,所述的X为-NH 2;和/或,所述的k独立地为2~8;和/或,所有的AA0独立地为Gly、BetaAla、Ac-Lys或Ahx;和/或,AA1为D-Tyr、D-Phe(2,4-DiCl)、D-2Fua、Thi、(S)-Pip或D-Phe(4-F);和/或,AA2为Hyp、Thi、A6c、Thz、Pro(diF)、Pro(4-NH 2)、D-2Fua、(S)-Pip、(R)-Pip或Oic;和/或,XX3为化学键;和/或,AA9为Arg(Me);和/或,AA10为Trp或2-Nal;和/或,P为OH或NH 2。
- 如权利要求1所述的肽类化合物1、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药,其特征在于,所述的化合物1为下列任一化合物:Ac-PEG4-(D-Tyr)-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-PEG8-(D-Tyr)-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Palm-PEG8-Gly-Gly-(D-Tyr)-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-Lys(Palm-PEG8)-Gly-Gly-(D-Tyr)-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Palm-PEG8-Gly-Gly-Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH2Palm-PEG8-Gly-Gly-[3-(2-furyl)-D-Ala]-DifluorPro-Asn-Thr-Phe-A6c-Leu-Arg(Me)-Trp-NH2Palm-PEG8-Gly-Gly-DTyr-Hyp-Asn-Thr-Phe-A6c-Leu-Arg(Me)-Trp-NH2Palm-PEG8-(D-2Fua)-Pro(diF)-Asn-Thr-Phe-A6c-Leu-Arg(Me)-Trp-NH2Palm-PEG8-G-G-DY-A6c-Asn-Thr-Phe-azaG-Leu-Arg(Me)-Trp-NH2C18 diacid-OEG-OEG-DY-Hyp-Asn-Thr-Phe-azaG-Leu-Arg(Me)-Trp-NH2Palm-PEG8-Gly-Gly-(D-Tyr)-Hyp-Asn-Thr-Phe-Aze-Leu-Arg(Me)-Trp-NH2Palm-PEG8-Gly-Gly-(D-Tyr)-Hyp-Asn-Thr-Phe-(D-2Fua)-Leu-Arg(Me)-Trp-NH2Hexanoyl-(D-Tyr)-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Nonanoyl-OEG-(D-Tyr)-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Dodecanoyl-PEG4-PEG4-(D-Tyr)-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Palm-DY-Hyp-N-T-F-azaG-L-R(Me)-W-NH2Palm-PEG8-(D-Tyr)-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Nonanoyl-PEG4-(D-Tyr)-Hyp-Asn-Thr-Phe-Aze-Leu-Arg(Me)-Trp-NH2Dodecanoyl-PEG4-(D-Tyr)-Hyp-Asn-Thr-Phe-(D-2Fua)-Leu-Arg(Me)-Trp-NH2Palm-PEG8-Gly-Gly-(D-Tyr)-Hyp-Asn-Thr-Phe-Alg-Leu-Arg(Me)-Trp-NH2Palm-PEG8-Gly-Gly-(D-Phe(4-I))-Hyp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH2{ }-Gly-Gly-(D-Tyr)-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2
- 一种如权利要求1~24任一项所述的肽类化合物1、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药在制备药物中的应用,所述的药物用于治疗和/或预防与亲吻肽受体相关的疾病。
- 如权利要求25所述的应用,其特征在于,所述的与亲吻肽受体相关的疾病为与激素相关的疾病、细胞增殖性疾病、和、与胎盘功能相关的疾病中的一种或多种。
- 如权利要求26所述的应用,其特征在于,所述的与激素相关的疾病为前列腺癌、乳腺癌、子宫内膜异位症、子宫肌瘤、中枢性性早熟症、雌激素受体阳性、性功能性疾病、不育症、抑郁症、或怀孕;和/或,所述的细胞增殖性疾病为良性前列腺增生症或癌症;和/或,所述的与胎盘功能相关的疾病为绒毛膜癌、侵袭性痣、流产、胎儿发育不全、糖代谢异常或脂质代谢异常。
- 如权利要求27所述的应用,其特征在于,所述的癌症为前列腺癌、乳腺癌、卵巢癌、子宫癌、宫颈癌、子宫内膜癌、甲状腺癌、膀胱癌、肝癌、黑色素瘤、胰腺癌、胃癌、肾细胞癌、食管癌、膀胱癌或脑癌。
- 一种药物组合物,其包含如权利要求1~24任一项所述的化合物1、其药学上可接受的盐、其互变异构体、其晶型、其溶剂合物或其前药,以及药用辅料。
- 一种肽类化合物3、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药,其特征在于,所述的化合物3为下列任一化合物:Ac-Dap(Dnp)-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-[D-Phe(2,4-DiCl)]-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-(D-2Fua)-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-Pro(5Ph)-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-(D-Tyr)-Thz-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-2Pal-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-3Pal-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-Phe(3-Cl)-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-Phe(4-F)-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-Phe(4-Me)-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-(D-Tyr)-diFluorPro-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-(D-Tyr)-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-2Nal-NH2Ac-(D-Tyr)-Pro(4-NH2)-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-(D-Tyr)-Thi-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-(D-Tyr)-(S-Pip)-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-Ala(dip)-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-(D-Tyr)-Hyp-Asn-2Fua-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-(D-Tyr)-Hyp-Asn-Thi-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-(D-Tyr)-ACPA-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-(D-Tyr)-Hyp-Asn-Thr-Phe-Aze-Leu-Arg(Me)-Trp-NH2Ac-(D-Tyr)-(D-2Fua)-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-(D-Tyr)-Hyp-Asn-[3-(2-furyl)-D-Ala]-Phe-azaGly-L-Arg(Me)-Trp-NH2Ac-(D-Tyr)-Hyp-Asn-Thr--(D-2Fua)-azaGly-L-Arg(Me)-Trp-NH2Ac-(D-Tyr)-Hyp-Asn-Thr-Phe-[3-(2-furyl)-D-Ala]-Leu-Arg(Me)-Trp-NH2Ac-[D-Phe(4-F)]-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-(D-Tyr)-A6c-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-(D-Tyr)-Hyp-Asn-Thr-Phe-A6c-Leu-Arg(Me)-Trp-NH2Ac-[D-Phe(2,4-DiCl)]-Thi-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-[D-Phe(2,4-DiCl)]-Pro(diF)-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-(D-2Fua)-(S-Pip)-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-[D-Phe(2,4-DiCl)]-(S-Pip)-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-(D-2Fua)-Pro(diF)-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-[D-Phe(2,4-DiCl)]-Hyp-Asn-Thr-Phe-Aze-Leu-Arg(Me)-Trp-NH2Ac-(D-Tyr)-Thi-Asn-Thr-Phe-Aze-Leu-Arg(Me)-Trp-NH2Ac-(D-Tyr)-(S-Pip)-Asn-Thr-Phe-Aze-Leu-Arg(Me)-Trp-NH2Ac-[D-Phe(4-F)]-Hyp-Asn-Thr-Phe-A6c-Leu-Arg(Me)-Trp-NH2Ac-[D-Phe(2,4-DiCl)]-Hyp-Asn-Thr-Phe-A6c-Leu-Arg(Me)-Trp-NH2Ac-(D-2Fua)-Hyp-Asn-Thr-Phe-A6c-Leu-Arg(Me)-Trp-NH2Ac-[3-(2-furyl)-D-Ala]-DiFluorPro-Asn-Thr-Phe-A6c-Leu-Arg(Me)-Trp-NH2Ac-(D-Tyr)-Hyp-Asn-Thr-{(S)-2-(1-amino-2-phenylethyl)-1H-imidazole-5-carboxylicacid}-Leu-Arg(Me)-Trp-NH2Ac-(D-Tyr)-Hyp-Asn-Thr-{(S)-5-(1-amino-2-phenylethyl)-4H-1,2,4-triazole-3-carboxylicacid}-Leu-Arg(Me)-Trp-NH2Ac-[D-Phe(4-F)]-DiFluorPro-Asn-Thr-Phe-A6c-Leu-Arg(Me)-Trp-NH2Ac-[D-Phe(4-F)]-DiFluorPro-Asn-Thr-Phe-Aze-Leu-Arg(Me)-Trp-NH2Ac-[D-Phe(4-Cl)]-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-[D-Phe(3-Cl)]-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-(D-Tyr)-Hyp-Asn-Thr-Tic-azaGly-Leu-Arg(Me)-Trp-NH2Ac-(D-Tyr)-Hyp-Asn-Thr-Phe-Ind-Leu-Arg(Me)-Trp-NH2Ac-(D-Tyr)-(S-Pip)-Asn-Thr-Phe-A6c-Leu-Arg(Me)-Trp-NH2Ac-(D-Tyr)-Oic-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-(D-Tic)-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-[D-Phe(2,4-DiCl)]-(S-Pip)-Asn-Thr-azaPhe-Gly-Leu-Arg(Me)-Trp-NH2Ac-(D-Tyr)-A6c-Asn-Thr-Phe-A6c-Leu-Arg(Me)-Trp-NH2Ac-D-Phe(2,4-DiCl)-DiFluorPro-Asn-Thr-Phe-A6c-Leu-Arg(Me)-Trp-NH2Ac-DTyr-DiFluorPro-Asn-Thr-Phe-A6c-Leu-Arg(Me)-Trp-NH2Ac-DTyr-Hyp-Asn-Thr-Phe-ψ(NHCS)G-Leu-Arg(Me)-Trp-NH2Ac-D-Phe(2,4-DiCl)-DiFluorPro-Asn-Thr-Phe-ψ(NHCS)G-Leu-Arg(Me)-Trp-NH2Ac-D-Phe(2,4-DiCl)-A6c-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-A6c-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-(D-2Fua)-A6c-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-(D-Tyr)-Hyp-Asn-Thr-Phe-cycloLeu-Leu-Arg(Me)-Trp-NH2Ac-GRKKRRQRRRPQ-beta-Ala-beta-Ala-DY-Hyp--N-T-F-azaGly-L-R(Me)-W-NH2Ac-(D-Tyr)-Hyp-Asn-Thr-Phe-ψ(NHCO)Gly-Leu-Arg(Me)-Trp-NH2Ac-[D-Phe(2,4-diCl)]-HomoPro-Asn-Thr-Phe-ψ(NHCO)Gly-Leu-Arg(Me)-Trp-NH2Ac-(D-2Fua)-HomoPro-Asn-Thr-Phe-ψ(NHCO)Gly-Leu-Arg(Me)-Trp-NH2Ac-[D-Phe(2,4-diCl)]-Pro(diF)-Asn-Thr-Phe-ψ(NHCO)Gly-Leu-Arg(Me)-Trp-NH2Ac-(D-Tyr)-Hyp-Asn-Thr-Phe-Alg-Leu-Arg(Me)-Trp-NH2Ac-(D-Tyr)-Hyp-Asn-Thr-Phe-morpholino cyclic amino acid-Leu-Arg(Me)-Trp-NH2Ac-(D-Tyr)-Hyp-Asn-Thr-Phe-Beta-(thiazoly-4-yl)-L-Ala-Leu-Arg(Me)-Trp-NH2Ac-(D-Phe(4-I))-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-(D-Tyr)-AlphaMeLeu-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-(D-Tyr)-Cba-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-(D-Tyr)-A6c-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-(D-Tyr)-Aze-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-(D-Tyr)-Cpa-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-(D-Tyr)-ACBC-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-(D-Tyr)-Hyp-Asn-A6c-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-(D-Tyr)-Hyp-Asn-Aze-Phe-azaGly-Leu-Arg(Me)-Trp-NH2Ac-(D-Tyr)-Hyp-Asn-beta,beta-diMe-L-serine-Phe-azaGly-Leu-Leu-Arg(Me)-Trp-NH2。
- 一种如权利要求30所述的肽类化合物3、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药在制备药物中的应用,所述的药物用于治疗和/或预防与亲吻肽受体相关的疾病。
- 如权利要求31所述的应用,其特征在于,所述的与亲吻肽受体相关的疾病为与激素相关的疾病、细胞增殖性疾病、和、与胎盘功能相关的疾病中的一种或多种。
- 如权利要求32所述的应用,其特征在于,所述的与激素相关的疾病为前列腺癌、乳腺癌、子宫内膜异位症、子宫肌瘤、中枢性性早熟症、雌激素受体阳性、性功能性疾病、不育症、抑郁症、或怀孕;和/或,所述的细胞增殖性疾病为良性前列腺增生症或癌症;和/或,所述的与胎盘功能相关的疾病为绒毛膜癌、侵袭性痣、流产、胎儿发育不全、糖代谢异常或脂质代谢异常。
- 如权利要求33所述的应用,其特征在于,所述的癌症为前列腺癌、乳腺癌、卵巢癌、子宫癌、宫颈癌、子宫内膜癌、甲状腺癌、膀胱癌、肝癌、黑色素瘤、胰腺癌、胃癌、肾细胞癌、食管癌、膀胱癌或脑癌。
- 一种药物组合物,其包含如权利要求30所述的化合物3、其药学上可接受的盐、其互变异构体、其晶型、其溶剂合物或其前药,以及药用辅料。
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FR3128958A1 (fr) * | 2021-11-09 | 2023-05-12 | Institut National De Recherche Pour L'agriculture L'alimentation Et L'environnement | Composés peptidiques cycliques agonistes du récepteur kiss1r et leurs utilisations thérapeutiques |
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