WO2024032457A1 - 一种长效特立帕肽化合物 - Google Patents

一种长效特立帕肽化合物 Download PDF

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WO2024032457A1
WO2024032457A1 PCT/CN2023/110943 CN2023110943W WO2024032457A1 WO 2024032457 A1 WO2024032457 A1 WO 2024032457A1 CN 2023110943 W CN2023110943 W CN 2023110943W WO 2024032457 A1 WO2024032457 A1 WO 2024032457A1
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teriparatide
compound
type
integer
leu
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PCT/CN2023/110943
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English (en)
French (fr)
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周述靓
王鹏
邓岚
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成都奥达生物科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/29—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • 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
    • C07K14/575—Hormones
    • 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
    • C07K14/575—Hormones
    • C07K14/635—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates to the field of pharmaceutical synthesis, in particular to a long-acting teriparatide compound.
  • Teriparatide is a synthetic peptide hormone, which is the 1-34 amino acid fragment of human parathyroid hormone PTH. This fragment is the biologically active N-terminal region of endogenous parathyroid hormone PTH containing 84 amino acids.
  • the immunological and biological properties of teriparatide are identical to those of endogenous parathyroid hormone PTH and bovine parathyroid hormone PTH (bPTH).
  • Teriparatide stimulates bone formation and bone resorption, reduces the incidence of fractures in postmenopausal women, and can increase or decrease bone density, depending on how it is administered. Continuous infusion results in sustained increases in parathyroid hormone (PTH) concentrations and therefore produces greater bone resorption than daily injections, which cause only transient increases in serum parathyroid hormone (PTH) concentrations. In addition, teriparatide does not inhibit platelet aggregation in the adenosine diphosphate-induced pathway or the collagen-induced pathway.
  • Teriparatide reaches its peak plasma concentration 0.5 hours after subcutaneous injection, takes effect in 3 months, and has a bioavailability of 95%.
  • the duration of administration after a single intramuscular injection is 6 hours.
  • the volume of distribution after intravenous injection is 0.1L/kg.
  • Teriparatide may be broken down into fragments by hepatic non-specific proteolytic enzymes and then excreted by the kidneys with a renal clearance rate of 90%.
  • the overall clearance rate of teriparatide is approximately 90L/h in men and 60L/h in women.
  • the elimination half-life of teriparatide is 1 hour for subcutaneous administration and 5 minutes for intravenous administration.
  • the present invention provides a long-acting teriparatide compound.
  • the invention provides teriparatide compounds, including:
  • AA1 in structure I is selected from the group consisting of D-type or L-type Lys, D-type or L-type Dap, D-type or L-type Dab, D-type or L-type Orn , D-type or L-type Dah, or D-type or L-type Dao;
  • the AA2 is selected from NH 2 or OH;
  • the R is selected from HO 2 C(CH 2 ) n1 CO-(AA3) n2 -(PEG n3 (CH2) n4 CO) n5 - or HO 2 C(CH 2 ) n1 CO-(AA3) n2 -(AA4) n6- :
  • n1 is selected from an integer from 10 to 20;
  • n2 is selected from an integer from 1 to 5;
  • n3 is selected from 1 or an integer from 3 to 30;
  • n4 is selected from an integer from 1 to 5;
  • n5 is selected from 0 or an integer from 1 to 10;
  • n6 is selected from 0 or an integer from 1 to 10;
  • AA3 is selected from ⁇ Glu, ⁇ Lys, ⁇ -Ala, ⁇ -aminobutyric acid or 5-Ava;
  • AA4 is selected from Gly, Ser, Thr, Asp, Glu, Aad, Lys, Orn, Dab or Dap.
  • the invention also provides a preparation method of the teriparatide compound, which includes the following steps:
  • Step 1 Obtain the peptide resin of the teriparatide compound through solid-phase peptide synthesis
  • Step 2 acidolysis and purification to prepare the teriparatide compound.
  • step 1 include sequentially accessing the corresponding Fmoc-protected amino acids or protected amino acids or fragments in the sequence on the carrier resin through solid-phase coupling synthesis;
  • the dosage of the Fmoc-protected amino acid or protected amino acid fragment is 1.2 to 6 times the total moles of the resin fed; preferably 2.5 to 3.5 times;
  • the substitution value of the carrier resin is 0.2-1.0 mmol/g resin, and the preferred substitution value is 0.3-0.5 mmol/g resin.
  • the solid-phase coupling synthesis method is: the protected amino acid-resin obtained in the previous step reaction removes the Fmoc protecting group and then undergoes a coupling reaction with the next protected amino acid;
  • the deprotection time for deprotecting Fmoc is 10 to 60 minutes, preferably 15 to 25 minutes; the coupling reaction time is 60 to 300 minutes, preferably 100 to 140 minutes.
  • the condensation reagent used in the coupling reaction is selected from the group consisting of DIC (N,N-diisopropylcarbodiimide), N,N-dicyclohexylcarbodiimide, Fluorophosphoric acid benzotriazol-1-yl-oxytripyrrolidinylphosphonium, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl Urea hexafluorophosphate, benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate or O-benzotriazole-N,N,N',N'- One of the tetramethylurea tetrafluoroborates;
  • the molar amount of the condensation reagent is 1.2 to 6 times the total number of moles of amino groups in the amino resin, preferably 2.5 to 3.5 times.
  • the activating reagent added in the coupling reaction is selected from 1-hydroxybenzotriazole or N-hydroxy-7-azabenzotriazole, preferably 1-hydroxybenzotriazole. triazole;
  • the amount of the activating reagent is 1.2 to 6 times the total molar number of amino groups in the amino resin, preferably 2.5 to 3.5 times.
  • the reagent for deprotecting Fmoc is a PIP/DMF (piperidine/N,N-dimethylformamide) mixed solution, and the mixed solution contains 10 to 10% of piperidine. 30% (V); the dosage of the Fmoc deprotecting reagent is 5 to 15 mL per gram of amino resin; preferably 8 to 12 mL per gram of amino resin.
  • the acidolysis agent used in the acidolysis in step 2 is a mixed solvent of trifluoroacetic acid (TFA), 1,2-ethanedithiol (EDT) and water; the mixed solvent
  • TFA trifluoroacetic acid
  • EDT 1,2-ethanedithiol
  • water water
  • the volume ratio of the mixed solvent is: TFA is 89-91%, EDT is 4-6%, and the balance is water;
  • the volume ratio of the mixed solvent is: TFA is 90%, EDT is 5%, and the balance is water.
  • the amount of acidolysis agent required is 4 to 15 mL of acidolysis agent per gram of peptide resin; preferably, the amount of acidolysis agent required per gram of peptide resin is 7 to 10 mL of acidolysis agent;
  • the lysis time using the acidolytic agent is 1 to 6 hours at room temperature
  • the lysis time is 3 to 4 hours.
  • the present invention also provides teriparatide compounds prepared by the preparation method.
  • the present invention also provides the use of any of the following items in the preparation of medicines for preventing and/or treating diseases:
  • the disease includes osteoporosis.
  • the present invention also provides medicines, including any of the following items and pharmaceutically acceptable excipients or auxiliaries:
  • the present invention also provides pharmaceutical combinations, including the medicine and any other active ingredients.
  • the invention also provides a method of treating a disease, comprising administering to a subject any of the following:
  • the disease includes osteoporosis.
  • the invention provides a long-acting teriparatide compound.
  • the invention provides patients with a long-acting teriparatide compound, which can have a longer half-life in the body, reduce the frequency of administration, and improve the patient's medication compliance.
  • the long-acting teriparatide compound of the present invention is used to prepare a pharmaceutical composition for treating diseases, and the pharmaceutical composition is used in the prevention and treatment of osteoporosis.
  • the invention discloses a long-acting teriparatide compound, which can be achieved by those skilled in the art by drawing on the contents of this article and appropriately improving the process parameters. It should be noted that all similar substitutions and modifications are obvious to those skilled in the art, and they are deemed to be included in the present invention.
  • the methods and applications of the present invention have been described through preferred embodiments. Relevant persons can obviously make modifications or appropriate changes and combinations to the methods and applications described herein without departing from the content, spirit and scope of the present invention to achieve and Apply the technology of this invention.
  • the invention provides a long-acting teriparatide compound, which retains the biological activity of teriparatide, has the same physiological function as teriparatide, and can be used for the treatment of osteoporosis.
  • the present invention first provides a compound represented by structure I, a pharmaceutically acceptable salt, solvate, chelate or non-covalent complex formed by the compound, and a medicine based on the compound. precursor, or any mixture of the above forms.
  • AA1 in structure I is D-type or L-type Lys, or is D-type or L-type Dap, or is D-type or L-type Dab, or is D-type or L-type Orn, or is D-type or L-type Type Dah, or D-shaped or L-shaped Dao;
  • AA2 in structure I is NH 2 or OH
  • R in structure I is HO 2 C(CH 2 ) n1 CO-(AA3) n2 -(PEG n3 (CH2) n4 CO) n5 -; or HO 2 C(CH 2 ) n1 CO-(AA3) n2 - (AA4) n6 -:
  • n1 is an integer from 10 to 20;
  • n2 is an integer from 1 to 5;
  • n3 is 1, or an integer from 3 to 30;
  • n4 is an integer from 1 to 5;
  • n5 is 0, or an integer from 1 to 10;
  • n6 is 0, or an integer from 1 to 10;
  • AA3 is ⁇ Glu, or ⁇ Lys, or ⁇ -Ala, or ⁇ -aminobutyric acid, or 5-Ava;
  • AA4 is Gly, Ser, Thr, Asp, Glu, Aad, Lys, Orn, Dab, or Dap.
  • the invention also provides pharmaceutical compositions comprising compounds according to the invention, and pharmaceutical compositions of compounds according to the invention for the preparation of medicaments for the treatment of diseases.
  • the pharmaceutical composition is used in preventing and treating osteoporosis.
  • the chemical structural formula when there are differences or doubts between the chemical structural formula and the chemical name of a compound, the chemical structural formula is used to define the compound exactly.
  • the compounds described herein may contain one or more chiral centers, and/or double bonds and the like structures, and may also exist as stereoisomers, including double bond isomers (such as geometric isomers), optical rotation Enantiomers or diastereomers.
  • any chemical structure within the scope of the description of this article, whether it contains the above-mentioned similar structures in part or the whole structure includes all possible enantiomers and diastereomers of this compound, including Any pure stereoisomer (such as pure geometric isomer, pure enantiomer or pure diastereomer) and any mixture of these isomers.
  • Any pure stereoisomer such as pure geometric isomer, pure enantiomer or pure diastereomer
  • mixtures of racemic isomers and stereoisomers can also be further separated into the enantiomers or stereoisomers of their constituent components by those skilled in the art using continuous separation techniques or chiral molecule synthesis methods. body.
  • the compounds of structural formula I include, but are not limited to, optical isomers, Racemates and/or other mixtures.
  • a single enantiomer or diastereomer, such as an optically active isomer can be obtained by asymmetric synthesis or racemate resolution.
  • the resolution of the racemates can be achieved by different methods, such as conventional recrystallization using reagents that assist resolution, or by chromatographic methods.
  • the compounds of formula I also include cis and/or trans isomers with double bonds.
  • the compounds described in the present invention include, but are not limited to, the compounds represented by Structural Formula I and all their different pharmaceutically available forms.
  • the different pharmaceutically acceptable forms of these compounds include various pharmaceutically acceptable salts, solvates, complexes, chelates, non-covalent complexes, prodrugs based on the above substances and the above forms. Any mixture.
  • the compound represented by structure I provided by the present invention has the activity of preventing or treating osteoporosis.
  • the preparation method includes: the starting resin is Rink Amide MBHA resin, a solid-phase peptide synthesis method is used to prepare the peptide resin, the peptide resin is then acidolyzed to obtain a crude product, and finally the crude product is purified to obtain a pure product; wherein the solid-phase peptide synthesis method is used to prepare the peptide resin
  • the step is to sequentially access the corresponding protected amino acids or fragments in the sequence on the carrier resin through a solid-phase coupling synthesis method to prepare the peptide resin.
  • the dosage of the Fmoc-protected amino acid or protected amino acid fragment is 1.2 to 6 times the total moles of resin fed; preferably 2.5 to 3.5 times.
  • the substitution value of the carrier resin is 0.2-1.0 mmol/g resin, and the preferred substitution value is 0.3-0.5 mmol/g resin.
  • the solid-phase coupling synthesis method is as follows: the protected amino acid-resin obtained in the previous reaction step removes the Fmoc protecting group and then undergoes a coupling reaction with the next protected amino acid.
  • the deprotection time for deprotecting Fmoc is 10 to 60 minutes, preferably 15 to 25 minutes.
  • the coupling reaction time is 60 to 300 minutes, preferably 100 to 140 minutes.
  • the coupling reaction requires the addition of a condensation reagent, which is selected from DIC (N,N-diisopropylcarbodiimide), N,N-dicyclohexylcarbodiimide, and benzotriazole hexafluorophosphate.
  • DIC N,N-diisopropylcarbodiimide
  • N,N-dicyclohexylcarbodiimide N,N-dicyclohexylcarbodiimide
  • benzotriazole hexafluorophosphate benzotriazole hexafluorophosphate
  • -1-yl-oxytripyrrolidinylphosphonium 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate , benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate or O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoro
  • One of the borate esters preferably N,N-diisopropylcarbodiimide.
  • the molar amount of the condensation reagent is 1.2 to 6 times the total number of moles of amino groups in the amino resin, preferably 2.5 to 3.5 times.
  • the coupling reaction requires adding an activating reagent, and the activating reagent is selected from 1-hydroxybenzotriazole or N-hydroxy-7-azabenzotriazole, with 1-hydroxybenzotriazole being preferred.
  • the amount of activating reagent is 1.2 to 6 times the total number of moles of amino groups in the amino resin, preferably 2.5 to 3.5 times.
  • the reagent for removing Fmoc protection is a PIP/DMF (piperidine/N,N-dimethylformamide) mixed solution, and the mixed solution contains 10 to 30% piperidine (V ).
  • the dosage of Fmoc deprotecting reagent is 5 to 15 mL per gram of amino resin, preferably 8 to 12 mL per gram of amino resin.
  • the peptide resin is acidolyzed to simultaneously remove the resin and side chain protecting groups to obtain a crude product:
  • the acidolysis agent used in the acidolysis of the peptide resin is a mixed solvent of trifluoroacetic acid (TFA), 1,2-ethanedithiol (EDT) and water, and the volume ratio of the mixed solvent is: TFA is 80 ⁇ 95%, EDT is 1 to 10%, and the balance is water.
  • the volume ratio of the mixed solvent is: TFA is 89-91%, EDT is 4-6%, and the balance is water.
  • the volume ratio of the mixed solvent is: TFA is 90%, EDT is 5%, and the balance is water.
  • the amount of acidolysis agent required is 4-15 mL of acidolysis agent per gram of peptide resin; preferably, 7-10 mL of acidolysis agent is required per gram of peptide resin.
  • the lysis time using an acidolytic agent is 1 to 6 hours at room temperature, preferably 3 to 4 hours.
  • the crude product was purified by high performance liquid chromatography and freeze-dried to obtain the pure product.
  • the raw materials and reagents used in the long-acting teriparatide compound provided by the invention can be purchased from the market.
  • High performance liquid chromatography was used for purification.
  • the chromatographic filler for purification was 10 ⁇ m reversed-phase C18.
  • the mobile phase system was 0.1% TFA/water solution-0.1% TFA/acetonitrile solution.
  • the flow rate of the 30mm ⁇ 250mm chromatographic column was 20mL/min.
  • the purified intermediate concentrate was filtered with a 0.45 ⁇ m filter membrane for later use.
  • High-performance liquid chromatography was used for salt exchange.
  • the mobile phase system was 1% acetic acid/water solution-acetonitrile.
  • the chromatographic filler for purification was 10 ⁇ m reversed-phase C18, 30 mm ⁇ 250 mm.
  • the flow rate of the chromatographic column is 20mL/min (the corresponding flow rate can be adjusted according to the chromatographic columns of different specifications); use gradient elution and cyclic loading method, load the sample into the chromatographic column, start the mobile phase elution, collect the spectrum, and observe Changes in absorbance, collect the salt-exchanged main peak and use analytical liquid phase to detect the purity, combine the salt-exchanged main peak solutions, and concentrate under reduced pressure to obtain a pure acetic acid aqueous solution, freeze-dry to obtain the pure product.
  • UMR-106 cells can highly express PTH receptors and can specifically bind to PTH compounds, causing intracellular cAMP levels to rapidly increase.
  • the relative light units (RLU) after stimulating cells at each dose are measured using homogeneous time-resolved fluorescence technology. , and then calculate the EC50 of the agonist.
  • the present invention uses the UMR-106 cell line that stably expresses PTH-R, stimulates the cells with different concentrations of agonists, and obtains the EC50 of the compound by measuring the relative light units after stimulation of the cells at each dose.
  • test animals were cynomolgus monkeys, and 2 male cynomolgus monkeys were administered subcutaneously at a dose of 0.1 mg/kg before the drug (0h) and 1h, 2h, 3h, 4h, 8h, 12h, and 18h after the drug.
  • 24h, 48h, 96h, 144h, 168h, venous blood was taken, the plasma samples were separated by centrifugation, and the plasma concentrations of the corresponding compounds in the plasma samples were measured using liquid mass spectrometry.
  • the half-life of the compounds after subcutaneous (SC) administration is shown in the table below:

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Abstract

本发明公开了一种长效特立帕肽化合物。本发明所述一种长效化合物用于制备治疗疾病的药物组合物，所述药物组合物在预防和治疗骨质疏松症中的应用。

Description

一种长效特立帕肽化合物
本申请要求于2022年08月10日提交中国专利局、申请号为202210957714.6、发明名称为“一种长效特立帕肽化合物”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及医药合成领域，特别涉及一种长效特立帕肽化合物。
背景技术
特立帕肽是一种合成的多肽激素，为人甲状旁腺素PTH的1-34氨基酸片段，该片段是含有84个氨基酸的内源性甲状旁腺素PTH具有生物活性的N-末端区域。特立帕肽的免疫学和生物学特性与内源性甲状旁腺素PTH以及牛甲状旁腺素PTH(bPTH)完全相同。
特立帕肽刺激骨形成和骨吸收，可减少绝经后妇女骨折的发生率，根据给药方式的不同，还能提高或降低骨密度。连续输注可导致甲状旁腺素PTH浓度持续增高，因此比仅引起血清甲状旁腺素PTH浓度短暂增高的每日注射法产生的骨吸收作用更强。此外，特立帕肽不抑制二磷酸腺苷诱导途径或者胶原诱导途径的血小板聚集反应。
特立帕肽皮下注射后0.5小时达血药浓度峰值，3个月起效，生物利用度为95％。肌内注射单次给药后持续时间为6小时。静脉注射后分布容积为0.1L/kg。特立帕肽可能经肝非特异性蛋白水解酶分解为片段，然后经肾脏***，肾清除率为90％。而特立帕肽总体清除率男性约为90L/h，女性约为60L/h。特立帕肽消除半衰期皮下给药为1小时，静脉注射为5分钟。
由于特立帕肽在体内半衰期短，患者需要每天皮下给药，患者顺应性差。
因此，提供一种在体内半衰期长、减少给药频率的特立帕肽化合物具有重要的现实意义。
发明内容
有鉴于此，本发明提供一种长效特立帕肽化合物。
为了实现上述发明目的，本发明提供以下技术方案：
本发明提供了特立帕肽化合物，包括：
(Ⅰ)、具有式Ⅰ所示的氨基酸序列；或
Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-AA1(R)-His-Leu-Asn-Ser-Met-Glu-Arg-Val-Glu-Trp-Leu-Arg-Lys-Lys-Leu-Gln-Asp-Val-His-Asn-Phe-AA2
式Ⅰ
(Ⅱ)、在如(Ⅰ)所示的氨基酸序列的基础上经取代、缺失、添加和/或替换1个或多个氨基酸的序列；或
(Ⅲ)、与(Ⅰ)所示的氨基酸序列同源性90％以上
的序列；或
(IV)、具有如式Ⅰ所示特立帕肽化合物所成的可药用的盐、溶剂化物、螯合物或非共价复合物；和/或
(V)、基于具有如式Ⅰ所示特立帕肽化合物基础上的药物前体；和/或
(VI)、包括(IV)和/或(V)的任意混合物。
在本发明的一些具体实施方案中，所述结构I中的AA1选自D型或L型的Lys，D型或L型的Dap，D型或L型的Dab，D型或L型的Orn，D型或L型的Dah，或D型或L型的Dao；
所述AA2选自NH2，或为OH；
所述R选自HO2C(CH2)n1CO-(AA3)n2-(PEGn3(CH2)n4CO)n5-或HO2C(CH2)n1CO-(AA3)n2-(AA4)n6-：
其中：n1选自10至20的整数；
n2选自1至5的整数；
n3选自1或3至30的整数；
n4选自1至5的整数；
n5选自0或1至10的整数；
n6选自0或1至10的整数；
AA3选自γGlu，εLys，β-Ala，γ-氨基丁酸或5-Ava；
AA4选自Gly，Ser，Thr，Asp，Glu，Aad，Lys，Orn，Dab或Dap。
本发明还提供了所述特立帕肽化合物的制备方法，包括如下步骤：
步骤1：经固相多肽合成获得所述特立帕肽化合物的肽树脂；
步骤2：酸解、纯化，制得所述特立帕肽化合物。
在本发明的一些具体实施方案中，所述步骤1的具体步骤包括在载体树脂上通过固相偶联合成法依次接入序列中相对应的Fmoc-保护氨基酸或保护氨基酸或片段；
所述Fmoc-保护氨基酸或保护氨基酸片段的用量为所投料树脂总摩尔数的1.2～6倍；优选为2.5～3.5倍；
所述载体树脂的取代值为0.2～1.0mmol/g树脂，优选的取代值为0.3～0.5mmol/g树脂。
在本发明的一些具体实施方案中，所述固相偶联合成法为：前一步反应得到的保护氨基酸-树脂脱去Fmoc保护基后再与下一个保护氨基酸偶联反应；
所述脱去Fmoc保护的脱保护时间为10～60分钟，优选为15～25分钟；所述偶联反应时间为60～300分钟，优选为100～140分钟。
在本发明的一些具体实施方案中，所述偶联反应采用的缩合试剂选自DIC(N,N-二异丙基碳二亚胺)、N,N-二环己基碳二亚胺，六氟磷酸苯并***-1-基-氧基三吡咯烷基磷、2-(7-氮杂-1H-苯并三氮唑-1-基)-1,1,3,3-四甲基脲六氟磷酸酯、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐或O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯中的一种；
优选为N,N-二异丙基碳二亚胺；所述缩合试剂的摩尔用量为氨基树脂中氨基总摩尔数的1.2～6倍，优选为2.5～3.5倍。
在本发明的一些具体实施方案中，所述偶联反应添加的活化试剂选自1-羟基苯并***或N-羟基-7-氮杂苯并三氮唑，优选为1-羟基苯并***；
所述活化试剂的用量为氨基树脂中氨基总摩尔数的1.2～6倍，优选为2.5～3.5倍。
在本发明的一些具体实施方案中，所述脱去Fmoc保护的试剂为PIP/DMF(哌啶/N,N-二甲基甲酰胺)混合溶液，所述混合溶液中含哌啶为10～ 30％(V)；所述去Fmoc保护试剂的用量为每克氨基树脂5～15mL；优选为每克氨基树脂8～12mL。
在本发明的一些具体实施方案中，步骤2所述酸解采用的酸解剂为三氟醋酸(TFA)、1,2-乙二硫醇(EDT)和水的混合溶剂；所述混合溶剂的体积配比为：TFA为80～95％，EDT为1～10％，余量为水。
优选地，所述混合溶剂的体积配比为：TFA为89～91％、EDT为4～6％，余量为水；
最优地，所述混合溶剂的体积配比为：TFA为90％、EDT为5％，余量为水。
在本发明的一些具体实施方案中，所述酸解剂的用量为每克肽树脂需要4～15mL酸解剂；优选地，所述用量每克肽树脂需要7～10mL酸解剂；
使用所述酸解剂裂解的时间为室温条件下1～6小时；
优选地，所述裂解的时间为3～4小时。
在上述研究的基础上，本发明还提供了所述制备方法制得的特立帕肽化合物。
本发明还提供了如下任意项在制备预防和/或治疗疾病的药物中的应用：
(I)、所述特立帕肽化合物；和/或
(II)、所述制备方法制得的特立帕肽化合物。
在本发明的一些具体实施方案中，所述疾病包括骨质疏松症。
本发明还提供了药物，包括如下任意项以及药学上可接受的辅料或助剂：
(I)、所述特立帕肽化合物；和/或
(II)、所述制备方法制得的特立帕肽化合物。
本发明还提供了药物组合，包括所述药物以及其他任意有效成分。
本发明还提供了治疗疾病的方法，其包含向受试者施用以下任意项：
(I)、所述特立帕肽化合物；和/或
(II)、所述制备方法制得的特立帕肽化合物；和/或
(III)、所述药物；和/或
(IV)、所述药物组合。
在本发明的一些具体实施方案中，所述疾病包括骨质疏松症。
本发明提供了一种长效特立帕肽化合物。本发明为患者提供了一种长效的特立帕肽化合物，其在体内的半衰期可以更长且可以减少给药频率，提高患者用药顺应性。本发明所述一种长效特立帕肽化合物用于制备治疗疾病的药物组合物，所述药物组合物在预防和治疗骨质疏松症中的应用。
具体实施方式
本发明公开了一种长效特立帕肽化合物，本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明的方法及应用已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。
本发明提供了一种长效特立帕肽化合物，该长效化合物保留了特立帕肽的生物活性，具有与特立帕肽一样的生理功能，可用于骨质疏松症的治疗。
为实现上述目的，本发明首先提供了一种结构I所示的化合物，该化合物所成的可药用的盐、溶剂化物、螯合物或非共价复合物，基于该化合物基础上的药物前体，或上述形式的任意混合物。
Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-AA1(R)-His-Leu-Asn-Ser-Met-Glu-Arg-Val-Glu-Trp-Leu-Arg-Lys-Lys-Leu-Gln-Asp-Val-His-Asn-Phe-AA2
结构I
结构I中的AA1为D型或L型的Lys，或为D型或L型的Dap，或为D型或L型的Dab，或为D型或L型的Orn，或为D型或L型的Dah，或为D型或L型的Dao；
结构I中的AA2为NH2，或为OH；
结构I中的R为HO2C(CH2)n1CO-(AA3)n2-(PEGn3(CH2)n4CO)n5-；或为HO2C(CH2)n1CO-(AA3)n2-(AA4)n6-：
其中：n1为10至20的整数；
n2为1至5的整数；
n3为1，或为3至30的整数；
n4为1至5的整数；
n5为0，或为1至10的整数；
n6为0，或为1至10的整数；
AA3为γGlu，或为εLys，或为β-Ala，或为γ-氨基丁酸，或为5-Ava；
AA4为Gly，或为Ser，或为Thr，或为Asp，或为Glu，或为Aad，或为Lys，或为Orn，或为Dab，或为Dap。
本发明还提供了包括根据本发明化合物的药物组合物，以及提供了本发明化合物的药物组合物用于制备治疗疾病的药物用途。
作为优选，所述药物组合物在预防和治疗骨质疏松症的应用。
本发明所涉及到的更多内容在以下有详细描述，或者有些也可以在本发明的实施例中体会。
除非另有所指，本文中所用来表示不同成分的数量、反应条件，在任意情况下都可解读为“大致的”、“大约的”意思。相应的，除有明确的特指外，在下述以及权利要求中所引用的数字参数都是大致的参数，在各自的实验条件下由于标准误差的不同，有可能会得到不同的数字参数。
本文中，当一个化合物的化学结构式和化学名称有分歧或疑义时，以化学结构式确切定义此化合物。本文所描述的化合物有可能含有一个或多个手性中心，和/或者双键以及诸如此类的结构，也可能存在立体异构体，包括双键的异构体(比如几何异构体)、旋光对映异构体或者非对映异构体。相应的，在本文描述范围内的任意化学结构，无论是部分或整体结构中含有上述类似结构，都包括了此化合物的所有可能的对映异构体和非对映异构体，其中也包括了单纯的任一种立体异构体(如单纯的几何异构体、单纯的对映异构体或者单纯的非对映异构体)以及这些异构体的任意一种混合物。这些消旋异构体和立体异构体的混合物由本领域技术人员利用不停的分离技术或手性分子合成的方法也可进一步被拆分成其组成成分的对映异构体或立体异构体。
结构式I的化合物包含了，但并不仅限于，这些化合物的光学异构体、 消旋体和/或其他的混合物。上述情况下，其中单一的对映异构体或非对映异构体，如有旋光的异构体，可以用不对称合成的方法或消旋体拆分的方法获得。消旋体的拆分可用不同的方法实现，如常规的用助拆分的试剂重结晶，或用色谱方法。另外，结构式I的化合物也包含了带双键的顺式和/或反式的异构体。
本发明所述化合物包含但不限于，结构式I所示化合物以及他们所有的在药学上可用的不同形式。这些化合物的药学上可用的不同形式包括各种可药用的盐、溶剂化物、络合物、螯合物、非共价的复合物、基于上述物质基础上的药物前体和上述这些形式的任意混合物。
本发明提供的结构I所示的化合物具有预防或治疗骨质疏松症的活性。
本发明中涉及的英文缩写所对应的中文名称见下表所示：
制备方法，包括：起始树脂为Rink Amide MBHA树脂，用固相多肽合成法制备肽树脂，肽树脂再经酸解得到粗品，最后粗品经过纯化得到纯品；其中固相多肽合成法制备肽树脂的步骤为在载体树脂上通过固相偶联合成法依次接入序列中相对应的保护氨基酸或片段，制备得到肽树脂。
上述制备方法中，所述的Fmoc-保护氨基酸或保护氨基酸片段的用量为所投料树脂总摩尔数的1.2～6倍；优选为2.5～3.5倍。
上述制备方法中，所述的载体树脂取代值为0.2～1.0mmol/g树脂，优选的取代值为0.3～0.5mmol/g树脂。
作为本发明优选的方案，所述固相偶联合成法为：前一步反应得到的保护氨基酸-树脂脱去Fmoc保护基后再与下一个保护氨基酸偶联反应。所述的去Fmoc保护的脱保护时间为10～60分钟，优选的为15～25分钟。所述的偶联反应时间为60～300分钟，优选的为100～140分钟。
所述的偶联反应需添加缩合试剂，缩合试剂选自DIC(N,N-二异丙基碳二亚胺)、N,N-二环己基碳二亚胺，六氟磷酸苯并***-1-基-氧基三吡咯烷基磷、2-(7-氮杂-1H-苯并三氮唑-1-基)-1,1,3,3-四甲基脲六氟磷酸酯、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐或O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯中的一种；优选的为N,N-二异丙基碳二亚胺。所述缩合试剂的摩尔用量为氨基树脂中氨基总摩尔数的1.2～6倍，优选为2.5～3.5倍。
所述的偶联反应需添加活化试剂，活化试剂选自1-羟基苯并***或N-羟基-7-氮杂苯并三氮唑，优选的为1-羟基苯并***。活化试剂的用量为氨基树脂中氨基总摩尔数的1.2～6倍，优选的为2.5～3.5倍。
作为本发明优选的方案，所述的脱去Fmoc保护的试剂为PIP/DMF(哌啶/N,N-二甲基甲酰胺)混合溶液，混合溶液中含哌啶为10～30％(V)。去Fmoc保护试剂的用量为每克氨基树脂5～15mL，优选的为每克氨基树脂8～12mL。
优选的，肽树脂经酸解同时脱去树脂及侧链保护基得到粗品：
进一步优选的，所述肽树脂酸解时采用的酸解剂为三氟醋酸(TFA)、1,2-乙二硫醇(EDT)和水的混合溶剂，混合溶剂的体积配比为：TFA为80～ 95％，EDT为1～10％，余量为水。
更进一步优选的，混合溶剂的体积配比为：TFA为89～91％、EDT为4～6％，余量为水。最优的，混合溶剂的体积配比为：TFA为90％、EDT为5％，余量为水。
所述酸解剂用量为每克肽树脂需要4～15mL酸解剂；优选的，每克肽树脂需要7～10mL酸解剂。
使用酸解剂裂解的时间为室温条件下1～6小时，优选的为3～4小时。
进一步的，粗品经高效液相色谱纯化、冻干得到纯品。
本发明提供的一种长效特立帕肽化合物中所用原料及试剂均可由市场购得。
下面结合实施例，进一步阐述本发明：
实施例1化合物的制备
1、肽树脂的合成
使用Rink Amide BHHA树脂为载体树脂，通过去Fmoc保护和偶联反应，依次接入序列中对应的保护氨基酸，制得肽树脂。
(1)接入主链第1个保护氨基酸
取3mmol第1个保护氨基酸和3mmol HOBt，用适量DMF溶解；另取3mmol DIC，搅拌下慢慢加入至保护氨基酸DMF溶液中，于室温环境中搅拌反应30分钟，得到活化后的保护氨基酸溶液，备用。
取1mmol的Rink amide MBHA树脂(取代值约0.4mmol/g)，采用20％PIP/DMF溶液去保护25分钟，洗涤过滤得到去Fmoc的树脂。
将活化后的第1个保护氨基酸溶液加入到已去Fmoc的树脂中，偶联反应60～300分钟，过滤洗涤，得含1个保护氨基酸的树脂。
(2)接入主链第2～34护氨基酸
采用上述接入主链第1个保护氨基酸同样方法，依次接入上述对应的第2～34护氨基酸，得含主链34基酸的树脂。
(3)接入侧链第1个保护氨基酸
取3mmol侧链第1个保护氨基酸和3mmol HOBt，用适量DMF溶解；另取3mmol DIC，搅拌下慢慢加入至保护氨基酸DMF溶液中，于室温环 境中搅拌反应30分钟，得到活化后的保护氨基酸溶液。
取2.5mmol四三苯基膦钯和25mmol苯硅烷，用适量二氯甲烷溶解，去保护4小时，过滤洗涤，得到去Alloc的树脂备用。
将加入活化后的侧链第1个保护氨基酸液加入到已去Alloc的树脂，偶联反应60～300分钟，过滤洗涤，得含侧链第1个保护氨基酸的树脂。
(4)接入侧链保护氨基酸
采用上述接入主链第1个保护氨基酸同样方法，依次接入侧链对应的保护氨基酸和单保护脂肪酸，得到肽树脂。
2、粗品的制备
取上述肽树脂，加入体积比为TFA︰水︰EDT＝95︰5︰5的裂解试剂(裂解试剂10mL/克树脂)，搅拌均匀，室温搅拌反应3小时，反应混合物使用砂芯漏斗过滤，收集滤液，树脂再用少量TFA洗涤3次，合并滤液后减压浓缩，加入无水***沉淀，再用无水***洗沉淀3次，抽干得类白色粉末即为粗品。
3、纯品的制备
取上述粗品，加水搅拌至完全溶解，溶液用0.45μm混合微孔滤膜过滤，纯化备用；
采用高效液相色谱法进行纯化，纯化用色谱填料为10μm的反相C18，流动相***为0.1％TFA/水溶液-0.1％TFA/乙腈溶液，30mm×250mm的色谱柱流速为20mL/min，采用梯度***洗脱，循环进样纯化，取粗品溶液上样于色谱柱中，启动流动相洗脱，收集主峰蒸去乙腈后，得纯化中间体浓缩液。
纯化中间体浓缩液用0.45μm滤膜滤过备用，采用高效液相色谱法进行换盐，流动相***为1％醋酸/水溶液-乙腈，纯化用色谱填料为10μm的反相C18，30mm×250mm的色谱柱流速为20mL/min(可根据不同规格的色谱柱，调整相应的流速)；采用梯度洗脱，循环上样方法，上样于色谱柱中，启动流动相洗脱，采集图谱，观测吸收度的变化，收集换盐主峰并用分析液相检测纯度，合并换盐主峰溶液，减压浓缩，得到纯品醋酸水溶液，冷冻干燥，得纯品。
用上述方法制备得到以下化合物：

实施例2生物活性的测定
1、测定方法
UMR-106细胞可高表达PTH受体，可与PTH化合物特异性结合，使细胞胞内cAMP水平迅速升高，再通过均相时间分辨荧光技术测定各剂量刺激细胞后的相对光单位(RLU)，进而计算出激动剂的EC50。
本发明采用了稳定表达PTH-R的UMR-106细胞系，用不同浓度的激动剂刺激细胞，通过测定各剂量刺激后细胞后的相对光单位，进而得到化合物的EC50。
2、测定结果
测定结果见下表。
上述试验结果表明，经过长效化修饰后，所得修饰化合物的活性明显降低，但有部分化合物的保留了特立帕肽20％以上的生物活性，满足长 效化要求。
实施例3初步药代特性的测定
试验动物为食蟹猴，雄性食蟹猴2只，皮下给药，剂量为0.1mg/kg，分别于药前(0h)、以及给药后1h、2h、3h、4h、8h、12h、18h、24h、48h、96h、144h、168h静脉取血，离心分离血浆样本，用液质联用法分别测定血浆样本中相应化合物的血药浓度，化合物皮下(SC)给药半衰期见下表：
对生物活性最高的修饰化合物(化合物10)进行了初步药代特性的测定，试验结果表明化合物10半衰期为89.4hrs，换算成的人的半衰期约178.8hrs，远高于特立帕肽半衰期(1hrs)。
以上对本发明所提供的一种长效特立帕肽化合物进行了详细介绍。本文应用了具体个例对本发明的原理及实施方式进行了阐述，以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于本技术领域技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。

Claims (10)

  1. 特立帕肽化合物，其特征在于，包括：
    (Ⅰ)、具有式Ⅰ所示的氨基酸序列；或
    Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-AA1(R)-His-
    Leu-Asn-Ser-Met-Glu-Arg-Val-Glu-Trp-Leu-Arg-Lys-Lys-Leu-Gln-Asp-Val-His-Asn-Phe-AA2
    式Ⅰ
    (Ⅱ)、在如(Ⅰ)所示的氨基酸序列的基础上经取代、缺失、添加和/或替换1个或多个氨基酸的序列；或
    (Ⅲ)、与(Ⅰ)所示的氨基酸序列同源性90％以上的序列；或
    (IV)、具有如式Ⅰ所示特立帕肽化合物所成的可药用的盐、溶剂化物、螯合物或非共价复合物；和/或
    (V)、基于具有如式Ⅰ所示特立帕肽化合物基础上的药物前体；和/或
    (VI)、包括(IV)和/或(V)的任意混合物。
  2. 如权利要求1所述的特立帕肽化合物，其特征在于，所述结构I中的AA1选自D型或L型的Lys，D型或L型的Dap，D型或L型的Dab，D型或L型的Orn，D型或L型的Dah，或D型或L型的Dao；
    所述AA2选自NH2，或为OH；
    所述R选自HO2C(CH2)n1CO-(AA3)n2-(PEGn3(CH2)n4CO)n5-或HO2C(CH2)n1CO-(AA3)n2-(AA4)n6-：
    其中：n1选自10至20的整数；
    n2选自1至5的整数；
    n3选自1或3至30的整数；
    n4选自1至5的整数；
    n5选自0或1至10的整数；
    n6选自0或1至10的整数；
    AA3选自γGlu，εLys，β-Ala，γ-氨基丁酸或5-Ava；
    AA4选自Gly，Ser，Thr，Asp，Glu，Aad，Lys，Orn，Dab或Dap。
  3. 如权利要求1或2所述特立帕肽化合物的制备方法，其特征在于，包括如下步骤：
    步骤1：经固相多肽合成获得所述特立帕肽化合物的肽树脂；
    步骤2：酸解、纯化，制得所述特立帕肽化合物。
  4. 如权利要求3所述制备方法制得的特立帕肽化合物。
  5. 如下任意项在制备预防和/或治疗疾病的药物中的应用：
    (I)、如权利要求1或2所述的特立帕肽化合物；和/或
    (II)、如权利要求4所述的特立帕肽化合物。
  6. 如权利要求5所述的应用，其特征在于，所述疾病包括骨质疏松症。
  7. 药物，其特征在于，包括如下任意项以及药学上可接受的辅料或助剂：
    (I)、如权利要求1或2所述的特立帕肽化合物；和/或
    (II)、如权利要求4所述的特立帕肽化合物。
  8. 药物组合，其特征在于，包括如权利要求7所述的药物以及其他任意有效成分。
  9. 治疗疾病的方法，其特征在于，其包含向受试者施用以下任意项：
    (I)、如权利要求1或2所述的特立帕肽化合物；和/或
    (II)、如权利要求4所述的特立帕肽化合物；和/或
    (III)、如权利要求7所述的药物；和/或
    (IV)、如权利要求8所述的药物组合。
  10. 如权利要求9所述的方法，其特征在于，所述疾病包括骨质疏松症。
PCT/CN2023/110943 2022-08-10 2023-08-03 一种长效特立帕肽化合物 WO2024032457A1 (zh)

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CN108601833A (zh) * 2016-02-01 2018-09-28 伊莱利利公司 甲状旁腺激素-抗rankl抗体融合化合物
CN109789189A (zh) * 2016-09-29 2019-05-21 阿森迪斯药物骨疾病股份有限公司 控释pth化合物的剂量方案
CN111848778A (zh) * 2019-04-30 2020-10-30 上海医药工业研究院 特立帕肽类似物
CN114057863A (zh) * 2020-08-06 2022-02-18 珠海联邦制药股份有限公司 一种甲状旁腺激素相关肽类似物及其应用

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CN102731643A (zh) * 2012-06-26 2012-10-17 深圳翰宇药业股份有限公司 一种治疗骨质疏松多肽的制备方法
CN108601833A (zh) * 2016-02-01 2018-09-28 伊莱利利公司 甲状旁腺激素-抗rankl抗体融合化合物
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