CN117586372A - Long-acting teriparatide compound - Google Patents

Long-acting teriparatide compound Download PDF

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Publication number
CN117586372A
CN117586372A CN202210957714.6A CN202210957714A CN117586372A CN 117586372 A CN117586372 A CN 117586372A CN 202210957714 A CN202210957714 A CN 202210957714A CN 117586372 A CN117586372 A CN 117586372A
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CN
China
Prior art keywords
compound
teriparatide
integer
leu
resin
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Pending
Application number
CN202210957714.6A
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Chinese (zh)
Inventor
周述靓
王鹏
邓岚
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Chengdu Aoda Biotechnology Co ltd
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Chengdu Aoda Biotechnology Co ltd
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Priority to CN202210957714.6A priority Critical patent/CN117586372A/en
Priority to PCT/CN2023/110943 priority patent/WO2024032457A1/en
Publication of CN117586372A publication Critical patent/CN117586372A/en
Pending legal-status Critical Current

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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 (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 (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

Abstract

The invention relates to the field of medicine synthesis, and discloses a long-acting teriparatide compound. The long-acting compound is used for preparing a pharmaceutical composition for treating diseases, and the pharmaceutical composition is applied to preventing and treating osteoporosis.

Description

Long-acting teriparatide compound
Technical Field
The present invention relates to a long-acting teriparatide compound which is useful in the treatment of osteoporosis.
Background
Teriparatide is a synthetic polypeptide hormone, a 1-34 amino acid fragment of human parathyroid hormone PTH, which is the N-terminal region of the 84 amino acid endogenous parathyroid hormone PTH with biological activity. 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 bone fracture in postmenopausal women, and increases or decreases bone density depending on the mode of administration. Continuous infusion can result in sustained increases in parathyroid hormone PTH concentration and thus greater bone resorption than would occur with daily injections which only result in a brief increase in serum parathyroid hormone PTH concentration. In addition, teriparatide does not inhibit platelet aggregation response of either the adenosine diphosphate-induced pathway or the collagen-induced pathway.
The peak value of the blood concentration is reached 0.5 hour after the subcutaneous injection of teriparatide, the effect is achieved in 3 months, and the bioavailability is 95%. The duration of time after a single administration of intramuscular injection was 6 hours. The volume of distribution after intravenous injection was 0.1L/kg. The medicine may be decomposed into fragments by liver nonspecific proteolytic enzyme, and then excreted by kidney, and the clearance rate of kidney is 90%. Whereas the total clearance of the medicine is about 90L/h for men and about 60L/h for women. Teriparatide elimination half-life was given subcutaneously for 1 hour and intravenously for 5 minutes.
Disclosure of Invention
The present invention provides a long-acting teriparatide compound which is useful for the treatment of osteoporosis.
To achieve the above object, the present invention provides a compound of the formula I, a pharmaceutically acceptable salt, solvate, chelate or non-covalent complex thereof, a prodrug based on the compound, or a mixture of any of the above forms.
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
Structure I
AA1 in structure I is Lys of D or L form, or Dap of D or L form, or Dab of D or L form, or Orn of D or L form, or Dah of D or L form, or Dao of D or L form;
AA2 in structure I is NH 2 Or is OH;
r in structure I is HO 2 C(CH 2 ) n1 CO-(AA3) n2 -(PEG n3 (CH2) n4 CO) n5 -; or is as follows
HO 2 C(CH 2 ) n1 CO-(AA3) n2 -(AA4) n6 -：
Wherein: 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 γglu, or εlys, or β -Ala, or γ -aminobutyric acid, or 5-Ava;
AA4 is Gly, or Ser, or Thr, or Asp, or Glu, or Aad, or Lys, or Orn, or Dab, or Dap.
The invention also provides a pharmaceutical composition comprising the compound according to the invention, and the use of the pharmaceutical composition of the compound for preparing a medicament for treating a disease.
Preferably, the pharmaceutical composition is used for preventing and treating osteoporosis.
Further details of the invention are set forth in the accompanying drawings and the description below, or may be learned by practice of the invention.
Unless otherwise indicated, the amounts of the various components, reaction conditions, and the like, are used herein and are to be construed in any sense as "generally", "about". Accordingly, unless explicitly indicated otherwise, the numerical parameters set forth in the following claims are approximations that may vary depending upon the standard deviation employed under the particular circumstances.
Herein, when the chemical structural formula and chemical name of a compound are divergent or ambiguous, the compound is defined exactly by the chemical structural formula. The compounds described herein may contain one or more chiral centers, and/or double bonds and the like, and stereoisomers, including isomers of double bonds (such as geometric isomers), optical enantiomers or diastereomers, may also be present. Accordingly, any chemical structure within the scope of the description herein, whether partial or whole containing such structures, includes all possible enantiomers and diastereomers of the compound, including any single stereoisomer (e.g., a single geometric isomer, a single enantiomer, or a single diastereomer), and mixtures of any of these isomers. These racemic isomers and mixtures of stereoisomers may also be resolved further into their constituent enantiomers or stereoisomers by methods known to those skilled in the art using continuous separation techniques or chiral molecule synthesis.
The compounds of formula I include, but are not limited to, optical isomers, racemates and/or other mixtures of these compounds. In the above cases, single enantiomers or diastereomers, such as optical isomers, may be obtained by asymmetric synthesis or resolution of racemates. Resolution of the racemate can be accomplished in various ways, such as recrystallization with conventional resolution-aiding reagents, or by chromatographic methods. In addition, the compounds of the formula I also contain cis-and/or trans-isomers with double bonds.
The compounds of the present invention include, but are not limited to, the compounds of formula I and all of their various pharmaceutically acceptable forms. Pharmaceutically useful different forms of these compounds include various pharmaceutically acceptable salts, solvates, complexes, chelates, non-covalent complexes, prodrugs based on the above, and mixtures of any of these forms.
The compound shown in the structure I provided by the invention has stable performance and has the activity of preventing or treating osteoporosis.
Detailed Description
The invention discloses a long-acting teriparatide compound, and a person skilled in the art can appropriately improve related parameters by referring to the content of the specification. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and are deemed to be included in the present invention. While the process of the present invention has been described in terms of preferred embodiments, it will be apparent to those skilled in the relevant art that variations and modifications can be made in the compounds and methods of preparation described herein, or in appropriate combinations, without departing from the spirit and scope of the invention.
The Chinese names corresponding to the English abbreviations in the invention are shown in the following table:
example 1 preparation of Compounds
The preparation method comprises the following steps: the initial resin is RinkAmide MBHA resin, the peptide resin is prepared by a solid-phase polypeptide synthesis method, the peptide resin is acidolyzed to obtain a crude product, and finally the crude product is purified to obtain a pure product; wherein the step of preparing peptide resin by solid-phase polypeptide synthesis method is to sequentially access the corresponding protected amino acid or fragment in the sequence on the carrier resin by solid-phase coupling synthesis method, so as to prepare the peptide resin.
In the preparation method, the dosage of the Fmoc-protected amino acid or the protected amino acid fragment is 1.2-6 times of the total mole number of the resin; preferably 2.5 to 3.5 times.
In the preparation method, 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.
As a preferred scheme of the invention, the solid phase coupling synthesis method is as follows: the protected amino acid-resin obtained in the previous step is subjected to Fmoc protecting group removal and then is subjected to coupling reaction with the next protected amino acid. The deprotection time for Fmoc deprotection 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 needs to add a condensation reagent, wherein the condensation reagent is selected from DIC (N, N-diisopropyl carbodiimide), N, N-dicyclohexylcarbodiimide, benzotriazol-1-yl-oxy-tripyrrolidinylphosphine hexafluorophosphate, 2- (7-aza-1H-benzotriazol-1-yl) -1, 3-tetramethylurea hexafluorophosphate, benzotriazol-N, N, N ', N' -tetramethylurea hexafluorophosphate or O-benzotriazol-N, N, N ', N' -tetramethylurea tetrafluoroborate; n, N-diisopropylcarbodiimide is preferred. The molar amount of the condensing agent is 1.2 to 6 times, preferably 2.5 to 3.5 times, the total molar amount of the amino groups in the amino resin.
The coupling reaction needs to add an activating reagent, and the activating reagent is selected from 1-hydroxybenzotriazole or N-hydroxy-7-azabenzotriazole, and is preferably 1-hydroxybenzotriazole. The amount of the activating agent to be used is 1.2 to 6 times, preferably 2.5 to 3.5 times, the total mole number of the amino groups in the amino resin.
As a preferred scheme of the invention, the Fmoc protection removing reagent is PIP/DMF (piperidine/N, N-dimethylformamide) mixed solution, and the mixed solution contains 10-30% (V) of piperidine. The Fmoc-removing protective agent is used in an amount of 5-15 mL per gram of amino resin, preferably 8-12 mL per gram of amino resin.
Preferably, the peptide resin is subjected to acidolysis and simultaneously the resin and side chain protecting group are removed to obtain a crude product:
further preferably, the acidolysis agent used in 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 as follows: 80-95% of TFA, 1-10% of EDT and the balance of water.
Still more preferably, the volume ratio of the mixed solvent is: 89-91% TFA, 4-6% EDT and the balance water. Optimally, the volume ratio of the mixed solvent is as follows: TFA 90%, EDT 5%, balance water.
The dosage of the acidolysis agent is 4-15 mL of acidolysis agent required by each gram of peptide resin; preferably, 7 to 10mL of acidolysis agent is required per gram of peptide resin.
The time for cleavage with acidolysis agent is 1 to 6 hours, preferably 3 to 4 hours, at room temperature.
Further, purifying the crude product by high performance liquid chromatography, and lyophilizing to obtain pure product.
1. Synthesis of peptide resins
The RinkAmide BHHA resin is used as carrier resin, and the peptide resin is prepared by removing Fmoc protection and coupling reaction and sequentially accessing corresponding protected amino acid in the sequence.
(1) Access to backbone 1 st protected amino acid
Taking 3mmol of the 1 st protected amino acid and 3mmol of HOBt, and dissolving the 1 st protected amino acid and the 3mmol of HOBt with a proper amount of DMF; and 3mmol of DIC is taken, slowly added into the protected amino acid DMF solution under stirring, and stirred and reacted for 30 minutes in a room temperature environment to obtain an activated protected amino acid solution for later use.
1mmol of Rink amide MBHA resin (substitution value about 0.4 mmol/g) was taken and deprotected with 20% PIP/DMF solution for 25 min, washed and filtered to give Fmoc-removed resin.
And adding the activated 1 st protected amino acid solution into Fmoc-removed resin, performing coupling reaction for 60-300 minutes, and filtering and washing to obtain the resin containing 1 protected amino acid.
(2) Amino acid 2-34 of access main chain
The same method of accessing the 1 st protected amino acid of the main chain is adopted, and the corresponding 2 nd to 34 th protected amino acids are sequentially accessed to obtain the resin containing 34 th base acid of the main chain.
(3) Access to side chain 1 st protected amino acid
Taking 3mmol of the 1 st protected amino acid of the side chain and 3mmol of HOBt, and dissolving the protected amino acid and the HOBt with a proper amount of DMF; and 3mmol of DIC is taken, slowly added into the protected amino acid DMF solution under stirring, and stirred and reacted for 30 minutes in a room temperature environment to obtain the activated protected amino acid solution.
2.5mmol of tetraphenylphosphine palladium and 25mmol of phenylsilane are taken, dissolved with a proper amount of dichloromethane, deprotected for 4 hours, filtered and washed to obtain dealloc resin for later use.
Adding the 1 st protective amino acid liquid of the side chain after the activation into the dealloc-removed resin, carrying out coupling reaction for 60-300 minutes, and filtering and washing to obtain the resin containing the 1 st protective amino acid of the side chain.
(4) Access side chain protected amino acids
The same method of accessing the 1 st protected amino acid of the main chain is adopted, and the protected amino acid and the single protected fatty acid corresponding to the side chain are sequentially accessed to obtain the peptide resin.
2. Preparation of crude product
Adding a cracking reagent (10 mL/g resin) with a volume ratio of TFA to water to EDT=95 to 5 into the peptide resin, uniformly stirring, stirring at room temperature for reaction for 3 hours, filtering a reaction mixture by using a sand core funnel, collecting filtrate, washing the resin with a small amount of TFA for 3 times, combining the filtrates, concentrating under reduced pressure, adding anhydrous diethyl ether for precipitation, washing the precipitation with anhydrous diethyl ether for 3 times, and pumping to obtain white-like powder which is a crude product.
3. Preparation of pure product
Adding water into the crude product, stirring until the crude product is completely dissolved, filtering the solution by using a 0.45 mu m mixed microporous filter membrane, and purifying for later use;
purifying by high performance liquid chromatography, wherein the chromatographic packing for purification is reverse phase C18 with the size of 10 μm, the mobile phase system is 0.1% TFA/water solution-0.1% TFA/acetonitrile solution, the flow rate of a chromatographic column with the size of 30mm is 250mm is 20mL/min, eluting by a gradient system, circularly sampling and purifying, sampling the crude product solution into the chromatographic column, starting mobile phase eluting, collecting main peaks, evaporating acetonitrile, and obtaining the purified intermediate concentrated solution.
Filtering the purified intermediate concentrate with 0.45 μm filter membrane for use, changing salt by high performance liquid chromatography, wherein the mobile phase system is 1% acetic acid/water solution-acetonitrile, the chromatographic column flow rate of purification column is 20mL/min (corresponding flow rate can be adjusted according to chromatographic columns of different specifications) with reversed phase C18 of 10 μm and 30mm x 250 mm; adopting a gradient elution and cyclic loading method, loading in a chromatographic column, starting mobile phase elution, collecting a spectrum, observing the change of absorbance, collecting a salt-exchange main peak, analyzing the liquid phase to detect purity, combining the salt-exchange main peak solutions, concentrating under reduced pressure to obtain a pure acetic acid aqueous solution, and freeze-drying to obtain a pure product.
The following compounds were prepared using the above procedure:
example 2 determination of biological Activity
1. Measurement method
UMR-106 cells can highly express PTH receptor, can be specifically combined with PTH compound, so that intracellular cAMP level of the cells is rapidly increased, and then Relative Light Units (RLU) after each dose of stimulated cells are measured through a homogeneous phase time-resolved fluorescence technology, so that EC50 of the agonist is calculated.
The UMR-106 cell line which stably expresses PTH-R is used to stimulate cells with different concentrations of agonist, and the EC50 of the compound is obtained by measuring the relative light units of the cells after each dose of stimulation.
2. Measurement results
The measurement results are shown in the following table.
Numbering of compounds EC50(pmol) Relative biological Activity%
Teriparatide 702.24 100.00
Compound 1 5831.00 12.04
Compound 2 3809.00 18.44
Compound 3 7674.00 9.15
Compound 4 9751.00 7.20
Compound 5 4904.15 14.32
Compound 6 4022.65 17.46
Compound 7 6321.00 11.11
Compound 8 18556.65 3.78
Compound 9 3369.43 20.84
Compound 10 2597.16 27.04
Compound 11 3944.00 17.81
Compound 12 5071.00 13.85
Compound 13 4006.08 17.53
Compound 14 3287.00 21.36
Compound 15 3252.00 21.59
EXAMPLE 3 determination of Primary drug substitution Properties
Test animals were cynomolgus monkeys, 2 male cynomolgus monkeys, were subcutaneously administered at a dose of 0.1mg/kg, and blood concentrations of the respective compounds in the plasma samples were measured by intravenous blood sampling at 1h, 2h, 3h, 4h, 8h, 12h, 18h, 24h, 48h, 96h, 144h, 168h, respectively, before administration (0 h), and after administration, and the Subcutaneous (SC) administration half lives of the compounds were shown in the following table:
compounds of formula (I) t 1/2 (h)
Compound 10 89.4

Claims (4)

1. A long acting teriparatide compound having the structural formula i:
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
structure I
AA1 in structure I is Lys of D or L form, or Dap of D or L form, or Dab of D or L form, or Orn of D or L form, or Dah of D or L form, or Dao of D or L form;
AA2 in structure I is NH 2 Or is 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 -：
Wherein: 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 γglu, or εlys, or β -Ala, or γ -aminobutyric acid, or 5-Ava;
AA4 is Gly, or Ser, or Thr, or Asp, or Glu, or Aad, or Lys, or Orn, or Dab, or Dap.
2. The long acting teriparatide compound according to claim 1, comprising a pharmaceutically acceptable salt, solvate, chelate or non-covalent complex of the compound, a prodrug based on the compound, or a mixture of any of the above forms.
3. A long acting teriparatide compound according to claim 1 and claim 2 for use in the preparation of a pharmaceutical composition for the treatment of a disease.
4. A pharmaceutical composition according to claim 3 for use in the prevention and treatment of osteoporosis.
CN202210957714.6A 2022-08-10 2022-08-10 Long-acting teriparatide compound Pending CN117586372A (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN202210957714.6A CN117586372A (en) 2022-08-10 2022-08-10 Long-acting teriparatide compound
PCT/CN2023/110943 WO2024032457A1 (en) 2022-08-10 2023-08-03 Long-acting teriparatide compound

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202210957714.6A CN117586372A (en) 2022-08-10 2022-08-10 Long-acting teriparatide compound

Publications (1)

Publication Number Publication Date
CN117586372A true CN117586372A (en) 2024-02-23

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WO (1) WO2024032457A1 (en)

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102731643A (en) * 2012-06-26 2012-10-17 深圳翰宇药业股份有限公司 Method for preparing polypeptide used for treating osteoporosis
AU2017214277B2 (en) * 2016-02-01 2020-02-27 Eli Lilly And Company Parathyroid hormone – anti-RANKL antibody fusion compounds
US11590207B2 (en) * 2016-09-29 2023-02-28 Ascendis Pharma Bone Diseases A/S Dosage regimen for a controlled-release PTH compound
CN111848778B (en) * 2019-04-30 2024-03-19 上海医药工业研究院 Teriparatide analogues
CN114057863B (en) * 2020-08-06 2023-10-20 珠海联邦制药股份有限公司 Parathyroid hormone related peptide analogue and application thereof

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