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CN-122029215-A - Amino group-containing acetal-type releasable polyoxyethylene derivative, process for producing the same, and amino group-containing acetal-type releasable polyoxyethylene conjugate

CN122029215ACN 122029215 ACN122029215 ACN 122029215ACN-122029215-A

Abstract

An amino group-containing acetal-type releasable polyoxyethylene derivative represented by a specific formula, a process for producing the same, and an amino group-containing acetal-type releasable polyoxyethylene conjugate.

Inventors

  • Yu Cunjian
  • DOHI Reina

Assignees

  • 日油株式会社

Dates

Publication Date
20260512
Application Date
20241011
Priority Date
20231016

Claims (10)

  1. 1. An amino group-containing acetal-type releasable polyoxyethylene derivative represented by the following formula (1), formula (2), formula (3) or formula (4): in the formulas (1), (2), (3) and (4), B 1 is a hydrogen atom or-C (R 1 )(R 2 )OC(O)E 1 , E 1 is a leaving group and, P 1 is a polyoxyethylene derivative moiety, W is an integer of 1 to 8, R 1 、R 2 、R 3 、R 4 、R 5 and R 12 are each independently a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, R 6 is a hydrogen atom or a hydrocarbon group having 1 to 24 carbon atoms which may be substituted, R 7 、R 8 、R 9 、R 10 and R 11 are each independently an electron-withdrawing substituent, an electron-donating substituent or a hydrogen atom, R 13 is a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms which may be substituted, R 14 is a hydrocarbon group having 1 to 10 carbon atoms which may be substituted, R 13 can be bonded to R 14 , an M is 0 or 1.
  2. 2. The amino group-containing acetal type releasable polyoxyethylene derivative according to claim 1, wherein m is 0, R 1 and R 2 are each a hydrogen atom, and R 3 、R 4 、R 5 and R 12 are each independently a hydrogen atom or a methyl group.
  3. 3. The amino group-containing acetal releasable polyoxyethylene derivative according to claim 1 or 2, wherein, M is 0 and is the number of the three-dimensional space, R 1 and R 2 are each a hydrogen atom, R 3 、R 4 、R 5 and R 12 are each independently a hydrogen atom or a methyl group, R 13 and R 14 in L 1 are bonded to each other, R 13 is a hydrocarbon group represented by the following formula (5), and R 14 is a hydrocarbon group represented by the following formula (6): in the above-mentioned formula (5), R 15 and R 16 are each independently a hydrogen atom or a hydrocarbon group having 1 to 4 carbon atoms which may be substituted, Q1 is an integer of 1 to 4, ( 1) Represents a bond point with N, and ( 2) Represents the bonding point with R 14 , In the above-mentioned formula (6), R 17 and R 18 are each independently a hydrogen atom or a hydrocarbon group having 1 to 4 carbon atoms which may be substituted, R 19 is CR 20 or a nitrogen atom, R 20 is a hydrogen atom or a hydrocarbon group having 1 to 4 carbon atoms which may be substituted, Q2 is an integer of 0 to 3, Z 1 is a single bond or a divalent spacer linking P 1 to a carbon or nitrogen atom of R 19 , ( 3) Indicating the point of bonding to N, ( 4) Represents the bond point with R 13 , and ( 5) Indicating the bond point to P 1 .
  4. 4. The amino group-containing acetal releasable polyoxyethylene derivative according to claim 3, wherein, M is 0 and is the number of the three-dimensional space, R 1 and R 2 are each a hydrogen atom, R 3 、R 4 、R 5 and R 12 are each independently a hydrogen atom or a methyl group, R 13 and R 14 are bonded to each other, R 15 and R 16 are each a hydrogen atom, Q1 is a number of times which is 2, R 17 and R 18 are each a hydrogen atom, R 19 is a methine group or a nitrogen atom, and Q2 is 2.
  5. 5. A method for producing an amino group-containing acetal-type releasable polyoxyethylene derivative according to claim 1, 2, 3 or 4, which comprises: a coupling step of coupling a polyoxyethylene derivative with a benzaldehyde derivative or a phenyl ketone derivative to obtain a coupled product represented by the following formula (7) or (8); An acetalization step of reacting, after the coupling step, the coupling product represented by the following formula (7) or (8) with a phenol having a hydroxymethyl group at the 2-position and a substituent (-ch=cb 1 )C(R 1 )(R 2 ) -OH at the 4-or 6-position under acidic conditions to obtain an acetal structure, wherein B 1 、m、R 1 and R 2 are as described above, and A leaving group structure introducing step of introducing a leaving group structure (-OC (O) E 1 ) to the terminal of the substituent at the 4-position or the 6-position, wherein E 1 is a leaving group, In formula (7) and formula (8), P 1 、w、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 13 and R 14 are as described above.
  6. 6. The method for producing an amino group-containing acetal releasable polyoxyethylene derivative according to claim 5, further comprising: A dialkylation step of reacting the coupled product represented by the formula (7) or the formula (8) with a monohydric alcohol under acidic conditions between the coupling step and the acetalization step to obtain a dialkylacetal structure represented by the following formula (9) or the following formula (10): [ chemical formula 10] In the formulas (9) and (10), R 21 and R 22 are each independently a hydrocarbon group having 1 to 10 carbon atoms, and P 1 、w、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 13 and R 14 are as described above.
  7. 7. The method for producing an amino group-containing acetal releasable polyoxyethylene derivative according to claim 5, further comprising, between the acetalization step and the leaving group structure introducing step: a deprotection step of deprotecting an amino group protected by a protecting group in the coupled product, and A step of introducing a functional group capable of reacting with a biofunctional molecule to the amino group which has been deprotected, after the deprotection step.
  8. 8. The method for producing an amino group-containing acetal releasable polyoxyethylene derivative according to claim 6, further comprising, between the acetalization step and the leaving group structure introducing step: A deprotection step of deprotecting an amino group protected by a protecting group in the dialkylacetal structure, and A step of introducing a functional group capable of reacting with a biofunctional molecule to the amino group which has been deprotected, after the deprotection step.
  9. 9. An amino group-containing acetal-form releasable polyoxyethylene conjugate represented by the following formula (11), formula (12), formula (13) or formula (14) and which breaks under physiological conditions, [ Chemical formula 11] [ Chemical formula 12] [ Chemical formula 13] [ Chemical formula 14] In the formula (11), the formula (12), the formula (13) and the formula (14), B 2 is a hydrogen atom or-C (R 1 )(R 2 )OC(O)NHD 1 , D 1 is a residue obtained by removing an amino group constituting a urethane bond from amino groups contained in a biofunctional molecule, P 2 is a polyoxyethylene derivative moiety or a combination of a polyoxyethylene derivative moiety and a biologically functional molecule, W is an integer of 1 to 8, R 1 、R 2 、R 3 、R 4 、R 5 and R 12 are each independently a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, R 6 is a hydrogen atom or a hydrocarbon group having 1 to 24 carbon atoms which may be substituted, R 7 、R 8 、R 9 、R 10 and R 11 are each independently an electron-withdrawing substituent, an electron-donating substituent or a hydrogen atom, R 13 is a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms which may be substituted, R 14 is a hydrocarbon group having 1 to 10 carbon atoms which may be substituted, R 13 can be bonded to R 14 , an M is 0 or 1.
  10. 10. A method of producing an amino group-containing acetal releasable polyoxyethylene conjugate according to claim 9, the method comprising: A coupling step of reacting the acetal releasable polyoxyethylene derivative according to claim 1 or 2 with a biofunctional molecule in a neutral or alkaline buffer solution, which may comprise a water-soluble organic solvent, and A purification step, after the coupling step, of purifying under neutral or alkaline conditions.

Description

Amino group-containing acetal-type releasable polyoxyethylene derivative, process for producing the same, and amino group-containing acetal-type releasable polyoxyethylene conjugate Technical Field The present invention relates to an amino group-containing acetal-type releasable polyoxyethylene derivative, a method for producing the same, and a conjugate with a biofunctional molecule, namely an amino group-containing acetal-type releasable polyoxyethylene conjugate. Background In general, when a drug such as a hormone, a cytokine, an enzyme, or the like is administered into an organism using a bio-functional molecule, it is rapidly discharged from the organism through glomerular filtration in the kidney and ingestion of macrophages in the liver or spleen. Therefore, the half-life of the drug in blood is short, and it is often difficult to obtain a sufficient pharmacological effect. To solve this problem, attempts have been made to chemically modify biofunctional molecules with water-soluble polymers such as Polyoxyethylene (PEG). As a result, the half-life of the biofunctional molecules in the blood can be prolonged by increasing the molecular weight and forming a hydration layer. It is well known that such modifications can produce effects such as reduced toxicity and antigenicity of the biofunctional molecules, improved agglutination properties, etc. On the other hand, it is known that a bio-functional molecule chemically modified with a water-soluble polymer such as PEG may have adverse effects such as reduced interaction with a target bio-endogenous molecule or receptor, reduced intrinsic pharmacological effects of the bio-functional molecule, or changes in vivo or intracellular behaviors due to the formation of a hydration layer of the water-soluble polymer or steric shielding effect at an active site. As a method for solving the above-mentioned problems, a method of chemically modifying a biofunctional molecule with a water-soluble polymer via a temporary bond and releasing the biofunctional molecule without chemical modification by breaking the temporary bond in vivo, i.e., a prodrug forming method, is used. In recent years, for a biofunctional molecule modified with a water-soluble polymer, the techniques described in patent documents 1 and 2 are known as techniques capable of preventing a decrease in the intrinsic pharmacological action of the biofunctional molecule and a kinetic change of an organism or a cell by using a prodrug forming method. Patent documents 1 and 2 report that pegylated hGH and pegylated IL-2 obtained by modifying human growth hormone (hGH) and interleukin 2 (IL-2) as biofunctional molecules with PEG, respectively, via a linker which is decomposed at an appropriate rate under physiological conditions, i.e., in an enzyme-independent manner under neutral conditions, the pegylated hGH and the pegylated IL-2 are capable of having an extended half-life in blood, and the decrease in pharmacological effects caused by pegylation can be improved by releasing the biofunctional molecules upon the decomposition of the linker. Therefore, prodrug forming technology is very important, which is capable of extending the half-life of a bio-functional molecule in blood and of releasing the bio-functional molecule at an appropriate rate under physiological conditions in an enzyme-independent manner to exert pharmacological effects. Patent document 3 reports a compound that cleaves a temporary bond in a biofunctional molecule chemically modified with PEG independently of enzyme and releases the biofunctional molecule that has not been chemically modified. Specifically, it is reported that hydrolysis of a linker having an acetal structure hydrolyzed under acidic conditions initiates cleavage of a urethane bond as a temporary bond by 1, 4-or 1, 6-benzyl detachment, and releases a biologically functional molecule which is not chemically modified. Prior art documents Patent literature JP2018-150311A in patent document 1 Patent document 2 JP2022-000043A Patent document 3 JP2018-172648A Disclosure of Invention Problems to be solved by the invention In the example of patent document 3, a structure capable of releasing a bio-functional molecule in an enzyme-independent manner and capable of releasing a bio-functional molecule under acidic conditions is exemplified. However, there has been no description of a prodrug forming technology capable of releasing a bio-functional molecule at an appropriate rate under physiological conditions, i.e., neutral conditions of pH about 7.4, in an enzyme-independent manner to exert pharmacological effects. In view of the above problems, an object of the present invention is to provide a polyoxyethylene derivative containing an amino group and having an acetal structure, which is characterized in that a biologically functional molecule is formed as a prodrug and gradually released under physiological conditions, a stable production method thereof, and an acetal-type relea