JPWO2021250059A5

JPWO2021250059A5 -

Info

Publication number: JPWO2021250059A5
Application number: JP2022575708A
Authority: JP
Publication date: 2024-06-14

Claims

A process for preparing a compound of formula (I), comprising the steps of:
In the above-mentioned manufacturing method,
Compound of formula (II)
in reaction step (a) with iodine (I ₂ ), N-bromosuccinimide or N-iodosuccinimide, iodine monochloride, iodine monobromide, or bis(pyridine)iodonium tetrafluoroborate, in particular iodine, to give a compound of formula (I),
In the formula,
Z is selected from SH, S-trityl (STrt), S-acetamidomethyl (SAcm), S-diphenylmethyl (SDpm), S-monomethoxytrityl (SMmt) and S-tert-butyl (StBu), in particular Z is selected from SH, S-trityl (STrt), S-acetamidomethyl (SAcm), S-diphenylmethyl (SDpm), S-monomethoxytrityl (SMmt) and S-tert-butyl (StBu), especially Z is STrt;
Y is unsubstituted or hydroxyl-, halogen-, carbohalide-, alkynyl-, olefin-, cyano-, protected carboxylate- and/or carboxamide-substituted indole, in particular unsubstituted or hydroxyl-, halogen-, carbohalide-, alkynyl-, olefin-, cyano-, protected carboxylate- and/or carboxamide-substituted indole;
L ¹ is an unsubstituted or Me-substituted C ₁ -C ₂ alkyl linker, in particular L ¹ is CH ₂ ;
L ² is an unsubstituted or Me-substituted C ₁ -C ₂ alkyl linker, in particular L ¹ is CH ₂ or -C(CH ₃ ) ₂ -;
B is an α-amino acid, a β-amino acid backbone, an α-methyl amino acid, in particular B is an α-amino acid backbone (NH-CHR-C=O where R is ^L1 or ^L2 ):
- all A are independently selected from proteinogenic and non-proteinogenic α-amino acids in the L- or D-configuration, or β-amino acids, in particular all A are independently selected from proteinogenic and non-proteinogenic α-amino acids in the L- or D-configuration;
n is an integer selected from 2, 3, and 4;
However,
consists of 14 to 26 bonds, particularly 15 to 21 bonds, and especially 18 bonds;
C and D are each independently selected from proteinogenic and non-proteinogenic α-amino acids in the L- or D-configuration, where either C or D of formula (II) is resin-linked or has a protected N-terminus:
m and k are each independently selected from an integer from 0 to 4, in particular the sum of m and k is an integer between 0 and 4;
X is (-(-indole-S-) or (-S-indole-)-), said indole being unsubstituted or hydroxyl-, halogen-, carbohalide-, alkynyl-, olefin-, cyano-, protected carboxylate and/or carboxamide-substituted indole;
Optionally, the sulfur atom of X may be subsequently oxidized.

The method according to claim 1, wherein either C or D of formula (II) is linked to a resin and reacted with iodine ( _I2 ), in particular with iodine at a concentration ratio of 2:1 iodine/compound of formula (II).

The method according to claim 1, wherein either C or D of formula (II) has a protected N-terminus and is reacted with iodine ( _I2 ), in particular with a concentration ratio of iodine/compound of formula (II) of 1:1.

The method according to any one of claims 1 to 3 ,
Oxidizing the sulfur atom of Z, in particular
The sulfur atom of Z is
(i) manganese ions are used to convert a compound, in particular a compound of formula (V)
with Mn(OTf) ₂ _and _H2O2 ;
(ii) with PPO, dibenzoyl peroxide, tert-butyl peroxybenzoate, or lauroyl peroxide; or with mCPBA;
(iii) with iodine and oxygen,
Oxidize, method.

A process for preparing a compound of formula (VI), comprising the steps of:
In the above manufacturing method,
Compound of formula (VII)
(Wherein,
R ^NHA1 is an amino protecting group, in particular an amino protecting group cleavable under acidic or reducing conditions, especially Boc, Cbz, or triisopropylsilyl (TIPS), most especially Boc;
R ^NHA2 is an amino protecting group, in particular an amino protecting group cleavable under acidic or reducing conditions, especially Boc or Cbz, most especially Boc;
^RPG is a protecting group for a phenolic OH group, in particular a phenolic OH protecting group which is cleavable under basic or reducing conditions, especially under reducing conditions, in particular ^RPG is benzyl or acetyl, most particularly ^RPG is benzyl,
R ^COON is a carboxyl protecting group, especially a carboxyl protecting group cleavable under basic conditions, especially methyl, ethyl, benzyl, or tert-butyl, most especially methyl.
of,
H ₂ , an organometallic rhodium or ruthenium complex, and an organophosphorus ligand, in particular H ₂ , an organometallic rhodium complex, an organophosphorus ligand, especially H ₂ , bis(1,5-cyclooctadiene)rhodium(I) ⁺ , bis(2,2'-bipyridine)rhodium(I) ⁺ or bis(norbornadiene)rhodium(I) ⁺ and a monovalent anion and an organophosphorus ligand selected from (R)-MonoPhos or (1R,1'R,2S,2'S)-DuanPhos or (R,R)-DIPAMP, most especially H ₂ ,Rh(COD) ₂ BF ₄ and (R)-MonoPhos,
and reacting said compound with a deprotecting agent which removes R ^NHA1 , R ^NHA2 , R ^PGP , and R ^COON to obtain a compound characterized by (VI).

6. The method of claim 5 ,
Compound of formula (VIII)
(Wherein, ^RNHA1 and ^RPGP have the same meanings as described in claim 5. )
is reacted in reaction step (b) under basic conditions with a protected 2-phosphonoglycine methyl dimethyl ester, in particular with Boc-2-phosphonoglycine-methyl dimethyl ester, Cbz-2-phosphonoglycine-benzyl dimethyl ester or Cbz-2-phosphonoglycine-methyl dimethyl ester under basic conditions, in particular with a base selected from DBU and tetramethylguanidine, to obtain a compound characterized by (VII).

Compounds of formula (IIIa) and (IIIb),
Or a compound of formula (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), or (IVh);
In the formula,
X is either Q-R in formulas [(IVa), (IVb), (IVc) and (IVd)] or R-Q in formulas [(IVe), (IVf), (IVg) and (IVh)];
Q is unsubstituted or CF ₃ -, alcohol-, alkyl-, O-alkyl-, hydroxyl- and/or halogen-substituted imidazole or indole, in particular Q is unsubstituted or alkyl-, O-alkyl-, hydroxyl- and/or halogen-substituted indole, especially Q is selected from unsubstituted indole, 6-OH-indole, 5-OH-indole, 5-F-indole, 5-Me-indole, 5-OMe-indole, 4-F-indole and 5-Br-indole;
R is S, SO, or _SO2 ;
L ¹ is an unsubstituted or Me-substituted C ₁ -C ₂ alkyl linker, in particular L ¹ is an unsubstituted C ₁ alkyl linker;
^L2 is an unsubstituted or Me-substituted _C1 - _C2 alkyl linker;
B is an α-amino acid backbone;
AA ¹ is selected from DHIle (dihydroxyisoleucine), Ile, DHLeu (dihydroxyleucine), HVal (hydroxyvaline), HIle (5-hydroxyisoleucine or 4-hydroxyisoleucine), Gly, D-Pro, L-Pro, D-Ala, Aib (2-aminoisobutyric acid) and Ala, in particular selected from Gly and D-Pro, DHIle (dihydroxyisoleucine), Ile, DHLeu (dihydroxyleucine), HVal (hydroxyvaline), HIle (5-hydroxyisoleucine or 4-hydroxyisoleucine);
^AA2 is selected from Gly, D-Pro, D-Ala, Aib (2-aminoisobutyric acid), Asn, Asp, Ser, Cys, Arg, Lys, Gln, Glu, and L-propargyl-Gly, in particular Asn, Asp, Gln, Glu; and Ala, Gly, and D-Pro;
- AA ³ is selected from Ile, Leu, Val, photoLeu, and L-propargyl-Gly, L-propargyl-Gly, Pro, Gly, Aib, trans-4-Hyp, Hyp, 4-F-Pro, 4-NH ₂ -Pro, photo-Pro, L-pipecolic acid, L-azetidine-2-carboxylic acid, (S)-indoline-2-carboxylic acid, L-4-thiazolidinecarboxylic acid, Tle, in particular trans-4-Hyp, 4-F-Pro, and 4-NH ₂ -Pro; especially selected from Ile;
AA ⁴ is selected from Gly, D-Pro, D-Ala, Aib (2-aminoisobutyric acid), Asn, Asp, Ser, Cys, Arg, Lys, Gln, Glu, and L-propargyl-Gly, Sar, Acc, in particular Asn, Asp, Gln, Glu, and Ala, and especially AA ² is selected from Gly and D-Pro;
AA ⁵ is selected from Asn, Asp, Ser, Cys, Arg, Lys, Gln, Glu, and L-propargyl-Gly, D-Pro, D-Ala, Aib (2-aminoisobutyric acid), and Ala, in particular Gly and D-Pro, Asn, Asp, Gln, and Glu;
AA ⁶ is selected from Pro, Gly, Aib, trans-4-Hyp, Hyp, 4-F-Pro, 4-F ₂ -Pro, 4-NH ₂ -Pro, photo-Pro, L-pipecolic acid, L-azetidine-2-carboxylic acid, (S)-indoline-2-carboxylic acid, L-4-thiazolidinecarboxylic acid, Ile, Leu, Val, photoLeu and L-propargyl-Gly, in particular Ile and L-propargyl-Gly, trans-4-Hyp, 4-F-Pro and 4-NH ₂ -Pro;
In particular, with the proviso that in formula (IIIa), either the N-terminus of AA ¹ is linked to the C-terminus of AA ⁶ via an amide bond; and in formula (IIIb), the N- or C-terminus of AA ⁴ is linked to the N-terminus of AA ³ via an amide bond; AA ³ is linked to the C-terminus of AA ⁶ via an amide bond; and in formula (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), or (IVh), the C-terminal amino acid is optionally linked to the resin, in particular with the proviso that the direction from left to right is from N-terminus to C-terminus, or from C-terminus to N-terminus.

8. The compound according to claim 7 ,
A compound that does not consist of any combination of the following:
Q is unsubstituted or alkyl-, O-alkyl-, hydroxyl-, and/or halogen-substituted indole;
R is S, SO, or _SO2 ;
^L1 is _CH2 ;
^L2 is _CH2 ;
AA ¹ is selected from DHIle (dihydroxyisoleucine), Ile, and HIle (hydroxyisoleucine);
^AA2 is GIy;
^AA3 is He;
^AA4 is GIy;
^AA5 is Asn or Asp; and
AA ⁶ is Pro or Hyp (hydroxyproline);
or
-Q is unsubstituted or alkyl-, O-alkyl-, hydroxyl-, and/or halogen-substituted indole;
R is S, SO, or _SO2 ;
^L1 is _CH2 ;
^L2 is _CH2 ;
AA ¹ is DH Ile or Ile;
one of ^AA2 and ^AA4 is GIy and the other is Ala, or both ^AA2 and ^AA4 are Ala;
^AA3 is He;
^AA5 is Asn; and
AA ⁶ is Hyp (hydroxyproline);
or
-Q is unsubstituted or alkyl-, O-alkyl-, hydroxyl-, and/or halogen-substituted indole;
R is S, SO, or _SO2 ;
^L1 is _CH2 ;
^L2 is _CH2 ;
AA ¹ is selected from DHLeu (dihydroxyleucine), and HVal (hydroxyvaline);
^AA2 is GIy;
^AA3 is He;
^AA4 is GIy;
^AA5 is Asn; and
- AA ⁶ is Hyp (hydroxyproline).

9. A compound according to claim 7 or 8 ,
Compounds wherein ^AA2 is GIy and/or ^AA4 is GIy, in particular where both ^AA2 and ^AA4 are GIy.

9. A compound according to claim 7 or 8 ,
AA ² is GIy and AA ⁴ is D-Pro; or
A compound wherein AA ² is D-Pro or L-Pro and AA ⁴ is Gly.

Use of a compound according to any one of claims 7 to 10 in the manufacture of an antibody drug conjugate.

12. The use according to claim 11 ,
The use wherein the compound is selected from the group of compounds comprising: