JPWO2020257870A5

JPWO2020257870A5 -

Info

Publication number: JPWO2020257870A5
Application number: JP2021577007A
Authority: JP
Publication date: 2023-07-03

Claims

structure:
AYB
(In the formula, A is

is represented by
During the ceremony,
b and w are each independently an integer from 0 to 7 and v is an integer from 0 to 5, with the proviso that:
the sum of b, v, and w is at least 3;
the sum of b and w is 0 to 7;
z is 1 or 2;
X is selected from -S-, -S(=O)- and -S(=O) ₂ -;
Z ₁ and Z ₂ are each independently -O-, -NR-, -S-, S(=O), S(=O) ₂ -, -C(=O)O-, -OC( =O)-, -C(=O)NR-, -NRC(=O)-, -C(=O)S-, -SC(=O)-, OC(=O)O-, NRC(= O) selected from the group consisting of O-, -OC(=O)NR-, and -NRC(=O)NR-;
R ₁₁ , R ₁₂ , R _x , R _y , R ₁₄ , R ₁₅ , R ₁₆ , and R ₁₇ are each independently H or C ₁ -C ₆ aliphatic;
R, R ₁₃ and R ₁₈ are each independently H or C ₁ -C ₆ aliphatic;
R ₁₉ is H, C ₁ -C ₆ aliphatic, amino protecting group, L ₃ -C(=O)-, or A ₂ ;
each of L ₁ and L ₂ is independently C ₅ -C ₂₁ aliphatic or C ₄ -C ₂₀ heteroaliphatic;
L ₃ is C ₁ -C ₂₁ aliphatic or C ₂ -C ₂₀ heteroaliphatic;
_A2 is an amino acid or peptide;
any one of R, _R11 , _R12 , _R13 , _R14 , _R15 , _R16 , _R17 , _R18 , _R19 , _Rx , Ry, _L1 _, _L2 , and _L3 any aliphatic or heteroaliphatic present in is optionally substituted;
Y is

and
wherein R ₁ and R ₂ are independently H, —CH ₂ OH, —CH ₂ CH ₂ OH, —CH(CH ₃ )OH, —CH ₂ OPO(OH) ₂ , —CH ₂ C( =O)NH ₂ , -CH ₂ CH ₂ C(=O)OH and -CH ₂ CH ₂ C(=O)OR ₈ , wherein any one of said alkyl hydrogen is halogen can be replaced with;
R ₈ is selected from the group consisting of H and linear or branched C ₁ -C ₆ alkyl;
B represents polyethylene glycol (PEG))
a compound comprising
or a pharmaceutically acceptable salt, solvate or prodrug thereof.

A compound comprising A and PEG, wherein A and PEG are linked by a glycine, serine, homoserine, threonine, phosphoserine, asparagine or glutamine residue, or an ester of a glutamine residue;
here,
A in said compound has the structure:

has
During the ceremony,
b and w are each independently an integer from 0 to 7 and v is an integer from 0 to 5, such as 2 to 5, with the proviso that:
the sum of b, v, and w is at least 3;
the sum of b and w is 0 to 7;
z is 1 or 2;
X is selected from -S-, -S(=O)- and -S(=O) _2-- ;
Z ₁ and Z ₂ are each independently -O-, -NR-, -S-, -S(=O)-, S(=O) ₂ -, -C(=O)O-, - OC(=O)-, -C(=O)NR-, -NRC(=O)-, -C(=O)S-, -SC(=O)-, -OC(=O)O-, selected from the group consisting of NRC(=O)O-, -OC(=O)NR-, and -NRC(=O)NR-;
R ₁₁ , R ₁₂ , R _x , R _y , R ₁₄ , R ₁₅ , R ₁₆ and R ₁₇ in each instance of b, v, w and z are each independently H or C ₁ -C ₆ is aliphatic;
R, R ₁₃ and R ₁₈ are each independently H or C ₁ -C ₆ aliphatic;
R ₁₉ is H, C ₁ -C ₆ aliphatic, amino protecting group, L ₃ -C(=O)-, or A ₂ ;
each of L ₁ and L ₂ is independently C ₅ -C ₂₁ aliphatic or C ₄ -C ₂₀ heteroaliphatic;
L ₃ is C ₁ -C ₂₁ aliphatic or C ₂ -C ₂₀ heteroaliphatic;
_A2 is an amino acid or peptide;
any one of R, _R11 , _R12 , _R13 , _R14 , _R15 , _R16 , _R17 , _R18 , _R19 , _Rx , Ry, _L1 _, _L2 , and _L3 optionally substituted any aliphatic or heteroaliphatic present in the compound;
or a pharmaceutically acceptable salt, solvate or prodrug thereof.

The following formula:

(wherein R ₁ and R ₂ are independently H, —CH ₂ OH, —CH ₂ CH ₂ OH, —CH(CH ₃ )OH, —CH ₂ OPO(OH) ₂ , —CH ₂ C (=O)NH ₂ , -CH ₂ CH ₂ C(=O)OH and -CH ₂ CH ₂ C(=O)OR ₈ , wherein any one of said alkyl hydrogen is can be substituted with halogen;
R ₈ is selected from the group consisting of H and linear or branched C ₁ -C ₆ alkyl;
b and w are each independently an integer from 0 to 7 and v is an integer from 0 to 5, with the proviso that:
the sum of b, v, and w is at least 3;
the sum of b and w is 0 to 7;
z is 1 or 2;
X is selected from -S-, -S(=O)- and -S(=O) _2-- ;
Z ₁ and Z ₂ are each independently -O-, -NR-, -S-, -S(=O)-, -S(=O) ₂ -, -C(=O)O-, -OC(=O)-, -C(=O)NR-, -NRC(=O)-, -C(=O)S-, -SC(=O)-, -OC(=O)O- , -NRC(=O)O-, -OC(=O)NR-, and -NRC(=O)NR-;
R ₁₁ , R ₁₂ , R _x , R _y , R ₁₄ , R ₁₅ , R ₁₆ and R ₁₇ in each instance of b, v, w and z are each independently H or C ₁ -C ₆ is aliphatic;
R, R ₁₃ and R ₁₈ are each independently H or C ₁ -C ₆ aliphatic;
R ₁₉ is H, C ₁ -C ₆ aliphatic, amino protecting group, L ₃ -C(=O)-, or A ₂ ;
each of L ₁ and L ₂ is independently C ₅ -C ₂₁ aliphatic or C ₄ -C ₂₀ heteroaliphatic;
L ₃ is C ₁ -C ₂₁ aliphatic or C ₂ -C ₂₀ heteroaliphatic;
_A2 is an amino acid or peptide;
any one _of R, _R11 , _R12 , _R13 , _R14 , R15, _R16 , _R17 , _R18 , _R19 , _Rx , Ry, _L1 _, _L2 , and _L3 optionally substituted for any aliphatic or heteroaliphatic present in
A compound comprising
a compound covalently attached to polyethylene glycol (PEG),
or a pharmaceutically acceptable salt, solvate or prodrug thereof.

The PEG is represented by the following formula:

is a substituted PEG represented by
During the ceremony,
n is 3 to 100;
m is 1, 2, 3 or 4;
p is 2, 3 or 4;
q is zero or one;
when R ₃ is H, —NH ₂ or —OH and q is zero then R ₃ is H and when q is 1 then R ₃ is —NH ₂ or —OH;
L is zero or consists of 1 to 10 units, where each unit is or is derived from a natural alpha amino acid and has the formula:

is represented by
wherein R ₄ is H;
R ₅ is a side chain or a second hydrogen of the amino acid;
Preferably said compound is of formula (VI):

(In the formula,
n is 3 to 100;
m is 1, 2, 3 or 4;
p is 2, 3 or 4;
q is zero or one;
R ₁ and R ₂ are independently H, —CH ₂ OH, —CH ₂ CH ₂ OH, —CH(CH ₃ )OH, —CH ₂ OPO(OH) ₂ , —CH ₂ C(=O) NH ₂ , —CH ₂ CH ₂ C(=O)OH and CH ₂ CH ₂ C(=O)OR ₈ , wherein any one of said alkyl hydrogens can be substituted with halogen; ;
R ₈ is selected from the group consisting of H and linear or branched C ₁ -C ₆ alkyl;
when q=1, R ₃ is —NH ₂ or —OH;
if q=0, then R ₃ is H;
L is zero or consists of 1 to 10 units, where each unit is or is derived from a natural alpha amino acid and has the formula:

is represented by
wherein R ₄ is H;
R ₅ is the side chain or second hydrogen of said amino acid;
b and w are each independently an integer from 0 to 7 and v is an integer from 0 to 5, with the proviso that:
the sum of b, v, and w is at least 3;
the sum of b and w is 0 to 7;
z is 1 or 2;
X is selected from -S-, -S(=O)- and -S(=O) ₂ -;
Z ₁ and Z ₂ are each independently -O-, -NR-, -S-, -S(=O)-, -S(=O) 2 -, -C(=O) _O- , -OC(=O)-, -C(=O)NR-, -NRC(=O)-, -C(=O)S-, -SC(=O)-, -OC(=O)O- , -NRC(=O)O-, -OC(=O)NR-, and -NRC(=O)NR-;
R ₁₁ , R ₁₂ , R _x , R _y , R ₁₄ , R ₁₅ , R ₁₆ and R ₁₇ in each instance of b, v, w and z are each independently H or C ₁ -C ₆ is aliphatic;
R, R ₁₃ and R ₁₈ are each independently H or C ₁ -C ₆ aliphatic;
R ₁₉ is H, C ₁ -C ₆ aliphatic, amino protecting group, L ₃ -C(=O)-, or A ₂ ;
each of L ₁ and L ₂ is independently C ₅ -C ₂₁ aliphatic or C ₄ -C ₂₀ heteroaliphatic;
L ₃ is C ₁ -C ₂₁ aliphatic or C ₂ -C ₂₀ heteroaliphatic;
A2 is an amino acid or peptide _;
_any one of _R , R11 _, R12 , R13 _, _R14 , R15 , R16 _, R17 _, R18 _, _R19 , Rx , _Ry , _L1 _, L2 _, and _L3 optionally substituted for any aliphatic or heteroaliphatic present in
or
Formula (VII):
A-Y-NH-(CH ₂ ) _p -O-(CH ₂ -CH ₂ -O) _n -[(CH ₂ ) _m -CO-L-] _q R ₃
(VII)
(In the formula,
A is the structure:

has;
Y is

and
wherein R ₁ and R ₂ are independently H, —CH ₂ OH, —CH ₂ CH ₂ OH, —CH(CH ₃ )OH, —CH ₂ OPO(OH) ₂ , —CH ₂ C( =O)NH ₂ , -CH ₂ CH ₂ C(=O)OH and -CH ₂ CH ₂ C(=O)OR ₈ , wherein any one of said alkyl hydrogen is halogen can be replaced with;
R ₈ is selected from the group consisting of H and linear or branched C ₁ -C ₆ alkyl;
n is 3 to 100;
m is 1, 2, 3 or 4;
p is 2, 3 or 4;
q is zero or one;
when q is 1, R ₃ is —NH ₂ or —OH;
when q is zero, R ₃ is H;
L is zero or consists of 1 to 10 units, where each unit is or is derived from a natural alpha amino acid and has the formula:

is represented by
wherein R ₄ is H;
R ₅ is the side chain or second hydrogen of said amino acid;
b and w are each independently an integer from 0 to 7 and v is an integer from 0 to 5, with the proviso that:
the sum of b, v, and w is at least 3;
the sum of b and w is 0 to 7;
z is 1 or 2;
X is selected from -S-, -S(=O)- and -S(=O) ₂ -;
Z ₁ and Z ₂ are each independently -O-, -NR-, -S-, -S(=O)-, -S(=O) 2 -, -C(=O) _O- , -OC(=O)-, -C(=O)NR-, -NRC(=O)-, -C(=O)S-, -SC(=O)-, -OC(=O)O- , -NRC(=O)O-, -OC(=O)NR-, and -NRC(=O)NR-;
R ₁₁ , R ₁₂ , R _x , R _y , R ₁₄ , R ₁₅ , R ₁₆ and R ₁₇ in each instance of b, v, w and z are each independently H or C ₁ -C ₆ is aliphatic;
R, R ₁₃ and R ₁₈ are each independently H or C ₁ -C ₆ aliphatic;
R ₁₉ is H, C ₁ -C ₆ aliphatic, amino protecting group, L ₃ -C(=O)-, or A ₂ ;
each of L ₁ and L ₂ is independently C ₅ -C ₂₁ aliphatic or C ₄ -C ₂₀ heteroaliphatic;
L ₃ is C ₁ -C ₂₁ aliphatic or C ₂ -C ₂₀ heteroaliphatic;
A2 is an amino acid or peptide _;
_any one of _R , R11 _, R12 , R13 _, _R14 , R15 , R16 _, R17 _, R18 _, _R19 , Rx , _Ry , _L1 _, L2 _, and _L3 optionally substituted for any aliphatic or heteroaliphatic present in
a compound of;
or a pharmaceutically acceptable salt, solvate or prodrug thereof .

5. The compound of claim 4 , or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein q is 1.

6. The compound of claim 4 or 5 , or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein n is 10-14.

A compound according to any one of claims 4 to 6 , or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein n is 24 to 30, preferably n is 27 .

A compound, or a pharmaceutically acceptable salt, solvate or prodrug thereof, according to any one of claims 4 to 7 , wherein m is 1 to 3, preferably m is 2 .

A compound according to any one of claims 1 to 8, wherein v is 2 to 5, preferably b is 0, more preferably w is an integer from 1 to 7, or a pharmaceutical acceptable salts, solvates or prodrugs of

10. A compound according to any one of claims 1 to 9 , wherein R _x , R _y , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ , R ₁₅ , R ₁₆ and R ₁₇ are H, or A pharmaceutically acceptable salt, solvate or prodrug.

Said compound has a chiral center indicated by ^* :

is the R stereoisomer of said compound around and/or
The following formula:

is in the ^L configuration, and/or
The following formula:

The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein the chiral center denoted by ^*** in is in the L configuration .

Compounds 1-36 below

or a pharmaceutically acceptable salt, solvate or prodrug thereof, according to any one of claims 1 to 11 , selected from any one of

A composition comprising a compound according to any one of claims 1 to 12 , or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient. thing.

to enhance an innate immune response in a subject ,
to prevent disease caused by an infectious agent in a subject,
to treat and/or prevent a respiratory disease or condition associated with a viral or bacterial infection in a subject;
to treat and/or prevent respiratory infections in a subject,
to reduce airway inflammation in a subject,
for controlling a respiratory disease or condition during a respiratory viral infection in a subject, preferably wherein said infection is not a rhinovirus infection,
to treat and/or prevent a disease or condition associated with the TLR2 receptor
13. A compound according to any one of claims 1 to 12 , or a pharmaceutically acceptable salt, solvate or prodrug thereof , used for one or more of

A method of acting on TLR2 activity in a cell comprising contacting said cell with a compound of any one of claims 1-12 or a pharmaceutically acceptable salt, solvate or prodrug thereof. method involving