JPWO2019165114A5

JPWO2019165114A5 -

Info

Publication number: JPWO2019165114A5
Application number: JP2020544485A
Authority: JP
Publication date: 2022-03-02
Anticipated expiration: 2039-02-21

Claims

The compound of formula (I),

Or its pharmaceutically acceptable salt [in the formula,
L ¹ is -OH or -X (CR ^1a R ^1a' ) _m _Op Ar ¹ ;
L ² is -Y (CR ^2a R ^2a' ) _n O _q Ar ² ;
X and Y are independently of -OC (O)-, -NR ^a C (O)-, -NR ^b C (S)-, -NR ^c- , -SO ₂ NR ^c- , -O-, respectively. And -OC (O) CH = CH-;
R ^a , R ^b , and R ^c are independently selected from hydrogen and _C1 to _C4 alkyl;
m is 0, 1 or 2;
n is 0, 1 or 2;
R ^1a , R ^1a' , R ^2a and R ^2a' , if present, are independently selected from hydrogen and C1 to _C4 alkyl, _respectively ;
p is 0 or 1;
q is 0 or 1;
Ar ¹ and Ar ² are each independently selected from aryl or heteroaryl, where each aryl or heteroaryl is independently hydrogen, C ₁ to C ₁₂ alkyl, hydroxy, C ₁ to C ₁₂ alkoxy, halo. , C ₁ to C ₄ haloalkyl, Ar ³ , C ₁ to C ₈ alkoxy-C ₁ to C ₈ alkoxy, C ₁ to C ₈ alkoxy-C ₁ to C ₈ alkyl, hydroxy-C ₁ to C ₈ alkyl, amino, Independent of Nitro, -NH-Ar ⁴ , C ₁ to C ₈ Alkoxy-Ar ⁵ , C ₁ to C ₈ Alkoxysulfonyl, and C ₁ to C ₈ Alkoxy-C ₁ to C ₈ Alkoxy-C ₁ to C ₈ Alkoxy It may or may not be substituted with 1, 2, 3, 4, or 5 substituents selected, or the substituents are optionally combined with the atom to which they are attached. To form an aryl ring; where each heteroaryl may contain 1, 2, 3, 4, or 5 heteroatoms selected from O, S or N;
Ar ³ , Ar ⁴ and Ar ⁵ are independent of C ₁ to C ₄ alkyl, hydroxy, C ₁ to C ₄ alkoxy, halo, C ₁ to C ₄ haloalkyl, and C ₁ to C ₄ hydroxy alkyl, respectively. Selected from aryls or heteroaryls independently substituted or substituted with 1, 2, 3, or 4 substituents selected]; and here.
6,6'-bis (2-methoxybenzoyl) -α, α-D-trehalose,
6,6'-bis (benzoylamino) -α, α-D-trehalose,
6,6'-bis (2-hydroxybenzoyl) -α, α-D-trehalose,
6,6'-bis (2-hydroxybenzoylamino) -α, α-D-trehalose,
6,6'-bis (2-methylbenzoyl) -α, α-D-trehalose,
6,6'-bis (2-methylbenzoylamino) -α, α-D-trehalose,
6,6'-bis (4-methoxybenzoyl) -α, α-D-trehalose,
6,6'-bis (4-methoxybenzoylamino) -α, α-D-trehalose,
6,6'-bis (4-hydroxybenzoyl) -α, α-D-trehalose,
6,6'-bis (4-hydroxybenzoylamino) -α, α-D-trehalose,
6,6'-bis (4-benzyloxybenzoyl) -α, α-D-trehalose,
6,6'-bis (2,3-dimethoxybenzoyl) -α, α-D-trehalose,
6,6'-bis (2,3-dimethoxybenzoylamino) -α, α-D-trehalose,
6,6'-bis (2,6-difluorobenzoyl) -α, α-D-trehalose,
6,6'-bis (2,6-difluorobenzoylamino) -α, α-D-trehalose,
6,6'-bis (2,6-dichlorobenzoyl) -α, α-D-trehalose,
6,6'-bis (2,3-dihydroxybenzoyl) -α, α-D-trehalose,
6,6'-bis (2,4-dihydroxybenzoyl) -α, α-D-trehalose,
6,6'-bis (2,4-dihydroxybenzoylamino) -α, α-D-trehalose,
6,6'-bis (2,3-dibenzyloxybenzoyl) -α, α-D-trehalose,
6,6'-bis (2-hydroxy-3-methoxybenzoyl) -α, α-D-trehalose,
6,6'-bis (2-benzyloxy-3-methoxybenzoyl) -α, α-D-trehalose,
6,6'-bis (2-methyl-6-aminobenzoyl) -α, α-D-trehalose,
6,6'-bis (3-methoxy-4-fluorobenzoyl) -α, α-D-trehalose,
6,6'-bis (3,4,5-trimethoxybenzoyl) -α, α-D-trehalose,
6,6'-bis (3,4,5-trimethoxybenzoylamino) -α, α-D-trehalose,
6,6'-bis (2,4-dihydroxy-6-methylbenzoyl) -α, α-D-trehalose,
6,6'-bis (2,4-dimethoxy-6-methylbenzoyl) -α, α-D-trehalose,
6,6'-bis (2-hydroxy-4-n-heptyloxybenzoyl) -α, α-D-trehalose,
6,6'-bis (2-hydroxy-4-n-pentyloxybenzoyl) -α, α-D-trehalose,
6,6'-bis (2-hydroxy-4-methoxybenzoyl) -α, α-D-trehalose,
6,6'-bis (4-n-pentyloxybenzoyl) -α, α-D-trehalose,
6,6'-bis (2,4-dihydroxy-6-methylbenzoyl) -α, α-D-trehalose,
6,6'-bis (cinnamoylamino) -α, α-D-trehalose,
6,6'-bis (3,4-dimethoxycinnamoylamino) -α, α-D-trehalose,
A compound that is not 6,6'-bis (isonicotinoylamino) -α, α-D-trehalose, or 6,6'-bis (pyrazine-2-carbonylamino) -α, α-D-trehalose.

The compound according to claim 1, wherein p and q are 0, or a pharmaceutical salt thereof.

L ¹ is

And;
m is 0, 1 or 2;
When R ^1a and R ^1a'are present, they are independently selected from hydrogen and C ₁ to C ₄ alkyl; and R ^2a , R ^3a , R ^4a , R ^5a , and R ^6a , respectively, independently. Hydrogen, C ₁ to C ₁₂ Alkoxy, Hydroxy, C ₁ to C ₁₂ Alkoxy, Halo, C ₁ to C ₄ Alkoxy, Aryl, C ₁ to C ₈ Alkoxy-C ₁ to C ₈ Alkoxy, C ₁ to C ₈ Alkoxy- C ₁ to C ₈ alkyl, hydroxy-C ₁ to C ₈ alkyl, amino, nitro, arylamino, C ₁ to C ₈ alkoxy-aryl, C ₁ to C ₈ alkyl sulfonyl, and C ₁ to C ₈ alkoxy-C ₁ The compound according to claim 1 or 2, which is selected from ~ C ₈ alkoxy-C ₁ ~ C ₈ alkoxy, or together with an atom to which they are bonded, optionally together to form an aryl ring, or a compound thereof. Pharmaceutical salt.

The compound according to any one of claims 1 to 3, or a pharmaceutical salt thereof, wherein R ^1a'is hydrogen when present.

R ^2a , R ^3a , R ^4a , R ^5a , and R ^6a are independently hydrogen, C ₁ to C ₈ alkyl, hydroxy, C ₁ to C ₈ alkoxy, halo, C ₁ to C ₄ halo alkyl, aryl, respectively. Selected from C ₁ to C ₈ Alkoxy-C ₁ to C ₈ Alkoxy, C ₁ to C ₈ Alkoxy-C ₁ to C ₈ Alkoxy, and Hydroxy-C ₁ to C ₈ Alkoxy;
The compound according to claim 3 or 4, or a pharmaceutical salt thereof, wherein R ^3a and R ^4a are optionally combined with the carbon atom to which they are bonded to form an aryl ring.

L ² is

And;
n is 0, 1 or 2;
If R ^1b and R ^1b'are present, they are independently selected from hydrogen and C ₁ to C ₄ alkyl; and R ^2b , R ^3b , R ^4b , R ^5b , and R ^6b , respectively, independently. Hydrogen, C ₁ to C ₁₂ alkyl, hydroxy, C ₁ to C ₁₂ alkoxy, halo, C ₁ to C ₄ haloalkyl, aryl, C ₁ to C ₈ alkoxy-C ₁ to C ₈ alkoxy, C ₁ to C ₈ alkoxy- C ₁ to C ₈ alkyl, hydroxy-C ₁ to C ₈ alkyl, amino, nitro, arylamino, C ₁ to C ₈ alkoxy-aryl, C ₁ to C ₈ alkyl sulfonyl, and C ₁ to C ₈ alkoxy-C ₁ 1-C ₈ Alkoxy- according to any one of claims 1-5, which is selected from C ₁ to C ₈ alkoxy, or optionally together with an atom to which they are bonded to form an aryl ring. Compounds, or pharmaceutical salts thereof.

The compound according to any one of claims 1 to 6, or a pharmaceutical salt thereof, wherein R ^1b'is hydrogen when present.

R ^2b , R ^3b , R ^4b , R ^5b , and R ^6b are independently hydrogen, C ₁ to C ₈ alkyl, hydroxy, C ₁ to C ₈ alkoxy, halo, C ₁ to C ₄ halo alkyl, aryl, respectively. Selected from C ₁ to C ₈ Alkoxy-C ₁ to C ₈ Alkoxy, C ₁ to C ₈ Alkoxy-C ₁ to C ₈ Alkoxy, and Hydroxy-C ₁ to C ₈ Alkoxy;
Here, the compound according to any one of claims 1 to 7, wherein R ^3b and R ^4b , together with the carbon atom to which they are bonded, optionally together to form an aryl ring, or a pharmaceutical salt thereof. ..

Compound of formula (Ia):

Or its pharmaceutically acceptable salt [in the formula,
X and Y are independently selected from -OC (O)-and-NR ^a C (O)-;
^Ra is independently selected from hydrogen and C1 _- _C4 alkyl;
m is 0, 1 or 2;
n is 0, 1 or 2;
R ^1a , R ^1a' , R ^1b and R ^1b' , if present, are hydrogen, respectively; and R ^2a , R ^2b , R ^3a , R ^3b , R ^4a , R ^4b , R ^5a , R ^5b , respectively. The compound according to claim ₁ , wherein R ^6a and R ^6b are independently selected from hydrogen, C1 to _C8 alkyl, and hydroxy.

The compound according to claim 9, wherein m and n are 0, or a pharmaceutically acceptable salt thereof.

Compound of formula (Ib):

Or its pharmaceutically acceptable salt [in the formula,
X and Y are independently selected from -OC (O)-and-NR ^a C (O)-;
^Ra is independently selected from hydrogen and C1 _- _C4 alkyl;
R ^2a , R ^2b , R ^3a , R ^3b , R ^4a , R ^4b , R ^5a , R ^5b , R ^6a , and R ^6b are independently hydrogen, C ₁ to C ₁₂ alkyl, hydroxy, C ₁ to, respectively. It is selected from C ₁₂ alkoxy, C ₁ to C ₄ haloalkyl, Ar ³ and -NH-Ar ⁴ , or together with the atoms to which they are attached, optionally together to form an aryl ring;
Ar ³ , Ar ⁴ and Ar ⁵ are independent of C ₁ to C ₄ alkyl, hydroxy, C ₁ to C ₄ alkoxy, halo, C ₁ to C ₄ haloalkyl, and C ₁ to C ₄ hydroxy alkyl, respectively. The compound according to claim 1, wherein the compound is selected from aryls or heteroaryls that are not independently substituted or substituted with 1, 2, 3, or 4 substituents selected.

The compound according to claim 11 , or a pharmaceutically acceptable salt thereof, wherein R ^3a , R ^3b , R ^5a , and R ^5b are C ₁ to C ₅ alkoxy, respectively.

The compound according to claim 12 , or a pharmaceutically acceptable salt thereof, wherein R ^2a , R ^2b , R ^4a , R ^4b , R ^6a , and R ^6b are hydrogen, respectively.

At least two of R ^3a , R ^4a , and R ^5a are C ₅ to C ₁₂ alkoxy, and at least two of R ^3b , R ^4b , and R ^5b are C ₅ to C ₁₂ alkoxy, and R ^2a . , R ^2b , R ^6a , and R ^6b are hydrogen, respectively, the compound according to claim 11 , or a pharmaceutically acceptable salt thereof.

The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein R ^3a , R ^3b , R ^5a , and R ^5b are C ₅ to C ₁₂ alkoxy, respectively.

The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein R ^4a and R ^4b are C ₅ to C ₁₂ alkoxy, respectively.

6,6'-bis (3,5-diethoxybenzoyl) -α, α-D-trehalose,
6,6'-bis (2-hydroxy-3,5-di-tert-butylbenzoyl) -α, α-D-trehalose,
6,6'-bis (3,5-dipentyloxybenzoyl) -α, α-D-trehalose,
6,6'-bis (3,4,5-triethoxybenzoyl) -α, α-D-trehalose, and 6,6'-bis (2-hydroxy-3,5-di-tert-butylbenzoylamino) -Α, α-D-trehalose,
The compound according to claim 1, which is selected from the group consisting of 6,6'-bis (2,6-hydroxy-3,5-di-tert-butylbenzoylamino) -α, α-D-trehalose, or a compound thereof. A pharmaceutically acceptable salt.

An adjuvant composition comprising an effective amount of the compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof.

The adjuvant composition according to claim 18 , for inducing an enhancement of the immune response of the subject .

A vaccine composition comprising (a) an antigen; (b) an adjuvant composition comprising an effective amount of the compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof.

An effective amount of the compound according to any one of claims 1 to 17 , or a pharmaceutically acceptable salt thereof, which is a pharmaceutical composition for inducing or enhancing the immunogenicity of the target antigen. Including , pharmaceutical composition .

A pharmaceutical composition for regulating an immune response of a subject, comprising an effective amount of the compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof .