Compounds as modulators of TLR2 signaling
Inventors
Natala, Srinivasa Reddy • Wrasidlo, Wolfgang
Assignees
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Publication Number
US-11345713-B2
Publication Date
2022-05-31
Expiration Date
Abstract
The present disclosure relates to compounds, pharmaceutical compositions comprising such compounds, and use of such compounds in methods of treatment or in medicaments for treatment of inflammatory diseases and certain neurological disorders that are related to inflammatory signaling processes, including but not limited to misfolded proteins.
Core Innovation
The invention relates to substituted chemical compounds of Formula (A), including tautomers and pharmaceutically acceptable salts, having a ring that is saturated, partially unsaturated, or fully unsaturated and an attachment in either the E or Z configuration. The structure is governed by G1 through G7 and substituent groups R1 through R6d, with R1 as —OH, R2 as CHO, and Y as —C(O)— or absent.
G1 and G2 are each independently CRx, with Rx hydrogen or halogen. G3, G4, G5, and G6 are selected from CH(Xi—R6), C(Xi—R6), N, N(Xi—R6), S, O, or absent as defined, G7 is N, C, or CH, X1, X2, X3, and X4 are each independently absent, and m is 1-6.
R3 is C1-C6 alkoxy or halogen, with the C1-C6 alkoxy being unsubstituted or substituted with one or more halogen. Conditional rules apply when G5 is N, including that at least one of G3, G4, and G6 is not CH, R4 and R5 come together to form —S—, and R3 is —OCH3 or halo. The disclosure also excludes compounds of Table 1X and presents example embodiments featuring (E)-configured styryl-benzaldehyde or related derivatives with fluorinated, hydroxyl, methoxy, halogen, heterocyclic, and amino substituent patterns.
Claims Coverage
The consolidated claim coverage centers on one independent compound claim for Formula (A) with multiple inventive structural constraints, together with method claims directed to TLR2 heterodimerization. In total, six inventive features are captured: the compound scaffold, the defined R1-R3 and Y/R4/R5 pattern, the G1-G7 framework, the R6a-R6d substituent sets, the quantitative and structural limits on substituent presence and m, and the TLR2 heterodimerization treatment/interference uses.
Substituted formula (a) compound scaffold
A compound of Formula (A), or a tautomer or a pharmaceutically acceptable salt, wherein the ring is saturated, partially unsaturated, or fully unsaturated, and attachment is in either the E or Z configuration.
Defined R1-R3 and Y/R4/R5 pattern
R1 is —OH; R2 is CHO; R3 is C1-C6 alkoxy or halogen with the C1-C6 alkoxy of R3 unsubstituted or substituted with one or more halogen; and Y is —C(O)— or absent, with R4 and R5 each H when Y is —C(O)— or absent.
G1-G7 framework with conditional rules when G5 is N
G1 and G2 are each independently CRx, with Rx hydrogen or halogen; G3, G4, G5, and G6 are selected from CH(Xi—R6), C(Xi—R6), N, N(Xi—R6), S, O, or absent as defined; G7 is N, C, or CH; and additional conditions apply when G5 is N.
Allowed R6a-R6d substituent sets
R6a, R6b, R6c, and R6d are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halo, —OH, —NRpRq, aryl, heterocyclyl, heteroaryl, —C1-C6 alkyl-heterocyclyl, —OC(O)-heterocyclyl, —C(O)Rh, —S(O)2NRw1Rw2, —S(O)2Ry, or —NRz1S(O)2Rz2, with additional substitution rules for these groups.
Quantitative and ring-formation limits on substituents and m
X1, X2, X3, and X4 are each independently absent; m is 1-6; no more than one of R6a, R6b, R6c, and R6d is C1-C6 alkoxy or —OH; and, for specified G5/G6 forms, R6c and R6d taken together form a 6-membered aryl, 6-membered heterocyclyl, or 6-membered heteroaryl ring.
Treatment of disease associated with tlr2 heterodimerization
A method of treating a disease or condition associated with TLR2 heterodimerization by administering to a subject an effective amount of at least one compound according to claim 1, or its tautomer or pharmaceutically acceptable salt.
Interfering with tlr2 heterodimerization in a cell
A method of interfering with the heterodimerization of TLR2 in a cell by contacting the cell with an effective amount of at least one compound according to claim 1, or its tautomer or pharmaceutically acceptable salt, wherein contacting is in vitro, ex vivo, or in vivo.
The claim coverage is anchored by a Formula (A) substituted compound with defined E/Z attachment, ring saturation/unsaturation, fixed R1-R3 and Y/R4/R5 assignments, a constrained G1-G7 framework, extensive R6a-R6d substituent options, and explicit limits on X1-X4, m, and the number of C1-C6 alkoxy or —OH substituents. Separate method claims extend this coverage to treating diseases or conditions associated with TLR2 heterodimerization and to interfering with TLR2 heterodimerization by contacting cells in vitro, ex vivo, or in vivo.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating a disease or condition associated with TLR2 heterodimerization by administering to a subject an effective amount of at least one compound according to claim 1, or its tautomer or pharmaceutically acceptable salt.
Interfering with the heterodimerization of TLR2 in a cell by contacting the cell with an effective amount of at least one compound according to claim 1, wherein contacting is in vitro, ex vivo, or in vivo.
The disease or condition is selected from enumerated neurological, inflammatory, infectious, and cancer-related conditions, including categories such as anti-fungal, anti-bacterial, antiviral, and antitumor diseases or conditions.
Examples document synthesis and characterization of substituted (E/Z)-styryl benzaldehydes and related benzaldehyde products.
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