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KR-102964465-B1 - Itaconate and methyl itaconate prodrugs

KR102964465B1KR 102964465 B1KR102964465 B1KR 102964465B1KR-102964465-B1

Abstract

Prodrugs of itaconic acid and 1- and 4-methyl itaconic acid and their use for treating inflammation-related diseases, disorders, or pathological conditions are disclosed.

Inventors

  • 슬러셔, 바바라
  • 이슬람, 모하메드
  • 레이즈, 라나
  • 가르자, 루이스
  • 벨, 벤자민
  • 메이저, 파벨
  • 테노라, 루카스
  • 스나이더, 이반
  • 크렉메로바, 마르셀라

Assignees

  • 더 존스 홉킨스 유니버시티
  • 인스티튜트 오브 오가닉 케미스트리 앤드 바이오케미스트리 에이에스 씨알 브이.브이.아이.

Dates

Publication Date
20260512
Application Date
20201029
Priority Date
20191029

Claims (11)

  1. Compound of the following chemical formula (I): In the above formula, R 1 and R 2 are selected from one of the following combinations: (a) R1 is -OR 3 , and R2 is and Selected from; (b) R 1 is and, R 2 is -OR 3 and Selected from; (c) R 1 is and R 2 is selected from -OR 3 ; (d) R 1 is (Here, R 7 is -C(=O)-OR 8 ) and R 2 is -OR 3 ; (e) R 1 is (Here, R 7 is (is) and R 2 is -OR 3 ; (f) R 1 is (Here, R 7 is (Im) and R 2 is -OR 3 ; and (g) R 1 is (Here, R 7 is (is) and R 2 is -OR 3 ; Here: n is an integer selected from 1, 2, 3, and 4; m is an integer selected from 1, 2, 3, and 4; p is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20; q is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; r is 1 and; u is an integer selected from 1, 2, 3, and 4; R3 is selected from H, C1 - C6 straight-chain unsubstituted alkyl, C1 - C6 straight-chain substituted alkyl, C1 - C6 branched unsubstituted alkyl, and C1 - C6 branched substituted alkyl; R 4 is -OR 5 and; R5 is selected from C1 - C6 straight-chain unsubstituted alkyl, C1 - C6 straight-chain substituted alkyl, C1 - C6 branched unsubstituted alkyl, and C1 - C6 branched substituted alkyl; R6 is selected from C1 - C6 straight-chain unsubstituted alkyl, C1 - C6 straight-chain substituted alkyl, C1 - C6 branched unsubstituted alkyl, and C1 - C6 branched substituted alkyl; R8 is selected from C1 - C6 straight-chain unsubstituted alkyl, C1 - C6 straight-chain substituted alkyl, C1 - C6 branched unsubstituted alkyl, and C1 - C6 branched substituted alkyl; R9 is selected from H, C1 - C4 straight-chain unsubstituted alkyl, C1 - C4 straight-chain substituted alkyl, C1 - C4 branched unsubstituted alkyl, and C1 - C4 branched substituted alkyl; R 10 is selected from C 1 -C 6 straight-chain unsubstituted alkyl, C 1 -C 6 straight-chain substituted alkyl, C 1 -C 6 branched unsubstituted alkyl, and C 1 -C 6 branched substituted alkyl; R 11 and R 12 are each independently H or protectors; R 13 is selected from C 1 -C 6 straight-chain unsubstituted alkyl, C 1 -C 6 straight-chain substituted alkyl, C 1 -C 6 branched unsubstituted alkyl, and C 1 -C 6 branched substituted alkyl; R 14 is selected from H, C 1 -C 4 straight-chain unsubstituted alkyl, C 1 -C 4 straight-chain substituted alkyl, C 1 -C 4 branched unsubstituted alkyl, and C 1 -C 4 branched substituted alkyl; R 15 is selected from C 1 -C 6 straight-chain unsubstituted alkyl, C 1 -C 6 straight-chain substituted alkyl, C 1 -C 6 branched unsubstituted alkyl, and C 1 -C 6 branched substituted alkyl; R 16 and R 17 are each independently selected from H, C 1 -C 4 straight-chain unsubstituted alkyl, C 1 -C 4 straight-chain substituted alkyl, C 1 -C 4 branched unsubstituted alkyl, C 1 -C 4 branched substituted alkyl, and protecting groups; R 18 is aryl; R 20 is selected from H, C 1 -C 4 straight-chain unsubstituted alkyl, C 1 -C 4 straight-chain substituted alkyl, C 1 -C 4 branched unsubstituted alkyl, and C 1 -C 4 branched substituted alkyl; R 21 is -OR 22 , where R 22 is selected from C 1 -C 6 straight-chain unsubstituted alkyl, C 1 -C 6 straight-chain substituted alkyl, C 1 -C 6 branched unsubstituted alkyl, and C 1 -C 6 branched substituted alkyl; or R 21 is -NR 23 R 24 , where R 23 and R 24 are each independently selected from H, C 1 -C 4 straight-chain unsubstituted alkyl, C 1 -C 4 straight-chain substituted alkyl, C 1 -C 4 branched unsubstituted alkyl, and C 1 -C 4 branched substituted alkyl; The straight-chain substituted alkyl and the branched-chain substituted alkyl each independently comprise one or more substituents selected from halogen, aryl, alkoxyl, hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate, cyano, and mercapto.
  2. A compound according to claim 1, wherein R1 and R2 are selected from one of the following combinations: (a) R 1 is and R 2 is -OR 3 ; (b) R 1 is and R 2 is -OR 3 ; (c) R 1 is (Here, R 7 is -C(=O)-OR 8 ) and R 2 is -OR 3 ; (d) R 1 is (Here, R 7 is (is) and R 2 is -OR 3 ; (e) R 1 is (Here, R 7 is (Im) and R 2 is -OR 3 ; and (f) R 1 is (Here, R 7 is ...is) and R 2 is -OR 3 .
  3. A compound according to claim 1, wherein R3 , R5 , R6 , R8 , R10 , R13 , R15 , and R22 are each independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, iso-butyl, and t-butyl.
  4. A compound according to claim 1, wherein R 9 , R 14 , R 16 , R 17 , R 20 , R 23 , and R 24 are each independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, iso-butyl, and t-butyl.
  5. A compound according to claim 1, wherein the protecting group is selected from tertiary-butoxycarbonyl (boc).
  6. A compound according to claim 1, wherein R 18 is phenyl.
  7. In claim 1, the compound of formula (I) A compound selected from.
  8. In claim 1, the compound of formula (I) and A compound selected from.
  9. In claim 1, the compound of formula (I) Phosphorus, compound.
  10. delete
  11. delete

Description

Itaconate and methyl itaconate prodrugs Federally funded research or development This invention was made with government support under grants AR068280 and AR064297 awarded by the National Institutes of Health. The government holds specific rights to this invention. Inflammatory macrophages exhibit significant accumulation of itaconate, which has been shown to display potent anti-inflammatory activity by inducing electrophilic stress that inhibits succinate dehydrogenase and activates NRF2-dependent antioxidant responses. However, given its charged properties, itaconate itself does not exhibit superior pharmacokinetic or cell permeability characteristics. Therefore, the therapeutic potential of exogenous itaconate administration has not yet been realized. outline The subject matter disclosed herein provides the use of itaconic acid and 1- and 4-methyl itaconic acid prodrugs for treating diseases, disorders, or pathological conditions associated with inflammation. More particularly, in some embodiments, the subject matter disclosed herein provides a compound of the following formula (I) and a pharmaceutically acceptable salt thereof: In the above formula, R1 and R2 may be the same or different, and each independently (a) -OR 3 (wherein R 3 is H or C 1 -C 6 straight-chain or branched unsubstituted or substituted alkyl); (b) (wherein n is an integer selected from 1, 2, 3, and 4; R₄ is a C₁ - C₆ straight-chain or branched unsubstituted or substituted alkyl, or -OR₅ , where R₅ is a C₁ - C₆ straight-chain or branched unsubstituted or substituted alkyl); (c) (wherein m is an integer selected from 1, 2, 3, and 4; p is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20; and R6 is a C1 - C6 straight-chain or branched unsubstituted or substituted alkyl); (d) [Here, R 7 is (i) -C(=O)-OR 8 (where R 8 is a C 1 -C 6 straight-chain or branched unsubstituted or substituted alkyl); (ii) (wherein R9 is H or a C1 - C4 straight-chain or branched unsubstituted or substituted alkyl; R10 is a C1 - C6 straight-chain or branched unsubstituted or substituted alkyl; R11 and R12 are each independently H or a protecting group; and R13 is a C1 - C6 straight-chain or branched unsubstituted or substituted alkyl); (iii) (wherein q is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; R11 and R12 are each independently H or a protecting group; R14 is H or a C1 - C4 straight-chain or branched unsubstituted or substituted alkyl; and R15 is a C1 - C6 straight-chain or branched unsubstituted or substituted alkyl); (iv) (wherein R 16 and R 17 are each independently selected from H, C 1 -C 4 straight-chain or branched unsubstituted or substituted alkyls, and protecting groups; and R 18 is an aryl)]; (e) (wherein R 19 is a C 1 -C 4 straight-chain or branched unsubstituted or substituted alkyl); (f) (wherein u is an integer selected from 1, 2, 3, and 4; R20 is an H or C1 - C4 straight-chain or branched unsubstituted or substituted alkyl; R21 is -OR22 , where R22 is a C1 - C6 straight-chain or branched unsubstituted or substituted alkyl or -NR23R24 , where R23 and R24 are each independently an H or C1 - C4 straight-chain or branched unsubstituted or substituted alkyl); and selected from one or more combinations thereof, and However, R1 and R2 may not both be -OH or both may not be -OR3 . In another aspect, the subject matter disclosed herein provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In another aspect, the subject matter disclosed herein provides a method for treating a disease, disorder, or pathological condition associated with inflammation, comprising administering a compound of formula (I) or a pharmaceutical composition thereof to a subject requiring treatment thereof. Specific aspects of the subject matter disclosed herein mentioned above are covered in whole or in part in the subject matter disclosed herein, and other aspects will become apparent as the description progresses when understood in conjunction with the attached embodiments and drawings, as best described below. The patent or application file contains at least one color drawing. A copy of this patent or patent application publication containing the color drawing will be provided by the Patent Office upon request and payment of the necessary fees. Accordingly, the subject matter disclosed herein is described in general terms, and reference will now be made to the attached drawings, which are not necessarily drawn in a specific scale. Figure 1 shows the mouse plasma stability for a representative prodrug; Figure 2 shows the release of active monomethyl itaconate (in plasma) from a representative prodrug; Figure 3 shows the release of active itaconic acid (in plasma) from a representative prodrug. details Now, the subject matter disclosed herein will be described more fully below with reference to the accompan