Novel prodrugs of itaconate and methylitaconate

Abstract

We provide a prodrug of itaconic acid used to treat inflammation-related diseases, disorders, or conditions. [Solution] Compound of formula (I): JPEG2026102683000193.jpg2548 (In the formula, R1 and R2 may be the same or different, and are selected from -OR3 (where R3 is H or a C1-C6 linear or branched unsubstituted or substituted alkyl group).)

Claims

1. Compound of formula (I): 【Chemistry 1】 (In the formula: R １ and R ２ They may be the same or different, and include one or more of the following and combinations thereof. Each element is selected independently from the combination: (a) - OR ３ (R ３ is H or C １ -C ６ Linear or branched unsubstituted or substituted (It is alkyl); (b) 【Chemistry 2】 (where n is an integer selected from 1, 2, 3, and 4; R ４ is C １ - C ６ straight chain Alternatively, branched unsubstituted or substituted alkyl or -OR ５ And here R ５ C １ -C ６ (Linear or branched unsubstituted or substituted alkyl groups); (c) 【Transformation 3】 (In the formula, 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 It is an integer selected from 20; and R ６ C １ -C ６ Linear or branched unsubstituted (or substituted alkyl); (d) 【Chemistry 4】 In the formula, R ７ The following can be selected: (i)-C(=O)-OR ８ (R ８ C １ -C ６ Linear or branched non-substituted or (It is a substituted alkyl group); (ii) 【Transformation 5】 (In the formula, R ９ is H or C １ -C ４ Linear or branched unsubstituted or substituted alkyl groups be; R １０ C １ -C ６ It is a linear or branched unsubstituted or substituted alkyl group; R １１ and R １２ Each is independently either H or a protecting group; and R １３ C １ -C ６ (Linear or branched unsubstituted or substituted alkyl groups); (iii) 【Transformation 6】 (In the formula, q is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10) ru; R １１ and R １２ Each is independently either H or a protecting group; R １４ H also is C １ -C ４ It is a linear or branched unsubstituted or substituted alkyl group; and R １５ teeth, C １ -C ６ (Linear or branched unsubstituted or substituted alkyl groups); and (iv) 【Transformation 7】 (In the formula, R １６ and R １７ H and C are respectively １ -C ４ Linear or branched non-substituted or Selected independently from substituted alkyl groups and protecting groups; R １８ (is an arrow); (e) 【Transformation 8】 (In the formula, R １９ C １ -C ４ (Linear or branched unsubstituted or substituted alkyl groups); (f) 【Chemistry 9】 (wherein u is an integer selected from 1, 2, 3, and 4; R ２０ is H or C １ -C ４ It is a linear or branched unsubstituted or substituted alkyl group; R ２１ ha-OR ２２ dea Here, R ２２ C １ -C ６ Linear or branched unsubstituted or substituted alkyl groups or -NR ２３ R ２４ And here R ２３ and R ２４ These are H or C, respectively, independently. １ -C ４ (Linear or branched unsubstituted or substituted alkyl groups); However, R １ and R ２ Both are either -OH at the same time or -OR at the same time ３ This is (That's impossible.) and its pharmaceutically acceptable salts.

2. The compound according to claim 1: (Here, (a) R １ ha-OR ３ And R ２ teeth 【Chemistry 10】 Selected from, in the formula, R ７ teeth 【Chemistry 11】 Selected from; (b) R １ teeth 【Chemistry 12】 And R ２ teeth 【Chemistry 13】 Selected from, in the formula, R ７ teeth 【Chemistry 14】 Selected from; (c) R １ teeth 【Chemistry 15】 And R ２ teeth 【Chemistry 16】 Selected from, in the formula, R ７ teeth 【Chemistry 17】 Selected from; (d) R １ teeth [Chemistry 18] And R ２ teeth 【Chemistry 19】 Selected from, in the formula, R ７ teeth 【Chemistry 20】 Selected from; (e) R １ teeth 【Chemistry 21】 And R ２ teeth 【Chemistry 22】 Selected from, in the formula, R ７ teeth 【Chemistry 23】 Selected from; (f) R １ teeth 【Chemistry 24】 And in the formula, R ７ ha-C(=O)-O-R ８ And R ２ teeth 【Chemistry 25】 Selected from, in the formula, R ７ teeth 【Chemistry 26】 Selected from; (g) R １ teeth 【Chemistry 27】 And in the formula, R ７ teeth 【Chemistry 28】 And R ２ teeth 【Chemistry 29】 selected from, wherein R ７ is 【Transformation 30】 Selected from; (h)R １ teeth 【Chemistry 31】 And in the formula, R ７ teeth 【Chemistry 32】 And R ２ teeth 【Transformation 33】 Selected from, in the formula, R ７ teeth 【Transformation 34】 Selected from; and (i) R １ teeth 【Chemistry 35】 And in the formula, R ７ teeth 【Transformation 36】 and R ２ is 【Chemistry 37】 Selected from, in the formula, R ７ teeth 【Transformation 38】 Selected from; However, R １ and R ２ Both are either -OH at the same time or -OR at the same time ３ This is (That's impossible.) and its pharmaceutically acceptable salts.

3. The compound according to claim 1: where, (a-i)R １ is -OH, and R ２ teeth 【Chemistry 39】 Selected from, in the formula, R ７ ha-C(=O)-O-R ８ It is; (a-ii)R １ ha-OR ３ And R ２ teeth 【Chemistry 40】 Selected from, in the formula, R ７ teeth 【Chemistry 41】 Selected from; (b) R １ teeth 【Chemistry 42】 And R ２ teeth 【Chemistry 43】 Selected from; (c) R １ teeth 【Chemistry 44】 And R ２ ha-OR ３ It is; (d) R １ teeth 【Chemistry 45】 And R ２ ha-OR ３ and 【Chemistry 46】 Selected from; (e) R １ teeth 【Chemistry 47】 And in the formula, R ７ ha-C(=O)-O-R ８ And R ２ ha-OR ３ It is; (f) R １ teeth 【Chemistry 48】 And in the formula, R ７ teeth 【Chemistry 49】 And R ２ ha-OR ３ It is; (g) R １ teeth [Transformation 50] And in the formula, R ７ teeth 【Chemistry 51】 And R ２ ha-OR ３ It is; (h)R １ teeth 【Chemistry 52】 And in the formula, R ７ teeth 【Chemistry 53】 And R ２ ha-OR ３ is; and (i) R １ teeth 【Chemistry 54】 And R ２ ha-OR ３ That is the case.

4. R ３ , R ４ , R ５ , R ６ , R ８ , R ９ , R １０ , R １３ , R １５ and R ２２ Each Methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, is o-butyl, t-butyl, pentyl, isopentyl, neopentyl, n-hexyl, 2- Methylpentane, 3-methylpentane, 2,2-dimethylbutane, and 2,3-dimethyl A compound according to any one of claims 1 to 3, independently selected from Louboutin.

5. R ９ , R １４ , R １６ , R １７ , R １９ , R ２０ , R ２３ and R ２４ Each of these is, Isopropyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl A compound according to any one of claims 1 to 4, independently selected from tyl and t-butyl. 。

6. The protecting group is tert-butoxycarbonyl (boc), carbobenzyloxy (C bz), p-methoxybenzylcarbonyl (Moz or MeOZ), 9-fluorenyl Methyloxycarbonyl (Fmoc) group, benzyl (Bn), p-methoxybenzyl (P MB), 3,4-dimethoxybenzyl (DMPM), tosyl (Ts), Troc (Triq (Loroethyl chloroformate), (4-nitrophenyl)sulfonyl (Nosyl), A selected compound from and nitrophenylsulfenyl (Nps), as described in any one of claims 1 to 5. The compound listed.

7. R １８ The compound according to any one of claims 1 to 6, wherein is selected from phenyl.

8. A compound according to any one of claims 1 to 7: where, (a-i)R １ is -OH, and R ２ teeth 【Transformation 55】 Selected from; (a-ii)R １ ha-OCH ３ , -OCH(CH ３ ) ２ and -OC(CH ３ ) ３ from Selected, R ２ teeth 【Transformation 56】 Selected from; (b) R １ teeth 【Chemistry 57】 And R ２ teeth 【Transformation 58】 It is; (c) R １ teeth 【Chemistry 59】 And R ２ ha-OCH ３ (12, 13) (d) R １ teeth 【Transformation 60】 And R ２ teeth 【Chemistry 61】 Selected from; (e) R １ teeth 【Transformation 62】 And R ２ ha-OCH ３ (14) (f) R １ teeth 【Transformation 63】 And R ２ ha-OCH ３ (17, 19) (g) R １ teeth 【Chemistry 64】 And R ２ ha-OCH ３ (15, 16) (h)R １ teeth 【Transformation 65】 And R ２ ha-OCH ３ (18, 20) and (i) R １ teeth [Chemical Formula 66] And R ２ ha-OCH ３ (3, 4)

9. The compound of formula (I) is 【Chemistry 67-1】 【Chemistry 67-2】 【Chemistry 67-3】 and their pharmaceutically acceptable salts A compound according to any one of claims 1 to 8, selected from the above.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 and a pharmaceutically acceptable excipient. thing.

11. Methods for treating diseases, disorders, or conditions related to inflammation, and for treating such conditions The required target is the compound according to any one of claims 1 to 9 or the composition according to claim 10. A method that involves administering a substance.

Images