ANALOGS OF CDDO-2P-IM AND CDDO-3P-IM
20230365621 · 2023-11-16
Inventors
Cpc classification
C07J63/008
CHEMISTRY; METALLURGY
International classification
Abstract
The present disclosure relates to synthetic triterpenoids, methods for preparing such synthetic triterpenoids, and methods of using such synthetic triterpenoids to treat and/or prevent diseases or disorders such as cancers, particularly brain tumors, neuropsychiatric disorders, and neurodegenerative diseases.
Claims
1. A compound or an N-oxide thereof or a pharmaceutically acceptable salt thereof, wherein the compound has a structure corresponding to Formula (I) or Formula (III): ##STR00054## wherein n is an integer selected from 1 to 4 and R.sup.1 is halogen, optionally substituted carboxamide, or optionally substituted C.sub.1-6-haloalkyl.
2. The compound, N-oxide, or salt of claim 1, wherein n is 1.
3. The compound, N-oxide, or salt of claim 1, wherein R.sup.1 is C.sub.1-6-haloalkyl.
4. The compound, N-oxide, or salt of claim 1, wherein R.sup.1 is C.sub.1-6-fluoroalkyl.
5. The compound, N-oxide, or salt of claim 1, wherein R.sup.1 is —CF.sub.3.
6. The compound, N-oxide, or salt of claim 1, wherein R.sup.1 is an optionally substituted carboxamide.
7. The compound, N-oxide, or salt of claim 1, wherein R.sup.1 is —C(O)NH.sub.2.
8. A compound or an N-oxide thereof or a pharmaceutically acceptable salt thereof, wherein the compound has a structure corresponding to Formula (II) or Formula (IV): ##STR00055## wherein n is an integer selected from 1 to 4 and R.sup.1 is halogen, optionally substituted carboxamide, or optionally substituted C.sub.1-6-haloalkyl.
9. The compound, N-oxide, or salt of claim 8, wherein n is 1.
10. The compound, N-oxide, or salt of claim 8, wherein R.sup.1 is C.sub.1-6-haloalkyl.
11. The compound, N-oxide, or salt of claim 8, wherein R.sup.1 is C.sub.1-6-fluoroalkyl.
12. The compound, N-oxide, or salt of claim 8, wherein R.sup.1 is —CF.sub.3.
13. The compound, N-oxide, or salt of claim 8, wherein R.sup.1 is an optionally substituted carboxamide.
14. The compound, N-oxide, or salt of claim 8, wherein R.sup.1 is —C(O)NH.sub.2.
15. The compound, N-oxide, or salt of claim 8, wherein the compound has a structure corresponding to: TABLE-US-00005 Compound Structure 101
16. A method for modulating Nrf2 activity in a patient in need thereof, the method comprising: administering to the patient the compound, or N-oxide, or salt of claim 1.
17. A method for treating cancer in a patient in need thereof, the method comprising: administering to the patient the compound, or N-oxide, or salt of claim 1.
18. The method of claim 17, wherein the cancer is a brain cancer.
19. A method for treating a neurodegenerative disease in a patient in need thereof, the method comprising: administering to the patient the compound, or N-oxide, or salt of claim 1.
20. The method of claim 19, wherein the neurodegenerative disease is Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), or Huntington disease.
21. A method for treating an inflammatory disease or condition in a patient in need thereof, the method comprising: administering to the patient the compound, or N-oxide, or salt of claim 1.
22. The method of claim 21, wherein the inflammatory disease or condition is a neuropsychiatric disorders, particularly, depression.
23. A pharmaceutical composition comprising (i) the compound, or N-oxide, or salt of claim 1 and (ii) a pharmaceutically acceptable excipient.
Description
F. EXAMPLES
Example 1
A. Preparation of (6aS,6bR,8aS,12bR,14bS)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-8a-(4-(6-(trifluoromethyl) pyridin-2-yl)-1H-imidazole-1-carbonyl)-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile (Compound 104).
[0083] ##STR00031##
Stille Coupling
[0084] ##STR00032##
[0085] 4-(Tributylstannyl)-trityl-1H-imidazole was prepared according to methods known in the art. See Jetter et al., Synthesis 6:829 (1998).
[0086] To a stirred solution of 4-(Tributylstannyl)-trityl-1H-imidazole (4.29 g. 7.15 mmol) in toluene (20 mL) was charged 2-bromo-6-(trifluoromethyl)pyridine (1.6 g, 7.08 mmol) and the mixture degassed with nitrogen for 15 minutes. Tetrakis(triphenylphosphine)palladium (0.245 g, 0.212 mmol) was added and the mixture heated to 100° C. and stirred for 18 h. The reaction mixture was cooled to 25° C. and 10% aqueous potassium fluoride (16 mL) solution was added and stirred for 30 minutes. The mixture was filtered through celite and the phases separated. The organic layer was washed twice with water (16 mL) and dried over anhydrous magnesium sulfate and concentrated. Purification by column chromatography (heptane/Ethyl acetate 4:1) gave the desired product as a yellow foam in 80% yield.
Trityl Deprotection
[0087] ##STR00033##
[0088] 2-(trifluoromethyl)-6-(1-trityl-1H-imidazol-4-yl)pyridine (3.22 g, 7.07 mmol) was dissolved in dioxane (65 mL) and heated to 100° C. HCl in dioxane (5.3 mL, 21.2 mmol, 4M) was added and the mixture heated for 1 h. The mixture was cooled to RT, filtered and washed with dioxane (2×10 mL) and dried under vacuum to give the desired product as a white solid in 90% yield.
Coupling With CDDO
[0089] ##STR00034##
[0090] CDDO was obtained from a commercial supplier. To a stirred solution of CDDO (1 g, 2.03 mmol) in dichloromethane (10 mL) was added DMF (8 μL, 0.1 mmoL). Oxalyl chloride (0.25 mL, 2.85 mmol) was added over 15 min and the mixture stirred at RT for 2 h then concentrated to dryness under vacuum. The residue was redissolved in dichloromethane (4 mL) and added to a mixture of 2-(1H-imidazol-4-yl)-6-(trifluoromethyl) pyridine hydrochloride (0.611 g, 2.136 mmol) and triethylamine (0.94 mL, 6.71 mmol) in dichloromethane (8 mL) and stirred for 2 h. Water (6 mL) was added and the phases were separated and the organic layer dried over anhydrous magnesium sulfate and concentrated. Purification by column chromatography (DCM/MeOH) gave the product as a pale yellow solid in 65% yield.
[0091] The following compounds were prepared in a similar manner to that described for Compound 104.
B. (6aS,6bR,8aS,12bR,14bS)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-8a-(4-(3-(trifluoromethyl) pyridin-2-yl)-1H-imidazole-1-carbonyl)-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile (Compound 101).
[0092] ##STR00035##
C. (6aS,6bR,8aS,12bR,14bS)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-8a-(4-(4-(trifluoromethyl) pyridin-2-yl)-1H-imidazole-1-carbonyl)-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile (Compound 102).
[0093] ##STR00036##
D. (6aS,6bR,8aS,12bR,14bS)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-8a-(4-(5-(trifluoromethyl) pyridin-2-yl)-1H-imidazole-1-carbonyl)-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile (Compound 103).
[0094] ##STR00037##
Example 2
A. Preparation of 6-(1-((4aS,6aR,6bS,12aS,14aR)-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicene-4a-carbonyl)-1H-imidazol-4-yl)picolinamide (Compound 204).
[0095] ##STR00038##
[0096] Compound 204 was prepared in a similar manner to Compound 104 except that a bromo-cyanopyridine was used in place of the corresponding bromo-trifluoromethyl pyridine. An additional hydrolysis step was performed prior to trityl deprotection to convert the nitrile to primary amide.
##STR00039##
[0097] 6-(1-trityl-1H-imidazol-4-yl)picolinonitrile (4.46 g, 10.81 mmol) was suspended in t-BuOH (42.37 ml)
[0098] Potassium tert-butoxide (3.75 g, 32.4 mmol) was added and the reaction mixture heated to reflux for 2 h. The reaction mixture was cooled to RT and Water (44.6 ml) was added. The reaction mixture was extracted with ethyl acetate, washed with brine and dried over anhydrous magnesium sulfate and concentrated to afford the product in quantitative yield as a yellow solid that was used in the next step without further purification.
[0099] The following compounds were prepared in a similar manner to that described for Compound 204.
B. 2-(1-((4aS,6aR,6bS,12aS,14aR)-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,2,3,4,4a, 5,6,6a,6b,7,8, 8a,9,10,12a,14,14a,14b-octadecahydropicene-4a-carbonyl)-1H-imidazol-4-yl)nicotinamide (Compound 201).
[0100] ##STR00040##
C. 2-(1-((4aS,6aR,6bS,12aS,14aR)-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,2,3,4,4a, 5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicene-4a-carbonyl)-1H-imidazol-4-yl)isonicotinamide (Compound 202).
[0101] ##STR00041##
D. 6-(1-((4aS,6aR,6bS,12aS,14aR)-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,2,3,4,4a, 5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicene-4a-carbonyl)-1H-imidazol-4-yl)nicotinamide (Compound 203).
[0102] ##STR00042##
Example 3
A. Preparation of (6aS,6bR,8aS,12bR,14bS)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-8a-(4-(5-(trifluoromethyl) pyridin-3-yl)-1H-imidazole-1-carbonyl)-3,4,4a,5,6,6a,6b,7,8, 8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile (Compound 303).
[0103] ##STR00043##
Stille Coupling
[0104] ##STR00044##
[0105] 4-(Tributylstannyl)-trityl-1H-imidazole was prepared according to methods known in the art. See Jetter et al., Synthesis 6:829 (1998).
[0106] To a stirred solution of 4-(Tributylstannyl)-trityl-1H-imidazole (4.55 g. 7.60 mmol) in toluene (21 mL) was charged 3-bromo-5-(trifluoromethyl)pyridine (1.7 g, 7.52 mmol) and the mixture degassed with nitrogen for 15 minutes. Tetrakis(triphenylphosphine)palladium (0.261 g, 0.226 mmol) was added and the mixture heated to 100° C. and stirred for 18 h. The reaction mixture was cooled to 25° C. and 10% aqueous potassium fluoride (17 mL) solution was added and stirred for 30 minutes. The mixture was filtered through celite and the phases separated. The organic layer was washed twice with water (17 mL) and dried over anhydrous magnesium sulfate and concentrated. Purification by column chromatography (DCM/MeOH 97:3) gave the desired product as a yellow foam in 88% yield.
Trityl Deprotection
[0107] ##STR00045##
[0108] 3-(trifluoromethyl)-5-(1-trityl-1H-imidazol-4-yl)pyridine (3.43 g, 7.53 mmol) was dissolved in dioxane (67 mL) and heated to 100° C. HCl in dioxane (5.65 mL, 22.6 mmol, 4M) was added and the mixture heated for 1 h. The mixture was cooled to RT, filtered and washed with dioxane (2×10 mL) and dried under vacuum to give the desired product as a white solid in 85% yield.
Coupling With CDDO
[0109] ##STR00046##
[0110] CDDO was obtained from a commercial supplier. To a stirred solution of CDDO (1.6 g, 3.27 mmol) in dichloromethane (16 mL) was added DMF (13 μL, 0.16 mmoL). Oxalyl chloride (0.4 mL, 4.58 mmol) was added over 15 min and the mixture stirred at RT for 2 h then concentrated to dryness under vacuum. The residue was redissolved in dichloromethane (6.4 mL) and added to a mixture of 3-(1H-imidazol-4-yl)-5-(trifluoromethyl)pyridine dihydrochloride (0.984 g, 3.44 mmol) and triethylamine (1.56 mL, 10.8 mmol) in dichloromethane (13 mL) and stirred for 2 h. Water (10 mL) was added and the phases were separated and the organic layer dried over anhydrous magnesium sulfate and concentrated. Purification by column chromatography (DCM/MeOH) gave the product as a pale yellow solid in 58% yield.
[0111] The following compounds were prepared in a similar manner to that described for Compound 303.
B. (6aS,6bR,8aS,12bR,14bS)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-8a-(4-(2-(trifluoromethyl) pyridin-3-yl)-1H-imidazole-1-carbonyl)-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile (Compound 301).
[0112] ##STR00047##
C. (6aS,6bR,8aS,12bR,14bS)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-8a-(4-(4-(trifluoromethyl) pyridin-3-yl)-1H-imidazole-1-carbonyl)-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile (Compound 302).
[0113] ##STR00048##
D. (6aS,6bR,8aS,12bR,14bS)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-8a-(4-(6-(trifluoromethyl) pyridin-3-yl)-1H-imidazole-1-carbonyl)-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile (Compound 304).
[0114] ##STR00049##
Example 4
[0115] Compounds 401-404 are prepared in a similar manner as Example 3 except that a bromo-cyanopyridine is used in place of the corresponding bromo-trifluoromethyl pyridine. An additional hydrolysis step is performed prior to trityl deprotection to convert the nitrile to primary amide.
[0116] A. CDDO-3P-Im-2-carboxamide (Compound 401).
##STR00050##
[0117] B. CDDO-3P-Im-4-carboxamide (Compound 402).
##STR00051##
[0118] C. CDDO-3P-Im-5-carboxamide (Compound 403).
##STR00052##
[0119] D. CDDO-3P-Im-6-carboxamide (Compound 404).
##STR00053##
[0120] It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations, or methods, or any combination of such changes and modifications of use of the invention, may be made without departing from the spirit and scope thereof.
[0121] All references (patent and non-patent) cited above are incorporated by reference into this patent application. The discussion of those references is intended merely to summarize the assertions made by their authors. No admission is made that any reference (or a portion of any reference) is relevant prior art (or prior art at all). Applicant reserves the right to challenge the accuracy and pertinence of the cited references.