WO2021141984A1 - Substituted triazine compounds and uses thereof - Google Patents
Substituted triazine compounds and uses thereof Download PDFInfo
- Publication number
- WO2021141984A1 WO2021141984A1 PCT/US2021/012303 US2021012303W WO2021141984A1 WO 2021141984 A1 WO2021141984 A1 WO 2021141984A1 US 2021012303 W US2021012303 W US 2021012303W WO 2021141984 A1 WO2021141984 A1 WO 2021141984A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- triazine
- dithiol
- amino
- compound
- phenyl
- Prior art date
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- 150000003918 triazines Chemical class 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 180
- 150000003839 salts Chemical class 0.000 claims abstract description 32
- 238000011282 treatment Methods 0.000 claims abstract description 14
- 208000035150 Hypercholesterolemia Diseases 0.000 claims abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 121
- 125000000217 alkyl group Chemical group 0.000 claims description 43
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 150000002367 halogens Chemical class 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 229910052717 sulfur Inorganic materials 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 239000003937 drug carrier Substances 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- JRIBICQMROUOPQ-UHFFFAOYSA-N 2-(4-anilinoanilino)-6-(diethylamino)-1H-1,3,5-triazine-4-thione Chemical compound CCN(CC)c1nc(=S)nc(Nc2ccc(Nc3ccccc3)cc2)[nH]1 JRIBICQMROUOPQ-UHFFFAOYSA-N 0.000 claims description 3
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- MHNVUHDIZCTZCM-UHFFFAOYSA-N 2-(propan-2-ylamino)-6-[4-[[6-(propan-2-ylamino)-4-sulfanylidene-1H-1,3,5-triazin-2-yl]amino]anilino]-1H-1,3,5-triazine-4-thione Chemical compound CC(C)Nc1nc(=S)nc(Nc2ccc(Nc3nc(=S)nc(NC(C)C)[nH]3)cc2)[nH]1 MHNVUHDIZCTZCM-UHFFFAOYSA-N 0.000 claims description 3
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- VJGAGCAFQKOFOA-UHFFFAOYSA-N 6-(4-anilinoanilino)-1h-1,3,5-triazine-2,4-dithione Chemical compound N1C(=S)NC(=S)N=C1NC(C=C1)=CC=C1NC1=CC=CC=C1 VJGAGCAFQKOFOA-UHFFFAOYSA-N 0.000 claims description 3
- KRBGYJXDLGSDEX-UHFFFAOYSA-N 6-(diethylamino)-1h-1,3,5-triazine-2,4-dithione Chemical compound CCN(CC)C1=NC(=S)NC(=S)N1 KRBGYJXDLGSDEX-UHFFFAOYSA-N 0.000 claims description 3
- MFOJAYIIJKPUMC-UHFFFAOYSA-N 6-(ethylamino)-1h-1,3,5-triazine-2,4-dithione Chemical compound CCNC1=NC(=S)NC(=S)N1 MFOJAYIIJKPUMC-UHFFFAOYSA-N 0.000 claims description 3
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
- C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
- C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
- C07D251/40—Nitrogen atoms
- C07D251/42—One nitrogen atom
- C07D251/46—One nitrogen atom with oxygen or sulfur atoms attached to the two other ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
- C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
- C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
- C07D251/40—Nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
- C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
- C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
- C07D251/40—Nitrogen atoms
- C07D251/42—One nitrogen atom
- C07D251/44—One nitrogen atom with halogen atoms attached to the two other ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
- C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
- C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
- C07D251/40—Nitrogen atoms
- C07D251/48—Two nitrogen atoms
- C07D251/52—Two nitrogen atoms with an oxygen or sulfur atom attached to the third ring carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
- C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
- C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
- C07D251/40—Nitrogen atoms
- C07D251/54—Three nitrogen atoms
- C07D251/70—Other substituted melamines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- Figure 8 shows that DL-1 has no impact on hepatic lipid accumulation compared to an MTTP inhibitor.
- Figure 11 shows a dose-response analysis of DL-1 derivatives.
- representative compounds of the invention include:
- tautomeric forms of the compounds of formula (I) are meant to comprise those compounds of formula (I) wherein e.g. an enol group is converted into a keto group (keto-enol tautomerism).
- Tautomeric forms of the compounds of formula (I) or of intermediates of the present invention are intended to be embraced by the ambit of this invention.
- alkyl groups include, but are not limited to, lower alkyl groups include methyl, ethyl, propyl, /-propyl, //-butyl, /-butyl, /-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecycl and hexadecyl.
- lower alkyl groups include methyl, ethyl, propyl, /-propyl, //-butyl, /-butyl, /-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecycl and hexadecyl.
- nitrogen-containing groups such as amines (e.g. amino, mono- or di-alkylamino, aminoalkyl, mono- or di-alkylaminoalkyl), azides, nitriles (e.g. cyano, cyanoalkyl), nitro; sulfur-containing groups such as thiols, thioethers, sulfoxides and sulfones (e.g.
- alkoxy, aryloxy, alkoxyalkyl, aryloxyalkyl aldehydes (e.g. carboxaldehyde), ketones (e.g. alkylcarbonyl, alkylcarbonylalkyl, arylcarbonyl, arylalkylcarbonyl, arycarbonylalkyl), acids (e.g. carboxy, carboxyalkyl), acid derivatives such as esters (e.g. alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl), amides (e.g.
- a compound or compounds of the present invention, as well as their pharmaceutically useable salts, together with one or more conventional excipients, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages.
- the pharmaceutical compositions and unit dosage forms may be comprised of conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
- compositions may be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use.
- a typical preparation will contain from about 5% to about 95% active compound or compounds (w/w).
- preparation or “dosage form” is intended to include both solid and liquid formulations of the active compound and one skilled in the art will appreciate that an active ingredient can exist in different preparations depending on the target organ or tissue and on the desired dose and pharmacokinetic parameters.
- “Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.
- Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxy ethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid,
- the compounds of the present invention may be formulated for administration as suppositories.
- a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, for example, by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and to solidify.
- the compounds of the present invention may be formulated for vaginal administration.
- DL-1 was synthesized from commercially available N-phenyl-l,4-benzenediamine. The latter reacted with cyanuric chloride in the presence of anhydrous potassium carbonate at room temperature under nitrogen atmosphere, affording compound 2 in 61% yield.
- the compound 2 reacted with sodium hydrosulfide (NaSH) in dimethylformamide (DMF) at 90°C, producing crude DL-1.
- NaSH sodium hydrosulfide
- DMF dimethylformamide
- the product was recrystallized from DMF, affording DMF containing DL-1.
- the residual DMF was removed by dissolving the DMF containing DL-1 in dimethyl sulfoxide (DMSO) in small volume by heating, pouring the DMSO solution into water and collecting the white precipitate by filtration. After drying in the air, purified DL-1 was resulted in 88% yield.
- the compounds 2 and DL-1 were characterized by proton NMR spectroscopy and ESI TOF mass spectrometry
- the resulted solutions were measured using a UV-vis spectrophotometer for UV absorbances with the maximum absorbances. The values were subtracted by that of a blank, 1 x PBS buffer. The corrected absorbances were then used to calculate the corresponding concentrations using the formula (1) and extinction coefficients (Table 1) shown above. The individual concentrations were then used to calculate the solubilities in 1.0 mL of water and 1 x PBS buffer. The results were listed in Table 1 as well.
- the compounds were dissolved in DMSO to either 50 mg/ml, 10 mg/ml or 5 mg/ml solutions, which were diluted to 0.5 mg/ml with DMSO. These solutions were then diluted to 5 ug/ml with 1 x PBS buffer. The resulted solutions were then measured in a UV-vis spectrophotometer for UV scanning from 240 nm to 400 nm at 25 °C. The absorbance values were subtracted by that of a blank, 1 x PBS buffer containing DMSO. The total volume of the solutions was 300 uL and the path length for each well was 0.7 cm in a UV 96-well plate. The extinction coefficients of the compounds were then calculated based on molar concentrations and the corrected UV absorbances at the maximum absorption (Table 1).
- C Human iPSC-derived hepatocytes were treated with 2 pg/mL of DL-1 for 24 hours.
- A mRNA level of hepatic markers (ALB, AFP, HNF4a, SLC10A1, ASGR1) were determined via real-time qPCR.
- B Cells were fixed and immunofluorescence was performed to determine HNF4 and ALB level.
- H Human iPSC derived hepatocytes were treated with DL-1 (2 pg/mL) and MTTP inhibitor CP- 346086 (20 nM) for 72 hours.
- Figure 8 shows that DL-1 has no impact on hepatic lipid accumulation comparing to MTTP inhibitor.
- iPSCs Human induced pluripotent stem cells
- Differentiated human hepatocyte-like cells were treated with representative compounds of the invention (2 pg/mL) or equivalent amount of DMSO (0.5%) as the placebo group for 24 hours.
- Culture medium before or after compound treatment were harvested for analysis.
- Pre- and Post drug medium were both incubated exactly 24 hours in order to compare the differences in secreted LDL-C level in the same period of time.
- the secreted level of apolipoprotein B (APOB- 100), the core protein of LDL-C were determined via enzyme-linked immunosorbent assay (ELISA).
- human iPSCs were seeded on Matrigel-coated tissue culture plates with the density of 7x 10 5 / mL to form a monolayer.
- Cells were induced to form definitive endoderm by the addition of 100 ng/ml Activin A for 5 days. Definitive endoderm was then converted to hepatic progenitor cells by addition of Bone Morphogenetic Protein 4 (20 ng/ml) and Fibroblast Growth Factor 2 (10 ng/ml) for an additional 5 days.
- Immature hepatocytes were generated by the inclusion of Hepatocyte Growth Factor (20 ng/ml).
- Cells were induced to mature hepatocyte- like cells by the addition of Oncostatin M (20 ng/ml) for 5 days.
- K3 iPSCs were differentiated to hepatocyte-like cells in 96-well plates.
- a 24 hours pre-drug treatment sample of the medium was collected before the addition of drugs from the South Carolina Compound Collection library (representative set) for 24 hours at 2 pg/mL, and post drug medium were harvested for analysis.
- APOB levels in the collected medium were determined using a standard curve, and Four Parameter Logistic (4PL) regression model in both pre-and post-drug treated samples by ELISA.
- the APOB levels in the pre-drug and post-drug medium were combined and expressed as a delta- APOB ratio (post-drug [APOB]: pre-drug [APOB]).
- iPSC-heps were treated with 0, 3, 12, 48 pg/mL of DL-9 for 24 hours, and cells were fixed in 4% PFA followed by 0.1% Triton-X-100 penetration. Cells were then incubated with primary antibodies (anti- APOB 1:100, Mabtech; anti-LAMPl, 1:100, Cell Signaling, anti-SORTILIN, 1:100, Abeam) overnight at 4 degrees and switched to secondary antibodies as mentioned above. Images were taken using KEYENCE BZ- 800 and Leica SP8 confocal microscopy. Integrated fluorescent intensity was normalized by total cell counts, which is determined by DAPI staining.
- Cell viability assay was performed using CellTiter-Glo® luminescent cell viability assay kit following the manufacturer’s instructions (Promega, WI, US). Experimental and control groups were processed identically.
- Cell Culture medium was harvested from human iPSC-derived hepatocytes (Day 20) before and after 24 hours of DL-1 (2 pg/mL) or vehicle treatment. Pre-drug and Post-drug medium were concentrated using Amico® Ultra 10K Centrifugal Filters (Sigma-Aldrich, #Z740171), and total cholesterol levels were determined using the colorimetric cholesterol assay kit (Sigma-Aldrich, #MAK043) following the manufactural instructions.
- Colella AD Chegenii N, Tea MN, Gibbins IL, Williams KA, Chataway TK: Comparison of Stain-Free gels with traditional immunoblot loading control methodology.
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EP21738601.0A EP4087837A4 (en) | 2020-01-06 | 2021-01-06 | Substituted triazine compounds and uses thereof |
CA3163816A CA3163816A1 (en) | 2020-01-06 | 2021-01-06 | Substituted triazine compounds and uses thereof |
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Title |
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AIKO OKI , SHINPEI OHKI , KAZUYA KOIZUMI , YUKIHARU SATO HITOSHI KONO , PETER BÖGER , KO WAKABAYASHI : "Phytotoxicity Caused by Peroxidizing Herbicides Is Alleviated by 2-Substituted 4,6- Bis(ethylamino)-1,3,5-triazines", JOURNAL OF PESTICIDE SCIENCE, vol. 22, no. 4, 20 November 1997 (1997-11-20), pages 309 - 313, XP055940536, ISSN: 1348-589X, DOI: 10.1584/jpestics.22.309 * |
MORIMOTO ET AL.: "Comparative Pharmacology of Pentamethylmelamine and Hexamethyl melamine in Mice", CANCER RESEARCH, vol. 40, no. 8, August 1980 (1980-08-01), pages 2762 - 2767, XP055840610 * |
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