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Bemfivastatin, PPD 10558, RBx 10558
Bemfivastatin, PPD 10558, RBx 10558
cas 805241-79-6
| Molecular Weight | 588.67 |
|---|---|
| Formula | C34H37FN2O6 |
- PPD-10558 calcium salt
- Ppd-10558(calcium salt)
- 805241-64-9
- ppd-10558 calcium
- 3I8G750MW3
- calcium;(3R,5R)-7-[2-(4-fluorophenyl)-4-[[4-(hydroxymethyl)phenyl]carbamoyl]-3-phenyl-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoate
- C68H72CaF2N4O12
- 1H-PYRROLE-1-HEPTANOIC ACID, 2-(4-FLUOROPHENYL)-.BETA.,.DELTA.-DIHYDROXY-4-(((4-(HYDROXYMETHYL)PHENYL)AMINO)CARBONYL)-5-(1-METHYLETHYL)-3-PHENYL-, CALCIUM SALT (2:1), (.BETA.R,.DELTA.R)-
- calcium;(3R,5R)-7-[2-(4-fluorophenyl)-4-[[4-(hydroxymethyl)phenyl]carbamoyl]-3-phenyl-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoate
- UNII-3I8G750MW3
- 1H-Pyrrole-1-heptanoic acid, 2-(4-fluorophenyl)-beta,delta-dihydroxy-4-(((4-(hydroxymethyl)phenyl)amino)carbonyl)-5-(1-methylethyl)-3-phenyl-, calcium salt (2:1), (betaR,deltaR)-
- Bemfivastatin calcium
- Bemfivastatin hemicalcium
Bemfivastatin (PPD 10558) is an orally active, HMG-CoA Reductase (HMGCR) inhibitor, also known as Statin. Bemfivastatin enhances the activity of liver extraction. Bemfivastatin exhibits little developmental toxicity effects in pregnant rats and rabbits via daily oral doses during organogenesis period. The no observed adverse effect level (NOAEL) are ≥320 mg/kg/day for rats developmental toxicity, 12.5 mg/kg/day for rabbits maternal toxicity, and 25 mg/kg/day for rabbits developmental toxicity, respectively. Bemfivastatin can be used for research on Statin-related hypercholesterolemic myalgia with inability to tolerate statins.
Korean Patent No. 10-1329113 describes a method for preparing (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxymethylphenylamino)carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid hemicalcium salt, as shown in the following reaction scheme.
SCHEME
MAIN
PATENT
WO2020040614
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020040614&_cid=P11-M8VDBE-14315-1
Step 3: Preparation of tert-butyl (3R,5R)-7-(2-(4-fluorophenyl)-4-((4-(hydroxymethyl)phenyl)carbamoyl)-5-isopropyl-3-phenyl-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate
[499]In step 2, tert-butyl 2-((4R,6R)-6-(2-(3-((4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)carbamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (5 g) was dissolved in methanol (37 ml) and THF (37 ml), 1 N HCl aqueous solution (37 ml) was added, and the mixture was stirred at room temperature for 2 hours. EA was added to the reaction solution, diluted, and washed several times with distilled water and brine. The extracted organic layer was dried over Na
2 SO
4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure, EA and hexane were added, and the mixture was purified by recrystallization to obtain the title compound.
[500]White solid 4.6 g (yield quantitative);
[501]
1H NMR (500 MHz, CDCl 3): 7.24-7.14 (m, 9H), 7.06 (d, J = 8.5 Hz, 2H), 6.99 (t, J = 8.5 Hz, 2H), 6.87 (br s, 1H), 4.57 (s, 2H), 4.45-4.08 (m, 2H), 3.96-3.90 (m, 1H), 3.75-3.71 (m, 1H), 3.58 (sep, J = 7.0 Hz, 1H), 2.32 (d, J = 6.5 Hz, 2H), 1.73-1.65 (m, 1H), 1.64-1.58 (m, 1H), 1.54 (d, J = 7.0 Hz, 6H), 1.45 (s, 9H), 1.27-1.22 (m, 2H), MH+ 645.
Step 4: Preparation of (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-((4-hydroxymethylphenylamino)carbonyl)-pyrrol-1-yl)-3,5-dihydroxyheptanoic acid hemicalcium salt
[503]In step 3, tert-butyl (3R,5R)-7-(2-(4-fluorophenyl)-4-((4-(hydroxymethyl)phenyl)carbamoyl)-5-isopropyl-3-phenyl-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate (4.19 g) obtained was dissolved in MeOH (65 ml) and THF (65 ml), and stirred in an ice bath. NaOH pellets (5 eq, 1.3 g) were added, and the mixture was stirred for 1 more hour at room temperature. After concentrating the reaction solution under reduced pressure, distilled water (44 ml) was added until the formed solid was completely dissolved. After concentrating the reaction solution under reduced pressure, distilled water (430 ml) was added until the solid was completely dissolved. 1 M Ca(OAc)
2 aqueous solution (3.6 ml) was slowly added dropwise, and the mixture was stirred for 15.5 hours at room temperature. After the generated solid was filtered under reduced pressure, it was washed several times with distilled water and the filtered solid was dried in an oven.
[504]2.98 g of white solid (yield 76%);
[505]
1H NMR (500 MHz, DMSO-d 6) δ 9.78 (br s, 1H), 7.46 (d, J = 8.5 Hz, 2H), 7.26-7.23 (m, 2H), 7.19 (t, J = 9.0 Hz, 2H), 7.15 (d, J = 8.5 Hz, 2H), 7.09-7.05 (m, 4H), 7.02-6.98 (m, 1H), 6.41 (br s, 1H), 5.04 (t, J = 5.5 Hz, 1H), 4.75 (br s, 1H), 4.39 (d, J = 5.5 Hz, 2H), 3.98-3.91 (m, 1H), 3.79-3.69 (m, 2H), 3.55-3.50 (m, 1H), 3.22 (sep, J = 7.0 Hz, 1H), 2.03 (dd, J = 15.0 Hz, 4.0 Hz, 1H), 1.90 (dd, J = 15.0 Hz, 8.0 Hz, 1H), 1.63-1.57 (m, 1H), 1.54-1.47 (m, 1H), 1.41-1.36 (m, 1H), 1.37 (d, J = 7.0 Hz, 6H), 1.23-1.16 (m, 1H), MH+ (acid+1) 589.
Step 5: Preparation of (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-((4-hydroxymethylphenylamino)carbonyl)-pyrrol-1-yl)-3,5-dihydroxyheptanoic acid hemicalcium salt
[540]The title compound was prepared in the same manner as in step 4 of Example 15.
[541]
1H NMR (500 MHz, DMSO-d 6) δ 9.78 (br s, 1H), 7.46 (d, J = 8.5 Hz, 2H), 7.26-7.23 (m, 2H), 7.19 (t, J = 9.0 Hz, 2H), 7.15 (d, J = 8.5 Hz, 2H), 7.09-7.05 (m, 4H), 7.02-6.98 (m, 1H), 6.41 (br s, 1H), 5.04 (t, J = 5.5 Hz, 1H), 4.75 (br s, 1H), 4.39 (d, J = 5.5 Hz, 2H), 3.98-3.91 (m, 1H), 3.79-3.69 (m, 2H), 3.55-3.50 (m, 1H), 3.22 (sep, J = 7.0 Hz, 1H), 2.03 (dd, J = 15.0 Hz, 4.0 Hz, 1H), 1.90 (dd, J = 15.0 Hz, 8.0 Hz, 1H), 1.63-1.57 (m, 1H), 1.54-1.47 (m, 1H), 1.41-1.36 (m, 1H), 1.37 (d, J = 7.0 Hz, 6H), 1.23-1.16 (m, 1H), MH+ (acid+1) 589.
KR2001835 63%
KR2016103248
- [1]. Faqi AS, et al. Developmental toxicity of the HMG-CoA reductase inhibitor (PPD10558) in rats and rabbits. Birth Defects Res B Dev Reprod Toxicol. 2012 Feb;95(1):23-37. [Content Brief][2]. Wierzbicki A, et al. Drugs in development for the management of dyslipidaemia[J]. Future Prescriber, 2012, 13(2): 12-15.
/////////Bemfivastatin, PPD 10558, PPD-10558, RBx-10558; PPD10558, RBx10558, PPD 10558, RBx 10558, bemfivastatin CA, RBx 10558
Umifoxolaner, ML 878
Umifoxolaner, ML 878
CAS 2021230-37-3
| Molecular Weight | 643.86 |
|---|---|
| Formula | C26H16ClF10N3O3 |
- 4-[(5S)-5-[3-Chloro-4-fluoro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide (ACI)
- 4-{(5S)-5-[3-chloro-4-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl}-N-{2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl}naphthalene-1-carboxamide
- ML 878
- 4-[(5S)-5-[3-chloro-4-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-1,2-oxazol-3-yl]-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]naphthalene-1-carboxamide
- WHO 11642
umifoxolaner (ML-878) is a γ-aminobutyric acid (GABA) regulated chloride channels antagonist. Umifoxolaner is an anti-parasitic agent
Animals such as mammals and birds are often susceptible to parasite infestations/infections. These parasites may be ectoparasites, such as insects, and endoparasites such as filariae and other worms. Domesticated animals, such as cats and dogs, are often infested with one or more of the following ectoparasites:
– fleas (e.g. Ctenocephalides spp., such as Ctenocephalides felis and the like);
– ticks (e.g. Rhipicephalus spp., Ixodes spp., Dermacentor spp., Amblyomma spp., and the like);
– mites (e.g. Demodex spp., Sarcoptes spp., Otodectes spp., and the like);
– lice (e.g. Trichodectes spp., Cheyletiella spp., Linognathus spp. and the like);
– mosquitoes (Aedes spp., Culex spp., Anopheles spp. and the like); and
– flies (Haematobia spp., Musca spp., Stomoxys spp., Dermatobia spp., Cochliomyia spp. and the like).
Fleas are a particular problem because not only do they adversely affect the health of the animal or human, but they also cause a great deal of psychological stress. Moreover, fleas are also vectors of pathogenic agents in animals and humans, such as dog tapeworm {Dipylidium caninum).
Similarly, ticks are also harmful to the physical and psychological health of the animal or human. However, the most serious problem associated with ticks is that they are the vector of pathogenic agents in both humans and animals. Major diseases which are caused by ticks include borreliosis (Lyme disease caused by Borrelia burgdorferi), babesiosis (or piroplasmosis caused by Babesia spp.) and rickettsioses (also known as Rocky Mountain spotted fever). Ticks also release toxins which cause inflammation or paralysis in the host. Occasionally, these toxins are fatal to the host.
Likewise, farm animals are also susceptible to parasite infestations. For example, cattle are affected by a large number of parasites. A parasite which is very prevalent among farm animals is the tick genus Rhipicephalus {Boophilus), especially those of the species microplus (cattle tick), decolor atus and annulatus. Ticks, such as Rhipicephalus {Boophilus) microplus, are particularly difficult to control because they live in the pasture where farm animals graze.
Animals and humans also suffer from endoparasitic infections including, for example, helminthiasis which is most frequently caused by a group of parasitic worms categorized as cestodes (tapeworm), nematodes (roundworm) and trematodes (flatworm or flukes). These parasites adversely affect the nutrition of the animal and cause severe economic losses in pigs, sheep, horses, and cattle as well as affecting domestic animals and poultry. Other parasites which occur in the gastrointestinal tract of animals and humans include Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella, Capillaria, Toxocara, Toxascaris, Trichuris, Enterobius and parasites which are found in the blood or other tissues and organs such as filarial worms and the extra intestinal stages of Strongyloides, Toxocara and Trichinella.
SCHEME
Patents
WO2017176948
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017176948&_cid=P12-M8S60W-88110-1
Cinchonanium, 9-hydroxy-6′-methoxy-1-[[3,4,5-tris(phenylmethoxy)phenyl]methyl]-, chloride (1:1), (8α,9R)- 2138407-51-7, HYDROXYL AMINE, NAOH, MDC , WATER]
Example 5: Synthesis of (R)-IA-3 using chiral phase transfer catalyst (IIIb-13-1)
Step 1 : Synthesis of intermediate 4-2.
1) The substituted iodobenzene starting material (SM) (200.0 g, 1.0 eq.) and THF (400 ml, 10 volumes) were placed into a 1 L reactor and the mixture was cooled to -10 to -5° C.
2) /‘-PrMgCl (340 ml, 1.1 eq.) added dropwise over 1.5 hours at -10 to -5°C to the mixture. 3) After the addition was complete, the mixture was stirred for 1 h at -10 to -5°C.
4) TLC analysis showed the complete consumption of SM (quenching sample with 1 M HCl).
5) CF3COOMe (94.7 g, 1.2 eq.) was added over an hour at -10~-5°C to the reaction mixture.
6) The mixture was stirred for another 12 hours -10~-5°C.
7) TLC analysis showed the almost complete consumption of intermediate 4-1 (quench with 1M HCl).
8) 1 M HCl 1000 ml was added dropwise to the reaction mixture slowly at 0~5°C over 2 hours.
9) The reaction mixture was extracted with hexane twice (1000 ml, 500 ml).
10) Add ^-toluenesulfonic acid 1.0 g to the organic layer and then the mixture was refluxed for 30 min.
11) The resulting mixture was then concentrated under vacuum at 20~25°C to remove the hexane.
12) Sodium bicarbonate (NaHC03, 300mg) was added and the mixture distilled in vacuum to afford compound 4-2 at 80~82°C, as a red liquid (85.0 grams, purity was 92.5% by HPLC, and the yield was 47.0%).
Step 2: Preparation of the compound of Formula (IIA-3):
4-1 IIA-3
1) Compound 4-2 (70.0 g, 1.0 eq.) and acetonitrile (ACN, 350ml, 5 volumes) were placed into a 1 L reactor. The solid was dissolved completely.
2) Compound 4-1 (70.2 g, 1.2 eq.) was then added to the mixture, and the mixture was heated to 90-95° C.
3) The ACN/water azeotrope was removed by distillation (b.p. 79°C).
4) K2C03 (2.0 g, 0.1 eq.) was then added to the mixture.
5) Distillation was continued to remove ACN/water at 90~95°C for about 6 hours.
6) After this time, about 28% Compound 4-2 remained by HPLC.
7) The mixture was cooled to 15~20°C over 1.5 hours and solid precipitated.
8) Water (50 ml) was added and then the mixture was cooled further to 0° C over 40 min.
9) The mixture was then held at 0° C for 40 minutes.
10) The mixture was filtered and the cake was washed with 100 ml of cold ACN/water (ACN/water, 25:6v/v) to yield 75.0 g of a yellow solid after drying (purity: 95.1%, yield: 50.0%).
Step 3 : Preparation of (R)-IA-3 using chiral phase transfer catalyst IIIb-13-1
1) The Compound of Formula IIA-3 (40.0 g, 1.0 eq.) and DCM (1.2 L, 30 volumes) were placed into a 2 L reactor; the solid was dissolved completely.
2) The mixture was cooled to 0° C and some starting material precipitated out.
3) The catalyst of formula IIIb-13-1 (1.47g, 3% mol) was added to the mixture and the mixture was cooled to -10° C.
4) Hydroxylamine (21. Og, 5.0 eq., 50% in water) was added to a solution of NaOH (15.3 g, 6.0 eq., in 5 volumes of water) in another reactor and stirred for 30 minutes.
5) The hydroxylamine/NaOH solution was then added dropwise to the 2 L reactor over about 4 hours.
6) The resulting reaction mixture was stirred for 16 h at -10°C.
7) In-process samples were taken and analyzed by HPLC until the content of starting material was < 1.0%.
8) When the reaction was complete, the mixture was warmed to 10°C and 200 ml of water was added. The mixture was stirred for 10 minutes.
9) After mixing, the mixture was allowed to stand to separate the aqueous and organic layers and the organic layer was collected.
10) The organic layer was washed with 200 ml of 5% KH2PO4.
11) The two layers were allowed to separate and organic layer was collected.
12) The organic layer was then washed with 200 ml brine, the two layers allowed to separate and the organic layer was again collected.
13) The resulting organic layer was concentrated under vacuum at 25-30°C to about 2 volumes.
14) Toluene (400 ml, 10 volumes) was charged to the vessel and concentration under vacuum was continued at 40~45°C to about 3 volumes. The solvent exchange was repeated twice more using the same procedure.
15) When the solvent exchange was complete, the solution was heated to 55-60°C.
16) The mixture was then cooled to 40° C over 1.5 hours and stirred at 40°C for 3 hours.
17) The mixture was then cooled to 25°C over 2 hours and stirred at 25°C for 3hours.
18) The mixture was finally cooled to 5-10°C over 1 hour and stirred at 8° C for 12 hours.
19) After this time, the mixture was filtered and the filter cake was washed with cold toluene (80 ml, 2 volumes).
20) The product was dried under vacuum at 70~75°C for 12h to yield a white solid (22.0 g, chiral purity: 98.0% by area using the chiral HPLC method described in Example 3, chemical purity: 97.1% by area (HPLC), yield: 48.8%). The 1H MR and LCMS spectra are consistent with the structure of the product.
Example 6: Preparation of (S)-IA-3 using chiral phase transfer catalyst IIIa-13-1
) The compound of Formula IIA-3 (11.6 g, 1.0 eq.) and DCM 360 ml, 30 volumes) were placed into a 1 L reactor; the solid was dissolved completely.
) The mixture was cooled to 0°C and some starting material was precipitated out.
) The catalyst (0.43 g, 3% mol) was added to the resulting mixture, and the mixture was cooled to -10° C.
) Hydroxylamine (6.1 g, 5.0 eq., 50% in water) was added to a solution of NaOH (4.4 g, 6.0 eq., in 5 volumes of water) in another reactor, and the mixture was stirred for 30 minutes.
) The hydroxylamine and NaOH solution was added dropwise to the 1 L reactor over about 2 hours, after which the mixture was stirred for 16 h at -10° C.
) Samples were taken and analyzed by HPLC to monitor the extent of reaction until the content of starting material was < 1.0%.
) When the reaction was complete, the mixture was warmed to 10°C and 50 ml of water was added. The mixture was stirred for 10 minutes.
) The mixture was allowed to settle to separate the aqueous and organic layers and the organic layer was collected.
) The organic layer was washed with 50 ml of 5% KH2PO4.
0) The mixture was allowed to separate and the organic layer was collected.
1) The organic layer was washed with 50 ml brine and the organic layer was again collected. 2) The organic layer was concentrated under vacuum at 25-30°C to about 2 volumes.
3) Toluene (230 ml, 10 volumes) was charged and concentration under vacuum was continued at 40~45°C to about 3 volumes. The solvent exchange was repeated twice more using the same procedure.
14) After the solvent exchange was complete, the solution was heated to 55-60°C.
15) The mixture was then cooled to 40° C over 1.5 hours and stirred at 40° C for 3 hours.
16) The mixture was cooled to 25° C over 2 hours and stirred at 25° C for 3 hours.
17) Finally, the mixture was cooled to 5-10° C over 1 hour and stirred at 8° C for 12 hours, after which the mixture was filtered.
18) The filter cake was washed with cold toluene (25 ml, 2 volumes).
19) The product was dried under vacuum at 85~90°C for 24h, resulting in the product as a white solid (6.8 g, chiral purity: 98.7% by area using the chiral FTPLC method described in Example 3, chemical purity: 99.3% by area (FTPLC), yield: 52.1%).
SEE ALSO US20170239218
//////////Umifoxolaner, ML 878, ML878, CS072E2C38, ML-878, WHO 11642
Bavtavirine
Bavtavirine, CAS 1956373-71-9
- KAJ2CK6ZYE
- 4-((4-Amino-8-(4-((1E)-2-cyanoethenyl)-2,6-dimethylphenyl)-2-quinazolinyl)amino)benzonitrile
- Benzonitrile, 4-((4-amino-8-(4-((1E)-2-cyanoethenyl)-2,6-dimethylphenyl)-2-quinazolinyl)amino)-
C26H20N6 416.48
Benzonitrile, 4-[[4-amino-8-[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]-2-quinazolinyl]amino]-
Gilead Sciences, Inc.; Institute of Organic Chemistry and Biochemistry of the AS CR, v.v.i.
Bavtavirine is a potent non-nucleoside reverse transcriptase inhibitors (NNRTIs). Bavtavirine is part of highly active antitiretroviral therapy (HAART) treatment regimen. Bavtavirine can be used for HIV disease research.
SCHEME
PATENT
WO2016105564
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016105564&_cid=P11-M8QXHF-67832-1
A mixture of compound 2a (100 mg, 0.30 mmol), 4-cyanoaniline (46 mg, 0.388 mmol, Sigma-Aldrich) and hydrogen chloride solution in 1,4-dioxane (4M, 7 μL, 0.03 mmol) in dry N-methyl-2-pyrrolidone (2 mL) was heated at 120 °C for 2 hours. The reaction mixture was cooled down to room temperature and triethylamine (0.1 mL, 0.72 mmol) was added. After 15 minutes, water (5 mL) was added and the solid product was filtered off and washed with water. The crude residue was taken up in a mixture of dichloromethane and diethyl ether (1:1,5 mL) and then treated in a sonic bath for 3 minutes. The solid compound was filtered off and washed with diethyl ether (5 mL) to afford the title compound 2. 1H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 1H), 8.18 (dd, J = 8.2, 1.5 Hz, 1H), 7.74 (d, J = 16.7 Hz, 1H), 7.70 (d, J = 8.9 Hz, 2H), 7.51 (s, 2H), 7.48 (dd, J = 7.1, 1.3 Hz, 1H), 7.34 (dd, J = 8.2, 7.1 Hz, 1H), 7.26 (d, J = 8.9 Hz, 2H), 6.54 (d, J = 16.7 Hz, 1H), 1.91 (s, 6H). HRMS: (ESI+) calculated for C26H2,N6 [M+H] 417.1822, found 417.1820. LCMS (m/z) 417.2 [M+H], Tr = 4.68 min (LCMS method 1).
////////////Bavtavirine
Uplarafenib
Uplarafenib
1425485-87-5
494.5 g/mol
| Molecular Formula | C22H21F3N4O4S |
| Molecular Weight | 494.487 |
- B-Raf IN 10
- TQU3V7CXC3
- N-[2,4,5-trifluoro-3-(3-morpholin-4-ylquinoxaline-6-carbonyl)phenyl]propane-1-sulfonamide
- B-Raf IN 10; B-Raf IN-10; B-Raf-IN-10
UPLARAFENIB is a small molecule drug with a maximum clinical trial phase of II and has 1 investigational indication. Neupharma, Inc.
There are at least 400 enzymes identified as protein kinases. These enzymes catalyze the phosphorylation of target protein substrates. The phosphorylation is usually a transfer reaction of a phosphate group from ATP to the protein substrate. The specific structure in the target substrate to which the phosphate is transferred is a tyrosine, serine or threonine residue. Since these amino acid residues are the target structures for the phosphoryl transfer, these protein kinase enzymes are commonly referred to as tyrosine kinases or serine/threonine kinases.
The phosphorylation reactions, and counteracting phosphatase reactions, at the tyrosine, serine and threonine residues are involved in countless cellular processes that underlie responses to diverse intracellular signals (typically mediated through cellular receptors), regulation of cellular functions, and activation or deactivation of cellular processes. A cascade of protein kinases often participate in intracellular signal transduction and are necessary for the realization of these cellular processes. Because of their ubiquity in these processes, the protein kinases can be found as an integral part of the plasma membrane or as cytoplasmic enzymes or localized in the nucleus, often as components of enzyme complexes. In many instances, these protein kinases are an essential element of enzyme and structural protein complexes that determine where and when a cellular process occurs within a cell.
The identification of effective small compounds which specifically inhibit signal transduction and cellular proliferation by modulating the activity of tyrosine and serine/threonine kinases to regulate and modulate abnormal or inappropriate cell proliferation, differentiation, or metabolism is therefore desirable. In particular, the identification of compounds that specifically inhibit the function of a kinase which is essential for processes leading to cancer would be beneficial
SCHEME
Patent
WO2022119905 69%
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2022119905&_cid=P20-M8O7NY-07177-1
Example 1: Preparation of N-(2,4,5-trifluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)propane-l-sulfonamide (Compound A)
[181] Step l : To a solution of quinoxalin-2(lH)-one (54.64 g, 374 mmol, 1.0 eq.) in HO Ac (1000 mL) was added a solution of Bn (19.18 mL, 374 mmol, 1.0 eq.) in HOAc (200 mL) dropwise. The resulting mixture was stirred at rt for 12 h, then poured into ice-water. The precipitate was collected by filtration and dried to afford 7-bromoquinoxalin-2(lH)-one as an off-white solid (74 g, 88%).
[182] Step l : To a suspension of 7-bromoquinoxalin-2(lH)-one (224 g, 1 mol, 1.0 eq.) in POCl3 (1000 mL) was added DMF (3.65 g, 0.05 mol, 0.05 eq.). The resulting mixture was stirred at 120 °C for 2 h, then cooled to rt and slowly poured into ice-water with vigorous stirring. The precipitate was collected by filtration and dried to afford 7-bromo-2-chloroquinoxaline as brown solid (180 g, 75%).
[183] Step 3 : To a solution of 7-bromo-2-chloroquinoxaline (50 g, 0.2mol, 1.0 eq.) in CH3CN (200 mL) were added morpholine (89 g, 1.02 mol, 5.0 eq.) and K2CO3 (85 g, 0.61mol, 3.0 eq). The resulting mixture was stirred at 90 °C for 2 h, then cooled and filtered. The filtrate was concentrated and the residue was re-crystallized from EA to afford 4-(7-bromoquinoxalin-2-yl)morpholine (59 g, 98.3%).
[184] Step 4 : To a solution of 4-(7-bromoquinoxalin-2-yl)morpholine (59 g, 0.2 mol, 1.0 eq.) in DMF (500 mL) was added TEA (139 mL, 1.0 mol, 5.0 eq.), EtsSiH (127 mL, 0.8 mol, 4.0 eq) and Pd(dppf)C12.CH2C12 (8.16 g, 0.01 mol, 0.05 eq.). The resulting mixture was stirred at 90 °C for 12h in an autoclave under CO (1 MPa), then cooled and concentrated. The resulting residue was purified by flash column chromatography(EA/PE=l/l) to afford 3-morpholinoquinoxaline-6-carbaldehyde as a yellow solid (40 g, 82.3%).
[185] Step 5 : To a solution of N-(2,4,5-trifluorophenyl)pivalamide (550 mg, 2.4 mmol, E2 eq.) in THF (30 mL) cooled at -78 °C was added LDA (4.1 mL, 4.8mmol, 2.4 eq.) dropwise. The resulting mixture was stirred at -78 °C for 1 h, then a solution of 3-morpholinoquinoxaline-6-carbaldehyde (486 mg, 2.0 mol, 1.0 eq.) in THF (20 mL) was added dropwise. The resulting mixture was stirred at -78 °C for 1 h, then quenched by the addition of NH4CI solution. The mixture was extracted with EA (20 mL X 3) and the combined organic layers were dried over Na2SO4 and concentrated. The resulting residue was purified by flash column chromatography (MeOH/DCM=l/50, v/v) to afford N-(2,4,5-trifluoro-3-(hydroxy(3-morpholinoquinoxalin-6-yl)methyl)phenyl)pivalamide (620 mg, 65.2%).
[186] Step 6 : The solution of N-(2,4,5-trifluoro-3-(hydroxy(3-morpholinoquinoxalin-6-yl)methyl)phenyl)pivalamide (620 mg, 1.3 mmol, 1.0 eq.) in DCM (10 mL) was added MnCb (358 mg, 6.5 mmol, 5.0 eq.). The resulting mixture was stirred at 50 °C overnight, then cooled and filtered. The filtrate was concentrated and the residue was purified by flash column chromatography (PE/EA=l/2,v/v) to afford N-(2,4,5-trifluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)pivalamide (560 mg, 90%).
[187] Step 7 : To a solution of N-(2,4,5-trifluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)pivalamide (560 mg , 1.2 mmol, 1.0 eq. ) in HO Ac (10 mL) was added cone. HC1 (50 mL). The mixture was stirred at 110 °C for 4h, then poured onto ice. The mixture was adjusted to pH 10 by the addition of IN NaOH solution, then extracted with DCM (100 mL X 3). The combined organic layers were dried over Na2SO4 and concentrated. The resulting residue was purified by flash column chromatography (PE/EA=l/4,v/v) to afford (3-amino-2,5,6-trifluorophenyl)(3-morpholinoquinoxalin-6-yl)methanone as brown solid (410 mg, 88 % yield).
[188] Step 8 : To a solution of (3-amino-2,5,6-trifluorophenyl)(3-morpholinoquinoxalin-6-yl)methanone (40 mg, 0.1 mmol, 1.0 eq.) in DCM (10 mL) was added TEA (101 mg, 1 mol, 10 eq.) and propane- 1 -sulfonyl chloride (0.5 mL, 0.5 mmol, 5.0 eq.). The resulting mixture was stirred at rt for 1 h, then washed with water and extracted with DCM (lOmL X 3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The resulting residue was purified by flash column chromatography (PE/EA=2/1, v/v) to afford N-(propylsulfonyl)-N-(2,4,5-trifluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)propane-l-sulfonamide (41 mg, 62.2%).
[189] Step 9 : To a solution of N-(propylsulfonyl)-N-(2,4,5-trifluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)propane-l -sulfonamide (41 mg, 0.068 mmol, 1.0 eq.) in MeOH/THF (10 mL /10 mL) was added 1 N NaOH (0.15 mmol, 2.2 eq.). The resulting mixture was stirred at rt for 1 h, then concentrated. The resulting residue was purified by flash column chromatography (PE/EA=l/l,v/v) to afford N-(2,4,5-trifluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)propane-l -sulfonamide (Compound A) (23 mg, 68.9%). LRMS (M+H+) m/z calculated 495.1, found 495.1. XH NMR (CDCh, 400 MHz) 8 8.67 (s, 1 H), 7.98-8.03 (m, 3 H), 7.66-7.73 (m, 1 H), 6.72 (s, 1 H), 3.78-3.88 (m, 8H), 3.12-3.16 (t, 2 H), 1.87-1.92 (q, 2 H), 1.05-1.09 (t, 3 H).
Example 2. Preparation of Crystalline Form I of Compound A
[190] N-(2,4,5-trifluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)propane-l-sulfonamide (2.53 kg) and ethyl acetate (EA) (9.1 kg) were added to the reactor. The mixture was stirred under refluxing for 2h. The solution was cooled to room temperature. The resulting precipitate was filtered, washed with EA (1 kg), and dried under vacuum at 45 °C to afford Crystalline Form I of N-(2,4,5-trifluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)propane-1-sulfonamide (1.94 kg, 76.7%).
Example 3. Preparation of Crystalline Form II of Compound A
[191] N-(2,4,5-trifluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)propane-l-sulfonamide (4.01 kg) was dissolved in EA (60 kg), and water (20 kg) was added. The organic phase was separated and concentrated to 4-6 kg under vacuum at 40-45 °C. The resulting residue was dissolved in EA (6 kg) and stirred for 4 hours at 10-20 oC. The solid was filtered, washed with EA (1.5 kg), and dried under vacuum at 50-55 oC to afford Crystalline Form II of N-(2,4,5-trifluoro-3 -(3 -morpholinoquinoxaline-6-carbonyl)phenyl)propane- 1 -sulfonami de (3.15 kg, 78.6%).
SEE
US20130053384 69%
Avenciguat
Avenciguat, 1579514-06-9
BI-685509, 582.7 g/mol, C34H38N4O5
UNII ZA7KTB4PSP
5-ethoxy-1-[6-[3-methyl-2-[[5-methyl-2-(oxan-4-yl)-3,4-dihydro-1H-isoquinolin-6-yl]methoxy]phenyl]pyridin-2-yl]pyrazole-4-carboxylic acid
Avenciguat (BI-685509) is a potent and orally active sGC activator. Avenciguat restores cyclic guanosine monophosphate (cGMP) and improves functionality of nitric oxide (NO) pathways. Avenciguat can be used in research of chronic kidney disease (CKD) and diabetic kidney disease (DKD).
Avenciguat is under investigation in clinical trial NCT05282121 (A Study to Test Whether BI 685509 Alone or in Combination With Empagliflozin Helps People With Liver Cirrhosis Caused by Viral Hepatitis or Non-alcoholic Steatohepatitis (NASH) Who Have High Blood Pressure in the Portal Vein (Main Vessel Going to the Liver)).
Avenciguat (development name BI 685509) is a soluble guanylate cyclase activator developed by Boehringer Ingelheim for kidney disease,[1][2] and cirrhosis.[3][4][5]
SCHEME
Ref
PAPER
Journal of Pharmacology and Experimental Therapeutics (2023), 384(3), 382-39
PATENT
Boehringer Ingelheim International GmbH
WO2014039434
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014039434&_cid=P12-M29UB4-37937-1
PATENT
US20230293513
WO2020011804
| Clinical data | |
|---|---|
| Other names | BI 685509 |
| Legal status | |
| Legal status | Investigational |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 1579514-06-9 |
| PubChem CID | 89992620 |
| UNII | ZA7KTB4PSP |
| Chemical and physical data | |
| Formula | C34H38N4O5 |
| Molar mass | 582.701 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
^ Cherney, David Z. I.; de Zeeuw, Dick; Heerspink, Hiddo J. L.; Cardona, Jose; Desch, Marc; Wenz, Arne; Schulze, Friedrich; Nangaku, Masaomi (August 2023). “Safety, tolerability, pharmacodynamics and pharmacokinetics of the soluble guanylyl cyclase activator BI 685509 in patients with diabetic kidney disease: A randomized trial”. Diabetes, Obesity and Metabolism. 25 (8): 2218–2226. doi:10.1111/dom.15099. PMID 37232058. S2CID 258909393.
^ Reinhart, Glenn A.; Harrison, Paul C.; Lincoln, Kathleen; Chen, Hongxing; Sun, Peng; Hill, Jon; Qian, Hu Sheng; McHugh, Mark C.; Clifford, Holly; Ng, Khing Jow; Wang, Hong; Fowler, Danielle; Gueneva-Boucheva, Kristina; Brenneman, Jehrod B.; Bosanac, Todd; Wong, Diane; Fryer, Ryan M.; Sarko, Chris; Boustany-Kari, Carine M.; Pullen, Steven S. (March 2023). “The Novel, Clinical-Stage Soluble Guanylate Cyclase Activator BI 685509 Protects from Disease Progression in Models of Renal Injury and Disease”. Journal of Pharmacology and Experimental Therapeutics. 384 (3): 382–392. doi:10.1124/jpet.122.001423. PMID 36507845. S2CID 254387173.
^ Lawitz, Eric J.; Reiberger, Thomas; Schattenberg, Jörn M.; Schoelch, Corinna; Coxson, Harvey O.; Wong, Diane; Ertle, Judith (November 2023). “Safety and pharmacokinetics of BI 685509, a soluble guanylyl cyclase activator, in patients with cirrhosis: A randomized Phase Ib study”. Hepatology Communications. 7 (11). doi:10.1097/HC9.0000000000000276. PMC 10615399. PMID 37889522.
^ Jones, Amanda K.; Chen, Hongxing; Ng, Khing Jow; Villalona, Jorge; McHugh, Mark; Zeveleva, Svetlana; Wilks, James; Brilisauer, Klaus; Bretschneider, Tom; Qian, Hu Sheng; Fryer, Ryan M. (July 2023). “Soluble Guanylyl Cyclase Activator BI 685509 Reduces Portal Hypertension and Portosystemic Shunting in a Rat Thioacetamide-Induced Cirrhosis Model”. Journal of Pharmacology and Experimental Therapeutics. 386 (1): 70–79. doi:10.1124/jpet.122.001532. PMID 37230799. S2CID 258909514.
^ Reiberger, Thomas; Berzigotti, Annalisa; Trebicka, Jonel; Ertle, Judith; Gashaw, Isabella; Swallow, Ros; Tomisser, Andrea (24 April 2023). “The rationale and study design of two phase II trials examining the effects of BI 685509, a soluble guanylyl cyclase activator, on clinically significant portal hypertension in patients with compensated cirrhosis”. Trials. 24 (1): 293. doi:10.1186/s13063-023-07291-3. PMC 10123479. PMID 37095557.
////////////Avenciguat, 1579514-06-9, BI 685509,
VALILTRAMIPROSATE
VALILTRAMIPROSATE
1034190-08-3
- (S)-3-(2-Amino-3-methylbutanamido)propane-1-sulfonic acid
- BLU8499
- WHO 11912
| Molecular Weight | 238.30 |
|---|---|
| Formula | C8H18N2O4S |
| CAS No. | 1034190-08-3 |
ALZ-801
Synonyms: valiltramiprosate, NRM-8499, homotaurine prodrug, 3-APS
This is a prodrug of homotaurine, a modified amino acid previously developed under the names tramiprosate and Alzhemed™. ALZ-801 is converted to homotaurine in vivo, but is more easily absorbed and lasts longer in the blood than tramiprosate.
Tramiprosate was reported to inhibit Aβ42 aggregation into toxic oligomers (Gervais et al., 2007; Kocis et al., 2017). Both ALZ-801 and tramiprosate are metabolized to 3-sulfopranpanoic acid (3-SPA), which is normally found in brain and also inhibits Aβ42 aggregation (Hey et al., 2018). A more recent study found that homotaurine activates GABA receptors, and suggests an alternative mechanism of action for ALZ-801 (Meera et al., 2023).
After tramiprosate failed in Phase 3, its maker, NeuroChem, marketed it as a nutritional supplement. Years later, a subgroup analysis of the trial data indicated a potential positive effect in participants who carried two copies of ApoE4 (Abushakra et al., 2016; Abushakra et al., 2017). Alzheon licensed ALZ-801 from NeuroChem and is developing it for Alzheimer’s disease.
ALZ-801 is a potent and orally available small-molecule β-amyloid (Aβ) anti-oligomer and aggregation inhibitor, valine-conjugated proagent of Tramiprosate with substantially improved PK properties and gastrointestinal tolerability compared with the parent compound. ALZ-801 is an advanced and markedly improved candidate for the treatment of alzheimer’s disease.
SCHEME
REF 1
US20080146642
https://patents.google.com/patent/US20080146642A1/en
HCL WATER, Dowex™ Marathon™ C ion-exchange column
General/Typical Procedure: [0311] (i) The solid material was dissolved in water (25 mL). The solution was passed through a Dowex™ Marathon™ C ion-exchange column (strongly acidic, 110 g (5 eq), prewashed). The strong acidic fractions were combined and treated with concentrated HCl (10 mL). The mixture was stirred at 50° C. for 30 minutes, and then was concentrated to dryness. The residual material was co-evaporated with EtOH (ethanol) to completely remove water. EtOH (100 mL) was added to the residue. The mixture was stirred at reflux for 1 h, and then cooled to room temperature. The solid material was collected by filtration. The solid material was dissolved in water (10 mL). The solution was added drop wise to EtOH (100 mL). The product slowly crystallized. The suspension was stirred at room temperature for 30 minutes. The solid material was collected by filtration and it was dried in a vacuum oven (60° C.). ID A2. 1H NMR (D2O).δ. 0.87-0.90 (m, 6H), 1.83 (qt, J = 7.2 Hz, 2H), 2.02-2.09 (m, 1H), 2.79 (t, J = 7.8 Hz, 2H), 3.20-3.29 (m, 2H), 3.60 (d, J = 6.3 Hz, 2H); 13C NMR (D2O).δ. 17.20, 17.77, 24.11, 30.00, 38.29, 48.63, 58.96, 169.35; m/z 237 (M-1).
- [1]. John A. Hey, et al. Discovery and Identification of an Endogenous Metabolite of Tramiprosate and Its Prodrug ALZ-801 that Inhibits Beta Amyloid Oligomer Formation in the Human Brain. CNS Drugs. 2018; 32(9): 849–861.[2]. Hey JA, et al. Clinical Pharmacokinetics and Safety of ALZ-801, a Novel Prodrug of Tramiprosate in Development for the Treatment of Alzheimer’s Disease. Clin Pharmacokinet. 2018 Mar;57(3):315-333. [Content Brief]
////////VALILTRAMIPROSATE, ALZ-801, ALZ 801, BLU 8499, WHO 11912
VICATERTIDE
VICATERTIDE
1251838-01-3
L-Leucyl-L-glutaminyl-L-valyl-L-valyl-L-tyrosyl-L-leucyl-L-histidine
C42H66N10O10
L-Histidine, L-leucyl-L-glutaminyl-L-valyl-L-valyl-L-tyrosyl-L-leucyl- (ACI)
871.04
SB-01, HY-P5542, CS-0887146
(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-2-amino-4-methylpentanoyl]amino]-5-oxopentanoyl]amino]-3-methylbutanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-methylpentanoyl]amino]-3-(1H-imidazol-5-yl)propanoic acid
- L-Leucyl-L-glutaminyl-L-valyl-L-valyl-L-tyrosyl-L-leucyl-L-histidine (ACI)
- 1: PN: KR983182 SEQID: 1 claimed sequence
- Vevoctadekin
- LQVVYLH
Vicatertide is a TGF beta-1 inhibitor[1].
KR983182
SEQ ID NO: 1 (LQVVYLH: SEQ ID NO: 1)
<Example 1> Preparation of peptides
A peptide having the amino acid sequence of SEQ ID NO: 1 (LQVVYLH: SEQ ID NO: 1) was produced by Peptron Inc. Specifically, coupling was performed one by one starting from the C-terminus using the Fmoc SPPS (9-Fluorenylmethyloxycarbonyl solid phase peptide synthesis) method using an automatic synthesizer (ASP48S, Peptron Inc).
NH 2 -His(Trt)-2-chloro-Trityl Resin , in which the first amino acid at the C-terminus of the peptide was attached to the resin, was used. All amino acid raw materials used in peptide synthesis have the N-terminus protected by Fmoc, and all residues are trityl (Trt), t-butyloxycarbonyl (Boc), t-butyl (t-Bu), etc., which are removed by acid. The protected one was used. As a coupling reagent, HBTU (2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate)/HOBt (Hydroxxybenzotriazole)/NMM (N-methylmorpholine) was used. (1) Protected amino acid (8 equivalents) and coupling reagent HBTU (8 equivalents)/HOBt (8 equivalents)/NMM (16 equivalents) were dissolved in DMF (Dimethylformamide) and added, followed by reaction at room temperature for 2 hours. (2) Fmoc removal was performed twice for 5 minutes at room temperature by adding 20% piperidine in DMF. After repeating reactions (1) and (2) to create the basic peptide skeleton, TFA (trifluoroacetic acid)/EDT (1,2-ethanedithiol)/Thioanisole/TIS (triisopropylsilane)/H 2 O=90/ 2.5 / Peptides were separated from the resin using 2.5/2.5/2.5. After purification by reverse phase HPLC using a Vydac Everest C18 column (250 mm × 22 mm, 10 μm), water-acetonitrile linear gradient (10~75% ( v/v) of acetonitrile) method. The molecular weight of the purified peptide was confirmed using LC/MS (Agilent HP1100 series) and lyophilized.
Ref
[1]. WHO D rug Information. Vol. 37, No. 2, 2023.
////VICATERTIDE, SB-01, SB 01, HY P5542, CS 0887146
Vorbipiprant
Vorbipiprant,
CR6086
1417742-86-9
4-[1-[[[(5R)-6-[[4-(Trifluoromethyl)phenyl]methyl]-6-azaspiro[2.5]oct-5-yl]carbonyl]amino]cyclopropyl]benzoic acid
Benzoic acid, 4-[1-[[[(5R)-6-[[4-(trifluoromethyl)phenyl]methyl]-6-azaspiro[2.5]oct-5-yl]carbonyl]amino]cyclopropyl]-
| Molecular Weight | 472.50 |
|---|---|
| Formula | C26H27F3N2O3 |
Vorbipiprant (CR6086) is an EP4 receptor antagonist, serving as a targeted immunomodulator. Thus, Vorbipiprant is also a potential immune checkpoint inhibitor, to turn cold tumors into hot tumors. Vorbipiprant also antagonizes PGE2-stimulated cAMP production (IC50=22 nM). Vorbipiprant exhibit striking DMARD effects in rodents, and anti-inflammatory activity to inhibt immune-mediated inflammatory diseases.
SCHEME
PATENT
Rottapharm S.p.A.
World Intellectual Property Organization, WO2013004290
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013004290&_cid=P10-M25P3U-15334-1
Example 7: 4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl)benzoic acid (single unknown enantiomer) (E7)
Procedure A:
The title compound (E7) (54 mg) was prepared according to the general procedure for esters hydrolysis (Method B) starting from methyl 4-(1 -(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl)benzoate (D122b) (100mg). (LiOH: 4 eq; Reaction time: 18 hrs; RT)
MS: (ES/+) m/z: 473.4 [MH+] C26H27F3N2O3 requires 472.20
Chiral HPLC: [DAICEL AD-H; Mobile phase A: 90% n-heptane (+0.2% TFA), B: 10% EtOH; DAD: 245 nm]: Peak retention time: 18.97 min.
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 7.97 (d, J = 8.0 Hz, 2 H), 7.74 – 7.35 (m, 5 H), 7.26 (br. s., 1 H), 3.86 (d, J = 14.1 Hz, 1 H), 3.38 (d, J = 14.1 Hz, 1 H), 3.08 (d, J = 7.8 Hz, 1 H), 2.91 (d, J = 9.8 Hz, 1 H), 2.27 (br. s., 1 H), 2.05 (t, J = 1 1 .2 Hz, 1 H), 1 .84 (br. s., 1 H), 1 .50 – 1 .24 (m, 4 H), 1 .14 (br. s., 1 H), 0.98 (d, J = 12.7 Hz, 1 H), 0.53 – 0.23 (m, 4 H)
Procedure B:
methyl 4-(1 -(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl)benzoate (D123)) (17.7 g, 36.38 mmol) was partitioned between dioxane (485 ml) and water (242 ml) prior addition of LiOH H2O (6.1 g,
145.5 mmol). The mixture was stirred at RT for 10 hrs. Water (200 ml) was added followed by addition of acetic acid (5.27 ml). Dioxane was evaporated off and acetic acid was added until the pH of the aqueous solution reached the value of ~ 4. The white solid was filtered from the reaction and dried under vacuum overnight then 24 hrs under vacuum at 40 °C affording the title compound (E7) (16.7g).
MS: (ES/+) m/z: 473.3 [MH+] C26H27F3N203 requires 472.20
Chiral HPLC: [DAICEL AD-H; Mobile phase A: 90% n-heptane (+0.2% TFA), B: 10% EtOH; DAD: 245 nm]: Peak retention time: 19.07 min.
1 H NMR (400 MHz, DMSO-d6) δ (ppm): 12.92 – 12.51 (m, 1 H), 8.83 – 8.62 (m, 1 H), 7.85 – 7.75 (m, 2 H), 7.74 – 7.57 (m, 4 H), 7.26 – 7.14 (m, 2 H), 3.87 – 3.72 (m, 1 H), 3.27 – 3.20 (m, 1 H), 2.99 – 2.86 (m, 1 H), 2.79 – 2.69 (m, 1 H), 2.19 – 1 .98 (m, 2 H), 1 .86 – 1 .70 (m, 1 H), 1 .32 – 1 .07 (m, 5 H), 0.94 – 0.82 (m, 1 H), 0.46 -0.17 (m, 4 H).
//////////Vorbipiprant, CR 6086
ATUZAGINSTAT
ATUZAGINSTAT, COR388
cas 2211981-76-7
Cyclopentanecarboxamide, N-[(1S)-5-amino-1-[2-(2,3,6-trifluorophenoxy)acetyl]pentyl]-
Cyclopentanecarboxamide, n-((1s)-5-amino-1-(2-(2,3,6-trifluorophenoxy)acetyl)pentyl)-N-((3s)-7-amino-2-oxo-1-(2,3,6- trifluorophenoxy)heptan-3-yl)cyclopentanecarboxamide
C19H25F3N2O3
386.415
UNII-DGN7ROZ8EN
- OriginatorCortexyme
- DeveloperQuince Therapeutics
- ClassAnti-inflammatories; Antibacterials; Antidementias; Antineoplastics; Antiparkinsonians; Neuroprotectants; Small molecules
- Mechanism of ActionPeptide hydrolase inhibitors
- Phase II/IIIAlzheimer’s disease
- Phase IIPeriodontal disorders
- PreclinicalParkinson’s disease; Squamous cell cancer
- 27 Jan 2023COR 388 licensed to Lighthouse Pharmaceuticals in the US
- 01 Aug 2022Atuzaginstat is available for licensing as of 01 Aug 2022. http://www.quincetx.com
- 01 Aug 2022Cortexyme is now called Quince Therapeutics
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This small molecule is an orally available protease inhibitor targeting the lysine proteases of the periodontal pathogen Porphyromonas gingivalis. Known as gingipains, these proteases penetrate gingival tissue and cause inflammation at the site of periodontitis (O’Brien-Simpson et al., 2009). Periodontitis has been linked epidemiologically to cognitive impairment, and P. gingivalis bacterial lipopolysaccharide has been detected in postmortem brain tissue of people with AD (Poole et al., 2013). Oral P. gingivalis has been called a risk factor for Alzheimer’s disease (Kanagasingam et al., 2020).
Cortexyme’s approach is based on the theory that P. gingivalis invades the brain, where gingipains contribute to Alzheimer’s pathology (see Sabbagh and Decourt, 2022). The company reported elevated gingipain in brain tissue from people with AD, and a correlation between levels of gingipain and tau proteins in postmortem middle temporal gyrus from AD and healthy control tissue. P. gingivalis DNA was detected in postmortem cortices from people with AD and healthy controls, and in CSF of AD patients (Jan 2019 news on Dominy et al., 2019). In the same study, they show that in mice, oral P. gingivalis infection led to the appearance of bacterial DNA in the brain, increased brain Aβ42 production, neuroinflammation, and hippocampal degeneration. The first three findings were reported to be reduced by atuzaginstat; results for hippocampal cell death were not reported.
In preclinical work from other labs, infection with P. gingivalis was reported to worsen AD pathology and cognitive impairment in AD transgenic mice, and to cause neuroinflammation, memory impairment, neurodegeneration, micro- and astrogliosis, increased brain Aβ and phospho-tau, and neurofibrillary tangles in wild-type C57Bl6 mice (Ishida et al., 2017; Ilievski et al., 2018; Ding et al., 2018). For a review of the preclinical literature, see Costa et al., 2021.
In human neurons grown in culture, P. gingivalis infection led to tau phosphorylation and degradation, synapse loss, and cell death (Haditsch et al., 2020).
P. gingivalis is associated with cardiovascular disease. In rabbits, oral infection was reported to increase arterial plaque and levels of the inflammatory marker CRP. Both were reversed by treatment with COR388 (2020 AAIC abstract). In aged dogs with periodontal disease, ninety days of COR388 reduced oral bacterial load and gum pathology (Arastu-Kapur et al., 2020). In addition, older dogs had bacterial antigens and ribosomal RNA in their brains, consistent with systemic infection seen in humans.
Findings
Two Phase 1 trials of atuzaginstat were completed by June 2019. In a single-dose study of 5 to 250 mg capsules in 34 healthy adults, the compound was safe and well-tolerated. A multiple-dose study assessed safety and tolerability in 24 healthy older adults (mean age of 60 years) and nine with AD (mean age 72). According to a company press release and a poster presentation at the 2018 CTAD conference, healthy adults received 25, 50, or 100 mg COR388 or placebo every 12 hours for 10 days; AD patients took 50 mg or placebo every 12 hours for 28 days. The pharmacokinetic profiles of COR388 in AD and controls were reported to be similar. All volunteers with AD had P. gingivalis DNA fragments in their CSF at baseline. COR388 caused no serious adverse reactions, and no one withdrew. Gingipains also were reported to degrade ApoE, and 28 days of treatment with COR388 was claimed to reduce CSF ApoE fragments (2020 AAIC abstract).
A Phase 2/3 trial (GAIN) evaluating a 48-week course of COR388 in 643 people with mild to moderate AD began in April 2019. Participants took either 40 mg, 80 mg, or placebo twice daily. The primary endpoint was to be ADAS-Cog11 score, and the ADCS-ADL was added later as a co-primary functional endpoint. Further outcomes included CDR-SB, MMSE, NPI, the Winterlight Speech Assessment, MRI brain scans, and change in periodontal disease status. Investigators assessed CSF Aβ and tau, plus P. gingivalis DNA and gingipains in CSF, blood, and saliva, before and after treatment. A dental substudy of 228 participants is assessing effects of COR388 on periodontal disease. This trial involves 93 sites in the U.S. and Europe. The U.S. sites are offering a 48-week open-label extension.
According to a presentation at the 2020 CTAD, GAIN was fully enrolled. At baseline, more than 80 percent of participants had CSF Aβ and tau levels consistent with amyloid positivity or an AD diagnosis. All had detectable antibodies to P. gingivalis in their blood. In the dental substudy, 90 percent had periodontal disease. In December 2020, an independent data-monitoring committee recommended continuing the trial after a planned futility analysis of 300 patients treated for six months (press release).
In February 2021, the FDA placed a partial clinical hold on GAIN because of liver abnormalities in some participants (press release). Dosing in the open-label extension was stopped, but the placebo-controlled portion of GAIN continued. Cortexyme characterized the liver effects as reversible and showing no risk of long-term effects.
In October 2021, Cortexyme announced top-line results indicating the trial had missed its co-primary endpoints of ADAS-Cog11 and ADCS-ADL (press release). The company reported a statistically significant 57 percent slowing of decline on the ADAS-Cog11 in a subgroup with detectable saliva P. gingivalis DNA at baseline who took the higher dose; a 42 percent slowing on the lower dose did not reach statistical significance. This prespecified subgroup analysis included 242 participants; it found no effect on the ADCS-ADL. Improvements in ADAS-Cog and other cognitive endpoints correlated with reductions in saliva P. gingivalis DNA, according to data presented at CTAD 2021 in November. The most common treatment-related adverse events were gastrointestinal, occurring in 12 to 15 percent of treated participants. The treatment groups had dose-related liver enzyme elevations greater than three times the upper limit of normal, in 7 and 15 percent of participants on low and high doses, respectively, with bilirubin elevation reported in two participants on the high dose. The elevations occurred mainly in the first six weeks of treatment, and all resolved without long-term effects. Discontinuations due to transaminase elevations numbered one on placebo, and five and 17 in the 40 mg and 80 mg groups, respectively. The overall dropout rate was 25 percent in the placebo group, and 40 percent in atuzaginstat groups. There were five deaths in the high dose arm, and one in the low dose. All were deemed unrelated to drug. There was no evidence of ARIA or other imaging abnormalities.
At CTAD, the company announced plans for a confirmatory trial, pending discussions with regulators. The plan was to test atuzaginstat in people with mild to moderate AD and evidence of P. gingivalis infection, at the lower dose of 40 mg twice daily, reached by titration to minimize liver effects. The company was also planning a trial in Parkinson’s disease to begin in 2022. These trials were never registered.
In September 2021, Cortexyme began a Phase 1 trial of a second-generation lysin-gingipain inhibitor, COR588 (press release). This compound is expected to require only once-daily dosing. Results were expected in May 2022.
In January 2022, the company announced that the FDA had placed a full clinical hold on atuzaginstat due to concerns about liver toxicity (press release). The company said it intended to develop its backup compound, COR588, for Alzheimer’s disease, pending Phase 1 results. In July 2022, Cortexyme announced that COR588 had met safety and tolerability endpoints in a single- and multiple-ascending dose study in healthy adults (press release).
In August 2022, Cortexyme discontinued the gingipain inhibitor program, and offered it for external licensing (press release). The company changed its name to Quince, and its focus to bone disease. In January 2023, Quince put out word that it had sold Cortexyme’s legacy small molecule protease inhibitor portfolio to Lighthouse Pharmaceuticals, a company co-founded by a former Cortexyme CEO (press release).
For all trials of atuzaginstat, see clinicaltrials.gov.
SCHEME
Patent
- US10730826, Compound 1a-racemic
- US10730826, Compound 1a-non-racemic
- Ketone inhibitors of lysine gingipainPublication Number: EP-3512846-A1Priority Date: 2016-09-16
- Ketone inhibitors of lysine gingipainPublication Number: US-2019210960-A1Priority Date: 2016-09-16
- Ketone inhibitors of lysine gingipainPublication Number: WO-2018053353-A1Priority Date: 2016-09-16
- Ketone inhibitors of lysine gingipainPublication Number: US-10730826-B2Priority Date: 2016-09-16Grant Date: 2020-08-04
- Ketone inhibitors of lysine gingipainPublication Number: US-2021053908-A1Priority Date: 2016-09-16
PATENT
WO2018053353
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018053353&_cid=P10-M1OFBK-46119-1
VIII. Examples
Example 1. Preparation of (S)-N-(7-amino-2-oxo-1-(2,3,6-trifluorophenoxy)heptan-3- yl)cyclopentanecarboxamide(1)hydrochloride
[0224] To a mixture of compound 1.4 (23.0 g, 67.2 mmol, 1.00 eq) in THF (200 mL) was added NMM (6.79 g, 67.2 mmol, 7.38 mL, 1.00 eq), isobutyl carbonochloridate (9.17 g, 67.2 mmol, 8.82 mL, 1.00 eq), and diazomethane (5.65 g, 134 mmol, 2.00 eq) at -40 °C under N2 (15 psi). The mixture was stirred at 0 °C for 30 min. LCMS showed the reaction was completed. FLO (200 mL) was added to the reaction and extracted with two 300-mL portions of ethyl acetate. The combined organic phase was washed with two 200-mL portions of brine (200, dried with anhydrous Na2SO4, filtered and concentrated under vacuum to provide crude compound 1.3 (30.0 g, crude) as a yellow oil.
[0225] To a mixture of compound 1.3 (20.0 g, 54.6 mmol, 1.00 eq) in EtOAc (300 mL) was
added hydrogen bromide(29.8 g, 121.7 mmol, 20.0 mL, 33% purity, 2.23 eq) at -20 °C under
N2 (15 psi). The mixture was stirred at -20 °C for 10 min. TLC (petroleum ether : ethyl
acetate = 0:1) showed the reaction was completed. The reaction was basified by addition of
saturated NaHCO3 until the pH of the mixture reached 8, and the mixture was extracted with
three 500-mL portions of EtOAc. The combined organic phase was washed with two 200-mL portions of brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum
to afford crude compound 1.2 (15.0 g, crude) as a yellow solid.
[0226] To a mixture of compound 1.2 (4.00 g, 9.54 mmol, 1.00 eq) in DMF (40.0 mL) was
added 2,6-difluorophenol (1.49 g, 11.4 mmol, 1.20 eq) and KF (1.66 g, 28.6 mmol, 670 μL,
3.00 eq) at 25 °C. The mixture was stirred at 25 °C for 3 h. TLC (petroleum ether: ethyl
acetate = 1:1) showed the reaction was completed. H2O (150 mL) was added to the mixture
and extracted with two 200-mL portions of ethyl acetate. The combined organic phase was
washed with two 100-mL portions of brine, dried with anhydrous Na2SO4, filtered, and
concentrated under vacuum. The residue was purified by silica gel chromatography
(petroleum ether: ethyl acetate = 100:1, 5:1) to afford compound 1.1 (2.50 g, 5.35 mmol,
56.1 % yield) as a yellow solid.
[0227] To a mixture of compound 1.1 (4.00 g, 8.22 mmol, 1.00 eq) in EtOAc (3.00 mL) was added HCl/EtOAc (40.0 mL) at 25 °C. The mixture was stirred at 25 °C for 2 h. TLC (petroleum ether : ethyl acetate=2:1) showed the reaction was completed. The mixture was concentrated in reduced pressure to provide (.S)-N-(7-amino-2-oxo-1-(2,3,6-trifluorophenoxy)heptan-3-yl)cyclopentanecarboxamide 1 hydrochloride salt (1.34 g, 3.16 mmol) as a light yellow solid. LCMS (ESI): m/z: [M + H] calcd for C19H25N2F3O3: 387.2; found 387.1; RT=2.508 min. 1HNMR (400 MHz, DMSO-d6) δ ppm 1.21 – 1.83 (m, 15 H) 2.60 – 2.81 (m, 3 H) 4.30 (ddd, J=9.70, 7.17, 4.52 Hz, 1 H) 5.02 – 5.22 (m, 2 H) 7.12 – 7.24 (m, 2 H) 7.98 (br s, 3 H) 8.32 (d, J=7.28 Hz, 1 H).
Paper Citations
- Raha D, Broce S, Haditsch U, Rodriguez L, Ermini F, Detke M, Kapur S, Hennings D, Roth T, Nguyen M, Holsinger LJ, Lynch CC, Dominy S. COR388, a novel gingipain inhibitor, decreases fragmentation of APOE in the central nervous system of Alzheimer’s disease patients: Abstract. Alzheimer’s & Dementia, 07 December 2020
- O’Brien-Simpson NM, Pathirana RD, Walker GD, Reynolds EC. Porphyromonas gingivalis RgpA-Kgp proteinase-adhesin complexes penetrate gingival tissue and induce proinflammatory cytokines or apoptosis in a concentration-dependent manner. Infect Immun. 2009 Mar;77(3):1246-61. Epub 2008 Dec 29 PubMed.
- Poole S, Singhrao SK, Kesavalu L, Curtis MA, Crean S. Determining the presence of periodontopathic virulence factors in short-term postmortem Alzheimer’s disease brain tissue. J Alzheimers Dis. 2013 Jan 1;36(4):665-77. PubMed.
- Kanagasingam S, Chukkapalli SS, Welbury R, Singhrao SK. Porphyromonas gingivalis is a Strong Risk Factor for Alzheimer’s Disease. J Alzheimers Dis Rep. 2020 Dec 14;4(1):501-511. PubMed.
- Sabbagh MN, Decourt B. COR388 (atuzaginstat): an investigational gingipain inhibitor for the treatment of Alzheimer disease. Expert Opin Investig Drugs. 2022 Oct;31(10):987-993. Epub 2022 Sep 1 PubMed.
- Dominy SS, Lynch C, Ermini F, Benedyk M, Marczyk A, Konradi A, Nguyen M, Haditsch U, Raha D, Griffin C, Holsinger LJ, Arastu-Kapur S, Kaba S, Lee A, Ryder MI, Potempa B, Mydel P, Hellvard A, Adamowicz K, Hasturk H, Walker GD, Reynolds EC, Faull RL, Curtis MA, Dragunow M, Potempa J. Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors. Sci Adv. 2019 Jan;5(1):eaau3333. Epub 2019 Jan 23 PubMed.
- Ishida N, Ishihara Y, Ishida K, Tada H, Funaki-Kato Y, Hagiwara M, Ferdous T, Abdullah M, Mitani A, Michikawa M, Matsushita K. Periodontitis induced by bacterial infection exacerbates features of Alzheimer’s disease in transgenic mice. NPJ Aging Mech Dis. 2017;3:15. Epub 2017 Nov 6 PubMed.
- Ilievski V, Zuchowska PK, Green SJ, Toth PT, Ragozzino ME, Le K, Aljewari HW, O’Brien-Simpson NM, Reynolds EC, Watanabe K. Chronic oral application of a periodontal pathogen results in brain inflammation, neurodegeneration and amyloid beta production in wild type mice. PLoS One. 2018;13(10):e0204941. Epub 2018 Oct 3 PubMed.
- Ding Y, Ren J, Yu H, Yu W, Zhou Y. Porphyromonas gingivalis , a periodontitis causing bacterium, induces memory impairment and age-dependent neuroinflammation in mice. Immun Ageing. 2018;15:6. Epub 2018 Jan 30 PubMed.
- Costa MJ, de Araújo ID, da Rocha Alves L, da Silva RL, Dos Santos Calderon P, Borges BC, de Aquino Martins AR, de Vasconcelos Gurgel BC, Lins RD. Relationship of Porphyromonas gingivalis and Alzheimer’s disease: a systematic review of pre-clinical studies. Clin Oral Investig. 2021 Mar;25(3):797-806. Epub 2021 Jan 20 PubMed.
- Haditsch U, Roth T, Rodriguez L, Hancock S, Cecere T, Nguyen M, Arastu-Kapur S, Broce S, Raha D, Lynch CC, Holsinger LJ, Dominy SS, Ermini F. Alzheimer’s Disease-Like Neurodegeneration in Porphyromonas gingivalis Infected Neurons with Persistent Expression of Active Gingipains. J Alzheimers Dis. 2020;75(4):1361-1376. PubMed.
- Ermini F, Rojas P, Dean A, Stephens D, Patel M, Haditsch U, Roth T, Rodriguez L, Broce S, Raha D, Nguyen M, Kapur S, Lynch CC, Dominy SS, Holsinger LJ, Hasturk H. Targeting porphyromonas gingivalis to treat Alzheimer’s disease and comorbid cardiovascular disease: abstract. Alzheimer’s & Dementia, 07 December 2020
- Arastu-Kapur S, Nguyen M, Raha D, Ermini F, Haditsch U, Araujo J, De Lannoy IA, Ryder MI, Dominy SS, Lynch C, Holsinger LJ. Treatment of Porphyromonas gulae infection and downstream pathology in the aged dog by lysine-gingipain inhibitor COR388. Pharmacol Res Perspect. 2020 Feb;8(1):e00562. PubMed.
///////ATUZAGINSTAT, COR388, COR 388, Cortexyme, Quince Therapeutics
Votoplam
Votoplam
CAS 2407849-89-0
| Molecular Formula | C21H25N9O |
| Molecular Weight | 419.4829 |
2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)triazolo[4,5-c]pyridazin-6-yl]-5-(triazol-2-yl)phenol
UNII D7EZ7B585X
Votoplam is a gene splicing modulator, used to inhibit Huntington’s disease.
Target: DNA/RNA Synthesis
Pathway: Cell Cycle/DNA Damage
Huntington’s disease (HD) is a progressive, autosomal dominant neurodegenerative disorder of the brain, having symptoms characterized by involuntary movements, cognitive impairment, and mental deterioration. Death, typically caused by pneumonia or coronary artery disease, usually occurs 13 to 15 years after the onset of symptoms. The prevalence of HD is between three and seven individuals per 100,000 in populations of western European descent. In North America, an estimated 30,000 people have HD, while an additional 200,000 people are at risk of inheriting the disease from an affected parent. The disease is caused by an expansion of uninterrupted trinucleotide CAG repeats in the “mutant” huntingtin (Htt) gene, leading to production of HTT (Htt protein) with an expanded poly-glutamine (polyQ) stretch, also known as a “CAG repeat” sequence. There are no current small molecule therapies targeting the underlying cause of the disease, leaving a high unmet need for medications that can be used for treating or ameliorating HD. Consequently, there remains a need to identify and provide small molecule compounds for treating or ameliorating HD.
SCHEME
PATENT
PTC Therapeutics Inc., WO2022104058
WO2022103980’
PATENT
WO2020005873
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020005873&_cid=P20-M1EWD1-90833-1
Example 37
Preparation of Compound 163
- Novel rna transcriptPublication Number: US-2022162610-A1Priority Date: 2020-11-12
- Novel rna transcriptPublication Number: WO-2022103980-A1Priority Date: 2020-11-12
- Novel rna transcriptPublication Number: WO-2022103980-A9Priority Date: 2020-11-12
- Heterocyclic and heteroaryl compounds for treating Huntington’s diseasePublication Number: JP-2021528467-APriority Date: 2018-06-27
- Heterocyclic and heteroaryl compounds for treating huntington’s diseasePublication Number: US-2021238186-A1Priority Date: 2018-06-27
References
REFERENCES
[1]. Sydorenko, et al. Preparation of heterocyclic and heteroaryl compounds for treating Huntington’s disease. World Intellectual Property Organization, WO2020005873 A1.
2020-01-02.
20240216369THE USE OF A SPLICING MODULATOR FOR A TREATMENT SLOWING PROGRESSION OF HUNTINGTON’S DISEASE
20240132509HETEROCYCLIC AND HETEROARYL COMPOUNDS FOR TREATING HUNTINGTON’S DISEASE
20230405000TABLET FOR USE IN TREATING HUNTINGTON’S DISEASE AND METHOD OF MAKING THE SAME
20220162610NOVEL RNA TRANSCRIPT
20210238186Heterocyclic and heteroaryl compounds for treating Huntington’s disease
3814357HETEROCYCLIC AND HETEROARYL COMPOUNDS FOR TREATING HUNTINGTON’S DISEASE
112654625HETEROCYCLIC AND HETEROARYL COMPOUNDS FOR TREATING HUNTINGTON’S DISEASE
WO/2020/005873HETEROCYCLIC AND HETEROARYL COMPOUNDS FOR TREATING HUNTINGTON’S DISEASE
/////////PTC Therapeutics, Votoplam
DR ANTHONY MELVIN CRASTO
ORGANIC SPECTROSCOPY
New Drug Approvals 
