Bocodepsin, OKI-179

CAS 1834513-65-3

1834513-67-5 (besylate)  

K5D067O1SW

S-((3E)-4-((6S,9S)-12,12-DIMETHYL-4,8,11,14-TETRAOXO-9-(PROPAN-2-YL)-7-OXA -3,10,13-TRIAZA-1(2,4)-(1,3)THIAZOLACYCLOTETRADECAPHAN-6-YL)BUT-3-EN-1-YL) (2S)-2-AMINO-3-METHYLBUTANETHIOATE
S-(4-((7S,10S)-4,4-DIMETHYL-2,5,8,12-TETRAOXO-7-(PROPAN-2-YL)-9-OXA-16-THIA- 3,6,13,18-TETRAAZABICYCLO(13.2.1)OCTADECA-15(18),17-DIEN-10-YL)BUT-3-EN-1-YL) (2S)-2-AMINO-3-METHYLBUTANETHIOATE

Molecular Weight	581.75
Formula	C26H39N5O6S2

• L-Valine, S-L-valyl-(3S,4E)-3-hydroxy-7-mercapto-4-heptenonyl-2-(aminomethyl)-4-thiazolecarbonyl-2-methylalanyl-, (5–>2)-lactone
• S-{(3E)-4-[(6S,9S)-12,12-dimethyl-4,8,11,14-tetraoxo-9-(propan-2-yl)-7-oxa-3,10,13-triaza-1(2,4)-[1,3]thiazolacyclotetradecaphan-6-yl]but-3-en-1-yl} (2S)-2-amino-3-methylbutanethioate
• S-{4-[(7S,10S)-4,4-dimethyl-2,5,8,12-tetraoxo-7-(propan-2-yl)-9-oxa-16-thia-3,6,13,18-tetraazabicyclo[13.2.1]octadeca-15(18),17-dien-10-yl]but-3-en-1-yl} (2S)-2-amino-3-methylbutanethioate

• Originator OnKure Therapeutics
• Class Antineoplastics; Small molecules
• Mechanism of ActionHDAC1 protein inhibitors

Phase I/II Malignant melanoma; Solid tumours

• No development reportedHaematological malignancies

29 Jan 2025 OnKure Therapeutics completes the phase-I/II Nautilus trial in Malignant melanoma (Late-stage disease, Metastatic disease, Second-line therapy or greater, Combination therapy) in USA (PO) (NCT05340621),

• 11 Oct 2023Pharmacodynamics data from a preclinical studies in Solid tumours presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics 2023 (AACR-NCI-EORTC-2023 2023)
• 11 Oct 2023Initial efficacy and adverse events data from a phase Ib/II NAUTILUS trial in Melanoma presented at the International Conference on Molecular Targets and Cancer Therapeutics 2023 (AACR-NCI-EORTC-2023)

Bocodepsin (OKI-179) is an orally active and selective HDAC inhibitor, with antitumor activity. Bocodepsin can be used for suppression on solid tumor and hematologic malignancies.

SCHEME

PATENT

WO2017201278

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017201278&_cid=P12-M9WKU5-87067-1

Examples

[00127] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention.

[00128] Example 1: Preparation of (R)-S-((E)-4-((7S,10S)-7-isopropyl-4,4-dimethyl-2,5,8,12- tetraoxo-9-oxa-16-thia-3,6,13,18-tetraazabicyclo[13.2.1]octadeca-l(17),15(18)-dien-10- yl)but-3-en-l-yl) 2-amino-3-methylbutanethioate hydrochloride.

Step 1 : Preparation of (R)-S-((E)-4-((7S,10S)-7-isopropyl-4,4-dimethyl-2,5,8,12- tetraoxo-9-oxa-16-thia-3,6,13,18-tetraazabicyclo[13.2.1]octadeca-l(17),15(18)-dien-10- yl)but-3-en-l-yl) 2-((tert-butoxycarbonyl)amino)-3-methylbutanethioate. (7S,10S)-10-((E)- 4- chlorobut-l-en-l-yl)-7-isopropyl-4,4-dimethyl-9-oxa-16-thia-3,6,13,18- tetraazabicyclo[13.2.1]octadeca-l(17),15(18)-diene-2,5,8,12-tetraone (15 g, 0.03 mol), (R)-2- ((tert-butoxycarbonyl)amino)-3-methylbutanethioic S-acid (12.5 g, 0.06 mol), K2CO₃ (11.2 g, 0.09 mol), and KI (0.89 g, 0.006 mol) were dissolved in 150mL of acetonitrile and the resulting mixture was warmed to 60-65°C and stirred under nitrogen. After 16 hours, the mixture was cooled to 20°C, 300 mL of water was added, and the resulting suspension was extracted with ethyl acetate (2X200 mL). The combined organic phases were dried with anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (elution with ethyl acetate/petroleum ether = 1/1 to 4/1) to give (R)- 5- ((E)-4-((7S,10S)-7-isopropyl-4,4-dimethyl-2,5,8,12-tetraoxo-9-oxa-16-thia-3,6,13,18- tetraazabicyclo[13.2.1] octadeca-l(17),15(18)-dien-10-yl)but-3-en-l-yl) 2-((tert- butoxycarbonyl)amino)-3-methylbutanethioate (17.0 g, 80% yield).

Step 2: Preparation of (R)-S-((E)-4-((7S,10S)-7-isopropyl-4,4-dimethyl-2,5,8,12- tetraoxo-9-oxa-16-thia-3,6,13,18-tetraazabicyclo[13.2.1]octadeca-l(17),15(18)-dien-10- yl)but-3-en-l-yl) 2-amino-3-methylbutanethioate hydrochloride. (R)-S-((E)-4-((7S,10S)-7- isopropyl-4,4-dimethyl-2,5,8,12-tetraoxo-9-oxa-16-thia-3,6,13,18- tetraazabicyclo[l 3.2.1] octadeca- 1 ( 17), 15 (18)-dien- 10-y l)but-3-en- 1 -y 1) 2-((tert-butoxy carbony l)amino)-3-methylbutanethioate (1.7 g, 0.025 mol) was dissolved in 150 mL of dichloromethane and trifluoroacetic acid (22.5 mL) was added at 10°C. After stirring at 10°C for 4 hours under nitrogen, the mixture was concentrated to dryness and the residue was dissolved in 100 mL of ethyl acetate and treated with 10 mL of 4M HCl/ethyl acetate solution. The mixture was then treated with petroleum ether (100 mL) and the resulting white solid was collected by filtration and dried to give (R)-S-((E)-4-((7S,10S)-7-isopropyl-4,4-dimethyl-2,5,8,12-tetraoxo-9-oxa-16-thia-3,6,13,18- tetraazabicyclo[13.2.1] octadeca-l(17),15(18)-dien-10-yl)but-3-en-l-yl) 2-amino-3-methylbutanethioate hydrochloride (0.40 g, 26% yield). Mass Spec(m/z): 582.8 (M+l).

129] Example 2: Preparation of (S)-S-((E)-4-((7S,10S)-7-isopropyl-4,4-dimethyl-2,5,8,12-tetraoxo-9-oxa-16-thia-3,6,13,18-tetraazabicyclo[13.2.1]octadeca-l(17),15(18)-dien-10-yl)but-3-en-l-yl) 2-amino-3-methylbutanethioate hydrochloride.

Step 1 : (S)-S-((E)-4-((7S,10S)-7-isopropyl-4,4-dimethyl-2,5,8,12-tetraoxo-9-oxa-16-thia-3,6,13,18-tetraazabicyclo[13.2.1]octadeca-l(17),15(18)-dien-10-yl)but-3-en-l-yl) 2-((tert-butoxy carbony l)amino)-3 -methy lbutanethioate. (7S,10S)-10-((E)-4-chlorobut- 1 -en- 1 -yl)-7-isopropyl-4,4-dimethyl-9-oxa-16-thia-3,6,13,18-tetraazabicyclo[13.2.1]octadeca-l(17),15(18)-diene-2,5,8,12-tetraone (40 g, 0.0825 mol), (S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanethioic S-acid (38.5 g, 0.165 mol), K₂C0₃ (34.1 g, 0.247 mol), and KI (2.7 g, 0.0163 mol) were dissolved in 400 mL of acetonitrile and stirred at 60-65°C under nitrogen for 20 hours. The mixture was cooled to 20°C, water (300 mL) was added and the resulting suspension was extracted with ethyl acetate (2X200 mL). The organic phases were combined, dried with anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (elution with ethyl acetate/petroleum ether = 1/1 to 4/1) to give (S)-S-((E)-4-((7S,10S)-7-isopropyl-4,4-dimethyl-2,5,8,12-tetraoxo-9-oxa-16-thia-3,6,13,18-tetraazabicyclo[13.2.1]octadeca-l(17),15(18)-dien-10-yl)but-3-en-l-yl) 2-((tert-butoxycarbonyl)amino)-3-methylbutanethioate (49.8 g, 89% yield).

Step 2: (S)-S-((E)-4-((7S,10S)-7-isopropyl-4,4-dimethyl-2,5,8,12-tetraoxo-9-oxa-16-thia-3,6,13,18-tetraazabicyclo[13.2.1]octadeca-l(17),15(18)-dien-10-yl)but-3-en-l-yl) 2-amino-3-methylbutanethioate hydrochloride. (S)-S-((E)-4-((7S,10S)-7-isopropyl-4,4-dimethyl-2,5,8,12-tetraoxo-9-oxa-16-thia-3,6,13,18-tetraazabicyclo[13.2.1]octadeca-1 ( 17), 15( 18)-dien- 10-y l)but-3-en- 1 -y 1) 2-((tert-butoxy carbony l)amino)-3 -methylbutanethioate (47.8 g, 0.07 mol) was dissolved in dichloromethane (400 mL) and trifluoroacetic acid (65 mL) was added dropwise at 10 to 20°C while stirring under nitrogen. After the addition, the mixture was stirred at 15 to 20°C for 3 hours at which time an additional aliquot of trifluoroacetic acid (20 mL) was added and stirring at 15 to 20°C was continued for an additional 1.5 hours. The solution was then concentrated under vacuum to near dryness and the residue dissolved in ethyl acetate (250 mL). 20 mL of 4M HCl/ethyl acetate solution was then added while stirring at a temperature between 10 to 15°C resulting in the formation of a slurry. 250 mL n-heptane was then added and the solids were filtered, rinsed with n-heptane and dried in vacuo to give (S)-S-((E)-4-((7S,10S)-7-isopropyl-4,4-dimethyl-2,5,8,12-tetraoxo-9-oxa-16-thia-3,6,13,18- tetraazabicyclo[13.2.1] octadeca-l(17),15(18)-dien-10-yl)but-3-en-l-yl) 2-amino-3 -methylbutanethioate hydrochloride as a white solid which contained some residual heptane. (49.0 g, 100% yield). Mass Spec(m/z): 582.8 (M+l)

130] Example 3: Preparation of (S)-S-((E)-4-((7S,10S)-7-isopropyl-4,4-dimethyl-2,5,8,12-tetraoxo-9-oxa-16-thia-3,6,13,18-tetraazabicyclo[13.2.1]octadeca-l(17),15(18)-dien-10-yl)but-3-en-l-yl) 2-amino-3 -methylbutanethioate benzenesulfonate.

The product of Example 2, step 1 ((S)-S-((E)-4-((7S,10S)-7-isopropyl-4,4-dimethyl-2,5,8,12-tetraoxo-9-oxa-16-thia-3,6,13,18-tetraazabicyclo[13.2.1]octadeca-l(17),15(18)-dien-10-yl)but-3-en-l-yl) 2-((tert-butoxycarbonyl)amino)-3-methylbutanethioate) (1 eq.) was dissolved in acetonitrile (10 vol) at 20-25°C and the mixture was treated with

benzenesulfonic acid (3 eq.). After stirring at room temperature for 5 hours, the solvent was removed by decanting, the residual oil was treated with THF (5vol), and the resulting mixture was stirred over night at room temperature. The resulting white solid was collected by filtration and dried in vacuo to give (S)-S-((E)-4-((7S,10S)-7-isopropyl-4,4-dimethyl-2,5,8,12-tetraoxo-9-oxa-16-thia-3,6,13,18-tetraazabicyclo[13.2.1]octadeca-l(17),15(18)-dien-10-yl)but-3-en-l-yl) 2-amino-3-methylbutanethioate benzenesulfonate (90% yield; 98% purity). ¹HNMR (d₆-DMSO) δ: 0.56 to 0.57 (m, 3H), 0.76 to 0.78 (m, 3H), 0.92 to 0.94 (m, 3H), 0.96 to 0.98 (m, 3H), 1.45 to 1.48 (m, 3H), 1.70 to 1.72 (m, 3H), 2.07 to 2.16 (m, 2H), 2.27 to 2.28 (m, 2H), 2.93 to 2.95 (m, 1H), 2.94 to 2.95 (m, 1H), 2.97 to 3.1 (m, 1H), 4.13 to 4.15 (m, 1H), 4.28 to 4.33 (1H), 4.92 to 5.0 (m, 1H), 5.61 to 5.64 (m, 3H), 7.29 to 7.32 (m, 3H), 7.57 to 7.60 (m, 2H), 7.88 to 7.92 (m, 1H), 8.17 (s, 1H), 8.32 (s, 3H), 8.48 to 8.50 (m, 1H).

[1]. Diamond JR, et al. Preclinical Development of the Class-I-Selective Histone Deacetylase Inhibitor OKI-179 for the Treatment of Solid Tumors. Mol Cancer Ther. 2022 Mar 1;21(3):397-406.  [Content Brief]

///////////Bocodepsin, K5D067O1SW, OKI-179, Malignant melanoma, Solid tumours, OnKure Therapeutics, OKI 006