Rugocrixan

CAS911715-90-7

MF C19H25N5OS2, MF 403.6 g/mol

(2R)-2-[[2-amino-5-[(1S)-1-phenylethyl]sulfanyl-[1,3]thiazolo[4,5-d]pyrimidin-7-yl]amino]-4-methylpentan-1-ol

1-Pentanol, 2-[[2-aMino-5-[[(1S)-1-phenylethyl]thio]thiazolo[4,5-d]pyriMidin-7-yl]aMino]-4-Methyl-, (2R)-

(R)-2-((2-Amino-5-(((S)-1-phenylethyl)thio)thiazolo[4,5-d]pyrimidin-7-yl)amino)-4-methylpentan-1-ol

(2R)-2-[(2-amino-5-{[(1S)-1-phenylethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol
CX3C chemokine receptor 1 (CX3CR1) antagonist, antiinflammatory, KAND567, AZD8797, KAND 567, AZD 8797, S9Y83SS7PQ

Rugocrixan (also known by its developmental codes KAND567 and AZD8797) is a first-in-class, orally active small molecule drug candidate developed by Novakand Pharma (formerly Kancera). It acts as a potent, non-competitive allosteric antagonist of the CX3CR1 receptor, which is commonly referred to as the fractalkine receptor. By blocking this specific pathway, the drug prevents hyperinflammation and inhibits the proliferation and DNA repair mechanisms of certain cancer cells.

KAND567, a small molecule, blocks the fractaline (CX3CL1) receptor, which mediates the immune system response to inflammation. Because COVID-19 involves cytotoxic cells associated with this pathway, KAND567 is currently being tested as a treatment for those with the illness.

KAND567, a small molecule, blocks the fractaline (CX3CL1) receptor, which mediates the immune system response to inflammation. Because COVID-19 involves cytotoxic cells associated with this pathway, KAND567 is currently being tested as a treatment for those with the illness.

Key Clinical Developments and Therapeutic Focus

Originally acquired from AstraZeneca, the drug has advanced into multiple Phase II clinical trials. Novakand Pharma transitioned its core business strategy to focus heavily on orphan drug designations for niche, treatment-resistant conditions. Its primary areas of investigation include:

• Ovarian Cancer: Evaluated in the Phase IIa “KANDOVA” clinical trial for patients with treatment-resistant ovarian cancer. It functions by suppressing DNA repair in tumor cells, which enhances the effectiveness of platinum-based chemotherapy and drives the cancer cells into programmed cell death.
• Hematological Cancers: In preclinical studies alongside institutions like the Karolinska Institutet, rugocrixan has demonstrated a capability to block the unwanted growth-promoting effects of immune cells on advanced blood cancers, such as chronic lymphocytic leukemia (CLL).
• Cardioprotection: Investigated via the “FRACTAL” Phase IIa trial in patients suffering from acute myocardial infarction (STEMI) undergoing angioplasty. The drug met its safety endpoints and showed signals of protecting heart tissue by reducing myocardial bleeding and the risk of thrombosis.

Companion Prodrug

Novakand Pharma is also developing a second-generation, water-soluble phosphate prodrug named fosrugocrixan (KAND145). Once administered, fosrugocrixan is metabolized into the active form of rugocrixan, offering enhanced product properties for intravenous or alternative delivery methods.

Because rugocrixan targets a brand-new pharmacological pathway, the World Health Organization (WHO) assigned it a unique suffix stem, establishing it as the international nomenclature standard for this entire new class of CX3CR1 antagonists

• A Study to Evaluate the Safety of KAND567, in Combination With Carboplatin Therapy, in Women With Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal CancerCTID:NCT06087289Phase:Phase 1/Phase 2Status:CompletedDate:2025-06-08
• Safety, Tolerability and Pharmacokinetics After Continuous Infusion of KAND567CTID:NCT06030375Phase:Phase 1Status:CompletedDate:2023-09-11
• KAND567 Versus Placebo in Subjects Hospitalized With COVID-19CTID:NCT06012565Phase:Phase 2Status:TerminatedDate:2023-08-25
• KANDOVA – A two-part Phase Ib/IIa study to evaluate the safety and tolerability of KAND567, in combination with carboplatin therapy, and to determine the Recommended Phase II Dose (RPIID) of KAND567. An open-label, multicenter dose escalation study with an expansion cohort in women with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer.EudraCT:2022-002792-11Phase:Phase 2Status:Trial now transitionedDate:2023-03-27
• KAND567 Versus Placebo in Subjects Hospitalized with COVID-19. A Phase II, Randomized, 2-Arm Parallel-Group, Double-blind Study to Evaluate Efficacy, Safety, Tolerability, and Pharmacokinetics.EudraCT:2020-002322-85Phase:Phase 2Status:Completed, Prematurely EndedDate:2020-07-02

SYN

compound 18a [PMID: 23516963]

PAT

WO 2006/107258.

PAT

EP1869056

https://patentscope.wipo.int/search/en/detail.jsf?docId=EP14857146&_cid=P20-MTP714-98881-1

Example 12

(2R)-2-[{2-Amino-5-[(1-phenylethyl)thio][1,3]thiazolo[4,5-d]pyrimidin-7-yl}(methyl)amino]-4-methylpentan-1-ol

a) (2R)-2-[[2-Amino-5-(benzylthio)[1,3]thiazolo[4,5-d]pyrimidin-7-yl](methyl)amino]-4-methylpentan-1-ol

[0097]  5-(Benzylthio)-7-chloro[1,3]thiazolo[4,5 -d]pyrimidin-2-amine (1.5 g, 4.86 mmol), DIPEA (691 mg, 5.35 mmol) and ( R)- N-methylleucinol (956 mg, 7.29 mmol) were mixed in NMP (7.5 mL). The resulting solution was stirred at 110 °C under a nitrogen atmosphere for 2 days. After cooling to room temperature the reaction mixture was poured onto ice. The resulting yellow precipitate was collected by filtration, washed with water and dried in vacuo. The crude product was purified by flash column chromatography on silica (DCM:EtOAc 50:50 to 0:100) to give 1.42 g (72% yield) of the title compound as a yellow solid.
¹H NMR (DMSO-d ₆) 7.97 (br s, 2H), 7.40 (m, 2H), 7.28 (m, 2H), 7.21 (m, 1H), 4.73 (dd, 1H), 4.64 (br s, 1H), 4.32 (br s, 2H), 3.52-3.37 (m, 2H), 3.00 (s, 3H), 1.55-1.35 (m, 2H), 1.27 (m, 1H), 0.88 (d, 3H), 0.80 (d, 3H);
MS (ESI ⁺) m/ z 404 [M+H] ⁺.

PAT

RU0002411245

PAT

WO2019219771

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019219771&_cid=P20-MTP714-98881-2

(2R)-2-[(2-amino-5-{[(1S)-1- phenylethyl]thio}[1 ,3]thiazolo[4,5-c/]pyrimidin-7-yl)amino]-4-methylpentan-1-ol is known to be a potent antagonist .

3.4 Preparation of (2R)-2-r(2-amino-5-(r(1 S)-1 -phenylethyllthio)ri ,3lthiazolor4,5-c/1Pyrimidin-7-yl)aminol-4-methylpentan-1 -ol.xHCI (5)

.xHCI

Compound 4 (1 .852 g, 5.74 mmol), DIPEA (1.1 12 g, 8.61 mmol) and D-leucinol (1.008 g, 8.61 mmmol) were dissolved in NMP (12 ml.) and the mixture was stirred at 120 °C in a sealed pyrex tube (start: 17:40).

HPLC after 15.5 h: ca. 98% conversion

HPLC after 19.5 h: >99% conversion

Work up: Ice water was poured into the mixture. Initially a solid was formed, but at the end of the addition the solid collapsed to a dark brown oil. EtOAc (50 ml.) was added and the phases were separated. The aqueous phase was extracted with EtOAc (2×25 ml_), and the combined organic phases were washed with water (8 ml_), sat. NaHC03 (3×8 ml_), water (8 ml.) and brine (8 ml_), dried over MgS04, filtered and evaporated. Dried in vacuum to yield 2.697 g of crude material as a brown oil. HPLC purity: ca. 92%. The oil was dissolved in MEK (ca. 18 mL) and cone. HCI (12.5 M, 574 pL, 7.18 mmol) was added. There was no spontaneous precipitation of the HCI salt. The mixture was gently stirred at RT and after ca. 20 min precipitation occurred. The mixture was stirred gently for 2.5 h and the solid was isolated by filtration on a P3 sintered glass filter. The solid was washed with three portions of MEK and was then dried in vacuum at 60 °C for 2.5 days. Yield (batch 1 ): 1 .224 g (48.5%) of the product as hydrochloride salt.

HPLC purity: 99.0% (basic method);

97.4% (acidic method).

A substantial amount of solids passed through the filter into the filtrate. The solids were isolated by centrifugation and the supernatant was removed by pipette. The solid was washed with two portions (ca. 2×5 mL) of MEK. After the last supernatant was removed the product was dried in vacuum at 60 °C for 2.5 days. Yield (batch 2): 324 mg (12.8%) of the product as hydrochloride salt.

HPLC purity: 99.0% (basic method);

97.5% (acidic method).

Combined yield: 1.548 g (61 .3%)

Both batches contain ca. 0.07% DMF (w/w). The DMF was already present in the starting material.

Further purification of the combined batches

The two batches of compound 5 were combined (1.338 g, 3.041 mmol) in a 50 mL roundbottomed flask and water (6 mL) was added followed by 2M NaOH (1.6 mL, 3.2 mmol). The mixture was stirred and EtOAc (40 mL) was added. An additional 0.5 mL (1 mmol) 2M NaOH was added during stirring. After 15 min all of the solids were dissolved and the phases were separated. The pH of the aqueous phase was measured with a pH stick =>pH=7. More 2M NaOH (0.4 mL, 0.8 mmol) was added to the aqueous phase resulting in a pH of 10. The aq. phase was extracted with EtOAc (25 mL) and the phases were separated. The combined organic phases were dried over Na₂S0₄, filtered and evaporated to yield the free base as a crystalline beige solid. The free base was dissolved in MEK (15 mL) and HCI (37%, 12.5 M, 255 pL, 3.19 mmol) was added during stirring. A white precipitate was immediately formed. The mixture was stirred gently for 2 h and the solid was collected by filtration on a P4 sintered glass filter. The solids were washed with MEK (5 mL) and dried in vacuum at 60 °C for 3 h. Yield: 1.187 g (89% based on the unpurified material) of 99% pure product as a white solid. ¹H NMR (600 MHz, CD30D) d ppm 7.49 (d, J=7.3 Hz, 2 H) 7.37 (t, J=7.6 Hz, 2 H) 7.27 – 7.32 (m, 1 H) 5.23 (q, J=7.0 Hz, 1 H) 4.60 – 4.70 (m, 1 H) 3.55 (d, J=5.5 Hz, 2 H) 1.83 (d, J=7.3 Hz, 3 H) 1.67 – 1.76 (m, 1 H) 1.58 -1.65 (m, 1 H) 1.48 – 1.54 (m, 1 H) 1.00 (d, J=6.7 Hz, 3 H) 0.98 (d,J=6.7 Hz, 3 H). MS (ESI+) m/z 404 [M+H]⁺

The diasteromeric ratio of the final product reflects the enantiomeric ratio of the starting material (compound 1 ), which was 99.7% (S).

¹H NMR: The spectrum looks very pure. Trace amounts of DMF were, however, detected.

Comparative Example 4 – Process scale two-step procedure for the synthesis of 6-amino-2-{r(1S)-1-phenylethvnsulfanyl)pyrimidin-4-ol (1 )

Step 1 Step 2

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References

• Novel 5-substituted 7-amino-[1,3]thiazolo[4,5-d]pyrimidine derivativesPublication Number:CA-2604017-CPriority Date:2005-04-06Grant Date:2012-03-06
• Novel 5-substituted 7-amino [1,3] thiazolo [4,5-D] pyrimidine derivativesPublication Number:JP-5165553-B2Priority Date:2005-04-06Grant Date:2013-03-21
• Novel 5,7-Disubstituted [1,3]Thiazolo[4,5-D]Pyrimidin-2(3H)-One Derivatives 794Publication Number:US-2009124637-A1Priority Date:2005-04-06
• New derivatives of 5, 7-disubstituted [1, 3] thiazolo[4, 5-d] pyrimidine-2(3h)-onePublication Number:RU-2411245-C9Priority Date:2005-04-06Grant Date:2011-05-27
• Novel 5-Substituted 7-Amino-[1,3]Thiazolo[4,5-D]Pyrimidine Derivatives 793Publication Number:US-2008214578-A1Priority Date:2005-04-06
• NEW DERIVATIVES OF 5-SUBSTITUTED 7-AMINO-[1, 3] THIAZOLO [4, 5-d]PYRIMIDINEPublication Number:RU-2419623-C2Priority Date:2005-04-06Grant Date:2011-05-27
• Novel 5,7-disubstituted [1,3] thiazolo [4,5-D] pyrimidin-2 (3H) -one derivativesPublication Number:JP-2008535834-APriority Date:2005-04-06

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