TEREVALEFIM
Molecular Formula
- C9-H8-N2-S
Molecular Weight
- 176.2382
RN: 1070881-42-3
UNII: GG91UXK2M5
- 5-((E)-2-Thiophen-2-yl-vinyl)-lh-pyrazole
- 1H-Pyrazole, 3-((1E)-2-(2-thienyl)ethenyl)-
- ANG-3777
- SNV-003
- OriginatorAngion Biomedica
- ClassAnti-ischaemics; Antifibrotics; Heart failure therapies; Pyrazoles; Small molecules; Thiophenes; Urologics; Vascular disorder therapies
- Mechanism of ActionProto oncogene protein c met stimulants
- Orphan Drug StatusYes – Renal failure
- Phase IIIDelayed graft function
- Phase IIAcute kidney injury; Acute lung injury; Renal failure
- PreclinicalBrain injuries
- No development reportedHeart failure
- DiscontinuedHepatic fibrosis; Myocardial infarction; Stroke
- 02 Aug 2022Vifor Pharma has been acquired by CSL and renamed to CSL Vifor
- 14 Dec 2021Efficacy and adverse events data of a phase II GUARD trial in Acute kidney injury released by the company
- 26 Oct 2021Top-line efficacy and adverse events data from the phase III trial GIFT (Graft Improvement Following Transplant) trial in Delayed graft function released by Angion Biomedica and Vifor Pharma
Terevalefim, an hepatocyte growth factor (HGF) mimetic, selectively activates the c-Met receptor.
PATENT
WO 2004/058721
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2004058721
PATENT
PCT Application No. PCT/US2003/040917, filed December 19, 2003 and published as WO2004/058721 on July 15, 2004, the entirety of which is hereby incorporated by reference, describes certain compounds that act as HGF/SF mimetics . Such compounds include terevalefim:
Terevalefim has been demonstrated to be remarkably useful for treatment of a variety of conditions including, for example, fibrotic liver disease, ischemia-reperfusion injury, cerebral infarction, ischemic heart disease, renal disease, lung fibrosis, damaged and/or ischemic organs, transplants or grafts, stroke, cerebrovascular disease, and renal fibrosis, among others (see, for example, WO 2004/058721, WO 2010/005580, US 2011/0230407, US 7879898, and WO 2009/064422, each of which is hereby incorporated by reference.) Exemplary methods of using terevalefim for, eg, treating delayed graft function after kidney transplantation and acute lung injury, are described in WO 2021/087392 and WO 2021/183774, each of which is hereby incorporated by reference. In particular, Terevalefim is or has been the subject of clinical trials for delayed graft function in recipients of a deceased donor kidney (Clinicaltrials.gov identifier: NCT02474667), acute kidney injury after cardiac surgery involving cardiopulmonary bypass (Clinicaltrials.gov identifier: NCT02771509), and COVID -19 pneumonia (Clinicaltrials.gov identifier: NCT04459676). Without wishing to be bound by any particular theory, it is believed that terevalefim’s HGF mimetic capability imparts a variety of beneficial attributes and activities.
[0035] Terevalefim has a CAS Registry No. of 1070881-42-3 and is also known by at least the following names:
● 3-[(1E)-2-(thiophen-2-yl)ethen-1-yl]-1H-pyrazole; and
● (E)-3-[2-(2-thienyl)vinyl]-1H-pyrazole.
Synthesis of Terevalefim
[0057] In some embodiments, the present disclosure provides methods for preparing compounds useful as HGF/SF mimetics, such as terevalefim. A synthesis of terevalefim is described in detail in Example 7 of WO 2004/058721 (“the ‘721 Synthesis”). The ‘721 Synthesis is depicted in Scheme 1:
The ‘721 Synthesis includes certain features which are not desirable for preparation of terevalefim at scale and/or with consistency and/or with suitable purity for use in humans. For example, the ‘721 Synthesis includes preparation of aldehyde compound 1.2, a viscous oil that is difficult to purify with standard techniques. Additionally, the ‘721 Synthesis uses a diethoxyphosphorylacetaldehyde tosylhydrazone reagent in step 1-2. As such, step 1-2 has poor atom economy and results in multiple byproducts that must be purified away from the final product of terevalefim. Step 1-2 also uses sodium hydride, a highly reactive base that can be difficult to control and often results in byproducts that must be purified away from the final product of terevalefim. Such purification steps can be costly and time-consuming. In some embodiments, the present disclosure encompasses the recognition that one or more features of the ‘721 Synthesis can be improved to increase yield and/or increase reliability and/or increase scale and/or reduce byproducts. In some embodiments, the present disclosure provides such a synthesis, as detailed herein.
[0059] In some embodiments, the present disclosure provides a synthesis of terevalefim as depicted in Scheme 2:
Scheme 2
wherein X and R 1 are defined below and in classes and subclasses as described herein.
[0060] It will be appreciated that compounds described herein, eg, compounds in Scheme 2, may be provided and/or utilized in a salt form. For example, compounds which contain a basic nitrogen atom may form a salt with a suitable acid. Alternatively and/or additionally, compounds which contain an acidic moiety, such as a carboxylic acid group, may form a salt with a suitable base. Suitable counterions are well known in the art, eg, see generally, March ‘s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, MB Smith and J.
March, 5 th Edition, John Wiley & Sons, 2001. All forms of the compounds in Scheme 2 are contemplated by and within the scope of the present disclosure.
Step 2-1 of Scheme 2
[0061] Step 2-1 includes a condensation-elimination reaction between commercially available thiophene-2-carboxaldehyde (1.1) and acetone to provide an α,β-unsaturated ketone compound (2.1).
[0062] In some embodiments, the present disclosure provides a method comprising steps of:
(i) providing compound 1.1:
(ii) contacting compound 1.1 with acetone in the presence of a suitable base,
to compound provide 2.1:
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///////TEREVALEFIM, ANG-3777, SNV-003, Phase 3, Delayed graft function
C(=C\c1cccs1)/c2cc[nH]n2
