DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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Laselipag
Laselipag
CAS 475085-57-5
MF C25H29N3O3 MW 419.52
2-[4-[(5,6-diphenylpyrazin-2-yl)-propan-2-ylamino]butoxy]acetic acid
{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}acetic acid
prostanoid receptor agonist, ACT-333679, ACT 333679, ACT333679, E9PC7N0DID, MRE 269
ACT-333679 is a member of the class of pyrazines that is {4-[(propan-2-yl)(pyrazin-2-yl)amino]butoxy}acetic acid carrying two additional phenyl substituents at positions 5 and 6 on the pyrazine ring. The active metabolite of selexipag, an orphan drug used for the treatment of pulmonary arterial hypertension. It has a role as an orphan drug, a platelet aggregation inhibitor, a prostacyclin receptor agonist, a vasodilator agent and a drug metabolite. It is an aromatic amine, an ether, a member of pyrazines, a sulfonamide, a tertiary amino compound and a monocarboxylic acid.
SYN
SYN
PAT
- Heterocyclic compound derivatives and medicinesPublication Number: CA-2445344-CPriority Date: 2001-04-26Grant Date: 2011-07-26
- Heterocyclic compound derivatives and medicinesPublication Number: US-2004102436-A1Priority Date: 2001-04-26
- DERIVATIVES OF HETEROCYCLIC COMPOUNDS AND MEDICINAL PRODUCTSPublication Number: DE-60217674-T2Priority Date: 2001-04-26Grant Date: 2007-10-11
- Heterocyclic compound derivatives and medicinesPublication Number: EP-1400518-B1Priority Date: 2001-04-26Grant Date: 2007-01-17
- Heterocyclic compound derivatives and medicinesPublication Number: US-7205302-B2Priority Date: 2001-04-26Grant Date: 2007-04-17
- Heterocyclic compound derivatives and medicinesPublication Number: CA-2445344-A1Priority Date: 2001-04-26
- Heterocyclic derivatives and pharmaceuticalsPublication Number: JP-4479152-B2Priority Date: 2001-04-26Grant Date: 2010-06-09
- DERIVATIVES OF HETEROCYCLIC COMPOUNDS AND MEDICINESPublication Number: RU-2003134190-APriority Date: 2001-04-26
- Heterocyclic derivatives and drugsPublication Number: JP-WO2002088084-A1Priority Date: 2001-04-26
- DERIVATIVES OF HETEROCYCLIC COMPOUNDS AND MEDICINAL PRODUCTS CONTAINING THEMPublication Number: PT-1400518-EPriority Date: 2001-04-26
- Heterocyclic compound derivatives and medicinesPublication Number: EP-1400518-A1Priority Date: 2001-04-26
- DERIVATIVES OF HETEROCICLIC COMPOUNDS AND MEDICINES.Publication Number: ES-2276931-T3Priority Date: 2001-04-26Grant Date: 2007-07-01
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//////laselipag, prostanoid receptor agonist, ACT-333679, ACT 333679, ACT333679, E9PC7N0DID, MRE 269
Laroprovstat
Laroprovstat
CAS 2455427-91-3
MF C20H20F2N6O2 MW414.4 g/mol
1-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]pyridin-2-one
- 1-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]pyridin-3-yl]pyridin-2-one
- 6′-(((1S,3S)-3-((5-(Difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one
- 6′-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2H-[1,3′-bipyridin]-2-one
6′-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2H-[1,3′-bipyridin]-2-one
proprotein convertase subtilisin/kexin type 9 (PCSK9), inhibitor, antihyperlipidaemic, 9EEL3YMY29, PCSK9-IN-12, AZD 0780, AZD-0780
- OriginatorDogma Therapeutics
- DeveloperAstraZeneca; Parexel International; Quotient Sciences
- ClassAmines; Antihyperlipidaemics; Cardiovascular therapies; Cyclopentanes; Ethers; Fluorinated hydrocarbons; Hepatoprotectants; Ketones; Pyridines; Pyrimidines; Small molecules; Vascular disorder therapies
- Mechanism of ActionPCSK9 protein inhibitors
- Phase IIIAtherosclerosis; Cardiovascular disorders; Dyslipidaemias; Hyperlipoproteinaemia type II
- Phase ILiver disorders
- 30 Dec 2025AstraZeneca completes a phase I pharmacokinetics trial (In volunteers) in USA (PO) (NCT07216131),
- 10 Nov 2025AstraZeneca initiates enrolment in a phase I pharmacokinetics trial (In volunteers) in USA (PO)(NCT07216131),
- 29 Oct 2025AstraZeneca completes a phase I trial in Dyslipidaemias (Combination therapy) in USA, United Kingdom (PO) (NCT06742853)
SYN
PAT
PAT
- PCSK9 Inhibitors and Methods of Use ThereofPublication Number: US-2020231584-A1Priority Date: 2019-01-18
- Pcsk9 inhibitors and methods of use thereofPublication Number: US-2022220122-A1Priority Date: 2019-01-18
- Pcsk9 inhibitors and methods of use thereofPublication Number: WO-2024013209-A1Priority Date: 2022-07-13
- PCSK9 Inhibitors and Methods of Use ThereofPublication Number: US-2020291041-A1Priority Date: 2019-01-18
- Pcsk9 inhibitors and methods of use thereofPublication Number: WO-2020150473-A2Priority Date: 2019-01-18
- Pcsk9 inhibitors and methods of use thereofPublication Number: WO-2020150474-A1Priority Date: 2019-01-18
- PCSK9 inhibitors and methods of use thereofPublication Number: US-11248001-B2Priority Date: 2019-01-18Grant Date: 2022-02-15
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/////////laroprovstat, antihyperlipidaemic, 9EEL3YMY29, PCSK9-IN-12, AZD 0780, AZD-0780
Istisociclib
Istisociclib
KB 130742
CAS 2416873-83-9
MF C16H25N5, 287.40 g/mol
trans-(1S,3S)-3-N-(5-pentan-3-ylpyrazolo[1,5-a]pyrimidin-7-yl)cyclopentane-1,3-diamine
- (1S,3S)-N1-[5-(1-Ethylpropyl)pyrazolo[1,5-a]pyrimidin-7-yl]-1,3-cyclopentanediamine
- 1,3-Cyclopentanediamine, N1-[5-(1-ethylpropyl)pyrazolo[1,5-a]pyrimidin-7-yl]-, (1S,3S)-
(1S,3S)-N1-[5-(pentan-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl]cyclopentane-1,3-diamine
cyclin-dependent kinase (CDK) inhibitor, antineoplastic, KB-0742, 2416873-83-9, KB 0742, F7J6KSY5I8, UB-18422, KB-130742, KB 00130742
Istisociclib is a small molecule drug. The usage of the INN stem ‘-ciclib’ in the name indicates that Istisociclib is a cyclin dependant kinase inhibitor. Istisociclib is under investigation in clinical trial NCT04718675 (A Study of KB-0742 in Participants With Relapsed or Refractory Solid Tumors Including Platinum Resistant High Grade Serous Ovarian Cancer (HGSOC)). Istisociclib has a monoisotopic molecular weight of 287.21 Da.
Istisociclib is an orally bioavailable, selective inhibitor of the serine/threonine cyclin-dependent kinase 9 (CDK9), the catalytic subunit of the RNA polymerase II (RNA Pol II) elongation factor positive transcription elongation factor b (PTEF-b; PTEFb), with potential antineoplastic activity. Upon oral administration, istisociclib targets, binds to and blocks the phosphorylation and kinase activity of CDK9, thereby preventing PTEFb-mediated activation of RNA Pol II, leading to the inhibition of gene transcription of various anti-apoptotic proteins and oncogenic transcription factors including MYC and androgen receptor (AR). This induces cell cycle arrest and apoptosis and prevents tumor cell proliferation. CDK9 regulates elongation of transcription through phosphorylation of RNA Pol II at serine 2 (p-Ser2-RNAPII), and is an important cofactor for various oncogenic transcription factors. It is upregulated in various tumor cell types and plays a key role in the regulation of Pol II-mediated transcription of anti-apoptotic proteins. Tumor cells are dependent on anti-apoptotic proteins for their survival.
ISTISOCICLIB is a small molecule drug with a maximum clinical trial phase of II and has 1 investigational indication.
A Study of KB-0742 in Participants With Relapsed or Refractory Solid Tumors Including Platinum Resistant High Grade Serous Ovarian Cancer (HGSOC)
CTID: NCT04718675
Phase: Phase 1/Phase 2
Status: Terminated
Date: 2025-02-17
REF
- Discovery of KB-0742, a Potent, Selective, Orally Bioavailable Small Molecule Inhibitor of CDK9 for MYC-Dependent CancersPublication Name: Journal of Medicinal ChemistryPublication Date: 2023-11-15PMCID: PMC10726352PMID: 37967851DOI: 10.1021/acs.jmedchem.3c01233
- CDK9 inhibitors in cancer researchPublication Name: RSC Medicinal ChemistryPublication Date: 2022-06-22PMCID: PMC9215160PMID: 35814933DOI: 10.1039/d2md00040g
- From Structure Modification to Drug Launch: A Systematic Review of the Ongoing Development of Cyclin-Dependent Kinase Inhibitors for Multiple Cancer TherapyPublication Name: Journal of Medicinal ChemistryPublication Date: 2022-04-29PMID: 35485642DOI: 10.1021/acs.jmedchem.1c02064
- Lessons Learned from Past Cyclin-Dependent Kinase Drug Discovery EffortsPublication Name: Journal of Medicinal ChemistryPublication Date: 2022-03-02PMID: 35235745DOI: 10.1021/acs.jmedchem.1c02190
PAT
(lS,3S)-N1-(5-(pentan-3-yl)pyrazolo[l,5-a]pyrimidin-7-yl)cyclopentane-l,3-diamine is a pharmaceutically active compound that has been studied for various uses, such as for the treatment of cancer. As used herein, the term “Compound A” is used to refer to both the free base and salt forms of (lS,3S)-N1-(5-(pentan-3-yl)pyrazolo[l,5-a]pyrimidin-7-yl)cyclopentane-l,3-diamine. The free base of Compound A has the CAS number of 2416873-83-9 and structure of formula (I):
SYN
Example 35: (1S,3S)-N3-[5-(1-ethylpropyl)pyrazolo[1,5-a]pyrimidin-7-yl]cyclopentane-1,3-diamine (35)
2-Ethylbutanoic acid (7.5 g, 64.57 mmol) was dissolved in THF (150 mL) and cooled to 0 °C. Within 20 min CDI (16.23 g, 100.08 mmol) was added portion-wise. The reaction warmed to room temp (rt) and the mixture was stirred at rt overnight (Solution A). In another flask MgCl2 (6.14 g, 64.57 mmol) and potassium 3-ethoxy-3-oxo-propanoate (17 g, 100.1 mmol) were mixed with THF (150 mL) and stirred under argon overnight at 50 °C. The resultant white suspension was cooled to rt and solution A was added dropwise over 10 min and the reaction mixture (RM) was stirred for 16h at room temperature. After several minutes a sticky, amorphous solid appeared whereupon after several hours the reaction mixture became homogenous in appearance. The RM was concentrated to about a third, taken up in half sat. potassium bisulphate solution and extracted twice with ethyl acetate. The organic layers were subsequently washed with a sat. sodium bicarbonate solution, combined, dried over anhydrous sodium sulfate, filtered and evaporated. Purification by column chromatography gave ethyl 4-ethyl-3-oxo-hexanoate (4.3 g, 23.087 mmol, 35.8% yield) as a transparent liquid. The RM was monitored by TLC (10% EA in Hex, Product Rf=0.6, SM Rf=0.1).
Step 2
To a suspension of ethyl 4-ethyl-3-oxo-hexanoate (4.4 g, 23.62 mmol) in acetic acid (11 mL) at 70 °C was added 1H-pyrazol-5-amine (4.71 g, 56.7 mmol) in two portions (the second portion was added after 2 hours of stirring the first portion) over a 4 hour period. Upon consumption of SM as indicated by TLC, the reaction was cooled to rt and the solvent was evaporated in a rotary evaporator. The residue was treated with ethyl acetate and filtered to give 5-(1-ethylpropyl)-4H-pyrazolo[1,5-a]pyrimidin-7-one (3.7 g, 17.7 mmol, 74.9% yield) as an off-white solid. The reaction mixture was monitored by TLC (5% MeOH in DCM, Product Rf=0.3, SM Rf=0.8).
Step 3
A stirred solution of 5-(1-ethylpropyl)-4H-pyrazolo[1,5-a]pyrimidin-7-one (3.7 g, 18.03 mmol) in POCl3 (33.7 mL, 360.52 mmol) was heated to reflux for 4 hours. The reaction mixture was cooled to room temperature, excess reagent was evaporated in a rotary evaporator, and the residue was treated with ice-water. The chlorinated product was extracted from aqueous mixture by DCM. The organic layer was separated, dried over anhydrous Na2SO4, filtered and purified by column chromatography to give 7- chloro-5-(1-ethylpropyl)pyrazolo[1,5-a]pyrimidine (3.1 g, 13.9 mmol, 76.9% yield) as a light yellow liquid. The reaction mixture was monitored by TLC (20% EA in Hex, Product Rf=0.6, SM Rf=0.1).
To a stirred solution 7-chloro-5-(1-ethylpropyl)pyrazolo[1,5-a]pyrimidine (2.3 g, 10.28 mmol), tert-Butyl ((1S,3S)-3-aminocyclopentyl)carbamate (2.27 g, 11.31 mmol) and K2CO3 (4.26 g, 30.84 mmol) in MeCN (20 mL) were heated to reflux for 16 hours. The reaction mixture was filtered, concentrated under reduced pressure and purified by column chromatography, eluent 30% EA in hexane to give tert-butyl N-[(1S,3S)-3-[[5-(1-ethylpropyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino]cyclopentyl]carbamate (4.5 g, 11.6 mmol, 112.8% yield) as an off-white solid. The reaction mixture was monitored by TLC (40% EA in Hex, Product Rf=0.5, SM Rf=0.7).
Step 5
To tert-butyl N-[(1 S,3S)-3-[[5-(l-ethylpropyl)pyrazolo[l,5-a]pyrimidin-7-yl]amino]cyclopentyl]carbamate (1.0 g, 2.58 mmol) in l,4-Dioxane (0.2 mL), 4 M HC1 in Dioxane (3.22 mL, 12.9 mmol) was added and stirred at room temperature for 4 hours. The reaction mixture was evaporated in vacuo, triturated with pentane and lyophilized from MeCN:H20 to give [(lS,3S)-3-[[5-(l-ethylpropyl)pyrazolo[l,5-a]pyrimidin-4-ium-7-yl]amino]cyclopentyl]ammonium dichloride (0.9 g, 2.5 mmol, 96.8% yield) as a pale-yellow sticky solid. The reaction mixture was monitored by TLC ( 100% EA, Product Rf=0.l, SM Rf=0.8). 1H NMR (400 MHz, DMSO-d6) d 15.00 (s, 1H), 9.93-9.86 (m, 1H), 8.51 (s, 3H), 8.30 (s, 1H), 6.84 (s, 1H), 6.58 (s, 1H), 4.95 (q, J = 7.8 Hz, 1H), 3.77- 3.66 (m, 1H), 2.84-2.71 (m, 1H), 2.29-2.05 (m, 4H), 1.94-1.63 (m, 6H), 0.81 (t, J = 7.4 Hz, 6H). LC-MS (m/z 287.21, found 288.0 [M+H+])
Step 6
To [(1S,3S)-3-[[5-(l-ethylpropyl)pyrazolo[I,5-a]pyrimidin-4-ium-7-yl]amino]cyclopentyl]ammonium-di chloride (0.2 g, 0.5600 mmol) in aq. NH3 (4.0 mL, 0.56 mmol) was added and stirred at room temperature for 4 hours. The reaction mixture was evaporated in vacuo, triturated with pentane and lyophilized from MeCN:H20 to give (lS,3S)-N3-[5-(l-ethylpropyl)pyrazolo[l,5-a]pyrimidin-7-yl]cyclopentane-l,3-diamine (140 mg, 0.49 mmol, 87.8% yield) as a pale-yellow sticky solid. The reaction mixture was monitored by TLC (100% EA, Product Rf=0.1, SM Rf=0.8). 1H NMR (400 MHz, DMSO-d6) d 7.95 (d, J = 2.2 Hz, 1H), 6.86 (s, 1H), 6.29 (d, J = 2.2 Hz, 1H), 5.95 (s, 1H), 4.31-4.19 (m, 1H), 3.57-3.44 (m, 1H), 2.52-2.44 (m, 1H), 2.36-2.22 (m, 1H),
2.09–1.79 (m, 3H), 1.80–1.59 (m, 5H), 1.58–1.24 (m, 3H), 0.83 (t, J = 7.4 Hz, 6H). LC-MS (m/z 287.21, found 288.5 [M+H+]).
PAT
- Compounds, compositions and methods for modulating CDK9 activityPublication Number: CN-112996790-BPriority Date: 2018-10-30Grant Date: 2023-11-03
- Compounds, compositions, and methods for modulating cdk9 activityPublication Number: US-2024132506-A1Priority Date: 2018-10-30
- Compounds, Compositions, and Methods for Modulating CDK9 ActivityPublication Number: US-2020131189-A1Priority Date: 2018-10-30
- Compounds, compositions, and methods for modulating cdk9 activityPublication Number: US-2022002305-A1Priority Date: 2018-10-30
- Compounds, compositions, and methods for modulating cdk9 activityPublication Number: EP-3873911-A1Priority Date: 2018-10-30
- Substituted pyrazolo[1,5-a]pyrimidines for modulating CDK9 activityPublication Number: US-11845754-B2Priority Date: 2018-10-30Grant Date: 2023-12-19
- Substituted pyrazolo[1,5-a]pyrimidines for modulating CDK9 activityPublication Number: US-11155560-B2Priority Date: 2018-10-30Grant Date: 2021-10-26
- Compounds and methods for modulating cdk9 activityPublication Number: EP-4240422-A1Priority Date: 2020-11-05
- Compounds and methods for modulating cdk9 activityPublication Number: WO-2022098843-A1Priority Date: 2020-11-05
- Compounds and methods for modulating cdk9 activityPublication Number: US-2025188084-A1Priority Date: 2020-11-05
- Chimeric degraders of cyclin-dependent kinase 9 and uses thereofPublication Number: WO-2021216828-A1Priority Date: 2020-04-24
- Chimeric degraders of cyclin-dependent kinase 9 and uses thereofPublication Number: US-2023158159-A1Priority Date: 2020-04-24
- Polymorphic and salt forms of (ls,3s)-n-(5-(pentan-3- yl)pyrazolo[l,5-a]pyrimidin-7-yl)cyclopentane-l,3-diaminePublication Number: EP-4436569-A1Priority Date: 2021-11-24
- Polymorphs and salt forms of (1S,3S)-N1-(5-(pentan-3-yl)pyrazolo[1,5-A]pyrimidin-7-yl)cyclopentane-1,3-diaminePublication Number: KR-20240110634-APriority Date: 2021-11-24
- Compositions and methods for enhanced protein productionPublication Number: EP-4412621-A2Priority Date: 2021-09-22
- Compositions and methods for enhanced protein productionPublication Number: US-2024252688-A1Priority Date: 2021-09-22
- Compositions and methods for enhanced protein productionPublication Number: WO-2023056202-A2Priority Date: 2021-09-22
- A cdk9 inhibitor for use in the treatment of cancer in a subject having an asxl1 mutationPublication Number: WO-2025217597-A1Priority Date: 2024-04-12
- Polymorphic and salt forms of (1s,3s)-n1-(5-(pentan-3- yl)pyrazolo[1,5-a]pyrimidin-7-yl)cyclopentane-1,3-diaminePublication Number: WO-2023096922-A8Priority Date: 2021-11-24
- Polymorphic and salt forms of (ls,3s)-n1-(5-(pentan-3- yl)pyrazolo[l,5-a]pyrimidin-7-yl)cyclopentane-l,3-diaminePublication Number: WO-2023096922-A1Priority Date: 2021-11-24
- Polymorphic and salt forms of (1s,3s)-n1-(5-(pentan-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl) cyclopentane-1,3-diaminePublication Number: US-2025059193-A1Priority Date: 2021-11-24
- Polymorphic forms and salt forms of (1S,3S)-N1-(5-(pentan-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl)cyclopentane-1,3-diaminePublication Number: CN-118678952-APriority Date: 2021-11-24
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……
//////istisociclib, cyclin-dependent kinase (CDK) inhibitor, antineoplastic, KB-0742, 2416873-83-9, KB 0742, F7J6KSY5I8, UB-18422, KB-130742, KB 00130742
Istisociclib
Istisociclib
KB 130742
CAS 2416873-83-9
MF C16H25N5, 287.40 g/mol
trans-(1S,3S)-3-N-(5-pentan-3-ylpyrazolo[1,5-a]pyrimidin-7-yl)cyclopentane-1,3-diamine
- (1S,3S)-N1-[5-(1-Ethylpropyl)pyrazolo[1,5-a]pyrimidin-7-yl]-1,3-cyclopentanediamine
- 1,3-Cyclopentanediamine, N1-[5-(1-ethylpropyl)pyrazolo[1,5-a]pyrimidin-7-yl]-, (1S,3S)-
(1S,3S)-N1-[5-(pentan-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl]cyclopentane-1,3-diamine
cyclin-dependent kinase (CDK) inhibitor, antineoplastic, KB-0742, 2416873-83-9, KB 0742, F7J6KSY5I8, UB-18422, KB-130742, KB 00130742
Istisociclib is a small molecule drug. The usage of the INN stem ‘-ciclib’ in the name indicates that Istisociclib is a cyclin dependant kinase inhibitor. Istisociclib is under investigation in clinical trial NCT04718675 (A Study of KB-0742 in Participants With Relapsed or Refractory Solid Tumors Including Platinum Resistant High Grade Serous Ovarian Cancer (HGSOC)). Istisociclib has a monoisotopic molecular weight of 287.21 Da.
Istisociclib is an orally bioavailable, selective inhibitor of the serine/threonine cyclin-dependent kinase 9 (CDK9), the catalytic subunit of the RNA polymerase II (RNA Pol II) elongation factor positive transcription elongation factor b (PTEF-b; PTEFb), with potential antineoplastic activity. Upon oral administration, istisociclib targets, binds to and blocks the phosphorylation and kinase activity of CDK9, thereby preventing PTEFb-mediated activation of RNA Pol II, leading to the inhibition of gene transcription of various anti-apoptotic proteins and oncogenic transcription factors including MYC and androgen receptor (AR). This induces cell cycle arrest and apoptosis and prevents tumor cell proliferation. CDK9 regulates elongation of transcription through phosphorylation of RNA Pol II at serine 2 (p-Ser2-RNAPII), and is an important cofactor for various oncogenic transcription factors. It is upregulated in various tumor cell types and plays a key role in the regulation of Pol II-mediated transcription of anti-apoptotic proteins. Tumor cells are dependent on anti-apoptotic proteins for their survival.
ISTISOCICLIB is a small molecule drug with a maximum clinical trial phase of II and has 1 investigational indication.
A Study of KB-0742 in Participants With Relapsed or Refractory Solid Tumors Including Platinum Resistant High Grade Serous Ovarian Cancer (HGSOC)
CTID: NCT04718675
Phase: Phase 1/Phase 2
Status: Terminated
Date: 2025-02-17
REF
- Discovery of KB-0742, a Potent, Selective, Orally Bioavailable Small Molecule Inhibitor of CDK9 for MYC-Dependent CancersPublication Name: Journal of Medicinal ChemistryPublication Date: 2023-11-15PMCID: PMC10726352PMID: 37967851DOI: 10.1021/acs.jmedchem.3c01233
- CDK9 inhibitors in cancer researchPublication Name: RSC Medicinal ChemistryPublication Date: 2022-06-22PMCID: PMC9215160PMID: 35814933DOI: 10.1039/d2md00040g
- From Structure Modification to Drug Launch: A Systematic Review of the Ongoing Development of Cyclin-Dependent Kinase Inhibitors for Multiple Cancer TherapyPublication Name: Journal of Medicinal ChemistryPublication Date: 2022-04-29PMID: 35485642DOI: 10.1021/acs.jmedchem.1c02064
- Lessons Learned from Past Cyclin-Dependent Kinase Drug Discovery EffortsPublication Name: Journal of Medicinal ChemistryPublication Date: 2022-03-02PMID: 35235745DOI: 10.1021/acs.jmedchem.1c02190
PAT
(lS,3S)-N1-(5-(pentan-3-yl)pyrazolo[l,5-a]pyrimidin-7-yl)cyclopentane-l,3-diamine is a pharmaceutically active compound that has been studied for various uses, such as for the treatment of cancer. As used herein, the term “Compound A” is used to refer to both the free base and salt forms of (lS,3S)-N1-(5-(pentan-3-yl)pyrazolo[l,5-a]pyrimidin-7-yl)cyclopentane-l,3-diamine. The free base of Compound A has the CAS number of 2416873-83-9 and structure of formula (I):
SYN
Example 35: (1S,3S)-N3-[5-(1-ethylpropyl)pyrazolo[1,5-a]pyrimidin-7-yl]cyclopentane-1,3-diamine (35)
2-Ethylbutanoic acid (7.5 g, 64.57 mmol) was dissolved in THF (150 mL) and cooled to 0 °C. Within 20 min CDI (16.23 g, 100.08 mmol) was added portion-wise. The reaction warmed to room temp (rt) and the mixture was stirred at rt overnight (Solution A). In another flask MgCl2 (6.14 g, 64.57 mmol) and potassium 3-ethoxy-3-oxo-propanoate (17 g, 100.1 mmol) were mixed with THF (150 mL) and stirred under argon overnight at 50 °C. The resultant white suspension was cooled to rt and solution A was added dropwise over 10 min and the reaction mixture (RM) was stirred for 16h at room temperature. After several minutes a sticky, amorphous solid appeared whereupon after several hours the reaction mixture became homogenous in appearance. The RM was concentrated to about a third, taken up in half sat. potassium bisulphate solution and extracted twice with ethyl acetate. The organic layers were subsequently washed with a sat. sodium bicarbonate solution, combined, dried over anhydrous sodium sulfate, filtered and evaporated. Purification by column chromatography gave ethyl 4-ethyl-3-oxo-hexanoate (4.3 g, 23.087 mmol, 35.8% yield) as a transparent liquid. The RM was monitored by TLC (10% EA in Hex, Product Rf=0.6, SM Rf=0.1).
Step 2
To a suspension of ethyl 4-ethyl-3-oxo-hexanoate (4.4 g, 23.62 mmol) in acetic acid (11 mL) at 70 °C was added 1H-pyrazol-5-amine (4.71 g, 56.7 mmol) in two portions (the second portion was added after 2 hours of stirring the first portion) over a 4 hour period. Upon consumption of SM as indicated by TLC, the reaction was cooled to rt and the solvent was evaporated in a rotary evaporator. The residue was treated with ethyl acetate and filtered to give 5-(1-ethylpropyl)-4H-pyrazolo[1,5-a]pyrimidin-7-one (3.7 g, 17.7 mmol, 74.9% yield) as an off-white solid. The reaction mixture was monitored by TLC (5% MeOH in DCM, Product Rf=0.3, SM Rf=0.8).
Step 3
A stirred solution of 5-(1-ethylpropyl)-4H-pyrazolo[1,5-a]pyrimidin-7-one (3.7 g, 18.03 mmol) in POCl3 (33.7 mL, 360.52 mmol) was heated to reflux for 4 hours. The reaction mixture was cooled to room temperature, excess reagent was evaporated in a rotary evaporator, and the residue was treated with ice-water. The chlorinated product was extracted from aqueous mixture by DCM. The organic layer was separated, dried over anhydrous Na2SO4, filtered and purified by column chromatography to give 7- chloro-5-(1-ethylpropyl)pyrazolo[1,5-a]pyrimidine (3.1 g, 13.9 mmol, 76.9% yield) as a light yellow liquid. The reaction mixture was monitored by TLC (20% EA in Hex, Product Rf=0.6, SM Rf=0.1).
To a stirred solution 7-chloro-5-(1-ethylpropyl)pyrazolo[1,5-a]pyrimidine (2.3 g, 10.28 mmol), tert-Butyl ((1S,3S)-3-aminocyclopentyl)carbamate (2.27 g, 11.31 mmol) and K2CO3 (4.26 g, 30.84 mmol) in MeCN (20 mL) were heated to reflux for 16 hours. The reaction mixture was filtered, concentrated under reduced pressure and purified by column chromatography, eluent 30% EA in hexane to give tert-butyl N-[(1S,3S)-3-[[5-(1-ethylpropyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino]cyclopentyl]carbamate (4.5 g, 11.6 mmol, 112.8% yield) as an off-white solid. The reaction mixture was monitored by TLC (40% EA in Hex, Product Rf=0.5, SM Rf=0.7).
Step 5
To tert-butyl N-[(1 S,3S)-3-[[5-(l-ethylpropyl)pyrazolo[l,5-a]pyrimidin-7-yl]amino]cyclopentyl]carbamate (1.0 g, 2.58 mmol) in l,4-Dioxane (0.2 mL), 4 M HC1 in Dioxane (3.22 mL, 12.9 mmol) was added and stirred at room temperature for 4 hours. The reaction mixture was evaporated in vacuo, triturated with pentane and lyophilized from MeCN:H20 to give [(lS,3S)-3-[[5-(l-ethylpropyl)pyrazolo[l,5-a]pyrimidin-4-ium-7-yl]amino]cyclopentyl]ammonium dichloride (0.9 g, 2.5 mmol, 96.8% yield) as a pale-yellow sticky solid. The reaction mixture was monitored by TLC ( 100% EA, Product Rf=0.l, SM Rf=0.8). 1H NMR (400 MHz, DMSO-d6) d 15.00 (s, 1H), 9.93-9.86 (m, 1H), 8.51 (s, 3H), 8.30 (s, 1H), 6.84 (s, 1H), 6.58 (s, 1H), 4.95 (q, J = 7.8 Hz, 1H), 3.77- 3.66 (m, 1H), 2.84-2.71 (m, 1H), 2.29-2.05 (m, 4H), 1.94-1.63 (m, 6H), 0.81 (t, J = 7.4 Hz, 6H). LC-MS (m/z 287.21, found 288.0 [M+H+])
Step 6
To [(1S,3S)-3-[[5-(l-ethylpropyl)pyrazolo[I,5-a]pyrimidin-4-ium-7-yl]amino]cyclopentyl]ammonium-di chloride (0.2 g, 0.5600 mmol) in aq. NH3 (4.0 mL, 0.56 mmol) was added and stirred at room temperature for 4 hours. The reaction mixture was evaporated in vacuo, triturated with pentane and lyophilized from MeCN:H20 to give (lS,3S)-N3-[5-(l-ethylpropyl)pyrazolo[l,5-a]pyrimidin-7-yl]cyclopentane-l,3-diamine (140 mg, 0.49 mmol, 87.8% yield) as a pale-yellow sticky solid. The reaction mixture was monitored by TLC (100% EA, Product Rf=0.1, SM Rf=0.8). 1H NMR (400 MHz, DMSO-d6) d 7.95 (d, J = 2.2 Hz, 1H), 6.86 (s, 1H), 6.29 (d, J = 2.2 Hz, 1H), 5.95 (s, 1H), 4.31-4.19 (m, 1H), 3.57-3.44 (m, 1H), 2.52-2.44 (m, 1H), 2.36-2.22 (m, 1H),
2.09–1.79 (m, 3H), 1.80–1.59 (m, 5H), 1.58–1.24 (m, 3H), 0.83 (t, J = 7.4 Hz, 6H). LC-MS (m/z 287.21, found 288.5 [M+H+]).
PAT
- Compounds, compositions and methods for modulating CDK9 activityPublication Number: CN-112996790-BPriority Date: 2018-10-30Grant Date: 2023-11-03
- Compounds, compositions, and methods for modulating cdk9 activityPublication Number: US-2024132506-A1Priority Date: 2018-10-30
- Compounds, Compositions, and Methods for Modulating CDK9 ActivityPublication Number: US-2020131189-A1Priority Date: 2018-10-30
- Compounds, compositions, and methods for modulating cdk9 activityPublication Number: US-2022002305-A1Priority Date: 2018-10-30
- Compounds, compositions, and methods for modulating cdk9 activityPublication Number: EP-3873911-A1Priority Date: 2018-10-30
- Substituted pyrazolo[1,5-a]pyrimidines for modulating CDK9 activityPublication Number: US-11845754-B2Priority Date: 2018-10-30Grant Date: 2023-12-19
- Substituted pyrazolo[1,5-a]pyrimidines for modulating CDK9 activityPublication Number: US-11155560-B2Priority Date: 2018-10-30Grant Date: 2021-10-26
- Compounds and methods for modulating cdk9 activityPublication Number: EP-4240422-A1Priority Date: 2020-11-05
- Compounds and methods for modulating cdk9 activityPublication Number: WO-2022098843-A1Priority Date: 2020-11-05
- Compounds and methods for modulating cdk9 activityPublication Number: US-2025188084-A1Priority Date: 2020-11-05
- Chimeric degraders of cyclin-dependent kinase 9 and uses thereofPublication Number: WO-2021216828-A1Priority Date: 2020-04-24
- Chimeric degraders of cyclin-dependent kinase 9 and uses thereofPublication Number: US-2023158159-A1Priority Date: 2020-04-24
- Polymorphic and salt forms of (ls,3s)-n-(5-(pentan-3- yl)pyrazolo[l,5-a]pyrimidin-7-yl)cyclopentane-l,3-diaminePublication Number: EP-4436569-A1Priority Date: 2021-11-24
- Polymorphs and salt forms of (1S,3S)-N1-(5-(pentan-3-yl)pyrazolo[1,5-A]pyrimidin-7-yl)cyclopentane-1,3-diaminePublication Number: KR-20240110634-APriority Date: 2021-11-24
- Compositions and methods for enhanced protein productionPublication Number: EP-4412621-A2Priority Date: 2021-09-22
- Compositions and methods for enhanced protein productionPublication Number: US-2024252688-A1Priority Date: 2021-09-22
- Compositions and methods for enhanced protein productionPublication Number: WO-2023056202-A2Priority Date: 2021-09-22
- A cdk9 inhibitor for use in the treatment of cancer in a subject having an asxl1 mutationPublication Number: WO-2025217597-A1Priority Date: 2024-04-12
- Polymorphic and salt forms of (1s,3s)-n1-(5-(pentan-3- yl)pyrazolo[1,5-a]pyrimidin-7-yl)cyclopentane-1,3-diaminePublication Number: WO-2023096922-A8Priority Date: 2021-11-24
- Polymorphic and salt forms of (ls,3s)-n1-(5-(pentan-3- yl)pyrazolo[l,5-a]pyrimidin-7-yl)cyclopentane-l,3-diaminePublication Number: WO-2023096922-A1Priority Date: 2021-11-24
- Polymorphic and salt forms of (1s,3s)-n1-(5-(pentan-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl) cyclopentane-1,3-diaminePublication Number: US-2025059193-A1Priority Date: 2021-11-24
- Polymorphic forms and salt forms of (1S,3S)-N1-(5-(pentan-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl)cyclopentane-1,3-diaminePublication Number: CN-118678952-APriority Date: 2021-11-24
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//////istisociclib, cyclin-dependent kinase (CDK) inhibitor, antineoplastic, KB-0742, 2416873-83-9, KB 0742, F7J6KSY5I8, UB-18422, KB-130742, KB 00130742
Isomiosamine
Isomiosamine
CAS 53844-46-5
MF C9H10N2 MW
146.19 g/mol
3-(3,4-dihydro-2H-pyrrol-2-yl)pyridine
rac-(3R)-3-(3,4-dihydro-2H-pyrrol-2-yl)pyridine
tumor necrosis factor alpha (TNFα) inhibitor, MyMD-1, MYMD-1, Isomyosamine, 3A50Y1J4LP, MyMD Pharmaceuticals
synthetic derivative of tobacco alkaloids
Isomyosamine, also known as MyMD-1 or MYMD-1, is a synthetic derivative of tobacco plant alkaloids being developed as a metabolic- and immunomodulator by MyMD Pharmaceuticals. To date, isomyosamine has been shown to suppress the production of IFN-γ, IL-2, IL-10, and TNF-α, and decrease the severity of experimental thyroiditis in a murine model.[1] Trials in humans are being planned, and some are underway, examining the potential benefits of isomyosamine in autoimmune diseases such as rheumatoid arthritis, and in sarcopenia and frailty.[2]
MyMD Pharmaceuticals claim that MYMD-1 is not immunosuppressive, and thus should not be associated with the dangerous side effects such as infections that are seen in currently used TNF-α inhibitors such as adalimumab.[3] While it is true that there currently is no evidence of immunosuppression in isomyosamine recipients, this has not yet been tested in large clinical trials
Safety and Efficacy of Isomyosamine in Reducing Inflammation and Treating Muscle Loss in Older Adults After Hip or Thigh Bone Fractures
CTID: NCT06942182
Phase: Phase 2
Status: Not yet recruiting
Date: 2025-04-24
SYN
Isomyosmine
[08] Isomyosmine (3-(3,4-dihydro-2H-pyrrol-2-yl)-pyridine) is a nicotine related alkaloid present in solanecea plants containing nicotine.
PAT
| Unless otherwise clear from context, all percentages referred to herein are expressed as percent by weight based on the total weight of the composition. Percentages expressed herein as “w/v” refer to mass, in grams, of the component per 100 ml of solvent. For example, a 1% (w/v) composition of isomyosmine contains lg (1000 mg) of isomyosmine per 100 ml of solvent, which is equivalent to 10 mg/ml. |
| Isomyosmine (3-(3,4-dihydro-2H-pyrrol-2-yl)-pyridine) is a nicotine related alkaloid present in solanecea plants containing nicotine. |
PAT
- Method of Treating Substance AddictionsPublication Number: US-2017333415-A1Priority Date: 2015-02-19
- Method of treating addictions to opioidsPublication Number: US-10471052-B2Priority Date: 2015-02-19Grant Date: 2019-11-12
- Method of treating cocaine addictionPublication Number: US-11331310-B2Priority Date: 2015-02-19Grant Date: 2022-05-17
- Method of treating disorders associated with chronic inflammationPublication Number: US-2021106578-A1Priority Date: 2015-03-31
- Method of Treating Substance AddictionsPublication Number: US-2020215045-A1Priority Date: 2015-02-19
- Compositions for e-cigarettesPublication Number: WO-2016133890-A1Priority Date: 2015-02-19
- Method of treating substance addictionsPublication Number: US-9884055-B2Priority Date: 2015-02-19Grant Date: 2018-02-06
- Method of Treating Substance AddictionsPublication Number: US-2018140590-A1Priority Date: 2015-02-19
- Methods of treating sarcopeniaPublication Number: US-11219620-B2Priority Date: 2015-03-31Grant Date: 2022-01-11
- Methods of Treating Apoptosis and Altering Programmed Cell DeathPublication Number: US-2018021321-A1Priority Date: 2015-03-31
- Methods of reversing normal aging process and extending lifespanPublication Number: US-11179382-B2Priority Date: 2015-03-31Grant Date: 2021-11-23
- Method of treating viral infectionsPublication Number: US-10786493-B2Priority Date: 2015-03-31Grant Date: 2020-09-29
- Methods of treating cancer, autoimmune disorders, and other conditions associated with chronic inflammationPublication Number: CN-107666907-BPriority Date: 2015-03-31Grant Date: 2022-05-13
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Scientific studies
Preclinical studies
One preliminary murine study comparing isomyosamine to rapamycin, the best-characterised drug slowing the progression of aging, reported an increase in lifespan in the isomyosamine cohort, indicating anti-aging activity. Isomyosamine’s anti-proliferative effects were similar to those of rapamycin.[4]
Clinical trials
A phase I randomised double-blind placebo-controlled trial on healthy volunteers examining the safety and pharmacokinetic properties of different amounts of isomyosamine found no serious adverse events, but 3 cases of mild dysgeusia in the highest-dose (600 mg) cohort. A preliminary decrease in TNF-α levels was reported in the lowest-dose (150 mg) cohort, but not in the placebo cohort.[5]
| Identifiers | |
|---|---|
| CAS Number | 53844-46-5 |
| 3D model (JSmol) | Interactive image |
| ChemSpider | 9461533 |
| PubChem CID | 11286546 |
| UNII | 3A50Y1J4LP |
| CompTox Dashboard (EPA) | DTXSID80461155 |
| InChI | |
| SMILES | |
| Properties | |
| Chemical formula | C9H10N2 |
| Molar mass | 146.193 g·mol−1 |
| Related compounds | |
| Related compounds | Myosmine Nicotine |
| Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).Infobox references | |
References
- Di Dalmazi, Giulia; Chalan, Paulina; Caturegli, Patrizio (2019-03-01). “MYMD-1, a Novel Immunometabolic Regulator, Ameliorates Autoimmune Thyroiditis via Suppression of Th1 Responses and TNF-α Release”. The Journal of Immunology. 202 (5): 1350–1362. doi:10.4049/jimmunol.1801238. ISSN 0022-1767. PMID 30674573. S2CID 59226562.
- “MyMD Pharmaceuticals® Provides Dosing Update on Phase 2 Multi-Center Clinical Trial of MYMD-1® as a Therapy for Delaying Aging and Extending Healthy Lifespan”. MyMD. Retrieved 2023-08-13.
- “MYMD-1®”. MyMD. Retrieved 2023-08-13.
- Sabini, Elena; O’Mahony, Alison; Caturegli, Patrizio (2023-02-24). Anderson, Rozalyn M (ed.). “MyMD-1 Improves Health Span and Prolongs Life Span in Old Mice: A Noninferiority Study to Rapamycin”. The Journals of Gerontology: Series A. 78 (2): 227–235. doi:10.1093/gerona/glac142. ISSN 1079-5006. PMID 35914953.
- Brager, Jenna; Chapman, Chris; Dunn, Leonard; Kaplin, Adam (2022-11-11). “A Double-blind, Placebo-controlled, Randomized, Single Ascending, and Multiple Dose Phase 1 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Oral Dose Isomyosamine Capsules in Healthy Adult Subjects”. Drug Research. 73 (2): 95–104. doi:10.1055/a-1962-6834. ISSN 2194-9379. PMC 9902179. PMID 36368677.
/////////////isomiosamine, tumor necrosis factor alpha (TNFα) inhibitor, MyMD-1, MYMD-1, Isomyosamine, 3A50Y1J4LP, MyMD Pharmaceuticals, ANAX, ADVECT, BLUE JET
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