design, synthesis and application of novel bicyclic...
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Design, synthesis and application of novel bicyclic amines
in drug discovery
Pavel Mykhailiuk2018
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Amines in drug discovery
Conformational restriction
21th centuryN N
N
Cyclic amines Bicyclic amines
> 50 FDA-drugs
fused bridged spiro
Practical synthesisis needed!
2
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Fused amines
Three topics
Bridged amines
Spirocyclic amines
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Fused bicyclic amines in drug discovery
N
O
CO2HH
H
Mitiglinideantidiabetic drug
RNHO
Nt-Bu
H
H
O NH O
NH2
O
Telaprevirantihepatitis drug
N
O
NH2 OHCN
Saxagliptinantidiabetic drug
N
CO2HH
HO
NH
CO2Et
PhN
CO2HH
HO
NH
CO2Et
Ramiprilantihypertensive drug
Perindoprilantihypertensive drug
Belaperidone
EcenofloxacinAntibacterial agent
Antischizophrenia agent
N N
OCO2HF
N
H2NH
NN
NH
O
OH
HF
Trovafloxacine
N N
OHO2C
F
F
F
N
NH2
H
HNHBicifadin
Analgetic agentAntibacterial agent
4
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Our recent synthesis:
A. Denisenko et al. J. Org. Chem. 2017, 9627.
20 EUR / kg25 EUR / kg
These chemicals are availablein every synthetic laboratory worldwide!!!
20 EUR / kg
5
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20 mgglass tube
Photochemical step
N
Ph
O
Ph
N
Ph
O
Ph
H H
88%
366 nmPh2CO[2+2]
CH3CN, rt
5 g1L glass flask (DURAN)
Alex Denisenko
50 g6L plastic bottle
A. Denisenko et al. J. Org. Chem. 2017, 9627.
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Photochemical step
Jenia Skalenko
NBn
O
H H
NO
H HNBn
O
H H
NBn
O
H H
F
F
F
NO
H HNBn
O
H H
NBn
O
H H
MeO
MeO
MeO
BnBn
NBn
O
F H
CF3
NO
H H
Ph
NO
H H
Ph
F
NBn
O
H
BelaperidoneAntischizophrenia agent
NN
NH
O
OH
HF
A. Denisenko et al. J. Org. Chem. 2017, 9627. 7
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N-benzyl maleimide
Tania Druzhenko
T. Druzhenko et al. J. Org. Chem. 2018, submitted.
20 EUR / kg
8
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Acetophenone
E. Skalenko, et al. J. Org. Chem. 2018, in press (DOI: 10.1021/acs.joc.7b02910)..
10 EUR / kg
Jenia Skalenko
Rigid Proline
9
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Photochemical step
A. Denisenko et al. J. Org. Chem. 2017, 9627.
Photoreactor
Fused amines
T. Druzhenko et al. J. Org. Chem. 2018, submitted.E. Skalenko, et al. J. Org. Chem. 2018, in press (DOI: 10.1021/acs.joc.7b02910). 10
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Fused amines
Three topics
Bridged amines
Spirocyclic amines
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Melogliptinantibacterial agent
N CN
F
OHN
N
N
N
Glenmark Prarm.
chiral Achiral
12
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NH
CO2H
F
N CO2Me
F
BzN CO2Me
F
Bz
H2N CO2H
OHF
OMs
73%
366 nm
[2+2]
HCl
99%
77%
POCl3MeOH
71% H2N CO2Me
Cl BzCl
HN CO2Me
Cl
82%
Bz
KOtBu
Ph2CO
CH3CN
F-2,4-methano-Proline
5 g
A. Tkachenko et al. Org. Lett. 2009, 5674.
Anton Tkachenko
P. Mykhailiuk et al. J. Org. Chem. 2017, 8831.13
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2,4-Methanopyrrolidines
A. Tkachenko et al. Org. Lett. 2009, 5674.P. Mykhailiuk et al. J. Org. Chem. 2017, 8831.V. Levterov et al. J. Org. Chem. 2018, submitted.
Vadym Levterov
14
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20 mg scale 5 g scale
Photochemical step
1000 g scalein flow
A. Tkachenko et al. Org. Lett. 2009, 5674.P. Mykhailiuk et al. J. Org. Chem. 2017, 8831.V. Levterov et al. J. Org. Chem. 2018, submitted.
Vadym Levterov
15
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Stabilization of trans-amides
Vova Kubyshkin
P. Mykhailiuk , V. Kubyshkin et al. J. Org. Chem. 2017, 8831. 16
www.enamine.netP. Mykhailiuk , V. Kubyshkin et al. J. Org. Chem. 2017, 8831. 17
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1,4-Disubstituted piperidine drugs
18
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Piperidine
Piperidine analogue
Conformational analysis
19
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Advanced building blocksCommon building block
T. Druzhenko et al. Org Lett 2015, 1922.O. Denisenko et al. Org Lett 2010, 4372.O. Denisenko et al. Tetr Lett 2010, 1790.O. Denisenko et al. Synthesis 2010, 493. 20
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Bridged scaffolds in two steps!
Alex Denisenko
T. Druzhenko et al. Org Lett 2015, 1922.O. Denisenko et al. Org Lett 2010, 4372.
Tania Druzhenko
O. Denisenko et al. Tetr Lett 2010, 1790.O. Denisenko et al. Synthesis 2010, 493. 21
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Fused amines
Three topics
Bridged amines
Spirocyclic amines
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Spirocyclic amines in drug discovery
N N
OCO2H
N
F
ZabofloxacinAntibacter ial drug
2007, Dong Wha Pharm.
N
N
O NH2
N
SO
OAntiviral agent2013, Roche
N
OCO2H
N
F
DV-7751Potent antibacter ial agent
2000, Daiichi Pharm.
O
HN
NO
H2NN
OCO2H
F
N
F
Cl
SitafloxacinAntibacterial drug
2008, Daiichi Sankyo
N
OHN
MeO2C
N
HN
LedipasvirAntihepatitisl drug
2014, Gilead Sciences
N
CO2H
Antiinf lamatory agent2012, ONO Pharm.
N
NN
N
N
N
H2N
AN
A
N
Carreira, Mueller et. al ANIE 2010, 3603.
lipophilicitysolubilitymetab. stability
23
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Spiro-scaffolds in only two steps!
Bohdan Chalyk
B. Chalyk et al. Eur. J. Org. Chem. 2017, 4530.B. Chalyk et al. Chem. Eur. J. 2017, 16782.
24
www.enamine.netB. Chalyk et al. Chem. Eur. J. 2017 , 16782. B. Chalyk et al. Eur. J. Org. Chem. 2017, 4530.
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2-Substituted piperidines: 18-FDA drugs
N N
conformationalrestr iction
still unknown18 FDA-drugs
26
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Spirocycles for 2-substituted piperidines
Alex Kirichok
A. Kirichok et al. Angew. Chem. Int. Ed. 2017, 8865.A. Kirichok et al. Chem. Eur. J. 2018, in press (DOI: 10.1002/chem.201800193). 27
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+ ++Spiro-analoguewas more active
than Bupivacaine!
28A. Kirichok et al. Angew. Chem. Int. Ed. 2017, 8865.A. Kirichok et al. Chem. Eur. J. 2018, in press (DOI: 10.1002/chem.201800193).
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Amines in drug discovery
Conformational restriction
21th centuryN N
N
Cyclic amines Bicyclic amines
> 50 FDA-drugs
fused bridged spiro
Practical synthesisis needed!
29
www.enamine.net
Alex Denisenko
Alex Kirichok
Bohdan Chalyk Vadym Levterov
Tania Druzhenko
Jenia Skalenko
Vova Kubyshkin
Who actually did the job:
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