Calcium Channel Blockers PDF

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Dr. Duffy...

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05/03/2017

CHEM30320:

Advanced Medicinal Chemistry

Dr. Liam Duffy: [email protected]

Topic 2: Calcium channel blockers: treatment of angina and hypertension

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Angina • Usually a symptom of Coronary Heart Disease: responsible for 15% of male deaths and 10% of female deaths in 2014 (total cardiovascular 28, 26%) - UK data • ‘Heavy’ or tight chest pain that results from oxygen deficiency in cardiac muscle (reduced blood supply) • Prevalence increasing with ageing population (effects over 55’s and males to a higher degree) Risk Factors include: - Hypertension - Smoking - Diabetes - Obesity - Lack of exercise

Arterial Occlusion

1 atm = 760 mmHg • Occlusion causes increase in b.p. • If blood volume to tissues decreases, so does O2 supply to muscles

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Structure of the Heart and ECG Basics

To pump effectively the heart needs a constant, well oxygenated blood supply

The Role of Calcium in Myocardial Contraction Extracellular [Ca2+] ~ 10,000 fold Heart muscle cell membrane Intracellular region

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Voltage Dependent/Gated Calcium Channels • Embedded in membrane of excitable muscle and neuron cells • Controlled by changes in electrical potential across cell membrane • ‘Gate’ opens when activated by ‘depolarized potentials’ • Influx of Ca2+ ions results in muscular contraction

Almost all CCBs either preferentially or exclusively block voltage dependant calcium channels (VDCC’s)

Calcium Channel Blockers (CCB’s)

1) Reduce heart rate by lowering electrical activity (undesired negative inotropic effects vary from drug to drug). 2) Decrease systemic vascular resistance via smooth muscle relaxation (vasodilation) 3) Reduce ‘afterload’ on heart – heart requires less pressure to eject blood into aorta 4) Increase blood volume and O2 supply to cells

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Blood vessel overview

CCB’s have little effect on venous smooth muscle Selective vasodilation of arterial smooth muscle avoids negative inotropy (reduced force of contraction). Dihydropyridines mainly target smooth muscle.

CCB Family of Drugs

Cl

NO2 EtO2C

CO2Et

MeO2C N H

N H

nifedipine

CO2Et

O

NH2

amlodipine

OMe H S

H O

NC N

OMe

O N

OMe

O N

diltiazem

verapamil

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Synthesis of nifedipine

NO2 EtO2C

CO2Et N H

• Based on a dihydropyridine core • Symmetrical molecule – no chiral centre! • What methods do we know for pyridine construction?

Hantzsch Synthesis

NO2

MeOH, reflux16 h

CHO EtO2C

CO2Et O

O

NO2 EtO2C

CO2Et N H

NH3

Q - Look up the mechanism for the Hantzsch synthesis

Impurities became an issue on larger scale production

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Alternative synthesis:

EtO2C

HOAc, piperidine

+ NO2 O

NO2 EtO2C

CO2Et + H2N

CHO O

EtOH, reflux 16 h

NO2 EtO2C

CO2Et N H

Enables isolation of initial condensation product Q – what’s the mechanism of the first step?

Second generation drugs

Cl MeO2C

CO2Et N H

O

NH2

Amlodipine

• Longer duration of action than nifedipine • Single daily dose to manage hypertension Note: this compound is chiral!

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Due to difference in esters:

Cl MeO2C

Cl MeO2C

CO2Et N H

CO2Et N H

O

NH2

(R)

O

NH2

(S)

S – enantiomer is >1000 more active

First synthetic route: racemic

MeO2C

HOAc, piperidine

+ Cl O

Cl MeO2C

CO2Et + O

CHO

O

O

N3

NH4OAc EtOH, reflux 2.5 h

Cl MeO2C

H2 / Pd

CO2Et N H

O

Cl MeO2C

NH2

CO2Et N H

O

N3

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Later synthesis – access to single enantiomers: O CN

O

Cl O MeO2C

O

O +

N3

Cl NH2

CHO

MeO2C N H

reflux, 2 h

CN

O

O N3

NaOH, rt, 2 h

Cl Cl

NaO

O

OMe

MeO2C

MeO2C

OMe

N H

N H

O

*

CO2H

O

O N3

N3

Can now separate diastereoisomers * Ester groups now differentiated – provides a handle

Separate diastereoisomers, then:

Cl

Cl

O MeO2C

1., 2.

O N H

MeO2C

CO2Et

OMe O

N H N3

O

NH2

1. EtOH, NaOEt – transesterification 2. H2 / Pd

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Side effects possible with this class of compound Grapefruit Juice – effect on felodipine

5mg tablet with juice: felodipine stays in plasma longer Without juice

Inhibits metabolism:

Cl

Cl

Cl

H3C

Cl

CO2CH3

H3CO2C N H

CYP3A4

CO2CH3

H3CO2C

CH 3

H3C

N

CH3

D.G. Bailey, et al.; Br J Clin Pharmacol 1998, 46:101-110

Synthesis of Diltiazem OMe

S

O O

N O N

• A benzothiazepine: originally developed as anti-depressant • Side effect noted: potent coronary vasodilation • Hence used in angina/hypertension (Viagra far from the first successful ‘side effect’ drug)

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Original synthetic route: racemic approach HS

CO2Me

CO2Me

[O]

OMe NO2

O2N

O

S

heat HO

CO2Me

OMe

OMe

resolve OMe NO2 S

OMe

H MeO2C

H OH

S

O O

N O N

OMe

OMe NH2

NO2

S

i) NaOH

S

H

H MeO2C

ii) H2 Pd-C

H OH

heat

H OH

HO2C

*

OMe

S OMe

OMe OH

S

O O

N

N H

Ac2O

S

*

i) NaH Cl

OH N

O N

O

O

N

N

Q - what are mechanisms of steps marked: *

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Later asymmetric route: Sharpless Asymmetric Epoxidation OAc

OAc

SHARPLESS

OAc

i) [O] ii] Me2SO4

*KEY*

O

O

HO

HO

CO2Me

py.HCl source of Cl HS

OMe

OMe NO2

Similar to racemic route

O2N

S

H Cl

H MeO2C

H OH

MeO2C

H OH

NB - Write brief notes on Sharpless asymmetric epoxidation of allylic alcohols

Synthesis of Verapamil

NC MeO

N

MeO

OMe OMe

• First calcium channel blocker to be licensed in USA • At the time mechanism of action unknown • Sold as racemate, even though (S) isomer more active

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CN

CN

i) NaNH2

MeO

ii) iPr-Br

MeO

MeO

MeO

NC

MeO

i) NaNH2

MeO

ii) allyl-Br

i) B2H6/H2O2 hydroboration /oxidation

MeO

MeO

MeO

NC

MeO

NC

OH

2 potential pathways to introduce amine fragment:

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Original racemic route

MeO

i) NaNH2

CN

MeO

N

+

CN

iPr-Br

MeO

OMe

Cl

MeO

OMe

NaNH2

NC N

MeO

OMe OMe

MeO

Resolution used to access single enantiomers:

MeO

i) base

CO2Me

i) base

MeO CO2Me

iPr-I

MeO

MeO Br

MeO

MeO

CO2Me

KOH

MeO CO2H

MeO

NC MeO MeO

N

RESOLVE

MeO

chiral amine "salt"

MeO

CO2H

OMe OMe

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steps

hydroboration MeO

MeO

MeO

MeO CO2R

CO2R

MeO

OH

MeO

HN

CN

Cl

OMe

OMe

NC

N

MeO

OMe

S MeO

OMe

Q - Suggest reagents and look up a mechanism for “hydroboration” of an alkene

Useful references Nifedipine: US Patent, 1969, 3,485,847 Amlodipine: J. Med. Chem., 1992, 35, 3341. Diltiazem: Tetrahedron, 1994, 50, 4323. Verapamil J. Org. Chem., 1987, 52, 1309

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