Chemistry of Heterocyclic Compounds, Vol. 31, No.

6, 1995

P Y R I D I N E D E R I V A T I V E S IN T H E D R U G A R S E N A L (150 Y E A R S
OF PYRIDINE CHEMISTRY)

1~. Lukevits

Almost 150 years ago, T. Anderson reported isolation of picoline from coal tar at a meeting of the Edinburgh Royal
Society (April, 1846). Several years later, he isolated lutidine and pyridine from a bone oil fraction. Not inconsiderable efforts
were still required to prove its structure (Kerner, 1869; Dewar, 1871), to synthesize it (Ramsay, 1877), and to formulate the
idea of pyridine as an azabenzene (Ladenburg, 1888). But the first step had been taken. Three reports by T. Anderson laid out
the beginning of the chemistry of pyridine, whose derivatives proved to be also widely distributed in living matter and in most
cases exhibited high biological activity (for example, the coenzyme nicotinamide adenine dinucleotide; the alkaloids nicotine,
anabasine, ricinine, atropine, and cocaine).
A number of rather simple pyridine derivatives also exhibit high biological activity, nicotinic acid and its amide are
contained in the organs of animals and are prosthetic groups of the enzymes codehydrogenase I and codehydrogenase II, which
are hydrogen transfer agents and accomplish oxidation-reduction processes.
The daily requirement for nicotinic acid (niacin) for a human adult is about 20 mg; pellagra develops when a deficiency
is preseflt. Nicotinic acid (and its amide) is a specific pellagra preventative, but it also exhibits vasodilating action and
hypocholesterinemic activity. Considering this, for more than 75 years new biologically active substances have been sought
among the derivatives of nicotinic acid and other pyridine derivatives, which has led to the discovery of a number of important
classes of drugs.
Back in the 1920's, the analeptic cordiamin (diethylnicotinamide) was introduced into medical practice and used for
acute and chronic circulatory disorders, reduction of vascular tone, and respiratory insufficiency. At the end of the 1940's,
antituberculars based on isonicotinic acid hydrazide appeared (isoniazid, gluconiazide, pasiniazide, streptoniazide, and later
phthivazid). In the 1950's, pyridinaldoxime salts acquired special importance as cholinesterase reactivators: antidotes in
poisoning by organophosphorus compounds (dipiroxime, obidoxime). In the 1960's, tetrahydropyridine- and piperidine+
containing neuroleptics of the butyrophenone series occupied their own place in the drug arsenal (droperidol, benperidol,
bromperidol), in addition to the antiemetic domperidone, anti-inflammatory drugs based on aminopyridine (piroxicam), the
aminopyridone-based cardiotonic amrinone, the antiatherosclerotic drug Parmidine (2,6-bishydroxymethylpyridine carbamate),
spasmolytics and antihistaminics based on piperidine (the highest sales at the end of the 1980's were for terfenadine), the
antiasthmatic drug ketotifen.
At the beginning of the 1990's, of the 1500 most familiar drugs, 91 are piperidine derivatives and 73 are pyridine
derivatives. A special place belongs to 1,4-dihydropyridines+ A new class of calcium antagonists has been created based on
them. The principal representative of these drugs (whose annual sales exceed two billion US dollars) is nifedipine (Adalat from
the Bayer company, Procardia from the Pfizer company), used to reduce blood pressure and for stenocardia.
At the present time, already dozens of drugs of the 1,4-dihydropyridine series have been created which have more
specific or prolonged action. Some of them inhibit aggregation of thrombocytes and potentiate the action of antineoplastics.
A number of drugs based on pyridine derivatives are presented in the following list of drugs, and the entire issue of
this journal is devoted to pyridine chemistry, which celebrates its 150 years with new ideas and results.

Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 723-734, June, 1995.

0009-3122/95/3106-0639512.50 ©1996 Plenum Publishing Corporation 639

 PYRIDINE DERIVATIVES

Vitamins
CHzOH

~ COOH
~ CONH~ HO~CHzOH

Me~ "N"
lh P. P. factor (niacinamide) B6 (pyridoxine)

Tranquilizer Sedative Antidepressant

~ ~_~~,o /''N CONHNHCH2

CH2C1t2-N N--C6HaF-p CH2
) \ /
NHCH CONHCH2Ph
I I

Bromazepam Niaprazine Nialamide

Analeptics
Me,~tMe

@ /CONEt z
~ ,
o~,~ ~c.~o~-

Nicethamide Me
Camphotamide
(Cordiamin)

Analgesics

@.. Mo ~
o,,
EtOOCHN. A

/.CIICHz--N ) I
k~N,"~NI ICI.12CItph NHz"~N~NHCHzC~H4F-t
COEt
Propiram Phenyramidol Flupirtine

640
 Anti-inflammatorydrugs

~ COOCHzR

R= - ~ Clonixin R = CHzOBu Nicoboxil

Me ~ CI
R= --~ ~ Nifluril R= --~ Nicotafuryl
"~-CF3
~CONH

O~,~N'-Me
Me
C£
NIMe £3 O-~

I v -C/L"CONH- "N"
Ph II
Nifenazone 0
Piroxicam
Antiarrhythmic Anticholinesterase Cardiotonic

[~,.,/OCO NMe2 -NH2

/CI LCH~N(Pr-i), Br- N O
N2./.c.. - " - %~ 5J
Ph CONH2 I
Me
Disopyramide Pyridostigminebromide Amrinone
Spasmolytics and Vasodilators

[ coo I 3
Me... ~
o
/CH~CIt,NHCH,.

I
Aluminum nicotinate Me Pimephylline

~ COOCH2"~N_OI f

[ @-/COOCH213 C-C61t13

I
Hepronicate Nicergoline Me
Antihypertensives

Br~CONHz

Bupicomide
QTN.
Ofornine 0

641
 Antiatherosclerotics

~
CHzOCONItMe

CHzOCONHMe

Pyridinol carbamate (Parmidine) Nicoclonate " Niceritrol

Mc
I
~COOCH2CH2OOC~-O-~CI

Ethofibrate

Antihistaminics

I
R

Pheniramine X= H Carbinoxamine R = H, X = CI
Brompheniramme X = Br Doxylamine R = Me, X = H
Chlorpheniramine X = CI

O..~NICHzCH2NMe2
I
CI I2R
Fripelennamine 1~.= Methyapyrilene R = . ~

Chloropyramine R = - - - - ~ C I Thenyldiamine R = "~

Mepiramine R = ---~OMe Chloropicilene R= -~"CI

Q ~~Me H CH2CHzNMe2
Me~ C H C H 2 - N ~

Triprolidine Dimethindene
 Laxatives

~ C H ~ "/OMe
CH
A~OSO~Na

"" "

~ O M c ~OSO3Na
Bisacodyl Picosulfol

Cholinesterase reactors

CH~NOH HON-~-CH CH=NOH

~CH~NOH
Me
I
CI-
I
CH2CH~CH 2
Br-
©2x_I
CH2--R--CH 2
I

Pralidoxime Alloxime R = CHz, X = Br Dipiroxime

R = O, X = CI Obidoxime

Antituberculars

CONHNHR CONHN: C H ~ O H CSNH-,

,=Z.oMo
R=H Isoniazid Phthivazid R = Et Ethionamide
R = i-Pr Iproniazid R = Pr Protionamide

Antiseptics Fungicide
Me

CI-
I
C1~H3~

Cetylpyridinium chloride Phenazopyridine Ciclopirox

643
 Antibacterials

OH
HOOC~ 0

~ Et
COOH

Salazosulfapyridine Rosoxacin

ff~CHzCONH ~

o~-~~_~
COO-
O
Cephaloridine
H H
N~----SCH2CONIq~"~ 1
\-/ ~I--'.M.
0 T "CH2OAc
COOH
Cephapirin

Antineoplastics

f•-I1/CHz•N•.
~COCH2SOMe ~o.&-~A~o --c~
Oxisuran Ciamexon(immunomodulator)

TETRAHYDROPYRIDINEDERIVATIVES

Neuroleptic

O
F-O
c°c.2c.2c.2-N~-
8
Droperidol

644
 DIHYDROPYRIDINE DERIVATWES

Antihypertensives and Vasodilators of the 1,4-dihydropyridine

[ f ~ NO2

0 0 ~'''~ Ph
R3OO COOR s ~ ( P. ~ ~COOCHzCHzNCHzPh

R2f ~,N f ~R 6 Me" "N" "Me

H
Efonidipine

Name R1 # R3 R5 R

Amlodipine H Me Me El 2-CI

Darodipine H Me Me Et El ,2

Isradipine H Me Me Me Pr-i ,2

Nicardipine H Me Me Me (CH2) 2NMeCH2Ph 3-NO2

Niguldipine H Me Me Me ,3
3-NO2

Nilvadipine It Me CN Pr-i Me 3-NO2

Niludipine H Me Me CH2CH2OPr CH2CH2OPr 3-NO2

Nimodipine 1t Me Me Pr-i CH2CH2OMe 3-NO2

Nisoldipine H Me Me Me CH2CtlMe2 2-NO2

Nitrendipine H i Me Me Me Et 3-NO2

Nifedipine H Me Me Me Me 2-N02

,4
Oxodipine H Me Me Me Me

Riodipine H Me Me Me Me 2-OCHF2

Felodipine H : Me Me Me Et 2,3-di-CI

Flordipine ,5 Me Me El
Et 2-CF3

.2 m
* CH2OCH2CH2NH2;

.4 O... °s /"-'N
2,3- o I C H 2 ; CHzCHz-N 0
\ /

645
 PIPERIDINE DERIVATIVES

Neuroleptics

F----~COCH 2CH2CH2~N~12
R1 R2 R1 R2

Melperone H Me Benperidol H
Moperone OH - - - ~ M e H

Trifluperidol OH - - ~ C F 3 Pipamperone CONH2 - - N ~

O
Bromperidol OH - - - - ~ B r Spiperone ,~NH
Haloperidol OH "s--]
i'h

F CHCH2CHgCH*~N 2

R1 R2 R1 R2

Pimozide \
H Penfluridol OH ~ C I ~F3
H O
Fluspirilene /I~NH
"-,N--I
Ph

I
CltzR
X
H
Pecazine _.~N.M e

Pericyazine (CH2)z_N(~_OH CN

Perimethazine CHOHCH2-N~---OH OMe

Piperacetazine (CH2)z-N~"-(CH2)2OH COMe

Pipotiazine CH2CIt2-N~--CH2CH2OH SO2NMe2

646
 Sedative Antidepressant Analeptic

%~ Ph
Ph
Etr

I
Me
Mesoridazine Dioxadrol Bemegride

Analgesics

R1 R2 R3
0
Piperylone Me

Ph
Sufentanil ~/...CHzCH z COEt CHzOMe

Fentanyl PhCH2CHz COEt Ph

Rl R2 R3

Anileridine H2N--~CH2CH 2 COOEt Ph

Ketobemidone Me COEt -~o.

Piritramide Ph2C(CN)CH2CH2 CONH2

Phenoperidine PhCH(OH)CHzCH2 COOEt Ph

Antiparkinsonians

oH

(3-'~-c.2c.2-
R
'!>(---X:~--C=e,
Ph- \ /

Cycrimine R= ~ Budipine Methixene \

Me
Trihexyphenidyl R= - - ~

Biperiden R= - - ~

647
 Local Anesthetics
Me
R--~COO(CH2)3~N~% ~ NHCO~

Me Me R
Piperocaine R=H Mepivacaine R = Me
Cyclomethycaine R = - O ~ _ _ ~ Bupivacaine R = Bu

BuO-@COCH2CH2-N~ ~ NHCOOCHCHzOCONH~
I /"--X ~
CHz-N~_~
Dyclonine Diperodon

Muscle relaxant

Br-~CO~HC112--N~
Me
Eperisone

Antiarrhythmic Antihypertensive

H
N N--O ..NHz

NH2
Flecainide Minoxidil (stimulateshair growth)

Antiemetics

O O

~CH2CH2CH2-N~----CONH2

Domperidone Metopimazine X = SOzMe

Pipamazine X = CI

648
 Spasmolytics, Vasodilators

OH OH
PhzICCOO~ Br- Ph,[ C C O O C H 2 ~ MeOSO3-
~--'-N - /N..._.
\ d
l\
Me R Me Me
Mepenzolate bromide R = Me Bevonium
Pipenzolate bromide R = Et
CONHz
PhCHCOO--~N--Me Ph2~C-CHzCH2-/~/+)
PhzCHCOO~N
I \ / Br-
I Me CHEt
Et
Piperidolate Pentapiperide Fenpiverinium bromide

Ph--CHCOOCH2CHzNEtx
I

© Ph,~OyCH,CHz-N~

phoA_ -
Me N / - - ~
~
COOEt
"Ph

Bietamiverine Pipoxolan Pethidine

o
OMe
/-'-'N+ IM e P
PhzC=~_.~N"Me
/k
Me Me COOCHzCHz-N~_/)
MeOSO3-
Diphemanil Timepidium bromide Flavoxate

OH

Me OH
Tolperisone Fenprodil

Antidiarrheals

CN CONH2 OH
I ~ _~COOR
Ph2CCH2CHz--N~j/~ph Ph2I C C H 2 C H 2 - N ~ ~ ~ . _ C 1

Difenoxin R=H Loperamide

Diphenoxylate R = Et
Butoxylate R = Bu

649
 Antihistaminics

~'~ iph
Me--N~-.---OCHPh 2 Me--N~j/'~'-N~.CHzR
Diphenylpyraline Bamipine R = Ph c '

Thenalidine R = ....~o,~

Oil
O O
PhC]lzCH~ N / - " ~ t " ~ ph. ICClt,CH,CH2__N/---~
. . \ /
- M___/x,~

Fenspiride Diphenidol

OH ~ OH
i I
Ph2C-~ ~N--(CH2)3CH~ ~ - ~ Me

Terfenadine ) Ketotifen
(antiasthmatic)
Me

Diuretics

SO.~NH2 Me

Me
Clopamide Etozolin

650