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`.Progress in Pharmacology
`
`Editors
`
`H. Grobecker, Frankfurt a.M.
`G. F. Kahl, Mainz
`W. Klaus, Koln
`H. Schmitt, Paris
`P. A. van Zwieten, Amsterdam
`
`Editorial Board
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`
`Progr. Pharmacol.
`Vol. 3 · No.1 {1980)
`
`~ ..
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`Stnh
`inC
`and
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`"'.' .. \.
`\ .
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`. ;
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`}_ .
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`. · .. '·
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`Structure-Activity Relationships
`in Clonidine-Like Imidazolidines
`and Related Compounds
`
`·\· .. · ; .
`
`'.
`
`P. B. M. W. M. Timmermans · W. Hoefke
`H. Stahle and P. A. van Zwieten
`
`62 figures and 39 tables
`
`Gustav Fischer Verlag · Stuttgart · New York · 1980
`
`!
`
`. .
`
`Ji/~1111 i
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`ie.
`
`eo.y, wo
`
`·~
`
`-
`
`. (' ..
`
`•..;.·
`
`.:.:.
`
`EIT,
`
`at
`yore
`
`ae” Ee te Oe
`Seat
`
`“
`
`~·.
`
`~
`
`oa oe
`we
`
`<=
`
`no
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`Dr. P. B. M. W. M. Timmermans and Professor Dr. P. A. van Zwieten
`Department of Pharmacy, Division of Pharmacotherapy, University of Amsterdam, Plantage Muidergracht 24,
`1018 TV Amsterdam, The Netherlands
`Dr. W. Hoefke and Dr.H. Stahle
`Department of Pharmacology and Department of Medicinal Chemistry, C. H. Boehringer Sohn, D-6507
`lngelheim/Rhein, West-Germany
`
`Content\
`
`.· '.-.,.
`I. Gnsnal._..
`1.1. lnll~r .. (
`PrnwtW · ~;-~1~
`1.2. Mn~ .it
`AnhhYJ4iiUw•
`Clonad.ftlr
`~ •
`1.3. S.:Of'C' ~ 4iin
`'T'f ••• • • •
`
`II. The(~
`StrU<1•..1y a,
`(Ar,.._._
`tt•"lnl oC ~
`2.1.
`2.2. Stnrtwn-: A#J'
`~nJ ~
`lmtJ.u...-..
`2.!.1. Au•ltt.W ~
`2.2.2. Rr.aJ.I~ ~
`Jurn. ~ ·-~'·
`
`Ill.
`
`CIP-Kurztitelaufnahme der Deutschen Bibliothek
`
`Structure-activity relationships in clonidine-like
`imidazolidines and related compounds
`P. B. M. W. M. Timmermans ... - Stuttgart,
`New York: Fischer, 1980.
`(Progress in pharmacology ; Vol. 3. No. 1)
`ISBN 3-437-10637-6 (Stuttgart)
`ISBN 0-89574-091-5 (New York)
`
`NE: Timmermans, P.B.M.W.M. [Mitarb.)
`
`Progress in Pharmacology ISSN 0340-465 X
`
`©Gustav Fischer Verlag · Stuttgart · New York · 1980
`Aile Rechte vorbehalten
`Gesamtherstellung: Vereinigte Druckereibetriebe Laupp & Gobel, Tubingen
`· Printed in Germany
`
`Ph, wc:ac-....u
`a~""
`Scftti
`and
`·~·
`
`3.1.
`3.2.
`
`lnuo.!u.;t_.
`l>monas.- (.
`\cftw
`o~nJ
`lm•J.u~
`3.2.1. pK'. \'.alw.t,:
`3.2.2. Curu·Lte.-.,;
`Su""munJG ' -
`3.3. l.J~.., ..
`ruull•· ft4-u..i l
`1.1.1. r .~rr.r~JG c-tl'
`3.\.2 Rclo~r•~ j
`o~nJ th~~
`.l.J.J l.tpurhol.,;Jil ~
`J.-1.
`~lok.;ul.tr
`jlf
`Suu,tutt' ,.- (J
`lnu.Lati~
`.l.-1.1. src.:~r.-."rc ~
`l.-1.1. Crnullo."CC.,...a..
`J.-I.J. Q~o~ntum (.~
`J.-1.-1. Cund..J•nc 11411
`
`-
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`---·
`
`~·:..··.:-~ ...
`• ,-=:-_-:._· - ..:-~-~~-z::.~~;::--
`
`- -.. ~-'t':::::"-:-•
`~~
`
`-
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`~~ :.--.. _.lr~._ •:-.;-:~-=. n;_-_ ..
`~---.:;--~ .. ~ .... .:~.;..;..==..-.
`
`-,
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`Structure-Activity Relationships in
`Clonidine-Like lmidazolidines and
`Related Compounds
`. . . . . . . .
`Introduction
`. . . . . . . .
`4.1.
`4.2. Structure-Activity
`Relationships
`with Respect
`to Cardiovascular
`Actions . . . . . . . . . . . . . .
`4.2.1. Hypotensive Activity
`4.2.2. Central Hypotensive Activity
`4.2.3. Anrihypertensive Activity
`.
`4.2.4. Bradycardic Activity
`·
`4.2.5. Hypertensive Activity . . . .
`4.3. Structure-Activity
`Relationships
`with Respect
`to Various Phar(cid:173)
`macological Actions
`and Side-
`Effects . • . . . . . . . . .
`4.3.1. Sedation
`. . . . . . . . . . . . .
`4.3.2. Adrenergic Activity at Rabbit Intes-
`tine . . . . . . . . . . . . . . . .
`4.3.3. Local Anaesthetic Activity
`4.3.4. Antisecretory Activity (Reduction of
`Gastric Acidity)
`. . . . . . . . . . 53
`4.3.5. Effects on Histamine H 2-Receptors 57
`4.3.6. Presynaptic Activity
`. .
`58
`4.3.7. Miscellaneous Actions
`60
`
`IV.
`
`Contents
`
`luidergracht 24,
`
`Sohn, D-6507
`
`I.
`1.1.
`
`1.2.
`
`1.3.
`
`. . . . . . .
`General Introduction
`Influence of Clonidine on Arterial
`Pressure . . . . . . . . . . . . . .
`Mechanism of
`the Hypotensive/
`Antihypertensive
`Activity
`of
`Clonidine . . . . . . . . . . . . .
`Scope and Aims of the Present Sur-
`vey . . . . . . . . . . . . . . . . .
`
`II.
`
`The Chemistry of Clonidine and
`Structurally Related Derivatives; 2-
`(Arylimino) imidazolidines ..
`..
`History of Development
`Synthetic Approach to Clonidine
`and
`Structurally
`Related
`..
`Imidazolidines
`. . . .
`. .
`...
`2.2.1. Available Methods
`2.2.2. Readily Applicable Synthetic Proce-
`. . . . . . .
`dures . ...
`
`2.1.
`2.2.
`
`l
`
`III.
`
`Physicochemical
`and Quantum
`Chemical Properties of Clonidine
`and
`Structurally
`Related
`. . .
`Imidazolidines ....
`. .
`Introduction .. . .
`3.1.
`3.2. Dissociation Constants of Clonidine
`and
`Structurally
`Related
`Imidazolidines
`. . . . . . . . • . .
`3.2.1. pK'. Values . . . . . . . . . . . .
`3.2.2. Correlations of pK'. with Electronic
`Substituent Constants
`3.3. Lipophilicity of Clonidine and Struc(cid:173)
`turally Related lmidazolidines
`3.3.1. Partition Coefficients
`. . . . . .
`3.3.2 Relationships Between Log P, ARM
`and Hydrophobicity Constants
`3.3.3 Lipophilicity and Brain Disposition
`3.4. Molecular
`and Conformational
`Structure of Clonidine and Related
`lmidazolidines
`. . . . . . . .
`•.
`.1.4.1. Spectroscopic Studies
`. . .
`'··L!. Crystallographic Studies
`.l.·Ll. Qua mum Chemical Studies
`.'.4.4. Concluding Remarks
`
`2
`
`3
`
`3
`3
`
`4
`4
`
`6
`
`8
`8
`
`8
`8
`
`10
`
`12
`12
`
`14
`15
`
`16
`16
`17
`18
`20
`
`21
`21
`
`22
`22
`41
`./
`43
`45/
`48
`
`5 0 /
`50
`
`52
`53 ,....r--'
`
`. . . . . .
`
`v.
`
`5.1.
`5.2.
`
`5.3.
`
`5.4
`
`5.5.
`
`Comparison Between Various Phar(cid:173)
`macological Actions of Clonidine
`and Related Compounds . . .
`Introduction
`. . . . . . . . . . .
`Hypotensive Activity Versus Seda(cid:173)
`tion and Antisecretory Activity
`Central Versus
`Peripheral
`Adrenergic Effects
`. . . . .
`Hypotensive Activity Versus Brady-
`cardic Potency
`. .
`Hypotensive Activity
`Animal Species
`
`in Various
`. .
`. .
`
`a-
`
`VI.
`
`6.1.
`
`Quantitative
`Relationships
`Imidazolidines
`Introduction
`
`Structure-Activity
`in Clonidine-Like
`
`62
`62
`
`62
`
`65
`
`69
`
`71
`
`73
`73
`
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`6.7. QSAR in Clonidine-like
`Imidazolidines at the Level of the
`. .
`Central a-Adrenoceptor
`6.8. The a-Adrenoceptor; Speculations
`Concerning its Properties
`6.8. I. Considerations about the Nature of
`the Peripheral, Vascular a-
`. •
`Adrenoceptor
`. . . .
`6.8.2. The Nature of
`the Central a(cid:173)
`Adrenoceptor; Mode of Interaction 85
`87
`6.9. Concluding Remarks
`
`8 I
`
`84
`
`84
`
`VII. Ackm>wledgements
`
`. . _ . . .
`
`VIII. References
`
`IX.
`
`Subject Index
`
`89
`
`89
`
`99
`
`VI
`
`· Contents
`
`6.2. Quantitative Approach to Structure(cid:173)
`Activity Relationship Studies; the
`. . . . . . . . . . . 73
`Hansch Model
`6.3. Parameters
`. . . . . . . . .
`74
`and
`6.4. QSAR
`in
`lmidazolidines
`lmidazolines with Respect
`to a(cid:173)
`Adrenergic Activity on Isolated Rab-
`bit Intestine
`. . . . . . . . . .
`6.5. QSAR in Clonidine-like
`to
`lmidazolidines with Respect
`Peripherally Mediated Hypertensive
`. . . . . . . . . . . . . . 76
`Activity
`6.6. QSAR in Clonidine-like
`lmidazolidines with Respect to the
`Centrally Mediated Hypotensive
`Intravenous
`Activity
`Following
`Administration to Rats and Rabbits 77
`
`75
`
`.,
`
`I. Gcner;
`
`lmidazoline
`irm·rcst of ph.a
`;uc mainly apr
`in practical n
`Well-known
`xylomet3Zolinc
`pounds, which
`dccongestanrs.
`applied in pra.~
`minantly a-s,
`therapeutic a.,
`porarily relie'
`rhinitis or COOl
`striction withrr
`dilatation in in
`histamine and ;
`dilators is thu'
`imidazoline der
`other vasocon
`The interest fu
`recei\·ed a nc'
`clonidine.
`Clonidine
`dazolidine) ,. ....
`aim to obtain .
`gestant. Clonu
`155. The nour
`Stahle, who '
`molecule and .
`imidazolidine •
`numbers as ,_,.,
`
`1.1. Inf1ucr
`Preuur
`
`In 1962 cion
`hcing pru,·en p:
`
`"!:
`
`r,.:. I: Eflc.:t ul
`.IO.IC\IhciUCJ "'''
`
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`~ .~~
`
`. '
`"4 . .' .
`
`' ...
`
`: ..
`
`,. .... ·
`
`·~' .·
`
`':
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`·-like
`the Level of the
`·ptor
`or; Speculations
`'erties
`•ut the Nature of
`~ular a-
`
`81
`
`84
`
`84
`
`the Central a-
`Je of Interaction 85
`:s ......... 87
`........ 89
`
`89
`
`99
`
`I. General Introduction
`
`Imidazoline derivatives have attracted the
`inrerest of pharmacologists and clinicians. They
`are mainly applied as sympathomimetic agents
`in practical medicine as decongestive drugs.
`Well-known
`examples
`are
`naphazoline,
`xylometazoline, tramazoline and other com(cid:173)
`pounds, which.are commercially available nasal
`imidazoline compounds
`decongestants. The
`applied in practical pharmacotherapy are predo(cid:173)
`minantly a-sympathomimetic agents. Their
`therapeutic activity is modest: they can tem(cid:173)
`porarily relieve the unpleasant symptoms of
`rhinitis or conjunctivitis, as a result of vasocon(cid:173)
`striction within the congested tissues. The vaso(cid:173)
`dilatation in inflamed tissues, brought about by
`histamine and probably other endogenous vaso(cid:173)
`dilators is thus diminished by topically applied
`imidazoline derivatives and theoretically also by
`other vasoconstrictor agents, like adrenaline.
`The interest for imidazoli(di)ne derivatives has
`received a new impetus by the discovery of
`doni dine.
`(2-(2,6-dichlorophenylimino)imi(cid:173)
`Clonidine
`dazolidine) was developed in the sixties with the
`aim to obtain an additional imidazoline decon(cid:173)
`gestant. Clonidine was initially known as St-
`155. The notation St is derived from the chemist
`Stahle, who was the first to synthesize this
`molecule and a considerable number of related
`imidazolidine derivatives withStand STH code
`numbers as well.
`
`1.1. Influence of Clonidine on Arterial
`Pressure
`
`In 1962 clonidine synthesized by Stahle, after
`being proven pharmacologically as nasal decon-
`
`gestant, was submitted as a 0.3 % solution to
`the medical department of C. H. Boehringer
`Sohn, lngelheim in order to test irs compatibility
`in man. Mrs. Schwandt, a member of the trial
`group, administered to herself 10- 15 drops
`(about 1 to 2 mg), instead of 2, since she had a
`cold. • What could happen to harmless nose ~­
`drops?• However, all sorts of things happened,
`for the dose amounted to about 10-fold of the
`therapeutic one applied at present. Strong seda(cid:173)
`tion, dryness of the mouth, bradycardia and
`hypotension were observed. These effects con(cid:173)
`tinued for more than 24 hours. After this very
`first experiment on that lady Dr. Martin Wolf, a
`physician and member of the trial group, rested
`the compound systematically himself and recog(cid:173)
`nized that the drug's decongestant properties
`were far less interesting than its potent hypoten(cid:173)
`sive activity (Wolf, 1962, personal communica(cid:173)
`tion).
`The influence of clonidine on arterial pressure
`is biphasic: both in animals and man clonidine
`causes an initial but transient rise in blood
`pressure, which is followed by a more prolonged
`and pronounced depressor phase (fig. 1). The
`initial pressor effect reflects vasoconstriction,
`brought about by the stimulation of peripheral
`a-adrenoceptors in the arterioles. This action is
`hardly unexpected in view of the imidazoline
`structure of the drug. The potent hypotensive
`and antihypertensive properties of clonidine,
`however, were rather surprising and prompted
`further investigations. A detailed analysis of its
`pharmacological effects has been presented by
`Hoefke and Kobinger (1966). Thereupon this
`compound has been introduced into clinical
`medicine for the treatment of arterial hyperten-
`
`mm Hg
`
`:::j~
`
`5 min
`
`0
`
`1 "'"'''"' 12pg/kg,l•.l
`
`Fig. 1: Effect of intravenous clonidine (2JJglkg) o~ arterial pressure and heart rate of a normotensive rat
`anaesthetized with pentobarbitone (75 mg/kg, i.p.). From Timmermans and van Zwieten (unpublished result).
`
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`2 · P. B. M. W. M. Timmermans, W. Hoefke, H. Stahle and P. A. van Zwieten
`
`sion. In various countries the drug was regis(cid:173)
`tered under the commercial names Catapresan®
`or Catapres®. In humans its effective dose can be
`as low as 75-150 1-'g per os daily.
`In the present review paper we shall not dis(cid:173)
`cuss the clinical advantages or disadvantages of
`clonidine compared with those of the various
`other antihypertensive agents, nor shall we deal
`with other applications of this drug. We only
`mention the possibility to apply clonidine in
`special cases of migraine without further discus(cid:173)
`sing this possibility.
`
`1.2. Mechanism of the Hypotensive/
`Antihypertensive Activity of
`Clonidine
`
`Soon after the discovery of the potent blood
`pressure
`lowering properties of clonidine,
`experimental arguments were presented
`in
`favour of a central hypotensive effect, at least in
`acute animal experiments. The mechanism of
`the acute, centrally-induced hypotensive effect
`of clonidine and
`related drugs has been
`described in full detail in review papers by the
`following authors: Schmitt, 1971, 1977; Ko(cid:173)
`binger, 1973, 1978; Stahle and Hoefke, 1975;
`van Zwieten, 1975a; Hoefke, 1976, 1980; Wal(cid:173)
`land, 1977. The general opinion concerning the
`central hypotensive effect of clonidine may be
`summarized by the following theory, which has
`received ample experimental evidence from vari(cid:173)
`ous groups: Clonidine is a relatively lipophilic
`··drug, which easily penetrates into the central
`nervous system, where it achieves a high con(cid:173)
`centration in the brain and the cerebrospinal
`fluid. In the ponto-medullary area a-adrenocep(cid:173)
`tors have been demonstrated to occur. These
`receptors are excited by clonidine, an a(cid:173)
`adrenoceptor stimulant drug. The a-receptor
`stimulation leads to an increased activity of
`hypothetical inhibitory neurons, probably the
`bulbospinal neurons, thus reducing the tone of
`the peripheral sympathetic nervous system.
`Consequently, arterial blood pressure and car(cid:173)
`diac frequency will diminish. The a-adrenocep(cid:173)
`tor stimulant activity of clonidine is blocked by
`a-sympatholytic drugs which can penetrate into
`the central nervous system. Accordingly, pipero(cid:173)
`xan and yohimbine (Schmitt et al., 1971, 1973)
`
`and also prazosin (Cavero and Roach, 1978;
`Timmermans et al., 1979a) interfere with the
`acute hypotensive effect of clonidine, probably
`by a competitive mechanism of interaction. This
`mechanism of clonidine proves to be a general
`principle which can be extended to its structur(cid:173)
`ally related derivatives. It may also hold true for
`the central hypotensive effect of a-methyl(cid:173)
`DOPA (review by van Zwieten, 1976).
`Most elegant studies in tetraplegic patients by
`Reid and coworkers (1977) have demonstrated
`unequivocally that the hypotensive mechanism
`of clonidine in man is also located within the
`·centra I nervous system.
`During the last few years the attention has
`been focused upon the considerable agonistic
`activity of clonidine at presynaptic a-adrenocep(cid:173)
`tors (for reviews on the basic principles see
`Langer, 1977; Starke et al., 1977, Westfall,
`1977)\ Most of the studies which have led to this
`view were carried out on isolated organ prepara(cid:173)
`tions. Attempts have been made to extrapolate
`these findings towar.ds a stimulation of central,
`presynaptic a-adrenoceptors by clonidine as an
`initiation of its central hypotensive effect. This
`hypothesis, however, is still subject to debate. A
`presynaptic nature of the receptive sites is
`favoured by the observations that clonidine
`diminishes the turnover of noradrenaline in the
`b~ain (Anden et al., 1970, 1976) and reduces the
`stimulation-induced release of neurotransmitter
`from brain slices (Farncbo. ~nd Hamberger,
`1971; Starke and Montel, 1973). Moreover, the
`central hypotensive effect of clonidine can be
`readily reduced by piperoxan and yohimbine, a(cid:173)
`sympatholytic drugs preferentially acting at pre(cid:173)
`synaptic a-adrenoccptors (Starke et al., 1975a;
`Borowski et al., 1976; Drew 1976; Doxey et al.,
`1977). On the contrary, some reports strongly
`suggest
`that
`the cardiovascular ·depressant
`action of clonidine is due to activation of cen(cid:173)
`tral, postsynaptic a-adrcnoceptors, or at least of
`a-adrenoceptors
`on
`non-catecholaminergic
`neurons, since the drug acts independently of
`storage
`and
`synthesis
`of
`endogenous
`catecholamines in the central nervous system
`(Haeusler, 1974; Kobinger and Pichler, 1976;
`Warnke and Hoefke, 1977)>in addition, prazo(cid:173)
`sin which preferably blocks postsynaptic a(cid:173)
`adrenoceptors (Cambridge et al., 1977; Doxey
`and Easingwood, 1978) has also been shown to
`
`'
`
`.I nl.lfotUOilr
`dumJult' ~ (
`m.an1 ct .al.,
`It h.a, h
`h~·potrnwu·
`I f:·hl\umu><
`U.JteJ 10 r.al\
`r o~l-1->u' (I fOC'
`domJ•ne hJ
`t.Jmlne H~·r•
`nunn, l~i'l
`Audi\IC'f tt •
`
`re\:epu~·r \llr
`an rhe h~·r"''
`.. "IOU\• rcn...ai
`I '1-:"h) o~nJ .!.
`unpubh\hc<l
`
`1.3. S'"'
`SuP
`
`llu\ re~ 1r
`rd.JIIOO\hlp'
`1 m1J.uuluim:
`rr'J'C'" to '~
`
`II. The
`· 2-(A
`
`Structure>
`'i1g. 11; hl..c
`ox~· mci.ILuil:
`h~·Jroxyphc::
`dlmt•thyl-4-r
`pounJ\ .1rt: '
`dccongnr.w:
`'tricwr dic-e
`h.wJ, toiJt•
`tol.umnt·
`; :\
`,I roln·pht•n\'!.
`.1 gents. The-.·
`111 wh11.:h th•:
`Into Jn inu.i.
`
`Page 14 of 116
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`

`

`·ero and Roach, 1978;
`79a) interfere with the
`of clonidine, probably
`1ism of interaction. This
`proves to be a general
`·xtended to its structur(cid:173)
`r may also hold true for
`-: effect of a-methyl(cid:173)
`: wieten, 1976).
`n tetraplegic patients by
`•77) have demonstrated
`1ypotensive mechanism
`1lso located within the
`
`:ears the attention has
`..:onsiderable agonistic
`esynaptic a-adrenocep(cid:173)
`;e basic principles see
`·r al., 1977, Westfall,
`·s which have led to this
`isolated organ prepara(cid:173)
`·n made to extrapolate
`stimulation of central,
`rors by clonidine as an
`ypotensive effect. This
`:ill subject to debate. A
`the receptive sites is
`:;Hions that clonidine
`If noradrenaline in the
`. 1976) and reduces the
`.se of neurotransmitter
`:cbo and Hamberger,
`, 1973). Moreover, the
`·t of clonidine can be
`-xan and yohimbine, a(cid:173)
`:rentially acting at pre-
`( Starke et al., 1975a;
`ew 1976; Doxey et al.,
`-;orne reports strongly
`avascular depressant
`: to activation of cen(cid:173)
`oceptors, or at least of
`10n-catecholaminergic
`:1cts independently of
`:s
`of
`endogenous
`·nrral nervous system
`a and Pichler, 1976;
`7). ~n addition, prazo(cid:173)
`•cks postsynaptic a(cid:173)
`·: et al., 1977; Doxey
`:1s also been shown to
`
`antagonize the central hypotensive effect of
`donidine (Cavero and Roach, 1978; Timmer(cid:173)
`mans et al., 1979a).
`It has been postulated
`the central
`that
`hypotensive effect of clonidine might involve
`Hrhistamine receptors in the brain as demons(cid:173)
`trated in rats (Karppanen et al., 1976, 1977) and
`rabbits (Hoefke, unpublished results). In fact,
`donidine has been reported to activate his(cid:173)
`tamine H 2-receptors (Karppanen and Wester(cid:173)
`mann, 1973; Csongrady and Kobinger, 1974;
`Audisier et al., 1976). However, H 2-histamine
`receptive sites could not be shown to play a role
`in the hypotensive response to clonidine in con(cid:173)
`scious, renal hypertensive cats (Finch and Hicks,
`1976) and dogs (Delbarre, Huchet and Schmitt,
`unpublished results).
`
`1.3. Scope and Aims of the Present
`Survey .
`
`This review will treat the srructure-activity
`relationships·
`(SAR)
`of
`clonidine-like
`imidazolidines and related compounds with
`respect to various cardiovascular actions. Apart
`
`SAR in Clonidine-like drugs · 3
`
`from the SAR concerning circularory effects
`attention will be paid to other pharmacological
`and physiological properties of clonidine and its
`analogues, like sedation, local anaesthetic acti\'(cid:173)
`ity, inhibition of gastric secretion, action on H 1-
`histamine receptors etc. It is the aim of the
`present review to obtain insight into the rela(cid:173)
`tionship between molecular structure and
`biological activity of imidazolidines and related
`molecules. In addition, attempts will be made to
`differentiate between the various pharmacologi(cid:173)
`cal actions within series of structurally related
`· imidazolidines.
`Several structural, physicochemical and quan(cid:173)
`tum chemical parameters will be described as
`well. These molecular properties have been used
`to generate quantitative
`relationships. The
`emphasis of the present survey will be laid upon
`the interaction between clonidine and its struc(cid:173)
`turally related imidazolidine compounds and the
`a-adrenoceprors within the central nervous sys(cid:173)
`tem. From quantitative SAR studies a certain
`the features of
`this central a(cid:173)
`picture: of
`adrenoceptor has emerged. Finally, speculations
`about new antihypertensive drugs, based upon
`the present knowledge of
`the central a(cid:173)
`adrenoceptor, will be submitted.
`
`II. The Che~istry of Clonidine and Structuraliy related Derivatives;
`'2-(Arylimi~o )imidazolidines
`
`2.1. History of Devel~pmen(
`
`Structures possessing an imidazoline moiety
`(fig. 2), like naphazoline (Ar = a-naphthyl),
`oxymetazoline (Ar = 2,6-dimethyl-4-t-butyl-5-
`hydroxyphenyl), xylometazoline (Ar = 2,6-
`dimethyl-4-t-butylphenyl) and similar com(cid:173)
`pounds are classical drugs and are used as nasal
`decongestants because of their local vasocon(cid:173)
`strictor effect (also see Chapter 1). On the other
`hand, tolazoline (Ar = phenyl) and phen(cid:173)
`tolamine (Ar = N-4-methylphenyl, N-3-hy(cid:173)
`Jroxyphenylamino) are known as a-adrenolytic
`agcnts.These molecules are substituted amidines
`·in which the amidine function is incorporated
`·into an imidai.oline ring. Additionally, this por-
`
`tion is connected with an aromatic nucleus via a
`methylene (-CH2-) bridge.
`
`Fig. 2: . General srructure o( the classical 2-(aryl(cid:173)
`methylene)imidazolines.
`
`The first fundamental alteration of this basic
`structure was reported by Najer et al. (1959.
`1960). They replaced the imidazolint; ring by .m
`oxazoline nucleus and the -Cf:-ll· rin~ jun.-tton
`
`Page 15 of 116
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`

`T~hlc- 1: Suo.-,.,.
`rc-~m•. trom ~.aJI·.
`
`4 · P. B. M. W. M. Timmermans, W. Hoefke, H. Stahle and P. A: van Zwieten
`
`by an -NH- group. This gave rise to the general
`structure depicted in fig. 3.
`
`Fig. 3: General structure of 2-(arylimino)(cid:173)
`oxazolidines.
`
`The compounds also exhibited strong va(cid:173)
`soconstrictor activity (Guidicelli et al., 1959).
`The same authors prepared a number of sub(cid:173)
`stituted 2-(phenylimino)imidazolidines (Najer et
`al., 1961), which are cyclic guanidine derivatives
`(fig. 4).
`
`General
`Fig. 4:
`imino)imidazolidines.
`
`structure
`
`of
`
`2-(aryl-
`
`These compounds, however, appeared less
`active than similar derivatives possessing a
`methylene bridge with respect to vasoconstrictor
`activity. At approximately the same time a
`patent application was filed by C. H. Boehringer
`for
`an
`(W. Germany)
`Sohn,
`Ingelheim
`imidazolidine with the code designation St-155
`(fig. 5).
`
`Fig. 5: Structural formula of clonidine (2-[2,6-dichlo(cid:173)
`rophenylimino]imidazolidine).
`
`St-155, later known as clonidine, was unique
`in having a double ortho-substitution by
`chlorine at the phenyl·ring.
`The more or less accidental discovery of
`
`,
`
`clonidine as a potent antihypertensive drug (see
`Chapter I) has led to the synthesis of a large
`number of derivatives, mainly at the research
`of
`C. H. Boehringer
`Sohn,
`laboratories
`lngelheim, by Stahle and his co-workers. In spite
`of this great number none of them has become a
`therapeutically useful antihypertensive drug
`more beneficial than clonidine itself (Graubner
`and Wolf, 1966).
`St-600
`(2-[2-methyl-5 -fluorophenylimino](cid:173)
`imidazolidine) seemed an exception in this
`is
`less active than
`respect. This substance
`clonidine, but acts longer and probably posses(cid:173)
`ses a more favourable ratio between antihyper(cid:173)
`tensive efficacy and side effects (Stahle, 1974;
`Hoefke et al., 1975; Kho et al., 1975).
`Compounds more or less related to the funda(cid:173)
`structure of clonidine have been
`mental
`developed more recently by several companies.
`The most important of them have been sum(cid:173)
`marized in table 1. Some of these hypotensive
`agents have been subjected to detailed phar(cid:173)
`macological studies (cfr. Stahle, 1974; van
`Zwieten, 1975a; Schlittler, 1977). In spite of a
`considerable research e.ffort none of these com(cid:173)
`pounds has as yet been iittroduced into clinical
`medicine. Many of these structures will be
`treated separately in the course of this review.
`
`2.2. Synthetic Approach to Clonidine
`and Structurally Related
`Imidazolidines
`
`2.2.1. Available Methods
`
`A study of the literature concerning the avail(cid:173)
`able synthetic routes leading to imidazolidines
`of the clonidine-type reveals that, apart from
`some remarks in current journals (see section
`11.1.) one is completely at the mercy of industrial
`patents. After the discovery of clonidine it was
`solely industrial research that gave the impulse
`to the development of the synthetic methods and
`the optimization of the reaction conditions, so
`that many derivatives became available for
`pharmacological screening. The most important
`preparative pathways to the title compounds
`have been reviewed recently (Timmermans,
`1976). Upon closer examination of these synthe(cid:173)
`tic methods a division into two general classes
`can be made.
`
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`

`.1crrensive drug (see
`ynthesis of a large
`o1ly at the research
`ioehringer
`Sohn,
`-:o-workers. In spite
`them has become a
`hypertensive drug
`ne itself (Graubner
`
`luorophenylimino](cid:173)
`exception in this
`than
`less active
`td probably posses(cid:173)
`between antihyper(cid:173)
`::cts (Stahle, 1974;
`31., 1975).
`elated to the funda(cid:173)
`tidine have been
`several companies.
`m have been sum(cid:173)
`f these hypotensive
`to detailed phar(cid:173)
`.::;rahle, 1974; van
`I 977). In spite of a
`:1one of these com(cid:173)
`,duced into clinical
`structures will be
`rse of this review.
`
`h to Clonidine
`.elated
`
`mcerning the avail(cid:173)
`~ to imidazolidines
`~ that, apart from
`urnals (see section
`mercy of industrial
`of clonidine it was
`;r gave the impulse
`rhetic methods and
`rion conditions, so
`1me available for
`"he most important
`:: title compounds
`tly (Timmermans,
`ton of these synthe(cid:173)
`wo general classes
`
`r.thl.: I: Survey of hypotensive agents structurally more or less related to clonidine developed by several researc