Journal of Medicinal and Pharmaceutical Chemistry VOL. I, NO. 1 (1969)
Review
Hypotensive Hydrazinophthalazines and Related Compounds J. DRUEY and A. MARXER C I B A Research Laboratories, Basle, Suiitzerland
Introduction The medicinal treatment of high blood pressure is one of the more recent achievements of medicinal-chemical research. Many symptoms of the widespread disease of hypertension have been recognized since ancient times; but it was not until a scientific method of the measurement of blood pressure in humans was devised, Le. a ' bloodless ' procedure widely applicable in clinical practice, that they could be objectively portrayed. Such a method was developed towards the end of the last century; thereafter the first experiments for lowering abnormally elevated blood pressure were undertaken. From those early days of medicinal therapy of hypertension the use of thiocyanates, for example, has lasted up to the present day.l For many years such efforts met with little success, and even as recently as ten years ago specialists in the field were still highly pessimistic regarding this subject. Typical of the situation is the fact that in his excellent book Medicinal Chemistry,2 published in 1951, BURGERdevotes a total of only eight lines to the subject of hypertension. I n the eight years that have since elapsed a great change has occurred. Among the first products contributing to this revolution was 1-hydrazinophthalazine (hydralazine"), being the first medicinal compound to contain a hydrazino group and the first representative of a ring system which has never been used before medicinally. Numerous studies deriving from this structural principle have
* Apresoline 1
1
@
2
J. DRUEY AND A. MARXER
been undertaken in our laboratories since 1945, and it is with these that the present review is concerned. Sympathicolytic drugs for the medicinal therapy of hypertension were of course in use before, but the reduction in blood pressure effected by them was generally of too short a duration. I n the middle of the 1940s, too, came the discovery of another class of products that were to prove successful clinically as antihypertensives, i.e. the ganglionic blocking agents. A large number of them, differing chemically from one another, have since been introduced into therapy ; for example, hexamethonium, azamethonium", pentoliniumt, trimethaphanel, chlorisondamine 0,mecamylaminel/, and perolysen"". A drug that was to meet with considerably wider clinical use in the treatment of high blood pressure was reserpine, introduced about two years after hydralazine. It was not able, however, to displace the phthalazines ; and the combination o i both (reserpine and hydralazinett) represents a t present one of the best available remedies. The newest class of medicaments for treatment of hypertension is derived from diuretically active cyclic sulfonamides, i.e. clilorothiazide$$ and the ten times more active hydro-chlorothiazide $9. This new class seems to afford another starting point for yet wider research. Research in the class of hydralazine has been rather broad, too, but this type of structure so far remains unique. It exhibits certain peculiarities in its action as compared with other hypotensive agents, which are shared by few compounds only, such as the very closely related dihydrazinophthalazine (dihydralazinelill) and a few others. Dihydralazine has become especially well known in Europe, The following summary on 'chemical constitution and biological activity', dealing as it does with over 250 modifications of the hydralazine molecule prepared by us, should therefore be of interest. It should be mentioned a t the outset that the number of compounds that have progressed as far as a clinical trial has hardly reached half a dozen.
* Pendiomide 8 Ecolid @.
@.
t Ansolyseii@ . /I InversinB).
tt Serpasil @ and Apresoline @, Adelphan @
$5 Esidrix @.
1111 Nepresol @.
:I Arfonad @.
** Pempidin @. $ 3 Diuril @.
HYPOTEKSIVE HYDRAZINOPHTHALAZIKES
3
Hydralazine and its long-lasting hypotensive action was first reported by OUF laboratories in 1950.32 The preparation of the hydrazinophthalazines and of a few derivatives and related compounds was described by DRUEYand RINGIER.5 A brief summary on the constitution and activity of this group was given by DRUEYin April 1955 a t a meeting of the American Chemical Society in Cincinnati. The mode of action of these compounds has been discussed by many workers (cf.", l8). There is evidence for a central attack,6,'i, 8, 9,l o as well as for one of a peripheral nature.6,l o , 11, l8 The increase in renal blood flow has also been emphasized in detailed st~idies.~,12, 13, l 4 The experiments of both MEIER et a l . 1 5 and WEHRLEet aL16 indicate that the hypotensive hydrazines also possess considerable activity as inhibitors of certain enzymes such as amine oxidase and histaminase. The parallelism between these two activities appears to be significant. Antagonism to epinephrine and norepinephrine has also been demonstrated.6, 7 , 10, 17, 1 8 The hypotensive hydrazinophthalazines are also capable of diminishing the lipaemia of experimentally hyperlipaemic rats, thus acting as lipaemia clearing substances. Hydralazine and dihydralazine exhibit a strong tendency to form metal complexes, or rather chelates, particularly with iron. It is not yet possible to say with certainty whether the especially characteristic ferrous or cobaltous chelates have any connection with the hypotensive properties, a clear-cut parallel between the complex-forming tendency and hypotensive activity not having and E R L E N N E Y E R ~have ~ been traced in every case, as FALLAB reported. To avoid confusion, the present survey of the compounds has been set up according to a chemical classification. The hydrazinophthalazines and hydrazinopyridazines with various substituents will be discussed first (Tables I-111), then the hydrazino derivatives of other heterocycles (Table IV), and finally the replacement of the hydrazino group by other radicals, and openring structures. I n reviewing the results, we were faced with the problem of characterizing more than 250 compounds in as simple a manner as possible without entering into pharmacological details. We 99
4
J. DRUEY AND A. MARXER
have chosen three simple signs to indicate the effect on blood pressure. Thus, compounds comparable to the typical longlasting hypotensive type of hydralazine are entered in the Tables with a + sign; 5 indicates preparations with a definite blood pressure lowering effect, but evidently of a different type, be it of short duration or low intensity; 0 means little or no activity. The blood pressure activity which is discussed in this manner is based on the measurement of the lowering action of a drug on the carotid pressure of the urethan-anaesthetized rabbit. 1. Substituted Hydrazinophthalazines and Pyridazines (Tables 1-111)
Of the hydrazinophthalazines substituted in one of the two rings, a few compounds besides hydralazine and dihydralazine (Table I, 1 and 12) showed good hypotensive activity, for instance those with lower alkyl substituents in the 4-position (Table I, 2 and 3), and to a lesser extent the 4-benzyl compound (Table I, 9.) The pharmacological properties of the two pyridylniethyl derivatives (Table I, 14 and 15) must be especially mentioned, the activity in these cases equalling that of hydralazine and being worthwhile for further studies. The synthesis of these phthalazino derivatives follows the which ~ methods already described by DRUEYand R I N ~ I E R consist in the preparation of phthalazones or phthalazdiones, some of which were already known, chlorination with phosphorus oxychloride, and reaction with hydrazine hydrate in alcoholic solution. The synthesis of the pyridylmethylphthalazones required the development of further methods. Condensation of y-picoline and phthalic anhydride gave y-pyrophthalone, to which the formula of a picolylidenephthalide (I) has recently been ascribed,20 but which is referred to in older papers as a 2-pyridylindan-l,3-dione (II).21Formula I1 seemed to us more probable*. While benzalphthalide may easily be converted with alcoholic hydrazine solution to 4-benzylphthala~one,~~ a red hydrazine salt is isolated under the same conditions from y-pyrophthalone. Only on
* Since having writteii this review the paper of confirming our view.
hIANLY
et aLZ6has appeared
HYPOTEKSIVE H Y U K A Z I N O P H T H A L ~ ~ Z I ~ E S Table I. Phthalazines and pyridazines with substituents in the heterocyclic ring
K
/\/a,
1
i),AKHX'H, K
so.
1
31.13.""
H (hydralazine)
HCI TIC1
17 3-1 75 271 dec. 285 doc. 208 185 193 290-291
HC1
173-1 75 155 dec.
HC1 HCl HCl
7
i
3 4 1
li
7
S
HCI 9
-CH,C,H, HCl
10
-OH
I1 12
-CI --SHSH, (dihydralamne)
13
-CH ,CONHNH
14
HC1 HC1
Hypoteiisi\.c activity
203 170 145-146 148 dec. 240 dec. 260 dec.
foaming from 200
180 2 HC1 2 5 3 dec H,SO, 253 dec.
265 H,SO, 220 (foaming) 181; 207 doc-. 245 (second
melting) 2 H C I 283-285 15
I!HCl 230-232 doc.
* If not otherwise indicated, thc melting point of the free base is given; HCl nieaning hydrochloride, 2 HCl siinilarlp stands for dihydrochloride, H,SO, for sulphate salt e t c . ; the melting points are not corrected.
J . DRUEY AND A. XARXER
G
16
J1.p."
1:
NO.
--CH,
HC1 15 18
---CH,CH=CH, -CH,C,H, HC1
19
-CHgCH,N(C,H,)
20
-/.
0
H,
SO.
21 22
\-Cl
CH *
-C,H,
R4
R,
H
H
H
33
-.
202-204
0
I\I.p."
-
7-
0
Hypotensive activity
75 221-222
HC1
144 231-233 170-172 202 dec.
i
HC1 H
HC1
201 dec.
i
HC1
218 dec.
i
162-163
f
H
-cy1
H
H
26
- C ) -OCH3
H
H
I
__
A-
HC1
25
OCH,
-
230 240-242 64-65 200-202 220 dec. 144-145
H
24
Hypotensive activity
zk
+
HYPOTENSIVE HYDRAZINOPHTHALAZlNER
R9
NO.
R,
R.5
J1.p."
7
Hypotensive activity
H
HCl
230-232
+
28
H
HCI
205
i
29
H
HCl
229-531
i
H --Ce.H,
€IC1 HCl
240-241 133 135-140 dec. 163 168-169
i
HC1
126
rt:
27
Cl
30
---C6H6
31
-C,H,
32 33
34 35
36 37
38
-fi--OCH,
\=/
- C,H,
-C&
H H
-C,H;
13
CH,O HCI H HC1 H HSO, CH, HCI CH3 H,SO,
220-221 214-217 191-192 doc. 216-220 dec. 197-198 248 deo.
+ +
Z t
-i-
-c
+ 0
heating with excess hydrazine hydrate without solvent is a good yield of 4-(y-picoly1)-plzthalazone (111)obtained. The preparation of the a-picolyl compound follows an analogous course. This seems to suggest that the more stable indandione ring (11)is split only under more energetic conditions, the phthalide (I) reacting much more easily. Purther transformation through the 1-chloro compound to l-hydrazino-4-(~-picolyl)phthalazine takes place in a manner similar t o that described previously. The 1-hydrazino-4-phthalazoneswith substituents on the phthalazine nitrogen (Table I, 16-20) showed lower or no hypotensive activity.
J. DRUEY AKD A. MARXER
8
0 I1
11 0
ii I
111
Parallel with the search for more active compounds in the phthalazine series, we turned to the pyridazines, also intensively studied in our l a b o r a t o r i e ~in ,~~ the hope of discovering analogies. A few active structures were indeed found, particularly in the phenyl-substituted series. 6-Hydrazino-3-phenylpyridazine (Table I, 2 2 ) , for example, exhibited strong hypotensive properties. It was surpassed by substances containing two phenyl residues, especially by 6-hydrazino-3,4-diphenylpyridazine (Table I, 30), followed by 6-hydrazino-3,6-diphenylpyridazine (Table I, 31) which acted somewhat more weakly. The compound given in Table I, 30, proved to be cllnically valuable, the blood pressure lowering effect being of the same type as that of hydralazine but somewhat less effeLt'ive. While the 6-hydrazino-3-methyl derivative (Table I, 2 1) was of weaker activity than the similarly constructed member of the phthalazine series, the dihydralazine analogue, Table I, 35, exhibited marked hypotensive properties. The complete inactivity of 4-hydrazinopyridazine, Table I, 38, is notable, as is the diminution in activity on substitution of the phenyl ring in Table I, 23-26. By contrast, there is an increase in activity on going from the monochloro- to the dichlorophenyl substituent (Table I, 2 7 ) , the latter attaining once again the intensity of compound 2 2 in Table 1. The preparation of the diphenylpyridazones, for which a new approach was adopted, has been reported,24 and the methylated pyridazones have also been the subject of a c ~ m m u n i c a t i o n . ~ ~ The new method consists in reacting a-diketones with hydrazine and 13-dioxo compounds. Thus 30 in Table I, for instance, is obtained by condensation of benzil monohydrazone (IV) and diethyl malonate in the presence of sodium ethoxide to the ester V, and subsequent hydrolysis and decarboxylation to VI. 1
IIYPOTEKSIVE H Y D X A Z I N O P H T H A L B Z I N E S
Further transformation of the pyridazone to the hydrazinopyridazine follows by a method analogous to that described for similar cases.5 None of the substituents in the benzenoid ring of the phthalazine examined enhance the activity of the unsubstituted substance (Table 11); among the compounds tested, mention should be made Table 11. Phthalazines with substituents in the aromatic ring RI
NHNH,
R,
NO.
1 2 3 4
H H H H
5
-CH2
R 7-OH i-OCH, 6-C1 7-C1
j-'N \=/
31.p."
HC1 HC1 HC1 HC1
307 243 275 230
dec. dec. dec. dec.
6- or 7-XHCOCH, 142-144 deo. 2 HC1 264-266 dec.
Hypotensive activity I
+ -t __ -
.-
of 7-methoxy- 1-hydrazinophthalazine (Table 11, 2) and its 6-chloro analogue (Table 11, 3). The fall in intensity to the 7-chloro substituent (Table 11, 4) is noteworthy. A few interesting conclusions may be drawn from the coinpounds in Table 111. All hydrazinophtlialazines substituted in
J . DRUEY AND A. NARXER
10
the hydrazino group by alkyl or aryl substituents (Table 111, 18-31 ) were practically inactive as hypotensives ; the hydrazones of hydralazine i.e. the alkylidene derivatives (Table 111, 2-9) are effective. The lack of activity of the reduced compounds, e.g. 30 and 31 in Table IJI, allows the conclusion that the high activity of the hydrazones mentioned is due to their cleavage to hydralazine in the organism, while this possibility does not exist in the case of the alkylhydrazinophthalazines. Paradoxically. however, diisopropylidene-dihydralazine (Table 111, 14), that Table 111. Hgdrazinophthalazines and -pyridazines with substituents in the hydrazino group It
I
R,
J1.p."
Hypoteiisivo activity
So.
K
1
H
2
CH,
CH,
114
CH, CH,
C,H, C,H,,
iG-77
5
H H H H
84
6
H
C,H,
C,"
177-178
7
H H
C,H, CH, cycZoPentyliden
146-146
8 9
H
cycZoHexyliden
87-88
+ + + + + + + + +
10
€1
CH,
COOH
1 i9-180 dec.
j,
11
H
13
-(CHOH),CH,OH (Glucose)
amorphous
I
12
H
H
-(CHOH),CH,OH (Galactose)
amorphous
-
13
c1
CH,
CI-I,
117-118
i
3
4
11,
H CH,
H
11G
H
147
113-114
HYPOTENSIVE HYDRAZINOPHTHALAZINES
11
dk 'Ra
I
NHN=C
/Kl \
'R', so.
RZ
J1.p."
Hypotensive activity
14 16
-CH3 --C",
-CH, -COOH
96-97 dec. 227-228 dec.
rt i
16
-H
O S ( C H , ) ,
226-269 dec.
. L 1 .
J i
-H
310
J. DRUEY AXD A. MARXER
RI.p.0 25
-C6H5
H
26
HCI
146-147 195 dec.
HCl
235-237
27
H
-c6H6
192-194
28
H
-41
216-2 18
29
-c6H6
-c6H5
1i
HCl 30
o
183 108-109
31
75-76
32
152-153
(34%
33
NHNH,
I
34
Hypotensive activity
C6H6
I
188 dec. H,S04 201 dec.
HCl
259-264
+
i
HYPOTENSIVE HYDRAZINOPHTHALAZINES
35
Hypotensive activity
Formula
NO.
17
N h
216
0
zinoisoquinoline (Table IV, 5 ) was sufficiently active in the animal to warrant clinical studies. It proved to be active in humans but did not show any advantage over hydralazine. I n the isoquinoline series also, further substitution led t o a weakening or loss of the activity (Table IV, 6-8). Our survey of all the other heterocycles listed above coiifirms the high structural specificity of the earlier hypotensive members of these series. Only 1,4-dihydrazin0-8-azaphthalazine (Table IV, 33), with a structure similar to dihydralazine, and a triazine (Table IV, 25) were active. All other compounds from the wide range of heterocycles chosen were found to be devoid of any hypotensive action including 27 and 29, Table IV, the analogues of the valuable pyridazines 22 and 30 in Table I. Some conclusions can be drawn regarding correlation between constitution and activity. Hypotensive properties seem to be connected with six-membered rings possessing the sequence
NH-NH,
I n the active compounds which have been discussed so far, this structural feature can appear in the form of various heterocyclic rings, e.g.
NHNH
NHNH,
NHNH
NHNH,
18
J . DRUEP AND A. MARXER
The only exception to this rule is 1-hydrazinoisoquinoline (Table IV, 5 ) , but the inactivity of 4-hydrazinoquinazoline (Table IV, 15) conforms to the rules. Based on these empirically found conditions which seem to be necessary although not sufficient for activity, mme of the properties mentioned before can be predicted, e.g. the inactivity of 2-hydrazinoquinoline (Table IV, 2), 4-hydrazinopyridazine (Table I, 38) and 4-hydrazinocinnoline (Table IV, 14). 3. Aryl and Aralkyl Hydrazines
The aryl and aralkyl hydrazines are only mentioned here briefly, since the phenyl and benzylhydrazines, carefully examined during our early work, showed no effective hypotensive action; it is tempting to regard this as a verification of the hypothesis just advanced. 4. Replacement of the Hydrazino Group by other Radicals and
Open Structures
It seemed attractive to exchange the hydrazino group for the greatest possible number of other basic groups. To avoid including tables containing predominantly negative evidence, the groups examined will be summarized briefly. I n the phthalazine series they include the following basic groups: amino, monoor dialkylamino, piperidino, morpholino, piperazino, aminoethylamino, dialkylaminoalkylamino, heterocyclic aminoalkylamino, hydroxyethylamino, and aminomethyl groups. A few of these compounds showed blood pressure lowering properties, even pronouncedly so, but in no instance was the long-lasting type of hydralazine encountered. I n the same way, inany experiments were also undertaken with other heterocycles. Eight phthalazines having a sulphur-containing side chain in place of the hydrazino group were tested. Only one of these, 1-mercaptophthalazine (VII), was found to possess hypotensive
HYPOTEXSIVE HPDliAZINOPHTHALXZIKES
19
activity a t high doses. 1-Mercaptoisoquinoline was inactive, in contrast to the similarity of action between I -hydrazinoisoquinoline and hydralazine. Another sulphur-containing compound, 1,3-dimethyl-6-thiono1,B-dihydropyridaziiie (VIII),exhibited interesting blood pressure
lowering properties. Clinical trials with this conipouiid, however, proved disappointing. 1-Phenyl or 3-methoxy analogues of VI11 were without activity. It remains to be mentioned that ainidines or hydrazidines having the hetero-ring of the phthalazine opened. i.e. compounds ' with the skeleton IX, showed no promise for further study.
I
NHNH,
IX Summary. The search for hypotensive substances led to the development of hydrazino derivatives in the phthalazine series. Among the earliest substances found to be active were 1-hydrazinophthalazine and 1,4-dihydrazinophthalazine. I n order to elucidate the connection between constitution and activity more than 250 analogues were synthesized and evaluated pharmacologically. The results of these studies, listed partly in tabular form, are discussed in detail. Few compounds attained the activity of the two compounds mentioned, so that a high structiiral specificity is evident.
Acknowledgement. The authors wish t o acknowledge the contribution of substances to the project reviewed, by Drs. K. Eichenberger, A. Huni, E. F. Jenny, Kd. Meier, B. H. Ringie~-,~ and P. Schmidt. 2 4 * 2 5 It is also a pleasure t o thank Drs. F. Gross, H. J. Bein, J. Tripod, and W. Schuler of
20
J. DRUEY AND A. MARXER
our Biological Department, Direction, Professor R . Meier, for pharmacological data, and Drs. A. F. Thomas and E . F. Jenny for the translation of this article.
(Revised M S . reccived 8 September, 1958.)
References
E
9
lo
l1 12
l3 l4
l5
l7
lQ 2"
21
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HPPOTEX3IVE HYDRAZINOPHTHALAZINES
Chem. Ber., 25, 705 (1893)
22
GABRIEL,S. and NEUMANN, A.
23
Cf.,e.g., DRUEY,J. Angew. Chem., 70, 5
24 25
21
(1958) SCHMIDT, P. and DRUEY,J. Helv. chim.acta, 37, 134 (1954) SCHMIDT, P. and DRUEY,J. Helv. chim.acta, 37, 1467 (1954) SfANLY, D. G., RICHARDSOX, A . J R . , STOCK,A. Af., TILBORD, C. H. and AMSTUTZ, E. D. J. org. Chem. 23, 373 (1958)
