Imidazole Derivatives with Sympathomimetic Activity

the circulatory system. Within this group there are quite a number of substances which cause a marked rise in blood pressure, even in very high diluti...
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IMIDAZOLE DERIVATIVES WITH SYMPATHOMIMETIC ACTIVITY C . R. SCHOLZ Ciba Pharmaceutical Products, Inc., Summit, N.J.

-a number of natural products from either plants or animals, which contain the imidazole ring-for instance, the alkaloids pilocarpine and pilosine, or histidine and histamineshow definite pharmacological activity. For this reason quite a number of synthetic imidazole and imidazoline derivatives were tested pharmacologically, and it was found that compounds containing the imidazoline ring and substituted in position 2 by either alkyl, aryl, or aralkyl, have a definite influence o n the circulatory system. Within this group there are quite a number of substances which cause a marked rise in blood pressure, even in very high dilutions. These substances, upon local application, cause constriction of peripheral vessels for an unusually prolonged period of time, and this specific property offers unique advantages as vasoconstrictors. A tentative correlation of the pharmacological activity and for the chemical constitution of the imidazoline series is given.

ATURE has produced a number of compounds having the imidazole ring as part of their structure; some of them possess a strong and specific pharmacological action. A few examples follow: Histidine belongs to the group of essential amino acids. Histamine, the decarboxylation product of histidine, plays a n important although not yet completely elucidated role in the animal organism. The betaine of histidine, hercynine, is found in a variety of fungi, Several alkaloids, as for instance pilocarpine, isopilocarpine, pilocarpidine, pilosine, pilosinine, etc., also contain the imidazole nucleus. All compounds mentioned so far are imidazole derivatives having substituents or side chains on the various atoms of the imidazole ring as such. The topic of this report concerns another class of derivatives, characterized by the partially reduced imidazole nucleus, and a summary will be presented of compounds containing the 3,4-dihydroimidazole or imidazoline ring which are substituted in the 2-position. The literature reveals that substances of this type were synthesized for the first time by Hofmann in 1888 (6). H e prepared the 2-methylimidaeoline, also called “lysidine”. A few years later Forssel (Z?) synthesized the first aryl derivative of imidazoline. Since that time many 2-substituted imidazolines have been prepared and put to use for a large variety of purposes-for example, as vulcanizers and accelerators in general, as wetti’ng, emulsifying, and cleansing agents, and also in the dye industry. It might be of interest to mention at least some of the methods used in the synthesis of such 2-substituted imidazoline derivatives. According to Hartmann and Panizzon (4) partial reduction of imidazole or its derivatives is not possible. Therefore, the imidazoline ring has to be built up from ethylenediamine; for example, a diamide, such as the diacetamide, can be condensed to form the 2-methylimidazoline:

N

CeHb-CS-NHz

>-CH3

+

280” c .

CHz---NH

A similar result is obtained if the monoacetamide of ethylenediamine is heated with calcium oxide. Equation 3, where a mixture of the ethylenediamine hydrochloride and its diamide is condensed by heat, works on the same principle. With this method higher yields are obtained. Reaction 4 is also similar but has the advantage over 3 that the intermediate diamide need not be prepared specially; one can just mix the ethylenediamine with the respective acid and then carry out the condensation by heating the mixture. The condensation of ethylenediamine with thiobenzamide is illustrated in Equation 5 , although it is of less general interest, whereas the reaction between imino ethers and ethylenediamine is in common use (Equation 6). The imidazolines which have been found to have a certain pharmacological action are derivatives substituted in the 2position by alkyl, aralkyl, and aryl groups. 2-ALKYLATED IMIDAZOLINES

Of the alkylated imidazolines, the 2-methylimidazoline has already been mentioned. Ladenburg stated in 1894 ( 7 ) that, when he injected 0.45 gram of 2-methylimidazoline carbonate into a rabbit, no visual effect was observed, but when it was injected into a human, diagnosed to suffer from “chronic gout”, the patient is said to have been cured rapidly; no details are given on this finding.

CH~-CO-NH-CH~-CH~--NH-CO-CH~~ CHz-X”

I

1 mol lauric acid

(1)

CR2--N 120

P e h a q , 1945

INDUSTRIAL AND ENGINEERING CHEMISTRY

A year bter Klingenstein (6) published the synthesis of 2ethyl- a.4 Zn-propylimidazoline, but no data on pharmaemlogid e x p ~ r n e n t are s given. The. avaihble literature speaks of no further work on this type of c o r n p o d s until 1935, when a paper by Chitwood and Reid appeared ( 1 1. They prepared eleven alkylated 2-imidazolines b y condensing the emresponding ethylenediamides a t a higher temperature (270" C.) in the presence of magnesium or sodium mekd, the dkyl radical of which contained from one to eleven carbon atoms in a straight chain. Only the first five members of this series--i.e., up to and including the amylirnidazoline-were studied pharmacologically by Macht ( 1 ) . Half a gram per kilogram of any one of these five compounds, given via the stomach, was not toxic for rabbits and did not impair their kidney func&ions. Only the methyl derivative increased the acidity of the urine, a n observation which might have some bearing on Ladenburg's finding in human gout. The toxicity was also studied, and t h e author makes a special point of the finding that, contrary to che usual pharmacological experience, the toxicity decreases instead of increases with the chain length of the alkyl radical. I n contrast to this statement, however, are the experimental results obtained by the late Fjitz Uhlmann in Ciba's laboratories at Bask, Switzerland, published by Hartmann and Isler in 1939 ( 3 ) . Uhlmann studied the same compounds as Macht, and in addition the isobutyl-, isopentyl-, n-hexyl-, n-heptyl-, and az-octylimidazolines, and he found that the toxicity increases rather than decreases with the lengthening of the side chain. T h e pharmacologists have offered no explanation for these divergent findings; thus, I can present only the facts. A similar increase in toxicity was found when these substances were tested on the isolated frog heart. Here, the longer the side chain, the smaller was the minimal dose which produced standstill in dimtolic position.

121

These alkylated imidazolines all dilate peripheral vessels and thereby decrease the blood pressure. Their action, however, is very weak and can be demonstrated only with a comparatively high minimal dose of 10 mg. per kg.

The two cycloalkylimidazolines studied, 2-cyclohexylmethylirnidazoline (formula 8) and 2-cyclohexenylmethylimidazoline (formula 9) are somewhat less toxic than the corresponding alkyl derivative with the same number of carbon atoms. The vasodilator activity is about the same in magnitude as is that of the alkyl derivative, but the partially dehydrogenated compound is somewhat more active than the cyclohexyl derivative. The influence of unsaturation on activity is remarkable when the cyclohexenyl ring is replaced by the phenyl radical, as in 2-benzylimidazoline (formula 10); the minimal dose is 0.1 mg. per kg. or 100 times less than for the alkylated imidazolines. 2-ARALKYLATED IMIDAZOLINES

This group of derivatives is of much greater interest pharmacologically. Before discussing the various compounds within this group, attention should be called to a structural similarity

Reaction Kettles Used in Production of Privine (a-Naphthyl-2-methylimidazoline) in Ciba Laboratories

I N D U S T R I A L A N D E N G I N E E R I N G CHEMISTRY

122

between these compounds and the naturally occurring substances which influence the blood vessels:

Vol. 37, No. 2

If the imidazoline ring is substituted on the nitrogen atom-for instance, in 1-methyl-2-benzylimidazoline (16) or in ethyleneI,l-bis-2-benzylimidazoline(17), the action on the circulatory system is reversed as compared to the 2-benzylimidazoline (15). Compound 17 is interesting because of its contradictory blood pressure effect; Le., given in small doses, it raises the blood pressure considerably (+6), whereas in larger doses it causes a slight fall. The third compound studied in this group was 2benzylhexahydrobenzimidazoline (18) which has the substitution on the 4,5-carbon atom. This compound was found to be a weak dilator, and therefore it seems that substitution on the oarbon atoms in the imidazoline ring does not change the type of action but varies only the degree. CHANGES I N CARBON BRIDGE BETWEEN RINGS

Histamine (ll),ephedrine (12), and epinephrine (13) all have the ethylamine group in common, which seems to be one of the factors responsible for their action on the circulatory system. This same grouping is present in the structure of 2-benzylimidazoline (14) if we visualize the imidazoline ring split by the broken line. This, of course, is purely paper chemistry; nevertheless, it seems to warrant consideration in synthetic work because this observation has been confirmed to some extent by experimental findings on substances of this type. To compare the vascular qualities of the compounds to be discussed, we use the reciprocal value of the minimal effective dose (gram per kilogram) as a unit of measure. If the experimental findings are presented in this way, the value for activity increases when the minimal dose decreases. Furthermore, to operate more conveniently with small figures, Hartmann and Isler proposed to present this value as the logarithm. The activity thus is expressed by the term,

The next five compounds may be classified under subgroup H . One ethyl group was added in one instance, two ethyl radical’s in the next, and in the third, one hydrogen atom was substituted by an allyl group, producing 2-(a-phenyl-7~-propyl)-imidazoline (19), the 2- [a,a,a-(phenyldiethy1)-methyl]-imidazoline(20), and the 2-(a-phenylbuteny1)-imidazoline(31) :

ik

kH

BC/

I S

1 log min. effective dose

I

\c/

NH

I

and the figures so obtained are designated with “plus” if the substance is essentially hypertensive and with “minus” if the substance is essentially hypotensive. Calculated in this way, the activity for the 2-benzylimidazoline previously mentioned would be -5, which is comparatively high. The 2-benzylimidazoline has the simplest structure of any aralkylated imidazoline. Substituents or radicals can be attached to three parts of this molecule: ( A ) to the imidazoline ring, ( B ) to the methylene group which forms the carbon atom bridge between the two rings, or (C) to the benzene ring.

CH-CH,

I

-CH=CH~

(XI,

I

CH,

I

’

I/ I

CH

8

0 0

(21)

(22)

(23)

The action on the blood pressure of compounds 19, 20, and 21 is practically the same for each one and is only slightly lower than that of the basic compound. Even lengthening of the bridge, Three representatives of subgroup A have been synthesized in which in itself may be satuorder to study the effect of changes made on the imidazoline ring rated or unsaturated, as in 2with regard to their action on blood pressure: ( p - p h en y l e t h y I)-imidasoline /CH CH2 (22) or in 2-styrylimidazoline CH2 ‘-L)CH, (23) does not alter the type of CHS-CH, CH,-C€f, CH2-CIIS CHZ-CH, \CHH action but only the degree. I / ‘ I I 1 I 1 The activity of these five coms N N-CHS N N-CHZ-CHZ-N S K NH \C/ \C/ \C/ BC/ pounds varies between - 2 and -3; in other words, the I I I 1 1 ClT* CHz CHz CHz C& addition of alkyl groups to I I I the methylene bridge has little influence on the physiological properties of the compound, (15) (16) as far as blood pressure is concerned. (17) (18) CHANGES O N THE IMIDAZOLINE RING

’\[>YH ’

0 6

8

0

0

INDUSTRIAL AND ENGINEERING CHEMISTRY

February, 1945

CHANGES I N THE BENZENE RING

Only one compound of subgroup C has been made which contains an alkyl radical in the para position-Le., 2-(4’-methylbenzyl)-imidazoline (24). I t also lowers the blood pressure, similarly to the original compound, with an activity of -4. Here again it seems that an alkyl substituent does not change the type of action, but no conclusions can be drawn from this one example. A variety of compounds has been made and studied where the aromatic ring is substituted with functional groups, such as hydroxy, methoxy, and others:

I

OH (25)

CH2-CH2

CHz-CHz

N NH \C/

N \C/

I

I

1

I

I

I

NH

I

I

CHn

HO-\ I

0

-OH

CHz--CHz

I

I

N NH \C/

AHz I

123

in other words, 2-(4’-hydroxybenzy1)-imidazoline (25) has a marked hypertensive effect (+5). The introduction of a second hydroxyl in the %position, as shown in compound 26, 2-(3’,4’dihydroxybenzy1)-imidazoline, increases the activity considerably (+7); the addition of a third hydroxyl group in the 5position, giving the 2-(3’,4’,5’-trihydroxybenzy1)-imidazoline (27), has an activity of +6, which means that the activity lies between those of substances 25 and 26. This remarkable change in character from the compound without functional groups t o the three just mentioned is made even more interesting by the fact that methylation of the compounds with one and two hydroxy groups to methoxy groups shows again a reverse of activity. The 2-(4’-methoxybenzyl)-imidazoline (28) and 2-(3‘,4‘-dimethoxybenzy1)-imidazoline(29) act very much like the unsubstituted parent substance, having an activity of -4. This reversing of activity holds true only for these two compounds carrying functional groups, and seems to be an exception in the relation between activity and chemical constitution as far as can be seen from the relatively small number of compounds studied. When compound 27 was methylated t o 2-(3’,4’,5’-trimethoxy. benzyl)-imidazoline (30), the activity was exactly the same as that of the starting material-i.e., +6. Also the last three compounds of this group-2-(2’,3‘,4’-trimethoxybenzyl)-imidazolines (31), 2-(3’,4’-methylenedioxybenzy1)-imidazoline (32), and 2(3’-iodo-4’-hydroxybenzyl)-imidazoline(33)-proved to be effective vasoconstrictors with a similar degree of activity. A comparison between substances 30 and 31 shows that the position of the 3-methoxy groups present has some, although rather subordinate, influence on the activity. Compound 31 has an activity of +5 as compared with +6 for substance 30. Compound 33 seems to be of particular interest because it contains an iodine atom; this shows that even the substitution by a halogen does not alter the general character of action in this series of substances. The next three compounds carry substituents on the benzene ring as well as on the methylene bridge:

CH NI

CHz NH

\C/

kCH2-CHzAH \C/

hH--OH

AH--OH

CHz-CHa NI NH 1

\C/ AH-OH

I

(34)

I mentioned before that the basic compound, 2-benzylimidazoline, is a strong vasodilator. If the hydrogen atom in the 4-position (i.e., para to the methylimidazoline group) is replaced by a hydroxyl, the action on the circulatory system is reversed;

(35)

O--CHz (36)

These three-2-(3’,a-dihydroxybenzyl)-imidazoline (34), 2-(3’,5’dimethoxy-a-hydroxybenzyl)-imidazoline (35), and 2-(3’,4’methylenedioxy-or-hydroxybenzy1)-imidazoline (36)-have an alcoholic hydroxyl group at the methylene bridge, and are substituted in the benzene ring by hydroxy, methoxy, and methylenedioxy, respectively. They all come into the class of vasoconscrictors, which means g r ~ u pto f i e .bridge e action. I n this conne phedrine and epinephrine have an aliphatic hydroxyl group in the same position. The degree of action seems to be influenced only slightly by the addition of the alcoholic hydroxy group, even though we one example of direct comparison-i.e., compound nsubstied only tuted compound 32. If a t all, the action slightly by the addition of the hydroxyl group at the methylene bridge. Reviewing the relation between chemical constitution and activity of the various substituted benzylimidazolines, we may conclude that in general the addition of free or methylated

124

INDUSTRIAL AND ENGINEERING CHEMISTRY

phenolic hydroxy groups produce strong vasoconstrictors, reversing the mtivity of the parent or basic substance, The only exceptions are the methyl ethers of the mono- and dihydroxybenzylimidazolines which are, like the parent substance, vasodilators. As far as toxicity is concerned, however, we find a difference between the compounds with free hydroxyls and thoie with blocked hydroxyls-for instance, methoxy and methylenedioxy groups. In general, at1 compounds which carry free hydroxyl groups are more toxic than the parent substance, whereas those which :ire substituted with a blocked hydroxyl group have the same or even a lesser toxicity. Furthermore, the substitution with a phenolic hydroxyl group has a strong influence on activity and toxicity. I n contrast, the addition of an alcoholic hydroxyl group to the bridge carbon atom merely changes the degree of activity and toxicity slightly; Le., both are raised somewhat. REPLACEMENT OF PHENYL RADICAL

I n the next group of compounds the phenyl radical has been replaced by a n unsubstituted or a substituted naphthyl radical or by a quinolyl or indolyl radical:

-

Vol. 37, No. 2

-

2 - (Kaphthyl - 1’ -methyl) imidazoline (37), 2 (4’-hydroxynaphthyl- 1’ -methyl) imidazoline (38), 2 (4’-methoxynaphthyl-1 ’-methyl)-imidazoline (39), an isomer of No. 39 (40). 2 - (quinolyl - 8’ - methyl) - imidazoline (41), and 2 (indolyl3 ’-methyl)-imidazoline (42). All four compounds containing the naphthyl radical are powerful vasoconstrictors with activities of +7 to f8. The rule regarding free or substituted phenolic hydroxyls seems to be applicable to this group of substances also. However, there is one rather astonishing fact: The unsubstituted 2-(naphthyl-1 ’methyl)-imidazoline (37), which incidentally is used therapeutically, is one of the strongest vasoconstrictors in this series of imidazoline derivatives, whereas the 2-benzylimidazoline, as mentioned previously, is a strong vasodilator. The only difference between these two substances is that in the first instance a naphthyl and in the second, a phenyl radical, is attached to the 2methylimidazoline. Both radicals are aromatic hydrocarbons, and this pharmacological difference between them is rather difficult to emlain because, chemically - speakinp. -. they - are similar. When comparing the activity of 2-(4’-methoxynaphthyl-1’methyl)-imidazoline (39) with that of the isomeric compound (40) which carries the methoxy group in the 2- instead of in the 4-position, it was found that compound 40 is somewhat less active. This same phenomenon was also found in the benzyl-substituted imidazoline series. The rule, however, concerning toxicity in relation to the free and substituted phenolic hydroxyl groups, which was brought forward for the benzylimidazolines, does not apply in the case of naphthylmethylimidazolines. All three substituted compounds of this group are much more toxic than the unsubstituted parent compound. Compounds 41 and 42 are imidazoline derivatives substituted with heterocyclic radicals. Compound 41 proved to be a strong vasodilator, which is even stronger in action (-6) than the 2-benzylimidazoline, but i t is much more toxic. I n contrast, compound 42 has a blood-pressure raising effect of +6, which is as high as some of the substituted 2benzylimidazolines; but it is too toxic t o have any therapeutic value.

-

-

-

ETHYL-AMINE RULE

Filling and Packaging Containers for Privine Solution

So far, only those derivatives have been discussed which have a methylene bridge between the imidazoline ring and the alkyl group or the aromatic ring system. The following six synthesized compounds have the imidazoline ring directly attached to the aromatic hydrocarbon or heterocyclic radical:

INDUSTRIAL AND ENGINEERING CHEMISTRY

February, 1945 CH*-CHz

CHz-CHz

I N

I

125

CHz-CHz

result of studies made with the aim of obtaining a rough ides about the possible therapeutic value of new compounds rather N NH N NH than an extensive study of relations between structure and \C/ \C/ \C/ action. The pharmacologists who have gathered these data are I I I aware of the definite shortcomings of a method which takes blood pressure as a criterion. Blood pressure is a complex phenomenon controlled and regulated by a multitude of factors, and cannot be used to analyze in detail the mechanism of pharmacological action of new chemical compounds; but it is a convenient and quick method. (45) Some of the compounds mentioned have been studied in greater detail. The results of these experiments have not yet been CHz-CHz CH2-CHz CH2-CH2 published; I have not reported them, first because I did not want I I I I I / to detract your attention from the main topic, and second beN NH N NH N NH cause this unpublished work must be considered still the mental \C/ \C/ property of the investigators. Whereas many questions are unanswered, it appears that the site of action of the imidasolines will be found rather complex and that they will not lend themselves easily to classification into sympathomimetic or parasympathomimetic drugs. I must refrain from trespassing on pharmacological territory, where chemical knowledge is of little help for orientation; therefore I 2-Phenyl-imidazoline (43), 2- (3’,4 ’,5 ’-trimethoxypheny1)-imida- . restrict myself to the following conclusions, and even these should not be taken too rigidly because the number of comzoline (44), 2-(naphthyl-1 ’)-imidasoline (45), 2- (pyridyl-3 ’)imidazoline (46), 2-(2’-methylquinolyl-4’)-imidazoline (47), and pounds studied in this series of 2-imidazoline derivatives is rather 2-(2’-phenylquinolyl-4’)-imidazoline(48). limited. On the basis of the general formula, When these six compounds were studied pharmacologically in the laboratory animal, it was found that none of them have any X Y activity or the activity is so small that they are of no therapeutic interest, a t least as far as their effect on blood presAH-L sure is concerned. This finding may support the previously A-z made statement that the ethyl-amine group is one of the factors \C/ responsible for the action on the circulatory system. The toxicity of these six compounds was rather low. ( Hz)n The last three imidazoline derivatives to be discussed also seem I to follow this ethyl-amine rule, if I may call it that. All R three contain this grouping but have a prolonged bridge, this it might be said that the most active compounds are those in time not with another carbon atom but with a nitrogen or an which: oxygen atom. 1. The substituents X, Y , and Z on the imidazoline ring are nothing but a hydrogen atom; in other words, the imidazoline ring should not be substituted in any except the 2-position. 2. The factor n a t the bridge between the imidaeoline ring and the radical R should be 1. A simple methylene group leads to the most active compound; it might, however, be substituted by an alcoholic hydroxyl group. If n is 0 or 2, the activity is practically nil or a t least a thousand times diminished, respectively. 3. The radical R should be an aromatic hydrocarbon or an aromatic heterocyclic. Even though the unsubstituted radicals of this series are already very active, they can still bembstituted by either a hydroxyl, a methoxy, or a methylenedioxy group. However, if R is an alkyl or cycloalkyl group, the activity is reduced g, thousand or even a million fold-i.e., to practically zero. Depending on what substituents are used as R, the (49) (50) (51) toxicity varies over a wide range.

I NH

I

I

1

k

b

- -

-

2 ( 0 Diphenyloxymethyl) imidazoline (49), 2 - (phenylaminomethyl)-imidazoline (50), and 2-(phenylmethylaminomethy1)imidazoline (51) are all active on the circulatory system. When compounds 50 and 51 are compared with Z(P-phenylethy1)imidasoline (compound 22), it was found that by substituting the a-carbon atom of the bridge by a nitrogen atom, the type of action on the blood pressure was reversed. Whereas compound 22 was a vasodilator, compounds 50 and 51 are vasoconstrictors, and so is compound 49. CONCLUSIONS Before summarizing the few conclusions which can be drawn concerning the relation between the structure of these imidazoline compounds and their pharmacodynamic activities, I wish to state t h a t I am no pharmacologist. The data reported are‘tire

ACKNOWLEDGMENT The author wishes t o emphasize that the findings reported here are not his personal work but are the results of research performed by others, mostly in Ciba’s laboratories i n Basle, Switzerland, and published by them. LITERATURE CITED (1) Chitwood, H. C., and Reid, E. E., J. Am. Chem. Soc., 57, 2424 (1935). (2) Forssel. G.,Ber., 25, 2132 (1892). (3) Hartmann, M., and Isler, Hans, Arch. exptl. Path. Pharmakol., 192, 141 (1939). (4) Hartmann, .M., and Panizzon, L., Helw. Chim. Acta, 21, 1692 (1938). (5) Hofmann, A. W., Bsr., 21, 2332 (1888). (6) Klingenstein, E., Ibid., 28, 1173 (1895). (7) Ladenburg, A.,Ibid., 27, 2952 (1894).