Molecular Modification in Drug Design - American Chemical Society

11 Molecular Modification in the Development of Phenothiazine Drugs MAXWELL GORDON, PAUL N. CRAIG, and CHARLES L. ZIRKLE

Downloaded by CHINESE UNIV OF HONG KONG on March 3, 2016 | http://pubs.acs.org Publication Date: January 1, 1964 | doi: 10.1021/ba-1964-0045.ch011

Smith Kline and French Laboratories, Philadelphia, Pa.

In the phenothiazine area, it has been amply demonstrated that structural changes, in addi tion

to

producing

expected

quantitative

changes in tranquilizing activity, also produce unexpected qualitative changes

in biological

activity. As a result antipruritic, antispasmodic, anticonvulsant, antibacterial, antiemetic, anti motion sickness, anthelmintic, and antidepres sant compounds have been developed by mo lecular modification of the phenothiazines.

Ύ he discovery of the phenothiazine tranquilizing drugs provides an outstanding example of the totally unpredictable, but often useful, results which may be obtained by structural modification of prototype drug molecules. The ancestry of these agents may be traced back to the original antihistamines of the benzodioxane type discovered by Bovet and collaborators in 1937 (7, 34). With the benzodioxanes as a starting point, a long series of molecular modifications was carried out in various laboratories over the next decade in a search for other types of antihistaminic agents. This slow, gradual process eventually led to the synthesis of phenothiazine derivatives and the discovery of their therapeutic utility. In turn, the phenothiazines have served as structural prototypes for further studies in molecular modification. Even small changes in the structure of a substituted phenothiazine can lead to marked changes in potency, toxicity, or degree and types of side effects, or even to new and useful medicinal agents that are qualitatively different from the prototypes. The steps which led to the phenothiazine drugs are outlined in Figure 1. Variations of the benzodioxane structures (I) led to ethers of the ethanolamine type (II), which were further developed in two directions: first, toward the benzhydryl ethers of the diphenylhydramine type (III), and second, toward the ethylenediamine types (IV). The ethylenediamine types, in turn, were evolved further in two directions: first, to the pyribenzamine type (V) (tripelennamine), and second, via the diphenylamine types to phenothiazine derivatives such as the anti-Parkinson agent diethazine (VI) (15, 17) and the antihistamine promethazine (VII) (6, 23, 25). 140 In Molecular Modification in Drug Design; Schueler, Fred W.; Advances in Chemistry; American Chemical Society: Washington, DC, 1964.

II.

GORDON ET AL,

Phenothiazine Drugs

^ A

0

A

C

H

2

N

(

C

H

g

)

141

2

l

ι -0-CH CH N(CH ) 2


π

3

2

\ /CH

Q /

/CH

3

N-CH2CH2N \C H

3

CH3CH2

/CH3 N-CH2CH2N

\C H

3

CH-O-CH2CH2N

\C H

\

IV

.1SL/

2

3

III

'N' I 3

CH CH N(C H5)2 2

2

2

VI

Figure 1.

Evolution of the phenothiazines

Promethazine is a potent antihistaminic drug. In the course of its clinical use, sedation was noted as a prominent side effect. In an effort to enhance this sedative effect, the Rhone-Poulenc research group studied many modifications of promethazine, which led to chlorpromazine (VIII). Chlorpromazine, in marked contrast to promethazine, has diminished antihistaminic activity, and

Λ

CR

3

CH

3

VII has pronounced sedative and antipsychotic activity. Therefore, relatively minor molecular modifications of a sedative antihistamine resulted in a major tran quilizer which helped spark the revolution in the therapy of the mentally ill. Phenothiazines vary in degree of tranquilizing activity, but possess other useful biological properties. For purposes of this discussion, the index of

In Molecular Modification in Drug Design; Schueler, Fred W.; Advances in Chemistry; American Chemical Society: Washington, DC, 1964.

142

MOLECULAR MODIFICATION IN DRUG DESIGN


tranquilizing activity is blockade of the conditioned avoidance response in the rat, which is blocked selectively by tranquilizers such as chlorpromazine (8, 9, 10). In general, although there are some conspicuous exceptions, blockade of the conditioned avoidance response in rats correlates well with antipsychotic activity in man. Relative to chlorpromazine, trimeprazine (IX) (32) has greatly reduced conditioned response blocking activity and greatly enhanced antihistaminic and antipruritic activities; it has found wide clinical use as an antipruritic and antihistaminic agent.

The levo isomer of the 2-methoxy derivative of trimeprazine, known as levomepromazine (X) (11, 16), has not only conditioned response blocking and tranquilizing activity comparable to chlorpromazine, but also pronounced antihistaminic activity. Levomepromazine is active in the hot-plate analgetic test, but not in the tail-pinch method in the rat, and is reported to be an analgetic agent in man (26). There are some reservations about the possible analgetic activity of levomepromazine, inasmuch as it is reported to have analgetic activity by the parenteral route, but not by the oral route. Yet, drowsiness is seen after oral administration, so the drug must be absorbed when given orally. Additional experimentation in man will be necessary to resolve these discrepancies. The methylsulfonylpiperazinopropylphenothiazine derivative (XI) is also claimed to have analgetic activity (33). Replacement of the dimethylaminopropyl side chain of promazine by an N-methyl-3-pyrrolidinomethyl side chain gives methdilazine (XII), a compound with a low degree of conditioned avoidance response-blocking activity, but with antipruritic activity (27, 29).

CH

2

f—-1— CH

S

XII Replacement of the 10-aminoalkyl chain by ^ C O O C ^ C ^ N O C H g ^ gives a compound with antispasmodic activity (XIII) (13), which is devoid of con-


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GORDON ET AL.

143

Phenothiazine Drugs


ditioned response blocking activity. Similarly, antispasmodic activity is observed for the quaternary salt of promethazine (XIV, Multergan) (1, 24). Antispasmodic activity is also seen where the 2-carbon atom of the propyl side chain in promazine is replaced by a dimethylamino group as in aminopromazine (XV) (35). This compound is devoid of tranquilizing and conditioned escape response-blocking activity.

HC

X

3

X

CH

3

XIII Unsubstituted phenothiazine (XVI) is, of course, well known as an anthelmintic agent, and is devoid of tranquilizing properties (12). Another unalkylated phenothiazine, methylene blue (XVII) (21), is known to have antibacterial activity and to be devoid of tranquilizing properties. Antibacterial activity is also claimed for XVIII (28). Compound XIX with a dimethylsul-

CH

2

S

I CH

2

I CH i

2

A CH

3

CH

3

XVIII fonamido group in the 2-position, shows potent tranquilizing properties, but also has relatively greater antiemetic activity. This property is shared by many of the piperazinopropylphenothiazines (20).


144


CH CH CH N^\~CH 2

2

2

Ç=0

3

XIX

^


NH I CH

2

CH

2

N(CH ) XX 3

2

Compound X X has antimotion sickness properties and some stimulant effects, but is relatively devoid of tranquilizing properties (18). A phenothiazine with an aminoalkoxyalkyl carbamate side chain (XXI) has antitussive activity (dimethoxanate), but it is devoid of tranquilizing and conditioned escape response-blocking activity. Compound XXII similarly has antitussive activity, but is not stated to have analgetic and tranquilizing activities (14).

CH

3

XXI

CH

3

COOC Hs 2

XXII Therefore, changes in the ring substituents and in the side chain produce marked qualitative and quantitative changes in biological activity. Isosteres of these phenothiazine drugs also vary greatly in biological activity relative to that of chlorpromazine. For example, if the sulfur of chlorpromazine is replaced by oxygen to give a phenoxazine (XXIII), the resulting compound is only one tenth as active as chlorpromazine in reducing the motor activity of mice (5). The xanthene drug, dimeprazan (XXIV), also is less active than


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Phenothiazine Drugs

chlorpromazine (4). On the other hand, replacing the nitrogen of chlorpromazine by carbon leads to a thiaxanthene derivative, cHo^rothixene ( X X V ) , which is approximately equal to chlorpromazine in the conditioned escape response test and in tranquilizing activity in man (30).

OCH H CH CH N(CH ) Downloaded by CHINESE UNIV OF HONG KONG on March 3, 2016 | http://pubs.acs.org Publication Date: January 1, 1964 | doi: 10.1021/ba-1964-0045.ch011

2

2

XXIII

2

3

2

CHCHaCHjfNiCHa). XXIV

CH-CH CH KT ^CH 2

2

3

XXV Replacement of the sulfur atom in promazine by two methylene groups leads to imipramine (XXVI) which is not a tranquilizer, but is instead a clinically useful antidepressant agent (22, 25). Similarly, the dibenzocycloheptadiene analog, amitriptylene (XXVII) (2), is devoid of tranquilizing activity and is a useful antidepressant like imipramine.

CH N(CH ) 3

2

3

XXVIII

XXVII XXVI Cyproheptadine (XXVIII) (36), an analog of amitriptylene, is devoid of antidepressant and tranquilizing activities, but possesses potent antiserotonin and antihistaminic activities. Antipruritic compounds have been obtained by appropriate molecular modification of both the phenothiazine tranquilizers and the dibenzocycloheptadiene antidepressants (compare IX and XXVIII). Replacement of the side chain of imipramine by a carbamoyl group as in compound XXIX ( G 32883, Tegretol, Geigy) gives a compound without tranquilizing or antidepressant activity, which is claimed to have anticonvulsant activity (3).

X)NH

2

XXIX The phenothiazine tranquilizers presumably act by interaction with cellular receptor sites in the central nervous system, although the mechanisms involved and the nature of the drug receptors are unknown. However, for the



146

X

CHg-N

H IN.

N-CH£

CH^

II


A

II

B

C

F'giire 2. Possible conformation of prochlorperazine molecule interacting with receptor surface XXX sake of a brief discussion of structure-activity relationships in the phenothiazine series, we refer to structure X X X , which depicts schematically one of perhaps many possible conformations that a prochlorperazine molecule might assume in interacting with a receptor surface. Replacement of the chlorine in the 2-position (Figure 2, C) by hydrogen results in a decrease in activity, whereas replacement by a trifluoromethyl or dimethylsulfonamido group results in an increase in activity. Placement of the ring substituent in position 1, 3, or 4 results in a marked loss in tranquilizing activity, as does simultaneous substitution in both aromatic rings. As far as tranquilizing activity is concerned, the three-carbon side chain seems to be optimal (Figure 2, B). A derivative with a substituent at the 2-carbon atom of the side chain is optically active, and the levo isomer is by far the more active isomer of the enantiomorphic pair. According to a hypothesis of Pfeiffer (31), the amount of structural specificity at any given point in a biologically active molecule is in proportion to the ratio of activities of the optical isomers. In keeping with this hypothesis, one would expect a great deal of structural specificity at the 2-position, and this is indeed the case. For example, replacement at the 2-carbon by phenyl, dimethylamino, or hydroxyl results in an almost complete loss of tranquilizing activity. On the other hand, substitution by a small group—e.g., hydrogen or methyl—results in retention of activity. If the 2-carbon is incorporated into a ring as in methdilazine (XII), there is a marked loss in tranquilizing activity. On the other hand, if only the terminal carbon is involved in a ring, as in thioridazine (XXXI), activity is retained in man, although the conditioned escape response-blocking activity is much reduced in animals. The receptor into which the molecule fits

XXXI


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GORDON ET AL.

Phenothiazine Drugs

147

seems to be long and narrow, since replacement of the methyl group on the nitrogen (Figure 2, A ) of the piperazine ring by such a bulky group as the p-aminophenethyl can result in no loss of activity (19). In Figure 2, A, the piperazino group usually leads to more active com pounds than the dimethylamino group. On the terminal nitrogen of the piper azine the N-^-hydroxyethyl group leads to higher activity than the N-methyl.


Literature Cited

A.

(1) Ambrus, J. L., J. Pharm.Pharmacol.4, 466 (1952). (2) Besendorf, H., Steiner, F. Α., Hürlimann, Α., Schweiz. Med. Wochschr. 92, 244 (1962). (3) Blom,S.,Neurology 9, 285 (1963). (4) Bonvicino, G. E., Arlt, H. G., Pearson, Κ. M., Hardy, R. Α., J. Org. Chem. 26, 2383 (1961). (5) Bonvicino, G. E., Yogodzinski,L.H.,Hardy,R.Α.,Ibid., 26, 2797 (1961). (6) Bovet, D., Compt. Rend. Soc. Biol. 144, 7, 514 (1950). (7) Bovet, D., Staub,A.M.,Ibid., 124, 547 (1937). (8) Cook, L., Toner, J. J., J. Pharm. Exptl. Therap. 110, 12 (1954). (9) Cook, L., Weidley, E. F., Morris,R.W.,Ibid., 113, 11a (1955). (10) Courvoisier, S., Fourmel, J., Ducrot, R., Kolsky, M., Koetschat, P., Arch. Intern. Pharmacodyn. 92, 305 (1953). (11) Courvoisier, S., Leau,O.,Compt. Rend. 248, 3227 (1959). (12) Craig, J. C.,Tate, M. R., Progr. Drug Res. 3, 75 (1961). (13) Dahlbom, R., Ekstrand, T., Acta Chem. Scand. 5, 102 (1951); 6, 1285 (1952); Subsidia Med. Vienna 1, 68 (1955). (14) Davis, Μ. Α., (to American Home Products) U. S. Patent 3,094,528 (June 18, 1963). (15) DeMaar, E., Arch. Intern. Pharmacodyn. 105, 349 (1956). (16) Deneau, C. Α., Seevers, M. H., Bull. Drug Addiction and Narcotics, 23rd Mtg., Addendum 1 (1960). (17) Frichel,H.,Arzneimittel-Forsch. 4, 171 (1954). (18) Frommel, E., Ibid., 13, 573 (1963). (19) Gordon,M.,Cook, L., Tedeschi,D.H.,Tedeschi, R. E., Ibid., 13, 318 (1963). (20) Gordon, M., McCandless, R. F., "Handbook of Toxicology," Vol. IV, W. B. Saunders, Philadelphia, 1959; Lancet 1961, II, 698. (21) Greenberg, Β. E., Brodney,M.L.,N.England J. Med. 209, 1153 (1933). (22) Haefliger, F., Schindler,W.,U.S.Patent 2,554,736 (1951). (23) Halpern, Β. N., J. Allergy 18, 263 (1947). (24) Kreppel, E., Arch. Intern. Pharmacodyn. Therap. 112, 20 (1957). (25) Kuhn, R., Am.J.Psychiat. 115, 459 (1958). (26) Lasagna, L., DeKornfeld,T.J.,J.Am. Med. Assoc. 178, 887 (1961). (27) Mead, Johnson, Belg. Patent 583,822 (1960). (28) Meyers, G. S., Davis, M. A. (to American Home Products), U. S. Patent 2,951,077 (1960). (29) Modern Drug Encyclopedia, 8thed.,R.H.Donnelly Corp., Chicago, 1961. (30) Moller Nielsen, I., Hougs, W., Lassen, N., Holm, T., Petersen, P. V., Acta Pharmacol.Toxicol.19, 87 (1962). (31) Pfeiffer, C. C., Science 124, 29 (1956). (32) Pillsbury,D.M.,Shelley, W. B., Hambrick, G. W., Hamilton, W. L., Messenger, L., Current News in Dermatology 45, 1 (1957). (33) Rhone-Poulenc, Ger. Patent 1, 132, 136 (1962). (34) Ungar, G., Parrot, J. L., Bovet, D., Compt. Rend. Soc. Biol. 124, 445 (1937). (35) Vasey, H., Praxis (Berne) 48, 1164 (1959). (36) Welsh, A. L., Ede,M.,J.New Drugs 2, 88 (1962). RECEIVED December 9, 1963.

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