370 Journal of Medicinal Chemistry, 1976, Vol. 19, No. 3
Rossle et ai.
Synthesis and Biological Activity of New 2-Substituted Analogs of Fluphenazine Paul C. Bossle,* C. Parker Ferguson, Walter E. Sultan, Willard J. Lennox, Gaston E. Dudley, Thomas H. Rea, and Jacob I. Miller Chemical Research Division, Chemical Laboratory, Edgewood Arsenal, Aberdeen Proving Ground, Maryland 21010. Received October 2, 1974 A series of 2-substituted analogs of fluphenazine, namely the nitro, cyano, dicyanoethenyl, and nitroethenyl compounds, was synthesized and tested as potential neuroleptics.
Based on a literature review of the pharmacological effectiveness of phenothiazines, it was theorized that neuroleptic activity could be greatly enhanced by replacing the trifluoromethyl substituent of fluphenazine (la) with a substituent possessing greater electron-withdrawing properties either by inductive or resonance interaction.1 A 2-substituent with greater electron-attracting properties would decrease the availability of electrons on the sulfur atom of the ring for sulfoxide formation, since the 2substituent is para to the sulfur atom in the 5 position. Sulfoxide formation drastically reduces neuroleptic potency,2 which may be due to an increase in water solubility.1
Scheme I
3
,' I
c H,
NC/N c c
H~ P, O H
l a , R = -CF, (fluphenazine) b, R = -NO, C , R = -CH=C(CN), d, R = -CH=CHNO, e, R = -CN
Accordingly, a series of 2-substituted analogs of la were prepared for biological evaluation. This series consisted of the following new compounds: 2-nitro-10-[3-[4-(2hydroxyethy1)- 1-piperazinyl]propyl]phenothiazine (1b), 2-( 2,2-dicyanoetheny1)-10-[ 3- [ 4- (2-hydroxyethyl)-lpiperazinyl]propyl]phenothiazine (IC), and 2-(2-nitroetheny1)-10-[ 3- [ 4- (2-hydroxyethy1)-l-piperazinyllpropyllphenothiazine ( I d ) . In addition, 10-[3-[4-(2hydroxyethyl)-l-piperazinyl]propyl]phenothiazine-2carbonitrile (le) was prepared following the method of Benko e t al.3 (The authors thank the Industrial Liason Office of the Chemical Laboratory for small quantities of le for initial studies.) Chemistry. Compound l b was prepared in two synthetic steps (Scheme I). The first step consisted of alkylating 2-nitrophenothiazine4 (2) with l-bromo-3chloropropane to produce l0-(3-chloropropyl)-2-nitrophenothiazine (3), alkylation being accomplished by first converting 2 to the anionic species using the strong base, sodamide. Following the procedure of Yale and Sowinski,j 3 was treated with 1-(2-hydroxyethyl)piperazine (4) in refluxing 2-butanone, in the presence of sodium iodide, to yield lb, which was then characterized as the dimaleate salt. The most direct method to prepare IC and I d was to synthesize the common precursor 10-[3-[4-(2-hydroxyethyl)-1-piperazinyl]propyl]phenothiazine-2-carboxaldehyde (5), followed by a Knoevenagel-type condensation with malononitrile and nitromethane, respectively. Following the facile one-step nitrile-to-aldehyde reduction procedure of van Es and Staskun,G phenothiazine-2carbonitrile7 (6) was converted to phenothiazine-2carboxaldehyde (7) in a refluxing Raney alloy-aqueous
lb
Scheme I1
H
,/
7
9
8
Scheme 111
Id
formic acid mixture (Scheme 11). In addition, a sample of 7 was prepared from phenothiazine 2-carboxyhydrazide by the procedure of McFadyen-Stevens8 as modified by Fattorusso.9 The samples prepared by the two different methods were identical. In the same manner, the conversion of le appropriately yielded 5 (Scheme 111). The Knoevenagel condensation of 7 with malononitrile and with nitromethane gave l,l-dicyano-Z-(Z-phenothiaziny1)ethene (8) and l-nitrc-2-(2-phenothiazinyl)ethene (9), respectively. Piperidine was used as the catalyst in the preparation of 8. The procedure of Burger and Schmalzlo satisfactorily produced the fl-nitrovinyl derivative 9.
Journal of Medicinal Chemistry, 1976, Vol. 19, No. 3 371
2-Substituted Analogs of Fluphenazine
Table I. Cataleptogenic Potency Data of Phenothiazines in Male Albino Mice Mean re1 No. la (standard)
Form Dihydrochloride
lb
Dimaleate Dimaleate DimaleateC Dihy drochloride
IC
Id le
CD,,, mnol/kg 1.6 ( 28)b. 0.29 (10)’ 0.62 ( 14)b
potencyapd
1.0
No. of Compd significantly determi- exceeded one-sided t nations test,p < 0.05 IC,I d
2.2
0.92
2
IC,I d
2.3 28 >57 0.99
0.078
