Synthesis of spiro[isobenzofuran-1(3H),4\'-piperidines as potential central nervous system agents. 2. Compounds containing a heteroatom attached to nitrogen

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610 Journal of Medicinal Chemistrq. 1977, Vol. 20, .Yo. 4


Synthesis of Spiro[isobenzofuran-l(3H),4’-piperidines] as Potential Central Nervous System Agents. 2.’ Compounds Containing a Heteroatom Attached to Nitrogen Solomon S. Klioze,’ Victor J. Bauer. Chemical Research Department

and Harry M. Geyer, I11 Department of Pharmacology, Hoechst-Roussel Pharmaceuticals. Inc , Sorneri ille, iVeic Jercei 08876. Received November 4 , 1976 The synthesis and antitetrabenazine activity of a series of 3-heteroatom derivatives of 3-phenylspiro[isobenzofuran-l,4’-piperidines] are reported. Optimal antitetrabenazine activity is associated with compounds containing a sterically unhindered, basic nitrogen. Hydroxvlamines 6. 11, 12, and 13 possess the most significant activity with EDj0’s of 1.4, 3.5, 4.7, and 4.0, respectively

We have recently described the synthesis and antitetrabenazine activity of a series of 3-phenylspiro[isobenzofuran-1 (3EP),4’-piperidines] having the general formula 1.’ Potent antitetrabenazine activity in this series was shown to be associated with those compounds having



? /N\

3, R

l,R 5,R 6.R 5,


Y - H , X 6-OCH, XpH,Y-4-F

a basic nitrogen substituted with a hydrogen or small alkyl moiety. In order to further define the steric and electronic requirements of the piperidine nitrogen for optimal activity, we have undertaken the synthesis of compounds of the general formula 2 which contain another heteroatom attached directly to this nitrogen. In this paper the synthesis and antitetrabenazine activity of these compounds are reported. ZR



w‘ Y

2, Z = 0 , N H

Chemistry. The N-amino derivative 3 was prepared in the classical manner from l a via nitrosation to afford nitrosamine 4 followed by zinc-acetic acid reduction. Hydrazine 3 was in turn reductively alkylated with acetonesodium cyanoborohydride’ to afford isopropylamino derivative 5 . The preparation of the N-hydroxy derivative 6 was effected by oxidation of la with benzoyl peroxide to give the N-benzoyloxyamine 7 followed by basic hydrolysis to 6.3 Nuclear-substituted compounds 11, 12, and 13 were prepared in an analogous manner via intermediate hi-


8, R 9. I1 10, R 11. R 12. R

X=Y= H X H , Y I-OCH,

la, R = b, R C, R = d,R




N H , , X - Y Fi NO,X Y H NHCM(CH,)2.S Y

H 0H.X Y - H OC(-O)C,H,,X Y- H OC(=O)C,,H,,X H,Y O C H , OC( O)C,W OCH , Y H OC(-:0)V6H




4,6-dichloropyrimidine, giving 5-amino-4-N-[2a,3P-dihydroxy-4a- (hydroxymethyl)cyclopent-la-yllamino-6chloropyrimidine (6) as a white powder (72% from ethanol, mp 184-186 "C). Anal. (C1JIljN4O3Cl)C, H, N, C1. Ring closure of 6 with diethoxymethyl acetate gave the 6chloropurine 7 as white granules (72% from ethanol, m p 212-214 "C dec). Anal. (CllHI3N4O3C1)C, H, N, C1. Treatment of 7 with liquid ammonia gave the desired (&)-9-[2n,3P-dihydroxy-4a-(hydroxymethy1)cyclopentla-ylladenine (C-ara-A) (8) as a white powder [76% from water; mp 252.5-254.5 "C dec; UV max in nm (e X 10.') (0.1 N HC1) 258.5 (14.8), 210 sh (21.3); (HZO) 260 (15.4); (0.1 N NaOM) 260 (15.5)]. Anal. (CllH15N503-H20)C, H, N. A more detailed presentation of the chemistry of these compounds and related derivatives will be p~b1ished.l~ The cytotoxicity of C-ara-A was evaluated by growing P-388mouse lymphoid leukemia cells in the presence of either 8 or ora-A using a method previously described.lS Both ara-A and C-ara-Aexhibited LDw concentrations of

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