Proton nmr (CDC13) 5.13 (s, 2 H, CH20N02), 4.75 (d, JHf = 17.0 Hz, 2 H, FCCH2-), and 4.48 (s, 2 H, CH2); fluorine nmr 109.4 (poorly resolved triplet).Acknowledgment. -The author wishes to thank Dr. K. Baum for useful discussion.Registry 2, (2-fluoro-2,2dinitroethoxy)acetaldehyde, 40696-31-9; l-(2-fluoro-2,2-dinitroethoxy)-2,3-propanediol, 40696-32-0; periodic acid, 10450-60-9;(2-fluoro-2,2-dmitroethoxy)acetaldoxime, 40696-33-1; hydroxylamine hydrochloride, 5470-11-1; sodium acetate, 127-09-3; bis-(2-fluoro-2,2-dinitroethyl) ether, 30290-64-3; 2-chloro-2,2-dinitroethyl 2-fluoro-2,2-dinitroethyl ether, 40696-35-3; methyl vinyl ketone, 78-94-4; 3-2-fluoro-2,2-dinitroethyl glycidyl ether, 40696-32-0; l,3-bis(2-fluoro-2,2-dinitroethoxy)acetone, 40696-41-1;1,3-bis (2-fluoro-2,2-dinitroethoxy )acetone oxime, 40696-42-2; 2-fluoro-2,2-dinitroethyl propargyl ether, 40696-43-3; 2-fluoro-2,2-dinitroethyl-2,3-dibromoallyl ether, 40696-44-4; bromine, 7726-95-6; (2-fluoro-2,2-dinitroethoxy)acetone, 25172-32-1; l-chloro-3-(2-fluoro-2,2-dinitroethoxy)-2-propanol, 40696-46- 40696-47-7; hydrobromic acid, 10035-10-6; l-iodo-3-(2-fluoro-2,2dinitroethoxy)-2-propanol, 40696-48-8; hydriodic acid, 10034-85-2; 1-(2-fluoro-2,2-dinitroethoxy )-3-nitrato-2-propanol, 40696-49-9; nitric acid, 7697-37-2; 3-(2-fluoro-2,2-dinitroethoxy)-2hydroxy-l-propyl pivalate, 40696-50-2; 3-(2-fluoro-2,2-dinitroethoxy)-!,2-propanediol, 40696-32-0; pyridine, 110-86-1; 1chloro-3-(2-fluoro-2,2-dinitroethoxy)acetone, 40696-52-4; 3-(2fluoro-2,2-dinitroethoxy)-2-oxo-l-propyl pivalate, 40696-53-5; 1-(2-fluoro-2,2-dinitroethoxy)-3-nitratoacetone, 40696-54-6.
Reactions in ether between methyl-lithium and diphenylketimine, or between phenyl-lithium and phenyl cyanide, give a red solution of diphenylketiminolithium, Ph,C:NLi, from which unsolvated (Ph,C:NLi), may be obtained as a yellow amorphous and presumably polymeric solid, m. p. 260" (decomp.). Diphenylketiminoltthium forms the coloured crystalline adducts Ph,C:NLi,py, m. p. 108-1 10" (red)and Ph,C:NLi,tetrahydrofuran, m. p. 127" (orange) which dissociate in benzene and deposit (Ph,C:NLi),.Phenyl cyanide and methyl-lithium give yellow amorphous (PhCMe:NLi),t, m. p. 196". t-Butyl cyanide does not react with methyl-or ethyl-lithium a t or below 20". but methyl and ethyl cyanides with these alkyl-lithium compounds cleave alkane to give amorphous insoluble highly reactive solids believed to contain >C=C=N-groups. A similarly reactive and apparently polymeric, insoluble solid results when dimethylcyanamtde and methyl-lithium react and evolve methane. NNN'N'-Tetramethylguanidine and methyl-lithium give methane and the crystalline derivative [(Me,N),C:NLi],which is dimeric in benzene (by cryoscopy) and is also soluble in ether and toluene.DESPITE their frequent occurrence as intermediates in characterised. For example, although the derivatives reactions between elemental lithium or organolithium Ph,C:NLi and PhCMeINLi were recently used by Chan compounds and unsaturated nitrogen compounds or and Rochow 2 to prepare some azomethine derivatives compounds with N-H links, relatively few amino-of silicon, germanium, and tin, the lithium compounds derivatives of lithium, R2NLi, and no azomethine were not isolated. Such derivatives pose interesting derivatives, R2C:NLi, appear to have been isolated and structural and valence problems in that, if unsolvated, 1
2-(Diethylamino)-N-[4-(2-fluorobenzoyl)-1,3-dimethyl-1H-pyrazol-5-yl] acetamide (1) was recently found to have an antipsychotic-like profile in behavioral animal tests but, unlike clinically available antipsychotic agents, did not interact with dopamine receptors. Compound 1 was apparently metabolized to (5-amino-1,3-dimethyl-1H-pyrazol-4-yl)(2-fluorophenyl)methanone (2), which was both active in the behavioral animal tests and toxic. The synthesis and pharmacological evaluation of a series of 1,3-dialkyl-4-(iminoarylmethyl)-1H-pyrazol-5-ols are described in which the hydroxy and imine functionalities were selected as possible isosteric replacements for the amino and ketone groups of the earlier series. The initial target, 1,3-dimethyl-4-(iminophenylmethyl)-1H-pyrazol-5-ol (28), like known antipsychotics, reduced spontaneous locomotion in mice at doses that did not cause ataxia, and unlike known agents, it did not bind to D2 dopamine receptors in vitro. An examination of the SAR of related compounds indicated that maximal activity was obtained with analogues containing methyl groups at the 1- and 3-positions on the pyrazole ring and with a 3-chloro substituent on the phenyl ring. Replacement of the hydrogen atom of the imine moiety with various substituents led to loss of activity. Attempts to synthesize the 2-fluorophenyl compound analogous to 2 resulted in ring-closure to 1,3-dimethyl[1]benzopyrano[2,3-c]pyrazol-4-(1H)-one (65). 4-[(3-Chlorophenyl)iminomethyl]-1,3-dimethyl-1H-pyrazol-5-ol (41) was evaluated in additional tests. It inhibited conditioned avoidance responding in both rats and monkeys but, unlike available antipsychotic drugs, did not elicit dystonic movements in a primate model of antipsychotic-induced extrapyramidal side effects.
Diphenylketimine and trimethylgallium form a crystalline adduct Ph,C:NH,GaMe, which a t 100" loses methane to form the azomethine derivative (Ph,C:N*GaMe,),.In the systems Ph,C:NH-GaR, (R = Et or Ph) the 1 :1 mixtures of the components are viscous liquids whose proton magnetic resonance (p.m.r.) spectra provide evidence of weak complex formation. Both systems lose R H readily a t 100-1 20' to form azomethine derivatives (Ph,C:N*GaR,)2.Features of the infrared, p.m.r., and mass spectra of these compounds are discussed.
Resynthesis of NSC 341,964, which had been assigned structure 1 (1-[[3-(7-chloro-4-oxo-4H-3,l-benzoxazin-2-yl)phenyl]methyl]pyridinium chloride) was approached via 7-chloro-2-(3-methylphenyl~4H-3,1-benzoxazin-4one (5) obtained from 3-methylbenzoyl chloride (2) and 2-amino-4-chlorobenzoic acid (3) followed by dehydration in acetic anhydride. Radical bromination provided 6 which with pyridine afforded the bromide analog 7 of 1. Ion exchange, however, gave ring-opened henzoic acid 8 rather than 1. The original sample of NSC 341,964 also proved to be ring-opened material. However, 7 upon standing exhibited slow hydrolysis to 8 so that the structure of the original NSC 341,964 remains uncertain. A more direct route to compound 8 is also described. Chern., 23, 249 (1986). J. HeterocyclicIn order to provide the National Cancer Institute with additional material for biological evaluation, we were asked to prepare NSC-341,964. This compound had been assigned the structure 1-[[3-(7-chloro-4-oxo-4H-3,1-benzoxazin-2-yl)phenyl]methyI]pyridinium chloride (1, Scheme I) by
On the basis of a structural model of the postsynaptic dopaminergic antagonist pharmacophore, a series of 1-[3-(diarylamino)propyl]piperidines and related compounds was synthesized and evaluated for potential antipsychotic activity. For a rapid measure of activity, the target compounds were initially screened in vitro for inhibition of [3H]haloperidol binding and in vivo in a test of locomotor activity. Behavioral efficacy of compounds identified from the initial screens was more accurately measured in rats by using a suppression of high base-line medial forebrain bundle self-stimulation test model. The propensity of these compounds for causing extrapyramidal side effects was evaluated by using a rat catalepsy method. On the basis of these test models, we have shown that the methine carbon of the 1-(4,4-diarylbutyl)piperidines can be advantageously replaced with a nitrogen atom. The 1-[3-(diarylamino)propyl]piperidines were less cataleptic than the corresponding 1-(4,4-diarylbutyl)piperidines. The compounds with the widest separation between efficacious dose and cataleptic dose are 8-[3-[bis(4-fluorophenyl)amino]propyl]-1-phenyl-1,3,8-triazaspiro [4. 5]decan-4-one (6), 1-[1-[3-[bis(4-fluorophenyl)amino]propyl]-4-piperidinyl]-1,3-dihydro- 2H-benzimidazol-2-one (11), 1-[1-[3-[bis(4-fluorophenyl)amino]propyl]-1,2,3,6-tetrahydro-4- pyridinyl]-1,3-dihydro-2H-benzimidazol-2-one (22), and 1-[3-[bis(4-fluorophenyl)amino]propyl]-4-(2-methoxyphenyl)piperazine (26).
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