Synthetic Analgesics and Antispasmodics

Donald, Gavin M. S (1950) Synthetic Analgesics and Antispasmodics. PhD thesis, University of Glasgow.

Abstract

Synthetic Analgesics and Antispasmodics. Three types of compound were investigated, the 1:4-bisdialkylaminoalkylnaphthalenes, certain 4-phenyl-4-hydroxypiperidines and a number of substituted deca-hydroisoquinolines. In order that a preliminary estimate might be made of the antispasmodic and analgesic potentialities of the 1:4-bisdialkylaminoalky lnaphthalene type of structure, three compounds of this type, 1:4-bisdiethyl-aminomethylnaphthalene, 1:4-bisisothiocarbamidomethyl-naphthalene and 1:4-bis-N-piperidylmethylnaphthalene were prepared by condensation of 1:4-bischloromethylnaphthalene with the appropriate base, and were submitted for testing in the form of the hydrochlorides. Reports on the first two of these indicate that, while the antispasmodic activity is slight, they possess an analgesic potency of the same order as that of pethidine. This is a new class of compound to show pronounced analgesic activity. 2:2:6-Trimethyl- and 1:2:2:6-tetramethyl-4-phenyl-4-hydroxypiperidine were prepared with a view to investigating the therapeutic effect of nuclear alkyl substituents in the 4-phenyl-4-hydroxypiperidine esters, which are known to be potent analgesics. Mesityl oxide was condensed with ammonia to form 4-amino-4-methylpentan-2-one (di-acetonamine), which then condensed with acetal to give 2:2:6-trimethyl-4-piperidone (vinyldiacetonamine); treatment of this with phenylmagnesium bromide and decomposition of the resultant complex gave 2:2:6-trimethyl-4-phenyl-4-hydroxypiperidine, from which 1:2:2:6-tetramethy1-4-phenyl-4-hydroxypiperidine was obtained by methylation with formaldehyde. The ease with which these piperidols underwent dehydration, however, rendered the preparation of the desired esters impracticable, though some estimate of the effect of the substituents may be obtained from the piperidols themselves, which were submitted for testing in the form of the hydrochlorides. A number of related compounds prepared in the course of this work are also described. On the model of the octahydroisoquinoline portion of the morphine molecule a series of N-alkyl-4-phenyl-l-methyldecahydroisoquinolines was prepared for testing for analgesic activity. alpha-2-AcetyIcyclohexylphenyl- acetonitrile, prepared by the Michael condensation of 1-acetylcyclohex-1-ene and phenylacetonitrile, underwent reductive-cyclisation when hydrogenated in alcohol solution over copper chromite catalyst to yield two stereoisomeric N-alkyl-4-phenyl-1-methyldecahydroisoquinolines, the nature of the N-alkyl group depending on the alcohol used as solvent. The N-methyl, N-ethyl and N-n-propyl compounds were prepared and submitted for testing. The similar reductive-cyclisation of the oxime of ethyl alpha-2-acetylcyclo-hexyl phenylacetate was also investigated, and the method was extended in a modified form to the synthesis of 1-benzyldecahydroisoquinoline.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Pharmacology
• Date of Award: 1950
• Depositing User: Enlighten Team
• Unique ID: glathesis:1950-79743
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 31 Mar 2020 09:09
• Last Modified: 31 Mar 2020 09:09
• URI: https://theses.gla.ac.uk/id/eprint/79743