Oxidation of Carbon Atoms α to carbonyls and imines

1. Metabolic Changes of Drugs andRelated Organic CompoundsOrganic Pharmaceutical Chemistry I3rd Year Pharmacy2018-2019

2. Oxidation of Carbon Atoms α to carbonyls and imines The oxidation of benzodiazepins to their corresponding 3-hydroxymetabolites, for example diazapam (Valium), flurazepam (Dalmane) and nimetazepam occurs at α atoms (C-3). Further N-demethylation of the latter gives oxazepam.

3. The hydroxylation at carbon atoms α to C= O generally occurs to a limited extent e.g. in glutethimide to the 4-hydroxyglutithimide.

4. Oxidation of Aliphatic and Alicyclic Carbon Atoms Oxidation of aliphatic carbon atom occurs at ω and or ω -1 (penaltimate-next to-the-last-carbon). The alcoholic product is subjected to further oxidation to aldehydes, ketone or carboxylic acids. Examples are valproic acid (depakene), amobarbital (Amital). EXC: Label the site of oxidation as ω and ω -1 in the compounds below.

5. Oxidation of Aliphatic and Alicyclic Carbon Atoms Other examples include, ibuprofen (at ω ) and at ω -1 for meprobamate, gluthimide, ethosuxinide and phenylbutazone. EXC: State the metabolites of oxidation in the drugs below.

6. Oxidation of Aliphatic – Cyclohexyl Group Oxidation occurs at C3 or C4 carbons of cyclohexyl group leading to cis and trans isomers as in acetohexamide, glipizide , phencyclidin and minoxidil.

7. Oxidation Involving Carbon Heteratom System Metabolic oxidation of C- N, C-O, C-S systems involves two types of biotransformations; • Hydroxylation at α -carbon atom attached directly to the heteroatom (N, O, S). (catalysed by CYP). Metabolites from this reaction decompose through oxidative deamination. EXC: Demonstrate the above statement. 2. Oxidation of the heteroatom (N, S) only as N- hydroxylation, N-oxides, sulfoxide and sulfone formation. These reactions are catalyzed by CYP and N-oxidazes.

8. Oxidation Involving Carbon-Nitrogen Systems N-containing compounds can be divided into aliphatic and alicyclic, aromatic and amides. The oxidative dealkylation from tertiary and alicyclic amines involves two steps; hydroxylation at alpha Carbon to N followed by dealkylation. The removal of alkyl groups (particularly methyl groups ) from tertiary aliphatic and alicyclic amines is carried out by CYP and referred to as oxidative N-dealkylation.

9. Oxidation of 3o Aliphatic • The initial step involves α-carbon hydroxylation to form carbinolamine intermediate which is unstable and undergoes heterolytic C-N cleavage to give a secondary amine and an aldehyde or ketone. • However, the tertiary butyl group present in many drugs such as terbutadiene and salbutamol remains intack and does not appear to undergo any significant metabolism.

10. How Fast Oxidative Metabolism is? Bisdealkylation of the tertiary amine to the primary amine occurs very slowly as in imipramine by removal of formaldehyde molecules twice to give the primary amine. In contrast to this compound, extensive metabolism takes place as in lidocaine with removal of two acetaldehyde groups.

11. Examples of Metabolism of aliphatic Amine Drugs • Large number of tertiary aliphatic amines drugs are metabolised by oxidative N-dealkylation. Some of these include disopyramide, tamoxifen, diphenyldramine, chlorpromazine and prpoxyphene.(p64) • EXC: Demonstrate the oxidation of the drugs below.

12. Oxidation of 3o Aliphatic, Size Effect • In general, small alkyl groups such as methyl, ethyl and isopropyl. N-dealkylation from t-butyl groups is not possible through the carbinolamine pathway because α-carbon hydroxylation cannot occur. • The first alkyl group from a tertitary amine is removed more rapidly than the second alkyl group, e.g. benzphetamine. (p64)

13. Cyclization and Bisdealkylation The oxidative metabolism of methadone undergoes involves cycliyzation. (p 64) On the other hand brompheniramine undergoes bisdealkylation to the primary amine then to the carboxylic acid.

14. Oxidation of 3o Alicyclic Amines Alicyclic 3o amines are like aliphatic amines are susceptible to oxidative N-dealkyation e.g. the oxidation of mepridine, morphine, N-ethylnormorphine and dextromethorphan.

15. Direct N-dealkylation of t-butyl groups, is not possible by thre alpha –carbinolamine formation. In vitro studies indicate that t-butyl-norchlorocyclizine is metabolized by loss of t-butyl group. Careful studies showed that the t-butyl group is removed in converting it to secondary amine by the removal of one methyl group of the t-alkyl group through carbinol intermediate or alcohol product then to caboxylic acid..

16. On losing CO2, the latter is converted to the scondary amine which will lose the remaining secondary alkyl group through carbinol. The metabolism of t-butyl-norchlorocyclazine demonstrate this. (top p66)

17. Examples of No Oxidative Metabolism Indirect dealkylation of 3o butyl group is not observed significantly such as terbutaline and salbutamol does not appear to undergo any significant metabolism.

18. Oxidation of Alicyclic t-amines Alicyclic t-amines form lactam metabolites via carbinol formation. Examples include nicotine, cyproheptadine and didiphenidol.

19. N-Oxidation of Tertiary Amines Several tertiary amines drugs are oxidised by N-oxidation. These include orphenadrine, tripelennamine, phenothiazine and morphine, codeine and meperidine. These N-oxides are metabolially active similar to the parent drug, e.g. N-oxide imipramine with imipramine Metabolic N-oxidation hydroxylamine formation.