gamfexine

{{Drugbox

| Verifiedfields = changed

| verifiedrevid = 451554162

| IUPAC_name = 1-phenyl-1-cyclohexyl-3-dimethylaminopropane

| image = Gamfexine.png

| image_class = skin-invert-image

| tradename =

| pregnancy_category =

| legal_status = Unscheduled

| routes_of_administration = Oral

| bioavailability =

| metabolism =

| elimination_half-life =

| excretion =

| CAS_number_Ref = {{cascite|correct|??}}

| ATC_prefix = none

| ATC_suffix =

| PubChem = 31041

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 3U2V80KPAL

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D04298

| CAS_number = 7273-99-6

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

| ChemSpiderID = 28799

| StdInChI_Ref = {{stdinchicite|changed|chemspider}}

| StdInChI = 1S/C17H27N/c1-18(2)14-13-17(15-9-5-3-6-10-15)16-11-7-4-8-12-16/h3,5-6,9-10,16-17H,4,7-8,11-14H2,1-2H3

| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}

| StdInChIKey = AJDSHXKJJDQZCJ-UHFFFAOYSA-N

| C=17 | H=27 | N=1

| smiles = c1ccccc1C(CCN(C)C)C2CCCCC2

}}

Gamfexine (WIN-1,344) is a centrally acting stimulant drug, which was tested as an adjunct treatment for withdrawn patients with schizophrenia, but while effective for treating withdrawal it made psychotic symptoms worse.{{cite journal | vauthors = Biel JH | title = Antidepressants, Stimulants, Hallucinogens. | journal = Annual Reports in Medicinal Chemistry | date = January 1967 | volume = 2 | pages = 11–23 (18) | publisher = Academic Press | doi = 10.1016/S0065-7743(08)61499-2 }}

It was stated that gamfexine was the progenitor in the discovery of venlafaxine.Yardley, J. P.; Husbands, G. E. M.; Stack, G.; Butch, J.; Bicksler, J.; Moyer, J. A.; Muth, E. A.; Andree, T.; Fletcher h, H.; James, M. N. (1990). "2-Phenyl-2-(1-hydroxycycloalkyl)ethylamine derivatives: synthesis and antidepressant activity". Journal of Medicinal Chemistry 33 (10): 2899–2905. doi:10.1021/jm00172a035. PMID 1976813. This could be the reason why both agents share the same suffix.

Synthesis

The precursor chemical is made from benzyl cyanide and bromocyclohexane.{{cite journal | journal=Organic Syntheses | title=a-CYCLOHEXYLPHENYLACETONITRILE | volume=25 | pages=25 | date= 1945 | doi=10.15227/orgsyn.025.0025}} This compound serves dual use in the synthesis of drofenine, hexasonium & feclemine.

The synthesis of gamfexine has been discussed:Ruddy, A. Wayne (1951). "Antispasmodics. II. Substituted α-(β-Aminoethyl)-phenylacetonitriles and 3-Phenylpropylamines". Journal of the American Chemical Society. 73 (9): 4096–4098. doi:10.1021/ja01153a013.The organic chemistry of drug synthesis, volume 2, Daniel Lednicer & Lester Mitscher (page 56). Patents:Mario D Aceto, Louis S Harris, Alexander Ernest John, Alonzo M Lands, {{US patent|3328249}} (1967 to Sterling Drug Inc).Mario D Aceto, et al. {{US patent|3485873}} (1969 to STWB Inc). The method discussed by Lednicer & Mitscher is slightly different from the patented procedure and uses 2-Cyclohexylidene-2-phenylacetonitrile [10461-98-0].Eyal BEN-ARI, WO2018207191 (to Agan Aroma and Fine Chemicals Ltd). This chemical is an odoriferous substance. It is known to have been used in the synthesis of Fenclexonium.

File:Gamfexine synthesis.svg

Alkylation of cyclohexylphenylacetonitrile [3893-23-0] (1) with 2-chloroethyldimethylamine (2), using NaNH2 as base, gives nitrile, [https://pubchem.ncbi.nlm.nih.gov/compound/412902 PC412902] (3). Removal of the nitrile group apparently occurred upon reaction with more NaNH2. This completed the synthesis of Gamfexine (4).

N.B. Note that the removal of cyanide also occurs in one of the syntheses of chlorpheniramine. Here though, sulfuric acid was used as the reagent for this step.

An alternative synthesis strategy is envisioned to consist of Mannich reaction & organometallic addition to the carbonyl group (c.f. trihexyphenidyl), followed by reductive removal of the tertiary hydroxyl group; or by starting form Benzoylcyclohexane [712-50-5].

References

Category:Stimulants

Category:Dimethylamino compounds

gamfexine

Synthesis

See also

References