Quinoline-4-methanols

Quinine (1) is the oldest example of this class which has been used as a "lead molecule" to design quinoline-4-methanols with improved antimaiarial activity. The most successful outcome of this effort had been the discovery of mefloquine (71) as an antimaiarial. A discussion on the development of mefloquine and related quino-line-4-methanols is given in chapter 14 (sec. 2.1.1.1). 

Fig. 39.12. Structural similarity between quinine and the 8-aminoquinolines () and between quinine and the quinoline-4-methanols () ...

III. Quinoline-methanol derivatives Mefloquine (MEFLOC) 15 mg/kg single dose (for treatment, maximum 1 g) 5 mg/kg, up to 250 mg per wk (for prophylaxis in areas with multidrug resistance)... 

Quinine Quinoline methanol Oral and intravenous1 treatment of P falciparum infections... 

Quinidine Quinoline methanol Intravenous therapy of severe infections with P falciparum... 

Mefloquine hydrochloride is a synthetic 4-quinoline methanol that is chemically related to quinine. It can only be given orally because severe local irritation occurs with parenteral use. It is well absorbed, and peak plasma concentrations are reached in about 18 hours. Mefloquine is highly protein-bound, extensively distributed in tissues, and eliminated slowly, allowing a single-... 

Quinine Quinoline methanol Oral treatment of infections with chloroquine-resistant P falciparum... 

Over decades of sublethal exposure the resistance of all types of malaria has increased to a point where chloroquine no longer offers certain protection (217). With the partial exception of quinine and dihydroquinine (218), resistance to antimalarials had reached the stage at the time of the Vietnam war where more research was required. The development of mefloquine (164) was a continuation of the World War II effort, with a gap of about 20 years. Resistance to chloroquine had developed widely during that period, but surprisingly less so to quinine, given the obvious similarities in structure. This observation stimulated a reappraisal of quinolines, known as quinoline methanols, which bear a hydroxy group on the a-carbon of a substituent at-... 

Mefloquine, a fluorinated derivative of 4-quinoline methanol, is a product of the US Army s antimalarial research program. It is active against chloroquine-resistant Plasmodium falciparum, and has an excellent schizonti-cidal effect in the blood in experimentally induced Plasmodium vivax infections in volunteers. It is not gametocidal. P. vivax infections can persist after successful treatment of the falciparum infection with other drugs the fact that mefloquine is effective against both organisms is thus of practical importance (SEDA-13, 808). 

The synthesis of new quinoline methanols,13,14 phenanthrene methanols,15,16 and naphthalene methanols continued, aimed at finding compounds of high activity and low phototoxicity. Against Plasmodium berghei in mice, II was active at 2.5 mg/kg and phototoxic at 100 mg/kg III was the most active of the benzoquinolines but its phototoxicity was not determined. Among the phenanthrene methanols, IV was active at 20 mg/kg and V at 1.25 mg/kg. The naphthalene methanol VI was curative against P. berghei in mice at 10 mg/kg. Phototoxicity appeared to be absent from the series. 

The diastereomers of phenanthrene methanols and quinoline methanols showed striking differences in antimalarial activity,18 postulated to relate to the distance between oxygen and the nonaromatic nitrogen atoms. No exciting new structures were described but activity was found in (4-oxo-2-oxazolin-2-yl)piperazinesl9 and 1,2,4-triazines.20... 

H. Okada, V. Stella, J. Haslam, mid N. Yata, Photolytic degradation of a-[(dibutylamino)methyl]-6,8-di-chloro-2-(30, 4 -dichlorophenyl)-4-quinoline methanol An experimental antimalarial, J. Pharm. Sci. 64, 1665-1667 (1975). 

This is the outcome of many years of research by the United States department of the Army. It belongs to the 4-quinoline methanol series, several of which were foimd to have potent schizonticidal activity but could not be used clinically, because they possessed photosensitizing activity in man. Mefloquine is devoid of this effect. 

Methyl from hydroxymethyl groups. A degassed soln. of 2-phenyl-4-quinoline-methanol in methanol irradiated in a Pyrex vessel with unfiltered light from a 1000 w. high-pressure Hg-vapor lamp until the startg. m. has disappeared 2-phenyl-4-methylquinoline. Y >95%. F. e. and limitations s. M.B. Rubin and C. Fink, Tetrah. Let. 1970, 2749 cf. V. I. Stenberg and E. F. Travecedo, J. Org. Chem. 35, 4131 (1970). 

B) Methiodi s. Members of Classes (i), (ii) and (iv) combine wdth methyl iodide (some very vigorously) to form quaternary methiodides. It is best to add the amine to an excess of methyl iodide dissolved in about twice its volume of methanol, allow any spontaneous reaction to subside, and then boil under reflux for 30 minutes (extend to 1 hour for Class (iv) except pyridine and quinoline). The methiodide may crystallise when the reaction-mixture cools if not, evaporate the latter to small bulk or to dryness, and recrystallise, (M.ps., pp. 553-554 )... 

Treatment of quinoline with cyanogen bromide, the von Braun reaction (17), in methanol with sodium bicarbonate produces a high yield of l-cyano-2-methoxy-l,2-dihydroquinoline [880-95-5] (5) (18). Compound (5) is quantitatively converted to 3-bromoquinoline [5332-24-1], through the intermediate (6) [66438-70-8]. These conversions are accompHshed by sequential treatment with bromine in methanol, sodium carbonate, or concentrated hydrochloric acid in methanol. Similar conditions provide high yields of 3-bromomethylquinoHnes. 

Reaction of 1-ethoxycyclohexene (34) with dichlorocarbene gives 1-ethoxy-7,7-dichloronorcarane (35) in 87 % yield. Rearrangement of dichlorocyclo-propane (35) in hot quinoline results in loss of both chlorine atoms to give l-ethoxycyclohepta-l,3,5-triene (37) in 37% yield. Hydrolysis of enol ether (37) with a very small quantity of hydrochloric acid in methanol produces cyclohepta-3,5-dienone (38) in 91 % yield. ... 

Acetone Carbon tetrachloride, chloroform/o-chlorophenol, chloroform// -cresol, chloroform/hexafluoroisopropanol, chloroform/methanol (up to 60%), o-dichlorobenzene, dimethylformamide, dimethyl sulfoxide, dioxane, ethylacetate, FC-113, haxane, methylethylketone, N-methylpyrrolidone, pyridine, quinoline, cyclohexane, dodecane... 

Carboxylic acids with labile a-methylene protons react with isatin in the presence of strong aqueous base. In the total synthesis of methoxatin, the coenzyme of methanol dehydrogenase and glucose dehydrogenase, Weinreb employs a Pfitzinger condensation of an isatin 37 and pyruvic acid as a key step to provide the 4-quinolinic acid 38 in 50% yield under the standard basic conditions. ... 

Bromoisoquinoline can be aminated under vigorous conditions (concentrated NH4OH, 165°, 16 hr), - but attempted methoxyla-tion (methanolic methoxide, 235°, 7 hr) gave isoquinoline (50% yield) via the reductive reaction observed with 6- and 8-bromo-quinoline. ... 

Deca/octahydro 6-alkyloxazolo /-fused quinolines 17 were prepared and evaluated as dopaminergics (87EUP1). A series of linearly annelated 8-alkyl-deca/ octahydrooxazoloquinolines 18 and their salts were prepared for use as dopamine D2-agonists and hypertensive agents. The rran.s-( )-l-propyl-6-oxodecahydro-quinoline was brominated, then treated with urea in methanol to give the 2-amino... 

Absorption and emission spectra of six 2-substituted imidazo[4,5-/]quinolines (R = H, Me, CH2Ph, Ph, 2-Py, R = H CH2Ph, R = Ph) were studied in various solvents. These studies revealed a solvent-independent, substituent-dependent character of the title compounds. They also exhibited bathochromic shifts in acidic and basic solutions. The phenyl group in the 2-position is in complete conjugation with the imidazoquinoline moiety. The fluorescence spectra of the compounds exhibited a solvent dependency, and, on changing to polar solvents, bathochromic shifts occur. Anomalous bathochromic shifts in water, acidic solution, and a new emission band in methanol are attributed to the protonated imidazoquinoline in the excited state. Basic solutions quench fluorescence (87IJC187). 

Chloro-1 -methyl-5-phenyl-s-trizolo[4,3-a]quinoline A stirred mixture of 6triethyl-orthoacetate (0.925 g,0.0057 mol) and xylene (100 ml) was refluxed, under nitrogen, for 2 hours 40 minutes. During this period the ethanol formed in the reaction was removed by distillation through a short,glass helix-packed column. The mixture was concentrated to dryness In vacuo and the residue was crystallized from methanol-ethyl acetate to give 1.28 g of 7-chloro-1-methyl-5-phenyl-s-triazolo[4,3-a]-quinoline (83.9% yield). The analytical sample was crystallized from methylene chloride methanol and had a melting point 252.5°-253.5°C. 

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