Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D459/00—Heterocyclic compounds containing benz [g] indolo [2, 3-a] quinolizine ring systems, e.g. yohimbine; 16, 18-lactones thereof, e.g. reserpic acid lactone

Definitions

• This invention relates to novel substituted-methylene derivatives of ring E keto yohimbe alkaloids and, more particularly, is concerned with novel substituted-18-methylene derivatives of l7-ketoyohimbane which may be represented by the following general formula:
• R is lower alkylthio, lower alkylamino, di(lower alkyl)amino, lower cycloalkylamino, anilino, substituted anilino, naphthylamino, pyrrolidino, piperidino, morpholino, pyridylamino, pyridylmethylamino, 4-substituted piperazino, 4-substituted piperidino, lower alkoxy(lower alkyl)amino and di(lower alkyl)amino(lower alkyl)- amino.
• Suitable di(lower alkyl)amino substituents contemplated by the present invention are those having from 2 to 8 carbon atoms such as, for example, dimethylamino, diethylamino, di-n-propylamino, di-n-butylamino, (N-ethyl-N-hexyl)amino, etc.
• Suitable lowercycloalkylamino substituents may be cyclopropylamino, cyclopentylamino, cyclohexylamino, and the like.
• Suitable substituted anilino groups may be, for example, lower alkoxyanilino and lower alkylanilino wherein the lower alkoxy and lower alkyl groups are from 1 to 3 carbon atoms, haloanilino, acetamidoanilino and di(lower alkyl)aminoanilino wherein the di(lower alkyl)amino group is from 2 to 6 carbon atoms.
• Pyridylamino is exemplified by 2- pyridylamino, 3-pyridylarnino and 4-pyridylamino; whereas pyridylmet-hylamino is exemplified by Z-pyridylmethylamino, 3-pyridylmethylamino and 4-pyridylmethylamino.
• Suitable 4-substituted .piperazino substituents may be represented by the following formula:
• R is phenyl, lower alkyl of from 1 to 4 carbon 3,250,768 Patented May 10, 1966 atoms, lower alkoxycarbonyl of from 2 to 4 carbon atoms or a side chain of the formula:
• n is a whole number from 1 to 4 and R" is cyano, acetamidomethyl, lower alkoxy of from 1 to 4 carbon atoms, lower alkanoyl of from 2 to 4 carbon atoms, lower alkanoyloxy of from 2 to 4 carbon atoms, lower alkoxycarbonyl of from 2 to 4 carbon atoms or a side chain of the formula:
• n is a whole number from 1 to- 4.
• Suitable lower alkoxy(lower -alkyl)amino substituents contemplated by the present invention may be represented by the following formula: NHC H -OR" wherein R' is lower alkyl of from 1 to 3 carbon atoms and n is a whole number from 2 to 4.
• Suitable di(lower alkyl)-amino(lower alkyl)amino substituents contemplated -by the present invention may be represented by the following general formula:
• novel compounds of the present invention are, in general, white to tan crystalline solids, the free bases of which are soluble in organic solvents such as lower alkanols, chloroform, dimethylformamide, dioxane, pyridine and the like; and the salts of which are soluble in polar solvents such as water or lower alkanols.
• the organic free bases of this invention form non-toxic acid addition salts with a variety of organic and inorganic salt-forming agents.
• acid-addition salts formed by admixture of the organic free base with an acid, suitably in a neutral solvent, are formed with such acids as sulfuric, phosphoric, hydrochloric, hydrobromic, sulfamic, citric, lactic, tartaric, acetic, gluconic and the like.
• the free bases are equivalent to their non-toxic acid-addition salts.
• novel compounds of the present invention are valuable hypotensive agents of low toxicity and may be administered orally or parenterally. When so administered they have been found to exhibit hypotensive action in amounts ranging from about 25 to about 350 milligrams per kilogram of body weight. of the novel compounds of the present invention are also useful as anorexigenic agents and some have been found to exhibit tranquilizing action.
• novel compounds of the present invention may be prepared from yohimban-l7-one which has been described by Witkop, Ann. 554, 83 (1943).
• the first step in the synthesis of the novel compounds of the present invention In addition, some 'benzene was added 14 ml. of ethyl formate.
• IS-hyone intermediate may be treated with an appropriate 1 primary or secondary amine at temperatures of from 50 .C. to 100 C. for periods of time ranging from half an hour to 5 hours whereby the corresponding monosubstituted aminomethylene or disubstituted aminomethylene derivatives of yohimban-l7-one may be readily obtained.
• novel compounds of the present invention may be used as such but more preferably are used in the form of their non-toxic acid-addition salts which may be readily prepared as described hereinabove.
• Example I.Preparati0n 0 18-hydroxymethyleneyohimban-17-0ne To a cooled mixture of 10.0 g. of yohimban-17-one, 10.0 g. of sodium methoxide, and 300 ml. of sodium-dried The mixture was stirred under nitrogen at room temperature for 20 hours and poured onto a mixture of 300 g. of ice and 200 ml. of water. The organic layer was separated and washed with three, 100-ml. portions of 0.1 N sodium hydroxide. The basic washings and aqueous layer were combined and neutralized in the cold with acetic acid. Filtration afforded 9.4 g.
• Example 2 Preparation of 18-hydr0xymethylene yohimban-U-one A mixture of 5.0 g. of yohimban-l7-one, 5.0 g. of
• Example 3 Preparati0n of 18-n-butylthiomethyleneyohimban-J 7-0ne
• a mixture of 0.663 g. of lS-hydroxymethyleneyohimban-17-one, 2.0 g. of magnesium sulfate, and 5.0 ml. of l-butanethiol was added ml. of acetic acid.
• the mixture was stirred at room temperature for 20 hours and filtered. The filtrate was partitioned between 50 ml.
• Example 4 Preparation of 18-n-butylaminometlzylerzeyohimban-I 7-0ne
• Example 5 Preparaii0n of 18-is0butylamin0metlzyleneyohimban-17-0ne
• Example 8.-Preparati0n 0f 18-di-n-pr0plaminomethyleneyalzimban-I 7-0ne A mixture of 8.29 g. of 18-hydroxyyohimban-17-one, 6.0 ml. of dipropylarnine and 100 ml. of ethanol was refluxed for 1.5 hours. The mixture was chilled and filtered to give 7.75 g. of yellow crystals, M.P. 241 245 C. (dec.). Recrystallization from ethanol gave 6.70 g. of 18-di-n-propylaminomethyleneyohirnban-17-one as tan crystals, M.P. 236-238 C. (dec.).
• Example 9.-Preparati0n of 18-cyclohexylaminomezhyleneyohim'ban-l 7 -one A mixture of 8.29 g. of -1S-hydroxymethyleneyohimban-17-one, 6.0 ml. of cyclohexylamine and 100 ml. of ethanol was refluxed for 1.5 hours. The mixture was .chilled and filtered to give 5.6 g. of tan crystals, M.P.
• Example 10 Preparati0n of 1-8-anilin0methyleneyolzimban-l7-one
• the mixture was cooled and filtered to give 2.55 g. of l8 anilinomethyleneyohimban- 17-one, containing one-fourth mole of water of crystallization, as yellow crystals, M.P. 305-310 C. (dec.). Recrystallization from N,N-dimethyltormamide afforded yellow crystals, M.P. 303 -3 07 C. (dec.).
• Example 11-Preparati0n of 18-pyrr0lidin0methyleneyohim ban-1 7-0ne A mixture of 2.0 g. of 18-hydr0xymethyleneyohimban- 17-one and 1.5 of distilled pyrrolidine in 30 ml. of absolute ethanol was refluxed for two and one-half hours. Cooling and filtration gave 1.49 g. of 18-pyrrolidinomethyleneyohimban-l7-one as yellow crystals, M.P.
• Another compound which can be prepared according to the above-described procedure is 18-piperidinomethyleneyohimban-17-one.
• Example 12.Preparati0n of 18-m0rph0lin0methyleneyohimban-I 7-0ne A mixture of 6.63 g. of 18hydroxymethyleneyohimban-17-one, 2.0 m1. of morpholine and ml. of ethanol was refluxed for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate-acetone (:5) was treated with activated carbon and filtered. The filtrate was chilled and filtered and the precipitate was washed with ethyl acetate to give 4.1 g. of orange amorphous solid. The solid was dissolved in dichloromethane and chromatographed over 3.5 g. of Florsil.
• Example 13 --Preparati0n of 18-(2-pyridylamin0) methyleneyohimban-l 7-0ne
• Example 14 Preparati0n of 18-(3-pyridylamin0)methyleneyohim ban-1 7-0ne
• the mixture was chilled and filtered to give 5.5 g. of yellow crystals, M.P. 308311 C. (dec.). Concentration of the filtrate gave an additional 1.3 g. of product, M.P. 300-304 C. (dec.).
• the two crops of crystals were combined, dissolved in dichloromethane-acetone, and the solution con centrated. Chilling and filtering gave 3.0 g. of 18-(3- pyridylamino)methyleneyohimban-l7-one as yellow crystals, M.P. 311 -314 C. (dec.).
• Example I5.Preparazi0n of 18-(4-pyridylamino )methyleneyohimban-l 7-0ne A mixture of 6.63 g. of l8-hydroxymethyleneyohimban-17-one, 2.07 g. of 4-aminopyridine and 75 ml. of ethanol was refluxed for 2 hours. The dark solution was treated with activated carbon, filtered and the filtrate diluted with cyclohexane. The mixture was chilled and filtered and the filtered concentrated to a glass. The glass was dissolved in acetone and the solution diluted with water. Chilling and filtering gave 1.8 g. of product which was recrystallized from acetone to give 18 (4- pyridylamino)methyleneyohimban-l7-one as tan crystals, M.P. 306-309 C. (dec.).
• Example J6.-Preparati0n of 18-(2-pyridylmethylamino)methyleneyohimban-1 7-0ne A mixture of 6.63 g. of 18-hydroxymethyleneyohim- :ban-17-one, 2.38 g. of 2-aminomethylpyridine and 75 ml. of ethanol was refluxed for 1.5 :hours. The solvent was removed under reduced pressure and the residue was dis- 7 solved in acetone. The solution was diluted with ethyl acetate and the insoluble gum which separated was removed by filtration. The filtrate was concentrated under reduced pressure to give a glass which was dissolved in 50 ml. of hot benzene. Dilution with ml.
• Ch-illing and filtering gave 3.58 g. of 18-(2- pyridylmethylamino)methyleneyohimban-17-one as a tan amorphous solid, sinters above 100 C. to a red glass which slowly changes to a dark liquid.
• Example 17 Preparation of 18-(3-pyriaylmethylamino) methyleneyohimban-l 7-one A mixture of 6.63 g. of 18-hydroxymethyleneyohimban- 17-one, 2.38 g. of 3-aminomethylpyridine and 75 ml. of
• Example 1 8 Prepaiati0n of 1 8-( 4 -pyridylmethylamino meihyleneyohimban-I 7-0ne
• Example 19 Preparati0n of l8-(4-etlzoxycarbonyl-1- piperazinyl -metkyleney0himban-l 7-0ne A mixture of 8.29 g. of 1S-hydroxymethyleneyohim- 18- (4methoxycarb onyl- 1 -pip erazinyl) methyleneyohimban-17-one,
• Example 20 Preparati0n 0 f 18- [4-(3-dimethylaminopropyl -I-piperazinylmethylene] yohimban-l 7-0ne
• the solvent was removed under reduced pressure and benzene 3 was added several times and the solvent removed after each addition under reduced pressure.
• the residue was dissolved in acetone and the solution was treated with activated carbon and filtered. ,The filtrate was diluted with heptane and filtered.
• Example 2 Preparatz'on 0 f 18- [4- (3-dimetlzylaminopropyl -pz'peridin0methylene] yohim ban-I 7-one
• Example 23 Preparati0n of 18- (3-dimethylaminopropylamino) methyleneyohimban-l 7-0ne
• Several recrystallizations from acetone with the aid of activated charcoal give 3.2 g. of 18-(3-dimethylaminopropylamino)methyleneyohimban 17 one as tan crystals, MP. 201 203 C. (dec.).
• Example 24 Preparati0n of 18-(4-acetamid0methyl-4- phenylpiperz'dino)methyleneyohimban-17-0ne l8-(4-cyano-4-phenylpiperidino)methyleneyohimbanl7-one, 18-(4-ethoxycarbonyl-4-phenylpiperidino)methyleneyohimban-l7-one, 18-(4-acetyl-4-phenylpiperidino)methyleneyohimban- 17-one, 1 8- (4-ethoxy-4-phenylpiperidino )methyleneyohimbanl7-one, l8-(4-acetoxy-4-phenylpiperidino)methyleneyohimbanl7-one.
• R is selected from the group consisting of lower alkylthio; lower alkylamino; di(lower alkyl) amino; lower cycloalkylamino; anilino; lower alkoxyanilino; lower alkylanilino; haloanilino; acetamidoanilino; di(lower alkyl)aminoanilino; naphthylamino; pyrrolidino; piperidino; morpholino; pyridylamino; pyridylmethylamino; 4- substituted piperazino of the formula:
• R is selected from the group consisting of phenyl, lower alkyl, lower alkoxycarbonyl and a side chain of the formula:
• n is a whole number from 1 to 4 and R" is selected from the group consisting of cyano, acetamidomethyl, lower alkoxy, lower alkanoyl, lower alkanoyloxy, lower alkoxycarbonyl and a side chain of the formula:
• R is lower alkyl and n is a whole number from 2 to 4 and di(lower alkyl) amino(lower alkyl)amino.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Hydrogenated Pyridines (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 0
  • FR FR187D patent/FR187F/fr active Active
• 1965
  • 1965-04-28 US US451627A patent/US3250768A/en not_active Expired - Lifetime
• 1966
  • 1966-04-14 GB GB16476/66A patent/GB1089509A/en not_active Expired
  • 1966-04-22 NL NL6605424A patent/NL6605424A/xx unknown
  • 1966-04-22 BE BE679907D patent/BE679907A/xx unknown
  • 1966-04-22 ES ES0325829A patent/ES325829A2/es not_active Expired

Non-Patent Citations (1)

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