US3285914A - 3-n-substituted derivatives of oripavine and thebaine - Google Patents

Description

United States Patent 3,285,914 3-N-SUBSTITUTED DERIVATIVES 0F ORIPAVINE AND THEBAINE Maxwell Gordon, Elkins Park, Pa., assignor to Smith Kline & French Laboratories, Philadelphia, Pa., a corporation of Pennsylvania No Drawing. Filed June 11, 1964, Ser. No. 374,242

15 Claims. (Cl. 260-2475) This invention relates to novel thebaine and oripavine derivatives which have analgetic action of long duration.

It is well known that thebaine, a morphine congener, is a powerful central nervous system stimulant, almost a convulsant, and possessing very little analgetic activity; see Morphine & Allied Drugs, Reynolds and Randall, U. of Toronto Press, 1957, p. 169. Thebaine is generally conceded to be a clinically useless drug because of this stimulating effect. It is also known to the art that certain other morphine analogs, such as oripavine, are also central nervous system stimulants.

I have surprisingly discovered that certain thebaine and oripavine derivatives are not central nervous system stimulants, but on the contrary are potent central nervous system depressants. Furthermore, these new compounds have analgetic activity and as to other analgetics, they are antagonistic. These compounds also have utility as intermediates for preparing further central nervous system depressant compounds as will become apparent to those skilled in the art.

The compounds of this invention are graphically represented by the following structural formula:

Formula T wherein:

R is methoxymethyl, nicotinoyl, or morpholinoethyl;

R is cyclopropylmethyl, dimethylallyl, or propargyl; and

R is lower alkyl having 1 to 5 carbon atoms, or phenacyl.

Advantageous compounds are those wherein R represents either nicotinoyl or methoxymethyl, and R represents cyclopropylmethyl or dimethylallyl.

Advantageous and preferred compounds are those wherein R and R are the same as in the advantageous compounds and further wherein R" is a lower alkyl.

The most preferred compounds are those wherein R represents either nicotinoyl or methoxymethyl, R represents cyclopropylrnethyl, and R represents butyl.

This invention also includes, as well as the basic compounds of Formula I, the N-oxide derivatives thereof, and the nontoxic acid addition or quaternary ammonium salts of the thebaine and oripavine bases or the N-oxides thereof.

The N-oxide derivatives of this invention are more specifically represented by the following structural formula:

Formula II wherein:

R is methoxymethyl, nicotinoyl, or morpholinoethyl;

R is cyclopropylmethyl, dimethylallyl, or propargyl; and

R is lower alkyl having 1 to 5 carbon atoms, or phenacyl.

For example, the acid addition salts are those with pharmaceutically acceptable acids such as hydrochloric, maleic, sulfuric, phosphoric, sulfamic, benzoic, salicylic, acetic, hydrobromic, ethanedisulfonic, etc. acids. The pharmaceutically acceptable quaternary ammonium salts are those with active quaternizing agents such as lower alkyl iodides, chlorides or bromides, benzyl chloride, ethylene chlorohydrin, lower alkyl sulfates, etc. These acid addition or quaternary salts of the thebaine or oripavine compounds, and the N-oxides thereof, are prepared by methods well known to the art such as reacting the base in an organic solvent With an equivalent amount of the acid or quaternizing agent.

The compounds of Formula I are generally prepared by treatment of thebaine with the appropriate ketone to form a 6,l4-endoetheno-7a-(2-one-2-alkyl)-tetrahydrothebaine. The latter ketone is treated with a Grignard reagent to yield the corresponding tertiary alcohol, a 6,14- endoetheno c (2 hydroxy 2 alkyl) tetrahydrothebaine. This alcohol is the starting intermediate for synthesis of the novel thebaine and oripavine derivatives of this invention.

The tertiary alcohol is next converted to the corresponding nor compound by treatment with a cyanogen halide, followed by an alkali metal hydroxide to form 6,14 endoetheno 70c (2 hydroxy 2 n alkyl)- tetrahydronorthebaine. This latter compound is treated with an alkanoyl halide to form an N-alkanoyl intermediate, followed by reduction to the corresponding N-alkyl thebaine with a bimetallic hydride, such as lithium aluminum hydride.

Depending upon what substituents are desired for R, various oripavine derivatives can next be prepared by re placing the phenolic methyl group with other selected substituents, such as hydrogen or a hydrocarbon group. Typically the last mentioned thebaine derivative is treated with an alkali metal hydroxide dispersed in a polar hydrocarbon solvent to form its oripavine analog, an N-alkyl- 6,14 endoetheno 71x (2 hydroxy 2 n alkyD-tetrahydronororipavine.

The oripavine derivative is then treated with a reagent such as nicotinoyl halide in the presence of pyridine medium. The recovered product is a 3-subs'tituted oripavine, such as 3-nicotinoyloxy-N-alkyl-6,14-endoetheno-7oc- (2-hydroxy-2-n-alkyl)-tetrahydronororipavine.

The N-oxide derivatives of this invention (Formula II) are prepared by reacting the base of Formula I with an excess of peracid or 30% aqueous hydrogen peroxide, usually with gentle heating. These N-oxide derivatives. form acid addition or quaternary salts as noted herea-bove. The acyl derivatives (Formula I, R=acyl) are prepared by reacting the compounds of Formula I, in which R is hydrogen with an equivalent or an excess of the appropriate acyl chloride or anhydride usually in the presence I of an acid binding agent such as pyridine or triethylamine benzene. The nicotinoyl esters are particularly useful.

These methods of synthesis will become apparentton one skilled in the art by the following generalized reaction scheme coupled with the exemplification set forth in the examples that follow i r to give the desired 3-nicotinoyl derivative of N-cyclopropylmethyl 6,14 endoetheno-7oc (2 hydroxy-Z-npentyl)-tetrahydronororipavine.

Example 2 The corresponding compound in the 7B-series, 3-nicotinoyloxy-N-cyclopropylmethyl-6,l4-endoetheno 75 (2- hydroxy-Z-n-pentyl)-tetrahydronororipavine, is prepared by starting with the corresponding thebaine isomer, that is, with 6,l4-endoetheno-7,8-(Z-hydroxy-Z-m-pentyl)-tetrahydrothebaine.

Example 3.Preparatin of 3-meth0xymethyl ether of N-(3',3'-dimethylallyl)6,14-end0etheno 7a (2 hydr0xy-4 0x0-4-phenyl-2-n-butyl) tetrahydronororipavine Five grams of N-(3,3-dirnethylallyl)-6,l4-endoetheno- 7a-(2-hydroxy-4-oxo-4-phenyl-2-n-butyl) tetrahydronororipavine is prepared from 6,14-endoetheno-7u-(Z-hydroxy-4-oxo-4-phenyl-2-n-butyl) tetrahydrothebaine, by demethylation of both the nitrogen and 3-oxygen and reaction With 3,3-dimethylacrylyl chloride followed by lithium aluminum hydride reduction, as described in Example 1. The oripavine derivative is dissolved in a warm solution of 11 ml. of a 2:1 ethanol-water mixture into which had been suspended 0.48 g. of sodium hydride. Benzene is added and distilled off several times until the water is azeotroped off. The residue is dried over concentrated sulfuric acid. Freshly distilled chloromethyl ether (0.75 g.) is added to the sodium salt of the nororipavine in 20 ml. of dry chloroform, and then the mixture is stoppered and after vigorous shaking is allowed to stand overnight. The mixture is then washed with bicarbonate solution, dried and the solvent evaporated. The residue is chromatographed on 100 mg. of alumina giving the 3-rnethoxymethyl ether of N-(3',3-dimethylallyl) 6,14 endoetheno-7u-(Z-hydroxy-4-oxo-4-phenyl- Z-n-butyl) -tetrahydronororipavine.

Example 4 The corresponding compound in the 7fi-series, 3- methoxymethoxy-N-(3',3-dimethylallyl) 6,14 endoetheno- 7B (2-hydroxy-4-oxo-4phenyl-2-butyl) tetrahydronororipavine, is also prepared, starting with N-(3',3'-dimethylallyl) 6,l4-endoetheno-7fl-(2-hydroxy-4-oxo-4-phenyl- 2-butyl) -tetrahydronororipavine.

Example 5 .Preparation of a nicotinoyloxy N cyclopropylmethyl-6,14-end0ethen0-7-3-(2 hydroxy-4-phenyl-4-0x0-2-butyl -tetrahy dronororipavine Example 6 The corresponding 7,8-derivatives, 3-nicotinoyloxy-N- cyclopropylmethyl-6,14-endoetheno 7,8 (2-hydroxy-4- phenyl-4-oxo-2-butyl) tetrahydronororipavine, is prepared starting with 6,14-endoetheno-7fi-(2-hydroxy-4- phenyl-3 -ketobutyl -tetrahydrothebaine.

Example 7 N-cyclopropylmethyl 6,14 endoethen-o 7a (2-hydroxy-4-phenyl-4-oxo-2-butyl)-tetrahydronororipavine intermediate of Example 5 is converted to the 3-methoxymethyl ether, as described in Example 3.

Example 8 The corresponding 7p-derivatives, 3-methoxy-methoxy- N-cyclopropylmethyl 6,14-endoetheno 7p-(2-hydroxy- 8 4-phenyl-4-oxo-2-butyl) tetrahydronororipavine, is also prepared starting with N-cyclopropylmethyl 6,14-endoetheno-7p (Z-hydroxy-4-phenyl-4-oxo-2-butyl)-tetrahy dronororipavine.

Example 9.Preparati0n of N-propargyl-6,I4-end0ethelm-7a-(Z-hydroxy-Z-n-pemyl)-tetrahydr0n0rthebaine Ten grams of 6,14-endoetheno-7a-(2-hydroxy-2-n-pentyl)-tetrahydronorthebaine (from Example 1) is heated in ethanol for 30 hours under reflux with 10 g. of sodium carbonate and 3 g. propargyl bromide. The mixture is filtered to remove salt and evaporated to give a viscous syrup which can be recrystallized from benzene to give N-propargyl 6,14-endoetheno-7a (Z-hydroxy-Z-n-pentyl) -tetrahydronorthebaine.

Example 10.--Preparati0n of 3-m0rpholin0ethyl-N-propargyl 6,14-end0etheno-7a (2-hydroxy-2-n-pentyl)- tetrahydronorthebaine N-propargyl-6,l4-endoetheno-7a (2-hydroxy-2-n-pentyl)-tetrahydronorthebaine is demethylated as described in Example 1 to give N-propargyl-6,l4-endoetheno-7u- (Z-hydroxy-Z-n-pentyl)-tetrahydronororipavine. The sodium salt of 5 g. of the latter compound, prepared as in Example 3, is reacted with 2 g. of 2-N-(rnorpholino)- ethyl chloride in 20 ml. of dry chloroform by shaking in a stoppered flask and allowing to stand overnight. The product is worked up by washing with bicarbonate solution, drying, and evaporation of the chloroform. Chromatography on alumina gives the 3-(2'-N-morpholino)- ethyl ether of N-propargyl-6,l4 endoetheno-7a-(2-hydroxy-Z-n-pentyl -tetrahydronorthebaine.

What is claimed is:

1. A compound selected from the group consisting of a base, and the pharmaceutically acceptable acid addition salts thereof, said base being of the structure:

wherein R is a member selected from the group consisting of methoxymethyl, nicotinoyl and morpholinoethyl; R is a member selected from the group consisting of cyclopropylmethyl, propargyl and dimethylallyl; and R is a member selected from the group consisting of lower alkyl having 1 to 5 carbon atoms, and phenacyl. 2. A compound selected from the group consisting of a base, and the pharmaceutically acceptable acid addition salts thereof, said base being of the structure:

wherein R is nicotinoyl; R is a member selected from the group consisting of cyclopropylmethyl, propargyl and dimethylallyl; and R" is a member selected from the group consisting of lower alkyl and phenacyl.

3. A compound selected from the group consisting of a base, and the pharmaceutically acceptable acid addition salts thereof, said base being of the structure:

wherein R is methoxymet'hyl;

R is a member selected from the group consisting of cyclopropylmethyl, propargyl and dimethylallyl; and

R" is a member selected from the group consisting of lower alkyl having 1 to 5 carbon atoms, and phenacyl.

4. 3-nicotinoy1oxy N-cyclopropy-lrnethyl 6,14-endoetheno-7u (2-hydroxy Z-n-pentyl) tetrahydronororipavine.

5. 3-nic0tinoy10xy N-cyclopropylmethyl 6,14-endoetheno-7/3 (Z-hydroxy Z-n-pentyl) tetrahydronororipavine.

6. N-(3',3'-dimethy1a11yl) 6,14-endoetheno 7a-(2- hydroxy-Z-n-pentyl -tetrahydronororipavine.

7. N-(3,3-dimethyla11y1) 6,14-endoetheno 75-(2- hydroxy-Z -n-penty1) -tetrahydronororip avine.

References Cited by the Examiner FOREIGN PATENTS 969,263 9/1964 Great Britain.

ALEX MAZEL, Primary Examiner.

HENRY R. JILES, Examiner.

DONALD G. DAUS, Assistant Examiner

Claims (1)

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A BASE, AND THE PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF, SAID BASE BEING OF THE STRUCTURE: