US3755367A - Substituted 1,4-benzodioxanes - Google Patents

Abstract

THE INVENTION PROVIDES BASICALLY 2-SUBSTITUTED 1,4-BENZODIOXANES HVAING THE GENERAL FORMULA:

2-(R1-SO2-(CH2)N-NH-CH2-),R-1,4-BENZODIOXANE

WHERE R IS A HYDROGEN ATOM, A HALOGEN ATOM HAVING AN ATOMIC NUMBER NOT EXCEEDING 35 OR AN ALKYL OR ALKOXY GROUP HAVING FROM ONE TO SIX CARBON ATOMS, R1 IS A SATURATED ALIPHATIC GROUP HAVING ONE TO EIGHT CARBON ATOMS, AND N IS AN INTEGER FROM 2 TO 6 AND ACID ADDITION SALTS OF SUCH BENZODIOXANES. THE COMPOUNDS ENCHIBIT AN UNUSUSAL COMBINATION OF TRANQUILISING, TAMING AND AGGRESSION-BUILDING ACTIVITY WHEN ADMINISTERED TO RATS.

Description

United States Patent 3,755,367 SUBSTITUTED 1,4-BENZODIOXANES Peter Nichol! Green, Liverpool, and Maurice Shapero, Edgeware, England, assignors to Ward Blenkmsop & Company Limited, Wemhley, England No Drawing. Filed Sept. 24, 1971, Ser. No. 183,684 Claims priority, application Great Britain, Sept. 24, 1970, 45,671/70 Int. Cl. C07d 15/12 US. Cl. 260-3403 6 Claims ABSTRACT OF THE DISCLOSURE The invention provides basically Z-substituted 1,4-benzodioxanes having the general formula:

where R is a hydrogen atom, a halogen atom having an atomic number not exceeding 35 or an alkyl or alkoxy group having from one to six carbon atoms,

R is a saturated aliphatic group having one to eight carbon atoms, and

n is an integer from 2 to 6 and acid addition salts of such benzodioxanes. The compounds exhibit an unusual combination of tranquilising, taming and aggression-building activity when administered 10 rats.

This invention relates to the production of pharmacologically valuable 1,4-benzodioxanes.

The present invention provides a basically 2-substituted 1,4-benzodioxane having the general formula:

NH H .R I O CHz (C 2) S02 (1) in which R is a hydrogen atom, a halogen atom having an atomic number not exceeding 35 or an alkyl or alkoxy group having one to six, preferably one or two, carbon atoms, R is a saturated aliphatic group having one to eight, preferably two to six, carbon atoms and n is an integer from Q, to 6, and acid addition salts of such benzodioxanes.

The substituent R may be present in any of the four available positions in the benzene ring of the '1,4-benzodioxane nucleus, i.e., in the 5-, 6-, 7- or 8-position. The group R may be, for example, chlorine, bromine, methyl, ethyl, methoxy or ethoxy, but is most preferably hydrogen.

The acid addition salt may be any pharmacologically acceptable salt, for example, the hydrochloride, hydrobromide, sulphate, phosphate, acid maleate, acid succinate, acid tartrate or lactate of the said 1,4-benzodioxanes.

The substituent R may be an alkyl group having one to eight, preferably tWo to six, carbon atoms and may be a straight chain orbranched chain alkyl group. When it is a branched chain alkyl group it may be atertiary-alkyl group. Examples of suitable alkyl groups are methyl ethyl, isopropyl, n-butyl, isobutyl, secondary-butyl, tertiary-butyl, secondary-amyl, tertiary-amyl, n-hexyl, 2,2-dimethyl-nbutyl, 3,3-dimthyl-n-propy1, tertiary-heptyl and tertiaryoctyl. Alternatively R may be a cycloalkyl group, for example a cyclohexyl group.

The group (CH is a'polymethylene group containing not more than six carbon atoms: it is preferred that this group consist of two, threeor four methylene groups.

According to a feature of the invention basically substi- 3,755,367 Patented Aug. 28, 1973 with a mono-substituted alkyl sulphone having the general formula in which formulae R, R and n are as above-defined, one of X and Z is a halogen atom and the other is a primary amino group.

Thus the reaction may be between a Z-aminomethyl- 1,4-benz-odioxane and a straight chain omega-haloalkyl sulphone in which the second organic group attached to sulphur is a saturated aliph'atic group having 1 to 8 carbon atoms, or between a 2-halomethyl-1,4-benzodioxane and a straight chain omega-aminoalkyl sulphone in which the second organic group attached to sulphur is a saturated aliphatic group having 1 to 8 carbon atoms. Both of these reactions lead to the formation of a hydrohalide of the 2-substituted 1,4-benzodioxane. This hydrohalide may be subsequently decomposed by treating the crude product with an acid acceptor. It is preferred to use an inorganic acid acceptor and to carry out the reaction in the presence of a solvent for the base being liberated. After separation of the organic phase containing the free sulphone base, solvent and any low boiling volatile materials can be removed therefrom, the residue taken up in a volatile solvent and treated with a solution of an acid in order to form the corresponding salt.

The Z-aminomethyl-l,4-benzodioxane from which the compounds of the present invention may be obtained include Z-aminomethyl-1,4-benzodioxane, 2-aminomethyl-7-chloro-1,4-benzodioxane, Z-aminomethyl-S-methyl-l,4-benzodioxane and 2-aminomethyl-8-methoxy-1,4-benzodioxane.

compounds of the present invention may also be obtained include Z-chloromethyl-1,4-benzodioxane, 2-bromomethyl-1,4-benzodioxane, 2-chloromethyl-7-chloro-1,4-benzodioxane, Z-chloromethyl-S-methyl-1,4-benzodioxane and Z-chloromethyl-S-methoxy-1,4-benzodioxane.

Examples of straight chain omega-aminoalkyl sulphones which may be reacted with the 2-halomethyl-1,4-benzodioxanes include tertiary-butyl-Z-aminoethyl sulphone, methyl 3-amino-n-propyl sulphone, ethyl 3-amino-n-propy1 sulphone, iso-propyl S-amino-n-propyl sulphone, tertiarybutyl 3-amino-n-propyl sulphone, tertiary-amyl 3-aminon-propyl sulphone, tertiary-butyl 4-amino-n-butyl sulphone, tertiary-butyl S-amino-n-pentyl sulphone, tertiarybutyl 6-amino-n-hexyl sulphone and cyclohexyl 3-amino-npropyl sulphone.

According to an alternative feature of the invention basically substituted 1,4-benzodioxanes having the first general formula given above may also be prepared by a process which comprises reacting a solution in an organic solvent of an acylated 2-substituted 1,4-benzodioxane having the general formula:

in which R, R and n are as defined above with a miscible solution of hydrogen peroxide in an organic organic solvent, and thereafter hydrolysing the N-acyl group with a strong acid.

The acylated Z-substituted 1,4-benzodioxanes are in turn prepared by the acylation of basically 2-substituted 1,4-benzodioxanes having the general formula in which R, R and n are as above defined. Suitable acylating agents are the acid halides and anhydrides of aliphatic and aromatic monocarboxylic acids such as acetic and propionic anhydrides and benzoyl chloride.

The basically substituted 1,4-benzodioxanes having the General Formula V may be prepared by the reaction of a Z-monosubstituted-methyl 1,4-benzodioxane having the General Formula II with a mono-substituted alkyl sulphide having the general formula in which R Z and n are as above defined. The preparation of such compounds in which R is a hydrogen atom or an alkoxy group is described in ED. Auslegeschrift No. 1,118,218: amongst the compounds disclosed therein are 2- w-methylmercapto-n-butylaminomethyl l ,4

benzodioxane,

2- (w-methylmercapto-n-propylaminomethyl) 1 ,4-

benzodioxane,

2-(w-ethylmercapto-n-propylaminomethyl)-1,4-

benzo dioxane,

2- w-butylmercapto-n-propylaminomethyl) -1 ,4-

benzo dioxane,

5-methoxy-2- w-me thylmercapto-n-propylarninomethyl 1,4-benzodioxane,

8 -methoxy-2- w-methylmercap to-n-propylaminomethyl) 1,4-benzodioxane and 8 ethoxy 2-(w-methylmercapto-n-propylamiuomethyl)- 1,4benzodioxane. Those compounds containing in the benzene ring of the 1,4-benzodioxane nucleus a halogen atom or an alkyl group may be prepared by analogous procedures. When produced by this process the compounds of the invention are conveniently obtained as the salts thereof with the acid used to effect the deacylation.

With respect to the oxidation of the acylated 2-substituted 1,4-benzodioxanes with hydrogen peroxide it is preferred to use the same organic solvent for both the acylated 1,4-benzodioxane and the hydrogen peroxide. The normally liquid alkane monocarboxylic acids, especially acetic acid, are suitable for this purpose. The oxidation is an exothermic reaction and it is therefore desirable to add the hydrogen peroxide solution over a period of time so as to prevent the temperature of the reaction mixture exceeding a predetermined maximum of, for example, 50 C. After completion of the reaction the resulting sulphone is conveniently isolated by taking advantage of its solubility in an organic solvent in which the organic solvent used to carry out the reaction is substantially insoluble, the solution freed from any residual hydrogen peroxide, and the produce then hydrolysed with a strong acid, conveniently after removal of the organic solvent.

The compounds of the present invention have been tested upon mice and rats and have been found to exert muscle relaxant, sedative, tranquilising and taming properties thereon.

An unusual feature of the compounds of the invention is their ability to induce agressive behaviour in male rats 12 to 24 hours after administration.

At suitable dose levels, the compounds of the invention appear able to induce in rats a characteristic combination of quietness or tameness and self-confidence in the face of aggression. This effect is however biphasic, and is superseded at higher dose levels by relaxant effects.

These compounds in which R is a branched chain alkyl group and n is three have been found to exert muscle relaxant properties in rats for which ED is 0.1-1.0 mg. per kilogram bodyweight when administered subcutaneously and 10-100 mg./kg. when administered orally. The approximate LD values were 400 mg. per kilogram bodyweight when administered subcutaneously and greater'than 400 mg. per kilogram when administered orally.

When administered subcutcaneously to mice muscle relaxant properties have been observed for the same compounds for which the ED5G value is about 36 mg. per kilogram bodyweight and the LD value is about 285 mg. per kilogram bodyweight: the corresponding values when administered orally being 25 mg./kg. and 400 mg./ kg; respectively.

Doses of 10, 20, 40, 60 and mgJkg. in 1% Tween 80 of the products of Examples 1, 2/3, 8 and 9 set out below were injected into rats intraperitoneally daily for 4 days. On the 4th day the rats were tested for the drugs elfect on behaviour. 8 male rats were used per dose and a similar number recevied 1% Tween 80 as a control.

A significant increase in aggressive behaviour over the controls was found in the groups receiving 20 mg.'/kg. (P 0.025), with the maximum effect at 40 mg'/kg. (P 0.05). Doses greater than 80 mg./kg. depressed aggressive behaviour. The approximate acute oral and subcutaneous LD in rats is 400 mg./kg.

A single dose of 10 mg./kg. intraperitoneally in a group of ten mice reduced exploratory behaviour when placed in a Y-maze. The results were statistically significant (P 0.-02). The approximate acute oral LD is 400 mg./kg.: subcutaneously it is 250 rug/kg.

A statistical test for significance between the treated rats and the controls was evaluated by the Mann-Whitney U-test. 5 mg/kg. intramuscularly produced muscle relaxation in the monkey. No adverse side effects were observed. 1

An unusual feature of the compounds of the invention is their ability to induce aggressive behaviour in male rats 12 to 24 hours after administration.

The following examples illustrate the production of the compounds of the invention:

EXAMPLE 1 2- (3 '-tertiary-amylsulphonyl-n-propyl) aminomethyl1- 1,4-benzodioxane Z-aminomethyl-l,4-benzodioxane (26.1 g.) and 3-tertiary-amylsulphonyl-n-propylchloride 16.7 g.) were heated at C. for two hours prior to mixing with 2 N caustic soda (40 mls.) and extracted with chloroform (once with 20 mls. and twice with 10 mls.). The chloroform extracts were combined and the combined extracts distilled to a final residue temperature of 220 C; at 0.05 mm. of mercury. 5 N hydrochloric acid (55 mls.) was added to the cooled residue and the mixtures refluxed whilst ethanol (16 mls.) was added, thus giving homogeneity. After cooling, the solution was extractedwith chloroform (once with 25 mls. and twice with 10 mls.) and anhydrous diethyl other (225 mls.) added to the combined chloroform extracts. The mixture was allowed EXAMPLE 2 2- (3 '-tertiary-butylsulphonyl-n-propyl) aminomethyl] -1,4benzodioxane Z-aminomethyl-1,4-benzodioxane (82.5 g.) and 3- tertiary butylsulphonyl-n-propylchloride (50 g.) were heated at 150 C. for 2 hours prior to mixing with 2 N caustic soda (125 mls.) and then extracted with chloroform (oncewith 6O mls. and twice with 25 mls.). The chloroform extracts were combined, Washed with water and distilled to a final residue temperature of 215 C. at 0.1 mm. to give a dark brown oil. 5 N hydrochloric acid (175 mls.) was added to the cooled residue and the mixture refluxed with the addition of charcoal, filtered hot, cooled, scratched and allowed to stand overnight in the ice box. The crystalline produce is filtered and the residue on the filter washed twice withcold 5 N hydrochloric acid then four times with anhydrous diethyl ether. Drying under reduced pressure gave the crude hydrochloride (52.9 g.), melting point 157-160 C.

Recrystallisation from isopropyl alcohol have the product as white crystals, melting point 157 to 160 C.

Analysis-Calculated for C H NSClO (percent): C,

52.81; H, 7.20; N, 3.85; S, 8.81; CI, 9.74. Found (percent): C, 52.91; H, 7.00; N, 4.02; S, 9.02; Cl. 9.68.

EXAMPLE 3 2- (3 '-tertiary-butylsulphonyl-n-propyl) aminomethyl1- 1,4-benzodioxane 2-(3-tertiary-butylthio n propyl)aminomethyl-1,4- benzodioxane (18.2 g.) and acetic anhydride (6.7 mls.) were heated on a steam bath under reflux for thirty minutes, the volatile materials evolved were 'then removed under reduced pressure at 100 C. and the residue dissolved in acetic acid (60 mls.). After cooling to room temperature a mixture of acetic acid (22.5 mls.) and hydrogen peroxide (22.5 mls. of 100 vol.) was added with stirring and cooling at such a rate that the temperature did not exceed 50 C. The mixture was then refluxed for one hour prior to pouring into water (600 mls.) and extraction with chloroform (once with 50 mls. and twice with 20 mls.). The chloroform extracts were combined and then washed with water (thrice with 20 mls.)-a few drops of 20% w./w. sodium sulphite solution being added to the last portion of water until a negative peroxide indication was obtained. After removal of the chloroform under reduced pressure the residual oil was mixed with 5 N hydrochloric acid (60 mls.) and refluxed for nine hours. On cooling and scratching and standing overnight in the ice box, crystals separated: these crystals were filtered 011 and twice washed with cold 5 N hydrochloric acid, then four times with anhydrous diethyl ether followed by drying under reduced pressure to give the crude product (9 g.), melting point 153 to 156 C.

Two recrystallisations from isopropyl alcohol gave the product as the hydrochloride, melting point 157 to 160 C. Mixed melting point with the product of Example 2 gave no depression.

EXAMPLE 4 2- (3 -is opropylsulphonyl-n-propyl) aminomethyll ,4- benzodioxane 2-aminomethyl-1,4-benzodioxane (33 g.) and 3-isopropylsulphonyl-n-propyl chloride (18.45 g.) were heated at 150 C. for 2 hours prior to working up as described, in Example 2. Drying under reduced pressure gave the crude hydrochloride (16.5 g.), melting point to 148 C. Recrystallisation from a mixture of isopropanol (70 mls.) and ethanol (20 mls.) gave the productas white crystals, melting point 148 to 150 C.

Analysis.-Calculated for C H 'NSClO (percent): C, 51.48; H, 6.91; S, 9.16; CI, 10.14; N, 4.00. Found (percent): C, 5l.40; H, 6.80; S, 9.27; Cl, 10.32; N, 3.78.

EXAMPLE 5 2- 3 -ethylsulphonyl-n-propyl) -aminomethyl-1,4-benzodioxane 2-aminomethyl-l,4-benzodioxane (33 g.) and 3-ethylsulphonyl-n-propyl chloride (17 g.) were heated at 150 C. for 2 hours prior to working up as described in Example 2. Drying under reduced pressure gave the crude hydrochloride (25.9 g.), melting point 167 to 169 C.

Recrystallisation from a mixed solvent of methanol (75 mls.), and ethanol (50 mls.) gave the product as white crystals, melting point 172 to 174 C.

Analysis-Calculated for C14H2qNSclO4 (percent): C, 50.07; H, 6.61; N, 4.17; S, 9.55; CI, 10.56. Found (percent): C, 50.18; H, 6.63; N, 4.11; S, 9.25; CI, 10.20.

EXAMPLE 6 2-(4'-tertiary-butylsulphonyl-n-butyl) aminomethyl-1,4-benzodioxane 2-(4'-tertiary-butylthio-n-butyl) aminomethyl-1,4-benzodioxane (15.3 g.) and acetic anhydride (5.6 mls.) were reacted and worked up as described in Example 3. The acylated compound was then treated with hydrogen peroxide and acetic acid, the further treatment and working up also proceeding as described in Example 3. Drying under reduced pressure gave the crude hydrochloride (7.3 g.), melting point 182 to 184C.

Recrystallisation from ethanol gave the product as white crystals, melting point 186 to 188 C.

Analysis.-Calculated for C1I7H23NSC1O4 (percent): C, 54.04; H, 7.47; N, 3.71; S, 8.49; Cl, 9.38. Found (percent): C, 53.73; H, 7.49; N, 3.56; S, 8.37; CI, 9.35.

EXAMPLE 7 2-(3'-cyclohexylsulphonyl-n-propyl) aminomethyl-l,4-benzodioxane i onmnomomoms O -O 2-aminomethyl-1,4-benzodioxane (33 g.) and 3-cyclohexylsulphonyl-n-propyl chloride (22.45 g.) were heated at 150 C. for two hours prior to Working up as in Example 2. Drying under reduced pressure gave the crude hydrochloride (33.5 g.), melting point 171-175 C.

Recrystallisation from ethanol gave the product as white crystals, melting point 173176 C.

Analysis.-Calculated for C H NSClO (percent): C, 55.46; H, 7.24; N, 3.59. Found (percent): C, 55.66; H,

EXAMPLE 8 2- 3 '-tert-butylsulphonyl-n-propyl) aminoethyl-8-methyl-1,4-benzodioxane CH3 0 CHgNHCHgCH CHgS Ori -CH3 CHa H;

2-aminomethyl-8-methyl 1,4 benzodioxane (26.1 g.) and 3-tert-b'utylsulphonyl-n-propyl chloride (14.9 g.) were heated at 150 C. for two hours and then worked up as in Example 1. Drying under reduced pressure gave the crude hydrochloride (24 g.), melting point 104-134 C.

. 7 Recrystallisation from isoprop yl alcohol gave the product as white crystals, melting point 147-151 C.

Analysis.-Calculated for C H NSClO (percent): C, 54.04; H, 7.47; N, 3.71; S, 8.49; Cl, 9.38. Found (percent): C, 54.14; H, 7.38; N, 3.62; S, 8.69; Cl, 9.62.

EXAMPLE 9 2-(3'-tert-amy1sulphonyl-n-propyl) aminomethyl-7-chloro-1,4-benzodioxane lnn 01 onmnomomomso p-omen.

EXAMPLE 2-(2-tert-amylsulphonylethyl) aminomethyl-1,4-benzodioxane CH NHCH CH SO CCH CHa 0 3 2-aminoethyl-1,4-benzodioxane (6.6 g.) and Z-tertamylsulphonyl ethyl chloride (4.0 g.) were heated at 155 C. for two hours and then worked up as in Exampie 1. Drying under reduced pressure gave the crude hydrochoride. Recrystallisation from isopropyl alcohol gave the product as white crystals, melting point 186-187 C. Analysis-Calculated for C H ClNO S (percent): C, 52.80; H, 7.20; N, 3.85; S, 8.81; Cl, 9.74. Found (percent): C, 52.45; H, 7.16; N, 3.85; S, 8.64; Cl, 9.69.

EXAMPLE 11 Preparation of 2-(3-tert-amylsulphonyl-n-propyl) aminomethyl-8-methoxy-benzo-L4-dioxan (hydrochloride) A mixture of 2-chloromethyl-8-methoxybenzo-1,4-dioxan (6.0 g., 0.03 mole) and tert-amylsulphonyl-n-propylamine (10.8 g., 0.06 mole) was heated at 150 for 2 hours. The mixture was cooled, a solution of sodium hydroxide (2.4 g., 0.06 mole) in water (30 ml.) was added and the mixture was extracted with chloroform (3x30 1111.). The solvent was removed by distillation under reduced pressure and unchanged amine was distilled ofi at 130-150" at 0.5 mm. Hg. The residue was subjected to chromatography on alumina (i) eluting with chloroform (ii) eluting with ethanol 8 Hydrochloric .acid (8 ml., 50%) was added 'to the appropriate fractionand the mixture refluxed for 0.5 hr. The mixture was cooled and extracted with chloroform. Anhydrous ether was added to the extract when an oil separated out. This oil was dried overnight in vacuo over phosphorus pentoxide when crystallisation occurred. The solid was recrystallised twice from ethylacetate/ether.

Weight-2,00 mg, m. 147-150 Calculated for (percent): C, 53.00; H, 7.41; N, 3.43; 7.85; Cl, 8.68. Found (percent): C, 52.54; H, 7.23; 3.67; S, 7.53; Cl, 9.01.

Weclaim: 1. Basically 2-'substituted 1,4-benzodioxane having the formula: i

where Ris hydrogen, halogen having an atomic number not exceeding 35 or alkyljor alkoxy having from one tosix carand pharmacologically acceptable acid addition salts of such benzodioxane.

2. Basically Z-substituted 1,4-benzodioxane as claimed in claim 1, wherein R is hydrogen, 7- or 8-chlorine or 7- or S-methyl, -ethyl, '-methoxy or -ethoxy.

3. Basically Z-substituted 1,4-benzodioxane as claimed in claim 1, wherein R isa straight chain or branched chain alkyl having from 2 to 6 carbon atoms or cyclohexyl.

4. Basically 2-substituted 1,4-benzodioxane as claimed in claim '3, wherein R is tertiary-butyl or tertiary amyl.

5. Basically 2-substituted1,4-benzodioxane as claimed in claiml, wherein n is 2,3 or 4.

6. 2-[(3' tertiary amylsulphonyl n propyl)aminomethyl]-1,4-benzodioxane.

References Cited UNITED STATES PATENTS 2,887,484 5/1959 Funke 260340.3 3,170,933 2/1965 Schmidt 260340.3 3,438,992 4/1969 Shen et al. 260-340.} X

OTHER REFERENCES Dunbar et al.: Chemical Abstracts, vol. 52 (1958), col. 9134d.

ALEX MAZEL, Primary Examiner J. H. TURNIPSEED, Assistant Examiner U.S. Cl. X.R. 424-278