US3274058A - 5, 5-dioxodibenzo[1, 2, 5]thiadiazepines derivatives and method of use - Google Patents
5, 5-dioxodibenzo[1, 2, 5]thiadiazepines derivatives and method of use Download PDFInfo
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- a lkN FORMULA I These substances are novel organic compounds comprising a new class of heterocyclic products known as the 5,5-dioxodibenzo[1,25]thiadiazepines. The various positions of this tricyclic nucleus are numbered as shown in the formula.
- R and R are attached to the respective benzene rings in the l, 2, 3, 4, or in the 7, 8, 9, or positions as is indicated.
- R represents from one to two substituents which are selected from the following: hydrogen, halogen, methyl, trifluoromethyl, alkoxy, alkylthio, and alkylsulfonyl, each having up to four carbon atoms.
- R is hydrogen, halogen, methyl, trifluoromethyl, dimethylsulfamyl, dimethylamino, carbalkoxy, alkylthio, :alkylsulfonyl, alkoxy, or alkanoyl, each of which may contain up to four carbon atoms.
- R is lower alkyl having up to four carbon atoms, or benzyl.
- Alk is an alkylene group having two to four carbon atoms which is attached to the nitrogen atom in the ll-position of the dioxodibenzothiadiazepine nucleus and separates the amino group of the side chain therefrom by two or three carbon atoms.
- Alk is an ethylene or trimethylene group which may be further substituted by a methyl or ethyl group.
- the amino substituent R1 which is attached to the Alk group is pyrrolidino, piperidino, morpholino, thiamorpholino, or 4-R -piperazino in which R is alkyl, or hydroxyalkyl having up to four carbon atoms, or an ester thereof with an alkanoic acid having one to three carbon atoms, or it is a tertiary amino group in which R is alkyl or hydroxyalkyl having up to four carbon atoms or an ester thereof with an alkanoic acid having one to three carbon atoms, and R contains up to four carbon atoms and is alkyl.
- the preferred compounds of the present invention include the pharmaceutica-lly acceptable acid addition salts of those in which the benzo substituents R and R are hydrogen, R is methyl, and Alk is trimethylene, and
- R and R are alkyl containing up to four carbon atoms.
- the compounds of Formula I are prepared by reaction of an aminoalkyl ester such as a chloride, bromide, iodide, methanesulfonate, p-toluenesulfonate, sulfate, carbonate, etc. of the formula R2 X-Alk-N wherein X is chlorine, bromine, iodine, p-C H SO CH SOC-, SO -OCO C H OC0 etc., with a corresponding dioxodibenzo thiadiazepine of the above formula bearing a hydrogen atom in the ll-position according to the following scheme:
- an aminoalkyl ester such as a chloride, bromide, iodide, methanesulfonate, p-toluenesulfonate, sulfate, carbonate, etc. of the formula R2 X-Alk-N wherein X is chlorine, bromine, iodine, p-
- condensation illustrated by this equation is preferably carried out under anhydrous conditions employing an inert solvent as reaction medium.
- a strong base is required as condensing agent in carrying out this process and elevated temperatures of the order of i200 C. assist in bringing reaction to completion within a convenient period of time.
- the strong alkali metal bases such as the oxides, alkoxides, hydrides, alkyls, aryls, and amides are preferred as condensing agents. It is thought that the acidic hydrogen in the ll-position of the dioxodibenzothiadiazepine ring is first neutralized with the formation of the alkali metal salt which then reacts with the aminoalkyl ester.
- Alkali metal salt-forming reagents suitably serve as condensing agents and include sodium amide, lithium amide, sodium hydride, butyl lithium, potassium t-butoxide, phenyl lithium, et
- the alkali metal salt of the dioxodibenzothiadiazepine reactant may be prepared as a separate preliminary step before carrying out the reaction with the aminoalkyl ester. A further quantity of condensing agent in addition to that used to form the alkali metal salt is not then required.
- dioxodibenzothiadiazepine reactants referred to in the above scheme are prepared by means of a four-step process which is referred to in my copendin-g application Serial No. 328,476, filed herewith.
- steps involved in the process are:
- the compounds of the present invention are useful as psychotropic agents and muscle relaxants having low toxicities and remarkable freedom from side effects. They 3 may be administered orally or parenterally in doses in the range 0.1 to 100 mg./kg.
- 6-methyl 11 (3-dimethylamino-1-propyl)-5,5-di0xodibenzo[1,2,5]tl1iadiazepine hydrochloride is classed as an antidepressant drug which possesses an excitant component differing from that of amphetamine in that it has little tendency to cause motor stimulation. It has an oral LD in the mouse in excess of 200 mg./kg.,- no deaths having occurred at this dosage. The intraperitoneal LD is approximately 198 mg./kg., but signs of excitement and muscle relaxation are apparent at intraperitoneal doses of 12.5 mg./kg. or less.
- This substance has an oral ED in preventing reserpine ptosis in the mouse of 1.5 mg./kg., and While eliciting excitant signs at this dose, it fails to reverse reserpine ptosis in the mouse at doses four times larger.
- Reversal of reserpine ptosis is characteristic of conventional central nervous stimulants such as amphetamine.
- the ability to prevent reserpine ptosis is a character of pharmaceuticals of established clinical utility as anti-depressants.
- the excitant character of the product is further differentiated from that of amphetamine in that increased toxicity thereof is not observed when treated mice are grouped rather than housed singly.
- the product is about equivalent to imipramine in antagonizing i.v. histamine induced bronchoconstriction in the guinea pig employing a modified procedure of Lands, et al., J. Pharmacol. Exp. Therap. 95, 45 (1949).
- This substance has a water solubility of 19 mg./ml.
- a 1% aqueous solution thereof has pH 5.4. On neutralization to pH 7.0, no precipitate forms.
- Example 2.6-melhyl 11 (3-dimethylamin0pr0pyl)- 5,5 di0x0dibenz0l[1,2,5] thiadiazepine hydrochloride-
- the procedure of Example 1 is repeated, substituting 24 g. (0.16 mole) of 3-dimethylamino 1-propyl chloride hydrochloride for the 2 diethylaminoethyl bromide reactant specified in that example.
- a reaction period of 6 hrs. at -95 C. is employed.
- the free base form of the product is recovered as specified in Example 1 and the final product is converted to the hydrochloride salt and recrystallized from isopropanol as stated, M.P. 199-200 C.
- This material hasv a water solubility of 800 mg./ml. A 1% solution thereof has pH 5.5 and no precipitation occurs on adjusting such solution to pH 7.0.
- alkali metal salt-forming reagents may be substituted on a chemical equivalent basis for sodium hydride in Examples 1 and 2.
- substantially similar operation and results follow from the use of sodium amide, lithium amide, btuyl lithium, sodium triphenylmethyl, or potassium t-butoxide in those procedures.
- Examples 336-Synthesis of additional structural variants The procedures of Examples 1 and 2 are adapted to synthesis of the products listed in the following table from the aminoalkyl halide and dioxodibenzothiadiazephine reactants listed when substituted on a molecular equivalent basis.
- the products are most readily purified as acid addition salts such as the hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, or p-toluenesulfonate salts.
- salts of the products with a great variety of acids may be formed including those of carboxylic acids such as acetic, propionic, benzoic, tartaric, citric, mucic, maleic, and gluconic acid, organic and sulfonic and sulfuric acids such as methane, ethane, and benzene sulfonic acids, lauryl sulfuric acid, etc.
- carboxylic acids such as acetic, propionic, benzoic, tartaric, citric, mucic, maleic, and gluconic acid
- organic and sulfonic and sulfuric acids such as methane, ethane, and benzene sulfonic acids, lauryl sulfuric acid, etc.
- salts with optically active acids may be formed for the purpose of separating the resulting diastereometric salts.
- salts with non-toxic acids having pharmaceutically elegant physical properties are prew ferred.
- Example 37-Parenteral s0luti0n.A solution for injection is prepared as follows: 6-methyl-1l-(3-dimethylamino 1 propyl) 5,5 dioXodi benzo[l,2,5]thiadiazepine hydrochloride, 500 g., is dissolved in 9 l. of water for injection, U.S.P. The solution is adjusted to pH 7.0 with dilute aqueous sodium hydroxide, diluted to 10 1. and filtered sparkling clear. It is then filled into 1 ml. glass ampoules, the ampoules sealed, and sterilized by heating in an autoclave at 121 C. for min.
- the moist granulation is screened through No. 12 screen, and dried at 130 F. until the moisture is less than 2%.
- the dry granules are then reduced in size by passage through a No. screen and the following materials are thoroughly blended with the screened granulation:
- the resulting blend is then compressed into tablets, each containing 25.0 mg. of active ingredient.
- dosage forms are suitable for use in human beings. Doses in the range of 40 mg. to 300 mg. per day may be employed, "but in any event the precise dose is to be selected by the physician.
- R is from one to two substitutents selected from the group consisting of hydrogen, halogen, methyl, trifiuoromethyl, alkoxy, alkylthio, and alkylsulfonyl and contains up to four carbon atoms;
- R is selected from the group consisting of lower alkyl having one to four carbon atoms, and benzyl;
- R is selected from the group consisting of hydrogen, halogen, methyl, trifluoromethyl, dimethylamino, dimethylsulfamyl, carbalkoxy, alkylthio, alkylsulfonyl, alkoxy, and alkanoyl, and contains up to four carbon atoms;
- Alk is selected from the group consisting of ethylene and tirmethylene haviing up to one alkyl substituent containing up to two carbon atoms;
- R and R are selected from the group consisting of alkyl, hydroxyalkyl having up to four carbon atoms and alkanoxyalkyl having up to seven carbon atoms, and
- R contains up to four carbon atoms and is alkyl.
- R and R are hydrogen, R is methyl, Alk is ethylene, R is alkyl having up to four carbon atoms, and R is alkyl having up to four carbon atoms.
- R and R are hydrogen, R is methyl, Alk is trimethylene, R is alkyl having up to four carbon atoms, and R is alkyl having up to four carbon atoms.
- R and R are hydrogen, R is methyl, Alk is ethylene bearing a methyl substituent, and R and R are each alkyl having up to four carbon atoms.
- the therapeutic process which comprises administering to a mammalian host a dose of from 0.1 mg. to 100 mg, of a compound claimed in claim l per kilogram of body weight of said host.
- a pharmaceutical composition in dosage unit form adapted for administration to a mammalian host comprising a pharmaceutical carrier and sufiicient of a compound claimed in claim 1 to provide a daily dose of from 0.1 mg. to 100 mg. thereof per kilogram of body weight of said host.
- a pharmaceutical composition in dosage unit form comprising from to 300 mg. of a compound selected from the group consisting of 6-methyl-ll-(3-dimethylamino-I-propyl)-5,5-dioxodibenzo[1,2,5]thiadiazepine and the pharmaceutically acceptable acid addition salts thereof and a pharmaceutical carrier therefor.
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Description
United States Patent Ofifice 3,274,058 Patented Sept. 20, 1966 The present invention is concerned with compounds having the following structure and acid addition salts thereof.
A lkN FORMULA I These substances are novel organic compounds comprising a new class of heterocyclic products known as the 5,5-dioxodibenzo[1,25]thiadiazepines. The various positions of this tricyclic nucleus are numbered as shown in the formula.
The substituent groups R and R are attached to the respective benzene rings in the l, 2, 3, 4, or in the 7, 8, 9, or positions as is indicated. R represents from one to two substituents which are selected from the following: hydrogen, halogen, methyl, trifluoromethyl, alkoxy, alkylthio, and alkylsulfonyl, each having up to four carbon atoms. R is hydrogen, halogen, methyl, trifluoromethyl, dimethylsulfamyl, dimethylamino, carbalkoxy, alkylthio, :alkylsulfonyl, alkoxy, or alkanoyl, each of which may contain up to four carbon atoms. R is lower alkyl having up to four carbon atoms, or benzyl.
The group as a whole refers to an -aminosubstituted alkyl side chain. Alk is an alkylene group having two to four carbon atoms which is attached to the nitrogen atom in the ll-position of the dioxodibenzothiadiazepine nucleus and separates the amino group of the side chain therefrom by two or three carbon atoms. In other words, Alk is an ethylene or trimethylene group which may be further substituted by a methyl or ethyl group.
The amino substituent R1 which is attached to the Alk group is pyrrolidino, piperidino, morpholino, thiamorpholino, or 4-R -piperazino in which R is alkyl, or hydroxyalkyl having up to four carbon atoms, or an ester thereof with an alkanoic acid having one to three carbon atoms, or it is a tertiary amino group in which R is alkyl or hydroxyalkyl having up to four carbon atoms or an ester thereof with an alkanoic acid having one to three carbon atoms, and R contains up to four carbon atoms and is alkyl.
The preferred compounds of the present invention include the pharmaceutica-lly acceptable acid addition salts of those in which the benzo substituents R and R are hydrogen, R is methyl, and Alk is trimethylene, and
R and R are alkyl containing up to four carbon atoms.
The compounds of Formula I are prepared by reaction of an aminoalkyl ester such as a chloride, bromide, iodide, methanesulfonate, p-toluenesulfonate, sulfate, carbonate, etc. of the formula R2 X-Alk-N wherein X is chlorine, bromine, iodine, p-C H SO CH SOC-, SO -OCO C H OC0 etc., with a corresponding dioxodibenzo thiadiazepine of the above formula bearing a hydrogen atom in the ll-position according to the following scheme:
RB s o -1LT R3 R X-Alk-N e SO I T R2 A1kN The condensation illustrated by this equation is preferably carried out under anhydrous conditions employing an inert solvent as reaction medium. A strong base is required as condensing agent in carrying out this process and elevated temperatures of the order of i200 C. assist in bringing reaction to completion within a convenient period of time.
The strong alkali metal bases such as the oxides, alkoxides, hydrides, alkyls, aryls, and amides are preferred as condensing agents. It is thought that the acidic hydrogen in the ll-position of the dioxodibenzothiadiazepine ring is first neutralized with the formation of the alkali metal salt which then reacts with the aminoalkyl ester. Alkali metal salt-forming reagents suitably serve as condensing agents and include sodium amide, lithium amide, sodium hydride, butyl lithium, potassium t-butoxide, phenyl lithium, et If desired, the alkali metal salt of the dioxodibenzothiadiazepine reactant may be prepared as a separate preliminary step before carrying out the reaction with the aminoalkyl ester. A further quantity of condensing agent in addition to that used to form the alkali metal salt is not then required.
The dioxodibenzothiadiazepine reactants referred to in the above scheme are prepared by means of a four-step process which is referred to in my copendin-g application Serial No. 328,476, filed herewith. In general terms, the steps involved in the process are:
(1) Reaction of an o-bromoaniline with an o-nitrobenzenesulfonyl halide to form a 2-nitro-2'-brorno benzene sulfonanilide.
(2) Alkylation at the sulfonamide nitrogen atom to intro duce the R group.
(3) Reduction of the 2-nitro group to a Z-amino group,
and preferably acylation thereof.
(4) Ring closure.
The compounds of the present invention are useful as psychotropic agents and muscle relaxants having low toxicities and remarkable freedom from side effects. They 3 may be administered orally or parenterally in doses in the range 0.1 to 100 mg./kg.
6-methyl 11 (3-dimethylamino-1-propyl)-5,5-di0xodibenzo[1,2,5]tl1iadiazepine hydrochloride, a preferred product of the present invention, is classed as an antidepressant drug which possesses an excitant component differing from that of amphetamine in that it has little tendency to cause motor stimulation. It has an oral LD in the mouse in excess of 200 mg./kg.,- no deaths having occurred at this dosage. The intraperitoneal LD is approximately 198 mg./kg., but signs of excitement and muscle relaxation are apparent at intraperitoneal doses of 12.5 mg./kg. or less. This substance has an oral ED in preventing reserpine ptosis in the mouse of 1.5 mg./kg., and While eliciting excitant signs at this dose, it fails to reverse reserpine ptosis in the mouse at doses four times larger. Reversal of reserpine ptosis is characteristic of conventional central nervous stimulants such as amphetamine. The ability to prevent reserpine ptosis is a character of pharmaceuticals of established clinical utility as anti-depressants. The excitant character of the product is further differentiated from that of amphetamine in that increased toxicity thereof is not observed when treated mice are grouped rather than housed singly. The product is about equivalent to imipramine in antagonizing i.v. histamine induced bronchoconstriction in the guinea pig employing a modified procedure of Lands, et al., J. Pharmacol. Exp. Therap. 95, 45 (1949).
The following examples are provided to further illustrate the manner of practicing the present invention. They are not to be considered the sole embodiments thereof, however, and are provided only for illustrative purposes.
Example 1.6-methyl-11-(Z-diethylaminoethyl)-5,5-di- 0x0dibenz0[1,2,5] thiadiazepine hydr0chl0ride.-A mixture of 19.5 g. (0.075 mole) of 6-methyl5,5-dioxodibenzo,[1,2,5]thiadiazepine and 170 ml. of dry dirnethylformamide, which serves as liquid reaction medium, is warmed to 100 C. in a reaction vessel equipped with a thermometer, stirrer, and reflux condenser and for exclusion of atmospheric moisture. A suspension of 10.5 g. (0.225 mole) of sodium hydride in mineral oil is then added portionwise in order to avoid an unduly violent exothermic reaction. The yellow suspension of the sodium salt of the thiadiazepine reactant which forms is treated with 35 g. (0.150 mole) of Z-diethylaminoethyl bromide hydrobromide during a 10 min. period while maintaining the temperature in the range l00-120 C. The suspension is agitated while heating is continued at 115-120 C. for 3 hrs. It is then cooled to room temperature, poured into ice water, and the white precipitate collected. It is dissolved in dilute hydrochloric acid, insoluble material removed by filtration, and the filtrate neutralized to pH 9.0 with concentrated sodium hydroxide, resulting in precipitation of the desired product as the free base. The precipitate is collected, dissolved in isopropanol, and treated with slightly more than one molecular proportion of hydrochloric acid, resulting in precipitation of the hydrochloride salt of the desired product as a white powder, M.P. 217-219 C. The material is recrystallized from isopropanol to afford the purified hydrochloride salt as clusters of white needles, M.P. 223-224 C.
Analysis.Cl, 8.73; N, 10.54; S, 8.15.
This substance has a water solubility of 19 mg./ml. A 1% aqueous solution thereof has pH 5.4. On neutralization to pH 7.0, no precipitate forms.
Example 2.6-melhyl 11 (3-dimethylamin0pr0pyl)- 5,5 di0x0dibenz0l[1,2,5] thiadiazepine hydrochloride- The procedure of Example 1 is repeated, substituting 24 g. (0.16 mole) of 3-dimethylamino 1-propyl chloride hydrochloride for the 2 diethylaminoethyl bromide reactant specified in that example. A reaction period of 6 hrs. at -95 C. is employed. The free base form of the product is recovered as specified in Example 1 and the final product is converted to the hydrochloride salt and recrystallized from isopropanol as stated, M.P. 199-200 C.
Analysis-Cl, 9.01; N, 10.95; S, 8.40.
This material hasv a water solubility of 800 mg./ml. A 1% solution thereof has pH 5.5 and no precipitation occurs on adjusting such solution to pH 7.0.
Other alkali metal salt-forming reagents may be substituted on a chemical equivalent basis for sodium hydride in Examples 1 and 2. For instance, substantially similar operation and results follow from the use of sodium amide, lithium amide, btuyl lithium, sodium triphenylmethyl, or potassium t-butoxide in those procedures.
Examples 336-Synthesis of additional structural variants.The procedures of Examples 1 and 2 are adapted to synthesis of the products listed in the following table from the aminoalkyl halide and dioxodibenzothiadiazephine reactants listed when substituted on a molecular equivalent basis. The products are most readily purified as acid addition salts such as the hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, or p-toluenesulfonate salts. Since the compounds are all relatively strong bases, salts of the products with a great variety of acids may be formed including those of carboxylic acids such as acetic, propionic, benzoic, tartaric, citric, mucic, maleic, and gluconic acid, organic and sulfonic and sulfuric acids such as methane, ethane, and benzene sulfonic acids, lauryl sulfuric acid, etc. In those instances where stereoisomers exist due to asymmetry in the molecule, salts with optically active acids may be formed for the purpose of separating the resulting diastereometric salts. For pharmaceutical purposes, salts with non-toxic acids having pharmaceutically elegant physical properties are prew ferred.
Examples 3-36 Starting Materials 8.. Aminoalkyl halide b. Thiadiazepine Example N0.
*Footnote at end of table.
(CHahNOHaCHr 7-CF (CH3)2NCHzCH2CHr Examples 3-36C0ntinued Starting Materials a. Aminoalkyl halide b. Thiadlazepine 3-dimethylarnino-1-propyl chloride 2-eth0xy-6methyl-5,5-dioxodihenzo[l,2,5]:
thiadiazepine.
. 3-dimethylamino-l-propyl chloride 2,3,G-trirnethyl-fi,5-dioxodibenzo[1,2,5]-
thiadiazepine.
. 3-dlmethylamino-l-propyl chloride 2,4,6-tri1nethyl-5,5-di0x0dibenzo[l,2,5]-
thiadiazepine.
. 3-dimethylarnino-1-propyl chloride 6-methyl-7-bromo-5,5-dioxodibenzo[l,2,5]-
thiadiazepine.
. 3-dimethylamino-1-propyl chloride- 6-methyl-8-fluoro-5,5-dioxodibenz0[1,2,5]-
thiadiazepine.
. 3-dimethylamino-1-propyl chloride. 6-methyl-8-i0do-5,5-dioxodibenzo[1,2,5]-
thiadiazepine.
. B-dirnethylamino-l-propyl chloride 6methyl-8-chloro-5,fi-dioxodibenzo[1,2,5]-
thiadiazepinc.
. 3-dimethylamino-l-propyl chloride 6,9-dimethyl-5,5-dioxodibenzo[l,2,5]-
thiadiazepine.
. S-dimethylamino-l-propyl chloride 6-methyl-8-dimethylamino-5,5 dioxodibenzo- [1,2,51-thiadiazepine.
3-dimethylarnin0-1-propyl chloride G-methyl-8-carbomethoxy-5,5-dioxodibenzo- [1,2,5]thiadiazepine.
. 3-dirnethylarnino-1-propyl chloride 2-bromo-6-methy1-5,5-dioxodibenzo[l,2,5]-
thiadiazepine.
. ZdirnethylaminOethyl bromide fi-methyl-S-ethoxy-S,5-dioxodibenzo[1,2,5]-
thiadiazepine.
CH3 (CH3)zNOHzCHzCHz- CH3 (CHa)zNCHzCHzCHg CH3 (CHa)2 C 2CH2CH2 8-F.. CH3- (CHshNCHzCHzOHz- CH (GHzhNCHzCHzCHr- CH3 (O'HahNCHzCHzCHr- 8-(CH3)zN CH3 (CHa)2NCHzCHzCHz B-COzCH; CH: (CH )2NCH2CH2CH2 8 C H5O CH3 (CH gNCHzCHz- Hydrochloride salt; slightly hygroscopic a. precipitate forms on neutralization to pH 7.
AnaZysis.-C, 55.36; H, 6.04; N, 11.26; S, 8.83.
Example 37-Parenteral s0luti0n.A solution for injection is prepared as follows: 6-methyl-1l-(3-dimethylamino 1 propyl) 5,5 dioXodi benzo[l,2,5]thiadiazepine hydrochloride, 500 g., is dissolved in 9 l. of water for injection, U.S.P. The solution is adjusted to pH 7.0 with dilute aqueous sodium hydroxide, diluted to 10 1. and filtered sparkling clear. It is then filled into 1 ml. glass ampoules, the ampoules sealed, and sterilized by heating in an autoclave at 121 C. for min.
Example 38Tablets.-A dry blend of 165 g. of lactose, U.S.P. and 1.0 g. of acacia powder, U.S.P., is prepared and granulated with a 10% w./-w. starch paste containing 3.0 g. of corn starch, U.S.P. The moist granulation is screened through No. 12 screen, and dried at 130 F. until the moisture is less than 2%. The dry granules are then reduced in size by passage through a No. screen and the following materials are thoroughly blended with the screened granulation:
G. 6 methyl 11 (3 dimethylamino 1 propyl)- 5,5 dioxodibenzo[1,2,5]thiadiazepine hydrochloride 25.0 Talc 4.0 Stearic acid, powdered 2.0
The resulting blend is then compressed into tablets, each containing 25.0 mg. of active ingredient.
The preceding dosage forms are suitable for use in human beings. Doses in the range of 40 mg. to 300 mg. per day may be employed, "but in any event the precise dose is to be selected by the physician.
Example 392 methoxy 6 methyl 11 [4 (2- hydr0xyethyl)piperazino]ethyl-5,5 dioxodibenzo[1,2,5]
white powder, M.P. 222223 0.; water solubility 1 g./ml.; 1% aqueous solution exhibits pH 4.5 from which thiadz'azepine hydr0chl0ride.--A mixture of 0.4 g. of sodium hydroxide, 20 ml. of. water, 20 ml. of dioxane, and 4.88 g. of the product of Example 6 is agitated at room temperature overnight. The mixture is then poured into ml. of water, the insoluble material removed by filtration, dissolved in isopropanol, and treated with hydrogen chloride, resulting in precipitation of the desired product.
While several particular embodiments of this invention are shown above, it will be understood that the invention is not to be limited thereto, since many modifications may be made, and it is contemplated by the appended claims to cover any such modifications as fall within the true spirit and scope of the invention.
What is claimed is:
1. A compound selected from the group having the formula and the acid addition salts thereof wherein R is from one to two substitutents selected from the group consisting of hydrogen, halogen, methyl, trifiuoromethyl, alkoxy, alkylthio, and alkylsulfonyl and contains up to four carbon atoms;
R is selected from the group consisting of lower alkyl having one to four carbon atoms, and benzyl;
R is selected from the group consisting of hydrogen, halogen, methyl, trifluoromethyl, dimethylamino, dimethylsulfamyl, carbalkoxy, alkylthio, alkylsulfonyl, alkoxy, and alkanoyl, and contains up to four carbon atoms;
Alk is selected from the group consisting of ethylene and tirmethylene haviing up to one alkyl substituent containing up to two carbon atoms;
is selected from the group consisting of pyrrolidino, piperidino, morpholino, thiamorpholino, 4-R -piperazino, and amino wherein R and R are selected from the group consisting of alkyl, hydroxyalkyl having up to four carbon atoms and alkanoxyalkyl having up to seven carbon atoms, and
R contains up to four carbon atoms and is alkyl.
2. The compound of claim 1 wherein R and R are hydrogen, R is methyl, Alk is ethylene, R is alkyl having up to four carbon atoms, and R is alkyl having up to four carbon atoms.
3. The compound of claim 1 wherein R and R are hydrogen, R is methyl, Alk is trimethylene, R is alkyl having up to four carbon atoms, and R is alkyl having up to four carbon atoms.
4. The compound of claim 1 wherein R and R are hydrogen, R is methyl, Alk is ethylene bearing a methyl substituent, and R and R are each alkyl having up to four carbon atoms.
5. 6 methyl l1 (3 dimethylamino 1 propyl)- 5,5-dioxodi benzo 1,2,5] thiadiazepine.
6. 6 methyl 11 (2 diethylamino 1 ethyl)- 5,5-dioxodibenzo 1,2,5] thiadiazepine.
7. 6 methyl 11 (2 dimethylamino 1 ethyl)- 5 ,5 -dioxodi benzo 1 ,2,5 thiadiazepine.
8. The therapeutic process which comprises administering to a mammalian host a dose of from 0.1 mg. to 100 mg, of a compound claimed in claim l per kilogram of body weight of said host.
9. A pharmaceutical composition in dosage unit form adapted for administration to a mammalian host comprising a pharmaceutical carrier and sufiicient of a compound claimed in claim 1 to provide a daily dose of from 0.1 mg. to 100 mg. thereof per kilogram of body weight of said host.
10. A pharmaceutical composition in dosage unit form comprising from to 300 mg. of a compound selected from the group consisting of 6-methyl-ll-(3-dimethylamino-I-propyl)-5,5-dioxodibenzo[1,2,5]thiadiazepine and the pharmaceutically acceptable acid addition salts thereof and a pharmaceutical carrier therefor.
11. 6 methyl 11 (3 dimethylamino 1 propy1)- 5,5-dioxodibenzo[1,2,5]thiadiazepine hydrochloride.
12. 6 methyl 11 (2 diethylamino 1 ethyl)- 5,5-dioxodibenzo 1,2,5] thiadiazepine hydrochloride.
13. 6 methyl 11 (2 dimethylamino 1 ethyl)- 5,5-dioxodibenzo[1,2,5] thiadiazepine hydrochloride.
References Cited by the Examiner UNITED STATES PATENTS 5/1964 Yale et a1. 260293.4 6/1965 Yale et a1 260-2934 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent Noc 3,274,058 September 20, 1966 Abraham Weber It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.
Column 1, line 27, after "2" insert a comma; column 2,
lines 4 and 11, for "p", each occurrence, read M p in italics; line 61, for "o-", each occurrence, read M o in italics; column 3, line 14, for "105" read 1105 line 28, for "95" read 95 in italics; column 4, line 13, for "dioxodibenzol", in italics, read M dioXodibenz-o in italics; line 30, for "btuyl" read butyl line 51, for "t" read t in italics; line 37, for "thiadiazephine" read m thiadiazepine line 41, for "p" read M pin italics;
columns 5 and 6, in the table, opposite Example No, 10, for that portion of the formula reading read, N
same Table, opposite Example No, 18 first column, for "e" read a column 9, line 9, for "tirmethylene" read trimethylene Signed and sealed this 22nd day of August 19670 (SEAL) Attest:
ERNEST W. SWIDER EDWARD J U BRENNER Attesting Officer Commissioner of Patents
Claims (2)
1. A COMPOUND SELECTED FROM THE GROUP HAVING THE FORMULA AND THE ACID ADDITION SALTS THEREOF
8. THE THERAPEUTIC PROCESS WHICH COMPRISES ADMINISTERING TO A MAMMALIAN HOST A DOSE OF FROM 0.1 MG TO 100 MG. OF A COMPOUND CLAIMED IN CLAIM 1 PER KILOGRAM OF BODY WEIGHT OF SAID HOST.
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US328506A US3322789A (en) | 1963-12-06 | 1963-12-06 | 5, 5-dioxodibenzo[1, 2, 5]thiadiazepines and process |
| US328460A US3274058A (en) | 1963-12-06 | 1963-12-06 | 5, 5-dioxodibenzo[1, 2, 5]thiadiazepines derivatives and method of use |
| GB49540/64A GB1093187A (en) | 1963-12-06 | 1964-12-04 | Dibenzothiadiazepine dioxide derivatives |
| DE19641470110 DE1470110A1 (en) | 1963-12-06 | 1964-12-05 | Process for the preparation of dioxodibenzothiadiazepine derivatives |
| FR997596A FR3971M (en) | 1963-12-06 | 1964-12-05 |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US328506A US3322789A (en) | 1963-12-06 | 1963-12-06 | 5, 5-dioxodibenzo[1, 2, 5]thiadiazepines and process |
| US328460A US3274058A (en) | 1963-12-06 | 1963-12-06 | 5, 5-dioxodibenzo[1, 2, 5]thiadiazepines derivatives and method of use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3274058A true US3274058A (en) | 1966-09-20 |
Family
ID=26986387
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US328460A Expired - Lifetime US3274058A (en) | 1963-12-06 | 1963-12-06 | 5, 5-dioxodibenzo[1, 2, 5]thiadiazepines derivatives and method of use |
| US328506A Expired - Lifetime US3322789A (en) | 1963-12-06 | 1963-12-06 | 5, 5-dioxodibenzo[1, 2, 5]thiadiazepines and process |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US328506A Expired - Lifetime US3322789A (en) | 1963-12-06 | 1963-12-06 | 5, 5-dioxodibenzo[1, 2, 5]thiadiazepines and process |
Country Status (4)
| Country | Link |
|---|---|
| US (2) | US3274058A (en) |
| DE (1) | DE1470110A1 (en) |
| FR (1) | FR3971M (en) |
| GB (1) | GB1093187A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3458516A (en) * | 1968-02-16 | 1969-07-29 | American Cyanamid Co | 11-(piperazinyl)dibenz(b,f)(1,4)oxazepines and analogous thiazepines |
| US3519633A (en) * | 1967-08-02 | 1970-07-07 | Mead Johnson & Co | Certain substituted 5,11-dihydro-10,10-dioxo - dibenz(c,f)(1,2)thiazepin - 5 - yloxyamines |
| US3542790A (en) * | 1966-12-07 | 1970-11-24 | Mead Johnson & Co | Substituted 5,11-dihydro-10,10-dioxodibenzo(c,f)(1,2)thiazepines |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3464996A (en) * | 1967-05-16 | 1969-09-02 | Upjohn Co | 6h - dibenzo(c,g)(1,2,5)thiadiazocine - 5,5-dioxides and method for their production |
| BE754406A (en) * | 1969-08-06 | 1971-02-04 | Wander Ag Dr A | NEW DIBENZO-OXAZEPINE DERIVATIVES THEIR PREPARATION AND MEDICINAL PRODUCTS CONTAINING THESE DERIVATIVES |
| IT1225729B (en) * | 1988-08-12 | 1990-11-26 | Menarini S A S Firenze A | DERIVATIVES OF 5,5-DIOXIDE-6,11-DIIDRODIBENZO (C, F) (1,2,5) THIADIAZEPINE, THEIR SALTS AND RELATED MANUFACTURING PROCEDURES |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3133936A (en) * | 1961-02-20 | 1964-05-19 | Olin Mathieson | Dihydrodibenzoxazepines |
| US3188322A (en) * | 1962-08-08 | 1965-06-08 | Olin Mathieson | Dihydrodibenzothiazepines |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3225032A (en) * | 1965-12-21 | Derivatives of dibenz[b,f]azepines | ||
| US3185679A (en) * | 1965-05-25 | Azepine derivatives | ||
| FR1179968A (en) * | 1956-08-01 | 1959-05-29 | Rhone Poulenc Sa | Nu-substituted derivatives of dimethylsulfamido phenothiazine and process for their preparation |
-
1963
- 1963-12-06 US US328460A patent/US3274058A/en not_active Expired - Lifetime
- 1963-12-06 US US328506A patent/US3322789A/en not_active Expired - Lifetime
-
1964
- 1964-12-04 GB GB49540/64A patent/GB1093187A/en not_active Expired
- 1964-12-05 DE DE19641470110 patent/DE1470110A1/en active Pending
- 1964-12-05 FR FR997596A patent/FR3971M/fr not_active Expired
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3133936A (en) * | 1961-02-20 | 1964-05-19 | Olin Mathieson | Dihydrodibenzoxazepines |
| US3188322A (en) * | 1962-08-08 | 1965-06-08 | Olin Mathieson | Dihydrodibenzothiazepines |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3542790A (en) * | 1966-12-07 | 1970-11-24 | Mead Johnson & Co | Substituted 5,11-dihydro-10,10-dioxodibenzo(c,f)(1,2)thiazepines |
| US3519633A (en) * | 1967-08-02 | 1970-07-07 | Mead Johnson & Co | Certain substituted 5,11-dihydro-10,10-dioxo - dibenz(c,f)(1,2)thiazepin - 5 - yloxyamines |
| US3458516A (en) * | 1968-02-16 | 1969-07-29 | American Cyanamid Co | 11-(piperazinyl)dibenz(b,f)(1,4)oxazepines and analogous thiazepines |
Also Published As
| Publication number | Publication date |
|---|---|
| FR3971M (en) | 1966-02-28 |
| US3322789A (en) | 1967-05-30 |
| DE1470110A1 (en) | 1969-11-20 |
| GB1093187A (en) | 1967-11-29 |
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