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 PDF

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Publication number
US3274058A
US3274058A US328460A US32846063A US3274058A US 3274058 A US3274058 A US 3274058A US 328460 A US328460 A US 328460A US 32846063 A US32846063 A US 32846063A US 3274058 A US3274058 A US 3274058A
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methyl
thiadiazepine
dioxodibenzo
carbon atoms
dimethylamino
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US328460A
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English (en)
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Weber Abraham
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Mead Johnson and Co LLC
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Mead Johnson and Co LLC
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Priority to US328460A priority Critical patent/US3274058A/en
Priority to US328506A priority patent/US3322789A/en
Priority to GB49540/64A priority patent/GB1093187A/en
Priority to FR997596A priority patent/FR3971M/fr
Priority to DE19641470110 priority patent/DE1470110A1/de
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/36—Seven-membered rings

Definitions

  • 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
US328460A 1963-12-06 1963-12-06 5, 5-dioxodibenzo[1, 2, 5]thiadiazepines derivatives and method of use Expired - Lifetime US3274058A (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
US328460A US3274058A (en) 1963-12-06 1963-12-06 5, 5-dioxodibenzo[1, 2, 5]thiadiazepines derivatives and method of use
US328506A US3322789A (en) 1963-12-06 1963-12-06 5, 5-dioxodibenzo[1, 2, 5]thiadiazepines and process
GB49540/64A GB1093187A (en) 1963-12-06 1964-12-04 Dibenzothiadiazepine dioxide derivatives
FR997596A FR3971M (it) 1963-12-06 1964-12-05
DE19641470110 DE1470110A1 (de) 1963-12-06 1964-12-05 Verfahren zur Herstellung von Dioxodibenzothiadiazepinderivaten

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US328460A US3274058A (en) 1963-12-06 1963-12-06 5, 5-dioxodibenzo[1, 2, 5]thiadiazepines derivatives and method of use
US328506A US3322789A (en) 1963-12-06 1963-12-06 5, 5-dioxodibenzo[1, 2, 5]thiadiazepines and process

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US328506A Expired - Lifetime US3322789A (en) 1963-12-06 1963-12-06 5, 5-dioxodibenzo[1, 2, 5]thiadiazepines and process

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Cited By (3)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
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 (fr) * 1969-08-06 1971-02-04 Wander Ag Dr A Nouveaux derives de la dibenzo-oxazepine leur preparation et medicaments contenant ces derives
IT1225729B (it) * 1988-08-12 1990-11-26 Menarini S A S Firenze A Derivati della 5,5-diossido-6,11-diidrodibenzo (c,f)(1,2,5) tiadiazepina, loro sali e relativi procedimenti di fabbricazione

Citations (2)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3185679A (en) * 1965-05-25 Azepine derivatives
US3225032A (en) * 1965-12-21 Derivatives of dibenz[b,f]azepines
FR1179968A (fr) * 1956-08-01 1959-05-29 Rhone Poulenc Sa Dérivés nu-substitués de la diméthylsulfamido phénothiazine et leur procédé de préparation

Patent Citations (2)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
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

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DE1470110A1 (de) 1969-11-20
GB1093187A (en) 1967-11-29
FR3971M (it) 1966-02-28
US3322789A (en) 1967-05-30

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