US3716544A - CERTAIN 6,11-DIHYDRO-11-(3-ALPHA-TROPANYLOXY)-DIBENZO[b,e]THIEPINE-5-OXIDES AND THE CORRESPONDING DIOXIDES AND DERIVATIVES THEREOF - Google Patents

CERTAIN 6,11-DIHYDRO-11-(3-ALPHA-TROPANYLOXY)-DIBENZO[b,e]THIEPINE-5-OXIDES AND THE CORRESPONDING DIOXIDES AND DERIVATIVES THEREOF Download PDF

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Publication number
US3716544A
US3716544A US00162290A US3716544DA US3716544A US 3716544 A US3716544 A US 3716544A US 00162290 A US00162290 A US 00162290A US 3716544D A US3716544D A US 3716544DA US 3716544 A US3716544 A US 3716544A
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United States
Prior art keywords
thiepine
compound
formula
dibenzo
dihydro
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Expired - Lifetime
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US00162290A
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English (en)
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F Gadient
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Sandoz AG
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Sandoz AG
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Priority claimed from CH1073670A external-priority patent/CH529783A/de
Priority claimed from CH1073770A external-priority patent/CH529784A/de
Priority claimed from CH1073870A external-priority patent/CH529785A/de
Priority claimed from CH1073570A external-priority patent/CH528538A/de
Application filed by Sandoz AG filed Critical Sandoz AG
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D337/00—Heterocyclic compounds containing rings of more than six members having one sulfur atom as the only ring hetero atom
    • C07D337/02—Seven-membered rings
    • C07D337/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D337/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D337/12—[b,e]-condensed

Definitions

  • ABSTRACT The invention concerns new dibenzothiepines of the wherein R is alkyl of one to four carbon atoms and n is l or 2, or
  • R is alkyl of two to four carbon atoms and n is 0, and pharmaceutically acceptable acid addition salts thereof.
  • the compounds are useful in the prophylaxis and treatment of gastric ulcers.
  • R is alkyl of one to four carbon atoms and n is I or 2, or R is alkyl of two to four carbon atoms and n is 0,
  • a compound of formula I is obtained by a process comprising a. reacting a compound of formula III,
  • R is alkyl ofone to four carbon atoms, with a compound of formula II,
  • n 1 or 2 or, when R in the compound of formula III is alkyl of two to four carbon atoms, n is 0, and X is the acid radical of a reactive ester, in the presence of an inert organic solvent, or b. reacting a compound of formula Ia,
  • R' is alkyl oftwo to four carbon atoms, in neutral or weakly acid solution, with an alkali metal Salt or alkaline earth metal salt of periodic acid, or with the stoichiometric amount of an organic peracid or with the stoichiometric amount of hydrogen peroxide, to obtain a compound of formula lb,
  • R is alkyl of one to four carbon atoms, 0. oxidizing a compound of formula la or lb in acid solution with hydrogen peroxide or an organic peracid to a compound of formula Ic,
  • R is alkyl of one to four carbon atoms, and, where an acid addition salt is required, converting the resulting compound of formula I into such salt.
  • R is alkyl of one to four carbon atoms, and R is alkyl of two to four carbon atoms.
  • Process variant (a) may, for example, be effected as follows: A solution of a compound of formula II, wherein X is preferably chlorine, bromine, iodine or fluorine, or the radical of an organic sulphonic acid, in an inert solvent, e.g., an aromatic hydrocarbon such as absolute toluene or absolute benzene, is added dropwise at an elevated temperature, conveniently under reflux at the boiling temperature of the reaction mixture, optionally in the presence of an acid-binding agent, e.g., an alkali metal carbonate such as sodium or potassium carbonate, or a tertiary organic base such as triethylamine, to a solution of a nortropine or pseudonortropine alkyl derivative (nortropan-3a-ol or nortropan-3B-ol derivatives) in the same solvent.
  • an inert solvent e.g., an aromatic hydrocarbon such as absolute toluene or absolute benzene
  • an acid-binding agent
  • Process variant (b) is preferably effected at a low temperature, preferably between and 50 C, and optionally in an inert solvent, e.g., acetic acid or acetone. Reaction times under preferred conditions are of the order of to hours.
  • Process variant (c) is preferably effected using an excess of hydrogen peroxide or an organic peracid.
  • An inert solvent e.g., glacial acetic acid or acetone, is preferably used.
  • the reaction is suitably carried out at an elevated temperature, preferably at a temperature between about 50 and l50 C, and may have a duration of about 3 to l0 hours under preferred conditions.
  • the resulting compounds of formula I may be worked up and optionally purified in accordance with known methods.
  • the steric configuration remains unchanged, so that, e.g., when nortropan- Sa-ol derivatives are used in accordance with embodiment (a) of the process, the corresponding ll-(8-alkyl- 3a-nortropanyloxy)-6,l l-dihydrodibenzo- ⁇ b,e]thiepine derivatives are obtained, and this configuration is also maintained in the case of an oxidation in accordance with process variants (b) and (c).
  • n is O, l or 2
  • X is the radical of an organic sulphonic acid
  • n 0, l or 2
  • organic sulphonic acid halide in an inert solvent, or b. a compound offormula llb,
  • n 0, l or 2
  • n is 0, l or 2
  • X' is chlorine or bromine, with a metal fluoride, or d.
  • a compound of formula llb is produced by reacting a compound of formula IV with thionyl chloride or bromide, or phosphorus chloride, bromide or iodide.
  • Process (a) is preferably carried out in a basic medium and an organic basic solvent, e.g., pyridine, or a lower trialkylamine such as triethylamine, is preferably used as inert solvent, or the reaction is effected in an inert organic solvent with the addition of pyridine or a lower trialkylamine.
  • organic basic solvent e.g., pyridine, or a lower trialkylamine such as triethylamine
  • An anhydrous aromatic hydrocarbon such as benzene may, for example, be used as solvent in process (b).
  • the ll-iodo derivative may likewise be produced from the l l-bromo derivative by reaction with sodium iodide in acetone.
  • phosphorus trichloride tribromide or pentachloride may, for example, be used as phosphorus halide.
  • X is as defined above, in neutral or weakly acid solution, with an alkali or alkaline earth salt of periodic acid, or with the stoichiometric amount of an organic peracid or with the stoichiometric amount of hydrogen peroxide, in a manner analogous to process variant (b) for the production of compounds of formula lb.
  • X is as defined above, may be obtained by oxidizing a compound of formula He or llfin acid solution with hydrogen peroxide or an organic peracid, in a manner analogous to embodiment (c) of the process for the production of compounds of formula lc.
  • a compound of formula la may be obtained by reacting a compound of formula llfwith a compound of formula III in accordance with process variant (a).
  • the compounds of formula I and pharmaceutically acceptable acid addition salts thereof are useful because they possess pharmacological activity in animals.
  • the compounds are useful in the prophylaxis and treatment of gastric ulcers as indicated by the anticholinergic and histaminolytic tests in guinea pigs, the mydriasis test in mice, and further by an inhibition of phenylbutazone-induced ulcer formation in rats.
  • the dosage administered will, of course, vary depending upon the compound employed, the mode of administration and the treatment desired. However, in general, satisfactory results are obtained when administered at a daily dosage of from about 0.05 to about mg per kilogram animal body weight, conveniently given in divided doses 2 to 3 times a day, or in sustained release form.
  • the total daily dosage is in the range of from about 2 to 10 mg
  • dosage forms suitable for oral administration comprise from about 0.6 to about 5 mg of the compound, in association with a solid or liquid pharmaceutical carrier or diluent.
  • the compounds of formula I may be administered in pharmaceutically acceptable acid addition salt form.
  • Such salts possess the same order of activity as the free bases and are readily prepared in conventional manner.
  • Suitable such salt forms include mineral acid salts such as the hydrochloride, hydrobromide and sulphate, and organic acid salts such as the fumarate, maleate, tartrate, methane ethaneand benzene-sulphonate, citrate and malate.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising as active agent a compound of formula l, or pharmaceutically acceptable acid addition salt thereof, in association with a pharmaceutically acceptable carrier or diluent.
  • the crude l l-chloro-6,l ldihydrodibenzo-[b,e]thiepine is then dissolved in cc of absolute xylene, and this solution is added dropwise to a boiling solution of I55 g of N-ethyl-nortropine in 50 cc of absolute xylene over a period of IS minutes.
  • the reaction mixture is then heated to the boil under reflux for 1 hour, is cooled to room temperature, diluted with lOO cc of diethyl ether and extracted twice with 50 cc amounts of 2 N hydrochloric acid.
  • the aqueous extract is rendered alkaline with 2 N caustic soda solution, is extracted thrice with cc amounts of ether, the combined ether extracts are dried over magnesium sulphate, purified with animal charcoal, and the solvent is completely distilled off.
  • the oily residue, i.e., the title compound, is converted into the methanesulphonate, which has an M.P. of 198-200 after recrystallization from ethanol.
  • EXAMPLE 5 dropwise to a boiling solution of 14.1 g of tropine (tropan-3a-ol) in 50 cc of absolute xylene over a period of 15 minutes.
  • the reaction mixture is subsequently heated to the boil under reflux for 1 hour, is then cooled to room temperature, diluted with 100 cc of diethyl ether and extracted twice with 50 cc amounts of 2 N hydrochloric acid.
  • the aqueous extract is then rendered alkaline with 2 N caustic soda solution, is extracted thrice with 100 cc amounts of ether, the combined ether extracts are dried over magnesium sulphate, purified with animal charcoal, and the solvent is completely distilled off.
  • the oily residue i.e., the title compound, is converted into the hydrogen fumarate, which has an MP. of l25-l27 after recrystallization from methanol.
  • the starting material is obtained as follows:
  • the xylene phase is subsequently added dropwise within minutes to a boiling mixture of 8.6 g of tropine and 24.6 g of sodium carbonate in 50 cc of absolute xylene.
  • the reaction mixture is heated under reflux for 6 hours and after cooling, is diluted with 200 cc of diethyl ether and extracted twice with 100 cc amounts of water.
  • the organic phase is extracted with 100 cc of N hydrochloric acid, the hydrochloric acid extract is rendered. alkaline with 2 N caustic soda solution and is extracted thrice with 300 cc amounts of diethyl ether. After drying the ether extract over sodium sulphate, the solvent is distilled off at reduced pressure.
  • the oily residue i.e., the title compound
  • the aqueous phase is extracted thrice with 100 cc amounts of ether, the combined ether extracts are dried over magnesium sulphate and the solvent is completely concentrated at reduced pressure.
  • the oily residue, i.e., the title compound is then converted into the hydrogen fumarate with fumaric acid in ethanol. After recrystallization from methanol the hydrogen fumarate ofthe title compound has an M.P. of l25-l 27.
  • the 6,l l-dihydro-l l-(3a-tropanyloxy)dibenzo[b,e] thiepine, required as starting material, may be produced as follows:
  • thionyl chloride 7.3 g of thionyl chloride are added to 14.0 g of 6,1 ldihydrodibenzo[b,e]thiepiri 1l ol in 40 cc of absolute xylene, and the mixture is heated to for 1 hour. After cooling to room temperature, 3.0 g of calcium chloride are added and the xylene phase is filtered in the absence of moisture. The xylene phase is subsequently added dropwise within l5 minutes to a boiling mixture of 8.6 g of tropine (tropan-Ba-ol) and 24.6 g of sodium carbonate in 50 cc of absolute xylene.
  • the reaction mixture is heated under reflux for 6 hours and after cooling, is diluted with 200 cc of diethyl ether and extracted twice with 100 cc amounts of water.
  • the organic phase is extracted with 100 cc of N hydrochloric acid, the hydrochloric acid extract is rendered alkaline with 2 N caustic soda solution and is extracted thrice with 300 cc amounts of diethyl ether.
  • the ether extract is dried over sodium sulphate, is subsequently concentrated and the oily residue is distilled, whereby the title compound distills over at l90-2(l0 and 0.02 mm of Hg.
  • the mixture After cooling to room temperature, the mixture is diluted with 70 cc of water and the solution is rendered alkaline with a 25 percent ammonia solution while cooling.
  • the aqueous phase is then extracted thrice with 200 cc amounts of chloroform, the combined chloroform phases are dried over magnesium sulphate and the solvent is distilled off at reduced pressure.
  • the oily residue, i.e., the title compound is then converted into the methanesulphonate with methanesulphonic acid in methanol. After recrystallization from methanol, the methanesulphonate of the title compound has an MP. of 225230.
  • EXAMPLE 1 61 l-Dihydro-l 1-(3a-tropanyloxy)-dibenzo[b,e] thiepine-5,5-dioxide
  • the title compound is obtained by treating 6,11- dihydro-l 1-(3a-tropanyloxy)dibenzo[b,e]thiepine-5- oxide with hydrogen peroxide in accordance with the process described in Example 9.
  • the methanesulphonate of the title compound has an M.P. of 225-230.
  • n 1 or 2
  • m 1 or 2
  • a pharmaceutically acceptable acid addition salt thereof

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
US00162290A 1970-07-15 1971-07-13 CERTAIN 6,11-DIHYDRO-11-(3-ALPHA-TROPANYLOXY)-DIBENZO[b,e]THIEPINE-5-OXIDES AND THE CORRESPONDING DIOXIDES AND DERIVATIVES THEREOF Expired - Lifetime US3716544A (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CH1073670A CH529783A (de) 1970-07-15 1970-07-15 Verfahren zur Herstellung neuer Dibenzothiepinderivate
CH1073770A CH529784A (de) 1970-07-15 1970-07-15 Verfahren zur Herstellung neuer Dibenzothiepinderivate
CH1073870A CH529785A (de) 1970-07-15 1970-07-15 Verfahren zur Herstellung neuer Dibenzothiepinderivate
CH1073570A CH528538A (de) 1970-07-15 1970-07-15 Verfahren zur Herstellung neuer Dibenzothiepinderivate

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US3716544A true US3716544A (en) 1973-02-13

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US (1) US3716544A (enrdf_load_stackoverflow)
AU (1) AU3116571A (enrdf_load_stackoverflow)
BE (1) BE769968A (enrdf_load_stackoverflow)
DE (1) DE2134820A1 (enrdf_load_stackoverflow)
FR (1) FR2100908B1 (enrdf_load_stackoverflow)
GB (1) GB1354538A (enrdf_load_stackoverflow)
HU (1) HU163777B (enrdf_load_stackoverflow)
NL (1) NL7109301A (enrdf_load_stackoverflow)
SE (1) SE368955B (enrdf_load_stackoverflow)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3558107A (en) * 1968-07-29 1971-01-26 William Thomas Williams Foaming agent mixer and method
US4237296A (en) * 1973-03-26 1980-12-02 Sandoz Ltd. Quaternary tropane ethers
US4929625A (en) * 1987-08-04 1990-05-29 John Wyeth And Brothers Limited Ethers

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3234235A (en) * 1962-01-19 1966-02-08 American Home Prod Heterocyclic carbinols
US3413296A (en) * 1965-06-28 1968-11-26 Sandoz Ltd Certain 11-(3-tropanyloxy)-6, 11-dihydro-dibenzo[b, e] thiepin derivatives

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3234235A (en) * 1962-01-19 1966-02-08 American Home Prod Heterocyclic carbinols
US3413296A (en) * 1965-06-28 1968-11-26 Sandoz Ltd Certain 11-(3-tropanyloxy)-6, 11-dihydro-dibenzo[b, e] thiepin derivatives

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3558107A (en) * 1968-07-29 1971-01-26 William Thomas Williams Foaming agent mixer and method
US4237296A (en) * 1973-03-26 1980-12-02 Sandoz Ltd. Quaternary tropane ethers
US4929625A (en) * 1987-08-04 1990-05-29 John Wyeth And Brothers Limited Ethers
US4997839A (en) * 1987-08-04 1991-03-05 John Wyeth & Brother Limited 2-quinolyl ethers
US5082843A (en) * 1987-08-04 1992-01-21 John Wyeth And Brother Limited Pyrazinyl and pyridazinyl ethers

Also Published As

Publication number Publication date
DE2134820A1 (de) 1972-01-20
BE769968A (fr) 1972-01-13
NL7109301A (enrdf_load_stackoverflow) 1972-01-18
FR2100908A1 (enrdf_load_stackoverflow) 1972-03-24
FR2100908B1 (enrdf_load_stackoverflow) 1975-02-07
HU163777B (enrdf_load_stackoverflow) 1973-10-27
AU3116571A (en) 1973-01-18
SE368955B (enrdf_load_stackoverflow) 1974-07-29
GB1354538A (en) 1974-06-05

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