US3505355A - Certain dihydrobenzo-thiepin-5(2h)-ones - Google Patents
Certain dihydrobenzo-thiepin-5(2h)-ones Download PDFInfo
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- US3505355A US3505355A US753018A US3505355DA US3505355A US 3505355 A US3505355 A US 3505355A US 753018 A US753018 A US 753018A US 3505355D A US3505355D A US 3505355DA US 3505355 A US3505355 A US 3505355A
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- benzothiepin
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- 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
- C07D337/08—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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- This invention relates to certain novel dihydrobenzothiepin-5(2H)-ones. More particularly, this invention is concerned with dihydrobenzothiepin-S(2H)-ones having the formula wherein R is a member selected from the group consisting of diloweralkylaminomethyl, pyridylmethylene and piperidinomethyl; and the non-toxic, acid addition salts and the therapeutically active loweralkyl quaternary ammonium derivatives thereof.
- loweralkyl may be straight or branch chained and have from 1 to 6 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl and the like.
- the therapeutically active non-toxic acid addition salts of these compounds are prepared by treatment with an appropriate acid such as an inorganic acid, e.g., hydrochloric, hydrobromide, hydriodic, sulfuric, nitric or phosphoric; an organic acid such as acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, maleic, malic, fumaric, tartaric, citric, benzoic, mandelic, cinnamic, methane sulfonic, benzene sulfonic, salicyclic, 2-phenoxybenzoic.
- an appropriate acid such as an inorganic acid, e.g., hydrochloric, hydrobromide, hydriodic, sulfuric, nitric or phosphoric
- an organic acid such as acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, maleic, malic, fumaric, tartaric, citric,
- novel compounds may be converted into the corresponding quaternary ammonium compounds by reaction of the tertiary bases with alkylating agents, i.e., alkyl or aralkyl halides or esters formed by reacting alkonals with an oxygen-containing acid such as methyl iodide, ethyl bromide, propyl chloride; lower alkenyl halides allyl bromide; dilower alkylsufatesdimethysufate, diethylsulfate; lower alkylarylsulfonates-methyl p-toluenesulfonate or aralkyl halidesbenzyl chloride.
- alkylating agents i.e., alkyl or aralkyl halides or esters formed by reacting alkonals with an oxygen-containing acid such as methyl iodide, ethyl bromide, propyl chloride; lower alkenyl halides allyl bro
- the quaternizing reaction may be performed in the presence or absence of a solvent, at room temperature or under cooling, at atmospheric pressure or in a closed vessel under pressure.
- Suitable solvents for this purpose are ethers such as diethylether and tetrahydrofuran, hydrocarbons such as benzene and heptane, ketones such as acetone and butanone, lower alkanols such as ethanol, propanol or butanol; or organic acid amides such as formamide or dimethylformamide.
- diethyl ether and benzene are the preferred solvents.
- the compounds of this invention have been found to possess valuable pharmacological properties.
- a hypotensive (blood pressure lowering) effect of 4066 mm. of Hg. is observed following intraveneous administration to anesthetized dogs at doses of 10 mg./kg. of body weight.
- Those compounds in which R is diloweralkylaminomethyl are vasopressor agents in dogs. For example, doses of 2 mg./ kg. of body weight, administered intraveneously, cause the blood pressure to rise 12 mm. of Hg.
- R is pyridylmethylene
- Those compounds in which R is pyridylmethylene are useful as anti-inflammatory agents as judged by their ability to inhibit koalin induced edema in the rat paw. For example, an 18% inhibition is observed after oral administration of about 100 -mg./kg.' of body weight.
- the corresponding acid addition salts have the same utilities as the basic compounds.
- R is diloweralkylaminomethyl
- a diloweralkylamine hydrochloride and formaldehyde or a polymer thereof such as paraformaldehyde in a suitable solvent such as ethanol in the presence of an acid such as concentrated hydrochloric acid under reflux conditions.
- R is a pyridylmethylene
- the compound of this invention wherein R is piperidinomethyl is prepared by reacting a solution of piperidine in a suitable solvent such as ethanol together with 3,4- dihydro-l-benzothiepin-S(2H)-one and formaldehyde or a polymer thereof such as paraformaldehyde under acidic conditions such as that provided by the addition of an acid, for example, concentrated hydrochloric acid, and under reflux conditions.
- a suitable solvent such as ethanol
- formaldehyde or a polymer thereof such as paraformaldehyde
- acidic conditions such as that provided by the addition of an acid, for example, concentrated hydrochloric acid, and under reflux conditions.
- the by drochloride salt is converted to the free base and then to crystalline acid fumarate salt by the addition of methanolic fumaric acid to the free base.
- the fumarate salt is recrystallized twice from methanol to give piperidinomethyl-3,4-dihydro-l-benzothiepin-S(2H) one fumarate; M.P. ISO-151 C.
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Description
United States Patent 3,505,355 CERTAIN DIHYDROBENZO-THIEPIN-(2H)-ONES Richard J. Mohrbacher, Fort Washington, and Vasken Paragamian, Dresher, Pa., assignors to McNeil Laboratories, Incorporated, a corporation of Pennsylvania No Drawing. Continuation-impart of application Ser. No. 635,389, May 2, 1967. This application Aug. 12, 1968, Ser. No. 753,018
Int. Cl. C07d 67/00 US. Cl. 260-327 2 Claims ABSTRACT OF THE DISCLOSURE The compounds are of the class of dihydrobenzothiepin-5(2H)-ones, useful for their respective pharmacological properties, such as hypotensive, vasopressor or antiflammatory activity, depending upon the type of derivative considered.
This application is a continuation-in-part of our copending application Ser. No. 635,389, filed May 2, 1967 (now abandoned) which was co-pending with our application Ser. No. 462,403, filed June 8, 1965 (now abandoned).
This invention relates to certain novel dihydrobenzothiepin-5(2H)-ones. More particularly, this invention is concerned with dihydrobenzothiepin-S(2H)-ones having the formula wherein R is a member selected from the group consisting of diloweralkylaminomethyl, pyridylmethylene and piperidinomethyl; and the non-toxic, acid addition salts and the therapeutically active loweralkyl quaternary ammonium derivatives thereof.
As used herein loweralkyl may be straight or branch chained and have from 1 to 6 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl and the like.
The therapeutically active non-toxic acid addition salts of these compounds are prepared by treatment with an appropriate acid such as an inorganic acid, e.g., hydrochloric, hydrobromide, hydriodic, sulfuric, nitric or phosphoric; an organic acid such as acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, maleic, malic, fumaric, tartaric, citric, benzoic, mandelic, cinnamic, methane sulfonic, benzene sulfonic, salicyclic, 2-phenoxybenzoic. Conversely, the salt form may be converted in the usual manner into the free base.
The novel compounds may be converted into the corresponding quaternary ammonium compounds by reaction of the tertiary bases with alkylating agents, i.e., alkyl or aralkyl halides or esters formed by reacting alkonals with an oxygen-containing acid such as methyl iodide, ethyl bromide, propyl chloride; lower alkenyl halides allyl bromide; dilower alkylsufatesdimethysufate, diethylsulfate; lower alkylarylsulfonates-methyl p-toluenesulfonate or aralkyl halidesbenzyl chloride. The quaternizing reaction may be performed in the presence or absence of a solvent, at room temperature or under cooling, at atmospheric pressure or in a closed vessel under pressure. Suitable solvents for this purpose are ethers such as diethylether and tetrahydrofuran, hydrocarbons such as benzene and heptane, ketones such as acetone and butanone, lower alkanols such as ethanol, propanol or butanol; or organic acid amides such as formamide or dimethylformamide. When lower alkyl halogenides are used as quaternizing agents, diethyl ether and benzene are the preferred solvents.
The compounds of this invention have been found to possess valuable pharmacological properties. For example, in those compounds in which R is piperidinomethyl, a hypotensive (blood pressure lowering) effect of 4066 mm. of Hg. is observed following intraveneous administration to anesthetized dogs at doses of 10 mg./kg. of body weight. Those compounds in which R is diloweralkylaminomethyl are vasopressor agents in dogs. For example, doses of 2 mg./ kg. of body weight, administered intraveneously, cause the blood pressure to rise 12 mm. of Hg. Those compounds in which R is pyridylmethylene are useful as anti-inflammatory agents as judged by their ability to inhibit koalin induced edema in the rat paw. For example, an 18% inhibition is observed after oral administration of about 100 -mg./kg.' of body weight. The corresponding acid addition salts have the same utilities as the basic compounds.
The compounds of this invention wherein R is diloweralkylaminomethyl are prepared by reacting 3-4-dihydrol-benzothiepin-5(2H)-one with a diloweralkylamine hydrochloride and formaldehyde or a polymer thereof such as paraformaldehyde in a suitable solvent such as ethanol in the presence of an acid such as concentrated hydrochloric acid under reflux conditions.
The compounds of this invention wherein R is a pyridylmethylene are prepared by reacting a mixture of 3,4- dihydro-1-benzothiepin-5(2H)-one and a pyridinecarboxaldehyde with an alkali such as potassium hydroxide dissolved in a suitable solvent such as methanol.
The compound of this invention wherein R is piperidinomethyl is prepared by reacting a solution of piperidine in a suitable solvent such as ethanol together with 3,4- dihydro-l-benzothiepin-S(2H)-one and formaldehyde or a polymer thereof such as paraformaldehyde under acidic conditions such as that provided by the addition of an acid, for example, concentrated hydrochloric acid, and under reflux conditions.
The following examples are intended to illustrate the present invention.
EXAMPLE I A solution of 11.2 g. (0.16 mole) of hydroxylamine hydrochloride in 16 m1. of water is added to a stirred slurry of 17.8 g. (0.1 mole) of 3,4-dihydro-l-benzothiepin-5 (2H)-one in 60 ml. of 95% ethanol. Aqueous potassium hydroxide (15.7 g., 0.28 mole of potassium hydroxide in 15.7 ml. of water) is then added and the slurry is heated under reflux for 2 hours, cooled, poured into ice water and acidified with concentrated hydrochloric acid. White crystals form. The crystals are recovered by filtration. Three recrystallizations from 95% ethanol yield white crystals of 3,4-dihydro-l-benzothiepin-S(2H)-one oxime; M.P. 97-99 C.
EXAMPLE II A mixture of 17.8 g. (0.1 mole) of 3,4-dihydro-1- benzothiepin-5(2H)-one, 10.6 g. (0.13 mole) of dimethylamine hydrochloride, 3.96 g. (0.044 mole) of paraformaldehyde and 0.2 ml. of concentrated hydrochloric acid in 20 ml. of 95 ethanol is refluxed with stirring for 3 hours. After slight cooling ml. of acetone is added. Cooling in the refrigerator yields white crystals. Two recrystallizations from ethanol-acetone produces white crystals of 4-di-methylaminomethyl-3,4-dihydro-1-benzothiepin 5 (2H)-one hydrochloride; M.P. 182-184 C.
EXAMPLE III To a stirred mixture of 7.1 g. (0.04 mole) of 3,4-dihydro-l-benzothiepin-S(2H)-one and 4.28 g. (0.04 mole) of 2-pyridinecarboxaldehyde is added dropwise 40 ml.
of a solution of 2 g. of potassium hydroxide in 50 ml. of methanol. The solution is stirred for 3 hours whereupon crystals appear, and then for an additional hour in an ice bath. The crystals are recovered by filtration. Two recrystallizations from ethyl acetate produce white crystals of 4-(2-pyridylmethylene)-3,4-dihydro-l-benzothiepin 5 (2H)-one; M.P. 120l22 C.
EXAMPLE IV A solution of 13.2 g. (0.16 mole) of piperidine in ethanol, 21.4 g. (0.12 mole) of 3,4-dihydr0-l-benzothiepin- 5(2H)-one, 4.8 g. of paraformaldehyde and enough concentrated hydrochloric acid to make the solution acidic is heated under reflux for 18 hours. After removal of some of the ethanol in vacuo, the solution is cooled and poured into ice water to yield crystals of piperidinomethyl-3,4-dihydrO-l-benzothiepin-S(2H)-one hydrochloride. The by drochloride salt is converted to the free base and then to crystalline acid fumarate salt by the addition of methanolic fumaric acid to the free base. The fumarate salt is recrystallized twice from methanol to give piperidinomethyl-3,4-dihydro-l-benzothiepin-S(2H) one fumarate; M.P. ISO-151 C.
EXAMPLE V Using the procedure of Example II and replacing dimethylamine hydrochloride 'with an equivalent amount of diethylamine hydrochloride, dipropylamine hydrochloride, diisobutylamine hydrochloride and dibutylamine hydrochloride the appropriate 4-diloweralkylaminomethyl-3,4- dihydro-hbenzothiepin-S (2H)-one is produced, namely 4-dirnethylaminomethyl-3,4-dihydro-l-benzothiepin-S 2H) -one;
4-dipropylaminomethyl-3,4-dihydro-1-benzothiepin-5 2H) -one;
4 1 4-diisobutylarninomethylfi,4-dihydro- 1 benzothiepin-S (2H -one; 4-dibntylaminomethyl-3,4-dihydro-1-benzothiepin-5 2H) -one.
EXAMPLE VI Using the procedure of Example III and replacing 2- pyridinecarboxaldehyde with an equivalent amount of 3- pyridinecarboxaldehyde and 4 pyridinecarboxaldehyde, the products obtained are 4-(3-pyridylmethylene)-3,4-dihydro-l-benzothiepin-S(2H)-one and 4-(4-pyridylmethylene -3 ,4-dihydro-1-abenzothiepin-5 (2H) -one.
What is claimed is:
1. A member selected from the group consisting of dihydrobenzothiepin-S(2H)-ones having the formula wherein R is a member selected from the group consisting of diloweralkylaminomethyl; and the non-toxic acid addition salts thereof.
2. 4-dimethylaminomethyl-3,4-dihydro-l-benzothiepiu-S (2H) -one.
References Cited UNITED STATES PATENTS 3,243,439 3/1966 Mohrbacher et al. 2'60307 HENRY R. JILES, Primary Examiner C. M. SHURKO, Assistant Examiner U.S. C1. X.R.
"H050 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3, 5 5,355 Dated April 7, 97
Inventor) Richard J. Mohrbacher and Vasken Paragamian It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:
[- In column 1, line 17, the word "antiflammatory" should read --anti- 1 inflammatory Column 2, line 63, the degrees sign after the "80" should be eliminated. Column 3, line 33, the word "dimethylaminomethyl" should read diethylaminomethyl Column lines 15 20, the "R" on the left hhnd side of the formula should read "0''.
alum] mw SEALED NOV 3 It mm. Edwardlm mm 1 Omission
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US75301868A | 1968-08-12 | 1968-08-12 | |
US87093169A | 1969-07-22 | 1969-07-22 | |
US87093269A | 1969-07-22 | 1969-07-22 |
Publications (1)
Publication Number | Publication Date |
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US3505355A true US3505355A (en) | 1970-04-07 |
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ID=27419438
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US753018A Expired - Lifetime US3505355A (en) | 1968-08-12 | 1968-08-12 | Certain dihydrobenzo-thiepin-5(2h)-ones |
US870931*A Expired - Lifetime US3597432A (en) | 1968-08-12 | 1969-07-22 | 4-piperidinomethyl - 3,4 - dihydro-1-benzothiepin-5(2h)-ones |
US870932*A Expired - Lifetime US3551435A (en) | 1968-08-12 | 1969-07-22 | Certain 4-(pyridylmethylene)-3,4-dihydro-1-benzothiepin-5(2h)-ones |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
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US870931*A Expired - Lifetime US3597432A (en) | 1968-08-12 | 1969-07-22 | 4-piperidinomethyl - 3,4 - dihydro-1-benzothiepin-5(2h)-ones |
US870932*A Expired - Lifetime US3551435A (en) | 1968-08-12 | 1969-07-22 | Certain 4-(pyridylmethylene)-3,4-dihydro-1-benzothiepin-5(2h)-ones |
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4166126A (en) * | 1974-09-26 | 1979-08-28 | Ciba-Geigy Corporation | 1-benzothiepin-4-carboxamides |
US4185109A (en) * | 1974-09-26 | 1980-01-22 | Ciba-Geigy Corporation | 1-Benzothiepin-4-carboxamides |
US4226998A (en) * | 1974-09-26 | 1980-10-07 | Ciba-Geigy Corporation | 1-Benzothiepin-4-carboxamides |
US4242266A (en) * | 1974-09-26 | 1980-12-30 | Ciba-Geigy Corporation | 1-Benzothiepin-4-carboxylic acid derivatives |
US4329357A (en) * | 1980-02-08 | 1982-05-11 | Ciba-Geigy Corporation | 1-Benzothiepin-4-carboxyamides |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3243439A (en) * | 1965-06-24 | 1966-03-29 | Mcneilab Inc | Benzothiepin oxazoles |
-
1968
- 1968-08-12 US US753018A patent/US3505355A/en not_active Expired - Lifetime
-
1969
- 1969-07-22 US US870931*A patent/US3597432A/en not_active Expired - Lifetime
- 1969-07-22 US US870932*A patent/US3551435A/en not_active Expired - Lifetime
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3243439A (en) * | 1965-06-24 | 1966-03-29 | Mcneilab Inc | Benzothiepin oxazoles |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4166126A (en) * | 1974-09-26 | 1979-08-28 | Ciba-Geigy Corporation | 1-benzothiepin-4-carboxamides |
US4185109A (en) * | 1974-09-26 | 1980-01-22 | Ciba-Geigy Corporation | 1-Benzothiepin-4-carboxamides |
US4226998A (en) * | 1974-09-26 | 1980-10-07 | Ciba-Geigy Corporation | 1-Benzothiepin-4-carboxamides |
US4242266A (en) * | 1974-09-26 | 1980-12-30 | Ciba-Geigy Corporation | 1-Benzothiepin-4-carboxylic acid derivatives |
US4329357A (en) * | 1980-02-08 | 1982-05-11 | Ciba-Geigy Corporation | 1-Benzothiepin-4-carboxyamides |
Also Published As
Publication number | Publication date |
---|---|
US3597432A (en) | 1971-08-03 |
US3551435A (en) | 1970-12-29 |
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