US3849405A - Thieno-(2,3-e)(1,4)diazepin-2-ones - Google Patents

Thieno-(2,3-e)(1,4)diazepin-2-ones Download PDF

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Publication number
US3849405A
US3849405A US00116240A US11624071A US3849405A US 3849405 A US3849405 A US 3849405A US 00116240 A US00116240 A US 00116240A US 11624071 A US11624071 A US 11624071A US 3849405 A US3849405 A US 3849405A
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US
United States
Prior art keywords
thieno
diazepin
dihydro
melting
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US00116240A
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English (en)
Inventor
M Shiroki
M Nakanishi
K Araki
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mitsubishi Tanabe Pharma Corp
Original Assignee
Yoshitomi Pharmaceutical Industries Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from JP45015819A external-priority patent/JPS4910955B1/ja
Priority claimed from JP45019403A external-priority patent/JPS4940000B1/ja
Priority claimed from JP45056154A external-priority patent/JPS4932549B1/ja
Priority claimed from JP45067442A external-priority patent/JPS4940238B1/ja
Application filed by Yoshitomi Pharmaceutical Industries Ltd filed Critical Yoshitomi Pharmaceutical Industries Ltd
Application granted granted Critical
Publication of US3849405A publication Critical patent/US3849405A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/36—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/78—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems condensed with rings other than six-membered or with ring systems containing such rings

Definitions

  • each of R and R is a member selected from the group consisting of H and a lower alkyl group of from 1 to 4 carbon atoms, and wherein R and R may also combine to form a member selected from the group consisting of trimethylene and pentamethylene;
  • R is a member selected from the group consisting of H and a lower alkyl group of from 1 to 4 carbon atoms; and
  • R is a member selected from the group consisting of H, a halogen atom, CF and a lower alkoxy group of from 1 to 4 carbon atoms, providing that R does not represent H when each of R and R is a member selected from the group consisting of H and a lower alkyl group of from 1 to 4 carbon atoms; and the pharmaceutically acceptable acid addition salts thereof, and process for preparing same.
  • the compounds encompassed by the above formula exhibit pharmacological activity in narcosis potentiation, suppression of fighting behaviour and anti-convulsant activity.
  • the present invention relates to novel and therapeutically valuable thieno-[2,3-e][l,4]diazepin-2-ones of the formula:
  • the compounds (I) can be produced by the following methods:
  • the reaction is usually carried out in a solvent such as benzene, toluene, xylene, chloroform, tetrahydrofuran, dimethylformamide or pyridine, at an elevated temperature and preferably at refluxing temperature. It is also preferred that the water formed be continuously removed azeotropically.
  • a solvent such as benzene, toluene, xylene, chloroform, tetrahydrofuran, dimethylformamide or pyridine
  • reaction is usually carried out in a solvent such as benzene, toluene, chloroform, tetrahydrofuran, dimethylformamide or pyridine at an elevated temperature, preferably at refluxing temperature, preferably the water or 'alkanol formed being removed continuously.
  • a solvent such as benzene, toluene, chloroform, tetrahydrofuran, dimethylformamide or pyridine
  • the reaction is usually carried out in a solvent first by converting a compound (1) into an alkali metal salt with a metalating agent, such as an alkali metal (Li, Na or K) or an alkali metal compound (hydride, alkoxide or amide of an alkali metal), and then reacting the alkali metal salt with compound (VI), at a temperature of from room temperature to refluxing temperature.
  • a metalating agent such as an alkali metal (Li, Na or K) or an alkali metal compound (hydride, alkoxide or amide of an alkali metal
  • the starting compounds (II) and (III) are new compounds and can be produced, for example, by the following methods:
  • the compounds of formula (I) can be converted into the corresponding acid addition salts in a conventional manner by treatment with various inorganic and organic acids, for example, hydrochloric, hydrobromic, nitric, sulfuric, phosphoric, p-toluenesulfonic, citric, maleic, fumaric, succinic, formic, acetic and tartaric acid.
  • various inorganic and organic acids for example, hydrochloric, hydrobromic, nitric, sulfuric, phosphoric, p-toluenesulfonic, citric, maleic, fumaric, succinic, formic, acetic and tartaric acid.
  • the compound of formula (I) and pharmaceutically acceptable acid addition salts thereof have excellent pharmacological activities in narcosis potentiation, suppression of fighting behavior and anticonvulsant effect as shown, for example, by the following tests.
  • Pentylenetetrazol 150 mg./kg. was administered subcutaneously to eight groups each consisting of 6 mice, minutes after the intraperitoneal administration of the test compound. The number of dead mice were counted within 3 hours after the administration of pentylenetetrazol, and then the ED the dose required to suppress the lethal rate to 50%, was determined graphically.
  • the pharmaceutical preparations can take any conventional form such as tablets, capsules or powders.
  • Formulation Example 5 mg. and 10 mg. tablets are prepared from the following compositions:
  • tablet tablet tablet Compound (1) mg 5.0 10. 0 Lactose, mg 62. 3 57. 3 Corn starch, mg 25.0 25. 0 Microcrystalline cellulose, mg 6.0 6. 0 Methyl cellulose, mg 1. 0 1. 0 Magnesium stearate, mg 0. 7 0. 7
  • powder powder Compound (I) percent 1.0 10. 0 Lactose, percent 88.0 79. 0 Mieroerystalline cellulose, percent 10.0 10. 0 Methyl cellulose, percent 1. 0 1. 0
  • EXAMPLE 1 A solution of 7.5 g. of 2 aminoacetamido-3-benzoyl- 5,6-dihydro 4H [1]cyclopentathiophene in 50 ml. of pyridine, 1.5 g. of acetic acid and 15 ml. of benzene is refluxed for 3 hours in a flask provided with a waterremoving adaptor. The solvent is distilled off, water is added to the residue, the solution is made alkaline with sodium hydrogen carbonate and extracted with chloroform.
  • the chloroform layer is dried over sodium sulfate, the chloroform is distilled off, and the crude crystals thus obtained are recrystallized from ethanol to give pale yellow crystalline 5 phenyl 1,2,7,8 tetrahydro-3H,6H [1]cyclopentathieno [2,3-e] [1,4]diazepin 2 one, melting at 243 C. with decomposition, in 73% yield.
  • the oily residue is crystallized 7 from hexane to give pale yellow crystalline -o-methoxyphenyl 7 ethyl 1,2-dihydro-3H-thieno-[2,3-e] [1,41diazepin-2-one, melting at l68l69 C. (from a mixture of ethanol and hexane).
  • the chloroform eluate containing the object compound is concentrated under reduced pressure, and the residue is treated with toluene to give white crystalline 5 o chlorophenyl 7 ethyl-1,2-dihydro-3H-thieno- [2,3-e][1,4]diazepin 2 one melting at 204206 C. (from a mixture of toluene and ethanol).
  • EXAMPLE 5 5 p chlorophenyl 6,7 dimethyl-1,2-dihydro-3H- thieno [2,3-e][l,4]diazepin 2 one (3.0 g.) is suspended in 70 ml. of toluene. The suspension is heated to 40 C. whereupon 0.58 g. of sodium methoxide is added, and the mixture is refluxed to make a homogeneous pale brown solution. After about ml. of the methanol and toluene are distilled off, 1.3 g. of dimethyl sulfate is added slowly, and the resulting mixture is refluxed for 1 hour.
  • R is a lower alkyl group of from 1 to 2 carbon atoms; R is a member selected from the group consisting of a hydrogen atom and a methyl group; and Hal represents a halogen atom; and the pharmaceutically acceptable acid addition salts thereof.
  • Th compound of Claim 1 5 o chlorophenyl-7- methyl 1,2 dihydro 3H thieno [2,3-e][1,4]diazepin-2-one.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
US00116240A 1970-02-17 1971-02-17 Thieno-(2,3-e)(1,4)diazepin-2-ones Expired - Lifetime US3849405A (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
JP1407070 1970-02-17
JP45015819A JPS4910955B1 (enrdf_load_stackoverflow) 1970-02-23 1970-02-23
JP45019403A JPS4940000B1 (enrdf_load_stackoverflow) 1970-03-07 1970-03-07
JP45056154A JPS4932549B1 (enrdf_load_stackoverflow) 1970-06-25 1970-06-25
JP45067442A JPS4940238B1 (enrdf_load_stackoverflow) 1970-07-31 1970-07-31

Publications (1)

Publication Number Publication Date
US3849405A true US3849405A (en) 1974-11-19

Family

ID=27519583

Family Applications (1)

Application Number Title Priority Date Filing Date
US00116240A Expired - Lifetime US3849405A (en) 1970-02-17 1971-02-17 Thieno-(2,3-e)(1,4)diazepin-2-ones

Country Status (9)

Country Link
US (1) US3849405A (enrdf_load_stackoverflow)
BE (1) BE763014A (enrdf_load_stackoverflow)
CA (1) CA927388A (enrdf_load_stackoverflow)
CH (1) CH568322A5 (enrdf_load_stackoverflow)
DE (1) DE2107356C3 (enrdf_load_stackoverflow)
FR (1) FR2081520B1 (enrdf_load_stackoverflow)
GB (1) GB1291684A (enrdf_load_stackoverflow)
NL (1) NL175723C (enrdf_load_stackoverflow)
SE (1) SE367415B (enrdf_load_stackoverflow)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4156009A (en) * 1977-03-31 1979-05-22 Hexachimie Diazepine derivatives
US4992437A (en) * 1987-12-22 1991-02-12 Yoshitomi Pharmaceutical Industries, Ltd. Thienodiazepine compounds and their pharmaceutical use
EP2935284A4 (en) * 2012-12-21 2016-04-27 Abbvie Inc HETEROCYCLIC MODULATORS OF HORMONE NUCLEAR RECEPTORS

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1340227A (en) * 1970-09-03 1973-12-12 Yoshitomi Pharmaceutical 5-pyridyl-thieno-2,3-e 1,4-diazepin 2-one derivatives their production and pharmaceutical compositions containing them
JPS5418280B2 (enrdf_load_stackoverflow) * 1971-10-30 1979-07-06
GB1387783A (en) * 1972-08-08 1975-03-19 Yoshitomi Pharmaceutical Thiophene derivatives, method for their preparation and pharmaceutical composition thereof
ES412186A1 (es) * 1973-02-28 1976-01-01 Made Labor Sa Un procedimiento para la preparacion de derivados de tieno-diazepinona.

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH540247A (de) * 1967-04-21 1973-09-28 Ciba Geigy Ag Verfahren zur Herstellung von heterocyclischen, Asthylendoppelbindungen enthaltenden Verbindungen
GB1256548A (enrdf_load_stackoverflow) * 1968-12-10 1971-12-08

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4156009A (en) * 1977-03-31 1979-05-22 Hexachimie Diazepine derivatives
US4992437A (en) * 1987-12-22 1991-02-12 Yoshitomi Pharmaceutical Industries, Ltd. Thienodiazepine compounds and their pharmaceutical use
EP2935284A4 (en) * 2012-12-21 2016-04-27 Abbvie Inc HETEROCYCLIC MODULATORS OF HORMONE NUCLEAR RECEPTORS

Also Published As

Publication number Publication date
DE2107356B2 (de) 1977-09-22
BE763014A (fr) 1971-07-16
NL175723C (nl) 1984-12-17
NL175723B (nl) 1984-07-16
CH568322A5 (enrdf_load_stackoverflow) 1975-10-31
DE2107356C3 (de) 1978-05-03
SE367415B (enrdf_load_stackoverflow) 1974-05-27
DE2107356A1 (de) 1971-08-26
GB1291684A (en) 1972-10-04
FR2081520B1 (enrdf_load_stackoverflow) 1974-08-30
CA927388A (en) 1973-05-29
NL7102066A (enrdf_load_stackoverflow) 1971-08-19
FR2081520A1 (enrdf_load_stackoverflow) 1971-12-03

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