US3830814A - N-oxides of dibenzo(b,f)thiepines - Google Patents

N-oxides of dibenzo(b,f)thiepines Download PDF

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Publication number
US3830814A
US3830814A US00096262A US9626270A US3830814A US 3830814 A US3830814 A US 3830814A US 00096262 A US00096262 A US 00096262A US 9626270 A US9626270 A US 9626270A US 3830814 A US3830814 A US 3830814A
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United States
Prior art keywords
thiepine
dihydrodibenzo
ethanol
methylpiperazino
chloro
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
US00096262A
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English (en)
Inventor
J Jilek
M Protiva
J Metysova
J Pomykacek
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Spofa Vereinigte Pharma Werke
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Spofa Vereinigte Pharma Werke
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Publication of US3830814A publication Critical patent/US3830814A/en
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Expired - Lifetime legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • C07D337/14—[b,f]-condensed

Definitions

  • the known psychotropic preparations such as chlorpromazine which is chemically 2-chloro-10-(3-dimethylaminopropyl)-phenothiazine exhibit a high tranquilizing activity along with the cataleptic action.
  • chlorpromazine which is chemically 2-chloro-10-(3-dimethylaminopropyl)-phenothiazine exhibit a high tranquilizing activity along with the cataleptic action.
  • this invention relates to a new series of N-oxides of dibenzo[b,f]thiepines and the salts thereof, as well as the production of these compounds, these compounds exhibiting a relatively high cataleptic activity with relatively no tranquilizing action.
  • the present invention mainly comprises new N-oxides of dibenzo ([b,f]thiepines of Formula I below:
  • R is selected from the group consisting of hydrogen, halogen, trifiuoromethy], alkyl of l-4 carbon atoms, alkoxy of 1-4 carbon atoms and alkylthio of 1-4 carbon atoms,
  • R is selected from the group consisting of alkyl of 1-4 carbon atoms and hydroxy alkyl of 2-4 carbon atoms, and
  • X is selected from the group consisting of sulfur, SO and S0
  • the present invention also relates to salts of the above compounds, particularly salts with nontoxic, physiologically compatible inorganic and organic compounds.
  • the above compounds exhibit a marked tranquilizing and psychotropic activity so that the same can be used ice as agents in the treatment of mental and nervous dis orders.
  • the compounds of the present invention are produced by reacting the basic tertiary amine of the following Formula II:
  • the carrying out of the method is extremely simple.
  • the oxidation reaction proceeds even at room temperature and the reaction is ended by heating to the boiling temperature of the reaction mixture.
  • the obtained basic product exhibits, contrary to the starting tertiary amine, a marked hydrophilic characteristic and it crystallizes preponderantly in the form of the hydrate.
  • the salts which are obtained by neutralization with inorganic or organic acids can be used to make preparations for different forms of administration.
  • EXAMPLE 1 6.6 g. of 25% hydrogen peroxide are added to a warmed solution at 10.0 g. of 10-(4-methylpiperazino)-l0,1l-dihydrodibenzo[b,f]thiepine base in 65 ml. of ethanol and the reaction mixture is permitted to stand at room temperature overnight. It is then heated for 3 hours to boiling under refluxing and an additional hour with a small platinum prism for the purpose of decomposing the excess peroxide. After filtration the filtrate is mixed with 20 ml. water and the solution evaporated under reduced pressure. The remaining crystalline mixture is diluted with 60 ml. of water and is allowed to crystallize for 12 hours.
  • the precipitated product is filtered off under suction, washed with a small amount of water and dried under vacuum over phosphorous pentoxide. There is obtained 7.4 g. (70% of the theoretical) of 10 (4 methylpiperazino)- 10,11 dihydrodibenzo[b,f]thiepine N oxide in the form of its dihydrate, which retains its water in crystallization even after recrystallization from benezene.
  • the melting point is 110-112 C.
  • After neutralization with hydrogen chloride in an ethanol-ether mixture the base is converted into the corresponding crystalline hydrochloride which crystallizes from ethanol-ether in the form of the hemihydrate and which melts at l78182 C.
  • EXAMPLE 2 2.0 ml. of 25% hydrogen peroxide are added to a solution of 3.45 g. of 8 chloro 10 (4 methylpiperazino)- 10,11 dihydrodibenzo [b,f] thiepine base in 18 ml. of 95% ethanol. The mixture is permitted to stand overnight at room temperature and it is then heated for 3 hours to boiling under refluxing, mixed with 30 ml. of water and evaporated under reduced pressure. The residue is mixed with an additional 50 ml. of water, the crystallized product is filtered 01f under suction and dried under vacuum over phosphorous pentoxide. There is obtained 3.4 g.
  • EXAMPLE 4 A solution of 3.5 g. of 8 chloro 10 [4 (3 hydroxypropyl)piperazino] 10,11 dihydrodibenzo[b,f]thiepine base in 18 ml. of 95% ethanol is oxidized with 2 ml. of 25 hydrogen peroxide in analogous manner to the preceding examples. There is obtained 2.1 g. of the pure monohydrate of 8 chloro 1O [4 (3 hydroxypropyl)- 'piperazino] 10,11 dihydrodibenzo[b,f]thiepine-N-oxide which melts at 156-159 C. (benzene). By neutralization with hydrogen chloride in ethanol the base is converted to the corresponding dihydrochloride-hemihydrate which melts at 155158 C. (ethanol).
  • R is hydrogen, halogen, alkyl of 1-4 carbon atoms, and alkoxy of 1-4 carbon atoms; R is alkyl of 1-4 carbon atoms or monohydroxy alkyl of 2 to 4 carbon atoms and their pharmaceutically acceptable acid addition salts.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
US00096262A 1969-12-10 1970-12-08 N-oxides of dibenzo(b,f)thiepines Expired - Lifetime US3830814A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CS8111A CS148851B1 (en, 2012) 1969-12-10 1969-12-10

Publications (1)

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US3830814A true US3830814A (en) 1974-08-20

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Family Applications (1)

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US00096262A Expired - Lifetime US3830814A (en) 1969-12-10 1970-12-08 N-oxides of dibenzo(b,f)thiepines

Country Status (11)

Country Link
US (1) US3830814A (en, 2012)
JP (1) JPS494463B1 (en, 2012)
AT (1) AT297714B (en, 2012)
BE (1) BE759999A (en, 2012)
CH (1) CH547307A (en, 2012)
CS (1) CS148851B1 (en, 2012)
DE (1) DE2060903B2 (en, 2012)
FR (1) FR2081339B1 (en, 2012)
GB (1) GB1277854A (en, 2012)
NL (1) NL7018025A (en, 2012)
SE (1) SE366747B (en, 2012)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3985750A (en) * 1970-07-30 1976-10-12 Spofa, Sdruzeni Podniku Pro Zdravotnickou Vyrobu Fatty acid esters of 8-substituted 10-[4-(hydroxyalkyl)piperazino]-10,11-dihydrodibenzo[b,f]thiepins
US4111261A (en) * 1977-03-14 1978-09-05 Halliburton Company Wellhead isolation tool
EP1339696A1 (en) * 2000-12-08 2003-09-03 Pfizer Products Inc. Benzyl(idene)-lactams and their use as 5ht1-receptor ligands

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS56125158U (en, 2012) * 1980-02-22 1981-09-24

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3985750A (en) * 1970-07-30 1976-10-12 Spofa, Sdruzeni Podniku Pro Zdravotnickou Vyrobu Fatty acid esters of 8-substituted 10-[4-(hydroxyalkyl)piperazino]-10,11-dihydrodibenzo[b,f]thiepins
US4111261A (en) * 1977-03-14 1978-09-05 Halliburton Company Wellhead isolation tool
EP1339696A1 (en) * 2000-12-08 2003-09-03 Pfizer Products Inc. Benzyl(idene)-lactams and their use as 5ht1-receptor ligands

Also Published As

Publication number Publication date
CS148851B1 (en, 2012) 1973-05-24
DE2060903B2 (de) 1976-07-22
SE366747B (en, 2012) 1974-05-06
FR2081339B1 (en, 2012) 1975-12-26
JPS494463B1 (en, 2012) 1974-02-01
FR2081339A1 (en, 2012) 1971-12-03
BE759999A (fr) 1971-05-17
NL7018025A (en, 2012) 1971-06-14
GB1277854A (en) 1972-06-14
CH547307A (de) 1974-03-29
DE2060903A1 (de) 1971-06-16
AT297714B (de) 1972-04-10

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