CA1110625A - Aminoalkylthiodibenzthiepins and related compounds, a method of preparing same and pharmaceutical and veterinary preparations including same - Google Patents
Aminoalkylthiodibenzthiepins and related compounds, a method of preparing same and pharmaceutical and veterinary preparations including sameInfo
- Publication number
- CA1110625A CA1110625A CA317,810A CA317810A CA1110625A CA 1110625 A CA1110625 A CA 1110625A CA 317810 A CA317810 A CA 317810A CA 1110625 A CA1110625 A CA 1110625A
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- Prior art keywords
- thiepin
- formula
- beta
- ethylthio
- dibenz
- Prior art date
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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
- C07D337/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D337/14—[b,f]-condensed
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Biomedical Technology (AREA)
- Public Health (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
The present application concerns novel amino-alkylthiodibenzthiepins of the formula I
I
wherein X is hydrogen, Y is hydrogen or halogen, and Z
represent halogen or
The present application concerns novel amino-alkylthiodibenzthiepins of the formula I
I
wherein X is hydrogen, Y is hydrogen or halogen, and Z
represent halogen or
Description
l~lQ6Z5 The invention relates to novel aminoalkylthiodibenz-thiepins and related compounds and to their physiological-ly tolerable acid addition salts which are useful as anti-depressant, analgetic and anticonvulsant agents, and to pharmaceutical and veterinary compositions containing such a compound as an essential active ingredient.
It is already known that Amethoclothepine of the formula:
H V O(CH2)2N(CH3)2 ~Cl possesses central depressant activity by M. Protvia, et al.
II Farmaco XXI 98 (1966).
Japaneses Patent No. 47-28998 entitled "A Method of Manufacturing Tricyclic Compounds Having an Enolic Ether Bond" pertains to the preparation of compounds depicted by the formula O-Rl-N
~ \ R
15 in which A is an alkylimino group, an oxy radical, a thio : group or a sulfonyl group, Rl is an alkylene group, R2 and R3 each represent an alkyl group or may be bonded cyclically either through the alkylimine or not through the alkylimine group.
, ~
. .
' ~- ' ' . . ' -: , ' ': : - ' , However, the compounds of the present invention possess significant differences with respect to the aforesaid prior art compounds. Furthermore, neither reference suggests the unique methodology required for the preparation of the compounds of the present invention.
The compounds of the present invention conform to the general formula ~S- (CH2)n-Z
X~ ~ I ~
wherein X and Y are the same or different and each can be hydrogen, halogen, trifluoromethyl, C1-C6-alkoxy, C1-C6-alkyl, C1-C6alkylthio, Cl-C6alkylsulfonyl, C1-C6-alkylsul-finyl, amino or nitro, Z is halogen or N~' wherein Ris hydrogen, straight or branched chain C1-C6alkyl, cyano, cycloalkyl-C1-C6alkyl wherein the cycloalkyl ring contains from 3 to 6 carbon atoms~ phenoxycarbonyl of the formula ; -C02- ~ , C1-C6-alkoxycarbonyl, C2-C6-alkenyl or C2-C6-alkynyl, R2 is straight or branched chain C1-C6alkyl or cyc-loalkyl-C1-C6-alkyl wherein the cycloalkyl ring contains from 3 to 6 carbon atoms; and when R1 and R2 are taken to-gether with the nitrogen atom to which they are attached, the group R1-N-R2 forms a heterocycle which is morpholino, piperidino, pyrrolidinyl, or N-substituted piperazinyl in which the N-substituent is C1-C6alkyl; m is the integer O
or 1; and n is an integer of from 2 to 4; and a physiolo-gically tolerable acid addition salt thereof.
~ ~ .
.
.. . . ..
~ ~, ,:,. ~ ., . . :
.. .. . ... .: ~. .
: . : .
.. . . . . .
l~Q625 , ~, - 4 - ~OE 77/F 274 Acids useful for preparing the pharmaceutically acceptable acid addition salts of the invention lncl~lde inorganic acids such as hydrochloric, hydrobro~ic, sulfuric, nit:ric, phosphoric and perchloric acids, as well as organic 5 acids such as tartaric, citric, acetic, succinic, ~aleic, ~u~aric, and oxalic acids.
Compounds of the invention are prepared by the me'~hods given below. With the exceptions noted, X, Y, Z, R1, R2, m and n are as defined earlier.
Method a) A 10,11-dihydro-10-hydroxy- or -10-oxo-dibenz/ b,f 7 thiepin, of the Pormula .~
R3 ~ 4 X ~ Y II
wherein X and Y are as defined in formula I and R3 and R4 are different and represent each hydrogen or hydroxy or to-gether represent oxygen is reacted with aminoalkylthiol of the formula ,Rl ' HS-(cl12~ N~R2 III
wherein R1 and R2 are the same or different and each can be a straight or branched chain C1-C6alkyl to produce a com-pound of the invention of the formula Rl ' S- (CH2) R~
,, , X~S ~Y
. ~ . .
, .
.: . ' ' , :: : ~ ':, ',' : ' ~llQ6Z5 ~~ _ 5 ~ 771F 'l4 Method b) A compound prepared in Method a) wherein Rl and R2 are each methyl, can be treated with a cyano~en halide such as cyanogen bromide in a suitable solvent and acld 5 scavenger to obtain a mixture of one compound of the invention of the formula S (C~2)nhal X ~ y Ib and another compound of the invention of the formula S(CM2)n N\
X~ ~_ y , This reaction is carried out at a temperature of from about ' ambient to reflux. These two compounds of the invention may be isolated and collected by column chromato~;raphy.
Method c) A compound prepared in Method ~)of formula Ia can be reacted in a known.fashion with a suitable amine to obtain .-the corresponding compound of the invention. of the formula ~Rl ' ~S- (CH,2)n-N\R2 Ia .
,', ', ' , ' ,'' '',' '' '' "
', . ' , , ' '. ' , , ' ' ' ~ ' " ~ ' .
.
' ~11~25 wherein R is hydrogen, straight or branched chain Cl-C6al-kyl, cycloalkyl-Cl-C6alkyl, C2-C6alkenyl or Cl-C6alkynyl;
R2 is straight or branched chain C1-C6alkyl; and when Rl and R2 are taken together with the nitrogen atom to which they are attached, the group R1-N-R2 forms a heterocycle which is N-substituted piperazinyl, morpholino, piperidino or pyrrolidinyl. A preferred method is carried out with a dimethylformamide solvent, an acid scavenger such as sodium bicarbonate and a reaction initiator such as potassium iodide at a temperature of from ambient to the reflux tem-perature of the reaction mixture.
Method d) A compound prepared in Method a) 'canhe treated with a chloroformate, e.g. an alkyl or phenyl chloroformate, at a temperature of from 25 to 125C, in a solvent such as methylene chloride, toluene or benzcne to provide the corresponding compound o~ the inven~ion in w~lich Z
is N~R2 with R1 being C1-C6-alkoxy or phenoxy carbonyl.
Method e) A co~pound prepared in Methodd) is treated ~ith a base such as sodium or ~otassium hydroxide in a solvent such as water, ethanol or ethylene ~lycol at a temperature o~ ~rom ambient to reflux or with an acid medium such as hydrogen bromide in glacial acetic acid at a temperature from about ambient to reflux to provide the corresponding compound of the invention in which Rl is hydrogen.
Method f) A compound prepared in Method e is treated with a straight or branched chain C1-c6alkyl halide, C2-C6 alky-: ' , ~ , l~lQ6ZS
,_ nyl halide or cycloalkyl-Cl-C6alkyl halide under conditions normal for such reactions to provide the corresponaing com-pound of the invention in which Rl is straight or branched chain Cl c6alkyl, C2-C6alkenyl, C2-C6alkynyl or cycloalkyl-Cl-C6alkyl. A preferred method is to carry out this sub-stitution in the presence of a solvent such as dimethyl-formamide, an acid scavenger such as sodium bicarbonate and a reaction initiator such as potassium iodide at the reflux temperature of the solvent.
Method g) A compound prepared in any of the above methods, which includes a nitro group can be reduced by a convent-ional method to produce the corresponding amino compound.
As is appreciated by those skilled in the art, specific reaction conditions in any of the above methods are dependent on and are a function of the ingredients of each procedure.
The compounds of the invention are useful in the treatment of depression in mammals which is evidenced by their ability to inhibit tetrabenazine-induced depression ; in mice [International Journal of Neuropharmacology 8, 73 (1969)], a standard assay for useful antidepressant properties Compounds of the invention are furthex useful as analgesic agents due to their ability to alleviate pain in mammals which is demonstrated in the phenyl-p-quinone writing assay in mice, a standard assay for analgesia [Proc.
Soc, Exptl. Biol. Med., 95, 729 (1957)].
, .
: ' '. . ' ' ' ' ' '' .
- . : , . : .
- .: : . . . ..
': :
-~ 8 Compounds of the present invention are still further useful as anticonvulsant agents for mammals, as evidenced by the method of Woodbury, L.A. and Davenport, V.D. in Arch. Int. Pharmacodynam, Vol. 92, (1952) at pages 97-107.
These compounds are useful, as any of the above three categories of pharmaceutical agents, when administ-ered in an amount ranging from about 0.1 to 100 mg per kg of body weight per day.
Examples of compounds of the invention include:
11-[r-(dimethylamino)propylthio]-2-ethylsulfonyl-dibenz[b,f]thiepin;
ll-[~-~bromo)ethylthio]-2-methoxy-10,11-dihydrodibenz-[b,f]thiepin;
It is already known that Amethoclothepine of the formula:
H V O(CH2)2N(CH3)2 ~Cl possesses central depressant activity by M. Protvia, et al.
II Farmaco XXI 98 (1966).
Japaneses Patent No. 47-28998 entitled "A Method of Manufacturing Tricyclic Compounds Having an Enolic Ether Bond" pertains to the preparation of compounds depicted by the formula O-Rl-N
~ \ R
15 in which A is an alkylimino group, an oxy radical, a thio : group or a sulfonyl group, Rl is an alkylene group, R2 and R3 each represent an alkyl group or may be bonded cyclically either through the alkylimine or not through the alkylimine group.
, ~
. .
' ~- ' ' . . ' -: , ' ': : - ' , However, the compounds of the present invention possess significant differences with respect to the aforesaid prior art compounds. Furthermore, neither reference suggests the unique methodology required for the preparation of the compounds of the present invention.
The compounds of the present invention conform to the general formula ~S- (CH2)n-Z
X~ ~ I ~
wherein X and Y are the same or different and each can be hydrogen, halogen, trifluoromethyl, C1-C6-alkoxy, C1-C6-alkyl, C1-C6alkylthio, Cl-C6alkylsulfonyl, C1-C6-alkylsul-finyl, amino or nitro, Z is halogen or N~' wherein Ris hydrogen, straight or branched chain C1-C6alkyl, cyano, cycloalkyl-C1-C6alkyl wherein the cycloalkyl ring contains from 3 to 6 carbon atoms~ phenoxycarbonyl of the formula ; -C02- ~ , C1-C6-alkoxycarbonyl, C2-C6-alkenyl or C2-C6-alkynyl, R2 is straight or branched chain C1-C6alkyl or cyc-loalkyl-C1-C6-alkyl wherein the cycloalkyl ring contains from 3 to 6 carbon atoms; and when R1 and R2 are taken to-gether with the nitrogen atom to which they are attached, the group R1-N-R2 forms a heterocycle which is morpholino, piperidino, pyrrolidinyl, or N-substituted piperazinyl in which the N-substituent is C1-C6alkyl; m is the integer O
or 1; and n is an integer of from 2 to 4; and a physiolo-gically tolerable acid addition salt thereof.
~ ~ .
.
.. . . ..
~ ~, ,:,. ~ ., . . :
.. .. . ... .: ~. .
: . : .
.. . . . . .
l~Q625 , ~, - 4 - ~OE 77/F 274 Acids useful for preparing the pharmaceutically acceptable acid addition salts of the invention lncl~lde inorganic acids such as hydrochloric, hydrobro~ic, sulfuric, nit:ric, phosphoric and perchloric acids, as well as organic 5 acids such as tartaric, citric, acetic, succinic, ~aleic, ~u~aric, and oxalic acids.
Compounds of the invention are prepared by the me'~hods given below. With the exceptions noted, X, Y, Z, R1, R2, m and n are as defined earlier.
Method a) A 10,11-dihydro-10-hydroxy- or -10-oxo-dibenz/ b,f 7 thiepin, of the Pormula .~
R3 ~ 4 X ~ Y II
wherein X and Y are as defined in formula I and R3 and R4 are different and represent each hydrogen or hydroxy or to-gether represent oxygen is reacted with aminoalkylthiol of the formula ,Rl ' HS-(cl12~ N~R2 III
wherein R1 and R2 are the same or different and each can be a straight or branched chain C1-C6alkyl to produce a com-pound of the invention of the formula Rl ' S- (CH2) R~
,, , X~S ~Y
. ~ . .
, .
.: . ' ' , :: : ~ ':, ',' : ' ~llQ6Z5 ~~ _ 5 ~ 771F 'l4 Method b) A compound prepared in Method a) wherein Rl and R2 are each methyl, can be treated with a cyano~en halide such as cyanogen bromide in a suitable solvent and acld 5 scavenger to obtain a mixture of one compound of the invention of the formula S (C~2)nhal X ~ y Ib and another compound of the invention of the formula S(CM2)n N\
X~ ~_ y , This reaction is carried out at a temperature of from about ' ambient to reflux. These two compounds of the invention may be isolated and collected by column chromato~;raphy.
Method c) A compound prepared in Method ~)of formula Ia can be reacted in a known.fashion with a suitable amine to obtain .-the corresponding compound of the invention. of the formula ~Rl ' ~S- (CH,2)n-N\R2 Ia .
,', ', ' , ' ,'' '',' '' '' "
', . ' , , ' '. ' , , ' ' ' ~ ' " ~ ' .
.
' ~11~25 wherein R is hydrogen, straight or branched chain Cl-C6al-kyl, cycloalkyl-Cl-C6alkyl, C2-C6alkenyl or Cl-C6alkynyl;
R2 is straight or branched chain C1-C6alkyl; and when Rl and R2 are taken together with the nitrogen atom to which they are attached, the group R1-N-R2 forms a heterocycle which is N-substituted piperazinyl, morpholino, piperidino or pyrrolidinyl. A preferred method is carried out with a dimethylformamide solvent, an acid scavenger such as sodium bicarbonate and a reaction initiator such as potassium iodide at a temperature of from ambient to the reflux tem-perature of the reaction mixture.
Method d) A compound prepared in Method a) 'canhe treated with a chloroformate, e.g. an alkyl or phenyl chloroformate, at a temperature of from 25 to 125C, in a solvent such as methylene chloride, toluene or benzcne to provide the corresponding compound o~ the inven~ion in w~lich Z
is N~R2 with R1 being C1-C6-alkoxy or phenoxy carbonyl.
Method e) A co~pound prepared in Methodd) is treated ~ith a base such as sodium or ~otassium hydroxide in a solvent such as water, ethanol or ethylene ~lycol at a temperature o~ ~rom ambient to reflux or with an acid medium such as hydrogen bromide in glacial acetic acid at a temperature from about ambient to reflux to provide the corresponding compound of the invention in which Rl is hydrogen.
Method f) A compound prepared in Method e is treated with a straight or branched chain C1-c6alkyl halide, C2-C6 alky-: ' , ~ , l~lQ6ZS
,_ nyl halide or cycloalkyl-Cl-C6alkyl halide under conditions normal for such reactions to provide the corresponaing com-pound of the invention in which Rl is straight or branched chain Cl c6alkyl, C2-C6alkenyl, C2-C6alkynyl or cycloalkyl-Cl-C6alkyl. A preferred method is to carry out this sub-stitution in the presence of a solvent such as dimethyl-formamide, an acid scavenger such as sodium bicarbonate and a reaction initiator such as potassium iodide at the reflux temperature of the solvent.
Method g) A compound prepared in any of the above methods, which includes a nitro group can be reduced by a convent-ional method to produce the corresponding amino compound.
As is appreciated by those skilled in the art, specific reaction conditions in any of the above methods are dependent on and are a function of the ingredients of each procedure.
The compounds of the invention are useful in the treatment of depression in mammals which is evidenced by their ability to inhibit tetrabenazine-induced depression ; in mice [International Journal of Neuropharmacology 8, 73 (1969)], a standard assay for useful antidepressant properties Compounds of the invention are furthex useful as analgesic agents due to their ability to alleviate pain in mammals which is demonstrated in the phenyl-p-quinone writing assay in mice, a standard assay for analgesia [Proc.
Soc, Exptl. Biol. Med., 95, 729 (1957)].
, .
: ' '. . ' ' ' ' ' '' .
- . : , . : .
- .: : . . . ..
': :
-~ 8 Compounds of the present invention are still further useful as anticonvulsant agents for mammals, as evidenced by the method of Woodbury, L.A. and Davenport, V.D. in Arch. Int. Pharmacodynam, Vol. 92, (1952) at pages 97-107.
These compounds are useful, as any of the above three categories of pharmaceutical agents, when administ-ered in an amount ranging from about 0.1 to 100 mg per kg of body weight per day.
Examples of compounds of the invention include:
11-[r-(dimethylamino)propylthio]-2-ethylsulfonyl-dibenz[b,f]thiepin;
ll-[~-~bromo)ethylthio]-2-methoxy-10,11-dihydrodibenz-[b,f]thiepin;
2-ethyl-11-[~-(methylamino)ethylthio]dibenz[b,f]
thiepin;
ll-[~-(ethylmethylar,lino)ethylthio]-2-methylsulfinyl-dibenz[b,f]thiepin;
~ -(ethylmethylamino)ethylthio]-2-methylthiodibenz-i [b,f]thiepin;
10,11-dihydro-10-[~-(piperidino)ethylthio]dibenz-~b,f]thiepin;
10,11-dihydro-10-[~-(N-methylpiperazino)propylthio]-dibenz[b,f]thiepin;
10,11-dihydro-10-[~-(piperidino)-n-butylthio]dibenz-[b,f]thiepin;
10-[~-(pyrrolidino)ethylthio]dibenz[b,f]thiepin;
thiepin;
ll-[~-(ethylmethylar,lino)ethylthio]-2-methylsulfinyl-dibenz[b,f]thiepin;
~ -(ethylmethylamino)ethylthio]-2-methylthiodibenz-i [b,f]thiepin;
10,11-dihydro-10-[~-(piperidino)ethylthio]dibenz-~b,f]thiepin;
10,11-dihydro-10-[~-(N-methylpiperazino)propylthio]-dibenz[b,f]thiepin;
10,11-dihydro-10-[~-(piperidino)-n-butylthio]dibenz-[b,f]thiepin;
10-[~-(pyrrolidino)ethylthio]dibenz[b,f]thiepin;
3-chloro-11-[~-(ethylmethylamino)ethylthio]dibenz-[b,f]thiepin;
' :, . .
fi~
, ~
ll-[~-(ethylamino)ethylthio]-10,11-dihydro-4-nitrodibenz[b,f]thiepin;
ll-[~-(ethylamino)ethylthio]-3-trifluoromethyl-dibenz[b,f]thiepin 2-amino-11-[~-(ethylamino)ethylthio]dibenz[b,f]-thiepin;
ll-[~-(ethylamino)ethylthio]-3-methoxydibenz-[b,f]thiepin;
ll-[~-(diethylamino)ethylthio]-2-n-propyldibenz-[b,f]thiepin;
ll-[~-(methylamino)ethylthio]-3-methylthiodibenz-[b,f]thiepin;
8-chloro-10,11-dihydro-10-[~-(dimethylamino)ethyl-thio]-2-methyldibenz[b,f]thiepin; :
3-fluoro-11-[~-(methylamino)ethylthio]dibenz-[b,f]thiepin;
2-bror,lo-7-fluoro-11-[~-tdimethylamino)ethylthio]-: aibenz-[b,f]thiepin;
3-ethyl~ [~-(methylamino)ethylthio]dibenz[b,f]-thiepin;
11-[ -(ethylamino)ethylthio]-4-nitrodibenz-[b,f]thiepin;
2-methyl-11-~3-(N-meth~l-N-methoxycarbonylamino)-ethylthio]dibenz[b,f]thiepin;
: 25 10-[~-(N-cyclopropylmethyl-N-methylamino)ethylthio]-dibenz[b,f]thiepin;
10-[~-(N-allyl-N-methylamino)ethylthio]dibenz-[b,f]thiepin; and . :;:
6;~5 10-[~-(N-methyl-N-propargylamino)ethylthio]dibenz-[b,f~thiepin.
Effective quantities of the compoundsof the invention may be administered to a patient by any one of various methods, for example, orally as in capsules or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously in the form of sterile solutions. The free base final products, while effective themselves, may be formulated and administered in the form of their pharmaceutically acceptable addition salts for purposes of stability, convenience of crystallization, increased solubility and the like.
The active compounds of the present invention may be orally administered, for example, with an inert diluent or with an edible carrier, or they may be enclosed in gelatin capsules, or they may be compressed into tablets.
For the purpose of oral therapeutic administration, the active compounds of the invention may be incorporated with excipients and used in the form of tablets, troches, capsules, elixiers, suspensions, syrups, wafers, chewing gum and the like. These preparations should contain at least 0.5% of active compound, but may be varied depending upon the particular form and may conveniently be between 4% to about 70% of the weight of the unit.
The amount of active compound in such compositions is ; such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention are prepared so that an oral dosage unit form ~j, '. .
contains between 1.0-300 milligrams of active compound.
The tablets, pills, capsules, troches and the like may also contain the following ingredients: a binder such as microcrystalline cellulose, gum tragacanth or gelatin;
an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, corn starch and the like; a lubricant such as magnesium stearate or Sterotex;
a glidant such as colloidal silicon dioxide; and a sweetening agent such as sucrose or saccharin may be added or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Other dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings. Thus, tablets or pills may be coated with sugar, shellac, or other enteric coating agents. A
syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes, colorings and flavors. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used.
For the purpose of parenteral therapeutic administr-ation the active compounds of the invention may be incorporated into a solution or suspension. These preparations should contain at least 0.1% of active compound, but may be varied to between 0.5% and about 30%
of the weight thereof. The amount of active compound in ' ' ' : ' ' ' ` ~ ' ~ '' ' ' ' "
' . ~ ' . ...
in suc~l compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention are prepared so that a parenteral dosage unit contains between 0.5 to 100 milligrams of active compound.
The solutions or suspensions may also include the following co~ponents: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediamine-tetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampuls, disposable syringes or multiple dose vials made of glass or plastic.
Example 1 63 ml of boron trifluoride etherate are added to a solution of 20.0 g of 2-chloro-10,11-dihydro-11-oxodibenz-[b,f]thiepin, 21.8 g of ~-dimethylaminoethanethiol hydrochloride and 218 ml of glacial acetic acid. After total addition the reaction mixture is stirred for 30 minutes and then permitted to stand for 48 hours.
Thereafter, the mixture is poured into 1200 ml of a 10%
sodium hydroxide solution and the basified mixture is extracted with methylene chloride. The combined methylene chloride fractions are successi~ely washed with . ~
water, dried and filtered and the filtrate evaporated to dryness leaving a red oil. The oil is column chromato-graphed through a silica gel/methylene chloride column with a 2-4% methanol in methylene chloride mixture as the eluant. The purified product is converted to its hydrogen chloride salt of 2-chloro-11-~-(dimethylamino)-ethylthio]dibenzEb,f]thiepin hydrochloride.
Analysis:
Calculated for C18H18ClNS2-HCl: 56.24%C; 4.98~H; 3.64~N.
Found: 56.35%C; 5.17%H; 3.47%~.
Example 2 A sample of lO,ll-dihydro-lO-oxodibenz[b,r]thiepin is treated according to the manipulative procedure of Example l to provide 10-[~-(dimethylamino)ethylthio]-dibenz[b,f]thiepin hydrochloride.
Example 3 To a mixture of 1.08 g of 6-dimethylaminoethanethiol - hydrochloride and 2.5 ml of boron trifluoride etherate is added dropwise a mixture of 1.0 g of 2-chloro-lO,ll-dihydro-ll-hydroxyspirodiben~[b,f]thiepin in 8 ml of glacial acetic ; acid. After total addition, the reaction mixture is stirred at ambient temperature for 30 minutes and then permitted to stand for 24 hours. Thereafter, the reaction is poured into 50 ml of a saturated potassium carbonate-ice solution where it is extracted with ether. The combined ether extracts are, successively, washed with a dilute potassium carbonate solution and water and dried, filtered and evaporated. The resulting oil is . . ~
, . : . . . : .
' . ~: ' . . ~ .
. ,: : . ~ ' ~ : .
~1$~5 "
chror.latographed through a silica gel/methylene chloride, a 5% methyl alcohol is methylene chloride eluant and then converted to the maleic acid salt, mp, 99-101C of 2-chloro-10,11-dihydro-11-[~-tdimethylamino)-ethylchio]-dibenz[b,f]thiepin maleate.
Analysis:
Calculated or C18 20 2 C4 4 4 Found: 56.70%C; 5.29%H; 3.03%N.
Example 4 A sample of 10-E~-(dimethylamino)ethylthio]dibenz-[b,f]thiepin, free base of Example 3, is treated according to the manipulative procedure of Example 3 to provide 10, ll-dihydro-10-[~-(dimethylamino)ethylthio]dibenzlb,f]thiepin hydrochloride.
Example 5 A solution of 1.0 g of 2-chloro-11-[~-(dimethylamino) -ethylthio]dibenz[b,f]thiepin, free base of Examyle 1, in 10 ml of methylene chloride is added dropwise to a stirring solution of 0.5 g of cyanogen bromide and 1.0 g o potassium carbonate in 7 ml of methylene chloride.
After total addition, the reaction is permitted to stand with complete reaction occuring after about four hours.
After the reaction is completed the mixture is filtered and the filtrate evaporated leaving an oil. The oil is chromatographed through a silica gel/methylene chloride column with methylene chloride as the eluant.
The desired fraction is evaporated to dryness leaving : ~ .
:- .
.Q6Z~;
2-chloro-11-[~-(N-cyano-l~-methyl)ar.~inoethylthio]dibenz(b,f]-thiepin, as a yellow oil -Analysis:
Calculated for C18H15ClN2 2 6 3%C;
Found: 60.62%C; 4.19%H; 7.75%N.
Example 6 To a stirring solution of 0.50 g of phenyl chloroformate and 0.2 g of sodium bicarbonate in 20 ml of methylene chloride is added dropwise a solution of 0.95 g of 2-chloro-11-[~-(dimethylamino)ethylthio]dibenz-[b,f]thiepin, free base of Example 1, in 10 ml of methylene chloride. After total addition the reaction is successively stirred at 25C for 24 hours, filtered, diluted with 25 rnl of methylene chloride, washed with a 10% sodium hydroxide solution, washed with water, dried and filtered. The filtrate is evaporated leaving a yellow oil which is chromatographed through a silica gel/methylene chloride column with methylene chloride as the eluant.
The purified product is the yellow oil of 2-chloro-11-[~-(N-methyl-N-phenoxycarbonylamino)-ethylthio]dibenz[b,f]-thiepin.
Analysis:
Calculated for C24H20ClNO2S2: 63.49~C; 4.44%H; 3.09%N.
Found: 63.76%C; 4.49~H; 2.90%N.
In a similar fashion a sample of 10-[~-(dimethyl-amino)ethylthio]dibenz[b,f]thiepin, free base of Example 2, is treated to provide 10-[~-(N-methyl-N-phenoxycarbonyl-amino)-ethylthio]dibenz[b,f]thiepin.
,, ..: . . .. . , :
. :: . :.' '. ~ ,;
6; :5 Example 7 A solution of 5.6 g of 2-chloro~ll-[~-(N-methyl-N-phenoxycarbonylamino)ethylthio]dibenz[b,f]thiepin, Example 6, 127 ml of ethylene gylcol and 10.8 g of potassium hydroxide is stirred at 150-155C for 30 minutes.
Thereafter the reaction mixture is poured onto 300 ml of ice-water and the aqueous mixture is extracted with an ether-toluene (1:1) mixture. The combined extracts, successively, are washed well with water, dried and filtered and the filtrate evaporated leaving an orange oil. The oil is converted to its hydrogen chloride acid salt which is recrystallized from a methanol-acetone-ether mixture to give the product, mp 194-196C of 2-chloro-11-[~-(methylamino)ethylthio]dibenz[b,f]thiepin hydrochloride.
Analysis:
Calculated for C17H16ClNS2 ~Cl: 55.13%C; 4.63%H; 3.78%N.
Found: 55.28%C; 4.71%H; 3.93%1~.
In a similar fashion, 10-[~-(N-methyl-N-phenoxycarbonylamino)ethylthio]dibenz[b,f]thiepin,hereinabove described, is treated to provide 10-[~-(methyl-amino)ethylthio]dibenz[b,f]thiepin hydrochloride.
Example 8 A solution of 2-chloro-lO,ll~dihydro-ll-[~-dimethyl-ar.lino)ethylthio]dibenz[b,f]thiepin, free base of Example3, in 10 ml of chloroform is added dropwise to a solution of a stoichiometric amount of cyanogen bromide and an excess amount of potassium carbonate in 5 ml of chloroform.
6Z~
,,~~ . .
After total addition the reaction mixture is permitted to stand for 10 minutes and then filtered. The filtrate is concentrated to dryness leaving the product 11~
brornoethylthio)-2-chloro-10,11-dihydrodibenz[b,f]thiepin.
Example 9 A mixture of stoichiometric amounts of 2-chloro-11-(~-bromoethylthio)-10,11-dihydrodibenz[b,f]thiepin, Example 8, and N-methylpiperzine, an excess amount of sodium bicarbonate, and 1.0 g of potassium iodide in 15 ml of dimethylformamide is stirred at 80C for 16 hours.
The mixture is permitted to cool before being diluted with water. The biphasic mixture is extracted thrice with 100 ml portions of ether, the ether extracts are combined and shaken vigorously with a large excess of 2N hydro-chloric acid. The acidic solution is basified, liberating the free amine which is extracted into benzene. The benzene solution is dried and the benzene removed under vacuum, leaving the product 2-chloro-10,11-dihydro-11[~-(4-methylpiperazinyl-1-yl)ethylthio]dibenz[b,f]thiepin.
In a similar fashion, substituting morpholine for N-methylpiperazine provides 2-chloro-10,11-dihydro-11-(~-morpholinoethylthio)dibenz[b,f]thiepin.
Examples 10 & 11 By following the manipulative procedure of Example 2, respectively substituting ~-diisopropylaminoethanethiol hydrochloride, ~-diethylaminoethanethiol hydrochloride for ~-dimethylaminoethanethiol hydrochloride provides Example 10, 10-[~-(diisopropylamino)ethylthio]dibenz[b,f]-.
': ' " "'. ~.` : ' ,' . ' .~ . ., ~, . . ........................... .
, . ~ . . .
~ 625 1~
thiepin hydrochloride and Example 11, 10~[~-(diethylamino)-ethylthio]dibenz[b,f]thiepin hydrochloride.
Example 12 a. A solution of stoichiometric amounts of 2-(4-methylsulfonylphenylthio)benzyl nitrile and 85% potassium hydroxide in an alcohol-water mixture is stirred at 115C
for 24 hours, Thereafter the reaction mixture is concen-trated to an oil. The oil is dissolved in water and the aqueous solution is successively, washed ~.ith ether, acidified with dilute hydrochloric acid again providing an oil. This oil is dissolved in methylene chloride and the solution, successively, is dried, filtered and concentrated to dryness leaving the product 2-(4-methyl-sulfonylphenylthio)phenylacetic acid.
b. A mixture of 1.0 g of 2-(4-methylsulfonyl-phenylthio)phenyl acetic acid and 10 ml of polyphosphoric acid under nitrogen is stirred at ~0-100C for 2 hours.
The reaction mixture is permitted to cool and then poured into 100 ml of ice-water slurry. The aqueous solution is basified with 20% sodium hydroxide before being extracted with rnethylene chloride. The combined extracts are dried and then evaporated to dryness leaving an oil. The oil is chromatographed through a silica gel column with a 2%
methanol in methylene chloride eluant. The chromatographed solution is evaporated to dryness providing 10,11-dihydro-2-methylsulfonyl-ll-oxodibenz[b,f]thiepin.
.
.: ~
~ .
, c. A solution of stoichiometric amounts o 10,11-dihydro-2-methylsulfonyl-11-oxodibenz[b,f]thiepin and dirnethylaminoethanethiol hydrochloride and 15 ml of boron trifluoride etherate in 37 ml of glacial acetic acid is stirred until reaction is completed. Thereafter the reaction mixture is poured into 300 ml of a cold sodium hydroxide solution and the resulting solution is extracted with methylene chloride. The combined extracts are washed with water and dried before being filtered. The filtrate is evaporated to dryness leaving an oil which is chromatographed through a silica gel/methylene chloride column with methanol (2-4~) in methylene chloride eluant.
The chromatographed solution is evaporated to dryness leaving ll-[(~-dimethylamino)ethylthio]-2-methylsulonyldi-benz[b,f]thiepin.
.: ~ .
' ' ' ~ .
.. . . . . .. . . .
.
' :, . .
fi~
, ~
ll-[~-(ethylamino)ethylthio]-10,11-dihydro-4-nitrodibenz[b,f]thiepin;
ll-[~-(ethylamino)ethylthio]-3-trifluoromethyl-dibenz[b,f]thiepin 2-amino-11-[~-(ethylamino)ethylthio]dibenz[b,f]-thiepin;
ll-[~-(ethylamino)ethylthio]-3-methoxydibenz-[b,f]thiepin;
ll-[~-(diethylamino)ethylthio]-2-n-propyldibenz-[b,f]thiepin;
ll-[~-(methylamino)ethylthio]-3-methylthiodibenz-[b,f]thiepin;
8-chloro-10,11-dihydro-10-[~-(dimethylamino)ethyl-thio]-2-methyldibenz[b,f]thiepin; :
3-fluoro-11-[~-(methylamino)ethylthio]dibenz-[b,f]thiepin;
2-bror,lo-7-fluoro-11-[~-tdimethylamino)ethylthio]-: aibenz-[b,f]thiepin;
3-ethyl~ [~-(methylamino)ethylthio]dibenz[b,f]-thiepin;
11-[ -(ethylamino)ethylthio]-4-nitrodibenz-[b,f]thiepin;
2-methyl-11-~3-(N-meth~l-N-methoxycarbonylamino)-ethylthio]dibenz[b,f]thiepin;
: 25 10-[~-(N-cyclopropylmethyl-N-methylamino)ethylthio]-dibenz[b,f]thiepin;
10-[~-(N-allyl-N-methylamino)ethylthio]dibenz-[b,f]thiepin; and . :;:
6;~5 10-[~-(N-methyl-N-propargylamino)ethylthio]dibenz-[b,f~thiepin.
Effective quantities of the compoundsof the invention may be administered to a patient by any one of various methods, for example, orally as in capsules or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously in the form of sterile solutions. The free base final products, while effective themselves, may be formulated and administered in the form of their pharmaceutically acceptable addition salts for purposes of stability, convenience of crystallization, increased solubility and the like.
The active compounds of the present invention may be orally administered, for example, with an inert diluent or with an edible carrier, or they may be enclosed in gelatin capsules, or they may be compressed into tablets.
For the purpose of oral therapeutic administration, the active compounds of the invention may be incorporated with excipients and used in the form of tablets, troches, capsules, elixiers, suspensions, syrups, wafers, chewing gum and the like. These preparations should contain at least 0.5% of active compound, but may be varied depending upon the particular form and may conveniently be between 4% to about 70% of the weight of the unit.
The amount of active compound in such compositions is ; such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention are prepared so that an oral dosage unit form ~j, '. .
contains between 1.0-300 milligrams of active compound.
The tablets, pills, capsules, troches and the like may also contain the following ingredients: a binder such as microcrystalline cellulose, gum tragacanth or gelatin;
an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, corn starch and the like; a lubricant such as magnesium stearate or Sterotex;
a glidant such as colloidal silicon dioxide; and a sweetening agent such as sucrose or saccharin may be added or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Other dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings. Thus, tablets or pills may be coated with sugar, shellac, or other enteric coating agents. A
syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes, colorings and flavors. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used.
For the purpose of parenteral therapeutic administr-ation the active compounds of the invention may be incorporated into a solution or suspension. These preparations should contain at least 0.1% of active compound, but may be varied to between 0.5% and about 30%
of the weight thereof. The amount of active compound in ' ' ' : ' ' ' ` ~ ' ~ '' ' ' ' "
' . ~ ' . ...
in suc~l compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention are prepared so that a parenteral dosage unit contains between 0.5 to 100 milligrams of active compound.
The solutions or suspensions may also include the following co~ponents: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediamine-tetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampuls, disposable syringes or multiple dose vials made of glass or plastic.
Example 1 63 ml of boron trifluoride etherate are added to a solution of 20.0 g of 2-chloro-10,11-dihydro-11-oxodibenz-[b,f]thiepin, 21.8 g of ~-dimethylaminoethanethiol hydrochloride and 218 ml of glacial acetic acid. After total addition the reaction mixture is stirred for 30 minutes and then permitted to stand for 48 hours.
Thereafter, the mixture is poured into 1200 ml of a 10%
sodium hydroxide solution and the basified mixture is extracted with methylene chloride. The combined methylene chloride fractions are successi~ely washed with . ~
water, dried and filtered and the filtrate evaporated to dryness leaving a red oil. The oil is column chromato-graphed through a silica gel/methylene chloride column with a 2-4% methanol in methylene chloride mixture as the eluant. The purified product is converted to its hydrogen chloride salt of 2-chloro-11-~-(dimethylamino)-ethylthio]dibenzEb,f]thiepin hydrochloride.
Analysis:
Calculated for C18H18ClNS2-HCl: 56.24%C; 4.98~H; 3.64~N.
Found: 56.35%C; 5.17%H; 3.47%~.
Example 2 A sample of lO,ll-dihydro-lO-oxodibenz[b,r]thiepin is treated according to the manipulative procedure of Example l to provide 10-[~-(dimethylamino)ethylthio]-dibenz[b,f]thiepin hydrochloride.
Example 3 To a mixture of 1.08 g of 6-dimethylaminoethanethiol - hydrochloride and 2.5 ml of boron trifluoride etherate is added dropwise a mixture of 1.0 g of 2-chloro-lO,ll-dihydro-ll-hydroxyspirodiben~[b,f]thiepin in 8 ml of glacial acetic ; acid. After total addition, the reaction mixture is stirred at ambient temperature for 30 minutes and then permitted to stand for 24 hours. Thereafter, the reaction is poured into 50 ml of a saturated potassium carbonate-ice solution where it is extracted with ether. The combined ether extracts are, successively, washed with a dilute potassium carbonate solution and water and dried, filtered and evaporated. The resulting oil is . . ~
, . : . . . : .
' . ~: ' . . ~ .
. ,: : . ~ ' ~ : .
~1$~5 "
chror.latographed through a silica gel/methylene chloride, a 5% methyl alcohol is methylene chloride eluant and then converted to the maleic acid salt, mp, 99-101C of 2-chloro-10,11-dihydro-11-[~-tdimethylamino)-ethylchio]-dibenz[b,f]thiepin maleate.
Analysis:
Calculated or C18 20 2 C4 4 4 Found: 56.70%C; 5.29%H; 3.03%N.
Example 4 A sample of 10-E~-(dimethylamino)ethylthio]dibenz-[b,f]thiepin, free base of Example 3, is treated according to the manipulative procedure of Example 3 to provide 10, ll-dihydro-10-[~-(dimethylamino)ethylthio]dibenzlb,f]thiepin hydrochloride.
Example 5 A solution of 1.0 g of 2-chloro-11-[~-(dimethylamino) -ethylthio]dibenz[b,f]thiepin, free base of Examyle 1, in 10 ml of methylene chloride is added dropwise to a stirring solution of 0.5 g of cyanogen bromide and 1.0 g o potassium carbonate in 7 ml of methylene chloride.
After total addition, the reaction is permitted to stand with complete reaction occuring after about four hours.
After the reaction is completed the mixture is filtered and the filtrate evaporated leaving an oil. The oil is chromatographed through a silica gel/methylene chloride column with methylene chloride as the eluant.
The desired fraction is evaporated to dryness leaving : ~ .
:- .
.Q6Z~;
2-chloro-11-[~-(N-cyano-l~-methyl)ar.~inoethylthio]dibenz(b,f]-thiepin, as a yellow oil -Analysis:
Calculated for C18H15ClN2 2 6 3%C;
Found: 60.62%C; 4.19%H; 7.75%N.
Example 6 To a stirring solution of 0.50 g of phenyl chloroformate and 0.2 g of sodium bicarbonate in 20 ml of methylene chloride is added dropwise a solution of 0.95 g of 2-chloro-11-[~-(dimethylamino)ethylthio]dibenz-[b,f]thiepin, free base of Example 1, in 10 ml of methylene chloride. After total addition the reaction is successively stirred at 25C for 24 hours, filtered, diluted with 25 rnl of methylene chloride, washed with a 10% sodium hydroxide solution, washed with water, dried and filtered. The filtrate is evaporated leaving a yellow oil which is chromatographed through a silica gel/methylene chloride column with methylene chloride as the eluant.
The purified product is the yellow oil of 2-chloro-11-[~-(N-methyl-N-phenoxycarbonylamino)-ethylthio]dibenz[b,f]-thiepin.
Analysis:
Calculated for C24H20ClNO2S2: 63.49~C; 4.44%H; 3.09%N.
Found: 63.76%C; 4.49~H; 2.90%N.
In a similar fashion a sample of 10-[~-(dimethyl-amino)ethylthio]dibenz[b,f]thiepin, free base of Example 2, is treated to provide 10-[~-(N-methyl-N-phenoxycarbonyl-amino)-ethylthio]dibenz[b,f]thiepin.
,, ..: . . .. . , :
. :: . :.' '. ~ ,;
6; :5 Example 7 A solution of 5.6 g of 2-chloro~ll-[~-(N-methyl-N-phenoxycarbonylamino)ethylthio]dibenz[b,f]thiepin, Example 6, 127 ml of ethylene gylcol and 10.8 g of potassium hydroxide is stirred at 150-155C for 30 minutes.
Thereafter the reaction mixture is poured onto 300 ml of ice-water and the aqueous mixture is extracted with an ether-toluene (1:1) mixture. The combined extracts, successively, are washed well with water, dried and filtered and the filtrate evaporated leaving an orange oil. The oil is converted to its hydrogen chloride acid salt which is recrystallized from a methanol-acetone-ether mixture to give the product, mp 194-196C of 2-chloro-11-[~-(methylamino)ethylthio]dibenz[b,f]thiepin hydrochloride.
Analysis:
Calculated for C17H16ClNS2 ~Cl: 55.13%C; 4.63%H; 3.78%N.
Found: 55.28%C; 4.71%H; 3.93%1~.
In a similar fashion, 10-[~-(N-methyl-N-phenoxycarbonylamino)ethylthio]dibenz[b,f]thiepin,hereinabove described, is treated to provide 10-[~-(methyl-amino)ethylthio]dibenz[b,f]thiepin hydrochloride.
Example 8 A solution of 2-chloro-lO,ll~dihydro-ll-[~-dimethyl-ar.lino)ethylthio]dibenz[b,f]thiepin, free base of Example3, in 10 ml of chloroform is added dropwise to a solution of a stoichiometric amount of cyanogen bromide and an excess amount of potassium carbonate in 5 ml of chloroform.
6Z~
,,~~ . .
After total addition the reaction mixture is permitted to stand for 10 minutes and then filtered. The filtrate is concentrated to dryness leaving the product 11~
brornoethylthio)-2-chloro-10,11-dihydrodibenz[b,f]thiepin.
Example 9 A mixture of stoichiometric amounts of 2-chloro-11-(~-bromoethylthio)-10,11-dihydrodibenz[b,f]thiepin, Example 8, and N-methylpiperzine, an excess amount of sodium bicarbonate, and 1.0 g of potassium iodide in 15 ml of dimethylformamide is stirred at 80C for 16 hours.
The mixture is permitted to cool before being diluted with water. The biphasic mixture is extracted thrice with 100 ml portions of ether, the ether extracts are combined and shaken vigorously with a large excess of 2N hydro-chloric acid. The acidic solution is basified, liberating the free amine which is extracted into benzene. The benzene solution is dried and the benzene removed under vacuum, leaving the product 2-chloro-10,11-dihydro-11[~-(4-methylpiperazinyl-1-yl)ethylthio]dibenz[b,f]thiepin.
In a similar fashion, substituting morpholine for N-methylpiperazine provides 2-chloro-10,11-dihydro-11-(~-morpholinoethylthio)dibenz[b,f]thiepin.
Examples 10 & 11 By following the manipulative procedure of Example 2, respectively substituting ~-diisopropylaminoethanethiol hydrochloride, ~-diethylaminoethanethiol hydrochloride for ~-dimethylaminoethanethiol hydrochloride provides Example 10, 10-[~-(diisopropylamino)ethylthio]dibenz[b,f]-.
': ' " "'. ~.` : ' ,' . ' .~ . ., ~, . . ........................... .
, . ~ . . .
~ 625 1~
thiepin hydrochloride and Example 11, 10~[~-(diethylamino)-ethylthio]dibenz[b,f]thiepin hydrochloride.
Example 12 a. A solution of stoichiometric amounts of 2-(4-methylsulfonylphenylthio)benzyl nitrile and 85% potassium hydroxide in an alcohol-water mixture is stirred at 115C
for 24 hours, Thereafter the reaction mixture is concen-trated to an oil. The oil is dissolved in water and the aqueous solution is successively, washed ~.ith ether, acidified with dilute hydrochloric acid again providing an oil. This oil is dissolved in methylene chloride and the solution, successively, is dried, filtered and concentrated to dryness leaving the product 2-(4-methyl-sulfonylphenylthio)phenylacetic acid.
b. A mixture of 1.0 g of 2-(4-methylsulfonyl-phenylthio)phenyl acetic acid and 10 ml of polyphosphoric acid under nitrogen is stirred at ~0-100C for 2 hours.
The reaction mixture is permitted to cool and then poured into 100 ml of ice-water slurry. The aqueous solution is basified with 20% sodium hydroxide before being extracted with rnethylene chloride. The combined extracts are dried and then evaporated to dryness leaving an oil. The oil is chromatographed through a silica gel column with a 2%
methanol in methylene chloride eluant. The chromatographed solution is evaporated to dryness providing 10,11-dihydro-2-methylsulfonyl-ll-oxodibenz[b,f]thiepin.
.
.: ~
~ .
, c. A solution of stoichiometric amounts o 10,11-dihydro-2-methylsulfonyl-11-oxodibenz[b,f]thiepin and dirnethylaminoethanethiol hydrochloride and 15 ml of boron trifluoride etherate in 37 ml of glacial acetic acid is stirred until reaction is completed. Thereafter the reaction mixture is poured into 300 ml of a cold sodium hydroxide solution and the resulting solution is extracted with methylene chloride. The combined extracts are washed with water and dried before being filtered. The filtrate is evaporated to dryness leaving an oil which is chromatographed through a silica gel/methylene chloride column with methanol (2-4~) in methylene chloride eluant.
The chromatographed solution is evaporated to dryness leaving ll-[(~-dimethylamino)ethylthio]-2-methylsulonyldi-benz[b,f]thiepin.
.: ~ .
' ' ' ~ .
.. . . . . .. . . .
.
Claims (16)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a compound of the formula I
I
wherein Z is hydrogen, Y is hydrogen, halogen or methylsulfonyl, and X represents halogen or wherein R1 is hydrogen, lower alkyl, cyano or phenoxycarbonyl and R2is lower alkyl, or R1-N-R2 forms a morpholino or a N-lower alkyl substituted piper-azinyl; m is the integer 0 or 1; and n is an integer of from 2 to 4; and the physiologically tolerable acid addition salts thereof, in which a) a compound of the formula II
II
wherein X and Y are as defined in formula I and R3 and R4 are different and each is hydrogen or hydroxy, or R3 and R4 together are oxygen, is reacted with aminoalkylthiol of the formula wherein R1 and R2 are the same or different and each represents lower alkyl in the presence of a catalyst/dehydrating agent and a solvent to produce a compound of the formula Ia Ia or b) a compound of the formula Ia wherein R1 and R2 are each methyl is reacted with cyanogen halide to obtain a mixture of one compound of the formula Ib Ib and another compound of the formula Ic Ic wherein X, Y, m and n are as defined in the formula I and hal is halogen, and each of the two compounds is isolated; or c) a compound of the formula Ib is reacted with an appropriate non-cyclic or cyclic amine to obtain the corresponding compound of the formula Ia Ia wherein X, Y, R1, R2, m and n are as defined in formula I; or d) a compound of the formula Ia, wherein R1 and R2 are the same or different and each is lower alkyl, and X, Y, m, n are as defined in the formula I is reacted with an alkyl or phenyl chloroformate to obtain a compound of the formula Ia wherein R1 is alkoxy or phenoxy carbonyl and R2, X, Y, m and n are as defined in formula I, or e) a compound of the formula Ia, wherein X, Y, m and n are as defined in formula I, R1 is lower alkoxy or phenoxy carbonyl and R2 is a lower alkyl, is reacted with a base or an acid medium to obtain a compound of the formula Ia wherein X, Y, m and n are as defined in the formula I, R2 is as defined above and R1 is hydrogen; or f) a compound of the formula Ia, wherein X, Y, m and n are as defined in formula I, R1 is hydrogen and R2 is lower alkyl is reacted with a lower alkyl halide, to obtain a compound of the formula Ia in which X, Y, m and n are as defined in the formula I, R1 is lower alkyl, and R2 is lower alkyl.
I
wherein Z is hydrogen, Y is hydrogen, halogen or methylsulfonyl, and X represents halogen or wherein R1 is hydrogen, lower alkyl, cyano or phenoxycarbonyl and R2is lower alkyl, or R1-N-R2 forms a morpholino or a N-lower alkyl substituted piper-azinyl; m is the integer 0 or 1; and n is an integer of from 2 to 4; and the physiologically tolerable acid addition salts thereof, in which a) a compound of the formula II
II
wherein X and Y are as defined in formula I and R3 and R4 are different and each is hydrogen or hydroxy, or R3 and R4 together are oxygen, is reacted with aminoalkylthiol of the formula wherein R1 and R2 are the same or different and each represents lower alkyl in the presence of a catalyst/dehydrating agent and a solvent to produce a compound of the formula Ia Ia or b) a compound of the formula Ia wherein R1 and R2 are each methyl is reacted with cyanogen halide to obtain a mixture of one compound of the formula Ib Ib and another compound of the formula Ic Ic wherein X, Y, m and n are as defined in the formula I and hal is halogen, and each of the two compounds is isolated; or c) a compound of the formula Ib is reacted with an appropriate non-cyclic or cyclic amine to obtain the corresponding compound of the formula Ia Ia wherein X, Y, R1, R2, m and n are as defined in formula I; or d) a compound of the formula Ia, wherein R1 and R2 are the same or different and each is lower alkyl, and X, Y, m, n are as defined in the formula I is reacted with an alkyl or phenyl chloroformate to obtain a compound of the formula Ia wherein R1 is alkoxy or phenoxy carbonyl and R2, X, Y, m and n are as defined in formula I, or e) a compound of the formula Ia, wherein X, Y, m and n are as defined in formula I, R1 is lower alkoxy or phenoxy carbonyl and R2 is a lower alkyl, is reacted with a base or an acid medium to obtain a compound of the formula Ia wherein X, Y, m and n are as defined in the formula I, R2 is as defined above and R1 is hydrogen; or f) a compound of the formula Ia, wherein X, Y, m and n are as defined in formula I, R1 is hydrogen and R2 is lower alkyl is reacted with a lower alkyl halide, to obtain a compound of the formula Ia in which X, Y, m and n are as defined in the formula I, R1 is lower alkyl, and R2 is lower alkyl.
2. A compound of the formula I as defined in claim 1, whenever obtained according to a process as claimed in claim 1 or by an obvious chemical equivalent thereof.
3. A process for the preparation of 2-chloro-11-[.beta.-(dimethylamino)ethylthio]dibenz[b,f]thiepin hydrochloride in which 2-chloro-10,11-dihydro-11-oxodibenz[b,f]thiepin is reacted with .beta.-dimethylaminoethanethiol hydrochloride in the presence of boron trifluoride etherate in glacial acetic acid, the product is isolated, treated with hydrochloric acid and the resultant product is subsequently isolated.
4. 2-Chloro-11-[.beta.-(dimethylamino)ethylthio]dibenz[b,f]-thiepin hydrochloride, whenever obtained according to a process as claimed in claim 3 or by an obvious chemical equivalent thereof.
5. A process for the preparation of 10-[.beta.-(dimethylamino)-ethylthio]dibenz[b,f]thiepin hydrochloride in which 10,11-dihydro-10-oxodibenz[b,f]thiepin is reacted with .beta.-dimethylaminoethane-thiol hydrochloride in the presence of boron trifluoride etherate and glacial acetic acid, the product is isolated, treated with hydrochloric acid and the resultant product is subsequently isolated.
6. 10-[.beta.-(Dimethylamino)ethylthio]dibenz[b,f]thiepin hydrochloride, whenever obtained according to a process as claimed in claim 5 or by an obvious chemical equivalent thereof.
7. A process for the preparation of 2-chloro-10,11-dihydro-11-[.beta.-(dimethylamino)ethylthio ]dibenz[b,f]thiepin maleate in which 2-chloro-10,11-dihydro-11-hydroxyspirodibenz[b,f]thiepin is reacted with .beta.-dimethylaminoethanethiol hydrochloride in the presence of boron trifluoride etherate in glacial acetic acid, the product is isolated, treated with maleic acid and the resultant product is subsequently isoiated.
8. 2-Chloro-10,11-dihydro-11-[.beta.-(dimethylamino)ethylthio]-dibenz[b,f]thiepin maleate, whenever obtained according to a process as claimed in claim 7 or by an obvious chemical equivalent thereof.
9. A process for the preparation of 10,11-dihydro-10-[.beta.-(dimethylamino)ethylthio]dibenz[b,f]thiepin hydrochloride in which 10,11-dihydro-10-hydroxydibenz[b,f]thiepin, is reacted with .beta.-dimethylaminoethanethiol hydrochloride in the presence of boron trifluoride etherate in glacial acetic acid, the product is isolated, treated with hydrochloric acid and the resultant product is subsequently isolated.
10. 10,11-Dihydro-10-[.beta.-(dimethylamino)ethylthio]dibenz-[b,f]thiepin hydrochloride, whenever obtained according to a process as claimed in claim 9 or by an obvious chemical equivalent thereof.
11. A process for the preparation of 11-(.beta.-bromoethylthio)-2-chloro-10,11-dihydrodibenz[b,f]thiepin in which 2-chloro-10,11-dihydro-11-hydroxyspirodibenz[b,f]thiepin is reacted with .beta.-dimethylaminoethanethiol hydrochloride in the presence of boron trifluoride etherate in glacial acetic acid, 2-chloro-10,11-dihydro-11-[.beta.-(dimethylamino)ethylthio]dibenz[b,f]thiepin is isolated, dissolved in chloroform, the resultant solution is added to a solution of a stoichiometric amount of cyanogen bromide and an excess of potassium chloride in chloroform and the resultant product is subsequently isolated.
12. 11-(.beta.-Bromoethylthio)-2-chloro-10,11-dihydrodibenz-[b,f]thiepin, whenever obtained according to a process as claimed in claim 11 or by an obvious chemical equivalent thereof.
13. A process for the preparation of 1-[.beta.-dimethylamino)-ethylthio]-2-methylsulfonyldibenz[b,f]thiepin in which 10,11-dihydro-2-methylsulfonyl-11-oxodibenz[b,f]thiepin is reacted with dimethylaminoethanethiol hydrochloride in the presence of boron trifluoride etherate in glacial acetic acid, and the resultant product is subsequently isolated.
14. 11-[(.beta.-Dimethylamino)ethylthio]-2-methylsulfonyldibenz-[b,f]thiepin, whenever obtained according to a process as claimed in claim 13 or by an obvious chemical equivalent thereof.
15. A process for the preparation of 10-[.beta.-(methylamino)-ethylthio]dibenz[b,f]thiepin hydrochloride in which 10,11-dihydro-10-oxodibenz[b,f]thiepin is reacted with .beta.-dimethylamino-ethanethiol hydrochloride in the presence of boron trifluoride etherate in glacial acetic acid, a solution of the resultant 10-[.beta.-(dimethylamino)ethylthio]dibenz[b,f]thiepin hydrochloride in ethylene glycol and potassium hydroxide is stirred, the product is isolated, treated with hydrochloric acid and the resultant product is subsequently isolated.
16. 10-[.beta.-(Methylamino)-ethylthio]dibenz[b,f]thiepin hydro-chloride, whenever obtained according to a process as claimed in claim 15 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US86008277A | 1977-12-13 | 1977-12-13 | |
| US860,082 | 1977-12-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1110625A true CA1110625A (en) | 1981-10-13 |
Family
ID=25332450
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA317,810A Expired CA1110625A (en) | 1977-12-13 | 1978-12-12 | Aminoalkylthiodibenzthiepins and related compounds, a method of preparing same and pharmaceutical and veterinary preparations including same |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0002500B1 (en) |
| JP (1) | JPS5498794A (en) |
| AT (1) | AT369740B (en) |
| CA (1) | CA1110625A (en) |
| DE (1) | DE2862219D1 (en) |
| ES (6) | ES475769A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008096755A1 (en) * | 2007-02-07 | 2008-08-14 | Nippon Suisan Kaisha, Ltd. | Vanilloid receptor (vr1) inhibitor and use thereof |
-
1978
- 1978-12-06 ES ES475769A patent/ES475769A1/en not_active Expired
- 1978-12-07 EP EP78101593A patent/EP0002500B1/en not_active Expired
- 1978-12-07 DE DE7878101593T patent/DE2862219D1/en not_active Expired
- 1978-12-12 CA CA317,810A patent/CA1110625A/en not_active Expired
- 1978-12-12 AT AT0883878A patent/AT369740B/en not_active IP Right Cessation
- 1978-12-13 JP JP15908878A patent/JPS5498794A/en active Granted
-
1979
- 1979-06-01 ES ES481188A patent/ES481188A1/en not_active Expired
- 1979-06-01 ES ES481185A patent/ES481185A1/en not_active Expired
- 1979-06-01 ES ES481187A patent/ES481187A1/en not_active Expired
- 1979-06-01 ES ES481186A patent/ES481186A1/en not_active Expired
- 1979-06-01 ES ES481189A patent/ES481189A1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| ES481187A1 (en) | 1980-08-16 |
| AT369740B (en) | 1983-01-25 |
| EP0002500B1 (en) | 1983-03-30 |
| DE2862219D1 (en) | 1983-05-05 |
| JPS633860B2 (en) | 1988-01-26 |
| ES481185A1 (en) | 1980-08-16 |
| EP0002500A1 (en) | 1979-06-27 |
| JPS5498794A (en) | 1979-08-03 |
| ES481188A1 (en) | 1980-08-16 |
| ATA883878A (en) | 1982-06-15 |
| ES481189A1 (en) | 1980-09-01 |
| ES475769A1 (en) | 1980-01-16 |
| ES481186A1 (en) | 1980-08-16 |
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Legal Events
| Date | Code | Title | Description |
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| MKEX | Expiry |