CA1101420A - Aminoalkylthiodibenzoxepins and precursors therefor a method of preparing same and pharmaceutical and veterinary preparations including same - Google Patents
Aminoalkylthiodibenzoxepins and precursors therefor a method of preparing same and pharmaceutical and veterinary preparations including sameInfo
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- CA1101420A CA1101420A CA317,773A CA317773A CA1101420A CA 1101420 A CA1101420 A CA 1101420A CA 317773 A CA317773 A CA 317773A CA 1101420 A CA1101420 A CA 1101420A
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- oxepin
- compound
- dibenz
- ethylthio
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
- C07D313/02—Seven-membered rings
- C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
- C07D313/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D313/14—[b,f]-condensed
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- 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
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- 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
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- 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, ***e
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Abstract
Abstract of the disclosure:
The present application relates to novel aminoalkylthio-dibenzoxepins, physiologically tolerable acid and salts thereof, a method for preparing same and pharmaceutical and veterinary prepartions including same. These compounds are useful as anti-depressant, analgesic tranquilizing and anticonvulsant agents.
The present application relates to novel aminoalkylthio-dibenzoxepins, physiologically tolerable acid and salts thereof, a method for preparing same and pharmaceutical and veterinary prepartions including same. These compounds are useful as anti-depressant, analgesic tranquilizing and anticonvulsant agents.
Description
11(~1420 . - 2 -This invention relates to novel aminoalkylthiodi-benzoxepins and to their physiologically tolerable acid addition salts which are useful as antidepressant, analgesic and anti-convulsant agents, and to pharmaceutical and veterinary com-positions containing such a compound as an essential activeingredient.
It is already known that Amethoclothepine of the formula O(CH2)2N(CH3)2 possess central depressant activity by M. Protvia, et al. II
Farmaco XXI, 98 (1966).
Japanese 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 ~ 2 ~X
in which A is alkylimino, oxy, thio or sulfinyl, Rl is alkylene, R2 and R3 each represent an alkyl group or may be bonded cyclically either through an alkylimino group or not through an alkylimino group and X stands for hydrogen, halogen, alkyl, alkoxy, alkylthio, dialkyl sulfamoyl or nitro.
~' ;~
The compounds of the present invention conform to the general ~ormula S- (CH2)n-Z
. l x~
wherein X and Y are the same or different and each can be hydrogen, halogen, trifluoromethyl, C1-C6alkoxy, Cl-C6 alkyl, 5 Cl-C6alkylthio, Cl-C6alkylsul~onyl, Cl-C6alkylsulfinyl, amino, or nitro; Z is halo~en or N 2 ; Rl is hydrogen, straight or branched chain Cl-C6alkyl, cyano, cycloalkyl Cl-C6alkyl wherein the cycloalkyl ring contains from 3 to 6 carbon atoms, phen-oxycarbonyl of the formula -CO2 ~ X
wherein X is defined as above, Cl-C6alkoxycarbonyl, C2-C6alkenyl or C2-C6alkynyl; R is straight or branched chain Cl-C6alkyl or cycloalkyl Cl-C6alkyl wherein the cycloalkyl ring contains from 3 to 6 carbon atoms; and when Rl and R2 are taken together with the nitrogen atom to which they are attached, the group Rl-N-R2 forms a heterocycle which is morpholino, piperidino, pyrrolidinyl, piperazinyl or N~substituted piperazinyl in which the N-substituent is Cl-C6alkyl and in which a nitrogen or carbon atom of the heterocycle is attached to the termina~ carbon atom of the (CH2) group; m is the integer 0 or 1; and n is an integer of from 2 to 4; and a physiologically tolerable acid addition salt thereof.
Acids useful for preparing the pharmaceutically acceptable acid addition salts of the invention include inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, 1 phosphoric and perchloric acid, as well as organic acids such as tartaric, citric, acetic, succinic, maleic, fumaric, and oxalic acids.
Compounds of the invention are prepared by the methods given below. With the exception 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]
oxepin, of the formula R4 X ~ O ~ II
wherein R3 and R4 are different and each is hydrogen or hydroxy or together represent oxygen, is reacted with aminoalkylthiol of the formula HS-' / R
( 2)n N ~ R2 wherein Rl and R2 are the same or different and each can be straight or branched chain Cl-C6alkyl to produce a compound of the invention of the formula R
S-(CH ) -N -X /~ Ia I
This reaction is carried out with a cataylst/dehydrating agent ; of boron trifluoride etherate and in the presence of a suitable solvent such as glacial acetic acid at a temperature of about ambient to reflux.
, .;
Method b A compound prepared in Method A in which m is the integer 1 can be treated with magnesium in a suitable solvent to effect reduction to its corresponding saturated aminoalkylthiodibenzoxepin.
S A preferred method of carrying out this reduction involves the use of magn~sium shavings with a solvent of methanol.
Method c A compound prepared in Method a or b, wherein Rl and R2 are each methyl, can be treated with a cyanogen halide such as cyanogen bromide in a suitable solvent and acid sca-venger to obtain a mixture of one compound of the invention of the formula S(CH ~ h 1 ~ m ~ Ib and another compound of the invention of the formula S(CH ~ ~ CH3 X = Ic ` 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 chromatography.
11~1420 Method d A compound prepared in Method c) of formula Ib can be re-acted in a known fashion with a suitable amine to obtain the corresponding compound of the invention of the formula Rl ~S~(C~12)n-~
~ _) ~ Ia 10- wherein R1 is hydrogen, straight or branched chain C1-C6alkyl, cycloalkylC1-C6alkyl, C2-C6alkenyl or C2-C6alkynyl~ R2 is straight or branched chain C1-C6alkyl or cycloalkylC1-C6-alkyl; and when R1 and R2 are taken together with the nitrogen atom to which they are attached, the group R1-N-R forms a heterocycle which is piperazinyl, N-substituted piperazinyl, morpholino, piperidino or pyrrolidinyl. A preferred method is carried out with a dimethylformamide solvent, a catalyst such ~s sodium bicarbonate and a reaction initiator such as potassium iodide at a temperature of from ambient to the reflux tempera-20 ~ure of the reaction mixture.Method e A compound prepared in Method a) or b) can be treated ~ith a chloroformate, e.g. an alkyl or phenyl chlo00formate, - at a temperature of from 25 to 125C, in a solvent such as methylene chloride, toluene or benzene to provide the corre-sponding compound of the invention in which Z is N'R2 with R
being C1-C6alkoxy- or phenoxy carbonyl.
.
."' '' ' ' ' ~ ~ .
` _ 7 ~ 1420 Method f A compound prepared in Method e) is treated with an or-ganic base such as triethylamine or an inorganic base such as sodium or potassium hydroxide in a solvent such as water, ethanol, or ethylene glycol at a temperature of from ambient to reflux to provide the corresponding compound of the inven-tion in which R1 is hydrogen.
Met.hod q A compound prepared in Method f) is treated with a 10 straight or branched chain C1-C6alkyl halide, C2-C6alkenyl, halide, C2-C6-aLkynyl halide or cycloalkylC1-C6alkyl halide under conditions normaL for such reactions to provide the corresponding compound of the invention in which R1 is straight or branched chain C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl or cycloalkyLC1-C6alkyl. A preferred method is to carry out this substitution in the presence of a solvent such as di-methyl.formamide, an acid scavenger such as sodium bicarbonate and a reaction initiator such as potassium iodide at the:re-f~ux temperature of the solvent.
. .
, ' ' ' :' ~ " " ' .
14~0 ~ethod h ....
A compound prepared in any of the above methods, which ~ncludes a nitro group can be reduced by a conventional method to produce the corresponding amino compound. Such conventional methods include but are not limited to use of metallic zinc and acetic acid or platinum on carbon.
As is appreciated by those skilled in the art, specific conditions in any of the above methods are dependent and are a function of the ingredients of each procedure.
The compounds of the present invention are useful in the treatment of depression in mammals, as demonstrated by their abiLity to inhibit tetrabenazine-induced depression in mice [International Journal o Neuropharmacology 8, 73 (196g)], a standard assay for useful antidepressant properties.
Thus, for instance, the intraperitoneal dose at which the following compounds effect a 50% inhibition of the ptosis o~
the tetrabenazine-induced depression (ED50) in mice are:
~E~--nd m~
It is already known that Amethoclothepine of the formula O(CH2)2N(CH3)2 possess central depressant activity by M. Protvia, et al. II
Farmaco XXI, 98 (1966).
Japanese 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 ~ 2 ~X
in which A is alkylimino, oxy, thio or sulfinyl, Rl is alkylene, R2 and R3 each represent an alkyl group or may be bonded cyclically either through an alkylimino group or not through an alkylimino group and X stands for hydrogen, halogen, alkyl, alkoxy, alkylthio, dialkyl sulfamoyl or nitro.
~' ;~
The compounds of the present invention conform to the general ~ormula S- (CH2)n-Z
. l x~
wherein X and Y are the same or different and each can be hydrogen, halogen, trifluoromethyl, C1-C6alkoxy, Cl-C6 alkyl, 5 Cl-C6alkylthio, Cl-C6alkylsul~onyl, Cl-C6alkylsulfinyl, amino, or nitro; Z is halo~en or N 2 ; Rl is hydrogen, straight or branched chain Cl-C6alkyl, cyano, cycloalkyl Cl-C6alkyl wherein the cycloalkyl ring contains from 3 to 6 carbon atoms, phen-oxycarbonyl of the formula -CO2 ~ X
wherein X is defined as above, Cl-C6alkoxycarbonyl, C2-C6alkenyl or C2-C6alkynyl; R is straight or branched chain Cl-C6alkyl or cycloalkyl Cl-C6alkyl wherein the cycloalkyl ring contains from 3 to 6 carbon atoms; and when Rl and R2 are taken together with the nitrogen atom to which they are attached, the group Rl-N-R2 forms a heterocycle which is morpholino, piperidino, pyrrolidinyl, piperazinyl or N~substituted piperazinyl in which the N-substituent is Cl-C6alkyl and in which a nitrogen or carbon atom of the heterocycle is attached to the termina~ carbon atom of the (CH2) group; m is the integer 0 or 1; and n is an integer of from 2 to 4; and a physiologically tolerable acid addition salt thereof.
Acids useful for preparing the pharmaceutically acceptable acid addition salts of the invention include inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, 1 phosphoric and perchloric acid, as well as organic acids such as tartaric, citric, acetic, succinic, maleic, fumaric, and oxalic acids.
Compounds of the invention are prepared by the methods given below. With the exception 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]
oxepin, of the formula R4 X ~ O ~ II
wherein R3 and R4 are different and each is hydrogen or hydroxy or together represent oxygen, is reacted with aminoalkylthiol of the formula HS-' / R
( 2)n N ~ R2 wherein Rl and R2 are the same or different and each can be straight or branched chain Cl-C6alkyl to produce a compound of the invention of the formula R
S-(CH ) -N -X /~ Ia I
This reaction is carried out with a cataylst/dehydrating agent ; of boron trifluoride etherate and in the presence of a suitable solvent such as glacial acetic acid at a temperature of about ambient to reflux.
, .;
Method b A compound prepared in Method A in which m is the integer 1 can be treated with magnesium in a suitable solvent to effect reduction to its corresponding saturated aminoalkylthiodibenzoxepin.
S A preferred method of carrying out this reduction involves the use of magn~sium shavings with a solvent of methanol.
Method c A compound prepared in Method a or b, wherein Rl and R2 are each methyl, can be treated with a cyanogen halide such as cyanogen bromide in a suitable solvent and acid sca-venger to obtain a mixture of one compound of the invention of the formula S(CH ~ h 1 ~ m ~ Ib and another compound of the invention of the formula S(CH ~ ~ CH3 X = Ic ` 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 chromatography.
11~1420 Method d A compound prepared in Method c) of formula Ib can be re-acted in a known fashion with a suitable amine to obtain the corresponding compound of the invention of the formula Rl ~S~(C~12)n-~
~ _) ~ Ia 10- wherein R1 is hydrogen, straight or branched chain C1-C6alkyl, cycloalkylC1-C6alkyl, C2-C6alkenyl or C2-C6alkynyl~ R2 is straight or branched chain C1-C6alkyl or cycloalkylC1-C6-alkyl; and when R1 and R2 are taken together with the nitrogen atom to which they are attached, the group R1-N-R forms a heterocycle which is piperazinyl, N-substituted piperazinyl, morpholino, piperidino or pyrrolidinyl. A preferred method is carried out with a dimethylformamide solvent, a catalyst such ~s sodium bicarbonate and a reaction initiator such as potassium iodide at a temperature of from ambient to the reflux tempera-20 ~ure of the reaction mixture.Method e A compound prepared in Method a) or b) can be treated ~ith a chloroformate, e.g. an alkyl or phenyl chlo00formate, - at a temperature of from 25 to 125C, in a solvent such as methylene chloride, toluene or benzene to provide the corre-sponding compound of the invention in which Z is N'R2 with R
being C1-C6alkoxy- or phenoxy carbonyl.
.
."' '' ' ' ' ~ ~ .
` _ 7 ~ 1420 Method f A compound prepared in Method e) is treated with an or-ganic base such as triethylamine or an inorganic base such as sodium or potassium hydroxide in a solvent such as water, ethanol, or ethylene glycol at a temperature of from ambient to reflux to provide the corresponding compound of the inven-tion in which R1 is hydrogen.
Met.hod q A compound prepared in Method f) is treated with a 10 straight or branched chain C1-C6alkyl halide, C2-C6alkenyl, halide, C2-C6-aLkynyl halide or cycloalkylC1-C6alkyl halide under conditions normaL for such reactions to provide the corresponding compound of the invention in which R1 is straight or branched chain C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl or cycloalkyLC1-C6alkyl. A preferred method is to carry out this substitution in the presence of a solvent such as di-methyl.formamide, an acid scavenger such as sodium bicarbonate and a reaction initiator such as potassium iodide at the:re-f~ux temperature of the solvent.
. .
, ' ' ' :' ~ " " ' .
14~0 ~ethod h ....
A compound prepared in any of the above methods, which ~ncludes a nitro group can be reduced by a conventional method to produce the corresponding amino compound. Such conventional methods include but are not limited to use of metallic zinc and acetic acid or platinum on carbon.
As is appreciated by those skilled in the art, specific conditions in any of the above methods are dependent and are a function of the ingredients of each procedure.
The compounds of the present invention are useful in the treatment of depression in mammals, as demonstrated by their abiLity to inhibit tetrabenazine-induced depression in mice [International Journal o Neuropharmacology 8, 73 (196g)], a standard assay for useful antidepressant properties.
Thus, for instance, the intraperitoneal dose at which the following compounds effect a 50% inhibition of the ptosis o~
the tetrabenazine-induced depression (ED50) in mice are:
~E~--nd m~
2-~luoro-11-[~-~ethylamino)ethylthio]dibenz[b,f]- 0.3 oxepin malea~e 10-1~-(methylamino)ethylthio]dibenz[b,f]oxepin oxalate 3.4 2-chloro-10,11-dihydro--11-[(~-dimethylamino~-ethylthio]dlbenz[b,f]oxepin oxalate 3.5 2-fluoro-11-[~-(dimethylamino)ethylthio]-dibenz[b,f]oxepin hydrobro~ide 4.3 10,11-dihydro-10-[(~-dimethylamino)ethylthio]-dibenz[b,f]oxepin oxalate 7.0 2-L luoro-10,11-dihydro-11-[~-~dimethylamino)- "
ethylthio]dibenz[b,f]oxepin oxalate 7.6'`
*oral dose ..
.. . . _ . . .
.
~ 9 ~ ll~l~ZO
These data illustrate that the compounds of the invention are useful in the treatment of depression in mammals when administered in an a~.ount ranging from 0.1 to SO mg per kg of body weight per day.
Compounds of the invention are further useful as analgesic agents due to their ability to alleviate pain in mammals. The analgesic utility of compounds of this invention is demonstrated in the phenyl-p-quinone writhing assay in mice, a standard assay for analgesia [Proc. Soc. Exptl. Biol Med., 95 729 (1957)]. Thus for instance, the subcutaneous dose effecting an approximately 50% inhibition of writhing (ED50 in mice produced in this assay is as follows:
Compound m~/kg 15 2-fluoro-10,11-dihydro-11-~-(dimethylamino)-ethylthio]dibenz[b,f]oxepin oxalate 1.9 2-fluoro-11-[~-(methylamîno)ethylthio]-diben~[b,r]oxepln maleate 2.3 10-[~-(methylamino)ethyltllio]dibenz-[b,f]oxepin oxalate 2.3 These data illustrate that the compounds of this invention are useful for the alleviation of pain in mammals when administered in an amount ranging ~rom 0.1 to about 50 mg per kg of body weight per day.
Compounds of the present invention are still further useful as anticonvulsant agents for mammals, as determined by the method of l~oodbury, L.A.and Davenport, V.D~, in Arch. Int.
Pharmacodynam, Vol. 92. ~1952) at pages 97 to 107. Thus, for instance, the following intraperitoneal doses at which an approximately 50% protective (ED50) from the e~fect of supra-maximal electro shock in mice are:
1101420 l~D50 Compound mg/lcg dihydro-10-[B-(dimethylamino)ethylthio]- 7 7 dibenz[b,f]oxepin oxalate 2-fluoro-10,11-dihydro-11-[~-(dimethylamino)-ethylthio]dibenz[b,f]oxepin o~alate 9.0 2-fluoro-11-[~-(dimethylamino)ethylthio]dibenz-lb.f]oxepin hydrobromide . 9 2 2-fluoro-11-[~-(methylamino)ethylthio]dibenz-[b,f~oxepin maleate 9.9 2-chloro-10,11-dihydro-11-[~-(dimethylamino)-ethylthio]dibenz[b,f]oxepin oxalate 19.4 10-[~-(methylamino)ethylthio]dibenz[b,f]-oxepin oxalate 21 These data il.lustrate the utility of compounds of the invention for the treatment of convulsion in mammals ~hen adminis~ered in an amount ranging from about 0.1 to 100 mg per kg of body ~eight per day.
Other examples of compounds of the invention include:
11-~y-(dimethylamino)propylthio]-2-ethylsulfonyldlbenz[b,f]oxepin;
B-(bromoethyl)thic]-2-methQxy-lo~ll-dihydrodibenz[b~f]oa;epin;
2-ethyl-11-[~-(methylamino)ethylthio]dibenz[b,f]oxepin;
B-(ethylmethylamino)ethylthio]-2-methylsulfiTlyldiben [b,f]oxepin;
~ .
25 10,11-dihydro-10-[~-(piperi~ino)ethylthio]dlbenz[b,f]oxepin;
lo~ll-dihydro-lo-[y-(piperazinyl)propylthio]dibenz[b~f]oxepin;
lO,ll-dihydro-10-[~ -(piperidino)-n-butylthio]dibenz[b~f]oxepin;
(~ referring to position on piperidino ring);
10-[~-(pyrrolidino)ethylthio]dibenz[b,f]oxepin;
ethylthio]dibenz[b,f]oxepin oxalate 7.6'`
*oral dose ..
.. . . _ . . .
.
~ 9 ~ ll~l~ZO
These data illustrate that the compounds of the invention are useful in the treatment of depression in mammals when administered in an a~.ount ranging from 0.1 to SO mg per kg of body weight per day.
Compounds of the invention are further useful as analgesic agents due to their ability to alleviate pain in mammals. The analgesic utility of compounds of this invention is demonstrated in the phenyl-p-quinone writhing assay in mice, a standard assay for analgesia [Proc. Soc. Exptl. Biol Med., 95 729 (1957)]. Thus for instance, the subcutaneous dose effecting an approximately 50% inhibition of writhing (ED50 in mice produced in this assay is as follows:
Compound m~/kg 15 2-fluoro-10,11-dihydro-11-~-(dimethylamino)-ethylthio]dibenz[b,f]oxepin oxalate 1.9 2-fluoro-11-[~-(methylamîno)ethylthio]-diben~[b,r]oxepln maleate 2.3 10-[~-(methylamino)ethyltllio]dibenz-[b,f]oxepin oxalate 2.3 These data illustrate that the compounds of this invention are useful for the alleviation of pain in mammals when administered in an amount ranging ~rom 0.1 to about 50 mg per kg of body weight per day.
Compounds of the present invention are still further useful as anticonvulsant agents for mammals, as determined by the method of l~oodbury, L.A.and Davenport, V.D~, in Arch. Int.
Pharmacodynam, Vol. 92. ~1952) at pages 97 to 107. Thus, for instance, the following intraperitoneal doses at which an approximately 50% protective (ED50) from the e~fect of supra-maximal electro shock in mice are:
1101420 l~D50 Compound mg/lcg dihydro-10-[B-(dimethylamino)ethylthio]- 7 7 dibenz[b,f]oxepin oxalate 2-fluoro-10,11-dihydro-11-[~-(dimethylamino)-ethylthio]dibenz[b,f]oxepin o~alate 9.0 2-fluoro-11-[~-(dimethylamino)ethylthio]dibenz-lb.f]oxepin hydrobromide . 9 2 2-fluoro-11-[~-(methylamino)ethylthio]dibenz-[b,f~oxepin maleate 9.9 2-chloro-10,11-dihydro-11-[~-(dimethylamino)-ethylthio]dibenz[b,f]oxepin oxalate 19.4 10-[~-(methylamino)ethylthio]dibenz[b,f]-oxepin oxalate 21 These data il.lustrate the utility of compounds of the invention for the treatment of convulsion in mammals ~hen adminis~ered in an amount ranging from about 0.1 to 100 mg per kg of body ~eight per day.
Other examples of compounds of the invention include:
11-~y-(dimethylamino)propylthio]-2-ethylsulfonyldlbenz[b,f]oxepin;
B-(bromoethyl)thic]-2-methQxy-lo~ll-dihydrodibenz[b~f]oa;epin;
2-ethyl-11-[~-(methylamino)ethylthio]dibenz[b,f]oxepin;
B-(ethylmethylamino)ethylthio]-2-methylsulfiTlyldiben [b,f]oxepin;
~ .
25 10,11-dihydro-10-[~-(piperi~ino)ethylthio]dlbenz[b,f]oxepin;
lo~ll-dihydro-lo-[y-(piperazinyl)propylthio]dibenz[b~f]oxepin;
lO,ll-dihydro-10-[~ -(piperidino)-n-butylthio]dibenz[b~f]oxepin;
(~ referring to position on piperidino ring);
10-[~-(pyrrolidino)ethylthio]dibenz[b,f]oxepin;
3-chl~ro-lo-[B-(ethylmethylamino)ethylthio]dibenz[b~f]oxepin;
-- lo-~B-(ethylamino)ethylthio~lc~ll-dihydro-4-nitrodiben [b,f]oxepin;
8-chloro-10,11-dihydro-10-[~-(dimethylamîno)ethylthio]-2-methyldibenz[b,f]oxepin;
- 35 . 2-bromo-7-fluoro-11-[~-(dimethylamino)ethylthio]dibenz[b,f]oxepin;
.
, - " llQ1~20 10-[~-(ethy].a~nino)ethyltllio]-3-tri~l.uoromethyldibenz[b,f]-- ox~pin;
2-amino~-O-~-(ethylamino)eth~ilthio]dibenz[b,f~oxepin;
lo~ (ethylamino)eth~lthio]-3-methoxvdibenz[b~f]oxepin;
5 10-[~-(diethylamino)ethylthio]-2-n-propyldibenæ[b,f]oxepin;
10-[~-(methylamino)ethylthio]-3-methylthiodibenz[b,f]oxepin;
3-fluoro-11--[~-(me~hylamino)ethylthio]dibenz[b,~]oxepin;
3-ethyl-ll-[~-(methylamino)ethylthio3dibenz[b,f30xepin;
l~-[s-(ethylamino)et}lylthio]-4-nitrodibenz[b~f]oxepin; and 2-methyl-11-~ -me~hyl-N-methoxycarbonyl)aminoethylthio]-dibenz[b,f]oxepin.
Effective quantities of the compounds of 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 steri]e solutions or suspensions, and in some cases intravenously in the form of sterile solutions. The free base i.nal products, while effective themselves, may be formulated and administered in a form of their pharmaceutically acceptable addition salts for purposes of stability, convenience or crystal-lization, increased solubility and the like.
The active compounds of the present invention maybe orally administered, for example, with an inert diluent or with an edible carrier, or they may be enclosed in gelatin capsules, or tney may be compressed into tablets. For the - 25 purpose of oral therapeutic administration, the active com-pounds of the inven~ion may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, che~ing gum and the like. These preparations should contain a~ least 0.5~ of active compound, .
, . ~, . _ ___ . . ... .. .. . .. . .
- l2 ~ 14ZO
but may ~e ~aried ~epending 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 com-positions is such that a suitable dosage will be obtained.
S Preferred composltions and preparations according to the present invention are prepared so that an oral dosage unit form 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 . 10 as microcrystalline cellulose, gum tragacanth or gelatin;
and excipient such as starch or lactose, a disintegra~ing.
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 ~lavoring.
~en the dosage unit form is a capsule, i.t may contain, in addi.~ .
~ion to ~aterials of the above type, a liquid carrier such as a fatty oil. Other dosage unit forms may contain other various materials ~hich 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 and colorings and flavors. Materials used in preparing these various com-positions should be pharmaceutically pure and non-toxic in the amounts used.
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- 13 - ¦10 ~ 4 20 For the purpose o~ paren1eral therapeutic administration - the active compounds of the invention may be incorporated into a solution or suspension. These preparations should contain at least 0. l~/o of active compo~md, but may be varied to be between 0.5 and about 30% of the ~eight thereof. The amount of active compound in such compositions is sùch that a suitable dosage ~Jill 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 ~ollowing components: a sterile diluent such as water for in-jection, 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 ethylenediaminetetraacetic acid; buffers such as ~cetates,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 .ials made of glass or pIastic.
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,, ' ` .
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Examl~ 1 e A mixture of 1.6 g of 10,11-dihydro-10-hydroxydibet-z-lb,f]oxepin, 2.2 g o~ ~-dimethylaminoethylthiol hydrochloride and 4 ml of boron trifluoride etherate in 8 ml of glacial acetic acid which ~as permitted to stand at ambient tem?erature for 64 hours is added dropwise to a stirring, cold 20C/o sodium hydroxide solution. The liberated amine is extracted into ether, washed successively with sodium hydroxide and a saturated sodium chloride solution and dried. The e~her is removed under ~ 10 reduced pressure leaving a thick oil which is dissolved in ,~ .
acetone and converted to its crystalline oxa].ate. The salt is recrystalli~ed from a methanol-acetone mixture leaving color-less crystals, mp 163-169C, o~ 10,11-dihydro-10-[~.-(dimethyl-amino)ethylthio]dibenz E b,f]oxepin o~alate.
Analysis:
Calculated for C18H21r~0S C2H24 Foun~: 61.50~C; 6.01%H; 3.54%N; 8.38%S.
~xample 2 .
A solution of 2.5 g of 10,11-dihydro-10-hydroxydibenz-[b,f]oxepin, 4.01 g of ~-diethylaminoethylthiol hydrochloride, 8:ml of boron trlfluoride etherate in 13 ml of ~lacial acetic acid which was permitted to stand for 48 hours is concentrated and then poured into a cold 25% sodium hy~lroxide solution. The resulting oi.l is extracted into ether. ~he ether extracts are combined, and washed successively ~Jith dilute sodium hydroxide and water, and then dried. The dried solution is filtered and - the filtrate evaporated to dryness leaving an oil. The oil is .
.
.' ~ ' .
- 15 - 1 1~ 14 2 0 stirred witl~ a 40% sodium hydroxide s~lution and then extrac~ed into cther and dried. The ethereal solution is filtered, and the ether removed leaving another oil which is chromatographed through a silica gel column ~7ith a 20%
methanol in chloroform eluant. The chromatographed product is converted to its oxalate, the white salt, mp 109-111C, of 10-[~ -(diethylamino)ethylthio~-10,11-dihydrodibenz[b,f]-- oxepin oxalate.
Analysis: -,.-~ ..
~ .
Calculated for C20H24NOS C2H2O4 6~44~oC; 6 29V/~ll; 3 36-N-Found: 63~54/~C; 6~57/li; 3~23%1~1~
.
Example 3 A solution of 0.55 g of 10,11-dihydro-10-[~-(dimethylamino~ethylthio~dibenz[b,f]oxepin, free base of ~xample 1, in 10 ml of chloroform is ad{led dropwise to a solution of 0.28 g of cyanogen bromide ~nd 0.6 g of potassium carbonate in 5 ml of chloroform. After total addition the re-action mixture is permitted to stand fo~ 10 minutes and then filtered. The filtrate is concentrated to dryness leaving 2 thick oil~ich crystallizes upor.standin~. T~ cryst~lline mass - is recrystallized from 10~J boiling petroleum ether to give colorless needles, mp 77-78C, of 10-(~-bromoethylthio~10,11-dihydrodibenz[b,f]oxepin.
Analysis:
Calculated or C16H15BrOS: 57.32~/oC, 4.51%H; 23.84%Br.
- ~ - Found: 57.58~/oC; 4.5~ H; 24.20%Br.
. ', ~ .
~ 16 ~ 420 ~xaml~le 4 A mixture of 1.5 g o~ 10-(~-bromoethylt.hio)-10,11-dihydrodibenz[b,f]o,cepin, Example 3, 0.5 g of N-methylpipera~ine, l.0 g of sodium bicarbonate, 1.0 g of potassium iodide in lS ml of dimethylformamide is stirred at 80C for 16 hours. The ~ixture is permitted ~o cool before bein~ diluted ~ith water. The biphasic mixture is extracted thrice with 100 ml portions of ether. the ether extracts combined and shaken vigorously ~ith a large excess of 2N hydrochloride acid. The acidic solution is basified to liberate the free amlne. The amine is extracted into benzene, the benzene solution dried and the benzene removed - under vacuun~ leaving a pale yello~ish oil. The oil is dis~
solved in ether an~ converted to a crystalline dihydrobromide which is recrystallized from a methanol-acetone mixture to give white needles, mp 180-182.5C, of 10,11-dihydro-10-[B-(4-met}lylDiperazin-l-yl)ethyl~hio]dlbenz[blf]oxepin di-hydrobromide.
Analysis:
', Calculated for C21H21N2OS 21~Br: 48.84%Ci 5-46'~H; 5-42%11-Found: 48.g3%C; 5.66%H; 5.29%1d.
~:xample 5 A mixture of 1.5 g of 10-(~-bromoethylthio)-10,11-dihydrodibenz[b,f]oxepin, ~xample 3, O.S g of morpholine, 1.0 g of sodium bicarbonate and 1.0 g of potassium iodide in lS ml of dimcthylformamide is s~irred at 60-70C for 64 hours.
.. . .
___.,.. _.. ,.. _ - 17 ~ 1420 The reaction mixture is permi.tted to cool before being diluted ~.Jith ~ater. The biphasic mixture is extracted with ether and the combined ether extracts are shaken ~ith a larg~.
excess of 2N hydrochloric acid. The acid solution is basified witl~ potassium carbonate liberating the amine as an oi]. which is ~xtracted into ether. The ethereal solution is dried and the ether is removed under vacuum regeneratin~ an oil which is converted to i~s oxalate. The salt is recrystallized from a methanol-acetone-ether mixture to give co].orless plates, mp ,.
196-198C of 10,11-dihydro-10-(~-morpholinoethylthio)dibenz-[b,f]oxepin oxalate.
Analysis:
Calculated for C20H231lO2S C2~I2. 4 Found: 60.77%C; 5.88%l-l; 3.20%N.
E.xample 6 A sample of 3.8g of 2.-chloro-10,11-dihydro-11-hydroxydibenz[b,f~oxepin is treated with 3.3g of ~-dimethyl-aminoethylthiol hydrochloride in a manner consistent ~Jith the procedure of Example 1, to provide granular crystals, mp 139-141C of 2-chloro-10,11-dihydro~ [~-(dimethylamillo)-ethylthio]-dibenzlb,f]oxePin oxalate.
Analysis:
Calculated for C18H28ClMOS-C2~1~04: 56.66%C; 5.23%H; 3.31%~1.
Found: 56.58%C; 5.27%H; 3.31C/~
.. . _ ., _.,. _ . ,_ .. .. ~. _ _ . .. . ... .. _ . ,.. _ ... _ . . . .
~ 13 ~ 20 Example 7 ~ solution of 2.0 g of 10,11-dihydro-10--oxodibenz-[b,f]oxepin, ?..96 ~ of y-dimethylaminopropylthiol hydro-chloride and ~ ml of boron trifluoride etherate in 8 ml of glacia]. acetic acid which was permitted to stand for 16 hours is refluxed on a stream bath for 30 minutes, cooled and poured into a 6~1sodium hydroxide solution. The reactioa~ ture is extracted with ether and the combined ether extracts are washed successively ~ith a 25% sodium hydroxide solution and water and dried.
The dried solution is filtered and the filtrate concentrated ' leaving an oil. The oil is chromatographed through a silic~
gel column with an eluant of 10C/~ methanol in chloroform. The chromatographed oil is converted to its oxalic acid salt, mp 151-152C, which is 10-[y-~dimethylamino)propylthio]-dibenz[b,f]oxepin oxalate.
Analysis:
Calculated for ClgH21NOS C2H2O4: 62.82%C; 5.77C/uH; 3.49C/~N.
Found: 62.71%C; 5.7~a/OH; 3~43V/
Example 8 A miY~ture of 1.2 g of lO,ll-dihydro-10-oxodibenz-tb,f]oxepin, 2.l~ g of ~-dimethylaminoethylthiol hydrochloride and 2 ml of boron trifluoride etherate in 10 ml of glacial acetic acid which was stirred at ambient temperature for 16 hours is warmed on a steam bath for 30 minutes. The warm mixture is poured onto 200 g of ice-water and the diluted mixture basified with a 40% sodium hydroxide solution liberating an oil which is dissolved ln ether. The ether solution is , - 19 ~ zo d~ied and concentrated leaving a thick oil which is converted in ether to a crystalline oxaiic acid salt.
The salt is recrystallized from a methanol-ether mixture to give granules, 147-148C of 10-[~-(dimethylamino)-- 5 ethylthio]dibenæ~b,f]oxepin oxalate.
Analysis:
Calculated for C18HlgNOS-C2H204: 62.00~/~; 5.~:6/~1; 3.61%II; 8.28C/~S.
Found: 61.88~/2C; 5.46%H;3.55%~; 8.22%S.
Examp]e 9 To a stirrin~ solu~ion o 0.36 g o cyanogen bromlde, 2.28 g of potassium carbonate in 10 ml of chloroform is added dropwise a solution of 1.0 g of 10-[~-(dimethylamino)ethylthio]-dibenz[b,f]oxepin, Example 8, in chloroform. After total addition the reaction mixture is refluxed for 2 hours and the solvent removed leaving an oil. The oil is dissolved in 10 ml of methanol and the methanolic solution refluxed for 10 mi.nutes and again concentrated to recover the oil. The oil is chroma-tographed through a silica ~,el column with an eluant of ether.
The top fraction is collected and concentrated leaving a white solid, mp 106-107C of lO- [~-(bromo)ethylthlo~dibenz[b,f]oxepin.
Analysis:
Calculated for C16H13BrOS: 57.66%C; 3.93%H; 9.62%S; 23.98~/,Br.
Found: 58.38%C; 3. 89~ 1; 9.34%S; 24.12%Br.
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- 20 - 11~1~20 Example 10 To a stirring solution of d. 36 g of cyanogen bromide, 2.28 g of potassium carbonate in lO ml of chloroform is added dropwise a solution of 1.0 g of lO-[~-(dimethylami.no)~
ethylthio]dibenzEb,f~oxepin, Example &, in 20 ml of chloroform.
After total addition the reaction mixture is treated according to Example 9. Following column chromato~raphy the middle fraction is collected and concentrated leaving the whlte product, mp 54-56 DC, ol~ 10-[,B-(N-Cyano-N-methylamino)el~hylthio]-dibenz[b,f]oxepin.
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:Analysis:
ted ~or C1~16N2CS: 70.10%C; 5.23/.H.
Found: 69.99%C; 5.28%H.
~11 A solution of 2.0 g of 10,11-dihydro-lO-oxodibenz-lb,f]oxepin, 3.76 g of ~- diisopropylaminoethy~thiol hydro-chloride, and 8 ml of boron trifluoride etherate in ].0 ml of glacial acetic acid is treated according to Example 7 to pro-duce a yellow oil. The oil is chro~atographed through a silica 20 gel column with an eluant of 5% methanol in chloroform. The chromatographed oil soli.difie.s upon scratching to a pale ye].low powder, mp 65-66C, of 10-[~-(diisopropylamino)ethylthio]-dibenz[b,f]oxepin.
Analysis:
.25 C~lculated for C22H27NOS: 74.74%C; 7.70%H; 3.96%~.
Found: 74.95%C; 7.71%H; 4.06%N.
- 21 ~ 1420 .. Example 12 A mixture of 1.14 g of 10~ (bromo)ethylthio]-dibenz~b,f3oXepin, Example 9, 0.36 g of morpholine, 0.92 g of sodium bicarbonate and 0.93 ~ of potassium iodide in ].5 ml of dimethylformamide is stirred for 16 hours while main-taining the mixture between 60 and 65C. Thereafter the mixture is poured into 150 ml of water, the biphasic mixture extracted with ether and the ether extracts combined and dried. The dried ether solution is filtered and the filtrate lO concentrated leaving an oil which is chromatographed through a silica gel column with an eluant of 5% methanol in chloroform.
The chromatographed oil is converted to its white oxalic acid . .
salt, mp 181-183C, of lO-[ ~tmorpholino)ethylt}lio~dihe;lz-[b,f]oxepin oxalate.
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Analysis:
Calculated for C20H2lNO~S C2~2 4 Found: 61.33%C; 5.35%H; 3.34','N.
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Example 13 To a sti.rred solution of 2.08 g of 10-[~-(di.methyl-amino)ethylthio]dibenz[b,f~oxepin, free base of Example 8, in 10 ml of methylene chloride is added dropwise ~ solution of 1.26 g of phenyl chloroformate in 10 ml of methylene chloride.
After total addition the reaction mixture is permitted to stir at ambient temperature for 16 hours and then concen~rated leaving an oily residue. The residue is triturated ~ith hexane and then chllled at -20C F ~fect a solid. The solid is .
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- 22 - 11~20 recrystallized from an ether-hexane mixture to gi.ve ~hite needles, mp 103-103.5C, of 10-[~-(N-methyl-ll-phenoxy-carbonyl)aminCethylthio]dibenz[b~f]oxepin.
Analysis:
Calculated for C24H21NO3S: 71.42/,C; 5.24~1~H; 3.47%N.
Found: 71.37%C; 5.31C/~H; 3 51%N.
Example 14 A stirring suspension of 1.6 g of 10-[~ -methyl-N-phenoxycarbonylamino)ethyl~hio~dibenz[b,f}oxepin, ~xample 13, and 3.4 g of potassium hydroxide pellets in 40 ml of ethylene glycol is heated to between 150 and 160C over a 60 minu~e span. Sti.rring is continued at this temperature for an additional 30 minutes. The mixture is cooled, diluted ~ith water and the biphasic mixture extracted with an excess of ether. The ether extracts are combined, washed with ~a~er and dried and the solvent removed leavin~ a clear, mobi.le oil.
The oil is converted to its oxalic acid salt and recrys~alli.zed from methanol to give shiny needles, mp 207-208C(dec), of 10-~(methylamino)ethylthio]dibenz[b,f]oxepin oxalate.
Analysis:
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Calculated for C17H17NS C2~12~4 Found: 60.8S7,C; 5.14%H, 3.78';'~.
Example 15 A mixture of 1.82 g of : 10-[~-~me~hylamino)-ethylthlo]dibenz[b,f]oxepill, free base of Example 14, 0.72 g of cyclopropylmetltyl chloride~ 1.93 g of sodium bica~bonate .
, - 23 ~ 20 - and a few crystals o potassium iodide in 50 ml of dillletllylformamide is stirred at 80C for 16 hours. The reaction mixture is permitted to cool and filtered and the ~iltrate concentrated leaving an oil which is converted to ttle oxalic acid salt,mp 137-139C., of 10-[~-(M-cyclopropyl-~ethyl-N-methylamino)eLhylthio~dibenz[b,f]oxepin oxaiate.
Analysis: ~
Calculated for C21H23NOS C2H204. 64.61%C; 5.89~H; 3.2g%N
Found: 64.80%C; 5.96/u~l; 3.24%N.
rxample 16 A mi~ture of l.S g of 10 [~-(methy].~mino)-ethylthio]di~enz[b,f]oxepin, free base of Example 14, 1.1 g of ethyl iodide, 1.48 g of sodium ~icarbonate and 1.46 g of potassium iodide in 20 ml of dimethylformamide is stirred at 80-85~C for 16 hours. The reaction miY~ture is permltted to cool and diluted with 75 ml of water and then extracted thrice with 75 ml portions of ether. The ether extracts are combined, washed with 75 ml of a saturated sodium chloride solution and then dried. The dried solution is filtered and the filtrate concentrated leaving an oil. The oil is chroma-tographed through an alumina column with an eluant o ether.
The chromatographed oil is converted to its oxalic acid salt which is recrystallized from an acetone-ether nixture to gi~e the white product, mp 126-128~C, of 10-[B~ -e~hyl-ll-methyl-amino)ethylthio]dibenz[b,f]oxepin oxalate.
Analysis:
Calculated for ClgH2lNOS C2H204: 62.82r,~C; 5.77r/'H; 3.4g%N.
Found: 62.39%C; 5.69%H; 3.56%N
_ - 24 - ~ zo Example 17 The substitution of propargyl bromide for ethy].
i.odide into the procedure of ~xample 16 provides the ~Jhite solid, mp 140-142C, of 10-[~-(N-methyl-~-propargyl)-aminoethylthio]dibenz[b,f]oxepin oxalate.
Analysis:
Calculated for C20H19MS C2~24 64-21/~C; 5-Found: 64.49~; 5.22%1~; 3.41%N.
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E_ample 1~
To a mixture at a temperature OI O C of 2.~ g of ~-diethylaminoethylthiol hydrochloride in 5 m]. of acetic acid and S ml of boron trifluoride etherate is added drop-wise a solution of 2.0 g of 2-chloro-10,11-dihydro-11~
hydroxydiben?.[b,f]oxepin in 6 ml of ~lacial acetic acid.
After total addition the reaction mixture at 0 C is stirred for 20 minutes and thereafter at ambient temperature or 16 hours. The well stirred mixture is added slow to 50 ml of a 20% sodiul~ hydroxide solution at 0 C. After this addition ether is added and the biphasic mixture filtered and permitted to form separate layers. The aqueous layer is extracted twice with 50 ml portions of ether and the e~her extracts com-bined with the organic (ethereal) phase. The combined solutions are washed successively with one portion each of 40 ml of 20%
sodium hydroxide solution, 30 ml of 10% sodiu~ hydroxide, SO ml of water and 30 ml of a saturated sodium chloride solution and then dried over potassium carbonate and potassium hydroxidc ' ,' , ~ .
- pellets ].eavin~ an oil. The oil is chrornatographe~ through a silica gel column with a 5~,~ methanol chloroforrn mixture to obta~n a purified oil ~7hich is disso].ved in ether and treated with an ethereal oxalic acid solution to obtain ~he correspond-ing oxalic acid salt which is recrystallized frorn acetone to give a white powder, mp 1~6.5-128.5C, of 2-chloro-ll-[,B(diethylami.no)ethylthio]-10,11-dihydrodibenz[b,f]oxepin oxalate.
~nalysis: , Calculated for C20H23ClMOS C2H2~ 58-60%C; 5.59%~i; 3.11%~l;
7.~6%Cl.
Found: . 58.68%C; 5.7~%II; 2.95%I~I;
- . ~.27~Cl.
' Example 19 To a stirred solution of ~.. 5 g of 10,11-dih~dro-10-hydroxydibenz[b,fJoxepin, 3.7 g oE y dimethylaminopropylthio h~drochloride in 13 ml of glacial acetic acid ~re added ~ ml of boron trifluoride etherate. The reaction mixture is pe~itted to s~and for 2~ hours before being poured into 50 m]. of a chilled 25% sodium hydroxide solution. The basic mix~ure is extrac,,ed with ether, the ether extracts combined ~hich are was,hed succ,essively with a 20% sodium hyclroxide solu~ion and water, dried and filtered and the filtrate evaporated leaving an oil. The oil is chromatographed through a silica gel column with a 5% me~hanol in chloroform eluant an~ thc eluate is - 26 - ~ zo evaporated leavin~, a purified oil which is converted t:o a white ~,ranular oxalic acid sal " mp 179-181C, of 10,-~ dihydro-10-[~-(dimethylamino)p~opylthio]dibenz[~,f]oxe~in.
Analysis:
Calculated for ClgH22~0S C2~20~
Found: 62.60C/~C; 6.26%H; 3.64%N.
~xample 20 A mixture of 1.5 g of 10-[~-bromoethyl)thio]-, 10,11-dihydrodibenz[b,f]oxepin, Example 3, and 1.0 g of potassium iodide in 15 ml of dimethylformami.de is bubbled for five minutes with ethylamine. The reaction mixture is per-mitted to cool to ambient temperature and then stirred for ]6 hours. Ice-water is added and the biphasic rnixture is extracted thrice with ben~ene and the combined ~en~e~le extrac~s are dried audevaporated to dryness leaving a crude l?roduct ~hich is con-verted in acetone to it:s oxalic acid salt. The sal.t is re-crystallized from 90% ethanol to give cvlorless prisms, mp 205-207C, dec, of 10-[~ -(ethylamino)e~hylthio]-10,].1-dlhydro-, debenz~b,f~oxepin oxalate.
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~nalysis:
Calculated for C]~T21~0S C2ll204: 61.67~J; 5.95%1~; 3.60%1~.
61.68~/~; 5.97%~1; 3.39%N.
Found:
EY.amp].e 21 To a solution of 2.5 g of 10,11-dihydro-2-methylthio-ll-oxodibenz[b,f]oxepin, 2.8~of ~-dimethyl-aminoethylthiol hydrochloride and 24 ml of glacial acetic scid 27 ~ 1420 which was s~irred at am~ient ~emperature for 30 minutes is added,with additional stirring,8 ml of boron trifluoride etherate. After total addition,stirring is discontinued and the reaction mixture is permitted to stand for 72 hour5 before bein~
added to 50 ml of ice-water. The diluted mixture is rnade strongly alkaline with a 10% sodium hydroxide solution and the strongly alkaline mixture is extracted ~ith ether. The combined ether extracts are dried and evaporated ~o dryness leaving an oil. The oil is chromatograplled through a silica gel column with a 5% methanol in chloroorm eluant and the desired fractions were collected and concentrated leaving a purifi.ed oil. The oil was converted to a white granular oxalic acid salt of ll-[~-(dimethylamino)e~hylthio~2~methylthio-dibenz[b,f]oxepin oxalate.
Analysis: -Calculated for C19}121NOS2 C2H24 5~ ;
~otl~lcl: 57.99/~C; 5. 26D/~H;
xample 22 To a solution of 1.0 g of 2-fluoro-10,11-clihydl:o~
ll-oxodibenzrb,f]oxepin and 1.2 g of dimethylaminoethanthiol hydrochloride in 11 ml of glacial acetic acid is added 3.3 ml of boron trifluoride etherate. After total addition the reaction mixture is stirred at ambient te~lperature ~or 6~ hours and them poured into 25 ml of solution at 0C of 20% sodium hydroxide and the aqueous mixture extract~d ~Jith ether. The combined ether extracts are ~7ashed successively with two porti.ons of 20% sodiu~ hydroxide, one portion of water and one portion of .
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a saturated sodium chloride solution and then dried to give an oil. The oil is chromatographed through a si].ica gel column wit:h a 5~/J methanol in chloroform solution to give a purified oil which is treated with ethereal hydrogen S bromide solution efecting ~ white precipitate. The pre-cipitate is washed with ether and recrystallized from acetone to give a white powder, mp 197-198.5C of 2-fluoro-ll-[~-(dimethylamino)ethylthio]dibellz[b,f]oxepin hy~ro-bromide.
Analysis:
Calculated for C18H17F~OS H~r: 54.55%C; 4. ~3C/"H; 3 5~CioM; 20 . ].7/OBr~
Found: ' 54.49%C; 4,30C~ ; 3.50~ 1; 20,1~%Br.
The 2-fluoro-10,11-dihydro-11-oxodibellz[b,f]oxepin, starting material for Example 22, can be prepared by the following se~uence of reactions:
a. l'o 147 g of iodobenzoic acid and 45.5 g of votassium carbonate are added 57 ml of nitroben~ene. The mixture is heated with stirring at 160C for 40 minutes. To the heated ~lixture is added an additionai 46.5 g o~ potassium carbona~e and then successively 73.1 g of 4-fl.uorophenol, anot~her (~6.5 g of potassium carbonate and 0.3 g of copper powder. After these additions, the mixture is stirred at 160~C for 45 minutes and the result,ing solid is cooled to 0~C. The cooled solid is mixed with 100 ml of water and 220 ml of 6M hydrochloric acid. The acidic mix-ture is diluted with water to a volume of one liter and then mixed with 450 ml of chloroform. The white soli.d is filtered - 29 11~14Z~
o~f and washed tlitll chloroform and ~ater. The solid is dissolved in hot acetone cooled and filered to leave a white crystalline product mp 1~ 147C of 2-(4-fluoro-phenoxy)bcnzoic acid.
b. To 3.28 g of 2-(4-fluorophenoxy)benzoic acid is added 5.6 ml of 97% thionyl chloride. The reaction mixture is heated on a steam bath for 10 minutes and any excess thionyl chloride is then removed under reduced pressure. The residual liquid is dissolved in 30 m]. of 1 2~dichloroethane and added dropwise over a 30 minute span to a ~ixture of 1.9 g of aluminum chloride in 5 ml of 1 2-dichloroethane. -After total addition the reaction.mixture is stirred at re~lux for 2 hours and allowed to s~ancl at ambient temperature ~or 64 hours. Thc mix~ure is poured on~o i5 a mixture of 150 ml of ice and water and 125 ml of ether. The biphasic n~ixture is filtered through paper and separate~. The aqueous layer is collected and extracted twice wiLh two portions (50 Inl) of ether. The combined ether extracts are ~ashec~
successively with two 25 ml portions o~ a sa~urated sodium bicarbonate soltuion and one 25 ml portion of saturated sodium chloride solution and then dried to give an oil. The oil is treated with hexane and the resulting solution clecanted off and evaporated leaving a bright yellow crystalline solid. The solid is chromotographed ~hrough a silica-ge] column with a chloroform eluant and is recrystallized from cyclohexalle to ~ive a yello~ hite.crystalline so]id mp 85.5-87.5C of 2-fluoro-10,].1 dihydro-ll oxodibenztb ~]oxepin.
~he ~etones of which are starting materials of other examples may be prepared in a fashion similar to the procedure - outlined above.
zo Example 2_ To a solution which was stirred at amhient temperature for 30 minutes, 2.5 g of 2~chloro-10,]1-dihydro-ll-oxodibenz[b,f]oxepin, 2.9 g of ~-dimethylaminoethylthiol S hydrochloride in 25 ml of glacial acetic acid is added with continuous stirring 5 ml of boron trifluoride etherate.
After total addition the stirring is discontinued and the reaction mixture is permitted to stand or 24 hours. The re-action is basified with 10~/~ sodium hydroxide solution and extract~ed ~ith ether. The combined e~her extracts are dried and filtered and then the solvent removed leaving an oil.
The oil is chromatographed tlll-ough a silica gel column ~7ith a 5% methanol in chloroform eluant to obtain a purified oil which is converted to a white oxa]ic acid salt, mp 183-184C
of 2-chloro-11-[~-(dimethylamino)ethylthio]dibenz[b,f]oxepin oxalate.
~nalysis:
Calculated for C]8Hl8cll~os c2~l2o4 56.93%C; 4 78%H-Found: 56.67%C; 4.70%~1.
~xample 24 To a solution of 2.5 g of 10,11-dihydro-2-(methyl-thio)-ll-oxodibenz[b,fJoxepin, 3.33 g of ~-die~hylamino-ethylthiol hydrochloride and 24 ml of glacial acetic acid whicll was stirred for 30 minutes is added 8 ml of boron trifluoride etherate. After this addition the reaction mix-ture is permitted to stand for 72 hours bcfore its addition - 31 - 11~1420 to 50 ml of ice water. The diluted mixture is made strongly alkalinc with a 10% sodium hydroxide solution and then ex-tracted with ether. The combined ether extracts are dried, filtered and the ether evaporated off ],eaving a yello~i oil.
The oil is chromatographed through a silica gel in chloroform colu~n with an eluant of 5~/~ m.ethanol in chloroform to purify the oil which is converted to its hydrogen bromide acid sal~
hich is rec-rystallized fro~ acetone to give t'he salt, mp 184-186~C, of ll-[~-(dimethylamino)ethy].thio]-2-(methyltllio)-di~enz[b,f]oxepin hydrobromide.
, .
Analysis:
Calculated for C21}125NOS2-l~Br: 55.74%C; 5-79%H; 3-10%N-~ound: 55.83/,C; 5.85/,~1; 3.05%~.
Example 25 To a stirring solution of 11.3 g of ll~ (dimethyl-alllino)ethylthio]-2-(methylthio)dibenz[b,f]oxepill, free base of Example 21, and 10.0 g of potassium carbonate in 50 m] of ~ethylene chloride is added drop~ise a solution o~ 5.7 g of phenylchloroformate in 50 ml of methylene chloride. ~fter total addition the reaction mixture is stirred at,ambient temperature for 24 hours and then evaporated to dryness. The residue is trlturated with ether and the ethercal solution is sequentially washed successively with a 10% sodium hydroxide solution and ~ater, dried and filtered and the filtra~e evap-orated to dryness leaving a yellow oil. The oil is chromato-' graphed throu~h a silica gel column with a methylene chloride - 32- ~ 4;~0 eluant to obt~ain the pu~ ied orange oil of 11- [~ etl~yl-N-pheno~ycar~onylamino)ethylthio]-2~ ethyltllio)-dibenz[b,f]-oxepin.
~nalysis:
Calculated for C25H231~03S2: 66.79%C; 5.16%1~; 3.12C~N.
Foun~: 66.~41~/.C; ~.93C/,~; 3.06C/,Il.
Example 26 mixture of 8.3 g of ll-~ methyl-N-phenoxy-c~rbonyl)a~inoethylthio]-2-(methyl~hio)-dibenz[b,f]oxepin, Example 25, 190 ml of ethylene glycol C~dl6 ~ of potassium hydroxide is stirred at 155C for 30 minutes. The reaction mixture is cooled and then poured onto 500 ml of ice wa~er.
The biphasic mi~ture is extracted ~;~ith a 1:1 ether benzene ~ixture and the combi.ned extracts are washed with ~ater and dried. The c~ri.ed soiution is iltered and the filtrate evapo rated to dryness leaving an oil. The oil is converted ~o i~s maleic acid salt ~hich is recrys~al3.ized from ace~onc leaving the salt, mp 160-162C of ll-~-(methylamino)ethylthio~-2-(methylthio)dibenz[b,f]oxepin maleate.
Analysis:
Calculated for C18Hlg~OS2-C4H404 59.30%C; 5.20~ ; 3.1/l%N.
Found: 59.40~/~C; 5.23%H; 3.08C/~N.
Exa~ple 27 A reaction solution of 1.9 g of ll-[~-(methyl-amino)ethyltllio]-2-(methyltbio)dibenz[b,f]oxepin, free base , , .
33 ~ 4Z~
of Example 26, 1.2 g of ethyl iodide and 1.60 g of sodium bicarbonate in 25 ml of di~ethylforn.amide is stirred with heating for 72 hours. The solution is diluted wi~h 100 ml of water and the ~iphasic mixture extracted with eLher. The combined ether extracts are wa~hed ~ith ~ater, ~ried and then iltered and ~he filtrate evaporated to dryness leaving an oil. 'rhe oil is converted to a ~hite salt, mp 112-114C
of ll-[~-ethylmethylamino)ethylthio]-2-(me~hylthio)dibenz[b,f~-oxepin maleate.
Analysis:
for C20I~23NOS2-C4~404: 60.~6%C; 5.75C,/,~I; 2 96%~
Found: 6].11%C; 5.74%I~; 2.87%N.
Examples 28 and 29 By following the procedure of F.xample 25, 2-fluoro-ll-[~-(d~.~.ethylamino)ethylthi.o]dibcnz[b,f]oxepin, free base of Example 22, and 2-chloro-10,11-dihydro-11-[~-(dimethylamino~-ethy3.~.hio]dibenz~b,f]oxepin, free based of Example 6, are ~reated respectively to obtain 2-f].uoro-ll-[~ -methy]-~-pl~en carbonylami.no)ethylthio]dibenz[ D, f]oxepin, Example 28, and 2-chloro-11-[~ -methy]-Id-phenoxycarbonyl~mino)ethylthio~-dibenz[b,f]oxepin, Example 29.
Ana]ysis: [~xample 28]
Calculated for C24H20F~IO3S: 68.40%C; 4.78%1-l; 3.32%~; 4.51%F.
Found: 6S.25%C; 4.85C/vH; 3.28%~1; 4.80%F.
.
- 34 ~ 20 ~,xample 30 A reaction solution of 5.1 g of 2-fluoro-ll-[~-(M-methyl-N-phenoxycarbonylamino)ethylthio]dibenz[b,f]-oxepin and 10.6 g of potassium hydroxide in 125 ml of ethylene -glycol is stirred ~ith heating at fro~ 80 to 155C for 30 minutes and then at 155C for 30 minutes. Then the reaction is permitted to stand a~ 0C for 16 hours before being poured onto 350 ml of ice water. The biphasic mixture is extracted thrice ~7ith 125 ml portions of 1 1 e~her-benzene mixture.
The combined orgallic l~yers are washed successively with three portions of water and one portion of a saturated sodi~m chloride solution and then dried ].eaving a clear orange oil.
The oil is swirled with a 50 ml portion and 0.25 ml portion - of boiling hexane and decanted from any residue effecting a yellow oil. The oil is treated in ether ~ith ethereal maleic acid effecting a salt which is recrys~alli.zed from a methanol-acetone-ether mix~ure to give a white po-7der, mp 135.5--~36C, of 2-~luoro-11-[~-(methylamino)ethylthio]dibcnz[b,f]oxepin maleate.
' ' . .
Analysis: ~
Calculated for C17H16F~lOS C411404: 60.43~1~C; 4.83%H; 3.36%N; 4.5S%~.
Found: 60.42%C; 4.86~/~H; 3.26%N; 4.85%F.
.
- . Example 31 A reaction mixture of 4.0 g of 2-chloro-11-[~-(N-methyl-N-phenoxycarbonylamino)ethylthio~iben7.[b,f~0xepi.n, Example 29, and 8.5 g of po~assium-hydroxide in 80 ml of ethylene ~ ~ 35 ~ 1 1~ 14 ~0 glycol is s~irred at 155C for 30 minutes. The mixture is permitted to cool and ice is added. The mixture is extracted with ether and the combined ether extracts are dried and ~he ethe~ evaporated o~f leaving an oil.. The oil is ~reated in ether with ethereal maleic acid and the resulting salt recrystallized from a methanol-ether mixture to give colorless prisms, mp 153-]54C, of 2-chloro-11-[~-(methyl-amino)ethylthio]dibenz[b,f]oxepin maleate.
Analysis: -,.
Calculated for C17lll6Cl/lOS C4H404: 58.12~/.C; 4.64/,11; 3.22%~1; 8.17%C~
Found: 58.15%C; 4.77%H; 3.~4%i~; 8.33~/oCl Example 32 To a mixture of 1.1 g of ~-dimetllylaminoethanethiol hydrochloride and 2.8 ml of boron tri1uori.cle etllerate in 5 ml of glacial a.cetic acid is added dropwise a solution of 0.9 of 2~fluoro-10,11-dihydro-11-hydroxydibenz[b,f]oxepin in ~
ml of glacial ace~ic acid. After total addition the reaction mixture is permitted to stir for 16 hours before being poured onto a mixture of 30 ml of.a 20% sodium hydroxide solution and ice. The mixture is extracted with ether and the combined ether extracts are washed successively with two-portions of a 20% sodium hydroxide solution, one portion of wa~er and one portion of a saturated sodium chloride solution. The washed extracts are dried producin~ an oil which is chroma~ographed throu~h a silica gel column with an eluant of 5V/~ methanol in chlorofo-rm to obtain a purified oil.. The oil is converted - 36 ~ 20 to its o~alic acid sal~ which is recrystallized from acetone to ~ive a white po~der, mp 169-170.5~C, of 2-f].uoro-10>-ll-dihy~o-ll-[~-(dim~thylamino)ethylthio]dibenz[b,f]oxepi oxalate.
Analysis:
Calculated for C18~20F~S-C21124 Found: 59.17%C; 5.1~4%H. 3.51%~; 4.~1%F.
- ~xample 33 -. To a mixture of 2.3 g of cyanogen bromide and 5.0 g of potassium carbollate in 40 ml of chloroform is added portlon-wise over a 50 minutes span a solu~ion o~ 4.8 of 2-fluoro-10,-ll-dihy~-o~ [~-(dimethylamiIIo)ethylthlo]dibenz[b,f]oxepin, free base of Example 32, in 85 ml of ch~o]^oform. After total addition, the mixture is stirred for 20 minutes before being filtere~.
The filt~ate is evaporated to leave an oil which is treated with three portions of boiling hexane. The combined hexane portions are eva?orated leaving an oi.l ~hich is chromatographed throu~h a silica gel column ~ith an eluant of l~ethylene chloride and is recrystalli.zed from cold hexanc to ~ive a white powder, m~
46-48C of ll-~-(bromo)eth~lthio]-2-fluoro-10,11-dihvdrodibenz-[b,']oxe~in.
Analysis:
Calculated for C16H14BrFOS: 54.41C/~C; 4.00/~H; 22.63V~r; 5.3~%~.
Found: 54.36%C; ~Oi~/o~i; 22.91%Br; 5.69~.F.
~ 37 ~ 1;4z~
~xa~ le 34 Methylamine is bubbled into 10 ml of dimethylsulfoxide for 5 minutes. To this solution is added dropwise a SO].U~iOII
of 2.2 g of ll [B-(bromoethyl)thi~}2-fluoro-]-olll-dih~drodiben [b,f)oxepin in 11 ml of dimethylsul.fo~ide. Sufficient methyl-amine is bubbled into the reaction mixture to complete the reaction. Thereafter the reac,ion mix~ure is permitted to stand or 64 ilours. The reaction mixture is poured onto 125 rlll of ice ~ater, and the biphasic mixture is extracted with three portions of ether. The combined ether extracts are washed .
successively ~ith two ~0 ml portions of ~7ater and one 10 ml portion of saturated sodium chloride solu~ion and dried to produce an oil. The oil is dissoved in ether and treated with ethereal ma]elc acid ~hich precipita~.es a salt which is re-crystallized from an acetone-ether mixture to gi.ve a whi.te solid, mp 11~-119.5 C, of 2-fluoro-10,].1-dihydro-ll-[~-(methyl-amino)ethylthio]di.benz[b,f]oxepin maleate.
Analysis:
, ~"
C17~.18FNOS C4H404: 60.14%C; 5.29%H; 3 34%N; 4 53%F
Found: 60.11%C; 5.19%H; 3.19%N; ~.80'~F.
rxample 35 To a stirring solu~ion of 2.8 g of ~-dimethylamino-ethylthioi hydrochloride and 7 ml of boron trifluorine etherate in lO ml of glacial acetic acid is added dropwise a solution of 2.5 g of 10,11-dihydro-11-hydroxy-2-methylthiodiben~[b,f]--oxepin in 10 ml of glacial acetic acid. After to~al addition , .
': ~
~ 3g ~ ~ 20 the reaction mixture was permitted to stand for 2l~ hours before bein~ added to 50 ml of a cold 25% sodium hydroxide solution. The reaction mixture is extracted with ether and the combined ether eY~tracts are successively washed witll a 20% sodium hydroxide solution and water and~dried. The dried solution is ~iltered and the filtrate is e~Taporated to dr~ness leaving an oil ~;~hich is dissolved in chloroform. The chloroform solution is chromatographed through a silica gel column ~ith an - eluant of 5~ methanol in chloroform to obtain a purified oil.
The purified product lS conver~ed to its maleic acid salt, a white powder, mp 100-102C of 10,11-dihydro-11-[~-(dimethyl-amino)ethylthio]-2-(methylthio~dibenz[b,f]oxepin maleate.
Analysis:
. ClgH23NOS2-C4l-1404: 59.84%C,; 5.90%1I; 3 0~l%N
Found: 59.92%C; 5.93%H; 3.00%N.
; Example 36 By the procedure of Example 35, ~-diethylamino-ethylthiol hydrochloride is treated with 10,11-dihydro 11-hydroxy-2-1Ilethylthiodibenz[b,f]oxepill to obtain an oil of ll-[~-diethylamino)ethylthio] 10,11-dihydro-2 (me~hylthio)-~; dibenz[b,f]oxepin. The oil is chromatographed throu~h a silica gel methylene chloride column ~ith an eluant of a 5~/, me~hanol in methylene chloride to purify the oil. The purified oil is converted to its white oxalate salt, mp 118-120C.
Analysis:
' ~ Calculated for C21~12?NOS2 C2~124 Found: ~ 59.30%C; 6.32%11; 2.93%N.
.
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.
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~ 39 11~420 Exam~le 37 A sample of 10,11-dihydro~ [R-(dimethylamino)-ethylthio]-2-(methylthio)di~enz[b,f]oxepin, free base of Example 35, is treated according to the procedure of Example 33, to obtain 11-(~-bromoethylthio)-10,11-dihydro-2-(methyl-thio)dibenz[b,f]oxepin. The oil is. dissolved in hexane and cooled in a dry/acetone bath to effect crystallization of the oil to a white solid, mp 64-66C.
Analysis: .
.~;~ ' .
Calculated for Cl7H17~rOS2: 53.54%C; ~.49%H; 20.9~%Br.
Found: 53.72%C; 4~47C/oH; 21.0~%Br.
Example 38 To a mi.xture of 2.0 g of 2-fluoro-11-[~-dimethyl-amino)ethylthio]dibenz[b,f]oxepin, free base of Example 22, in 62 ml of methanol are added 6.1 g of magnesium shavings. l'he reaction is stirred for 90 minutes with sufficient coolin~ to maintain the reaction at a~bient temperature. The methanolic 3 mixture is decanted off and then cooled. The cooled mixture is then treated with careful addition of 60 ml of 6N hydro-chloric acid. The acidi~ied mixture is permitted to reach ambient tcmperature before being diluted with 60 ml of water and the diluted mixture is extracted wi'~h chloroform. The combined chloroform extracts are successively washed wlth 80 ml of a 10% sodium hydroxide solution, 100 ml of water and 25 ml of saturated sodium chloride solution and dried to effect a yellow oil ~ The oil is extracted thrice with 30 ml portions of hot pentane . .
? . .
~ o 1~ 20 and the com~ined pentane extracts are e~aporated le~ving purer oil 17hich is treated in ether with ethereal ox~lic acid to precipitate out a salt. The salt is ~ashed well with .
ether leaving a white solid, mp 167-169G of 2-fluoro-10,-ll-dihydro-ll-~-(dimethylamino)ethylthio]dibenz[b,f]oxepin oxalate identical to the product described in r,xample 32.
- Example 39 A solution of 1.5 g of ll-[~-(bromo)etl~ylthio]-10,11-dihydro-2-(methylthio)diben7[b,f]oxepin, F,xample 37, ~ 10 and 0.9 g of potassium iodide in 15 ml of dimethylformamide is stirred a~ ambient temperature ~hile methylamine is bubbled into the solution over a 5 minut:e span. ~fter ~otal addition,the solution is permitted to stir for 16 hours before being successively poured into 100 mi of ice water, extrac.ed with benzene,and the combined benzene extracts dried. The dried solution is filtered and then evaporated to dryness leaving a yellow oil ~hich is converted to its maleic acid salt as a granular powder ~hich is recrystallized from a methanoi-e~her mixture to provide the product, mp 138-140~C, of 10,11-dihydro-ll-[~-(methylamino)ethylthio]-2-methyl-thiodibenz[b,f]oxepin maleate.
Analysis:
Calculated for C18H2ll~0S2 4 4 4 Found: 58.~3%C; 5.43%1-1; 2.90%M.
' .:
, Example 40 Into a solution of 2.6 g of 10~ bro~oethylthio)-10,11-dihydrodibenz~b,f]oxepirl, F.xample 3, in 15 ml of dimethyl-- formamide is bubbled methylamine over a 20 ~inu~e span. After tota~ addition the reaction m-ixture is permitted to stand at ambient temperature for 16 hours. Tllereafter, ice water is added and the biphasic mixture is extrac~ed thrice with ether and the combined ether extracts are ~ashed ~ith ~ater. The ethereal solution is dried and the resulting product is con-verted to its maleic acid salt. The salt is recrystal]ized froman acetone-ether mixture to provide prisms "np 102-104C
of 10,11-dihydro-10-[(~-methylamino)etllylthio]dibcnz[b,f]oxepin maleate.
Analysis:
'"" - ~ . .
Calculated for C17HlgNOS-C4H4O~: 62.82%C; 5.77%H; 3.49%M; 7.99%S.
Yound: 62.30~/,C; 5.77%~1; 3. 36~/oM; ~ . 1S%S .
le 41 A mixture of 2-chloro-10,11-dihydro-11 [~-(dimethyl~
amino)ethylthio]dibenz[b,f]oxepin, free base of Example 6, 0.7 g of cyanogen bromide, and 0.8 g of potassium carbonate in 20 ml of methylene chloride is stirred at ambient temperature or ~ hours. Thereafter the mixture is filtered and the filtrate concentrated under vacuum,leaving a viscous oil. The oil is chromatographed over silica gel, leaving a pale yellowish oil, Rf of 0.8, of 11-(~-bromoethylthio~2-chloro 10,11-dihydrodibenz-lb.f]oxepin.
. .
Analysis:
' '. ' .
.
.
,~ :
- ~2 - 1~420 Calc~llated ~or C16Hl~BrClOS: 51.98~/~C; 3.82C/oH; 8.67%S.
Found: 52.26/,C; 3.76/,EI; 8. 61~oS.
Example 42 Into a solution of 1.5 g of ll-[~-(bromo)ethyl~hio~-2-chloro-10,11-dihydrodibenz[b,f]oxepin, E~ample 41, in 20 ml of dimeth~lformamide is bubbled methylamine over a 10 - minute span. Thereafte~, the solution is permit~ed to stand at ambient temperature for 16 hours. Then the solutiorl is evaporated to dryness leaving a yellowish oily residue which is equilibrated with sodium bicarbonate and ether. The ethereal phase is collected and then dried before being concentrated under vacuum leaving a clear oil which is converted to a crystalline ~naleic acid salt. The.sal.t is recrys~allized fro~n an acetone-etller mixture to provide white prisms, mp 13~-140C
of 2-chloro-]0,11-dihydro-11-[~-(methylamino)ethylthio~dibenz-[b,f~oxepin ~aleate.
Analysis:
.~
Calculated ior C17H18ClNOS C4H404: 57.86%C; 5-09/~11; 3-21%M; ~ 13%Cl ~ound: 57.62%C; 5.00%~1; 3.0S%N; 8~33~/oCl Example 43 _ a. A solution of 28.4 g of 2-(4-methylsulfonyl-phenoxy)benzyl nitrile, 99 ml of 95% ethanol, 15.2 g of 85%
potassium hYdroxide and 25 ml of water is stirred at 115C
for 24 hours. Thereafter, the reaction mixture is concentrated to an oil. The oil is dissolved in water and the aqueous .
solution is washed with ether, acidified with dilute hydrochloric acid providing an oil. This oil is dissolved in methylene chloride and the solution, successively, is dried, filtered and concentrated to dryness leaving a light yellow solid. The solid is chromatographed through a silica ge]/ether column with a 10% methancl in ether eluant to provide the product 2-(4-methylsulfonylphenoxy)phenylacetic acid, mp 1~5-127C.
b. A mixture of 1.0 g of 2-(4-methylsulfonylphenoxy~-phenylacetic acid and lO ml of polyphosophoric acid under nitrogen is stirred at 90-100C for 2 hours. The reaction mixture is permitted to cool and then poured into 100 ml of an ice-water slurry. The aqueous solution is basified with 20% sodium hydroxide before being extracted with methylene chloride. 'rhe combined extracts are dried and then evaporated ~o dryness leaving an oil. The oil is chromatographed through a silica gel/methy]ene chloride column with 2% methanol in methylene chloride. The chromatographed solution is evapora~ed to dryness leaving an oil which solidifies on s~anding. The solid is triturated with pentane to provide 10,11-dihydro-2-methylsulfonyl-ll-oxodibenz[b,f]oxepin, mp 105-106~C.
c. A stirring solution of 4.4 g of 10,11-dihydro-2-methylsulfonyl-11-oxodibenz[b,f]oxepin, 4.3 g of dimethyl-aminoethylthlol hydrochloride and 37 ml of glacial acetic acid is treated with 15 ml of boron trifluoride etherate. Thereafter the reaction mixture is poured into 300 ml of a cold lOC,' - sodium hydroxide solution and the resulting solution is extracted witb methylello hlor de. The combined ~xtracts Ire washed w,th , - 44 ~ 1420 t~7ater and dried before being filtered. The filtrate is evapor-ated to d~yness leaving an oil which is chromatographed through silica gel/methylene chloride ~ith a 2-4C' meth~lol chloride - eluant. The chromatographed solution is evaporated to dryness and the resulting oil is converted to a white maleic acid salt, mp 137-139C of ll-[(~-dimethylamino)ethylthio]-2-methyl-- sulfonyldibenz[b,~]oxepln maleate.
Analysis:
or Cl9H21~13S2 C~ 44 56 19%C; 5.13%17; 2.85%1~
Found: 56 . ~4//oC; 5 . lSV/oH, 2 . 36~oN.
.
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-- lo-~B-(ethylamino)ethylthio~lc~ll-dihydro-4-nitrodiben [b,f]oxepin;
8-chloro-10,11-dihydro-10-[~-(dimethylamîno)ethylthio]-2-methyldibenz[b,f]oxepin;
- 35 . 2-bromo-7-fluoro-11-[~-(dimethylamino)ethylthio]dibenz[b,f]oxepin;
.
, - " llQ1~20 10-[~-(ethy].a~nino)ethyltllio]-3-tri~l.uoromethyldibenz[b,f]-- ox~pin;
2-amino~-O-~-(ethylamino)eth~ilthio]dibenz[b,f~oxepin;
lo~ (ethylamino)eth~lthio]-3-methoxvdibenz[b~f]oxepin;
5 10-[~-(diethylamino)ethylthio]-2-n-propyldibenæ[b,f]oxepin;
10-[~-(methylamino)ethylthio]-3-methylthiodibenz[b,f]oxepin;
3-fluoro-11--[~-(me~hylamino)ethylthio]dibenz[b,~]oxepin;
3-ethyl-ll-[~-(methylamino)ethylthio3dibenz[b,f30xepin;
l~-[s-(ethylamino)et}lylthio]-4-nitrodibenz[b~f]oxepin; and 2-methyl-11-~ -me~hyl-N-methoxycarbonyl)aminoethylthio]-dibenz[b,f]oxepin.
Effective quantities of the compounds of 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 steri]e solutions or suspensions, and in some cases intravenously in the form of sterile solutions. The free base i.nal products, while effective themselves, may be formulated and administered in a form of their pharmaceutically acceptable addition salts for purposes of stability, convenience or crystal-lization, increased solubility and the like.
The active compounds of the present invention maybe orally administered, for example, with an inert diluent or with an edible carrier, or they may be enclosed in gelatin capsules, or tney may be compressed into tablets. For the - 25 purpose of oral therapeutic administration, the active com-pounds of the inven~ion may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, che~ing gum and the like. These preparations should contain a~ least 0.5~ of active compound, .
, . ~, . _ ___ . . ... .. .. . .. . .
- l2 ~ 14ZO
but may ~e ~aried ~epending 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 com-positions is such that a suitable dosage will be obtained.
S Preferred composltions and preparations according to the present invention are prepared so that an oral dosage unit form 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 . 10 as microcrystalline cellulose, gum tragacanth or gelatin;
and excipient such as starch or lactose, a disintegra~ing.
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 ~lavoring.
~en the dosage unit form is a capsule, i.t may contain, in addi.~ .
~ion to ~aterials of the above type, a liquid carrier such as a fatty oil. Other dosage unit forms may contain other various materials ~hich 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 and colorings and flavors. Materials used in preparing these various com-positions should be pharmaceutically pure and non-toxic in the amounts used.
.
- 13 - ¦10 ~ 4 20 For the purpose o~ paren1eral therapeutic administration - the active compounds of the invention may be incorporated into a solution or suspension. These preparations should contain at least 0. l~/o of active compo~md, but may be varied to be between 0.5 and about 30% of the ~eight thereof. The amount of active compound in such compositions is sùch that a suitable dosage ~Jill 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 ~ollowing components: a sterile diluent such as water for in-jection, 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 ethylenediaminetetraacetic acid; buffers such as ~cetates,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 .ials made of glass or pIastic.
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Examl~ 1 e A mixture of 1.6 g of 10,11-dihydro-10-hydroxydibet-z-lb,f]oxepin, 2.2 g o~ ~-dimethylaminoethylthiol hydrochloride and 4 ml of boron trifluoride etherate in 8 ml of glacial acetic acid which ~as permitted to stand at ambient tem?erature for 64 hours is added dropwise to a stirring, cold 20C/o sodium hydroxide solution. The liberated amine is extracted into ether, washed successively with sodium hydroxide and a saturated sodium chloride solution and dried. The e~her is removed under ~ 10 reduced pressure leaving a thick oil which is dissolved in ,~ .
acetone and converted to its crystalline oxa].ate. The salt is recrystalli~ed from a methanol-acetone mixture leaving color-less crystals, mp 163-169C, o~ 10,11-dihydro-10-[~.-(dimethyl-amino)ethylthio]dibenz E b,f]oxepin o~alate.
Analysis:
Calculated for C18H21r~0S C2H24 Foun~: 61.50~C; 6.01%H; 3.54%N; 8.38%S.
~xample 2 .
A solution of 2.5 g of 10,11-dihydro-10-hydroxydibenz-[b,f]oxepin, 4.01 g of ~-diethylaminoethylthiol hydrochloride, 8:ml of boron trlfluoride etherate in 13 ml of ~lacial acetic acid which was permitted to stand for 48 hours is concentrated and then poured into a cold 25% sodium hy~lroxide solution. The resulting oi.l is extracted into ether. ~he ether extracts are combined, and washed successively ~Jith dilute sodium hydroxide and water, and then dried. The dried solution is filtered and - the filtrate evaporated to dryness leaving an oil. The oil is .
.
.' ~ ' .
- 15 - 1 1~ 14 2 0 stirred witl~ a 40% sodium hydroxide s~lution and then extrac~ed into cther and dried. The ethereal solution is filtered, and the ether removed leaving another oil which is chromatographed through a silica gel column ~7ith a 20%
methanol in chloroform eluant. The chromatographed product is converted to its oxalate, the white salt, mp 109-111C, of 10-[~ -(diethylamino)ethylthio~-10,11-dihydrodibenz[b,f]-- oxepin oxalate.
Analysis: -,.-~ ..
~ .
Calculated for C20H24NOS C2H2O4 6~44~oC; 6 29V/~ll; 3 36-N-Found: 63~54/~C; 6~57/li; 3~23%1~1~
.
Example 3 A solution of 0.55 g of 10,11-dihydro-10-[~-(dimethylamino~ethylthio~dibenz[b,f]oxepin, free base of ~xample 1, in 10 ml of chloroform is ad{led dropwise to a solution of 0.28 g of cyanogen bromide ~nd 0.6 g of potassium carbonate in 5 ml of chloroform. After total addition the re-action mixture is permitted to stand fo~ 10 minutes and then filtered. The filtrate is concentrated to dryness leaving 2 thick oil~ich crystallizes upor.standin~. T~ cryst~lline mass - is recrystallized from 10~J boiling petroleum ether to give colorless needles, mp 77-78C, of 10-(~-bromoethylthio~10,11-dihydrodibenz[b,f]oxepin.
Analysis:
Calculated or C16H15BrOS: 57.32~/oC, 4.51%H; 23.84%Br.
- ~ - Found: 57.58~/oC; 4.5~ H; 24.20%Br.
. ', ~ .
~ 16 ~ 420 ~xaml~le 4 A mixture of 1.5 g o~ 10-(~-bromoethylt.hio)-10,11-dihydrodibenz[b,f]o,cepin, Example 3, 0.5 g of N-methylpipera~ine, l.0 g of sodium bicarbonate, 1.0 g of potassium iodide in lS ml of dimethylformamide is stirred at 80C for 16 hours. The ~ixture is permitted ~o cool before bein~ diluted ~ith water. The biphasic mixture is extracted thrice with 100 ml portions of ether. the ether extracts combined and shaken vigorously ~ith a large excess of 2N hydrochloride acid. The acidic solution is basified to liberate the free amlne. The amine is extracted into benzene, the benzene solution dried and the benzene removed - under vacuun~ leaving a pale yello~ish oil. The oil is dis~
solved in ether an~ converted to a crystalline dihydrobromide which is recrystallized from a methanol-acetone mixture to give white needles, mp 180-182.5C, of 10,11-dihydro-10-[B-(4-met}lylDiperazin-l-yl)ethyl~hio]dlbenz[blf]oxepin di-hydrobromide.
Analysis:
', Calculated for C21H21N2OS 21~Br: 48.84%Ci 5-46'~H; 5-42%11-Found: 48.g3%C; 5.66%H; 5.29%1d.
~:xample 5 A mixture of 1.5 g of 10-(~-bromoethylthio)-10,11-dihydrodibenz[b,f]oxepin, ~xample 3, O.S g of morpholine, 1.0 g of sodium bicarbonate and 1.0 g of potassium iodide in lS ml of dimcthylformamide is s~irred at 60-70C for 64 hours.
.. . .
___.,.. _.. ,.. _ - 17 ~ 1420 The reaction mixture is permi.tted to cool before being diluted ~.Jith ~ater. The biphasic mixture is extracted with ether and the combined ether extracts are shaken ~ith a larg~.
excess of 2N hydrochloric acid. The acid solution is basified witl~ potassium carbonate liberating the amine as an oi]. which is ~xtracted into ether. The ethereal solution is dried and the ether is removed under vacuum regeneratin~ an oil which is converted to i~s oxalate. The salt is recrystallized from a methanol-acetone-ether mixture to give co].orless plates, mp ,.
196-198C of 10,11-dihydro-10-(~-morpholinoethylthio)dibenz-[b,f]oxepin oxalate.
Analysis:
Calculated for C20H231lO2S C2~I2. 4 Found: 60.77%C; 5.88%l-l; 3.20%N.
E.xample 6 A sample of 3.8g of 2.-chloro-10,11-dihydro-11-hydroxydibenz[b,f~oxepin is treated with 3.3g of ~-dimethyl-aminoethylthiol hydrochloride in a manner consistent ~Jith the procedure of Example 1, to provide granular crystals, mp 139-141C of 2-chloro-10,11-dihydro~ [~-(dimethylamillo)-ethylthio]-dibenzlb,f]oxePin oxalate.
Analysis:
Calculated for C18H28ClMOS-C2~1~04: 56.66%C; 5.23%H; 3.31%~1.
Found: 56.58%C; 5.27%H; 3.31C/~
.. . _ ., _.,. _ . ,_ .. .. ~. _ _ . .. . ... .. _ . ,.. _ ... _ . . . .
~ 13 ~ 20 Example 7 ~ solution of 2.0 g of 10,11-dihydro-10--oxodibenz-[b,f]oxepin, ?..96 ~ of y-dimethylaminopropylthiol hydro-chloride and ~ ml of boron trifluoride etherate in 8 ml of glacia]. acetic acid which was permitted to stand for 16 hours is refluxed on a stream bath for 30 minutes, cooled and poured into a 6~1sodium hydroxide solution. The reactioa~ ture is extracted with ether and the combined ether extracts are washed successively ~ith a 25% sodium hydroxide solution and water and dried.
The dried solution is filtered and the filtrate concentrated ' leaving an oil. The oil is chromatographed through a silic~
gel column with an eluant of 10C/~ methanol in chloroform. The chromatographed oil is converted to its oxalic acid salt, mp 151-152C, which is 10-[y-~dimethylamino)propylthio]-dibenz[b,f]oxepin oxalate.
Analysis:
Calculated for ClgH21NOS C2H2O4: 62.82%C; 5.77C/uH; 3.49C/~N.
Found: 62.71%C; 5.7~a/OH; 3~43V/
Example 8 A miY~ture of 1.2 g of lO,ll-dihydro-10-oxodibenz-tb,f]oxepin, 2.l~ g of ~-dimethylaminoethylthiol hydrochloride and 2 ml of boron trifluoride etherate in 10 ml of glacial acetic acid which was stirred at ambient temperature for 16 hours is warmed on a steam bath for 30 minutes. The warm mixture is poured onto 200 g of ice-water and the diluted mixture basified with a 40% sodium hydroxide solution liberating an oil which is dissolved ln ether. The ether solution is , - 19 ~ zo d~ied and concentrated leaving a thick oil which is converted in ether to a crystalline oxaiic acid salt.
The salt is recrystallized from a methanol-ether mixture to give granules, 147-148C of 10-[~-(dimethylamino)-- 5 ethylthio]dibenæ~b,f]oxepin oxalate.
Analysis:
Calculated for C18HlgNOS-C2H204: 62.00~/~; 5.~:6/~1; 3.61%II; 8.28C/~S.
Found: 61.88~/2C; 5.46%H;3.55%~; 8.22%S.
Examp]e 9 To a stirrin~ solu~ion o 0.36 g o cyanogen bromlde, 2.28 g of potassium carbonate in 10 ml of chloroform is added dropwise a solution of 1.0 g of 10-[~-(dimethylamino)ethylthio]-dibenz[b,f]oxepin, Example 8, in chloroform. After total addition the reaction mixture is refluxed for 2 hours and the solvent removed leaving an oil. The oil is dissolved in 10 ml of methanol and the methanolic solution refluxed for 10 mi.nutes and again concentrated to recover the oil. The oil is chroma-tographed through a silica ~,el column with an eluant of ether.
The top fraction is collected and concentrated leaving a white solid, mp 106-107C of lO- [~-(bromo)ethylthlo~dibenz[b,f]oxepin.
Analysis:
Calculated for C16H13BrOS: 57.66%C; 3.93%H; 9.62%S; 23.98~/,Br.
Found: 58.38%C; 3. 89~ 1; 9.34%S; 24.12%Br.
. . ~ .
- 20 - 11~1~20 Example 10 To a stirring solution of d. 36 g of cyanogen bromide, 2.28 g of potassium carbonate in lO ml of chloroform is added dropwise a solution of 1.0 g of lO-[~-(dimethylami.no)~
ethylthio]dibenzEb,f~oxepin, Example &, in 20 ml of chloroform.
After total addition the reaction mixture is treated according to Example 9. Following column chromato~raphy the middle fraction is collected and concentrated leaving the whlte product, mp 54-56 DC, ol~ 10-[,B-(N-Cyano-N-methylamino)el~hylthio]-dibenz[b,f]oxepin.
~ - .
:Analysis:
ted ~or C1~16N2CS: 70.10%C; 5.23/.H.
Found: 69.99%C; 5.28%H.
~11 A solution of 2.0 g of 10,11-dihydro-lO-oxodibenz-lb,f]oxepin, 3.76 g of ~- diisopropylaminoethy~thiol hydro-chloride, and 8 ml of boron trifluoride etherate in ].0 ml of glacial acetic acid is treated according to Example 7 to pro-duce a yellow oil. The oil is chro~atographed through a silica 20 gel column with an eluant of 5% methanol in chloroform. The chromatographed oil soli.difie.s upon scratching to a pale ye].low powder, mp 65-66C, of 10-[~-(diisopropylamino)ethylthio]-dibenz[b,f]oxepin.
Analysis:
.25 C~lculated for C22H27NOS: 74.74%C; 7.70%H; 3.96%~.
Found: 74.95%C; 7.71%H; 4.06%N.
- 21 ~ 1420 .. Example 12 A mixture of 1.14 g of 10~ (bromo)ethylthio]-dibenz~b,f3oXepin, Example 9, 0.36 g of morpholine, 0.92 g of sodium bicarbonate and 0.93 ~ of potassium iodide in ].5 ml of dimethylformamide is stirred for 16 hours while main-taining the mixture between 60 and 65C. Thereafter the mixture is poured into 150 ml of water, the biphasic mixture extracted with ether and the ether extracts combined and dried. The dried ether solution is filtered and the filtrate lO concentrated leaving an oil which is chromatographed through a silica gel column with an eluant of 5% methanol in chloroform.
The chromatographed oil is converted to its white oxalic acid . .
salt, mp 181-183C, of lO-[ ~tmorpholino)ethylt}lio~dihe;lz-[b,f]oxepin oxalate.
.
Analysis:
Calculated for C20H2lNO~S C2~2 4 Found: 61.33%C; 5.35%H; 3.34','N.
. . .
Example 13 To a sti.rred solution of 2.08 g of 10-[~-(di.methyl-amino)ethylthio]dibenz[b,f~oxepin, free base of Example 8, in 10 ml of methylene chloride is added dropwise ~ solution of 1.26 g of phenyl chloroformate in 10 ml of methylene chloride.
After total addition the reaction mixture is permitted to stir at ambient temperature for 16 hours and then concen~rated leaving an oily residue. The residue is triturated ~ith hexane and then chllled at -20C F ~fect a solid. The solid is .
.
- 22 - 11~20 recrystallized from an ether-hexane mixture to gi.ve ~hite needles, mp 103-103.5C, of 10-[~-(N-methyl-ll-phenoxy-carbonyl)aminCethylthio]dibenz[b~f]oxepin.
Analysis:
Calculated for C24H21NO3S: 71.42/,C; 5.24~1~H; 3.47%N.
Found: 71.37%C; 5.31C/~H; 3 51%N.
Example 14 A stirring suspension of 1.6 g of 10-[~ -methyl-N-phenoxycarbonylamino)ethyl~hio~dibenz[b,f}oxepin, ~xample 13, and 3.4 g of potassium hydroxide pellets in 40 ml of ethylene glycol is heated to between 150 and 160C over a 60 minu~e span. Sti.rring is continued at this temperature for an additional 30 minutes. The mixture is cooled, diluted ~ith water and the biphasic mixture extracted with an excess of ether. The ether extracts are combined, washed with ~a~er and dried and the solvent removed leavin~ a clear, mobi.le oil.
The oil is converted to its oxalic acid salt and recrys~alli.zed from methanol to give shiny needles, mp 207-208C(dec), of 10-~(methylamino)ethylthio]dibenz[b,f]oxepin oxalate.
Analysis:
. .
Calculated for C17H17NS C2~12~4 Found: 60.8S7,C; 5.14%H, 3.78';'~.
Example 15 A mixture of 1.82 g of : 10-[~-~me~hylamino)-ethylthlo]dibenz[b,f]oxepill, free base of Example 14, 0.72 g of cyclopropylmetltyl chloride~ 1.93 g of sodium bica~bonate .
, - 23 ~ 20 - and a few crystals o potassium iodide in 50 ml of dillletllylformamide is stirred at 80C for 16 hours. The reaction mixture is permitted to cool and filtered and the ~iltrate concentrated leaving an oil which is converted to ttle oxalic acid salt,mp 137-139C., of 10-[~-(M-cyclopropyl-~ethyl-N-methylamino)eLhylthio~dibenz[b,f]oxepin oxaiate.
Analysis: ~
Calculated for C21H23NOS C2H204. 64.61%C; 5.89~H; 3.2g%N
Found: 64.80%C; 5.96/u~l; 3.24%N.
rxample 16 A mi~ture of l.S g of 10 [~-(methy].~mino)-ethylthio]di~enz[b,f]oxepin, free base of Example 14, 1.1 g of ethyl iodide, 1.48 g of sodium ~icarbonate and 1.46 g of potassium iodide in 20 ml of dimethylformamide is stirred at 80-85~C for 16 hours. The reaction miY~ture is permltted to cool and diluted with 75 ml of water and then extracted thrice with 75 ml portions of ether. The ether extracts are combined, washed with 75 ml of a saturated sodium chloride solution and then dried. The dried solution is filtered and the filtrate concentrated leaving an oil. The oil is chroma-tographed through an alumina column with an eluant o ether.
The chromatographed oil is converted to its oxalic acid salt which is recrystallized from an acetone-ether nixture to gi~e the white product, mp 126-128~C, of 10-[B~ -e~hyl-ll-methyl-amino)ethylthio]dibenz[b,f]oxepin oxalate.
Analysis:
Calculated for ClgH2lNOS C2H204: 62.82r,~C; 5.77r/'H; 3.4g%N.
Found: 62.39%C; 5.69%H; 3.56%N
_ - 24 - ~ zo Example 17 The substitution of propargyl bromide for ethy].
i.odide into the procedure of ~xample 16 provides the ~Jhite solid, mp 140-142C, of 10-[~-(N-methyl-~-propargyl)-aminoethylthio]dibenz[b,f]oxepin oxalate.
Analysis:
Calculated for C20H19MS C2~24 64-21/~C; 5-Found: 64.49~; 5.22%1~; 3.41%N.
~ .
E_ample 1~
To a mixture at a temperature OI O C of 2.~ g of ~-diethylaminoethylthiol hydrochloride in 5 m]. of acetic acid and S ml of boron trifluoride etherate is added drop-wise a solution of 2.0 g of 2-chloro-10,11-dihydro-11~
hydroxydiben?.[b,f]oxepin in 6 ml of ~lacial acetic acid.
After total addition the reaction mixture at 0 C is stirred for 20 minutes and thereafter at ambient temperature or 16 hours. The well stirred mixture is added slow to 50 ml of a 20% sodiul~ hydroxide solution at 0 C. After this addition ether is added and the biphasic mixture filtered and permitted to form separate layers. The aqueous layer is extracted twice with 50 ml portions of ether and the e~her extracts com-bined with the organic (ethereal) phase. The combined solutions are washed successively with one portion each of 40 ml of 20%
sodium hydroxide solution, 30 ml of 10% sodiu~ hydroxide, SO ml of water and 30 ml of a saturated sodium chloride solution and then dried over potassium carbonate and potassium hydroxidc ' ,' , ~ .
- pellets ].eavin~ an oil. The oil is chrornatographe~ through a silica gel column with a 5~,~ methanol chloroforrn mixture to obta~n a purified oil ~7hich is disso].ved in ether and treated with an ethereal oxalic acid solution to obtain ~he correspond-ing oxalic acid salt which is recrystallized frorn acetone to give a white powder, mp 1~6.5-128.5C, of 2-chloro-ll-[,B(diethylami.no)ethylthio]-10,11-dihydrodibenz[b,f]oxepin oxalate.
~nalysis: , Calculated for C20H23ClMOS C2H2~ 58-60%C; 5.59%~i; 3.11%~l;
7.~6%Cl.
Found: . 58.68%C; 5.7~%II; 2.95%I~I;
- . ~.27~Cl.
' Example 19 To a stirred solution of ~.. 5 g of 10,11-dih~dro-10-hydroxydibenz[b,fJoxepin, 3.7 g oE y dimethylaminopropylthio h~drochloride in 13 ml of glacial acetic acid ~re added ~ ml of boron trifluoride etherate. The reaction mixture is pe~itted to s~and for 2~ hours before being poured into 50 m]. of a chilled 25% sodium hydroxide solution. The basic mix~ure is extrac,,ed with ether, the ether extracts combined ~hich are was,hed succ,essively with a 20% sodium hyclroxide solu~ion and water, dried and filtered and the filtrate evaporated leaving an oil. The oil is chromatographed through a silica gel column with a 5% me~hanol in chloroform eluant an~ thc eluate is - 26 - ~ zo evaporated leavin~, a purified oil which is converted t:o a white ~,ranular oxalic acid sal " mp 179-181C, of 10,-~ dihydro-10-[~-(dimethylamino)p~opylthio]dibenz[~,f]oxe~in.
Analysis:
Calculated for ClgH22~0S C2~20~
Found: 62.60C/~C; 6.26%H; 3.64%N.
~xample 20 A mixture of 1.5 g of 10-[~-bromoethyl)thio]-, 10,11-dihydrodibenz[b,f]oxepin, Example 3, and 1.0 g of potassium iodide in 15 ml of dimethylformami.de is bubbled for five minutes with ethylamine. The reaction mixture is per-mitted to cool to ambient temperature and then stirred for ]6 hours. Ice-water is added and the biphasic rnixture is extracted thrice with ben~ene and the combined ~en~e~le extrac~s are dried audevaporated to dryness leaving a crude l?roduct ~hich is con-verted in acetone to it:s oxalic acid salt. The sal.t is re-crystallized from 90% ethanol to give cvlorless prisms, mp 205-207C, dec, of 10-[~ -(ethylamino)e~hylthio]-10,].1-dlhydro-, debenz~b,f~oxepin oxalate.
.
~nalysis:
Calculated for C]~T21~0S C2ll204: 61.67~J; 5.95%1~; 3.60%1~.
61.68~/~; 5.97%~1; 3.39%N.
Found:
EY.amp].e 21 To a solution of 2.5 g of 10,11-dihydro-2-methylthio-ll-oxodibenz[b,f]oxepin, 2.8~of ~-dimethyl-aminoethylthiol hydrochloride and 24 ml of glacial acetic scid 27 ~ 1420 which was s~irred at am~ient ~emperature for 30 minutes is added,with additional stirring,8 ml of boron trifluoride etherate. After total addition,stirring is discontinued and the reaction mixture is permitted to stand for 72 hour5 before bein~
added to 50 ml of ice-water. The diluted mixture is rnade strongly alkaline with a 10% sodium hydroxide solution and the strongly alkaline mixture is extracted ~ith ether. The combined ether extracts are dried and evaporated ~o dryness leaving an oil. The oil is chromatograplled through a silica gel column with a 5% methanol in chloroorm eluant and the desired fractions were collected and concentrated leaving a purifi.ed oil. The oil was converted to a white granular oxalic acid salt of ll-[~-(dimethylamino)e~hylthio~2~methylthio-dibenz[b,f]oxepin oxalate.
Analysis: -Calculated for C19}121NOS2 C2H24 5~ ;
~otl~lcl: 57.99/~C; 5. 26D/~H;
xample 22 To a solution of 1.0 g of 2-fluoro-10,11-clihydl:o~
ll-oxodibenzrb,f]oxepin and 1.2 g of dimethylaminoethanthiol hydrochloride in 11 ml of glacial acetic acid is added 3.3 ml of boron trifluoride etherate. After total addition the reaction mixture is stirred at ambient te~lperature ~or 6~ hours and them poured into 25 ml of solution at 0C of 20% sodium hydroxide and the aqueous mixture extract~d ~Jith ether. The combined ether extracts are ~7ashed successively with two porti.ons of 20% sodiu~ hydroxide, one portion of water and one portion of .
.
.
, ' - 23,-ZO
a saturated sodium chloride solution and then dried to give an oil. The oil is chromatographed through a si].ica gel column wit:h a 5~/J methanol in chloroform solution to give a purified oil which is treated with ethereal hydrogen S bromide solution efecting ~ white precipitate. The pre-cipitate is washed with ether and recrystallized from acetone to give a white powder, mp 197-198.5C of 2-fluoro-ll-[~-(dimethylamino)ethylthio]dibellz[b,f]oxepin hy~ro-bromide.
Analysis:
Calculated for C18H17F~OS H~r: 54.55%C; 4. ~3C/"H; 3 5~CioM; 20 . ].7/OBr~
Found: ' 54.49%C; 4,30C~ ; 3.50~ 1; 20,1~%Br.
The 2-fluoro-10,11-dihydro-11-oxodibellz[b,f]oxepin, starting material for Example 22, can be prepared by the following se~uence of reactions:
a. l'o 147 g of iodobenzoic acid and 45.5 g of votassium carbonate are added 57 ml of nitroben~ene. The mixture is heated with stirring at 160C for 40 minutes. To the heated ~lixture is added an additionai 46.5 g o~ potassium carbona~e and then successively 73.1 g of 4-fl.uorophenol, anot~her (~6.5 g of potassium carbonate and 0.3 g of copper powder. After these additions, the mixture is stirred at 160~C for 45 minutes and the result,ing solid is cooled to 0~C. The cooled solid is mixed with 100 ml of water and 220 ml of 6M hydrochloric acid. The acidic mix-ture is diluted with water to a volume of one liter and then mixed with 450 ml of chloroform. The white soli.d is filtered - 29 11~14Z~
o~f and washed tlitll chloroform and ~ater. The solid is dissolved in hot acetone cooled and filered to leave a white crystalline product mp 1~ 147C of 2-(4-fluoro-phenoxy)bcnzoic acid.
b. To 3.28 g of 2-(4-fluorophenoxy)benzoic acid is added 5.6 ml of 97% thionyl chloride. The reaction mixture is heated on a steam bath for 10 minutes and any excess thionyl chloride is then removed under reduced pressure. The residual liquid is dissolved in 30 m]. of 1 2~dichloroethane and added dropwise over a 30 minute span to a ~ixture of 1.9 g of aluminum chloride in 5 ml of 1 2-dichloroethane. -After total addition the reaction.mixture is stirred at re~lux for 2 hours and allowed to s~ancl at ambient temperature ~or 64 hours. Thc mix~ure is poured on~o i5 a mixture of 150 ml of ice and water and 125 ml of ether. The biphasic n~ixture is filtered through paper and separate~. The aqueous layer is collected and extracted twice wiLh two portions (50 Inl) of ether. The combined ether extracts are ~ashec~
successively with two 25 ml portions o~ a sa~urated sodium bicarbonate soltuion and one 25 ml portion of saturated sodium chloride solution and then dried to give an oil. The oil is treated with hexane and the resulting solution clecanted off and evaporated leaving a bright yellow crystalline solid. The solid is chromotographed ~hrough a silica-ge] column with a chloroform eluant and is recrystallized from cyclohexalle to ~ive a yello~ hite.crystalline so]id mp 85.5-87.5C of 2-fluoro-10,].1 dihydro-ll oxodibenztb ~]oxepin.
~he ~etones of which are starting materials of other examples may be prepared in a fashion similar to the procedure - outlined above.
zo Example 2_ To a solution which was stirred at amhient temperature for 30 minutes, 2.5 g of 2~chloro-10,]1-dihydro-ll-oxodibenz[b,f]oxepin, 2.9 g of ~-dimethylaminoethylthiol S hydrochloride in 25 ml of glacial acetic acid is added with continuous stirring 5 ml of boron trifluoride etherate.
After total addition the stirring is discontinued and the reaction mixture is permitted to stand or 24 hours. The re-action is basified with 10~/~ sodium hydroxide solution and extract~ed ~ith ether. The combined e~her extracts are dried and filtered and then the solvent removed leaving an oil.
The oil is chromatographed tlll-ough a silica gel column ~7ith a 5% methanol in chloroform eluant to obtain a purified oil which is converted to a white oxa]ic acid salt, mp 183-184C
of 2-chloro-11-[~-(dimethylamino)ethylthio]dibenz[b,f]oxepin oxalate.
~nalysis:
Calculated for C]8Hl8cll~os c2~l2o4 56.93%C; 4 78%H-Found: 56.67%C; 4.70%~1.
~xample 24 To a solution of 2.5 g of 10,11-dihydro-2-(methyl-thio)-ll-oxodibenz[b,fJoxepin, 3.33 g of ~-die~hylamino-ethylthiol hydrochloride and 24 ml of glacial acetic acid whicll was stirred for 30 minutes is added 8 ml of boron trifluoride etherate. After this addition the reaction mix-ture is permitted to stand for 72 hours bcfore its addition - 31 - 11~1420 to 50 ml of ice water. The diluted mixture is made strongly alkalinc with a 10% sodium hydroxide solution and then ex-tracted with ether. The combined ether extracts are dried, filtered and the ether evaporated off ],eaving a yello~i oil.
The oil is chromatographed through a silica gel in chloroform colu~n with an eluant of 5~/~ m.ethanol in chloroform to purify the oil which is converted to its hydrogen bromide acid sal~
hich is rec-rystallized fro~ acetone to give t'he salt, mp 184-186~C, of ll-[~-(dimethylamino)ethy].thio]-2-(methyltllio)-di~enz[b,f]oxepin hydrobromide.
, .
Analysis:
Calculated for C21}125NOS2-l~Br: 55.74%C; 5-79%H; 3-10%N-~ound: 55.83/,C; 5.85/,~1; 3.05%~.
Example 25 To a stirring solution of 11.3 g of ll~ (dimethyl-alllino)ethylthio]-2-(methylthio)dibenz[b,f]oxepill, free base of Example 21, and 10.0 g of potassium carbonate in 50 m] of ~ethylene chloride is added drop~ise a solution o~ 5.7 g of phenylchloroformate in 50 ml of methylene chloride. ~fter total addition the reaction mixture is stirred at,ambient temperature for 24 hours and then evaporated to dryness. The residue is trlturated with ether and the ethercal solution is sequentially washed successively with a 10% sodium hydroxide solution and ~ater, dried and filtered and the filtra~e evap-orated to dryness leaving a yellow oil. The oil is chromato-' graphed throu~h a silica gel column with a methylene chloride - 32- ~ 4;~0 eluant to obt~ain the pu~ ied orange oil of 11- [~ etl~yl-N-pheno~ycar~onylamino)ethylthio]-2~ ethyltllio)-dibenz[b,f]-oxepin.
~nalysis:
Calculated for C25H231~03S2: 66.79%C; 5.16%1~; 3.12C~N.
Foun~: 66.~41~/.C; ~.93C/,~; 3.06C/,Il.
Example 26 mixture of 8.3 g of ll-~ methyl-N-phenoxy-c~rbonyl)a~inoethylthio]-2-(methyl~hio)-dibenz[b,f]oxepin, Example 25, 190 ml of ethylene glycol C~dl6 ~ of potassium hydroxide is stirred at 155C for 30 minutes. The reaction mixture is cooled and then poured onto 500 ml of ice wa~er.
The biphasic mi~ture is extracted ~;~ith a 1:1 ether benzene ~ixture and the combi.ned extracts are washed with ~ater and dried. The c~ri.ed soiution is iltered and the filtrate evapo rated to dryness leaving an oil. The oil is converted ~o i~s maleic acid salt ~hich is recrys~al3.ized from ace~onc leaving the salt, mp 160-162C of ll-~-(methylamino)ethylthio~-2-(methylthio)dibenz[b,f]oxepin maleate.
Analysis:
Calculated for C18Hlg~OS2-C4H404 59.30%C; 5.20~ ; 3.1/l%N.
Found: 59.40~/~C; 5.23%H; 3.08C/~N.
Exa~ple 27 A reaction solution of 1.9 g of ll-[~-(methyl-amino)ethyltllio]-2-(methyltbio)dibenz[b,f]oxepin, free base , , .
33 ~ 4Z~
of Example 26, 1.2 g of ethyl iodide and 1.60 g of sodium bicarbonate in 25 ml of di~ethylforn.amide is stirred with heating for 72 hours. The solution is diluted wi~h 100 ml of water and the ~iphasic mixture extracted with eLher. The combined ether extracts are wa~hed ~ith ~ater, ~ried and then iltered and ~he filtrate evaporated to dryness leaving an oil. 'rhe oil is converted to a ~hite salt, mp 112-114C
of ll-[~-ethylmethylamino)ethylthio]-2-(me~hylthio)dibenz[b,f~-oxepin maleate.
Analysis:
for C20I~23NOS2-C4~404: 60.~6%C; 5.75C,/,~I; 2 96%~
Found: 6].11%C; 5.74%I~; 2.87%N.
Examples 28 and 29 By following the procedure of F.xample 25, 2-fluoro-ll-[~-(d~.~.ethylamino)ethylthi.o]dibcnz[b,f]oxepin, free base of Example 22, and 2-chloro-10,11-dihydro-11-[~-(dimethylamino~-ethy3.~.hio]dibenz~b,f]oxepin, free based of Example 6, are ~reated respectively to obtain 2-f].uoro-ll-[~ -methy]-~-pl~en carbonylami.no)ethylthio]dibenz[ D, f]oxepin, Example 28, and 2-chloro-11-[~ -methy]-Id-phenoxycarbonyl~mino)ethylthio~-dibenz[b,f]oxepin, Example 29.
Ana]ysis: [~xample 28]
Calculated for C24H20F~IO3S: 68.40%C; 4.78%1-l; 3.32%~; 4.51%F.
Found: 6S.25%C; 4.85C/vH; 3.28%~1; 4.80%F.
.
- 34 ~ 20 ~,xample 30 A reaction solution of 5.1 g of 2-fluoro-ll-[~-(M-methyl-N-phenoxycarbonylamino)ethylthio]dibenz[b,f]-oxepin and 10.6 g of potassium hydroxide in 125 ml of ethylene -glycol is stirred ~ith heating at fro~ 80 to 155C for 30 minutes and then at 155C for 30 minutes. Then the reaction is permitted to stand a~ 0C for 16 hours before being poured onto 350 ml of ice water. The biphasic mixture is extracted thrice ~7ith 125 ml portions of 1 1 e~her-benzene mixture.
The combined orgallic l~yers are washed successively with three portions of water and one portion of a saturated sodi~m chloride solution and then dried ].eaving a clear orange oil.
The oil is swirled with a 50 ml portion and 0.25 ml portion - of boiling hexane and decanted from any residue effecting a yellow oil. The oil is treated in ether ~ith ethereal maleic acid effecting a salt which is recrys~alli.zed from a methanol-acetone-ether mix~ure to give a white po-7der, mp 135.5--~36C, of 2-~luoro-11-[~-(methylamino)ethylthio]dibcnz[b,f]oxepin maleate.
' ' . .
Analysis: ~
Calculated for C17H16F~lOS C411404: 60.43~1~C; 4.83%H; 3.36%N; 4.5S%~.
Found: 60.42%C; 4.86~/~H; 3.26%N; 4.85%F.
.
- . Example 31 A reaction mixture of 4.0 g of 2-chloro-11-[~-(N-methyl-N-phenoxycarbonylamino)ethylthio~iben7.[b,f~0xepi.n, Example 29, and 8.5 g of po~assium-hydroxide in 80 ml of ethylene ~ ~ 35 ~ 1 1~ 14 ~0 glycol is s~irred at 155C for 30 minutes. The mixture is permitted to cool and ice is added. The mixture is extracted with ether and the combined ether extracts are dried and ~he ethe~ evaporated o~f leaving an oil.. The oil is ~reated in ether with ethereal maleic acid and the resulting salt recrystallized from a methanol-ether mixture to give colorless prisms, mp 153-]54C, of 2-chloro-11-[~-(methyl-amino)ethylthio]dibenz[b,f]oxepin maleate.
Analysis: -,.
Calculated for C17lll6Cl/lOS C4H404: 58.12~/.C; 4.64/,11; 3.22%~1; 8.17%C~
Found: 58.15%C; 4.77%H; 3.~4%i~; 8.33~/oCl Example 32 To a mixture of 1.1 g of ~-dimetllylaminoethanethiol hydrochloride and 2.8 ml of boron tri1uori.cle etllerate in 5 ml of glacial a.cetic acid is added dropwise a solution of 0.9 of 2~fluoro-10,11-dihydro-11-hydroxydibenz[b,f]oxepin in ~
ml of glacial ace~ic acid. After total addition the reaction mixture is permitted to stir for 16 hours before being poured onto a mixture of 30 ml of.a 20% sodium hydroxide solution and ice. The mixture is extracted with ether and the combined ether extracts are washed successively with two-portions of a 20% sodium hydroxide solution, one portion of wa~er and one portion of a saturated sodium chloride solution. The washed extracts are dried producin~ an oil which is chroma~ographed throu~h a silica gel column with an eluant of 5V/~ methanol in chlorofo-rm to obtain a purified oil.. The oil is converted - 36 ~ 20 to its o~alic acid sal~ which is recrystallized from acetone to ~ive a white po~der, mp 169-170.5~C, of 2-f].uoro-10>-ll-dihy~o-ll-[~-(dim~thylamino)ethylthio]dibenz[b,f]oxepi oxalate.
Analysis:
Calculated for C18~20F~S-C21124 Found: 59.17%C; 5.1~4%H. 3.51%~; 4.~1%F.
- ~xample 33 -. To a mixture of 2.3 g of cyanogen bromide and 5.0 g of potassium carbollate in 40 ml of chloroform is added portlon-wise over a 50 minutes span a solu~ion o~ 4.8 of 2-fluoro-10,-ll-dihy~-o~ [~-(dimethylamiIIo)ethylthlo]dibenz[b,f]oxepin, free base of Example 32, in 85 ml of ch~o]^oform. After total addition, the mixture is stirred for 20 minutes before being filtere~.
The filt~ate is evaporated to leave an oil which is treated with three portions of boiling hexane. The combined hexane portions are eva?orated leaving an oi.l ~hich is chromatographed throu~h a silica gel column ~ith an eluant of l~ethylene chloride and is recrystalli.zed from cold hexanc to ~ive a white powder, m~
46-48C of ll-~-(bromo)eth~lthio]-2-fluoro-10,11-dihvdrodibenz-[b,']oxe~in.
Analysis:
Calculated for C16H14BrFOS: 54.41C/~C; 4.00/~H; 22.63V~r; 5.3~%~.
Found: 54.36%C; ~Oi~/o~i; 22.91%Br; 5.69~.F.
~ 37 ~ 1;4z~
~xa~ le 34 Methylamine is bubbled into 10 ml of dimethylsulfoxide for 5 minutes. To this solution is added dropwise a SO].U~iOII
of 2.2 g of ll [B-(bromoethyl)thi~}2-fluoro-]-olll-dih~drodiben [b,f)oxepin in 11 ml of dimethylsul.fo~ide. Sufficient methyl-amine is bubbled into the reaction mixture to complete the reaction. Thereafter the reac,ion mix~ure is permitted to stand or 64 ilours. The reaction mixture is poured onto 125 rlll of ice ~ater, and the biphasic mixture is extracted with three portions of ether. The combined ether extracts are washed .
successively ~ith two ~0 ml portions of ~7ater and one 10 ml portion of saturated sodium chloride solu~ion and dried to produce an oil. The oil is dissoved in ether and treated with ethereal ma]elc acid ~hich precipita~.es a salt which is re-crystallized from an acetone-ether mixture to gi.ve a whi.te solid, mp 11~-119.5 C, of 2-fluoro-10,].1-dihydro-ll-[~-(methyl-amino)ethylthio]di.benz[b,f]oxepin maleate.
Analysis:
, ~"
C17~.18FNOS C4H404: 60.14%C; 5.29%H; 3 34%N; 4 53%F
Found: 60.11%C; 5.19%H; 3.19%N; ~.80'~F.
rxample 35 To a stirring solu~ion of 2.8 g of ~-dimethylamino-ethylthioi hydrochloride and 7 ml of boron trifluorine etherate in lO ml of glacial acetic acid is added dropwise a solution of 2.5 g of 10,11-dihydro-11-hydroxy-2-methylthiodiben~[b,f]--oxepin in 10 ml of glacial acetic acid. After to~al addition , .
': ~
~ 3g ~ ~ 20 the reaction mixture was permitted to stand for 2l~ hours before bein~ added to 50 ml of a cold 25% sodium hydroxide solution. The reaction mixture is extracted with ether and the combined ether eY~tracts are successively washed witll a 20% sodium hydroxide solution and water and~dried. The dried solution is ~iltered and the filtrate is e~Taporated to dr~ness leaving an oil ~;~hich is dissolved in chloroform. The chloroform solution is chromatographed through a silica gel column ~ith an - eluant of 5~ methanol in chloroform to obtain a purified oil.
The purified product lS conver~ed to its maleic acid salt, a white powder, mp 100-102C of 10,11-dihydro-11-[~-(dimethyl-amino)ethylthio]-2-(methylthio~dibenz[b,f]oxepin maleate.
Analysis:
. ClgH23NOS2-C4l-1404: 59.84%C,; 5.90%1I; 3 0~l%N
Found: 59.92%C; 5.93%H; 3.00%N.
; Example 36 By the procedure of Example 35, ~-diethylamino-ethylthiol hydrochloride is treated with 10,11-dihydro 11-hydroxy-2-1Ilethylthiodibenz[b,f]oxepill to obtain an oil of ll-[~-diethylamino)ethylthio] 10,11-dihydro-2 (me~hylthio)-~; dibenz[b,f]oxepin. The oil is chromatographed throu~h a silica gel methylene chloride column ~ith an eluant of a 5~/, me~hanol in methylene chloride to purify the oil. The purified oil is converted to its white oxalate salt, mp 118-120C.
Analysis:
' ~ Calculated for C21~12?NOS2 C2~124 Found: ~ 59.30%C; 6.32%11; 2.93%N.
.
. ' .
.
.. ~. ' . :
~ 39 11~420 Exam~le 37 A sample of 10,11-dihydro~ [R-(dimethylamino)-ethylthio]-2-(methylthio)di~enz[b,f]oxepin, free base of Example 35, is treated according to the procedure of Example 33, to obtain 11-(~-bromoethylthio)-10,11-dihydro-2-(methyl-thio)dibenz[b,f]oxepin. The oil is. dissolved in hexane and cooled in a dry/acetone bath to effect crystallization of the oil to a white solid, mp 64-66C.
Analysis: .
.~;~ ' .
Calculated for Cl7H17~rOS2: 53.54%C; ~.49%H; 20.9~%Br.
Found: 53.72%C; 4~47C/oH; 21.0~%Br.
Example 38 To a mi.xture of 2.0 g of 2-fluoro-11-[~-dimethyl-amino)ethylthio]dibenz[b,f]oxepin, free base of Example 22, in 62 ml of methanol are added 6.1 g of magnesium shavings. l'he reaction is stirred for 90 minutes with sufficient coolin~ to maintain the reaction at a~bient temperature. The methanolic 3 mixture is decanted off and then cooled. The cooled mixture is then treated with careful addition of 60 ml of 6N hydro-chloric acid. The acidi~ied mixture is permitted to reach ambient tcmperature before being diluted with 60 ml of water and the diluted mixture is extracted wi'~h chloroform. The combined chloroform extracts are successively washed wlth 80 ml of a 10% sodium hydroxide solution, 100 ml of water and 25 ml of saturated sodium chloride solution and dried to effect a yellow oil ~ The oil is extracted thrice with 30 ml portions of hot pentane . .
? . .
~ o 1~ 20 and the com~ined pentane extracts are e~aporated le~ving purer oil 17hich is treated in ether with ethereal ox~lic acid to precipitate out a salt. The salt is ~ashed well with .
ether leaving a white solid, mp 167-169G of 2-fluoro-10,-ll-dihydro-ll-~-(dimethylamino)ethylthio]dibenz[b,f]oxepin oxalate identical to the product described in r,xample 32.
- Example 39 A solution of 1.5 g of ll-[~-(bromo)etl~ylthio]-10,11-dihydro-2-(methylthio)diben7[b,f]oxepin, F,xample 37, ~ 10 and 0.9 g of potassium iodide in 15 ml of dimethylformamide is stirred a~ ambient temperature ~hile methylamine is bubbled into the solution over a 5 minut:e span. ~fter ~otal addition,the solution is permitted to stir for 16 hours before being successively poured into 100 mi of ice water, extrac.ed with benzene,and the combined benzene extracts dried. The dried solution is filtered and then evaporated to dryness leaving a yellow oil ~hich is converted to its maleic acid salt as a granular powder ~hich is recrystallized from a methanoi-e~her mixture to provide the product, mp 138-140~C, of 10,11-dihydro-ll-[~-(methylamino)ethylthio]-2-methyl-thiodibenz[b,f]oxepin maleate.
Analysis:
Calculated for C18H2ll~0S2 4 4 4 Found: 58.~3%C; 5.43%1-1; 2.90%M.
' .:
, Example 40 Into a solution of 2.6 g of 10~ bro~oethylthio)-10,11-dihydrodibenz~b,f]oxepirl, F.xample 3, in 15 ml of dimethyl-- formamide is bubbled methylamine over a 20 ~inu~e span. After tota~ addition the reaction m-ixture is permitted to stand at ambient temperature for 16 hours. Tllereafter, ice water is added and the biphasic mixture is extrac~ed thrice with ether and the combined ether extracts are ~ashed ~ith ~ater. The ethereal solution is dried and the resulting product is con-verted to its maleic acid salt. The salt is recrystal]ized froman acetone-ether mixture to provide prisms "np 102-104C
of 10,11-dihydro-10-[(~-methylamino)etllylthio]dibcnz[b,f]oxepin maleate.
Analysis:
'"" - ~ . .
Calculated for C17HlgNOS-C4H4O~: 62.82%C; 5.77%H; 3.49%M; 7.99%S.
Yound: 62.30~/,C; 5.77%~1; 3. 36~/oM; ~ . 1S%S .
le 41 A mixture of 2-chloro-10,11-dihydro-11 [~-(dimethyl~
amino)ethylthio]dibenz[b,f]oxepin, free base of Example 6, 0.7 g of cyanogen bromide, and 0.8 g of potassium carbonate in 20 ml of methylene chloride is stirred at ambient temperature or ~ hours. Thereafter the mixture is filtered and the filtrate concentrated under vacuum,leaving a viscous oil. The oil is chromatographed over silica gel, leaving a pale yellowish oil, Rf of 0.8, of 11-(~-bromoethylthio~2-chloro 10,11-dihydrodibenz-lb.f]oxepin.
. .
Analysis:
' '. ' .
.
.
,~ :
- ~2 - 1~420 Calc~llated ~or C16Hl~BrClOS: 51.98~/~C; 3.82C/oH; 8.67%S.
Found: 52.26/,C; 3.76/,EI; 8. 61~oS.
Example 42 Into a solution of 1.5 g of ll-[~-(bromo)ethyl~hio~-2-chloro-10,11-dihydrodibenz[b,f]oxepin, E~ample 41, in 20 ml of dimeth~lformamide is bubbled methylamine over a 10 - minute span. Thereafte~, the solution is permit~ed to stand at ambient temperature for 16 hours. Then the solutiorl is evaporated to dryness leaving a yellowish oily residue which is equilibrated with sodium bicarbonate and ether. The ethereal phase is collected and then dried before being concentrated under vacuum leaving a clear oil which is converted to a crystalline ~naleic acid salt. The.sal.t is recrys~allized fro~n an acetone-etller mixture to provide white prisms, mp 13~-140C
of 2-chloro-]0,11-dihydro-11-[~-(methylamino)ethylthio~dibenz-[b,f~oxepin ~aleate.
Analysis:
.~
Calculated ior C17H18ClNOS C4H404: 57.86%C; 5-09/~11; 3-21%M; ~ 13%Cl ~ound: 57.62%C; 5.00%~1; 3.0S%N; 8~33~/oCl Example 43 _ a. A solution of 28.4 g of 2-(4-methylsulfonyl-phenoxy)benzyl nitrile, 99 ml of 95% ethanol, 15.2 g of 85%
potassium hYdroxide and 25 ml of water is stirred at 115C
for 24 hours. Thereafter, the reaction mixture is concentrated to an oil. The oil is dissolved in water and the aqueous .
solution is washed with ether, acidified with dilute hydrochloric acid providing an oil. This oil is dissolved in methylene chloride and the solution, successively, is dried, filtered and concentrated to dryness leaving a light yellow solid. The solid is chromatographed through a silica ge]/ether column with a 10% methancl in ether eluant to provide the product 2-(4-methylsulfonylphenoxy)phenylacetic acid, mp 1~5-127C.
b. A mixture of 1.0 g of 2-(4-methylsulfonylphenoxy~-phenylacetic acid and lO ml of polyphosophoric acid under nitrogen is stirred at 90-100C for 2 hours. The reaction mixture is permitted to cool and then poured into 100 ml of an ice-water slurry. The aqueous solution is basified with 20% sodium hydroxide before being extracted with methylene chloride. 'rhe combined extracts are dried and then evaporated ~o dryness leaving an oil. The oil is chromatographed through a silica gel/methy]ene chloride column with 2% methanol in methylene chloride. The chromatographed solution is evapora~ed to dryness leaving an oil which solidifies on s~anding. The solid is triturated with pentane to provide 10,11-dihydro-2-methylsulfonyl-ll-oxodibenz[b,f]oxepin, mp 105-106~C.
c. A stirring solution of 4.4 g of 10,11-dihydro-2-methylsulfonyl-11-oxodibenz[b,f]oxepin, 4.3 g of dimethyl-aminoethylthlol hydrochloride and 37 ml of glacial acetic acid is treated with 15 ml of boron trifluoride etherate. Thereafter the reaction mixture is poured into 300 ml of a cold lOC,' - sodium hydroxide solution and the resulting solution is extracted witb methylello hlor de. The combined ~xtracts Ire washed w,th , - 44 ~ 1420 t~7ater and dried before being filtered. The filtrate is evapor-ated to d~yness leaving an oil which is chromatographed through silica gel/methylene chloride ~ith a 2-4C' meth~lol chloride - eluant. The chromatographed solution is evaporated to dryness and the resulting oil is converted to a white maleic acid salt, mp 137-139C of ll-[(~-dimethylamino)ethylthio]-2-methyl-- sulfonyldibenz[b,~]oxepln maleate.
Analysis:
or Cl9H21~13S2 C~ 44 56 19%C; 5.13%17; 2.85%1~
Found: 56 . ~4//oC; 5 . lSV/oH, 2 . 36~oN.
.
'
Claims (10)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a compound of the formula I
I
wherein X and Y are the same or different and each can be hydrogen, halogen, trifluoromethyl, C1-C6alkoxy, C1-C6alkyl, alkylthio, C1-C6alkylsulfonyl, C1-C6alkylsulfinyl, amino or nitro; Z is halogen or ; R1 is 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 , C1-C6-alkoxycarbonyl, C2-C6alkenyl or C2-C6alkynyl; R2 is straight or branched chain C1-C6alkyl or cycloalkylC1-C6-alkyl wherein the cycloalkyl ring contains from 3 to 6 carbon atoms; and when R1 and R2 are taken together with the nitrogen atom to which they are attached, the group R1-N-R2 forms a heterocycle which is morpholino, piperi-dino, pyrrolidinyl, piperazinyl or N-substituted pipera-zinyl in which the N-substituent is C1-C6alkyl; 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 above and R3 and R4 are different and each is hydrogen or hydroxy or R3 and R4 together are oxygen, is reacted with an aminoalkylthiol of the formula III
III
wherein n is as defined above and R1 and R2 are the same or different and each can be straight or branched chain C1-C6alkyl, in the presence of a catalyst/dehydrating agent and a solvent at a temperature of from about ambient to reflux, to produce a compound of the formula Ia Ia; or b) a compound of the formula Ia, wherein X, Y and n are as defined in the formula I, R1 and R2 are as defined above and m is the integer 1, is reduced to obtain a compound of the formula Ia wherein m is the integer 0, or c) 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, n and m are as defined in formula I and hal is halogen, and each of the two compounds is isolated, or d) a compound of the formula Ib is reacted in a known fashion with an appropriate non-cyclic amine to obtain the corresponding compound of the formula Ia Ia wherein X, Y, n and m are as defined in formula I and R1 is hydrogen, straight or branched chain loweralkyl, cyclo-alkylloweralkyl, loweralkenyl or loweralkynyl; R2 is straight or branched chain loweralkyl or cycloalkylloweralkyl; and when R1 and R2 are taken together with the nitrogen atom to which they are attached, the group R1-N-R2 forms a heterocycle which is piperazinyl, N-substituted piperazinyl in which the N-substituent is loweralkyl, morpholino, piperidino or pyrrolidinyl; or e) a compound of the formula Ia wherein X, Y, n and m are as defined in the formula I, and R1 and R2 are the same or different and each is a straight or branched chain C1-C6alkyl, is reacted with a C1-C6alkyl or phenyl chloroformate to obtain a compound of the formula Ia wherein X, Y, m and n are as defined in formula I, R1 is alkoxy- or phenoxycarbonyl and R2 is straight or branched chain C1-C6alkyl; or f) a compound of the formula Ia, wherein X, Y, m and n are as defined in the formula I, R1 is alkoxy- or phenoxy carbonyl and R2 is straight or branched chain C1-C6alkyl is reacted with a base 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 g) a compound of the formula Ia wherein X, Y, m and n are as defined in the formula I, R1 is hydrogen and R2 is a straight or branched chain C1-C6alkyl, is reacted with a straight or branched chain C1-C6alkyl halide, C2-C6alkenyl halide, C2-C6-alkynyl halide or cycloalkyl-C1-C6alkyl halide to obtain a compound of the formula Ia wherein X, Y, m and n are as defined in the formula I, R1 is a straight or branched chain C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl or cycloalkyl-C1-C6alkyl and R2 is as defined above; or h) a compound of the formula I wherein X, Y, Z, m and n are as defined above with the exception that X or Y or both must be nitro is reduced effecting conversion of the nitro group to an amino group.
I
wherein X and Y are the same or different and each can be hydrogen, halogen, trifluoromethyl, C1-C6alkoxy, C1-C6alkyl, alkylthio, C1-C6alkylsulfonyl, C1-C6alkylsulfinyl, amino or nitro; Z is halogen or ; R1 is 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 , C1-C6-alkoxycarbonyl, C2-C6alkenyl or C2-C6alkynyl; R2 is straight or branched chain C1-C6alkyl or cycloalkylC1-C6-alkyl wherein the cycloalkyl ring contains from 3 to 6 carbon atoms; and when R1 and R2 are taken together with the nitrogen atom to which they are attached, the group R1-N-R2 forms a heterocycle which is morpholino, piperi-dino, pyrrolidinyl, piperazinyl or N-substituted pipera-zinyl in which the N-substituent is C1-C6alkyl; 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 above and R3 and R4 are different and each is hydrogen or hydroxy or R3 and R4 together are oxygen, is reacted with an aminoalkylthiol of the formula III
III
wherein n is as defined above and R1 and R2 are the same or different and each can be straight or branched chain C1-C6alkyl, in the presence of a catalyst/dehydrating agent and a solvent at a temperature of from about ambient to reflux, to produce a compound of the formula Ia Ia; or b) a compound of the formula Ia, wherein X, Y and n are as defined in the formula I, R1 and R2 are as defined above and m is the integer 1, is reduced to obtain a compound of the formula Ia wherein m is the integer 0, or c) 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, n and m are as defined in formula I and hal is halogen, and each of the two compounds is isolated, or d) a compound of the formula Ib is reacted in a known fashion with an appropriate non-cyclic amine to obtain the corresponding compound of the formula Ia Ia wherein X, Y, n and m are as defined in formula I and R1 is hydrogen, straight or branched chain loweralkyl, cyclo-alkylloweralkyl, loweralkenyl or loweralkynyl; R2 is straight or branched chain loweralkyl or cycloalkylloweralkyl; and when R1 and R2 are taken together with the nitrogen atom to which they are attached, the group R1-N-R2 forms a heterocycle which is piperazinyl, N-substituted piperazinyl in which the N-substituent is loweralkyl, morpholino, piperidino or pyrrolidinyl; or e) a compound of the formula Ia wherein X, Y, n and m are as defined in the formula I, and R1 and R2 are the same or different and each is a straight or branched chain C1-C6alkyl, is reacted with a C1-C6alkyl or phenyl chloroformate to obtain a compound of the formula Ia wherein X, Y, m and n are as defined in formula I, R1 is alkoxy- or phenoxycarbonyl and R2 is straight or branched chain C1-C6alkyl; or f) a compound of the formula Ia, wherein X, Y, m and n are as defined in the formula I, R1 is alkoxy- or phenoxy carbonyl and R2 is straight or branched chain C1-C6alkyl is reacted with a base 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 g) a compound of the formula Ia wherein X, Y, m and n are as defined in the formula I, R1 is hydrogen and R2 is a straight or branched chain C1-C6alkyl, is reacted with a straight or branched chain C1-C6alkyl halide, C2-C6alkenyl halide, C2-C6-alkynyl halide or cycloalkyl-C1-C6alkyl halide to obtain a compound of the formula Ia wherein X, Y, m and n are as defined in the formula I, R1 is a straight or branched chain C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl or cycloalkyl-C1-C6alkyl and R2 is as defined above; or h) a compound of the formula I wherein X, Y, Z, m and n are as defined above with the exception that X or Y or both must be nitro is reduced effecting conversion of the nitro group to an amino group.
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-fluoro-11-[.beta.-(dimethylamino)ethylthio]dibenz[b,f]oxepin hydrobromide in which 2-fluoro-10,11-dihydro-11-oxodibenz[b,f]oxepin is reacted with dimethylaminoethanthiol hydrochloride in the presence of boron trifluoride etherate in glacial acetic acid, the product is isolated, treated with ethereal hydrogen bromide and the resultant product is subsequently isolated.
4. 2-Fluoro-11-[.beta.-(dimethylamino)ethylthio]dibenz[b,f]-oxepin hydrobromide, 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.(methylamino)-ethylthio]dibenz[b,f]oxepin oxalate in which 10,11-dihydro-10-oxodibenz[b,f]oxepin is reacted with .beta.-dimethylaminoethylthiol hydrochloride in the presence of boron trifluoride etherate in glacial acetic acid, the resultant 10-[.beta.-(dimethylamino)ethylthio dibenz[b,f]oxepin in methylene chloride is added to a solution of phenyl chloroformate in methylene chloride, the resultant 10-[.beta.-(N-methyl-N-phenoxycarbonylamino)ethylthio]dibenz[b,f]-oxepin is formed into a suspension with potassium hydroxide in ethylene glycol, the product is isolated, treated with oxalic acid and the resultant product is subsequently isolated.
6. 10-[.beta.(Methylamino)ethylthio]dibenz[b,f]oxepin oxalate 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 10,11-dihydro-10-[.beta.-(dimethylamino)ethylthio]dibenz[b,f]oxepin oxalate in which 10,11-dihydro-10-hydroxydibenz[b,f]oxepin is reacted with .beta.-dimethylaminoethylthiol hydrochloride in the presence of boron trifluoride etherate in glacial acetic acid, the product is isolated, treated with oxalic acid and the resultant product is subsequently isolated.
8. 10,11-Dihydro-10[.beta.-(dimethylamino)ethylthio]dibenz-[b,f]oxepin oxalate, 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 2-fluoro-10,11-dihydro-11-[.beta.-(dimethylamino)ethylthio]dibenz[b,f]oxepin oxalate in which 2-fluoro-10,11-dihydro-11-hydroxydibenz[b,f]oxepin is reacted with .beta.-dimethylaminoethanethiol hydrochloride in the presence of boron trifluoride etherate in glacial acetic acid, the product is subsequently isolated, treated with oxalic acid and the resultant product is subsequently isolated.
10. 2-Fluoro-10,11-dihydro-11-[.beta.-(dimethylamino)ethylthio]-dibenz[b,f]oxepin oxalate, whenever obtained according to a process as claimed in claim 9 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US86008377A | 1977-12-13 | 1977-12-13 | |
| US860,083 | 1977-12-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1101420A true CA1101420A (en) | 1981-05-19 |
Family
ID=25332451
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA317,773A Expired CA1101420A (en) | 1977-12-13 | 1978-12-12 | Aminoalkylthiodibenzoxepins and precursors therefor a method of preparing same and pharmaceutical and veterinary preparations including same |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0002508B1 (en) |
| JP (1) | JPS5495583A (en) |
| AT (1) | AT369738B (en) |
| AU (1) | AU520460B2 (en) |
| CA (1) | CA1101420A (en) |
| DE (1) | DE2861712D1 (en) |
| ES (7) | ES475770A1 (en) |
| ZA (1) | ZA786957B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4496582A (en) * | 1983-12-12 | 1985-01-29 | Hoechst-Roussel Pharmaceuticals Inc. | Analgesic dibenz[b,f]oxepins |
| EP0200132A3 (en) * | 1985-04-23 | 1987-08-26 | Hoechst-Roussel Pharmaceuticals Incorporated | (aminoalkylthio)hydroxydibenzoxepins, a process for their preparation and their use as medicaments |
| WO2008096755A1 (en) * | 2007-02-07 | 2008-08-14 | Nippon Suisan Kaisha, Ltd. | Vanilloid receptor (vr1) inhibitor and use thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH509306A (en) * | 1969-02-14 | 1971-06-30 | Fujisawa Pharmaceutical Co | Tricyclic enol-ethers psychotropic neurotropic |
-
1978
- 1978-12-06 ES ES475770A patent/ES475770A1/en not_active Expired
- 1978-12-08 DE DE7878101618T patent/DE2861712D1/en not_active Expired
- 1978-12-08 EP EP78101618A patent/EP0002508B1/en not_active Expired
- 1978-12-12 ZA ZA00786957A patent/ZA786957B/en unknown
- 1978-12-12 AU AU42421/78A patent/AU520460B2/en not_active Expired
- 1978-12-12 CA CA317,773A patent/CA1101420A/en not_active Expired
- 1978-12-12 AT AT0883978A patent/AT369738B/en not_active IP Right Cessation
- 1978-12-13 JP JP15908978A patent/JPS5495583A/en active Granted
-
1979
- 1979-06-01 ES ES481212A patent/ES481212A0/en active Granted
- 1979-06-01 ES ES481210A patent/ES481210A1/en not_active Expired
- 1979-06-01 ES ES481213A patent/ES481213A0/en active Granted
- 1979-06-01 ES ES481214A patent/ES481214A1/en not_active Expired
- 1979-06-01 ES ES481209A patent/ES481209A1/en not_active Expired
- 1979-06-01 ES ES481211A patent/ES481211A1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| ES8102117A1 (en) | 1980-12-16 |
| EP0002508A1 (en) | 1979-06-27 |
| ES8102116A1 (en) | 1980-12-16 |
| DE2861712D1 (en) | 1982-05-06 |
| ES481211A1 (en) | 1980-09-01 |
| AU4242178A (en) | 1979-06-21 |
| EP0002508B1 (en) | 1982-03-31 |
| ES481213A0 (en) | 1980-12-16 |
| AT369738B (en) | 1983-01-25 |
| ES481214A1 (en) | 1980-09-01 |
| ATA883978A (en) | 1982-06-15 |
| AU520460B2 (en) | 1982-02-04 |
| ES481209A1 (en) | 1980-09-01 |
| JPS5495583A (en) | 1979-07-28 |
| ES475770A1 (en) | 1980-01-16 |
| ZA786957B (en) | 1979-11-28 |
| ES481212A0 (en) | 1980-12-16 |
| ES481210A1 (en) | 1980-09-01 |
| JPS6411632B2 (en) | 1989-02-27 |
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| MKEX | Expiry |