CA1119592A - Chlorinated tetrahydro-2-benzazepines, n-methyl transferase inhibitors - Google Patents
Chlorinated tetrahydro-2-benzazepines, n-methyl transferase inhibitorsInfo
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- CA1119592A CA1119592A CA000306684A CA306684A CA1119592A CA 1119592 A CA1119592 A CA 1119592A CA 000306684 A CA000306684 A CA 000306684A CA 306684 A CA306684 A CA 306684A CA 1119592 A CA1119592 A CA 1119592A
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- benzazepine
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Abstract
Abstract of the Disclosure This invention provides a series of novel chloro-and dichlorotetrahydro-1H-2-benzazepines which are useful as inhibitors of norepinephrine N-methyl transferase.
Description
~llg592 This inventlon provides a series of novel chloro-and dichlorotetrahydro-lH-2-benzazepines which are useful as inhibitors of norepinephrine N-methyl transferase.
Tetrahydro-2-benzazepines and tetrahydro-3-benzazepines are both known in the art. von Braun and Zobel, Ber. _, 69G, (1923) prepared both compounds as did Deady, et al., J.C.S., Perkin Trans 782 (1973) by a different route. In addition, Deady et al (loc. cit.) prepared the previously unreported 7-methyl derivative of tetrahydro-lH-2-benzazepine as well as 7-chlorotetrahydro-lH-2-benzazepine. No utility was given for any of these products.
According to Kasparek, writing in Advances in Heterocyclic Chemistry, Vol. 17, pp. 45 _ ~. (Katritzky and Boulton, ed., Academic Press, 1974), 2-benzazepines have been tested as anti-hypertensives, adrenergic blockers, and cholinesterase inhibitors. 3-Benzazepines have been tested as hypoglycemics, analgesics, depressants, anorectics, and ganglionic blocking agents. l-Benzazepines have also been found to have analgesic, antidepressant, anti-fibrillant, hypotensive, anti-neoplastic, diuretic, hypoglycemic, and anti-arrhythmic activities. N-Substituted tetrahydro-2-benzazepines have been prepared [see for example, Chemical Abstracts 74, 53575a (1971); 72, 66776a (1970); and 68, 59453g (1968)]. ~elleau prepared N-(~-chloroethyl)-2-benzazepine as an adrenergic blocking agent [(J. Med. Pharm.
Chem. 1, 343 (1959)]. The compound blocked epinephrine at a level about 2.5 times lower than did dibenamine.
X-46~0 _~_ ~19S92 U.S. Patent 3,988,3~9 discloses a number of 7-and/or 8-substituted 1,2,3,4-tetrahydroisoquinolines, useful as phenylethanolamine N-methyl transferase inhibitors (NMT
inhibitors, also referred to as norepinephrine N-methyl transferase inhibitors). 7,8-Dichloro-1,2,3,4-tetrahydro-isoquinoline was said to inhibit NMT by 50 percent at a concentration of 1.2 x 10 7 molar. U.S. Patent 3,939,164, the parent of U.S. Patent 3,988,399, discloses a limited group of 7- and 8-halo-substituted tetrahydroiso-quinoiines.
The active pressor principle of suprarenal extracts was named epinephrine by Able in 1899 and was synthesized soon thereafter by Stolz and Dakin. Epinephrine is the major hormone produced by the adrenal medulla. It is a potent vasopressor and yields a rapid rise in blood pressure upon intravenous in~ection. It constricts the smaller arterioles and precapillary sphincters as well as veins and large arteries. Epinephrine is a powerful cardiac stimu-lant; the compound can also cause cardiac arrhythmias.
Epinephrine is released in significant quantities into the blood stream during periods of stress. It is this burst of epinephrine which enables mammals, including humans, to take immediate evasive action. Continuous stress and therefore continuous injection of epinephrine into the blood stream, however, nas a deleterious effect in that blood pressure may be elevated permanently or arrhythmias may be induced. Continued stress over long periods may result in malignant hypertension or chronic heart disease.
X-46~0 -3-~,,~ ~=, ,),,, ~1959;~
The last stage in the biosynthesis of epinephrinein the mammal is the methylation of the neurohumoral trans-mitter for most sympathetic postganglionic fibers, nore-pinephrine. The enzyme responsible for this final synthetic step is known as norepinephrine N-methyl transferase.
Inhibitors of this enzyme (NMT inhibitors) are useful in preventing the secretion by the adrenal into the blood stream of large quantities of epinephrine during periods of stress by inhibiting the last step in the formation of this compound.
This invention provides novel chlorinated tetra-hydro-2-benzazepines of the formula ~/~ j1-2~
\~j \5 ~
wherein n is 1 or 2, provided that when n is 2, the chlorine atoms are vicinal, and that, when n is 1, the chlorine atom occupies the 8-position; and pharmaceutically-acceptable acid addition salts thereof.
This invention also comprises novel and useful pharmaceutical compositions valuable for reducing the forma-tion of epinephrine in a mammal which comprise a pharma-ceutically-acceptable inert carrier and a compound of the formula ~1~3159Z
Cl - ~ ~
\6~ 4 II
wherein~t~e chlorine atom occupies the 6, 7 or 9 position;
and pharmaceutically-acceptable acid addition salts thereof.
The compounds of Formulae I and II are prepared by reacting a compound of the formula H H H H H
1~ /~ IIIII
~-C-N-C-C-C-Ha l o III
. .
wherein n is as defined a~ove, provided that none of the chlorine atoms occupies a position ortho to the side chain, with a Friedel-Crafts catalyst of the Lewis acid type or by reacting a compound of the formula C~n~\ ~
. . ~ , wherein n is as defined above, with an azide in the presence of a strong acid to prepare a compound of the formula V
,~ _ 5 _ ~19159Z
and reacting the compound of formula V with a reducing agent;
and if desired recovering the compound of Formula I or II
in the form of a pharmaceutically-acceptable salt.
This invention also comprises a process for preparing a novel chlorinated tetrahydro-2-benzazepine of the formula lo n~\ ~
wherein n is 1 or 2, provided that none of the chlorine atoms occupies the 9-position, that when n is 2, the chlorine atoms are vicinal, and that, when n is 1, the chlorine atom occupies the 8-position; and pharmaceutically-acceptable acid addition salts thereof; which process is characterized by reacting a compound of the formula H H H H H
/~ I I I I I
R t-c-N-c-c-c-Ha l o \~
wherein n is as defined above, provided that none of the chlorine atoms occupies a position ortho to the side chain, with a Friedel-Crafts catalyst of the Lewis acid type.
~ - 5a -~959;2 The pharmaceutically-acceptable acid addition . salts of compounds useful in the process of this invention ~ include salts derived from inorganic acids such as hydro-i chloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydriodic acid, nitrous acid and phos-phorous acid, as well as salts derived from nontoxic organic acids such as aliphatic mono and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic and alkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such pharmaceutically-acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphos-phate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, butyn-1,4-dioate, hexyn-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dlnitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenyl-butyrate, citrate, lactate, ~-hydroxybutyrate, glycollate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-l-sulfonate, naphthalene-2-sulfonate and the like salts.
.~.~
~5~;~
When a starting compound of formula III is used,the halo atom at the end of the side chain is preferably bromine. The starting compound of formula III is reacted with a Friedel-Crafts catalyst of the Lewis acid type, preferably aluminum chloride. Such other metal halides as aluminum bromide, zinc chloride, boron trifluoride, boron trichloride, boron tribromide, titanium tetrachloride, stannic chloride, bismuth trichloride and ferric chloride are also well known ~ewis acid Friedel-Crafts catalysts and are useful in the present reaction.
The reaction may be carried out in a solvent or without one. If a solvent is used, it should be a high-boiling solvent such as decalin, because the reaction should be carried out at a high temperature from 100C. to 200C. If aluminum chloride is the catalyst, it is possible to use no solvent and to carry out the reaction at or above the fusion temperature.
When the process begins with a starting compound of formula IV, the first step is to react the starting compound with an azide. The azide may be supplied in the form of an azide salt, particularly and preferably an alkali metal azide, or in the form of hydrazoic acid. Whichever form of the azide is preferred, the reaction of the compound of formula IV is carried out in the presence of a strong i - 7 ~1~959Z
acid. Sulfuric acid is preferred, but other typical strong acids such as phosphoric acid and trifluoroacetic acid may also be used. The reaction of the starting compound of Formula IV with an azide is carried out in a solvent which is inert to the reactants. The halogenated solvents are particularly useful. Such halogenated solvents as chloro-form, dichloromethane, the dichloroethanes and the chlorinated benzenes are particularly useful. The temperature of the azide reaction is preferably from 0C. to the ambient temperature.
The intermediate compound of Formula V is then reduced to prepare the compound of Formulae I or II. The preferred reducing agent is diborane (B2H6). Other typical effective reducing agents, particularly lithium aluminum hydride, may also be used. The reduction may be carried out in any inert solvent, of which tetrahydrofuran is preferred.
Other inert solvents, such as diethyl ether and 1,2-dimethoxy-ethane may also be effectively used. The reduction is best carried out at a temperature from the ambient temperature to 100C., preferably at the reflux temperature of the reaction mixture.
Preparation 1 A solution was prepared from 90 g. of o-chloro-benzyl chloride in 200 ml. of 3-aminopropanol. The solution immediately became hot, and external heating was applied slowly until reflux temperature was reached. The reaction mixture was then cooled, and the cooled solution was diluted ~lg592 with one liter of water. The aqueous mixture was made basic with 200 ml. of 5N aqueous sodium hydroxide. 3~ Chloro-benzylamino)propanol formed in the above reaction, being insoluble in aqueous base, separated and was extracted into ether. The ether extract was separated, washed twice with water and once with saturated aqueous sodium chloride solution. The ether extract was then dried and the ether removed by evaporation in vacuo, yielding a residue con-sisting of 98 g. of a yellow liquid. Distillation of the residue yielded 3-(_-chlorobenzylamino)propanol distilling in the range 127-138C. at 0.1 mm/hg. Yield = 83.5 g.
Analysis; Calc.: C, 60.15; H, 7.07; N, 7.01; Cl, 17.75;
Found: C, 60.09; H, 7.01; N, 6.99; Cl, 17.92 32.8 g. of 3-(o-chlorobenzylamino)propanol were added slowly to 100 ml. of 48 percent aqueous hydrobromic acid and kept at about 0C. A 250 ml. round-bottom flask fitted with a mechanical stirrer and a distillation head was used as a reaction vessel. After the addition had been completed, the reaction mixture was heated to refluxing temperature and then to a temperature of about 127C. in order to remove constant boiling hydrobromic acid. The residue remaining, containing 3-(_-chlorobenzylamino)propyl bromide hydrobromide, was cooled. The resulting solid was dissolved in acetone and the volatile constituents removed by evaporation in vacuo. This operation was repeated twice more and the resulting residue was crystallized from 400 ml.
of ethyl acetate and methanol to yield 38.76 g. of 3-(_-chlorobenzylamino)propyl bromide hydrobromide formed in the above reaction melting at 128-130C.
X-4680 _9_ ~9592 Analysis; Calc.: C, 34.97; H, 4.11; N, 4.08; Cl, 10.32;
Br, 46.12;
Found: C, 34.76; H, 3.94; N, 3.99; Cl, 10.12;
Br, 46.41 ~ - 10 - .
Example 1 Preparation of 6,7-dichloro-2,3,4,5-tetrahydro-lH-2-benzaæepine A solution of 10.1 g. of 5,6-dichloro-2-tetralone in 200 ml. of chloroform was prepared. 3.57 g. of sodium azide were added while the reaction mixture was being cooled to about 15C. 50 ml. of 36N aqueous sulfuric acid were added in dropwise fashion while maintaining the temperature in the range 15-20C. The reaction mixture was stirred for an additional 15 minutes after the addition of the acid had ~lg~92 been completed and was then poured into an ice-water mixture.
The organic layer was separated and the separated layer washed with lO percent aqueous sodium carbonate and saturated aqueous sodium chloride. After drying, evaporation of the volatile constituents from the organic layer yielded 10.42 g.
of a greenish oil consi5ting of a 50:50 mixture of 6,7-dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine-3-one and 6,7-dichloro-1,3,4,5-tetrahydro-2H-3-benzazepine-2-one formed in the above reacti~n. Ten g. of the reaction mixture containing the isomeric benzazepinones were dis-solved in chloroform and the chloroform solution chromato-graphed over 500 g. of silica gel (Woelm activity IV). The chromatogram was developed with chloroform; 500 ml. fractions were taken. Fractions 17-18 were found to contain 100 percent of the 3-benzazepinone and fractions 20-25 were found to contain predominately the 2-benzazepinone isomer.
Those latter fractions were combined and recrystallized from 75 ml. of hot benzene. A yield of 1.422 g. of pure 6,7-dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine-3-one melting at about 188-190C. was thus obtained.
Analysis; Calc.: C, 52.20; H, 3.94; N, 6.09; Cl, 30.82;
Found: C, 52.18; H, 3.88; N, 6.00; Cl, 30.65 The structure of the isomer was verified by NMR.
1.30 g. of 6,7-dichloro-2,3,4,5-tetrahydro-lH-
Tetrahydro-2-benzazepines and tetrahydro-3-benzazepines are both known in the art. von Braun and Zobel, Ber. _, 69G, (1923) prepared both compounds as did Deady, et al., J.C.S., Perkin Trans 782 (1973) by a different route. In addition, Deady et al (loc. cit.) prepared the previously unreported 7-methyl derivative of tetrahydro-lH-2-benzazepine as well as 7-chlorotetrahydro-lH-2-benzazepine. No utility was given for any of these products.
According to Kasparek, writing in Advances in Heterocyclic Chemistry, Vol. 17, pp. 45 _ ~. (Katritzky and Boulton, ed., Academic Press, 1974), 2-benzazepines have been tested as anti-hypertensives, adrenergic blockers, and cholinesterase inhibitors. 3-Benzazepines have been tested as hypoglycemics, analgesics, depressants, anorectics, and ganglionic blocking agents. l-Benzazepines have also been found to have analgesic, antidepressant, anti-fibrillant, hypotensive, anti-neoplastic, diuretic, hypoglycemic, and anti-arrhythmic activities. N-Substituted tetrahydro-2-benzazepines have been prepared [see for example, Chemical Abstracts 74, 53575a (1971); 72, 66776a (1970); and 68, 59453g (1968)]. ~elleau prepared N-(~-chloroethyl)-2-benzazepine as an adrenergic blocking agent [(J. Med. Pharm.
Chem. 1, 343 (1959)]. The compound blocked epinephrine at a level about 2.5 times lower than did dibenamine.
X-46~0 _~_ ~19S92 U.S. Patent 3,988,3~9 discloses a number of 7-and/or 8-substituted 1,2,3,4-tetrahydroisoquinolines, useful as phenylethanolamine N-methyl transferase inhibitors (NMT
inhibitors, also referred to as norepinephrine N-methyl transferase inhibitors). 7,8-Dichloro-1,2,3,4-tetrahydro-isoquinoline was said to inhibit NMT by 50 percent at a concentration of 1.2 x 10 7 molar. U.S. Patent 3,939,164, the parent of U.S. Patent 3,988,399, discloses a limited group of 7- and 8-halo-substituted tetrahydroiso-quinoiines.
The active pressor principle of suprarenal extracts was named epinephrine by Able in 1899 and was synthesized soon thereafter by Stolz and Dakin. Epinephrine is the major hormone produced by the adrenal medulla. It is a potent vasopressor and yields a rapid rise in blood pressure upon intravenous in~ection. It constricts the smaller arterioles and precapillary sphincters as well as veins and large arteries. Epinephrine is a powerful cardiac stimu-lant; the compound can also cause cardiac arrhythmias.
Epinephrine is released in significant quantities into the blood stream during periods of stress. It is this burst of epinephrine which enables mammals, including humans, to take immediate evasive action. Continuous stress and therefore continuous injection of epinephrine into the blood stream, however, nas a deleterious effect in that blood pressure may be elevated permanently or arrhythmias may be induced. Continued stress over long periods may result in malignant hypertension or chronic heart disease.
X-46~0 -3-~,,~ ~=, ,),,, ~1959;~
The last stage in the biosynthesis of epinephrinein the mammal is the methylation of the neurohumoral trans-mitter for most sympathetic postganglionic fibers, nore-pinephrine. The enzyme responsible for this final synthetic step is known as norepinephrine N-methyl transferase.
Inhibitors of this enzyme (NMT inhibitors) are useful in preventing the secretion by the adrenal into the blood stream of large quantities of epinephrine during periods of stress by inhibiting the last step in the formation of this compound.
This invention provides novel chlorinated tetra-hydro-2-benzazepines of the formula ~/~ j1-2~
\~j \5 ~
wherein n is 1 or 2, provided that when n is 2, the chlorine atoms are vicinal, and that, when n is 1, the chlorine atom occupies the 8-position; and pharmaceutically-acceptable acid addition salts thereof.
This invention also comprises novel and useful pharmaceutical compositions valuable for reducing the forma-tion of epinephrine in a mammal which comprise a pharma-ceutically-acceptable inert carrier and a compound of the formula ~1~3159Z
Cl - ~ ~
\6~ 4 II
wherein~t~e chlorine atom occupies the 6, 7 or 9 position;
and pharmaceutically-acceptable acid addition salts thereof.
The compounds of Formulae I and II are prepared by reacting a compound of the formula H H H H H
1~ /~ IIIII
~-C-N-C-C-C-Ha l o III
. .
wherein n is as defined a~ove, provided that none of the chlorine atoms occupies a position ortho to the side chain, with a Friedel-Crafts catalyst of the Lewis acid type or by reacting a compound of the formula C~n~\ ~
. . ~ , wherein n is as defined above, with an azide in the presence of a strong acid to prepare a compound of the formula V
,~ _ 5 _ ~19159Z
and reacting the compound of formula V with a reducing agent;
and if desired recovering the compound of Formula I or II
in the form of a pharmaceutically-acceptable salt.
This invention also comprises a process for preparing a novel chlorinated tetrahydro-2-benzazepine of the formula lo n~\ ~
wherein n is 1 or 2, provided that none of the chlorine atoms occupies the 9-position, that when n is 2, the chlorine atoms are vicinal, and that, when n is 1, the chlorine atom occupies the 8-position; and pharmaceutically-acceptable acid addition salts thereof; which process is characterized by reacting a compound of the formula H H H H H
/~ I I I I I
R t-c-N-c-c-c-Ha l o \~
wherein n is as defined above, provided that none of the chlorine atoms occupies a position ortho to the side chain, with a Friedel-Crafts catalyst of the Lewis acid type.
~ - 5a -~959;2 The pharmaceutically-acceptable acid addition . salts of compounds useful in the process of this invention ~ include salts derived from inorganic acids such as hydro-i chloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydriodic acid, nitrous acid and phos-phorous acid, as well as salts derived from nontoxic organic acids such as aliphatic mono and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic and alkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such pharmaceutically-acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphos-phate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, butyn-1,4-dioate, hexyn-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dlnitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenyl-butyrate, citrate, lactate, ~-hydroxybutyrate, glycollate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-l-sulfonate, naphthalene-2-sulfonate and the like salts.
.~.~
~5~;~
When a starting compound of formula III is used,the halo atom at the end of the side chain is preferably bromine. The starting compound of formula III is reacted with a Friedel-Crafts catalyst of the Lewis acid type, preferably aluminum chloride. Such other metal halides as aluminum bromide, zinc chloride, boron trifluoride, boron trichloride, boron tribromide, titanium tetrachloride, stannic chloride, bismuth trichloride and ferric chloride are also well known ~ewis acid Friedel-Crafts catalysts and are useful in the present reaction.
The reaction may be carried out in a solvent or without one. If a solvent is used, it should be a high-boiling solvent such as decalin, because the reaction should be carried out at a high temperature from 100C. to 200C. If aluminum chloride is the catalyst, it is possible to use no solvent and to carry out the reaction at or above the fusion temperature.
When the process begins with a starting compound of formula IV, the first step is to react the starting compound with an azide. The azide may be supplied in the form of an azide salt, particularly and preferably an alkali metal azide, or in the form of hydrazoic acid. Whichever form of the azide is preferred, the reaction of the compound of formula IV is carried out in the presence of a strong i - 7 ~1~959Z
acid. Sulfuric acid is preferred, but other typical strong acids such as phosphoric acid and trifluoroacetic acid may also be used. The reaction of the starting compound of Formula IV with an azide is carried out in a solvent which is inert to the reactants. The halogenated solvents are particularly useful. Such halogenated solvents as chloro-form, dichloromethane, the dichloroethanes and the chlorinated benzenes are particularly useful. The temperature of the azide reaction is preferably from 0C. to the ambient temperature.
The intermediate compound of Formula V is then reduced to prepare the compound of Formulae I or II. The preferred reducing agent is diborane (B2H6). Other typical effective reducing agents, particularly lithium aluminum hydride, may also be used. The reduction may be carried out in any inert solvent, of which tetrahydrofuran is preferred.
Other inert solvents, such as diethyl ether and 1,2-dimethoxy-ethane may also be effectively used. The reduction is best carried out at a temperature from the ambient temperature to 100C., preferably at the reflux temperature of the reaction mixture.
Preparation 1 A solution was prepared from 90 g. of o-chloro-benzyl chloride in 200 ml. of 3-aminopropanol. The solution immediately became hot, and external heating was applied slowly until reflux temperature was reached. The reaction mixture was then cooled, and the cooled solution was diluted ~lg592 with one liter of water. The aqueous mixture was made basic with 200 ml. of 5N aqueous sodium hydroxide. 3~ Chloro-benzylamino)propanol formed in the above reaction, being insoluble in aqueous base, separated and was extracted into ether. The ether extract was separated, washed twice with water and once with saturated aqueous sodium chloride solution. The ether extract was then dried and the ether removed by evaporation in vacuo, yielding a residue con-sisting of 98 g. of a yellow liquid. Distillation of the residue yielded 3-(_-chlorobenzylamino)propanol distilling in the range 127-138C. at 0.1 mm/hg. Yield = 83.5 g.
Analysis; Calc.: C, 60.15; H, 7.07; N, 7.01; Cl, 17.75;
Found: C, 60.09; H, 7.01; N, 6.99; Cl, 17.92 32.8 g. of 3-(o-chlorobenzylamino)propanol were added slowly to 100 ml. of 48 percent aqueous hydrobromic acid and kept at about 0C. A 250 ml. round-bottom flask fitted with a mechanical stirrer and a distillation head was used as a reaction vessel. After the addition had been completed, the reaction mixture was heated to refluxing temperature and then to a temperature of about 127C. in order to remove constant boiling hydrobromic acid. The residue remaining, containing 3-(_-chlorobenzylamino)propyl bromide hydrobromide, was cooled. The resulting solid was dissolved in acetone and the volatile constituents removed by evaporation in vacuo. This operation was repeated twice more and the resulting residue was crystallized from 400 ml.
of ethyl acetate and methanol to yield 38.76 g. of 3-(_-chlorobenzylamino)propyl bromide hydrobromide formed in the above reaction melting at 128-130C.
X-4680 _9_ ~9592 Analysis; Calc.: C, 34.97; H, 4.11; N, 4.08; Cl, 10.32;
Br, 46.12;
Found: C, 34.76; H, 3.94; N, 3.99; Cl, 10.12;
Br, 46.41 ~ - 10 - .
Example 1 Preparation of 6,7-dichloro-2,3,4,5-tetrahydro-lH-2-benzaæepine A solution of 10.1 g. of 5,6-dichloro-2-tetralone in 200 ml. of chloroform was prepared. 3.57 g. of sodium azide were added while the reaction mixture was being cooled to about 15C. 50 ml. of 36N aqueous sulfuric acid were added in dropwise fashion while maintaining the temperature in the range 15-20C. The reaction mixture was stirred for an additional 15 minutes after the addition of the acid had ~lg~92 been completed and was then poured into an ice-water mixture.
The organic layer was separated and the separated layer washed with lO percent aqueous sodium carbonate and saturated aqueous sodium chloride. After drying, evaporation of the volatile constituents from the organic layer yielded 10.42 g.
of a greenish oil consi5ting of a 50:50 mixture of 6,7-dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine-3-one and 6,7-dichloro-1,3,4,5-tetrahydro-2H-3-benzazepine-2-one formed in the above reacti~n. Ten g. of the reaction mixture containing the isomeric benzazepinones were dis-solved in chloroform and the chloroform solution chromato-graphed over 500 g. of silica gel (Woelm activity IV). The chromatogram was developed with chloroform; 500 ml. fractions were taken. Fractions 17-18 were found to contain 100 percent of the 3-benzazepinone and fractions 20-25 were found to contain predominately the 2-benzazepinone isomer.
Those latter fractions were combined and recrystallized from 75 ml. of hot benzene. A yield of 1.422 g. of pure 6,7-dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine-3-one melting at about 188-190C. was thus obtained.
Analysis; Calc.: C, 52.20; H, 3.94; N, 6.09; Cl, 30.82;
Found: C, 52.18; H, 3.88; N, 6.00; Cl, 30.65 The structure of the isomer was verified by NMR.
1.30 g. of 6,7-dichloro-2,3,4,5-tetrahydro-lH-
2-benzazepine-3-one were slurried in 20 ml. of tetrahydro-furan (THF~. This suspension was added slowly to 20 ml. of a 1 molar diborane solution in THF maintained at ambient temperature. The consequent reaction mixture was refluxed for 16 hours under a nitrogen atmosphere and then cooled.
Excess diborane was destroyed with 2N aqueous hydrochloric acid. The THF was evaporated and the aqueous residue was made basic with 5~ aqueous sodium hydroxide and 6,7-dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine being insoluble in the alkaline layer was separated and extracted into ether. The ether extract was washed with saturated aqueous sodium chloride and dried. Evaporation of the ether yielded 1.21 g. of a clear oily residue of 6,7-dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine which crystallized upon standing.
10The hydrochloride salt of 6,7-dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine was formed by dissolving the crystalline residue in ether and passing gaseous hydrogen chloride through the resulting solution. The hydrochloride salt, being insoluble in ether, separated and was collected by filtration. Recrystallization of the filter cake from a 1:3 ethyl acetate/isopropanol solvent mixture yielded 1.12 g. of 6,7-dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine hydrochloride melting at 231-233C.
Analysis; Calc.: C, 47.55; H, 4.79; N, 5.55; Cl, 42.11;
20Found: C, 47.53; H, 4.54; N, 5.48; Cl, 41.85 Example 2 Preparation of 7,8-dichloro-2,3,4,5-tetra-hydro-lH-2-benzazepine Following the procedure of Example 2, 6,7-dichloro-2-tetralone was reacted with sodium azide in the presence of sulfuric acid at 10C. to yield a mixture of 7,8-dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine-3-one and 7~-dichloro-1,3,4,5-tetrahydro-2H-3-benzazepine-2-one. The ~- isomer mixture was isolated by the procedure of Example 2 and i~ components separated by chromatography over silica gel (Woelm activity IV) using chloroform to develop the chromatogram. The percentage of each isomer in fractions shown to contain the compounds was determined by NMR.
Fractions containing predominately the 2-benzazepine-3-one isomer (weight 2.4 g.) were recrystallized from 125 ml. of benzene. The first fraction weighing 1.25 g. was shown by NMR to contain 88 percent of the desired isomer. The second fraction was obtained from the mother liquors and weighed 470 mg. It was æhown to contain 85 percent of the desired isomer. Further recrystallization of these combined fractions from benzene yielded 1.258 g. of 7,8-dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine-3-one melting at 199-204C.
shown to be 97 percent pure of the desired isomer by NMR.
Analysis; Calc.: C, 52.20; H, 3.94; N, 6.09; Cl, 30.82;
Found: C, 52.10; H, 3.73; N, 6.37: Cl, 30.74 Following the pro~edure of Example 2, the 2-benzazepine-3-one obtained as above was reduced with diborane in THF solution. 860 mg. of 7,8-dichloro-2,3,4,5-tetra-hydro-lH-2-benzazepine were obtained. The free base was converted to the hydrochloride salt by the procedure o~
Example 2 and the salt recrystallized from an isopropanol-methanol solvent mixture. 7,8-Dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine hydrochlorid~ thu8 prepared sublimed at 250C; pKa = 8 ~.
X-~680 -14-~19592 Analysis; Calc.: C, 47.55; ~, 4.79; N, 5.55; Cl, 42.11;
Found: C, 47.73; H, 4.58; N, 5.80; Cl, 42.08 Example 3 Preparation of 7-chloro-2,3,4,5-tetrahydro-lH-2-benzazepine Following the procedure of Example 2, 22.6 g. of 6-chloro-2-tetralone was reacted with sodium azide in the presence of sulfuric acid at 15C. to yield a mixture of 7-chloro-2,3,4,5-tetrahydro-lH-2-benzazepine-3-one and lQ 7-chloro-1,3,4,5-tetrahydro-2H-3-benzazepine-2-one. The isomer mixture was purified by the procedure of Example 2 , , ~and chromatographed over Woelm activity IV silica gel using a chloroform-benzene mixture and pure chloroform as eluants.
Fractions shown to be rich in the 2-benzazepine-3-one isomer by NMR were collected and recrystallized from a 3:1 benzene/
cyclohexane solvent mixture. The first recrystallization yieldçd m~terial,containing more than 80 percent of the desired isomer. The 2-benzazepine-3-one free base was further recrystallized from the cyclohexane/benzene solvent mixture e~entually yielding crystalline material shown to ~10 contain in excess of 95 percent of the desired isomer by NMR.
The,7-chloro-2,3,4,5-tetrahydro-lH-2-benzazepine-
Excess diborane was destroyed with 2N aqueous hydrochloric acid. The THF was evaporated and the aqueous residue was made basic with 5~ aqueous sodium hydroxide and 6,7-dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine being insoluble in the alkaline layer was separated and extracted into ether. The ether extract was washed with saturated aqueous sodium chloride and dried. Evaporation of the ether yielded 1.21 g. of a clear oily residue of 6,7-dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine which crystallized upon standing.
10The hydrochloride salt of 6,7-dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine was formed by dissolving the crystalline residue in ether and passing gaseous hydrogen chloride through the resulting solution. The hydrochloride salt, being insoluble in ether, separated and was collected by filtration. Recrystallization of the filter cake from a 1:3 ethyl acetate/isopropanol solvent mixture yielded 1.12 g. of 6,7-dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine hydrochloride melting at 231-233C.
Analysis; Calc.: C, 47.55; H, 4.79; N, 5.55; Cl, 42.11;
20Found: C, 47.53; H, 4.54; N, 5.48; Cl, 41.85 Example 2 Preparation of 7,8-dichloro-2,3,4,5-tetra-hydro-lH-2-benzazepine Following the procedure of Example 2, 6,7-dichloro-2-tetralone was reacted with sodium azide in the presence of sulfuric acid at 10C. to yield a mixture of 7,8-dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine-3-one and 7~-dichloro-1,3,4,5-tetrahydro-2H-3-benzazepine-2-one. The ~- isomer mixture was isolated by the procedure of Example 2 and i~ components separated by chromatography over silica gel (Woelm activity IV) using chloroform to develop the chromatogram. The percentage of each isomer in fractions shown to contain the compounds was determined by NMR.
Fractions containing predominately the 2-benzazepine-3-one isomer (weight 2.4 g.) were recrystallized from 125 ml. of benzene. The first fraction weighing 1.25 g. was shown by NMR to contain 88 percent of the desired isomer. The second fraction was obtained from the mother liquors and weighed 470 mg. It was æhown to contain 85 percent of the desired isomer. Further recrystallization of these combined fractions from benzene yielded 1.258 g. of 7,8-dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine-3-one melting at 199-204C.
shown to be 97 percent pure of the desired isomer by NMR.
Analysis; Calc.: C, 52.20; H, 3.94; N, 6.09; Cl, 30.82;
Found: C, 52.10; H, 3.73; N, 6.37: Cl, 30.74 Following the pro~edure of Example 2, the 2-benzazepine-3-one obtained as above was reduced with diborane in THF solution. 860 mg. of 7,8-dichloro-2,3,4,5-tetra-hydro-lH-2-benzazepine were obtained. The free base was converted to the hydrochloride salt by the procedure o~
Example 2 and the salt recrystallized from an isopropanol-methanol solvent mixture. 7,8-Dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine hydrochlorid~ thu8 prepared sublimed at 250C; pKa = 8 ~.
X-~680 -14-~19592 Analysis; Calc.: C, 47.55; ~, 4.79; N, 5.55; Cl, 42.11;
Found: C, 47.73; H, 4.58; N, 5.80; Cl, 42.08 Example 3 Preparation of 7-chloro-2,3,4,5-tetrahydro-lH-2-benzazepine Following the procedure of Example 2, 22.6 g. of 6-chloro-2-tetralone was reacted with sodium azide in the presence of sulfuric acid at 15C. to yield a mixture of 7-chloro-2,3,4,5-tetrahydro-lH-2-benzazepine-3-one and lQ 7-chloro-1,3,4,5-tetrahydro-2H-3-benzazepine-2-one. The isomer mixture was purified by the procedure of Example 2 , , ~and chromatographed over Woelm activity IV silica gel using a chloroform-benzene mixture and pure chloroform as eluants.
Fractions shown to be rich in the 2-benzazepine-3-one isomer by NMR were collected and recrystallized from a 3:1 benzene/
cyclohexane solvent mixture. The first recrystallization yieldçd m~terial,containing more than 80 percent of the desired isomer. The 2-benzazepine-3-one free base was further recrystallized from the cyclohexane/benzene solvent mixture e~entually yielding crystalline material shown to ~10 contain in excess of 95 percent of the desired isomer by NMR.
The,7-chloro-2,3,4,5-tetrahydro-lH-2-benzazepine-
3-one was reduced with diborane in THF according to the procedure of Example 2. 7-Chloro-2,3,4,5-tetrahydro-lH-2-benzazepine,thus prepared was purified and converted to the hydrochloride salt by the procedure of Example 2. Re-crystallization of 7-chloro-2,3,4,5-tetrahydro-lH-2-benz-azepine hyd,rochloride from isopropanol yielded 1.5 g. of crystalline matçrial melting at 246-249C. which was shown by,NMR to be a pure isomer; pka 8.8.
Analysis; Calc.: C, 55.06; H, 6.01; N, 6.42; Cl, 32.51;
Found: C, 54.95; H, 6.11; N, 6.25; Cl, 32.28 Preparation 2 39.8 Grams of 4-(_-chlorophenyl)butyric acid were heated with 500 g. of polyphosphoric acid at 100C. for 4 hours, The reaction mixture was poured over ice and 7-chloro-l-tetralone formed in the above reaction was extracted ~llg~2 with ethyl acetate. The ethyl acetate extract was separated, washed successively with water, 10 percent sodium carbonate and saturated aqueous sodium chloride and then dried.
Evaporation of the solvent yielded a yellow solid residue comprising 7-chloro~l-tetralone. The compound melted at 94-96C. after recrystallization from hexane.
Analysis; Calc.: C, 66.49; H, 5.02; Cl, 19.63;
Found: C, 66.30; H, 4.89; Cl, 19.65 16 Grams of 7-chloro-1-tetralone were added to a slurry of 7.8 g. of sodium borohydride in 250 ml. of anhydrous ethanol at about 0C. The reaction mixture was stirred at ambient temperature for about 20 hours r and was worked up in standard fashion to yield 16 g. of 7-chloro-1-tetralol.
Infrared spectrum showed an absence of peaks attributable to a carbonyl function indicating the reduction to the tetralol was substantially complete.
16 Grams of 7-chloro-1-tetralol were dissolved in 250 ml. of benzene and the solution placed in a 500 ml.
round-bottom flask fitted with Dean-Stark evaporator and condenser. 1.0 g. of _-toluene sulfonic acid was added and the reaction mixture was reflu~ed overnight. 1.8 ml. of water were collected indicating that the dehydration reaction to form 7-chloro-3,4-dihydronaphthalene had proceeded to completion. The reaction mixture was cooled, and the benzene layer washed twice with 10 percent aqueous sodium bicarbonate and once with saturated aqueous sodium chloride.
The benzene layer was dried and the benzene removed by evaporation in vacuo. The dihydronaphthalene derivative remaining as a residue was used without purification.
The dihydronaphthalene residue was mixed with 20 g. of 80 percent purity m-chloroperbenzoic acid in 250 ml. of chloroform at 0C. The reaction mixture was stirred at about 30C. for 18 hours, and then washed twice with 10 percent sodium car~onate solution and dried.
Evaporation of the solvent yielded 6-chlorooxirano[a]-2,3-dihydronaphthalene formed in the above reaction. The compound was again used without further purification.
The crude oxirane was dissolved in benzene and the solution was cooled to 0C. and then saturated with anhydrous boron trifluoride. The reaction mixture was stirred at ambient temperature for 1.5 hrs.; 19.3 g. of 7-chloro-2-tetralone were formed and were obtained as a residual dark pale liquid after a standard purification procedure.
Example 4 Preparation of 8-chloro-2,3,4,5-tetra-hydro-lH-2-benzazepine Following the procedure of Example 2, 14.3 g. of 7-chloro-2-tetralone were reacted with sodium azide in the presence of sulfuric acid at 5-10C. to yield 13.25 g. of a 50-50 mixture of 8-chloro-2,3,4,5-tetrahydro-lH-2-benz-azepine-3-one and 8-chloro-1,3,4,5-tetrahydro-2H-3-benz-azepine-2-one. The icomer mixture was partially separated by chromatography over Woelm (activity IV) silica gel using chloroform as an eluant. Fractions shown by NMR to contain predominately the 2-benzazepine-3-one isomer were collected and combined. Evaporation of the solvent yielded 4.0 g. of '.~
~1~9S92 solid which were recrystallized from 100 ml. of benzene.
2.g3 g. of crystalline material containing predominately the desired 2-benzazepine-3-one isomer were obtained. Following the procedure of Example 2, the separated isomer was reduced with diborane in THF to yield 8-chloro-2,3,4,5-tetrahydro-lH-2-benzazepine. The product was isolated and purified and the purified free base converted to the hydrochloride salt by the method of Example 2. Recrystallization of the hydrochloride salt from isopropanol yielded 1.88 g. of 8-chloro-2,3,4,5-tetrahydro-lH-2-benzazepine hydrochloride which sublimed at 260C.; pKa = 8.75.
Analysis; Calc.: C, 55.06; H, 6.01; N, 6.42; Cl, 32.51;
Found: C, 55.29; H, 5.98; N, 6.23; C1, 32.46 Example 5 Preparation of 6-chloro-2,3,4,5-tetra-hydro-lH-2-benzazepine Following the procedure of Example 2, 15.9 g. of 5-chloro-2-tetralone were reacted with 7.15 g. of sodium azide and 100 ml. of 36N sulfuric acid in 400 ml. of chloroform at 5-10C. The mixture was then allowed to warm to ambient temperature o~er 30 minutes. The product of this reaction was shown by NMR to consist of equal amounts of 6-chloro-2,3,4,5-tetrahydro-lH-2-benzazepine-3-one and 6-chloro-1,3,4,5-tetrahydro-2H-3-benzazepine-2-one. The isomer mixture was separated by chromatography over silica gel (Woelm Activity IV) using chloroform as the eluant and taking 500 ml. fractions. Fractions 9 and 10 were shown by NMR to consist of 100 percent of the 3-benzazepine-2-one isomer. Fractions 12-20, shown by NMR to contain the lll~S92 2-benzazepine~3-one isomer, were recrystallized from 175 ml.
of benzene. The first fraction was shown by NMR to be 97 percent pure 2-benzazepine-3-one isomer. Recrystallization of this fraction from 125 ml. of benzene yielded 3.40 g. of the desired isomer; mp = 184-187C.; shown by NMR to be 100 percent pure.
Analysis; Calc.: C, 61.39; H, 5.15; N, 7.16; Cl, 18~12;
Found: C, 61.35; H, 5.23; N, 7.19; Cl, 17.99 Reduction of the 6-chloro-2,3,4,5-tetrahydro-lH-2-benzazepine-3-one with diborane by the procedure of Example 2 yielded 6-chloro-2,3,4,5-tetrahydro-lH-2-benzazepine which was purified as the hydrochloride salt; mp = 235-8C. pKa =
8.75.
Analysis; Calc.: C, 55.06; H, 6.01; N, 6.42; Cl, 32.51;
Found: C, 54.84; H, 5.98; N, 6.58; Cl, 32.24 The compounds of this invention, either in the form of the free base, or as a pharmaceutically-acceptable acid addition salt thereof, are enzyme inhibitors. In particular, as previously stated, they are inhibitors of norepinephrine N-methyl transferase ~NMT or phenethanol-amine N-methyl transferase--see Axelod, J. Bio. Chem. 237, 1657 (1962)]. Compounds which inhibit the conversion of norepinephrine to epinephrine are capable of lowering a high epinephrine-norepinephrine ratio in mammals, a physiological condition frequently associated with essential hypertension.
The compounds of this invention are thus capable of ameli-orating the epinephrine-norepinephrine imbalance in essen-tial hypert~nsion, an important aspect of the treatment of this disease state.
gZ
The effectiveness of the compounds as N-methyl transferase inhibitors has been measured in vitro using NMT
from rabbit adrenals. By using a series of decreasing concentrations of the inhibiting amine, usually starting with 1 x 10 4M continuing with 3 x 10 5M, 1 x 10 5M, etc., it was possible to determine a concentration at which the 50 percent inhibition of NMT was achieved. The negative reciprocal logarithm (pI50) of this number was also cal-culated as a useful index. Table 1, which follows, summarizes the information thus obtained; i.e., the determination of enzyme inhibition activity for the compounds of this invention.
In the table, column 1 gives the name of the compound, column 2, the concentration at which 50 percent inhibition of NMT is obtained and column 3, the pI50.
`~
,,~ o o ,1 o a ~9 ~ ~ co ~D, In ~ o~ D
L~
o In ~ ~ ~o ~o , ~o ~o 10 a) ~ ,, ~ o ~ ~1 O X X, X ,~.. ..
o O I ,~
- .4 H
I I ~ , ~ I ~ O O
o o o ,~ ~
~ ~ ~ o ~ o I o I o n~ ~ S O ~ ~.C ~.C
~J ~ ~ o Z ~ In ~ h n~l ` O `~
~,~ ~ a) ~
.C ~ O ~ O
O ~ I ~ ~ ~ Q
O ~ O N O N I rl N ~1 N
..C ~ ,.C N ,5 N I I N I N
I ~
~ Q r~ ~
....,. ~
I
~1~95~Z
The compounds of this invention are used as NMT
inhibitors, preferably in the form of an acid addition salt.
These salts can be mixed with one or more standard pharma-ceutical excipients and loaded into empty telescoping gelatin capsules or compressed into tablets. Aqueous solutions of these salts can be employed for parenteral administration, with an isotonic solution being particularly adapted for IV use. The compounds can be administered in dosage unit form for oral administration comprising an amount effective to inhibit epinephrine N-methyl transferase comprising a pharmaceutical carrier and as the active ingredient a chlorinated tetrahydro-2-benzazepine of formula I or II above. The amount of chlorinated tetrahydro-2-benzazepine present is about 50-500 mg. per dosage unit.
The compounds are administered to mammals at concentrations varying from about 1 to about 100 mg./kg. orally per day.
959;~:
SUPPLEMENTARY DISCLOSURE
Further investigations into the processes of making chlorinated tetrahydro-2-benzazepines according to the invention have confirmed that all compounds of the invention can be produced by reacting a suitable compound of the formula \ ~ \./ IV
with an azide in the presence of a strong acid to prepare a compound of the formula Cln~ I ~
v and reacting the compound of formula V with a reducing agent, as described previously. However, it has also been found that nqt all the compounds of the invention ~ -can be produded in any significant amount by reacting a compound of the formula H H H H H
~!-C-~C-C-C-Ha l o \~ III
with a Friedel-Crarts catalyst.
When compounds of formula III which have a chlorine atom in ortho-position to the side chain are reacted with a Friedel-crafts catalyst none or very `` ~119S92 little 9-chloro- or 8,9-dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine are produced. It appears that the presence of the ortho-chloro substituent in compounds of formula III activates a molecular rearrangement in which the halogen moiety, which preferably is a bromine moiety, of the benzylaminopropylhalogenide starting material is moved one carbon atom down the chain, thus forming the corresponding 8-chloro- or 7,~-dichloro-4-methyl-1,2,3,4-tetrahydroiso~uinoline.
Compounds of formula III which have no chlorine atom in ortho-position to the side chain will form, when reacted with a Friedel-Crafts catalyst according to the process of the invention, chlorinated tetrahydro-2-benzazepines.
This invention then, in a further aspect, provides a process for preparing a novel chlorinated tetrahydro-2-benzazepine of the formula Cl `1'~ ' ~
i7 and pharmaceutically-acceptable acid addition salts thereof. The process is characterized by reacting a compound of the formula Cl / ~
~ IV
\ ,,' \~/
~herein n is as defined above, with an azide in the presence of a stron~ acid to prepare a compound of the formula ~ r ,~
111~5~Z
Cl Cl ~ --~ H
Il I . >~ V~
and reacting the compound of formula V' with a reducing agent; and if desired recovering the compound of Formula I' in the form of a pharmaceutically-acceptable salt.
This invention further provides the novel compound 8,9-dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine and its pharm-aceutically acceptable acid addition salts.
The invention is further illustrated by the follow-ing examples.
Example 6 Preparation of 9-chloro-2,3,4,5-tetrahydro-lH-2-benzazepine In a 500 ml. three-neck, round-bottom flask equipped with magnetic stirrer, drying tube, thermometer, and addition funnel were placed 15 g. of 8-chloro-2-tetralone, 6 g. of sodium azide and 200 ml. of chloroform. The reaction mixture was cooled to about 15C. 50 Milliliters of 18N sulfuric acid were added thereto in dropwise fashion while keeping the temper-ature of the reaction between 15 and 20C. After the sulfuric acid had all been added, the reaction mixture was stirred at room temperature for two hours. It was then poured into a mixture of ice and water. The chloroform layer was separated and the aqueous layer extracted three times with chloroform.
The chloroform ex~racts were combined and the combined extracts washed with both 10 percent aqueous sodium carbonate and satur-ated aqueous sodium chloride and were then dried. Evaporation of the chloroform in vacuo yielded 16.4 g. of a solid com-30 prising a mixture of 9-chloro-2,3,4,5-tetrahydro-lH-2-benzazepin-3-one and the corresponding 3-benzazepine-2-one isomer. Six 1119~92 recrystallizations from toluene yielded 3.23 g~ of 9-chloro-2,3,4,5-tetrahydro-lH-2-benzazepin-3-one substantially free of its 3-benzazepin-2-one isomer. The compound melted at about 197-199C.
Analysis: Calc.: C, 61.39; H, 5.15; N, 7.16;
Cl, 18.12 Found: C, 61.53; H, 5.09; N, 7.40;
CL, 18.37 Following the procedure of Example 2 following, 3.3 g. of 9-chloro-2,3,4,5-tetrahydro-lH-2-benzazepin-3-one were reduced with diborane in tetrahydrofuran (THF) solution to yield 9-chloro-2,3,4,5-lH-2-benzazepine. 2.95 Grams of base were obtained following the purification procedure of Example 2.
The free base was converted to the corresponding hydrochloride salt which melted at about 244-246C. with decomposition after recrystallization from a 95:5 ethyl acetatemethanol solvent mixture; yield = about 2.2 g.
Analysis' Calc.: C, 55.06; H, 6.01; N, 6.42;
Cl, 32.51 Found: C, 54.75; H, 5.74; N, 9.46;
Cl, 32.68 Alternatively, the mixture of 9-chloro-2,3,4,5-tetrahydro-lH-2-benzazepin-3-one and its 3-benzazepine-2-one isomer can be reduced with diborane in THF to a mixture of the corresponding benzazepines. This isomer mixture can be readily separated via high pressure liquid chromatography with better yields than are found by crystallization of the benzazepinones from toluene. The HPLC system employed was a waters prep. l.c. system 500 with one silica 500 prep pack cartridge. The solvent used was an 8 1 gradient, consisting of
Analysis; Calc.: C, 55.06; H, 6.01; N, 6.42; Cl, 32.51;
Found: C, 54.95; H, 6.11; N, 6.25; Cl, 32.28 Preparation 2 39.8 Grams of 4-(_-chlorophenyl)butyric acid were heated with 500 g. of polyphosphoric acid at 100C. for 4 hours, The reaction mixture was poured over ice and 7-chloro-l-tetralone formed in the above reaction was extracted ~llg~2 with ethyl acetate. The ethyl acetate extract was separated, washed successively with water, 10 percent sodium carbonate and saturated aqueous sodium chloride and then dried.
Evaporation of the solvent yielded a yellow solid residue comprising 7-chloro~l-tetralone. The compound melted at 94-96C. after recrystallization from hexane.
Analysis; Calc.: C, 66.49; H, 5.02; Cl, 19.63;
Found: C, 66.30; H, 4.89; Cl, 19.65 16 Grams of 7-chloro-1-tetralone were added to a slurry of 7.8 g. of sodium borohydride in 250 ml. of anhydrous ethanol at about 0C. The reaction mixture was stirred at ambient temperature for about 20 hours r and was worked up in standard fashion to yield 16 g. of 7-chloro-1-tetralol.
Infrared spectrum showed an absence of peaks attributable to a carbonyl function indicating the reduction to the tetralol was substantially complete.
16 Grams of 7-chloro-1-tetralol were dissolved in 250 ml. of benzene and the solution placed in a 500 ml.
round-bottom flask fitted with Dean-Stark evaporator and condenser. 1.0 g. of _-toluene sulfonic acid was added and the reaction mixture was reflu~ed overnight. 1.8 ml. of water were collected indicating that the dehydration reaction to form 7-chloro-3,4-dihydronaphthalene had proceeded to completion. The reaction mixture was cooled, and the benzene layer washed twice with 10 percent aqueous sodium bicarbonate and once with saturated aqueous sodium chloride.
The benzene layer was dried and the benzene removed by evaporation in vacuo. The dihydronaphthalene derivative remaining as a residue was used without purification.
The dihydronaphthalene residue was mixed with 20 g. of 80 percent purity m-chloroperbenzoic acid in 250 ml. of chloroform at 0C. The reaction mixture was stirred at about 30C. for 18 hours, and then washed twice with 10 percent sodium car~onate solution and dried.
Evaporation of the solvent yielded 6-chlorooxirano[a]-2,3-dihydronaphthalene formed in the above reaction. The compound was again used without further purification.
The crude oxirane was dissolved in benzene and the solution was cooled to 0C. and then saturated with anhydrous boron trifluoride. The reaction mixture was stirred at ambient temperature for 1.5 hrs.; 19.3 g. of 7-chloro-2-tetralone were formed and were obtained as a residual dark pale liquid after a standard purification procedure.
Example 4 Preparation of 8-chloro-2,3,4,5-tetra-hydro-lH-2-benzazepine Following the procedure of Example 2, 14.3 g. of 7-chloro-2-tetralone were reacted with sodium azide in the presence of sulfuric acid at 5-10C. to yield 13.25 g. of a 50-50 mixture of 8-chloro-2,3,4,5-tetrahydro-lH-2-benz-azepine-3-one and 8-chloro-1,3,4,5-tetrahydro-2H-3-benz-azepine-2-one. The icomer mixture was partially separated by chromatography over Woelm (activity IV) silica gel using chloroform as an eluant. Fractions shown by NMR to contain predominately the 2-benzazepine-3-one isomer were collected and combined. Evaporation of the solvent yielded 4.0 g. of '.~
~1~9S92 solid which were recrystallized from 100 ml. of benzene.
2.g3 g. of crystalline material containing predominately the desired 2-benzazepine-3-one isomer were obtained. Following the procedure of Example 2, the separated isomer was reduced with diborane in THF to yield 8-chloro-2,3,4,5-tetrahydro-lH-2-benzazepine. The product was isolated and purified and the purified free base converted to the hydrochloride salt by the method of Example 2. Recrystallization of the hydrochloride salt from isopropanol yielded 1.88 g. of 8-chloro-2,3,4,5-tetrahydro-lH-2-benzazepine hydrochloride which sublimed at 260C.; pKa = 8.75.
Analysis; Calc.: C, 55.06; H, 6.01; N, 6.42; Cl, 32.51;
Found: C, 55.29; H, 5.98; N, 6.23; C1, 32.46 Example 5 Preparation of 6-chloro-2,3,4,5-tetra-hydro-lH-2-benzazepine Following the procedure of Example 2, 15.9 g. of 5-chloro-2-tetralone were reacted with 7.15 g. of sodium azide and 100 ml. of 36N sulfuric acid in 400 ml. of chloroform at 5-10C. The mixture was then allowed to warm to ambient temperature o~er 30 minutes. The product of this reaction was shown by NMR to consist of equal amounts of 6-chloro-2,3,4,5-tetrahydro-lH-2-benzazepine-3-one and 6-chloro-1,3,4,5-tetrahydro-2H-3-benzazepine-2-one. The isomer mixture was separated by chromatography over silica gel (Woelm Activity IV) using chloroform as the eluant and taking 500 ml. fractions. Fractions 9 and 10 were shown by NMR to consist of 100 percent of the 3-benzazepine-2-one isomer. Fractions 12-20, shown by NMR to contain the lll~S92 2-benzazepine~3-one isomer, were recrystallized from 175 ml.
of benzene. The first fraction was shown by NMR to be 97 percent pure 2-benzazepine-3-one isomer. Recrystallization of this fraction from 125 ml. of benzene yielded 3.40 g. of the desired isomer; mp = 184-187C.; shown by NMR to be 100 percent pure.
Analysis; Calc.: C, 61.39; H, 5.15; N, 7.16; Cl, 18~12;
Found: C, 61.35; H, 5.23; N, 7.19; Cl, 17.99 Reduction of the 6-chloro-2,3,4,5-tetrahydro-lH-2-benzazepine-3-one with diborane by the procedure of Example 2 yielded 6-chloro-2,3,4,5-tetrahydro-lH-2-benzazepine which was purified as the hydrochloride salt; mp = 235-8C. pKa =
8.75.
Analysis; Calc.: C, 55.06; H, 6.01; N, 6.42; Cl, 32.51;
Found: C, 54.84; H, 5.98; N, 6.58; Cl, 32.24 The compounds of this invention, either in the form of the free base, or as a pharmaceutically-acceptable acid addition salt thereof, are enzyme inhibitors. In particular, as previously stated, they are inhibitors of norepinephrine N-methyl transferase ~NMT or phenethanol-amine N-methyl transferase--see Axelod, J. Bio. Chem. 237, 1657 (1962)]. Compounds which inhibit the conversion of norepinephrine to epinephrine are capable of lowering a high epinephrine-norepinephrine ratio in mammals, a physiological condition frequently associated with essential hypertension.
The compounds of this invention are thus capable of ameli-orating the epinephrine-norepinephrine imbalance in essen-tial hypert~nsion, an important aspect of the treatment of this disease state.
gZ
The effectiveness of the compounds as N-methyl transferase inhibitors has been measured in vitro using NMT
from rabbit adrenals. By using a series of decreasing concentrations of the inhibiting amine, usually starting with 1 x 10 4M continuing with 3 x 10 5M, 1 x 10 5M, etc., it was possible to determine a concentration at which the 50 percent inhibition of NMT was achieved. The negative reciprocal logarithm (pI50) of this number was also cal-culated as a useful index. Table 1, which follows, summarizes the information thus obtained; i.e., the determination of enzyme inhibition activity for the compounds of this invention.
In the table, column 1 gives the name of the compound, column 2, the concentration at which 50 percent inhibition of NMT is obtained and column 3, the pI50.
`~
,,~ o o ,1 o a ~9 ~ ~ co ~D, In ~ o~ D
L~
o In ~ ~ ~o ~o , ~o ~o 10 a) ~ ,, ~ o ~ ~1 O X X, X ,~.. ..
o O I ,~
- .4 H
I I ~ , ~ I ~ O O
o o o ,~ ~
~ ~ ~ o ~ o I o I o n~ ~ S O ~ ~.C ~.C
~J ~ ~ o Z ~ In ~ h n~l ` O `~
~,~ ~ a) ~
.C ~ O ~ O
O ~ I ~ ~ ~ Q
O ~ O N O N I rl N ~1 N
..C ~ ,.C N ,5 N I I N I N
I ~
~ Q r~ ~
....,. ~
I
~1~95~Z
The compounds of this invention are used as NMT
inhibitors, preferably in the form of an acid addition salt.
These salts can be mixed with one or more standard pharma-ceutical excipients and loaded into empty telescoping gelatin capsules or compressed into tablets. Aqueous solutions of these salts can be employed for parenteral administration, with an isotonic solution being particularly adapted for IV use. The compounds can be administered in dosage unit form for oral administration comprising an amount effective to inhibit epinephrine N-methyl transferase comprising a pharmaceutical carrier and as the active ingredient a chlorinated tetrahydro-2-benzazepine of formula I or II above. The amount of chlorinated tetrahydro-2-benzazepine present is about 50-500 mg. per dosage unit.
The compounds are administered to mammals at concentrations varying from about 1 to about 100 mg./kg. orally per day.
959;~:
SUPPLEMENTARY DISCLOSURE
Further investigations into the processes of making chlorinated tetrahydro-2-benzazepines according to the invention have confirmed that all compounds of the invention can be produced by reacting a suitable compound of the formula \ ~ \./ IV
with an azide in the presence of a strong acid to prepare a compound of the formula Cln~ I ~
v and reacting the compound of formula V with a reducing agent, as described previously. However, it has also been found that nqt all the compounds of the invention ~ -can be produded in any significant amount by reacting a compound of the formula H H H H H
~!-C-~C-C-C-Ha l o \~ III
with a Friedel-Crarts catalyst.
When compounds of formula III which have a chlorine atom in ortho-position to the side chain are reacted with a Friedel-crafts catalyst none or very `` ~119S92 little 9-chloro- or 8,9-dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine are produced. It appears that the presence of the ortho-chloro substituent in compounds of formula III activates a molecular rearrangement in which the halogen moiety, which preferably is a bromine moiety, of the benzylaminopropylhalogenide starting material is moved one carbon atom down the chain, thus forming the corresponding 8-chloro- or 7,~-dichloro-4-methyl-1,2,3,4-tetrahydroiso~uinoline.
Compounds of formula III which have no chlorine atom in ortho-position to the side chain will form, when reacted with a Friedel-Crafts catalyst according to the process of the invention, chlorinated tetrahydro-2-benzazepines.
This invention then, in a further aspect, provides a process for preparing a novel chlorinated tetrahydro-2-benzazepine of the formula Cl `1'~ ' ~
i7 and pharmaceutically-acceptable acid addition salts thereof. The process is characterized by reacting a compound of the formula Cl / ~
~ IV
\ ,,' \~/
~herein n is as defined above, with an azide in the presence of a stron~ acid to prepare a compound of the formula ~ r ,~
111~5~Z
Cl Cl ~ --~ H
Il I . >~ V~
and reacting the compound of formula V' with a reducing agent; and if desired recovering the compound of Formula I' in the form of a pharmaceutically-acceptable salt.
This invention further provides the novel compound 8,9-dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine and its pharm-aceutically acceptable acid addition salts.
The invention is further illustrated by the follow-ing examples.
Example 6 Preparation of 9-chloro-2,3,4,5-tetrahydro-lH-2-benzazepine In a 500 ml. three-neck, round-bottom flask equipped with magnetic stirrer, drying tube, thermometer, and addition funnel were placed 15 g. of 8-chloro-2-tetralone, 6 g. of sodium azide and 200 ml. of chloroform. The reaction mixture was cooled to about 15C. 50 Milliliters of 18N sulfuric acid were added thereto in dropwise fashion while keeping the temper-ature of the reaction between 15 and 20C. After the sulfuric acid had all been added, the reaction mixture was stirred at room temperature for two hours. It was then poured into a mixture of ice and water. The chloroform layer was separated and the aqueous layer extracted three times with chloroform.
The chloroform ex~racts were combined and the combined extracts washed with both 10 percent aqueous sodium carbonate and satur-ated aqueous sodium chloride and were then dried. Evaporation of the chloroform in vacuo yielded 16.4 g. of a solid com-30 prising a mixture of 9-chloro-2,3,4,5-tetrahydro-lH-2-benzazepin-3-one and the corresponding 3-benzazepine-2-one isomer. Six 1119~92 recrystallizations from toluene yielded 3.23 g~ of 9-chloro-2,3,4,5-tetrahydro-lH-2-benzazepin-3-one substantially free of its 3-benzazepin-2-one isomer. The compound melted at about 197-199C.
Analysis: Calc.: C, 61.39; H, 5.15; N, 7.16;
Cl, 18.12 Found: C, 61.53; H, 5.09; N, 7.40;
CL, 18.37 Following the procedure of Example 2 following, 3.3 g. of 9-chloro-2,3,4,5-tetrahydro-lH-2-benzazepin-3-one were reduced with diborane in tetrahydrofuran (THF) solution to yield 9-chloro-2,3,4,5-lH-2-benzazepine. 2.95 Grams of base were obtained following the purification procedure of Example 2.
The free base was converted to the corresponding hydrochloride salt which melted at about 244-246C. with decomposition after recrystallization from a 95:5 ethyl acetatemethanol solvent mixture; yield = about 2.2 g.
Analysis' Calc.: C, 55.06; H, 6.01; N, 6.42;
Cl, 32.51 Found: C, 54.75; H, 5.74; N, 9.46;
Cl, 32.68 Alternatively, the mixture of 9-chloro-2,3,4,5-tetrahydro-lH-2-benzazepin-3-one and its 3-benzazepine-2-one isomer can be reduced with diborane in THF to a mixture of the corresponding benzazepines. This isomer mixture can be readily separated via high pressure liquid chromatography with better yields than are found by crystallization of the benzazepinones from toluene. The HPLC system employed was a waters prep. l.c. system 500 with one silica 500 prep pack cartridge. The solvent used was an 8 1 gradient, consisting of
4 1 100% CHC13 and 4 1 of 98% CHC13-2% MeOH with 20 ml 14 N
NH40H. Thirty 250 ml fractions were collected at a flow rate ~ - SD27 -~19SgZ
of 250 ml/min. The effluent was monitored by absorbance at 280 mm.
Example 7 Preparation of 8,9-Dichloro-2,3,4,5-Tetrahydro-lH-2-benzacepine In a 4 liter beaker equipped with mechanical stirrer were placed 370 ml. of 12N aqueous hydrochloric acid.
162 Grams of 2,3-dichloroaniline were added with stirring.
The solution of the hydrochloride salt thus formed was cooled to about 0C. with an ice bath. Next, a solution of 73 g. of sodium nitrite in 200 ml. of water was added while maintaining the temperature below about 5C. After all of the sodium nitrite solution had been added, the diazotization reaction was stirred for an additional 45 minutes by which time all of the aniline hydrochloride had dissolved. The diazonium chloride solution was then neutralized by the addition of solid sodium carbonate. During the addition, the reaction temperature was maintained below about 5C. The reaction mixture foamed and, from the solution upon reaching neutrality, a precipitate separated. About 150 g. of sodium carbonate were used.
While the diazotization reaction was being carried out, in a separate 4 1. beaker equipped with mechanical stirrer were placed 138 g. of 90 percent cuprous chloride in 750 ml. of water. 160 Grams of sodium cyanide were added.
The reaction temperature rose to about 70C. The reaction mix-ture containing cuprous cyanide thus formed was cooled to room temperature.
Next, the cuprous cyanide solution was cooled to about 0C. and 500 ml. of toluene were added thereto.
The neutral diazonium solution formed as above was added slowly to the cuprous cyanide solution with vigorous stirring while maintaining the temperature below about 5C. by adding ll~g59Z
ice to the reaction mixture as needed. The reaction tempera-ture was maintained in the range 0 to 5C. for about 30 minutes. After all of the diazonium carbonate solution had been added, the reaction temperature was allowed to warm to room temperature overnight. The reaction mixture was then heated to about 50C. and was then cooled. The reaction mixture was extracted three times with toluene, the toluene extracts were combined and insoluble material removed therefrom by filtration. The combined toluene extracts were washed twice with water and once with saturated aqueous sodium chloride solu-tion, and were then dried. The solvent was removed therefrom in vacuo. Distillation of the residue in vacuo yielded 2,3-dichlorophenylcyanide formed in the above reaction boiling in the range 108-116C. at 7 torr; weight = 98.8 g. 2,3-Dichloro-phenylcyanide thus prepared was crystallized from hexane to yield 87 g. of a white crystalline material melting at 59-60C.
~nalysis Calc~: C, 48.88; H, 1.76; N, 8.14;
Cl, 41.72 Found: C, 48.65; H, 1.83; N, 8.28;
Cl, 42.04(41.94) One mole of methyl magnesium bromide in ethyl ether was placed in a 2 1., three-necked, round-bottom flask equipped with magnetic stirrer, condenser, calcium sulfate drying tube, and addition funnel under a nitrogen atmosphere.
87 Grams of 2,3-dichlorophenylcyanide were dissolved in 210 ml. of tetrahydrofuran. This solution was added in dropwise fashion to the methyl Grignard reagent at a rate such as to maintain gentle reflux of the ether. Reflux 2 hrs. after addi-tion was complete. The reaction mixture refluxed for 2 hrs.
after the addition had been completed and was then cooled and poured into 400 ml. of a mixture of ice and 12N aqueous hydrochloric acid. The acidic reaction mixture was allowed to 111~59Z
remain a~ room temperature overnight after which time it was extracted three times with ether. The ether extracts were combined and the combined extracts washed with water, 10 percent aqueous sodium carbonate and saturated aqueous sodium chloride.
The ether solution was dried and the solvent removed from the dried solution in vacuo. 96 Grams of a reddish oil, constituting 2,3-dichloroacetophenone remained as a residue in the flask.
Distillation of the residue yielded about 88.9 g. of 2,3-di-chloroacetophenone boiling in the range 77-84C. at .05 torr.
Next, 2,3-dichloroacetophenone was transformed to the corresponding phenyl acetic acid via a Willgerodt reaction as follows: 26.6 g. of 2,3-dichloroacetophenone were placed in a 200 ml., round-bottom flask equipped with magnetic stirrer, condenser, and drying tube. 10 Grams of sulfur were added plus 27.5 ml. of morpholine. The reaction mixture was heated in an oil bath to about 130C. overnight and was then cooled. The cooled mixture was poured into a mixture of toluene and water.
This consequent mixture was stirred until most of the solid material had dissolved. The mixture was then filtered through super cel to remove remaining insoluble matter. The toluene layer was separated and the aqueous layer extracted twice more with toluene. The toluene layers were combined and the combined layers washed with water followed by a saturated aqueous sodium chloride wash. The toluene solution was dried and the toluene removed by evaporation in vacuo. 33.2 Grams of a solid compris-ing N-(2,3-dichlorophenylthioacetyl)morpholine were obtained.
This solid was refluxed overnight with a 15 percent aqueous potassium hydroxide solution (88 g. of 85 percent KOH plus 500 ml. of water). The hydrolysis mixture was cooled and the cool-ed mixture extracted 3 times with ether. These ether extractswere discarded. The alkaline aqueous layer was then made acidic by the addition of 2N aqueous hydrGchloric acid. The acidic :~ 7' , layer was extracted 3 times with ether. The ether extracts were combined and the combined extracts washed with satura~ed aqueous sodium chloride. The ether extracts were dried and the ether removed therefrom by evaporation in vacuo. The residue weighing about 13.6 g. comprised 2,3-dichlorophenylacetic acid formed in the above reaction. The acid was recrystallized from water after decolorization with carbon. 6.4 Grams of 2,3-dichlorophenylacetic acid melting at about 126-128C were obtained.
In a 500 ml., round-bottom flask equipped with magnetic stirrer, condenser, and drying tube were placed 14.156 g. of 2, 3-dichlorophenylacetic acid and 200 ml. of carbon tetrachloride.
To this solution were added in dropwise fashion 29.5 ml. of oxalyl chloride. The reaction mixture was heated to refluxing tempera-ture for about 3 hours after which time it was cooled. Excess oxalyl chloride and carbon tetrachloride were removed by evapora-tion in vacuo. Distillation of the residue at 6 torr. yielded 12.8 g. of 2,3-dichlorophenylacetylchloride formed in the above reaction boiling at 126-127C.
A mixture of 15.2g. of anhydrous aluminum chloride and 200 ml. of methylene dichloride was placed in a 500 ml. four-neck, round-bottom flask equipped with magnetic stirrer, drying tube, thermometer, addition funnel, and sintered glass ethylene inlet under a nitrogen atmosphere. The mixture was cooled to about 5C. 12.8 Grams of 2,3-dichlorophenylacetylchloride in 50 ml. of methylenedichloride were added thereto in dropwise fashion while keeping the temperature below 5C. After the addition had been completed, ethylene was bubbled into the reac-tion mixture while still maintaining the temperature below about 10C. The stream of ethylene was bubbled in slowly for a period of about 6 hours. The reaction mixture was then stirred over-night at room temperature after which time it was poured onto ice. The methylenedichloride layer was separated and the aqueous 1~1959Z
mixture extracted twice more with methylenedichloride. The methylenedichloride extracts were combined and the combined ex-tracts washed with saturated aqueous sodium chloride solution and dried. Evaporation of the methylenedichloride yield as a residue 24.7 g. of an oil comprising 7,8-dichloro-~-tetralone formed in the above reaction. The residual oil solidified on cooling and was recrystallized from ether to yield 6.67 g. of the dichloro-tetralone melting at about 68-70C.
In a 500 ml., three-neck, round bottom flask equipped with magnetic stirrer, drying tube, thermometer, and addition funnel were placed 13.7 g. of 7,8-dichloro-2-tetralone, 4,6 g.
sodium azide and 200 ml. of chloroform. The reaction mixture was cooled to about 15C. and 50 ml. of 18N sulfuric acid were added thereto in dropwise fashion, while keeping the reaction temperature between 15 and 20C. After the addition of the sulfuric acid had been completed, the reaction mixture was stirred at room temperature for an additional two hours, after which time it was poured onto ice. The chloroform layer was separated and the aqueous mixture extracted three more times with chloroform. The chloroform extracts were combined and the combined extracts washed with 10 percent aqueous sodium carbonate and saturated aqueous sodium chloride solution and were then dried. Evaporation of the chloroform in vacuo yielded as a residue 14.4 g. of a mixture of 8,9-dichloro-3-benzazepin-2-one and 8,9-dichloro-2-benzazepin-3-one. The desired 2-benzazepin-3-one isomer was obtained by recrystallization from toluene. A
five-fold recrystallization yielded pure 8,9-dichloro-2-benzazepin-3-one melting at about 192-194C; yield = 1.8 g.
Thin layer chromatography indicated that none of the 8,9-di-chloro-3-benzazepin-2-one was present.
Analysis; Calc.: C, 52.20; H, 3.94; N, 6.09 Found: C, 52.45; H, 4.06; N, 5.94 ll:l9S~;2 Following the procedure of Example 2, 1.7 g. of 8,9-dichloro-2-benzazepin-3-one were reduced with 23 ml. of a lM
diborane ~olution in THF. 8,9-Dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine formed in the above reaction was purified by the procedure of Example 2 and was obtained as a white solid melting at about 61-63C.; yield = 1.667 g.
The corresponding hydrochloride salt was prepared in ether. Recrystallization of the ether-insoluble precipitate from a mixture of isopropanol and methanol (90:10) yielded 1.237 g. of 8,9-dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine hydrochloride melting 259-261C.
Analysis; Calc.: C, 47.55; H, 4.79; N, 5.55;
Cl, 42.11 Found: C, 47.79; H, 5.03; N, 5.65;
Cl, 42.21 - SD 32a -~gS9Z
The compounds of the invention including the 9-chloro and 8,9-chloro compounds are, as previously stated, inhibitors of norepinephrine N-methyl transferase (NMT). The effectiveness of 9-chloro- and 8,9-dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine and their pharmaceutically acceptable acid addition salts have been measured in the same way as described above.
Table 2, which follows, summarizes the results.
In the table, column 1 gives the name of the compound, column 2, the concentration at which 50% inhibition of NMT is obtained and column 3, pI50.
Table 2 i Name 50~ Inhibitory pI50 Concentration 9-Chloro-2,3,4,5-tetrahydro-lH-2-benzazepine maleate 1.0 x 10 6 5.98 2.0 x 10 6 5.70*
8,9-dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine 7 hydrochloride 1.5 x 10 6.81 7.8 x 10 8 7.11*
* - NMT from rat brain As previously stated, the compounds are preferably administered in the form of an acid addition salt mixed with 1 or more standard pharmaceutical excipients.
-~ - SD 33
NH40H. Thirty 250 ml fractions were collected at a flow rate ~ - SD27 -~19SgZ
of 250 ml/min. The effluent was monitored by absorbance at 280 mm.
Example 7 Preparation of 8,9-Dichloro-2,3,4,5-Tetrahydro-lH-2-benzacepine In a 4 liter beaker equipped with mechanical stirrer were placed 370 ml. of 12N aqueous hydrochloric acid.
162 Grams of 2,3-dichloroaniline were added with stirring.
The solution of the hydrochloride salt thus formed was cooled to about 0C. with an ice bath. Next, a solution of 73 g. of sodium nitrite in 200 ml. of water was added while maintaining the temperature below about 5C. After all of the sodium nitrite solution had been added, the diazotization reaction was stirred for an additional 45 minutes by which time all of the aniline hydrochloride had dissolved. The diazonium chloride solution was then neutralized by the addition of solid sodium carbonate. During the addition, the reaction temperature was maintained below about 5C. The reaction mixture foamed and, from the solution upon reaching neutrality, a precipitate separated. About 150 g. of sodium carbonate were used.
While the diazotization reaction was being carried out, in a separate 4 1. beaker equipped with mechanical stirrer were placed 138 g. of 90 percent cuprous chloride in 750 ml. of water. 160 Grams of sodium cyanide were added.
The reaction temperature rose to about 70C. The reaction mix-ture containing cuprous cyanide thus formed was cooled to room temperature.
Next, the cuprous cyanide solution was cooled to about 0C. and 500 ml. of toluene were added thereto.
The neutral diazonium solution formed as above was added slowly to the cuprous cyanide solution with vigorous stirring while maintaining the temperature below about 5C. by adding ll~g59Z
ice to the reaction mixture as needed. The reaction tempera-ture was maintained in the range 0 to 5C. for about 30 minutes. After all of the diazonium carbonate solution had been added, the reaction temperature was allowed to warm to room temperature overnight. The reaction mixture was then heated to about 50C. and was then cooled. The reaction mixture was extracted three times with toluene, the toluene extracts were combined and insoluble material removed therefrom by filtration. The combined toluene extracts were washed twice with water and once with saturated aqueous sodium chloride solu-tion, and were then dried. The solvent was removed therefrom in vacuo. Distillation of the residue in vacuo yielded 2,3-dichlorophenylcyanide formed in the above reaction boiling in the range 108-116C. at 7 torr; weight = 98.8 g. 2,3-Dichloro-phenylcyanide thus prepared was crystallized from hexane to yield 87 g. of a white crystalline material melting at 59-60C.
~nalysis Calc~: C, 48.88; H, 1.76; N, 8.14;
Cl, 41.72 Found: C, 48.65; H, 1.83; N, 8.28;
Cl, 42.04(41.94) One mole of methyl magnesium bromide in ethyl ether was placed in a 2 1., three-necked, round-bottom flask equipped with magnetic stirrer, condenser, calcium sulfate drying tube, and addition funnel under a nitrogen atmosphere.
87 Grams of 2,3-dichlorophenylcyanide were dissolved in 210 ml. of tetrahydrofuran. This solution was added in dropwise fashion to the methyl Grignard reagent at a rate such as to maintain gentle reflux of the ether. Reflux 2 hrs. after addi-tion was complete. The reaction mixture refluxed for 2 hrs.
after the addition had been completed and was then cooled and poured into 400 ml. of a mixture of ice and 12N aqueous hydrochloric acid. The acidic reaction mixture was allowed to 111~59Z
remain a~ room temperature overnight after which time it was extracted three times with ether. The ether extracts were combined and the combined extracts washed with water, 10 percent aqueous sodium carbonate and saturated aqueous sodium chloride.
The ether solution was dried and the solvent removed from the dried solution in vacuo. 96 Grams of a reddish oil, constituting 2,3-dichloroacetophenone remained as a residue in the flask.
Distillation of the residue yielded about 88.9 g. of 2,3-di-chloroacetophenone boiling in the range 77-84C. at .05 torr.
Next, 2,3-dichloroacetophenone was transformed to the corresponding phenyl acetic acid via a Willgerodt reaction as follows: 26.6 g. of 2,3-dichloroacetophenone were placed in a 200 ml., round-bottom flask equipped with magnetic stirrer, condenser, and drying tube. 10 Grams of sulfur were added plus 27.5 ml. of morpholine. The reaction mixture was heated in an oil bath to about 130C. overnight and was then cooled. The cooled mixture was poured into a mixture of toluene and water.
This consequent mixture was stirred until most of the solid material had dissolved. The mixture was then filtered through super cel to remove remaining insoluble matter. The toluene layer was separated and the aqueous layer extracted twice more with toluene. The toluene layers were combined and the combined layers washed with water followed by a saturated aqueous sodium chloride wash. The toluene solution was dried and the toluene removed by evaporation in vacuo. 33.2 Grams of a solid compris-ing N-(2,3-dichlorophenylthioacetyl)morpholine were obtained.
This solid was refluxed overnight with a 15 percent aqueous potassium hydroxide solution (88 g. of 85 percent KOH plus 500 ml. of water). The hydrolysis mixture was cooled and the cool-ed mixture extracted 3 times with ether. These ether extractswere discarded. The alkaline aqueous layer was then made acidic by the addition of 2N aqueous hydrGchloric acid. The acidic :~ 7' , layer was extracted 3 times with ether. The ether extracts were combined and the combined extracts washed with satura~ed aqueous sodium chloride. The ether extracts were dried and the ether removed therefrom by evaporation in vacuo. The residue weighing about 13.6 g. comprised 2,3-dichlorophenylacetic acid formed in the above reaction. The acid was recrystallized from water after decolorization with carbon. 6.4 Grams of 2,3-dichlorophenylacetic acid melting at about 126-128C were obtained.
In a 500 ml., round-bottom flask equipped with magnetic stirrer, condenser, and drying tube were placed 14.156 g. of 2, 3-dichlorophenylacetic acid and 200 ml. of carbon tetrachloride.
To this solution were added in dropwise fashion 29.5 ml. of oxalyl chloride. The reaction mixture was heated to refluxing tempera-ture for about 3 hours after which time it was cooled. Excess oxalyl chloride and carbon tetrachloride were removed by evapora-tion in vacuo. Distillation of the residue at 6 torr. yielded 12.8 g. of 2,3-dichlorophenylacetylchloride formed in the above reaction boiling at 126-127C.
A mixture of 15.2g. of anhydrous aluminum chloride and 200 ml. of methylene dichloride was placed in a 500 ml. four-neck, round-bottom flask equipped with magnetic stirrer, drying tube, thermometer, addition funnel, and sintered glass ethylene inlet under a nitrogen atmosphere. The mixture was cooled to about 5C. 12.8 Grams of 2,3-dichlorophenylacetylchloride in 50 ml. of methylenedichloride were added thereto in dropwise fashion while keeping the temperature below 5C. After the addition had been completed, ethylene was bubbled into the reac-tion mixture while still maintaining the temperature below about 10C. The stream of ethylene was bubbled in slowly for a period of about 6 hours. The reaction mixture was then stirred over-night at room temperature after which time it was poured onto ice. The methylenedichloride layer was separated and the aqueous 1~1959Z
mixture extracted twice more with methylenedichloride. The methylenedichloride extracts were combined and the combined ex-tracts washed with saturated aqueous sodium chloride solution and dried. Evaporation of the methylenedichloride yield as a residue 24.7 g. of an oil comprising 7,8-dichloro-~-tetralone formed in the above reaction. The residual oil solidified on cooling and was recrystallized from ether to yield 6.67 g. of the dichloro-tetralone melting at about 68-70C.
In a 500 ml., three-neck, round bottom flask equipped with magnetic stirrer, drying tube, thermometer, and addition funnel were placed 13.7 g. of 7,8-dichloro-2-tetralone, 4,6 g.
sodium azide and 200 ml. of chloroform. The reaction mixture was cooled to about 15C. and 50 ml. of 18N sulfuric acid were added thereto in dropwise fashion, while keeping the reaction temperature between 15 and 20C. After the addition of the sulfuric acid had been completed, the reaction mixture was stirred at room temperature for an additional two hours, after which time it was poured onto ice. The chloroform layer was separated and the aqueous mixture extracted three more times with chloroform. The chloroform extracts were combined and the combined extracts washed with 10 percent aqueous sodium carbonate and saturated aqueous sodium chloride solution and were then dried. Evaporation of the chloroform in vacuo yielded as a residue 14.4 g. of a mixture of 8,9-dichloro-3-benzazepin-2-one and 8,9-dichloro-2-benzazepin-3-one. The desired 2-benzazepin-3-one isomer was obtained by recrystallization from toluene. A
five-fold recrystallization yielded pure 8,9-dichloro-2-benzazepin-3-one melting at about 192-194C; yield = 1.8 g.
Thin layer chromatography indicated that none of the 8,9-di-chloro-3-benzazepin-2-one was present.
Analysis; Calc.: C, 52.20; H, 3.94; N, 6.09 Found: C, 52.45; H, 4.06; N, 5.94 ll:l9S~;2 Following the procedure of Example 2, 1.7 g. of 8,9-dichloro-2-benzazepin-3-one were reduced with 23 ml. of a lM
diborane ~olution in THF. 8,9-Dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine formed in the above reaction was purified by the procedure of Example 2 and was obtained as a white solid melting at about 61-63C.; yield = 1.667 g.
The corresponding hydrochloride salt was prepared in ether. Recrystallization of the ether-insoluble precipitate from a mixture of isopropanol and methanol (90:10) yielded 1.237 g. of 8,9-dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine hydrochloride melting 259-261C.
Analysis; Calc.: C, 47.55; H, 4.79; N, 5.55;
Cl, 42.11 Found: C, 47.79; H, 5.03; N, 5.65;
Cl, 42.21 - SD 32a -~gS9Z
The compounds of the invention including the 9-chloro and 8,9-chloro compounds are, as previously stated, inhibitors of norepinephrine N-methyl transferase (NMT). The effectiveness of 9-chloro- and 8,9-dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine and their pharmaceutically acceptable acid addition salts have been measured in the same way as described above.
Table 2, which follows, summarizes the results.
In the table, column 1 gives the name of the compound, column 2, the concentration at which 50% inhibition of NMT is obtained and column 3, pI50.
Table 2 i Name 50~ Inhibitory pI50 Concentration 9-Chloro-2,3,4,5-tetrahydro-lH-2-benzazepine maleate 1.0 x 10 6 5.98 2.0 x 10 6 5.70*
8,9-dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine 7 hydrochloride 1.5 x 10 6.81 7.8 x 10 8 7.11*
* - NMT from rat brain As previously stated, the compounds are preferably administered in the form of an acid addition salt mixed with 1 or more standard pharmaceutical excipients.
-~ - SD 33
Claims (20)
1. A process for preparing a novel chlorinated tetrahydro-2-benzazepine of the formula I
wherein n is 1 or 2, provided that when n is 2, the chlorine atoms are vicinal, and that, when n is 1, the chlorine atom occupies the 8-position; and pharmaceutically-acceptable acid addition salts thereof; which process is characterized by reacting a compound of the formula III
wherein n is as defined above,provided that none of the chlorine atoms occupies a position ortho to the side chain, with a Friedel-Crafts catalyst of the Lewis acid type or by reacting a compound of the formula IV
wherein n is as defined above, with an azide in the presence of a strong acid to prepare a compound of the formula V
and reacting the compound of formula V with a reducing agent; and if desired recovering the compound of Formula I
in the form of a pharmaceutically-acceptable salt.
wherein n is 1 or 2, provided that when n is 2, the chlorine atoms are vicinal, and that, when n is 1, the chlorine atom occupies the 8-position; and pharmaceutically-acceptable acid addition salts thereof; which process is characterized by reacting a compound of the formula III
wherein n is as defined above,provided that none of the chlorine atoms occupies a position ortho to the side chain, with a Friedel-Crafts catalyst of the Lewis acid type or by reacting a compound of the formula IV
wherein n is as defined above, with an azide in the presence of a strong acid to prepare a compound of the formula V
and reacting the compound of formula V with a reducing agent; and if desired recovering the compound of Formula I
in the form of a pharmaceutically-acceptable salt.
2. A process for preparing a novel chlorinated tetrahydro-2-benzazepine of the formula I
wherein n is 1 or 2, provided that when n is 2, the chlorine atoms are vicinal, and that, when n is 1, the chlorine atom occupies the 8-position; and pharmaceutically-acceptable acid addition salts thereof; which process is characterized by reacting a compound of the formula IV
wherein n is as defined aobve, with an azide in the presence of a strong acid to prepare a compound of the formula V
and reacting the compound of formula V with a reducing agent; and if desired recovering the compound of Formula I
in the form of a pharmaceutically-acceptable salt.
wherein n is 1 or 2, provided that when n is 2, the chlorine atoms are vicinal, and that, when n is 1, the chlorine atom occupies the 8-position; and pharmaceutically-acceptable acid addition salts thereof; which process is characterized by reacting a compound of the formula IV
wherein n is as defined aobve, with an azide in the presence of a strong acid to prepare a compound of the formula V
and reacting the compound of formula V with a reducing agent; and if desired recovering the compound of Formula I
in the form of a pharmaceutically-acceptable salt.
3. A process for preparing a novel chlorinated tetrahydro-2-benzazepine of the formula I
wherein n is 1 or 2, provided that none of the chlorine atoms occupies the 9-position, that when n is 2, the chlorine atoms are vicinal, and that, when n is 1, the chlorine atom occupies the 8-position; and pharmaceutically-acceptable acid addition salts thereof; which process is characterized by reacting a compound of the formula III
wherein n is as defined above, provided that none of the chlorine atoms occupies a position ortho to the side chain, with a Friedel-Crafts catalyst of the Lewis acid type.
wherein n is 1 or 2, provided that none of the chlorine atoms occupies the 9-position, that when n is 2, the chlorine atoms are vicinal, and that, when n is 1, the chlorine atom occupies the 8-position; and pharmaceutically-acceptable acid addition salts thereof; which process is characterized by reacting a compound of the formula III
wherein n is as defined above, provided that none of the chlorine atoms occupies a position ortho to the side chain, with a Friedel-Crafts catalyst of the Lewis acid type.
4. The process of Claim 3 characterized in that a compound of Formula III is reacted with aluminum chloride.
5. The process of Claim 2 characterized in that a compound of Formula IV is reacted with sodium azide in the presence of a strong acid.
6. The process of Claim 2 characterized in that a compound of Formula IV is reacted with sodium azide in the presence of sulfuric acid.
7. The process of Claim 3 characterized in that a compound of Formula III is reacted with aluminum chloride at from 100°C. to 200°C.
8. The process of Claim 2 characterized in that a compound of Formula IV is reacted with sodium azide in the presence of sulfuric acid at from 0°C. to the ambient temperature.
9. The process of Claim 2 characterized in that a compound of Formula IV is reacted with an azide in the presence of a strong acid, and the resulting compound of Formula V is reduced with diborane.
10. The process of Claim 2 characterized in that a compound of Formula IV is reacted with an azide in the presence of a strong acid and the resulting compound of Formula V is reduced with diborane at from the ambient tem-perature to 100°C.
11. The process of Claim 2 for preparing 8-chloro-2,3,4,5,-tetrahydro-1H-2-benzazepine, characterized in that 7-chloro-2-tetralone is reacted with sodium azide, and the resulting 8-chloro-2,3,4,5-tetrahydro-1H-2-benzazepine-3-one is reduced with diborane.
12. The process of Claim 2 for preparing 6,7-dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine characterized in that 5,6-dichloro-2-tetralone is reacted with sodium azide, and the resulting 6,7-dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine-3-one is reduced with diborane.
13. The process of Claim 2 for preparing 7,8-di-chloro-2,3,4,5-tetrahydro-1H-2-benzazepine, characterized in that 6,7-dichloro-2-tetralone is reacted with sodium azide, and the resulting 7,8-dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine-3-one is reduced with diborane.
14. A novel chlorinated tetrahydro-2-benzazepine of the formula I
wherein n is 1 or 2, provided that when n is 2, the chlorine atoms are vicinal, and that, when n is 1, the chlorine atom occupies the 8-position; and pharmaceutically-acceptable acid addition salts thereof; whenever prepared by the process of claim 1 or an obvious chemical equivalent thereof.
wherein n is 1 or 2, provided that when n is 2, the chlorine atoms are vicinal, and that, when n is 1, the chlorine atom occupies the 8-position; and pharmaceutically-acceptable acid addition salts thereof; whenever prepared by the process of claim 1 or an obvious chemical equivalent thereof.
15. The compound of Claim 14, whenever prepared by the process of Claim 2, or 5 or an obvious chemical equivalent thereof.
16. The compound of Claim 14, whenever prepared by the process of Claim 9 or 10 or an obvious chemical equivalent thereof.
17. A novel chlorinated tetrahydro-2-benzazepine of the formula I
wherein n is 1 or 2, provided that none of the chlorine atoms occupies the 9-position, that when n is 2, the chlorine atoms are vicinal, and that, when n is 1, the chlorine atom occupies the 8-position; and pharmaceutically-acceptable acid addition salts thereof; whenever prepared by the process of Claim 3, 4 or 7 or an obvious chemical equivalent thereof.
wherein n is 1 or 2, provided that none of the chlorine atoms occupies the 9-position, that when n is 2, the chlorine atoms are vicinal, and that, when n is 1, the chlorine atom occupies the 8-position; and pharmaceutically-acceptable acid addition salts thereof; whenever prepared by the process of Claim 3, 4 or 7 or an obvious chemical equivalent thereof.
18. 8-Chloro-2,3,4,5-tetrahydro-1H-2-benzazepine and pharmaceutically acceptable acid addition salts thereof, whenever prepared by the process of claim 11 or an obvious chemical equivalent thereof.
19. 6,7-Dichloro-2,3,4,5-tetrahydro-1H-2-benz-azepine and pharmaceutically acceptable acid addition salts thereof, whenever prepared by the process of claim 12 or an obvious chemical equivalent thereof.
20. 7,8-Dichloro-2,3,4,5-tetrahydro-1H-2-benz-azepine and pharmaceutically acceptable acid addition salts thereof whenever prepared by the process of claim 13 or an obvious chemical equivalent thereof.
Claims supported by the Supplementary Disclosure SD 21. A process for preparing a novel chlorinated tetrahydro-2-benzazepine of the formula I' and pharmaceutically-acceptable acid addition salts thereof;
which process is characterized by reacting a compound of the formula IV' with an azide in the presence of a strong acid to prepare a compound of the formula V' and reacting the compound of formula V' with a reducing agent;
and if desired recovering the compound of Formula I' in the form of a pharmaceutically-acceptable salt.
SD22. The process of claim 21 characterized in that the compound of Formula IV' is reacted with sodium azide in the presence of a strong acid.
SD23. The process of claim 21 characterized in that the compound of Formula IV' is reacted with sodium azide in the presence of sulfuric acid.
SD24. The process of claim 21 characterized in that the compound of Formula IV' is reacted with sodium azide in the presence of sulfuric acid at from 0.C. to the ambient temperature.
SD25. The process of claim 21 characterized in that the compound of Formula IV' is reacted with an azide in the presence of a strong acid, and the resulting compound of Formula V' is reduced with diborane.
SD26. The process of claim 21 for preparing 8,9-dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine, characterized in that 7,8-dichloro-2-tetralone is reacted with sodium azide in the presence of a strong acid, and the resulting 8,9-dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine-3-one is reduced with diborane at from the ambient temperature to 100°C.
SD27. 8,9-dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine and pharmaceutically-acceptable acid addition salts thereof; whenever prepared by the process of claim 21, 24 or 26 or an obvious chemical equivalent thereof.
Claims supported by the Supplementary Disclosure SD 21. A process for preparing a novel chlorinated tetrahydro-2-benzazepine of the formula I' and pharmaceutically-acceptable acid addition salts thereof;
which process is characterized by reacting a compound of the formula IV' with an azide in the presence of a strong acid to prepare a compound of the formula V' and reacting the compound of formula V' with a reducing agent;
and if desired recovering the compound of Formula I' in the form of a pharmaceutically-acceptable salt.
SD22. The process of claim 21 characterized in that the compound of Formula IV' is reacted with sodium azide in the presence of a strong acid.
SD23. The process of claim 21 characterized in that the compound of Formula IV' is reacted with sodium azide in the presence of sulfuric acid.
SD24. The process of claim 21 characterized in that the compound of Formula IV' is reacted with sodium azide in the presence of sulfuric acid at from 0.C. to the ambient temperature.
SD25. The process of claim 21 characterized in that the compound of Formula IV' is reacted with an azide in the presence of a strong acid, and the resulting compound of Formula V' is reduced with diborane.
SD26. The process of claim 21 for preparing 8,9-dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine, characterized in that 7,8-dichloro-2-tetralone is reacted with sodium azide in the presence of a strong acid, and the resulting 8,9-dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine-3-one is reduced with diborane at from the ambient temperature to 100°C.
SD27. 8,9-dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine and pharmaceutically-acceptable acid addition salts thereof; whenever prepared by the process of claim 21, 24 or 26 or an obvious chemical equivalent thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA372,377A CA1122528A (en) | 1977-07-01 | 1981-03-05 | Chlorinated tetrahydro-2-benzazepines, n-methyl transferase inhibitors |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US81209677A | 1977-07-01 | 1977-07-01 | |
| US12233380A | 1980-02-19 | 1980-02-19 | |
| US122,333 | 1980-02-19 | ||
| US812,096 | 1985-12-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1119592A true CA1119592A (en) | 1982-03-09 |
Family
ID=26820416
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000306684A Expired CA1119592A (en) | 1977-07-01 | 1978-06-30 | Chlorinated tetrahydro-2-benzazepines, n-methyl transferase inhibitors |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1119592A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001049669A1 (en) * | 2000-01-03 | 2001-07-12 | Rpg Life Sciences Limited | A process for the preparation of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine, commonly known as lamotrigine |
| CN114620731A (en) * | 2020-12-14 | 2022-06-14 | 新疆新特晶体硅高科技有限公司 | Recovery method and recovery device for reduction tail gas of polycrystalline silicon |
-
1978
- 1978-06-30 CA CA000306684A patent/CA1119592A/en not_active Expired
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001049669A1 (en) * | 2000-01-03 | 2001-07-12 | Rpg Life Sciences Limited | A process for the preparation of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine, commonly known as lamotrigine |
| US6639072B1 (en) | 2000-01-03 | 2003-10-28 | Rpg Life Sciences Limited | Process for the preparation of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine, commonly known as lamotrigine |
| CN114620731A (en) * | 2020-12-14 | 2022-06-14 | 新疆新特晶体硅高科技有限公司 | Recovery method and recovery device for reduction tail gas of polycrystalline silicon |
| CN114620731B (en) * | 2020-12-14 | 2024-02-23 | 新疆新特晶体硅高科技有限公司 | Method and device for recovering reduction tail gas of polycrystalline silicon |
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