CA1077042A - (?)-4-hydroxy-1,2,9,10-tetraalkoxy-aporphine derivatives - Google Patents
(?)-4-hydroxy-1,2,9,10-tetraalkoxy-aporphine derivativesInfo
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Abstract
A B S T R A C T
The new 4-hydroxy-aporphine derivatives according to the present invention are compounds of the general formula:
(I) wherein R1, R2, R3 and R4, which may be the same or different, are methyl or ethyl radicals, R5 is a hydrogen atom or a straight-chained, cyclic or branched alkyl radical containing up to 5 carbon atoms and the symbol X or Y in the trans- pos-ition to the 6a hydrogen atom represents a hydroxyl group while the remaining X or Y symbol represents a hydrogen atom, with the proviso that when R5 is a methyl radical, then at least one of the substituents R1, R2, R3 or R4 is an ethyl radical.
These products useful on the cardiovascular system.
The new 4-hydroxy-aporphine derivatives according to the present invention are compounds of the general formula:
(I) wherein R1, R2, R3 and R4, which may be the same or different, are methyl or ethyl radicals, R5 is a hydrogen atom or a straight-chained, cyclic or branched alkyl radical containing up to 5 carbon atoms and the symbol X or Y in the trans- pos-ition to the 6a hydrogen atom represents a hydroxyl group while the remaining X or Y symbol represents a hydrogen atom, with the proviso that when R5 is a methyl radical, then at least one of the substituents R1, R2, R3 or R4 is an ethyl radical.
These products useful on the cardiovascular system.
Description
~0'7704'2 The new 4-hydroxy-aporphine derivatives according to the present invention are compounds of the general formula:
R 2 0~ H R S
11 1 .
wherein Rl R2, R3 and R4, which may be the same or different, are methyl or ethyl radicals, R5 is a hydrogen atom or a straight-chained, cyclic or branched alkyl radical containing up to 5 carbon atoms and the symbol X or Y in the trans- pos-ition to the 6a hydrogen atom represents a hydroxyl group while the remaining X or Y symbol represents a hydrogen atom, with the proviso that when R5 is a methyl radical, then at least one of the substituents Rl, R2, R3 or R4 is an ethyl radical.
The pharmaceutically acceptable acid addition salts are also encompassed by this invention.
The wavy line in the 6a-position of the formula indicates an a- or ~-bonding of the hydrogen atom. When the hydrogen atom has the ~- configuration, then X is a hydroxyl group and Y is a hydrogen atom. When the hydrogen atom has the ~-configuration, Y is a hydroxyl group and X is a hydrogen atom.
When R5 is a straight-chained alkyl radical, it may be a methyl, ethyl, n-propyl, n-butyl or n-pentyl radical.
Cyclic radicals include, for example cycloalkylalkyl radicals, ` ~07704Z
such as cyclopropylmethyl and cyclobutylmethyl radicals.
Branched-chain alkyl radicals include, for example, isopropyl, isobutyl and isopentyl radicals.
Compounds of general formula (I) are preferred in which Rl, R2, R3 and/or R4 is a methyl or ethyl radical and R5 is a hydrogen atom or a methyl, ethyl or n-propyl radical.
Prior to our invention, only a limited number of compounds with the aporphine structure according to general formula (I) (with a hydroxyl group in the 4-position) have been described. Besides the naturally-occuring (t)-cataline ( (~)-l-hydroxy-5-oxo-5H-pyrido l3~2a~1 phenoxazine-3-carboxylic acid) isolated from Glaucium flavum Cr. var. vestitum Tetra~
hedron Letters, p. 2033/1972, (~)-cataline has recently been synthesised by the oxidation of (t)-thaliporphine ((~)-5, 6, 6a, 7-tetrahydro-2, 9, 10-trimethoxy-6-methyl-4H-dibenzo [de, g~ quinolin-l-ol) with lead tetraacetate in acetic acid yield-ing (t)-4~-acetoxythaliporphine, which was then acid hydrolysed with hydrochloric acid at ambient temperature to give (t)_4~_ hydroxythaliporphine which was, in turn, 0-methylated with diazomethane (J.C.S. Chem. Comm., p. 306/1975).
Aporphine derivatives have also been prepared by the intramolecular, non-phenolic oxidative coupling of tetrahydro-isoquinolines (J.A.C.S., 95, 6861/1973). However, prior to our invention, 4-hydroxy-aporphine derivatives have not been obtain-able by this route. This coupling requires the cyclization of laudanosine in a solvent mixture of fluorosulphinic acid, methylene chloride and trifuloroacetic acid in a reaction solu-tion of vanadyl trifluoride in trifluoroacetic acid. This pro-cess yields glaucine which is unsubstituted in the 4-position.
1~77042 We have now found that the above-described reaction can be directed in such a manner that there is formed a 4-hydro-xy-substituted aporphine derivative of general formula (I) or general formula ~I') when, instead of the solvent mixture of methylene chloride and trifuloroacetic acid, there is used trifluoroacetic acid without the admixture of organic solvents.
This finding is extradordinarily surprising, since the hydroxylation effect according to our invention also in-volves a remarkably high regio-and stero-selectivity. It is also surprising that hydroxyaporphines are exclusively formed which carry the hydroxyl function in the 4-position since the aporphine system contains three reactive benzylic positions.
Since the l-position of general formula II contains a more reactive hydrogen atom, it would be expected that a hydroxyl-ation, if at all, would take place at this position, however, under the conditions of the process according to the present invention, the hydroxyl group enters preponderantly in the trans 4-position (referred to the 6a-hydrogen atom in general formula (I) or (I'). A further characteristic feature of the present invention is that the chiralic center in the tetrahydroisoquin-oline (C-l) and in the aporphine ring system (C-6a) remains intact under the reaction conditions, i.e. that when using the optically-active tetrahydroisoquinolines of general formula (II), the corresponding optically-active 4-hydroxyaporphine of formula (I) or (I') are obtained.
1~7704Z
Consequently, the present invention also provides a process for the preparation of compounds of the general formula:
X ' ~ , Y ' R' ~0~
R 2~;,N_Rl 5 I H (I ' ) R' 30~ ~
o R l 4 as well as of the salts thereof with organic and inorganic : acids, wherein R'l, R'2, R'3 and R'4, which may be the same or different, are methyl or ethyl radicals and R'5 is a hydro-gen atom or a straight-chained, cyclic or branched alkyl radi-cal containing up to 5 carbon atoms and the symbol X' or Y' in the trans-position to the 6a-hydrogen atom represents a hydroxyl group, while the remaining X' or Y' symbol represents a hydrogen atom, by the cyclisation of a compound of the general formula:
R ' 1 O~
R 2 ~ N-R 5 ~ (II), R ' 30 /[~
R l 4 wherein R'l, R'2, R'3, R'4 and R'5 have the same meanings as above, in trifluoroacetic acjd, by reaction with vanadyl tri-fluoride. The reaction is carried out at a temperature of from -50 to 10C, preferably from -15 to 0C., without the admixture of an organic solvent. The vanadyl trifluoride used in a molar excess and water being subsequently added. The compound of general formula (I') is thus obtained and, if desired, converted into an acid addition salt.
As starting materials for the process according to the present invention, there can be used not only the racemic but also the enantiomeric compounds of general formula (II).
Some of these starting materials are known, for example, laudanosine (l-C(3,4-dimethoyxphenyl)methyl] -1,2,3,4-tetra-hydro-6, 7-dimethoxy-2-methylisoquinoline) and N-ethyl- and N-propyl-tetrahydropapaverine. They are preferably prepared from the corresponding tetrahydroisoquinolines, for example tetrahydropapaverine, by alkylation (J. Chem. Soc., p. 1481/
1962) or from the corresponding isoquinolines, for example, papaverine (l-r(3,4-dimethoxyphenyl)methyl~-6,7-dimethoxyiso-quinoline) by alkylation and subsequent reduction, preferably by means of sodium borohydride (Ber. 90, 1997/1957).
For carrying out the reaction, the starting compounds of general formula (II) are dissolved, while cooling, in tri-fluoroacetic acid and mixed dropwise at -10 to -15C with an excess amount of a vanadyl trifluoride trifluoroacetic acid solution, the reaction mixture becoming a red-violet color.
It is generally preferable to use about a 2.5 mol excess of vanadyl fluoride per mol of tetrahydroisoquinoline to assure all the starting material is reacted.
After the addition of the vanadyl trifluoride solu-tion, the reaction mixture is further stirred for about 3 to ~07704'2 4 hours at -10 to -15C and thereafter allowed to rise to ambient temperature. After stirring for one hour at ambient temperature, the trifluoroacetic acid is removed in a vacuum and the residue, after being rendered alkaline, is partitioned between water and an organic solvent, for example, chloroform, methylene chloride or diethyl ether.
The 4-hydroxyaporphine may be obtained from the organic phase either by direct crystallization from an organic solvent or from an organic solvent mixture or after previous chromatographic separation on an inert carrier material, for example, silica gel or basic aluminum oxide by removal of the elution agent.
According to a preferred variant of the new process, the amount of expensive trifluoroacetic acid needed for the preparation of the vanadyl trifluoride solution (because of the poor solubility of vanadyl trifluoride in trifluoroacetic acid, relatively large volumes are necessary) is replaced by an inex-pensive liquified sulphur dioxide. In this case, it is preferable to place the vanadyl trifluoride in liquified sulphur dioxide and to add dropwise a solution of the tetra-hydroisoquinoline in trifluoroacetic acid at a temperature of from -15 to -50C. Here, too, a coloration of the reaction mixture towards red-violet is observed. At the end of the dropwise addition, the reaction mixture is stirred for 4 - 5 hours at -10 to -15C. The sulphur dioxide is then allowed to evaporate at ambient temperatures, the trifluoroacetic acid is removed in a vacuum and the residue treated as described above.
The salts of compounds of general formula (I) or (I') can be obtained by neutralization of the free bases with pharmacologically compatible inorganic or organic acids, for example, hydrochloric acid, sulphuric acid, phosphoric acid, '1~7704Z
hydrobromic acid, acetic acid, tartaric acid, lactic acid, citric acid, malic acid, salicyclic acid, ascorbic acid, malonic acid, maleic acid or succinic acid.
The following examples are given for the purpose of illustrating the present invention:
(t)-4-Hydroxy-1,2,9,10-tetramethoxyaporphine Variant A:
R 2 0~ H R S
11 1 .
wherein Rl R2, R3 and R4, which may be the same or different, are methyl or ethyl radicals, R5 is a hydrogen atom or a straight-chained, cyclic or branched alkyl radical containing up to 5 carbon atoms and the symbol X or Y in the trans- pos-ition to the 6a hydrogen atom represents a hydroxyl group while the remaining X or Y symbol represents a hydrogen atom, with the proviso that when R5 is a methyl radical, then at least one of the substituents Rl, R2, R3 or R4 is an ethyl radical.
The pharmaceutically acceptable acid addition salts are also encompassed by this invention.
The wavy line in the 6a-position of the formula indicates an a- or ~-bonding of the hydrogen atom. When the hydrogen atom has the ~- configuration, then X is a hydroxyl group and Y is a hydrogen atom. When the hydrogen atom has the ~-configuration, Y is a hydroxyl group and X is a hydrogen atom.
When R5 is a straight-chained alkyl radical, it may be a methyl, ethyl, n-propyl, n-butyl or n-pentyl radical.
Cyclic radicals include, for example cycloalkylalkyl radicals, ` ~07704Z
such as cyclopropylmethyl and cyclobutylmethyl radicals.
Branched-chain alkyl radicals include, for example, isopropyl, isobutyl and isopentyl radicals.
Compounds of general formula (I) are preferred in which Rl, R2, R3 and/or R4 is a methyl or ethyl radical and R5 is a hydrogen atom or a methyl, ethyl or n-propyl radical.
Prior to our invention, only a limited number of compounds with the aporphine structure according to general formula (I) (with a hydroxyl group in the 4-position) have been described. Besides the naturally-occuring (t)-cataline ( (~)-l-hydroxy-5-oxo-5H-pyrido l3~2a~1 phenoxazine-3-carboxylic acid) isolated from Glaucium flavum Cr. var. vestitum Tetra~
hedron Letters, p. 2033/1972, (~)-cataline has recently been synthesised by the oxidation of (t)-thaliporphine ((~)-5, 6, 6a, 7-tetrahydro-2, 9, 10-trimethoxy-6-methyl-4H-dibenzo [de, g~ quinolin-l-ol) with lead tetraacetate in acetic acid yield-ing (t)-4~-acetoxythaliporphine, which was then acid hydrolysed with hydrochloric acid at ambient temperature to give (t)_4~_ hydroxythaliporphine which was, in turn, 0-methylated with diazomethane (J.C.S. Chem. Comm., p. 306/1975).
Aporphine derivatives have also been prepared by the intramolecular, non-phenolic oxidative coupling of tetrahydro-isoquinolines (J.A.C.S., 95, 6861/1973). However, prior to our invention, 4-hydroxy-aporphine derivatives have not been obtain-able by this route. This coupling requires the cyclization of laudanosine in a solvent mixture of fluorosulphinic acid, methylene chloride and trifuloroacetic acid in a reaction solu-tion of vanadyl trifluoride in trifluoroacetic acid. This pro-cess yields glaucine which is unsubstituted in the 4-position.
1~77042 We have now found that the above-described reaction can be directed in such a manner that there is formed a 4-hydro-xy-substituted aporphine derivative of general formula (I) or general formula ~I') when, instead of the solvent mixture of methylene chloride and trifuloroacetic acid, there is used trifluoroacetic acid without the admixture of organic solvents.
This finding is extradordinarily surprising, since the hydroxylation effect according to our invention also in-volves a remarkably high regio-and stero-selectivity. It is also surprising that hydroxyaporphines are exclusively formed which carry the hydroxyl function in the 4-position since the aporphine system contains three reactive benzylic positions.
Since the l-position of general formula II contains a more reactive hydrogen atom, it would be expected that a hydroxyl-ation, if at all, would take place at this position, however, under the conditions of the process according to the present invention, the hydroxyl group enters preponderantly in the trans 4-position (referred to the 6a-hydrogen atom in general formula (I) or (I'). A further characteristic feature of the present invention is that the chiralic center in the tetrahydroisoquin-oline (C-l) and in the aporphine ring system (C-6a) remains intact under the reaction conditions, i.e. that when using the optically-active tetrahydroisoquinolines of general formula (II), the corresponding optically-active 4-hydroxyaporphine of formula (I) or (I') are obtained.
1~7704Z
Consequently, the present invention also provides a process for the preparation of compounds of the general formula:
X ' ~ , Y ' R' ~0~
R 2~;,N_Rl 5 I H (I ' ) R' 30~ ~
o R l 4 as well as of the salts thereof with organic and inorganic : acids, wherein R'l, R'2, R'3 and R'4, which may be the same or different, are methyl or ethyl radicals and R'5 is a hydro-gen atom or a straight-chained, cyclic or branched alkyl radi-cal containing up to 5 carbon atoms and the symbol X' or Y' in the trans-position to the 6a-hydrogen atom represents a hydroxyl group, while the remaining X' or Y' symbol represents a hydrogen atom, by the cyclisation of a compound of the general formula:
R ' 1 O~
R 2 ~ N-R 5 ~ (II), R ' 30 /[~
R l 4 wherein R'l, R'2, R'3, R'4 and R'5 have the same meanings as above, in trifluoroacetic acjd, by reaction with vanadyl tri-fluoride. The reaction is carried out at a temperature of from -50 to 10C, preferably from -15 to 0C., without the admixture of an organic solvent. The vanadyl trifluoride used in a molar excess and water being subsequently added. The compound of general formula (I') is thus obtained and, if desired, converted into an acid addition salt.
As starting materials for the process according to the present invention, there can be used not only the racemic but also the enantiomeric compounds of general formula (II).
Some of these starting materials are known, for example, laudanosine (l-C(3,4-dimethoyxphenyl)methyl] -1,2,3,4-tetra-hydro-6, 7-dimethoxy-2-methylisoquinoline) and N-ethyl- and N-propyl-tetrahydropapaverine. They are preferably prepared from the corresponding tetrahydroisoquinolines, for example tetrahydropapaverine, by alkylation (J. Chem. Soc., p. 1481/
1962) or from the corresponding isoquinolines, for example, papaverine (l-r(3,4-dimethoxyphenyl)methyl~-6,7-dimethoxyiso-quinoline) by alkylation and subsequent reduction, preferably by means of sodium borohydride (Ber. 90, 1997/1957).
For carrying out the reaction, the starting compounds of general formula (II) are dissolved, while cooling, in tri-fluoroacetic acid and mixed dropwise at -10 to -15C with an excess amount of a vanadyl trifluoride trifluoroacetic acid solution, the reaction mixture becoming a red-violet color.
It is generally preferable to use about a 2.5 mol excess of vanadyl fluoride per mol of tetrahydroisoquinoline to assure all the starting material is reacted.
After the addition of the vanadyl trifluoride solu-tion, the reaction mixture is further stirred for about 3 to ~07704'2 4 hours at -10 to -15C and thereafter allowed to rise to ambient temperature. After stirring for one hour at ambient temperature, the trifluoroacetic acid is removed in a vacuum and the residue, after being rendered alkaline, is partitioned between water and an organic solvent, for example, chloroform, methylene chloride or diethyl ether.
The 4-hydroxyaporphine may be obtained from the organic phase either by direct crystallization from an organic solvent or from an organic solvent mixture or after previous chromatographic separation on an inert carrier material, for example, silica gel or basic aluminum oxide by removal of the elution agent.
According to a preferred variant of the new process, the amount of expensive trifluoroacetic acid needed for the preparation of the vanadyl trifluoride solution (because of the poor solubility of vanadyl trifluoride in trifluoroacetic acid, relatively large volumes are necessary) is replaced by an inex-pensive liquified sulphur dioxide. In this case, it is preferable to place the vanadyl trifluoride in liquified sulphur dioxide and to add dropwise a solution of the tetra-hydroisoquinoline in trifluoroacetic acid at a temperature of from -15 to -50C. Here, too, a coloration of the reaction mixture towards red-violet is observed. At the end of the dropwise addition, the reaction mixture is stirred for 4 - 5 hours at -10 to -15C. The sulphur dioxide is then allowed to evaporate at ambient temperatures, the trifluoroacetic acid is removed in a vacuum and the residue treated as described above.
The salts of compounds of general formula (I) or (I') can be obtained by neutralization of the free bases with pharmacologically compatible inorganic or organic acids, for example, hydrochloric acid, sulphuric acid, phosphoric acid, '1~7704Z
hydrobromic acid, acetic acid, tartaric acid, lactic acid, citric acid, malic acid, salicyclic acid, ascorbic acid, malonic acid, maleic acid or succinic acid.
The following examples are given for the purpose of illustrating the present invention:
(t)-4-Hydroxy-1,2,9,10-tetramethoxyaporphine Variant A:
2 9. (t)-laudanosine is dissolved in 25 ml. trifluoro-acetic acid and mixed dropwise at -15C., while stirring and with the exclusion of moisture, with a solution of 1.73 9.
vanadyl (V) fluoride in 50 ml. trifluoroacetic acid. The dark red solution obtained is stirred for a total of 4 hours at -15C., then warmed to about 0C. and the greater part of the trifluoroacetic acid removed under slightly reduced pressure.
The residue is partitioned between water and chloroform. The organic phase is treated with an aqueous solution of ammonia and again washed with water. After drying in a vacuum, 2.1 9.
of a yellow syrup remains. Either by direct crystallization 2G (ethyl acetate/diethyl ether) or, after previous chromatography on silica gel or a basic aluminium oxide, there is obtained (t)-4-hydroxy-1,2,9,10-tetramethoxyaporphine; m.p. 152 - 153C.
The corresponding acetate melts at 169 - 170C. NMR spectrum (60 MHz, CDCL3) ~ 2.54 (s,3H,N-CH3), 3.63 (s,3H,OCH3), 3.90 (s,3H,OCH3), 3.93 (s,6H,20CH3), 4.50 (m,lH,4-H), 6.77 (s,lH, ArH), 6.90 (s,lH,ArH), 8.07 (s,lH,LL-H).
Variant B:
0.93 g. vanadyl fluoride is suspended in about 60 ml.
liquified sulphur dioxide. To the suspension is slowly added dropwise at -45C. a solution of 1.07 9 (-)-laudanosine in 5 ml.
trifluoroacetic acid; the reaction mixture becoming red-violet colored. After stirring for 2 hours at -45C., a clear, deep red solution is obtained. This solution is stirred for an additional 4 hours at -15C. By warming to ambient temperature, the sulphur dioxide is first evaporated off, ~ollowed by the trifluoroacetic acid under a vacuum. The residue is mixed with a aqueous solution of ammonia and extracted with chloroform.
Further working up is then carried out as described in Varient A. Chromatography on silica gel with chloroform containing 0.1% triethylamine as elution agent gives 300 mg. (t) 4_ hydroxy-1,2,9,10-tetramethoxyaporphine, as well as 300 mg. of the starting material, i.e. (~)-laudanosine.
(t)-4-HYdroxy-l~2~9~lo-tetramethoxyaporphine (cataline) and (-)-4-hydroxy-1,2,9,10-tetramethoxyaporphine.
2 9. (~)-lauanosine (Eur. J. Med. Chem., 9, 237/1974) is reacted, in the manner described in Example 1, with 1.73 9.
vanadyl (V) fluoride in trifluoroacetic acid. After analogous working up and crystallisation from diethyl ether, there is obtained (~)-4-hydroxy-1,2,9,10-tetramethoxyaporphine (cataline) in the form of colourless crystals; m.p. 180-182C; ~7D = +
139.7 (1.04 in chloroform).
Analysis:
calc : C 67.91%;H 6.78%; N 3.77%
found : 68.16~;6.72%; 3.55%
UV: A EaOXH : 217 (39.500), 230 (sh 29.000), 272 (sh 12.000j, 218 (14.500), 301 (13.600), 312 (sh 12.000) nm The corresponding acetate melts at 127C. after recrystallisation from diethyl ether/petroleum ether.
.... ~ ', ~ ' ~ , .
~07704Z
In a corresponding manner, from (-~-laudanosine there is obtained the enantiomeric (-)-4-hydroxy-1,2,9,10-tetramethoxyaporphine, which melts at 179 - 180C.; L a_/
-147.7 (0.9 in chloroform).
Analysis:
calc. : C 67.91%;H 6.78%;N 3.77%
found : 67.56%;6.75%; 3.59%
U~: ~ mtaOxH :218 (39.300), 281 (14.500), 302 (13.600), 313 (12.1oo) nm (~)-5,6,6a,7-Tetrahydro-1,2,9,10-tetraethoxy-6-methyl-4H-dibenzo ~de, g]quinolin-4-ol 2.31 g (~)-diethoxy-1-(3',4'-diethoxybenzyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline (Ber., 99, 2873/1966) is dissolved in 25 ml. trifluoroacetic acid and mixed dropwise at -15C. with a solution of 1.73 9. vanadyl fluoride in 50 ml. trifluoroacetic acid. The red-violet solution obtained is stirred for 4 hours at -15C. and for 1 hour at ambient temperature. The reaction mixture is evaporated in a vacuum, the residue mixed with ice water and 5% aqueous sodium bicar-bonate solution and extracted with chloroform. The crude product obtained after drying and removing the solvent is chromatographed on silica gel with methylene chloride/methanol (99:1 v/v) and the eluate obtained is evaporated to give 657 mg.
(~)-5,6,6a,7-tetrahydro-1,2,9,10-tetraethoxy-6-methyl-4H-dibenzo ~de,~a quinoline, the hydrobromide of which, after recrystallisation from ethanol/diethyl ether, melts at 198 - -199C., together with 721 mg.(~)-5,6,6a,7-tetrahydro-1,2,9,10-tetraethoxy-6-methyl-4H-dibenzo rde,g7quinolin-4-ol which, g _ after recrystallisation from diethyl ether/petroleum ether, melts at 140 - 142C. NMR spectrum (CDC13) ~ 1.43 (m,12H,OCH2 CH3), 2.47 (s,3H,N-CH3), 4.0 (m, -OCH2CH3), 4.42 (m,lH,4-H), 6.69 (s,lH,ArH), 6.80 (s,lH,ArH), 8.01 (s,lH,ll-H).
(~)-5,6,6a,7-Tetrahydro-1,2,9,10-tetramethoxy-6-n-propyl-4H-dibeno [de,~ quinolin-4-ol.
11.95 9. (~)-10(3,4-dimethoxybenzyl)-6,7-dimethoxy-2-n-propyl-1,2,3,4-tetrahydroisoquinoline (J. Chem. Soc., p.
1481/1962) is dissolved at 0C. in 50 ml. trifluoroacetic acid.
A solution of 9.6 9. vanadyl fluoride in 350 ml. trifluoroacetic acid is added dropwise, with stirring, to this solution at -15C. After the addition, the reaction mixture is stirred for 2 hours at -15C. and for 2 hours at ambient temperature.
The reaction mixture is worked up in the manner described in Example 1 and direct crystallisation of the crude product from diethyl ether gives 2.6 9. (~)-5,6,6a,7-tetrahydro-1,2,9,10-tetramethoxy-6-n-propyl-4H-dibenzo rde,~7 quinolin-4-ol, which melts at 153 - 154C. By chromatography on basic aluminum oxide (activity stage III) with methylene chloride/petroleum ether (1:1 v/v) as elution agent, further amounts of thin layer chromatographically pure product are obtained. NMR spectrum (60MHz,CDC13), ~ 0.96 (m,3H,CH3), 1.6 (m,2H), 3.65 (s,3H,OCH3),
vanadyl (V) fluoride in 50 ml. trifluoroacetic acid. The dark red solution obtained is stirred for a total of 4 hours at -15C., then warmed to about 0C. and the greater part of the trifluoroacetic acid removed under slightly reduced pressure.
The residue is partitioned between water and chloroform. The organic phase is treated with an aqueous solution of ammonia and again washed with water. After drying in a vacuum, 2.1 9.
of a yellow syrup remains. Either by direct crystallization 2G (ethyl acetate/diethyl ether) or, after previous chromatography on silica gel or a basic aluminium oxide, there is obtained (t)-4-hydroxy-1,2,9,10-tetramethoxyaporphine; m.p. 152 - 153C.
The corresponding acetate melts at 169 - 170C. NMR spectrum (60 MHz, CDCL3) ~ 2.54 (s,3H,N-CH3), 3.63 (s,3H,OCH3), 3.90 (s,3H,OCH3), 3.93 (s,6H,20CH3), 4.50 (m,lH,4-H), 6.77 (s,lH, ArH), 6.90 (s,lH,ArH), 8.07 (s,lH,LL-H).
Variant B:
0.93 g. vanadyl fluoride is suspended in about 60 ml.
liquified sulphur dioxide. To the suspension is slowly added dropwise at -45C. a solution of 1.07 9 (-)-laudanosine in 5 ml.
trifluoroacetic acid; the reaction mixture becoming red-violet colored. After stirring for 2 hours at -45C., a clear, deep red solution is obtained. This solution is stirred for an additional 4 hours at -15C. By warming to ambient temperature, the sulphur dioxide is first evaporated off, ~ollowed by the trifluoroacetic acid under a vacuum. The residue is mixed with a aqueous solution of ammonia and extracted with chloroform.
Further working up is then carried out as described in Varient A. Chromatography on silica gel with chloroform containing 0.1% triethylamine as elution agent gives 300 mg. (t) 4_ hydroxy-1,2,9,10-tetramethoxyaporphine, as well as 300 mg. of the starting material, i.e. (~)-laudanosine.
(t)-4-HYdroxy-l~2~9~lo-tetramethoxyaporphine (cataline) and (-)-4-hydroxy-1,2,9,10-tetramethoxyaporphine.
2 9. (~)-lauanosine (Eur. J. Med. Chem., 9, 237/1974) is reacted, in the manner described in Example 1, with 1.73 9.
vanadyl (V) fluoride in trifluoroacetic acid. After analogous working up and crystallisation from diethyl ether, there is obtained (~)-4-hydroxy-1,2,9,10-tetramethoxyaporphine (cataline) in the form of colourless crystals; m.p. 180-182C; ~7D = +
139.7 (1.04 in chloroform).
Analysis:
calc : C 67.91%;H 6.78%; N 3.77%
found : 68.16~;6.72%; 3.55%
UV: A EaOXH : 217 (39.500), 230 (sh 29.000), 272 (sh 12.000j, 218 (14.500), 301 (13.600), 312 (sh 12.000) nm The corresponding acetate melts at 127C. after recrystallisation from diethyl ether/petroleum ether.
.... ~ ', ~ ' ~ , .
~07704Z
In a corresponding manner, from (-~-laudanosine there is obtained the enantiomeric (-)-4-hydroxy-1,2,9,10-tetramethoxyaporphine, which melts at 179 - 180C.; L a_/
-147.7 (0.9 in chloroform).
Analysis:
calc. : C 67.91%;H 6.78%;N 3.77%
found : 67.56%;6.75%; 3.59%
U~: ~ mtaOxH :218 (39.300), 281 (14.500), 302 (13.600), 313 (12.1oo) nm (~)-5,6,6a,7-Tetrahydro-1,2,9,10-tetraethoxy-6-methyl-4H-dibenzo ~de, g]quinolin-4-ol 2.31 g (~)-diethoxy-1-(3',4'-diethoxybenzyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline (Ber., 99, 2873/1966) is dissolved in 25 ml. trifluoroacetic acid and mixed dropwise at -15C. with a solution of 1.73 9. vanadyl fluoride in 50 ml. trifluoroacetic acid. The red-violet solution obtained is stirred for 4 hours at -15C. and for 1 hour at ambient temperature. The reaction mixture is evaporated in a vacuum, the residue mixed with ice water and 5% aqueous sodium bicar-bonate solution and extracted with chloroform. The crude product obtained after drying and removing the solvent is chromatographed on silica gel with methylene chloride/methanol (99:1 v/v) and the eluate obtained is evaporated to give 657 mg.
(~)-5,6,6a,7-tetrahydro-1,2,9,10-tetraethoxy-6-methyl-4H-dibenzo ~de,~a quinoline, the hydrobromide of which, after recrystallisation from ethanol/diethyl ether, melts at 198 - -199C., together with 721 mg.(~)-5,6,6a,7-tetrahydro-1,2,9,10-tetraethoxy-6-methyl-4H-dibenzo rde,g7quinolin-4-ol which, g _ after recrystallisation from diethyl ether/petroleum ether, melts at 140 - 142C. NMR spectrum (CDC13) ~ 1.43 (m,12H,OCH2 CH3), 2.47 (s,3H,N-CH3), 4.0 (m, -OCH2CH3), 4.42 (m,lH,4-H), 6.69 (s,lH,ArH), 6.80 (s,lH,ArH), 8.01 (s,lH,ll-H).
(~)-5,6,6a,7-Tetrahydro-1,2,9,10-tetramethoxy-6-n-propyl-4H-dibeno [de,~ quinolin-4-ol.
11.95 9. (~)-10(3,4-dimethoxybenzyl)-6,7-dimethoxy-2-n-propyl-1,2,3,4-tetrahydroisoquinoline (J. Chem. Soc., p.
1481/1962) is dissolved at 0C. in 50 ml. trifluoroacetic acid.
A solution of 9.6 9. vanadyl fluoride in 350 ml. trifluoroacetic acid is added dropwise, with stirring, to this solution at -15C. After the addition, the reaction mixture is stirred for 2 hours at -15C. and for 2 hours at ambient temperature.
The reaction mixture is worked up in the manner described in Example 1 and direct crystallisation of the crude product from diethyl ether gives 2.6 9. (~)-5,6,6a,7-tetrahydro-1,2,9,10-tetramethoxy-6-n-propyl-4H-dibenzo rde,~7 quinolin-4-ol, which melts at 153 - 154C. By chromatography on basic aluminum oxide (activity stage III) with methylene chloride/petroleum ether (1:1 v/v) as elution agent, further amounts of thin layer chromatographically pure product are obtained. NMR spectrum (60MHz,CDC13), ~ 0.96 (m,3H,CH3), 1.6 (m,2H), 3.65 (s,3H,OCH3),
3.88 (s,9H,3xOCH3), 4.44 (m,lH,4-H), 6.77 (s,lH,Ar-H), 6.95 (s,lH,ArH), 8.02 (s,lH,ll-H).
- 10 ;., ~0'7704Z
(4S,6aS)-(~)-5,6,6a,7-Tetrahydro-1,2,9,10-tetramethoxy-6-n-propyl-4H-dibenzo Lde,g1 quinolin-4-ol.
14.8 9. (+)-1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-2-n-propyl-1,2,3,4-tetrahydroisoquinoline (-)-dibenzoyltartrate is converted into the base by treatment with ammonia and extra-ction with chloroform. The solvent is removed in a vacuum and the residue taken up in 35 ml. trifluoroacetic acid. A solu-tion of 6.38 9 vanadyl fluoride in 250 ml. trifluoroacetic acid is added dropwise to this solution at -15C., while stirring, in the course of 30 minutes. After completion of the addition, stirring is continued for 2 hours at -15 to -10C. and for 2 hours at ambient temperature, followed by working up in the manner described in Example 1. Chromatography on basic aluminum oxide with methylene chloride/petroleum ether (1:1 v/v) and crystallization from diethyl ether gives (4S,6aS)-( )-5,6,6a,7-tetrahydro-1,2,9,10-tetramethoxy-6-n-propyl-4H-dibenzorde,g¦
quinolin-4-ol in the form of colorless crystals which melt at 152 - 153C-; r~]D ~ 132.5 (0.5 in chloroform). NMR spectrum 20 (60 MHz, CDC13), ~ 1.0 (m,3H), 1.6 (m,2H), 3.64 (s,3H,OCH3), 3.89 (s,9H,3xOCH3), 4.44 (m,lH,4-H), 6.75 (s,lH,ArH), 6.83 (s,lH,Ar-H), 8.02 (s,lH,ll-H).
The dextrarotary 1-(3,4-dimethoxybenzyl)-6,7-dimeth-oxy-2-n-propyl-1,2,3,4-tetrahydroisoquinoline used as starting material was obtained as follows from the racemic compound (J. Chem. Soc., p. 1481/1962); 16 9. of racemic hydrochloride was converted into the base by treatment with ammonia. Extra-ction with chloroform, drying and evaporating in a vacuum gives the base in the form of a viscous oil which is taken up in - ' ' ' .' ~
!
ethanol and mixed with 14.30 9. (-) dibenzoyl-tartaric acid.
After seeding, the product is left to crystallize at ambient temperature. The crystals obtained are then recrystallized twice from hot isopropanol. The yield is 5 9. and the product melts at 155 - 156C.; [~]C =~17.9 (1 in chloroform).
The base is liberated from the salt by treatment with dilute aqueous ammonia solution. Extraction with chloro-form, drying, evaporation and subsequent recrystallization from aqueous ethanol gives crystalline (t)-1-(3,4-dimethoxy-benzyl)-6,7-dimethoxy-2-n-propyl-1,2,3,4-tetrahydroisoquino-line, which melts at 78 - 80C.; r~ ~D = f76.2 (1 in chloro-form).
(4R,6aR-(-)-5,6,6a,7-Tetrahydro-1,2,9,10-tetramethoxy-6-n-propyl-4H-dibenzo ~de,~ quinolin-4-ol.
11.35 9. (-)-(3,4-dimethoxybenzyl)-6,7-dimethoxy-2-n-propyl-1,2,3,4-tetrahydroisoquinoline (t)-dibenzoyl-tartrate is converted into the base by treatment with ammonia and extra-cted with chloroform. The base, after freeing from solvent and drying, is dissolved in 27 ml. trifluoroacetic acid and mixed, within the course of 30 minutes, at -15C. with a solu-tion of 4.89 9. vanadyl fluoride in 192 ml. trifluoroacetic acid. after further proceeding in a manner analogous to that described in Example 1, there is obtained, 5.02 9. of crude product which, for further purification, was chromatographed on 300 9. basic aluminium oxide (activity state III) with a mixture of petroleum ether/chloroform (85.15 v/v) as elution agent. The fractions containing the desired product are com- ;`
bined and evaporated in a vaccum and the residue is crystallized from diethyl ether. There is obtained (4R,6aR)-(-)-5,6,6a,7-tetrahydro-1,2,9,10-tetramethoxy-6-n-propyl-4H-dibenzo ~de,~ quinolin-4-ol in the form of colorless crystals which melt at 151 - 153C.i ~D = -142.4 (0.5 in chloroform).
The NMR spectrum is identical with the spectrum of the enantio-meric compound (see Example 5).
Laevorotary 1-(3,4-dimethylbenzyl)-6,7-dimethoxy-2-n-propyl-1,2,3,4-tetrahydroisoquinoline was obtained, analog-ously to the preparation of the dextrarotary enantiomer, from the racemic compound (J. Chem. Soc., p. 1481/1962), as the D-dibenzoyl-tartrate, which melts at 154 - 155C.; [ ~ D =
-18.2 (1 in chloroform). From the dibenzoyl-tartrate, the free base is obtained by treatment analogous to that described in Example 5. The free base melts at 78 - 79C.; [~]D =
-77.1 (1 in chloroform).
(t)-4-Hydroxy-1,2,9,10-tetramethoxy-N-noraporphine 2 9. (~)-Tetrahydropapaverine hydrochloride is con-verted into the base by treatment with semi-concentrated aqueous ammonia solution. It is extracted with chloroform, dried and the solvent removed in a vacuum. The residue is dissolved in 20 ml. trifluoroacetic acid and mixed dropwise at -15 C., while stirring, with a solution of 1.64 9. vanadyl fluoride in 100 ml.
trifluoroacetic acid within the course of 15 minutes. The mixture becomes deep red colored. The reaction mixture is further stirred for 1 hour at -15 to -10C. and for 4 hours at ambient temperature, followed by working up in the manner des-cribed in Example 1. The product obtained (2.11 9. of dark brown foam) is, for further purification, chromatographed on 100 9. basic aluminium oxide (activity stage III) with chloro-form/triethylamine (99:1 v/v) as elution agent. Besides 500 mg. (t)-N-norglaucine (yellow foam; hydrobromide m.p.
~077042 252 - 253C.), 720 mg. 4-hydroxy-N-norglaucine is obtained which, after recrystallization from diethyl ether, melts at 143 - 146C. NMR spectrum (60 MHz, CDC13) ~ 3.66 (s,3H,OCH3), 3.92 (s,9H,3xOCH3), 4.52 (m,lH,4-H), 6.73 (s,lH,ArH), 6.89 (s,lH,ArH), 8.10 (s,lH,ll-H).
The following compounds are prepared in an analogous manner:
(t)-5,6,6a,7-tetrahydro-1,2,9,10-tetramethoxy-6-isobutyl-4H-dibenzo rde,g1 quinolin-4-ol;
(~)-5,6,6a,7-tetrahydro-1,2,9,10-tetraethoxy-6-n-pentyl-4H-dibenzo ~de,~ quinolin-4-ol;
(t)-5,6,6a,7-tetrahydro-1,2,9,10-tetramethoxy-6-isopropyl-4H-dibenzo rde,g7quinolin-4-ol;
(~)-5,6,6a,7-tetrahydro-1,2,9,10-tetramethoxy-6-cyclopropyl-methyl-4H-dibenzo Lde,~7quinolin-4-ol;
(~)-5,6,6_,7-tetrahydro-1,2-diethoxy-9,10-dimethoxy-6-cyclobutylmethyl-4H-dibenzo rde,~7 quinolin-4-ol.
The preceding Examples are summarised in the follow-ing Table:
1~7704Z
__~ ~ 7~ t~ ~ t ~ t ~ 1 I I I _ Q O ~
~ ~ O I ~ ~ O Q_ ~ .
~_ O ~ O
C~l C~l C~l ~ ~ ~ , S _ S
~ I T I I I I O Q O ~ ~ (.) ~
1~ ~ ~ c~ ~_) ~ ~ ~_) ~ 'I ~ ~ ~
_ t~) N ~ ~) ~ ~ ~') C~l I I I I T I I I I I I
~ ~ ~ ~ C~ ~ C~ ~ L,~ t~ ~ ~ ~
_ I _ _ _ ~ ~ C" ~ C~l ~ ~ ~ ~ ~ ~ ~ ~ ~
O I I I T I I I I I T I
~ _ ~ ~_) ~ ~.) ~ ~ ~ ~ ~ t_~ ~ ~ C~
I_ ~ ~ ~ I _ _ ~ I I
I I I ` I I -r I I I I I I
_ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~
_ ~ _ _ _ T _ T
,: I ~ ~ ~
C~ ~ ~ t~) t~ ~') ~ N (~) ~ N
I I I ' I I I I I I I I
N ~ ~) C~ C,~ ~ ~.) C_~ ~ ~ ~ <_~
L, . ' ~L~ L ' ' ~
. ., E ~ c~l ~ d- In ~D I~ ~ I~ I~ I~ ~
o X ~,,,,, ., .i,__ __ . l _ 1 5 ,,: , ,' . , ~077~4Z
Some of the 4-hydroxyaporphines of general formula (I) obtained by the process according to the present invention are valuable intermediates for the preparation of pharmacolog-ically-effective products and some of them themselves possess interesting pharmacological properties. In particular, they have a remarkable action on the cardiovascular system.
Thus, they lower the blood pressure of hyper- and normotensive subjects. Therefore, those compounds not merely used as intermediates may also be used for the treatment of cardiovascular diseases which are to be attributed to hyper-tension.
The compounds of general formula (I) according to the present invention can be administered orally or parenter-ally in liquid or solid form. As injection solution, it is especially preferred to use water which contains the additives usual in the case of injection solutions, such as stabilizing agents, solubilizing agents or buffers.
Additives of this type include, for example, tartrate and citrate buffers, ethanol, complex-forming agents (such as ethylenediamine-tetraacetic acid and the non-toxic salts there-of), as well as high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation. Solid carrier materials include, for example, starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acid, high molecular weight fatty acids (such as stearic acid), gelatine, agar, agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high molecular weight polymers (such as polyethylene glycols); compositions suitable for oral administration can, if desired, contain flavoring and/or sweeting agents.
~077042 Thus, the present invention also provides pharma-ceutical compositions containing at least one of the new compounds according to the present invention, in admixture with a solid or liquid pharmaceutical diluent or carrier.
; . ' :
- 10 ;., ~0'7704Z
(4S,6aS)-(~)-5,6,6a,7-Tetrahydro-1,2,9,10-tetramethoxy-6-n-propyl-4H-dibenzo Lde,g1 quinolin-4-ol.
14.8 9. (+)-1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-2-n-propyl-1,2,3,4-tetrahydroisoquinoline (-)-dibenzoyltartrate is converted into the base by treatment with ammonia and extra-ction with chloroform. The solvent is removed in a vacuum and the residue taken up in 35 ml. trifluoroacetic acid. A solu-tion of 6.38 9 vanadyl fluoride in 250 ml. trifluoroacetic acid is added dropwise to this solution at -15C., while stirring, in the course of 30 minutes. After completion of the addition, stirring is continued for 2 hours at -15 to -10C. and for 2 hours at ambient temperature, followed by working up in the manner described in Example 1. Chromatography on basic aluminum oxide with methylene chloride/petroleum ether (1:1 v/v) and crystallization from diethyl ether gives (4S,6aS)-( )-5,6,6a,7-tetrahydro-1,2,9,10-tetramethoxy-6-n-propyl-4H-dibenzorde,g¦
quinolin-4-ol in the form of colorless crystals which melt at 152 - 153C-; r~]D ~ 132.5 (0.5 in chloroform). NMR spectrum 20 (60 MHz, CDC13), ~ 1.0 (m,3H), 1.6 (m,2H), 3.64 (s,3H,OCH3), 3.89 (s,9H,3xOCH3), 4.44 (m,lH,4-H), 6.75 (s,lH,ArH), 6.83 (s,lH,Ar-H), 8.02 (s,lH,ll-H).
The dextrarotary 1-(3,4-dimethoxybenzyl)-6,7-dimeth-oxy-2-n-propyl-1,2,3,4-tetrahydroisoquinoline used as starting material was obtained as follows from the racemic compound (J. Chem. Soc., p. 1481/1962); 16 9. of racemic hydrochloride was converted into the base by treatment with ammonia. Extra-ction with chloroform, drying and evaporating in a vacuum gives the base in the form of a viscous oil which is taken up in - ' ' ' .' ~
!
ethanol and mixed with 14.30 9. (-) dibenzoyl-tartaric acid.
After seeding, the product is left to crystallize at ambient temperature. The crystals obtained are then recrystallized twice from hot isopropanol. The yield is 5 9. and the product melts at 155 - 156C.; [~]C =~17.9 (1 in chloroform).
The base is liberated from the salt by treatment with dilute aqueous ammonia solution. Extraction with chloro-form, drying, evaporation and subsequent recrystallization from aqueous ethanol gives crystalline (t)-1-(3,4-dimethoxy-benzyl)-6,7-dimethoxy-2-n-propyl-1,2,3,4-tetrahydroisoquino-line, which melts at 78 - 80C.; r~ ~D = f76.2 (1 in chloro-form).
(4R,6aR-(-)-5,6,6a,7-Tetrahydro-1,2,9,10-tetramethoxy-6-n-propyl-4H-dibenzo ~de,~ quinolin-4-ol.
11.35 9. (-)-(3,4-dimethoxybenzyl)-6,7-dimethoxy-2-n-propyl-1,2,3,4-tetrahydroisoquinoline (t)-dibenzoyl-tartrate is converted into the base by treatment with ammonia and extra-cted with chloroform. The base, after freeing from solvent and drying, is dissolved in 27 ml. trifluoroacetic acid and mixed, within the course of 30 minutes, at -15C. with a solu-tion of 4.89 9. vanadyl fluoride in 192 ml. trifluoroacetic acid. after further proceeding in a manner analogous to that described in Example 1, there is obtained, 5.02 9. of crude product which, for further purification, was chromatographed on 300 9. basic aluminium oxide (activity state III) with a mixture of petroleum ether/chloroform (85.15 v/v) as elution agent. The fractions containing the desired product are com- ;`
bined and evaporated in a vaccum and the residue is crystallized from diethyl ether. There is obtained (4R,6aR)-(-)-5,6,6a,7-tetrahydro-1,2,9,10-tetramethoxy-6-n-propyl-4H-dibenzo ~de,~ quinolin-4-ol in the form of colorless crystals which melt at 151 - 153C.i ~D = -142.4 (0.5 in chloroform).
The NMR spectrum is identical with the spectrum of the enantio-meric compound (see Example 5).
Laevorotary 1-(3,4-dimethylbenzyl)-6,7-dimethoxy-2-n-propyl-1,2,3,4-tetrahydroisoquinoline was obtained, analog-ously to the preparation of the dextrarotary enantiomer, from the racemic compound (J. Chem. Soc., p. 1481/1962), as the D-dibenzoyl-tartrate, which melts at 154 - 155C.; [ ~ D =
-18.2 (1 in chloroform). From the dibenzoyl-tartrate, the free base is obtained by treatment analogous to that described in Example 5. The free base melts at 78 - 79C.; [~]D =
-77.1 (1 in chloroform).
(t)-4-Hydroxy-1,2,9,10-tetramethoxy-N-noraporphine 2 9. (~)-Tetrahydropapaverine hydrochloride is con-verted into the base by treatment with semi-concentrated aqueous ammonia solution. It is extracted with chloroform, dried and the solvent removed in a vacuum. The residue is dissolved in 20 ml. trifluoroacetic acid and mixed dropwise at -15 C., while stirring, with a solution of 1.64 9. vanadyl fluoride in 100 ml.
trifluoroacetic acid within the course of 15 minutes. The mixture becomes deep red colored. The reaction mixture is further stirred for 1 hour at -15 to -10C. and for 4 hours at ambient temperature, followed by working up in the manner des-cribed in Example 1. The product obtained (2.11 9. of dark brown foam) is, for further purification, chromatographed on 100 9. basic aluminium oxide (activity stage III) with chloro-form/triethylamine (99:1 v/v) as elution agent. Besides 500 mg. (t)-N-norglaucine (yellow foam; hydrobromide m.p.
~077042 252 - 253C.), 720 mg. 4-hydroxy-N-norglaucine is obtained which, after recrystallization from diethyl ether, melts at 143 - 146C. NMR spectrum (60 MHz, CDC13) ~ 3.66 (s,3H,OCH3), 3.92 (s,9H,3xOCH3), 4.52 (m,lH,4-H), 6.73 (s,lH,ArH), 6.89 (s,lH,ArH), 8.10 (s,lH,ll-H).
The following compounds are prepared in an analogous manner:
(t)-5,6,6a,7-tetrahydro-1,2,9,10-tetramethoxy-6-isobutyl-4H-dibenzo rde,g1 quinolin-4-ol;
(~)-5,6,6a,7-tetrahydro-1,2,9,10-tetraethoxy-6-n-pentyl-4H-dibenzo ~de,~ quinolin-4-ol;
(t)-5,6,6a,7-tetrahydro-1,2,9,10-tetramethoxy-6-isopropyl-4H-dibenzo rde,g7quinolin-4-ol;
(~)-5,6,6a,7-tetrahydro-1,2,9,10-tetramethoxy-6-cyclopropyl-methyl-4H-dibenzo Lde,~7quinolin-4-ol;
(~)-5,6,6_,7-tetrahydro-1,2-diethoxy-9,10-dimethoxy-6-cyclobutylmethyl-4H-dibenzo rde,~7 quinolin-4-ol.
The preceding Examples are summarised in the follow-ing Table:
1~7704Z
__~ ~ 7~ t~ ~ t ~ t ~ 1 I I I _ Q O ~
~ ~ O I ~ ~ O Q_ ~ .
~_ O ~ O
C~l C~l C~l ~ ~ ~ , S _ S
~ I T I I I I O Q O ~ ~ (.) ~
1~ ~ ~ c~ ~_) ~ ~ ~_) ~ 'I ~ ~ ~
_ t~) N ~ ~) ~ ~ ~') C~l I I I I T I I I I I I
~ ~ ~ ~ C~ ~ C~ ~ L,~ t~ ~ ~ ~
_ I _ _ _ ~ ~ C" ~ C~l ~ ~ ~ ~ ~ ~ ~ ~ ~
O I I I T I I I I I T I
~ _ ~ ~_) ~ ~.) ~ ~ ~ ~ ~ t_~ ~ ~ C~
I_ ~ ~ ~ I _ _ ~ I I
I I I ` I I -r I I I I I I
_ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~
_ ~ _ _ _ T _ T
,: I ~ ~ ~
C~ ~ ~ t~) t~ ~') ~ N (~) ~ N
I I I ' I I I I I I I I
N ~ ~) C~ C,~ ~ ~.) C_~ ~ ~ ~ <_~
L, . ' ~L~ L ' ' ~
. ., E ~ c~l ~ d- In ~D I~ ~ I~ I~ I~ ~
o X ~,,,,, ., .i,__ __ . l _ 1 5 ,,: , ,' . , ~077~4Z
Some of the 4-hydroxyaporphines of general formula (I) obtained by the process according to the present invention are valuable intermediates for the preparation of pharmacolog-ically-effective products and some of them themselves possess interesting pharmacological properties. In particular, they have a remarkable action on the cardiovascular system.
Thus, they lower the blood pressure of hyper- and normotensive subjects. Therefore, those compounds not merely used as intermediates may also be used for the treatment of cardiovascular diseases which are to be attributed to hyper-tension.
The compounds of general formula (I) according to the present invention can be administered orally or parenter-ally in liquid or solid form. As injection solution, it is especially preferred to use water which contains the additives usual in the case of injection solutions, such as stabilizing agents, solubilizing agents or buffers.
Additives of this type include, for example, tartrate and citrate buffers, ethanol, complex-forming agents (such as ethylenediamine-tetraacetic acid and the non-toxic salts there-of), as well as high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation. Solid carrier materials include, for example, starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acid, high molecular weight fatty acids (such as stearic acid), gelatine, agar, agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high molecular weight polymers (such as polyethylene glycols); compositions suitable for oral administration can, if desired, contain flavoring and/or sweeting agents.
~077042 Thus, the present invention also provides pharma-ceutical compositions containing at least one of the new compounds according to the present invention, in admixture with a solid or liquid pharmaceutical diluent or carrier.
; . ' :
Claims (15)
1. Process for the preparation of compounds of the general formula:- (I') in which R1, R2, R3 and R4 which may be the same or different, are methyl or ethyl radicals, R5 is a hydrogen atom or a straight-chained, cyclic or branched alkyl radical containing up to 5 carbon atoms and the symbol X or Y in the trans-position to the 6a-hydrogen atom is a hydroxyl group, whereas the other symbol X or Y represents a hydrogen atom with the proviso that when R5 is a methyl radical, then at least one of the substituents R1, R2, R3 or R4 is an ethyl radical, and of the salts thereof with organic and inorganic acids, wherein a compound of the general formula:-(II) in which R1, R2, R3, R4 and R5 have the same meanings as above, is cyclised in trifluoracetic acid by reaction with vanadyl trifluoride, the reaction being carried out at a temperature of from -50 to +10°C, without the admixture of an organic solvent, the vanadyl trifluoride being used in a molar excess, whereafter water is added and the com-pound obtained is then, if desired, converted into a salt by reaction with an organic or inorganic acid.
2. Process according to Claim 1, wherein the cyclising reaction is carried out at a temperature of from -15 to 0°C.
3. Process according to Claim 1 or 2, wherein the vanadyl trifluoride is added dropwise in the form of a solution in trifluoracetic acid or in liquified sulphur dioxide at an initial temperature of -10 to -15°C.
4. Process according to Claim 1 or 2, wherein a solution or suspension of vanadyl trifluoride in liquified sulphur dioxide is prepared and a solution of the starting compound of the general formula (II) given in Claim 1 is added dropwise at a temperature of from -15 to -50°C.
5. Process according to Claims 1 or 2, wherein the vanadyl trifluoride is added in approximately 2.5 molar excess.
6. Process according to Claims 1 or 2, wherein the reaction mixture, after completion of the addition of the vanadyl trifluoride, is stirred for several hours at a temperature of from -10 to -15°C. and then slowly warmed up to ambient temperature.
7. The process of Claim 1, wherein the starting com-pound II is (?)-landanosine and the product obtained is the (?)-4-hydroxy-1,2,9,10-tetramethoxyaporphine.
8. The process of Claim 1, wherein the starting com-pound II is (+) or (-)-1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-6-m-propyl-1,2,3,4-tetrahydroisoquinoline and the product obtained is the (+) or (-)-5,6,6a, 7-tetrahydro-1,2,9,10-tet-ramethoxy-6-m-propyl-4H-dibenzo [de,g]quinolin-4-ol.
9. The process of Claim 1, wherein compound II is the (?) tetrahydropapaverine and the product obtained is the (?)-4-hydroxy-1,2,9,10-tetramethoxy-N-noraporphine.
10. The process of Claim 1, wherein the starting com-pound II is the (?)-diethoxy-1-(3',4'-diethoxybenzyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline and the product obtained is the (?)-5,6,6a,7-tetrahydro-1,2,9,10-tetraethoxy-6-methyl-4H-dibenzo [de,g]quinolin-4-ol.
11. Compounds of the general formula:- (I) wherein R1, R2, R3 and R4, which may be the same or different, are methyl or ethyl radicals, R5 is a hydrogen atom or a straight-chained, cyclic or branched alkyl radical containing up to 5 carbon atoms and the symbol X or Y in the trans-position to the 6a-hydrogen atom represents a hydroxyl group, whereas the other substituent X or Y represents a hydrogen atom, with the proviso that when R5 is a methyl radical, then at least one of the substituents R1, R2, R3 and R4 is an ethyl radical; and the salts thereof with organic and inorganic acids, when prepared by the process defined in Claim 1 or by an obvious chemical equivalent.
12. The (?)-4-hydroxy-1,2,9,10-tetramethoxyaporphine, when prepared by the process defined in Claim 7 or by an obvious chemical equivalent.
13. The (+) or (-)-5,6,6a,7-tetrahydro-1,2,9,10-tetra-methoxy-6-n-propyl-4H-dibenzo[de,g]quinolin-4-ol, when prepared by the process defined in Claim 8 or by an obvious chemical equivalent.
14. The (?)-5,6,6a,7-tetrahydro-1,2,9,10-tetraethoxy-6-methyl-4H-dibenzo[de,g]quinolin-4-ol, when prepared by the process defined in Claim 10 or by an obvious chemical equiva-lent.
15. The (?)-4-hydroxy-1,2,9,10-tetramethoxy-N-nor-aporphine, when prepared by the process defined in Claim 9 or by an obvious chemical equivalent.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA279,800A CA1077042A (en) | 1977-06-03 | 1977-06-03 | (?)-4-hydroxy-1,2,9,10-tetraalkoxy-aporphine derivatives |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA279,800A CA1077042A (en) | 1977-06-03 | 1977-06-03 | (?)-4-hydroxy-1,2,9,10-tetraalkoxy-aporphine derivatives |
Publications (1)
Publication Number | Publication Date |
---|---|
CA1077042A true CA1077042A (en) | 1980-05-06 |
Family
ID=4108805
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA279,800A Expired CA1077042A (en) | 1977-06-03 | 1977-06-03 | (?)-4-hydroxy-1,2,9,10-tetraalkoxy-aporphine derivatives |
Country Status (1)
Country | Link |
---|---|
CA (1) | CA1077042A (en) |
-
1977
- 1977-06-03 CA CA279,800A patent/CA1077042A/en not_active Expired
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