IE50023B1 - Isoquinoline derivatives - Google Patents
Isoquinoline derivativesInfo
- Publication number
- IE50023B1 IE50023B1 IE1498/80A IE149880A IE50023B1 IE 50023 B1 IE50023 B1 IE 50023B1 IE 1498/80 A IE1498/80 A IE 1498/80A IE 149880 A IE149880 A IE 149880A IE 50023 B1 IE50023 B1 IE 50023B1
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- phenyl
- methoxy
- dimethoxy
- methyl
- propyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/18—Aralkyl radicals
- C07D217/20—Aralkyl radicals with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
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Abstract
The present invention relates to new 1-¢1-(3,4-dimethoxy-phenyl) -3-amino-propyl!-6,7-dimethoxy-isoquinolines having the general formula I : I in which R1 represents a hydrogen atom or a methyl group ; and R2 represents an alkyl group having from 1 to 5 carbon atoms or a cycloalkyl group having from 5 to 7 carbon atoms, the alkyl or cycloalkyl group optionally being substituted by a hydroxy, phenyl or phenoxy group and the cycloalkyl group optionally being substituted by an alkyl group having from 1 to 5 carbon atoms, therapeutically acceptable salts thereof and a process preparation of the same. These compounds are useful in the cardiac and vascular fields.
Description
The invention relates to isoquinoline derivatives and to processes for their preparation.
The invention provides derivatives of 1- [j-(3,4-diinethoxyphenyl)-3-amino-propyl3 -6,7-dimethoxy-isoquinoline having the general formula I:
in which R-j represents a hydrogen atom or a methyl group and R, represents an alkyl group having from 1 to 5 carbon atoms or a cycloalkyl group having from 5 to 7 carbon atoms, the alkyl or cycloalkyl group optionally being substituted by a hydroxy, phenyl, or phenoxy group and the cycloalkyl group optionally being substituted by an alkyl group having from 1 to 5 carbon atoms, and therapeutically acceptable salts thereof.
The compounds according to the invention are of interest for their therapeutic properties, particularly in the cardiac and vascular fields.
The invention further provides a process for the preparation of
1-J-(3,4-dimethoxy-phenyl)-3-amino-propyl]-6,7-dimethoxy-isoqui noli ne derivatives of the general formula I as above defined, the process comprising condensing, in a polar solvent, at from 0°C to 25°C,
1-: 1-(3,4-dimethoxy-phenyl)-3-oxo-propyl] -6,7-dimethoxy-i soqui noli ne, which has the formula II.
with a compound of the general formula HNR-jRg wherein
R1 and R2 are as above defined, and reducing the resultant compound by any of the conventional techniques, e.g. hydrogenation or, preferably, the action of sodium borohydride.
The solvent generally used ig an alcohol, preferably ethanol.
The tertiary derivatives can also be obtained starting from the secondary derivatives as well known nitrogen substitution techniques such as iodoalkylation or reductive formylation.
The starting material 1- 0-(3,4-dimethoxy-phenyl)-3-oxopropyf]-6,7-dimethoxy-isoquinoline II, may be prepared by the methods described in detail with reference to the Examples A,
B and C below. Regarding the analytical data given in the Examples A, B and C, and in the Examples 1 to 9 thereafter, which latter illustrate the invention, the thin layer chromatograph (TLC) data v/as obtained using *Merck F254 plates; the NMR spectra were recorded on Perkin-Elmer R 24 (60 MHz) apparatus; and the I.R. spectra was recorded on Perkin-Elmer 257 apparatus.
EXAMPLE A
Formation of the carbanion of 1-(^3,4-dimethoxy-phenyl)-methylJ 6,7-dimethoxy-isoquinoline a) Liquid airnionia/sodamide method
Into a 1 litre three-necked flask provided with stirring means and dry ice refrigeration means are successively introduced 300 ml of liquid ammonia, 0.1 g of ferric chloride acting as catalyst and 0.8 g (0.03 mole) of sodium (cf. Org. Synthese Coll., Vol. 5, p. 523). The reaction mixture is stirred for 1| hours and there is then added, in small portions, 10 g (0.0295 mole) of papaverine.
*Merck is a trade mark
To complete the formation of the carbanion, the mixture is stirred for 2 hours. A red solution is obtained, for use as such in Example B hereinbelow.
b) Butyl lithium/hexamethylphosphotriamide method
Into a 1 litre reactor, fitted with heating, cooling and stirring means, are poured 10 g (0.0295 mole) of papaverine and 100 ml of hexamethylphosphotriamide. Keeping the temperature at approximately 5°C, there is progressively added 18.5 ml (0.03 mole) of commercial butyl lithium in solution in hexane. After the addition is complete, stirring is continued for 1 hour at ambient temperature.
cj Sodium/hexamethylphosphotriamide method
Into the same apparatus as in method (b) above are poured 10 g (0.0295 mole) of papaverine and 30 ml of hexamethylphosphotriamide.
1.2 g (0.03 mole) of sodamide are added gently under stirring; the mixtures becomes red but there is not evolution of gases. The mixture is heated to 70-75°C, resulting in evolution of ammonia; stirring is continued for 3 hours until the gaseous evolution ends.
The reaction mixture is cooled for use as such in Example B hereinbelow.
d) Lithium diisopropylamide/tetrahydrofuran method
In the same apparatus as in method (a) above, cooled by an ethanol/dry ice bath, are poured 400 ml of dry tetrahydrofuran.
Lithium di isopropylamide is prepared in situ by adding dropwise at -30°C. 18.5 ml of butyl-lithium (0.03 mole) dissolved in hexane;
4.2 (0.03 mole) of di isopropylamine are added and the mixture is stirred for 15 minutes at 10°C; after cooling at -40°C, g (0.0295 mole) of papaverine (powder) are added and the mixture is stirred for 4 hours at -40°C.
500 23
e) Potassium amide/dimethyl formamide method
In the same apparatus as in method (b) above are poured 10 g (0.0295 mole) of papaverine and 35 ml of dimethyl formamide,
1.7 g (0.03 mole)of potassium amide are slowly added, under stirring.
After the end of the addition, stirring is maintained while the reacting mixture is warmed at 70°C for 3 hours and a half. The reaction mixture may be used as such, after cooling, in Example B hereinbelow.
’ For characterization and identification of the carbarn'on, the oxidation reaction leading to 1-(3,4-dimethoxy-benzoyl)-6,7-dimethoxy -isoquinoline (papaveraldine) is used. Into the solution of the carbanion prepared according to Example A (a) is bubbled for 2| hours a current of dry oxygen; then 200 ml of dry toluene is poured in and the ammonia is allowed to evaporate off. The solution is treated at ambient temperature with 200 ml of water and dried. m.p. 208°C (Literature: 209-210°).
EXAMPLE B
Formation of the acetal intermediate: l-_l-(3,4-dimethoxyphenyl). 3,3-diethoxy-propyf] -6,7-dimethoxyisoquinoline
To a solution containing 0.016 mole of the carbanion obtained by one of the methods described in Example A there is slowly added
.3 g (0.025 mole) of 2,2—ethoxy-ethyl-bromide. After stirring for 1 hour, 200 ml of dry toluene is added and the ammonia is allowed to evaporate off. At ambient temperature, 200 ml of water is added and the whole is filtered over celite. The toluene solution is then decanted, washed, dried over anhydrous sodium sulfate and concentrated. The oil obtained is directly hydrolyzed which gives 9.6 g of product. Yield 97« NMR (CC14) <5ppm 8.20 (d, 1H, CH-N=); 7 (m, 6H, aromatic protons); 4.25 (t, 1H, CH-CH2); 3.75 (m, 12H, 0CH3);
3.3 (m, 4H, CH );
0¾ och2ch3
2.4 (m, 3H, CHg-CH ); 1.1 (2t, 6H,\^ xoc2h5 )·
0CH2CH3
EXAMPLE C
Formation of the aldehyde: l-[_l-(3,4-dimethoxy-phenyl)-3-oxo-propylj6,7-dimethoxy-isoquinoline
8.7 g (0.014 mole) of the compound prepared in Example B above are hydrolyzed for 2 hours at 50°C in 200 ml of 2« hydrochloric acid solution. After alkalinisation at pH 12 with sodium carbonate, the mixture is extracted 3 times by 50 ml of dichloromethane. 7.25 g of an oil are obtained. Yield 95«.
IR vent'1: 2730, 1715 (CH = 0)
NMR (CDC13) δρρπι: 9.6 (s, 1H, CH = 0); 8.35 (d, 1H, CH-N=); 7(m, 6H, aromatic protons); 5.25 (t, 1H, CH); 3.8 (m, 12H, OCHj); 2.9
5Ό0 23 (m,
2H, CH, - C
H )·
In the following Examples 1 to 9 this compound is called the aldehyde.
EXAMPLE 1
1- 0-(3,4-dimethoxy-phenyl)-3-s. butyl ami ho-propylj 6,7-di methyl-i soqui no!i ne R-j = H, Rg = £. butyl g of the aldehyde, 2.5 g of £.butylamine and 120 ml of ethanol are stirred for 30 minutes over 1 g of molecular sieve at ambient temperature. The mixture is cooled to 0°C and 3 g of sodium borohydride is added. The mixture is stirred overnight at ambient temperature. The reaction medium is then concentrated under reduced pressure, water is added and the whole is extracted with di chloromethane. The extracts are washed with water and dried. The di chloromethane is evaporated off. 11.2 g of a yellow oil are isolated. This is dissolved in 100 ml of isopropanol and 25.4 ml of 1 N hydrochloric acid (1 equivalent) are added to form the hydrochloride. The solution is concentrated to dryness and the residue taken up in the minimum of hot isopropanol and allowed to recrystallize. 6.3 g of product are obtained, m.p. 246°C.
TLC (methanol/acetone/concentrated hydrochloric acid 90/10/4).
Rf = 0.5 1 spot
NMR (base) (CDC13) sppm: 8.45 (d, IH, = CH-N=); 7.3-7.5 (m, 2H, aromatic protons);
6.15-7 (m, 4H, aromatic protons):
4.85 (m, 1H23H-CH2);
3.95 (s, 6H, OCHg); 3.75 (s, 6H, OCHg; 2.1-3 (m, 5H); 1.1-1.6 (m, 3H of which 1H is exchangeable NH); 0.7-1 (m, 6H).
EXAMPLE 2 5 1- 0(3,4-dimethoxy-phenyl)-3-cyclohexylami no-propy i]-6,7dimethoxy-isoquinoline Rf = hr2 = cyclohexyi
Working as described in Example 1 but using cyclohexyl amine in place of the 1-methyl-propylamine, 8.1 g of the title compound was obtained. Yield 88%. m.p. NMR (CDClg) ippm: 8.35 (d, 1H, CH-N=); 7
4.8 (t, 1H, CH); 3.85
CH^-CHg-i
135°C (ethanol).
(m, 6H, aromatic protons); (m, 12H, OCHg); 2.4 (m. 5H, i-CHZ);
1.85 (1H, N-H); 1.4 (m, 10H, cyclic CH2)
Hydrochloride m.p.>250°C (ethanol) anhydrous content by titration: 100% (2 basic functions)
Elemental analysisC28H36N2°4- HC1 (500,5) Calc. C« 72.4 H% 7.76 N% 6.03 20 Found 72.31 7.65 5.94
EXAMPLE 3
1-0-(3,4-dimethoxy-phenyl )-3-(a-methyl-phenethyl ami no)-propyl] 6,7-dimethoxy-isoqulnoline
R^ = HR^ = α-methyl-phenethyl
7.6 g (0.02 mole) of the aldehyde are stirred with 2.7 g (0.02 mole) of α-methyl-phenethylamine in 80 ml of absolute ethanol in the presence of 500 mg of molecular sieve (3 R). After 1 hour of stirring the mixture is cooled at 0°C and 2 g of sodium borohydride is added in small portions. The mixture is stirred for 2 hours at ambient temperature and worked up as described in Example 1 to give
8.5 g of an oil as product. Yield 85%. The hydrochloride of this oil is formed using 8.5 ml of 2N hydrochloric acid in 100 ml of ethanol. The solution is concentrated and the residue is taken up in 50 ml of boiling isopropanol, m.p. 220°C. Anhydrous content by titration: 100% (2 basic functions).
NMR (CDClj) «ppm: 8.30 (d, 1H, CH-N=); 7.05 (m, 11H, aromatic protons);
4.70 (t, 1HLZ£H-CH2);
3.85 (m, 12H, 0CH3); 2.60 (m, 7H, C^-CHg-NH-),
2.30 (1H, NH); 1.0 (d, 3H, CHj-CH). Elemental analysisC31H36N2°4* HC1 (536.5) Calc. C% 69.3 H% 6.89 N% 5.22 Found 69.1 6.75 5.31
EXAMPLE 4
1-[ί-{3,4-dimethoxy-phenyl)-3-(N-methyl-α-methyi-benzyl ami no)propyl] -6,7-dimethoxy-isoquinoline
R1 = CH,, Rg = o-methyl-benzyl a^ Mixture of the two diastereoisomers
11.5 g of the aldehyde are stirred with 3.5 g of a-methylbenzylamine in 100 ml of ethanol in the presence of 1 g of molecular sieve. After 30 minutes stirring, the reaction mixture was cooled to 0-5°C and 2g of sodium borohydride was added incrementally.
Work-up is as described in Example 1. 14 g of an oil!are obtained.
g of this oil are gently refluxed for 2J hours in a solution of 18 ml of formic acid and 5 ml of a 30? aqueous solution of formaldehyde. The reaction mixture is cooled and poured into a saturated solution of sodium carbonate. It is extracted with chloroform and the extracts are washed with water and dried.
The extracts are then concentrated to give 7.5 g of an oil which is taken up in isopropanol and allowed to crystallize. The crystals are collected and dried to give 4.3 g of product, m.p. 130°C.
IR: 2790 cm'1 N-CH3
NMR (COC13) {ppm: 8.35 (d, 1H, CH-N=); 6.7-7.35 (m, 11H, aromatic protons);
4.8 (t, lHZZZCH-CHg);
3.95 (d, 6H, 0CH3); 3.75 (d, 6H, 0CH3); 3.65 (q, 1H, CH-CH3);
3-2 (m, 4H, CHo-CHo); 2.2 (s, 3H, N-CH,);
1.25 (d, 3H,
TLC: 2 spots (dichloromethane/methanol 80/20).
Rf - 0.7
The dihydrochloride is formed in alcohol. The alcohol is evaporated off and the meringue is dried.
b) Separation of the diastereoisomers
The remaining 7 g of the oil 1 are chromatographed on a silica gel column (90 g, eluant dichloromethane/methanol 98/2). There is collected first 2.8 g of a white product which is N-methylated as described in (a) above. There is thus isolated 2.3 g of an oil which crystallizes from isopropanol, m.p. 115°C. TLC: 1 spot (dichloromethane/methanol 80/20).
Rf— 0.7.
The dichydrochloride is prepared as in (a) above.
EXAMPLE 5
- [l - (3,4-dimethoxy-phenyl )-3-(N-methyl-1-methyl-2phenoxyethy1 ami no)-propylJ-6,7-dimethoxy-isoquinoline
R1 = CH,, R, = 1-methyl-2-phenoxy-ethyl g of the aldehyde, 4.75 g of 1-methyl-2-phenoxy-ethylamine and 125 ml of distilled ethanol are stirred over 1 g of molecular sieve for 30 minutes. The mixture is cooled to 0°C and 3 g of sodium borohydride is added in small portions. The reaction mixture is stirred overnight and worked up as in the previous Examples to give 13 g of an oil. The 13 g of oil are N-methylated following the method described in Example 4. After drying and evaporation there is obtained 13.5 g of an oil from which the hydrochloride is formed with IN hydrochloric acid in isopropanol. The solution is evaporated to dryness and the salt is chromatographed on a silica gel column (260 g, eluant dichloro-methane/methanol 95/5) giving 8 g of monohydrochloride isolated in the form of meringue.
TLC : 1 spot (methanol/acetone/conc. hydrochloric acid 90/10/4).
Rf = 0.5
IR (Base film: 2800 cm1 N-CH3)
NMR (base) (CDC13) ippm: 8.4 (d, 1H, CH = N); 6.6-7.5 (m, 11H, aromatic protons);
(m, 1H, = CH-CH2);
3.75-3.95 (m, 12H, OCHj); 2.35 (d, 3H, N-CHg);
1.05 (d, 3H, CH-CHg).
EXAMPLE 6
1- jj-(3,4-dimethoxy-phenyl)-3-benzylamino-propyl]-6,7di methoxy-isoqui no!i ne R^ = H, Rg = benzyl
Working as described in Example 1 but using benzylamine in place of the s-butylamine, the title compound was obtained in 80% yield. Hydrochloride m.p. 223°C (isopropanol) anhydrous content by titration: 99% (2 basic functions)
Elemental analysis C29^32N2°4,HC1 (508.5)
Calc. C% 68.5 H% 6.50 N% 5.50
Found 68.65 6.32 5.25
NMR (CDC13)
6ppm: 8.3 (d, 1H, CH-N =); 7.1 (m, 11H, aromatic protons);
4.8 (t, 1H, CH-CH2); 3.9 (m, 14H, OCH3 and
2.7 (m, 4H, CHg-CHg-N); 2.3 (s, IH, N-H).
EXAMPLE 7
-j_3,4-di methoxy-phenyl) -3- (N-methy 1 -4-t. butyl -cycl ohexyl ami no) propyf] -6,7-dimethoxy-i soqui noline
R2 = CH3, R2 = 4-t,butyl-cyclohexyl g of the aldehyde, 4.9 g of 4-t-butylcyclo-hexylamine and 120 ml of distilled ethanol are stirred for 30 minutes on a molecular sieve. Work-up is as described in the previous Examples. 13.8 g of an oil are obtained. This oil is then N-methylated as described in Example 4. There is obtained, after work-up, 14 g of a compound which is taken up in boiling diethyl ether and crystallized therefrom. 6.5 g of recrystallized material, m.p. 126°C, is obtained.
TLC (methanol/acetone/concentrated hydrochloric acid 90/10/4) spot Rf = 0.6 NMR (COC13)
6ppm: 8.4 (d, IH, = CH-N-); 7.2-7.5 (m, 2H, aromatic protons);
6.4-7 (m, 4H, aromatic protons);
4.8 (m, lH7ZkCH-CH3);
4.9 (s, 6H, OCHg); 4.75 (s, 6H, OCHg); 2.2 (s, 3H, N-CHg);
0.8 (s, 9H, tBu).
The monohydrochloride is formed and isolated in a meringue like form.
EXAMPLE 8
1- [3,4-dimethoxy-phenyl)-3-(4-phenyl-cyclohexylamino)-propylj 6,7-dimethoxy-isoquinoline R1 = HR2 = 4-Pheny1-cyclohexyl
12 g of the aldehyde, 5.5 of 4-phenyl-cyclohexylamine, 120 ml of absolute ethanol and 1 g of molecular sieve are stirred for 30 minutes. The mixture is cooled and 3 g of sodium borohydride is added. The mixture is stirred overnight and worked-up as in the previous Examples.
.6 g of an oil are obtained. The monohydrochloride is formed in isopropanol with 1 equivalent of N hydrochloric acid. The solution of the monohydrochloride is concentrated to dryness, taken up in the minimum amount of hot isopropanol, and allowed to recrystallize.
g of product are obtained, m.p. 160°C (HC1)
TLC (methanol/acetone/cone, hydrochloric acid 90/10/4).
1 spot Rf = 0.6
Elemental analysis C-^H^NgO^HCl Calc. Ci 70.70 Hi 7.11 Ni 4.85 Found 69.75 7.22 4.68
NMR (base) (CDC1,) «ppm: 8.4 (d, 1H, = CH-N=); 6.6-7.5 (m, 11H, aromatic protons);
495 (m, ΙΗζ CH - CH,);
3.9 (s, 6H. OCH,; 3.75 (s, 6H, OCH,);
1-3 (m, 15H of which 1H is exchangeable).
EXAMPLE 9
1- |j-(3,4-dimethoxy-phenyl)-3-(l-methyl-4-hydroxy-butylamino)-propyl] 6,7-dimethoxy-i soqui noli ne
R·] = H, Rg = 1 -methyl -4-hydroxy-butyl
11.7 g of the aldehyde, 3.2 g of 1-methyl-4-hydroxy-butylamine, 120 ml of ethanol and 1 g of molecular sieve are stirred for 30 minutes at ambient temperature. The mixture is cooled and 3 g of sodium borohydride is added in small portions. Work-up is as described in the previous Examples, 12.3 g of an oil are obtained.
The monohydrochloride is formed with 1 equivalent of 1 N hydrochloric acid in isopropanol. The solution of the monohydrochloride is concentrated to dryness, taken up in the minimum amount of hot isopropanol, and allowed to recrystallize over two days. 7.6 g of product are obtained, m.p. 166°C.
TLC (methanol/acetone/concentrated hydrochloric acid 90/10/4).
Rf = 0.6 1 spot
Elemental analysis C27H36N2°5,HC1
Calc.
Found
C?
64.22
64.00
H? 7.33 7.33
N% 5.55 5.48
NMR (base) (COC13) {ppm: 8.45 (d, 1H);
6.5-7.6 (m, 6H); 4.95 (m, 1H); 4 (d, 6H);
3.8 (s, 6H); 3.6 (m, 4H); 2.6 (m, 5H); 1.6 (m, 4H); 1 (d, 3H). TOXICITY
The toxicity of the compounds of the invention has been determined by the usual methods on mice (P.0, and Ι.Ρ.). The corresponding
LD 50 values are reported in Table 1 together with data of papaverine and prenylamine - reference compounds - (Figures in mg/kg).
TABLE 1
N° of example LD 50 P.0. 1 LD 50 l.P. papaverine 290 98 1 prenylamine 225 - ! i #500 #120* 2 #450 - 3 #900 - 4 #=400 # 140 5 #450 # 150 6 #450 # 150 7 #900 # 160* 8 #1000 # 150* 9 #900 # 150*
* solubilised with ascorbic acid.
PHARMACOLOGY
The compounds of the invention show a very favourable activity in the cardiovascular field. For the evaluation of the interest of the compounds of the invention, comparisons have been made with papaverine for the field of action and with prenylamine, N-(3,3-dipheny1-propyl)-a-methyl-phenethylamine, of similar chemical structure.
1/Cardiac studies (3 to 5 dogs for each determination)
Papaverine is known for its increasing action on heart rate and cardiac work. For this experimentation each batch of 3-5 dogs was treated by the intravenous route by 3 mg/kg for prenylamine or by the molecular equivalent for papaverine and for the compounds of Examples 1 to 9. No increase of heart rate was noticed either for prenylamine or for the compounds of Examples 1 to 9.
As to the cardiac work, it was determined on the same 11 compounds by the calculation of first derivation of left ventricular pressure (dp/dt). Prenylamine and the compounds of Examples 1, 3, 5, 7, and 9 either decrease dp/dt or do not show any activity in this field; compounds of Examples 2, 4, 6 and 8 show an increase of dp/dt at Figures between 11% and 26% of the Figure obtained for papaverine, which is a strong advantage for the compounds of the invention.
2/Anti-arrhythmic effect (Lawson test on mice)
For this experimentation each bath of 20 female mice (20-22 g) was treated orally at doses corresponding to 20% of the LD 50. The procedure consisted in a chloroform inhalation until apnoea, minutes after the administration of the dose, then thoractomy and measurement of the time in seconds, hetween apnoea and fibrillation.
If activity of prenylamine is settled at 100, the compounds of the Examples 1-9 show an activity comprised between 100 and 187. An appreciable activity was also noticed at the dosage of 10% of LD 50 for compounds of Examples 1, 3, 5 and 7 whereas prenylamine had no action at this dose.
3/ Adrenalytic activity on the rat
Adrenalytic activity has been determined on batches of 5-6 rats receiving orally 10% of LD 50 or each compound. After administration, norepinephrine or epinephrine were injected to the rats. If activity of prenylamine is settled at value 100 for reference, results gave values from 60 to 132 (norepinephrine) best compounds Example 8.
The values found for papaverine in this experimentation were 44 for norepinephrine and 93 for epinephrine.
4/ Study for hemodynamic factors (anaesthetised dogs)
After l.V. injection of 3 mg/kg of prenylamine or of the molecular equivalent of papaverine or the compounds 1-9 the following hemodynamic factors have been measured or calculated.
- Blood pressure (mBP)
- Total peripheral resistance calculated from blood pressure and aortic blood flow.
- Coronary blood flow.
The corresponding results are reported in Table 2 as comparison Figures with the action of papaverine on coronary blood flow settled as 100.
TABLE 2
COMPOUND ! mBP ~-, TPR FBF CBF , PRENY. -48% -54% +25% +50% PAPAV. -23 -67 +70 +100 2 0 -33 - +88 3 -22 -29 +69 +58 6 -36 -65 -33 +118 4 -33 -65 +82 +104 5 -40 0 0 + 86 1 -30 -29 +113 0 7 -46 -56 - + 98 8 -21 -38 +54 + 66 9 -31 I -38 -29 + 96
All compounds present an activity on the total peripheral resistance and/or on the coronary blood flow: this action is all the more interesting that the compounds of the invention do not show the undesirable side effect of papaverine as evidenced in 1/ above.
In the preceding experimentation the various compounds to be used in dissolved form were added to a molecular amount of ascorbic acid when they were insoluble in water.
PRESENTATION - POSOLOGY
The compounds of the invention may be administered orally under any therapeutical form e.g. as tablets or gelatine capsules comprising from 20 to 100 mg of active compound per dosage unit, together with an appropriate carrier such as, for instance, lactose.
Injectable forms include phials containing 10 to 50 mg of active ingredient, if necessary solubilized in water by addition of therapeutically acceptable acid such as, for instance, ascorbic acid.
Posology in human therapy is from 20 to 200 mg/day in oral form and from 10 to 100 mg/day in injectable (l.V.) form.
The compounds of the invention are to be used as anti-arrhythmics, as coronary and peripheral vasodilators. They have a highly favourable action on the protection of the myocardic cells against anoxia and prevent the loss of calcium in the myocard.
Claims (10)
1. - jl -(3,4-di methoxy-phenyl)-3-ami no-propyf]-6,7-dimethoxy-isoqui noli ne derivative according to any of claims 1 to 10 or a therapeutically acceptable salt thereof in admixture with a therapeutically
2. 1- [l-(3,4-Dimethoxy-phenyl)-3-s_.butylanrinopropyl]-6,7di methoxy-isoqui noli ne.
3. 1 -0 - (3,4-Di methoxy-phenyl) -3-cycl ohexyl ami nopropylj -6,7dimethoxy-i soqui noli ne.
4. 1 - 0 -(3,4- Di methoxy-phenyl) -3-(a-methyl phenethyl ami no) 10 propyl] -6,7-di methoxy-i soqui noli ne. 5. Reference to any of Examples 1 to 9. 13. A therapeutical composition comprising a
5. 1 - [I - (3,4-Di methoxy-phenyl) -3-(N-methyl -a-methyl benzyl ami no)-propyl] -6,7-di methoxy-i soqui noli ne.
6. 1-0-(3,4-Di methoxy-phenyl )-3-(N-methyl-1-methyl-2-phenoxyethy1 ami no)-propy]] -6,
7. -di methoxy-i soqui noli ne. 15 7. 1-0-(3,4-Dimethoxy-phenyl)-3-benzylamino-propyl]-6,7d i me thoxy-isoquinoline.
8. 1 - 0- (3,4-Di methoxy-phenyl) -3-(N-methyl -4-t. bu tylcyclohexylami no)-propyl] -6,7-di methoxy-i soqui noline.
9. 1-0-( 3,4-Dimethoxy-phenyl) -3- (4-phenyl cyclohexyl ami no) 20 propyl] -6,7-dimethoxy-i soqui nol i ne. 10. 1-0 - (3,4-Di methoxy-phenyl) -3- (1 -methyl -4-hydroxy-butyl ami no) -propyl]-6,7-di methoxy-i soqui noli ne. II. A process for the preparation of a compound according to claim 1 comprising condensing in a polar solvent, at from 25 0°C to 25°C, 1-0-(3,4-dimethoxy-phenyl-oxo-propylJ-6,7-dimethoxyi soqui noline with a compound of the general formula HNR^ wherein R 1 and Rg are as defined herein and reducing the resultant compound. 12. A process for the preparation of a compound according to claim 1, the process being substantially as described herein with
10. Acceptable diluent or carrier.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB7925276 | 1979-07-19 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE801498L IE801498L (en) | 1981-01-19 |
| IE50023B1 true IE50023B1 (en) | 1986-02-05 |
Family
ID=10506637
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE1498/80A IE50023B1 (en) | 1979-07-19 | 1980-07-18 | Isoquinoline derivatives |
Country Status (28)
| Country | Link |
|---|---|
| JP (1) | JPS5618964A (en) |
| AR (1) | AR228953A1 (en) |
| AT (1) | AT375649B (en) |
| AU (1) | AU538065B2 (en) |
| BE (1) | BE884242A (en) |
| CA (1) | CA1152998A (en) |
| CH (1) | CH644848A5 (en) |
| DE (1) | DE3027338C2 (en) |
| DK (1) | DK152124C (en) |
| EG (1) | EG14616A (en) |
| ES (1) | ES493503A0 (en) |
| FI (1) | FI77027C (en) |
| FR (2) | FR2461497A1 (en) |
| GR (1) | GR69195B (en) |
| IE (1) | IE50023B1 (en) |
| IL (1) | IL60482A (en) |
| IN (1) | IN154316B (en) |
| IT (1) | IT1237319B (en) |
| LU (1) | LU82608A1 (en) |
| MA (1) | MA18906A1 (en) |
| MX (1) | MX5962E (en) |
| NL (1) | NL8004053A (en) |
| NO (1) | NO155883C (en) |
| NZ (1) | NZ194280A (en) |
| OA (1) | OA06696A (en) |
| PT (1) | PT71578A (en) |
| SE (1) | SE448092B (en) |
| ZA (1) | ZA803993B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10320274A1 (en) * | 2003-05-07 | 2004-12-09 | Sennheiser Electronic Gmbh & Co. Kg | System for the location-sensitive reproduction of audio signals |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1400425A (en) * | 1971-09-22 | 1975-07-16 | Rolland Sa A | Substituted 3-hydroxymethyl-isoquinolines and derivatives |
| US3966724A (en) * | 1974-12-20 | 1976-06-29 | Armour Pharmaceutical Company | 1-(α-Aminomethylbenzyl)isoquinoline compounds |
| IT1143667B (en) * | 1977-05-30 | 1986-10-22 | Scharber Per L Ind Farmaceutic | PARAVEROLINIC DERIVATIVE WITH A DURABLE ACTION AND PROCEDURE TO OBTAIN IT |
| IN154317B (en) * | 1979-07-19 | 1984-10-13 | Andre Buzas |
-
1980
- 1980-07-02 ZA ZA00803993A patent/ZA803993B/en unknown
- 1980-07-02 FI FI802118A patent/FI77027C/en not_active IP Right Cessation
- 1980-07-02 IN IN491/DEL/80A patent/IN154316B/en unknown
- 1980-07-03 IL IL60482A patent/IL60482A/en unknown
- 1980-07-08 CH CH520780A patent/CH644848A5/en not_active IP Right Cessation
- 1980-07-08 MX MX808914U patent/MX5962E/en unknown
- 1980-07-09 BE BE0/201345A patent/BE884242A/en not_active IP Right Cessation
- 1980-07-09 NZ NZ194280A patent/NZ194280A/en unknown
- 1980-07-10 LU LU82608A patent/LU82608A1/en unknown
- 1980-07-15 GR GR62459A patent/GR69195B/el unknown
- 1980-07-15 MA MA19105A patent/MA18906A1/en unknown
- 1980-07-15 NL NL8004053A patent/NL8004053A/en not_active Application Discontinuation
- 1980-07-17 CA CA000356370A patent/CA1152998A/en not_active Expired
- 1980-07-17 FR FR8015781A patent/FR2461497A1/en active Granted
- 1980-07-17 FR FR8015780A patent/FR2461702A1/en active Granted
- 1980-07-17 AT AT0371980A patent/AT375649B/en not_active IP Right Cessation
- 1980-07-17 AR AR281799A patent/AR228953A1/en active
- 1980-07-18 NO NO802160A patent/NO155883C/en unknown
- 1980-07-18 DK DK310180A patent/DK152124C/en not_active IP Right Cessation
- 1980-07-18 PT PT71578A patent/PT71578A/en unknown
- 1980-07-18 AU AU60630/80A patent/AU538065B2/en not_active Ceased
- 1980-07-18 IT IT8023536A patent/IT1237319B/en active
- 1980-07-18 JP JP9765480A patent/JPS5618964A/en active Pending
- 1980-07-18 ES ES493503A patent/ES493503A0/en active Granted
- 1980-07-18 IE IE1498/80A patent/IE50023B1/en unknown
- 1980-07-18 DE DE3027338A patent/DE3027338C2/en not_active Expired
- 1980-07-18 SE SE8005260A patent/SE448092B/en not_active IP Right Cessation
- 1980-07-19 OA OA57177A patent/OA06696A/en unknown
- 1980-07-19 EG EG433/80A patent/EG14616A/en active
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