DE2030675A1 - 3-amino-4-phenyl-isoquinoline derivs - Google Patents

Abstract

3-Amino-4-phenyl-isoquinoline derivs. Novel cpds. of formula (I): (where R1 is NO2, -N(CH2)n or NR'R"; n = 2-7, and R' and R" are H, alkyl, alkanoyl or cycloalkyl, R2 and R3 are H, alkyl, alkanoyl, cycloalkyl or arylcarbonyl, R4 is H, alkyl, halogen, alkoxy or NH2, X is H alkoxy, or halogen) are CNS-depressants. Pref. cpd. is 3-amino-4-(p-aminophenyl)-isoquinoline which may be prepd. by redn. and debromination of 3-amino-1-bromo0-4-(p-nitrophenyl)-isoquinoline.

Description

Substituted isoquinolines and process for their preparation The present invention relates to new 3-amino (subst.-amino-4-aryl (subst.-aryl) -isoquinolines, Intermediates for their manufacture, the manufacture of these compounds as well pharmaceutical compositions containing them.

In one of its aspects, the invention relates to a class of chemical compounds represented by the following general formula can be reproduced, in which R1 has a remainder -NO2, (where n is an integer from 2 to 7) or -NR'R "(where Rt and R ??, which may be the same or different from one another, each represent a hydrogen atom, an alkyl or cycloalkyl radical or a radical mean), R2 and R, which can be the same or different from one another, each represent a hydrogen atom, an alkyl or cycloalkyl radical or a radical or represent, R4 represents a hydrogen atom, an alkyl or alkoxy radical, a halogen atom or a radical -NH2 and X represents a hydrogen atom, an alkoxy radical or a halogen atom.

Compounds according to this aspect of the invention have them own use properties, dampening effects on the central nervous system as determined by standard pharmacological test procedures.

Examples of these substituted isoquinolines and preferred compounds among them are those of the formula and acid addition salts thereof.

According to a further aspect, the invention relates to methods for Preparation of the various intermediates and the compounds of formula I. and their acid salts. A main object of the present invention is therefore that Creation of new chemical compounds, new intermediates to theirs synthesis and methods of making the chemical compounds and their intermediates. Another object of the invention is to provide compositions which Possessing properties of CNS depressants. Other objects and objects of the invention can be seen from the following description.

The invention therefore relates to the various stages and the Relationship of one or more such stages to each of the others and the connections and compositions showing the properties, characteristics and relationship of components as they are represented by the compounds described below and compositions are explained.

As used herein, AlkyL means saturated monovalent ones aliphatic radicals, including straight-chain and branched radicals, from 1 to 20 carbon atoms for which, without making a limitation, Methyl, n-amyl, n-heyl, 2-ileptyl, n-heptyl, 3-methyl-2-octyl, n-octyl, 2-nonyl, 2-tetradecyl, n-hexadecyl, 2-eicosanyl, and the like are examples. The term "cycloalkyl" means cyclic saturated aliphatic radicals with 3 to 8 carbon atoms, while the term "aryl" is used to denote an organic radical, which differs from an aromatic hydrocarbon by removing one hydrogen atom derived, such as phenyl and tolyl. The term "alkoxy" becomes the designation an alkyl radical bonded to the rest of the molecule through an oxygen atom is used.

According to one of its process aspects, the invention relates to the reduction and debromination of a compound of the formula to form the compound of formula II.

According to a further aspect of the method, the invention relates to the acylation of the compound of the formula II to form the compounds of the formula I for which R1 is a radical and the radical -BR2R3 is a radical NH2 or or R1 is a radical -NH2 and -NR2R3 a radical is. Yet another process according to the invention consists in the selective reduction of one or all of the compounds formed by such acylation. Preferred acylating agents are the acid anhydrides and the compounds of the formula Preferred selective reducing agents include diborane and lithium aluminum hydride.

The preparation of the compound of the formula II 'can serve as an example of the process according to the invention. According to a preferred embodiment of the process according to the invention, after purification with 1-bromo-4-nitrobenzene, commercially available a-cyano-o-tolunitrile is reacted in a suspension of potassium hydroxide in pyridine to carry out the arylation of the compound of formula IV according to the following reaction according to a method described by RB Davis and LC Pizzini for the synthesis of similar compounds (J. Org. Chem., 25, 1884, 1960). The cyclization of the α-cyano-α- (pnitrophenyl) -o-tolunitrile (compound V) obtained is then carried out by treating it in solution with hydrogen bromide and then reacting the hydrobromide obtained with potassium bicarbonate to form the free base according to the method of F. Johnson and WA Nasutavicus (J. Org. Chem., 27, 5953, 1962). This cyclization reaction can be represented as follows: The reduction of the -N02 group to the -NH2 group and the debromination can be carried out in two stages, first using a reducing agent such as SnC12 and then catalytic hydrogenation using palladium-carbon as the preferred catalyst. However, the reduction and debromination can also be carried out at the same time. The alternative ways of forming compound II can be represented as follows: Treatment of compound II with dilute hydrochloric acid leads to the stable dihydrochloride of the formula Treatment of the compound-II with acetic anhydride in pyridir (a typical example of an acylating agent) gives the monoacetyl compound VIII [3-amino-4- (p-acetamdiophenyl) isoquinoline] wherein -CH) is an example of an alkyl radical.

The substituted isoquinoline VIII can be selectively reduced with a suitable reducing agent, such as, for example, diborane, in order to form the compound of the formula I for which R1 is aminoalkyl, ie in the illustrated case a radical -NHCR2CH5-, according to the reaction It is also within the scope of the invention to prepare compounds of the formula I for which R2 is a hydrogen atom and R3 is an alkyl radical, a radical or a cycloalkyl radical O This preparation can be carried out by reacting the compound III with a suitable acylating agent, such as, for example, a compound of the formula as in the reaction be made. The reduction and debromination can then be carried out in one or two stages, as indicated above for the compound III, to give a compound of the formula and the compound XI can be further acylated to give a compound of the formula and then selectively reduced with a reducing agent such as B2H6 to give a compound of the formula to build.

By a process which is analogous to that for the preparation of the compound of the formula IX, compounds of the formula produce.

The other compounds of the formula I can be used in a corresponding manner getting produced.

The compounds of formula II, VIII, IX, XI and XII can be in the corresponding acid addition salts are converted, as described above in the case of Compound II is described. The free bases can be obtained from the acid addition salts formed be prepared in the usual way, i.e. by treating the salts with strong aqueous bases such as alkali hydroxides, alkali carbonates and alkali bicarbonates. The bases regenerated in this way can then be mixed with the same or a different acid be reacted to get back the same acid addition salt or a different one To form acid addition salt. So can the acid addition salts and the corresponding Bases are easily made and are within the scope of the present invention.

It has been found that the compounds according to the invention are based on of the common structural design have pharmacodynamic activity of a species, which is described in more detail below. This the invention Compounds inherent in pharmacodynamic activity can be valuable for pharmaceutical purposes by using the free bases themselves or the acid addition salts which are formed from pharmaceutically acceptable acids, i.e. Acids, the anions of which are harmless to the organism in effective doses of the salts so that those inherent in the general structure of the free bases are favorable Properties not adversely affected by side effects ascribable to the anions to be influenced.

When utilizing this pharmacodynamic activity of the inven The salts according to the invention are of course the use of pharmaceutically acceptable salts preferred. The pharmaceutical compositions according to the invention contain thus at least one of the compounds according to the invention in the form of the bases and / or the pharmaceutically usable salts.

Although water insolubility, high toxicity or a 'lack of crystalline Some special salts for use in a given pharmaceutical character Usage unsuitable or less can make suitable, so can the water-insoluble or toxic salts in the corresponding pharmaceutical usable bases by decomposition of the acid addition salts with an aqueous one Base as explained above or the acid addition salt can be converted into any desired pharmaceutically acceptable acid addition salt by double conversion with the participation of the anion, for example by ion exchange processes will.

Apart from their usefulness in pharmaceutical applications the salts according to the invention are also used as derivatives for characterization or Identification of free bases or for isolation or purification procedures useful. Such acid addition salts suitable for characterization or purification If desired, like all acid addition salts for the regeneration of the pharmaceutical usable free bases are used by reacting the salts with an aqueous base or the acid addition salts can be converted into a pharmaceutically acceptable salt, for example by ion exchange processes.

From the above it can be seen that all acid addition salts and bases useful and valuable compounds, regardless of considerations regarding solubility, toxicity, physical form and the like Scope of the present invention.

The novel features of the compounds according to the invention are in particular in the concept of the various forms of formula I and III.

Suitable acid addition salts are therefore those that differ from derive different acids, such as formic acid, acetic acid, isobutyric acid, α-mercaptopropionic acid, malic acid, fumaric acid, succinic acid, succinic acid monoamide, Tartaric acid, citric acid, lactic acid, benzoic acid, 4-methoxybenzoic acid, phthalic acid, Anthranilic acid, naphthalenecarboxylic acid (1), cinnamic acid, cyclohexanecarboxylic acid, mandelic acid, Tropic acid, crotonic acid, acetylenedicarboxylic acid, sorbic acid, furancarboxylic acid- (2), Cholic acid, pyrene carboxylic acid, pyridine-2-carboxylic acid, indole acetic acid- (3), Quinic acid, Sulfamic acid, methanesulfonic acid, isethionic acid, benzenesulfonic acid, p-toluenesulfonic acid, Benzenesulfinic acid, butylarsonic acid, diethylphosphinic acid, p-aminophenylarsinic acid, Phenylantimonic acid, phenylphosphinic acid, methylphosphinic acid, phenylphosphinic acid, Hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydriodic acid, Perchloric acid, nitric acid, sulfuric acid, phosphoric acid, picrolonic acid 9 barbituric acid and dglo The compound II and its dihydrochloride VII have as rested has been, pronounced neuromuscular blocking effect, anesthetic effect and analgesic effects at low doses in mice, chickens and dogs. These Activity demonstrates their usefulness as CNS depressants.

The compounds can be prepared for use by dissolving a salt of the Compounds in water (or an equivalent amount of a non-boxic acid, if the free base is used) or in a physiologically acceptable aqueous Medium, such as saline, prepared under sterile conditions and stored in ampoules for intramuscular injection. Alternatively you can them in unit dosage form as tablets or capsules for oral administration either alone or together with suitable adjuvants, such as calcium carbonate, Starch, lactose, talc, magnesium stearate, agar-agar and the like. Be brought. The compounds can also be used for oral administration in aqueous alcoholic, glycolic or oily solutions or in bl-water emulsions in the same way can be prepared in the same way as usual medicinal preparations are made.

The molecular structures of the compounds according to the invention were on the basis of the examination of their infrared and NMR spectra and their conversion products established and by the correspondence of the calculated values and those found Elemental analysis values confirmed for typical examples.

The following examples illustrate the invention without restricting it.

Example 1 3-Amino-1-bromo-4- (p-nitrophenyl) -isoquinoline (III) A. a-Cyano-a- (p-nitrophenyl) -o-tolunitrile (V) A mixture of approximately 450 g of potassium hydroxide chips (86%) and 500 ml of pyridine were ground in a ball mill overnight. The received Slurry was placed in a 5 liter three-stroke flask fitted with a mechanical Stirrer, thermometer and addition funnel. Another 300 ml of pyridine were added. The mixture was cooled to about 5 ° C. A mixture of 100 g (0.705 mol) a-cyano-o-tolunitrile (F = 77-790C) and 143 g (0.709 mol) 1-Bromo-4-nitrobenzene in 1 liter of pyridine were added to the potassium hydroxide suspension of 4 hours added.

The a-cyano-o-tolunitrile was obtained by recrystallizing a commercially obtainable material from carbon tetrachloride ethanol mixtures.

After about two-thirds of the reagents were added, it became Mixture very thick and an additional 300 ml of pyridine was added. The deep blue The reaction mixture was stirred for a total of 5 hours and then treated with 2 liters of benzene.

The bluish black precipitate was on a suction filter using a layer of glass cloth instead of a filter paper. The solid substance was washed with benzene and then stirred with 3 l of water. The mixture was through Adding about 600 ml of acetic acid made weakly acidic. The crude product (V) was extracted in 1 l of benzene and the benzene layer was twice with 2 iger hydrochloric acid, washed twice with water and once with brine. The benzene solution was then stirred with magnesium sulfate and decolorizing charcoal. The benzene was under vacuum removed and the remaining brown oil was dissolved in 1.5 l warm ethanol. Slow cooling and repeated scratching caused the crystallization of the Product V set in motion in the form of a light brown material. The product was collected on a nutsche, washed with small amounts of ethanol and then air dried. 111 g of product with an F = 81-830C were obtained in this way. An additional fraction of 16 g of product with an F = 78-800C was obtained by concentration of the mother liquor to 400 ml. The overall yield was 68% by recrystallization a small sample of the first fraction (F = 81-83 ° C9 from 2-propanol was the Melting point increased to 82.5 to 840C. Analytical data were from one material obtained, which is produced on a smaller scale, but under appropriate conditions the material was obtained by distillation, b.p. about 2350C (oven temperature) / 0.01 mm, has been cleaned.

Analysis C15H9N3O2 Calculated: C = 68.43 H = 3> 45 N = 15.96% Found: 68.56 3.92 15.64% The nitrile V forms on recrystallization from cold ethanol a solvate, m.p. 53-56 ° C. When these crystals are crushed and kept in vacuum the compound V, F = 80-830C, is obtained.

B. 3-Amino-1-bromo-4- (p-nitrophenyl) -isoquinoline (III) A solution of 105 g (0.4 mol) of compound V in a mixture of 850 ml of benzene and 250 ml of ether was cooled to 5 ° C. and saturated with gaseous hydrogen bromide The total reaction time was 5 hours. The orange-yellow precipitated hydrobromide the compound III was on a suction filter using a layer of glass cloth collected instead of a filter paper. It was washed with ether and so dry aspirated as possible. The solid was then dissolved in excess aqueous potassium bicarbonate solution introduced with stirring to release the base III. The connection was on suctioned off a suction filter and washed with water. To completely remove the inorganic salts, the orange-colored solid substance was stirred with water, collected, washed and dried in a drying cabinet (90-95 ° C).

The yield of compound III was 128 g (93%); F about 270 ° C (Decomp.) [F = 2750C (dec.) When immersed at 270 ° C]. The material from an earlier experiment was recrystallized from large amounts of toluene; F = 275-2760C (dec.).

Analysis C15H10N3O2Br Calculated: C = 52.35 H = 2.93 N = 12.21 Br = 23.22% Found: 52.55 3.02 12.07 23.47 ffi Example 2 3-Amino-1-bromo-4- (p-aminophenyl) -isoquinoline (VI) To a slurry of 2.8 g (0.008 mol) of the nitro compound III in one Mixture of 100 ml of glacial acetic acid and 5 ml of concentrated hydrochloric acid was. a solution of ii g (0.049 mol) of stannous chloride in 15 ml of concentrated hydrochloric acid was added. The mixture was stirred at room temperature for 4 hours and then cooled to 100 ° C.

The yellow solid was collected on a suction filter and with a Treated excess aqueous sodium hydroxide solution. The diamino compound VI was extracted in ether. The ether was removed and the solid product became an Recrystallized mixture of 30 ml of chloroform and 50 ml of n-hexane. It was 2.02 g (79%) of pure compound IV obtained from F = 1750C (decomp.).

Analysis C15H12N3Br Calculated: C = 57.34 H = 3.85 N = 13.37 Br = 25.44 % Found: 57.12 3.77 13.29 25.48% Example 3 3-Amino-4- (p-aminophenyl) -isoquinoline (II) The debromination of compound VI was carried out by dissolving a 1.15 sample g (0.0036 moles) of 3-amino-1-bromo-4- (p-aminophenyl) -isoquinoline (VI) and 1 g of potassium hydroxide carried out in 100 ml of ethanol. The mixture was made on a Parr apparatus hydrogenated in the presence of 0.1 g of 10% palladium-carbon. The hydrogen uptake occurred quickly and the pressure remained constant after about 15 minutes. The mixture was filtered and the filtrate concentrated to dryness. The inorganic salts were removed by treatment with water and the organic material was removed from 10 ml Recrystallized methanol. The yield was 0.45 g (52) of Ver connection II from F - 153-154.5 ° C.

Analysis C15H13N3 -Calculated: C = 76.57 H = 5.57 N = 17.86 ffi Found: 76.42 5.63 17.75% The direct reduction of a 2 g (0.0058 mole) slurry the compound III in 100 ml of ethanol in the presence of 1 g of potassium hydroxide and 0.2 g of 10% palladium-carbon proceeded relatively slowly (2 hours). That The filtrate was concentrated to dryness and the remaining solid substance with water extracted and recrystallized from 10 ml of ethanol. The yield was 0.55 g (40 %) on compound II from F = 152-1530C. A mixed melting point with one obtained previously Product showed no degradation and the infrared spectrum was identical.

Example 4 3-Amino-4- (p-aminophenyl) -isoquinoline hydrochloride (VII) A sample of 7> 8 g (0.033 mol) of the diamino compound II was dissolved in 150 ml of 0.5N hydrochloric acid solved. The solution was filtered and concentrated almost to dryness. The damp Dihydrochloride VII was treated with 50 ml of acetone and the yellow crystalline solid was collected on a suction filter, washed with acetone and under reduced pressure dried. The yield was 9.5 g (93%) of compound VII with an F = 292 + 100 (determined by differential thermal analysis).

Analysis C15H15N3Vl2 Calculated: C = 58.45 H = 4.90 N = 13.63 Cl = 23.01% Found: 58.64 4.92 13.95 22.83% Example 5 3-Amino-4- (p-acetamidophenyl) -isoquinoline (VIII) A 1.0 g (0.0032 mole) sample of the hydrochloride VII was dissolved in 20 ml of pyridine solved. A small amount of acetic anhydride (0.4 g; 0.0039 moles) was added all at once was added and the mixture was stirred at room temperature for 15 minutes. Then became the mixture poured into 300 ml of water, resulting in a grape solution from which 0.65 g (72%) of monoacetamide VIII of F = 235-2360C slowly crystallized out. The melting point was raised by recrystallization from a small amount of ethanol 235.5-2370C increased.

Analysis C17H15N3O Calculated: C. = 73.63 H = 5.45 N = 15.15% Found: 73.37 5.46 15.02% Example 6 3-Amino-4- [p- (ethylamino) phenyl] isochionoline (IX) A 4.1 g (0.0148 mole) sample of acetylated compound VIII became incomplete dissolved in 100 ml of tetrahydrofuran and 40 ml of an approximately 1 molar solution of diborane in the same solvent were added dropwise. The mixture was at Ice bath temperature for 1/2 hour and then stirred at room temperature for about 15 hours. The resulting mixture was a clear yellow solution. About 30 ml of acetone was added and then about 100 ml of 2% hydrochloric acid were added. The solution was concentrated to a volume of 70 ml and the concentrate in 300 ml of a saturated Poured potassium bicarbonate solution. The precipitated solid was collected, washed with water and dried. This gave 3.4 g of a sticky solid substance obtain. This crude product was recrystallized once from 25 ml of ethanol (1.4 G; F = 136 ° 140 ° C), once from 400 ml of n-hexane (1.03 g; F = 137.5 -142, ° C) and once from 10 ml of acetonitrile (0.77 gp F = 141 -143 ° C).

Analysis C17H17N3 Calculated: C = 77.53 H = 6.51 N = 15.96% Found: 77.71 6.59 16.15% It can thus be seen that the above given and from the above Description of the apparent objectives have been effectively achieved and that certain changes in performing the methods and compositions described above can be made without departing from the scope of the invention.

Claims (1)

P a t e n t a n s p r ü c h e 1. Compounds of the formula in R1 a remainder -NO2, (where n is 2 to 7) or -NRtR "(where R 'and R", which may be the same or different, each represent a hydrogen atom, an alkyl radical, a radical or a cycloalkyl radical) represents R2 and R3 hydrogen atoms, alkyl radicals, radicals Cycloalkyl radicals or radicals R4 represents a hydrogen atom, an alkyl radical, a halogen atom, an alkoxy radical or a radical -NH2 and X represents a hydrogen atom, an alkoxy radical or a halogen atom. 2. Compounds of the formula in which R1 is a radical -NO2, -N (CH2) n (in which n represents a value from 2 to 7) or -NR'R "(in which R 'and R", which can be the same or different from one another, each represent a hydrogen atom , an alkyl radical, a radical or represent a cycloalkyl radical) means R2 and R3 are hydrogen atoms, alkyl radicals, radicals Cycloalkyl radicals or radicals and X represents a hydrogen atom, an alkoxy group or a halogen atom. 3. 3-Amino-1-bromo-4- (p-nitrophenyl) -isoquinoline (Formula a: R1 = -NO2 R2 and R3 = hydrogen, X = bromine). 4. 3-Amino-1-bromo-4- (p-aminophenyl) -isoquinoline (Formula a: R1 = NH2> R2 and R5 - hydrogen, X = bromine). 5. 3-Amino-4- (p-aminophenyl) -isoquinoline (formula a: R1 = -NH2, R2 and R3 = hydrogen, X = hydrogen). 6. 3-Amino-4- (p-acetamidophenyl) -isoquinoline (Formula a: R1 = R2 and R3 = hydrogen, X = hydrogen) 7. 3-Amino-4- [p- (ethylamino) -phenyl] -isoquinoline (formula a: R1 = -NHCH2CH3, R2 and R2 = hydrogen, X = hydrogen). 8. 3-Acetamido-1-bromo-4- (p-nitrophenyl) -isoquinoline (Formula a: R1 = -NO2, R2 = hydrogen, R3 = X = bromine). 9 compounds of the formula wherein R§t is a hydrogen atom, an alkyl radical, a radical or denotes a cycloalkyl radical, R3 denotes a hydrogen atom, an alkyl radical, a radical a cycloalkyl radical or a radical represents and X represents a hydrogen atom, an alkoxy group or a halogen atom. 10. Acid addition salts of the compounds of the formula wherein R "is a hydrogen atom, an alkyl radical, a radical or a cycloalkyl radical, R3 is a hydrogen atom, an alkyl radical is a radical a cycloalkyl radical or a @@ represents and X represents a hydrogen atom, an alkoxy @ os @ or a halogen atom. 11. acid addition salts according to claim 10, characterized that the acid is hydrochloric acid. 12. p-Amino-4- (p-aminophenyl) -isoquinoline-dihydrochloride formula b: R ", R3 and X = hydrogen; acid = hydrochloric acid). 13. Process for the preparation of a compound of the formula characterized in that 3-amino-1-bromo-4- (p-nitrophenyl) -isoquinoline is reduced and debrominated. 14. The method according to claim 13, characterized in that the reduction a first reaction with a metal chloride and the debromination comprises catalytic hydrogenation of the resulting reduced compound.