DE2244832A1 - DIHYDRO-2-AMINOISOCHINOLINES AND THE METHOD FOR PREPARING THEREOF - Google Patents

Description

1244832

«REALLY WALTE

DR. JUk. DIFL-CHEM. WALTER BEIL

ALFRED HOEPPEMER ^U '

Df JuR. DIFL-CHiM. H.-J. WOLFP

To you. JUß. HANS GHi ?. Ax

023FRANSrURTAMMAJN-HOCHST

AUaOMSTSASSES

Our Kr. 18

& ruppo Iiepetit S.p.A. Milan / Italy

Dihydro-2-aminoisoquinolines and methods for their production.

-The invention relates to new Uihydro-2-aminoisoquinolines the jPormel I

• X

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in which X and Y are different and Hp or an oxygen atom, R is a hydrogen atom, a lower alkyl, lower alkylsulfonyl »benzenesulfonyl, lower alkenyl, aryl-lower-alkenyl, cycloalkenyl or lower alkynyl radical and R _{1 is} a lower alkenyl, aryl-lower alkenyl, cycloalkenyl or lower alkynyl radical "or R and R ₁ together with the adjacent nitrogen atom form an aryl-lower alkenylidene amino radical, and their pharmaceutically acceptable acid addition salts, and processes for their preparation.

The terms "lower alkyl radicals", "lower alkenyl radicals" and "lower Alkynyl radicals "include straight and branched chains with a maximum of 8 carbon atoms. Under the designation" aryl " are phenyl residues as well as chlorine, i'luor, hydroxyl groups, Amino, nitro, cyano, carboxy, trifluorinethyl, lower Alkoxy and lower alkyl groups meant mono- or polysubstituted phenyl groups.

The cycloalkylidene groups usually contain 5 or 6 Carbon atoms, such as in the cyclopentenyl or cyclohexenyl radical. The aryl-lower-alkenylideneamino radicals are defined by the above terms for "aryl" and "alkenyl". Typical examples of such residues are the cinnamylidene amino group and the like.

The compounds according to the invention can according to the im Main patent (patent application P 22 12 693.8)

described method can be obtained.

A suitable method for the preparation of compounds of the formula I in which R is a hydrogen atom and R _{1 is} a lower alkenyl or alkynyl radical, cycloalkenyl or aryl-lower

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alkenyl radical is * consists in the implementation of the corresponding Z-Benzolsulfonamido-isoquinoline derivative with an ent-, speaking alkenyl or alkynyl, cycloalkenyl or Aryl-alkeny! Halide, with subsequent hydrolysis of the Benzenesulfonamido group. ■ - ■ ^ -.

Compounds in which R and R ^ - a lower alkenyl, lower alkyl, cycloalkenyl? or aryl lower alkenyl radical are expediently prepared by reacting the corresponding 2-aminoisoehinoline derivative with a large excess of the corresponding lower alkenyl, lower alkynyl, cycloalkenyl or aryl lower alkenyl halides in the presence of a hydrogen halide acceptor. Depending on the reaction conditions and the quantitative ratio of the reactants, mixtures of mono- and disubstituted aminoisoquinoline derivatives are obtained in some cases. The two products can be separated by fractional crystal ionization, distillation or chromatography. In general, when using essentially equimolar amounts of the two reactants, the monosubstituted derivatives, ie compounds of the formula I in which R is a hydrogen atom and .R ^ is a lower alkenyl, lower alkynyl, cycloalkenyl or aryl-lower alkenyl radical, in practically pure form. , ■■ .-

The alkylations can also be carried out with compounds of the formula I be carried out in which R is a hydrogen atom and R ^ corresponds to one of the meanings given above.

-Uieses method is particularly suitable for -production of compounds in which R and R. are different and for example from a methyl and an allyl radical or consist of an ethyl and a cinnamyl radical ..

3 09882 / 13.6 2

It goes without saying that there is also the other in the patent mentioned processes described for the preparation of the present compounds are suitable. For example, you can Hydrazines of formula II

II (CH ₂ ) _n halogen

in which R and R _{1 have} the above meanings and m and η each mean the number 1 or m = 0, n «2 and" halogen "represents chlorine or bromine, cyclize intramolecularly.

The compounds where R and R ^ together with the nitrogen atom represent an aryl-lower-alkylideneamino radical, are made by condensation of the 2-aininoisoquinoline derivative with an aldehyde such as cinnamaldehyde.

The compounds of the invention have powerful anti-inflammatory properties Effect combined with low toxicity. Typical representatives of the dihydro-2-aminoisoquinolines according to the invention demonstrated remarkable effectiveness in the carrageenin and granuloma pellet test in experiments with rats. The compounds were also found to be orally active, i.e. they caused at least an inhibition of 2oj6 even with a dosage that is about 10 to 2 times was smaller than the toxic dose that was observed in rats oral administration is between 500 and more than 100 mg / kg. For example, the following percent inhibitions of carrageenin induced udema and the

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Granuloma pellet "in experiments with the compound 2-allylamino · 3,4-dihydroisoquinolin-1 (2H) -one hydrochloride determined:

[- Dose fo -Inhibition of fo InMMerung des / ^ gAg Granuloma Carrageenin-Oderas

2ο '28 27

5ο 37 43

1οο 46, 64

The same efficiency was also found in the G ranuloma pellet test found in adrenalectomized rats.

The anti-inflammatory effect was also determined by testing the compounds on adjuvant * induced arthritis in rats by the method of BB Newbould, Brit. J. Pharmacol. 2A_ _t 127 (1963) confirmed. Another notable property of these compounds is that they have very little ulcerogenic activity. The obtained with typical compounds ulcerogenic ED ^ values in stomach and small intestine of rats (dose at which 5o $ rat injury of the stomach or intestine to V / iesen) were prepared by the procedure of DA Brodie et al., Science, 17o _t 183 (I97o) and were found to be considerably higher than the values of known anti-inflammatory agents such as acetylsalicylic acid or phenylbutazone.

The compounds are preferably administered orally or rectally, but can also be given parenterally. For oral administration, the compounds are made into pharmaceutical dosage forms such as tablets, capsules, elixirs, solutions and the like. The dose unit can contain ¹ usual stretching

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I-. ■

contain agents such as starches, gums, alcohols, sugar, fatty acids and the like. For rectal administration, the Compounds in the form of suppositories mixed with common carriers such as cocoa butter, wax, whale oil or polyoxyethylene glycols and their derivatives. Me dose is between about 0.05 and about 2.0 g per day, the administration preferably being carried out in partial amounts.

example 1

2-Allylamino-3,4-dihydro-isoquinolin-1 (2H) -one hydrochloride.

A mixture of 25 g of 2- (N-allyl-N-benzenesulfonyl) -amino-3 _f 4-dihydro-isoquinolin-1 (2H) -one and 100 ml of concentrated sulfuric acid is kept at room temperature for about 4 hours, then to about 2oo Poured g of crushed ice, whereupon it is neutralized with 12o g of sodium carbonate and 15o ml of concentrated ammonium hydroxide solution. After extraction with diethyl ether, the organic phase is evaporated and the liquid residue is ^{distilled in vacuo at 125 °} C. and 0.6 mm. This gives 11 g of product. Treatment of a solution of the product in diethyl ether with dry hydrogen chloride, the hydrochloride is obtained -one of 156-158 ⁰ C of melting point 2-allylamino-3,4-dihydroisoquinoline-1 (2H).

Example 2

2-cinnamylideneamino-3,4-dihydro-isoquinolin-1 (2H) -one. To a solution of 5 g of 3,4-dihydroisoquinolin-1 (211) -one

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in 1b ml "dry ethanol" are added "4.1 g cinnamaldehyde" in 5 ml dry ethanol ". After 2 hours the precipitate is filtered off and triturated with a 1: 1 mixture of ethanol and diethyl ether. This gives the litelverbindung melting point "1'34-136 ⁰ C, yield 7.4 g.

Example 3

2- (N-Allyl-N-benzenesulfonyl) -amino-3,4 dihydro-isoquinolin-1 (2H) -one.

3o g of 2-benzenesulfonamido-3,4-dihydro-isoquinolin-1 (2H) -one turn "at 6o C in 18o ml 5 $ sodium hydroxide solution. 9.6 ml of allyl bromide are added to the warm solution, and after 30 minutes a further 8.6 ml of allyl bromide are added. After 1 hour at 6o C the solution is cooled and extracted with methylene chloride, the organic phase becomes washed with water, dried and evaporated. This gives an oily product which is crystallized several times from light petroleum. The yield is 32 g ($ 94), Melting point 100-110 ° G.

Example 4

2-2f "li (3-methyl-2-butenyl) -N-benzenesulfonyl7-amino-3,4-dihydroisoquinolin-1 (2H) -one.

If you repeat the procedure of the previous example, However, using 1-bromo-3-methyl-2-butene instead of the allyl bromide, the title compound is obtained in 92% Yield, melting point 99-11o ° C. '

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Example 5

2- ^ ^- N-cinnamyl-1-benzenesulfonyl-7-amino-3,4-dihydro-isoquinolin-1 (2H) -one.

The procedure of Example 3 is repeated, but below If cinnamyl bromide is used instead of allyl bromide, the title compound is obtained with a melting point of 100-102 ° C.

Example 6

2-cinnamylamino-3,4-dihydro-isoquinolin-1 (2H) -one.

5.7 g of triethylamine and then 3.1 g of cinnamyl chloride are added to 4 g of 2-amino-2,4-dihydro-isoquinolin-1 (2H) -one hydrochloride in 40 ml of dioxane. After refluxing for 11/2 hours, the reaction mixture is cooled and triethylamine salts are filtered off. The filtrate is then evaporated to dryness, the residue is dissolved in methylene chloride and the solution is washed with water and then concentrated in vacuo. The residue is chromatographed on silica gel while diluting with benzene plus 5 $ ethyl acetate. The first fractions, which contain a small amount of the disubstituted compound, are discarded. Evaporation of the following fractions of the title compound 2.2 g (39 $) is from 72-74 ⁰ F. G.

Example 7

2-propargylamino-3,4-dihydro-isoquinolin-1 (2H) -one hydrochloride.

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If the procedure of Example 6 is repeated, but using propargyl bromide instead of the cinnamyl chloride, the title compound is obtained as a crude product. It is purified by distillation "at 125-13o ° C and ο, 4 mm, yield 2o? Sixth The hydrochloride obtainable by addition of dry hydrogen chloride to a solution of the base in diethyl ether melts at 162-166 ⁰ C.

Example 8

a) 2- (2-butenyl) -amino-3,4-dihydro-isoquinolin-1 (2H) -one,

b) 2-bis (2-butenyl) -amino-5,4-dihydro-isoquinolin-1 (2H) -one.

According to the procedure of Example 6, when 6 g of 2-amino-3,4-dihydro-isoquinolin-1 (2H) -one hydrochloride are reacted with 6.1 g of 1-bromo-2-butene, 6 g of a crude product are obtained, which is chromatographed on silica gel while eluting with benzene / ethyl acetate (8o: 2o). The first fractions give after evaporation 0.2 g of 2-bis (2-butenyl) -amino-3,4-dihydroisoquinolin-1 (2H) -one, 'bp. _κ = 135-14o ° C. -One are obtained from the following fractions 3 g of 2- (2-butenyl) amino-3,4-dihydroisoquinoline-i (2H), bp _n-'13o c-135 ° C.

Example 9

a) 2-Allylamino-3,4-dihydro-isoquinolin-1 (2H) -one

b) 2-diallylamino-3,4-dihydro-isochindlin-1 (2H) -one.

If the procedure of Example 8 is repeated, but replacing the 1-bromo-2-butene with allyl bromide, then the following connections:

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" ^1o - 22AA832

a) 2-Allylamino-3,4-dihydro-i§oquinolin-i (2H) -one, bp,

b) 2-Diallylamino-3,4-dihydro-isoquinolin-1 -one (2H), Kp = _{0 9} 127-13o ° G.

Example · 1ο

2- (2-Methyl-2-propenyl) -amino-3,4-dihydro-isoquinolin-i (2H) -one.

According to the procedure of Example 6, 12 g of 2-amino-3,4-dihydro-isoquinolin-1 (2H) -one-hydrochloride are reacted with 9.7 ml of 1-bromo-2-methyl-2-propene to give 3.5 g of the title compound, boiling point _A = 128-134 ° C.

Other compounds of the invention can be prepared by the methods described above, e.g. 2- (3-Kethyl-2-butenyl) -amino-3,4-dihydroi so quinolin-1 (2H) -one, 2-Allylamino-1,4-dihydroisoquinolin-3 (2H) -one, 2-cinnamylamino-1,4-dihydroisoquinolin-3 (2H) -one, 2- (2-cyclopentenyl) -amino-3,4-dihydroisoquinolin-1 (2H) -one, 2- (2-Cyclohexenyl) -amino-3,4-dihydroisoquinolin-1 (2H) -one, 2- (2-propynyl) -amino-1,4-dihydroisoquinolin-3 (2H) -one, 2-Diinnamylamino-3,4-dihydroi, soquinolin-1 (2H) -one, 2-diallylamino-1 ^ -dihydroisoquinoline (2H) -one, 2- (3-butenyl) -amino-3,4-dihydroisoquinolin-1 (2H) -one, 2- (4-chloro-cinnamyl) -amino-3,4-dihydroisoquinolin-1 (2H) -one, 2- (2-heptinyl) -amino-3,4-dihydroi so quinolin-1 (2H) -one, 2- (2-chloro-2-hexenyl) -amino-3,4-dihydroisoquinolin-i (2H) -one, 2- (3-hexenyl) -amino-3,4-dihydroisoquinolin-i (2H) -one, 2- (i-Ethyl-2-butenyl) -amino-3,4-dihydroisoquinolin-1 (2H) -one, 2- (1-butyl-2-butenyl) amino-3,4-dihydroisoquinolin-1 (2H) -on.

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Claims (2)

according to patent (patent application 2 22 12 693.8), characterized in that R. is a hydrogen atom, a lower alkyl, lower alkylsulfonyl, benzenesulfonyl, lower alkenyl, aryl-lower-alkenyl, cycloalkenyl or lower-alkynyl radical and H. is a lower alkenyl, aryl-lower mean alkenyl, cycloalkenyl or lower alkynyl radical or R and S ₁ together with the adjacent nitrogen atom form an aryl-lower-alkenylideneamino radical. 2. Process for the preparation of a compound according to claim 1, characterized in that one
a) a combination of the! formula II H-YEAR in which R _{2 represents} a hydrogen atom, a lower alkylsulfonyl or benzylsulfonyl radical, with a compound of 309882/1362 Formula R ₁ -halogen, in which R. has the above meaning and the halogen consists of bromine or chlorine, reacts in the presence of a base as a hydrogen halide acceptor and b) if up a lower alkylsulfonyl or benzenesulfonyl radical is and in the end product R should be hydrogen, the compound obtained in step a) an acid hydrolysis subject and c) if in the end product R and R ₁ together with the adjacent nitrogen atom represent an aryl-lower-alkenylidene-amino radical, a compound of the formula II in which R "is a hydrogen atom is condensed with an aryl-substituted lower aliphatic unsaturated aldehyde. Pure: Gruppo Lepetit S.p.A. Milan / Italy Dr.HAisChr.8 Right saawa] 30 9 8 82/1362