NO750835L - - Google Patents

Description

Aminotetralol compounds and processes for their preparation.

The present invention relates to new aminotetralol compounds with the formula

12 1

wherein Z and Z are hydrogen or an alkyl group, and R is a substituted acyclic hydrocarbon group or a cyclic hydrocarbon group, as well as their pharmaceutically acceptable salts having excellent pharmacological activities such as strong bronchodilator activity or (3-adrenergic blocking activity,

and which can be used as medicines, e.g. for the treatment of asthma or arrhythmia.

As medicines for the treatment of asthma, isoproternol and metaproternol have often been used, both of which have a stimulating effect on the so-called β-adrenergic receptors. Now, however, it is the case that while isoproternol has a burn codilating effect which is associated with β-adrenergic receptors, it has strong side effects due to strong heart stimulation which is again associated with β-adrenergic receptors. Metaproternol, on the other hand, only has moderate side effects of the type mentioned above, but has a far worse bronchodilating effect. None of the above compounds has therefore been fully satisfactory as a selective bronchodilator.

New compounds (I) have now been synthesized which have strong bronchodilating activity and which have moderate or essentially lack the side effects produced by a β-adrenergic stimulation.

It is thus a principle aim of the present invention to provide compounds of formula (I) and their pharmaceutically acceptable salts, which can be used as medicines for the treatment of asthma and arrhythmia. Furthermore, it is an aim of the invention to provide a method for the production of said compounds as well as their pharmaceutically acceptable salts. Other purposes and benefits will

appear from the following description..

With regard to formula (I), the alkyl group denoted* by the symbols Z 1 and Z 2 can be a straight or branched alkyl group, preferably a lower alkyl group, especially with up to 6 carbon atoms, for example methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, i-pentyl, t-pentyl, n-hexyl, i-hexyl and so on.

The substituted acyclic hydrocarbon group denoted by the symbol R"1" can be a saturated or unsaturated and a straight or branched group. The acyclic hydrocarbon group can be exemplified by an alkyl group, preferably a lower alkyl group, and then with up to 6 carbon atoms, (e.g. methyl, ethyl, n-propyl, i-propyl, 1-methylpropyl, n-butyl, i -butyl, t-butyl, secondary-butyl, n-pentyl, i-pentyl, t-pentyl, n-hexyl, i-hexyl, etc), a lower alkenyl group then especially with up to 6 carbon atoms (e.g. ethenyl, propenyl, butenyl, pentenyl, hexenyl, etc), a lower alkynyl group, especially with up to 6 carbon atoms (eg ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc.) or the like. It is most advantageous with a lower alkyl group that branches in the a-position in relation to the amino group, especially with up to 4 carbon atoms, e.g. groups such as i-propyl, 1-methylpropyl and js-butyl. As the substituent or substituents in the aforementioned substituted acyclic hydrocarbon group, one can mention, among other things, a cycloalkyl group, preferably with from 3-7 atoms in the ring, (e.g. cyclopropyl, cycloputyl, cyclopentyl, cyclohexyl, cycloheptyl, etc), a cycloalkenyl group preferably with from 3-7 atoms in the ring (e.g.

2-cyclopentenyl, 3-cyclohexenyl, etc), a cycloalkylidene group, preferably with from 3-6 atoms in the ring (e.g. cyclohexylidene, cyclopentylidene, etc), an aryl group (e.g. phenyl, naphthyl, etc) , a heterocyclic group (eg, a heterocyclic group with one oxygen atom (eg, tetrahydrofuryl, tetrahydropyranyl, dihydropyranyl, furyl, etc), a heterocyclic group with one nitrogen atom (eg, piperidinyl, pyridyl, indolyl, quinolyl, etc), a heterocyclic group with one sulfur atom (eg thienyl, tetrahydrothienyl, etc), a heterocyclic group with 2 or more of the same or different heteroatoms (eg thiazolyl, pyrimidyl, oxazolyl, etc) ), etc), hydroxyl, a lower alkoxy group with from 1-4 carbon atoms (e.g. methoxy, ethoxy, propoxy, etc), an aryl ok sy group (e.g. phenoxy, naphthoxy, etc), halogen ( e.g. chlorine, fluorine, bromine, iodine, etc), an esterified hydroxyl, an alkoxycarbonyl group, an amino or a substituted amino group (where the substituent or either can be an alkyl group, an acyl group or other groups), nitro, cyano or other groups. The aforementioned cycloalkyl, cycloalkenyl, aryl and heterocyclic groups can further contain suitable substituents such as lower alkyl groups with from 1-4 carbon atoms (e.g. methyl, ethyl, propyl, etc), hydroxyl, a lower alkoxy group with from 1- 4 carbon atoms (e.g. methoxy, ethoxy, propoxy, etc), halogen (e.g. chlorine, bromine, iodine, fluorine). Among typical examples of the above

substituted acyclic hydrocarbon groups may be mentioned cyclohexylmethyl, 1-cyclohexylethyl, 2-cyclopentylethyl, 3-cyclohexyl-1-methylpropyl, 4-methylcyclohexylmethyl, 1-cyclohexenylmethyl, 1-cyclopentenylmethyl, benzyl, 4-methoxybenzyl, 4-hydroxybenzyl, a -methylbenzyl, 3>4-dimethoxybenzyl, a-methylphenethyl, 4-methoxy-a-methylphenethyl, 4-hydroxy-a-methylphenethyl, 4-hydroxy-a,a-d&methylphenethyl, 4-methoxy-a,a-dimethylphenethyl, 4 -chlorophenethyl, 3-phenylpropyl, phenethyl, 4-methoxyphenethyl, 2-phenylpropyl, α,4-dimethylphenethyl, 1-methyl-2-cyclohexylidene-ethyl, tetrahydropyran-2-ylmethyl, 2,3-dihydropyran-2-ylmethyl, tetrahydrofuran -2-ylmethyl, 2-(furan-2-yl)-1-methylethyl, 2-thienylmethyl, piperidin-2-ylmethyl, 2-(2-indolyl)-1-methylethyl, 2-pyridylmethyl, 2-(2- thiazolyl)ethyl, 2-hydroxyethyl, 2-methoxy-ethyl, 3-ethoxy-l-methylpropyl, 6-methoxyhexyl, l-methyl-2-

phenoxyethyl, 2-fluoro-l-methylethyl, 2-ethoxycarbonylethyl, 2-aminoethyl, 3-dimethylaminopropyl, 3-morpholino-l-methylpropyl, 2-piperidino-l-methylethyl, nitromethyl, 2-cyano-l-methylethyl, styryl, 3-phenyl-2-propenyl and so on.

With reference to formula (I), the cyclic hydrocarbon group denoted by the symbol R?~ can be exemplified by a cycloalkyl group preferably with from 3-7 atoms in the ring (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.), a cycloalkenyl group, preferably with from 3-7 atoms in the ring (e.g. cyclopentenyl, cyclohexenyl, etc.), an aryl group (e.g. phenyl, naphthyl, etc.) etc. Among the more preferred groups a cycloalkyl group with from 3 -7 atoms in the ring. These groups may optionally contain one or more substituents, such as a lower alkyl group, hydroxyl, lower alkoxy group, halogen or other groups mentioned above as the substituents for the above-mentioned cycloalkyl, cycloalkenyl, aryl or heterocyclic groups. Among typical examples of the aforementioned cyclic hydrocarbon groups, cyclopropyl can be mentioned. cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methylcyclopropyl, 2-methylcyclobutyl, 3-methylcyclobutyl, 2,2-dimethylcyclobutyl, 3,3-dimethylcyclobutyl, 4-methylcyclohexyl, 4-hydroxycyclohexyl, 4-methoxycyclohexyl, 2-chlorocyclopentyl, 2-cyclohexenyl, 2-cyclopentenyl, phenyl, oc-naphthyl, 4-chlorophenyl, 4-methoxyphenyl, 2-fluorophenyl, 4-hydroxyphenyl, 3,4-dimethoxyphenyl, etc.

The compound of formula (i) can, for example, be prepared by reducing a compound of the formula

1 2

where Z and Z . has the same meaning as defined above, X is ^C=O or i^CH-OH and Q is a group of the formula -NHR1 (where R''" has the same meaning as defined above), a group of the formula -NHCOR (where R is a substituted acyclic hydrocarbon group or a cyclic hydrocarbon group or a hetero-

cyclic group which may be substituted), or a group with

1 in

the formula

(where R^ is hydrogen or an alkyl group

and R is a substituted acyclic hydrocarbon group or a cyclic hydrocarbon group or a heterocyclic group which may be substituted, and this includes the case where R-' and R^ form a group together with the adjacent carbon atom), provided that when Q is a group with the formula -NHR"*" then X is not >CH-OH.

In formula (II) when Q is a group with the formula

-NHCOR 2 , then the substituted acyclic hydrocarbon group or the cyclic hydrocarbon group which may be substituted and which is denoted by the symbol R 2 can be exemplified by the groups mentioned above in connection with r\ and the heterocyclic group which may be substituted and also denoted by the symbol R 2 , can be exemplified by the heterocyclic groups that were particularly mentioned above in connection with the substituents on the acyclic hydrocarbon group

1 2

with the designation R . A group of the formula -NHCH9R which can be formed by a reduction of the group of the formula -NHCOR 2 corresponds in this case to -NHR"<*>" in connection with formula (I).

In the above formula (II) when Q is an erutæ with

formula

then the alkyl group which is denoted by the symbol R-5 can be exemplified by alkyl groups which were particularly mentioned above in connection with Z, Z or R. The substituted acyclic hydrocarbon group or the cyclic hydrocarbon or heterocyclic group which may be substituted, and each of which is denoted by the symbol R^, may be exemplified by the corresponding groups which were particularly mentioned in connection with R and R. It shall it is noted that R-^ and R^ can form a ring group together with the adjacent carbon atom, and examples of said ring group can include a cycloalkane group, preferably with from 3-7 atoms in the ring (cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, etc), cycloalkene group, preferably with from 3-7 atoms in the ring (e.g. cyclopentene, cyclohexene, etc), etc. Among the more advantageous groups is a cycloalkane group with from 3-7 atoms in the ring. In this case, a group with the formula -

which is formed by the reduction of the group with the formula

correspond to the group with the formula -NHR"^ in the for-

bonds of formula (I).

The reduction mentioned above can usually be carried out under suitable reducing conditions and depending on the starting material used. The following conventional and common methods can be used: (l) catalytic reduction with platinum, palladium, rhodium, nickel or the like as a catalyst, (2) reduction using a metal hydride such as a lithium aluminum hydride, lithium borohydride, lithium cyanoborohydride, sodium borohydride, sodium cyanoborohydride or the like, ( 3) Meerwein-Ponndorf-Verley reduction using aluminum altoxide, e.g. aluminum isopropoxide, (4) reduction by means of metallic sodium, metallic magnesium or the like, e.g. with alcohol, (5) reduction using zinc dust and a base such as caustic alkali, (6) reduction using a metal such as iron or zinc and an acid such as hydrochloric or acetic acid, (7) electrolytic reduction, (8) and a reduction using reducing enzymes. It is understood that, apart from the above-mentioned methods, one can of course use any method which is capable of reducing a carbon molecule to an alcohol or is capable of

to saturate the double bond in the group with the formula

Although the most advantageous reaction temperatures will depend on the starting material and the reduction methods used, the temperature will usually fall in the range from

-20 to +100°C. The reaction is usually carried out at atmospheric pressure, but can, if desired, be carried out at reduced or elevated pressure. The reduction is usually carried out in the presence of a suitable solvent. The solvent can be of any common type, provided that it is capable of dissolving more or less, the starting material and will not adversely affect the reaction, for example water, an alcohol

hol (e.g. methanol, ethanol, propanol, etc), an ether (e.g. dimethyl ether, diethyl ether, methyl ethyl ether, tetrahydrofuran, dioxane, etc), an ester (e.g. ethyl acetate, butyl acetate, etc), a ketone (eg acetone, methyl ethyl ketone, etc), an aromatic hydrocarbon (eg benzene, toluene, xylene, etc), an organic acid (eg acetic acid, propionic acid, etc), or a mixture of two or more such solvents.

In the present process, starting compounds of formula (II) will include various compounds which give the corresponding desired compounds of formula (I). Thus, depending on the starting material and the desired compound, one will choose reaction methods and conditions on the basis of the df mentioned above.

When you e.g. uses a compound with formula (II) as starting material where X is J2iC=0 and Q is the group with the formula -NHR"<*>", i.e. the following reaction nucleus

(where Z 1 , Z 2 and R 1 have the same meanings as given above), when Z 1 and Z 2 are an alkyl group, select reduction methods and conditions as mentioned above, while when both Z"^ and Z 2 are hydrogen, then it will be advantageous to use catalytic reduction.

When the compound of formula (II) has a group Q which is -NHCOR 2 as starting material, i.e. the following reaction nucleus

(where Z?~, Z<2>, X, R? and R<2> have the same meaning as stated above, and in this case R 1 will correspond to -CH2R ?), carry out the reduction with lithium aluminum hydride as mentioned under method (2), and use temperatures between 40 and 100°C.

When you use as starting material a compound of formula (II) where X is J>C=0 and Q is -NHCOR<2>, as an intermediate you will get a compound of formula (II) where X is ^CH- OH and Q is -NHCOR<2>.

When a compound is used as starting material

with formula (II) where Q is ■

form

i.e. the following reaction / 1 2 1 3 4 (where Z , Z , X, R , R- and R have the same meaning as stated above, and in this case R<1> will correspond preferably use the reduction methods mentioned under (1) and (2) nvpnfnr. The compound with (II) where Q is ■ can, for example, be prepared by reacting a compound with the formula (where Z 1 , Z 2 and X have the same meaning as stated above), with a carbonyl compound of the formula

/ 3 4

(where R and R have the same meanings as given above). This reaction usually takes place by mixing the compounds with the formulas (III) and (IV) in one of the aforementioned solvents, and if it is desired, the mixture can be heated or set aside for a certain time to ensure a complete reaction. Furthermore, certain dehydrating or condensing agents can also be used in the reaction.

In the event that the reduction is carried out in the presence of the compound of formula (III) and the carbonyl compound of (IV), the amino group in the compound of formula (III) will first react with the carbonyl compound (IV) so that the compound of formula (II) is produced ) where Q is.

which is then again reduced to the desired compound with formula (I), i.e. the following reaction scheme is obtained (where Z<1>, Z<2>, X, R<1>, R^ and R^ have the same meaning as stated above, and in this case R"'" will correspond

above reaction, it is possible to carry out the reaction by b using an excess of the carbonyl compound (IV) instead of using a solvent.

In the present method, when the aforementioned groups R 1 , R 2 or R 4 in the starting compound (II) are unsaturated, then most often an unsaturation that is different from an aromatic unsaturation is also reduced, and in the cases where one has an aromatic unsaturation, then one can selectively obtain the phosphonic compounds of formula (I) which contain such an unsaturated group or one which contains the corresponding saturated group, by regulating the reduction conditions.

The purified compounds (I) according to the present invention can be easily isolated from the respective reaction mixtures by separation and purification methods which are known per se, e.g. by concentration, filtration, recrystallization, column chromatography, etc.

Compounds of formula (I) can act as several stereoisomeric compounds, e.g. as geometrically isomeric compounds and as optically isomeric compounds, which is due to the presence of asymmetric carbon atoms, and will therefore often be obtained as a mixture of such isomers.

If desired, an optical geometric isomer (e.g. trans isomer or a cis isomer) can be obtained by suitable methods, e.g. by a (1) reduction using a starting compound (II) where X is Z>€H-OH having the same configuration as the desired compound of formula (I), (2) sterospecific reduction (e.g. can the compound of formula (I) which is a trans isomer is obtained by reduction of the parent compound (II) where X is^£=0 using sodium borohydride), (3) by isolating the optical isomer from a mixture of isomers using suitable selective methods among those mentioned above in connection with separation and purification, e.g. recrystallization, column chromatography, etc.

The racemic mixture can, if desired, be dissolved in a commonly known manner, e.g. by allowing it to form salts with optically active acids or bases, or alternatively by physical absorption on a porous absorbent resin. It is understood that all such individual isomeric forms as well as their mixtures are included in the present invention.

Compounds according to the present invention can, after isolation, be converted into pharmaceutically acceptable salts such as acid addition salts in the usual way, e.g. to an inorganic acid salt (e.g. a hydrochloride, hydrobromide, sulphate etc), an organic acid salt (e.g. maleate, fumarate, tartrate, toluenesulfonate, naphthalenesulfonate, methanesulfonate, etc).

Compounds according to the present invention (i) and their pharmaceutically acceptable salts have pharmacological activities such as an activity for stimulating or blocking β-adrenergic receptors, cardiac vasodilatory activity, analgesic activity, etc. Particularly noteworthy is the activity of stimulating β-adrenergic receptors, such as a bronchodilator Activity. Due to their disposable properties, they can be used in therapy and in prophylaxis for the treatment of disorders such as asthma, arrhythmia, angina pectoris, migraine, etc.

In practice, compounds and salts according to the present invention can be administered to mammals such as humans, either as such or in a mixture with a pharmaceutically acceptable carrier or diluent, and the administration can take place orally or in another way in dosage forms such as powders, granules, tablets, capsules, injection solutions, inhalation gases etc.

Pharmaceutical preparations containing one or more compounds of formula (I) or salts thereof can be prepared in a commonly known manner for the production of powders, granules, tablets, capsules, injection solutions, inhalation gases, etc. The choice of carriers and diluents will depend on the method of administration, the solubility of the compounds and their salts, etc.

Although an appropriate dose will depend on the individual patient's disorder and the symptoms to be treated, the method of administration and other conditions, advantageous dose levels for the treatment of asthma in adult patients will be in the range from 1 - 100 ml daily orally, from approx. 0.01 - 1 mg per dogen intravenously or approx. 0.1 - 10 mg per dose topically, e.g. in dosage forms such as nebulized products (an inhalation of aerosols).

Table 1 below shows the relaxing effect of typical compounds according to the present invention on

isolated tracheal muscles from calves or guinea pigs compared with the corresponding effect for isoproternol, a well-known

medicine for this purpose. The value is relative to the value of 100 for isoproternol.

<K>Determined by the usual method of E.J. Ari<g>ns which are described in the Ciba Foundation Symposium, pages 253 - 263

(1960).

Compounds according to the present invention can also be used as synthetic intermediates for the production of various medicines. E.g. can the compound with formula in 12

I) where Z and Z is an alkyl group, is easily converted into it

^ 12

corresponding compound (I) where both Z and Z are hydrogen, by methods known per se, e.g. by hydrolysis.

The starting compound (II) where Q is -N=C^R4 can be easily prepared by reacting the compound (III) with the carbonyl compound (IV) as mentioned above.

The compound of formula (III) where X is ^C=0 and

1 2

Z and Z are each an alkyl group, can e.g. is prepared by the method described in the literature (Journal of Medicinal Chemistry 12, 487 (1969)), or a method based on this method as indicated below.

The compound of formula (III) where X is —C=0 and

Z 1 and Z 2 are each hydrogen can be easily prepared, e.g. by hydrolyzing the compound (V) with hydrobromic acid.

The compound (III) where X is >CH-OH can be prepared by reducing the compound of formula (III) where X is .^C=0 (e.g. by reduction with sodium borohydride or catalytic reduction).

The starting compound of formula (II) where X is ^C=Q and Q is -NHCOR 2 can be prepared by acylating the aforementioned compound of formula (V) or a hydrolyzate thereof in the usual way (e.g. by a reaction with the corresponding acyl chloride in pyridine).

The starting compound of formula (II) where X is ^X!H-OH and .Q is -NHCOR 2 can be prepared by reducing the aforementioned compound (II) where X is >C=0 and Q is -NHCOR<2> (e.g. .by reduction with sodium borohydride or by catalytic reduction).

The starting compound (II) where X is ^=C=0 and Q is

-NHR"*" can e.g. is prepared by (a) reacting the compound of formula (III) where X is ^C=0 or its N-acylated compound with a halide or a substituted sulfonyoxy derivative of formula (VI) and, if necessary, hydrolyzing the above reaction product, or (b) by reacting the same compound (III) with the carbonyl compound (IV) under reductive conditions, as shown below in the following reaction core:

(where z\ Z<2>, R"*", R? and R^" have the same meaning as stated above, provided that when R"1" in method (b) corresponds to

then Y means halogen or a substituted sulfonyloxy-

group).

A further detailed explanation of the reaction from (a) to (b) is shown below.

The reaction (a) can be carried out by methods shown below using the following reaction nucleus:

(where Z 1, Z 2 , R 1 and Y have the same meaning as stated above,

5" 3 4

R is an acyl group, Z and Z are hydrogen, an alkyl group

1 2

as defined in connection with Z and Z , an acyl group with the same meaning as R 1 or a protecting group).

For the acylation of the starting compound of formula (III) where X is I^C=0, any acylating agent capable of introducing the forked acyl group R 5 into the 2-amino group in the compound of formula (III) where X is ^C= 0. Examples of said acylating agents include carboxylic acids such as acetic acid, trifluoroacetic acid, propionic acid, etc., carboxylic acid halides such as acetyl bromide, benzoyl chloride, trichloroacetyl chloride, ethyl chlorocarbonate, etc. In acid anhydrides such as acetic anhydride, trifluoroacetic anhydride, etc.; mixed acid anhydrides such as ethyl carbonate acetic anhydride, etc; as well as sulfonic acid halides such as methanesulfonyl chloride, toluenesulfonyl chloride, etc.

The aforementioned acylation reaction is usually carried out in water, an organic solvent or a mixture of these, or by using an excess of the acylating agent as solvent. In order to speed up the reaction, it can be carried out in the presence of a base such as sodium hydroxide, calcium carbonate, pyridine, triethylamine or the like. With regard to the amount of acylating agent, it is sufficient to use one molar equivalent in the indicated acylation, but usually the agent will be used in amounts of from 2-10 equivalents or in even larger amounts if it is also to be used as a solvent. The reaction rate can be regulated by carrying out the reaction during heating or cooling. Preferably, the reaction is carried out in the temperature range from -20 to +100°C.

As a result of the aforementioned acylation reaction, the corresponding acyl group is inserted into the 2-amino group in the compound of formula (III) where X is !^.C=0, whereby an imino compound is obtained. In this connection it may be mentioned

12

that when Z or/and Z in the compound of formula (III) is hydrogen, then a compound can also be produced with the corresponding acyl groups instead of said hydrogen atoms, all depending on the conditions of the reaction. Alternatively, Z or/and Z can be substituted with a protecting group for the acylation reaction. As a protecting group, any group can be used as an element to protect the hydroxy group in the above reaction, provided that said protecting group can be easily removed. Examples of such protecting groups include an aralkyl group (eg, benzyl, oc-methylbenzyl, etc.), etc.

In the compound of formula (VI), Y may be a halogen atom (e.g. chlorine, bromine, iodine, fluorine, etc.) or a substituted sulfonyloxy group (e.g. methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, p -bromobenzenesulfonyloxy, etc). The reaction with said compound (VI) is usually carried out in water f. an organic solvent or in mixtures thereof. Any organic solvent which does not affect the reaction can be used as the mentioned organic solvent, e.g. methanol, ethanol, acetone, chloroform, benzene, ethyl ether, tetrahydrofuran, dioxane, etc. To speed up the reaction, you can use a base such as sodium hydroxide, sodium carbonate, potassium hydroxide, potassium carbonate, sodium hydrogen carbonate, pyridine, picoline, triethylamine, sodium hydride, sodium alcoholate, t -butoxypotassium and the like as an acid acceptor. In order to obtain good yields, it may in certain cases be desirable to add antioxidants such as ascorbic acid, hydroquinone or the like and/or use inert gaseous reaction atmospheres such as nitrogen, helium or argon to possibly inhibit possible side reactions such as rinsing

its oxidation. The reaction takes place satisfactorily at room temperature, but can also be carried out under suitable heating or a<y>cooling to regulate the reaction rate. It is usually advantageous to carry out the reaction at temperatures from -20 to +100°C. The resulting compound (VII) can first be isolated from the reaction mixture in the usual way by e.g. concentration, distillation, filtration, recrystallization, chromatography and the like, and then subjected to the hydrolysis reaction mentioned below. Alternatively, said reaction mixture can be used as such in the hydrolysis reaction.

The hydrolysis reaction in the above reaction scheme can usually be carried out by allowing water, an acid or a base to act on the compound of formula (VII) in the presence of water and/or an organic solvent. Said acid can be fggeks. be an inorganic acid, e.g. hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or the like, an organic acid such as formic acid, acetic acid or the like, or a Lewis acid such as aluminum chloride, trivalent ferric chloride, zinc chloride, boron trifluoride, boron trichloride or the like. As the aforementioned base, one can e.g. use an inorganic base such as potassium hydroxide, sodium hydroxide, sodium carbonate, sodium hydrogen carbonate or the like, or an organic base such as pyridine, dimethylaniline, triethylamine or the like. Any organic solvent which does not adversely affect the reaction can be used as said organic solvent, for example methanol, ethanol, acetone, chloroform, benzene, ethyl ether, tetrahydrofuran, dioxane or the like can be mentioned. Although the above-mentioned hydrolysis reaction takes place satisfactorily at room temperature, the reaction can also be carried out at a suitable elevated or reduced temperature to regulate the reaction rate. The temperature used will usually lie in the range from 0 to 150°C.

In those cases when 7<?> and/or Z^ are acyl groups

which has been introduced by the aforementioned acylation reaction,

"5/4

or when Z^ and/or Z are protective groups in front of the acylation reaction, then these can be eliminated at the same time as

the hydrolysis reaction. If, however, these groups remain unchanged, they can be removed by methods known per se.

The resulting compound, i.e. one of formula (II) where X is —C=O and Q is —NHR 1 , can be readily isolated from the reaction mixture by separation and purification methods known per se, e.g. concentration, distillation, filtration, recrystallization, chromatography, etc.

Reaction (b) is carried out in the presence of the carbonyl compound (IV) under reductive conditions.

These reductive conditions can be achieved by means of the aforementioned reduction reactions as mentioned earlier, preferably by reducing with lithium cyanoborohydride or by catalytic reduction where palladium on charcoal is used as a catalyst in alcoholic solvents. Furthermore, the reaction can be easily carried out by using an excess of the carbonyl compound instead of a solvent. Although the effective reaction temperature varies depending on which reduction method is used, it is usually advantageous to carry out the reaction in the temperature range from -20 to +100°C. The reaction is usually carried out at atmospheric pressure, but may, if desired, be carried out at reduced or elevated pressure.

The resulting compound, i.e. one of formula (II) where X is ~>C=0 and Q is -NHR<1>, can be easily isolated from the reaction mixture in a conventional manner, e.g. by concentration, distillation, recrystallization, column chromatography, etc.

The compound of formula (II) obtained either by reaction (a) or (b) can also be isolated in the form of a salt, e.g. an acid addition salt with an inorganic acid, e.g. with help

of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or the like, or with an organic acid such as acetic acid, fumaric acid, maleic acid, tartaric acid, malic acid or the like.

The starting compound with formula (II) where X is II2C=0 and Q is -NHR<1> as described above, and this also includes the acid addition salt, also has sympathetic nerve stimulating and blocking activities and can be used for prophylaxis and therapy in connection with asthma or arrhythmia. When these compounds are used as medicines, they can be administered in oral dosage form in the form of tablets, capsules, powders, suspensions, syrups, etc., or in other forms such as parenteral injection solution, aerosols, etc. Although the dose used will depend on the disorder to be treated, the method of administration and the patient's general health, the oral dose level used for therapy in connection with asthma, e.g. usually be from 0.1 - 100 mg daily for an adult patient.

The trans- or cis-isomer of the compound of formula (III) where X is ZjCH-OH, which can be used to prepare the corresponding trans- or cis-isomers of the compound of formula (I), can e.g. easily produced using the following reaction core:

(where Bz is -CH2-^^> , Ts is -SC^<->^^<-C>H^ and NBS is N-bromosuccinimide). Bet<t>is it possible to obtain the trans- or cis-isomer of the compound of formula (I) via the compound of formula (II) where X is —CH—OH and Q is

by applying the corresponding

end isomer of the compound of formula (III) where X is "^"CH-OH in the isak ion with the carbonyl compound of formula (IV).

The aforementioned starting compound of formula (II) and the compound of formula (III) can each be used in their free form or can also be used in the present process as acid addition salts such as inorganic acid salts (i.e. hydrochloride, hydrobromide, sulfate, etc.) and organic acid salts ( eg maleate, fumarate, tartrate, toluenesulfonate, naphthalenesulfonate, methanesulfonate, etc).

The following reference examples and examples illustrate the invention. The invention is of course not limited to the methods described in these examples.

In the following examples, all parts are based on weight unless otherwise stated, and the ratio between "parts" and "volume parts" corresponds to the ratio between "grams" and "milli-liters".

Reference example 1

30 parts of 2-amino-5,6-dimethoxy-3,4-dihydro-1(2H)-naphthalenone hydrochloride were refluxed in 500 parts by volume of a 47% aqueous solution of hydrogen bromide for 3 hours, and then concentrated to dryness under reduced pressure. The residue was dissolved in methanol, then ethyl acetate was added and precipitated crystals were obtained. A filtration gave 31 parts of 2-amino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide.

This crystalline product showed no definite melting point, but gradually decomposes to black when the temperature exceeds 250°C.

>KBr —1

Infrared absorption spectrum Yma^ s cm

3500-2800, 1660, 1605, 1580,.1490, 1380, 1310, 1280, 1025, 905, 820

Reference example 2

In 50 parts by volume of water was dissolved 2 parts of 2-amino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide, and catalytic reduction was carried out using 0.5 parts of platinum oxide at normal temperature and pressure. The catalyst was filtered off, and a solvent mixture of ethyl ether and methanol was added dropwise to the filtrate, and 2-amino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide was precipitated as colorless prisms. Yield 1 part; melting point:

190 - 200°C (decomposition).

Elemental analysis: for C^QH-^O^N.HBr.I^O

Calculated: C 40.84, H 5.48, N 4.76

Found: C 40.49, H 5.37, N 4.61

Reference example 5

In a mixture of 200 parts by volume of dry methanol and 200 parts by volume of cyclohexanone, 10 parts of 2-amino-5,6-dimethoxy-3,4-dihydro-1(2H)-naphthalenone hydrochloride were dissolved and under nitrogen and cooling at 0°C 9 parts of a molecular compound consisting of 1 mol of lithium cyanoborohydride and 2 mol of dioxane (LiBH^CN.2C^HgO2) were added. At a constant temperature of 5°C, the mixture was stirred for 2 hours. After adding dilute hydrochloric acid, the methanol was distilled off. The remaining mixture was washed with benzene and evaporated to dryness under reduced pressure. The residue was dissolved in ethanol, treated with activated carbon and recrystallized from a mixture of ethanol and ethyl ether. The procedure yields 9.65 parts of 2-cyclohexylamino-5,6-dimethoxy-3,4-dihydro-1(2H)-naphthalenone hydrochloride as colorless crystals, melting point 180 - 190°C (decomposition).

Elemental analysis: for C-^gH^O^N. HC1

Calculated: C 63.61, H 7.71, N 4.12

Found: C 63.50, H 7.46, N 4.22

Reference example 4

In a mixture of 50 parts by volume of 4% hydrobromic acid

and 15 parts by volume of acetic anhydride, 5 parts of 2-cyclohexylamino-5,6-dimethoxy-3,4-dihydro-1(2H)-naphthalenone hydrochloride were dissolved, and the solution was kept at 140 - 160°C for approx. 3 hours. After cooling, the solvent was removed under reduced pressure and the residue was treated with activated carbon in ethanol. After addition of ethyl acetate, the filtrate was set aside and 2-cyclohexylamino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide was precipitated as colorless prisms. Yield 4.1 parts; mp 225 - 237°C (decomposition).

Nuclear magnetic resonance spectrum

fc(DMS0-d6): 6.91(lH,d,J=8.4), 7.43(lH,d,J=8.4) Reference Example 5

In the same way as in example 3, 10 parts of 2-amino-5,6-dimethoxy-3,4-dihydro-1(2H)-naphthalenone hydrochloride are reacted with 300 parts by volume of cyclopentanone. The procedure gives 10.2 parts of 2-cyclopentylamino-5,6-dimethoxy-3,4-dihydro-1(2H)-naphthalenone hydrochloride as colorless crystals melting at 158-167°C (decomposition).

Elemental analysis: for C^yH^O^N.HCl

Calculated: C 62.67, H 7.42, N 4.30

Found: C 62.91, H 7.15 N 4.35

Reference example 6

In the same way as in reference example 3, 10.5 parts of 2-amino-5,6-dimethoxy-3,4-dihydro-1(2H)-naphthalenone hydrochloride were reacted with 10 parts by volume of cyclobutanone. The process yields 8.2 parts of 2-cyclobutylamino-5,6-dimethoxy-3,4-dihydro-1(2H)-naphthalenone hydrochloride. Melting point: 146 - 164°C (decomposition).

Elemental analysis: for Cl6H210^N.HCl.l/4H20

Calculated: C 60.76, H 7.17, N 4.43

Found: C 60.78, H 7.26, N 4.29

Reference example 7

In the same way as in Reference Example 4, 5.6 parts of 2-cyclobutylamino-5,6-dimethoxy-3,4-dihydro-1(2H)-naphthalenone hydrochloride were hydrolyzed in a mixture of 75 parts by volume of 48% hydrobromic acid and 15 parts by volume of acetic anhydride . The procedure yields 4 parts of 2-cyclobutylamino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide. Melting point: 229-240°C (decomposition).

Elemental analysis: for C^H^yO^N.HBr.&HgO

Calculated: C 49.86, H 5.68, N 4.15

Found: C 50.10, H 5.58, N 4.12

Reference example 8

In 300 parts by volume of ethanol, 5 parts of 2-amino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide were dissolved and after the addition of 50 parts of |3-phenylpropionaldehyde, catalytic reduction was carried out at ordinary temperature and pressure using palladium on charcoal as a catalyst.

When a stoichiometric amount of hydrogen had been absorbed, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The procedure yields 3.5 parts of 2-(3-phenylpropyl)amino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide as colorless crystals, melting point 215 - 217°C Elemental analysis for C-j^gH ^-^O^N.HBr

Calculated: C 58.17, H 5.65, N 3.57

Found: C 58.39, H 5.69, N 3.18

Reference example 9

In 1000 parts by volume of ethanol, 10 parts of 2-amino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide were dissolved, after which 100 parts of 4-methoxyphenylacetaldehyde were added. By using palladium on carbon as a catalyst,

a catalytic reduction was carried out at ordinary temperature and pressure. When a stbkbmetric amount of hydrogen had been absorbed, the reaction mixture was filtered and the filtrate concentrated under reduced pressure. The procedure gives 8 parts of 2-(4-methoxyphenethyl)amino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide as colorless crystals, m.p.

198 - 203°C

Elemental analysis: for C-^gH^O^N.HBr

Calculated: C 55.89, H 5.43, N 3.43

Found: C 56.30, H 5.38, N 3.05

Reference example 10

500 parts of trifluoroacetic anhydride were added to 20 parts of 2-amino-5,6-dimethoxy-3,4-dihydro-1(2H)-naphthalenone hydrochloride. The mixture was left at room temperature for half an hour, after which a small amount of ethyl ether and 1000 parts by volume of n-hexane were added. The resulting crystals were recovered by filtration. This procedure gives 24 parts of 2-trifluoroacetamido-5,6-dimethoxy-3,4-dihydro-1(2H)-naphthalenone, melting point 166 - 167°C.

Elemental analysis: for C-^H-^O^NF^

Calculated: C 52.98, H 4.45, N 4.42

Found: C 52.54, H 4.38, N 4.14 15 parts of the above product were dissolved in 1500 parts by volume of acetone previously saturated with nitrogen gas, after which 50 parts of potassium carbonate and 30 parts of 4-methoxyphenethyl bromide were added. The mixture was stirred under nitrogen for 2 dbgn. The resulting product was refluxed for 3 hours in 200 parts by volume of a 47% aqueous solution of hydrogen bromide.

The reaction product was extracted with ethyl acetate, and the aqueous layer was filtered by adding a small amount of activated carbon. The filtrate was concentrated under reduced pressure, and at a temperature not exceeding 50°C. The residue was dissolved in methanol and ethyl ether was added dropwise to the solution until a white turbidity was obtained. The mixture was then placed in a refrigerator for a week, and the resulting crystals recovered by filtration. This procedure gives 3 parts of 5,6-dihydroxy-2-(4-methoxyphenethylamino)-3,4-dihydro-1(2H)-naphthalenone hydrobromide, melting point 198 - 203°C (decomposition).

Elementary analysis: for C-j^H^O^N.HBr

Calculated: C 55.89, H 5.43, N 3.43

Found C 56.51, H 5.30, N 3.17

Reference example 11

500 parts of trifluoroacetic anhydride were added to 20 parts of 2-amino-5,6-methylenedioxy-3,4-dihydro-1(2H)-naphthalenone hydrochloride, and after standing for 30 minutes at room temperature, 1000 parts by volume of n-hexane were added. The overlying liquid was poured off, and the precipitated 2-trifluoroacetamido-5,6-methylenedioxy-3,4-dihydro-1(2H)-naphthalenone was dissolved in 2500 parts by volume saturated with nitrogen gas. After addition of 80 parts of potassium carbonate and 60 parts of cyl-3-hexanol-p-toluenesulfonic acid ester, the solution was stirred in nitrogen for 7 days. The insoluble solids were filtered off, and the filtrate was distilled under reduced pressure, yielding a crude product of 2-(N-cyclohexyl-N-trifluoroacetamido)-5,6-methylene-dioxy-3,4-dihydro-1 (2H)-Naphthalenone. To this product was added 800 parts by volume of a 47% aqueous solution of hydrogen bromide, and the mixture was refluxed for 3 hours. After cooling, the mixture was extracted with ethyl acetate. A small amount of activated carbon and 500 parts by volume of methanol saturated with nitrogen gas were added to the water layer, and the whole was filtered. The filtrate was evaporated to dryness under reduced pressure, and the residue was dissolved in methanol. Mon. obtained a white turbid solution by the addition of a few drops of ethyl ether, and the mixture was kept in a refrigerator for 2 weeks, after which the resulting crystals were recovered by filtration. The procedure gives 2 parts of 2-cyclohexylamino-5,6-di-hydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide, melting point 225 - 237°C. (decomposition).

Elemental analysis: for C-^gl^^O^N.HBr

Calculated: C 53.94, H 6.00, N 3.93

Found: C 53.67, H 6.22, N 3.79

Mass spectrum (m/e): 275(M<+>^

Reference example 12

20 parts of 2-amino-5,6-dibenzyloxy-3,4-dihydro-1(2H)-naphthalenone hydrochloride were subjected to the procedure described in Reference Example 11, and the resulting 5,6-dibenzyloxy-2-trifluoroacetamido- 3,4-Dihydro-1(2H)-naphthalenone was reacted with 60 parts of 3-phenylpropanol-p-toluenesulfonic acid ester under the same conditions as stated in reference example 11. The reaction product was then hydrolyzed in a 47% deionized solution of hydrogen bromide, whereby 3 parts of 5,6-dihydroxy-2-(3-phenylpropylamino)-3,4-dihydro-1(2H)-naphthalene-non-hydrobromide were obtained, melting point 215 - 217°C (decomposition).

Elementary analysis: for C-^gH2-j_0^N.fBr

Calculated: C 58.17, H 5.65, N 3.57

. Found: C 58.00, H 5.17, N 3.25

Example 1

2 parts of 2-amino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide were dissolved in 200 parts by volume of ethanol, after which 20 parts of (3-phenylpropionaldehyde) were added, and 2- (3-phenylpropylideneamino)-1,5,6-tri-hydroxy-1,2,3,4-tetrahydronaphthalene. Using palladium on carbon as a catalyst, the reaction mixture was subjected to a catalytic reduction at ordinary temperature and pressure. After the stoichiometric amount of hydrogen had been absorbed,

the reaction mixture was filtered to remove the catalyst, after which 5000 parts by volume of ethyl ether was added to the filtrate. The procedure gives 2 parts of 2-(3-phenylpropylamino)-1,5,6-tri-hydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide as white crystals, melting point 136 - 139°C (decomposition).

Elemental analysis: for C-^P^O^N.HBr•å^O

Calculated: C 56.58, H 6.25, N 3.47

Found: C 56.60, H 5.89, N 3.25

Example 2-7

In the same way as indicated in Example 1, the products indicated in Table 2 were prepared via the corresponding intermediates by reacting 2-amino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide with the corresponding carbonyl compounds as listed in Table 2.

1

/

Example 8

2 parts of 2-amino-1,5£-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide were dissolved in 200 parts by volume of ethanol, after which 20 parts of phenylacetone and 0.7 parts of triethylamine were added. By using palladium on carbon as a catalyst, a catalytic reduction was carried out at normal temperature and pressure. After 24 hours, the reaction mixture was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure at room temperature. An alcoholic solution of 1 part fumaric acid was added to the residue. Then 50 parts by volume became water and 2000 parts by volume ether. added successively and the whole mixture was then cooled. The process yields 6 parts of trans-2-(oc-methylphenethylamino)-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene fumarate as colorless granules melting at 145-148°C (decomposition).

Elemental analysis: for C^g^^O^N.C^H^O^

Calculated: C 64.32, H 6.34, N 3.26

Found: C 63.94, H 6.69, N 3.51

Nuclear magnetic resonance spectrum £(DMS0-dg): 4.54 (lH,d,J=

9Hz)

Example 9

3 parts of 2-amino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide were dissolved in 300 parts by volume of ethanol, after which 20 parts of 4-methoxyphenylacetone and 1.5 parts of triethylamine were added. By using palladium on carbon as a catalyst, a catalytic reduction was carried out in a hydrogen stream at normal temperature and pressure for 3 dbgn. The reaction mixture was filtered to remove the catalyst, and after addition of 1.5 parts of fumaric acid, the filtrate was concentrated under reduced pressure. The residue was added to water and the resulting solution was extracted with ethyl ether to remove insoluble solids.

The aqueous layer was neutralized with an aqueous solution of sodium hydrogen carbonate and extracted three times with chloroform. The chloroform solution of 2-(4-methoxy-α-methylphenethylamino)-1,5,6-trihydroxy-1,2,3,4-:tetrahydronaphthalene was then dried over sodium sulfate and after the addition of 1.5 parts of fumaric acid concentrated under reduced pressure. The residue was recrystallized from ethanol. The process yields 1 part of "trans-2-(4-methoxy-α-methylphenethylamino)-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene-furamate as colorless crystals, melting point 150 - 153°C ( decomposition).

Elemental analysis: for C20H25°4N,C4H4O4

Calculated: C 62.73, H 6.36, N 3.05

Found: C 63.17, H 6.59, N 3.10

Nuclear magnetic resonance spectrum $ (DMSO-dg):

4.60(lH,d,J=9Hz)

Example 10

Using 1.91 parts of 5% palladium on carbon, 1.89 parts of 2-cyclohexylamino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide in 50 parts by volume of water were catalytically reduced at room temperature and thick. When a stoichiometric amount of hydrogen had been absorbed, the reaction mixture was filtered to remove the catalyst, and the filtrate was freeze-dried. The residue was recrystallized from a mixture of ethanol and ethyl acetate, and 2-cyclohexylamino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide was obtained as colorless crystals. Yield: 1.38 parts, melting point: 230 - 236°C (decomposition.

Nuclear magnetic resonance spectrum $(DMS0-dg+D2O): 4.56-4.80(1H,m), 6/Æ>-6.70(2H,m)

Example 11

Using 2 parts of 5% palladium on carbon, 2 parts of 2-cyclopentylamino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide in 50 parts by volume of water was subjected to a catalytic reduction at normal temperature and pressure. When a stoichiometric amount of hydrogen had been absorbed, the reaction was terminated and the catalyst was filtered off. The filtrate was freeze-dried, and the residue crystallized from a mixture of ethanol and ethyl acetate. The procedure yields 1.54 parts of 2-cyclopentylamino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide as colorless crystals, melting point 210 - 218°C (decomposition).

Mass spectrum:

m/e: 263(M<+>)

Nuclear magnetic resonance spectrum:

B (DMS0-d5+D20): 4.62(1H,d,J=8Hz), 6.60-6.90(2H,m)

Examples 12 - 21

In the same way as described in example 10 or 11, the products indicated in the table below were prepared by catalytic reduction of the corresponding 3,4-dihydro-2-substituted amino-5,6-dihydroxy-1(2H) -naphthalenone hydrobromides.

Example 22

In a mixture of 50 parts by volume of cyclohexanone and 200 parts by volume of ethanol, 0.151 parts of 2-amino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide were dissolved and 2-cyclohexylideneamino-5, 6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone.

The resulting mixture was subjected to a catalytic reduction with 0.16 parts of platinum dioxide and 0.57 parts of anhydrous sodium acetate at ordinary temperature and pressure. When a stoichiometric amount of hydrogen had been absorbed, 1 volume of 48% hydrobromic acid was added and the catalyst removed by filtration. The ethanol was removed by distillation, and the residue diluted with water and washed with benzene. The aqueous layer was freeze-dried, and the residue recrystallized from a mixture of ethanol and ethyl acetate. This process gives 2-cyclohexylamino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide. Melting point: 230 - 234°C (decomposition). The product was identical to the compound from Example 10.

Example 23

In a mixture of 20 parts by volume of cyclopentanone and 100 parts by volume of ethanol, 1 part of 2-amino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide was dissolved and 2-cyclopentylideneamino-5 was prepared, 6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone. The resulting mixture was subjected to a catalytic reduction with 0.1 part platinum dioxide and 0.39 part anhydrous sodium acetate at ordinary temperature and pressure.

When a stoichiometric amount of hydrogen gas had been absorbed, 1 part by volume of 48% hydrobromic acid was added, and the catalyst was filtered off. The ethanol was removed from the filtrate by distillation, and the residue was diluted with water and washed with benzene.

The aqueous layer was freeze-dried and the residue recrystallized from a mixture of ethanol and ethyl acetate.

This procedure gives 0.5 parts of 2-cyclopentyl-amino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide as colorless crystals, melting point 308 - 218°C (decomposition). The product was identical to the compound from Example 11.

Example 24

In 100 parts by volume of methanol, 1 part of 2-benzylamino-5,6-dimethoxy-3,4-dihydro-1(2H)-naphthalenone hydrochloride was dissolved, and with stirring, 2 parts of sodium borohydride were added in smaller portions. The mixture was stirred at room temperature for 10 minutes, after which 500 parts by volume of water were added. The mixture was then extracted with chloroform. The extract was dried over sodium sulfate and concentrated under reduced pressure.

Finally, the residue was recrystallized from ethyl ether and 0.4 parts of trans-2-benzylamino-5,6-dimethoxy-1-hydroxy-1,2,3,4-tetrahydronaphthalene were obtained as colorless crystals, melting point 133 - 135°C ( decomposition).

Elementary analysis: for C-^ gK^ OjN

Calculated: C 72.82, H 7.40, N 4.47

Found: C 72.42, H 7.32, N 4.45

Example 25

50 parts by volume of tetrahydrofuran was added to 1 part of 2-benzp'5flamino-5,6-dimethoxy-3,4-dihydro-1(2H)-naphthalenone and 0.2 parts of lithium aluminum hydride, and the mixture was refluxed for 4 hours. The reaction mixture was then made sufficiently acidic with 1N hydrochloric acid and was extracted with chloroform to remove non-basic components.

The aqueous layer was made alkaline with 1N aqueous sodium hydroxide and then extracted with chloroform. The chloroform solution was dehydrated and evaporated to dryness. The residue was recrystallized from ethyl ether, and 0.4 parts of trans-2-benzylamino-5,6-dimethoxy-1-hydroxy-1,2,3,4-tetrahydronaphthalene were obtained as colorless crystals, melting point 133 -

135°C (decomposition).

The product was identical to the compound from example 24, which could be shown by the so-called mixed melting point.

Example 26

2 parts of 2-amino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide were dissolved in 200 parts by volume of ethanol. after which 20 parts of cinnamaldehyde were added.

With 5% palladium on carbon as catalyst, a catalytic reduction was carried out at normal temperature and pressure until no more hydrogen was absorbed. The catalyst was removed by filtration, and 5000 parts by volume of ethyl ether were added to the filtrate. The mixture was set aside and the precipitated colorless crystals were recovered by filtration. The procedure yields 1.5 parts of 2-(3-phenylpropylamino)-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide, melting point: 136 - 139°C (decomposition).

Elementary analysis: for C^gH^-jO^N.HBr.<t>^HgO

Calculated: C 56.58, H 6.25, N 3.47

Found: C 56.18, H 6.18, N 3.19

Examples 27 - 31

In the same way as indicated in example 26, the products indicated in Table 4 below were synthesized from 2-amino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide and unsaturated carbonyl compounds.

Example 32

In the presence of 2 parts of 5% palladium on carbon, 2 parts of 2-(3,4-dihydro-2H-pyran-2-yl)methylamino-5,6-dihydroxy-3,4-dihydro-l( 2H)-naphthalenone hydrobromide catalyzed in 50 parts by volume of water at ordinary temperature and pressure until hydrogen was no longer absorbed. The catalyst was filtered off. and the filtrate freeze-dried. This procedure gives 2 parts of 2-(tetrahydropyran-2-yl)methylamino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide as colorless crystals, melting point 155 - 158°C (decomposition). The product was identical to the product from example 5, which is shown by the so-called mixed melting point).

Examples 33 - 34

In the same way as indicated in example 32, the compounds indicated in the following table were synthesized.

Example 35

In the presence of 1.53 parts 5% palladium on carbon was

1.5 parts of 2-cyclobutylamino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide in 200 parts by volume of water was subjected to a catalytic reduction at ordinary temperature and pressure. When a stoichiometric amount of hydrogen had been absorbed, the reaction mixture was filtered to remove the catalyst, and the filtrate was freeze-dried. The residue was recrystallized from a mixture of water, ethanol and ethyl ether, and 2-cyclobutylamino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide was obtained as colorless crystals. Dividend 0.65 parts; melting point: 190 - 200°C (decomposition).

Elementary analysis: for C^H-j^<O>^<N.>HBr

Calculated: C 50.92, H 6.10, N 4.24

Found: C 50.68, H 5.85, N 4.05

Nuclear magnetic resonance spectrum 8 (dg-DMSO+D2O): 4.58(lH,d,J=8Hz), 6.70(lH,d,J=8Hz), 6.84(1H,d,J=8Hz)

jHBr —1

Infrared absorption spectrum ^ max(cm"):

3370, 3120, 2930, 2780, 1620, 1595, 1500, 1295,

1010, 890, 815

Example 56

In the same way as in example 23, 1 part of 2-amino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide was reacted with 20 parts by volume of cyclobutanone. 6.5 parts of 2-cyclobutylamino-1,5,6-trihydroxy-1,2,3, 4-tetrahydronaphthalene hydrobromide as colorless crystals, melting point 190 - 200°C (decomposition). The product was identical to the compound from Example 35, which could be demonstrated by the mixed melting point.

Example 57

In the same way as in example 9, 3 parts of cis-2-amino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide were reacted with 10 parts of cyclobutanone. Via cis-2-cyclobutylideneamino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene, 1.0 parts of cis-2-cyclobutylamino-1,5,6-trihydroxy-1,2 ,3,4-tetrahydronaphthalene fumarate as colorless crystals melting at 171 - 172°C (decomposition).

Nuclear magnetic resonance spectrum S (DMS0-dg+D20):

4.66(lH,d,J=3Hz)

Example 38

In the same way as in Example 9, 3 parts of trans-2-amino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide were reacted with 10 parts of cyclobutanone. Via trans-2-cyclobutylideneamino -1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene 1.5 parts of trans-2-cyclobutylamino-1,5,6-trihydroxy-1, 2, 3,4-tetrahydronaphthalene were produced f umarate as colorless crystals which melted at 211-214°C (decomposition).Nuclear magnetic resonance spectrum $(DMS0-dg+D20):

4.56(lH,d,J=9Hz)

Example 59

In the same way as in example 9, 4 parts of 2-amino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide'

reacted with 20 parts of 3-indolylacetone, and the reaction product

was recrystallized from a mixture of ethyl acetate and ether. The process yields 1.2 parts of trans-2-(2-(indol-3-yl)-1-methyl7-ethylamino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene-fuma-

rat like colored crystals.

This compound shows no fixed melting point and gradually decomposes on heating.

Elemental analysis: for C2-^H2^0^N2.C^H^O^

Calculated: C 64.09, H 6.02, N 5.98

Found: C 64.30, H 5.98, N 5.70

Nuclear magnetic resonance spectrum £ (DMS0-dg+D20):

4.74(lH,d,J=8Hz)

Example 40

In the same manner as stated in example 9, 4 parts of 2-amino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide were reacted with 20 parts of 4-hydroxyphenylacetone. The reaction product was dissolved in ethanol, and ethyl acetate was added to the solution. The procedure gives 2 parts of 2-(4-hydroxy-α-methyl-phenethylamino)-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene fumarate as colorless crystals and melting at 137 - 141°C.

This product showed no melting point depression when mixed with the compound from Example 21.

Example 41

In a similar manner to Example 35, 3.16 parts of 2-cyclopropylamino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide were subjected to a catalytic reduction. The reaction mixture was filtered to remove "<->catalyst, and after addition of 0.72 parts of triethylamine, the filtrate was concentrated under reduced pressure. To the residue was added 500 parts by volume of water, and the resulting solution was extracted three times each time with 300 parts by volume of n-butanol and then 2 parts of fumaric acid were added. The extract was then concentrated under reduced pressure. To the residue was added 1000 parts by volume of ethyl ether and the resulting precipitate collected by filtration, and 0.3 parts of 2-cyclopropylamino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene fumarate were obtained as a colorless powder, melting point 155 - 160°C (decomposition).

Elemental analysis: for C-j^^H^yO^N.-g-C^H^O^.H^

Calculated: C 57.86, H-6.80, N 4.50

Found: C 57.48, H 6.38, N 4.71

Example 42

In the following, a number of examples of preparation forms in which compounds according to the present invention can be used, e.g. as a bronchodilator:

A. (Tablet)

per tablet After mixing ingredients (1) and (2) as well as 26 mg of corn starch, the mixture was granulated into a paste made from 7 mg of corn starch. Ingredient (4) and the remaining 5 mg of corn starch were added to the granules, and the mixture was pressed into a tablet with a diameter of 7 mm. B. (Capsule)

per capsule All ingredients were mixed and filled into a size No. 3 hard gelatin capsule (described in the Pharmacopeia of Japan, eighth edition).

C. (Injection solution)

All ingredients were dissolved in distilled water so that 1.0 ml of solution was obtained (pH 5.0). The solution was then filled into an ampoule. The atmosphere in the ampoule was replaced with nitrogen gas. All procedures were carried out under sterile conditions.

D. (Inhalation)

water to 100.0 ml solution which was then filtered through a membrane filter with a porosity of 0.22 microns.

E. (Aerosol for inhalation)

In a mixture of ingredients (2) and (3), ingredient (1) was dispersed homogeneously so that a concentrate was obtained. The concentrate and propellant (ingredient (4)) were then packed in a metal container under elevated pressure.

Claims (5)

1. Procedure for the preparation of compounds of the formula 12 1 where Z and Z are hydrogen or an alkyl group, and R is a substituted acyclic hydrocarbon group or a cyclic hydrocarbon group, characterized in that reduces a compound with the formula hføor Z 1 and Z 2 have the same meaning as stated above, X is —C=0 or "^CH-OH and Q is a group of the formula -NHR <1> (where R 1 has the same meaning as given above), a group of the formula -NHCOR (where R is a substituted acyclic hydrocarbon group or a cyclic hydrocarbon group or heterocyclic group which may be substituted), or a group with the formula (where R^ is hydrogen or a alkyl group and R 4 is a substituted acyclic hydrocarbon group or a cyclic hydrocarbon group or heterocyclic group which may be substituted, this also includes the case when R-3 ^ and R 4 form a ring together with the corresponding carbon atom), provided that when Q is a group of the formula -NHR <1> , then X is not ^CH-OH. 2. Method according to claim 1, characterized in that the compound of formula (I) is prepared in the form of a pharmaceutically acceptable salt. 3. Method according to claim 1, characterized in that X is —C=0 and Q is a group with the formula -NHR <1> . 4. Method according to claim 1, characterized in that Q is a group with the formula -NHCOR 2. 5. Method according to claim 1, characterized in that Q is a group with the formula 6. Method according to claim 1, characterized in that the starting compound with formula (II) where Q is a group with the formula (where R^ is hydrogen or an alkyl group, R 4 is a substituted acyclic hydrocarbon group or a cyclic hydrocarbon or hetero-3 4 cyclic group which may be substituted, and where R and R may form a ring together with the adjacent carbon atom), is prepared by reacting a connection with the formula where Z 1 and Z 2 are hydrogen or an alkyl group, and X is—C=0 or CH-QH, with a carbonyl compound of the formula 3 4 where R and R have the same meaning as stated above.