CH617180A5 - Process for the preparation of novel aminotetralol compounds - Google Patents

Description

The invention relates to a process for the preparation of new aminotetralol compounds of the formula:

(I)

only in which Q is a group of the formula -NHCOR2 or -N = CR3R4, in which R2 is a substituted acyclic hydrocarbon group, a cyclic hydrocarbon group or an optionally substituted heterocyclic group, R3 is hydrogen or an alkyl group and R4 is a substituted acyclic hydrocarbon group, is a cyclic group Hydrocarbon group or an optionally substituted heterocyclic group, including those cases in which R3 and R4 together with the adjacent carbon atom form a ring group and Z1 and Z2 have the meanings given above, the group -NHCOR2 or -N = CR3R4 is also reduced.

4. The method according to claim 3, characterized in that a compound of formula (II ') is used, wherein Q is a group of the formula —NHCOR2.

5. The method according to claim 3, characterized in that a compound of formula (II ') is used, wherein O is a group of the formula:

-R3

-N = CC

means.

45 wherein Z1 and Z2 are each hydrogen or an alkyl group and R1 is a substituted acyclic hydrocarbon group or a cyclic hydrocarbon group, and their pharmaceutically acceptable salts. As a special group among these compounds, there can be mentioned those in which the group -NHR1 stands for -NHCH2R2 or-NHCHR3R4; therein R2 represents a substituted acyclic hydrocarbon group, a cyclic hydrocarbon group or an optionally substituted heterocyclic group, R3 is hydrogen or an alkyl group and R4 is a substituted acyclic hydrocarbon group, a cyclic hydrocarbon group or an optionally substituted heterocyclic group, including those cases in which R3 and R4 together with the adjacent carbon atom form a ring group.

60 These compounds have excellent pharmacological activity, such as. B. strong bronchodilator effects or blocking effects on the secretion of ß-adrenaline. They are therefore valuable medicines for the treatment of asthma or arrhythmia.

65 So far isoproterenol [Brit. J. Pharmac. Chemother. 33, 552-559 (1968)] and metaproterenol [Drugs Made in Germany 4,123-131 (1961)] for the medicinal treatment of asthma, since both stimulate

exert an effect on the / 3-adrenergic receptors. However, although the isoproterenol has a bronchodilatory effect, which is due to the connection with the ß2. -adrenergic receptors, it causes severe side effects due to its strong cardiac stimulating effect, which is attributed to the connection with the ß-adrenergic receptors. The metaprotere-nol, on the other hand, has only minor side effects of the type mentioned above, but is clearly inferior in terms of its bronchodilatory effect. Therefore, neither of these two drugs has been considered a selective bronchodilator.

This fact gave the incentive to investigate which led to the production of the new compound of formula (I), which has a strong bronchodilatory effect, but which has only minor side effects due to or is essentially free from beta-adrenergic stimulation.

The aim of the present invention is therefore to provide the compound of the formula (I) and its pharmaceutically acceptable salts which are suitable for the medicinal treatment of asthma or arrhythmia. That is, the aim of the invention is a process for the preparation of the new compound of formula (I) and its pharmaceutically acceptable salts.

In formula (I), the alkyl group denoted by the symbols Z1 and Z2 denotes a straight or branched alkyl group, advantageously a lower alkyl group, in particular one having up to 6 carbon atoms, such as, for example, B. methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, i-pentyl, t-pentyl, n-hexyl, i -Hexyl or the like

The substituted, acyclic hydrocarbon group in the formula (I) denoted by the symbol R1 can be saturated or unsaturated and straight or branched chain. An example of the acyclic hydrocarbon group is an alkyl group, preferably a lower alkyl group, especially one with up to 6 carbon atoms, such as. B. methyl, ethyl, n-propyl, i-propyl, 1-methylpropyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, i-pentyl, t-pentyl, n-hexyl , i-He-xyl, or a lower alkenyl group, especially one with up to 6 carbon atoms, such as. B. ethenyl, propenyl, butenyl, pentenyl, hexenyl, a lower alkynyl group, especially one having up to 6 carbon atoms, such as. B. ethynyl, propynyl, butynyl, pentynyl, hexynyl or the like. Particularly preferred is a lower alkyl group which branches in the “position to the amino group of the compound of formula (I), in particular one with up to 4 carbon atoms, such as. B. isopropyl, 1-methylpropyl and tert-butyl. As a substituent ^) of the substituted acyclic hydrocarbon groups mentioned above, u. a. Cycloalkyl groups, preferably with a 3- to 7-membered ring, such as. B. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or the like. Cycloalkenyl groups, advantageously with a 3- to 7-membered ring, such as. B. 2-cyclopentenyl, 3-cyclohexenyl or the like., Cycloalkylidengruppen, advantageously with a 3- to O-membered ring, such as. B. cyclohexylidene, cyclopentylidene or the like. Aryl groups, such as. B. phenyl, naphthyl or the like., Heterocyclic groups, for. B. those with an oxygen atom, such as. B. tetrahydrofuryl, tetrahydropyranyl, dihydropyranyl, furyl od, etc., heterocyclic groups having a nitrogen atom, such as. B. piperidinyl, pyridyl, indolyl, quinolyl, or the like., Heterocyclic groups with a sulfur atom, such as. B. thienyl, tetrahydrothienyl or the like., Heterocyclic groups with two or more, the same or different hetero atoms, such as. B. thiazolyl, pyrimidyl, oxazolyl or the like., Hydroxyl, lower alkoxy groups having 1 to 4 carbon atoms, such as. B. methoxy, ethoxy, propoxy, u. Like., Aryloxy groups, such as. As phenoxy, naphthoxy or the like. Halides, such as. B.

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Chlorine, fluorine, bromine and iodine, or the like, esterified hydroxyls, alkoxycarbonyl groups, amino or substituted amino groups (in which the substituent or substituents can be alkyl, acyl or other groups), nitro or cyano - and other groups. The above-mentioned cycloalkyl, cycloalkenyl, aryl and heterocyclic groups can furthermore have one or more corresponding substituents, such as. B. lower alkyl groups with 1 to 4 carbon atoms, such as. B. methyl, ethyl, propyl, or the like. Hydroxyl, a lower alkoxy group having 1 to 4 carbon atoms, such as. B. methoxy, ethoxy, propoxy, or halides, such as. B. chlorine, bromine, iodine or fluorine.

Examples of the above-mentioned substituted, acyclic hydrocarbon groups are cyclohexyl-methyl, 1-cyclohexylethyl, 2-cyclopentylethyl, 3-cyclohexyl-

1-methyl-propyl, 4-methylcyclohexylmethyl, 1-cyclohexenyl-methyl, 1-cyclopentenylmethyl, benzyl, 4-methoxybenzyl, 4-hydroxybenzyl, a-methylbenzyl, 3,4-dimethoxybenzyl, a-methylphenethyl, 4-methoxy-a- methylphenethyl, 4-hydroxy-a-methylphenethyl, 4-hydroxy-aa-dimethylphenethyl, 4-methoxy-a, a-dimethylphenethyl, 4-chlorophenethyl, 3-phenylpropylphenethyl, 4-methoxyphenethyl, 2-phenylpropyl, a, 4-Dimethylphenäthyl, l-methyl-2-cyclohexylidenäthyl, Te-trahydropyran-2-yl-methyl, 2,3-dihydropyran-2-yl-methyl, Te-trahydrofuran-2-yl-methyl, 2- (furan -2-yl) -l-methylethyl, 2-thienylmethyl, piperidin-2-yl-methyl, 2- (2-indolyl) -methyl-ethyl, 2-pyridylmethyl, 2- (2-thiazolyl) -ethyl, 2- Hydroxyethyl,

2-methoxyethyl, 3-ethoxy-l-methylpropyl, 6-methoxyhexyl, l-methyl-2-phenoxyethyl, 2-fluoro-l-methylethyl, 2-ethoxycarbonylethyl, 2-aminoethyl, 3-dimethylaminopropyl, 3-morpholino called l-methylpropyl, 2-piperidino-l-methylethyl, Ni-tromethyl, 2-cyano-l-methylethyl, styryl, 3-phenyl-2-propenyl.

Examples of the cyclic hydrocarbon group denoted by R1 in the formula (I) are cycloalkyl groups, preferably having a 3- to 7-membered ring, such as, for. B. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or the like., Cycloalkenyl groups, preferably with a 3- to 7-membered ring, such as. B. Cyclopentenyl, cyclohexenyl or the like., And aryl groups, such as. B. phenyl, naphthyl and. Like., and others. A cycloalkyl group with a 3- to 7-membered ring is particularly preferred from the groups mentioned above. These groups can have one or more corresponding substituents, such as. B. the lower alkyl, hydroxyl, lower alkoxy groups, halides and. a. Groups which have been mentioned above as substituents) for the cycloalkyl, cycloalkenyl, aryl and heterocyclic groups mentioned in connection with the substituted, acyclic hydrocarbon groups. Typical examples of the above-mentioned cyclic hydrocarbon groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methyls cyclopropyl, 2-methylcyclobutyl, 3-methylcyclobutyl, 2,2-dimethylcyclobutyl, 3,3-dimethylcyclobutyl, 4-methylcyclohexyl, 4-hydroxycyclohexyl, 4-methoxycyclohexyl, 2-chlorocyclopentyl, 2-cyclohexenyl, 2-cyclopentenyl, phenyl, a-naphthyl, 4-chlorophenyl, 4-methoxyphenyl, 2-fluorophenyl, 4-hy-hydroxyphenyl, 3, 4-dimethoxyphenyl or the like

The process according to the invention consists in that a compound of the formula:

nhr

3rd

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reduced or that you have a compound of the formula:

(II »)

in which Q stands for the group -NHCOR2 or -N = CR3R4, which group is also reduced. R2, R3 and R4 have the meanings given above.

The optionally substituted heterocyclic group denoted by R2 is one of those heterocyclic groups which have been specifically mentioned in connection with the substituents on the acyclic hydrocarbon group denoted by R1.

If in the formula (II ') Q the group of the formula

C.

means, the alkyl group denoted by R3 corresponds to that alkyl group which has already been mentioned in detail in connection with Z1 and Z2 or R1. The substituted acyclic hydrocarbon group or optionally substituted cyclic hydrocarbon group or heterocyclic group denoted by R4 corresponds to the groups specifically mentioned under R1 and R2. It should be noted

that R3 and R4 can form a ring together with the adjacent C atom. Examples of such ring groups, which preferably have a 3- to 7-membered ring, are cycloalkane groups, such as, for. As cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, or the like., Cycloalken groups, which advantageously have a 3- to 7-membered ring, such as. B. Cyclopentene, cyclohexene or the like. Of particular advantage is a cycloalkane group with a 3- to 7-membered ring.

The reduction reaction in the above-mentioned process can, depending on the starting material used, be carried out by any reduction process, such as. B. be carried out according to one of the conventional methods listed below:

1. catalytic reduction using a catalyst, such as. B. platinum, palladium, rhodium, nickel or the like.,

2. Reduction using a metal hydride, such as. B. lithium aluminum hydride, lithium borohydride, lithium cyanoborohydride, sodium borohydride, sodium cyanoborohydride or the like.

3. Meerwein-Ponndorf-Verley reduction using an aluminum alkoxide, such as. B. aluminum isopropoxide,

4. Reduction using metallic sodium, metallic magnesium or the like with z. B. alcohol,

5. reduction with zinc dust with a base such as caustic potash,

6. reduction with a metal such as iron or zinc with an acid such as hydrochloric acid or acetic acid,

7. electrolytic reduction,

8. Reduction using reducing enzymes.

In addition to the processes mentioned above, any process which is suitable for reducing a carbonyl group to an alcohol and the double bond of the group of the formula can be used

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-N = C '

to saturate. Although the reaction temperature depends on the starting materials and the reduction processes used, it is generally within a range from about -20 to about 100 ° C. This reaction is generally carried out at atmospheric pressure, but can also be carried out under reduced or elevated pressure. The reduction is usually carried out in the presence of a suitable solvent. Any solvent is suitable for this purpose, provided that it more or less dissolves the starting materials and does not have an adverse effect on the reaction. Examples include water, alcohols, such as. B. methanol, ethanol, propanol and. Like., ether, such as. B. dimethyl ether, diethyl ether, methyl ethyl ether, tetrahydrofuran, dioxane, esters such as ethyl acetate, butyl acetate and the like. Like., Ketones, such as. B. acetone, methyl ethyl ketone or the like., Aromatic hydrocarbons such as benzene, xylene, toluene or the like., Organic acids such as acetic acid, propionic acid or the like. Or mixtures of two or more of these substances.

In the process according to the invention, the suitable reducing agents and conditions are selected depending on the starting materials used and the compounds to be produced.

Is z. B. as a starting material a compound of formula (II) is chosen, in those cases in which Z1 and Z2 are alkyl groups, the reducing agents and conditions are chosen from the options listed above; however, if Z1 and Z2 are hydrogen, the catalytic reduction is preferred.

If, however, a compound of the formula (II ') is used in which Q denotes —NHCOR2, lithium aluminum hydride is most frequently used as a reducing agent by the process mentioned under 2. and heated to about 40 to about 100 ° C. An intermediate can be obtained from the compound of formula (II ') with Q = -NHCOR2, in which Q is -NHCOR2 and a hydroxyl group adheres to the 1-position of the tetrahydronaphthyl ring.

If a compound of the formula (II ') is used as the starting material, in which Q denotes —N = CR3R4, the reduction processes mentioned under 1. and 2. above can be used.

The compound of formula (II '), wherein Q is -N = CR3R4, can e.g. B. be prepared by using a compound of the formula:

0 zxo

(III)

wherein Z1 and Z2 have the meaning given above, with a carbonyl compound of the formula

R

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R

"> = 0

(IV)

wherein R3 and R4 have the meaning given above, is implemented. In general, this reaction occurs when

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the compound of the general formula (III) and the carbonyl compound of the formula (IV) are mixed in the solvent mentioned above in connection with the reduction, but the mixture can also be heated or left to ensure that the reaction proceeds, Various dehydrating agents or condensing agents can also be used in the reaction.

If the reduction is carried out in the presence of the compound of the formula (III) and the carbonyl compound of the formula (IV), the amino group of the compound of the formula (III) is first subjected to a reaction with the carbonyl compound of the formula (IV) to give the compound of formula (II ') in which Q

-N:

: G <

R-

R

This means that this compound is in turn subjected to the reduction in order to obtain the desired compound of the formula (I):

The above-mentioned reaction can also be carried out using an excess of the carbonyl compound of the formula (IV) instead of the solvent.

If the above-mentioned groups R1, R2 or R4 of the starting compound of the formula (II) or (II ') are unsaturated, the unsaturation with the exception of aromatic unsaturation is frequently also reduced in the process according to the invention; in the case of aromatic unsaturation, a desired compound of formula (I) containing such an unsaturated group or a compound of formula (I) containing a corresponding saturated group can be obtained selectively by adjusting the reduction conditions.

The novel compound of the formula (I) obtainable according to the invention can be isolated from the corresponding reaction mixtures by methods of separation and purification known per se, such as concentration, filtration, recrystallization, column chromatography or the like.

The compounds of formula (I) can occur in various stereoisomers such as geometric isomers and optical isomers, which are due to the presence of asymmetric carbon atoms. It is generally obtained as a mixture of such isomers.

If necessary, an optical isomer (such as, for example, a trans or cis isomer) can be prepared using appropriate methods, such as, for example. B.

1. reduction using the compound of formula (II), which compound has the same configuration as the desired compound of general formula (I),

2. by stereospecific reduction (for example, the trans isomer of the compound of the formula (I) can be prepared by reducing the starting compound of the formula (II) using sodium borohydride),

3. Isolation of the isomer from a mixture of isomers by using one of the above separation and purification methods, such as. B. recrystallization, column chromatography or the like can be obtained.

The racemic mixture can be prepared using conventional methods, e.g. B. by optically

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active acid or base can form a salt, or by physical. Adsorption on a porous, adsorbent resin to be separated. All individual isomeric forms and their mixtures are within the scope of the invention.

The desired compound of formula (I) can also be isolated after being converted into pharmaceutically acceptable salts such as e.g. B. acid addition salts was transferred. Examples of such salts are inorganic acid salts such as those of hydrochloric acid, hydrogen bromide, sulfuric acid or the like and salts of organic acids such as maleate, fumarate, tartrate, toluenesulfonate, naphthalenesulfonate, methanesulfonate or the like.

The new compounds of formula (I) thus prepared and their pharmaceutically acceptable salts have pharmacological activity, such as. B. the effect of stimulating or blocking the ß-adrenergic receptors, vasodilatory effects on the coronary arteries, analgesic effect u. The like. Their effect on the stimulation of the /? 2-adrenergic receptors is particularly strong. H. their bronchodilatory effects. Because of these properties, the compounds of formula (I) and their salts are valuable for therapy and prophylaxis in diseases such as asthma, arrhythmia, angina pectoris, migraine and the like. the like

As a pharmaceutical, the desired compound and its salts can be administered to humans and mammals as they are or mixed with one or more pharmaceutically acceptable carrier (s) orally or otherwise in dosage forms such as powders, granules, tablets, capsules, injections, inhalations and the like. Like. Be administered.

Pharmaceutical compositions containing one or more compound (s) of formula (I) or their salts can, according to conventional procedures, be used for the production of powders, granules, tablets, capsules, injections, inhalations and the like. Like. Be produced. The choice of carrier depends on the type of administration, the solubility of the compound of formula (I) and its salts and the like. Like.

Although the dosage level depends on the disease in question and the symptoms to be controlled, the type of

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Administration and other conditions, advantageous dosage levels in adult asthma therapy range from about 1 to about 100 mg per day for oral administration, about 0.01 to about 1 mg per day for intravenous administration, or about 0.1 to s about 10 mg per dose with other modes of administration such as e.g. B. in sprays (aerosol inhalations).

Table 1 below shows the relaxing effect of typical compounds on isolated tracheostomy muscles of calves or guinea pigs compared to the corresponding effect of the known isoproterenol. The values given are given in relation to the value 100 for isoproterenol.

Table 1 15

Connection relaxing effect on the isolated tracheostomy muscle *

2- (3-phenylpropy! Amino) -l, 5,6-tri-

hydroxy-l, 2,3,4-tetrahydro-

naphthalene hydrobromide

2-cyclopentylamino-l, 5,6-trihydroxy-

1,2,3,4-tetrahydronaphthalene

Hydrobromide

2- (4-hydroxy-a-methylphenethyl-amino) -1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene fumarate about 200 (calf) *

about 190 (calf) * about 600

(Guinea pig)*

30th

* determined according to the conventional method of E. J. Ariens, which is described in “Ciba Foundation Symposium”, pages 253-263 (1960).

The compound of formula (I) is also useful as an intermediate for the manufacture of various drugs.

So z. B. can the compound of formula (I), wherein Z1 and Z2 represent an alkyl group, easily by methods known per se, such as. B. by hydrolysis in the corresponding compound of formula (I), wherein Z1 and Z2 are hydrogen.

The compound of formula (III), wherein Z1 and Z2 each represent an alkyl group, can, for. B. according to the described in [Journal of Médicinal Chemistry 12, 487 (1969)] or by a method based thereon, as set out below.

20th

35

40

A

u do

OJ

.0)

O

x!

SH

CM

CM

W

K

O

C.

•H

at su

£

a

•H

o o o

o o o

•H

o o - o

CM

>>

K

P4

O

Ä.

CM

O

Ü

«-M

•H

O

617180

The compound of formula (III), wherein Z1 and Z2 each represent hydrogen, can easily, e.g. B. by hydrolyzing a compound of formula (V) with hydrogen bromide.

The starting compound of the formula (II '), in which Q denotes -NHCOR2, can be obtained by acylating the above-mentioned compound of the formula (V) or a hydrolyzate thereof according to processes known per se (such as, for example, reaction with the corresponding acyl chloride in Pyridine).

The starting compound of formula (II) z. B. by

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a) reaction of the compound of formula (III), or its N-acylated compound, with a halide or a substituted sulfonyloxy derivative of the general formula R * Y (VI), in which Y is halogen or a substituted sulfonyloxy group, and if necessary Hydrolyzing the above-mentioned reaction product,

b) by reacting the same compound of formula (III) with the carbonyl group of formula (IV) under reduction conditions according to the reaction scheme given below

2 Z ^ O

0

(b)

4 ^ 0 = 0; Reduction R (IV) conditions are produced in which Z1, Z2, R3 and R4 have the meaning given above.

A more detailed explanation of the reactions is given below. Reaction a) can be carried out according to the following reaction.

given a) and b). 25 scheme.

Z ^ o

^ —Ng Z40

îm2 (2) RXY (VI)

hydrolysis

\ pl

Only where Z1, Z2, R1 and Y have the meaning given above, Rs is an acyl group and Z3 and Z4 are hydrogen, an alkyl group as stated for Z1 and Z2, an acyl group as specified for Rs or a protective group.

For the acylation of the starting compound shown in the above reaction scheme, i.e. H. the compound of formula (III), z. B. carboxylic acids such as acetic acid, trifluoroacetic acid, propionic acid or the like., Carboxylic acid halides, such as. As acetyl bromide, ben-zoyl, chloride, trichloroacetyl chloride, ethyl chlorocarbonate or the like., Acid anhydrides such as acetic anhydride, trifluorosacetic anhydride, or the like. Mixed acid anhydrides, such as. B. Ethyl carbonate acetic anhydride or the like. And sulfonic acid halides, such as. B. methanesulfonyl chloride, toluenesulfonylchloride and. Like. Be called.

The above-mentioned acylation reaction is generally carried out in water, an organic solvent or a mixture thereof, an excess of acylating agent can also be used as the solvent. The course of the reaction can by the simultaneous presence of a base such. B. sodium hydroxide, potassium carbonate, pyridine, triethylamine or the like can be accelerated. As far as the proportion of acylating agent is concerned, that of one molar equivalent is sufficient, but in most cases the acylation is carried out using about 2 to 10 molar equivalents, but if the acylating agent also serves as a solvent, an even larger proportion is used. The rate of reaction can be increased by heating or cooling

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of the reaction mixture are regulated, but in general the reaction temperature is within a range from about -20 to about 100 ° C.

As a result of the above-mentioned acylation reaction, the corresponding acyl group is incorporated into the 2-amino group of the compound of the formula (III), whereby an acylamino compound is formed. If Z1 and / or Z2 in the compound of the formula (III) are hydrogen, in this case, depending on the reaction conditions, a compound can be obtained which has the corresponding acyl groups instead of the hydrogen. Alternatively, Z1 and / or Z2 can be substituted by a protecting group prior to acylation. Any protective group which protects the hydroxyl group from the acylation reaction and is easily removable is suitable as a protective group. Examples of such groups are aralkyl groups, such as. B. benzyl, a-methyl-benzyl or the like. And others.

In the compound of formula (VI), Y represents a halide, such as. B. chlorine, bromine, fluorine or the like. Or a substituted sulfonyloxy group, such as. As methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, p-bromobenzenesulfonyloxy or the like. The reaction with the compound (VI) is usually carried out in water, an organic solvent or a mixture thereof. Any organic solvent which does not adversely affect the reaction such as e.g. B. methanol, ethanol, acetone, chloroform, benzene, ethyl ether, tetrahydrofuran, dioxane or the like. To accelerate the reaction, a base such as sodium hy

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hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, pyridine, picoline, triethylamine, sodium hydride, sodium alcohol, tert-butoxy potassium or the like can be used as the acid acceptor. In some cases, it is advisable to add an antioxidant such as ascorbic acid, hydrochi-non or the like to increase the yield and the reaction in an inert, gaseous medium, such as. B. nitrogen, helium or argon to prevent possible side effects caused by oxidation. The reaction takes place at room temperature, but can also be carried out with heating or cooling to regulate the speed. It is usually advantageous to perform them within a temperature range of about -20 to about 100 ° C. The resulting compound of formula (VII) can first from the reaction mixture by a conventional isolation and purification process such. B. isolated by concentration, distillation, filtration, recrystallization, chromatography and / or the like and then subjected to the above-mentioned hydrolysis.

The hydrolysis shown in the above reaction scheme is generally carried out by exposing the compound of formula (VII) to water, an acid or a base in the presence of water and / or an organic solvent. Examples of such acids are inorganic acids such as hydrochloric acid, hydrogen bromide, hydrogen iodide, sulfuric acid, nitric acid, phosphoric acid or the like, organic acids such as formic acid, acetic acid or the like or Lewis acids such as aluminum chloride, iron chloride, zinc chloride, boron trifhioride, boron trichloride or the like. Like. Examples of bases are inorganic bases, such as. As potassium hydroxide, sodium hydroxide, sodium carbonate, sodium bicarbonate or the like. Or organic bases, such as. B. pyridine, dimethylaniline, triethylamine or the like. Any organic solvent which has no adverse effect on the course of the reaction, such as As methanol, ethanol, acetone, chloroform, benzene, ethyl ether, tetrahydrofuran, dioxane or the like. Although the hydrolysis takes place at room temperature, the rate of its expiration can be regulated by increasing or decreasing the temperature accordingly. Generally, it is carried out within a temperature range of about 0 to about 150 ° C.

If Z3 and / or Z4 are the acyl groups or protective groups incorporated by the above-mentioned acylation or protective groups which have been incorporated before the acylation, they can be removed simultaneously during the hydrolysis. However, if these groups remain unchanged, they can be removed by conventional methods.

The compound of formula (II) obtained can easily by known separation and purification methods such. B. concentration, distillation, filtration, recrystallization, chromatography u. Like., Are removed from the reaction mixture.

The reaction b) is carried out in the presence of the carbonyl group of the general formula (IV) under reduction conditions.

The desired reduction conditions can be advantageous in the inventive method, for. B. by using lithium cyanoborohydride or by catalytic reduction using palladium on carbon in alcoholic solvents. The reduction can also be carried out using an excess of carbonyl compound of the formula (IV) instead of a solvent. Although the reaction temperatures depend on the reduction process chosen, it is advantageous to carry out the reaction within a temperature range from about -20 to about 100 ° C. The reaction according to the invention is usually carried out at atmospheric pressure, but it can also be carried out under increased or reduced pressure.

The compound of formula (II) obtained can easily be isolated from the reaction mixture by isolation and purification methods known per se, such as concentration, distillation, recrystallization, column chromatography or the like.

The compound of formula (II) prepared by reaction a) or b) can also be isolated in the form of a salt, e.g. B. an acid addition salt with an inorganic acid, such as. As hydrochloric acid, hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid or the like. Or with an organic acid such as. B. acetic acid, fumaric acid, maleic acid, tartaric acid, malic acid or the like.

The compound of formula (II) described in detail above, including its acid addition salts, also has a stimulating or blocking effect on the sympathetic nervous system and can therefore be used in prophylaxis and therapy for asthma or arrhythmia. If these compounds are used as medicaments, they can be administered orally in the form of tablets, capsules, powders, suspensions, syrups or the like, in the form of parenteral injections, inhalations or the like. Although the dosage amount depends on the symptoms to be treated, the route of administration or the like, the dosage amount for oral administration in asthma therapy is usually recommended to be 0.1 to 100 mg per adult per day.

The above-mentioned starting compound of formula (II) and the compound of formula (III) can be used in the process according to the invention either in free form or as acid addition salts, such as. B. as inorganic acid salts, such as. As hydrochloric acid, hydrogen bromide, sulfuric acid and organic acid salts, such as. B. as maleate, fumarate, tartrate, toluenesulfonate, naphthalenesulfonate, methanesulfonate or the like.

The present invention is explained in more detail with reference to the following reference and exemplary embodiments.

In the examples below, “parts” means parts by weight, unless expressly stated otherwise, the ratio between “parts” and “parts by volume” corresponds to that of g and ml.

Reference Example 1

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

This crystalline product has no definite melting point, but gradually decomposes with blackening at temperatures above 250 ° C.

IR spectrum: y ™ * cm-1: 3500-2800, 1660, 1605, 1580, 1490, 1380, 1310, 1280, 1025, 905, 820.

Reference Example 2

10 parts of 2-amino-5,6-dimethoxy-3,4-dihydro-l- (2H) -naphthalenone hydrochloride were dissolved in a mixture of 200 parts by volume of dry methanol and 200 parts by volume of cyclohexanone, then they were dissolved under nitrogen and with cooling to 0 9 parts of a molecular compound consisting of 1 mol of lithium cyanoborohydride and 2 mol of dioxane (LiBH3CN-2C4H802) were added. The reaction mixture was then stirred at a constant temperature of 5 ° C. for 2 hours. Then and after adding

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9

617 180

The hydrochloric acid was distilled off, the remaining mixture was washed with benzene and concentrated 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. Yield: 9.65 parts of 2-cyclohexylamino-5,6-dimethoxy-3,4-dihydro-l- (2H) -naphthalenone hydrochloride in the form of colorless crystals with a melting point of 180 to 190 ° C. (decomposition).

Elemental analysis for C18H2S03N-HC1:

calculated: C 63.61 H 7.71 N 4.12 found: C 63.50 H 7.46 N 4.22

Reference Example 3 In a mixture of 50 parts by volume of 48% hydrogen bromide and 15 parts by volume of acetic anhydride, 5 parts of 2-cyclohexylamino-5,6-dimethoxy-3,4-dihydro-l- (2H) -naphthalenone hydrochloride were dissolved and the solution became approx Heated to 140-160 ° C for 3 hours. After cooling, the solvent was distilled off under reduced pressure and the residue was treated with activated carbon in ethanol.

After addition of ethyl acetate, the filtrate was left to stand, the yield obtained was 4.1 parts of 2-cyclohexylamino-5,6-dihydroxy-3,4-dihydro-l- (2H) -naphthalenone hydrobromide in the form of colorless Prisms with a melting point of 225 to 237 ° C (decomposition).

NMR: Ò (DMSO-d6): 6.91 (IH, d, J = 8.4), 7.43 (1H, d, J = 8.4)

Reference Example 4 According to a procedure similar to Reference Example 2, 10 parts of 2-amino-5,6-dimethoxy-3,4-dihydro-l- (2H) -naphthalenone hydrochloride were reacted with 300 parts by volume of cyclopentanone. The yield obtained was 10.2 parts of 2-cyclopentylamino-5,6-dimethoxy-3,4-dihydro-l- (2H) -naphthalenone hydrochloride in the form of colorless crystals with a melting point of 158 to 167 ° C. (decomposition) . Elemental analysis for C17H2303N • HCl:

calculated: C 62.67 H 7.42 N 4.30 found: C 62.91 H 7.15 N 4.35

Reference Example 5 According to the similar procedure described in Example 2, 10.5 parts of 2-amino-5,6-dimethoxy-3,4-dihydro-l- (2H) -naphthalenone hydrochloride were reacted with 10 parts by volume of cyclo-butanone. The yield obtained was 8.2 parts of 2-cyclobutylamino-5,6-dimethoxy-3,4-dihydro-l- (2H) -naphthalinone hydrochloride with a melting point of 146 to 164 ° C. (decomposition).

Elemental analysis for C16H2103N-HC1- v4 H20:

calculated: C 60.76 H 7.17 N 4.43 found: C 60.78 H 7.26 N 4.29

Reference Example 6 By a procedure similar to that described in Reference Example 3, 5.16 parts of 2-cyclobutylamino-5,6-di-methoxy-3,4-dihydro-l- (2H) -naphthalenone hydrochloride in a mixture of 75 parts by volume was 48 % hydrogen bromide and 15 parts by volume of acetic anhydride hydrolyzed. The yield obtained was 4 parts of 2-cyclobutylamino-5,6-dihydroxy-3,4-dihydro-l- (2H) -naphthalenone hydrobromide with a melting point of 229 to 240 ° C. (decomposition). Elemental analysis for C14H1703N • HBr • 1 / 2H20:

calculated: C 49.86 H 5.68 N 4.15 found: C 50.10 H 5.58 N 4.12

Reference Example 7 In 300 parts by volume of ethanol, 5 parts of 2-amino-5,6-dihydroxy-3,4-dihydro-l- (2H) -naphthaIinone-Hydrobro-

mid dissolved, then after the addition of 50 parts / 5-phenyl-propionaldehyde, the catalytic reduction was carried out using palladium on carbon as a catalyst at normal pressure and normal temperature. After absorbing a stoichiometric amount of hydrogen, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The yield obtained was 3.5 parts of 2- (3-phenylpropyl) amino-5,6-dihydroxy-3,4-dihydro-l- (2H) -naphthalene-non-hydrobromide in the form of colorless crystals with a Melting point from 215 to 217 ° C.

Elemental analysis for C19H2i03N • HBr:

calculated: C 58.17 H 5.65 N 3.57 found: C 58.39 H 5.69 N 3.18

Reference Example 8 10 parts of 2-amino-5,6-dihydroxy-3,4-dihydro-l- (2H) -naphthalenone hydrobromide were dissolved in 1000 parts by volume of ethanol, and 100 parts of 4-methoxyphenylacetal dehyde were then added. The catalytic reduction was then carried out at room temperature and normal pressure using palladium on carbon as a catalyst. After absorbing a stoichiometric amount of hydrogen, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The yield obtained was 8 parts of 2- (4-methoxyphenethyl) amino-5,6-dihydroxy-3,4-dihydro-l- (2H) -naphthalenone hydrobromide in the form of colorless crystals with a melting point of 198 to 203 ° C. Elementary analysis for Ci9H2i04NHBr:

calculated: C 55.89 H 5.43 N 3.43 found: C 56.30 H 5.38 N 3.05

Reference Example 9 500 parts of trifluoroacetic anhydride were mixed with 20 parts of 2-amino-5,6-dimethoxy-3,4-dihydro-l- (2H) -naphthalenone hydrochloride. The mixture was left at room temperature for 30 minutes, after which time a small amount of ethyl ether and 1000 parts by volume of n-hexane were added. The crystals formed were filtered off; the yield obtained was 24 parts of 2-tri-fluoro-acetamido-5,6-dimethoxy-3,4-dihydro-l- (2H) -naphtha-linone with a melting point of 166 to 167 ° C. Elemental analysis for C14Hi404NF3:

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-mentioned product were dissolved in 1500 parts by volume of acetone which had previously been saturated with nitrogen then mixed with 50 parts of potassium carbonate and 30 parts of 4-methoxyphenethyl bromide. This mixture was stirred under nitrogen feed for 2 days. The resulting product was refluxed in 200 parts by volume of a 47% aqueous hydrogen bromide solution for 3 hours.

The reaction product was extracted with ethyl acetate and the water layer was filtered off with the addition of a small amount of activated carbon. The filtrate was concentrated under reduced pressure and a temperature of not more than 50 ° C. The residue was washed in methanol and ethyl ether was added dropwise to the solution until a whitish cloudiness occurred. The mixture was stored in a cool place for 1 week and the resulting crystals were filtered off after this period. The yield obtained was 3 parts of 5,6-dihydroxy-2- (4-methoxyphenäthylamino) -3,4-dihydro-l- (2 H) -naphthalenone hydrobromide with a melting point of 198 to 203 ° C (decomposition).

Elemental analysis for Ci9H2] 04N • HBr:

calculated: C 55.89 H 5.43 N 3.43 found: C 56.51 H 5.30 N 3.17

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

61.7180

10th

Reference Example 10 500 parts of trifluoroacetic anhydride were mixed with 20 parts of 2-amino-5,6-methylenedioxy-3,4-dihydro-l- (2 H) -naphthali non-hydrochloride and after standing at room temperature for 30 minutes with 1000 parts of n- Hexane added. The supernatant layer was then discarded and the precipitate, 2-trifluoroacetamido-5,6-methylene-dioxy-3,4-dihydro-l- (2H) -naphthalinone, was dissolved in 2500 parts by volume of acetone saturated with nitrogen gas. After adding 80 parts of potassium carbonate and 60 parts of cyclohexanol-p-toluenesulfonic acid ester, the solution was stirred for 7 days with the addition of nitrogen. After this period, the insoluble substances were filtered off and the filtrate was distilled under reduced pressure to give crude 2- (N-cyclohexyl-N-trifluoroacetamido) -5,6-methylenedioxy-3,4-dihydro-l- (2H) -naphthalinone. This product was placed in 800 volumes of a 47% hydrogen bromide solution and the mixture was refluxed for 3 hours. After cooling, the reaction mixture was extracted with ethyl acetate. A small amount of activated carbon and 500 parts by volume of nitrogen-saturated methanol were added to the water layer, then the solution was filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was dissolved in methanol. The whitely cloudy solution caused by the dropwise addition of ethyl ether was stored in a cool place for 2 weeks and the crystals formed were filtered off after this period. The yield obtained was 2 parts of 2-cyclohexylamino-5,6-dihydroxy-3,4-dihydro-l- (2H) -naphthalenone hydrobromide with a melting point of 225 to 237 ° C. (decomposition).

Elemental analysis for Ci6H2i03N • 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 11 20 parts of 2-amino-5,6-dibenzyloxy-3,4-dihydro-l- (2H) -naphthalenone hydrochloride were subjected to a procedure similar to that described in Reference Example 11, the resulting 5,6-dibenzyloxy-2- trifluoroacetamido-3,4-dihydro-l- (2H) -naphthalenone was reacted with 60 parts of 3-phenylpropanol-p-toluenesulfonic acid ester under the conditions described in Example 11. The reaction product was then hydrolyzed in a 47% aqueous hydrogen bromide solution; the yield obtained was 3 parts of 5,6-di-hydroxy-2- (3-phenylpropylamino) -3,4-dihydro-l- (2H) -naphthalinone hydrobromide with a melting point of 215 to 217 ° C. (decomposition ).

Elemental analysis for C19H2i03N • HBr:

calculated: C 58.17 H 5.65 N 3.57 found: C 58.00 H 5.17 N 3.25

example 1

Using 1.91 parts of 5% palladium on carbon, 1.89 parts of 2-cyclohexylamino-5,6-dihydroxy-3,4-dihydro-l- (2H) -naphthalenone hydrobromide in 50 parts by volume of water for catalytic reduction subjected at room temperature and normal pressure. After absorbing (taking up) a stoichiometric amount of hydrogen, the reaction mixture was filtered to remove the catalyst, and the filtrate was subjected to freeze drying. Recrystallization of the residue from a mixture of ethanol and ethyl acetate gave a yield of 1.38 parts of 2-cy-clohexylamino-l, 5,6-trihydroxy-l, 2,3,4-tetrahydro-naphtha-lin hydrobromide in the form of colorless crystals with a melting point of 230 to 236 ° C (decomposition).

Nuclear magnetic resonance spectrum:

ó (DMSO - d6 + D20): 4.56-4.80 (1H, m), 6.40-6.70 (2H, m)

Example 2

In the presence of 2 parts of 5% palladium on carbon as a catalyst, 2 parts of 2-cyclopentylamino-5,6-dihydroxy-3,4-dihydro-l- (2H) -naphthalenone hydrobromide in 50 parts by volume of water were used for the catalytic reduction subjected to normal temperature and pressure. After taking up a stoichiometric amount of hydrogen, the reaction was terminated and the catalyst was filtered off. The filtrate was subjected to freeze drying and the residue was recrystallized from a mixture of ethanol and ethyl acetate. The yield obtained was 1.54 parts of 2-cyclopentylamino-l, 5,6-trihydroxy-l, 2,3,4-tetrahydronaphthalene hydrobromide in the form of colorless crystals with a melting point of 210 to 218 ° C (decomposition).

Mass spectrum: m / e: 263 (M +)

Nuclear magnetic resonance spectrum:

<5 (DMSO - d6 + D20): 4.62 (1H, d, J = 8 Hz), 6.60-6.90 (2H, m).

Examples 3 to 12 Following similar procedures described in Examples 1 or 2, the products listed in the table below were obtained by catalytic reduction of the corresponding 3,4-dihydro-2-subst. Amino-5,6-dihydroxy-l- (2H ) -naph-45 thalinone hydrobromide obtained.

The compounds in Table 3 below can be prepared in a similar manner.

10th

15

20th

25th

30th

35

Be:

3rd

4th

5

6

7

8th

9

10th

11

12

11

Table 2

ho

Product ho

Oh

617 180

R

salt

Melting point

(Decomposition)

° C

"(®2VÖ

Hydrobromide

136-139

- (ch2V0

Hydrobromide

146-149

- (CH ^^ - och.

Hydrobromide

138-140

-ch2ch-

ch-

Hydrobromide

149-151

-GH

Û

2 "0

Hydrobromide

155-158

-ch.

r <5>

Hydrobromide

161-164

-ch2ch2och3

Hydrobromide

156-159

-ch-ch ch,

2 '

Fumarate

145-148

-ch-ch.

i <

ch,

, - <Qkoch5

Fumarate

150-153

-CK-CHp- ^ VoH ch,

Fumarate

137-141

617 180

HO

product

NHR «HBr

example

Carbonyl compound

R

Solvents for recrystallization

Melting point (decomposition)

(° C)

Elemental analysis molecular formula calculated (found)

13 phenylacet aldehyde

14 4-methoxyphenyl acetaldehyde

15 a -phenyipropion-

aldehyde

16 tetrahydropyran-2-carbaldehyde

17 Cyclohexane carbaldehyde

18 methoxyacet aldehyde

• (CH2) 2- <

• (CH2 ^ 2 "^ 3- ° CII3

-CHgCH-

CH,

-ü

-CH

-CHj-Q

.CH2CH20CH3

Ethanol 146-149 C18H2103NHBrH20 ether C 54.26 H 6.07 N 3.52

(C 54.64 H 6.04 N 3.16)

Ethanol- 138-140 C19H2304N ■ HBr • H20 ether C 53.28 H 6.12 N 3.27

(C 53.60 H 5.75 N 3.24)

Ethanol- 149-151 C19H2303NHBr-H20 ether C 55.33 H 6.35 N 3.40

(C 55.77 H 5.80 N 3.51)

Ethanol 155-158 C16H2304NHBrH20 ether C 49.98 H 6.68 N 3.57

(C 49.20 H 6.49 N 3.54)

Ethanol 161-164 C17H2503NHBrH20 ether C 52.31 H 7.23 N 3.59

(C 52.74 H 7.07 N 3.32)

Ethanol- 156-159 C13H1904N • HBr ether C 46.72 H 6.03 N 4.19

(C 46.46 H 5.99 N 4.29)

Example 19

In a mixture of 50 parts by volume of cyclohexanone and 200 parts by volume of ethanol, 0.151 part of 2-amino-5,6-dihydroxy-3,4-dihydro-l- (2H) -naphthalenone hydrobromide was dissolved to give 2-cyclohexylideneamino-5,6- dihydroxy-3,4-dihy-dro-l- (2H) -naphthalenone.

The resulting mixture was subjected to catalytic reduction in the presence of 0.16 part of platinum oxide and 0.57 part of anhydrous sodium acetate at normal temperature and pressure. After taking up a stoichiometric amount of hydrogen, 1 part by volume of 48% hydrogen bromide was added and the catalyst was filtered off. The ethanol was distilled off from the filtrate and the residue was diluted with water and washed with benzene. The aqueous layer was subjected to freeze drying and after recrystallization of the residue from a mixture of ethanol and ethyl acetate, 2-cyclohexylamino-l, 5,6-trihydroxy-l, 2,3,4-tetrahydronaphthalene hydrobromide with a melting point of 230 to 234 ° C (decomposition) obtained. This product was identified as corresponding to the compound listed in Example 10.

Example 20 65

1 part of 2-amino-5,6-dihydro-xy-3,4-dihydro-l- (2H) -naphthalenone hydrobromide was dissolved in a mixture of 20 parts by volume of cyclopentanone and 100 parts by volume of ethanol

Obtain 2-cyclopentylideneamino-5,6-dihydroxy-3,4-dihydro-l- (2H) -naphthalinone. The resulting mixture was subjected to catalytic reduction with 0.1 part of platinum oxide and 0.39 part of anhydrous sodium acetate at normal temperature and pressure.

After a stoichiometric amount of hydrogen gas had been taken up, 1 part by volume of 48% hydrogen bromide was added and the catalyst was filtered off. The ethanol was distilled off from the filtrate and the residue was diluted with water and washed with benzene.

The aqueous layer was subjected to freeze drying and the residue was recrystallized from a mixture of ethanol and ethyl acetate. The yield obtained by this process was 0.5 part of 2-cyclopentylamino-l, 5,6-trihydroxy-l, 2,3,4-tetrahydronaphthalene hydrobromide in the form of colorless crystals with a melting point of 208 to 218 ° C. (decomposition ). This product was identified as corresponding to the compound described in Example 11.

Example 21

1 part of 2-benzylamino-5,6-dimethoxy-3,4-dihydro-l- (2H) -naphthalenone-hydrochloride was dissolved in 100 parts by volume of methanol, then 2 parts of sodium borohydride were added in small portions with stirring admitted. The mixture was stirred at room temperature for 10 minutes, then 500 volumes of water were added. Then was

50

55

13

617 180

the mixture is extracted with chloroform, the extract is dried over sodium sulfate and concentrated under reduced pressure.

By recrystallization of the residue from ethyl ether, 0.4 part of trans-2-benzylamino-5,6-dimethoxy-l-hydroxy-1,2,3,4-tetrahydronaphthalene in the form of colorless 5 crystals with a melting point of 133 to Obtained 135 ° C (decomposition).

Elemental analysis for Q9H23O3N:

calculated: C 72.82 H 7.40 N 4.47

found: C 72.42 H 7.32 N 4.45 10

Example 22

50 parts by volume of tetrahydrofuran were added to 1 part of 2-benzoylamino-5,6-dimethoxy-3,4-dihydro-1 - (2H) -naphthalinone and 0.2 part of lithium aluminum hydride and the mixture was refluxed for 4 hours cooked. The reaction mixture was acidified sufficiently with hydrochloric acid and extracted with chloroform to remove the non-basic ingredients.

The aqueous layer was made alkaline with In aqueous sodium hydroxide and extracted with chloroform. The chloroform solution thus obtained was dehydrated and concentrated to dryness. By recrystallization of the residue from ethyl ether, 0.4 part of trans-2-benzylamino-5,6-dimethoxy-l-hydroxy-l, 2,3,4-tetrahydronaphthalene in the form of colorless crystals with a melting point of 133 to 135 ° C obtained (decomposition).

The product was identified by determining the mixed melting point as the compound described in Example 21.

Example 23

By using cinnamaldehyde, 2- (3-phenylpropylamino) -l, 5,6-trihydroxy-l, 2,3,4-tetrahydronaphtha-lin hydrobromide with a melting point of 136 to 139 ° C. can be obtained.

Elemental analysis for Ci9Ha303N- HBr - v2H20:

calculated: C 56.58 H 6.25 N 3.47 found: C 56.18 H 6.18 N 3.19

Examples 24-28 Following the similar procedure described in Example 20, the products listed in Table 4 below can be made from 2-amino-5,6-dihydroxy-3,4-dihydro-l- (2H) -naphthalenone hydrobromide and unsaturated carbonylver -bindings are made.

Table 4

Oh

Carbonyl compound (decomposition)

(° C)

24th

o = °

- <h)

A

230-236

25th

, D = °

- <3

A

210-218

26

O ^ -cho

A

155-158

27th

^^ - chgchgcho

- (ch2y (i)

B

160-162

28

<^ vch? chq

- (ch2)? - (h>

B

168-171

* Catalyst A: 5% palladium on carbon Catalyst B: platinum dioxide

Example 29

In the presence of 2 parts of 5% palladium on carbon, 2 parts of 2- (3,4-dihydro-2H-pyran-2-yl) -methylamino-no-5,6-dihydroxy-3,4-dihydro-l- (2H) -naphthalenone hydrobromide in 50 parts by volume of water at normal temperature and pressure to the catalytic reduction until no more hydrogen was taken up. The catalyst was then filtered off and the filtrate was subjected to freeze drying. The yield obtained was 2 parts of 2- (tetrahydropyran-2-yl) methylamino-l, 5,6-trihydroxy

1,2,3,4-tetrahydronaphthalene hydrobromide in the form of colorless 60 crystals with a melting point of 155 to 158 ° C (decomposition). The product was identified by mixing melting point determination as corresponding to the product described in Example 5.

65 Examples 30 to 31

Following the similar procedure described in Example 32, the compounds listed in the table below were prepared.

Example 32

In the presence of 1.53 parts of 5% palladium on carbon, 1.5 parts of 2-cyclobutylamino-5,6-dihydroxy-3,4-dihydro-l- (2H) -naphthalenone hydrobromide in 200 parts by volume of water for catalytic reduction subjected to normal temperature and pressure. After taking up a stoichiometric amount of hydrogen, the reaction mixture was filtered to remove the catalyst and subjected to freeze drying. By recrystallization of the residue from a mixture of water, ethanol and ethyl ether, 0.65 part of 2-cyclobutylamino-l, 5,6-trihydroxy-l, 2,3,4-tetrahydronaphthalene hydrobromide in the form of colorless crystals with a Melting point of 190 to 200 ° C achieved (decomposition).

Elemental analysis for C14HI903N • 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:

ô (d6 - DMSO + D20): 4.58 (1H, d, J = 8 Hz), 6.70 (1H, d, J = 8 Hz), 6.84 (1H, d, J = 8 Hz)

IR spectrum: y (cnr1): 3370, 3120, 2930, 1620, 1595 1500, 1295, 1010, 890, 815.

Example 33

Using a procedure similar to that described in Example 23, 1 part of 2-amino-5,6-dihydroxy-3,4-dihydro-l- (2H) -naphthalenone hydrobromide was reacted with 20 parts by volume of cyclobutanone. About 2-cyclobutylideneamino-5,6-dihydroxy-3,4-dihydro-l- (2H) -naphthalinone as an intermediate 0.5 parts of 2-cyclobutylamino-l, 5,6-trihydroxy-1,2,3 , 4-tetrahydronaphthalene hydrobromide in the form of colorless crystals with a melting point of 190 to 200 ° C obtained (decomposition).

This product was identified by mixing melting point determination as corresponding to the compound described in Example 32.

Example 34

By a procedure similar to that described in Example 32, 3.16 parts of 2-cyclopropylamino-5,6-dihydroxy-3,4-dihydro-l- (2H) -naphthalione hydrobromide was subjected to catalytic reduction. The reaction mixture was then filtered to remove the catalyst. After adding 0.72 part of triethylamine, the filtrate was concentrated under reduced pressure. 500 parts by volume of water were added to the residue and the resulting solution was extracted three times with 300 parts by volume each of n-butanol, then 2 parts of fumaric acid were added and the extract was concentrated under reduced pressure. The residue was mixed with 1000 parts by volume of ethyl ether and the yield obtained after recrystallization of the filtered precipitate was 0.3 part of 2-cyclopropylamino-l, 5,6-trihydroxy-l, 2,3,4-tetrahydronaphthalene fumarate in the form of a colorless powder with a melting point of 155 to 160 ° C (decomposition).

Elemental analysis for C13Hi703N-v2 C4H4O4 H20: calculated: C 57.86 H 6.80 N 4.50 found: C 57.48 H 6.38 N 4.71

Claims (4)

617 180 2nd PATENT CLAIMS 1. Process for the preparation of a new compound of the formula: 1 z 'o z2o. (I) nhr or of their salts, in which Z1 and Z2 each represent hydrogen or an alkyl group and R1 is a substituted acyclic hydrocarbon group or a cyclic hydrocarbon group, characterized in that a compound of the formula: di) nhr- 7. Application of the method according to claim 3 to starting compounds of the formula (II '), in which Q is a group of the formula: " R- R where R3 and R4 have the meanings given above, which are obtained by reacting a compound of the formula: 15 20th (iii) wherein Z1 and Z2 have the meanings given above, with a carbonyl compound of the formula: 25th in which R1, Z1 and Zz have the meanings given above, reduced. 2. The method according to claim 1, characterized in that process products obtained are converted into corresponding salts by reaction with an inorganic or organic acid. 3. A process for the preparation of a new compound of the formula (I) given and defined in claim 1 or of its salts, characterized in that a compound of the formula: 2 * lr z (II *) c = o 30th getting produced.