NO752138L - - Google Patents

Description

Process for the preparation of aminotetralin compounds.

The present invention relates to new and industrially applicable methods for the production of unpublished amino-tetralin compounds with the formula

where R is hydrogen, a hydrocarbon group which may be substituted 12 N or acyl, and where Z and Z are hydrogen or a protected group, as well as their physiologically acceptable salts, and where said compounds have excellent pharmacological activities such as strong bronchodilator activity or β-adrenergic blocking activity, and where said compounds can be used as medicines, e.g., for the treatment of asthma or arrhythmia, e.g. in humans. Furthermore, the invention relates to compounds of formula I, i.e. aminotetralin compounds of the formula

wherein R has the same meaning as stated above, Z<1>" and Z<2>" are aralkyl, and their physiologically acceptable salts, and wherein said

compounds can be used as intermediates for the preparation of compounds of formula I, where both Z 1 and Z 2 are hydrogen.

As medicines for the treatment of asthma, isoproterenol and metaproterenol have often been used, both of which have a stimulating effect on (3-adrenergic receptors. However, while isoproterenol has a bronchodilating effect which is associated with β-adrenergic receptors, it has strong side effects due to its strong cardiac stimulation which is said to be associated with P-^-adrenergic receptors, on the other hand, metaproterenol has only moderate side effects of the above type, but on the other hand has far inferior bronchodilator activity. None of the two mentioned compounds have therefore been considered to be satisfactory as a selective bronchodilator.

Compounds of formula I have now been synthesized which have strong bronchodilating activity and which have only moderate or essentially no side effects due to β-adrenergic stimulation, and industrially applicable methods for the production of such compounds have also been found.

It is thus a principle purpose of the present invention to provide industrially applicable methods for the production of compounds of formula I and their physiologically acceptable salts. Furthermore, it is an aim of the invention to provide new compounds of formula I' and their physiologically acceptable salts, and where said compounds can be used as medicines for the treatment of asthma or arrhythmia or used as intermediates. Other purposes of the invention will be apparent from the following description.

The new methods according to the present invention can be stated as follows:

Procedure 1

This method relates to the preparation of compounds of the following formula where R is hydrogen, a hydrocarbon group which may be substituted or acyl, and where Z 1 and Z 2 are hydrogen or a protected group, or its salts, which includes hydrolyzing a compound of the formula

1 2

where R, Z and Z have the same meaning as stated above.

Procedure 2

This is a method for producing compounds with the following formula

12 where Z and Z have the same meanings as stated above, and R' is hydrogen or a hydrocarbon group which may be substituted, or its salts, which include reducing a compound of the formula

12 1

where Z . and Z has the same meaning as above, A is a group which can be converted to -NHR' (wherein R' has the same meaning as above) by reduction, and where X is ^€=0 or

>CH-OH.

Approach

This is a method for preparing compounds with the formula

where Z 1 and Z 2 have the same meaning as stated above, and R" is (where R<1>is hydrogen or lower alkyl and R<2>is hydrogen or a hydrocarbon group which may be substituted, this includes the case where R 1 and R 2 forms a ring group together with the adjacent carbon atom) or their salts, which includes reducing a compound of the formula where Z 1, Z 2 and X have the same meaning as indicated above, and A<2> is a group which can convert to amino by reduction, in the presence of a carbonyl compound of the formula

where R 1 and R 2 have the same meaning as stated above.

Procedure 4

This is a method for preparing compounds with the formula

where R', Z 1 and Z 1 °- have the same meaning as indicated above, or their salts, which include subjecting a compound of the formula

where Rf has the same meaning as stated above, and Z , Z .,

Z-<3> and Z^ are hydrogen or a protected group, provided that at least one of them is a protected group, a reaction leading to the removal of the protecting group(s).

In the above methods, it is understood that all the compounds Ia, Ib and Ic are included in the general formula I.

When it concerns formulas I, I', Ia, Ic, II, III and VI, the hydrocarbon group designated by the symbol R or Rf can be an acyclic or a cyclic hydrocarbon group. The acyclic hydrocarbon group may be saturated or unsaturated or straight or branched, and advantageous examples are lower alkyl groups such as groups with up to six carbon atoms (eg 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, 1,1-dimethylpropyl etc), lower alkenyl then especially those with up to six carbon atoms ( eg ethenyl, propenyl, butenyl, pentenyl, hexenyl etc), lower alkynyl especially with up to six carbon atoms (eg ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc.) and so on. Among the more advantageous groups' are lower alkyl groups with up to four carbon atoms (e.g. methyl, ethyl, i-propyl, t-butyl etc), especially those which branch in their oc-position such as i-propyl, 1- methylpropyl and t-butyl. Such acyclic hydrocarbon groups may optionally be substituted. In this case, the substituent group can e.g. be a cycloalkyl group advantageously with from 3 to 7 atoms in the ring (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc), cycloalkenyl advantageously with from 3 to 7 atoms in the ring (e.g. 2-cyclopentenyl, 3-cyclohexenyl etc), the cycloalkylidene advantageously having from 3 to 6 atoms in the ring (e.g. cyclohexylidene, cyclopentylidene etc.), aryl (e.g. phenyl, naphthyl etc.), a heterocyclic group (e.g. a heterocyclic group with an oxygen atom (e.g. tetrahydrofuryl, tetrahydropyranyl, dihydropyranyl, furyl etc), a heterocyclic group with a nitrogen atom (e.g. piperidinyl, pyridyl, indolyl, quinolyl etc), a heterocyclic group with e.g. a sulfur- atom (e.g. thienyl, tetrahydrothienyl etc.), a heterocyclic group with from two or more of the same or different heteroatoms (e.g. thiazolyl, pyrimidyl, oxazolyl etc.)-, hydroxyl, lower alkoxy with from 1 to 4 carbon atoms (e.g. methoxy, ethoxy, propoxy etc.) aryloxy (e.g. phenoxy, naphthoxy etc.), hal and (e.g. chlorine, fluorine, bromine, iodine etc), esterified hydroxyl, lower alkoxycarbonyl (eg methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl etc), acyl (eg acetyl, propionyl, butyryl, benzoyl etc), amino or substituted amino (where the substituent or substituents may be alkyl, acyl or other groups), nitro, cyano and other groups. The aforementioned cycloalkyl, cycloalkenyl, aryl and heterocyclic groups may also contain suitable substituents such as lower alkyl with from 1 to 4 carbon atoms (e.g. methyl, ethyl, propyl etc), hydroxyl, lower alkoxy with from 1 to 4 carbon atoms (e.g. e.g. methoxy, ethoxy, propoxy etc.), halogen (e.g. chlorine, bromine, iodine, fluorine etc.). Typical examples of such substituted acyclic hydrocarbon groups include cyclohexyl-methyl, 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, a,a-dimethyl-phenethyl-, 4-me.thoxy-a-methylphenethyl, 4-methoxy-a,a-dimethylphenethyl, 4-hydroxy-a -methylphenethyl, 4-chlorophenethyl, J-phenylpropyl, phenethyl, 4-methoxyphenethyl, 2-phenylpropyl, α,4-dimethylphenethyl, l-methyl-2-cyclohexylideneethyl, tetrahydropyran-2-ylmethyl, 2,3-dihydropyran-2 - ylmethyl, tetrahydropyran-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-1-methylpropyl, 6-methoxyhexyl, 1-methyl-2-phenoxy-ethyl, 3-chloro-1-propylbutyl , 2-fluoro-1-methylethyl, 2-ethoxycarbonyl-ethyl, 2-aminoethyl, 3-dimethylaminopropyl,'3-morpholino-1-methylpropyl , 2-piperidino-1-methylethyl, nitromethyl, 2-cyano-1-methylethyl, styryl, 3-phenyl-2-propenyl and so on.

The cyclic hydrocarbon group mentioned above,

as the hydrocarbon group denoted by the symbol R or R', can be exemplified by cycloalkyl with from 3 to 7 atoms in the ring, (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc), cycloalkenyl advantageously with from 3 to 7 atoms in the ring (e.g. cyclopentenyl, cyclohexenyl etc.), aryl (e.g. phenyl, naphthyl etc.) etc. Among the more advantageous are cycloalkyl with from 3 to 7 atoms in the ring. These groups may optionally contain one or more suitable substituents such as lower alkyl, hydroxyl, lower alkoxy, halogen, or other groups mentioned above such as the substituent(s) which may be present on said cycloalkyl, cycloalkenyl, aryl or heterocyclic groups mentioned above in connection with the substituted acyclic hydrocarbon group. Typical examples of the aforementioned cyclic hydrocarbon groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-methylcyclopropyl, 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-hydroxy-phenyl, 3-4-dimethoxyphenyl, etc.

When it comes to the formulas I, I<*>and II, the acyl group denoted by the symbol R can e.g. be acyl groups derived from carboxylic acid, carboxylic acids etc., such as e.g. formyl, acetyl, propionyl, butyryl, 2-methyl-2-butenoyl, monochloroacetyl, dichloroacetyl, trifluoroacetyl, benzoyl, toluyl, mesitoyl, 4-chlorobenzoyl, 3-benzoylpropanoyl, ethoxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, etc.

In the case of formulas Ib and V, the lower alkyl group designated by the symbol R"<*>" can be straight or branched, advantageously with up to six carbon atoms such as methyl, ethyl, n-propyl, i-propyl, n-butyl , i-butyl, t-butyl, secondary-butyl, n-pentyl, i-pentyl, t-pentyl, n-hexyl, i-hexyl, etc. The hydrocarbon group with the symbol R 2 can be exemplified by

the hydrocarbon groups described above for R or R'.

The aforementioned groups R<1>and R 2 can together form a ring which together with the adjacent carbon atom. As examples of the ring, a cycloalkane group advantageously with from 3 to 7 atoms in the ring (e.g. cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, etc.), a cycloalkene group with from 3 to 7 atoms in the ring (e.g. .cyclobutene, cyclopentene, cyclohexene, etc.) etc. Among the more advantageous is a cycloalkane group with from 3 to 7 atoms in the ring.

In the case of the above formulas I, Ia, Ib, Ic, II, III, IV and VI, the protecting group denoted by 7" t Z , Z , Z , ZJ or Z<4>" can be any group which is capable of

to provide the desired protection for hydroxyl or amino. Thus, one can e.g. use lower alkyl advantageously with up to four carbon atoms (eg methyl, ethyl, n-propyl, i-propyl etc), lower alkenyl advantageously with up to four carbon atoms (eg vinyl, allyl etc), lower alkynyl, advantageously with up to four carbon atoms (eg propargyl etc), substituted C-^_^-alkyl (eg methoxymethyl, butoxymethyl etc), aralkyl, advantageously phenyl, C^_^-alkyl (eg benzyl, a -methylbenzyl, diphenylmethyl, trityl etc), a phenacyl group (eg phenacyl, p-bromophenacyl etc), acyl derived from carboxylic acid, sulphonic acid, carboxylic acid or carbamic acid (eg formyl, acetyl, propionyl, butyryl, 2 -methyl-2-butenoyl, monochloroacetyl, dichloroacetyl, triflu^pacetyl, benzoyl, toluyl, mesitoyl, 4-chlorobenzoyl, 3-Denz°ylProPanoyl, xanthene-9-carbonyl, benzenesulfonyl, toluenesulfonyl, methanesulfonyl, trifluoro-

methanesulfonyl, benzyloxycarbonyl, t-butyloxycarbonyl, i-bornyloxycarbonyl, carbamoyl, trichloromethylimidoyl etc), silyl (eg trimethylsilyl etc), an inorganic acid ester residue (eg nitric acid ester residue, sulfuric acid ester residue, boric acid ester residue, dibenzylphosphoryl, p-nitrobenzylphosphoryl, p-bromobenzyl-.phosphoryl etc), pyranyl, tetrahydropyranyl, tetrahydrofuranyl, thiopyranyl, 4_methoxytetrahydropyran-4-yl, etc. When both 7?~ and Z~ are protecting groups, they may be connected, Similarly

1*2'

can the groups Z and Z be connected. Examples of such connecting groups include lower alkylidene, - advantageously with up to six carbon atoms (e.g. methylidene, ethylidene, propylidene, isopropylidene, butylidene, pentylidene, hexylidene etc), substituted C-^ g -alkylidene (e.g. 1-methoxyethylidene, 1-ethoxyethylidene, benzylidene (phenylmethylidene), diphenylmethylidene, phenethylidene, 1-phenylethylidene, acetylisopropylidene, oxomethylidene, iminomethylidene, thioxomethylidene, etc.) etc.

Z^ may be associated with R'. As an example of such a connected group can be stated:

where Z, Z and ZJ have the same meaning as stated above, and R'M is a divalent group at the α-carbon atom in the aforementioned R' group. In this case, it is advantageous for Z and Z to be the protecting group other than lower alkyl. In particular, benzyl is more advantageous.

Z^" can also be connected with Z^ or with Z^ and Rf so that structures of the following type are formed:

1' 2'

where Z , Z , R', R"' have the same meaning as stated above,

and Z^ is hydrogen, lower alkyl of up to six carbon atoms (eg methyl, ethyl, propyl, butyl, pentyl, hexyl etc.), aryl (eg phenyl etc), aralkyl (eg benzyl, f enethyl etc), methyl-thio, methoxy or the like, and these groups may be substituted with one or more groups (eg hydroxyl, lower alkoxy, halogen etc) in one or more positions.

Among the above-mentioned protecting groups, it is advantageous as the group Z 1 * and// or Z 2' to use one that can be removed by the reaction in method 4* As an advantageous group such as Z"*" and/or Z^, one can use hydrogen .

In the case of formula I', the aralkyl group can

with the symbol Z 1" or Z 2" is exemplified by benzyl, diphenyl-

methyl, α-methylbenzyl, p-methoxybenzyl or the like. Among these, benzyl is particularly advantageous.

As regards formula III and the group which can be converted to -NHR' by reduction, and which is represented by the symbol a\, one can mention among others nitro, nitroso, isonitroso (oxyimino), hydroxylamino, imino, acyloxyimino, diazo, azido , phenylhydrazono, =N-R<*> (where R' has the same meaning as stated above) etc.

Among the more advantageous are nitro, nitroso or isonitroso. If one has a starting compound of formula III where A"'" is nitro, nitroso or isonitroso, and uses this in process 2, then the desired compound of formula Ia will be one where R' is hydrogen.

As regards formula IV and the group that can be converted to amino by reduction, and which is represented by A 2, this can be any group that can be converted to amino by reducing methods in method Thus, one can e.g. mention nitro, nitroso, isonitroso (oxyimino), hydroxylamino, imino, acyloxyimino, diazo, azido, phenylhydrazono, etc.

Among the more advantageous are also here nitro, nitroso

or isonitroso.

It will be apparent from the following description that the above-mentioned symbols such as R, R', R , R , Z and Z which are used both in the aforementioned starting compounds and the product compounds in these processes, only mean that each group belongs within the same definition and not necessarily that each specific group remains unchanged after the reaction.

The procedures 1 to 4 will now be described in more detail.

Procedure 1

Method 1 according to the present invention consists in hydrolyzing the compound of formula II, whereby the compound of formula I is selectively produced. This hydrolysis reaction is normally carried out in water, an organic solvent (e.g. methanol, ethanol, chloroform, benzene, tetrahydrofuran, ethyl ether, acetone, dioxane, dichloromethane, etc.) or a mixture of such solvents, and if necessary, in the presence of, a suitable catalyst. As said catalyst, an acid or a base can be used with advantage, especially an acid. As said acid, you can use an inorganic acid (e.g. hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, etc.), an organic acid (e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid, toluenesulfonic acid, etc.) or a Lewis acid (e.g. aluminum chloride, boron trifluoride, zinc chloride, trivalent iron chloride etc). The base can e.g. be an inorganic base (eg sodium hydroxide, potassium hydroxide, potassium carbonate, sodium bicarbonate, sodium sulphite etc) or an organic base (eg triethylamine, pyridine, piperidine, N-methylaniline, triethanolamine etc). Although said hydrolysis reaction takes place satisfactorily at room temperature, it can be increased or delayed by heating or cooling. An advantageous reaction temperature is normally in the range from -4-0°C to 150°C, then especially from 20 to 100°C. The reaction time is not critical, but will advantageously be in the range from approx. 5 minutes to approx. 4-0 hours.

In the present method, when Z 1 , Z 2 or R, for example, is a hydrolysable group, this can be hydrolysed at the same time in the hydrolysis reaction, so that a compound of formula I is obtained where the corresponding group has been hydrolysed. When e.g. Z Tl and/or Z Q in the starting compound with formula II is benzyl, the product compound with formula I can be prepared where Z and/or Z is hydrogen. When e.g. R in the starting compound of formula II is acyl, then this group can be removed so that a single-product compound of formula I with amino is obtained. In cases where R in the starting compound is acyloxyalkyl, a compound of formula I containing hydroxyalkylamino can be prepared. Such a hydrolysis can be carried out step by step.

The output connection with. formula II for this method, can e.g. is produced by the method shown below.

(where R, Z 1 and Z 2 have the same meaning as above, and NBS is N-bromosuccinimide).

Process 1 is characterized by hydrolysing the compound of formula II, whereby the stated compound I is produced where hydroxyl is introduced in the 1-position of the tetralin ring and amino or substituted amino in the 2-position. This reaction is thus a hitherto unknown site-specific reaction, very well suited for the preparation of compounds of formula I where R is a hydrocarbon group which branches in its oc-position.

Procedures 2 and 3

The reduction in method 2 or 3 is usually carried out by a reducing method which can be suitably selected according to the starting materials used, from common reduction methods such as (1) catalytic reduction with platinum, palladium, rhodium, nickel or the like as a catalyst, (2) reduction by means of a metal hydride such as lithium aluminum hydride, lithium borohydride, lithium cyanoborohydride, sodium borohydride, sodium cyanoborohydride and the like, (3) a Meerwein-Ponndorf-Verley reduction by means of aluminum alkoxide, 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 and (8) reduction by with the help of reducing enzymes. Among these, methods 1 and 2 are most advantageous. It goes without saying that apart from

above methods, you can use any method if you only achieve the purpose according to the present invention. Although the advantageous reaction temperatures will vary with the starting materials and the reduction method used, the temperatures will generally fall in the range of -20°C to 100°C. The reaction is usually carried out at atmospheric pressure, but can

if desired, carried out at reduced or elevated pressure. The reduction is usually carried out in the presence of a suitable solvent. The solvent is not critical as long as it is able to dissolve more or less of the starting material and will not adversely affect the reaction, and one can use water, an organic solvent, e.g. an alcohol (eg methanol, ethanol, propanol etc), an ether (eg dimethyl ether, diethyl ether, methyl ethyl ether, tetrahydrofuran, dioxane etc), an ester (eg 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) etc., or a mixture of two or more such solvents.

In the reduction in method 3, it is possible to carry out the reaction by using an excess of the carbonyl compound (V) instead of the solvent.

The reduction in method 2 or 3 can be carried out step by step, e.g. when the starting material has more than two groups that can be reduced, it is possible to prepare the compound Ia or Ib by reducing these groups step by step.

In method 2 or 3 according to the present invention, the starting compounds may include different compounds which respectively give the corresponding desired compounds. Depending on the output connection and the desired connection, a suitable reduction method and conditions can thus be selected based on what is mentioned above.

When using starting compounds of the formulas III, IV and V in methods 2 and 3" and having groups represented by

2 1/2''

if R', R , Z and/or Z are reducible groups, these can in certain cases be simultaneously reduced by the reaction included in methods 2 and 3> whereby the corresponding compounds are obtained

where the aforementioned groups are reduced. Nåo r e.g. Rf or R<2>

in the starting compound is an unsaturated group, then a final compound can be produced where you have the corresponding saturated group, and when Z 1 and/or Z 2 in the starting compound is benzyl,

then a final compound with a hydroxyl group can be produced.

The starting compounds of formulas III and IV used in methods 2 and 3 can be synthesized by methods known per se, e.g. by the following procedurei

12

(where Z and Z have the same meaning as stated earlier).

Procedures 2 and 3 are characterized by this

the number of steps necessary for the preparation of compounds Ia and Ib is reduced, because starting compounds with III or IV are used which have the group that can be converted into -NHR' or amino by reduction, such as A 1 or A 2. Method 3

is further characterized in that it is possible to easily prepare the desired various compounds Ib by using only the corresponding carbonyl compounds (V), and these can be easily prepared.

Procedure 4

The reaction in method 4 is carried out by subjecting the compound of formula VI to a reaction which leads to the removal of the protective group. This reaction can be any as long as it is capable of removing at least one of the protecting groups. Advantageous examples of such reactions include reduction, oxidation, solvolysis (eg, hydrolysis, alcoholysis, etc.), etc. More detailed examples of

these reactions are the following: (1) catalytic reduction with platinum, palladium, rhodium, Raney nickel or the like as a catalyst, (2) reduction using metallic sodium, metallic potassium or the like with liquid ammonia or an alcohol such as tethanol or butanol , (3) reduction using a metal hydride such as lithium aluminum hydride, sodium aluminum hydride, sodium borohydride or the like, (4) reduction using a metal such as zinc, iron or the like with an acid such as an organic acid (e.g. formic acid, acetic acid etc), an inorganic acid (e.g. hydrochloric acid, sulfuric acid etc.) or the like, (5) reaction using a Lewis acid such as aluminum chloride, aluminum bromide, zinc chloride, magnesium iodide, trivalent iron chloride, boron trichloride, boron tribromide or the like, (6) reaction by means of

an inorganic acid such as a hydrohalic acid (e.g. hydrogen fluoride, concentrated hydrobromic acid, hydrogen bromide-acetic acid, hydrogen chloride, hydrogen iodide etc), sulfuric acid, nitric acid, phosphoric acid, perchloric acid, boric acid or the like, or a solution of such an acid in an aqueous solution, an alcoholic solution or the like,

(7) reaction using an organic acid such as trifluoroacetic acid, acetic acid, oxalic acid, paratoluenesulfonic acid, formic acid or the like, or an aqueous solution of such an organic acid, (8) reaction using an inorganic base such as sodium hydroxide, potassium hydroxide, barium hydroxide, potassium carbonate, sodium hydrogen carbonate, aqueous ammonia, hydrazine hydrate or the like, or an organic base such as pyridine hydrochloride, tetramethylammonium hydroxide, collidin lithium iodide or the like, (9) reaction using an oxidizing agent such as concentrated nitric acid, chromic anhydride, potassium permanganate, ozone, benzoyl peroxide or the like , (10) reaction using a chemical compound such as thiourea, mercaptide, lead acetate or the like, (11) reaction using a solvent such as water, methanol, ethanol or the like, (12) physical treatment such as electrolytic reduction, electrolytic oxidation, irradiation with ultraviolet light or the like, (13) enzymatic reaction etc s. The reaction is usually carried out in the presence of a suitable solvent. The solvent is not critical if it is only able to dissolve more or less of the starting material, and will not adversely affect the reaction. One can e.g. use water, an organic solvent, e.g. an alcohol (e.g. methanol, ethanol, propanol etc), an ether (e.g. dimethyl ether, diethyl ether, methyl ethyl ether, tetrahydrofuran, dioxane etc), halogenated hydrocarbon (e.g. chloroform, dichloromethane etc.) etc., or a mixture of two or more such solvents. The advantageous reaction temperature will vary with the reaction method used, but will usually fall in the range from approx. -4-0°C to 150°C. The reaction is usually carried out at atmospheric pressure, but may, if desired, be carried out at reduced or elevated pressure.

The reaction in method 4 can be carried out step by step, e.g. when the starting compound (VI) has more than two protecting groups, it is possible to prepare the compound of formula Ic by removing these protecting groups step by step.

In this method, it will be advantageous for the groups Z 1 and/or Z 2 in the specified compound to be hydrogen.

In cases where a reduction is used (e.g.

1, 2, 3»4>etc.) as the reaction which leads to the removal of the protective group or groups, then one can, as said protective group Z It , Z pt , ZJ q and/or Z+ a in the starting compound with formula VI , advantageously use the aforementioned protecting groups, such as lower alkenyl, lower alkynyl, aralkyl, phenacyl, acyl or the like, benzyl or benzyloxycarbonyl, particularly advantageous is benzyl.

In those cases where a solvolysis is used (e.g. reaction 5>6, 7, 8, 11, etc), then one can advantageously use as the protecting group Z 1' , Z 2' and// or ZJ 3 a lower alkyl group, lower alkenyl, lower alkynyl, substituted lower alkyl, aralkyl, acyl, silyl, an inorganic acid ester residue, tetrahydropyranyl, tetrahydrofuranyl, thiopyranyl or the like; more advantageous is methyl, ethyl, benzyl, acetyl, benzyloxycarbonyl or free-fluoroacetyl. As an advantageous group such as the protecting group Z^, acyl can be used, especially acetyl, benzyloxycarbonyl or trifluoroacetyl.

Among the above-mentioned methods which can be used in method 4, it is particularly advantageous to use method 1, 5>6°S 7» Advantageous reaction temperatures in these methods lie in the range from 0-100°C.

The method can also take place when R' in the starting compound (VI) has substituents that can be changed in the above-mentioned reactions, as these substituents can be modified according to method 4"- When e.g. R' in the starting compound is a reducible group, then the desired compound Ic containing the corresponding reduced group can be prepared by using a reduction as a reaction in method 4>°g when R<*> is a solvolysable group, then one can obtain the desired compound Ic containing the corresponding solvolyzed group by using a solvolysis as reaction in method 4"

The starting compound (VI) for method 4 can e.g. are synthesized by the following methods.

(where R', R"', Z<1*>, Z<2>', Z^, Z^" and Z^ have the same meaning as stated above, Y is halogen and Ts is p-toluenesulfonyl).

In the above-mentioned methods a) and b), the reaction in step A can be chosen appropriately from reactions which are in themselves

Tf Ol or' known according to each of the groups Z or Z , e.g. when Z and

currently w

Z is methyl, then diazomethane can be used as an alkylating agent, and if Z 1 * and Z 2 * are aralkyl or lower alkyl, then a reaction with the corresponding halogenated aralkyl or halogenated alkyl in the presence of alkali can be used, and if Z 1' and Z 2 * are acyl, so the corresponding acid halide or acid anhydride can be used. The reaction in step B can be exemplified by a reduction after acylation, a reductive alkylation with a carbonyl compound, e.g. the carbonyl compound V, a reaction with a compound of the formula Rf-Q (where Q is an active group that can substitute the group R' for hydrogen in amino; such an active group is halogen, lower alkylsulfonyloxy, arylsulfonyloxy, etc.) or the like. The above-mentioned reduction and reductive alkylation can be exemplified by the same reaction as mentioned previously for methods 2 and 3" The reactions in steps C, E and G can be exemplified by the same reaction as in step B, and the reactions in steps D and F can be exemplified by the same reaction as in step A..

Method 4 is characterized in that it is

possible to easily obtain a desired isomer (e.g. trans isomer,

or cis-isomer) of the desired compound of formula Ic using the same starting compound of formula VI a compound of the corresponding isomeric form. Furthermore, method 4 is well suited for the production of compounds (Ic) where both 7?~ and

2 Z is hydrogen.

The specified compounds I, Ia, Ib and Ic produced by methods 1 to 4 according to the present invention can be easily isolated from the respective reaction mixtures by separation and purification techniques which are known in themselves, e.g. by concentration, filtration, recrystallization, column chromatography, etc.

The compounds I, Ia, Ib and Ic can appear in several stereoisomeric forms such as geometric isomeric forms and optical isomeric forms which are due to the presence of asymmetric carbon atoms, and they can therefore be easily obtained as mixtures of such isomeric forms.

If desired, an optical geometric isomer (eg, trans or cis isomer) can be prepared by suitable methods such as (1) stereospecific reaction, (2) reaction using a starting compound of the same configuration as in the desired compound, (3) isolation of an isomer from a mixture of isomers using suitable selective methods, - e.g. such as recrystallization, column chromatography, etc.

Racemic mixtures can, if desired, be dissolved by conventional techniques, e.g. by forming a salt with an optically active acid or base, or alternatively, by physical adsorption on a porous adsorbent 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

i.e. I, Ia, Ib and Ic can also be isolated as salts which include physiologically acceptable salts such as e.g. acid addition salts prepared in the usual way, and such acid addition salts include

an inorganic acid salt (e.g. hydrochloride, hydrobromide, sulfate etc.), an organic acid salt (e.g. maleate, fumarate, tartrate, toluenesulfonate, naphthalenesulfonate, methanesulfonate etc.) etc.

The compounds I, Ia, Ib and Ic according to the present invention and their physiologically acceptable salts are unknown compounds and have pharmacological activities such as activity to stimulate or block β-adrenergic receptors, a cardiovascular dilating activity, analgesic activity, etc.,

for all types of mammals such as e.g. human beings. Particularly noteworthy is the activity to stimulate Pg-adrenergic receptors, such as a bone dilating activity. Because of these useful properties, the compounds I, Ia, Ib and Ic as well as their salts can be very valuable in the therapy and prophylaxis of disorders such as asthma, arrhythmia, angina pectoris, migraine, etc.

For pharmaceutical use, said compounds and their salts can be administered to humans and other mammals, e.g. in mixtures with a pharmaceutically acceptable carrier, and they can be administered orally or in other ways in dosage forms such as powders, granules, tablets, capsules, injections, inhalations, etc.

Pharmaceutical preparations containing one or more of the compounds I, Ia, Ib and Ic or their salts can be prepared in the usual way for the production of powders, granules, tablets, capsules, injection solutions, inhalation gases and the like. The choice of carrier will depend on the desired delivery method, the solubility of the aforementioned compounds, etc.

The exact dose will depend on the disorder and the symptoms to be treated, the method of administration, the type of patient to be treated and other conditions, but advantageous dose levels for therapy in connection with asthma in adult patients lie in the range from 1 to 100 mg daily at orally, from 0.01 to 1 mg per day intravenously or approx. 0.1 to 10 mg per dose topically in such dosage forms as nebulized products (aerosol inhalation gases).

Products according to the present invention can also be used as synthetic intermediates for the production of various medicines.

The compound If which is part of the aforementioned compounds I, Ia, Ib and Ic and its salts are new compounds and are also usable as intermediates, e.g. for the manufacture of

"12

the compound I where both Z and Z are hydrogen, e.g. by method 4"

The following reference examples and examples illustrate the invention. It is of course understood that the invention is not limited to these examples only.

In the following description, g, mg, ml, °C and NMR mean: grams, milligrams, milliliters, degrees Celsius and nuclear magnetic resonance respectively.

Reference example year

a) While cooling with ice, 6.0 g of sodium borohydride was added to a solution of 15 g of 5>6-dimethoxy-3>4-[iihydro-1(2H)-naphthalenone in 200 ml of methanol, and the mixture was stirred for JO minutes. Then 1 liter of water was added and the reaction mixture was extracted with chloroform.

The chloroform extract was washed with water, dried and concentrated under reduced pressure, and the residue was recrystallized from benzene to give 15 g of 1-hydroxy-5>6-dimethoxy-1-,2,3>4-tetrahydronaphthalene as colorless prisms, m.p. 74-76°C.

b) A mixed solution of 15 g of 1-hydroxy-5»6-dimethoxy-1,2,3>4-tetrahydronaphthalene and 0.5 g of potassium bisulphate in

100 ml of benzene was refluxed for 2 hours and the by-product water was azeotropically removed.

The reaction mixture was washed with water, dried and concentrated under reduced pressure. This procedure gave 13 g of 7,8-dimethoxy-1,2-dihydronaphthalene as colorless needles, mp 3<8->39°C.

c) A solution of 13 g of 7>8-dimethoxy-1,2-dihydro-naphthalene in 130 ml of dimethyl sulfoxide was added to 3 g of water and 18 g

N-bromosuccinimide, and the mixture was stirred at 10-15°C for 20 minutes. The reaction mixture was diluted with 1 liter of water and extracted with benzene. The extract was washed with water, dried and concentrated under reduced pressure. The residue was then recrystallized from benzene-petroleum ether, and 11 g of 2-bromo-1-hydroxy-5,6-dimethoxy-1>2,3'4-tetrahydronaphthalene were obtained as colorless prisms, melting point 98-101°C.

d) In a closed tube, 5>0 g of the bromine derivative was prepared as described above in section c) and 50 ml of tert-butyl amine was heated to 110-120°C for 1 l/2 hours. Said tert-butylamine was distilled off, and the residue washed with water and extra-

hardened with benzene. The extract was washed with water, dried and concentrated under reduced pressure. The residue was dissolved in alcoholic hydrochloric acid and after treatment with activated carbon to

ethyl ether was added. The resulting crystals were collected by filtration to give 1.1 g of 1-tert-butylamino-2-hydroxy-5,6-dimethoxy-1,2,3>4-tetrahydronaphthalene hydrochloride as colorless needles, m.p. 209 -210°C. e) In a smaller amount of water, 1.0 g of the above-mentioned amino alcohol prepared as described under section d) was dissolved.

and the solution was made alkaline with sodium bicarbonate and extracted with chloroform. The extract was washed with water and dried. The chloroform was distilled off, and the residue dissolved in 100 ml of anhydrous benzene. After adding 0.9 g of triethylamine sulfate, the solution was heated for 1 hour. 6.0 g of anhydrous potassium carbonate were then added, and the solution was refluxed for 3 hours. After cooling, the reaction mixture was washed with water, dried and concentrated under reduced pressure. The procedure gave 0.4 g of 1,2-tert-butylamino-5,6-dimethoxy-1,2,3>4-tetrahydronaphthalene as a pale yellow oil.

NMR spectrum (CDCl1) <f: 0.95 <9H, s), 3.70 (3H, s), 3.85 (3H, s)

Reference example 2

In the same way as indicated in reference example 1 d) to e), 3 g of 2-bromo-1-hydroxy-5,6-dimethoxy-1,2,3,4-tetrahydronaphthalene was reacted with 11 g of cyclohexylamine, and the product was

then dehydrated to give 1,2-cyclohexylimino-5,6-dimethoxy-1>2,3>4-tetrahydronaphthalene as an oil.

NMR spectrum (CDCl?) (f: 3.8 (3<H>), 5.7 (3H), 1.0-2.2 (m).

Reference example 3

In the same way as in reference example 1 d) to

1 e) 1.5 g of 2-bromo-1-hydroxy-5>6-dimethoxy-1,2,3,4-tetrahydronaphthalene was reacted with 20 ml of isopropylamine and the product was then dehydrated, thereby obtaining 0.15 g of 1 ,2-isopropylimino-5,6-dimethoxy-1,2,3>4-tetrahydronaphthalene as an oil.

NMR spectrum (CDCl1) <$ : 3.<8>(3H), 3.7 (3H), 1.1 (d, 6H).

Reference example 4

a) 60 ml of anhydrous benzene was added to 3 g of 5,6-dimethoxy-3,4-dihydro-1(2H)-naphthalenone and 9 g of aluminum trichloride, after which

the mixture was refluxed for 2 hours. After cooling, 18 ml of 3N hydrochloric acid was gradually added, and the precipitate was collected by filtration. Recrystallization from water gave 2.3 g of 5,6-dihydroxy-3'4-dihydro-1(2H)-naphthalenone. Melting point: 198-199°c.

b) 112 mg of potassium hydroxide powder was suspended in 10 ml of acetone, after which 5 mg of sodium thiosulphate was added and

182 mg of 5,6-dihydroxy-3>4-dihydro-1(2H)-naphthalenone. The mixture was stirred for 5 minutes, after which 0.25 ml of benzyl chloride and 332 mg of potassium iodide were added. The mixture was then refluxed for 3 hours. After cooling, the acetone was distilled off, and the residue diluted with 10 ml of water and extracted with chloroform. The chloroform layer was washed with water, dried and concentrated. Recrystallization from methanol gave 5'6-dibenzyloxy-3,4-dihydro-1(2H)-naphthalenone. Melting point: 104-106°C.

Elementary analysis for ^ z/^ ZcPj

Calculated C 80.42, H 6.19

Found 6 80.10, H 6.23

Reference example 5

In the same way as mentioned in reference examples 1 a) to 1 e), 1,2-tert-butylimino-5,6-dibenzyloxy-1,2,3>4-'tetrahydronaphthalene was produced as an oil from 5>6-dibenzyloxy-3>4-dihydro-1(2H)-naphthalenone.

NMR spectrum (CDCl 2 ) δ : 7.3 (10H), 5.05 (2H), 4.95 (2H),

1.0 (9H).

Reference example 6

a) A colorless powdery sodium methoxide prepared from 313 mg of sodium metal was added dropwise to 12 ml of a solution of 1.1 ml of ethyl formate in anhydrous benzene. The reaction mixture was cooled to 0°C and 9 ml of a solution of 1.4 g of 5'6-dimethoxy-3,4-dihydro-1(2H)-naphthalenone in anhydrous benzene was gradually added in a stream of nitrogen. After standing for 4 hours at 0°C, the mixture was stirred at room temperature for 1 hour. The reaction mixture was added to ice water and then extracted with chloroform. The chloroform layer was washed with water, dried and concentrated. The residue was subjected to chromatography on silica gel and a benzene eluate was recrystallized from cyclohexane, whereby pale yellow crystals of 2-hydroxy-methylene-5,6-dimethoxy-3,4-dihydro-1(2H)-naphthalenone were obtained. Melting point: 83.0-83.5°C. b) In a mixture of 1 ml of dichloromethane, 5 ml of acetic acid and 0.25 ml of water, 84 mg of the hydroxymethylene derivative was dissolved

prepared as described under section a) above, and a solution of 50 mg of sodium nitrite in cold water (0.6 ml) was added dropwise at 1°C. The mixture was stirred at 1°C for 30 minutes and then extracted with dichloromethane. The dichloromethane layer was washed

■with water, dried and concentrated. The residue was recrystallized from ethyl acetate, whereby 2-isonitroso-5,6-dimethoxy-3,4-dihydro-1(2H)-naphthalenone was obtained as light brown needles.

Melting point: 170-182°C (decomposition).

Elementary analysis for ^ 2. 2^ 1^/^

Calculated C 61.27, H 5.57»N 5.96

Found C 61.20, H 5.64, N 5.83

Reference example 7

a) In the same way as indicated in reference example 6 a) and b) 2-isonitroso-5,6-dibenzyloxy-3>4-dihydro-1(2H)-naphthalenone was produced (melting point: 203-208°C from benzene) from 5,6-dibenzyloxy-3 > 4-dihydro-1(2H)-naphthalenone. b) In 10 ml of anhydrous tetrahydrofuran, 150 mg of the isonitroso sodium solution prepared as described above was dissolved, and

while cooling, 70 mg of sodium borohydride was added in small portions. The mixture was stirred for approx. 10 minutes. After addition of water and acetone, the mixture was extracted with dichloromethane.

The dichloromethane layer was dried and concentrated. The residue was recrystallized from benzene, and 2-isonitroso-1-hydroxy-5,6-dibenzyloxy-1,2,3,4-tetrahydronaphthalene was obtained as colorless needles. Melting point: 141-145°C.

Elementary analysis for Cg^H<g>^<O>^<N>

Calculated C 74.05, H 5.95, N 3.60

Found C 73.76, H 5.86, N 3.52

Reference example 8

a) I . 10 g of 5,6-dimethoxy-3>4-<iihydro-1(2H)-naphthalenone were dissolved in 300 ml of chloroform, after which one added

l6 g pyridinium hydrobromide perbromide. The mixture was reacted at 60°C for 5 minutes and, after cooling, poured into 200 ml of ice water. The chloroform layer was washed with water, dried and concentrated. The resulting yellow crystals were recrystallized from chloroform-n-hexane to give 2-bromo-5,6-dimethoxy-'3,4-dihydro-1(2H)-naphthalenone. Melting point: 108.5 - 109°C. b) 2.7 g of the bromine derivative, the preparation of which is described under section a) above, as well as 1.3 g of sodium nitrite and 1.5 g of phloroglucinol were dissolved in 30 ml of dimethylsulfonic acid. The mixture was stirred at room temperature for JO minutes and then completely

into water and extracted with chloroform. The extract was washed with water, dried and concentrated. The residue was recrystallized from aqueous alcohol, whereby 2-nitro-5,6-dimethoxy-3,4-dihydro-1(2H)-naphthalenone was obtained. Melting point: 113-116°C.

Elementary analysis for ^ i2^ 1J^^

Calculated C 57.37. H 5.22, N 5.58

Found C 57.59, H 5.19, N-5.06

Reference example 9

a) A solution of " J , 6 g of 5,6-dibenzyloxy-3>4-dihydro-1(2H)-naphthalenone in 60 ml of dichloromethane, was added 1.7 g

anhydrous calcium carbonate, after which a solution of 3.20 g of bromine in 40 ml of dichloromethane was added dropwise. After stirring at room temperature for 4 hours, water was added to the reaction mixture. The dichloromethane layer was washed with water, dried and evaporated. The residue was subjected to column chromatography on silica gel, and the benzene eluate was recrystallized from vcyclohexane, whereby 2-bromo-5,6-dibenzyloxy-3'4-clihydro-1(2H)-naphthalenone was obtained as colorless crystals, melting point 106-108°C.

b) 875 mg of the bromine derivative prepared as described above were dissolved in 20 ml of tetrahydrofuran, as well as 609 mg

benzylmethylamine, after which the mixture was refluxed for 21 hours under a stream of nitrogen. To the reaction mixture was added 200 ml of benzene, and the entire mixture was washed with 1N hydrochloric acid and water, after which it was dried and concentrated. The residue

was dissolved in a mixture of 10 ml of tetrahydrofuran and 15 ml of ethanol and then reduced with 790 mg of sodium borohydride under ice-cooling. Acetic acid was added to the reaction mixture under ice-cooling and then 50 ml of ethanol was added. The resulting crystals were collected by filtration and extracted with benzene. The benzene solution was washed with water, dried and concentrated. Recrystallization of the residue from chloroform gave 205 mg of 1-hydroxy-2-(N-benzyl-N-methylamino)-5,6-dibenzyloxy-1>2,3>4-'tetrahydronaphthalene (rich in the trajis isomer) as pale yellow flakes which melted at ll6-117°C.

Reference example 10

To a suspension of 2.0 g of 1,5,6-trihydroxy-2-amino-1>2,3,4-tetrahydronaphthalene hydrobromide in 60 ml of acetic anhydride was added 20 ml of pyridine, and the mixture was stirred overnight at room temperature. The reaction mixture was then concentrated under reduced pressure, and after adding 70 ml of water and a few drops of pyridine, it was extracted with chloroform. The extract was washed with water, dried and concentrated. After the residue had dissolved in acetone, ether was added. The resulting precipitate was filtered off and 2.03 g of impure 1,5>6-triacetoxy-2-acetyl-amino-1,2,3»4-tetrahydronaphthalene were obtained. This product was dissolved in 10 ml of acetone and then 100 ml of ether was added. After standing overnight at room temperature, the resulting crystals were filtered off, and 525 mg of cis-1,5,6-triacetoxy-2-acetyl-amino-1,2,3,4-tetrahydronaphthalene were obtained. Melting point: 196-197°C. NMR spectrum (DMSO-dg) 6'-5.95 (d, 1H, J=g, 2 Hz).

50 ml of ether was added to the mother liquor and after cooling the resulting crystals were filtered off and 1.02 g of trans-1,5,6-triacetoxy-2-acetylamino-1,2,3»4-tetrahydronaphthalene was obtained. This compound melts at 140-145°c°g then solidifies again after which it melts again at 183°C.

NMR spectrum (DMSO-dg) S : 5.81 (d, 1H, J=6.2 Hz).

Reference example 11

a) A mixture of 35 mg of 5,6-dibenzyloxy-3,4-dihydro-1(2H)-naphthalenone, 117 mg of potassium carbonate and 3 ml of methanol was added to a solution of 117 mg of hydroxylamine hydrochloride in 0.3 ml of water. The mixture was refluxed for 2 hours and after distilling off the solvent, 50 ml of water and 50 ml of chloroform were added. The organic layer was washed with water, dried and concentrated, whereby 350 mg of 5,6-dibenzyloxy-3,4-dihydro-1(2H)-naphthalenone oxime was obtained. Melting point: 135-137°C

(from methanol).

b) A solution of J& <$ > mg of p-toluenesulfonyl chloride in 2 ml of pyridine was added to a solution of 373 mg of the oxime

prepared as described above in 2 ml of pyridine at temperatures from 2-4°C. The mixture was stirred overnight at 5°c°g then completely poured into ice water, whereby 500 mg of 5,6-dibenzyloxy-3»4-dihydro- 1(2H)-naphthalenone-O-p-toluenesulfonyl oxime. Melting point: 143-145°C (from ethanol).

c) A solution of 8.2 g of O-p-toluenesulfonyl oxime was added dropwise at 4-5°C to a potassium ethoxide solution

prepared from 700 mg of potassium metal and 7 ml of anhydrous ethanol. After addition of 20 ml of anhydrous ethanol, the mixture was stirred overnight at 5-7°C. The reaction mixture was poured into 10 ml of 3N hydrochloric acid while cooling and concentrated to half its original volume, whereby 2-amino-5,6-dibenzyloxy-3,4-dihydro-1(2H)-naphthalenone hydrochloride was precipitated.

Infrared spectrum, (cm"<1>): 283O, 1675, I59O, I5OO,

1295, 1280.

Reference example 12

A mixture of 1.0 g of 2-amino-5,6-dibenzyloxy-3,4-dihydro-1(2H)-naphthalenone hydrochloride and 50 ml of acetic anhydride was held at 90°C for 3 minutes. After the excess of acetic anhydride was evaporated under reduced pressure, 20 ml of ethyl ether and 50 ml of petroleum ether were added to the residue, and the resulting colorless crystals were collected by filtration to give 0.8 g of 2-acetylamino-5,6-dibenzyloxy-3" 4-dihydro-1(2H)-naphthalenone, melting point 181-184°C.

Elementary analysis for ^26^25^4^

Calculated C 75.16, H 6.07, N 3.37

Found C 75.53, H 6.08, N 3.10

F Reference example 13 A solution of 8.3 g of 2-acetylamino-5,6-dibenzyloxy-3,4-dihydro-1(2H)-naphthalenone in 100 ml of chloroform and 20 ml of methanol was added dropwise to 4 g of sodium borohydride with stirring at room temperature. After stirring for an additional hour, ^ >00 ml of water was added to the mixture, and the chloroform layer was separated. The aqueous layer was further extracted with chloroform. The combined chloroform solution was dried and evaporated under reduced pressure. Addition of 50 ml of ethyl ether to the residue gave 8.0 g of trans-2-acetylamino-5,6-dibenzyloxy-1-hydroxy-1,2,3,4-tetrahydronaphthalene as colorless crystals melting at 200-203°C.

Elementary analysis for C2gH2(^0|N

Calculated C 74.80, H 6.52, N 3.36

Found C 74.8l, H 6.57, N 3.08

NMR spectrum (CDClq+DMSO-dg+D2O) δ: 4.47 (1H, d, J=7 Hz)

Reference example 14

A solution of 7 g of lithium aluminum hydride i

To 50 ml of tetrahydrofuran was added a solution of 8 g of trans-2-acetylamino-5,6-dibenzyloxy-1-hydroxy-1,2,3,4-tetrahydronaphthalene in 200 ml of tetrahydrofuran and the mixture was refluxed and stirred for two hours. The mixture was cooled with ice and 300 ml of ether and then water were added dropwise to precipitate a hydroxide complex which was filtered off and washed with 300 ml of chloroform. The filtrate and washing solution were combined. The organic layer was separated, dried and evaporated. The residue was added to 100 ml of ether. After standing, the resulting crystals were filtered off, and 5.4 g of trans-5,6-dibenzyloxy-2-ethylamino-1-hydroxy-1,2,3,4-tetrahydronaphthalene were obtained as colorless crystals melting at 145-147° c<

Elemental analysis for CggH<p>^<O>^<N>

Calculated C 77.39, H 7.24,. N 3.47

Found C 77.03, H 7.20, N 3.47

NMR spectrum (CDCl 1 ) 4.34 (1H, d, J=8 Hz).

Reference example 15

A mixture of 100 ml of tetrahydrofuran and 1.5 g of lithium aluminum hydride was added to 0.8 g of cis-2-acetylamino-1-acetoxy-5,6-dibenzyloxy-1,2,3,4-tetrahydronaphthalene and the whole mixture was refluxed for 3 1/2 hours. After cooling, 200 ml of ether and an excess of water were added, and the organic layer was separated. After drying, the layer was evaporated, and the residue was crystallized from ether to give 0.35 g of cis-5,6-dibenzyloxy-2-ethylamino-1-hydroxy-1,2,3,4-tetrahydronaphthalene as a colorless powder, m.p. 115-117°C NMR spectrum (CDCIl+D 2 O) <f : 4.54 (1H, d, J=4 Hz)

This compound was converted into a fumarate by the usual method, and colorless crystals melted at 1°/2-

. 195°C (decomposition).

Elemental analysis<see>CggH^O^N • l/2 C^H^O^

Calculated C 72.86, H 6.77, N 3.04

Found C 73.05, H 6.70, N 2.93

Reference example 16

In a mixture of 10 ml of anhydrous methanol and 5 ml of cyclopentanone, 377 mg of 1-hydroxy-2-amino-5,6-dibenzyloxy-1,2,3,4-tetrahydronaphthalene-p-toluenesulfonate were dissolved and under cooling at L0° C, 400 mg of a lithium cyanoborohydride-dioxane complex was added in small portions. The mixture was stirred at 0°C for 2 hours and then stirred overnight at room temperature. The methanol was distilled off from the reaction mixture, and water and ethyl acetate were added to the residue. The organic layer was washed with water, dried and evaporated under reduced pressure. The residue was dissolved in ether, and an ether solution of 77 mg of oxalic anhydride was added. The resulting colorless precipitate was collected by filtration and recrystallized from 95% ethanol to give 1-hydroxy-2-cyclopentylamino-5,6-dibenzyloxy-1,2,3,4-tetrahydronaphthalene oxalate. Melting point: 198-202°C (decomposition)

Elemental analysis for Cg^H^NO^ •CgHgO^

Calculated C 69.78, H 6.6l, N 2.62

Found C 69.73, H 6.56, N 2.63

Reference example 17

A suspension of 2.1 g of 2-amino-5,6-dibenzyloxy-1-hydroxy-1,2,3,4T"tetrahydronaphthalene-p-toluenesulfonate in 30 ml of methanol and 35 ml of acetone was added portionwise to 2 g of lithium cyanoborohydride at 0-2°C in a stream of nitrogen.The mixture was stirred at 0-2°C for 2 hours and then at room temperature overnight.

After addition of 3 ml of water, the mixture was evaporated under reduced pressure and the residue was extracted with ethyl acetate. The extract was washed with 1N sodium hydroxide and 20% sodium chloride and then dried. After adding 0.3 ml of acetic acid to the extract, the solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol-ether, whereby 870 mg of cis-5,6-dibenzyloxy-1-hydroxy-2-isopropylamino- 1,2,3,4-tetrahydronaphthalene acetate as colorless crystals, melting point 111-112°C (decomposition).

Elemental analysis for C2^<Hq>l0qN • CH^COOH CgH^OH

Calculated C 71.10, H 7.89, N 2.67

Found C 70.77, H 7.71, N 2.68

NMR spectrum (CDCl 2 + NaOD) 6 : 4.48 (1H, d, J=4.2 Hz)

The mother liquor from the recrystallization from ethanol-ether was evaporated, and after neutralization with 1N sodium hydroxide, the residue was extracted with chloroform.

The extract was washed with water, dried and evaporated. Recrystallization of the residue from n-hexane gives /\. 60 mg of trans-5,6-dibenzyloxy-1-hydroxy-2-isopropylamino-1,2,3,4ttetrahydronaphthalene as colorless crystals, melting point 94-99°c.

NMR spectrum (CDCl1) 6 : 4.29 (1H, d, J=7.8 Hz)

Reference example 18

A solution of 838 mg of trans-2-amino-5,6-dibenzyloxy-1-hydroxy-1,2,3,4-tetrahydronaphthalene and 1 g of cyclobutanone in JO ml of methanol was added portionwise to 2 g of a lithium cyanoborohydride-dioxane complex, and the mixture was stirred at 6-7°C

for 5 "h. After adding 3 ml of water, the solvent was evaporated and the residue extracted with ethyl acetate. To the extract which was washed with water and dried was added a solution of 89 mg of fumaric acid in 2 ml of ethanol. Recrystallization of the resulting precipitate from ethanol gave 4^0 mg of trans-5,6-dibenzyloxy-2-cyclobutylamino-1-hydroxy-1,2,3,4-tetrahydronaphthalene fumarate as colorless chalk figures, melting point 174-175°C (decomposition).

Elemental analysis for C2gHql0qN • l/2 C^H^O^

Calculated C 73.90, H 6.82, N 2.87

Found C 73.49, H 6.68, N 2.91

NMR spectrum (DMSO-dg) <f : 4.41 (1H, d, J=8.4 Hz)

Reference example 19

A solution of 1 g of cis-2-amino-5,6-dibenzyloxy*1-hydroxy-1,2,3,4-tetrahydronaphthalene-p-toluenesulfonate and 1 g of cyclobutanone in JO ml of methanol was added to 1.5 g of lithium cyanoborohydride- dioxane complex, and the mixture was reacted and worked up in the same manner as indicated in reference example 18, whereby 0.58 g of cis-5,6-dibenzyloxy-2-cyclobutylamino-1-hydroxy-1,2,3,4- tetrahydronaphthalene fumarate as colorless powder, melting point 86-88°C.

Elemental analysis for C2gHql0qN l/2 C^H^O^l/2 C2H^0H

Calculated C 72.92, H 7.11, N 2.74

Found C 72.84, H 7.14, N 2.80

NMR spectrum (DMSO-dg) Å : 4.62 (1H, d, J=2 Hz)

Reference example 20

1.2 g of 2-amino-5,6-dibenzyloxy-1-hydroxy-1,2,3,4-tetrahydronaphthalene-p-toluenesulfonate was reacted with 1.7 g of 3-indolylacetone in the same manner as indicated in reference Example 16, and the product was purified as a salt of fumaric acid to give 0.7 g of 5,6-dibenzyloxy-1-hydroxy-2-(2-(3-indolyl)-1-methylethylamino-1, 2,3,4-tetrahydronaphthalene hydrogen fumarate as colorless powder, melting point 114-118°C.

Elemental analysis for Cq^H^<gO>^<N2>•<C>^<H>^<O>^

Calculated C 72.20, H 6.22, N 4.32

Found C 72.40, H 6.04, • N 4.07

Example 1

A solution of 0.4 g of 1,2-tert-butylamino-5,6-dimethoxy-1,2,3,4-tetrahydronaphthalene in 20 ml of dioxane was added with 5 ml of 1N sulfuric acid, and the mixture was stirred at room temperature for 10 hours. The reaction mixture was diluted with water, made alkaline with 20% sodium hydroxide and extracted with benzene. The extract was washed with water and dried. The benzene was then distilled off under reduced pressure. To the residue was added an ether solution of fumaric acid, and the resulting fumarate was recrystallized from methanol-ethyl ether. The process yields 0.2 g of 2-tert-butylamino-1-hydroxy-5,6-dimethoxy-1,2,3,4-tetrahydro-naphthalene fumarate as colorless needles, melting point 218-220°C.

Elemental analysis for C1gH2^0qN * l/2 C/j1^0,^

Calculated C 64.07, H 8.06, N 4.15

Found C 64.30, H 8.15, N 3.90

Example 2

0.25 g of 1,2-cyclohexylimino-5,6-dimethoxy-1,2,3>4-tetrahydronaphthalene was dissolved in 5 nil dioxane and after the addition of 2 ml of a 5% aqueous solution of sulfuric acid, the mixture was placed in 1 hour. It was then neutralized with aqueous sodium bicarbonate and extracted with chloroform. The extract was dried and distilled under reduced pressure. The residue was dissolved in a small amount of ethanol, and an ether solution of fumaric acid was added. The resulting crystals were recovered by filtration. The procedure yields 0.1 g of 2-cyclohexyl-amino-1-hydroxy-5>6-dimethoxy-1,2,3'' 4-tetrahydronaphthalene fumarate.

Melting point: 2O3-206°C.

Elemental analysis for C^ U^ O^ N • C^H^O^

Calculated C 62.69, H 7.41, N 3.32

Found C 62.63, H 7»35>N 3»2<8>

Examples 3-5

By hydrolysis of the corresponding 1,2-substituted imino-5,6-dimethoxy-1,2,3>4~tetrahydronaphthalenes in the same manner as stated in example 1, the compounds stated in table 1 were produced.

Example 6

While cooling at -70 to -75°C, a solution of 1.5 g of boron tribromide in 10 ml of dichloromethane was added dropwise to a solution of 1 g of 5,6-dibenzyloxy-1,2-isopropylimino-1>2,3> 4-tetrahydronaphthalene in 50 ml of dichloromethane. The reaction mixture was stirred for 3 hours and then concentrated under reduced pressure.

The residue was diluted with 5 ml of water and stirred

at room temperature for 2 hours. The reaction mixture was treated with activated carbon and concentrated at 4-0°C. The residue was dissolved in a small amount of ethanol and then ether was added. The resulting crystals were recovered by filtration. This procedure gave 472 mg of 1,5,6-trihydroxy-2-isopropylamino-1,2,3>4-tetrahydronaphthalene hydrobromide, melting point 167-169°C (decomposition).

Examples 7 to 16

Hydrolysis of the corresponding 5,6-dibenzyloxy-1,2-substituted imino-1,2,3,4-tetrahydronaphthalenes in the same manner as indicated in Example 6 gives the compounds indicated in Table 2.

Example 17

A solution of 1 g of 5,6-dibenzyloxy-1,2-cyclopentylimino-1,2,3"4-tetrahydronaphthalene in 50 ml of dioxane was added with 3 ml of 1N acetic acid, and the mixture was kept at 100°C for about 2 hours. After cooling, the reaction mixture was made alkaline with sodium bicarbonate and then extracted with ethyl acetate. The extract was washed with water, dried and concentrated under reduced pressure. The resulting oil was dissolved in ethyl ether,

and an ether solution of oxalic acid was added. The resulting crystals were recovered by filtration and recrystallized from 95% ethanol. This procedure gives 4^3 mg of 5,6-dibenzyloxy-2-cyclophetylamino-1-hydroxy-1,2,3>4-tetrahydronaphthalene oxalate. Melting point: 198-202°C (decomposition).

Elemental analysis for C2gH^^N0^ •CgHgO^

Calculated C 69.78, H 6.6l, N 2.62

Found C 69.82, H 6.65, - N 2.46

Example 18

A solution of 1 g of 5,6-dibenzyloxy-1,2-isopropyl-imino-1,2,3,4-tetrahydronaphthalene in 5 ml of ethanol was added with 5% palladium on carbon, and a catalytic reduction was carried out by ordinary temperature and pressure until 2 mole equivalents of hydrogen had been absorbed. The resulting solution of 5,6-dihydroxy-1,2-isopropylimino-1,2,3,4-tetrahydronaphthalene was filtered off,

and the filtrate concentrated under reduced pressure. 20 ml of dioxane and 3 ml of 1N hydrochloric acid were added to the residue, after which the mixture was stirred at room temperature for 10 hours. The reaction mixture was neutralized with an aqueous solution of sodium bicarbonate and then extracted with n-butanol. A small amount of hydrobromic acid was added to the butanol layer, and the mixture was concentrated under reduced pressure and then ethyl ether was added. This procedure yields 53 mg of 1,5,6-trihydroxy-2-isopropylamino-1,2,3,4-tetrahydro-naphthalene hydrobromide. The product showed no reduced melting point when mixed with the compound prepared as indicated in Example 6.

Example 19

In the same way as described in example 18, 1,5,6-trihydroxy-2-(2-methoxyethylamino)-1,2,3,4-tetrahydronaphthalene hydrobromide was prepared from 5,6-dibenzyloxy-1,2- (2-methoxy-ethylimino)-1,2,3,4-tetrahydronaphthalene via 5,6-dihydroxy-1,2-

(2-Methoxyethylimino)-1,2,3>4-tetrahydronaphthalene. Melting point:

156-159°C (decomposition).

Example 20

In the same way as described in example 18, 1,5,6-trihydroxy-2-(α-methyl-p-methoxyphenethyl-amino)-1,2,3,4-tetrahydronaphthalene fumarate was produced from 5,6-dibenzyloxy-1 ,2-(cc-methyl-p-methoxyphenethylimino)-1,2,3,4-tetrahydronaphthalene via 5,6-dihydroxy-1,2-(α-methyl-p-methoxyphenethylimino)-1,2,3 »4-tetrahydronaphthalene. Melting point: 150-153°C (decomposition).

Example 21

By the method described in example 18, 5>6-dibenzyloxy-1,2-(3,4-dihydro-2H-pyran-2-yl)methyl-imino-1,2,3,4-tetrahydronaphthalene was reduced until 3 mole equivalents of hydrogen had been absorbed, and then the product was hydrolysed so that 1,5,6-trihydroxy-2-(tetrahydro-pyran-2-yl)-methylamino-1,2,3,4-tetrahydronaphthalene hydrobromide was obtained. Melting point: 155.-158°C (decomposition).

Example 22

Using the same method as described in example 21, 1,5,6Ttrihydroxy-2-n-propylamino-1,2,3,4-tetrahydronaphthalene hydrobromide was produced from 5,6-dibenzyloxy-1,2-allyl-imino-1,2 ,3,4-tetrahydronaphthalene. Melting point: l67-l68°C (decomposition).

Example 2S

A solution of 1.0 g of 5,6-diacetoxy-1,2-isopropyl-pylimino-1,2,3,4-tetrahydronaphthalene in 20 ml of dioxane was added with 3 ml of 1N sulfuric acid, after which the mixture was stirred at room temperature for 10 hours . The reaction mixture was neutralized with an aqueous solution of sodium bicarbonate and then extracted with n-butanol. A small amount of hydrobromic acid was added to the butanol layer and the mixture concentrated under reduced pressure. Ethyl ether was added to the residue, and 98 mg of 1,5,6-trihydroxy-2-isopropylamino-1,2,3,4-tetrahydronaphthalene hydrobromide were precipitated. This product showed no lowering of the melting point when mixed with the compound prepared as described in Example 6.

Example 24

By a method similar to that described in example 23, 95 mg of 1>5,6-trihydroxy-2-isopropylamino-1,2,3,4-tetrahydronaphthalene hydrobromide was produced from 1 g of 1,2-isopropylimino-5,6 -dimethoxymethyl-1,2,3 > 4-tetrahydronaphthalene.

Example 25

0.5 g of 5>6-dibenzyloxy-1,2-tert-butylimino-1,2,3,4-tetrahydronaphthalene was dissolved in 20 ml of dioxane, after which 5 ml of 5% sulfuric acid was added. The mixture was left at room temperature for 5 hours, and was then neutralized with an aqueous solution of sodium bicarbonate and extracted with chloroform. The extract was dried and concentrated under reduced pressure. The residue was dissolved in a small amount of ethanol, after which an ether solution of fumaric acid was added dropwise. This procedure gives 0.2 g of 5'6-dibenzyloxy-2-tert-butylamino-1-hydroxy-1,2,3,4-tetrahydronaphthalene fumarate. Melting point: ll8-121°C.

Elemental analysis for C2gH^^0^N • C^H^O^

Calculated C 70.18, H 6.8l, N 2.56

Found . C 70.38, H 6.83, N 2.45

Example 26

150 mg of 1,2-isopropylimino-5,6-dimethoxy-1,2,3,4-tetrahydronaphthalene was dissolved in 1 ml of acetone, after which 1 ml of aqueous sulfuric acid solution was added. The mixture was then left at room temperature for 5 minutes, then neutralized by adding aqueous sodium bicarbonate solution and then extracted with chloroform. The extract was dried and distilled under reduced pressure. The residue was then dissolved in a small amount of ethanol and, after addition of alcoholic hydrochloric acid, ethyl ether was added dropwise. This procedure yields 100 mg of 1-hydroxy-2-isopropylamino-5,6-dimethoxy-1,2,3,4-tetrahydro-naphthalene hydrochloride. Melting point: 198-200°C.

Elemental analysis for C-^Hg^O^N * HC1

Calculated C 59.69, H 8.02, N 4.64

Found C 59.65, H 7.95, N 4.66

Example 27

In the same way as described in example 18 was

1 g of 5,6-dibenzyloxy-1,2-tert.-butylimino-1,2,3,4-tetrahydro-naphthalene was subjected to catalytic reduction and hydrolysis, whereby 0.2 g of 2-tert.-butylamino- 1,5,6-trihydroxy-1,2,3»4-tetrahydronaphthalene fumarate via 1,2-tert-butylimino-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalene.

Melting point: 149-151°C.

Elemental analysis for C]_/j_H2i0^N'C^H/jO^

Calculated C 58.8£, H 6.86, N 3.8l

Found C 58.71, H 6.53, N 3.38

Example 28

By the same procedure as described in example 25, 5,6-dibenzyloxy-1,2-cyclobutylimino-1,2,3,4-tetrahydro-naphthalene was subjected to hydrolysis, and 5,6-dibenzyloxy-2-cyclobutylamino- 1-hydroxy-1,2,3,4-tetrahydro-naphthalene fumarate. Melting point: l60-l65°C.

Elemental analysis for C^gH^O^N * l/2c^h/j_0/j_

Calculated C 73.90, H 6.82, N 2.87

Found C 73.76, H 6.91, N 2.62

Example 29

A mixture of 3-8 g of 7-8-dibenzyloxy-1,2-dihydro-naphthalene, 80 ml of dimethoxyethane, 10 g of sodium azide and 20 ml of water was cooled with ice and sodium chloride. With vigorous stirring, 4.9 S N -bromosuccinimide was added to the mixture over 10 minutes. After stirring for a further 10 minutes, the reaction mixture was poured into an excess of water and then extracted with 200 ml of ethyl ether. To the dried extract was added a solution of 20 g of lithium aluminum hydride in 100 ml of ethyl ether. The mixture was stirred under reflux for 2 L/2 hours and water was added to the cooled reaction mixture to decompose excess reagent. The ether layer was separated, dried and evaporated to give 5,6-dibenzyloxy-1,2-imino-1,2,3,4-tetrahydronaphthalene as a syrup.

This compound was dissolved in 100 ml of dioxane and left overnight at room temperature after adding 100 ml of 5% sulfuric acid and then poured into water. The mixture was neutralized with sodium bicarbonate and extracted with chloroform. The extract was dried and evaporated. Methanol and an excess of oxalic acid were added to the residue, whereby a homogeneous solution was obtained, which was then added to ethyl ether to precipitate crystals. Recrystallization of the crystals from methanol gave 1.0 g of cis-2-amino-5,6-dibenzyloxy-1-hydroxy-1,2,3,4-tetrahydronaphthalene oxalate as colorless crystals with a melting point of 185-

195°C (decomposition).

Elemental analysis for C^H^C^N * l/2 CgHgO^• l/2 H20

Calculated C 69.91, H 6.34, N 3.26

Found C 69.41, H 5.96, N 3.14 1 g of this compound was dissolved in methanol by heating, and then the solution was neutralized with aqueous sodium bicarbonate and extracted with chloroform and dried. The extract was evaporated, and the residue added to ethyl ether to crystallize the free base of the above compound as colorless crystals, melting point 126-129°C (decomposition).

Elemental analysis for C^<H>^<O>^<N>

Calculated 076.77, H 6.71, N 3»73

Found C 76.94, H 6.67, N 3.46

NMR (DMS0-dg+D2O) <£: 4.62 (1H, d, J=3 Hz)

Example 30

3.5 S 1-cyclopropylamino-5,6-dibenzyloxy-2-hydroxy-1,2,3,4-tetrahydronaphthalene fumarate which was prepared from 6.9 g of 2-bromo-1-hydroxy-5,6-dibenzyloxy-1 ,2,3,4-tetrahydronaphthalene and 17 g of cyclopropylamine according to the method described in reference example 1 d), are reacted using the method described in reference example 1 e) and a total of 1 was obtained, 65 g of 1,2-cyclopropylimino-5,6-dibenzyloxy-1,2,3,4-tetrahydronaphthalene as an oil..

This compound was dissolved in 100 ml of dioxane, and 4 ml of water and 9 ml of acetic acid were added to the solution. The mixture was kept at 50-60°C for 3 hours, diluted with an excess of water and extracted with chloroform. The extract was dried and evaporated under reduced pressure. The oily material produced was chromatographed on silica gel, and the purified compound dissolved in methanol. After 0.3 g of oxalic acid had been dissolved in the solution, this was diluted with ethyl ether and 0.45 g of 2-cyclopropylamino-5,6-dibenzyloxy-1-hydroxy-1,2,3,4-tetrahydronaphthalene hydrogen oxalate was precipitated as colorless powder, melting point 193-195°C.

Elemental analysis for C^H^O^N • C2H20^

Calculated C 68.91, H 6.18,' N 2.77

Found C 68.72, H 5.90, N 2.57

Example 31

In a mixture of 20 ml of anhydrous ethanol, 20 ml of anhydrous acetone, 48 mg of triethylamine and 54 mg of 5% palladium on carbon, 100 mg of 2-isonitroso-5,6-dimethoxy-3»4-cl.ihydro-1(2H) -naphthalenone catalytically reduced at ordinary temperature and pressure until no more hydrogen gas was absorbed. The reaction mixture was filtered and, after addition of 3% HCl

to the filtrate, the solvent was removed by distillation. The residue was chromatographed on a column of XAD-2 and eluted with water. The eluate was recrystallized from ethanol-ethyl ether. This procedure gives 1-hydroxy-2-isopropylamine-5,6-dimethoxy-1,2,3,4-tetrahydronaphthalene hydrochloride as colorless crystals. Melting point: 190-192°C (decomposition).

Example 32

In the same manner as stated in Example J1, 50 mg of 2-isonitroso-5,6-dibenzyloxy-3>4-dihydro-1(2H)-naphthalenone was catalytically reduced. The reaction mixture was filtered, and a small amount of hydrogen bromide added to the filtrate. The solvent was distilled off, and the residue dissolved in ethanol, after which ethyl ether was added. The process gives 2-amino-1,5,6-tri-hydroxy-1,2,3»4-tetrahydronaphthalene hydrobromide.

Melting point: 192-200°C (decomposition).

Example 33

In a mixture of 5 ml of anhydrous acetone, 3 ml of anhydrous tetrahydrofuran, 2 ml of anhydrous methanol and 0.1 ml of triethylamine, 20 mg of 2-isonitroso-5,6-dibenzyloxy-3'4-dihydro-1(2H)-naphthalenone was catalytically reduced in the presence of 5% palladium on carbon as catalyst. The reaction mixture was filtered, and dilute hydrobromic acid added to the filtrate. The solvent was distilled off at low temperature and the remaining aqueous solution was lyophilized. The residue was recrystallized from ethanol-ethyl ether, and 1,5,6-trihydroxy-2-isopropylamino-1,2,3'' 4-tetrahydronaphthalene hydrobromide was obtained. Melting point: l67-l68°C (decomposition).

Example 34

Using the same procedure as described in example 33, 20 mg of 2-isonitroso-5,6-dibenzyloxy-3,4-dihydro-1(2H)-naphthalenone and 200 mg of 3-phenylpropionaldehyde were catalytically reduced in a mixture of 3 ml of anhydrous tetrahydrofuran , 2 ml of anhydrous methanol and 0.1 ml of triethylamine. The reaction mixture was filtered, and dilute hydrobromic acid was added to the filtrate. After washing with ethyl ether, the aqueous layer was lyophilized. The residue was dissolved in ethanol, after which ethyl ether was added. The process yields crystals of 1,5>6-trihydroxy-2-(3-phenylpropylamino)-1,2,3,4-tetrahydronaphthalene hydrobromide.

Melting point: 13o-138°C (decomposition).

Examples 35 to 48

In the same way as described in example 34, 2-isonitroso-5,6-dibenzyloxy-3,4-dlhydro-1(2H)-naphthalenone was treated with each of the carbonyl compounds indicated in the second column of table 3, thereby obtaining prepared the compounds, which are indicated in the third column of the same table.

Example 49

10 ml of anhydrous tetrahydrofuran was added to 50 mg of lithium aluminum hydride and, while cooling, 50 mg of 1-hydroxy-2-isonitroso-5,6-dibenzyloxy-1,2,3>4-tetrahydronaphthalene was added in small portions. The reaction mixture was refluxed for 4 hours and after cooling it was diluted with water and extracted with ethyl acetate. The organic layer was extracted with dilute hydrochloric acid, after which the aqueous layer was made alkaline with dilute sodium hydroxide and again extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried and concentrated. The residue was dissolved in a small amount of ethyl acetate-ethyl ether and then an ether solution of p-toluenesulfonic acid was added. The resulting precipitate was collected by filtration and recrystallized from ethanol-ethyl ether. This process yields 1-hydroxy-2-amino-5,6-dibenzyloxy-1,2,3'' 4-tetrahydro-naphthalene-p-toluenesulfonate. Melting point: l86-l89°C.

Elemental analysis for C2^H2^0^N • C^HgO^S

Calculated C 67.99, H 6.07, N 2.56

Found C 67.74, H 6.2.0, N 2.37

Example 50

1.08 g of 2-isonitroso-3,4-dihydro-5,6-dibenzyloxy-1(2H)-naphthalenone were dissolved in 50 ml of anhydrous tetrahydrofuran and, while cooling, 553 g of lithium aluminum hydride were added in small portions. The reaction mixture was refluxed for 5 hours and then treated as described in Example 49* The procedure gives 1-hydroxy-2-amino-5,6-dibenzyloxy-1,2,3,4-tetrahydronaphthalene-p-toluenesulfonate.

Example 51

In a mixture of 10 ml of anhydrous acetone and 5 ml of anhydrous methanol, 20 mg of 1-hydroxy-2-isonitroso-5,6-dibenzyloxy-1,2,3,4-tetrahydronaphthalene was catalytically reduced at ordinary temperature and pressure using 23 mg 5% palladium on carbon as catalyst. The catalyst was filtered off, and dilute hydrobromic acid added to the filtrate. The methanol and acetone were then distilled off at a low temperature. The residue was. lyophilized and recrystallized from ethanol-ethyl ether. This process gives 1,5,6,-trihydroxy-2-isopropylamino-1,2,3,4-tetrahydronaphthalene hydrobromide. The product was identical to the product produced as described in example 33*

Example 52 The procedure from example 51 was repeated except that cyclobutanone was used instead of acetone, whereby 2-cyclobutylamino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide was produced. Melting point: l°/5-200oC (decomposition).

Example 53

In 6 ml of anhydrous tetrahydrofuran, 164 mg of 1-hydroxy-2-isonitroso-5,6-dibenzyloxy-H*2,3,4-tetrahydronaphthalene was catalytically reduced using 5 f° of palladium on carbon as catalyst. The catalyst was filtered off and after adding diluting hydrobromic acid, the tetrahydrofuran was distilled off at low temperature. The residue was lyophilized and then dissolved in ethanol, after which ethyl ether was added. This procedure gave 1,5,6-trihydroxy-2-amino-1,2,3,4-tetrahydronaphthalene hydrobromide. The product was identical to the product from example 32«

Example 54

In 100 ml of acetic acid, 2.5 g of 2-nitro-5,6-dimethoxy-3,4-dihydro-1(2H)-naphthalenone were dissolved and catalytic reduction was carried out using 10% palladium on carbon as catalyst. The reaction mixture was filtered, and the solvent distilled off under reduced pressure. The residue was neutralized with a saturated aqueous solution of sodium bicarbonate and then extracted with chloroform. The chloroform layer was dried and concentrated under reduced pressure. The residue was recrystallized from ethyl ether and 2-amino-1-hydroxy-5,6sLimethoxy-1,2,3,4-tetrahydronaphthalene was obtained, melting point 122-124°C.

Elemental analysis for C-^H<->^<O>^<N>

Calculated C 64.55, H 7.68, N 6.27

Found C 64.21, H 7.98, N 5.78

Example 55

2.5 g of 2-nitro-5,6-dimethoxy-3,4-dihydro-1(2H)-naphthalenone was treated as described in Example 54, except that the reaction was carried out in the presence of 10 g of benzaldehyde. The reaction mixture was filtered, and a small amount of 1N hydrochloric acid was added to the filtrate. The solvent was distilled off under reduced pressure, and a small amount of water added

set the residue which was then extracted with ethyl ether. The aqueous layer was made alkaline with 1N aqueous sodium hydroxide and then extracted with chloroform. The chloroform layer was dried and concentrated. The residue was then recrystallized from ethyl ether, and crystals of 2-benzylamino-5,6-dimethoxy-1-hydroxy-1,2,3,4-tetrahydronaphthalene were obtained. Melting point: 132-135°C (decomposition).

Elemental analysis for C-^H^O^N

Calculated C 72.82, H 7.40 N 4.47

Found C 72.56, H 7.32 N 4.28

Example 56

2.2 g of 2-nitro-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone were dissolved in 400 ml of anhydrous ethanol and after the addition of 25 g of p-hydroxyphenylacetone and 1 g of triethylamine, a catalytic reduction at normal temperature and pressure using palladium on carbon as a catalyst. The catalyst was filtered off, and 1.1 g of fumaric acid added to the filtrate. The solvent was distilled off under reduced pressure, and the residue diluted with water and washed with ethyl ether. The aqueous layer was neutralized with an aqueous solution of sodium bicarbonate and then extracted with chloroform. After adding 1.1 g of fumaric acid, the extract was concentrated under reduced pressure. The residue was dissolved in ethanol and then ethyl acetate was added. The process yields 1,5,6-trihydroxy-2-(a-methyl-p-hydroxy-phenethyl-amino)-1,2,3,4-tetrahydronaphthalene fumarate.

Melting point: 136-141°C (decomposition).

Example 57

251 mg of 1-hydroxy-2-ethylamino-5,6-dimethoxy-1,2,3,4-tetrahydronaphthalene were dissolved in 50 ml of dichloromethane. A solution of 750 mg of boron tribromide in 10 ml of dichloromethane was then added dropwise to the solution. After stirring for several hours,

the reaction mixture was warmed to room temperature and concentrated under reduced pressure. The residue was added to ethanol and after heating for 10 minutes it was treated with activated carbon. Addition of ethyl ether to the mixture gives 1,5,6Ttrihydroxy-2-ethylamino-1,2,3,4-tetrahydronaphthalene hydrobromide, mp 170-171°C (decomposition).

Example 58

1.0 g of 1-hydroxy-2-amino-5,6-dibenzyloxy-1,2,3,4-tetrahydronaphthalene-p-toluenesulfonate was dissolved in 100 ml of water and by using 5 f° of palladium on carbon one carried out a catalytic reduction with ordinary temperature and pressure. After a stoichiometric amount of hydrogen had been absorbed, the reaction mixture was filtered to remove the catalyst, after which a small amount of hydrobromic acid was added to the filtrate and then concentrated under reduced pressure. The residue was dissolved in a small amount of water after which the mixture was washed with ethyl ether. The aqueous layer was neutralized with an aqueous solution of sodium bicarbonate and then extracted with chloroform. The extract was dried and after addition of a small amount of hydrobromic acid it was concentrated under reduced pressure. Recrystallization of the residue from water-methanol-ethyl ether gave 1,5,6-trihydroxy-2-amino-1,2,3,4-tetrahydronaphthalene hydrobromide, mp 1°/2-200°C (decomposition;).

Elemental analysis for C-^qH-^O^N * HBr • E^ O

Calculated C 40.84, H 5.48, N 4.76

Found C 40.48, H 5.47, N 4.66

Examples 59-71

In the same way as described in example 58 et seq

using the compounds indicated in the second column of Table 4 as starting compound instead of 1-hydroxy-2-amino-5,6-dibenzyloxy-1,2,3,4-tetrahydronaphthalene, the compounds indicated in the third column were prepared in the same table.

Examples 72- 74-

In the same manner as in Example 58, the compounds listed in the second column of Table 5 were used to prepare the desired compounds listed in the third column by using fumaric acid instead of hydrobromic acid.

Example 75

Into 50 ml of a 1% aqueous solution of hydrochloric acid was added 1.0 g of 2-acetylamino-1-hydroxy-5,6-dimethoxy-1,2,3,4-tetrahydronaphthalene, and the mixture was kept heated on a water bath for 3 "hours. After cooling, the reaction mixture was washed with ethyl ether, neutralized with an aqueous solution of sodium bicarbonate and then extracted with chloroform. The extract was dried and concentrated under reduced pressure. Recrystallization of the residue from ethyl ether gives 0.1 g of 2-amino-l- hydroxy-5,6-dimethoxy-1,2,3,4-tetrahydronaphthalene as colorless crystals, melting point 122-124°C.

Elemental analysis for C-^H-^O^N

Calculated C 64.55, H 7.68, N 6.27

Found C 64.09, H 7.89, N 5.87

Example 76

0.5 g of 1-hydroxy-2-benzylamino-5,6-dimethoxy-1,2,3,4-tetrahydronaphthalene was dissolved in 100 ml of ethanol. By using 5% palladium on carbon, a catalytic reduction was performed. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure. Recrystallization of the residue from ethyl ether gave 0.3 g of 2-amino-1-hydroxy-5,6-dimethoxy-1,2,3,4-tetrahydronaphthalene. This compound was identical to the compound from example 75*

Example 77

To a mixture of 5 ml of 47% hydrobromic acid and 1.5 ml of acetic acid was added 0.36 g of 1,5,6-triacetoxy-2-acetylamino-1,2,3,4-tetrahydronaphthalene. After refluxing in a stream of nitrogen, the reaction mixture was concentrated under reduced pressure. Recrystallization of the residue from ethyl ether-methanol-water gave 0.15 g of 1,5,6-trihydroxy-2-amino-1,2,3,4-tetrahydronaphthalene hydrobromide. This compound was identical to the compound from Example 58.

Example 78

In 150 ml of ethanol was suspended 0.7 g of 1-hydroxy-2-(N-benzyl-N-methylamino)-5,6-dibenzyloxy-1,2,3,4-tetrahydro-naphthalene, and catalytic reduction was performed in the presence of 5$ palladium on carbon and hydrogen at a pressure of 5 kg/cm . The catalyst was filtered off and after adding a small amount of hydrobromic acid, the filtrate was concentrated. Recrystallization of the residue from methanol-ethyl ether gave 1,5,6-trihydroxy-2-methylamino-1,2,3>4-tetrahydronaphthalene hydrobromide, melting point 165-169°C (decomposition).

Example 79

In the same way as in example "] Q, but by using 1,5-dihydroxy-2-(N-benzyl-N-methylamino)-6-benzyloxy-1,2,3,4-tetrahydronaphthalene as the starting compound, the 1,5,6-trihydroxy-2-methylamino-1,2,3,4-tetrahydronaphthalene hydrobromide. The compound was identical to the compound from Example "jQ,

Example 80

In a mixture of 15 ml of ethanol and 10 ml of acetone, 548 mg of 1-hydroxy-2-amino-5,6-dibenzyloxy-1,2,3,4-tetrahydronaphthalene-p-toluenesulfonate were dissolved, after which 100 mg of triethylamine was added. 1-Hydroxy-2-isopropylidene-amino-5,6-<iibenzyloxy-1,2,3,4-tetrahydronaphthalene was then produced which was subjected to a catalytic reduction using 5$ of palladium on carbon as a catalyst. The catalyst was filtered off and after adding a small amount of hydrobromic acid, the filtrate was concentrated under reduced pressure. Recrystallization of the residue from ethanol-ethyl ether gave 1,5,6-trihydroxy-2-isopropylamino-1»2,3»4-tetrahydronaphthalene hydrobromide, melting point 168°C (decomposition).

Example 8l

In the same way as in example 80, but by using acetaldehyde instead of acetone, via 5,6-dibenzyloxy-2-ethylideneamino-1-hydroxy-1,2,3,4-tetrahydronaphthalene 2-ethylamino-1,5, 6-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide. Melting point: 176-177°C (decomposition).

Example 82

In the same way as described in example 80, but

by using cyclobutanone instead of acetone, 2-cyclobutylamino-1,5,6-trihydroxy- 1,2,3,4-tetrahydronaphthalene hydrobromide. Melting point: 197-200°C (decomposition).

Example 83

In a mixture of 10 ml of 1.5N potassium carbonate and

0.24 g of 1-hydroxy-2-trifluoroacetylamino-5,6-dibenzyloxy-1,2,3''-4-tetrahydronaphthalene was added to 10 ml of chloroform. After vigorous stirring at room temperature for 2 hours under nitrogen, the chloroform layer was separated from the reaction mixture and washed with water and dried. The chloroform was distilled off under reduced pressure, and the residue dissolved in ethyl ether. To the solution was added a solution of 0.08 g of p-toluenesulfonic acid monohydrate in ethyl ether, and the resulting precipitate was collected by filtration and recrystallized from ethanol-ethyl ether to give 1-hydroxy-2-amino-5,6-dibenzyloxy-1, 2,3,4-tetrahydronaphthalene-p-toluene-sulfonate. This compound was identified with the compound from Example 49*

Example 84

To a mixture of 5 ml of 547% hydrobromic acid and 1.5 ml of acetic acid was added 0.25 g of 2-methyl-6,7-dimethoxy-3a,4,5,9D-tetrahydronaphtho(2,1-d)oxazole. After boiling under reflux

in a stream of nitrogen, the reaction mixture was concentrated under reduced pressure. Recrystallization of the residue from ethyl ether-methanol-water gave 1,5,6-trihydroxy-2-amino-1,2,3,4-tetra-■ hydronaphthalene hydrobromide. The product was identical to the product from Example 58.

Example 85 1-Hydroxy-2-amino-5,6-dimethyldioxy-1,2,3,4-tetrahydronaphthalene hydrochloride (0.24 g) was refluxed with 5 ml of 57% hydroiodic acid. The reaction mixture was concentrated under reduced pressure, and the residue dissolved in a small amount of water and neutralized with an aqueous sodium bicarbonate solution. By treating this solution as described in example 58, 1,5,6-trihydroxy-2-amino-1,2,3,4-tetrahydronaphthalene hydrobromide was produced.

Example 86

A solution of 1.0 g of 2-tert-butylamino-1-hydroxy-5,6-dimethoxy-1,2,3,4-tetrahydronaphthalene fumarate in a small amount of water was made alkaline with sodium bicarbonate and then extracted with 100 ml of dichloromethane . The extract was washed with water, dried and then this solution was added dropwise to a solution of boron tribromide (1.5 g) in 20 ml of dichloromethane while cooling at temperatures from -70 to -75°C. The resulting mixture was vigorously stirred for several hours at said temperature and then slowly warmed to room temperature and concentrated under reduced pressure. The residue was redissolved in a small amount of water, made alkaline with sodium bicarbonate and extracted with n-butanol. The extract was concentrated under reduced pressure,

and the residue was added to an ethereal solution of fumaric acid.

After recrystallization of the precipitate from ethanol-ethyl ether, 2-tert-butylamino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene fumarate was produced. Melting point: 149-151°C.'

Example 87

A solution of 0.6 g of 2-[1-methyl-2-(3-indolyl)-ethylamino)-1-hydroxy-5,6-dibenzyloxy-1,2,3,4-tetrahydronaphthalene in 20 ml of methanol was catalytically reduced in the presence of palladium on carbon. The catalyst was removed by filtration, and after dissolution of fumaric acid, the filtrate was concentrated under reduced pressure. Ethyl ether was added to the residue, and the mixture was cooled, whereby 0.2 g of 2-(1-methyl-2-(3-indolyl)ethylamino)-1,5,6-trihydroxy-1,2,3,4 -tetrahydronaphthalene fumarate. This compound has no fixed melting point and decomposes slowly when heated.

Elemental analysis for c2iH24°3N2 *<C>4<H>4°4

Calculated C 64.09, H 6.02, N 5.98

Found C 63.58, H 6.46, N 5.91

Example 88

100 mg of 5,6-dibenzyloxy-2-tert-butylamino-1-hydroxy-1,2,3,4-tetrahydronaphthalene fumarate was dissolved in a small amount of water. The solution was neutralized with an aqueous sodium bicarbonate solution and extracted with chloroform. The extract was dried and concentrated under reduced pressure. The produced residue was dissolved in ethanol and catalytically reduced using palladium on carbon as a catalyst. The catalyst was filtered off, and fumaric acid was dissolved in the filtrate. By concentrating the solution and adding ethyl ether, 33 mg of 2-tert-butylamino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene fumarate were precipitated. Melting point: 149-151°C.

Elemental analysis for C-^H^O^N • C4H4°4 * H2°

Calculated C 56.09, H 7.06 N 3.63

Found C 56.65, H 7.31 N 3.98

Example 89

A solution of 1.10 g of trans-1-hydroxy-2-(N-benzyl-N-methylamino)-5,6-dibenzyloxy-1,2,3'' 4-tetrahydronaphthalene in 10 ml of tetrahydrofuran and 20 ml of ethanol was hydrogenated over 10 fo palladium on carbon at ordinary temperature and pressure. After removal of the catalyst by filtration, a solution of 190 mg of fumaric acid dissolved in 450 ml of ethyl ether was added dropwise to the filtrate. The resulting mixture was evaporated under reduced pressure to a pale yellow oily substance which was dissolved in a mixture of 5 mL of water and 20 mL of ethanol and decolorized with charcoal. The solution was added to 200 ml of ethyl ether, and the mixture was left overnight at 5°C. Filtration of the resulting crystals gives 171 mg of trans-1,5»6-trihydroxy-2-methylamino-1,2,3»4-tetrahydronaphthalene fumarate , melting point 199°C (decomposition). NMR (DMS0-dg) 4$ : 4.52 (1H, d, J=9 Hz).

Example 90

1.10 g of cis-1-hydroxy-2-(N-benzyl-N-methylamino)-5,6-dibenzyloxy-1,2,3,4-tetrahydronaphthalene was catalytically hydrogenated in a similar manner as stated in Example 89. The catalyst was removed by filtration, and a solution of 180 mg of fumaric acid and 15 ml of ethanol was added dropwise to the filtrate. After addition of JO ml of ethyl ether, 10 ml of ethanol and 6 ml of water, the mixture was left overnight at 5°C. The precipitated crystals were collected by filtration and recrystallized from a mixture of 10 ml of water and 100 ml of acetone, whereby 3^5 mg of cis-1,5 > 6-trihydroxy-2-methylamino-1,2,3 >4-tetrahydronaphthalene fumarate as thin planes melting at 195°C (decomposition).

Elemental analysis for C-qHj^NO^' l/2 C4H4°4

Calculated C 58.41, H 6.41, N 5.24

Found C 58.20, H 6.26, N 5.47

NMR (DMSO-dg) 6 : 4.63 (1H, d, J=3 Hz)

Example 91

A resolution of /\. 10 mg of trans-1-hydroxy-2-iso-propylamino-5,6-dibenzyloxy-1,2,3,4-tetrahydronaphthalene in 2 ml of water and 20 ml of ethanol was catalytically hydrogenated over 5% palladium on carbon at ordinary temperature and Print. When the theoretical amount of hydrogen had been absorbed, the catalyst was removed by filtration, and the filtrate added dropwise to a mixture of 5 ml of ethanol and 2 ml of water. The resulting mixture was cooled overnight to give colorless crystals which were filtered off weighing 215 mg of fcrans-1,5>6-trihydroxy-2-isopropylamino-1,2,3>4-tetrahydronaphthalene fumarate, mp 180-210 °C.

Elemental analysis for C-j^<H->j^<N>O^• l/2 C^H^O^ • CgH^OH

Calculated C 59.8l, H 7.97, N 4.10

Found C 60.00, H 8.00, N 4.25

NMR (DMSO- d g + D 2 O) 6 : 4.57 (1H, d, J=10 Hz).

Example 92 ■

502 mg of cis-1-hydroxy-2-isopropylamino-5,6-dibenzyloxy-1,23,4-tetrahydronaphthalene (acetic acid salt) was catalytically reduced as indicated in Example 91* After the catalyst had been removed by filtration, the filtrate was added dropwise a solution of 6l mg of fumaric acid in 5 ml of ethanol. The mixture was evaporated almost to dryness and 150 ml of ethyl ether was added. The resulting precipitate was filtered off and recrystallized

from water, whereby cis-1,5,6-trihydroxy-2-isopropyl-amino-1,2,3,4-tetrahydronaphthalene fumarate was obtained as prisms, melting point 179-181°C.

Elementary analysis for C^H-^NO^ • l/2 C^1^0^ * H2°

Calculated C 57.50, H 7.40, N 4.47

Found C 57.56, H 7.25, N 4.31

NMR (DMSO-dg +D2O) rf:4.66 (1H, d,J=2.8Hz)

Example 93

A solution of 0.75 g of tris-2-amino-5,6-dibenzyloxy-1-hydroxy-1,2,3,4-tetrahydronaphthalene in 10 ml of methanol was hydrogenated over 10% palladium on carbon at ordinary temperature and pressure. To the solution was added 0.5 g of 47% hydrobromic acid, and the catalyst was then removed by filtration while 200 ml of ethyl ether was added dropwise to the filtrate. The resulting pink crystals were collected by filtration and dissolved in a mixture of 15 ml of ethanol and 4 ml of water. The solution was added 200 ml of ethyl ether slowly, whereby 0.4 g of trans-2-amino-1,5»6-trihydroxy-1,2,3>4-tetrahydronaphthalene hydrobromide was obtained as colorless prisms, melting point 210-213 °C (decomposition).

Elemental analysis for cj_oHi3°3N * HBr'H2°

Calculated C 40.84 H 5.48, N 4.76

Found C 40.95 H 5.49» N 4.43

NMR (DMSO-dg) rf: 4.53 (1H, d, J=9.0 Hz)

Example 94

455 mg of trans-2-cyclobutylamino-5,6-dibenzyloxy-1-hydroxy-1,2,3,4-tetrahydronaphthalene fumarate was added to 10 ml of 1N sodium hydroxide and then extracted with chloroform. The extract was washed with water, dried and evaporated. The residue was dissolved in 25 ml of ethanol and 2 ml of water and then subjected to catalytic reduction over 5% palladium on carbon at ordinary temperature and pressure. The catalyst was removed by filtration, after which a solution of 56.5mS fumaric acid in 5 ml of ethanol was added dropwise to the filtrate. The mixture was left at room temperature. The resulting precipitate was filtered off and washed with a small amount of cold ethanol, whereby trans-2-cyclobutylamino-1,5,6-trihydroxy-1,2,3'' 4-tetrahydronaphthalene fumarate was obtained, melting point 211-214°C ( decomposition).

Elementary analysis for C-^H-^O^N * l/2 ' i/4 CgH^OH

Calculated - C 62.15, H 7.11, N 4.39

Found C 61.92, H 7.04, N 4.32

NMR (DMSO-dg) 6 : 4.52 (1H, d, J=8.2 Hz)

Example 95

0.7 g of cis-5,6-dibenzyloxy-2-tert-butylamino-1-hydroxy-1,2,3»4-tetrahydronaphthalene oxalate was added to 100 ml of water and the solution was neutralized with 10% sodium hydroxide and then extracted with chloroform . The extract was evaporated under reduced pressure, and the residue added to 3° ml of methanol and hydrogenated over 10% palladium on carbon under ordinary temperature and pressure. After

the catalyst had been filtered off, 0.16 g of fumaric acid was added to the filtrate, after which the mixture was concentrated. Ethyl ether was added to the concentrated solution, whereby 0.3 g of cis-2-tert-butylamino-1,5,6-trihydroxy-1,2,3'' 4-tetrahydro-naphthalene fumarate was obtained, melting point 186 -187°C.

Elemental analysis for C-^Hp^O^N • l/2 C^H^O^3/2 H20

Calculated C 57.12,. H 7.79, N 4.16

Found C 57.09, H 7.40, N 4.82

NMR (DMSO-dg + Dp_0) : 1.40 (9H, s) , 4.66 (1H, d, J=3 Hz)

Example 96

In the same way as indicated in Example 95 > me(in a reaction of 0.7 g of trans-5,6-dibenzyloxy-2-tert-butylamino-1-hydroxy-1,2,3,4-tetrahydronaphthalene oxalate, 0, 32 g of trans-2-tert-butylamino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene fumarate, melting point 185-186°C.

Elemental analysis for C-^Hp^O^N • l/2 C^H^O^• 3/2 H20

Calculated C 57.12, H 7.79, N 4.16

Found C 56.50, H 7.54, N 4.74

NMR (DMSO-dg + Dp_O) 6 : 1.40 (9H, s) , 4.58 (1H, d, J=8 Hz)

Example 97

A solution of 5.4 g of trans-5,6-dibenzyloxy-2-ethylamino-1-hydroxy-1,2,3,4-tetrahydronaphthalene in 100 ml of methanol was subjected to catalytic reduction using 10% palladium on carbon as catalyst. The reaction mixture was added

3>5g of a 47% hydrobromic acid and 10 ml of water. After filtration, the filtrate was added to 1.5 liters of ethyl ether, which gives colorless powder-like crystals which were collected by filtration and dissolved in a mixture of 5© ml of methanol and 10 ml of water. 1 liter of ethyl ether was slowly added to the solution, and 3>3 g of trans-2-ethylamino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide were precipitated as colorless prisms which melt at 176-177°C (decomposition).

Elemental analysis for C-^H-^O^N * HBr • HgO

Calculated C 47.38, H 5.96, N 4.60

Found C 47.45, H 5.98, N 4.50

NMR (DMSO- dg + D 2 O) δ : 1.27 (3H, t, J=7 Hz), 4.63 (1H, d, J=8 Hz)

Example 98

0.4 g of 2-cyclopropylamino-5,6-dibenzyloxy-1-hydroxy-1,2,3,4-tetrahydronaphthalene oxalate was neutralized with aqueous sodium bicarbonate, and the resulting free base extracted with chloroform. The extract was evaporated to dryness under reduced pressure. The residue was dissolved in 20 ml of methanol and subjected to catalytic reduction in the presence of 10% palladium on carbon. After the catalyst had been removed by filtration, 0.1 g of fumaric acid was added, and the mixture was concentrated under reduced pressure. 300 ml of ethyl ether was added to the residue and the solution allowed to stand for 2 days, which gave 0.1 g of 2-cyclo -propylamino-1)5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene fumarate as colorless crystalline powder crystals, melting point 155-160°C.

Elemental analysis for C-^H^O^N<*>1/2 C^H^O^ * HgO

Calculated C 57.86, H 6.80, N 4.50

Found C 57.68, H 6.38, N 4.71

Example 99

In the same manner as in Example 98, 0.25 g of cis-5,6-dibenzyloxy-2-ethylamino-1-hydroxy-1,2,3,4-tetrahydro-naphthalene fumarate gave 0.1 g of cis_-2- Ethylamino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene fumarate, melting point 160-162°C (decomposition).

Elementary analysis for C-^H-^O^N'^ 2 C4H4°4"H2°

Calculated C 56.17, H 7.07, N 4.68

Found C 55.77, H 7.01, N 4.68

NMR (DMSO- dg + D 2 "O) 6 : 4.69 (1H, d, J=2 Hz)

Example 100

A solution of 0.4 g of cis_-2-amino-5,6-dibenzyloxy-1-hydroxy-1,2,3,4-tetrahydronaphthalene in 15 ml of methanol was subjected to catalytic reduction in the presence of 0.7 g of 10 % palladium on carbon at ordinary temperature and pressure. The catalyst was removed by filtration, and 500 ml of ethyl ether containing an equimolar amount of hydrogen bromide was added dropwise to the filtrate, whereby 0.15 g of cis-2-amino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene- hydrobromide as colorless crystals, melt-'

point l80-lcjO°C (decomposition).

Elemental analysis for C]_oH13^3N'HBr

Calculated C 43.50, H 5.11, N 5.07

Found C 43.04, H 5.20, N 4.95

NMR(-DMSO-dg + DpO) cf: 4.59 (1H, d, J=2 Hz)

Example 101

A reaction of 0.5 g of cis-2-cyclobutylamino-5,6-dibenzyloxy-1-hydroxy-1,2,3,4-tetrahydronaphthalene fumarate in the same manner as indicated in Example 94 followed by the formation of a fumaric acid salt by add methanolic solution of fumaric acid, gave 0.2 g of cis_-2-cyclobutylamino-1,5,6-trihydroxy-1,2,3,4-tetra-hydronaphthalene fumarate, melting point 171-172°C (decomposition).

Elementary analysis for C-^H-^O^N<*>l/2 C^H^O^ ' CH^OH • 2H20

Calculated C 54.39, H 7.79, N 3.73

Found C 54.50, H-7.50, N 4.09

NMR (DMSO-dg + DgO) cf: 4.66 (1H, d, J=3 Hz)

Claims (28)

1. Method for producing compounds with the formula where R is hydrogen, a hydrocarbon group which may be substituted or acyl and where Z 1 and Z 2 are hydrogen or a protecting group, or salts of such compounds, characterized by hydrolyzing a compound with the formula where R, Z 1 and Z 2 have the same meaning as stated above. 2. Method according to claim 1, characterized in that the hydrocarbon group is one that branches in its a-position. 3« Method according to claim 1, characterized in that the hydrolysis is carried out in the presence of an acid. 4» Procedure for making compounds with the formula where R' is hydrogen or a hydrocarbon group which may be substituted, and where Z 1 and Z 2 are hydrogen or a protecting group, or salts of such compounds, charac- serted by reducing a compound with the formula 12 1 where Z and Z have the same meaning as above, A is a group which can be converted to -NHR' (where R' has the same meaning as above) by reduction and X is 5. Method according to claim 4, characterized in that the group which can be converted to -NHR <»> by reduction is nitro, nitroso or isonitroso. 6. Method according to claim 4, characterized in that the reduction is carried out as a catalytic reduction or by means of a metal hydride. 7. Procedure for the preparation of compounds with the formula where R" is (where R 1 is hydrogen or' lower alkyl, R p is hydrogen or a hydrocarbon group which may be substituted, this includes the case where R 1 and R 2 can form a ring group together with the adjacent carbon atom) and Z 1 and Z <2> are hydrogen or a protecting group, or salts of such compounds, characterized by reducing shows a connection with the formula 12 2 where Z and Z have the same meaning as stated above, and A is. a group which can be converted to amino by reduction and X is in the presence of a carbonyl compound of the formula where R 1 and R 2 have the same meaning as stated above. 8. Method according to claim 7, characterized in that the m group which can be converted to amino by reduction is nitro, nitroso or isonitroso. 9"Procedure according to claim 7"characterized in that the reduction is carried out as a catalytic reduction or by means of a metal hydride. 10. Procedure for preparing compounds of the formula where R' is hydrogen or a hydrocarbon group which may be sub-1 2 substituted, and Z and Z are hydrogen or a protecting group, or salts of such compounds, characterized by carrying out one or more reactions which remove protective groups or a protective group in the form of bonds with the formula where RT has the same meaning as stated above, and Z <1> ' , Z 2 *, Z<J> and Z^" are hydrogen or a protecting group under the condition that at least one of said groups is a protecting group. 11. Method according to claim 10, characterized in that both Z 1 and Z 2 are hydrogen. 12. Method according to claim 10, characterized in that both Z 1 and Z 2 are hydrogen and both Z 1* and 2' Z is benzyl. 13. Method according to claim 10, characterized in that the reaction which leads to the removal of the protective group(s) is a reduction or a solvolysis. 14" Method according to claim 13, characterized in that the reduction is carried out as a catalytic reduction. 15. Method according to claim 13> characterized in that the solvolysis is carried out by using a Lewis acid, an inorganic or an organic acid. 16. Connections, characterized by the formula where R is hydrogen, a hydrocarbon group which may be substituted or acyl and where Z and Z~ 9" are aralkyl or salts of such compounds. 17. Compounds according to claim 16, characterized in that the aralkyl group is benzyl. 18. Compounds according to claim 16, characterized in that R is hydrogen or a hydrocarbon group. 19. Compounds according to claim 18, characterized in that the hydrocarbon group is lower alkyl or cycloalkyl. 20. Compounds according to claim 16, characterized by being in the form of a mixture of trans and cis isomers. 21. Compounds according to claim 16, characterized by essentially being in the form of a trans isomer. 22. Chemical compound according to claim 16, characterized by being 2-amino-5,6-dibenzyloxy-1-hydroxy-1,2,3,4-tetrahydronaphthalene. 23* Chemical compound according to claim 16, characterized by being 5,6-dibenzyloxy-2-ethylamino- 1-hydroxy-1,2,3,4-tetrahydronaphthalene. 24. Chemical compound according to claim 16, characterized by being 5,6-dibenzyloxy-1-hydroxy-2-isopropylamino-1,2,3»4-tetrahydronaphthalene. 25. Chemical compound according to claim 16, characterized by being 5,6-dibenzyloxy-2-tert-butylamino-1-hydroxy-1,2,3,4-tetrahydronaphthalene. 26. Chemical compound according to claim 16, characterized by being 2-cyclopropylamino-5,6-dibenzyloxy-1-hydroxy-1,2,3>4-tetrahydronaphthalene. 27• Chemical compound according to claim 16, characterized by being 2-cyclobutylamino-5>6-dibenzyloxy-1-hydroxy-1,2,3>4-tetrahydronaphthalene. 28. Chemical compound according to claim 16, characterized by being 2-cyclopentylamino-5,6-dibenzyloxy-1-hydroxy-1,2,3,4-tetrahydronaphthalene.