NO761525L - - Google Patents

Description

PROCEDURE FOR THE MANUFACTURE OF ALIPHATIC ALCOHOL DERIVATIVES.

The present invention provides a method for the production of N-heterocyclic derivatives of 1,4-methane and 1,4 ethane-^4-

dihydro and 1,2,3,4-tetrahydro-naphthyloxy aliphatic alcohols.

The compounds according to the invention have the following formula (I)

in which

the symbol - z^ jz. form a single or a double bond;

n is 1 or 2;

each of and R 2 is independently selected from the group consisting of hydrogen, halogen, hydroxy, C -C alkyl, C -C, alkoxy>trihalogen-16 l b

methyl, nitro, formyl, hydroxymethyl, amino, unsubstituted or substituted by one or two C^-C^ alkyl groups, C^-C^alkylthio, C1~C6alkylsulfinyl, C^-Cg alkylsulfonyl, C^-Og alkanesulfonamido,

a residue -NHCOR7, wherein R^ is C-^-C8 alkyl, a residue ■ hvpri each of Rg and Rg is independently selected from the group consisting of hydrogen and C-^-C8 alkyl;

is a saturated or unsaturated heterocyclic ring containing

holds at least one nitrogen atom and optionally one or more other heteroatoms selected from the group consisting of N, S, and 0, where said ring is substituted or unsubstituted by one or more substituents selected from the group consisting of ci~cq alkyl,. C 1 - C 6 alkoxy, nitro, halogen, -C00R, wherein R is hydrogen or C 1 -C 8 alkyl;

each of R 1 , R 1 , and R 1 is independently selected from the group consisting of hydrogen and C 1 -C 8 alkyl.

The object of the present invention is likewise salts of the compounds of formula (I) with pharmaceutically acceptable acids as well as the quaternary ammonium salts.

It should also be noted that the above definition of the compound according to the invention includes all possible diastereoisomers and stereoisomers, as well as their mixtures.

The alkyl, alkoxy and alkanesulfonamido groups can be branched or straight chains.

Preferably, the symbol - - - - constitutes a single bond.

Preferably, the ether chain bearing is a heterocyclic ring

in the manufacture.

Preferably, R 5 and R 1 are hydrogen and R 4 is hydrogen or C 1 -C 3 alkyl. When R 1 and/or R 2 is trihalomethyl, the trihalomethyl group is preferably trifluoromethyl.

Preferably, each of R₁ and R₂ is independently selected from the group consisting of hydrogen, halogen, hydroxy, C₁-C₁ alkyl, C₁-C₆ alkoxy, trifluoromethyl, formyl, hydroxymethyl, C₁-C₆ alkylthio, C₁-C₆ alkylsulfinyl, C -^-C 8 alkylsulfonyl and the residue -NHCOR 7 , in which R- is as indicated above.

When R^ and/or R^ is halogen, the halogen is preferably chlorine or bromine.

The heterocyclic ring

is either an mpnocyclic or bicyclic or tricyclic ring. represents a heteromonocyclic ring, it is preferably pyrrolidinyl, pyrazolidmyl, imidazolidinyl, pyrrolinyl, pyrazolinyl, imidazolinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, pyrazolyl, triazolyl or imidazolyl, unsubstituted or substituted as indicated above. is a bicyclic ring, it is preferably indolyl, isoindolyl, indazolyl or benzimidazolyl, unsubstituted or substituted as indicated above. is a tricyclic ring, it is preferably carbazolyl, phenothiazinyl or phenoxazinyl, unsubstituted or substituted as indicated above. Preferably is

a heteromonocyclic ring, esp

imidazolyl or imidazolinyl, especially imidazolyl.

Particularly preferred compounds according to the invention are those in which the symbol - - - - represents a single bond, R^ is halogen, especially chlorine in the 8-position, R2 is hydrogen or halogen,

especially chlorine in the 6-position, R^ and Rg are hydrogen, R^ are

hydrogen or methyl and

is imidazolyl or imidazolinyl, optionally substituted by one or two substituents selected from the group consisting of C 1 -C 4 alkyl and halogen. Preferably in these particular preferred compounds R 1 is hydrogen and imidazolyl.

Examples of pharmaceutically acceptable salts are either those with inorganic acids, e.g. hydrochloric acid>hydrobromic acid and sulfuric acid or with organic acids, e.g. citric-, wine-r> maleicT, f urna r-and methanesulfonic acid.

The compounds according to the invention are produced by a method consisting of:

(a) reaction of a compound of formula (II)

in which the symbol - £,n, R,, and R„ are as above indicated and Z is one of the residues and

in which R., R. and R. are as defined above and X is halogen,

4D D

with a compound of formula (III)

or a salt thereof wherein is as defined above; (b) reaction of a compound of formula (IV)

in which

the symbol - - - -, n, R^ and R2 are as defined above, or a salt thereof with a compound of formula (V)

is as defined above and Y is one of the following residues:

in which

X, R^, R^ and Rg are defined as above;

(c) reduction of a compound of formula (VI)

in which

the symbol - - - -, n, R^, R^, R^, R^ and

is as defined above, whereby a compound of the formula (I) is obtained in which R is hydrogen; 6 (d) turnover of. a compound of formula (VI) with one Grignard reagent of formula R^MgX, wherein X is as indicated above and R 6 . is C 1 -C 6 , alkyl, whereby a compound of formula (I) is obtained, in which Rcer is C 1 -C 6 alkyl;

D lb

and if desired, converting a compound of formula (I) into another compound of formula (I), and/or if desired reacting a compound of formula (I) with a pharmaceutically acceptable acid to give a salt thereof and/ or if desired convert a salt into a free base and/or if desired convert a compound of formula (I) into a quaternary ammonium salt thereof and/or if desired

wanted to dissolve a mixture of isomers into the individual isomers.

When the compounds with the formulas (III) and (IV) are reacted in the form of

a salt, this salt is preferably with an alkali metal atom or with a solvate atom.

X is preferably chlorine or bromine

The reaction of the compound of formula (II) with the compound of formula (III), or a salt thereof, is preferably carried out by a temperature between about 50°C and about 250°C, either in the presence or in the absence of solvents. When solvents are used, they are e.g. toluene, xylene and ethanol. When in the compound of formula (III) -NR R 3 represents an aromatic heterocyclic ring, e.g. pyrrolyl, pyrazolyl and imidazolyl, the reaction of the compound of formula (II) with a compound of formula (III) or a salt thereof is carried out, preferably in an organic solvent selected from the group consisting of dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide and dimethylsulfoxide in the presence of a base such as .ex. sodium hydride, sodium hydroxide, sodium ethoxide.

Likewise, the reaction of the compound of formula (IV) with a compound of formula (V) is carried out under the same conditions as reaction (a) and preferably in the presence of a base such as sodium hydroxide, potassium hydroxide and sodium methoxide.

When in the compound of formula (VI) the symbol is a double bond and it is desired to obtain a compound of formula (I) in which this symbol is an erical bond, the reduction of the compound of formula (VI) is carried out by catalytic hydrogenation by e.g. to use Pd/C or PtC^ as catalyst.

When, on the other hand, it is desired to reduce only the keto group in the compound of formula (VI), the reduction is preferably carried out using mixed metal hydrides such as sodium borohydride or lithium aluminum hydride in organic solvents such as ethyl ether and tetrahydrofuran and at a temperature between 0°C and around 60°C.

The Grignard reaction with the compound of formula (VI) is carried out

under the conditions that are usually used for this type of reaction, e.g. at reflux temperature in diethyl ether.

Either the conversion of a compound of formula (I) into another compound of formula (I) or the salt formation (or the conversion of a compound of formula (I) into the quaternary ammonium salt or the dissolution of a mixture of isomers into the individual isomers can be carried out by conventional methods.

Thus, e.g. a compound of formula (I) in which and/or R 2 is C 1 -C 8 alkoxy is selectively deetherified, e.g. by working at a temperature lower than 160°C to give a compound of formula (I) wherein R^ and/or R^ is hydroxy by reaction with a pyridine salt, e.g. pyridinium hydrochloride.

A compound of formula (I) wherein R 1 and/or R 2 is hydroxy

can be transferred in a compound of formula (I) in which R₁ and/or R₂ are C₁-C₆ alkoxy by salt formation of the hydroxy groups, e.g.

with an alkali hydroxide and then treat the resulting compound with C 1 -C 8 alkyl reactive esters of strong sides, e.g. ci_cg alkyl halides or c-^-cg dialkyl sulfates.

A compound of formula (I) wherein R 1 and/or R 2 is nitro

can be reduced to give a compound of formula (I) in which R 1 and/or R 2 is amino, e.g. by hydrogenation with Pd/C; in this case, when in the starting material the symbol - - - - represents a double bond, this double bond is also reduced to a single bond.

When the reaction is instead carried out e.g. with stannous chloride and hydrochloric acid in acetic acid, only the nitro group is reduced without reduction of any double bond present. A compound of formula (I) in which R 1 and/or R 2 is unsubstituted amino can be converted into a compound of formula (I) in which R 2 and/or R 2 is a mono- or di-alkyl substituted amino by known methods, e.g. e.g. by reaction with reactive esters of alcohols. The compounds used as starting materials are already known or, if they are new, they are prepared in an already known manner. The compound of formula (II) wherein Z is

, in which R 4 , R 5 and R 5 are as defined above, can be prepared by reacting a compound of formula (IV) with a compound of formula (VII)

in which

X, R^, Rj. and Rg is defined as above.

The reactions of the compound of formula (IV) with the compound of formula (VII) are preferably carried out at a temperature between about 0°C and about 150°C in a solvent, e.g. selected from the group consisting of water, dioxane, tetrahydrofuran, diethyl ether, dimethylformamide and dimethylsulfoxide in the presence of at least one equivalent of a base selected e.g. from the group consisting of

sodium hydroxide, potassium hydroxide, sodium amide and sodium methoxide.

The compound of formula (II) wherein Z is

wherein R4,

Rc, Rcog X are as above defined, can be produced by under

stay

analogous conditions reacting the compound of formula (IV) with the compound of formula (VII), however, in the presence of a catalytic amount of a base preferably selected from piperidine and pyridine, or treating the compound of formula (II) wherein Z is

hydrogen halogen acid. Alternatively, the compound of formula (II) wherein Z is ■

, wherein R4 and R5 are as above defined, and R& is hydrogen, is produced by reacting a for bond of formula (VIII)

in which

the symbol - - - -, nine R^, R2 and X are as defined above, with a diazoalkane of formula (IX)

in which

R^ and Rg are defined as above in an organic solvent such as diethyl ether, tetrahydrofuran and dioxane and then treat the resulting diazoketone in the same solvent with a hydrohalic acid, e.g. gaseous hydrochloric or hydrobromic acid, to give a compound of formula (X)

in which

the symbol - - - -, n, R^, R2, R^, R^, and X are as above defined, which are then reduced, e.g. with sodium borohydride in the presence of a base such as sodium or potassium hydroxide in a solvent such as alcohol (or tetrahydrofuran.

The compound of formula (VI) can be prepared, e.g. by reacting a compound of formula (X) with a compound of formula (III). The reaction can be carried out essentially as described above for reaction (a). In the connection with the formula (X), the keto group can optionally be protected by known methods, e.g. at the formation

of a ketal.

The compound of formula (VI) in which the symbol - - - represents a single bond can be prepared by conventional methods, e.g. according to Europ. J. Med. Chem. 9, 501 (1974).

Thus, e.g. the compound of formula (IV) in which R^ and/or R^ is chlorine and the symbol - -■■- is a single bond is prepared by reacting the compound of formula (IV) in which R^ and R2 is hydrogen, the symbol - - - - is a single bond and the hydroxy group is protected by the formation of a methyl ether, with sulfuryl chloride of the formula SO2C12 in a chlorinated solvent such as methylene chloride and chloroform, at a temperature between about -10°C and about +10°C, preferably at 0°C, and by subsequent deetherification of the methoxy group to give the free hydroxy group, e.g. by reaction with pyriding hydrochloride.

Depending on the molar ratios of the reagents used, it is possible to obtain either the monochloro derivative or the dichloro derivative. The compounds of formula (IV) in which R^ and/or R 2 are "bromine and the symbol - - - is a single bond can be obtained, for example, by bromination of the compound of formula (IV), in which R^dg R^ is hydrogen and the symbol - - - is a single bond with bromine in chlorinated solvents such as methylene chloride and chloroform at a temperature between about -40°C and about -10°C.

In this case too, either the monobromo derivative or the dibromo derivative is obtained depending on the molar ratios of the reagents. The compound of formula (IV), in which R^ and/or R 2 is fluorine and the symbol - - - is a single bond, can be obtained by diazotizing the compound of formula (IV), in which R-^ and/or R 2 is amino,

and the symbol - - - is a single bond, with HCl and NaN02 by subsequent reaction of the compound formed with fluoroboric acid and finally thermal cleavage of the diazbnium fluoroborate formed.

The compound of formula (IV) in which R 1 and/or R 2 are formyl and

the symbol - - "- is a single bond, can be obtained by

start with the compound of formula (IV), in which R, and/or R2 is hydrogen and the symbol - - - - is a single bond, by

a Vilsmeier-Haack reaction.

The compound of formula (IV), in which R^ and/or R2 are hydroxymethyl and the symbol - - - is a single bond can be prepared by reduction of the compound of formula (IV), in which R^ and/or R2

is formyl and the symbol - - - - is a single bond, e.g. with mixed metal hydrides such as NaBH^. The compound of formula (IV), in which the symbol - - - - is a double bond, can also be prepared by known methods.

Thus, e.g. the compound of formula (IV), wherein one of

R 1 and R 2 are hydroxy and the other is hydrogen, and the symbol

-i - - - represents a double bond is prepared by treating a quinone with the formula (XI)

with hydrochloric acid<p>g dichloromethane. The quinone can in turn be prepared by reacting jd-benzo-quinone with cyclohexadiene or cyclopentadiene.

The compound of formula (IV), in which R 1 and R 2 are hydrogen and the symbol - - - is a double bond can be obtained e.g. by treating 5,8-dioxo-1,4-methane-1,4-dihydronaphthalene or 5,8-dioxo-1,4-ethane-1,4-dihydronaphthalene,• which is already known (Diels et al., Ber., 62, 2337-2372 (1929)), with trialkoxy phosphine at a temperature of between about 15°C and about 30°C in an inert organic solvent such as e.g. benzene, toluene, for a period of time ranging from about 45 minutes to about 4 hours, and then reacting the resulting 5-alkosky-8-(di-O-alkylphosphono)-1,4-dihydro-1,4-ethane or 1 ,4-methane - naphthalene in an organic solvent such as diethyl ether with liquid ammonia and lithium, whereby the corresponding 5-alkyl-1,4-dihydro-1,4-ethane - or 1,4-methane - naphthalene is obtained.

The latter reaction is carried out by first adding, under stirring, at a temperature between around -80°C and around -35°C ammonia to a loan of 5-Alkoxy-8-(di-O-alkylphosphono)-1, 4-dihydro-1,4-ethane - or 1,4-methane -naphthalene in diethyl ether, also to. the reaction mixture to put around 2 moles of lithium per

moles of 1,4-ethane or 1,4-methane'-naphthalene derivative. The thus obtained 5-hydroxy-1,4-dihydro-1>4-ethane - or 1,4-methane - naphthalene is finally transferred into 5-hydroxy-1,4-dihydro-1,4-ethane>-or 1, 4-methane-naphthalene by reaction e.g. with around 10 mol sodium ethanethiolate per mol of 5-Alkoxy-1,4-dihydro-1,4-ethane or 1,4-methane-naphthalene in an organic solvent such as dimethylformamide at a temperature of around 100°c.

The compound of formula (IV), wherein one of R, and Rn is C.-C,

12. i b alkoxy , and the other is hydrogen and the symbol - - - is a double bond can be obtained e.g. by selective alkylation of the compound of formula (IV), in which one of R^ and R^ is hydroxy and the other is hydrogen, and the symbol - - - is a double bond, e.g. with a dialkyl sulfate.

The compound of formula (IV), wherein one of R. and R. is C.-C,

12 1b alkylthio and the other is hydrogen, and the symbol - - - is a double bond, can be prepared by reacting the compound of formula (IV), in which R^ and R are hydrogen and the symbol - - - -

is a double bond with a C±-C£ dialkyl sulfoxide in the presence of hydrochloric acid and subsequent pyrolysis. The corresponding sulfoxides and sulfines can be prepared by oxidizing e.g. with sodium periodate or respectively with peracetic acid, the compound of formula (IV), in which one of ^ and R 2 is C 1 -C 3 alkylthio and the other is hydrogen and the symbol - - - is a double bond and in which the hydroxy group is protected in a conventional manner e.g. by esterification. The compound of formula (IV), in which one of R 1 and R 2 is nitro and the other is hydrogen and the symbol - - - is a double bond, can be obtained by nitration, e.g. with a mixture of concentrated sulfuric acid and sodium nitrate in water,

or with a mixture of nitric acid and acetic anhydride of the compound of formula (IV), in which both R1 and R2 are hydrogen

and the symbol - - - is a double bond and upon subsequent separation, e.g. by fractional crystallization of the mixture of the thus obtained 8-nitro and 6-nitro derivatives.

The compound of formula (IV), in which one of R. and R2 is amino and the other is hydrogen and the symbol - is a double bond, can be obtained by hydrogenation of the corresponding nitro derivative, e.g. with NaBfr^S-j, which in turn can be prepared as described in Canad. J. Chem., 49, 2990 (1971).

If desired, a compound in which one of R 1 and R 2 is unsubstituted amino and the other is hydrogen can be alkylated in a conventional manner to give a compound in which the amino group is substituted by one or two C 1 -C 8 alkyl groups; if desired, the same compound may be alkylated in a conventional manner to give a compound in which the amino group is substituted by a -COR^ residue.

The compound with formula (IV), in which one of R. and R. is obtained by reacting the compound of formula (IV), in which one of R ± and R 2 is unsubstituted amino and the other is hydrogen and the symbol - - - is a double bond with the anhydride of the alkanesulfonic acid.

Also the remaining compounds of formula (IV), in which the symbol

- - - is a double bond and R^ and/or R 2 have the meanings stated above can be prepared in a conventional way, i.e. by usual methods in organic chemistry, e.g. by following the methods indicated above for the preparation of the compounds of formula (IV), in which the symbol - - - is a single bond and R1 and/or R2 have the corresponding meanings.

The compound according to the invention possesses strong anti-arrhythmic activity and has no effect on cardiac and bronchial (3-adrenergic receptors; The specific mode of action of these compounds provides the basis for effective use in the treatment of, for example, irregularities in cardiac rhythm caused by increased myocardial excitability and automatism dg or with pathological changes in the impulse line.

The antiarrhythmic activity of the compounds according to the invention was measured on isolated guinea pig auricles as follows

the method described by Dawes (G.S. Dawes, Brit. J. Pharm. Chemoter. 1946, 1, 90).

Their antiarrhythmic potential and ED 40% were compared with quinidine, whose antiarrhythmic activity was given the basic value 1. The results of this investigation are indicated in the following table:

The compound according to the invention is preferably administered orally and the pharmaceutical compositions containing them are preferably tablets, pills or gelatin capsules containing the active substance together with diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; or they may also contain binders such as starches, gum arabic, polyvinylpyrrolidone, disintegrants such as alginic acid and alginates, fizzy mixtures; dyes; sooting agents; humectants such as lecithin, polysorbates, lauryl sulphates. The pharmaceutical compositions for oral administration of the compound according to the invention can also be in liquid form such as drops or syrup.

The appropriate dosage for oral administration to adults is preferably around 30-100 mg per dose, e.g. 2-3 times a day.

The pharmaceutical compositions containing the compounds according to the invention may also be suitable for other administration methods, e.g. they may be suppositories for rectal administration or injectable solutions. Both suppositories and injectable solutions are manufactured in a conventional manner and contain usual carriers and respective solvents. E.g. suitable solvents for injections are sterile water, physiological saline solution, aqueous dextrose solutions.

The following examples illustrate, but . does not limit the present invention.

Example 1

5-hydroxy-1,2,3,4-tetrahydronaphthalene (44 g), 1,2-epoxy-3-chloro-propane (180 ml) and piperidine (0.5 ml) were refluxed for 12 hours. After drying, the residue was treated with a mixture of 10% sodium hydroxide (300 ml) and dioxane (400 ml). After stirring for two hours at room temperature, the dioxane was evaporated under vacuum. The basic water was extracted with ethyl ether, the ether was washed vigorously with water and after drying an oil was obtained which was crystallized from ethanol to give 5-(2,3-epoxy-propoxy)-1,2,3,4-tetrahydro-1 ,4-ethane-naphthalene (35 g) (KpQ2132-133°C).

By proceeding analogously, the following compounds were obtained: 6-(2,3-epoxy-propoxy)-1,2,3,4-tetrahydro-1,4-ethane-naphthalene, KpQ 2 130-132°C;

5-(2,3-epoxy-propoxy)-7-methyl-1,2,3,4-tetrahydro-1,4-ethane-naphthalene,

Kp0/15138°C{

,5-(2,3-epoxy-propoxy)-8-methyl-1,2,3,4-tetrahydro-1,4-ethane-naphthalene, Kp04145-150°C;

5-(2,3-epoxy-propoxy)-8-chloro-1,2,3,4-tetrahydro-1,4-ethanenaphthalene,

m.p. 74-75°C;

5-(2,3-epoxy-propoxy)-6,8-dichloro-1,2,3,4-tetrahydro-1,4-ethanenaphthalene,

m.p. 85-88°C;

5-(2,3-epoxy-propoxy)-6-chloro-1,2,3,4-tetrahydro-1,4-ethane N-naphthalene;

5-(2,3-epoxy-propoxy)-8-fluoro-1,2,3,4-tetrahydro-1,4-ethanenaphthalene;

5-(2,3-epoxy-propoxy)-8-methylthio-1,2,3,4-tetrahydro-1,4-ethanenaphthalene (oil);

5-(2,3-epoxy-propoxy)-8-methoxy-1,2,3,4-tetrahydro-1,4-ethane-naphthalene,

m.p. 52-55°C;

5-(2,3-epoxy-propoxy)-8-hydroxy-1,2,3,4-tetrahydro-1,4-ethane-naphthalene;

5-(2,3-epoxy-propoxy)-8-methylsulfonamido-1,2,3,4-tetrahydro-1,4-ethane-naphthalene;

5-(2,3-epoxy-propoxy)-8-nitro-1,2,3,4-tetrahydro-1,4-ethane-naphthalene,

m.p. 106-108°C;

5-(2,3-epoxy-propoxy)-6-chloro-8-hydroxy-1,2,3,4-tetrahydro-1,4-ethane-naphthalene;

5-(2,3-epoxy-propoxy)-1,2,3,4-tetrahydro-1,4-methane-naphthalene, KpO 2 122°C;

6-(2,3-epoxy-propoxy)-1,2,3,4-tetrahydro-1,4-methane-naphthalene, KpQ 2 120-123°C;

5-(2,3-epoxy-propoxy)-1,2,3,4-tetrahydro-1,4-methane-naphthalene, K<p>0 05114-116°C;

5-(2,3-epoxy-propoxy)-8-methyl-1,2,3,4-tetrahydro-1,4-methane-naphthalene;

5-(2,3-epoxy-propoxy)-8-chloro-1,2,3,4-tetrahydro-1,4-methane-naphthalene;

5-(2,3-epoxy-propoxy)-6,8-dichloro-1,2,3,4-tetrahydro-1,4-methane-naphthalene;

5-(2,3-epoxy-propoxy)-6-chloro-1,2,3,4-tetrahydro-1,4-methane-naphthalene;

5-(2,3-epoxy-propoxy)-8-fluoro-1,2,3,4-tetrahydro-1,4-methane-naphthalene;

5-(2,3-epoxy-propoxy)-8-methylthio-1,2,3,4-tetrahydro-1,4-methane-naphthalene;

5-(2,3-epoxy-propoxy)-8-methoxy-1,2,3,4-tetrahydro-1,4-methane-naphthalene;

5-(2,3-epoxy-propoxy)-8-hydroxy-1,2,3,4-tetrahydro-1,4-methane-naphthalene;

5-(2,3-epoxy-propoxy)-8-methylsulfonamido-1,2,3,4-tetrahydro-1,4-methane-naphthalene;

5-(2,3-epoxy-propoxy)-8-nitro-1,2,3,4-tetrahydro-1,4-methane-naphthalene;

5-(2,3-epoxy-propoxy)-6-chloro-8-hydroxy-1,2,3,4-tetrahydro-1,4-methane-naphthalene;

and the analogous 1,4-dihydro derivatives.

Example 2

5-hydroxy-1,2,3,4-tetrahydro-1,4-ethane-naphthalene (5 g) and 1,2-epoxy-3-bromobutane (5.3 g) in dimethylsulfoxide (20 ml) were treated with sodium hydroxide (1.4 g) dissolved in water (10 ml). The reaction mixture was heated at 60°C for 1 hour, then poured into water and extracted with ethyl ether. The organic extract was distilled off and 5-(2,3-epoxy-butoxy)-1,2,3,4-tetrahydro-1,4-ethanenaphthalene (4.9 g) was collected at 146°C/0, 5 mm.

By proceeding analogously, the following compounds were prepared: 5-(2,3-epoxy-butoxy)-1,2,3,4-tetrahydro-1,4-methane-naphthalene;

5-(2,3-epoxy-butoxy)-8-chloro-1,2,3,4-tetrahydro-1,4-methane-naphthalene;

5-(2,3-epoxy-butoxy)-6,8-dichloro-1,2,3,4-tetrahydro-1,4-methane-naphthalene;

5-(2,3-epoxy-butoxy)-8-chloro-1,2,3,4-tetrahydro-1,4-ethanenaphthalene,

Kp0^3145-148°C;

5-(2,3-epoxy-butoxy)-6,8-dichloro-1,2,3,4-tetrahydro-1,4-ethane-naphthalene;

as well as the other (2,3-epoxy-butoxy) derivatives, either of 1,2,3,4-tetrahydro-1,4-ethane-naphthalene or of 1,2,3,4-tetrahydro-1,4 -methane-naphthalene or of 1,4-dihydro-1,4-ethane-naphthalene or of, 1,4-dihydro-1,4-methane-naphthalene, in which R-1 and/or R2 have the same meanings as mentioned in example 1.

Example 3

5-(2,3-epoxy-propoxy)-1,2,3,4-tetrahydro-1,4-ethane-naphthalene (23 g;

0.1 mol) was dissolved in dioxane (600 ml), then 48% hydrobromic acid (100 ml) diluted with water (100 ml) was added. After stirring for 2 hours at room temperature, water (1000 ml) was added. Extraction with ethyl ether, washing the ether with water, drying, bleaching and drying gave a chromatographically pure oil, which on standing solidified to give 5-(3-bromo-2-hydroxy)-propoxy-1,2,3,4-tetrahydro -1,4-ethane-naphthalene in a practical quantitative yield (m.p. 65-68°C).

Proceeding analogously, the following compounds were prepared: 5-(3-bromo-2-hydroxy)-propoxy-1,2,3,4-tetrahydro-1,4-methane-naphthalene;

5-(3-bromo-2-hydroxy)-propoxy-8-chloro-1,2,3,4-tetrahydro-1,4-methane-naphthalene;

5-(3-bromo-2-hydroxy)-propoxy-6,8-dichloro-1,2,3,4-tetrahydro-1,4-methane-naphthalene;

5-(3-bromo-2-hydroxy)propoxy-8-chloro-1,2,3,4-tetrahydro-1,4-ethanenaphthalene;

5-(3-bromo-2-hydroxy)-propoxy-6,8-dichloro-1,2,3,4-tetrahydro-1,4-ethane-naphthalene;

as well as the other (3-bromo-2-hydroxy)-propoxy derivatives, either of 1,2,3,4-tetrahydro-1,4-ethane-naphthalene or of 1,2,3,4-tetrahydro-1 , 4-methane-naphthalene or of 1,4-dihydro-1,4-ethane-naphthalene or of 1,4-dihydro-1,4-methane-naphthalene, in which R 1 and/or R 2

have the same meanings as in example 1.

Example 4

5-(2,3-epoxy-butoxy)-1,2,3,4-tetrahydro-1,4-ethane-naphthalene (5 g) and morpholine (30 ml) were refluxed for 72 hours. After concentration in vacuo, dissolution in ethyl ether, extraction with 8% hydrochloric acid, filtration and alkalization with 5% NH^OH, an oil separated which was extracted with ethyl ether, then the ether was washed with water. Drying and saturation with gaseous HCl yielded a product which, after crystallization from isopropyl alcohol, gave 3-N-morpholinyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2 -butanol HCl, m.p. 213-216°C.

By proceeding analogously, the following compound was prepared: 3-N-pyrrolidinyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-butanol;

3- N -pyrazolidinyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-butanol;

3- N -imidazolidinyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-butanol;

3- N -piperidyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-butanol;

3-N-piperazinyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-butanol;

3-N-thiomorpholinyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-butanol;

3-N-morpholinyl-1-(1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-butanol;

3- N -pyrrolidinyl-1-(1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-butanol;

3-N-pyrazolidinyl-1-(1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-butanol;.

3- N -imidazolidinyl-1-(1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-butanol;

3- N -piperidyl-1-(1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-butanol;

3-N-piperazinyl-1-(1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-butanol;

3-N-thiomorpholinyl-1-(1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-butanol;

as well as 3-N-morpholinyl, 3-N-pyrrolidinyl, 3-N-pyrazolidinyl, 3-N-imidazolidinyl, 3-N-piperidyl, 3-N-piperazinyl, 3-N-thiomorpholinyl derivatives either of 1-(1 ,2,3,4-tetrahydro-1,4-ethane-naphthyloxy)-2-butanol or of 1-(1,2,3,4-tetrahydro-1,4-methane-naphthyloxy)-2-butanol or of 1-(1,4-dihydro-1,4-ethane-naphthyloxy)-2-butanol or of 1-(1,4-dihydro-1,4-methane-naphthyloxy)-2-butanol, wherein R , and/or R^ have the other meanings mentioned in example 1.

Example 5

To a suspension of sodium hydride (0.75 g) in dry dimethylformamide (300 ml), imidazole (2 g) was added portionwise, then after approx. half an hour, 5-(3-bromo-2-hydroxy)-propoxy-1,2,3,4-tetrahydro-1,4-ethane-naphthalene (10 g). After being allowed to stand at 60° C. for 8 hours, the solvent was evaporated, the residue dissolved in benzene and the benzene solution was vigorously washed with water. After drying, the residue was crystallized from toluene to give 3-N-imidazolyl-1-(1,2,3,4-tetrahydro-1T4-ethane-5-naphthyloxy)2-propanol (7.5 g;

m.p. 139-141°C).

By proceeding analogously, the following compounds were prepared: 3-N-imidazolyl-1-(1,2,3,4-tetrahydro-1,4-ethane-6-naphthyloxy)-2-propanol;

3- N -imidazolyl-1-(6-chloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3- N -imidazolyl-1-(7-methyl-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3- N-imidazolyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-ethane-5-riaphthyl-oxy)-2-propanol,

m.p. 125-129°C;

3-N-imidazolyl-1-(8-fluoro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol,

m.p. 146-148°C;

3-N-imidazolyl-1-(8-hydroxy-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol,

m.p. 153-156°C;

3-N-imidazolyl-1-(8-methyl-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-r propanol,

m.p. 112-114°C;

3-N-imidazolyl-1-(8-methylsulfonamido-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol,

m.p. 131-135°C;

3-N-imidazolyl-1-(8-nitro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol,

m.p. 116-119°C;

3-N-imidazolyl-1-(6-chloro-8-hydroxy-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3-N-imidazolyl-1-(6,8-dichloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

m.p. 139-141°C;

3-N-imidazolyl-1-(1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-imidazolyl-1-(6-chloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-imidazolyl-1-(7-methyl-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanolJ

3-N-imidazolyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy) 2-propanol;

3-N-imidazolyl-1-(8-fluoro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-imidazolyl-1-(8-hydroxy-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-imidazolyl-1-(8-methyl-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-imidazolyl-1-(8-methylsulfonamide-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-imidazolyl-1-(8-nitro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-imidazolyl-1-(6-chloro-8-hydroxy-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-imidazolyl-1-(6,8-dichloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-imidazolinyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3-N-imidazolinyl-1-(6-chloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3-N-imidazolinyl-1-(7-methyl-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2H-propanol;

3n-imidazolinyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3-N-imidazolinyl-1-(8-fluoro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3-N-imidazolinyl-1-(8-hydroxy-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3-N-imidazolinyl-1-(8-methyl-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3-N-imidazolinyl-1-(8-methylsulfonamido-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3-N-imidazolinyl-1-(8-nitro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3-N-imidazolinyl-1-(6-chloro-8-hydroxy-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3-N-imidazolinyl-1-(6,8-dichloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3-N-imiazolinyl-1-(1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol,

m.p. 106-109°C;

3-N-imidazolinyl-1-(6-chloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-imidazolinyl-1-(7-methyl-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-imidazolinyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-imidazolinyl-1-(8-fluoro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-imidazolinyl-1-(8-hydroxy-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-imidazolinyl-1-(8-methyl-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-imidazolinyl-1-(8-methylsulfonamido-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-imidazolinyl-1-(8-nitro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-imidazolinyl-1-(6-chloro-8-hydroxy-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-imidazolinyl-1-(6,8-dichloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-pyrazolyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3-N-pyrazolyl-1-(6-chloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3-N-pyrazolyl-1-(7-methyl-1,2,3,4-tetrahydroyl,4-ethane-5-naphthyloxy)-2-propanol; ;3- N -pyrazolyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol; ;3-N-pyrazolyl-1-(8-fluoro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol; ;3- N -pyrazolyl-1-(8-hydroxy-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol; ;3-N-pyrazolyl-1-(8-methyl-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol; ;3- N -pyrazolyl-1-(8-methylsulfonamido-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol; ;3-N-pyrazolyl-1-(8-nitro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol; ;3- N -pyrazolyl-1-(6-chloro-8-hydroxy-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol; ; 3-N-pyrazolyl-1-(6,8-dichloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol; ;3-N-pyrazolyl-1-(1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol; ;3-N-pyrazolyl-1-(6-chloro-1,2,3,4*-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-pyrazolyl-1-(7-methyl-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-pyrazolyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-methyl-5-naphthyloxy)-2-propanol;

3- N -pyrazolyl-1-(8-fluoro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

34tpyrazolyl-1-(8-hydroxy-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-pyrazolyl-1-(8-methyl-1,2,3,4-tetrahydrb-1,4-methane-5-naphthyloxy-2-propanol;

3-N-pyrazolyl-1-(8-methylsulfonamido-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-pyrazolyl-1-(8-nitro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-pyrazolyl-1-(6-chloro-8-hydroxy-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-pyrazolyl-1-(6,8-dichloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-pyrazolinyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propaneblf,

3- N -pyrazolinyl-1-(6-chloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol; -

3-N-pyrazolinyl-1-(7-methyl-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3-N-pyrazolinyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3-N-pyrazolinyl-1-(8-fluoro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3-N-pyrazolinyl-1-(8-hydroxy-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3-N-pyrazolinyl-1-(8-methyl-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3-N-pyrazolinyl-1-(8-methylsulfonamido-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3-N-pyrazolinyl-1-(8-nitro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3-N-pyrazolinyl-1-(6-chloro-8-hydroxy-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3-N-pyrazolinyl-1-(6,8-dichloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3-N-pyrazolinyl-1-(1,2,3,4-terahydro-1,4-methane-5-naphthyloxy,N-2-propanol;

3-N-pyrazolinyl-1-(6-chloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-pyrazolinyl-1-(7-methyl-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-pyrazolinyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-pyrazolinyl-1-(8-fluoro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-pyrazolinyl-1-(8-hydroxy-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-pyrazolinyl-1-(8-methyl-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-pyrazolinyl-1-(8-methylsulfonamido-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-pyrazolinyl-1-(8-nitro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-pyrazolinyl-1-(6-chloro-8-hydroxy-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-pyrazolinyl-1-(6,8-dichloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-triazolyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3-N-triazolyl-1-(6-chloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3-N-triazolyl-1-(7-methyl-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3-N-triazolyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3- N -triazolyl-1-(8-fluoro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3-N-triazolyl-1-(8-hydroxy-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy-2-propanol;

3-N-triazolyl-1-(8-methyl-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3-N-triazolyl-1-(8-methylsulfonamido-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3-N-triazolyl-1-(8-nitro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3- N -triazolyl-1-(6-chloro-8-hydroxy-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3-N-triazolyl-H6,8-dichloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)2-propanol;

3-N-triazolyl-1-(1,2,3,4-tetrahydro-1,4-methane-5-aminoethyloxy)-2-propanoyl;

3-N-triazolyl-1-(6-chloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-triazolyl-1-(7-methyl-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-triazolyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-triazolyl-1-(8-fluoro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-triazolyl-1-(8-hydroxy-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;,

3-N-triazolyl-1-(8-methyl-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-triazolyl-1-(8-methylsulfonamido-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-triazolyl-1-(8-nitro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-triazolyl-1-(6-chloro-8-hydroxy-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-triazolyl-1-(6,8-dichloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol,

as well as the other 3-N-imidazolyl, 3-N-imidazolinyl, 3-N-pyrazolyl, 3-N-pyrazolinyl and 3-N-triazolyl derivatives either of 1-(1,4-dihydro-1,4-ethane- naphthyloxy)-2-propanol or of 1-(1,4-dihydro-1,4-methane-naphthyloxy)-2-propanol, in which R, and/or R2 have the above meanings.

Example 6

To a suspension of sodium hydride (0.31 g) in anhydrous dimethyl formamide, imidazole (0.88 g) was added. The mixture was stirred for 30 minutes, then 5-(3-bromo-2-hydroxy)-propoxy-8-chloro-1,2,3,4-tetrahydro-1,4-ethane-naphthalene (4.5 g). After stirring for 24 hours at room temperature, filtering, drying under vacuum,

the residue was dissolved in chloroform, then after washing with water and drying 3-N-imidazolyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy) was again obtained - 2-propanol (3.9 g; m.p. 125-129°)

(crystallization from toluene).

3-N-imidazolyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4 ethane-5-naphthyloxy)-2-propanepl (3.9 g) was vigorously stirred in 23% HCl ( 150 ml) during dressing. After a few minutes, the hydrochloride of 3-N-imidazolyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol precipitates (3.8 g); m.p. 223-227°c).

By an analogous procedure, the hydrochlorides of the compounds mentioned were obtained

in examples 4 and 5 prepared.

Example 7

To a solution of 1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy-acetyl chloride (10 g) in ethyl ether (250 ml) containing triethylamine (5.7 ml) cooled to -5°C diazométane (2.6 g) dissolved in ethyl ether (400 ml) added. After stirring for 15 hours at 0°C, the hydrochloride of triethylamine was filtered off and the organic phase, after washing with water, was dried over MgSO 4 . The dry solution was then cooled to -15°C, then slowly saturated with gaseous. HBr. After standing overnight at room temperature, the ether solution was washed with water until neutral then dried and concentrated to give the crude bromoketone (9 g) as a reddish residue. To said crude bromoketone dissolved in tetrahydrofuran (100 ml), cooled to 5°C, NaBH 4 (2 g) dissolved in water (10 ml) was added in portions. After standing for 3 hours at room temperature, NaOH 2N (10 ml) was added. The mixture was then heated at 35°C for half an hour, concentrated under vacuum and the residue partitioned between water and ethyl ether. From the organic phase, a residue was obtained after usual treatment which was distilled in vacuum and gave 5-(.2, 3-epoxy-propoxy)-1, 2, 3, 4-tetrahydro-1,4-ethane-naphthalene (5 g ; boiling point: 117°C/0.2 mm).

By an analogous method, the following compound was prepared: 5-(2,3-epoxy-propoxy)-1,2,3,4-tetrahydro-1,4-methanenaphthalene, Kp0/2122°C;

5-(2,3-epoxy-propoxy)-8-chloro-1,2,3,4-tetrahydro-1,4-ethanenaphthalene, m.p. 74-75°C.

5-(2,3-epoxy-propoxy)-8-chloro-1,2,3,4-tetrahydro-1,4-methanenaphthalene;

5-(2,3-epoxy-propoxy)-6,8-dichloro-1,2,3,4-tetrahydro-1,4-ethanenaphthalene,

m.p. 85-88°C;

5-(2,3-epoxy-propoxy)-6,8-dichloro-1,2,3,4-tetrahydro-1,4-methane-naphthalene;

5-(2,3-epoxy-butoxy)-1,2,3,4-tetrahydro-1,4-ethanenaphthalene;

5-(2,3-epoxy-butoxy)-1,2,3,4-tetrahydro-1,4-methanenaphthalene;

5-(2,3-epoxy-butoxy)-8-chloro-1,2,3,4-tetrahydro-1,4-ethanenaphthalene;

5-(2,3-epoxy-butoxy)-8-chloro-1,2,3,4-tetrahydro-1,4-methane-naphthalene;

5-(2,3-epoxy-butoxy)-6,8-dichloro-1,2,3,4-tetrahydro-1,4-ethanenaphthalene,

5-(2,3-epoxy-butoxy)-6,8-dichloro-1,2,3,4-tetrahydro-1,4-methane-naphthalene,

as well as the other epoxy derivatives already described in examples 1 and 2.

Example 8

A solution of 5-hydroxy-1>2,3,4-tetrahydro-1,4-ethanenaphthalene (3.5 g) in ethyl alcohol (20 ml) containing the hydrobromide (6.3 g) of 1-bromo-3- N-morpholino-2-butanol and NaOH 2N (10 mL) were refluxed for 2 hours. After drying, the residue was partitioned between water and ethyl ether. The ether extract was saturated with hydrochloric acid gas and the solid precipitate was filtered off and crystallized from acetone/ethyl ether to give 3-N-aminopholinyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy) -2-butanol, hydrochloride (1.5 g; mp 213-216°C).

By analogous procedure, the hydrochloride of the following compound was prepared;

3-N-morpholinyl-1-(1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-butanol;

as well as the hydrochlorides of the other above mentioned compounds in example.'. 4.

Example 9

A solution of 1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-3-bromo-2-butanone (6.5 g) in tetrahydrofuran (50 mL) containing piperidine ( 4.3 ml) was left at room temperature for 5 days.

The precipitated piperidine hydrobromide was filtered off and the solvent evaporated under vacuum. The cake-like residue was treated with 23% HCl (50 mL) and ethyl ether (50 mL) and stirred for 30 minutes. The solid thus obtained was collected on a filter, then washed with 10% HCl and ethyl ether. The resulting white solid was then crystallized from isopropanol/ethyl ether to give 1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-3-N-piperidyl-2-butanone hydrochloride (4 .9 g) which was then dissolved in methanol (100 ml) and treated with NaOH IN (15.5 ml) and NaBH 2 (lg). After refluxing for 2 hours and concentrating to dryness, the product was isolated by extraction with ethyl ether. By saturating the ether extract with gaseous HCl and crystallization from acetone, the hydrochloride (4 g) of 3-N-piperidyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy) was obtained - 2-buranol (m.p. 195-196°C).

By an analogous procedure, the hydrochloride of the following compound was prepared: 3-N-piperidyl-1-(1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-butanol;

as well as the hydrochlorides of the other compounds mentioned in Example 4.

Example 10

To a solution kept at 5°C of imidazole (34 g) in dimethylformamide (60 ml), a solution of 1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-3 -bromo-2-propanone (25 g) in acetonitrile (60 ml) was added dropwise. After standing overnight at room temperature, the mixture was poured into an excess of water, then extracted with 1000 ml of ethyl ether. The ether was washed with water, and evaporated to dryness, the residue was dissolved in ethanol reduced by adding NaBH^ (3 g) portionwise to the solution at reflux temperature. The mixture was then refluxed for 10 minutes, then dried and taken up in HCl (200 mL). After neutralization with 8% NaOH, extraction with ethyl ether, vigorous washing with water and drying,

the residue crystallized from petroleum ether/toluene to give 3-N-imidazolyl-1-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol (16.2 g m.p. 139 -141°C).

By an analogous method, the following compounds are prepared: 3-N-imidazolyl-1-(1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol,

m.p. 106-109°C;

3-N-imidazolyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol,

m.p. 125-129°C;

3- N -imidazolyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3- N -imidazolyl-1-(6,8-dichloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol,

m.p. 139-141°C;

3-N-imidazolyl-1-(6,8-dichloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol,

as well as the other compounds mentioned in Example 5.

Example 11

To a solution of a Grignard reagent prepared from methyl iodide (3.4 g) and magnesium in ethyl ether, 3-N-imidazolyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5- naphthyloxy)-2-propanone (6 g). The mixture was refluxed for 3 hours,

then extracted with dilute HCl. Neutralization, extraction with ethyl ether, washing with water, drying and saturation with gaseous HCl gave 3-N-imidazolyl-2-methyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy )-2-propanol. HCl (3.1.g; mp 243-245°C).

By an analogous method, the hydrochlorides of the following compounds were prepared: 3-N-imidazolyl-2-methyl-1-(1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-imidazolyl-2-methyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3-N-imiazolyl-2-methyl-1-(8i-chloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-imidazolyl-2-methyl-1-(6,8-dichloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3-N-imidazolyl-2-methyl-1-(6,8-dichloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-pyrazolyl-2-methyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3- N -parazolyl-2-methyl-1-(1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-; 2-propanol;

3-N-pyrazolyl-2-methyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3-N-pyrazolyl-2-methyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-pyrazolyl-2-methyl-1-(6,8-dichloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3-N-pyrazolyl-2-methyl-1-(6,8-dichloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;,

3-N-pyrazolinyl-2-methyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3-N-pyrazolinyl-2-methyl-1-(1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-pyrazolinyl-2-methyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3-N-pyrazolinyl-2-methyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-pyrazolinyl-2-methyl-1-(6,8-dichloro-],2,3,4,-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3-N-pyrazolinyl-2-methyl-1-(6,8-dichloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-imidazolinyl-2-methyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3-N-imidazolinyl-2-methyl-1-(1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-imidazolinyl-2-methyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3-N-imidazolinyl-2-methyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-imidazolinyl-2-methyl-1-(6,8-dichloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3-N-imidazolinyl-2-methyl-1-(6,8-dichloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-triazolyl-2-methyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3-N-triazolyl-2-methyl-1-(1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-triazolyl-2-methyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;

3-N-triazolyl-2-methyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;

3-N-triazolyl-2-methyl-1-(6,8-dichloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;,

3-N-triazolyl-2-methyl-1-(6,8-dichloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol,

as well as the other 3-N-imidazolyl-2-methyl, 3-N-imidazolinyl-2-methyl, 3-N-pyrazolyl-2-methyl, 3-N-pyra£olinyl-2-methyl, and 3- N-triazolyl-2-methyl derivatives either of 1-(1,2,3,4-tetrahydro-1,4-ethane-naphthyloxy)-2-propanol or of 1-(1,2,3,4-tetrahydro- 1,4-methane-naphthyloxy)-2-propanol or of 1-(1,4-dihydro-1,4-ethane-naphthyloxy)-2-propanol or of 1-(1,4-dihydro-1,4- methane-naphthyloxy)-2-propanol in which R. and/or R2 have the other meanings mentioned in example 5.

Example 12

3-N-morpholinyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-

2-Butanol (2 g) was dissolved in toluene, and methyl iodide (2 ml) was added to the solution. After boiling for 3 hours and subsequent cooling, the crystalline solid thus obtained was filtered and gave 3-N-methyl-morpholinyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy) -2-butanol, hydroiodide.

Claims (1)

1. Process for the preparation of a compound of the following formula (I) in which the symbol - - - - represents a single or a double bond; n is 1 or 2; each of and is independently selected from the group consisting of hydrogen; halogen; hydroxy; C 1 - C 6 alkyl; C 1 - C 6 alkoxy; trihalomethyl; nitro; formyl; hydroxymethyl; amino, unsubstituted or substituted by one or two CX~C6 alkyl groups; C 1 -C 6 alkylsulfinyl; C 1 -C 8 alkylsulfinyl; Cx-C6 alkanesulfonamido; a residue -NHCOR 3 , wherein R 3 is C 1 -C 8 alkyl; a remainder wherein Rg and Rg are each independently selected from the group consisting of of hydrogen and C1-C6 alkyl; x 6 is a saturated or unsaturated heterocyclic ring containing at least one nitrogen atom and optionally one or more other heteroatoms selected from the group consisting of N, So and 0, where said ring is substituted or unsubstituted by one or more substituents selected from the group consisting of C± - C 1 -C 6 alkyl, C 1 -C 6 alkoxy, nitro, halogen, -CO0R, wherein R is hydrogen or C 1 -C 8 alkyl; R 1 , R 1 , and R 8 are each independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl; and pharmaceutical tolerable salts thereof as well as the quaternary ammonium salts thereof; characterized in that said method consists of: (a) reacting a compound of formula (II) in which the symbol - - - - n, Ri and Ro are defined as above and Z is one of the residues and in which R 4 , R 1 and R 2 are as defined above and X is halogen, med a compound of formula (III) or a salt thereof, i in which is as defined above; (b) conversion of a compound of formula (IV) in which the symbol - - - -, n, R^ and,'.R2 are as defined above, or a salt thereof with a compound of formula (V) in which is as defined above, and Y is one of the following residues: or in which X, R^ , Rj_ and Rg are as above defined; (c) reduction of a compound of the formula (VI) in which the symbol - - - , n, R±, R2 R 4-/ <R5> and is as defined above, whereby a compound of formula (I) is obtained in which R is hydrogen; 6 (dji reaction of a compound of formula (VI) with a Grignard reagent of formula R^ bM<g>X , in which X is as defined above and R& is C^Cg alkyl, whereby a compound of formula (I) is obtained, in which R& is Cx-<C>6 alkyl; and if desired, converting a compound of formula (I)' into another compound of formula (I), and/or if desired reacting a compound of formula (I) with a pharmaceutically acceptable acid to give a salt thereof and /or if desired converting a salt into a free base and/or if desired converting a compound of formula (I) into a quaternary ammonium salt thereof, and/or if desired dissolving a mixture of isomers into the individual isomers.