GB1597140A

GB1597140A - Tetralines

Info

Publication number: GB1597140A
Application number: GB50477/77A
Authority: GB
Original assignee: Sandoz AG
Current assignee: Sandoz AG
Priority date: 1976-12-07
Filing date: 1977-12-05
Publication date: 1981-09-03
Also published as: FR2373513A1; ATA871977A; DE2752659A1; NL7713364A; ES464747A1; PT67365A; NZ185884A; SU927110A3; FR2373513B1; IL53533A0; JPS6214540B2; PH13932A; PT67365B; AT366361B; IE45929B1; IL53533A; JPS5384955A; FI773595A; DK527877A; IE45929L

Description

(54) TETRALINES (71) We, SANDOZ LTD., of 15 Lichtstrasse, 4002 Basle, Switzerland, a Swiss Body Corporate, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- The present invention relates to 1,2,3,4tetrahydro-naphthalenes.

More particularly, this invention provides compounds of formula I,

wherein R1 is hydrogen, alkanoyl of 1 to 20 carbon atoms or a -CO-CH2)n-R7 group, n is a whole number from 0 to 5, R7 is a group of formula

and each of Y, and Y2 may independently be hydrogen, fluorine, chlorine, bromine, iodine, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or, when Y1 and Y2 are bonded to adjacent carbon atoms, Y1 and Y2 together may be methylenedioxy, R2 is hydrogen, hydroxy, alkanoyloxy of 1 to 20 carbon atoms, a -O-CO-(CH2)n-R7 group wherein n and R7 are as pre viously defined, fluorine, chlorine, bromine, iodine, alkyl of 1 to 4 carbon atoms, an alkylsulphonylamino group of 1 to 4 carbon atoms, CF3SO2NH, CCl3SO2NH, CH2OH, CH2-O-CO (CH2 )-R7, wherein n and R7 are as previously de fined, or -CH2-O-CO-R8, wherein R8 is hydrogen or alkyl of 1 to 19 carbon atoms, R3 is hydrogen or, when R2 is chlorine, R3 may also be chlorine, R4 is hydrogen, CH2OH, CH2O-CO-R8 or CH2-O-CO-(CH2)n-R7, wherein R7 and R8 are as previously defined, R5 is hydrogen, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 8 carbon atoms or (CH2)n-R9, wherein n is as pre viously defined and R9 is a group of formula,

wherein each of Y3, Y4 and Y5 may, independently, be hydrogen, fluorine, chlorine, bromine, iodine, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, -OH, -O-COR8, wherein R8 as previously defined, -O-CO-(CH2)n-R7, wherein n and R7 are as previously de fined or, when Y3 and Y4 are bonded to adjacent carbon atoms, Y3 and Y4 together may be methylenedioxy, R6 is hydrogen, alkyl of 1 to 4 carbon atoms or, together with R5, a -(CH2)4-, -(CH2)5 or (CH2)6 group, with the proviso that when two or more of the residues OR1, R2, Y3, Y4 and Y5 are a free or acylated OH group, these groups are identical, or when R2 and R4 are both free or acylated CH2-OH groups, these groups are identical, with the condition that when R4 is hydrogen and R2 is hydrogen, OH, alkyl or an acylated OH group, -NR5R6 is other than free amino or amino substituted by alkyl or benzyl, and is other than a hetero-ring, excepting as follows: a) when OR1 is in position 6 and R2 is hydrogen, -NR5R6 can be NH2 or b) when OR1 is in position 5 and R2 is hydrogen, -NR5R6 can be -NH2 or -NHCH3.

When R2, Y1, Y2, Y3, Y4 and Y5 are halogen, this is preferably fluorine or chlorine.

In the group -CO-(CH2)n-R7, n may be 0, 1, 2, 3, 4 or 5, preferably 0. R7 may be phenyl. Alternatively, R, may be phenyl mono- or di-substituted with fluorine, chlorine, bromine or iodine. In another group of compounds, R7 may be phenyl mono- or di-substituted with alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms. When bonded to adjacent carbon atoms, Y1 and Y, may form a methylenedioxy group.

R1 is preferably hydrogen.

The group -OR1 is preferably in the 5-, 6- or 7-position.

R2 is preferably hydrogen, halogen or an alkylsulphonamylamino group, especially hydrogen.

R5 is preferably hydrogen, alkyl or a -(CH2)n-R9 group.

In the group -(CH2)n-R9, n may be 0, 1, 2, 3, 4 or 5 preferebly 2, and R9 is preferably a 3,4-dihydroxy or a 3,4-dimethoxyphenyl residue.

R6 is preferably hydrogen or methyl.

When R1 is alkanoyl of 1 to 20 carbon atoms, this may, for example, be of 15 to 20 carbon atoms or of 10 to 14 carbon atoms.

Alternatively, R1 may be alkanoyl of 1 to 4 carbon atoms or of 5 to 9 carbon atoms.

When R2 is alkanoyl of 1 to 20 carbon atoms, this may, for example, be of 15 to 20 carbon atoms or of 10 to 14 carbon atoms.

R2 may also be fluorine, chlorine, bromine or iodine.

When R2 is alkyl of 1 to 4 carbon atoms, this is preferably methyl. When R2 is alkylsulphonylamino of 1 to 4 carbon atoms, this is preferably methylsulphonylamino. R2 may be CF3SO2NH or CCl3SO2NH. R2 may also be -CH2OH. Alternatively, R2 may be the group CH2-O-CO-(CH2)n-R7 as previously defined. R2 can also be the group CH2-O-CO-R8, wherein R8 is hydrogen or alkyl of 1 to 19 carbon atoms. When R8 is alkyl, this may, for example, be of 15 to 19 carbon atoms or of 10 to 14 carbon atoms.

Alternatively, R6 may be alkyl of 1 to 4 carbon atoms or of 5 to 9 carbon atoms. R8 may also be hydrogen.

R3 may be hydrogen. When R2 is chlorine, R3 may be hydrogen or chlorine.

R4 may be hydrogen. Alternatively, R4 may be CH2OH. R4 may be the group CH2O-CO-R8, wherein R8 is as previously defined. R4 may also be the group CH2-O-CO-(CH2)n-R7, wherein n and R7 are as previously defined.

R4 is preferably hydrogen or CH1OH.

R, may be hydrogen or alkyl of 1 to 4 carbon atoms. When R, is cycloalkyl of 3 to 8 carbon atoms, this is preferably of 5 or 6 carbon atoms.

R5 may be (CH2)n-R9, wherein n and R9 are as previously defined. R9 may be phenyl. Alternatively, R9 may be phenyl substituted by the groups Y3, Y4 and Y6 as previously defined. Y3, Y4 and Y5 may, independently, be fluorine, chlorine, bromine or iodine. Alternatively, each of Y3, Y4 and Y5 may independentyl, be alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms. One or more of Y3, Y4 and Y5 may be OH. In another group of compounds one or more of Y3, Y4 and Y5 may be -O-COR8, wherein R8 is as previously defined. In a further group of compounds, one or more of Y3, Y4 and Y5 may be -O-CO-(CH2)n-R7, wherein n and R7 are as previously defined.

When bonded to adjacent carbon atoms, Y3 and Y4 together may be methylenedioxy.

R6 may be hydrogen. Alternatively, R6 may be alkyl of 1 to 4 carbon atoms, for example, methyl.

R5 and R6 together may form a -(CH2)4-, -(CH2)5 or -(CH2)-6 group.

The invention further provides a process for the production of a compound of formula I comprising, a) producing a compound of formula Ia,

wherein R2' has the same significance as R2 with the exception of an alkanoyloxy or an -O-CO-(CH2)n-R7 group, R5' has the same significance as R5 with the exception of a (CH2)n-R9 group, wherein R9 contains an -O-COR8 or an -O-CO-( CH2 )n-IR, residue, by converting the alkoxy or benzyloxy group in a compound of formula II, to a hydroxy group by ether splitting,

wherein R10 is alkyl of 1 to 4 carbon atoms or benzyl, and R1l has the same significance as IR2, and, in addition, may signify alkoxy of 1 to 4 carbon atoms, or benzyloxy, b) producing a compound of formula Ib,

wherein IR1, is alkanoyl of 1 to 20 carbon atoms or -CO-(CH2)n-R7, R2" has the same significance as R2 with the exception of a free -OH group, and R5" has the same significance as R5 with the exception of a -(CH2)n-R9 group wherein the R9 group contains a free -OH group, by acylating a compound of formula III,

with a reactive derivative of a carboxylic acid of formula R8-COOH or R7-(CH2)n-COOH, or c) producing a compound of formula Ic,

wherein R2# is hydrogen, hydroxy, fluorine, chlorine, bromine or iodine, alkyl of 1 to 4 carbon atoms or CH20H, R4' is hydrogen or CH2OH, n' is a whole number from 1 to 5, and R9' has the same significance as R9 with the exception that R9 cannot contain an -O-COR8 or -O-CO-(CH2)n-R7 group, by reducing a compound of formula IV

Process variant a) can be effected in known manner for the splitting of ethers. The reaction may suitably be effected by means of a cleaving agent such as hydriodic acid, hydrobromic acid or hydrochloric acid, preferably in water or acetic acid, suitably at a temperature of from 0 to 1000 C, or boron tribromide, preferably in methylene chloride, suitably at a temperature of from 0 to 50"C. When employing hydrochloric acid, the reaction is preferably effected at a pressure of from 1 to 10 atm.

When Rlo is benzyl or when R11 is benzyloxy, the benzyl group can also be removed by catalytic hydrogenolysis. For these purposes, it is convenient to employ a noble metal catalyst, for example, a platinum catalyst, in quantities of from 2 to 10% (w/v) and to effect the reaction in ethanol.

In the case of the compounds of formula I wherein Y3) Y4 and/or Y6 is/are alkoxy, the appropriate starting material of formula II is selected in which Rlo is benzyl and the benzyl group is selectively removed.

Process variant b) can be effected according to known methods for the acylation of phenolic amino compounds. The acylation can, for example, be effected using an acylating agent, for example an acyl chloride or acid anhvdride. The reaction may suitably be effected in trifluoroacetic acid at room temperature.

Process variant c) can be effected according to known methods for the reduction of amides to amines. Diborane or a complex metal hydride, e.g. LiAIH4, may advantageously be used as reducing agent. The reduction is preferably effected in an inert solvent such as tetrahydrofuran at temperatures of from 25 to 750C. When R2"' Y3n Y4 and/or Y2 is/are halogen, diborane should be used as the reducing agent; otherwise, there is a possibility of at least partial removal of the halogen atoms from the benzene ring.

The resulting compounds of formula I may be isolated and purified using conventional techniques.

Free base forms of the compounds of formula I may be converted into acid addition salt forms and vice versa in conventional manner.

The compounds of formula I can exist in the form of enantiomers or in racemate form.

The racemates can be resolved into their optically active isomers in known manner.

The compounds of formula II, wherein R is hydrogen, are generally obtainable by known methods from known 5, 6, 7- or 8alkoxy (or benzyloxy) -2-aminotetralines (or analogues thereof which can be prepared by known processes), which can have a second alkoxy or benzyloxy group in the benzene ring and which, if required, are already substituted by alkyl groups on the nitrogen atom.

When such compounds possess a free amino group in the 2-position, this group may be converted into a --NR,'R, group by alkylation, arylation or aralkylation. The conversion can be effected according to known methods, e.g. by reductive alkylation or by means of an alkyl halide.

The introduction of the substituents IR2,,, and IR, can be effected as follows: a) Introduction of an alkyl-, trifluoro- or trichloromethylsulphonamido group: The alkoxyamino tetralines (wherein the amino group can, if required, be temporarily protected with an acyl group) used as start ing materials are first nitrated according to known methods, e.g. with nitrous acid in methylene chloride, the resulting isomeric mixture separated chromatographically and the nitro-compound so obtained reduced to the corresponding amino derivative, e.g. by means of palladium on charcoal. The amino compounds are finally converted to the alkyl trifluoro- or trichlorosulphonylamine deriva tives by means of an alkyl-trifluoromethyl or trichloromethylsulphonyl halide. b) Bromination, chlorination, iodination: The starting materials of formula II, wherein Rl1 (and, where appropriate, R3) is chlorine, bromine or iodine, can be prepared by reacting the alkoxytetraline (wherein the amino group may be temporarily protected with an acyl group) with an appropriate halo genating agent Suitable halogenating agents include, for example, sulphuryl chloride, bromine or iodine (in the presence of an equivalent quantity of silver trifluoroacetate) in an inert solvent such as methylene chloride.

The usual mixture of products, comprising compounds which have been halogenated in the > or p-position to the alkoxy group, is obtained and can be separated on Kieselgel. c) Florination: Alkoxyaminotetralines, which are substituted in the benzene ring with an -NH, group [preperable as under a)], are employed as starting materials and are converted to the corresponding fluorine derivatives according to a Balz-Schiemann reaction. The starting materials are thereby first diazotised, precipi tated in the form of the fluoroborate, isolated and thermally decomposed. d) Introduction of the CH,OH group: The introduction of the CH,OH group may advantageously be effected via formylation and subsequent reduction of the formyl group to the hydroxymethyl group. Alkoxytetralines (wherein the amino group can, if required, be protected with an acyl group) are employed as starting materials. The formylation can be effected, for example, according to the Gatterman reaction, with hydrogen cyanide in the nresence of a Friedel-Crafts catalyst. After separation of the isomers from the reaction mixture, the formyl group in the desired compound can be reduced to the hydroxymethyl group, for example, with a reducing agent such as diborane or LiAlHJ in an inert solvent such as tetranydroturan.

The compounds of formula II wherein R4 is a CH2OH group, R3, R5' and R6 are each hydrogen and R11 is hydrogen, alkyl, alkoxy or benzyloxy, can be obtained from the corresponding compounds of formula II wherein R4 is a COOH or a COOR (R = alkyl of 1 to 4 carbon atoms) group. These latter compounds are either known or can be produced by known methods for the preparation of aamini acids. For example, the compounds can be obtained from the corresponding tetralones by reaction with potassium cyanide and ammonium carbonate and subsequent dezom- position of the resulting hydantoin derivative.

The reduction of the compounds wherein R4 Is a COOH or COOR group to compounds wherein RS is CH2OH may be effected in known manner for the reduction of a carbonyl group to a hydroxymethyl group. The reduction can, for example, be effected with a reducing agent such as diborane or lithium aluminium hydride, in an inert solvent such as tetrahydrofuran or dioxane, at a temperature of from 0 to 100 C. The reduction of the compounds of formula III, wherein R is alkyl, may suitably be effected with a borohydride, preferably an alkali metal borohydride such as sodium borohydride, in ethanol, tetrahydrofuran, dioxane or water.

The introduction of the additional substituents R3, R11, R5' and R6 in the compounds of formula II wherein R4 is CH1OH can be effected in the same manner as for compounds wherein R4 is hydrogen. In most cases, the substitution will already have beer effected in the earlier step, ie. in the compounds wherein R4 is a COOH or a COOP group.

Compounds of formula II, wherein R and/or R4 are an acylated CH2OH group, can be prepared by acylation, e.g. as described in process variant b), of the corresponding compounds wherein R11 and/or RO are a free CH2OH group.

The starting materials of formula III can be prepared in accordance with process variant a) or c).

The starting materials of formula IV can be produced bv acylation of the corresponding unacylated compound with a reactive deriva tive of an acid of formula IR6'-(CH1)n'a-COOH.

Suitable reactive derivatives are, for example, acid chlorides or N-hydroxysuccin imide esters.

In the following Examples, all temperatures are in degrees Celsius.

EXAMPLE 1.

2-Amino-1,2,3,4-tetrahydro-8-hydroxy-2- hydroxy-methylnaphthalene. a) 2 - Amino - 2 - carboxy - 1,2,3,4 - tetra hydro - 8 - methoxynaphthalene.

28 g of potassium cyanide, followed by 76.5 g of ammonium carbonate, are added to a suspension of 50 g of 8-methoxy-2 tetralone in 350 ml of isopropanol. The mix ture is stirred at 60 for 20 hours, cooled to room temnerature, then 400 ml of water are added, and the reaction mixture left to stand at 40 in order to crystallise. 8-Methoxy-2 spirohydantoin tetraline crystallises out, with a melting point of 216-217 . 42 ml of a 49% aqueous sodium hydroxide solution are added to a suspension of 21 g of 8-methoxy 2-spirohydantoin tetraline in 130 ml of propylene glycol, and the reaction mixture heated, with stirring, for 24 hours to 19(a0.

The cooled solution is decolourised with acti vated charcoal, adjusted to a pH of 1 with concentrated hydrochloric acid, the resulting precipltate filtered off, and the mother liquor adjusted to a pH of 5.5 with a sodium bicarbonate/acetate acid buffer solution. The title compound which crystallises out has melting point of 228230 after isolation and drying. b) 2 - Amino - 1,2,3,4 - tetrahydro - 8 methoxy 2 hydroxymethylnaphtha lene.

A suspension of 14.5 g of 2 - amino - 22 - carboxy - 1,2,3,4 - tetrahydro - 8methoxynaphthalene in 400 ml of tetrahydrofuran is added dropwise with stirring (under a nitrogen atmosTrhere) to 525 ml of a 1molar solution of diborane in tetrahydrofuran.

The reaction solution is then boiled at reflux for 12 hours and cooled to room temperature.

400 ml of a solution of 2N hydrogen chloride in ethanol are added to the residue, the mixture is boiled at reflux for 2 hours, the cooled solution evaporated and the residue is shaken out with 1N aqueous sodium hydroxide/ methylene chloride solution. The organic phase is evaporated to dryness, the residue chromatographed on silica gel with a mixture of 10% ammonia-methylene chloride solution and methanol (9:1). The title compound, which is in the form of an oil, is dissolved in ethanol/ ether (1:1) and, in order to convert the compound into the hydrochloride form, one equivalent of an 4N ethereal hydrogen chloride solution is added, and the mixture left to stand at 40 so as to crystallise. The title compound is obtained in the form of the hydrochloride.

M.P. 153154o. c) 2 - Amino - 1,2,3,4 - tetrahydro - 8 hydroxy - 2 - hydroxy - methylnaphtha lene.

5 g of 2 - amino - 1,2,3,4 - tetrahydro - 8 methoxy - 2 - hydroxymethyl - naphthalenehydrochloride are suspended in 100 ml of methylene chloride, and 6.8 ml of boron tribromide are added. The reaction solution is stirred for 4 hours at room temperature, then 10 ml of methanol are added, and the reaction mixture evaporated. The residue is freed from boron esters by boiling down 5 times, each time with 50 ml of ethanol, then shaken out with a mixture of 1N aqueous potassium bicarbonate solution and methylene chloride/ isopropanol (2:1), and the residue of the dried concentrated organic phase is chromatographed on silica gel with a mixture of 10% ammoniamethylene chloride solution and methanol (7:3). The title compound, which is obtained as a foam, is dissolved in ethanol, ethereal hydrogen chloride solution is added, and the mixture left to stand at 100, whereby the title compound is obtained in the form of the hydrogen chloride. M.P. 191-1930C.

EXAMPLE 2.

2 - Amino - 1,2,3,4 - tetrahydro - 6 - acetoxy 2 - methylnaphthalen.

1 ml of acetyl chloride is added to a suspension of 1 g of 2 - amino - 1,2,3,4 - tetrahydro - 6 - hydroxy - 2 - hydroxymethylnaphthalene - hydrobromide in 12 ml of trs- fluoroacetic acid, whereupon the whole mixture immediately goes into solution, and gas develops. The reaction mixture is then stirred for 1* hours at room temperature and lyophilised. The residue is rubbed with 50 ml of ether, suctioned off and washed with 50 ml of ether.

NMR Spectrum (CDDCf3): e = 1.7 & 3H, s); 1.8 (3H, s); 2.2-3.3 (6H, m); 3.8 (2H, s); 6.4-7.0 (3H, m).

EXAMPLE 3.

N - [2 - (3,4 - dimethoxyphenyl)ethyl] - 2 methylamino - 1,2,3,4 - tetrahydro 6- hydroxynaphthalene - hydrochloride.

4.6 g of N - [2 - (3,4 - dimethoxyphenyl)acetyl] - 2 - methylamino - 1,2,3,4 - tetrahydroxynaphthalene are suspended in 70 ml of tetrahydrofuran with stirring. 65 ml of a 1 Molar solution of diborane in tetrahydrofuran are added dropwise and the reaction solution stirred for 3 hours at room temperature and finally for a further 3 hours at 60".

An excess of 4N hydrochloric acid is added to the cooled reaction mixture. The mixture is finally dried, methanol is added to the mixture, evaporated and the procedure repeated several times. The residue which is then ob tained is chromatographed on Kieselgel with methylene chloride/methanol (9:1). The title compound which is isolated, is dissolved in methanol, methanolic hydrogen chloride is added, and the mixture evaporated to dryness.

The residue is dissolved in 50 ml of iso propanol and the title compound, in the form of the hydrochloride, is precipitated by the addition of 300 ml of ether. M.P.: sinters at 95".

The N - [2 - (3,4 - dimethoxyphenyl) acetyl] - 2 - methylamino - 1,2,3,4 - tetra hydro - 6 - hydroxynaphthalene used as starting material is obtained by the reaction of 6 - hydroxy - 2 - methylamino - 1,2,3,4 tetrahydronaphthalene with the hydroxysuccin imide ester of 3,4-dimethoxyphenyl acetic acid in dimethylformamide at room temperature.

The following compounds can be obtained in manner analogous to those described in the aforementioned Examples employing appro priate starting materials in approximately equivalent amounts.

TABLE I (Compounds of Formula I, wherein R3 = H, R4 = CH2OR14)

Ex. No. OR1 R2 R14 R5 R6 M.P.

4 6-OH H H H H 248 (Hydrobromide) 1) 5 6-OH H H H H 300 Decomp. (Hydrochloride) 2) 6 6-OH H H H H 293 Decomp. (Hydrochloride) 3) 7 6-p-Toluoyloxy H p-Toluoyl H H 115 Effervesence (Hydrobromide) 8 6-Pivaloyloxy H Pivaloyl H H 100 Effervescence (Hydrobromide) 9 5-OH H H H H 218-21 (Hydrochloride) 10 6-OH H H CH3 H 233 (Hydrobromide) 11 6-OH H H CH3 CH3 226 (Hydrobromide) 12 6-OH H H i-C3H7 H 175 (Hydrobromide) 13 6-OH H H Benzyl H 235 (Hydrochloride) 14 6-OH 5-Cl H H H 235 (Hydrobromide) 15 6-OH 7-OH H H H 85 Effervescence (Hydrobromide) 16 7-OH H H H H 216-18 (Hydrochloride) 17 5-OH H H n-C3H7 n-C3H7 210-12 (Hydrochloride) 1) Racemate 2) L-Form 3) D-Form TABLE II (Compounds of Formula I, wherein R4 = H)

Ex. No. OR1 R2 R3 R5 R6 M.P.

18 5-OH H H H H 244-47 (Hydrobromide) 19 6-OH H H H H 302-05 (Hydrobromide) 20 5-OH H H CH3 H 258-62 (Hydrobromide) 21 5-OH 8-Cl H H H 202-04 (Hydrobromide) 22 6-OH 5-Cl H n-C3H7 H 270-72 (Hydrobromide) 23 6-OH 5-Cl H H H 333-39 (Hydrobromide) 24 5-OH 6-Cl H H H 273-75 (Hydrobromide) 25 5-CH3COO H H H H 225-26 (Hydrobromide) 26 6-OH 5-Br H H H 288-89 (Hydrochloride) 27 6-OH 5-Cl 7-Cl H H > 300 (Hydrobromide) 28 6-CH3COO H H H H 239-40 (Hydrobromide) 29 8-OH 5-Cl H H H 305-08 (Hydrobromide) 30 6-OH 5-Cl H n-C3H7 n-C3H7 220-23 (Hydrochloride) 31 6-OH 7-CH3SO2NH H H H 227-30 (Hydrochloride) 32 6-OH 5-CH3SO2NH H H H > 300 (Hydrochloride) TABLE II (Continued) (Compounds of Formula I, wherein R4 = H)

Ex. No. OR1 R2 R3 R5 R6 M.P.

220 (Hydrochloride) 33 8-OH 5-CH3SO2NH H H H s. 1) 276 (Hydrochloride) 34 5-OH 8-CH3SO2NH H H H s. 1) 35 8-OH 7-CH3SO2NH H H H s. 1) 160 (Hydrochloride) 36 6-OH 7-CH3SO2NH H CH3 CH3 207-10 (Hydrochloride) 37 5-OH 6-CH3SO2NH H H H > 300 (Hydrochloride) 38 5-OH 6-CH3SO2NH H n-C3H7 n-C3H7 222-25 (Hydrochloride) 39 6-OH 5-CH3SO2NH H n-C3H7 n-C3H7 237-39 (Hydrochloride) 40 5-OH 8-CH3SO2NH H n-C3H7 n-C3H7 s. 1) 135-140 (Hydrochloride) 41 5-OH 8-Cl H n-C3H7 n-C3H7 210-12 (Hydrochloride) 42 5-OH 6-Cl 8-Cl n-C3H7 n-C3H7 218-20 (Hydrochloride) 1) sinters TABLE III (Compounds of formula I, wherein R2, R3, R4 = H and R5 =

Ex. No. OR1 R6 Y3 Y4 M.P.

43 6-OH H 3-OH 4-OH 207 Effervescence (Hydrobromide) 44 6-OH H 3,4-Methylenedioxy 224-28 (Hydrochloride) 45 6-OH CH3 3-OH 4-OH s. 1) 70 (Hydrobromide) 46 6-OH CH3 3,4-Methylenedioxy 192-96 (Hydrochloride) 47 5-OH CH3 4-OCH3 H 177-80 (Hydrochloride) 48 5-OH CH3 4-OH H 170 (Hydrochloride) 1) sinters The compounds of formula I exhibit pharmalogical activity. In particular, the compounds exhibit activity for the treatment of heart con diticns, such as cardiac failure and shock, increased blood pressure and/or Parkinson's disease, as indicated in standard tests, for example, in observations in the "open-chest" dog.

The compounds are therefore indicated for use in the treatment of heart conditions, such as cardiac failure and shock, increased blood pressure and or Parkinson's disease.

The Example 1 compound exhibits interesting activity in tests in dicaling in the habitat of e.g. heart conditions, such as cardiac failure and shock.

For these uses, an indicated daily dose is from 5 to 200 mg, suitably from about 5 to about 100 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage fo

Claims

WHAT WE CLAIM IS:

1. A process for the production of a compound of formula I,

wherein R1 is hydrogen, alkanoyl of 1 to 20 carbon atoms or a -CO-( CH2 )-IRT group, n is a whole number from 0 to 5, R7 is a group of formula

and each of Y1 and Y2 may independently be hydrogen, fluorine, chlorine, bromine, iodine, alky lof 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or, when V1 and Y2 are bonded to adjacent carbon atoms, V1 and V2 together may be methylenedioxy, R2 is hydrogen, hydroxy, alkanoyloxy of I to 20 carbon atoms, a -O-CO-(CH2 )1-IR7 group wherein n and R7 are as previously defined, fluorine, chlorine, bromine, iodine, alkyl of 1 to 4 carbon atoms, an alkylsulphonylamino group of 1 to 4 carbon atoms, CF,S O2NH, CCI, S O2NH, CH2OH, CH2-O-CO-(CH2)n-R7, wherein n and R7 are as previously defined, or CH2-O-CO-R8, wherein R8 is hydrogen or alkyl of 1 to 19 carbon atoms, R3 is hydrogen or, when R2 is chlorine, R3 may also be chlorine, R4 is hydrogen, CH20H, CH2O-CO-IR1 or CH2-O-CO-(CH2)nR7, wherein R7 and R8 are as previously defined, R5 is hydrogen, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 8 carbon atoms or (CH2)n-R9, wherein n is as pre viously defined and R9 is a group of formula,

wherein each of Y3, Y4 and Y5 may, independently, be hydrogen, fluorine, chlorine, bromine, iodine, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, -OH, -O-COR8, wherein R8 is as previously defined, -O-CO-(CH2)n-R7, wherein n and R7 are as previously defined or, when Y, and Y, are bonded to adjacent carbon atoms, Y3 and Y4 together may be methylenedioxy, R6 is hydrogen, alkyl of 1 to 4 carbon atoms or, together with R5, a -(CH2)@-, -(CH2)5 or -(CH2)6- group, with the proviso that when two or more of the residues ORI, R2, YQ, Y4 and V2 are a free or acylated OH- group, these groups are identical, or when IR, and R4 are both free or acylated CH2-OH groups1 these groups are identical, with the condition that when R4 is hydrogen and R2 is hydrogen, OH, alkyl or an acylated OH group, -NR5R6 is other than free amino or amino substituted by alkyl or benzvl, and is other than a hetero-ring, excepting as follows: a) when OR1 is in position 6 and R2 is hydrogen, -NR5R6 can be NH2 or b) when OR1 is in position 5 and R2 is hydrogen, -NR5R6 can be -NH, or -NHCH8, comprising a) producing a compound of formula Ia,

wherein IR1, has the same significance as R2 with the exception of an alkanoyloxy or an -O-CO-(CH2)n-R7 group, R5' has the same significance as Rs with the exception of a (CH2)n-R9 group, wherein R9 contains an -O-COR8 or an -O-CO-(CH2)n-R7 residue, by converting the alkoxy or benzyloxv group in a compound of formula II, to a hydroxy group by ether splitting,

wherein R10 is alkyl of 1 to 4 carbon atoms or benzyl, and R11 has the same significance as R@' and, in addition, may signify alkoxy of 1 to 4 carbon atoms or benzyloxy, b) producing a compound of formula Ib,

wherein IR1, is alkanoyl of 1 to 20 carbon atoms or -CO-(CH2)n-R7, IR21, has the same significance as R2 with the exception of a free -OH grctlp, and R5" has the same significance as R5 with the exception of a -(CH2)n-R9 group wherein the R9 group contains a free -OH group, by acylating a compound of formula III,

with a reactive derivative of a carboxylic acid of formula COOH or IR-CH, ),,-COOH or c) producing a compound of formula Th

wherein R2" is hydrogen, hydroxy, fluorine, chlorine, bromine or iodine, alkyl of 1 4 carbon atoms or CH2OH, IR4, is a whole number hydrogen or CH2OH, n' is a whole number from 1 to 5, and R9' has the same significance as R9 with the exception that R9 cannot contain an -O-COR8 or -O-CO-(CH2)n-R7 group, by reducing a compound of formula IV

2. A process for the production of a compound of formula I, as defined in Claim 1, substantially as hereinbefore described with reference to any one of the Examples.

3. A compound of formula I, whenever produced by a process as claimed in Claim 1 or 2.

4. A compound of formula I, as defined in Claim 1.

5. A compound of Claim 4, wherein R1 is hydrogen, alkanoyl of 1 to 13 carbon atoms or a group -CO-(CH2)-R7 wherein n is a whole number from 0 to 5 and R7 is phenyl or phenyl monosubstituted with alkyl of 1 to 4 carbon atoms, R2 is hydrogen, hydroxy, alkanoyloxy of 1 to 13 carbon atoms or a group -O-CO-(CH2)n-R7 wherein n is a whole number from 0 to 5 and R7 is phenyl or phenyl monosubstituted with alkyl of 1 to 4 carbon atoms, R4 is -CH2OR1 wherein R1 is hydrogen, alkanoyl of 1 to 13 carbon atoms or a group -CO-(CH2)n-R7 wherein n is a whole number from 0 to 5 and R7 is phenyl or phenyl monosubstituted with alkyl of 1 to 4 carbon atoms, R is hydrogen, R5 is hydrogen or alkyl of 1 to 4 carbon atoms and R6 is hydrogen or alkyl of 1 to 4 carbon atoms.

6. A compound of Claim 4, wherein R1 is hydrogen, alkanoyl of 1 to 13 carbon atoms or a residue of formula

wherein each of Y1 and Y2, which may be the same or different, is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, fluorine, chlorine or bromine and each of R2, R3, R4, R5 and R6 is hydrogen.

7. 2 - Amino - 1,2,3,4 - tetrahydro - 8 hydroxy - 2 - hydroxy - methylnaphthalene.

8. 2 - Amino - 1,2,3,4 - tetrahydro - 6 acetoxy - 2 - methylnaphthalene.

9. N - [2 - (3,4 - dimethoxyphenyl)ethyl] 2 - methylamino - 1,2,3,4 - tetrahydro - 6 hydroxynaphthalene.

10. A compound of Claim 4, wherein R1, R,, R5 and R, are as defined, R, is hvdrogen and R4 is CH3OR14 wherein R14 is hydrogen, toluoyl or pivaloyl.

11. A compound of Claim 10 wherein OR1 is 6-OH and each of R2, R14, R5 and R6 is hydrogen.

12. A compound of Claim 10 wherein OR1 is 6-p-toluoyloxy, R14 is p-toluoyl and each of R2, R5 and R6 is hydrogen.

13. A compound of Claim 10 wherein OR1 is p-pivaloyloxy, R14 is pivaloyl and each of R,, R, and R6 is hydrogen.

14. A compound of Claim 10 wherein OR1 is 5-OH and each of R2, R14, R5 and R6 is hydrogen.

15. A compound of Claim 10 wherein ORl is 6-OH, R, is CH2 and each of R2, R14 and R6 is hydrogen.

16. A compound of Claim 10 wherein OR is 6-OH, each of R2 and R14 is hydrogen and each of R5 and R6 is CH3.

17. A compound of Claim 10 wherein OR1 is 6-OH, R5 is i-C3H7 and each of R2, R14 and R6 is hydrogen.

18. A compound of Claim 10 wherein OR, is 6-OH, R is benzyl and each of R2, Rl4 and R6 is hydrogen

19. A compound of Claim 10 wherein OR1 is 6-OH, R2 is 5-Cl and each of R14, R5 and R6 is hydrogen.

20. A compound of Claim 10 wherein ORl is 6-OH, R2 is 7-OH and each of R14, R5 and R6 is hydrogen.

21. A compound of Claim 10 wherein ORl is 7-OH and ecah of R2, R14, R5 and R6 is hydrogen.

22. A compound of Claim 10 wherein OR1 is 5-OH, each of R2 and R14 is hydrogen and each of R5 and R6 is n-C3H7.

23. A compound of Claim 4 wherein R4 is hydrogen.

24. A compound of Claim 23 wherein OR1 is 5-OH and each of R2, R3, R5 and R6 is hydrogen.

25. A compound of Claim 23 wherein OR1 is 6-OH and each of R2, R3, R5 and R6 is hydrogen.

26. A compound of Claim 23 wherein OR is 5-OH, R5 is C3 and each of R2, R3 and R6 is hydrogen.

27. A compound of Claim 23 wherein OR1 is 5-OH, R2 is 8-Cl and each of R3, R5 and R6 is hydrogen.

28. A compound of Claim 23 wherein OR1 is 6-OH, R2 is 5-Cl, R5 is n-C3H7 and each of R3 and R6 is hydrogen.

29. A compound of Claim 23 wherein OR1 is 6-OH, R2 is 7-CH3SO2NH, R3 is hydrogen and each of R5 and R6 is CH3.

30. A compound of Claim 23 wherein OR1 is 6-OH, R2 is 5-Cl and ecah of R3, R5 and R6 is hydrogen.

31. A compound of Claim 23 wherein OR1 is 5-OH, R2 is 6-Cl and each of R3, R5 and R6 is hydrogen.

32. A compound of Claim 23 wherein OR1 is 5-CH3COO and each of R2, R3, R5 and R6 is hydrogen.

33. A compound of Claim 23 wherein OR1 is 6-OH, R2 is S-Br and each of Rs, R5 and R6 is hydrogen.

34. A compound of Claim 23 wherein ORl is 6-OH, R2 is 5-Cl, R3 is 7-Cl and each of R5 and R6 is hydrogen.

35. A compound of Claim 23 wherein OR1 is 6-CH3COO and each of R2, R3, R5 and R6 is hydrogen.

36. A compound of Claim 23 wherein OR1 is 8-OH, R2 is 5-Cl and each of R3, R5 and R6 is hydrogen.

37. A compound of Claim 23 wherein OR1 is 6-OH, R2 is 5-Cl, R3 is hydrogen and each of R5 and R6 is n-C3H7.

38. A compound of Claim 23 wherein OR1 is 6-OH, R2 is 7-CH1SO,NH and each cf R3, R5 and R6 is hydrogen.

39. A compound of Claim 23 wherein OR1 is 6-OH, R, is 5-CH3SO2NH and each of R3, R5 and R6 is hydrogen.

40. A compound of Claim 23 wherein OR1 is 8-OH, R2 is 5-CH3SO2NH and each of R3, R5 and R6 is hydrogen.

41. A compound of Claim 23 wherein OR1 is 5-OH, R2 is 8-CH3SO2NH and each of R3, R5 and R6 is hydrogen.

42. A compound of Claim 23 wherein OR1 is 8-OH, R2 is 7-CH2SO2NH and each of R3, R5 and R6 is hydrogen.

43. A compound of Claim 23 wherein OR1 is S-OH, R, is 6-CH1SO,NH and each of R3, R5 and R6 is hydrogen.

44. A compound of Claim 23 wherein OR1 is 5-OH, R2 is 6-CH3SO2NH, R3 is hydrogen and each of R5 and R6 is n-C3H7.

45. A compound of Claim 23 wherein OR1 is 6-OH, R2 is 5-CH3SO2NH, R3 is hydrogen and each of R5 and R6 is n-C3H7.

46. A compound of Claim 23 wherein OR1 is 5-OH, R2 is 8-CH3SO2NH, R3 is hydrogen and each of R5 and R6 is n-C3H7.

47. A compound of Claim 23 wherein OR1 is 5-OH, R2 is 8-Cl, R3 is hydrogen and each of R5 and R6 is n-C3H7.

48. A compound of Claim 23 wherein OR1 is 5-OH, R2 is 6-Cl, R3 is 8-Cl and each of R5 and R6 is n-C3H7.

49. A compound of Claim 4 wherein each off R2, R3 and R4 is hydrogen, Rg is

wherein Y3 and Y4 are as defined and R6 is hydrogen or methyl.

50. A compound of Claim 49 wherein OR1 is 6-OH, R2 is hydrogen, Y3 is 3-OH and Y4 is 4-OH.

51. A compound of Claim 49 wherein OR1 is 6-OH, R6 is hydrogen and Y3 and Y4 together are 3,4-methylenedioxy.

52. A compound of Claim 49 wherein OR1 is 6-OH, R6 is CH3, Y3 is 3-OH and Y4 is 4-OH.

53. A compound of Claim 49 wherein OR1 is 6-OH, R6 is CH3 and Y3 and Y4 together are 3,4-methylenedioxy.

54. A compound of Claim 49 wherein OR1 is 5-OH, Rx6 is CH3, Y3 is 4-OCH3 and V4 is hydrogen.

55. A compound of Claim 49 wherein OR1 is 5-OH, R6 is CH3, Y3 is 4-OH and Y4 is hydrogen.

56. A compound according to any one of Claims 3 to 55 in racemate form.

57. A compound according to any one oi Claims 3 to 55 in L-form.

58. A compound according to any one of Claims 3 to 55 in D-form.

59. A compound according to any one of Claims 3 to 58 in free base form.

60. A compound according to any one of Claims 3 to 58 in acid addition salt form.

61. A pharmaceutical composition comprising a compound according to any one of Claims 3 to 58, in free base form or in association with a pharmaceutically acceptable diluent or carrier.