IE45929B1

IE45929B1 - Tetralines

Info

Publication number: IE45929B1
Application number: IE2462/77A
Authority: IE
Original assignee: Sandoz Ltd
Priority date: 1976-12-07
Filing date: 1977-12-05
Publication date: 1982-12-29
Also published as: SE7713471L; PT67365A; IE45929L; JPS5384955A; CA1105475A; FR2373513B1; IL53533A0; PH13932A; DE2752659A1; SU927110A3; JPS6214540B2; FR2373513A1; FI773595A; DK527877A; NZ185884A; IL53533A; PT67365B; ES464747A1; NL7713364A; ATA871977A

Abstract

The invension provides compounds of formula I, I wherein R1 is, for example, hydrogen or alkanoyl of 1 to 20 carbon atoms; R2 is, for example, hydrogen, hydroxy, alkanoyl of 1 to 20 carbon atoms, CF3SO2NH or CC13SO2NH; R3 is hydrogen or, when R2 is chlorine, R3 may also be chlorine; R4 is, for example, hydrogen, alkyl of 1 to 4 carbon atoms or cycloalkyl of 3 to 8 carbon atoms; and R6 is, for example, hydrogen, alkyl of 1 to 4 carbon atoms or, together with R5, a -(CH2)4-, -(CH2)5 or (CH2)6-group, which compounds possess pharmacological activity, for example in she treatment of cardiac diseases and Parkinson's disease.

Description

The present invention relates to 1,2,3,4tetrahydro-naphthalenes.

More particularly, this invention provides compounds of formula I, wherein R^ is hydrogen, alkanoyl of 1 to 20 carbon atoms or a -CO-(CH^^-R? group, n is a whole number from 0 to 5, R? 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 45329 to 4 carbon atoms or, when Y^ and Y2 are bonded to adjacent carbon atoms, and Y2 together may be methylenedioxy, R2 is hydrogen, hydroxy, alkanoyloxy of 1 to 5 20 carbon atoms, a -O-CO-(CH/n-R7 group wherein n and R? are as previously defined, fluorine, chlorine, bromine, iodine, alkyl of 1 to 4 carbon atoms, an alkylsulphonylamino group of 1 to 4 carbon io atoms, cf3so2nh, cci3so2nh, ch2oh, CH2~O-CO-(CH/ n"Ry< wherein n and R? are as previously defined, or CH2"O-CO-Rg, wherein Ro is hydrogen or alkyl of 1 to o carbon atoms, R3 is hydrogen or, when R2 is chlorine, R3 may also be chlorine, r4 is hydrogen, CH2OH, CH2O-CO-Rg or CH.-O-CO-(CH„) -Rn, wherein R_ and Ro 2 ζ n / / o are as previously defined, Rg is hydrogen, alkyl of 1 to 4 carbon atoms, cyeloalkyl of 3 to 8 carbon atoms or (CH2)n-Rg, wherein n is as previously defined and Rg is a group of formula, wherein each of Y4 and Yg may, independently, be hydrogen, fluorine,'chlorine, bromine, iodine, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, -OH, -0-C0Ro, wherein R„ is as previously o o defined, -O-CO-(CH2)n"R?, wherein n and R? are as previously defined or, when Y^ and Y^ are bonded to adjacent carbon atoms, Yg and Y4 together may be methylenedioxy, Rg is hydrogen, alkyl of 1 to 4 carbon atoms or, together with Rg, a -(CH2)4", -(CH2)5 or -(CH2)g- group, with the proviso that when two or more of the residues °R1' 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 R^ is hydrogen and R2 is hydrogen, OH, alkyl or an acylated OH group, -NR^Rg is other than free amino or amino substituted only by alkyl or benzyl, and is other than a hetero-ring, excepting as follows: a) when OR^ is in position 6 and R2 is hydrogen, -NR^R- can be NH. or 5 6 2 b) when OR^ is in position 5 and R2 is hydrogen, -NRgRg can be -NH3 ot -NHCH3· When R2, Y^, Y2, Y3, Y^ andY5 are halogen, this is preferably fluorine or chlorine.

In the group -CO-(CH2)n-R^, n may be 0, 1, 2, 3, 4 or 5, preferably 0. R? may be phenyl. Alternatively, R? may be phenyl mono- or di-substituted with fluorine, chlorine, bromine or iodine. In another group of compounds, R? 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, Y^ and Y2 may form a methylenedioxy group.

R^ is preferably hydrogen. - 5 459 29 The group -OR^ is preferably in the 5-, 6- or 7- position.

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

Rg is preferably hydrogen, alkyl or a -{CH2)n-Rg group.

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

Rg is preferably hydrogen or methyl.

When R^ 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, R^ 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. Alternatively, R2 may be alkanoyl of 1 to 4 carbon atoms or of 5 to 9 carbon atoms. r2 may also be fluorine, chlorine, bromine or iodine. - 6 45929 When R2 is alkyl of 1 to 4 carbon atoms, this is preferably methyl. When Rg is alkylsulphonylamino: of 1 to 4 carbon atoms, this is preferably methylsulphonylamino. Rg may be CFgSOgNH or CClgSOgNH. Rg may also be -CHgOH. Alternatively, Rg may be the group CHg-O-CO-(CHg)η"Κγ as previously defined. Rg can also be the group CHg-O-CO-Rg, wherein Rg is hydrogen- or alkyl of 1 to 19 carbon atoms. When Rg is alkyl, this may, for example, be of 15 to 19 carbon atoms or of 10 to 14 carbon atoms. Alternatively, Rg may be alkyl of to 4 oarbon atoms or of 5 to 9 carbon atoms. Rg may also be hydrogen.

Rg may be hydrogen. When Rg is chlorine, Rg may be hydrogen or chlorine.

R^ may be hydrogen. Alternatively, R4 may be CHgOH. R^ may be the group CHgO-CO-Rg, wherein Rg is as previously defined. R^ may also be the group CHg-O-CO-(CHg)n_R^, wherein n and R^ are as previously defined. R^ is preferably hydrogen or CHgOH.

Rg may be hydrogen or alkyl of 1 to 4 carbon - 7 45929 atoms. When Rg is cyeloalkyl of 3 to 8 carbon atoms, this is preferably of 5 or 6 carbon atoms.

R may be (CH_) -Rn, wherein n and Rft are as 3 2 π y b previously defined. Rg may be phenyl. Alternatively, Rg may be phenyl substituted by the groups Yg, Y^ and Yg as previously defined. Yg, Y^ and Yg may, independently, be fluorine, chlorine, bromine or iodine. Alternatively, each of Yg, Y^ and Yg may, independently, be alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms. One or more of Yg, Y^ and Yg may be OH.

In another group of compounds, one or more of Yg, Y^ and Yg may be -O-CORg, wherein Rg is as previously defined. In a further group of compounds, one or more of Yg, Y4 and Yg may be -O-CO-(CHgl^-Ry, wherein n and Ry are as previously defined. When bonded to adjacent carbon atoms, Yg and Y^ together may be methylenedioxy.

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

Rg and Rg together may form a -(CHg)^-, -(CHgig- or -(CH2)-g group.

The invention further provides a process for the production of a compound of formula I comprising, 9 2 9 a) producing a compound of formula Ia, R.

Rl R' V 5 tC OH la wherein R^ has the same significance as R2 with the exception of an alkanoyloxy or an -O-CO-(CR)n-R? group, has the same significance as Rg with the exception of a (CH_) -R„ group, wherein ζ n y Rg contains an -O-CORg or an -O-CO-(CH)-R residue, i n / by converting the alkoxy or benzyloxy group in a compound of formula II, to a hydroxy group by ether splitting, wherein is alkyl of 1 to 4 carbon atoms or benzyl, and R^^ 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 lb, wherein R| is alkanoyl of 1 to 20 carbon atoms or -CO-(CH2)n-R?, R2 has the same significance as R2 with the exception of a free -OH group, and Rg has the same significance as Rg vzith the exception of a -(CH.) -R_ group wherein z n y the Rg group contains a free -OH group, by acylating a compound of formula III, with a reactive derivative of a carboxylic acid of formula R.-COOH or R_-(CH„) -COOH, ο ζ ζ n or c) producing a compound of formula Ic, HO N-(CH2)n,Ic wherein Rj is hydrogen, hydroxy, fluorine, chlorine, bromine or iodine, alkyl of 1 to 4 carbon atoms or CHgOH, Rj is hydrogen or CH^OH, n1 is a whole number from 1 to 5, and Rj has the same significance as Rg with the exception that Rg cannot contain an -O-CORg or -O-CO-(CH/n~R7 group, by reducing a compound of formula iy R_ 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 9 29 temperature of from 0 to 100°C, or boron tribromide, preferably in methylene chloride, suitably at a temperature of from 0 to 50°C. When employing hydrochloric aoid, the reaction is preferably effected at a pressure of from 1 to 10 atm.

When is benzyl or when R^^ 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 plat10 inum 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 Yg, Y^ and/or Yg is/are alkoxy, the appropriate starting material of formula II is selected in which R^g 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 oan, for example, be effected using an acylating agent, for example an acyl chloride or acid anhydride. The reaction may suitably be effected in trifuloroacetic 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. LiAlH^, 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 75°C. When R^ Υ^, Y4 and/or Yg 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 aoid 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 8-alkoxy (or benzyloxy)-2-amino13 43929 tetralines (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 -NRgRg group by alkylation, arylation or aralkyl ation. 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 R^ and Rg can be effected as follows: a) Introduction of an alkyl-, trifluoro- or trichloro15 . methylsulphonamido group: The alkoxyamino tetralines (wherein the amino group can, if required, be temporarily protected with an acyl group) used as starting materials are first nitrated according to known methods, e.g. with nitrous acid in methylene chloride, the resulting isomeric mixture separated chromatographically and the nitrocompound so obtained reduced to the corresponding amino " derivative, e.g. by means of palladium on charcoal.

The amino compounds are finally converted to the alkyltrifluoro- or trichlorosulphonylamine derivatives by means of an alkyl- trifluoromethyl or trichloromethylo sulphonyl halide. b) Bromination, chlorination, iodination: The starting materials of formula II, wherein (and, where appropriate, Rg) is chlorine, bromine or iodine, can be prepared by reacting the alkoxy10 tetraline (wherein the amino group may be temporarily protected with an acyl group) with an appropriate halogenating 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 o— or £- position to the alkoxy group, is obtained and can be separated on Kieselgel. c) Fluorination: Alkoxyaminotetralines, which are substituted IS in the benzene ring with an -NH2 group [preparable 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, precipitated in the form of the fluoroborate, isolated and thermally decomposed. d) Introduction of the CH2OH group: The introduction of the CH2OH group may advan10 tageously 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 presence 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 hydroxy20 methyl group, for example, with a reducing agent such as diborane or LiAlH^ in an inert solvent such as tetrahydrofuran.

The compounds of formula II wherein is a CH2OH group, Rg, Rg and Rg are each hydrogen and R-^ is hydrogen, alkyl, alkoxy or benzyloxy, can be obtained, from the corresponding compounds of formula II wherein R^ 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 α-amino acids. For example, the compounds can be obtained from the corresponding tetralones by reaction with potassium cyanide and ammonium carbonate and subsequent decomposition of the resulting hydantoin derivative. The reduction of the compounds wherein R4 is a COOH or COOR group to compounds wherein R4 is CH2OH may be effected in known manner for the reduction of a car15 bonyl 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 cam20 pounds 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. _ 17 _ 40939 The introduction of the additional substituents Rg, Rj and Rg in the compounds of formula II wherein R^ is CHg OH can be effected in the same manner as for compounds wherein R4 is hydrogen. In most cases, the substitution will already have been effected in the earlier step, i.e. in the compounds wherein R^ is a ’ COOH or a COOR group.

Compounds of formula II, wherein R^ and/or R^ are an acylated CHgOH group, can be prepared by acylation, e.g. as described in process variant b), of the corresponding compounds wherein and/or R4 are a free CHgOH 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 by acylation of the corresponding unacylated compound with a reactive derivative of an acid of formula R'-(CH0) , .-COOH. Suitable reactive derivay ζ n -x tives are, for example, acid chlorides or N-hydroxy20 succinimide esters.

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

EXAMPLE 1: 2-Amino-1,2,3,4-tetrahydro-8-hydroxy-2hydroxy-methylnaphthalene a) ^-Amino^g^carboxy^lxgiSi^tetrahydro-S^methoxynaghthalene 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 mixture is stirred at 60° for 20 hours, cooled to room temperature, then 400 ml of water are added, and the reaction mixture left to stand at 4° in order to crystallise. 8-Methoxy-2-spirohydantoin tetraline crystallises out, with a melting point of 216-217°. ml of a 40% agueous sodium hydroxide solution are added to a suspension of 21 g of 8-methoxy-2-spiro15 hydrantoin tetraline in 130 ml of propylene glycol, and the reaction mixture heated, with stirring, for 24 hours to 190°. The cooled solution is decolourised with activated charcoal, adjusted to a pH of 1 with concentrated hydrochloric acid, the resulting precipitate filtered off, and the mother liquor adjusted to a pH of 5.5 with a sodium bicarbonate/'acetic acid buffer solution. The title compound which crystallises out 4 3 9Λ® has melting point of 228-230° after isolation and drying b) ^-Amino-l^^^S^^^tetrahydro^e-methoxy^^-h^drox^^ 5!££ilZiSSEii£ilSiSS§ A suspension of 14.5 g of 2-amino-2-carhoxy-l,2,3,45 tetrahydro-8-methoxynaphthalene in 400 ml of tetrahydrofuran is added dropwise with stirring (under a nitrogen atmosphere) to 525 ml of a 1-molar 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 IN 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 con20 vert the compound into the hydrochloride form, one equivalent of a 4N ethereal hydrogen chloride solution is added, and the mixture left to stand at 4° so as to ~ 20 459 29 crystallise. The title compound is obtained in the form of the hydrochloride. M.P. 153-154°. c) Z^Amino-li^Sj^-tetrahydro^S-hydroxy-^-hydroxy5 5 g of 2-amino-l,2,3,4-tetrahydro-8-methoxy2-hydroxymethyl-naphthalene-hydrochloride 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 10 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 IN aqueous potassium bicarbonate solution and methylene chloride/isopropanol (2:1), and the resi15 due 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 -10°, whereby the title compound is obtained in the form of the hydrogen chloride. M.P. 191-193°. " 9 29 EXAMPLE 2: 2-Amino-l,2,3,4-tetrahydro-6-acetoxy-2methylnaphthalene ml of acetyl chloride is added to a suspension of 1 g of 2-amino-l,2,3,4-tetrahydro-6-hydroxy-25 hydroxymethylnaphthalene-hydrobromide in 12 ml of trifluoroacetic acid, whereupon the whole mixture immediately goes into solution, and gas develops. The' reaction mixture is then stirred for 1 ^2 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 (CDClg): < = 1.7 (3H, s) f 1.8 (3H, s) 2.2-3.3 (611, m) ; 3.8 (2H 6.4-7.0 (3H, m).

EXAMPLE 3: N- [2- (3 ,4-dimethoxyphenyl)ethyl]-2-methy1amino-1,2,3,4-tetrahydro-6-hydroxynaphthalene-hydrochloride 4.6 g of N-[2-(3,4-dimethoxyphenyl)acetylJ-2methylamino-1,2,3,4- tetrahydro-6-hydroxynaphthalene are 20 suspended in 70 ml of tetrahydrofuran with stirring. ml of a 1 Molar solution of diborane in tetrahydro22 4 ο 9 2 θ furan 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 mix5 ture is finally dried, methanol is added to the mixture, evaporated and the procedure repeated several times.

The residue which is then obtained 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 isopropanol 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]-2methylamino-1,2,3,4-tetrahydro-6-hydroxynaphthalene used as starting material is obtained by the reaction of 6-hydroxy-2-methylamino-l,2,3,4-tetrahydronaphthalene with the hydroxysuccinimide ester of 3,4-dimethoxy20 phenyl acetic aoid in dimethylformamide at room temperature .

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

(Compounds of Formula I, wherein R, = H, R. = CH_OR.

CM CO rH Λ *φ 0 £ •H XX Φ Φ Φ Φ M XX /X Φ XX XX A •s 0 ϋ Ό 0 Φ Φ Φ '0 Φ (3) Φ X β ·Η β -fi rH Ή Ό ♦Hr0 0 Ό 2 8 o S A •Η •H ♦H •H « -d £ Ό ϋ 0 o o ϋ g ε g 0 g Φ g 0 E>i ω Μ ω M 0 0 0 o rH o ϋ 0 W E Φ Λ Φ Λ M Μ H Λ ω Μ Λ > 0 > 0 Ό Λ XI XJ 0 Φ Λ 0 *e Μ Μ Μ M >1 0 o ϋ o 0 > 0 & ϋ) Ό ω Ό a Μ M M M J-! Μ Μ fi fi Ή >ι Ή >1 XX •d Ί3 0 Ό B 8 >Η Β μ a >1 >1 >. >1 Ή >ι a W w 0 a a a E a ιη Β Q Q XX X-· XX xx xx W ~ CM • 0 0 0 0 0 0 0 0 0 o 0 04 co o ro ιη O CO ro KO in in in ιη ’S’ o σ» rH o rH ro CM r* ro ro co a CM ro CM Η iH CM CM CM rH CM CM KO 04 ro ® υ a a a a a a Ε a a a a Ρχ rH a >1 ro N in η a υ ro E o U ti Φ m a a a a a a ’Hl a a Η >1 rH 0 >1 G 0 »H 0 ti 'Φ > . Qi ♦H 04 a a E 04 a a a a E a a rH a rs 04 CJ o a a a a a a a a a a in Γχ >< X >, 0 X rH 0 >1 eH 0 >1 G 0 rH 0 ti > •H a a a I a a a a a a a H 01 O o o o OJ 04 a o CJ o o CJ o IO KD KO KO KO in KO KO KO KO KO KO x o o rH CM ro ΈΡ in w a in KO r* CO σ) rH rH rH rH rH rH 9 2 9 (Compounds of Formula I, wherein R, = H, R. = CH„OR. z"> a) υ Ό nJ •rl M 0 0 P P d a 0 □ 0 0 5-4 Ό nJ >1 >1 8 0 0 co d P P CM • vo o P P s d d Γ* 8 P U 1 , 8 a Cl Lf) r* 8 P U 1 a cl a a d 8 8 a a a P o o 8 1 o in , . H 0 vo r* W 3 P P o ft I Q P £ Pm I »4 Φ P β e β 0 o' Φ 0) 0) 0) 0) TJ a) Q) 0) rd tj TJ TJ TJ TS tJ TJ •rl tj tJ TJ •rl Ή •id •rl •rd μ •H •r| •«d μ g g g R fi fi ε ε υ ε ε ε 0 0 0 0 0 υ 0 υ 0 r—I 0 0 υ rd μ μ μ μ μ μ μ μ a μ μ μ tt tt tt tt tt tt tt XJ tt o tt tt XJ U 0 O 0 0 0 0 0 0 0 0 0 0 0 μ μ μ μ μ μ μ μ μ μ μ μ μ Ό TJ TJ TJ TJ TJ TJ tj TJ TJ TJ '0 TJ >1 >< >1 >1 >1 >1 £ £· >1 >1 >1 >? a a a a a a a a a ffl ffl ffl ffl %·»# *-· 0 0 o o o 0 o in 0 o o ο ο co o CO r-» in CM M1 Ό1 --O VO O r-> co r- CM co O CO S\ Ό* ο CM tt CM CO CM o ro CO in co cn m O w o in O r- co P- CM co CO ο CM II a CM cn cm CM CM co CM CM CM CM co CM rt* P* Pi ffl CO a 1 a H •rl vo ffl ffl a ffl a a ffl .a a-Ία a- a ffl fil H tt Γ* Γ* tt & ffl ffl ffl co co tf w co U - U H in ffl cl ΖΓ-- a a fil ffl a a u a ?a a a a a (ΰ - - -i ti rd ro - o 1 a 0 OS - a a a ffl a a a a a Γ* ffl ffl tt m 0 in TJ S3 rd rd μ rd rd 0 CM ffl o u CJ u a O υ u g* a a a co m tn vo a m in ffl LO in o ϋ o o o C) o o co co a a a a a a a a a ffl ffl a a rd ffl o o o o o o o υ u o υ O o o m vo in in VO VO in in vo vo vo 03 vo tt 0 co cn o rd CM co •o· in vo 00 O'» o tt & r-4 rd CM CM CM CM CM CM CM CM CM CM co II (Continued) a Ή Φ Η Φ I § Η Ο Cm rt Ο Ul Ό C β Ο I α Φ Ό •Η Η Ο Η X? ϋ Ο Η τί >1 W Φ φ (1) nJ TJ '0 » · «*><. Φ rt rt φ φ nJ H H '0 nJ •H 0 0 0 rt rt H rt rt Η H 0 Λ Χί Λ 0 0 ϋ 0 ϋ rt rt Xi 0 0 ϋ XJ Xi υ Η Η 0 ϋ 0 nJ '0 TJ 0 0 H >< >1 H H nJ a a a nj TJ >1 -*> -*· >, >« a a a o kO o 1 rt 0 Q CN Γ- kD 0 0 0 0 0 o o CM CM rt o O rt Ch CM o rt o rt a CM rt rt CM I rt — 1 rt 1 I <2? 1 t CO · rt Pi r- Zs rt rt rt γ- ο Z\ CN CN Γ- η rt Ul O rt a cm Ul U) Ul CM CM CM CN CM Γ- Γ r- Γ- r- a a a a a rt rt rt rt rt rt O u U U o kO a a a a a a a a a β| β| Gl β! β| r- r- r- r- r- a a a a a rt rt rt rt rt rt u U □ u u rt ti a a a a a a o a Gl Gl Gl β| Gl □ i co ti ο a a a a a a a a a a a a a a a a a a CM CN CM CN CN CM CM CM (N CM o o n n n n o o o o ω ω * ω ω ω in cn in in in rt rt rt rt rt rt rt rt rt rt a a a a a a a a a a H t> u □ u υ u u a υ u O I I r*· rt in 00 c— kD kD rt CO CO rt υ i kD a ο kD a ο ι rt rt rt rt rt a ο I CO a a a a a a a o o o o o o o kO rt rt kD in rt rt kO r- co σι o rM CN rt rt rt rt N· M· w H Φ +> β •rl ui 459 26 fO vPΛ <*· X φ Φ φ φ »ύ •ύ 'd »d •Η Ή •Η •Η Η ε Μ Μ (1) . Φ Φ 0 0 0 0 *d 0 Η Μ rd rd •rl CM β -rl .« Λ £ Λ 5d a φ ε 0 0 ϋ ϋ 0 u 0 0 0 Μ 0 ο rd 1 ω Μ Μ U Μ Μ a CM V Λ Τί >1 Τ3 'd 0 a > 0 >1 Β >1 >1 o u Μ Μ a Β Ε 54 1 (1) Ό *—* κ.» *d Ή >, ο X II <Μ Β ο ο 0 0 Μ " 00 Γ·» κο Ο in CM σι 00 ed • 0 1 I 0 CM Γ* νρ rd -ΓΜ— γ*· o Ό ο CM • σι x s g CM CM Φ rd rd rd a 11 Ν >, •4* a X W >! ed Ο 0 ο 0 VP 1 Ή 1 •Η ·» X •41 ΤΙ *4» Ό a ro cd Φ β Φ Λ - -r-' — Φ Φ * Η rd rt Λ £ +J 4J i*K c φ Φ •rl Φ a a a g ujkrt 54 Ο Ο-. o 0) co ! *» Η 1 1 Λ > X ΓΟ ΓΟ CO ΓΟ VP VI» H fd ΓΟ ΓΟ co co rd KO a a a « 2 cd a W ϋ α u o 54 0 44 ' 44 Β a a Β a a 0 r4 ο ο Ο Ο o o ω - »d β o ΚΟ ΚΟ ΙΟ κο in in 3 0 a ε • a o X 0 ω vj* m κο CO ϋ W 2 •4* νΡ νΡ VP •4* vP sinters The compounds of formula I exhibit pharmacological activity. In particular, the compounds exhibit activity for the treatment of heart conditions, 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 100 mg., conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from 1 to 100 mg, suitably from 1 to 50 mg, or in sustained release form.

The compounds of formula I may be administered in pharmaceutically acceptable acid addition salt form. Such acid addition salt forms exhibit the same order of activity as the free base forms and are readily prepared in conventional manner. Suitable acids for salt formation include inorganic acids such as hydrochloric and hydrobromic acids and organic acids such as maleic acid.

The present invention also provides a pharmaceutical composition comprising a compound of formula I, in free base form or in pharmaceutically acceptable acid addition salt form, in association with a pharmaceutically acceptable diluent or carrier. Such compositions may be formulated in conventional manner and may, for example, be a solution or a capsule.

In one group of compounds of formula I, as previously defined, R.| is hydrogen, alkanoyl of 1 to 13 carbon atoms or a group - CO - (CHg)- Ry wherein n is a whole number from 0 to 5 and Ry is phenyl or phenyl 5 monosubstituted with alkyl of 1 to 4 carbon atoms, Rg is hydrogen, hydroxy, alkanoyloxy of 1 to 13 carbon atoms or a group — 0 — CO- (CH2)n-Ry wherein n is a whole number from 0 to 5 and Ry is phenyl or phenyl monosubstituted with alkyl of 1 to 4 carbon atoms, R^ is -CHgOR^ wherein R^ is hydrogen, alkanoyl of 1 to 13 carbon atoms or a group — CO — (CH2)n—Ry wherein n is a whole number from 0 to 5 and Ry is phenyl or phenyl monosubstituted vzith alkyl of 1 to 4 carbon atoms, Rg is hydrogen, Rg is hydrogen or alkyl of 1 to 4 carbon atoms and Rg is hydrogen or alkyl of 1 to 4 carbon atoms.

In a second group of compounds of formula I, as previously defined, R1 is hydrogen, alkanoyl of 1 to 13 carbon atoms or a residue of formula wherein each of and Y2, which may be the same or different, is 20 hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, fluorine, chlorine or bromine and each of R2, Rg, R^, Rg and Rg is hydrogen.

Claims

1. To 4 carbon atoms or, when Y^ and Y 2 are bonded to adjacent carbon atoms, Y^ and Y 2 together may be methylenedioxy, R 2 is hydrogen, hydroxy, alkanoyloxy of 1 to 5 20 carbon atoms, a -O-CO-(CH/ n -R ^ group wherein n and R? are as previously defined, fluorine, chlorine, bromine, iodine, alkyl of 1 to 4 carbon atoms, an alkylsulphonylamino group of 1 to 4 carbon 1, A process for the production of a compound of formula I,

2. 2 n / / as previously defined, or CHj-O-CO-Rg, wherein R. is hydrogen or alkyl of 1 to o 19 carbon atoms, 15 r 3 is hydrogen or, when R 2 is chlorine, Rg may also be chlorine, R^ is hydrogen, CHgOH, CH 2 O-CO-Rg or CH -O-CO-(CH-) -R_, wherein R_ and R„ are as previously defined, 20 Rg is hydrogen, alkyl of 1 to 4 carbon atoms, cyeloalkyl of 3 to 8 carbon atoms or (ΟΗ/η-Κθ» wherein n is as previously defined and R g is a group of formula, wherein each of Yg, Y^ and Yg may, independently, be hydrogen, fluorine, chlorine,

3. A compound of formula I, whenever produced

4. A compound of formula I, as defined in Claim 1. 5. , 57. A compound according to any one of 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 5-OK, Rg is CHg, Yg is 4-OCHg and Y 4 is hydrogen. 45629 55. A compound of Claim 49 wherein OR^ is 5 ( rOH, Rg is CHg, Y g is 4-OH and Y^ is hydrogen. 56. A compound according to any one of Claims 3 to 55 in racemate form. 5 5-OH, Rg is 6-C1, Rg is 8-C1 and each of Rg and R g is n-CgH ? . 49. A compound of Claim 4 wherein each of wherein Yg and Y^ are as defined and Rg is hydrogen or methyl. 5- OH, Rg is 8-C1, Rg is hydrogen and each of Rg and Rg is n-CgH^. 48. A compound of Claim 23 wherein OR^ is 5- OH, Rg is 6-CHgSOgNH, Rg is hydrogen and each of Rg and Rg is n-CgH?. 45. A compound of Claim 23 wherein OR^ is 5 hydrogen. 41. A compound of Claim 23 wherein OR^ is 5-OH, Rg is 8-CHgSOgNH and each of Rg, Rg and Rg is hydrogen. 42. A compound of Claim 23 wherein OR^ is 5- CHgCOO and each of R 2 , Rg, Rg and R g is hydrogen. 33. A compound of Claim 23 wherein OR^ is 5 32. A compound of Claim 23 wherein OR^ is 5- OH and each of R 2 , R 14 , Rg and R g is hydrogen. 15. A compound of Claim 10 wherein OR^ is

5. A compound of Claim 4, wherein R^ is hydrogen, alkanoyl of 1 to 13 carbon atoms or 15 a group -CO- (CH 2 ) n ~R 7 wherein n is a whole number from 0 to 5 and Ry is phenyl or phenyl monosubstituted with alkyl of 1 to 4 carbon atoms, Rg is hydrogen, hydroxy, alkanoyloxy of 1 to 13 carbon atoms or a group 43929 -O-CO-(CH 2 ) n -R 7 wherein n is a whole number from 0 to 5 and Ry is phenyl or phenyl monosubstituted with alkyl of 1 to 4 carbon atoms, R^ is -CE^OR^ wherein R^ is hydrogen, alkanoyl of 1 to 13 carbon atoms or a group -CO-(CH2) n -Ry wherein n is a whole number from 0 to 5 and Ry is phenyl or phenyl monosubstituted with alkyl of 1 to 4 carbon atoms, Rg is hydrogen or alkyl of 1 to 4 carbon atoms and Rg is hydrogen or alkyl of 1 to 4 carbon atoms. 5 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. 5 6 i 3 comprising a) producing a compound of formula Ia, Ia wherein Rg has the same significance as Rg with the 15 exception of an alkanoyloxy or an -Ο-co-(CHg) n “Ry group, R' has the same significance as R_ with the o o exception of a (CHg) n -R g group, wherein R„ contains an -0-C0R o or an 9 o -0-C0-(CH 2 ) n -R ? residue, by converting the alkoxy or benzyloxy group in a compound of formula II, to a hydroxy group by ether splitting, wherein R^g is alkyl of 1 to 4 carbon atoms or benzyl, and R^i has the same significance as RJ, and, in addition, may signify alkoxy of 1 to 4 carbon atoms or benzyloxy, b) producing a compound of formula Ib, wherein R| is alkanoyl of 1 to 20 carbon atoms or II -CO-(CH 2 ) n -R 7 , has the same significance as R 2 with the exception of a free -OH group, and Rg has the same significance as Rg with the exception of a -(CH_) -R Q group wherein the Rg group contains a free -OH group, by acylating a compound of formula III, with a reactive derivative of a carboxylic acid of formula R -COOH or R_-(CH„) -COOH, o / ζ n or c) producing a compound of formula Ic, wherein Rj ls hydrogen, hydroxy, fluorine, chlorine, bromine or iodine, alkyl of 1 to 4 carbon atoms or CH^OH, Rj is a whole number hydrogen or Cf^OH, n' is a whole number from 1 to 5, and Rg has the same significance as R g with the exception that R g cannot contain an -0-C0R o or -O-CO-{CH„) -R_ group, ο ζ n / by reducing a compound of formula iy 5 bromine, iodine, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, -OH, -O-COR-, wherein R o is as previously o o defined, -0--C0-(CHg) n -R ? , wherein n and R ? are as previously defined or, when Yg 5 wherein R^ is hydrogen, alkanoyl of 1 to 20 carbon atoms or a -CO-(CH,) -R 7 group, n is a whole number from 0 to 5, R? is a group of formula 6. -OH, Rg is CHg, Yg is 3-OH and Y 4 is 4-OH. 53. A compound of Claim 49 wherein OR^ is 6-OH, Rg is CHg and Yg and Y 4 together are 3,4-methylenedioxy. 20 54. A compound of Claim 49 wherein OR^ is 6- OH, Rg is hydrogen, Yg is 3-OH and Y^ is 4-OH. 51. A compound of Claim 49 wherein OR^ is 6-OH, Rg is hydrogen and Yg and Y^ together are 3,4methylenedioxy. 15 52. A compound of Claim 49 wherein OR 7 is 6- OH, Rg is 5-CHgSOgNH, Rg is hydrogen and each of Rg 20 and Rg is n-CgH^. 46. A compound of Claim 23 wherein OR^ is 5-OH, Rg is 8-CHgSOgNIl, Rg is hydrogen and each of Rg and Rg is n-CgH?. Rg, Rg and R 4 is hydrogen, Rg is _ CH _ CH 47. A compound of Claim 23 wherein OR^ is 6-OH, Rg is 5-CHgSOgNH and each of Rg, Rg and Rg is hydrogen. 40. A compound of Claim 23 wherein OR^ is 8-OH, Rg is 5-CHgSOgNII and each of Rg, Rg and R g is 6- OH, R 2 is 5-Br and each of Rg, Rg and Rg is hydrogen. 34. A compound of Claim 23 wherein OR^ is 6-OH, Rg is 7-CHgSOgNH, Rg is hydrogen and each of 30. A compound of Claim 23 wherein OR^ is 6-OH, R 2 is 5-C1 and each of Rg, Rg and Rg is hydrogen. 31. A compound of Claim 23 wherein OR^ is 5-OH, R 2 is 6-C1 and each of Rg, Rg and Rg is hydrogen. 6-OH, each of Rg and R^ 4 is hydrogen and each of Rg and Rg is CHg. 17. A compound of Claim 10 wherein OR^ is 6-OH, Rg is i-CgH ? and each of Rg, R^ 4 and Rg is 20 hydrogen. 18. A compound of Claim 10 wherein OR^ is 6-OH, Rg is benzyl and each of Rg, R 14 and R g is hydrogen. 459 29 19. A compound of 6-OH, Rg is 5- -Cl and each of 20. A compound of 6-OH, Rg is 7- -OH and each of 5 21. A compound of 7-OH and each of Rg, R 14 , Rg 22. A compound of 5-OH, each of *2 and R 14 is 1 Rg is n-C : 3 H 7· 10 23’. A compound of hydrogen. - 24. Λ compound of 5-OH arid each 1 of Rg , Rg , Rg ( 25. A compound of 15 6-OII and each of R 2' R 3' R 5 ‘ 26. A compound of 5-OH, Rg is CHg and each of I 27. A compound of 5-OH, Rg is 8- Cl and each of 20 28. A compound of 6-OH, Rg is 5- ci, Rg is n-Cgl hydrogen. 29. A compound of Rg and Rg is CHg. 6- OH, Rg is CHg and each of Rg, R 14 and R g is hydrogen. 15 16. A compound of Claim 10 wherein OR^ is 6-£>-toluoyloxy, R^ 4 is £-toluoyl and each of R 2 , Rg and Rg is hydrogen.

6. A compound of Claim 4, wherein R^ is

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

8. 2-Amino-l,2,3,4-tetrahydro-6-acetoxy-2methylnaphthalene. 20

9. N-[2-(3,4-dimethoxyphenyl)ethyl]-2-methylamino-1,2,3,4-tetrahydro-6-hydroxynaphthalene. 10. 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 coniprising a compound according to any one of Claims 3 to 58, in 10 50. A compound of Claim 49 wherein OR^ is 10 8-OH, Rg is 7-CHgSOgNH and each of Rg, Rg and Rg is hydrogen. 43. A compound of Claim 23 wherein OR^ is 5-OH, Rg is 6-CHgSOgNH and each of Rg, Rg and Rg is hydrogen. 15 44. A compound of Claim 23 wherein OR^ is 10 6-OH, R 2 is 5-Cl, Rg is 7-C1 and each of Rg and Rg is hydrogen. 35. A compound of Claim 23 wherein OR^ is 6-CHgCOO and each of Rg, Rg, Rg and R g is hydrogen. 36. A compound of Claim 23 wherein ORg is 15 8-OH, Rg is 5-Cl and each of Rg, Rg and R g is hydrogen. 37. A compound of Claim 23 wherein OR^ is 6-OH, Rg is 5-Cl, Rg is hydrogen and each of Rg and Rg is n-CgH?. 38. A compound of Claim 23 wherein OR^ is 20 6-OH, Rg is 7-CHgSOgNH and each of Rg, Rg and R g is hydrogen. 39. A compound of Claim 23 wherein OR^ is 10 Rg is hydrogen.

10. A compound of Claim 4, wherein Rp R 2 , Rg and Rg are as defined, Rg is hydrogen and R 4 is CH 2 OR 14 wherein R 14 is hydrogen, toluoyl or pivaloyl. 10 hydrogen, alkanoyl of 1 to .........—y 10 by a process as claimed in Claim 1 or 2. 10 and Y^ are bonded to adjacent carbon atoms, Yg and Y^ together may be methylenedioxy, Rg is hydrogen, alkyl of 1 to 4 carbon atoms or, together with Rg, a -(CHg) 15 - (CHg) g or -(CHg)g- group, with the proviso that when two or more of the residues OR X , Rg, Yg, Y 4 and Yg are a free or acylated OH- group, these groups are identical, or when Rg and R 4 are both free or acylated CH^-OH groups, these groups are identical, with the condition that when R^ is hydrogen and Rg is hydrogen, OH, alkyl or an acylated OH group, -NR^Rg is other than free amino or amino substituted only by alkyl or benzyl, and is other than a hetero-ring, excepting as follows: a) when OR^ is in position 6 and Rg is hydrogen, -NRgRg can be NHg or b) when OR^ is in position 5 and Rg is hydrogen, -NR C R- can be -NH, or -NHCH,, 10 atoms, CFgSO^H, CClgSO/IH, CIL/H, CH„-O-CO-(CH„) -R-, wherein n and R_ are 10 and each of and Y 2 may independently be hydrogen, fluorine, chlorine, bromine, iodine, alkyl of 1 to 4 carbon atoms, alkoxy of

11. A compound of Claim 10 wherein OR^ is 6-OH and each of R 2 , R 14 , Rg and R g is hydrogen. 5

12. A compound of Claim 10 wherein OR^ is

13. A compound of Claim 10 wherein OR^ is 6-pivaloyloxy, R^ 4 is pivaloyl and each of R 2 , Rg and 13 carbon atoms or a residue of formula Κ ,—, ,/5)-= 0 wherein each of Y^ and Y 2 , 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 15 bromine and each of R 2 , Rg, R^, Rg and Rg is hydrogen.

14. A compound of Claim 10 wherein OR^ is

15. Free base form or in association with a pharmaceutically acceptable diluent or carrier.