AU597719B2 - Naphthalene and indan derivatives - Google Patents

Abstract

Naphthalene and indane derivatives of the formula <IMAGE> in which the substituents have the meaning given in the description, their enantiomers, their diastereomers and their acid addition salts with inorganic or organic acids which have useful pharmacological properties, in particular a heart rate-reducing action. The novel compounds can be prepared by processes known per se.

Description

~4I Australia PATENTS ACT 1952 597719 Form COMPLETE SPECIFICATION

(ORIGINAL)

FOR OFFICE USE Short Title: Int. Cl: Application Number: Lodged: Complete Specification-Lodged: Accepted: Lapsed: Published: SPrfority: I ~mrnmrr:ihi Cl "~61 arnc~l2 .2i2 )vinfjpg rT~y Related Art: Name of Applicant: Address of Applicant: Actual Inventor: Address for Service: TO BE COMPLETED BY APPLICANT DR. KARL THOMAE G.m.b.H.

D-7950 Biberach an der Riss, Federal Republic of Germany.

MANFRED PSIORZ, JOACHIM HEIDER, ANDREAS BOMHARD, NORBERT HAUEL, KLAUS NOLL, BERTHOLD NARR, CHRISTIAN LILLIE, WALTER KOBINGER and JURGEN DAMMGEN.

CALLINAN AND ASSOCIATES, Patent Attorneys, of 48-50 Bridge Road, Richmond, State of Victoria, Australia.

"NAPHTHALENE AND INDAN DERIVATIVES" Complete Specification for the invention entitled: i i The following statement is a full description of this invention, including the best mtethod of performing it known to me:-' SNote: The description is to be typed in double spacing, pica type fIce, In an area not exceeding 250 mm in depth "iii 60 mm in width, on tough white paper of good quality and it is to be inserted inside this form.

y w -I i ;I m

A

r-7-44 lA- MJ 52-007 Naphthalene and indan derivatives 9 .4 4 4@ .4 .4 4 4 4.

9* 4 .4.

0 44.

.4 4 4 0.44.4 ~0 4.4 4 The present invention relates to certain new naphthalene and indan derivatives, their preparation and pharmaceutical compositions containing them.

Tetrahydronaphthalenes which are substituted in the 2-position by a hydroxy group optionally substituted by an acyl group have been described in EP-A-177960.

These compounds have a marked calcium-antagonistic activity and can therefore be used in pharmaceutical 10 compositions, particularly for the treatment and prevention of angina pectoris, ischaemia, arrhythmia and high blood pressure.

We have now surprisingly found that certain new naphthalene and indan derivatives possess other valuable pharmacological properties, particularly a heart rate lowering effect and an effect of reducing the 0 2 -requirements of the heart.

According to one aspect of the present invention therefore we provide a compound of formula I 0 ~CtL'4 0 4 44444.

4 A N R 7

R

C3 ,1 2 )n R

R

6 (wherein n represents the integer 1 or 2; A represents a carbonyl group and R 7 represents a hydrogen atom, or 2- 8 A represents a group of formula -CH- (wherein R 8 represents a hydrogen atom or a hydroxy, alkanoyloxy or alkoxycarbonyloxy group) and R 7 represents a hydrogen atom, or A and R 7 together form a group of formula -CH=; E represents a straight-chained C3- 4 alkylene group optionally substituted by an alkyl group; G represents a straight chained C 2 5 alkylene group optionally substituted by an alkyl group;

R

1 represents a hydrogen or halogen atom, or a trifluoromethyl, nitro, amino, alkylamino, dialkylamino, 15 alkyl, hydroxy, alkoxy or phenylalkoxy group, and

R

2 represents a hydrogen or halogen atom or a hydroxy, alkoxy, phenylalkoxy or alkyl group, or R, and R 2 together represent a C 1 2 alkylenedioxy group; e.

o R 3 represents a hydrogen, an alkyl group or a 9* alkenyl group; **ss R 4 represents a hydrogen or halogen atom, or an alkyl, amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulphonylamino, bis(alkylsulphonyl)-amino, N-alkyl-alkylsulphonylamino, cyano, alkylmercapto, alkylsulphinyl or alkylsulphonyl group, or a hydroxy group optionally substituted by an alkyl, phenylalkyl, 2-hydroxyethyl, 3-hydroxyn-propyl, 2-hydroxy-n-propyl, alkylsulphonyl, cyanoalkyl, alkoxycarbonyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, trifluoromethyl, difluoromethyl or trifluoromethyl-' sulphonyl group, and 0 ifl alkyl, hydroxy, alkoxy, nitro, cyano or trifluoromethyl group, or

R

4 and R 5 together represent a C1_ 2 alkylenedioxy group; and

R

6 represents a hydrogen or halogen atom or an alkyl or alkoxy group; wherein unless otherwise defined any alkyl or alkoxy moiety contains 1 to 3 carbon atoms and any alkanoyl moiety contains 2 or 3 carbon atoms) or San enantiomer, diastereomer or acid addition salt 15 thereof. Insofar as the salts of the compounds of formula I are concerned, for pharmaceutical use the physiologically acceptable acid addition salts, e.g. with inorganic or organic acids, are of course preferred; nonetheless other salts may 20 be useful in the preparation of the physiologically 900 acceptable salts or of the free bases or of such salts or bases in particular stereoisomeric forms and so are seemed to fall within the scope of the present invention.

ft. The following are examples of atoms..or groups which comply with the definitions of the groups given hereinbefore:

R

1 may represent a hydrogen, fluorine, chlorine or bromine atom or a methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, nitro, amino, methylamino, ethylamino, n-propylamino, isopropylamino, dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, methylethylamino, methyl-n-propylamino, methyl-isopropylamino, ethyl-n-propylamino, benzyloxy, 1-phenylethoxy, -4- 1-phenyipropoxy, 2-phenylethoxy or 3-phenyipropoxy group, R 2 may represent a hydrogen, chlorine or bromine atom or a methyl, ethyl, n-propyl, isopropyl, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, benzyloxy, 1-phenylethoxy, 2-phenylethoxy, 2-phenylpropoxy or 3-phenylpropoxy group or together with R1it may represent a methylenedioxy or ethylenedioxy group, R 3 may represent a hydrogen atom or a methyl, ethyl, n-propyl, isopropyl, allyl, crotyl or n-pent-2group, R 4 may represent a hydrogen, fluorine, chlorine, bromine or iodine atom or a methyl, ethyl, n-propyl, isopropyl, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, amino, :nethylamino, ethylamino, n-Dropylamino, isopropylamino, dimethylamino, diethylamino, di,- *n-propylaminr), diisopropylamino, methyl-eth XIamino, methyl-n-propylamino, methyl-isopropylamino, ethyln-propylamino, acetylamino, propionylamino, methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, methylsuiphonylamino, ethylsulphonylamino, n-propylsulphonylamino, bis (methylsulphonyl) -aminio, bis (ethylsuiphonyl) -aminio, N-methyl-methylsulphonylamino, cyano, methylmercapto, ethylmercapto, n-propylmercapto, Joe**methylsulphinyl, ethylsulphinyl, isopropylsulphinyl, methylsuiphonyl, ethylsiudphonyl, n-propylsulphonyl, benzyloxy, 1-phenylethoxy, 2-phenylethoxy, 2-phenylpropoxy, 3-phenyipropoxy, 2-hydroxy-ethoxy, 2-hydroxyn-propoxy, 3-hydroxy-n-propoxy, methylsuiphonyloxy, C ethylsuiphonyloxy, isopropylsuiphonyloxy, methoxycarbonyloxy, ethoxycarbonyloxy, isopropoxycarbonyloxy, hydroxycarbonylmethoxy, 2- (hydroxycarbony1) -ethoxy, methoxycarbonylmethoxy, ethoxycarbonylmethoxy, -77 isopropoxycarbonylmethoxy, 2-(iethoxycarbonyl)ethoxy, 2-(n-propoxycarbonyl)-ethoxy, cyanomethoxy, 2-cyanoethoxy, 3-cyano-n-propoxy, trifluoromethoxy or difluoronethoxy group,

R

5 may represent a hydrogen, chlorine or bromine atom or a methyl, ethyl, n-propyl, isopropyl, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, nitro, cyano or trifluoromethyl group or R 4and R 5 together may represent a methylenedioxy or ethylenedioxy group

R

6 may represent a hydrogen, chlorine or bromine atom or a methyl, ethyl, n-propyl, isopropyl, hydroxy, 15 methoxy, ethoxy, n-propoxy or isopropoxy group, A may represent a methylene, hydroxymethylene, acetoxymethylene, propionyloxymethylene, methoxycarbonyloxymethylene, ethoxycarbonyloxymethylene, n-propoxycarbonyloxymethylene or carbonyl group, *R may represent a hydrogen atom or together with A it may represent a -CH= group, E may represent an n-propylene, 1-methyl-n-propylene, 2-methyl-n-propylene, 3-methyl-n-propylene, 1-ethyln-propylene, 2-n-propyl-n-propylene, 3-ethyl-npropylene, n-butylene, l-methyl-n-butylene or 1ethyl-n-butylene group, and G may represent an ethylene, 1-methyl-ethylene, i-ethyl-ethylene, 1-propyl-ethylene, 2-methyl-ethylene, 2-ethyl-ethylene, n-propylene, n-butylene, n-pentylene, 1-methyl-n-propylene, l-methyl-n-butylene, 1-methyln-pentylene, 1-ethyl-n-propylene, 2-ethyl-n-propylene or l-methyl-n-butylene group.

A -6 By way of example, the following are compounds which fall within the scope of the present invention: 6,7-dimethoxy-2-[3-( (2-(4-methylphenyl)-ethyl)methylamino) -propyl] 4-tetrahydronaphthalene; 6,7-dimethoxy--2-[3-( (2-(3-methylphenyl)-ethyl)methylamino) -propyl] 2,3, 4-tetrahydronaphthalene; 6,7-dimethoxy-2-[3-( (2-(3-methoxyphenyl) -ethyl)methylamino)-propyl]-1,2,3,4-tetrahydronaphthalene; 6,7-dimethoxy-2-[3-( (4-difluoromethoxyphenyl)ethyl) -methylamino) -propylll-1,2,3, 4-tetrahydronaphthalene; 6,7-dimethoxy-2-13-((2-(4-(2-hydroxyethoxy)-phenyl)ethyl) -methylarnino) -propyl] 4-tetrahydronaphthalene; 00 6,7-dimethoxy-2-[3-( (3-(4-amino-3,5-dibromo-phenyl)propyl)-methylamino)-propy1]--1,2,3,4-tetrahydronaphthalene; 6,7-dimethoxy-2-[3-( (3,4-methylenedioxyphenyl)ethyl)-methylamino)-propyl]-1,2,3,4-tetrahydronaphthalene; 6,7-dimethoxy-2-[3-( (2-(3,4-dichlorophenyl) -ethyl)methylamino)-propylll-1,2,3,4-tetrahydronaphthalene; 6,7-dimethoxy-2-13-( (3-(4-cyanophenyl)-propyl)methylamino) -propyl]-1-hydroxy-1, 2,3,4-tetrahydronaphthalene; 6,7-dimethoxy-2-[3- (4-methylsulphonylphenyl) ethyl) -methylamino) -propylij-1-hydroxy-1,2,3,4-tetrahydronaphthalene; 6,7-dimethoxy-2-[3-((2-(4-methoxyphenyl)-ethyl)methylamino) -propyl ]-l-hydroxy-l, 2,3, 4-tetrahydronaphthalene; -7- 6,7-dimethoxy-2-[3- ((2-phenyl-ethyl) -methylamino) propyl] -1-hydroxy-1,2,3, 4-tetrahydronaphthalene; 6,7-flimethoxy-2-[3-( (3-(4-bromophenyl)-propyl)methylamino) -propyl] -1-hydroxy-1,2, 3 ,4-tetrahydronaphthalene; 6,7-dimethoxy-2-13-( (2-(4-methylphenyl)-ethyl)methylamirio)-propyl]-l-hydroxy-1,2,3,4-tetrahydronaphthalene; 6,7-dimethoxy-2-[3-( (2-(3-methylphenyl) -ethyl)niethylamino) -propyl] -l-hydroxy-1, 2,3, 4-tetrahydro- **.naphthalene; 6,7-dimethoxy-2-[3-((2-(3--methoxyphenyl)-ethyl)methylamino) -propyl] -1-hydroxy-l 4-tetrahydronaphthalene; 6,7-dimethoxy-2-[3-( (4-trifluoromethylsulphonyloxyphenyl)-ethyl)-methylamino)-propyl]--1-hydroxy-1,2,3,4tetrahydronaphthalene; SOO:%6,7-dimethoxy-2-[3-((2-(4-cyanomethoxyphenyl)-ethyl)methylamino)-propyl]-1-hydroxy-1,2,3,4-tetrahydronaphthalene; 6,7,-dimethoxy-2-[3-( (2-(4-difluoromethoxypnenyl)ethyl)-methylamino)-propyl]-l-hydroxy-1,2,3,4-tetrahydronaphthalene; 6,7-dimethoxy-2-[3- (4-trifluoromethoxyphenyl) ethyl) -methylamino) -propyl] -l-hydroxy-1, 2,3, 4-tetrahydronaphthalene; 6,7-dimetho' (2-(4-methanesulphonylaminophenyl)ethyl)-methylamino)-propyl]-l-hydroxy-l,2,3,4-tetrahydronaphthalene; 'r'r -8- 6,7-dimethoxy-2-[3- (4-methoxycarbonylaminophenyl)ethyl) -methylamino) -propyl] -l--hydroxyt-1, 2,3, 4-tetrahydronaphthalene; 6,7-dimethoxy-2-[3-( (2-(4-ethoxycarbonylmethoxyphenyl)ethyl)methylamino)-propyl]-l-hydroxy-1,2,3,4-tetrahydronaphthalene; 6,7-dimethoxy-2-.3-( (2-(4-hydroxycarbonylrnethoxyphenyl)ethyl)-methylamino)-propyl]-l-hydroxy-1,2,3,4-tetrahydronaphthalene; 6,7-dimethoxy-2-13- ((3-(4-amino-3,5-dibromo-phenyl)propyl) -methyllamino) -propyl] -l-hydroxy-1, 2,3,4tetrahydronaphthalene; 0 006,7-dimethoxy-2-[3-( (2-(3,4-methylenedioxyphenyl)ethyl)-rnethylamino) -propyl] -1-hydroxy-1, 2,3, 4-tetrahydro- 6,7-dimethoxy-2-[3-( (2-(3,4-dichlorophenyl)-ethyl)- CR methylamino) -propyl] -1-hydroxy-1,2,3, 4-tetrahydro- C rnaphthalene; 6,7-dmethoxy-2-[3-( (3-(4-cyanophenyl)-propyl)-methylamiio)propyl] -1-oxo-1,2,3, 4-tetrahydronaphthalene; I C 6,7-dimethoxy-2-113-((2-(4-methylsulphonylphenyl)- C ethyl)-methylamino) -propyl]-1l-oxo-1,2,3,4-tetrahydronaphthalene; 6,7-dimethoxy-2-[3- ((2-(4-methox3yphenyl) -ethyl) methylamino) -propyl]-l-oxo-1, 2,3, 4-tetrahydronaphthalene; 6,7-dimethoxy-2-[3-( (2-phenyl-ethyl)-methylamino)propyl] -l-oxo-1, 2,3, 4-tetrahydronaphthalene; -9- 6,7-dimethoxy-2-[3-( (3-(4-bromophenyl)-propyl)methylamino) -propy -l-oxo-1, 2,3, 4-tetrahydroiaphthaleie; 6,7-dimethoxy-2-[3-( (2-(4-rnethylphenyl) -ethyl)methylamino)-propyl]-l-oxo-1,2,3,4-tetrahydroflaphthalele; 6,7-dimethoxy-2-[3-( (2-(3-methylphenyl)-ethyl)methylamino)-propyl]ll--oxo-1,2,3,4-tetrahydroflaphthalele; 6,7-dimethoxy-2-[3-( (2-(3-methoxyphenyl) -ethyl)inethylamino) -propyl]-l-oxo-1,2,3,4-tetrahydronaphthaleie; 6,7-dimethoxy-2-[3-( (4-trifluoromethylsulphonyloxys..,..phenyl) -ethyl) -methylanino) -propyl] -l-oxo-1, 2,3,4tetrahydronaphthalene; 6,7-dimethoxy-2-[3-( (2-(4-cyanornethoxyphenyl) -ethyl)methylamino)-propyl]-l-oxo-1,2,3,4-tetrahydroflaphthalele; 6,7-dimethoxy-2-[3-( (4-difluoromethoxyphenyl)ethyl)-methylamino)-propyl]-l-oxo-1,2,3,4-tetrahydroa naphthalene; '0400"6,7-dimethoxy-2-[3-( (2-(4-trifluoromethoxypheiyl)- 0 625 ethyl) -methylamino) -propyl] -l-oxo-1,2,3 ,4-tetrahydronaphthalene; I' 6,7-dimethoxy-2-[3-( (2-(4-methanesulphonylaminophenyl)ethyl) -methylamino) -propyl] -l-oxo-1,2,3 ,4-tetrahydronaphthalene; 6,7-dimethoxy-2-[3- (4-methoxycarbonylaminophenyl) ethyl) -methylamino) -propyl] -1-oxo-l, 2,3, 4-tetrahydronaphthalene; 6,7-dimethoxy-2-[3- ((2-(4-ethoxycarboriylmethoxyphenyl) ethyl) -methylamino) -propyl] -1-oxo-l, 2,3, 4-tetrahydronaphthalene; 10 6,7-dimethoxy-2-[3-((2-(4-hydroxycarbonylmethoxyphenyl)ethyl)-methylamino)-propyl]-1-oxo-1,2,3,4-tetrahydronaphthalene; 6,7-dimethoxy-2-[3-((3-(4-amino-3,5-dibromo-phenyl)propyl)-methylamino)-propyl]-1-oxo-1,2,3,4-tetrahydronaphthalene; 6,7-dimethoxy-2-[3-((2-(3,4-methylenedioxyphenyl)ethyl)-methylamino)-propyl]-1-oxo-1,2,3,4tetrahydronaphthalene; 6,7-dimethoxy-2-[3-((2-(3,4-dichlorophenyl)-ethyl)methylamino)-propyl]-1-oxo-1,2,3,4-tetrahydronaphthalene; 15 and the enantiomers, diastereomers and acid addition 9 90 salts thereof.

.9 Preferred among the compounds of the invention are those of formula I wherein too n represents the integer 1 or 2, A represents a carbonyl group and R, represents a hydrogen atom, or

R

A represents a group of formula -CH- (wherein R 1represents a hydrogen atom or a hydroxy group) and R 7 represents a hydrogen atom, or A and R together represent a group of formula -CH=, E represents an n-propylene group, G represents an ethylene or n-propylene group,

R

1 represents a methyl or methoxy group, ct rrr~ lle& I Vi 11

R

2 represents a hydrogen atom or a methoxy group,

R

3 represents a methyl group,

R

4 represents a hydrogen, chlorine or bromine atom, a hydroxy, methoxy, cyanop cyanomethoxy, hydroxycarbonylmethoxy, methoxycarbonylmethoxy, ethoxycarbonylmethoxy, methyl, amino, acetylamino, methoxycarbonylamino, methylsulphonyloxy, trifluoromethylsulphonyloxy, benzyloxy, methylsulphonylamino or bis(methylsulphonyl)amino group,

R

5 represents a hydrogen, chlorine or bromine atom or a methoxy or nitro group, and R6 iepresents a hydrogen, chlorine or bromine atom, and the enantiomers, diastereomers and acid addition salts of such compounds.

Particularly preferred compounds according to the invention include those of formula I wherein

R

1 to R 3 A, E, G and n are as hereinbefore defined, t Sr a I J a.

1 I 1I *r a t, t ~ri

R

4 represents a methoxy group,

R

5 represents a methoxy group, and

R

6 represents a hydrogen atom, and the enantiomers, diastereomers and acid addition salts thereof.

In another aspect of the present invention we provide a process for preparing the compounds of the invention, i sulphonyl group, and /3

J

12 said process comprising at least one of the following steps: a) (to prepare compounds of formula I wherein R 7 and R 8 each represent a hydrogen atom or R7 and A together represent a -CH= group) reacting a compound of formula II

A

R 7 C E -X

(II)

S t f I 1 I 4 t

I

00 4 I 04 (wherein

R

1

R

2 n and E are as hereinbefore defined;

R

A1 represents a group of formula -CH-(wherein

R

8 represents a hydrogen atom) and R 7 represents a hydrogen atom, or A 1 and R 7 together represent a -CH= group; and X represents a nucleophilically exchangeable group, such as a halogen atom or a sulphonyloxy group, e.g. a chlorine, bromine or iodine atom, a methanesulphonyloxy, p-toluenesulphonyloxy or ethoxysulphonyloxy group) with an amine of formula III 0*0 0 01 *0 6 C C C P

C

I,

I' t~ t~ #4

B

R,3 H If G

(III)

(wherein 'If 13 R 3 to R6and G are as hereinbefore defined); b) reacting a compound of formula IV

A

R2 C

(C

2 )n

(IV)

Ra

R

E-N

H

C.

96 pq,.

9.

9. 9 *q 0 9 9.

*0 S S 99 .9 9 999 .9 .9 999 9.

9 9 9999 9 9 99 0 t 9#

S

9 (wherein n. A, E, to R 3 and R7are as hereinbefore defined) with a compound of formula V Y -G (wherein Rto R 6 and G are as hereinbefore defined, and Y represents a nucleophilically exchangeable group, such as a halogen atom or a sulphonyloxy group, e.g. a chlorine, bromine or iodine atom or a methanesuiphonyloxy, p-toluenesulphonyloxy.,or ethoxysulphonyloxy group); c) (to prepare compounds of formula I wherein ,8 A represents a group of formula -CH- (wherein R.

represents a hydrogen atom or a hydroxy group) reducing a compound of formula VI p.

14

A

2 7

R

R C -1a (CH N

G

I

(VI)

R

5

S

I 050 .4.5 t9 *5 5 4. 0 *4 5* 0 0 *0 0 0*.

S

*00 0S 0 0 50 9 9 *5 9

S

I 555 S S 4 551.40* 0 (wherein n and R 1 to R 6 are as hereinbefore defined;

A

2 represents a carbonyl group and R 7 represents a hydrogen atom, or R8

A

2 represents a group of formula -CH- (wherein

R

8 represents a hydrogen atom or a hydroxy group) 15 and R 7 represents a hydrogen atom; E' and G' have the meanings given hereinbefore for E and G but with the exception that in the groups E' or G' a carbonyl group takes 20 the place of a inmthylene group adjacent to the N-R moiety); 3 d) (to prepare compounds of formula represents as carbonyl group) oxidizing a compound of formula VII

OH

n t I wherein A SH

R

^E

G

(VII)

(wherein n, E, G and R to R 6 are as hereinbefore.defined); p e) (to prepare compounds of formula I wherein R represents an alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsuiphonylamino, bis (alkylsuiphonyl) amino, N-alkyl-alkylsulphonylamino, alkylmercapto, alkoxy, alkoxycarbonyloxy, hydroxycarbonylalkoxy, alkoxycarbonylalkoxy, phenylalkoxy, trifluoromnethoxy, difluoromethoxy, cyanoalkoxy, alkylsuiphonyloxy or trifluoromethylsuiphonyloxy group) reacting a compound of formula VIII RI AR9 R2 C R 3 R 5 5

(VIII)

'EN G

R

6 2) 06R (wherein

R

1 ,R 2 R 3 R 5 R 6 R 7 A, E, G and n are as hereinbefore defined, and R 9represents a hydroxy, amino or C13alkylamino 0'':':group) with a compound of formula IX Z R 0(IX) (wherein Z represents a nucleophilically exchangeable group such as a halogen atom, e.g. a chlorine, bromine or iodine atom, and R 10represents an alkyl, alkanoyl, alkoxycarbonyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, alkylsulphonyl, phenylalkyl, trifluoromethyl, difluoromethyl or cyanoalkyl group, m m

*I

I 2 5 16 wherein any alkyl or alkoxy moieties each contain from 1 to 3 carbon atoms and any alkanoyl moiety contains 2 or 3 carbon atoms); f) (to prepare compounds of formula I wherein A and R 7 together represent a -CH= group) dehydrating a compound of formula X

R

1 R3 E-N

G

4 .4.

4 4 *4 4* 4 *4 4 o S6B *a t 4 0 (wherein n, E, G, RIR 2

,R

31

R

4

,R

5

,R

6 and R 7 are as hereinbefore defined); 20 g) if necessary, suheequently splitting off any protecting group used in the reaction steps a) to g) in order to protect reactive groups; h) converting a compound of formula I thus obtained wherein R 4 represents a benzyloxy group by debenzylation into the corresponding hydroxy compound; i) resolving a compound of formula I thus obtained, if it contains at least one chiral centre, into its diastereomers or its enantiomers; j) converting a compound of formula I thus obtained into an acid addition salt thereof, particularly its physiologically acceptable addition salt with 35 an inorganic or organic acid.

6" 1.

6 17 17 The reaction of step is conveniently carried out in a solvent or mixture of solvents such as acetone, diethylether, methylformamide, dimethylformamide, dimethylsulphoxide, benzene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran, dioxane or in an excess of the compounds of formulae II and/or III used and optionally in the presence of an acid binding agent, e.g. an alkoxide such as potassium tert.butoxide, an alkali metal hydroxide such as sodium or potassium hydroxide, an alkali metal carbonate such as potassium carbonate, an alkali metal amide such as sodium amide, an alkali metal hydride such as sodium hydride, a tertiary organic base such as triethylamine or Ow pyridine (the latter may simultaneously also serve as solvent), or a reaction accelerator such as potassium 15 iodide (depending on the reactivity of the nucleophilically S. exchangeable group), conveniently at temperatures of between 0 and 150 0 C, preferably at temperatures of between 50 and 120 0 C, e.g. at the boiling temperature of the solvent used. However the reaction may 20 also be carried out without a solvent. It is, however, particularly preferred to perform the reaction in the presence of a tertiary organic base or an excess of the amine of formula III used.

The reaction of step is conveniently carried C "AC| out in a solvent or mixture of solvents such as (i ttacetone, diethylether, methylformamide, dimethylformamide, dimethylsulphoxide, benzene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran, dioxane or in an excess of the compounds of formulae IV and/or V used and optionally in the presence of an acid binding agent, e.g. an alkoxide such as potassium tert.butoxide, i 'A metho~ycarbonylmethoxy, ethoxycarbonylmethoxy, 18 an alkali metal hydroxide such as sodium or potassium hydroxide, an alkali metal carbonate such as potassium carbonate, an alkali metal amide such as sodium amide, an alkali metal hydride such as sodium hydride, a tertiary organic base such as triethylamine or pyridine (the latter may simultaneously also serve as solvent), or a reaction accelerator such as potassium iodide (depending on the reactivity of the nuclepphilically exchangeable group), conveniently at temperatures of between 0 and 150 0 C, preferably at temperatures of between 50 and 120 0 C, e.g. at the boiling temperature of the solvent used. However the reaction may also be carried out without a solvent. It is, however, particularly preferred to perform the reaction in the presence of a tertiary S*I organic base or an excess of the amine of formula IV used.

The reduction of step is conveniently carried out in a solvent and is preferably carried out with a metal hydride such as lithium aluminium hydride or diborane or with a complex of borane and a thioether, e.g. with borane/dimethylsulphide complex, optionally in the presence of a Lewis acid such as boron trifluoride in a suitable solvent such as diethylether or tetrahydrofuran, at temperatures of between 0 and 80 0 C, but preferably at the boiling temperature of the solvent used, e.g. at temperatures of between 35 and 65 0

C.

If A2 in a compound of formula VI used represents a carbonyl group or R 8 represents a hydroxy group, in order to prepare compounds of formula I wherein

R

8 represents a hydrogen atom the reduction is preferably carried out in the presence of a Lewis acidi e.g. with borane-dimethylsulphide complex in the presence of boron trifluoride, or hydrxid, analkli mtalcarbnat suc aspotasiu 19 if A 2 in a compound of formula VI used represents the carbonyl group or R 8 represents a hydroxy group, in order to prepare compounds of formula I wherein

R

8 represents a hydroxy group the reduction is preferably carried out with lithium aluminium hydride.

Oxidation in step is preferably effected with an oxidising agent such as potassium permanganate, barium manganate, potassium dichromate or with a ketone in the presence of a base (Oppenauer method), e.g. with acetone/aluminium isopropoxide or benzophenone- /potassium tert.butoxide, in a suitable solvent such as water, water/dioxane, glacial acetic acid, S...water/acetic acid or toluene at temperatures of between 0 and 150 0 C. Oxidation with an inorganic 15 oxidising agent, however, is preferably carried S. out at temperatures of between 0 and 50 0 C and the Oppenauer oxidation, i.e. with an organic oxidising agent, is preferably carried out at the boiling temperature of the reaction mixture, e.g. at temperatures S 20 of between 50 and 115 0

C.

The reaction of step is conveniently carried out in a solvent or mixture of solvents such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, S" acetonitrile or dimethyl formamide, optionally r ct: in the presence of an acid-activating agent or a dehydrating agent, e.g. in the presence of ethyl chloroformate, thionyl chloride, phosphorus trichloride, F 30 phosphors pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N'-carbonyldiimidazole or N,N'-thionyl diimidazole, and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethyl- 20 amine or pyridine, the latter two of which may simultaneously be used as solvent, at temperatures of between -25 0 C and 250 0 C, but preferably at temperatures of between -10 0 C and the boiling temperature of i, 5 the solvent us;-d.

The dehydration of step is conveniently carried out in a solvent such as acetone, methanol, ethanol, tetrahydrofuran or dioxane and preferably in the presence of an acid such as hydrochloric or sulphuric acid, preferably in the presence of an alcoholic acid such as methanolic hydrochloric acid, at temperatures of between 0 and 50 0 C, preferably at ambient temperature.

15 In the reactions described hereinbefore, any reactive groups present such as hydroxy, amino or imino groups may be protected during the reaction by conventional protecting groups which may then be split off again after the reaction.

Suitable protecting groups for a hydroxy group include, for example, trimethylsilyl, acetyl, benzoyl, benzyl and tetrahydropyranyl groups and suitable protecting groups for an imino or amino group include the acetyl, benzoyl, ethoxycarbonyl and benzyl groups.

The optional subsequent splitting off of a protecting group used is preferably carried out by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water tetrahydrofuran/water or dioxane/water, in the presence of an acid such as hydrochloric or sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide, at temperatures of between 0 and 100 0 C, preferably at the boiling temperature of the reaction mixture.

However, a benzyl group is preferably split off 'r i l I 'i 1 21 21 by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid, at temperatures of between 0 and 50 0 C, but preferably at ambient temperature, under a hydrogen pressure of from 1 to 7 bar, preferably from 3 to 5 bar.

If a compound of formula I is obtained wherein R4 represents a benzyloxy group, this may be converted into the corresponding hydroxy compound by debenzylation.

The subsequent debenzylation of step is preferably S 15 carried out in a solvent such as water, water/ethanol, *methanol, glacial acetic acid, ethyl acetate or dimethyl formamide, conveniently with hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, platinum or palladium/charcoal, at temperatures of between 0 and 50 0 C, but preferably at ambient temperature.

If they have at least one chiral centre, the compounds of formula I obtained may be resolved by conventional methods into their diastereomers, for example by column chromatography, and into their enantiomers, S for example by column chromatography on a chiral phase or by crystallisation with optically active acids, e.g. with D- or L-monomethyl tartaric acid, 30 D- or L-diacetyl tartaric acid, D- or L-tartaric acid, D- or L-lactic acid, D- or L-camphoric acid, D- or L-dibenzoyl tartaric acid, D- or L-camphorsulphonic acid or D- or L-camphanoic acid.

The compounds of formula I obtained may also be converted into the acid addition salts thereof, particularly the physiologically acceptable acid 22 addition salts thereof with inorganic or organic acids for pharmaceutical use. Suitable acids include, for example, hydrochloric, hydrobromic, sulphuric, phosphoric, acetic, lactic, citric, tartaric, succinic, maleic, fumaric and oxalic acids.

The compounds of general formulae II to X used as starting materials are known from the literature in some cases or may be obtained using methods known per se.

For example, a starting compound of formula II may be obtained by reduction of a corresponding carboxylic acid of formula XI 0 20R2 CH E COOH

SH(XI)

(wherein

R

1

R

2 E and n are as hereinbefore defined) or t a corresponding ester to yield the corresponding alcohol and subsequent reaction with a halogenating agent such as phosphorus tribromide or hydrogen bromide. The carboxylic acid of formula XI required may be obtained by Michael Addition of a corresponding acrylic ester to a compound of formula XII RI 0 n

C

0 (cu R CH C R 1

(XII)

S(CH

2 23 (wherein R1, R 2 and n are as hereinbefore defined, and

R

11 represents a hydrogen atom or a lower (e.g.

C1-6) alkoxy group). The compound of formula XII required for this may, in turn, be obtained by reaction of a corresponding ketone with a formic acid ester or a dialkylcarbonate in the presence of a strong base such as an alkali metal alkoxide or an alkali me'al hydride.

A starting compound of formula IV may be obtained for example by reacting a carboxylic acid of formula XI with a corresponding amine in the presence of N,N'-carbonyldiimidazole and subsequent reduction 15 of the amide thus obtained.

.e A compound of formulae VI, VII, VIII or X used as starting material may be obtained by reacting a corresponding 4-halogen compound with a corresponding amine.

*0e already mentioned hereinbefore, the new compounds of formula I and the physiologically acceptable acid addition salts thereof with inorganic or organic acids have valuable pharmacological properties, particularly a heart rate lowering effect I and the effect of reducing the 0 -requirement of u the heart, with only minor side-effects on the central nervous system.

For example, the following compounds: A) 6,7-diethoxy-2-[3-((2-(3,4-dimethoxyphenyl)ethyl)-methylamino)-propyl]-l-oxo-l,2,3,4-tetrahydronaphthalene,

I~

i i i- BI;, -i a~ c_

I!

r *r 4 4, 4* 4 I 4 4i 24 B) 6,7-dimethoxy-2-[3-((2-(3,4-dimethoxyphenyl)ethyl)-methylamino)-propyl]-1,2,3,4-tetrahydronaphthalene hydrochloride, and C) 5,6-dimethoxy-2-[3-((2-(3,4-dimethoxyphenyl)ethyl)-methylamino)-propyl]-l-hydroxy-indan were tested for their biological properties as follows: The effect on heart rate in rats The effect of the test substances on heart rate was investigated, for each dosage, on 2 rats with an average weight of 250-300 g. The rats were 15 first anaesthetised with pentobarbital (50 mg/kg i.p. and 10 mg/kg The test substances were injected in aqueous solution into the jugular vein (0.1 ml/100 g).

20 The blood pressure was measured by means of a cannula inserted in a carotid artery and the heart rate was recorded from an ECG derived by means of needle electrodes (2nd or 3rd derivation). The heart rate of the animals in the control period was between 350 and 400 beats per minute (b/min).

The following Table shows the results obtained: Substance Dosage Lowering of heart rate, measured [mg/kg] 5 minutes after administration of substance [b/min] A 5.0 157 B 5.0 150 C 5.0 152 0!.

~g~knrrrarrrrrsm~*r~,-~I~ 25 The compounds prepared according to the invention have no toxic side effects whatever when administered in therapeutic doses. Thus, for example, when substances A and C were administered intravenously to mice, even at a high dosage of 10 mg/kg, no toxic side effects could be detected other than a slight sedation.

In view of their pharmacological properties, the compounds prepared according to the invention are suitable for the treatment of sinus tachycardia of various origins and for the prophylaxis and t treatment of ischaemic heart disease.

15 The dosage required to achieve this effect is conveniently from 0.03 to 0.4 mg/kg of body weight, preferably from 0.07 to 0.25 mg/kg of body weight, once or twice a day.

Thus, according to a further aspect of the present invention we provide a method of treatment of the r. human or non-human animal body to combat sinus 0# tachycardia or ischaemic heart disease comprising the adminstration to said body of a compound of formula I (as hereinbefore defined) or a physiologically acceptable acid addition salt thereof.

Sc: According to a yet further aspect of the present invention we provide the use of a compound of formula I (as hereinbefore defined) or a physiologically acceptable acid addition salt thereof for the manufacture of a therapeutic agent for use in a method of treatment of the human or non-human animal body to combat sinus tachycardia or ischaemic heart disease.

Thus, accotding to another aspect of the present invention we provide a pharmaceutical composition 7 1W (wherein ?Ui ii? c :ii i i a~' LIIIIIL- I~I--CU- i~ _ili.i ii-_.IYillli ld- T9':4 1 i- i; illllil:- i~__li l Li-i i i .1 I i I Iii-i: Al

I

26 comprising a compound of formula I as hereinbefore described or a physiologically acceptable acid addition salt thereof together with at least one pharmaceutical carrier or excipient.

The compounds of formula I and the physiologically acceptable acid addition salts thereof with inorganic or organic acids produced according to the invention may be incorporated, optionally together with other active substances, with one or more inert conventional carriers and/or diluents, e.g. with corn starah, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sor- 15 bitol, water/polyethyleneglycol, propylene glycol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, to produce conventional galenic preparations such as tablets, coated tablets, capsules, powders, suspensions, drops, ampoules, syrups or suppositories.

The following Examples are provided to illustrate the invention in a non-limiting manner (percentages and ratios are by weight unless otherwise specified): t I #t Vi r.

i S 9* I ii *i *9 .9 9 4 I 59 9449 *i 4 Icel t

I

lf--;r-

L

o i i 27 Example A 6,7-Dimethoxy-l-oxo-l,2,3,4-tetrahydronaphthalen- 2-carbaldehyde 187.5 g (0.909 mol) of 6,7-dimethoxy-l-oxo-1,2,3,4tetrahydronaphthalene are suspended in 4.0 litres of diethylether and 123.4 g (1.1 mol) of potassium tert.butoxide are added with stirring. After minutes, 89 ml (1.1 mol) of ethyl formate are added dropwise to the precipitate formed. After 5 hours, the reddish-blue suspension is mixed with 1 litre of water. The aqueous phase is separated off and acidified with concentrated hydrochloric acid, 15 whereupon a yellow precipitate is formed. The hydrochloric acid phase is extracted three times Example B Methyl 3-(6,7-dimethoxy-l-oxo-1,2,3,4-tetrahydro- 25 naphthalen-2-yl)-propionate 8 A mixture of 128.8 g (0.55 mol) of 6,7-dimethoxyc; 1-oxo-1,2,3,4-tetrahydronaphthalen-2-carbaldehyde, 125 ml (1.38 mol) of methyl acrylate and 82.5 ml (0.6 mtol) of triethylamine is refluxed for 6 hours.

The mixture is then evaporated down in vacuo and the residue obtained is chromatographed over 1600 g of aluminium oxide (neutral, activity II-III) with methylene chloride and then with increasing amounts of ethanolt (up to Yield: 186.2 g (87.4% of theory) 153-154point: 04-06 1 Example B Methyl 3-(6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydronaphthalen-2-yl)-propionate jA mixture of 128.8 g (0.55 mol) of 6,7-dimethoxy- 1-oxo-l,2,3,4-tetrahydronaphthalen-2-carbaldehyde, 125 ml (1.38 mol) of methyl acrylate and 82.5 ml (0.6 mol) of triethylamine is refluxed for 6 hours.

The mixture is then evaporated down in vacuo and the residue obtained is chromatographed over 1600 g of aluminium oxide (neutral, activity II-III) with methylene chloride and then with increasing amounts of ethanol (up to Yield: 144.5 g (90% of theory), Melting point: 104-106 0

C.

1 o L" .t -28- Example C 3- 7-Dimethoxy-l-oxo-1, 2,3, 4-tetrahydronaphthalen- 2-yl)-propionic acid 169 g (0.578 mol) of methyl 3-(6,7-dimet1~oxy-1,2,3,4tetrahydronaphthalen-2-yl) -propionate are suspended in 15litres of 8% sodium hydroxide solution and refluxed for 90 minutes. The mixture is then poured onto ice and acidified with concentrated hydrochloric acid. The precipitate formed is suction filtered.

Yield: 152.1 g (94.5% of theory), 156-158-C.

Example D .4 3-(6,7-Dimethoxy-l-oxo-1,2,3,4-tetrahydronaphthalel- 2-yl) 4-dimethoxyphenyl) -ethyl) -N-methylpropionic acid amide 8.35 g (0.03 mol) of 3-(6,7-dimethoxy-l-oxo-l,2,3,4tetrahydronaphthalen-2-yl) -propionic acid amide are suspended in 120 ml of ethyl acetate, mixed with 4.86 g (0.03 mol) of N,N'-carbonyldiimidazole and the mixture is stirred for 60 minutes. 5.86 g (0.030 mol) of N-methyl-homoveratrylamine, dissolved 30 ml of ethyl acetate, are added to this suspailsiorl.

After 1 hour the mixture is extracted twice with 8% sodium hydroxide solution. The organic phase is dried over magnesium rulphate and concentrated by evaporation in vacuo.

Yield: 12.4 g (91% of theory) R Rf value: 0.8 (aluminium oxide, neutral; eluant: 3% ethanol in methylene chloride).

Example E -29 3- (6,7-Dimethoxy-l-oxo-1, 2,3,4-tetrahydronaphthalen- 2-vi) (4-benzyloxyphenyl) -ethyl) -N-methylpropionic acid amide Prepared analogously to Example D from 3-(6,7-dimethoxyl-oxo-1, 2,3, 4-tetrahydronaphthalen-2-yl) -propionic acid, N,N'-carbonyldiimidazole and N-methyl-(2- (4-benzoyloxyphenyl) -ethylamine.

Yield: 91% of theory, 126-128-C.

Example F 3-(6,7-Dimethoxy-l-oxo-1,2,3,4-tetrahydronaphthalen- S 15 2-yl)-N-(2-(4-nitrophenyl)-ethyl)-N-methyl-propionic .:acid amide Prepared analogously to Example D from 3-(6,7-dimethoxy- 1-oxo-l,2,3, 4-tetrahydronaphthalen-2-yl) -propionic acid, N,N'-carbonyldiimidazole and N-methyl-2-(4nitrophenyl) ethylamine.

Yield: 87.8% of theory, 'A 41 128-130 0

C.

saw.&% Example G 3- 7-Dimethoxy-l-oxo-1,2,3, 4-tetrahydronaphthalen- 2-.yl)-N-(2-(4-aminophenyl)-ethyl)-N-methyl-propionic acid amide 10.0 g (0.023 mol) of 3-(6,7-dimethoxy-1-oxc;-l,2,3,4tetrahydronaphthalen-2-yl) (4-nitropheryl) ethyl)-N-methyl)-propionic acid amide are hydrogenated in 120 ml of methanol in the presence of 1.0 g of 10% palladium/charcoal for 2 hours at ambient temperature and under 5 bars of hydrogen. The catalyst is then removed by suction filtering and the methanol is distilled off in vacuo.

Yield: 9.3 g (100% of theory), Rf value: 0.4 (aluminium oxide, neutral; eluant: 3% ethanol in methylene chloride).

Example H E-Dimethoxy-l1-oxo-indane-2-carbaldehyde Prepared analogously to Example A from 5,6-dimethoxy- 1-oxo-indan.

Yield: 81% of theory, 145-147-C.

Example I Methyl 3 6 -dimethoxy-l-oxo-indan-2-y~l)-propionate *~*Prepared from 5, 6 -dimethoxy-l-oxo-indan-2-carbaldehyde and methyl acrylate analogously to Example B.

Yield: 38% of theory, 59-62 0

C.

Example K 0 0 3 6 -Dimethoxy-l-oxo-indan-.2-yl)-propionic acid Prepared from methyl 3- (5,6-dimethoxy-l-oxo-indan- 2-yl)-propionate analogously to Example C.

a: 0Yield: 60% of theory, .146-148*C.

r 31 Example L 04 So *5 9 3-(5,6-Dimethoxy-l-oxo-indan-2-yl)-N-(2-(3,4-dimethoxyphenyl)-ethyl)-N-methyl propionic acid amide Prepared from 3-(5,6-dimethoxy-l-oxo-indan-2-yl)propionic acid and N-methylhomoveratrylamine analogously to Example D.

Yield: 83% of theory, Rf value: 0.48 (aluminium oxide, neutral; methylene chloride 2% ethanol) Example M 6,7-Dimethoxy-2-(3-methylaminopropyl)-1,2,3,4-tetrahydronaphthalene a) 3-(6,7-Dimethoxy-l-oxo-l,2,3,4-tetrahydronaphthalen- 2-yl)-N-methyl propionic acid amide 8.35 g (0.03 mol) of 3-(6,7-dimethoxy-l-oxo-l,2,3,4tetrahydronaphthalen-2-yl)-propionic acid are suspended in 120 ml of ethyl acetate, mixed with 4.86 g (0.03 mol) of N,N'-carbonyldiimidazole and stirred for minutes at 50 0 C. 4.65 g (0.15 mol) of methylamine are introduced into this suspension within 30 minutes.

The mixture is stirred for a further 30 minutes, the precipitate is suction filtered and washed with cold ethyl acetate.

Yield: 6.9 g (79% of theory), 160-161 0

C,

Calculated: C 65.96 H 7.27 N 4.81 Found: 66.15 7.29 4.96 6 56 9* a,,oo 4 i.

ii

.,I

I

i 32 b) 6,7-Dimethoxy-2-(3-methylaminopropyl)-1, 2 3 4 tetrahydronaphthalene 6.7 g (0.023 mol) of 3-(6,7-dimethoxy-1-oxo-1, 2 3 4 tetrahydronapthalen-2-yl)-N-methyl-propionic acid amide are suspended in 80 ml of tetrahydrofuran.

Under nitrogen, 3.26 g (0.023 mol) of boron trifluoride etherate are added thereto and the whole is heated to 60 0 C. At this temperature, 5.8 ml (0.058 mol) of borane dimethylsulphide complex (10 molar solution) are then added dropwise. The mixture is then refluxed for 5 hours. After the reaction mixture has been cooled, methanol is added dropwise thereto, then 10 ml of methanolic hydrochloric acid are added 15 and the resulting mixture is refluxed for a further r 2 hours. After evaporation of the solvent the f.2 .mixture is taken up in 2 molar sodium hydroxide 54 solution and extracted with ethyl acetate. The organic phases are dried over magnesium sulphate, evaporated down in vacuo and the residue is purified over aluminium oxide (neutral, activity II-III) 4with methylene chloride and increasing quantities *of methanolic ammonia.

Yield: 33% of theory, 25 R value: 0.15 (aluminium oxide neutral, eluant: 3% ethanol in methylene chloride) .Example N 6,7-Dimethoxy-2-(3-bromopro pyl-l)-1,2,3,4-tetrahydronaphthalene a) 3-(6,7-Dimethoxy-1,2,3,4-tetrahydronaphthalen- 2-yl)-propan-l-ol Prepared analogously to Example M(b) from 3-(6,7dimethoxy-l-oxo-1,2,3,4-tetrahydronaphthalen-2-

L

th I I ii_ i r i -i 33 yl)-propionic acid.

Yield: 84% of theory, Rf value: 0.4 (silica gel plates manufactured by Macherey-Nagel, Polygram, eluant: 3% ethanol in methylene chloride).

b) 6,7-Dimethoxy-2-(3-bromoprop-l-yl)-1,2,3,4-tetrahydronaphthalene 3.8 g (0.0152 mol) of 3-(6,7-dimethoxy-l,2,3,4tetrahydronaphthalen-2-yl)-propan-l-ol are dissolved in 40 ml of toluene. Then 1.57 ml (0.0167 mol) of phosphorus tribromide dissolved in 5 ml of toluene are added dropwise within 30 minutes. The mixture 15 is stirred for a further hour at ambient temperature.

Water is added, whilst cooling with ice, and the mixture is then extracted 3 times with ethyl acetate.

The combined organic phases are dried over magnesium sulphate, filtered and concentrated by evaporation 20 in vacuo.

Yield: 4.4 g (92% of theory), Rf value: 0.9 (silica gel plates made by Macherey-Nagel, eluant: methylene chloride) 9*

S.,

0#

S

e 5

S

S S -i -a Ij.; ii

S

S

*0 S *0 S *0 r S '55 5 5 .4 *i S i09r 34 Example 1 6,7-Dimethoxy-2-[3-((2-(3,4-dimethoxyphenyl)-ethyl)methylamino)-propyl]-1-hydroxy-1,2,3,4-tetrahydronaphthalene 9.6 g (0.021 mol) of 3-(6,7-dimethoxy-l-oxo-1,2,3,4tetrahydronaphthalen-2-yl)-N-(2-(3,4-dimethc.xy-phenyl)ethyl)-N-methyl-propionic acid amide, dissolved in 50 ml of dry tetrahydrofuran, are added d:opwise to 1.60 g (0.042 mol) of lithium aluminium hydride in 150 ml of dry tetrahydrofuran. The mixture is then refluxed for 1 hour, then 1.6 ml of water, 1.6 ml of 15% sodium hydroxide solution and 5 ml 15 of water are added, whilst cooling is carried out with ice water. The precipitate is suction filtered, washed with tetrahydrofuran and the filtrate is evaporated down in vacuo.

Yield: 5.0 g (50% of theory), 20 Oil, Rf value: 0.61 (aluminium oxide, eluant: 3% ethanol in methylene chloride) Calculated: C 70.40 H 8.41 N 3.16 Found: 70.26 8.33 3.05 Example 2 6,7-Dimethoxy-2-[3-((2-(3,4-dimethoxyphenyl)-ethyl)methylamino)-propyl]-1,2,3,4-tetrahydronaphthalene hydrochloride To a solution of 2.73 g (0.006 mol) of 3-(6,7-dimethoxy- 1-oxo-l,2,3,4-tetrahydro-naphthalen-2-yl)-N-(2-(3,4dimethoxy-phenyl)-ethyl)-N-methyl-propionic acid amide in 30 ml of absolute tetrahydrofuran, 0.74 ml (0.006 mol) of boron trifluoride etherate are added, under nitrogen, and then 1.5 ml (0.015 mol) of borane-dimethylsulphide complex (10 molar solution) gt -I ~5 ii r r r I f 35 o 0 *i are added dropwise. The mixture is then refluxed for 6 hours. After the reaction mixture has cooled, methanol is added dropwise thereto. Then 5 ml of methanolic hydrochloric acid are added and the resulting mixture is refluxed for a further 2 hours.

The methanol and tetrahydrofuran are distilled off and after the addition of water to the residue it is neutralised with 2 molar sodium hydroxide solution. The greasy precipitate is extracted with methylene chloride. The organic phase is dried over magnesium sulphate, evaporated down in vacuo and the residue obtained is purified over 120 g of aluminium oxide (neutral, activity II-III) with methylene chloride and then increasing amounts 15 of ethanol (up to The hydrochloride is precipitated from a solution in acetone using methanolic hydrochloric acid.

Yield: 1.24 g (44.6% of theory), 143-145°C, Calculated: C 67.29 H 8.25 N 3.02 Found: 67.16 8.18 3.07 Example 3 6,7-Dimethoxy-2-[3-((2-(3,4-dimethoxyphenyl)-ethyl)methylamino)-propyll]-1-oxo-1,2,3,4-tetrahydronaphthalene hydrochloride A mixture of 4.43 g (0.01 mol) of 6,7-dimethoxy- 2-[3-((2-(3,4-dimethoxyphenyl)-ethyl)-methylamino)p lopyll]-l-hydroxy-1,2,3,4-tetrahydronaphthalene, 21 80 g (0.025 mol) of potassium tert.butoxide, 9.10 g (0.05 mol) of benzophenone and 100 ml of toluene is refluxed for 4 hours. After cooling, the reaction mixture is washed twice with water, then extracted three times with 1% hydrochloric acid. The hydrochloric acid phases are combined and neutralised with concentrated sodium hydroxide .e rr i.

r r r r Ci-(t~ L i rr i i

Q

IIUU4~- -36 solution. The greasy precipitate is extracted with methylene chloride. The organic phase is dried over magnesium sulphate, concentrated by evaporation in vacuo and purified over 300 g of aluminium oxide (neutral, activity II-III) with methylene chloride~ and then with increasing amounts of ethanol Cup to The hydrochloride is precipitated from a solution in acetone using methanolic hydrochloric acid.

Yield: 1.7 g (35.6% of theory), 160-162-C, Calculated: C 65.33 H 7.59 N 2.93 Found: 65.40 7.50 2.77 15 Example 4 0 6,7-Dimethoxy-2-[3-( (2-(4-benzyloxyphenyl)-ethyl)- *0 methylamino) -propyl]-1,2,3,_4-tetrahydronaphthalene hydrochloride Prepared analogously to Example 2 from 3-(6,7-dimethoxy- 000 l-oxo-l,2,3,4-tetrahydronaphthalen-2-yl) (2-(4-benzoyloxyphenyl) -ethyl) -N-methyl-propionic acid amide.

Yield: 21% of theory, "O.VO 25 171-173 0

C,

Calculated: C 72.99 H 7.90 N 2.75 Found: 73.10 8.07 2.71 Example 6,7-Dimethoxy-2-[3-( (4-aminophenyl) -ethyl) -methylamino) pro yl]l2,3,4-tetrahydronaphthalene dihydrochloride Prepared analogously to Example 2 from 3-(6,7-dimethoxy- 1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-N-(2-(4aminophenyl) ethyl) -N-methyl-propionic acid amide.

Yield: 320 mg (23% of theory), -37 220-C, Calculated: C 63.29 H 7.97 N 6.15 Found: 63.10 7.91 6.08 Example 6 6,7-Dimethoxy-2-[3-( (2-(4-nitrophenyl)-ethyl)_-methylamino) -propyll 4-tetrahydronaphthalene A mixture of 1.0 g (0.0038 mol) of 6,7-dimethoxy- 2- (3-methylaminopropyl) 4-tetrahydronaphthalene, 0.87 g (0.038 mol) of 2-(4-nitrophenyl)ethyl bromide and 1.1 ml (0.008 mol) of triethylamine is refluxed for 2 hours. After the reaction mixture has cooled it is dissolved in a mixture of 2 molar sodium hydroxide solution and methylene chloride. The organic phase is separated off, washed with water, dried over magnesium sulphate, evaporated down in vacuo and purified over 120 g of aluminium oxide (neutral, activity II-III) with methylene chloride and then with increasing amounts of ethanol (up to Yield: 210 mg (16% of theory), Oil, R f value: 0.69 (aluminium oxide, eluant: 2% ethanol in methylene chloride) Calculated: C 69.88 H 7.82 N 6.79 Found: 69.87 7.61 6.67 Example 7 6,7-Dimethoxy-_2-[3-( (2-(4-acetaminophenyl) -ethyl)methylamino) -propyl] 4-tetrahydronaphthalene hydrochloride 0.76 g (0.002 mol) of 6,7-dimethoxy-2-[3-((2-(4aminophenyl)-ethyl)-methylamino)-propyl]-l,2,3,4tetrahydronaphthalene and 0.3 ml (0.002 7 mol) 1 a

F

38 of triethylamine are dissolved in 10 ml of methylene chloride and 0.16 ml (0.0022 mol) of acetyl chloride are added dropwise with stirring. After 30 minutes, water is added. The aqueous phase is extracted three times with methylene chloride. The organic phase is dried over magnesium sulphate and evaporated down in vacuo. The hydrochloride is precipitated from a solution of the resulting residue in acetone, using ethereal hydrochloric acid.

Yield: 0.25 g (27% of theory), 129-131 0

C,

Calculated: C 67.73 H 8.09 N 6.08 Cl 7.69 Found: 67.60 8.45 5.89 7.73 t I#t t1 ~-4 I I 4* I *1 I I ~1

I.

I

I.

I.

III

I.

I I I 14* I 1.1 I

I.

1114 S I 9* I t I I S

S

*e~44JS S I 15 Example 8 6,7-Dimethoxy-2-[3-((2-(4-hydroxyphenyl)-ethyl)methylamino)-propyl]-1,2,3,4-tetrahydronaphthalene 9.1 g (0.019 mol) of 6,7-dimethoxy-2-[3-((2-(4benzyloxyphenyl)-ethyl)-methylamino)-propyl]-1,2,3,4tetrahydronaphthalene are hydrogenated in 100 ml of glacial acetic acid in the presence of 1.2 g of 10% palladium/charcoal for 5 hours at ambient 25 temperature under 5 bars of hydrogen. Then the catalyst is removed by suction filtering and the glacial acetic acid is distilled off in vacuo.

The residue obtained is mixed with 10% sodium hydroxide solution and extracted three times with ethyl acetate.

The organic phase is dried over magnesium sulphate and evaporated down in vacuo.

Yield: 6.1 g (83% of theory), 90-91 0

C,

Calculated: C 75.16 H 8.67 N 3.65 Found: 75.00 8.79 3.73

I

in 39 Example 9 6,7-Dimethoxy-2-[3-( (4-methanesulphonyloxyphcnyl) ethyl) -methylamino) -propyl] 4-tetrahydronaphthal.ene hydrochloride 0.96 g (0.0025 mol) of 6,7-dimethoxy-2-[3-((2-(4hydroxyphenyl) -ethyl) -methylamino) -propyll-1, 2,3,4tetrahydronaphthalene are dissolved in 5 ml of pyridine and 0.27 ml (0.0035 mol) of methanesuiphonic acid chloride are added dropwise with stirring.

-After 1 hour, 10% sodium hydroxide solution is added. The aqueous phase is extracted three times with methylene chloride. The organic phase is 15 dried over magnesium sulphate and evaporated down in vacuo and purified over 80 g of aluminium oxide (neutral, activity II-III) with methyl chloride.

The residue obtained is taken up in ether and the hydrochloride is precipitated with ethereal hydrochloric 20 acid.

Yield: 0.38 g (31% of theory) 145-146 0

C,

Calculated: C 60.29 H 7.29 N 2.81 S 6.44 Cl 7.12 Found: 60.35 7.38 2.85 6.27 7.39 C C( r C C C C C 4 t I I 4 cct 4 44 Example

I

(~I

S

9

S

4~4 9 6,7-Dimethoxv-2-[3-( (2-(4-benzyloxyphenyl) -ethyl)methylamino) -propyl]j-1,2,3,4-tetrahydronaphthalene hydrochloride Prepared analogously to Example 6 from 6,7-dimethoxy- 2- (3-bromopropyl) 2,3, 4-tetrahydronaphthalene and N-methyl- (4-benzyloxyphenyl) -ethylamine.

Yield: 43% of theory 171-1-i31-C

N

-I)

AW'

40 Example 11 6,7-Dimethoxy-2-[3-((2- (4-trifluoromethanesulphonyloxyphenyl) -ethyl) -methylamino) -propyll 4-tetrahydronaphthalene hydrochloride Prepared from 6,7-dimethoxy-2-j3-( (2-(4-hydroxyphenyl)ethyl) -methylamino) -propyll 4-tetrahydronaphthalene and trifiuoromethanesulphonic acid chloride analogously to Example 9.

Yield: 69% of theory, 135-137-C, Calculated: C 54.39 H 6.03 N 2.54 Cl 6.42 S 5.81 Found: 54.34 6.28 2.74 6.69 6.05 #0 t Example 12 ~6,7-Dimethoxy-2-73-( (4-cyanomethoxpey)-ty) methylamino) -propyll-1,2,3, 4-tetrahydronaphthalene hydrogen tartrate Prepared from 6,7-dimethoxy-2-[3- (4-hydroxyphenyl)- 0 Oae -methylamino) -propyl] 4-tetrahydronaphthalene and chloroacetonitrile analogously 425 to Example 16.

Yield: 31% of theory, 63-68-C Calculated: C 62.92 H 7.04 N 4.89 Foundfl 62.64 7.01 4.80 Example 13 6,7-Dimethoxy-2-[3-((2-(4-trifluoromethoxyphenyl)ethyl) -methylamino) -propyl] 4-tetrahydronaphthalene-hydrochloride Prepared from 6,7-dimethoxy-2- (3-methylaminopropyl) 1,2,3,4-tetrahydronaphthalene and 2-(4-trifluoromethoxy- -41phenyl)-ethyl bromide analogously to Example 6.

Yield: 50% of theory, M.P. 124-125 0

C

Calculated: C 61.53 H 6.82 N 2.87 Cl 7.27 Found: 61.43 7.03 2.85 7.55 Example 14 6,7-Dimethoxy-2-[3-( (2-(4-methanesulphonylaminophenyl)ethyl)-methylamino)-propyl]-1,2,3,4-tetrahydronaphthalene hydrochloride Prepared from 6,7-dimethoxy-2-[3-( (2-(4-aminophenyl)- -methylamino) -propyl] 4-tetrahydroaphthalene and methanesulphonic acid chloride analogously to Example 7.

Yield: 30% of theory, 177-179 0

C

Calculated: C 60.40 H 7.50 N 5.64 Found: 60.60 7.61 5.70 Example 6,7 Dimethoxcy-2-[3-( (2-(4-methoxycarbonylaminophenyl) 25 ethyl) -methylamino)-propyl]-1,2,3,4-tetrahydronaphthalene hydrogen fumarate ~*Prepared 'from 6,7-dimethoxy-2-[3-((2-(4-aminophenyl)ethyl) -methylamino) -propyl]-l,2,3, 4-tetrahydronaphthalene and methyl chloroformate analogously to Example 7.

Yield: 23% of theory, 156-160 0 C (decomposition) Calculated: C 64.73 H 7.24 N 5.03 Found: 65.03 7.08 5.20 42 Example 16 6,7-Dimethoxy-[3-((2-(4-ethoxycarbonylmethoxyphenyl)ethyl)-methylamino)-propyl]-1,2,3,4-tetrahydronaphthalene hydrochloride A mixture of 1.15 g (0.003 mol) of 6,7-dimethoxy- 2-[3-((2-(4-hydroxyphenyl)-ethyl)-nmethylamino)propyl]-1,2,3,4-tetrahydronaphthalene, 0.34 g (0.003 mol) of potassium tert.butoxide and 10 ml of dimethyl sulphoxide is heated to 50 0 C for 1 hour. Then g (0.003 mol) of bromoacetic acid ester are added and the mixture is heated to 50 0 C for a further hour. After the reaction mixture has cooled, water

I.

is added and it is extracted with ethyl acetate.

tes The organic phase is dried over magnesium sulphate, evaporated down in vacuo and purified over 60 g *0* of silica gel (32-63 microns, Messrs. Woelm) with methylene chloride and then with increasing amounts S" 20 of ethanol (up to The hydrochloride is precipitated from a solution in acetone using methanolic hydrochloric acid.

*4 Yield: 0.2 g (13% of theory), 134-136 0

C

's 25 Calculated: C 66.45 H 7.97 N 2.77 Cl 7.01 Found: 66.31 7.91 2.74 7.15 C"Eek Example 17 C a 6,7-Dimethoxy-2-[3-((2-(3,4-dimethoxyphenyl)-ethyl)methylamino)-propll-1,2-dihydronaphthalene hydrochloride g (0.011 mol) of 6,7-dimethoxy-2-[3-((2-(3,4dimethoxyphenyl)-ethyl)-methylamino)-propyl]-lhydroxy-1,2,3,4-tetrahydronaphthalene are dissolved in 40 mi of acetone and methanolic hydrochloric acid is added. The resulting mixture is.stirred 0I 4 J_ I 43 43 for 30 minutes at ambient temperature, then ether is added dropwise until slight turbidity occurs and the mixture is then stirred for a further minutes. The precipitate obtained is suction filtered and dried.

Yield: 4.8 g (92% of theory), 171-172 0

C

Calculated: C 67.59 H 7.85 N 3.03 Found: 67.51 8.06 3.27 Example 18 I 5,6-Dimethoxy-2-[3-((2-(3,4-dimethoxyphenyl)-ethyl)methylamino) -propyl]-l-hydroxy-indan ,i Is a, Prepared from 3-(5,6-dimethoxy-l-oxo-indan-2-yl)- N-(2-(3,4-dimethoxyphenyl)-ethyl)-N-methylpropionic acid amide analogously to Example 1.

Yield: 58% of theory, 20 83-85 0

C

Calculated: C 69.90 H 8.11 N 3.26 Found: 69.18 8.19 3.13 Example 19 5,6-Dimethoxy-2-[3-((2-(3,4-dimethoxyphenyl)-ethyl)- Sv methylamino)-propyl]-l-oxo-indan Prepared from 5,6-dimethoxy-2-[3-((2-(3,4-dimethoxyphenyl)ethyl)-methylamino)-propyl]-1-hydroxy-indan and benzophenone analogously to Example 3.

Yield: 16% of theory, 98-100oC Calculated: C 64.71 H 7.39 N 3.02 Found: 64.80 7.39 2.95 4 r" v4~.7 jT:l.~; I

I

~lrY~a~snrsl~nr~wars~~-i s"p"- I Qr,.

44 Example o 9 4 9 .o

S

4 9 6,7-Dimethoxy-2-[3-((2-(4-hydroxycarbonylmethoxyphenyl)ethyl)-methylamino)-propyl]-1,2,3,4-tetrahydronaphthalene 4.1 ml of 0.1 N sodium hydroxide solution are added dropwise to a solution of 700 mg (0.014 mol) of 6,7-dimethoxy-2-[3-((2-(4-ethoxycarbonylmethoxyphenyl)ethyl)-methylamino)-propyl]-l,2,3,4-tetrahydronaphthalene in 10 ml of methanol, then the mixture 10 is stirred for 25 minutes at ambient temperature and finally 4.1 ml of 0.1 N hydrochloric acid are added. The solution is extracted several times with ethyl acetate and after the combined organic phases have been dried over magnesium sulphate 15 they are evaporated down in vacuo. The residue is taken up in a little methylene chloride, filtered and the filtrate is evaporated to dryness.

Yield: 240 mg (36% of theory), 71 0

C

Calculated: C 70.72 H 7.99 N 3.17 Found: 70.49 7.74 3.06 Example 21 44444'

S

544544 L 4 25 6,7-Dimethoxy-2-[3-((2-(4-(N,N-bis-methanesulphonylamino)-phenyl)-ethyl)-methylamino)-propyl]-1,2,3,4tetrahydronaphthalene hydrochloride Prepared from 6,7-dimethoxy-2-[3-((2-(4-aminophenyl)ethyl)-methylamino)-propyl]-1,2,3,4-tetrahydronaphthalene and methanesulphonic a id chloride analogously to Example 14.

Yield: 15% of theory, 106-108 0 C (decomp.) Calculated: C 54.29 H 6.83 N 4.87 if ~s ~rl 7

I

45 Found:- 54.10 6.77 4.62

I:

I-

f. ttr It ft t I I ft I If I I I I I II

I.

4 I 4.

*4 *4 4 44* V V

V.

I

V

V# V 4k f I.ct ~.Ct t I Example 22 6,7-Dimethoxy-2-[3-( (3-(4-brornophenyl)-propyl) methylamino) -propyl 1-1,2,3, 4-tetrahydronaphthalerie hydrogen fumarate Prepared from 6,7-dimethoxy-2-(3-methylamino-propyl) 1,2,3,4-tetrahydronaphthalene and 3-(4-bromophenyl)- 1-bromopropane analogously to Example 6.

Yield: 35% of theory, 59-C Calculated: C 60.42 H 6.65 N 2.43 15 Found: 60.10 6.43 2.40 Example 23 6,7-Djmethoxy-2-13-( (3-(4-cyanophenyl)-propyl) 20 methylamino)-propyl]-1,2,3,4-tetrahydronaphthalene hydrogen fumarate Prepared from 6, 7-dimethoxy-2- (3-methylamino-propyl) l,2,3,4-tetrahydronaphthalene and 3-(4-cyano-phenyl) 1-bromopropane analogously to Example 6.

Yield: 58% of theory, decomposition from 57 0

C

Calculated: C 68.94 H 7.33 N 5.36 Found: 68.71 7.15 5.20 Example 24 6,7-Dimethoxy-2-13-( (2-(4-methylsulphonylphenyl) ethyl) -methylamino) -propyl 1-1,2,3, 4-tetrahydronaphthalene Prepared from 6,7-dimethoxy-2-(3-methylamino-propyl) i,2,3,4-tetrahydronaphthalene and 2- (4-methylsulphonyljj m -fig' -46 phenyl)-l-bromoethane analogously to Example 6.

Yield: 10.4% of theory, Oil, R f value: 0.63 (aluminium oxide, eluant: 3% ethanol in methylene chloride) Calculated: C 67.32 H 7.85 N 3.14 Found: 67.14 7.98 3.25 Example 6,7-Dimethoxy-2-[3-( (4-methoxyphenyl) -propyl) methylamino) -propyl]-1,2,3,4-tetrahydronaphthalene Ge.. Prepared from 6,7-dimethoxy-2- (3-methylamino-propyl) C l,2,3,4-tetrahydronaphthalene and 3-(4-methoxyphenyl)- .:15 1-bromopropane analogously to Example 6.

Yield: 68.7% of theory, 39-C Calculated: C 75.87 H 8.82 N 3.40 Found: 75.69 8.94 3.59 .Example 26 C 6,7-Dimethoxy-2-[3-( (2-phenyl-ethyl) -methylamino)propyl] 4-tetrahydronaphthalene Prepared from 2-phenyl-1-chloroethane and 6,7-dimethoxy- 2- (3-methylamino-propyl) 4-tetrahydronaphthalene analogously to Example 6.

Yield: 42% of theory, Oil, R f-value: 0.42 (aluminium oxide, eluant: 2% ethanol in methylene chloride) Calculated: C 78.43 H 9.05 N 3.81 Found: 78.63 9.29 3.66

IV~

47 Example 27 5,6-Dimethoxy-2- ((4-benzyloxyphenyl) -ethyl) -methylamino) -propyl) -1-hydroxy-indan Prepared from 3- (5 ,6-dimethoxy-l-oxo-indan-2-Yl) N-(2-(4-benzyloxyphenyl) -ethyl) -N-methyl propionic acid amide and lithium aluminium hydride analogously to Example 1.

#3 999 3 9 39 9 99 9 .3 9 *3 .9 9 *3 .9 .9.

S 993 9 9 93 4 99 a .9.99.

a a 4e9993 3 Yield: 90% of theory, 80-83 0

C

Calculated: C 75.76 Found: 75.58 H 7.84 N 2.95 8.01 2.79 Example 28 6, 7-Dimethoxy-2- (2-hydroxyethoxy) -phenyl) ethyl) -methylamino) -propyl 1-1,2,3, 4-tetrahydronaphthalene 20 hydrochloride Prepared from 6,7-dimethoxy-2-[3- ((2-(4-ethoxycarbonylmethoxyphenyl) -ethyl) -methylamino) -propyl 1-1,2,3,4tetrahydronaphthalene and lithium aluminium hydride analngously to Example 1.

Yield: 43% of theory, 141-143-C Calculated: C 67.30 H 8.25 N 3.02 Cl 7.64 Found: 67.20 -8.28 3.04 7.65 Example 29 6,7-Dimethoxy-2-_[3-( (2-(4-(4-benzyloxyphenyl)-ethvl)methylamino) -propyl] -l-hydroxy-1, 2,3, 4-tetrahydronaphthalene Prepared from 3-(6,7-dimethoxy-l-oxo-1,2,3,4-tetrahydronaphthalen-2-yi) (4-benzyloxyphenyl) -ethyl) N-methylpropionic acid amide and lithium aluminium

H

48 hydride analogously to Example 1.

Yield: 53.6% of theory, 75 0

C

Calculated: C 70.77 H 7.66 N 2.66 Found: 71.00 7.52 2.56 Example 6,7-Dimethoxy-2-[3-((2-(4-hydroxypheuyl)-ethyl)methylamino) -propyl] -l-hydroxy-1, 2,3, 4-tetrahydronaphthalene Prepared from 6,7-dimethoxy-2-[3-((2-(4-benzyloxyphenyl) -ethyl) -methylamino) -propyll -l-hydroxy-1, 2,3,4- 15 tetrahydronaphthalene and hydrogen analogously to Example 8.

Yield: 47.5% of theory, 97 0

C

Calculated: C 72.15 H 8.33 N 3.51 Found: 72.14 8.43 3.53 Example 31 9*49 6,7-Dimethoxy-2-[3-((2-(4-methanesulphonyloxy--phenyl)ethyl)-methylamino)-propyl]-l-hydroxy-1,2,3,4-tetrahydro- ***etc naphthalene Prepared from 6,7-dimethoxy-2-[3-((2-(4-hydroxyphenyl)-ethyl)-methylamino)-propyl-l-hydroxy-i,2,3,4tetrahydro-naphthalene and methanesulphonic acid chloride analogously to Example 9.

Yield: 16.7% of theory, oil, Rf value: 0.4 (aluminium oxide, eluant: 5% ethanol in methylene chloride) Calculated: C 62.87 H 7.39 N 2.93 Cl 6.71 Found: 62.05 7.50 2.75 6.88 a i P1- 49 Example 32 6,7-Dimethoxy-2-[3-( (2-(4-trifluoromethanesulphoflyloxyphenyl) -ethyl) -methylamino)-ppyj]-l-ydroxy-1, 2 3 4 tetrahydronaphthalene Prepared from 6,7-dimethoxy-2-[3-( (2-(4-hydroxyphenyl) -ethyl) -methylamino) -propyll -l-hydroxy-1, 2,3,4tetrahydronaphthalene and trifluoromethanesuiphonic acid chloride analogously to Example 9.

Yield: 54.8% of theory, 119-C Calculated: C 56.49 H 6.07 N 2.63 Cl 6.03 Found: 56.36 6.01 2.49 6.86

'I

ti 4 4 U It I 41 t 4 4 4 w ii

SI

44 4 4 44 .4 4 440 4 4*4 4* ~4 4 4 4. 4 44494 9 4 Example 33 6, 7-Dimethoxy-2- (4-ethoxycarbonylmethoxyv~henvl) -ethyl) -methylamino) -propyll -l-hydroxy-1, 2,3,4- 20 tetrahydronaphthalene Prepared from 6,7-dimethoxy-2-[3-( (2-(4-hydroxyphenyl) -ethyl) -methylamino) -propyl]-1-hydroxy-l,2,3,4tetrahydronaphthalene and ethyl bromoacetate analogously to Example 9.

Yield: 29% of theory, Oil, R f value: 0.2 (aluminium oxide, eluant: 3% ethanol in methylene chloride) Calculated: C 69.25 H 8.09 N 2.88 Found: 69.00 7.93 2.63 Aft rn F 50 Example 34 6,7-Dimethoxy-2-[3-( (4-hydroxycarbonylmethoxyphenyl) -ethyl) -methylamino) -propyl] -l-hydroxy-l, 2,3,4.tetrahydronaphthalene Prepared from 6,7-dimethoxy-2-113-( (4-hydroxyphenyl) -ethyl) -methylamino) -propyl] -l-hydroxy-l,2,3, 4tetrahydronaphthalene and ethyl bromoacetate/sodium hydroxide solution analogously to Example Yield: 37% of theory, 92-C Calculated: C 68.25 H 7.71 N 3.06 Found: 68.58 7.63 2.92 r ff@ S S I 55 I 5* a is 5 5# 5 *5 a.

S

a *5* p p5 p p.

S S 4* S *54 lIt

I

S

I I' I I I I Example 6,7-Dimethoxy-2-[3-((2-(4-benzyloxyphenyl)-ethyl)methylamino) -propyl]-l-oxo-1, 2,3, 4-tetrahydronaphthalene 20 hydrochloride Prepared from 6,7-dimethoxy-2-[3-( (2-(4-benzyloxyphenyl) -ethyl) -methylamino) -propyl] -l-hydroxy-l, 2,3,4tetrahydronaphthalene and potassium tert. butoxide/benzophenone analogously to Example 3.

Yield: 26% of theory, 191-C Calculated: C 71.04 H 7.31 N 2.67 Cl 6.76 Found: 71.12 7.24 2.61 6.87 Example 36 6,7-Dimethoxy-2-[3-((2-(4-benzyloxyphenyl)-ethyl)methy, lamino)-propyl]-3,4-dihydronaphthalene hydrochloride Prepared from 6,7-dimethoxy-2-[3-( (2-(4-benzyloxyphenyl) thyl) -methylamino) -propyl] -1-hydroxy-1,2,3, 4- -51tetrahydronaphthalene and hydrochloric acid analogously to Example 17.

Yield: 18.6% of theory, 185-C Calculated: C 73.28 H 7.54 N 2.76 Cl 6.98 Found: 73.66 7.20 2.78 7.43 Example 37 6,7-Dimethoxy-2-[3( ((2-(4-hyd,.o.,phenyl)-ethyl)methylamino) -propyl]-3 ,4-dihydronaphthalene Prepared from 6,7-dirnethoxy-2-[3-( (2-(4-hydroxya 4 t f phenyl) -ethyl) -methylamino) -propyl]-1-hydroxy-1, 2,3,4tetrahydronaphthalene and hydrochloric acid analogously to Example 17.

Yield: 65% of theory, 0 air Oil, R f value: 0.83 (aluminium oxide, eluant: ethanol in methylene chloride) Calculated: C 75.56 H 8.19 N 3.67 Found: 75.29 8.10 3.62 Exarm~ple 38 6,7-Dimethoxy-2-[3- (4-methanesulphonyloxyphenyl) ethyl) -methylamino) -propyl]-3 ,4-dihydronaphthalene hydrochloride Prepared from 6,7-dimethoxy-2-[3-( (2-(4-methanesulphonyloxy-phenyl)-ethyl)-methylamino)-propyl]- 1-hydroxy-1,2,3,4-tetrahydronaphthalene and hydrochloric acid analogously to Example 17.

Yield: 42.8% of theory, 81 0 C (sinters from 59 0

C)

Calculated: C 58.41 H 7.06 N 2.72 Cl 6.89 S 6.24 Found: 58.60 7.07 2.54 7.00 6.37 I

I

ijr--i a i.e ci.

CO

0* a. a

C@

a.

.i.

a 0 a.

*0 a *4* a.

a 0~* 9* a a.

a a. e 52 Example 39 6,7-Dimethoxy-2-[3-( (4-trifluoromethanesulphonyloxyphenyl) -ethyl) -methylamino) -propyll-3 ,4-dihydronaphthalene Prepared from 6,7-dimethoxy-2-[3-( (2-(4-trifluoromethanesuiphonyloxyphenyl) -ethyl) -methylamino) -propyll-hydroxy-l,2,3,4-tetrahydronaphthalene and hydrochloric acid analogously to Example 17.

Yield: 77% of theory, Oil, R f value: 0.92 (aluminium oxide, eluant: 3% ethanol in methylene chloride) Calculated: C 58.47 H 5.89 N 2.73 Cl 6.24 Found: 58.61 5.88 2.54 6.75 Example 6-Dimethoxy-2-[ 3- (4-methoxyphenyl) -ethyl) methylamino) -propylj-l-hydroxy-indan oxalate Prepared from 3- 6-dimethoxy-1-oxo-indan-2-yl) N- (4-methoxyphenyl) -ethyl) -N-methylpropionic acid amide and lithium aluminium hydride analogously to Example 1.

Yield: 90% of theory, 80-83 0

C

Calculated: C 63.79 H 7.21 N 2.86 Found: 63.55 7.31 3.02 Example 41 5,6-Dimethoxy-2-13- (4-methoxyphenyl) -ethyl) methylamino) -propyl]-l-oxo-indan hydrochloride Prepared from 5,6-dimethoxy-2-[3-( (2-(4-methoxyphenyl)ethyl) -methylamino) -propyl]-1-hydroxy-indan and benzophenone analogously to Example 13.

I t I *4 eat C a C Cit a a 11 53 Yield: 21% of theory, 193-194 0

C

Calculated: C 66.42 Found: 66.30 H 7.43 N 3.23 7.58 3.39 Cl 8. 17 8.30 9* 9 *9* .9 .9 9 *9 .9 .4 9 9 .4

S.

9 9.

*99 p 94 9 9 99 9S 9. 5 tr 9 1 5 1 5

S

Example 42 5,6-Digaethoxy-2-[3- (4-benzyloxyphenyl) -ethyl) methylamino) -propyllj-l-hydroxy-indan Prepared from 3-(5,6-dimethoxy-1-oxo-indan-2--yl)- N- (4-benzyloxyphenyl) -ethyl) -N-methylpropionic acid amide and lithium aluminium hydride analogously to Example 1.

15 Yield: 90% of theory, 80-83-C Calculated: C 75.76 H 7.84 N 2.95 Found: 75.58 8.07 2.79 20 Example 43 5,6-Dimethoxy-2-13- ((2--(4-benzyloxyphenyl) -ethyl) methylamino) -propyl]-l-oxo-indan hdrochloride Prepared from 5,6-dimethoxy-2-[3-( (2-(4-benzyloxyphenyl)ethyl) -methylamino) -propyl]-l-hydroxy-indan and benzophenone analogously to Example 3.

Yield: 12% of theory, 189-191 0

C

Calculated: C 70.64 H 7.11 N 2.75 C1 6.95 Found: 70.50 7.22 2.83 7.20 -11 e:reparea rrom to,/-aimetnoxy-z-(i-metnyiaminopropyl)-I l,2,3,4-tetrahydronaphthalene and 2-(4-trifluoromethoxy- 54 Example 44 5,6-Dimethoxy-2-[3-( (4-methylphenyl) -ethyl) methylamino) -propyl]-1-hydroxy-indan Prepared from 3- (5,6-dimethoxy-l-oxo-indan-2-yl) N- (4-methyiphenyl) -ethyl) -N-methylpropionic acid amide and lithium aluminium hydride analogously to Example 1.

Yield: 83% of theory, 89-90-C Calculated: C 75.16 H 8.67 N 3.65 Found: 74.96 8.65 3.58 15 Example 5,6-Dimethoxy-2-[3- (4-methylphenyl) -ethyl) 4.

4 S *4 9

S

SO

S.

*t 9 9 *9 4.

9..

methylamino) -propyl]-l-oxo-indan hydrochloride 9.

9# o 94, *4 @4 4*4e @4 9* 9 4.

444 44.~ 4.

4 20 Prepared from 5,6-dimiethoxy-2-[3- (4-methiylphenyl) ethyl) -methylamino) -propyl]-l-hydroxy-indan and benzophenone analogously to Exam~ple 3.

Yield: 19% of theory, 193-194 0

C

Calculated: C 68.96 H 7.72 N 3.35 Cl 8.48 Found: 68.86 7.72 3.45 8.63 Example 46 4-Methyl-2-t 3-C methylamino) -propyl]-1-hydroxy-indan oxalate Prepared from 3-(4-methyl-l-oxo-indan-2-yl)-N- (2- 5-dimethoxy-phenyl) -ethyl) -N-methylpropionic acid amide and lithium aluminium hydride analogously to Example 1.

Yield: 90% of theory, 7 p..

he 55 M.p.:82-83 0

C

Calculated: Found: C 65.94 66.03 H 7.45 N 2.96 7.55 3.05 r

I

I t LI I It

II

4 6 *1 4, 4 .44 .4 4.

444 4.

.4 4 4.

.444 4.

44 4

I

I

I

Example 47 4-Methyl-2-[3-( (2-(3,5-dimethoxyphenyl)-ethyl)methylamino) -propyl]-l-oxo-indan Prepared from 4-methyl-2-[3-( (2-(3,5-dimethoxyphenyl)ethyl) -methylamino) -propyl]-l-hydroxy-indan and benzophenone analogously to Example 3.

Example 48 20 4-Methyl-2-13-( (2-phenylethyl) -methylamino) -propyll- 1-hydroxy-indan oxalate Prepared from 3- (4-methyl-l-oxo-indan-2-yl) (2phenylethyl) -N-methylpropionic acid and lithium aluminium hydride an -'logously to Example 1.

Yield: 90% of theory, 88-90*C Calculated: C 69.71 H 7.56 N 3.39 Found: 69.57 7.63 3.31 Tqq Example 49 4-Methiyi-2-[ 3- ((2-phenyl-ethyl)-methylamino) -propyll- 3-oxo-indan fumarate Prepared from 4-methyl-2-[3-( (2-phenyl-ethyl)-methylamino)propyll-1-hydroxy-indan and benzophenone analogously

I

56 to Example 3.

yield: 5% of theory, 118-121 0

C

Calculated: C 71.37 Found: 71.91 H 7.14 N 3. 7.33 3.31 4.

4 444 44*4 4.

#4 4 44 4 4 9 4 44 4 9 49 4.

4 9 444 44 4 4 .4, 44 94 4 4 #4 ExaMplte 4-Methyl-2-13-( (2-(3,4,5-trimethoxyphenyl)-ethYl)methylamino) -propyi'J-l-hydroxy-indan Prepared from 3-t4-methyl-1-oxo-indan-2-yl) (3,4,5-trimethoxyphenyl)-ethyl) -N-methylpropionic acid amide and lithium aluminium hydride analogously 15 to Example 1.

,Yield: 85% of theory, 75-77*C Calculated: C 64.40 H 7.41 N 2.78 Found: 64.49 7.38 3.09 Example 51 .444 4 49 44 4 4-Methyl-2-[3-( (2-(3,4,5-trimethox phenyl)-ethyl)methylamino) -propyll-1-oxo-indan Prepared from 4-.methyl-2-[3-( (2-(3,4,5-trimethoxyphe,'nyl) -ethyl) -methylamino) propyl]-l-hydroxy-indan and benzophenone analogously to Example 3.

4' ('f

C

I C 4 -57 Example 52 5,6-Dimethoxy-2-[j3-( (2-(4-benzyloxypheny l)-ethylmethylamino)-propyl]-indene hydrochloride Prepared from 5,6-dimethoxy-2-13-( (2-(4-benzyloxyphenyl)ethyl) -methylamino) -propyl]-1-hydroxy-indan and hydrochloric acid analogously to Example 17.

Yield: 88% of theory, 181-183-C Calculated: C 72.93 H 7.34 N 2.84 Cl 7.18 Found: 72.50 7.39 2.62 7.32 Example 53 5,6-Dimethoxy-2-[3- (4-methoxyphenyl) -ethyl)methylamino) -propyl]-indene hydrochloride Prepared from 5,6-dimethoxy-2-[3-( (2-(4-methoxyphenyl)ethyl)-methylamino)-propyl]-l-hydroxy-indan and hydrochloric acid analogously to Example 17.

Yield: 68% of theory, aM.p.: 188-190 0

C

Calculated: C 68.96 H 7,72 N 3.35 Cl 8.48 Found: 68.86 7.72 3.25 8.68 Example 54 5,6-Dimethoxy-2-[3- (4-methylphenyl)-ethyl)methylamino)-propyl]-indene hydrochloride Prepared from 5,6-dimethoxy-2-[3-( (2-(4-methylphenyl)ethyl) -methylamino) -propyl]-l-hydroxy-indan and hydrochloric acid analogously to Example 17.

Yield: 72% of theory, 205-207 0

C

Calculated: C 71.71 H 8.02 N 3.48 Cl 8.82 1 1 58 Found: 71.63 8.04 3.48 8.94 Example 7-Methyl-2-[3-( methylamino) -propyl]-indene oxalate Prepared from 4-methyl-2-13-( (2-(3,5-dimethoxyphenyl)ethyl) -methylamino) -propyl]-1-hydroxy-indan and hydrochloric acid analogously to Example 17.

Yield: 37% of theory, 133-134-C Calculated: C 68.55 H 7.30 N 3.07 Found: 68.43 7.45 3.17 44' t 44 004 .0 Example 569 7-Methyl-2-I 3- ((2-phenylethyl) -methylamino) -propyl]indene fumarate Prepared from 4-methyl-2-[3- ((2-phenylethyl) -methylamino) propyl]-l-hydroxy-indan and hydrochloric acid analogously to Example 17.

Yield: 33% of theory, 124-126 0

C

Calculated: C 74.08 H 7.41 N 3.32 Found: 73.83 7.38 3.52 Example 57 7-Methyl-2-[3-((2-(3,4,5-trimethoxyphenyl)-ethyl)methylamino) -propyl]-indene oxalate Prepared from 4-methyl-2-[3-( (2-(3,4,5-trimethoxyphenyl)ethyl)-methylamino)-propyl]-l-hydroxy-indan and hydrochloric acid analogously to Example 17.

Yield: 28% of theory, A W1

I

59 102-104*C (decomp) Calculated: C 66.78 H 7.27 N 2.88 Found: 66.59 7.48 2.62 4 IE'( I- t f'~ 4, t 4£

I.

44 I 1£

'I

V C .9.

Ce

'C

a. gee b 04 4 b 4.

Example 58 5,6-Dimethoxy-2-[3-( (2-(4-benzyloxy,?henyl)-ethyl)methyl-amino) -propyl I-1-oxo- mnda hydrochlor ide Prepared from 5,6-dirnethoxy-2-[3-( (2-(4-benzyloxyphenyl)ethyl) -methylamino) -propyl]-l-hydroxy-indan and benzophenone analogously to Example 3.

Yield: 12% of theory, 189-191 0

C

15 Calculated: C 70.64 H 7.11 N 2.75 Cl1 6.05 Found: 70.50 7.22 2.83 7.10 Example 59 20 6,7-Dimethoxy-3-[3-( (2-(3-benzyloxyphenyl)-ethyl)methyl-amino) -propyl]-1,2-dihydro-naphthalene hydrochloride Prepared from 6 ,7-dimethoxy-2-[3- (3-benzyloxyphenyl) -ethyl) -methylamino) -propyl] 4-tetrahydro- 25 l-hydroxynaphthalene and hydrochloric acid analogously to Example 17.

Yield: 23% of theory, Calculated: C 73.28 H 7.54 N 2.76 Cl 6.98 Found: 73.12 7.46 2.89 7.02

IL

te kt -59a- Example 6, 7-Dimethoxy-2-[13- (4-methanesulphonyloxyphenyl ethyl)-methylamino )-propyl 11-l-oxo-l, 2, 3,4-tetrahydronaphthalene hydrochloride Prepared from 6, 7-dimethoxy-2- (2-(4-methanesulphonyloxy-phenyl )-ethyl )-methylamino)-propyl -l-hydroxy-l,2,3, 4-tetrahydronaphthalene and benzophenone analogously to Example 3.

Yield :53% of theory, Melting Point :183 0

C

Calculated C 58.64 H 6.69 N. 2.73 Cl 6.92 S 6.26 Found 58.48 6.93 2.68 7.22 6.50 Example 61 6,7-Dimethoxy-2-[ 3-methanesulphonyloxyphenyl ethyl )-methylamino)-propyl ]-l-oxo-l 2,3 ,4-tetrahydronaphthalene hydrochloride Prepared from 6,7-dimethoxy-2- 3-((2-(3-methanesulphonyloxyphenyl )-ethyl )-methylamino)-propyl -l-hydroxy-l ,2,3,4tetrahydronaphthalene and benzophenone analogously to Example 3.

Yield 28% of theory, 0 0 melting Point 81 ~C (sintering from 66 C) Calculated ;C58.64 H 6.69 N 2.74 Found .58.56 6.83 2.69 Example 62 6,7-Dimethoxy-2-[3-( (2-(3-benzyloxyphenyl)-ethyl)methylamino)-propylI-l-oxo- 2,3,4-tetrahydronaphthalene hydrochloride TF Prepared from 6,7-dimethoxy-2- (2-(3-benzyloxyphenyl)ethyl) -methylamino )-propyl -l-hydroxy-l 4-tetrahydronaphthalene and benzophenone analogously to Example 3.

Yield :27% of theory, Melting Point t 70 0 Calculated: C 71.04 H 7.31 N 2.67 Cl 6.77 Found 70.20 7.31 2.64 6.68 -59b- Example 63 6,7-Dimethoxy-2-[3-( (2-(3-hydroxyphenyl)-ethyl)methylamiino )-propyl]I-l-hydroxy- 2 4-tetrahydronaphthalene oxalate Prepared from 6,7-dimethoxy-2- (2-C 3-benzyloxyphenyl ethyl )-methylamino)-propyl -1-hydroxy 1,2,3, 4-tetrahydronaphthalene and hydrogen in the presence of palladium! charcoal analogously to Example 8.

Yield: 84% of theory, Melting Point: 77 C Calculated: C 63.79 H 7.21 N 2.86 Found 63.57 7.40 2.68 Example 64 6,7-Dimethoxy-2-[3-( (2-(3-hydroxyphenyl)-ethyl)methylamino)-propyl 3,4-tetrahydro-naphthalene hydrochloride Prepared from 6,7-dimethoxy-3- 3-C (2-(3-benzyloxyphenyl)ethyl) -methylamino) -propyl 1, 2-dihydronaphthalene and hydrogen in the presence of palladium/charcoal and in ethanol as solvent analogously to Example 8.

Yield: 65% of theory, S.0 Melting Point: sintering from 72 C Calculated: C 68.64 H 8.16 N 3.34 Cl 8.44 Found :68.50 7.95 3.02 8.84 Example 6,7-Dimethoxy-2-[3-( (2-(3-benzyloxyphenyl)-ethyl)methylamino )-propyl ]-l-hydroxy-1,2,3, 4-tetrahydronaphthalene oxalate Prepared from 7-dimethoxy-l-oxo-l, 2, 3,4-tetrahydronaphtha:Lene-2-yl 3-benzyloxyphenyl )-ethyl N-methylpropionic acid amide and lithium aluminium hydride analogously to Example 1.

Yield: 51% of theory, Melting Point: decomposition by 108 0

C

Calculated: C 68.37 H 7.13 N 2.42 Found :68.09 7.08 2.38 r 11I ExampleI Tablets containing 10 mg of 6,7-dimethoxy-2-3- 2 3 4 -dirnethoxyphenyl)-ethyl)-methylamino)propyl..

l-oxo-l, 2,3 ,4-tetrahydronaphithalene Composition: 1 tablet contains: Active substance Corn starch Lactose Polyvinylpyrrolidone Magnesium stearate 10.0 mg 57.0 mg 48.0 mg 4.0 mg 1.0 mg 120.0 mg 4.

4 *44 4.

4. 4 4. 4 4.

*4 4 4.

4 4.4 *4 04 o 4 .4 4.4.

4 9 4. 444404 4 4 *44*44 4 15 Preparation The active substance, corn starch, lactose and polyvinylpyrrolidone are mixed together and moistened with water. The moist mixture is pushed 20 through a screen with a mesh size of 1.5 mm and dried at about 45 0 C. The dry granulate is passed through a 1.0 mm mesh screen and mixed with magnesium stearate. The final mixture is compressed in a tablet press with dies 7 mm in diameter provided 25 with a dividing notch to form tablets.

Weight of tablet: 120 mg.

Example II Coated tablets containing 5 mg- of 6,7-dimethoxy- 30 2-f73-( 2 3 ,4-dimethoxyphenyl)-ethvl)-methvlamino)propyl] -l-oxo-l, 2,3, 4-tetrahydronaphthalene 1 tablet core contains: Active substance Corn starch Lactose Polyvinylpyr rol idone 5. 0 mg 41.5 mg 30.0 mg 3. 0 mg i. 61 Magnesium stearate Preparation 0.5 mg 80.0 mg The active substance, corn starch, lactose and polyvinylpyrrolidone are thoroughly mixed and moistened with water. The moist mass is forced through a 1 mm screen, dried at about 45 0 C and then the granulate is passed through the same screen. After magnesium stearate has been added, convex tablet cores with a diameter of 6 mm are compressed in a tablet making machine. The tablet cores thus produced are coated in known manner with a coating consisting essentially 15 of sugar and talc. The finished coated tablets are polished with wax.

Weight of coated tablet: 130 mg.

Example III Ampoules containing 5 mg of 6,7-dimethoxy-2-[3- ((2-(3,4-dimethoxyphenyl)-ethyl)-methylamino)-propyl]- 1-oxo-l,2,3,4-tetrahydronaphthalene

S..

SS S S S 0

S

S*

5 9 9

S

*4 *i t I t Sr 9c~

(O

L:

1 ampoule contains: 25 Active substance Sorbitol Water for injections ad 5.0 mg 50.0 mg 2.0 ml Preparation In a suitable mixing vessel the active substance is dissolved in water for injections and the solution is made isotonic with sorbitol. After being filtered through a diaphragm filter the solution is transfered under a current of N 2 into purified and sterilized ampoules and autoclaved for 20 minutes in a jet of steam.

62 Example IV Suppositories containing 15 mg of 6,7-dimethoxy- 2-[3-((2-(3,4-dimethoxyphenyl)-ethyl)-methylamino)propyl]-l-oxo-1,2,3,4-tetrahydronaphthalene 1 suppository contains: Active substance 0.015 g Hard fat Witepsol H 19 and W 45) 1.685 g 1.700 g Preparation ;r *4 4.

4.

.4 .4 .4 4 4 '.4.e

I

C

The hard fat is melted. At 38 0 C the ground active substance is homogeneously dispersed in the melt.

15 It is cooled to 35°C and poured into slightly chilled suppository moulds.

Example V Drops solution containing 10 mg of 6,7-dimethoxy- 20 2-[3-((2-(3,4-dimethoxyphenyl)-ethyl)-rthylamino)propyl]-1-oxo-1,2,3,4-tetrahydronaphthalene 100 ml of solution contain: Active substance Hydroxyethylcellulose Tartaric acid Sorbitol solution with dry matter Glycerol 30 Benzoic acid Dist. water 0.2 g 0.15g 0.1 g

S

4 30.0 g 10.0 g 0.1F g ad 100 ml Preparation The distilled water is heated to 70 0 C. The hydroxyethylcellulose, benzoic acid and tartaric acid are dissolved therein with stirring. The mixture is cooled to ail o r I-y I-q, 6 *0 9 9* #6 9 9 9 .9 #6.

6 *9* *P 9 -63 ambient temperature and the glycerol and sorbitol solution are added with stirring. At ambient temperature the active substance is added and stirred until completely dissolved. The syrup is then evacuated of any air with stirring.

K.

Claims (3)

1. A compound of formula I A R C 13 E N G 'CH2 E R (I) R 6 (wherein n represents the integer 1 or 2; 9, .99 *999 9 9 99 49 9 9 9 99 9 9* 9 9 9

4. 999 909 99 9 9 99 401k A represents a carbonyl group and R 7 represents a hydrogen atom, or R A represents a group of formula -CH- (wherein R 8 represents a hydrogen atom or a hydroxy, alkanoyloxy or alkoxycarbonyloxy group) and R 7 represents a hydrogen atom, or A and R 7 together form a group of formula -CH=; E represents a straight-chained C3- 4 alkylene group optionally substituted by an alkyl group; 9 499999 9 9

99.9.9 4 9 it. G represents a straight chained C2- 5 alkylene group optionally substituted by an alkyl group; R 1 represents a hydrogen or halogen atom, or a trifluoromethyl, nitro, amino, alkylamino, dialkylamino, alkyl, hydroxy, alkoxy or phenylalkoxy group, and R 2 represents a hydrogen or halogen atom or a hydroxy, alkoxy, phenylalkoxy or alkyl group, or _I jv i 1 4* *q 9* *r 0 0 U a a 0* .4 0* 65 R1 and R 2 together represent a C 1 2 alkylenedioxy group; R 3 represents a hydrogen, an alkyl group or a C3_ alkenyl group; R 4 represents a hydrogen or halogen atom, or an alkyl, amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulphonylamino, bis(alkyl- sulphonyl)-amino, N-alkyl-alkylsulphonylamino, cyano, alkylmercapto, alkylsulphinyl or alkylsulphonyl group, or a hydroxy group optionally substituted by an alkyl, phenylalkyl, 2-hydroxyethyl, 3-hydroxy- n-propyl, 2-hydroxy-n-propyl, alkylsulphonyl, cyanoalkyl, 15 alkoxycarbonyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, trifluoromethyl, difluoromethyl or trifluoromethyl- sulphonyl group, and R 5 represents a hydrogen or halogen atom or an 20 alkyl, hydroxy, alkoxy, nitro, cyano or trifluoromethyl group, or R 4 and R 5 together represent a C1- 2 alkylenedioxy group; and R 6 represents a hydrogen or halogen atom or an alkyl or alkoxy group; wherein unless otherwise defined any alkyl or alkoxy 30 moiety contains 1 to 3 carbon atoms and any alkanoyl moiety contains 2 or 3 carbon atoms) or an enantiomer, diastereomer or acid addition salt thereof. a 'C. EL 9 ai s *.00 I-r; 66 2. A compound of formula I as claimed in claim 1, wherein n represents the integer 1 or 2, A represents a carbonyl group and R 7 represents a hydrogen atom or R A represents a group of formula -CH- (wherein R 8 represents a hydrogen atom or a hydroxy group) and R 7 represents a hydrogen atom, or A and R 7 together represent a group of formula -CH=, E represents an n-propylene group, o* G represents an ethylene or n-propylene group, 4 R 1 represents a methyl or methoxy group, 20 R 2 represents a hydrogen atom or a methoxy group, R 3 represents a methyl group, R represents a hydrogen, chlorine or bromine atom, or a hydroxy, methoxy, cyano, cyanomethoxy, hydroxycarb- onylmethoxy, methoxycarbonylmethoxy, ethoxycarbonyl- methoxy, methyl, amino, acetylamino, methoxycarbonyl- amino, methylsulphonyloxy, trifluoromethylsulphonyloxy, I benzyloxy, methylsulphonylamino or bis(methylsulphonyl)- 30 amino group, R 5 represents a hydrogen, chlorine or bromine atom or a methoxy or nitro group, and R 6 represents a hydrogen, chlorine or bromine atom; i. 7 I I r a, a a *c a c a. Sc a Sa 4. ai a a. a., *i a 67 or an enantiomer, diastereomer or acid addition salt thereof. 3. A compound of formula I as claimed in either one of claims 1 and 2, wherein R 1 to R3, A, E, G and n are as defined in claim 1 or claim 2, R 4 represents a methoxy group, R 5 represents a methoxy group, and R 6 represents a hydrogen atom, or an enantiomer, diastereomer or acid addition salt thereof. 4. A compound of formula I as claimed in claim 1 being: 6,7-dimethoxy-2-[3-((2-(3,4-dimethoxyphenyl)- ethyl)-methylamino)-propyll-l-oxo-l,2,3,4-tetrahydro- naphthalene; 25 6,7-dimethoxy-2-[3-((2-(3,4-dimethoxyphenyl)- ethyl)-methylamino)-propyl]-1,2,3,4-tetrahydro- naphthalene; or an acid addition salt thereof. A compound as claimed in any one of claims 1 to 4 being a physiologically acceptable acid addition salt of a compound of formula I. 6. A pharmaceutical composition comprising a compound of formula I as claimed in any one of "i i i Ii 1 1 68 claims 1 to 4 or a physiologically acceptable acid addition salt thereof together with at least one pharmaceutical carrier or excipient. 7. A process for preparing compounds as claimed in any one of claims 1 to 5, said process comprising at least one of the following steps: a) (to prepare compounds of formula I wherein R 7 and R 8 each represent a hydrogen atom or R7 and A together represent a -CH= group) reacting a compound of formula II .9 9 V W9 S PS S 9*r *i V P4 A,1 A (C 2n -X (cH 2 )i (II) i 9. .1 o V .4 C PVV* (wherein R 1 R 2 n and E are as defined in claims 1 to 3; R 8 A 1 represents a group of formUla -CH- (wherein 25 R 8 represents a hydrogen atbm) and R 7 represents a hydrogen atom, or A 1 and R 7 and R 8 together represent a and X represents a nucleophilically exchangeable group) is reacted with an amine of formula III H 3- H N G (III) 4. J r-s- 0. C C *5 Sr o* 5 4 S S 9 5 69 (wherein R 3 to R 6 and G are as defined in any one of claims 1 to 3); b) reacting a compound of formula IV R 1 A R y 7 R2 CN R3 (IV) -O P /E N (CH 2 n E H (wherein n, A, E, R 1 to R 3 and R 7 are as defined in any one of claims 1 to 3) with a compound of formula V R4 Y- G 5 V) R 6 (wherein R 4 to R 6 and G are as defined in any one of claims 25 1 to 3, and Y represents a nucleophilically exchangeable group); c) (to prepare compounds of formula I wherein R8 A represents a group of formula -CH- (wherein R 8 represents a hydrogen atom or a hydroxy group)) reducing a compound of formula VI (7' y v j__I2 70 R A 2 R 2CH E N (G,.j 2 )n N ,C R (VI) R 6 ee 9 1 *0@ 04* 9 9* 9 S. 9 I 9. 9i *r *9 0 (wherein n and R 1 to R 6 are as defined in any one of claims 1 to 3; A 2 represents a carbonyl group and R 7 represents a hydrogen atom, or R 15 ,8 A 2 represents a group of formula -CH- (wherein R8 represents a hydrogen atom or a hydroxy group) and R 7 represents a hydrogen atom; 20 E' and G' have the meanings given in any one of claims 1 to 3 for E and G but with the exception that in the groups E' or G' a carbonyl group takes the place of a methylene group adjacent to the >N-R 3 25 moiety); d) (to prepare compounds of formula I wherein A represents a carbonyl group) oxidizing a compound of formula VII OH o I n *1 4 4t 9 9 n R 3 G (VII) R2 1- i -71 (where in n, E, G and Rlto R 6 are as defined in any one of claims 1 to 3); e) (to prepare compounds of formula I wherein R represents an aikylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulphonylamino, bis (alkyl- suiphonyl) amino, N-alkyl-alkylsulphonylamino, alkyl- mercapto, alkoxy, alkoxycarbonyloxy, hydroxycarbonyl- alkoxy, alkoxycarbonylalkoxy, phenylalkoxy, trifluoro- methoxy, difluoromethoxy, cyanoalkoxy, alkylsulphonyloxy or trifluoromethylsulphonyloxy group) reacting a compound of formula VIII R R IA 9 R9 R 6 6*9(wherein Rl, R j R r R 5 R r R A, E, G and n are as defined in any one of claims 1 to 3, and Rrepresents a hydroxy, amino or C alkylamino 9 C 1 3 group) with a compound of formula IX aa:Z R (IX) (wherein Z represents a nucleophilically exchangeable group, and R 10 represents an alkyl, alkanoyl, alkoxycarbonyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, alkylsulphonyl, phenylalkyl, trif'luoromethyl, difluoromethyl or cyanoalkyl group, 72 wherein any alkyl or alkoxy moieties each contain from 1 to 3 carbon atoms and any alkanoyl moiety contains 2 or 3 carbon atoms); f) (to prepare compounds of formula I wherein A and R 7 together represent a -CH= group) dehydrating a compound of formula X OH R I 'R4 CH 7 R2 C 5 (X) (CHN- G 2R 6 a• 0 0% 0 ao i h e r e in 00 n, E, G, R 1 R 2 R 3 R 4 R 5 R 6 and R are as defined in claims 1 to 3); g) if necessary, subsequently splitting off any protecting group used in the reaction steps a) to g) in order to protect reactive groups; h) converting a compound of formula I thus obtained wherein R 4 represents a benzyloxy group by debenzylation 04 0000 into the corresponding hydroxy compound; i) resolving a compound of formula I thus obtained, if it contains at least one chiral centre, into its diastereomers or its enantiomers; j) converting a compound of formula I thus obtained into an acid addition salt thereof, particularly a physiologically acceptable addition salt with an inorganic or organic acid. li-; l 73 8. A method of treatment of the human or non- human animal body to combat sinus tachycardia or ischaemic heart disease comprising the administration to said body of a compound of formula I (as defined in any one of claims 1 to 3) or a physiologically acceptable acid addition salt thereof. 9. Compounds of formula I as defined in claim 1 and salts thereof, substantially as herein disclosed in any one of the Examples. D A T E D this 9th day of March, 1990. DR. KARL THOMAW GMBH By its Patent Attorneys: *4 9 4 4 .4 9 9. 4~ CALLINAN LAWRIE ~IJ 4 9 V I I' t 94 49 9 4 44 rAIL 9 i411