NZ228277A - Substituted amino derivatives of benzocycloheptenes, their preparation and pharmaceutical compositions - Google Patents

Substituted amino derivatives of benzocycloheptenes, their preparation and pharmaceutical compositions

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Publication number
NZ228277A
NZ228277A NZ228277A NZ22827789A NZ228277A NZ 228277 A NZ228277 A NZ 228277A NZ 228277 A NZ228277 A NZ 228277A NZ 22827789 A NZ22827789 A NZ 22827789A NZ 228277 A NZ228277 A NZ 228277A
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New Zealand
Prior art keywords
group
amino
dimethoxy
methyl
tetrahydro
Prior art date
Application number
NZ228277A
Inventor
Manfred Psiorz
Manfred Reiffen
Joachim Heider
Andreas Bomhard
Jurgen Dammgen
Christian Lillie
Walter Kobinger
Volker Trach
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Thomae Gmbh Dr K
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Publication of NZ228277A publication Critical patent/NZ228277A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/60—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/74—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
    • C07C217/82—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring
    • C07C217/84—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C07C309/66—Methanesulfonates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/64—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/12—One of the condensed rings being a six-membered aromatic ring the other ring being at least seven-membered

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)

Description

<div class="application article clearfix" id="description"> <p class="printTableText" lang="en">New Zealand Paient Spedficaiion for Paient Number £28277 <br><br> n <br><br> 22B2J7 <br><br> NO DRAWINGS <br><br> Priority Dato(s): AQ.-.h.^. <br><br> Complete Specification Filed: .. <br><br> cites: «VS9. &amp;?&gt; . <br><br> .!.5,f,I <br><br> P.O. Journal, No: J&amp;f?. <br><br> Patents Form No. 5 <br><br> NEW ZEALAND <br><br> PATENTS ACT 1953 <br><br> COMPLETE SPECIFICATION BENZOCYCLOHEPTENE DERIVATIVE!^ <br><br> ^/We, OR KARL THOMAE GMBH/ A Body Corporate organised under the laws of the Federal Republic of Germany/ of D-7950'Biberach an der Riss/ FEDERAL REPUBLIC OF GERMANY <br><br> hereby declare the invention, for which X/we pray that a patent may be granted to jjife/us, and the method by which it is to be performed, to be particularly described in and by the following statement: <br><br> - 1 - <br><br> (followed by page la) <br><br> RO 53 785/001 <br><br> - la - <br><br> 22827 <br><br> Benzocycloheptene derivatives <br><br> This invention relates to certain novel benzocycloheptene derivatives and more particularly to these new compounds, to pharmaceutical compositions containing them and to processes for their preparation. <br><br> US-A-4680310 describes tetrahydronaphthalenes substituted in the 2-position by an optionally acyl substituted hydroxyl group. These compounds have a pronounced calcium-antagonistic effect and can therefore be used as pharmaceuticals, in particular for combatting angina pectoris, ischaemia, arrhythmias and high blood pressure. <br><br> It has now surprisingly been found that certain novel benzocycloheptenes have other valuable pharmacological properties, in particular a heart rate lowering effect and an effect of reducing the (^-requirement of the heart. <br><br> In one aspect, the present invention thus provides compounds of formula I <br><br> A]_ <br><br> 1 2 <br><br> (wherein <br><br> C. <br><br> X-^ represents a hydrogen atom, X2 represents a hydrogen atom, and represents a hydrogen atom or a hydroxyl or alkoxy group, or <br><br> - 2 - <br><br> 2 2 8 2 7 7 <br><br> I <br><br> X*l and Xg together represent another carbon-carbon bond and X2 represents a hydrogen atom, or <br><br> X^ and Xjf together with the intervening carbon atom, represent a carbonyl group and X3 represents a hydrogen atom; <br><br> A^ represents a straight-chain C3_^ alkylene group optionally substituted by a C^_3 alkyl group and in which any ethylene moiety bonded to the benzocycloheptene ring can be replaced by an ethenylene or ethynylene moiety; <br><br> A2 represents a straight-chain C2_jj alkylene group optionally substituted by a C1-3 alkyl group and in which any ethylene moiety bonded to a radical R4 wherein n is zero can be replaced by an ethenylene moiety; <br><br> R^ represents a hydrogen or halogen atom or a trifluoro-methyl, nitro, amino, C^-3 alkylamino, di(C^_3 alkyl)amino, C1-3 alkyl, hydroxyl, C1-3 alkoxy, or phenyl(C1-3 alkoxy) group and <br><br> R2 represents a hydrogen atom or halogen atom or a hydroxyl, C^_3 alkoxy, phenyl(C^_3 alkoxy) or C^-3 alkyl group, or <br><br> R^ and R2 together represent a C1-2 alkylenedioxy group; <br><br> R3 represents a hydrogen atom, a C-j_3 alkyl group or a C3_tj alkenyl group; and <br><br> R5 <br><br> R, represents a group | <br><br> /"VR&lt; <br><br> -(0)n-&lt; <br><br> R <br><br> * <br><br> ./ <br><br> o <br><br> - 3 - <br><br> n is 0 or 1; <br><br> Rg represents a hydrogen or halogen atom or a C1-3 <br><br> alkyl, nitro, amino, C^_3 alkylamino, di(C1_3 alkyl)-o amino, C2_3 alkanoylamino, (C-^ alkoxy)carbonylamino, <br><br> (Ci_3 alkyl)sulfonylamino, bis(C^_3 alkylsulfonyl)amino, N-(Cj_2 alkyl)-(C^_3 alkyl)sulfonylamino, cyano, C^_3 alkylmercapto, C^_3 alkylsulfinyl, alkylsulfonyl, <br><br> hydroxyl, C^_3 alkoxy, phenyl (C-^_3 alkoxy), 2-hydroxyethoxy, (3 3-hydroxy-n-propoxy, 2-hydroxy-n-propoxy, C1-3 alkyl sulf onyloxy, cyano(C^_3 alkoxy), (C^_3 alkoxy)carbonyloxy, hydroxycarbonyl (C2_3 alkoxy), (C^_3 alkoxy) carbonyl (C-^_3 alkoxy), trifluoromethoxy, difluoromethoxy or tri-fluoromethylsulfonyloxy group, and <br><br> Rg represents a hydrogen or halogen atom, or a C^_3 alkyl, hydroxyl, C1-3 alkoxy, cyano or trifluoromethyl group, or <br><br> R5 and Rg together represent a C1-2 alkylenedioxy group; and <br><br> Rj represents a hydrogen or halogen atom or a alkyl or (c1-3 alkoxy group) the enantioners thereof, the diasteroisomers thereof, and the acid addition salts thereof (in particular the physiologically acceptable acid addition salts thereof), e.g. th salts with organic or inorganic acids. <br><br> The unsaturated compounds of formula I also^gerve as intermediates for the preparation of the saturated compounds of formula I. <br><br> In the compounds of formula I: R^ may represent hydrogen, fluorine, chlorine and bromine atoms, or methyl, <br><br> ethyl, n-propyl, isopropyl, trifluoromethyl, hydroxyl, methoxy, ethoxy, n-propoxy, isopropoxy, nitro, amino, <br><br> - 4 - <br><br> 22 8 2 7 7 <br><br> methylamino, ethylamino, n-propylamino, isopropylamino, dimethylamino, diethylamino, di-n-propylamino, diisopropyl-amino, methyl-ethylamino, methyl-n-propylamino, methyl-isopropylamino, ethyl-n-propylamino, benzyloxy, 1-phenylethoxy, 1-phenylpropoxy, 2-phenylethoxy and 3-phenylpropoxy groups? <br><br> 1*2 may represent hydrogen, chlorine and bromine atoms, or methyl, ethyl, n-propyl, isopropyl, hydroxyl, <br><br> methoxy, ethoxy, n-propoxy, isopropoxy, benzyloxy, <br><br> 1-phenylethoxy, 2-phenylethoxy, 2-phenylpropoxy, and 3-phenylpropoxy groups; <br><br> or together with R2 may represent methylenedioxy or ethylenedioxy groups; <br><br> R3 may represent a hydrogen atom, or methyl, ethyl, n-propyl, isopropyl, allyl, crotyl, and n-penten- <br><br> 2-yl groups; <br><br> R5 may represent hydrogen, fluorine, chlorine, bromine and iodine atoms, or methyl, ethyl, n-propyl, isopropyl, hydroxyl, methoxy, ethoxy, n-propoxy, isopropoxy, <br><br> amino, methylamino, ethylamino, n-propylamino, isopropylamino, dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, methyl-ethylamino, methyl-n-propylamino, methyl-isopropylamino, ethyl-n-propylamino, acetylamino, propionylamino, methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, methylsulfonylamino, ethylsulfonyl-amino, n-propylsulfonylamino, bis(methylsulfonyl) amino, bis(ethylsulfonyl)amino, N-methyl-methylsulfonylamino, cyano, methylmercapto, ethylmercapto, n-propylmercapto, methylsulfinyl, ethylsulfinyl, isopropylsulfinyl, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, <br><br> benzyloxy, 1-phenylethoxy, 2-phenylethoxy, 2-phenylpropoxy, 3-phenylpropoxy, 2-hydroxy-ethoxy, 2-hydroxy-n-propoxy, 3-hydroxy-n-propoxy, methylsulfonyloxy, ethylsulfonyloxy, isopropylsulfonyloxy, methoxycarbonyloxy, <br><br> - 5 - <br><br> 22 8277 <br><br> ethoxycarbonyloxy, isopropoxycarbonyloxy, hydroxycarbonyl-methoxy, 2-(hydroxycarbonyl)-ethoxy, methoxycarbonylmethoxy, ethoxycarbonylmethoxy, isopropoxycarbonylmethoxy, 2-(methoxycarbonyl)-ethoxy, 2-(n-propoxycarbonyl)-ethoxy, cyanomethoxy, 2-cyanoethoxy, 3-cyano-n-propoxy, difluoromethoxy, trifluoromethoxy and nitro groups; <br><br> Rg may represent hydrogen, chlorine and bromine atoms, or methyl, ethyl, n-propyl, isopropyl, hydroxyl, <br><br> methoxy, ethoxy, n-propoxy, isopropoxy, cyano and trifluoromethyl groups; <br><br> or R5 together with Rg may represent methylenedioxy or ethylenedioxy groups; <br><br> Ry may represent a hydrogen atom, or hydroxyl, methoxy, ethoxy, n-propoxy and isopropoxy groups; <br><br> Aj may represent n-propylene, 1-methyl-n-propylene, <br><br> 2-methyl-n-propylene, 3-methyl-n-propylene, 1-ethyl-n-propylene, 2-n-propyl-n-propylene, 3-ethyl-n-propylene, n-butylene, 1-methyl-n-butylene, 1-ethyl-n-butylene, prop-l-enylene, n-but-l-enylene, 1-methyl-prop-l-enylene, 2-methyl-prop-l-enylene, 3-methyl-prop-l-enylene, prop-l-ynylene, 3-methyl-prop-l-ynylene and n-but-l-ynylene groups; and <br><br> A2 may represent ethylene, 1-methyl-ethylene, 1-ethyl-ethylene, 1-propyl-ethylene, 2-methyl-ethylene, 2-ethyl-ethylene, n-propylene, n-butylene, n-pentylene, 1-methyl-n-propylene, 1-methyl-n-butylene, 1-ethyl-n-propylene, 2-ethyl-n-propylene, 1-ethyl-n-butylene, prop-l-enylene, n-but-l-enylene, n-pent-l-enylene, 1-methyl-prop-l-enylene, 2-raethyl-prop-l-enylene, <br><br> 3-methyl-prop-l-enylene, 4-methyl-n-but-l-enylene and 5-methyl-n-pent-l-enylene groups. <br><br> - 6 - <br><br> 22 8 2 7 7 <br><br> Preferred compounds according to the invention, however, include compounds of formula I in which <br><br> X^ represents a hydrogen atom, X2 represents a hydrogen atom and X^ represents a hydrogen atom or a hydroxyl or methoxy group, or <br><br> X1 and X3 together represent a carbon-carbon bond and X2 represents a hydrogen atom, or <br><br> X^ and X2f together with the intervening carbon atom, represent a carbonyl group and x3 represents a hydrogen atom; <br><br> represents an n-propylene group in which an ethylene moiety bonded to the cycloheptene ring can be replaced by an ethenylene or ethynylene moiety; <br><br> A2 represents an ethylene or n-propylene group or an n-propylene group in which an ethylene moiety bonded to a radical R^ wherein n is zero is replaced by an ethenylene moiety; <br><br> R^ represents a hydrogen atom or a methyl or methoxy group; <br><br> R2 represents a hydrogen atom or a methyl or methoxy group; <br><br> R3 represents a methyl group; <br><br> n is 0 or 1; <br><br> Rg represents a hydrogen, fluorine, chlorine or bromine atom or a hydroxyl, methoxy, cyano, methyl, nitro, <br><br> amino, methylsulphonyloxy, trifluoromethylsulphonyloxy or benzyloxy group; <br><br> 22 8 2 7 7 <br><br> Rg represents a hydrogen, chlorine or bromine atom or a methoxy group; and <br><br> R^ represents a hydrogen, chlorine or bromine atom; <br><br> and the enantiomers thereof, the diastereomers thereof, and the acid addition salts thereof. <br><br> Particularly preferred compounds according to the invention include compounds of formula I in which <br><br> X^ and X2 represent hydrogen atoms, and Xg represents a hydrogen atom or a hydroxyl group, or <br><br> X^ and X3 together represent a carbon-carbon bond, and X2 represents a hydrogen atom, or <br><br> X^ and X2f together with the intervening carbon atom, represent a carbonyl group and Xg represents a hydrogen atom; <br><br> R^ represents R2 represents R^ represents A1 represents a methoxy group; a methoxy group; a methyl group; an n-propylene group; <br><br> A2 represents an ethylene or n-propylene group; r5 represents a methoxy or methylsulphonyloxy group; Rg represents a hydrogen atom or a methoxy group; R^ represents a hydrogen atom; and n is 0 or 1; and <br><br> - 8 - <br><br> 22 8 2 7 7 <br><br> the enantiomers thereof, the diastereomers thereof, <br><br> and the acid addition salts thereof. <br><br> The following compounds, which are covered by formula I, may also be mentioned by way of example: <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-((N-cinnamyl-N-methyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3—dimethoxy-7-hydroxy-7-[3-(N-(2-(4-benzyloxy-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-(2-(4-methoxy-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-(2-(3-methoxy-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-(3-(3,4-dimethyl-phenoxy)-propyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-(3-(3-methoxy-phenoxy)-propyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-(2-(3-benzyloxy-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> - 9 - <br><br> 228277 <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-(2-(3-benzyloxy-phenyl)-ethyl)-amino)-propen-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-(2-phenylethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-(3-phenylpropyl)- <br><br> amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-(2-(3-methyl-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-di.methoxy-7-methoxy-7-[3- (N-methyl-N- (2- (3,4-dimethoxy-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-((N-cinnamyl-N-methyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocyclo-heptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3,5-dimethoxy-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(4-benzyloxy-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(4-methoxy-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> - 10 - <br><br> 22 8 2 7 7 <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3-methoxy-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(3-(3,4-dimethyl-phenoxy)-propyl)-amino)-propyn-l-yl]-6,7, 8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(3-(3-methoxy-phenoxy)-propyl)-amino)-propyn-l-yl]-6,7,8,9—tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3-benzyloxy-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3-benzyloxy-phenyl)-ethyl)-amino)-propen-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-phenylethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(3-phenylpropyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3-methyl-phenyl) -ethyl)-amino) -propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-ethyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-L 3-(N-ethyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> - 11 - <br><br> 22 8 2 77 <br><br> 7-methoxy-7-[3-(N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocyclo-heptene, <br><br> 7-hydroxy-7-[3-(N-(2-(3,4-dimethoxy-phenyl)-ethyl) -amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocyclo-heptene, <br><br> 7-hydroxy-7-[3-(N-(2-(4-benzyloxy-phenyl)-ethyl)- <br><br> amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 7-hydroxy-7-[3-(N-(2-(4-methoxy-phenyl)-ethyl)-amino) -propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 7-hydroxy-7-[3-(N~(2-(3-methoxy-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 7-hydroxy-7-[3-(N-(3-(3,4-dimethyl-phenoxy)-propyl) -amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocyclo-heptene, <br><br> 7-hydroxy-7-[3-(N-(3-(3-methoxy-phenoxy)-propyl)- <br><br> amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 7-hydroxy-7-[3-(N-(2-(3-benzyloxy—phenyl)-ethyl)- <br><br> amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 7-hydroxy-7-[3-(N-(2-(3-benzyloxy-phenyl)-ethyl)- <br><br> amino)-propen-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 7-hydroxy-7-[3-(N-(2-phenylethyl)-amino)-propyn-l-yl] -6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 7-hydroxy-7-[3-(N-(3-phenylpropyl)-amino)-propyn-l-yl] -6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 7-hydroxy-7-[3-(N-(2-(3-methyl-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> - 12 - <br><br> 22 8 2 7 7 <br><br> 7-methoxy-7-[3-(N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 7-hydroxy-7-[3-(N-methyl-N- (2-(3,4-dimethoxy-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 7-hydroxy-7-[3-((N-cinnamyl-N-methyl)-amino)-propyn-l-yl ]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 7-hydroxy-7-[3-(N-methyl-N-(2-(3,5-dimethoxy-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 7-hydroxy-7-[3-(N-methyl-N- (2-(4-benzyloxy-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 7-hydroxy-7-[3-(N-methyl-N- (2-(4-methoxy-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 7-hydroxy-7-[3-(N-methyl-N-(2-(3-methoxy-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 7-hydroxy-7-[3-(N-methyl-N-(3-(3,4-dimethyl-phenoxy)-propyl)-amino)-propyn—1-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 7-hydroxy-7-[3-(N-methyl-N-(3-(3-methoxy-phenoxy)-propyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 7-hydroxy-7-[3-(N-methyl-N-(2-(3-benzyloxy-phenyl) -ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloneptene, <br><br> 22 8 2 7 7 <br><br> - 13 - <br><br> 7-hydroxy-7-[3-(N-methyl-N-(2-(3-benzyloxy-phenyl)-ethyl)-amino)-propen-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 7-hydroxy-7-[3-(N-methyl-N-(2-phenylethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 7-hydroxy-7-[3-(N-methyl-N-(3-phenylpropyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 7-hydroxy-7-[3-(N-methyl-N-(2-(3-methyl-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocyclo-heptene, <br><br> 7-hydroxy-7-[3-(N-ethyl-N-(2-(3-methoxy-phenyl)-ethyl) -amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocyclo-heptene, <br><br> 7-methoxy-7-[3-(N-allyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 7-hydroxy-7-[3-(N-allyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-(3-(3,4-methylenedioxy-phenoxy ) -propyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-(2-(4-fluoro-phenyl) -ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclo-heptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-(2- (3-methoxy-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclo-heptene. <br><br> - 14 - <br><br> 22 8 2 7 7 <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-{3-(3,4-dimethyl-phenoxy)-propyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N- (3-(3-methoxy-phenoxy)-propyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclo-heptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-(2-(3-hydroxy-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclo-heptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-(2- (3-methanesulphonyl-oxyphenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-(2-phenylethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-(3-phenylpropyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-(2-(3-methyl-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclo-heptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-(2- (3-methanesulphonyl-amino-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-(2-phenylethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[2-(N-(3-phenylpropyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-(2-(3-chloro-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclo-heptene, <br><br> - 15 - <br><br> 22 8 27 7 <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-(2-(3-acetylamino-phenyl) -ethyl) -amino) -propyl] -6 ,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-(2-(3-amino-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclo-heptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(3-(3,4-methylenedioxy-phenoxy)-propyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(4-fluoro-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3-methoxy-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(3-(3,4-dimethyl-phenoxy)-propyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(3-(3-methoxy-phenoxy)-propyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3-hydroxy-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3-methane-sulphonyloxy-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-phenylethyl) -amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> - 16 - <br><br> 22 8 2 7 7 <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(3-phenylpropyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3-methyl-phenyl) -ethyl)-amino)-propyl]-6,1,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3-methane-sulphonylamino-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-phenylethyl) -amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(3-phenylpropyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3-chloro-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3-acetylamino-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3-amino-phenyl) -ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-ethyl-N- (3-(3,4-methylenedioxy-phenoxy)-propyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-ethyl-N-(2-(3-methoxy-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> - 17 - <br><br> 22 8 27 7 <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-allyl-N-(2-(3-methoxy-phenyl)-ethyl)-amino)-propyl]-6, 7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-allyl-N-(3-(3,4-dimethyl-phenoxy)-propyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-allyl-N-(3-(3-methoxy-phenoxy)-propyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 7-hydr oxy-7-[3-(N-(3-(3,4-methylened ioxy-phenoxy)- <br><br> propyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 7-hydroxy-7-[3-(N-(2-(4-fluoro-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 7-hydroxy-7-[3-(N-(2-(3-methoxy-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[4-(N- (3-(3,4-methylenedioxy-phenoxy )-propyl)-amino)-butyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[4-(N-(3-phenylpropyl)-amino)-butyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[5-(N- (2-(3-methoxy-phenyl)-ethyl)-amino)-pentyl]-6,7,8,9-tetrahydro-5H-benzocyclo-heptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[5-(N-(3-phenylpropyl)-amino)-pentyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-hydroxy-7-[5-(N-methyl-N-(3-(3-methoxy-phenoxy)-propyl)-amino)-pentyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> - 18 - <br><br> 22 8 27 7 <br><br> 2,3-dimethoxy-7-[4-(N-(3—(3,4-dimethoxy-phenyl)-propyl)-amino)-butyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> 2,3-dimethoxy-7-[3-(N-(3-(3,4-methylenedioxy—phenoxy)-propyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclo-hepten-6-one, <br><br> 2,3-dimethoxy-7-[3-(N-(2-(4-fluoro-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one, <br><br> 2,3-dimethoxy-7-[3-(N-(2-(3-methoxy-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one, <br><br> 2,3-dimethoxy-7-[3-(N-(3-(3,4-dimethyl-phenoxy)-propyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one, <br><br> 2,3-dimethoxy-7-[3-(N-(3-(3-methoxy-phenoxy)-propyl) -amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one, <br><br> 2,3-dimethoxy-7-[3-(N-(2-(3-hydroxy-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one, <br><br> 2,3-dimethoxy-7-[3-(N-(2-(3-methanesulphonyloxy-phenyl) -ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one, <br><br> 2,3-dimethoxy-7-[3-(N-(2-phenylethyl)-amino)-propyl]- <br><br> 6,7,8,9-tetrahydro-5H-ben zocyclohepten-6-one, <br><br> ✓ <br><br> 2,3-dimethoxy-7-[3-(N-(3-phenylpropyl)-amino)-propyl] -6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one, <br><br> - 19 - <br><br> 22 8 2 7 7 <br><br> 2,3-dimethoxy-7-[3-(N-(2-(3-methyl-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one, <br><br> 2,3-dimethoxy-7-[3-(N-(2-(3-methanesulphonylamino-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one, <br><br> 2,3-dimethoxy-7-[3-(N-(2-phenylethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one, <br><br> 2,3-dimethoxy-7-[3-(N-(3-phenylpropyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one, <br><br> 2,3-dimethoxy-7-[3-(N-(2-(3-chloro-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one, <br><br> 2,3-dimethoxy-7-[3-(N-(2-(3-acetylamino-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one, <br><br> 2,3-dimethoxy-7-[3-(N-(2-(3-amino-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one, <br><br> 2,3-dimethoxy-7-[3-(N-methyl-N-(3-(3,4-methylenedioxy-phenoxy ) -propyl) -amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one, <br><br> 2,3-dimethoxy-7-[3-(N-methyl-N-(2-(4-fluoro-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclo-hepten-6-one, <br><br> 2,3-dimethoxy-7-[3-(N-methyl-N-(2- (3-methoxy-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclo-hepten-6-one, <br><br> - 20 - <br><br> 22 8277 <br><br> 2,3-dimethoxy-7-[3-(N-methyl-N-(3-(3,4-dimethyl-phenoxy) -propyl) -amino) -propyl] -6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one, <br><br> 2,3-dimethoxy-7-[ 3-(N-methyl-N-(3-(3-methoxy-phenoxy)-propyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclo-hepten-6-one, <br><br> 2,3-dimethoxy-7-[3-(N-methyl-N-(2-(3-hydroxy-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclo-hepten-6-one, <br><br> 2,3-dimethoxy-7-[3-(N-methyl-N-(2-(3-methanesulphonyl-oxy-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one, <br><br> 2,3-dimethoxy-7-[3-(N-methyl-N-(2-phenylethyl)-amino) -propyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one, <br><br> 2,3-dimethoxy-7-[3-(N-methyl-N-(3-phenylpropyl)-amino)- . propyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one, <br><br> 2,3-dimethoxy-7-[3-(N-methyl-N- (2-(3-methyl-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclo-hepten-6-one, <br><br> 2,3-dimethoxy-7-[3-(N-methyl-N- (2-(3-methanesulphonyl-amino-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one, <br><br> 2,3-dimethoxy-7-[3-(N-methyl-N-(2-phenylethyl)-amino) -propyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one, <br><br> 2,3-dimethoxy-7-[3-(N-methyl-N-(3-phenylpropyl)-amino) -propyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one, <br><br> - 21 - <br><br> 22 8 27 7 <br><br> 2,3-dimethoxy-7-[3-(N-methyl-N-(2-(3-chloro-phenyl) -ethyl) -amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclo-hepten-6-one, <br><br> 2,3-dimethoxy-7-[3-(N-methyl-N-(2-(3-acetylamino-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one, <br><br> 2,3-dimethoxy-7-[3-(N-methyl-N-(2-(3-amino-phenyl)-ethyl) -amino) -propyl] -6,7,8,9-tetrahydro-5H-benzocyclo-hepten-6-one, <br><br> 2,3-dimethoxy-7-[3-(N-ethyl-N-(3-(3,4-methylenedioxy-phenoxy ) -propyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one, <br><br> 2,3-dimethoxy-7-[3-(N-ethyl-N-(2-(3-methoxy-phenyl) -ethyl) -amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclo-hepten-6-one, <br><br> 2,3-dimethoxy-7-[3-(N-allyl-N-(2-(3-methoxy-phenyl) -ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclo-hepten-6-one, <br><br> 2, 3-dimethoxy-7-[3-(N-allyl-N-(3-(3,4-dimethyl-phenoxy) -propyl) -amino) -propyl] -6,7,8,9-tetrahydro-5H-benzocyclo-hepten-6-one, <br><br> 2,3—dimethoxy-7-[3-(N-allyl-N-(3-(3-methoxy-phenoxy)-propyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclo-hepten-6-one, <br><br> 7-hydroxy-7-[3-(N-(3-(3,4-methylenedioxy-phenoxy)- <br><br> propyl) -amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten- <br><br> 6-one, <br><br> 7-hydroxy-7-[3-(N-(2-(4-fluoro-phenyl)-ethyl)-amino) -propyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one, <br><br> . V . VT^rsSSSinSffijg <br><br> O^O"!" <br><br> £ .£ o l / <br><br> - 22 - <br><br> 7-hydroxy-7-[3-(N-(2-(3-methoxy-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one and <br><br> 2,3-dimethoxy-7-[4-(N-(3-(3,4-methylenedioxy-phenoxy)-propyl)-amino)-butyl]-6,7,8,9-tetrahydro-5H-benzocyclo-hepten-6-one, <br><br> O <br><br> the enantiomers, diastereomers and acid addition salts thereof. <br><br> In another aspect, the invention provides a process for preparing the compounds of the invention, said process comprising at least one of the following steps: <br><br> (a) reacting a compound of formula II <br><br> with a compound of formula III <br><br> Z2 " A2 " R4 <br><br> o <br><br> (in which Rl' R2' R4 <br><br> defined, or are protected forms thereof, <br><br> R^, R2, R4, Alf A2, X1# X2 and X3 are as hereinbefore one of the groups Z1 and Z2 represents an R^-NH group, where R3 is as hereinbefore defined, and the other one of the groups Z1 and Z2 represents a nucleophilic leaving group such as a halogen atom or a sulphonyloxy group, for example a chlorine, bromine or iodine atom, or a methanesulphonyloxy, p-toluenesulphonyloxy or ethoxysulphonyloxy group); <br><br> i <br><br> ?28277 <br><br> 23 <br><br> (b) (to prepare compounds of formula I in which A^ represents a straight-chain C3_4 alkylene group optionally substituted by a C1-3 alkyl group, A2 represents a straight-chain C2s alkylene group optionally substituted by a C1_3 alkyl group, and X3 represents a hydrogen atom) <br><br> catalytically hydrogenating a compound of formula IV <br><br> (in which <br><br> R^, R2, R3, R4, X^, X2 and A2 are as hereinbefore defined, and X4 represents a hydroxyl group and A1" is a moiety A1 as hereinbefore defined, or X.^ and X4 together represent a carbon-carbon bond and A^M is a moiety A^ as hereinbefore defined, or X4 and A1" together represent a straight chain C3_4 alkanylylidene group optionally substituted by a C1-3 alkyl group and in which any ethanylylidene moiety bonded to the benzocycloheptene ring can be replaced by an ethenylylidene moiety); <br><br> (c) (to prepare compounds of formula I in which X1 and X3 represent a carbon-carbon bond) <br><br> cleaving Off a moietv HZ_ from a comnound of formula V <br><br> R <br><br> 2 <br><br> (IV) <br><br> R <br><br> 2 <br><br> R <br><br> ? 2 8 2 7 7 <br><br> - 24 - <br><br> (in which <br><br> R., R_, R_, R., A. and A« are as hereinbefore defined 1 2 3 4 1 2 <br><br> and Z3 represents a leaving group such as a hydroxyl, alkoxy, acyloxy or alkylsulphonyloxy group); <br><br> (d) (to prepare compounds of formula I in which X3 represents a hydroxyl group) <br><br> reacting a compound of formula VI <br><br> (in which R1 and R2 <br><br> forms thereof) with a compound of formula VII <br><br> R1 and R2 are as hereinbefore defined, or are protected <br><br> M-A,-NR -A-R 1 3 2 4 <br><br> (in which <br><br> R3, R4, A1 and A2 are as hereinbefore defined, oj^ are protected forms thereof, and <br><br> M represents an alkali metal atom or a MgHal group, where Hal represents a chlorine, bromine or iodine atom) and subsequently hydrolysing, preferably with aqueous ammonium chloride solution. <br><br> (e) (to prepare compounds of formula I in which Rg represents an alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulphonylamino, bis(alkyl-sulphonyl)-amino, N-alkyl-alkylsulphonylamino, alkyl-mercapto, alkoxy, alkoxycarbonyloxy, hydroxycarbonyl- <br><br> - 25 - <br><br> alkoxy, alkoxycarbonylalkoxy, phenylalkoxy, trifluoromethoxy, difluoromethoxy, cyanoalkoxy, alkylsulphonyloxy or trifluoromethylsulphonyloxy group) <br><br> ?28 <br><br> o <br><br> reacting a compound of formula VIII <br><br> O <br><br> A,-N-A--R,* 1 2 4 <br><br> (VIII) <br><br> (in which <br><br> R^ R2, R3, Alf A2, X1, X2 and X3 are as hereinbefore defined, or are protected forms thereof, and R4• represents a group <br><br> O <br><br> wherein Rg and R7 are as hereinbefore defined, or are protected forms thereof, n is as hereinbefore defined, and Rg represents a hydroxyl, amino or C1-3 alkylamino group) with a compound of formula IX <br><br> /■—s o <br><br> - R, <br><br> (IX) <br><br> (in which <br><br> Z. represents a nucleophilic leaving group such as^- <br><br> halogen atom, for example a chlorine, bromine or iodine atom, and <br><br> Rg represents a C1-3 alkyl, C2-3 alkanoyl, (ci_3 alkoxy)carbonyl, hydroxycarbonyl(C1_3 alkyl), (C-^ alkoxy)carbonyl(C1_3 alkyl), (C1_3 alkyl)sulphonyl, phenyl(C1-3 alkyl), trifluoromethyl, difluoromethyl, cyano(C1-3 alkyl) group or protected forms thereof); <br><br> - 26 - <br><br> (f) (to prepare compounds of formula I) reducing a compound of formula X <br><br> (X) <br><br> (in which <br><br> Rl' R2' R3' R4' Al' X1 and X3 are as hereinbefore defined, and <br><br> A2» represents a straight-chained C1_4 alkylene group which is optionally substituted by a C1-3 alkyl group); <br><br> (g) (to prepare compounds of formula I in which A^ represents a straight-chain C3_4 alkylene group optionally substituted by a C1_3alkyl group and in which an ethylene moiety bonded to the benzocycloheptene ring may be replaced by an ethenylene moiety) <br><br> catalytically hydrogenating a compound of formula XI <br><br> (in which <br><br> R-,' <br><br> R2' R3 <br><br> 1-N-A--R., 2 4 <br><br> (XI) <br><br> R, <br><br> X2 and x3 <br><br> are as hereinbefore defined, and A^' represents a straight-chain alkylene group optionally substituted by a C1_3 alkyl group and in which an ethylene moiety bonded to the benzocycloheptene ring is replaced by an ethenylene or ethynylene moiety); <br><br> (h) eliminating any protective group used to protect a reactive group in any of reaction steps (a) to (g); <br><br> - 27 - <br><br> 22 8 2 7 7 <br><br> (i) debenzylating a compound of formula I in which Rg represents a benzyloxy group to produce the corresponding hydroxy compound; <br><br> (j) resolving a compound of formula I which contains at least one chiral centre into its diastereomers or into its enantiomers; and <br><br> (k) converting a compound of formula I into an acid addition salt thereof or converting an acid addition salt of a compound of formula I into the free base. <br><br> The reaction of step (a) is conveniently carried out in a solvent, or mixture of solvents, such as acetone, diethyl ether, methylformamide, dimethylforma-mide, dimethylsulphoxide, benzene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane, <br><br> or in an excess of the compounds of formulae II and/or III used, and optionally in the presence of an acid-binding agent, for example an alcoholate 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 pyridine (it also being possible for the latter simultaneously to act as solvent), or of a reaction accelerator such as potassium iodide, depending on the reactivity of the nucleophilic leaving group, conveniently at a temperature of between 0 and 150°C, preferably at a temperature of between 50 and 120°C, for example at the boiling point of the solvent used. However, the reaction may also be carried out without a solvent. The reaction is carried out particularly advantageously, however, <br><br> in the presence of a tertiary organic base or of an excess of one of the amines of formula II or III used. <br><br> - 28 - <br><br> 22 8 2 7 7 <br><br> The catalytic hydrogenation of step (b) is preferably carried out in a solvent such as methanol, ethanol, <br><br> glacial acetic acid, ethyl acetate or dimethylformamide, using hydrogen at a hydrogen pressure of 1 to 5 bar, preferably of 1 to 4 bar, in the presence of a hydrogenation catalyst such as platinum, palladium/charcoal or Raney nickel, optionally in the presence of an acid such as perchloric acid, at a temperature between 0 and 80°C, but preferably at a temperature between ambient temperature and 60°C. <br><br> If represents a hydroxyl group, the catalytic hydrogenation is conveniently carried out in the presence of an acid. <br><br> It is possible in the catalytic hydrogenation for double or triple bonds which are present simultaneously to be hydrogenated or, where appropriate, benzyl groups which are present to be eliminated. <br><br> The reaction of step (c) is preferably carried out in a solvent such as ethanol, isopropanol, tetrahydrofuran, dioxane or pyridine, optionally in the presence of an acid-binding agent such as sodium carbonate or pyridine, or in the presence of an acid such as hydrochloric acid or sulphuric acid, at a temperature of between 0 and 100°C, preferably at a temperature of between 20 and 80°C. <br><br> In the reagent of formula V, the group Zg may conveniently for example have a carbon atom content in any alkyl moiety of 1 to 3. <br><br> A mixture of isomers which may be obtained in this way and which consists of a compound of formula I in which X^ and Xg together represent a carbon-carbon bond, and of a compound of formula I in which X3/ <br><br> together with one hydrogen atom of the adjacent saturated <br><br> 22E277 <br><br> - 29 - <br><br> carbon atom of the moiety A1, represents a carbon-carbon bond, may subsequently be fractionated by f chromatography, for example on aluminium oxide (neutral). <br><br> [ The reaction of step (d) is preferably carried out <br><br> 4 in a solvent such as diethyl ether, methyl tert.butyl <br><br> • ether, tetrahydrofuran, dioxane, n-hexane or benzene, <br><br> optionally under inert protective gas such as nitrogen ' or argon, at a temperature of between 0 and 50°C, <br><br> but preferably at ambient temperature. <br><br> ji <br><br> J The reaction of step (e) is conveniently carried <br><br> | out in a solvent or mixture of solvents such as methylene. <br><br> "i j <br><br> /] chloride, chloroform, carbon tetrachloride, ether, <br><br> j tetrahydrofuran, dioxane, benzene, toluene, acetonitrile j or dimethylformamide, optionally also in the presence of an acid-activating agent, or of a dehydrating j agent, for example in the presence of ethyl chloroformate, <br><br> j thionyl chloride, phosphorus trichloride, phosphorus <br><br> -S - pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclo- <br><br> ••j hexylcarbodiimide/N-hydroxysuccinimide, N,N1 -carbonyldi- <br><br> ] imidazole or N,N'-thionyl diimidazole, and optionally j in the presence of an inorganic base such as sodium <br><br> I <br><br> carbonate, or of a tertiary organic base such as j triethylamine or pyridine (it also being possible <br><br> | for the two latter simultaneously to act as solvent), <br><br> | at a temperature of between -25 and 250°C, but preferably j at a temperature of between -10°C and the boiling <br><br> ••Vj <br><br> I <br><br> I f i <br><br> point of the solvent used. <br><br> If Rg in a compound of formula VIII denotes a hydrogen atom, unless the latter is protected during the reliction, e.g. by a customary protective group it will be simultaneously replaced by a corresponding Rg. <br><br> The reductioh of step (f) is preferably carried o with a hydride, for example a metal hydride, such lithium aluminium hydride, or diborane or wi^ih a co composed of borane ^ <br><br> 22 8 2 7 7 <br><br> and a thioether, for example with borane/dimethylsulphide complex, in a suitable solvent such as diethyl ether or tetrahydrofuran, at a temperature of between 0 and 80°C, but preferably at a temperature of between 10 and 45°C. <br><br> The catalytic hydrogenation of step (g) is preferably carried out in a solvent such as methanol, ethanol, glacial acetic acid, ethyl acetate or dimethylformamide, using hydrogen at a hydrogen pressure of 1 to 5 bar, preferably of 1 to 4 bar, in the presence of a hydrogenation catalyst such as platinum, palladium/charcoal or Raney nickel, optionally in the presence of an acid such as perchloric acid, at a temperature of between 0 and 80°C, but preferably at a temperature of between ambient temperature and 60°C. <br><br> For the preparation of compounds of formula I in which A^ contains a double bond, the catalytic hydrogenation of a compound of formula XI in which A-^' contains a triple bond is preferably carried out in the presence of Raney nickel or a Lindlar catalyst. <br><br> Furthermore it is possible in the catalytic hydrogenation for a double bond present in the moiety A2 to be simultaneously hydrogenated. <br><br> In the reactions described above, reactive groups, <br><br> such as hydroxyl, amino or imino groups, may optionally be protected during the reaction by customary protective groups which are removed again after the reaction. <br><br> Examples of protective groups suitable for a hydroxyl group include trimethylsilyl, acetyl, benzoyl, benzyl and tetrahydropyranyl groups, and examples of protective groups suitable for an imino or amino group include acetyl, benzoyl, ethoxycarbOnyl and benzyl groups. <br><br> - 31 - <br><br> 22 8 2 7 7 <br><br> The subsequent removal, where appropriate, of a protective group is preferably effected by hydrolysis in an aqueous solvent, for example in water, isopropanol/ water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as hydrochloric acid or sulphuric acid, or in the presence of an alkali such as sodium hydroxide or potassium hydroxide, at a temperature of between 0 and 100°C, preferably at the boiling point of the reaction mixture. However, a benzyl group is preferably eliminated by hydrogenolysis, for example using 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 a temperature between 0 and 50°C, but preferably at ambient temperature, and under a hydrogen pressure of 1 to 7 bar, but preferably of 3 to 5 bar. <br><br> If a compound of formula I in which Rg represents a benzyloxy group is obtained according to the invention, this can be converted by debenzylation into the corresponding hydroxyl compound. <br><br> The subsequent debenzylation is preferably carried out in a solvent such as water, water/ethanol, methanol, glacial acetic acid, ethyl acetate or dimethylformamide, conveniently with hydrogen in the presence of an hydrogenation catalyst such as Raney nickel, platinum or palladium/charcoal, at a temperature of between 0 and 50°C, preferably at ambient temperature. <br><br> The resulting compounds of the formula I can, where they contain at least one chiral centre, be separated by customary methods into their diastereomers, for example by column chromatography, and into their enantiomers, for example by column chromatography on a chiral phase or by crystallisation using optically active acids, for example using D- or L-monomethyl <br><br> 22 8 2 7 7 <br><br> tartaric acid, 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-camphanic acid. <br><br> The resulting compounds of formula I can furthermore be converted into their acid addition salts, in particular for their pharmaceutical use into their physiologically acceptable acid addition salts with inorganic or organic acids. Examples of acids suitable in this connection include hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, acetic acid, <br><br> lactic acid, citric acid, tartaric acid, succinic acid, maleic acid, fumaric acid and oxalic acid. <br><br> The compounds of formulae II to XI used as starting materials are in part known from the literature, <br><br> otherwise they can be obtained by processes known per se. <br><br> For example, a starting compound of formula II may be obtained by reaction of a corresponding benzocyclo-hepten-7-one with an appropriate organometallic compound and, where appropriate, subsequent dehydration and/or hydrogenation. A pyranyl-2-oxy compound which is obtained in this way can, where appropriate, subsequently be converted into a compound of formula II in which Z^ represents a halogen atom. <br><br> A compound of formula IV, V, VIII, X or XI used as a starting material may be obtained by reaction of a corresponding benzocycloheptene derivative with an appropriate alkyl halide or alkylamine. <br><br> As already mentioned herinbefore the new compounds of formula I and the physiologically acceptable acid addition salts thereof have valuable pharmacological <br><br> c. t-'O <br><br> - 33 - <br><br> properties, in particular a heart rate lowering, <br><br> ++ <br><br> blood pressure lowering, Ca -antagonist and/or antithrombotic effect, an antiischaemic effect on the heart, and an effect of reducing the (^-requirement of the heart, while the central side effects are slight. <br><br> Thus, in another aspect, the invention provides a pharmaceutical composition comprising a compound of formula I or a physiologically acceptable acid addition salt thereof together with at least one pharmaceutical carrier or excipient. <br><br> In another aspect, the invention provides a process for the manufacture of a pharmaceutical composition comprising admixing a compound of formula I or a physiologically acceptable acid addition salt thereof with at least one pharmaceutical carrier or excipient. <br><br> In a still further aspect, the invention provides the use of a compound of formula I or a physiologically acceptable acid addition salt thereof for the manufacture of a pharmaceutical agent for the treatment of a human or non-human animal to combat high blood pressure, <br><br> thrombosis or ischaemia of the heart. <br><br> In a yet still further aspect, the invention provides a method of treatment of the non-human animal body to combat high blood pressure, thrombosis or ischaemia of the heart, which method comprises administering to said body a compound of formula I or a physiologically acceptable acid addition salt thereof. <br><br> The compounds v <br><br> A = 2,3-dimethoxy-7-[3-(N-methyl-N-(2-(3,4-dimetho^, phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, ' <br><br> - 34 - <br><br> 22® 27 <br><br> B = 2,3-dimethoxy-7-[3-(N-methyl-N-(2-(4-methoxy- <br><br> phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> C = 2,3-dimethoxy-7-[3-(N-methyl-N-(2-(3-methoxy- <br><br> phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> D = 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2- <br><br> (3-methoxy-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> E = 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(3-(3-methoxy-phenoxy)-propyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, and <br><br> P = 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3-methanesulphonyloxy-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzo-cycloheptene have been investigated for their biological properties, <br><br> for example, as follows: <br><br> Effect on the heart rate of rats <br><br> The effect of the substances A-F on the heart rate was investigated for each dose on two rats with a mean weight of 250-300 g. For this purpose, the rats were anaesthetised with pentobarbitone (50 mg/kg i.p. and 10 mg/kg s.c.). The substances to be investigated were injected in aqueous solution into the jugular vein (0.1 ml/100 g) . jy*" ^ <br><br> /v <br><br> Iks _ <br><br> The blood pressure was measured via a cannula im *ji a carotid artery, and the heart rate was recorded*^ ^O'/J <br><br> from a ECG recorded with needle electrodes (lead^^fVj3 II or III)." The heart rate of the animalsL..in the control period was between 350 and 400 beats/min^8S^tep) . <br><br> - 35 - <br><br> 22 8 2 7 7 <br><br> The results obtained are set forth in the Table below: <br><br> Substance <br><br> Dose <br><br> Change of heart rate measured 5 <br><br> [mg/kg] <br><br> minutes after administration of <br><br> substance [bpm] <br><br> A <br><br> 5.0 <br><br> -173 <br><br> B <br><br> 5.0 <br><br> -170 <br><br> C <br><br> 5.0 <br><br> -180 <br><br> D <br><br> 5.0 <br><br> -155 <br><br> E <br><br> 5.0 <br><br> -167 <br><br> F <br><br> 5.0 <br><br> -130 <br><br> The compounds prepared according to the invention have shown no toxic side effects whatever at therapeutic doses. Thus, for example, with an intravenous administration to mice of substance A to F, even at a high dose of 10 mg/kg, no toxic side effects were observed, apart from slight sedation. <br><br> By reason of their pharmacological properties, the compounds prepared according to the invention are suitable for the treatment and prophylaxis of ischaemic heart disorders, for example for the treatment and prophylaxis of myocardial infarct, and for the treatment of sinus tachycardias. <br><br> The dosage required to achieve an appropriate effect is conveniently once or twice a day 0.03 to 0.4 mg/kg of body weight, preferably 0.07 to 0.25 mg/kg of body weight. For this purpose, the compounds of formula I or physiologically acceptable acid addition salts can be incorporated into customary pharmaceutical preparations such as tablets, coated tablets, capsules, powders, suspensions, drops, ampoules, syrups or suppositories, optionally in combination with other active substances, together with one or more customary <br><br> D <br><br> '••W* <br><br> O <br><br> m _36_ 22 8 2 7 7 <br><br> inert excipients and/or diluents, for example with maize starch, lactose, sucrose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, <br><br> citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, carboxymethylcellulose or fat-containing substances such as hard fat or suitable mixtures thereof. <br><br> The Examples which follow are intended to illustate the invention in detail without limiting its scope in any way (all percentages, parts and ratios are by weight unless otherwise specified): <br><br> O <br><br> O <br><br> 22 8 2 7 7 <br><br> - 37 - <br><br> Example A <br><br> N-Benzyl-N-methyl-propargylamine <br><br> 45.4 ml (0.6 mol) of propargyl bromide are added over 45 minutes to a solution of 78.9 ml (0.6 mol) of N-methyl-benzylamine and 83.6 ml (0.6 mol) of triethylamine in 500 ml of diethyl ether at 22°C, <br><br> while cooling in ice. After 2 hours at ambient temperature, the mixture is extracted with 500 ml of water, and the organic phase is dried over magnesium sulphate, evaporated down jLn vacuo and distilled. <br><br> Yield: 74.4 g (78% of theory), <br><br> B.P. 15-20 mm: 108-115°C. <br><br> Example B <br><br> 2,3-Dimethoxy-7-hydroxy-7- (3- (N-benzyl-N-methyl-amino)-propyn-l-yl)-6,7,8,9-tetrahydro-5H-benzocycloheptene <br><br> 170 ml of tetrahydrofuran are added dropwise at 15°C to a solution of ethyl magnesium bromide in 80 ml of diethyl ether freshly prepared from 11.4 g (0.467 mol) of magnesium in 40 ml of diethyl ether and 34.3 ml (0.467 mol) of ethyl bromide. Subsequently, at 20-37°C a solution of 74.2 g (0.467 mol) of N-benzyl-N-methyl-propargylamine in 80 ml of tetrahydrofuran is added dropwise. After the evolution of ethane has ceased, 82.2 g (0.373 mol) of 2,3-dimethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-one in 160 ml of tetrahydrofuran are added dropwise. After 30 minutes at about 30°C, 100 ml of 10% ammonium chloride solution are added, the mixture is extracted with diethyl ether, and washed with 50% saturated potassium carbonate solution and with water. The organic phase is separated off, <br><br> dried over magnesium sulphate and evaporated down in vacuo. The resulting crude product is purified on 3 kg of aluminium oxide (neutral, activity II-III) <br><br> 22 8 2 7 7 <br><br> using methylene chloride and subsequently using increasing proportions of ethanol (up to 1%). <br><br> Yield: 127 g (90% of theory), <br><br> Rp: 0.2 (aluminium oxide, mobile phase: 2% ethanol in methylene chloride). <br><br> Example C <br><br> 2,3-Dimethoxy-7-hydroxy-7- (3- (N-benzyl-N-methyl-amino) -propyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene <br><br> 24.2 g (0.064 mol) of 2,3-dimethoxy-7-hydroxy-7-(3-(N-benzyl-N-methyl-amino) -propyn-l-yl) -6,7, 8, 9-tetrahydro-5H-benzocycloheptene are hydrogenated in 300 ml of methanol in the presence of 4 g of Raney nickel at ambient temperature and under 5 bar of hydrogen for 20 hours. After filtration and evaporation jin vacuo, the crude product is purified on 1600 g of aluminium oxide (neutral, activity II-III) using methylene chloride and increasing proportions of ethanol (up to 3%). <br><br> Yield: 24 g (98% of theory), <br><br> Rp: 0.65 (aluminium oxide, mobile phase: 3% ethanol in methylene chloride). <br><br> Example D <br><br> Mixture of the isomers <br><br> 2,3-dimethoxy-7- (3- (N-benzyl-N-methyl-amino) -propyl) -8,9-dihydro-5H-benzocycloheptene and <br><br> 2,3-dimethoxy-7- (3- (N-benzyl-N-methyl-amino) -propylidene) -6,7,8,9-tetrahydro-5H-benzocycloheptene <br><br> 23.8 g (0.062 mol) of 2,3-dimethoxy-7-hydroxy-7-(3-(N-benzyl-N-methyl-amino) -propyl) -6,7,8,9-tetrahydro-5H-benzocycloheptene and 5.5 g (0.029 mol) of p-toluene- <br><br> ? 2 8 2 7 7 <br><br> sulphonic acid hydrate in 600 ml of toluene are boiled under a water separator for 6 hours. The mixture is extracted with saturated sodium bicarbonate solution, the organic phase is dried over magnesium sulphate and evaporated down in vacuo, and the crude product is purified on 1600 g of aluminium oxide (neutral, activity II-III) using methylene chloride. <br><br> Yield: 18.3 g (80% of theory), <br><br> R^,: 0.87-0.92 (aluminium oxide, mobile phase: cyclo-hexane + 50% ethyl acetate). <br><br> Example E <br><br> 2,3-Dimethoxy-7-(3-(N-methyl-amino)-propyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene <br><br> 8.3 g (0.0227 mol) of a mixture of the isomers 2,3-dimethoxy-7-(3-(N-benzyl-N-methyl-amino)-propyl)-8,9-dihydro-5H-benzocycloheptene and 2,3-dimethoxy-7-(3-(N-benzyl-N-methylamino)-propylidene)-6,7,8,9-tetrahydro-5H-benzocycloheptene are hydrogenated in 150 ml of glacial acetic acid in the presence of 1 g of 10% palladium on active charcoal at 50°C and under 2 bar of hydrogen for 4 hours. The filtrate is evaporated down jjn vacuo and then dissolved in methylene chloride, the solution is washed with saturated sodium hydrogen carbonate solution. The organic phase is dried over magnesium sulphate and evaporated down jln vacuo, and the resulting crude product is purified on aluminium oxide (neutral, activity II-III) using methylene chloride and increasing proportions of ethanol (up to 15%) . <br><br> Yield: 2.27 g (36.0% of theory), <br><br> Rp: 0.25 (aluminium oxide, mobile phase: 10% ethanol in methylene chloride) . <br><br> 22 8 2 <br><br> Example F <br><br> 2,3-Dimethoxy-7-hydroxy-7- (3- (N-methyl-amino) -propyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene <br><br> 8.15 g (0.0215 mol) of 2,3-dimethoxy-7-hydroxy-7-(3-(N-benzyl-N-methyl-amino)-propyn-l-yl)-6,7,8,9-tetrahydro-5H-benzocycloheptene are hydrogenated in 120 ml of ethanol in the presence of 2 g of 10% palladium on active charcoal at ambient temperature and under 5 bar of hydrogen for 7 hours. The filtrate is evaporated down tn vacuo, and the residue is purified on 500 g of aluminium oxide (neutral, activity II-III) using methylene chloride and increasing proportions of ethanol (up to 10%). <br><br> Yield: 4.55 g (72.1% of theory). <br><br> Melting point: 94-96°C. <br><br> Example G <br><br> 2,3-Dimethoxy-7-hydroxy-7-(3-(pyranyl-2-oxy)-propyn-l-yl) -6,7,8,9-tetrahydro-5H-benzocycloheptene <br><br> Prepared from 2,3-dimethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-one and 3-(pyranyl-2-oxy)-propyne analogously to Example B. <br><br> Yield: 96.5% of theory, <br><br> R^,: 0.67 (aluminium oxide, mobile phase: ethyl acetate). Example H <br><br> 2,3-Dimethoxy-7-methoxy-7-(3-(pyranyl-2-oxy)-propyn- <br><br> 1-yl) -6,7,8,9-tetrahydro-5H-benzocycloheptene <br><br> 4.7 g (13 mmol) of 2,3-dimethoxy-7-hydroxy-7-(3-(pyranyl- <br><br> 2-oxy)-propyn-l-yl)-6,7,8,9-tetrahydro-5H-benzocycloheptei dissolved in 80 ml of tetrahydrofuran, are added dropwise at -30°C to a solution of 8.7 ml (13.9 mmol) <br><br> 11 8 2 <br><br> of n-butyl lithium in n-hexane (about 15% strength) and 9.6 ml of tetrahydrofuran. 10 minutes later, 41.4 ml of dimethylsulphoxide are added dropwise at -25°C and, a further 8 minutes later, 1.22 ml (19.6 mmol) of methyl iodide are added dropwise. The mixture is then stirred at 0-15°C for one hour and at 50°C for one hour. It is poured onto saturated sodium chloride solution and extracted with diethyl ether. The organic phase is washed with water, <br><br> dried over magnesium sulphate and evaporated down in vacuo. The resulting crude product is purified on 400 g of aluminium oxide (neutral, activity II-III) using methylene chloride and increasing proportions of ethanol (up to 3%). <br><br> Yield: 3.5 g (72.0% of theory), <br><br> Melting point: 67-72°C. <br><br> Example I <br><br> 2,3-Dimethoxy-7-methoxy-7-(3-chloro-propyn-l-yl)-6,7,8,9-tetrahydro-5H-benzocycloheptene <br><br> A solution of 3.25 g (8.68 mmol) of 2,3-dimethoxy-7-methoxy-7-(3-(pyranyl-2-oxy)-propyn-l-yl)-6,7,8,9-tetrahydro-5H-benzocycloheptene and 6 ml (82 mmol) of thionyl chloride in 30 ml of chloroform is refluxed for 1 hour. The crude product obtained by evaporation down jji vacuo is purified on 350 g of aluminium oxide (neutral, activity II-III) using methylene chloride and 50% cyclohexane. <br><br> Yield: 2.0 g (74.6% of theory), <br><br> Melting point: 66-70°C. <br><br> Example J <br><br> 2,3-Dimethoxy-7-(3-(pyranyl-2-oxy)-propyn-l-yl)-8,9-dihydro-5H-benzocycloheptene <br><br> - 42 - <br><br> 218 27 7 <br><br> Prepared from 2,3-dimethoxy-7-hydroxy-7-(3-(pyranyl-2-oxy)-propyn-l-yl)-6,7,8,9-tetrahydro-5H-benzocyclo-heptene and methanesulphonyl chloride in pyridine at 45 °C. <br><br> Yield: 68.2% of theory, <br><br> Rp: 0.62 (aluminium oxide, mobile phase: methylene chloride) <br><br> Example K <br><br> 2,3-Dimethoxy-6,7-epoxy-7-(3-(pyranyl-2-oxy)-propyn- <br><br> 1-yl) -6,7,8,9-tetrahydro-5H-benzocycloheptene <br><br> 36.6 g (0.2 mol) of m-chloroperoxybenzoic acid, dissolved in 1000 ml of chloroform, are added to 27 g (0.078 mol) of 2,3-dimethoxy-7-(3-(pyranyl- <br><br> 2-oxy)-propyn-l-yl)-8,9-dihydro-5H-benzocycloheptene, dissolved in 800 ml of chloroform, and the mixture is stirred at ambient temperature for 14 hours. The remaining peroxide is decomposed using 400 ml of 10% sodium hydrogen sulphite solution. The organic phase is washed with saturated sodium hydrogen carbonate solution and with water, dried over magnesium sulphate and evaporated down in vacuo. The crude product is purified on 1600 g of aluminium oxide (neutral, activity II-III) using methylene chloride. Yield: 9.3 g (33% of theory), <br><br> R^: 0.48 (aluminium oxide, mobile phase: methylene chloride) <br><br> Example L <br><br> 2,3-Dimethoxy-7-(3-(pyranyl-2-oxy)-propyn-l-yl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one <br><br> 9.25 g (25.8 mmol) of 2,3-dimethoxy-6,7-epoxy-7-(3-(pyranyl-2-oxy)-propyn-l-yl)-6,7,8,9-tetrahydro-5H-benzocycloheptene are dissolved in 700 ml of <br><br> n <br><br> ( \ w <br><br> « 22 8277 <br><br> - 43 - ' <br><br> toluene and stirred with 2 g (10.5 mmol) of p-toluene-sulphonic acid hydrate at ambient temperature for 13 hours. After extraction with saturated sodium hydrogen carbonate solution, it is dried over magnesium sulphate and evaporated down jji vacuo, and the crude product is purified on 1000 g of aluminium oxide (neutral, activity II-III) using cyclohexane and methylene chloride (50/50). <br><br> Yield: 1.9 g (20.5% of theory), <br><br> Rf: 0.64 (aluminium oxide, mobile phase: methylene chloride and 3% ethanol) <br><br> Example M <br><br> X 2,3-Dimethoxy-7-(3-methanesulphonyloxy-propyn-l-yl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one <br><br> Prepared from 2,3-dimethoxy-7-(3-(pyranyl-2-oxy)-propyn-l-yl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one and methanesulphonyl chloride in pyridine at 45 °C. <br><br> Yield: 12.7% of theory. <br><br> (2) Example. N <br><br> —'2,3-Dimethoxy-7-{3-(N-methyl-N-(2-(3,4-dimethoxy- <br><br> phenyl) -ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one <br><br> Prepared from 2,3-dimethoxy-7-(3-methanesulphonyloxy-propyn-l-yl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one and two equivalents of N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amine at 80 °C. <br><br> Yield: 7.0% of theory. <br><br> 0 <br><br> r\ <br><br> | rs i <br><br> i <br><br> - 44 - <br><br> 22 82 77 <br><br> Example 1 <br><br> 2,3-Dimethoxy-7-[3-(N-methyl-N-(3-phenyl-propyl) -amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride <br><br> 3.2 g (0.0079 mol) of 2,3-dimethoxy-7-hydroxy-7-(3-(N-cinnamyl-N-methyl-amino)-propyn-l-yl)-6,7,8,9-tetrahydro-5H-benzocycloheptene are hydrogenated in 40 ml of glacial acetic acid and 2 ml of perchloric acid in the presence of 0.5 g of 10% palladium on active charcoal at 60°C and under 3.5 bar of hydrogen for 2 hours. The filtrate is evaporated down in vacuo, the residue is dissolved in methylene chloride and the solution is washed with saturated sodium hydrogen carbonate solution. The organic phase is dried over magnesium sulphate, and the crude product obtained by evaporation down in vacuo is purified on 280 g of aluminium oxide (neutral, activity II-III) using methylene chloride. The hydrochloride is subsequently precipitated using ethyl acetate/ethereal hydrochloric acid. <br><br> Yield: 1.77 g (51.9% of theory), <br><br> Melting point: 159-160.5°C <br><br> Calculated: C 72.28 H 8.87 N 3.24 CI 8.21 Found: 72.40 8.82 3.19 8.36 <br><br> Example 2 <br><br> 2,3-Dimethoxy-7-[3-(N-methyl-N-(2-(3,4-dimethoxy-phenyl) -ethyl) -amino)-propyn-l-yl]-8,9-dihydro-5H-benzocycloheptene <br><br> 0.2 ml of methanesulphonyl chloride is added at ambient temperature to a solution of 1.1 g (0.0025 mol) of 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2- <br><br> 22 8 ? <br><br> (3,4-dimethoxy-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene in 15 ml of pyridine, and the mixture is then stirred at 45°C for 2 hours. The crude product obtained by evaporation down iji vacuo is dissolved in methylene chloride/water and the organic phase is dried over magnesium sulphate, evaporated down in vacuo and purified on 100 g of aluminium oxide (neutral, <br><br> activity II-III) using methylene chloride and increasing proportions of ethanol (up to 1%). <br><br> Yield: 0.66 g (60.6% of theory), <br><br> Calculated: C 74.45 H 7.64 N 3.22 Found: 74.30 7.49 3.02 <br><br> Example 3 <br><br> 2,3-Dimethoxy-7-hydroxy-7-[3-(N-cinnamyl-N-methyl-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride <br><br> 1.0 g (0.003 mol) of 2,3-dimethoxy-7-hydroxy-7-13-(N-methyl-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, 0.5 g (0.003 mol) of cinnamyl chloride and 0.34 g (0.003 mol) of triethylamine are heated at 80°C for 1 hours. The mixture is cooled, 2 molar sodium hydroxide solution is added, and the mixture is extracted with methylene chloride. The organic phase is dried over magnesium sulphate and evaporated down jln vacuo. The resulting crude product is purified on 160 g of aluminium oxide (neutral, activity II-III) using methylene chloride, and the hydrochloride is precipitated using ethereal hydrochloric acid in acetone. <br><br> Yield: 300 mg (24% of theory), <br><br> Melting point: 234°C <br><br> Calculated: C 70.01 H 8.14 N 3.14 CI 7.95 Found: 69.86 8.25' 3.16 8.00 <br><br> 22 82 <br><br> - 46 - <br><br> Example 4 <br><br> 2,3-Dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(3-(4-bromo-phenyl)-propyl)-amino)-propyl] -6 , 7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride <br><br> Prepared from 3-(4-bromo-phenyl)-1-bromo-propane and 2,3-dimethoxy-7-hydroxy~7-[3- (N-methyl-amino) -propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene analogousy to Example 3. <br><br> Yield: 25% of theory, <br><br> Melting point: 174°C <br><br> Calculated: C 59.26 H 7.08 N 2.66 CI 6.73 Br 15.17 Found: 60.04 7.18 2.78 6.43 14.94 <br><br> Example 5 <br><br> 2,3-Dimethoxy-7-methoxy-7-[3-(N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene <br><br> 1.75 g (5.67 mmol) of 2,3-dimethoxy-7-methoxy-7- <br><br> (3-chloro-propyn-l-yl) -6,7,8, 9-tetrahydro-5H-benzocyclo- <br><br> heptene and 2.21 g (11.3 mmol) of N-methyl-2-(3,4- <br><br> dimethoxy-phenyl)-ethylamine are heated at 95°C <br><br> for 1.5 hours. The cooled crude product is purified on 400 g of aluminium oxide (neutral, activity <br><br> II-III) using methylene chloride and increasing proportions of ethanol (up to 1%). <br><br> Yield: 2.4 g (90.6% of theory). <br><br> Melting point: 67-70°C, <br><br> Calculated: C 71.92 H 7.98 N 3.00 <br><br> Found: 71.80 7.88 3.00 <br><br> - 47 - <br><br> 22 8 2 77 <br><br> Example 6 <br><br> 2, 3-Dimethoxy-7-hydroxy-7-[3- (N-methyl-N-(2-(3-trifluoromethanesulphonyloxy-phenyl)-ethyl)-amino) -propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride <br><br> 1.0 g (0.0024 mol) of 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3-hydroxy-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene and 0.5 g (0.0048 mol) of triethylamine are dissolved in 20 ml of methylene chloride, and 0.59 g (0.0035 mol) of trifluoromethanesulphonyl chloride is added dropwise. After 16 hours, the solution is evaporated down jjn vacuo, the crude product is purified on 160 g of aluminium oxide (neutral, activity II-III) using methylene chloride, and the hydrochloride is precipitated with ethereal hydrochloric acid in acetone. <br><br> Yield: 490 mg (97% of theory), <br><br> Melting point: 160°C, <br><br> Calculated: C 53.65 H 6.06 N 2.41 CI 6.09 S 5.51 Pound: 53.53 6.08 2.55 6.28 5.80 <br><br> Example 7 <br><br> a) N-(3-(2,3-Dimethoxy-7-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-propyl)-N-methyl-3,4-dimethoxy-cinnamide <br><br> 1.2 g (0.006 mol) of 3,4-dimethoxy-cinnamic acid are suspended in 60 ml of ethyl acetate, 1.0 g (0.006 mol) of N,N'-carbonyldiimidazole is added, and the mixture is stirred at 40°C for 15 minutes. To this suspension are added dropwise 2.0 g (0.006 mol) of 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, <br><br> - 48 - <br><br> 22 8 2 77 <br><br> and the mixture is refluxed for 28 hours. The mixture is cooled, 2 molar sodium hydroxide solution is added, and the mixture is extracted several times with ethyl acetate. The organic phases are dried over magnesium sulphate and evaporated down in vacuo. The crude product is purified on 380 g of aluminium oxide (neutral, activity II-III) using methylene chloride. <br><br> Yield: 1.3 g (45% of theory), <br><br> Melting point: 145-146°C, <br><br> Rp: 0.6 (aluminium oxide, mobile phase: 5% ethanol in methylene chloride). <br><br> b) 2,3-Dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(3,4-dimethoxy-cinnamyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride <br><br> 1.3 g (0.0027 mol) of N-(3-(2,3-dimethoxy-7-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-propyl)-N-methyl-3,4-dimethoxy-cinnamide, dissolved in 10 ml of dry tetrahydrofuran, are added dropwise at 5°C to 0.11 g (0.003 mol) of lithium aluminium hydride in 15 ml of dry tetrahydrofuran. After stirring at ambient temperature for 19 hours, the mixture is cooled in ice and 0.1 ml of water, 0.1 ml of 15% sodium hydroxide solution and 0.3 ml of water are successively added dropwise. The precipitate is suction filtered and washed with tetrahydrofuran, and the filtrate is evaporated down In vacuo. <br><br> The crude product is purified on 160 g of aluminium oxide (neutral, activity II-III) using methylene chloride, and then the hydrochloride is precipitated using ethereal hydrochloric acid in acetone. <br><br> Yield: 80 mg (6% of theory), <br><br> Melting point: 199°C, <br><br> Calculated: C 66.45 H 7.97 N 2.77 CI 7.01 Found: 66.30 8.81 2.89 7.05 <br><br> - 49 - 22 8 2 7 7 <br><br> Example 8 <br><br> 2,3-Dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene <br><br> 3.8 ml of tetrahydrofuran are added dropwise at 15°C to a solution of ethyl magnesium bromide freshly prepared from 0.26 g (10.6 mmol) of magnesium in 2 ml of diethyl ether and 0.85 ml (10.6 mmol) of ethyl bromide in 1 ml of diethyl ether. Subsequently a solution of 2.47 g (10.6 mmol) of 3-(N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino)-propyne in 2 ml of tetrahydrofuran is added dropwise at 20-27°C. After the evolution of ethane has ceased, 1.87 g (8.5 mmol) of 2,3-dimethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-one in 4 ml of tetrahydrofuran are added dropwise. After 30 minutes at about 30°C, 15 ml of 10% ammonium chloride solution are added, the mixture is extracted with diethyl ether, <br><br> and is washed with 50% saturated potassium carbonate solution and with water. The organic phase is dried over magnesium sulphate and evaporated down in vacuo. The resulting crude product is purified on 400 g of aluminium oxide (neutral, activity II-III) using methylene chloride and, subsequently, increasing proportions of ethanol (up to 3%) . <br><br> Yield: 2.27 g (59.0% of theory), <br><br> Melting point: 114-117°C, <br><br> Calculated: C 71.50 H 7.78 N 3.09 Found: 71.40 7.55 2.86 <br><br> Example 9 <br><br> 2,3-Dimethoxy-7-hydroxy-7-[3-((N-cinnamyl-N-methyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride <br><br> - 50 - <br><br> 22 8 2 7 7 <br><br> Prepared from 3-[(N-cinnamyl-N-methyl-amino)]-prop-1-yne and 2,3-dimethoxy-6,7,8,9-tetrahydro-5H-benzocyclo-hepten-7-one analogously to Example 8. <br><br> Yield: 39% of theory, <br><br> Melting point: 214°C, <br><br> Calculated: C 70.65 H 7.29 N 3.16 CI 8.02 Found: 70.53 7.43 2.98 8.28 <br><br> Example 10 <br><br> 2.3-Dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3,5-dimethoxy-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene prepared from 2,3-dimethoxy-6,7,8,9-tetrahydro- <br><br> 5H-benzocyclohepten-7-one and 3-(N-methyl-N-(2- <br><br> (3,5-dimethoxy-phenyl)-ethyl)-amino)-propyne analogously to Example 8. <br><br> Yield: 42.7% of theory, <br><br> Melting point: 112-113°C, <br><br> Calculated: C 71.50 H 7.78 N 3.09 <br><br> Found: 71.30 7.80 2.88 <br><br> Example 11 <br><br> 2,3-Dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(4-benzyloxy-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene <br><br> Prepared from 2,3-dimethoxy-6,7,8,9-tetrahydro- <br><br> 5H-benzocyclohepten-7-one and 3-(N-methyl-N-(2- <br><br> (4-benzyloxy-phenyl)-ethyl)-amino)-propyne analogously to Example 8. <br><br> Yield: 81-8% of theory, <br><br> Melting point: 86-88°C, <br><br> Calculated: C 76.92 H 7.46 N 2.80 <br><br> Found: 76.76 7.46 2.81 <br><br> - 51 - <br><br> 22 8 2 7 7 <br><br> Example 12 <br><br> 2 , 3-Dimethoxy-7-hydroxy-7-[3- (N-methyl-N-(2-(4-methoxy-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene <br><br> Prepared from 2,3~dimethoxy-6,7,8,9-tetrahydro- <br><br> 5H-benzocyclohepten-7-one and 3-(N-methyl-N-(2- <br><br> (4-methoxy-phenyl)-ethyl)-amino)-propyne analogously to Example 8. <br><br> Yield: 64.4% of theory, <br><br> Melting point: 101-104°C, <br><br> Calculated: C 73.73 H 7.85 N 3.31 <br><br> Found: 73.69 8.02 3.55 <br><br> Example 13 <br><br> 2,3-Dimethoxy-7-hydroxy-7-[3- (N-methyl-N- (2- (4-methoxy-phenyl) -ethyl) -amino) -propyl] -6,7,8,9-tetrahydr o-5H-benzocycloheptene oxalate <br><br> 3.3 g (0.008 mol) of 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(4-methoxy-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene are hydrogenated in 40 ml of glacial acetic acid in the presence of 0.3 g of 10% palladium on active charcoal at ambient temperature and under 1 bar of hydrogen for 0.5 hours. The filtrate is evaporated down in vacuo, the residue is dissolved in methylene chloride, and the solution is extracted with saturated sodium hydrogen carbonate solution, the organic phase is dried over magnesium sulphate and evaporated down in vacuo, and the resulting crude product is purified on 300 g of aluminium oxide (neutral, <br><br> activity II-III) using methylene chloride and increasing proportions of ethanol (up to 15%). Subsequently, the oxalate is precipitated with oxalic acid in ethyl acetate/diethyl ether. <br><br> 22 8 2 7 7 <br><br> - 52 - <br><br> Yield: 1.64 g (73.9% of theory), <br><br> Melting point: greater than 40°C (sintering). <br><br> Calculated: C 64.97 H 7.59 N 2.71 Pound: 65.00 7.72 2.52 <br><br> Example 14 <br><br> 2, 3-Dimethoxy-7-hydroxy-7-[ 3- (N-methyl-N- (2— (4— hydroxy-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene oxalate <br><br> Prepared from 2,3-dimethoxy-7-hydroxy-7-[ 3-(N-methyl- <br><br> N- (2- (4-benzyloxy-phenyl) -ethyl) -ami no) -propyn- <br><br> l-yl] -5,6,8,9-tetrahydro-benzocycloheptene analogously to Example 13. <br><br> Yield: 81.3% of theory. <br><br> Calculated: C 72.61 H 8.53 N 3.99 <br><br> Pound: 72.49 8.79 3.74 <br><br> Rp: 0.28 (aluminium oxide, mobile phase: 3% of ethanol in methylene chloride) <br><br> Example 15 <br><br> 2,3-Dimethoxy-7 - [ 3- (N-methyl-N- (2- (4-methoxy-phenyl) -ethyl) -amino) -propyl] -6,7,8, 9-tetrahydro-5H-benzocyclo-heptene hydrochloride <br><br> Prepared from the mixture of the isomers 2,3-dimethoxy-7-[3- (N-methyl-N- (2- (4-methoxy-phenyl) -ethyl) -amino) -propyl]-8, 9-dihydro-5H-benzocycloheptene and 2,3-dimethoxy-7-[3-(N-methyl-N-(2-(4-methoxy-phenyl) -ethyl)-amino)-propylidene]-5,6,8,9-tetrahydro-benzocycloheptene analogously to Example 16. <br><br> Yield: 55.6% of theory, <br><br> Melting point: 158-160°C, <br><br> Calculated: C 69.70 H 8.55 N 3.13 CI 7.91 Found: 68.95 8.60 3.17 7.40 <br><br> 22 8 2 77 <br><br> - 53 - <br><br> Example 16 <br><br> 2,3-Dimethoxy-7-[3-(N-methyl-N-(2-(3,4-dimethoxy-phenyl) -ethyl) -amino) -propyl] -6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride <br><br> 1.65 mg (3.75 mmol) of a mixture of the isomers 2,3-dimethoxy-7-[3- (n-methyl-n- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino) -propyl] -8,9-dihydro-5H-benzocyclo-heptene and 2,3-dimethoxy-7-[3-(n-methyl-n-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino)-propylidene]-6,7,8,9-tetrahydro-5H-benzocycloheptene are hydrogenated in 20 ml of ethanol in the presence of 0.2 g of 10% palladium on active charcoal at ambient temperature and under 5 bar of hydrogen for 7 hours. The filtrate is evaporated down iji vacuo, and the hydrochloride is precipitated with acetone/ethereal hydrochloric acid. <br><br> Yield: 0.85 g (47.5% of theory), <br><br> Melting point: 155-156°C, <br><br> Calculated: C 67.83 H 8.43 N 2.93 CI 7.42 Found: 67.85 8.33 2.97 7.76 <br><br> Example 17 <br><br> 2,3-Dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene <br><br> Prepared from 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3 r 4-dimethoxy-phenyl)-ethyl)-amino)-propyn-l-yl] -6,7,8,9-tetrahydro-5H-benzocycloheptene analogously to Example 13. <br><br> Yield: 60.6% of theory, <br><br> Melting point: 91°C, <br><br> Calculated: C 70.87 H 8.59 N 3.06 Found: 70.87 8.46 2.92 <br><br> n <br><br> - 54 - <br><br> Example 18 <br><br> 22 8 2 77 <br><br> 2,3-Dimethoxy-7-[3-(N-methyl-N-(2-(3-methoxy-phenyl) -ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclo- <br><br> heptene hydrochloride <br><br> Prepared from the mixture of isomers 2,3-dimethoxy-7-[3-(N-methyl-N-(2-(3-methoxy-phenyl)-ethyl)-amino)-propyl]-8,9-dihydro-5H-benzocycloheptene and 2,3-dimethoxy-7-[3-(N-methyl-N-(2-(3-methoxy-phenyl)-ethyl)-amino)-propylidene]-5,6,8,9-tetrahydro-benzocycloheptene analogously to Example 16. <br><br> Yield: 76.9% of theory, <br><br> Melting point: 164-165°C, <br><br> Calculated: C 69.70 H 8.55 N 3.13 Cl 7.91 Found: 69.63 8.53 3.11 8.02 <br><br> Example 19 <br><br> 2,3-Dimethoxy-7-[3-(N-methyl-N-(2-(4-hydroxy-phenyl) -ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclo-heptene hydrochloride <br><br> (2) Prepared from the mixture of isomers 2,3-dimethoxy- <br><br> 7-[3-(N-methyl-N-(2-(4-hydroxy-phenyl)-ethyl)-amino)-propyl]-8,9-dihydro-5H-benzocycloheptene and 2,3-dimethoxy-7-[3-(N-methyl-N-(2-(4-hydroxy-phenyl)-ethyl)-amino)-propylidene]-5,6,8,9-tetrahydro-benzo-cycloheptene analogously to Example 16. <br><br> Yield: 55.8% of theory, <br><br> Melting point: 204-206°C, <br><br> Calculated: C 69.18 H 8.36 N 3.23 Cl 8.17 Found: 68.98 8.57 3.03 8.28 <br><br> Example 20 <br><br> 2,3,7-Trimethoxy-7-f 3-(N-methyl-N-(2-(3,4-dimethoxy-phenyl) -ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride <br><br> - 55 - <br><br> 22 8 2 77 <br><br> Prepared from 2,3,7-trimethoxy-7-[3-(N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino)-propyn-l-yl] -6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride analogously to Example 13. <br><br> Yield: 83.1% of theory, <br><br> Melting point: 135-137°C, <br><br> Calculated: C 66.18 H 8.33 N 2.76 Cl 6.98 Found: 66.36 8.18 2.81 6.92 <br><br> Example 21 <br><br> 2,3-Dimethoxy-7-[3- (N-methyl-N- (2- (4-fluoro-phenvl) -ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclo-heptene hydrochloride <br><br> Prepared from 2, 3-dimethoxy-7-(3-(N-methyl-amino)-propyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene and 2-(4-fluorophenyl)-ethyl methanesulphonate analogously to Example 3. <br><br> Yield: 30.3% of theory, <br><br> Melting point: 122-124°C, <br><br> Calculated: C 68.87 H 8.09 N 3.21 Cl 8.13 Found: 68.75 8.18 3.12 8.15 <br><br> Example 22 <br><br> 2,3-Dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(4-benzyloxy-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride <br><br> Prepared from 2,3-dimethoxy-7-hydroxy-7-(3-(N-methyl-amino) -propyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene and 2-(4-benzyloxy-phenyl)-ethyl methanesulphonate analogously to Example 3. <br><br> Yield: 30.1% of theory, <br><br> Melting point: 170-171°C, <br><br> Calculated: C 71.18 H 7.84 N 2.59 Cl 6.57 Found: 70.93 7.91 2.57 6.67 <br><br> - 56 - 22 8 2 7 7 <br><br> Example 23 <br><br> 2,3-Dimethoxy-7-hydroxy-7-[3- (N-methyl-N- (2- (4-amino-3,5-dichloro-phenyl) -ethyl) -amino) -propyl] -6,7,8,9-tetrahydro-5H-benzocycloheptene oxalate <br><br> Prepared from 2,3-dimethoxy-7-hydroxy-7-(3-(N-methyl-amino) -propyl)-6,7,8, 9-tetrahydro-5H-benzocycloheptene and 2-(4-amino—3,5-dichloro-phenyl)-ethyl bromide analogously to Example 3. <br><br> Yield: 36.8% of theory. <br><br> Melting point: greater than 75°C (decomposition) , Calculated: C 56.74 H 6.35 N 4.90 Cl 12.41 Found: 56.57 6.58 4.74 12.59 <br><br> Example 24 <br><br> 2,3-Dimethoxy-7-hydroxy-7-[ 3- (N-methyl-N- (3- (4-amino-3,5-dibromo-phenoxy) -propyl) -amino) -propyl] -6,7,8,9-tetrahydro-5H-benzocycloheptene oxalate <br><br> Prepared from 2,3-dimethoxy-7-hydroxy-7-(3-(N-methyl-amino) -propyl) -6,7,8, 9-tetrahydro-5H-benzocycloheptene and 3-(4-amino-3,5-dibromo-phenoxy)-propyl chloride analogously to Example 3. <br><br> Yield: 44.9% of theory, <br><br> Melting point: greater than 80°C (decomposition), Calculated: C 48.71 H 5.55 N 4.06 Br 23.15 Found: 48.59 5.70 3.91 23.42 <br><br> Example 25 <br><br> 2, 3-Dimethoxy-7-hydroxy-7-[3- (N-methyl-N- (3- (4-cyano-phenyl) -propyl) -amino) -propyl] -6,7,8,9-tetrahydr o-5H-benzocycloheptene <br><br> Prepared from 2,3-dimethoxy-7-hydroxy-7-(3-(N-methyl-amino) -propyl) -6,7,8,9-tetrahydro-5H-benzocycloheptene <br><br> 22 8 2 7 7 <br><br> and 3-(4-cyano-phenyl)-propyl bromide analogously to Example 3. <br><br> Yield: 86.2% of theory. <br><br> Melting point: 79-81°C, <br><br> Calculated: C 74.28 H 8.31 N 6.42 <br><br> Found: 74.23 8.19 6.52 <br><br> Example 26 <br><br> 2,3-Dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2- (4-nitro-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene <br><br> Prepared from 2,3-dimethoxy-7-hydroxy-7-(3-(N-methyl- <br><br> amino) -propyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene and 2-(4-nitro-phenyl)-ethyl bromide analogously to Example 3. <br><br> Yield: 46.3% of theory, <br><br> Calculated: C 67.85 H 7.74 N 6.33 <br><br> Found: 67.75 7.98 6.55 <br><br> Rp: 0.25 (aluminium oxide, mobile phase: cyclohexane <br><br> + 50% ethyl acetate) <br><br> Example 27 <br><br> 2,3-Dimethoxy-7-[3-(N-methyl-N-(3-(4-amino-3,5-dibromo-phenoxy)-propyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride prepared from 2,3-dimethoxy-7-(3-(N-methyl-amino)- <br><br> propyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene and 3-(4-amino-3,5-dibromo-phenoxy)-1-chloropropane analogously to Example 3. <br><br> Yield: 21.8% of theory, <br><br> Melting point: 80°C (decomposition), <br><br> Calculated: C 50.30 H 6.01 N 4.51 Cl 5.71 Br 25.74 Found: 50.21 6.00 4.49 5.65 25.48 <br><br> ( <br><br> } sw^ <br><br> \ [&lt;J <br><br> 58 <br><br> 22 8 2 77 <br><br> Example 28 <br><br> 2,3-Dimethoxy-7-[3-(N-methyl-N-(3-(3,4-methylenedioxy-phenoxy)-propyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride <br><br> Prepared from 2,3-dimethoxy-7-(3-(N-methyl-amino)-propyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene and 3-(3,4-methylenedioxy-phenoxy)-1-chloropropane analogously to Example 3. <br><br> Yield: 21.1% of theory, <br><br> Melting point: 146-147°C, <br><br> Calculated: C 65.90 H 7.78 N 2.85 Cl 7.21 Found: 65.90 7.91 2.70 7.39 <br><br> Example 29 <br><br> 2,3-Dimethoxy-7-[3-(N-methyl-N- (3-(3-methyl-phenoxy) -propyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclo-heptene hydrochloride <br><br> Prepared from 2,3-dimethoxy-7-(3-(N-methyl-amino)-propyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene and 3-(3-methyl-phenoxy)-1-chloropropane analogously to Example 3. <br><br> Yield: 9.7% of theory, <br><br> Melting point: 126-127°C, <br><br> Calculated: C 70.18 H 8.73 N 3.03 Cl 7.67 Found: 69.97 8.81 2.93 7.54 <br><br> Example 30 <br><br> 2,3-Dimethoxy-7-[3-(N-methyl-N-(2-(4-trifluoromethane-sulphoxy-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride <br><br> Prepared from 2,3-dimethoxy-7-[3-(N-methyl-N-(2-(4-hydroxyphenyl)-ethyl)-amino)-propyl]-6,7,8,9- <br><br> - 59 - <br><br> 22 8 2 77 <br><br> tetrahydro-5H-benzocycloheptene and trifluoromethanesulphonyl chloride analogously to Example 6. <br><br> Yield: 76.4% of theory, <br><br> Melting point: 144-146°C, <br><br> Calculated: C 55.16 H 6.23 N 2.47 Cl 6.26 Found: 55.16 6.39 2.32 6.15 <br><br> Example 31 <br><br> 2,3-Dimethoxy-7-[3-(N-methyl-N-(2-(4-methanesulphonyloxy-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride <br><br> Prepared from 2,3-dimethoxy-7-[3-(N-methyl-N-(2-(4-hydroxy-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene and methanesulphonyl chloride analogously to Example 6. <br><br> Yield: 73.2% of theory, <br><br> Melting point: 162-164°C, <br><br> Calculated: C 60.98 H 7.48 N 2.74 Cl 6.92 Found: 60.83 7.47 2.63 6.96 <br><br> Example 32 <br><br> 2,3-Dimethoxy-7-[3-(N-methyl-N-(2-(4-hydroxy-3- <br><br> methoxy-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro- <br><br> 5H-benzocycloheptene <br><br> Prepared from 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2—(4-benzyloxy-3-methoxy-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene analogously to Example 1. <br><br> Yield: 67.2% of theory, <br><br> Melting point: 47°C, <br><br> Calculated: C 73.04 H 8.72 N 3.28 Found: ' 73.10 8.68 3.51 <br><br> 22 8 2 77 <br><br> - 60 - <br><br> Example 33 <br><br> 2,3-Dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(3-(3,4-methylenedioxy-phenoxy)-propyl)-amino)-propyn-l-yl] -6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride <br><br> Prepared from 3-(N-methyl-N-(3-(3,4-methylenedioxy-phenoxy)-propyl)-amino)-propyne and 2,3-dimethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-one analogously to Example 8. <br><br> Yield: 30% of theory, <br><br> Calculated: C 64.34 H 6.80 N 2.78 Cl 7.03 Found: 64.25 6.79 2.57 7.04 <br><br> Example 34 <br><br> 2,3-Dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(3-(3,4- <br><br> methylenedioxy-phenoxy)-propyl)-amino)-propyl]- <br><br> 6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride <br><br> Prepared from 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(3-(3,4-methylenedioxy-phenoxy)-propyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene analogously to Example 13. <br><br> Yield: 18% of theory, <br><br> Melting point: 167°C, <br><br> Calculated: C 63.83 H 7.54 N 2.76 Cl 6.98 Found: 63.72 7.66 2.79 7.02 <br><br> Example 3 5 <br><br> 2,3-Dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(4-fluoro-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride <br><br> Prepared from 3-(N-methyl-N-(2-(4-fluoro-phenyl)-ethyl)-amino)-propyne and 2,3-dimethoxy-6,7,8,9- <br><br> - 61 - <br><br> 22 8 2 7 7 <br><br> tetrahydro-5H-benzocyclohepten-7-one analogously to Example 8. <br><br> Yield: 42% of theory, <br><br> Melting point: 231°C, <br><br> Calculated: C 67.03 H 6.98 N 3.13 Cl 7.91 Found: 66.88 7.17 2.98 8.17 <br><br> Example 36 <br><br> 2,3-Dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(4-fluoro-phenyl) -ethyl) -amino) -propyl] -6,7,8,9-tetrahydr o-5H-benzocycloheptene hydrochloride <br><br> Prepared from 2,3-dimethoxy-7-hydroxy-[3-(N-methyl-N- (2- (4-fluoro-phenyl) -ethyl) -amino) -propyn-l-yl] -6,7,8,9-tetrahydro-5H-benzocycloheptene analogously to Example 13. <br><br> Yield: 28% of theory, <br><br> Melting point: 178°C, <br><br> Calculated: C 66.43 H 7.58 N 3.10 Cl 7.84 Found: 66.30 7.74 2.94 8.01 <br><br> Example 37 <br><br> 2,3-Dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3-methoxy-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride <br><br> Prepared from 3-(N-methyl-N-(2-(3-methoxy-phenyl)- <br><br> ethyl)-amino)-propyne and 2,3-dimethoxy-6,7,8,9- <br><br> tetrahydro-5H-benzocyclohepten-7-one analogously to Example 8. <br><br> Yield: 40% of theory, <br><br> Melting point: 187°C, <br><br> Calculated: C 67.89 H 7.45 N 3.04 Cl 7.71 Found: 67.92 7.61 3.03 7.97 <br><br> 22 8 2 7 7 <br><br> Example 38 <br><br> 2,3-Dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3-methoxy-phenyl)-ethyl)-amino)-propyl]-6,7 r 8,9-tetrahydro-SH-benzocycloheptene hydrochlor i de <br><br> Prepared from 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl- <br><br> N-(2-(3-methoxy-phenyl)-ethyl)-amino)-propyn-l- <br><br> yl] -6,7,8,9-tetrahydro-5H-benzocycloheptene analogously to Example 13. <br><br> Yield: 65% of theory, <br><br> Melting point: 149-150°C, <br><br> Calculated: C 67.29 H 8.25 N 3.02 Cl 7.64 Found: 67.44 8.39 3.04 7.76 <br><br> Example 39 <br><br> 2,3-Dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(3-(3,4-dimethyl-phenoxy) -propyl) -amino) -propyn-l-yl] -6,7,8,9-tetrahydro-5H-benzocycloheptene <br><br> Prepared from 3-(N-methyl-N-(3-(3,4-dimethyl-phenoxy)- <br><br> propyl)-amino)-propyne and 2,3-dimethoxy-6,7,8,9- <br><br> tetrahydro-5H-benzocyclohepten-7-one analogously to Example 8. <br><br> Yield: 58% of theory, <br><br> Melting point: 99-100°C, <br><br> Calculated: C 74.47 H 8.26 N 3.10 <br><br> Found: 74.70 8.23 3.10 <br><br> Example 40 <br><br> 2,3-Dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(3-(3,4-dimethyl-phenoxy)-propyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride <br><br> Prepared from 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(3-(3,4-dimethyl-phenoxy)-propyl)-amino)-propyn- <br><br> - 63 - <br><br> 22 8 2 7 7 <br><br> l-yl] -6,7,8,9-tetrahydro-5H-benzocycloheptene analogously to Example 13. <br><br> Yield: 63% of theory, <br><br> Melting point: 179°C, <br><br> Calculated: C 68.34 H 8.60 N 2.85 Cl 7.21 Pound: 68.21 8.70 2.85 7.42 <br><br> Example 41 <br><br> 2,3-D imethoxy-7-hydroxy-7-[ 3- (N-methyl-N-(3-(3-methoxy-phenoxy) -propyl) -amino) -propyn-l-yl] -6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride <br><br> Prepared from 3-(N-methyl-N-(3-(3-methoxy-phenoxy) - <br><br> propyl)-amino)-propyne and 2,3-dimethoxy-6,7,8,9- <br><br> tetrahydro-5H-benzocyclohepten-7-one analogously to Example 8. <br><br> Yield: 28% of theory, <br><br> Melting point: 168°C, <br><br> Calculated: C 66.18 H 2.86 N 7.40 Cl 7.24 Found: 66.01 2.76 7.37 7.31 <br><br> Example 42 <br><br> 2,3-Dimethoxy-7-hydroxy-7-[3- (N-methyl-N-(3-(3-methoxy-phenoxy) -propyl) -amino) -propyl] -6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride <br><br> Prepared from 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N- (3- (3-methoxy-phenoxy) -propyl) -amino) -propyn-l-yl] -6,7,8,9-tetrahydro-5H-benzocycloheptene hydro-chloride analogously to Example 13. <br><br> Yield: 41% of theory, <br><br> Melting point: 168°C, <br><br> Calculated: C 65.64 H 8.16 N 2.83 Cl 7.18 Found: 65.55 8.02 2.69 7.25 <br><br> 22 8 2 7 7 <br><br> - 64 - <br><br> Example 43 <br><br> 2g3-Dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3-benzyloxy-phenyl)-ethyl)-amino)-propyn-l-vl]-6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride <br><br> Prepared from 3-(N-methyl-N-(2-(3-benzyloxy-phenyl)- <br><br> ethyl)-amino)-propyne and 2,3-dimethoxy-6,7,8,9- <br><br> tetrahydro-5H-benzocyclohepten-7-one analogously to Example 8. <br><br> Yield: 36% of theory, <br><br> Melting point: 188-189°C, <br><br> Calculated: C 71.69 H 7.14 N 2.61 Cl 6.61 Pound: 71.58 7.28 2.61 6.67 <br><br> Example 44 <br><br> 2,3-Dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3-benzyloxy-phenyl)-ethyl)-amino)-propen-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride <br><br> 1.0 g (0.002 mol) of 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3-benzyloxy-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene is hydrogenated in 15 ml of ethanol in the presence of 0.15 g of Raney nickel at ambient temperature and under 1 bar of hydrogen for 3.5 hours. After filtration and evaporation down in vacuo, the crude product is purified on 360 g of aluminium oxide (neutral, activity II-III) using methylene chloride and increasing proportions of ethanol (up to 2%) . Subsequently the hydrochloride is precipitated in acetone with ethereal hydrochloric acid. <br><br> Yield: 180 mg (19% of theory), <br><br> Melting point: 165-166°C, <br><br> Calculated: C 71.44 H 7.31 N 2.60 Cl 6.59 Found: 71.36 7.49 2.70 6.77 <br><br> - 65 - <br><br> 22 8 2 7 7 <br><br> Example 45 <br><br> 2, 3-Dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3-hydroxy-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene <br><br> Prepared from 2,3-dimethoxy~7-hydroxy-7-[3-(N-methyl- <br><br> N-(2-(3-benzyloxy-phenyl)-ethyl)-amino)-propyn- <br><br> l-yl] -6 ,7,8,9-tetrahydro-5H-benzocycloheptene analogously to Example 13. <br><br> Yield: 50% of theory, <br><br> Calculated: C 72.61 H 8.53 N 3.39 <br><br> Found: 72.44 8.51 3.29 <br><br> Rpi 0.33 (aluminium oxide, mobile phase: 5% ethanol in methylene chloride) <br><br> Example 46 <br><br> 2,3-Dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3-methanesulphonyloxy-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride <br><br> Prepared from 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3-hydroxy-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene and methanesulphonyl chloride analogously to Example 6. <br><br> Yield: 20% of theory, <br><br> Melting point: 146-148°C, <br><br> Calculated: C 59.13 H 7.25 N 2.65 Cl 6.71 S 6.07 Found: 58.97 7.38 2.64 6.63 6.09 <br><br> Example 47 <br><br> 2,3-Dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-phenylethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride <br><br> Prepared from 3-[N-methyl-N-(2-phenylethyl)-amino] -propyne and 2,3-dimethoxy-6,7,8,9-tetrahydro-5H- <br><br> 22 8 2 77 <br><br> benzocyclohepten-7-one analogously to Example 8. <br><br> Yield: 97% of theory, <br><br> Melting point: 217°C, <br><br> Calculated: C 69.83 H 7.50 N 3.26 Cl 8.25 Found: 69.79 7.68 3.17 8.20 <br><br> Example 48 <br><br> 2,3-Dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-phenylethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride <br><br> Prepared from 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-phenylethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene analogously to Example 13. <br><br> Yield: 47% of theory, <br><br> Melting point: 194-195°C, <br><br> Calculated: C 69.18 H 8.36 N 3.23 Cl 8.17 Found: 69.00 8.29 3.21 8.25 <br><br> Example 49 <br><br> 2,3-Dimethoxy-7-hydroxy-7-[3- (N-methyl-N-(3-phenylpropyl)-amino)-propyn-l-vl]-6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride <br><br> Prepared from 3-(N-methyl-N-(3-phenylpropyl)-amino)-propyne and 2,3-dimethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-one analogously to Example 8. <br><br> Yield: 76% of theory, <br><br> Melting point: 184-195°C, <br><br> Calculated: C 70.33 H 7.72 N 3.15 Cl 7.99 Found: 70.26 7.84 3.04 8.08 <br><br> 22 8 2 77 <br><br> Example 50 <br><br> 2,3-3imethoxy-7-hydroxy-7-[3-(N-methyl-N-(3-phenylpropyl) -amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride <br><br> Prepared from 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl- <br><br> N-(3-phenylpropyl)-amino)-propyn-l-yl]-6,7,8,9- <br><br> tetrahydro-5H-benzocycloheptene analogously to <br><br> Example 13. <br><br> Yield: 40% of theory, <br><br> Melting point: 187°C, <br><br> Calculated: C 69.70 H 8.55 N 3.13 Cl 7.91 Found: 69.65 8.68 2.97 8.06 <br><br> Example 51 <br><br> 2,3-Dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3-methyl-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride <br><br> Prepared from 3-(N-methyl-N-(2-(3-methyl-phenyl)- <br><br> ethyl)-amino)-propyne and 2,3-dimethoxy-6,7,8,9- <br><br> tetrahydro-5H-benzocyclohepten-7-one analogously to Example 8. <br><br> Yield: 57% of theory. <br><br> Melting point: 185-186°C, <br><br> Calculated: C 70.33 H 7.72 N 3.15 Cl 7.99 Found: 70.18 7.66 3.07 8.05 <br><br> Example 52 <br><br> 2,3-Dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3-methyl-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride <br><br> Prepared from 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3-methyl-phenyl)-ethyl)-amino)-propyn-l-yl]- <br><br> - 68 - <br><br> 22 8 277 <br><br> 6,7, 8,9-tetrahydro-5H-benzocycloheptene analogously to Example 13. <br><br> Yield: 42% of theory, <br><br> Melting point: 169°C, <br><br> Calculated: C 69.70 H 8.55 N 3.13 Cl 7.91 Found: 69.56 8.58 3.22 7.94 <br><br> Example 53 <br><br> 2,3-D imethoxy-7- [ 3- (N-methyl-N- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one <br><br> Prepared from 2, 3-dimethoxy-7-[3-(N-methyl-N-(2- <br><br> (3,4-dimethoxy-phenyl) -ethyl) -amino) -propyn-l-yl] - <br><br> 6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one and hydrogen analogously to Example 13. <br><br> Yield: 22.4% of theory <br><br> IR spectrum (KBr) : CO 1725 cm-"*" (^,C=0) <br><br> M+: 455 <br><br> Example 54 <br><br> 2, 3-D imethoxy-7 - [ 3- (N-methyl-N- (2- (4-benzyloxy-phenyl) -ethyl) -amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride <br><br> Prepared from 2,3-dimethoxy-7-[3-(N-methyl-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene and 2-(4-benzyloxy-phenyl)-ethyl methanesulphonate analogously to Example 3. <br><br> Yield: 47.4% of theory Melting point: 160-161°C. <br><br> 22 8 2 77 <br><br> Example 55 <br><br> 7-Hydroxy-7-[3-(N-methyl-N- (2-(3,4-dimethoxy-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene prepared from 3-(N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino)-propyne and 6,7,8,9-tetrahydro-5H-benzocyclohepten-7-one analogously to Example 8. <br><br> Yield: 56.2% of theory, <br><br> Melting point: 85-89°C. <br><br> Example 56 <br><br> 7-Hydroxy-7-[3-(N-methyl-N- (2-(3,4-dimethoxy-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclo-heptene hydrochloride <br><br> Prepared from 7-hydroxy-7-[3-(N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene analogously to Example 13. <br><br> Yield: 64.6% of theory, <br><br> Melting point: 147-148°C. <br><br> Example 57 <br><br> 7 — T 3—(N-Methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino)-propyl]-8,9-dihydro-5H-benzocycloheptene hydrochloride <br><br> Prepared from the mixture of isomers 7-[3-(N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino)-propyl]-8, 9-dihydro-5H-benzocycloheptene and 7— £ 3—(N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino)-propylidene]-5,6,8,9-tetrahydro-benzocycloheptene analogously to Example 16. <br><br> Yield: 52.8% of theory, <br><br> Melting point: 141-142°C. <br><br> - 70 - <br><br> 22 8 2 77 <br><br> Example I <br><br> Tablets each containing 10 mq of 2,3-dimethoxy-7-[3-(N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino)-propyl]-6,1,8,9-tetrahydro-5H-benzocycloheptene <br><br> 1 tablet contains: <br><br> Active substance 10.0 mg <br><br> Maize starch 57.0 mg <br><br> Lactose 48.0 mg polyvinylpyrrolidone 4.0 mg <br><br> Magnesium stearate 1.0 mg <br><br> 120.0 mg <br><br> The active substance, maize starch, lactose and polyvinylpyrrolidone are mixed and moistened with water. The moist mixture is pressed through a screen with a mesh size of 1.5 mm and is dried at about 45°C. The dry granules are pressed through a screen with a mesh size of 1.0 mm and are mixed with magnesium stearate. The finished mixture is compressed in a tabletting machine with dies which have a diameter of 7 mm to form tablets weighing 120mg which are provided with a dividing notch. <br><br> Example II <br><br> Coated tablets each containing 5 mg of 2,3-dimethoxy-7-[3-(N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene <br><br> 1 tablet core contains: <br><br> Active substance 5.0 mg <br><br> Maize starch 41.5 mg <br><br> Lactose 30.0 mg <br><br> Polyvinylpyrrolidone 3.0 mg Magnesium stearate 0.5 mq <br><br> 80.0 mg <br><br> - i <br><br> "1 <br><br> . i \ <br><br> \ o i <br><br> i i ! <br><br> i j i <br><br> 22 8 277 <br><br> The active substance, maize starch, lactose and polyvinylpyrrolidone are thoroughly mixed and moistened with water. The moist composition is pressed through a screen with a mesh size of 1 mm and is dried at about 45°C, and the granules are subsequently pressed through the same screen. After magnesium stearate has been mixed in, biconvex tablet cores with a diameter of 6 mm are compressed in a tabletting machine. The tablet cores produced in this way are coated in a known manner with a coating which is essentially composed of sugar and talc. The finished coated tablets are polished with wax and weigh approximately 130 mg. <br><br> Example III <br><br> Ampoules each containing 5 mg of 2,3-dimethoxy-7-[3-(N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocvcloheptene <br><br> Each ampoule contains: <br><br> Active substance 5.0 mg <br><br> Sorbitol 50.0 mg <br><br> Water for injections ad 2.0 ml <br><br> The active substance is dissolved in water for injections in a suitable batch vessel, and the solution is made isotonic with sorbitol. <br><br> After filtration through a membrane filter, the solution is dispensed under a nitrogen atmosphere into cleaned and sterilised ampoules and is autoclaved for 20 minutes in a stream of steam. <br><br> Example IV <br><br> Suppositories each containing 15 mq of 2,3-dimethoxy-7-[3-(N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene <br><br></p> </div>

Claims (26)

<div class="application article clearfix printTableText" id="claims"> <p lang="en"> - 72 -<br><br> 22 8 2 7 7<br><br> Each suppository contains:<br><br> Active substance 0.015 g<br><br> Hard fat (e.g. Witepsol H 19<br><br> and W 45) 1.685 q<br><br> 1.700 g<br><br> The hard fat is melted. Ground active substance is homogeneously dispersed in the melt at 38°C. The mixture is cooled to 35°C and poured into slightly precooled suppository moulds.<br><br> Example V<br><br> Dropping solution containing 10 mq of 2,3-dimethoxy-7-[3-(N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl) -amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene<br><br> 100 ml of solution contain:<br><br> Active substance<br><br> 0.<br><br> 2<br><br> g<br><br> Hydroxyethylcellulose<br><br> 0.<br><br> 15<br><br> g<br><br> Tartaric acid<br><br> 0.<br><br> 1<br><br> g<br><br> Sorbitol solution, 70% dry matter<br><br> 30.<br><br> 0<br><br> g<br><br> Glycerol<br><br> 10.<br><br> 0<br><br> g<br><br> Benzoic acid<br><br> 0.<br><br> 15<br><br> g<br><br> Distilled water ad<br><br> 100<br><br> ml<br><br> Distilled water is heated to 70°C. It is stirred while hydroxyethylcellulose, benzoic acid and tartaric acid are dissolved therein. It is cooled to ambient temperature and, during this, the glycerol and the sorbitol solution are added while stirring. The active substance is added at ambient temperature, and the mixture is stirred until dissolution is complete. The solution is subsequently degassed by evacuation under stirring.<br><br> 228277<br><br> O<br><br> O<br><br> - 73 -<br><br> WHAT WE CLAIM IS:-<br><br>
1. Compounds of formula I<br><br> X^ represents a hydrogen atom,. X2 represents a hydrogen atom, and Xg represents a hydrogen atom or a hydroxyl or a C1_3 alkoxy group, or<br><br> X^ and Xg together represent a carbon-carbon bond and X2 represents a hydrogen atom, or<br><br> X^ and X2, together with the intervening carbon atom, represent a carbonyl group and Xg represents a hydrogen atom?<br><br> A^ represents a straight-chain Cg_4 alkylene group optionally substituted by a C^_g alkyl group and in which any ethylene moiety bonded to the benzocycloheptene ring can be replaced by an ethenylene or ethynylene moiety?<br><br> A2 represents a straight-chain C2_,- alkylene group optionally substituted by a C^_g alkyl group and in which any ethylene moiety bonded to a radical R4 wherein n is zero can be replaced by an ethenylene— moiety;<br><br> represents a hydrogen or a halogen atom or a trifluoromethyl, nitro, amino, C1_galkylamino, di(C^_galkyl)amino, C^_g alkyl, hydroxyl, C^_g alkoxy, or phenyl (C-^g alkoxy) group, and<br><br> &amp; NOV1990^11<br><br> J<br><br> n<br><br> - 74 -<br><br> .22827?<br><br> R2 represents a hydrogen or halogen atom or a hydroxyl, Cl-3 alkoxY' or phenyl(C^_g alkoxy) or C1-3 alkyl group, or and Rj together represent a C^_2 alkylenedioxy group;<br><br> R3 represents a hydrogen atom, a C^_g alkyl group or a Cg_g alkenyl group;<br><br> R4 represents a group<br><br> R,<br><br> n is 0 or 1;<br><br> R,. represents a hydrogen or halogen atom or a alkyl, nitro, amino, C^_3 alkylamino, di (C^_3 alkyl)<br><br> amino, ^2-3 alkanoylamino, (C^_g alkoxy)carbonyl-amino, (C1_g alkyl)sulfonylamino, bis(C1_3 alkylsulfonyl)-amino, N-(C^_g alkyl)-(C^_g alkyl)sulfonylamino,<br><br> cyano, (C^_g alkyl)mercapto, (c^_3 alkyl)sulfinyl, (C1-3 alkyl)sulfonyl, hydroxyl, C^_3 alkoxy, phenyl (C-j^g alkoxy), 2-hydroxyethoxy, 3-hydroxy-n-propoxy, 2-hydroxy-n-propoxy, (C1-3 alkyl)sulfonyloxy, cyano (C-^g alkoxy), (C^_3 alkoxy)carbonyloxy, hydroxycarbonyl(C^_g alkoxy), (Ci_3 alkoxy)carbonyl(C1_3 alkoxy), trifluoromethoxy, dif luoromethoxy or trif luoromethylsulfonylox/"~group,<br><br> and<br><br> Rg represents a hydrogen or halogen atom or a alkyl, hydtoxyl, C^_3 alkoxy, cyano or triflu group,<br><br> 22827<br><br> - 75 -<br><br> or R5 and Rg together represent a C1-2 alkylenedioxy group; and<br><br> Ry represents a hydrogen or halogen atom or a C^_3 alkyl or C1-3 alkoxy group) the enantiomers thereof, the diastereomers thereof and the acid addition salts thereof.<br><br>
2. Compounds as claimed in claim 1 being compounds of formula I wherein<br><br> R^ is as defined in claim 1;<br><br> X^ represents a hydrogen atom, X2 represents a hydrogen atom and X3 represents a hydrogen atom or a hydroxyl or methoxy group, or<br><br> X^ and Xg together represent a carbon-carbon bond and X2 represents a hydrogen atom, or<br><br> X^ and X2, together with a intervening carbon atom, represent a carbonyl group and X3 represents a hydrogen atom;<br><br> A^ represents an n-propylene group in which an ethylene moiety bonded to the cycloheptene ri can be replaced by an ethenylene or ethynylen moiety;<br><br> A2 represents an ethylene or n-propyleneg«oup or an n-propylene group in which an ethylene moie'ty j£<br><br> bonded to a group R^, wherein n is zero, is replaced by an ethenylene moiety;<br><br> R^ represents a hydrogen atom or a methyl or methoxy group;<br><br> R2 represents a hydrogen atom or a methyl or methoxy group;<br><br> - 76 -<br><br> .228277<br><br> Rg represents a methyl group;<br><br> n is 0 or 1;<br><br> R5 represents a hydrogen, fluorine, chlorine or bromine atom or a hydroxyl, methoxy, cyano, methyl, nitro, amino, methylsulphonyloxy, trifluoromethylsulphonyloxy or benzyloxy group;<br><br> Rg represents a hydrogen, chlorine or bromine atom or a methoxy group; and<br><br> R^ represents a hydrogen, chlorine or bromine atom;<br><br> and the enantiomers thereof, the diastereomers thereof, and the acid addition salts thereof.<br><br>
3. Compounds as claimed in either one of claims 1 and 2 being compounds of formula I wherein:<br><br> R^ is as defined in claim 1;<br><br> X^ and X2 represent hydrogen atoms and Xg represents a hydrogen atom or a hydroxyl group, or<br><br> Xn and Xg together represent a carbon-carbon bond and X2 represents a hydrogen atom, or<br><br> X^ and X2, together with the intervening carbon atom, represent a carbonyl group a hydrogen atom;<br><br> R^ represents a methoxy group;<br><br> R9 represents, a methoxy group;/<br><br> /<br><br> Rg represents a methyl group;<br><br> represents an n-propylene group?<br><br> - 77 -<br><br> 22 8 2 7 7<br><br> A2 represents an ethylene or n-propylene group; R5 represents a methoxy or methylsulphonyloxy group; Rg represents a hydrogen atom or a methoxy group; Rj represents a hydrogen atom; and n is 0 or 1;<br><br> and the enantiomers thereof, the diastereomers thereof, and the acid addition salts thereof.<br><br>
4. A compound as claimed in any one of claims 1 to 3 being:<br><br> 2,3-dimethoxy-7-[3- (N-methyl-N-(2-(3,4-dimethoxy-phenyl) -ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene,<br><br> 2,3-dimethoxy-7-[3-(n-methyl-n-(2-(4-methoxy-phenyl)-ethyl) -amino) -propyl] -6,7,8,9-tetrahydr o-5H-benzocyclo-heptene,<br><br> 2,3-dimethoxy-7-[3- (N-methyl-N- (2- (3-methoxy-phenyl) -ethyl) -amino) -propyl] -6,7,8,9-tetrahydro-5H-benzocyclo-heptene,<br><br> 2, 3-dimethoxy-7-hydroxy-7-[ 3- (N-methyl-N- (2- (3-methoxy-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene,<br><br> 2, 3-dimethoxy-7-hydroxy-7-[ 3- (N-methyl-N-(3-(3-methoxy-phenoxy)-propyl)-amino)-propyl] -6,7,8,9-tetrahydro-5H-benzocycloheptene, or<br><br> 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3-methanesulphonyloxy-phenyl) -ethyl) -amino) -propyl] -6,7,8,9-tetrahydro-5H-benzocycloheptene,<br><br> ? 2 8 2 7 7<br><br> - 78 -<br><br> or an enantiomer thereof, a diastereomer thereof or an acid addition salt thereof.<br><br>
5. A compound as claimed in claim 1 being 2,3-dimethoxy-7-[3-(N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino)-propyl-6,7,8,9-tetrahydro-5H-benzocyclo-heptene, or an enantiomer thereof, a diastereomer thereof, or an acid addition salt thereof.<br><br>
6. A compound as claimed in any one of claims 1 to 5 being a physiologically acceptable acid addition salt of a compound of formula I.<br><br>
7. A pharmaceutical composition comprising a compound of formula I as claimed in any one of claims 1 to 5, or a physiologically acceptable acid addition salt thereof, together with at least one pharmaceutical carrier or excipient.<br><br>
8. A process for the preparation of compounds as claimed in any one of claims 1 to 6, said process comprising at least one of the following steps:<br><br> (a) reacting a compound of formula II R,<br><br> with a compound of formula III<br><br> Z2 " A2 " R4<br><br> (in which<br><br> R2, R4, Ax, A2, Xx, X2 and X3 are as defined in any one of claims 1 to 5, or are protected forms thereof,<br><br> - 79 -<br><br> one of the groups Z1 and Z2 represents an R3-NH group, where R3 is as defined in any one of claims 1 to 5, and the other one of the groups Z1 and Z2 represents a nucleophilic leaving group);<br><br> (b) (to prepare compounds of formula I in which A1 represents a straight-chain C3_4 alkylene group optionally substituted by a C1-3 alkyl group, A2 represents a straight-chain C2_5 allcylene group optionally substituted by a C1-3 alkyl group, and X3 represents a hydrogen atom)<br><br> catalytically hydrogenating a compound of formula IV<br><br> (in which<br><br> Rlf R2, R3, R4, X^, X2, and A2 are as defined in any one of claims 1 to 5, and<br><br> X4 represents a hydroxyl group and A1" represents a moiety A1 as defined in any one of claims 1 to 5, or X^^ and X4 together represent a carbon-carbon bond and A^" represents a moiety A1 as defined in any one of claims 1 to 5, or<br><br> X4 and A^' together represent a straight-chain C3_4 alkanylylidene group optionally substituted by a C1_3 alkyl group and in which any ethanylylidene moiety bonded to the benzocycloheptene ring can be replaced by an ethenylylidene moiety);<br><br> (c) (to prepare compounds of formula I in which X1«g X3 together represent a carbon- carbon bond)<br><br> eliminating a moiety HZ3 from a compound of formula V<br><br> (IV)<br><br> f<br><br> - 80 -<br><br> 9 9<br><br> o w<br><br> a1-n-a2-r4<br><br> (V)<br><br> (in which<br><br> R^f R2, R3, R4, A1 and A2 are as defined in any one of claims 1 to 5, and Z3 represents a leaving group);<br><br> (d) (to prepare compounds of formula I in which X3 represents a hydroxyl group)<br><br> O<br><br> o reacting a compound of formula VI<br><br> r1<br><br> OO-•<br><br> (in which<br><br> R1 and R2 are as defined in any one of claims 1 to 5, or are protected forms thereof) with a compound of f^pKuia VII<br><br> m-arnr3"a2-r4<br><br> (in which<br><br> R„, R,, A- and A_ are as defined in any one of claims 1 3 4' 1 2 ^<br><br> to 5, or are protected forms thereof, and M represents an alkali metal atom or an MgHal group, where Hal represents a chlorine, bromine or iodine atom) %£■ ^ and subsequently hydrolysing^<br><br> i8'<br><br> (e) (to prepare compounds of formula I in which R5 represents an alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulphonylamino, bis(alkyl-sulphonyl)amino, N-alkyl-alkylsulphonylamino, alkyl-<br><br> - 81 -<br><br> mercapto, alkoxy, alkoxycarbonyloxy, hydroxycarbonyloxy, alkoxycarbonylalkoxy, phenylalkoxy, trifluoromethoxy, difluoromethoxy, cyanoalkoxy, alkylsulphonyloxy or trifluoromethylsulphonyloxy group)<br><br> reacting a compound of formula VIII<br><br> arn-a2-r4 '<br><br> (viii)<br><br> (in which<br><br> R^ R2, R3, A^, A2, X1# X2 and X3 are as defined in any one of claims 1 to 5, or are protected forms thereof, and R41 represents a group where<br><br> R- and R_ are as defined in any one of claims 1 to 5, or 6 /<br><br> are protected forms thereof, n is as defined in any one of claims 1 to 5, and<br><br> Rg represents a hydroxyl, amino or C1-3 alkylamino group) with a compound of formula IX<br><br> Z4 " R9<br><br> (in which<br><br> Z4 represents a nucleophilic leaving group, and Rg represents a C1_3 alkyl, C2-3 alkanoyl,' alkoxy)carbonyl, hydroxycarbonyl(C1-3 alkyl), (C1_ 3 alkoxy)carbonyl(C1-3 alkyl), (C1_3 alkyl)sulphonyl, phenyl(C1_3 alkyl), trifluoromethyl, difluoromethyl, cyano(C1_3 alkyl) group or protected forms thereof);<br><br> (f) (to prepare compounds of formula I) reducing a compound of formula X<br><br> r.<br><br> arn-c-a2-r4<br><br> (X)<br><br> (in which<br><br> R2, R3, R4, A^, X1 and X3 are as defined in any one of claims 1 to 5, and<br><br> A21 represents a straight-chained C1-4 alkylene group optionally substituted by a C1-3 alkyl group);<br><br> (g) (to prepare compounds of formula I in which A^ represents a straight-chain C3_4 alkylene group optionally substituted by a C1-3 alkyl group and in which an ethylene moiety bonded to the benzocycloheptene ring may be replaced by an ethenylene moiety) catalytically hydrogenating a compound of formula XI<br><br> al'-n-a2—r4<br><br> jgjxl)<br><br> (in which rj /1*2' ^3'<br><br> V A2'<br><br> 1' "2<br><br> one of claims 1 to 5, and a '<br><br> a1<br><br> and X3 are as defined in a x" X,<br><br> represents a straight-chain C3_4 alkylene group optionally substituted by a C1-3 alkyl group and in which an ethylene moiety bonded to the benzocycloheptene ring is replaced by an ethenylene or ethynylene moiety);<br><br> - 83 -<br><br> 22 8 2 7 7<br><br> (h) eliminating any protective group used to protect a reactive group in any of reaction steps (a) to (g) ;<br><br> (i) debenzylating a compound of formula I in which R5 represents a benzyloxy group to produce the corresponding hydroxy compound;<br><br> (j) resolving a compound of formula I which contains at least one chiral centre into its diastereomers or into its enantiomers; and<br><br> (k) converting of a compound of formula I into an acid addition salt thereof or converting an acid addition salt of a compound of formula I into the free base.<br><br>
9. A process as claimed in claim 8 wherein the reaction is carried out in a solvent.<br><br>
10. A process as claimed in either one of claims<br><br> 8 and 9 wherein the reaction of step (a) is carried out in the presence of an acid-binding agent.<br><br>
11. A process as claimed in either of claims<br><br> 8 and 9 wherein the reaction of step (a) is carried out at a temperature of between 0 and 150°C.<br><br>
12. A process as claimed in either one of claims 8 and 9 wherein the catalytic hydrogenation of step (b) or (g) is carried out in the presence of platinum, palladium/charcoal or Raney nickel.<br><br>
13. A process as claimed in either one of claims 8 and 9 wherein the catalytic hydrogenation of step (b) is carried out in the presence of an acid.<br><br> 22 8 2<br><br> - 84 -<br><br>
14. A process as claimed in either one of claims 8 and 9 wherein the catalytic hydrogenation of step (b) or (g) is carried out at a temperature of between 0 and 80°C.<br><br>
15. A process as claimed in either one of claims 8 and 9 wherein the reaction of step (c) is carried out in the presence of an acid-binding agent or an acid.<br><br>
16. A process as claimed in either one of claims 8 and 9 wherein the reaction of step (c) is carried out at a temperature of between 0 and 100°C.<br><br>
17. A process as claimed in any one of claims 8, 9, 15 and 16 wherein a resulting mixture of isomers is fractionated by chromatography.<br><br>
18. A process as claimed in either one of claims 8 and 9 wherein the reaction of step (d) is carried out under an inert gas and at a temperature of between 0 and 50 °C.<br><br>
19. A process as claimed in either one of claims 8 and 9 wherein the reaction of step (e) is carried out in the presence of an acid-activating agent or a water-abstracting agent.<br><br>
20. A process as claimed in either one of claims 8 and 9 wherein the reaction of step (e) is carried out at a temperature of between -25 and +250°C.<br><br>
21. A process as claimed in either one of claims<br><br> 8 and 9 wherein the reduction of step (f) is carried out with a metal hydride or with a complex of borane and a thioether.<br><br> - 85 -<br><br> 228277<br><br>
22. A process as claimed in either one of claims<br><br> 8 and 9 wherein the reduction of step (f) is carried out at a temperature of between 0 and 80°C.<br><br>
23. A process as claimed in any one of claims<br><br> 8 to 22 wherein the subsequent elimination in step (h) of a protective group is by hydrolysis, or where the protective group is a benzyl group by hydrogenolysis.<br><br>
24. The use of a compound of formula I as claimed in any one of claims 1 to 5 or of a physiologically acceptable acid addition salt thereof for the manufacture of a pharmaceutical agent for the treatment of the human or non-human animal body to combat ischaemic heart disorders or sinus tachycardias.<br><br>
25. A method of treatment of the non-<br><br> human animal body to combat ischaemic heart disorders or sinus tachycardias which method comprises administering to said body a compound of formula I as claimed in any one of claims 1 to 5 or a physiologically acceptable acid addition salt thereof.<br><br>
26. Compounds of formula I as defined in claim 1 and acid addition salts thereof substantially as herein disclosed in any one of the Examples.<br><br> DR KARL THOMAE GMBH<br><br> by their Attorneys BALDWIN, SON &amp; CAREY<br><br> </p> </div>
NZ228277A 1988-03-10 1989-03-08 Substituted amino derivatives of benzocycloheptenes, their preparation and pharmaceutical compositions NZ228277A (en)

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