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AU612471B2 - Benzocycloheptene derivatives - Google Patents

Benzocycloheptene derivatives Download PDF

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Publication number
AU612471B2
AU612471B2 AU31189/89A AU3118989A AU612471B2 AU 612471 B2 AU612471 B2 AU 612471B2 AU 31189/89 A AU31189/89 A AU 31189/89A AU 3118989 A AU3118989 A AU 3118989A AU 612471 B2 AU612471 B2 AU 612471B2
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Prior art keywords
group
amino
dimethoxy
methyl
alkyl
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AU31189/89A
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AU3118989A (en
Inventor
Andreas Bomhard
Jurgen Dammgen
Joachim Heiden
Walter Kobinger
Christian Lillie
Manfred Psiorz
Manfred Reiffen
Volker Trach
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Boehringer Ingelheim Pharma GmbH and Co KG
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Dr Karl Thomae GmbH
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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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  • General Chemical & Material Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
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  • Diabetes (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)

Description

AUSTRALIA
PATENTS ACT 1952 1247 1 COMPLETE SPECIFICATION
(ORIGINAL)
FOR OFFICE USE Short Title: Int. Cl: Application Number: Lodged: *t 6 Complete Specification Lodged: Accepted: Lapsed: Published: -Priority: Related Art: 1, 0 'q I TO BE COMPLETED BY APPLICANT 0 f0 0 Name of Applicant: DR. KARL THOMAE GMBH Address of Applicant: Actual Inventors: Address for Service: of d-7950 Biberach an der Riss, Germany.
Federal Republic of MANFRED PSIORZ, MANFRED REIFFE, JOACHIM HEIDEN, ANDREAS BOMHARD, JORGEN DAMMGEN, CHRISTIAN LILLIE, WALTER KOBINGER and VOLKER TRACH.
CALLINANS, Patent Attorneys, of 48-50 Bridge Road, Richmond 3121, Victoria, Australia.
Complete Specification for the invention entitled: "BENZOCYCLOHEPTENE
DERIVATIVES".
The following statement is a full description of this invention, including the best method of performing it known to us:la QL 53 785 Benzocycloheptene derivatives 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.
EP-A-177960 describes tetrahydronaphthalenes substituted in the 2-position 'y an optionally acyl substituted hydroxyl group. These compounds have a pronounced o0,o calcium-antagonistic effect and can therefore be 0 used as pharmaceuticals, in particular for combatting Boo angina pectoris, ischaemia, arrhythmias and high blood pressure.
0 0 Soo0. It has now surprisingly been found that certain novel benzocycloheptenes have other valuable pharmacological properties, in particular a heart rate lowering effect ".020 and an effect of reducing the 0 2 -requirement of the heart.
o"0 In one aspect, the present invention thus provides compounds of formula I
R
R A -N-A 2-R4 1 24 303 X1 X2 (wherein
X
1 represents a hydrogen atom, X 2 represents a hydrogen atom, and X 3 represents a hydrogen atom or a hydroxyl or C1-3 alkoxy group, or 2
X
1 and X 3 together represent another carbon-carbon bond and X 2 represents a hydrogen atom, or
X
1 and X 2 together with the intervening carbon atom, represent a carbonyl group and X 3 represents a hydrogen atom;
A
1 represents a straight-chain C3_ 4 alkylene group optionally substituted by a C 1 3 alkyl group and ]0 in which any ethylene moiety bonded to the benzocycloheptene ring can be replaced by an ethenylene or ethynylene moiety; 0 00 1
A
2 represents a straight-chain C2_ 5 alkylene group optionally substituted by a C 1 3 alkyl group and in which any ethylene moiety bonded to a radical R wherein n is zero can be replaced by an ethenylene 0 O 4 0O0, moiety; 0 0 R1 represents a hydrogen or halogen atom or a trifluoro- "o 0 methyl, nitro, amino, C-_ 3 alkylamino, di(C 1 3 alkyl)amino, o°o0: C, 3 alkyl, hydroxyl, C 1 3 alkoxy, or phenyl(C 1 3 o o 3 1-3 1 -3 alkoxy) group and 0 0 0 0 0
R
2 represents a hydrogen atom or halogen atom or a hydroxyl, C 1 3 alkoxy, phenyl(C 1 3 alkoxy) or C 1 -3 S alkyl group, or
R
1 and R 2 together represent a C 2 alkylenedioxy group;
R
3 represents a hydrogen atom, a C 1 3 alkyl group or a C3- 5 alkenyl group; and
R
R
4 represents a group I 4 h T 3 n is 0 or 1;
R
5 represents a hydrogen or halogen atom or a C 1 3 alkyl, nitro, amino, C1_ 3 alkylamino, di(C 1 -3 alkyl)amino, C2- 3 alkanoylamino, (C-3 alkoxy)carbonylamino,
(C
1 -3 alkyl)sulfonylamino, bis(C 1 3 alkylsulfonyl)amino,
N-(C
1 -3 alkyl)-(C 1 3 alkyl)sulfonylamino, cyano, C1-3 alkylmercapto, C 1 3 alkylsulfinyl or C-_ 3 alkylsulfonyl group or a hydroxyl group optionally substituted by a C 1 3 alkyl, phenyl(C 3 alkyl), 2-hydroxyethyl, 3-hydroxy-n-propyl, 2-hydroxy-n-propyl, C1-3 alkylsulfonyl, cyano(C 1 3 alkyl), (C 1 3 alkoxy)carbonyl, hydroxycarbonyl(C 1 3 alkyl), (Cl 3 alkoxy)carbonyl(Cl 1 3 alkyl), trifluoromethyl, 00o difluoromethyl or trifluoromethylsulfonyl group, ,5 and 0o0 0
R
6 represents a hydrogen or halogen atom, or a C 1 3 Salkyl, hydroxyl, C 1-3 alkoxy, cyano or trifluoromethyl group, or 0 .o
R
5 and R 6 together represent a C 1 2 alkylenedioxy 0o0." group; and o R 7 represents a hydrogen or halogen atom or a C-_ 3 alkyl or (C 1 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. the salts with organic or inorganic acids.
The unsaturated compounds of formula I also serve as intermediates for the preparation of the saturated compounds of formula I.
In the compounds of formula I: R 1 may represent hydrogen, fluorine, chlorine and bromine atoms, or methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, hydroxyl, methoxy, ethoxy, n-propoxy, isopropoxy, nitro, amino, ij 44 methylamino, ethylamino, n-propylamino, isopropylamino, dimethylamino, diethylamino, di-n-propylanino, diisopropylamino, methyl-ethylamino, methyl-n-propylamino, methylisopropylamino, ethyl-n-propylamino, benzyloxy, 1phenylethoxy, 1-phenyipropoxy, 2-phenylethoxy and 3-phenyipropoxy groups;
R
2 may represent hydrogen, chlorine and bromine atoms, or methyl, ethyl, n-propyl, isopropyl, hydroxyl, methoxy, ethoxy, n-propoxy, isopropoxy, benzyloxy, 1-phenylethoxy, 2-phenylethoxy, 2-phenyipropoxy, and 3-phenylpropoxy groups; or R 1 together with R 2 may represent methylenedioxy or ethylenedioxy groups; 0 R may represent a hydrogen atom, or methyl, ethyl, 0 n-propyl, isopropyl, allyl, crotyl, and n-penten- 2-yl groups; OR may represent hydrogen, fluorine, chlorine, bromine and iodine atoms, or methyl, ethyl, n*-propyl, isopropyl, hydroxyl, methoxy, ethoxy, n-propoxy, isopropoxy, 0 0025amino, methylamino, ethylamino, n-propylamino, isopropylamino, dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, methyl-ethylamino, methyl-n-propylamino, 00 methyl-isopropylamino, ethyl-n-propylamino, acetylamino, 41MEMpropionylamino, methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, methylsulfony-2 m.rio, ethylsulfonylamino, n-propylsulfonylamino, bis (methylsulfonyl) amino, bis (ethylsulfonyl) amino, N-methyl-methylsulfonylamino, cyano, methylmercapto, ethylmercapto, n-propylmercapto, methylsulfinyl, ethylsulfinyl, isopropylsulfinyl, methylsulfonyl, ethyisulfonyl, n-propylsulfonyl, benzyloxy, 1-phenylethoxy, 2-phenylethoxy, 2-phenylpropoxy, 3 -phenylpropoxy, 2-hydroxy-ethtxy, 2-hydroxyn-propoxy, 3-hydroxy-n-propoxy, methylsulfonyloxy, ethylsulfonyloxy, isopropylsulfonyloxy, methoxycarbonyloxy, i 3-n~ i_ t .175 0000 0 0 ethoxycarbonyloxy, isopropoxycarbonyloxy, hydroxycarbonylmethoxy, 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;
R
6 may represent hydrogen, chlorine and bromine atoms, or methyl, ethyl, n-propyl, isopropyl, hydroxyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyano and trifluoromethyl groups; or R 5 together with R 6 may represent methylenedioxy or ethylenedioxy groups;
R
7 may represent a hydrogen atom, or hydroxyl, methoxy, ethoxy, n-propoxy and isopropoxy groups; Al may represent n-propylene, 1-methyl-n-propylene, 2-methyl-n-propylene, 3-methyl-n-propylene, 1-ethyln-propylene, 2-n-propyl-n-propylene, 3-ethyl-n-propylene, n-butylene, l-methyl-n-butylene, l-ethyl-n-butylene, prop-l-enylene, n-but-1-enylene, 1-methyl-prop-lenylene, 2-methyl-prop-1-enylene, 3-methyl-prop-lenylene, prop-l-ynylene, 3-methyl-prop-l-ynylene and n-but-l-ynylene groups; and
A
2 may represent ethylene, 1-methyl-ethylene, 1-ethylethylene, 1-propyl-ethylene, 2-methyl-ethylene, 2ethyl-ethylene, n-propylene, n-butylene, n-pentylene, 1-methyl-n-propylene, 1-methyl-n-butylene, 1-ethyln-propylene, 2-ethyl-n-propylene, 1-ethyl-n-butylene, prop-l-enylene, n-but-l-enylene, n-pent-l-enylene, l-methyl-prop-l-enylene, 2-methyl-prop-l-enylene, 3-methyl-prop-l-enylene, 4-methyl-n-but-l-enylene and 5-methyl-n-pent-l-enylene groups.
-I T1I, 6 Preferred compounds according to the invention, however, include compounds of formula I in which
X
1 represents a hydrogen atom, X 2 represents a hydrogen atom and X 3 represents a hydrogen atom or a hydroxyl or methoxy group, or X1 and X 3 together represent a carbon--carbon bond and X 2 represents a hydrogen atom, or
X
1 and X 2 together with the intervening carbon atom, represent a carbonyl group and X 3 represents a hydrogen atom; S 0 Al represents an n-propylene group in which an ethylene .n moiety bonded to the cycloheptene ring can be replaced by an ethenylene or ethynylene moiety;
A
2 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 0oo by an ethenylene moiety;
R
1 represents a hydrogen atom or a methyl or methoxy group; 0i R2 represents a hydrogen atom or a methyl or methoxy gaa group;
R
3 represents a methyl group; n is 0 or 1;
R
5 represents a hydrogen, fluorine, chlorine or bromine atom or a hydroxyl, methoxy, cyano, methyl, nitro, amino, methylsulphonyloxy, trifluoromethylsulphonyloxy or benzyloxy group; 7 -7-
R
6 represents a hydrogen, chlorine or bromine atom or a methoxy group; and
R
7 represents a hydrogen, chlorine or bromine atom; and the enantiomers thereof, the diastereomers thereof, and the acid addition salts thereof.
Particularly preferred compounds according to the invention include compounds of formula I in which
X
1 and X 2 represent hydrogen atoms, and X 3 represents a hydrogen atom or a hydroxyl group, or o o 15 X 1 and X 3 together represent a carbon-carbon bond, and X 2 represents a hydrogen atom, or o o X 1 and X 2 together with the intervening carbon atom, represent a carbonyl group and X 3 represents a hydrogen atom; 0 o R 1 represents a methoxy group; ea 0: R 2 represents a methoxy group;
R
3 represents a methyl group; ma A 1 represents an n-propylene group;
A
2 represents an ethylene or n-propylene group;
R
5 represents a methoxy or methylsulphonyloxy group;
R
6 represents a hydrogen atom or a methoxy group;
R
7 represents a hydrogen atom; and n is 0 or 1; and -8the enantiomers thereof, the diastereomers thereof, and the acid addition salts thereof.
The following compounds, which are covered by formula 1, may also be mentioned by way of example: 2,3-dimethoxy-7-hydroxy-7-[3-(N-(2-(3,4-dimethoxyphenyl)-ethyl)-amino)-propyn-1-yl-6,7,8,9-tetrahydro- 2, 3-dimethoxy-7-hydroxy-7-[3- ((N-cinnamyl-N-methyl) amino) -propyn-l-yl] 8, a 2,3-dimethoxy-7-hydroxy-7-[3-(N-(2-(4-benzyloxy-phenyl)ethyl)-amino)-propyn-1-yl]-6,7,8,9-tetrahydro-5Hbenzocycloheptene, 2,3-dimethoxy-7-hydroxy-7-[3- (4-methoxy-phenyl) a a ethyl) -amino) -propyn-1-yl] benzocycloheptene, a at 2,3-dimethoxy-7-hydroxy-7-[3-(N-(2-(3-methoxy-phenyl)a ethyl) -amino) -propyn-l-yl] benzocycloheptene, 2,3-dimethoxy-7-hydroxy-7-[3-(N-(3-(3,4-dimethyl- Q ~phenoxy) -propyl) -amino) -propyn-1-yl] 9-tetrahydro- .1 SE-ben zocycloheptene, -i e h x -y r x -3 -3 -e h x -h n x propyl)-amino)-propyn-1-yl]-6,7,8,9-tetrahydro-5Hbenzocycloheptene, 2, 3-dimethoxy-7-hydroxy-7-[3- (3-benzyloxy-phenyl) ethyl)-amino)-propyn-l-yl]-6,7, 8,9-tetrahydro-5Hbenzocycloheptene, -9- 2, 3-dimethoxy-7-hydroxy-7- (3-benzyloxy-phenyl) ethyli -amino) -propen-l-yl] benzocycloheptene, 2,3-dimethoxy-7-hydroxy-7-1i3-(N-(2-phenylethyl)-amino)propyn-l-yl]-6,7, 8,9-tetrahydro-5H-benzocycloheptene, 2,3-dimethoxy-7-hydroxy-7-[3-(N-(3-phenylpropyl)amino) propyn-1-ylI-6, 7, 8,9-tetrahydro-5H-benzocycloheptene, 2, 3-dimethoxy-7-hydroxy-7-13- (3-methyl-phenyl) ethyl) -amino) -propyn-l-yl] 8, benzocycloheptene, 2,3-dimethoxy-7-methoxy-7-[3-(N-methyl-N-(2-(3,4dimethoxy-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9o 2,3-dimethoxy-7-hydroxy-7-[3- (N-methyl-N-(2- (3,4dimethoxy-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9- 0o~ 0 2,3-dimethoxy-7-hydroxy-7-[3-(C(N-cinnamyl-N-methyl) amino)-propyn-1-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3,5dimethoxy-phenyl) -ethyl) -amino) -propyn-l-yl] 8,9- 2,3-dimethoxy-7-hydroxy-7-113-(N-methyl-N-(2-(4-benzyloxyphenyl)-ethyl)--amino)--propyn-l-ylI-6,7,8,9-tetrahydro- 352, 3-dimethoxy-7-hydroxy-7-[3- (N-methyl-N- (4-methoxyphenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro- 511-benzocycloheptene, 2, 3-dimethoxy-7-hydroxy-7- (N-methyl-N- (3-methoxyphenyl) -ethyl) -amino) -propyn-l-yl] 9-tetrahydro- 2,3-dimethoxy-7-hydroxy-7-113-(N-methyl-N-(3-(3,4dimethyl-phenoxy) -propyl) -amino) -propyn-l-yl] 8,9- 2,3-dimethoxy-7-hydroxy-7-[3- (N-methyl-N- (3-metho yphenoxy)-propyl)-amino)-propyn-1-yl]-6,7,8,9-tetrahydro- 2, 3-dimethoxy-7-hydroxy-7-13- (N-methyl-N-(2- (3-benzyloxy- 0 ~phenyl) -ethyl) -amino) -propyn-l-yl] 9-tetrahydro- 2, 3-dimethoxy-7-hydroxy-7-[3- (N-methyl-N- (3-benzyloxyphenyl) -ethyl) -amino) -propen-l-yl] 9-tetrahydro- 2,3-dimethoxy--7-hydroxy-7-[3- (N-methyl-N- (2-phenylethyl)amino) -propyn-l-yl] 7,8, 00 2, 3-dimethoxy-7-hydroxy-7-[3- (N-methyl-N- (3-phenylpropyl) amino)-propyn-1-yll-6,7,8,9-tetrahydro-5H-benzocycloheptene, 0 3-dimethoxy-7-hydroxy-7-13- (N-methyl-N- (3-methylphenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro- 2, 3-dimethoxy-7-hydroxy-7-13- (N-ethyl-N- (3,4-dimethoxyphenyl) -ethyl) -amino) -propyn-l-yl] 8, 9-tetrahydro- 352, 3-dimethoxy-7-hydroxy-7-13- (N-ethyl-N-(2- 4-dimethoxyphenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro- I -3 11 7-methoxy-7-[3- (N-(2-(3,4-dimethoxy-phenyl)-ethyl) amnino) -propyn-l-yl] heptene, 7-hydroxy-7-[3-(N-(2-(3,4-dimelthoxy-pheflyl)-ethyl)amino) -propyn-1-yl] 7,8, heptene, 7-hydroxy-7-[3- (4-benzyloxy-phenyl) -ethyl) amino)-propyn-1-yl]-6,7,8,9-tetrahydro-5-bezocycloheptele, 7-hydroxy-7-[3-(N-(2-(4-methoxy-phenyl)-ethyl)-amilo)propyn-1-yl] 9-tetrahydro-5H-benzocyc3.oheptene, 7-hydroxy-7-[3-(N-(2-(3-methoxy-phelyl)-ethyl)-amino)- 0 propyn-l-yl]-6,7, 8,9-tetrahydro-5H-benzocycloheptene, 0 7-hydroxy-7-13-(N-(3-(3,4-dimethyl-phenoxy)-propyl)amino) -propyn-l-ylI-6,7, 8, heptene, 7-hydroxy-7-113-(N-(3-(3-methoxy-phenoxy)-propyl)amino) -propyn-1-yl] 8, 7-hydroxy-7-[3-(N-(2-(3-benzyloxy-phenyl)-ethyl)amino) -propyn--1-yl1 7, 8,9-tetrahydro-5H-benzocyclohepteie, 7-hydroxy-7-[3-(N-(2-(3-benzyloxy-phenyl)-ethyl)amino) -propen-1-yl] 8, 7-hydroxy-7-13-(N- (2-phenylethyl)-amino)-propyn-lyl] 8, 7-hydroxy-7-[ 3- (3-phenyipropyl) -amino) -propynl-yl]-6,7, 8,9-tetrahydro-5H-benzocycloheptene, 7-hydroxy-7-[3- (3-meth~'1-phenyl) -ethyl) -ami-'no) propyn-1-yl] 8, R 5 represents a hydrogen or halogen atom or a CI 3 alkyl, nitro, amino, C 1 3 alkylamino, di(C 1 3 alkyl) amino, C 2 3 alkanoylamino, (C 1 3 alkoxy)carbonyl.
3 12 7-methoxy-7- (N-methyl-N- 4-dimethoxy-phenyl) ethyl) -amino) -propyn-1-yll 8, benzocycloheptene, 7-hydroxty-7-[3- (N-methyl-N- (3,4-dimethoxy-phenyl)ethyl) -amino) -propyn-l-yl] 7,8, benzocyclohepte'e, 7-hydroxy-7-[3- ((N--cinnamyl-N-methyl) -amino) -propynl-yl] 7, 8,9-tetrahydro-5H-benzocycloheptene, 7-hydroxy-7-[3-(N-methyl-N-(2-(3,5-dimethoxy-phenyl)ethyl) -amino) -propyn-l-yl] 8, benzocycloheptene, 7-hydroxy-7-[3- (N-methyl-N- (4-benzyloxy-phenyl) ethyl) -amino) -propyn-1-yl] 8, benzocycloheptene, 7-hydroxy-7-[3- (N-methyl-N- (2-(4-methoxy-phenyl)ethyl) -amino) -propyn-l-yl] 8, benzocycloheptene, 7-hydroxy-7-[ 3- (N-methyl-N- (3-methoxy-phenyl) ethyl) -amino) -propyn-1-yl] 8, benzocycloheptene, 7-hydroxy-7-[3- (N-methyl-N- 4-dimethyl-phenoxy) propyl) -amino) -propyn-l-yl] 8, benzocycloheptene, 7-hydroxy--7-[3- (N-methyl-N-(3- (3-methoxy-phenoxy)propyl)-amino)-propyn-l-yl]- 6 7,8,9-tetrahydro-5Hbenzocycloheptene, 7-hydroxy-7-[3- (N-methyl-N- (3-benzyloxy-phenyl) ethyl) -amino) -propyn-1-yl] 8,9-tetrahydro-51benzocycloheptene, -13 7-hydroxy-7- (N-methyl-N- (3-benzyloxy-phenyl) ethyl) -amino) -propen"-l-ylI benzocycloheptene, 7-hydroxy-7-[ 3- (N-methyl-N- (2-phenylethyl) -amino) propyn-l-yl]-6,7, 8,9-tetrahydro-5H-benzocycloheptene, 7-hydroxy-7-[3- (N-methyl-N- (3-phenylpropyl) -amino)propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, 7-hydroxy-7-[3-(N-methyl-N-(2-(3-methyl-phenyl)-ethy l)amino)-propyn-1-yl] 8,9-tetrahydro-5H-benzocycloheptene, 000 7-hydroxy-7-[3-(N-ethyl-N-(2-(3-methoxy-phenyl)-ethyl)amino)-propyn-1-yllj-6,7,8,9-tetrahydro-5H-benzocyclo- 00000:heptene, 7-methoxy-7-113- (N-allyl-N- (3,4-dimethoxy-phenyl)ethyl)-amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5Hbenzocycloheptene, 7-hydroxy-7-[3-(N-allyl-N-(2-(3,4-dimethoxy-phenyl)- 0: ethyl)-amino)-propyn-1-yl]-6,7,8,9-tetrahydro-5ibenzocycloheptene, 2,3-dimethoxy-7-hydroxy-7-[3-(N-C3-(3,4-methylenedioxyphenoxy)-propyl)-amino)-propyl]-6,7,8,9-tetrahydro- 2, 3-dimethoxy-7-hydroxy-7-[3- (4-fluoro-phenyl) ethyl) -amino) -propyl] 7,8, heptene, 2,3-dimethoxy-7-hydroxy-7-[3- (3-methoxy-phenyl)ethyl) -amino) -propyl] 7, 8,9-tetrahydro-5H-benzocycloheptene, -14 2,3-dimethoxy-7-hydroxy-7-[3- (3,4-dimethylphenoxy)-propyl)-amino)-propyll-6,7,8,9-tetrahydro- 2,3-dimethoxy-7-hydroxy-7-[3-(N-(3-(3-methoxy-phenoxy)propyl)-amino)-propyl] 8,9-tetrahydro-5H-benzocycloheptene, 2,3-dimethoxy-7-hydroxy-7-[3-(N-(2-(3-hydroxy-phenyl).
ethyl)-amino)-propyll-6,7,8,9-tet heptene, 2,3-dimethoxy-7-hydroxy-7-[3- (3-methanesuiphonyloxyphenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro.
2 3 -dimethoxy-7-hydroxy-7-[3-(N-(2-pheiyethy)aino).
propyl]-6,7, 8,9-tetrahydro-5H-benzocycloheptene, 2,3-dimethoxy-7-hydroxy-7-[3-(N-(3-phenylpropyl).
amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, 2 ,3-dimethoxy-7-hydroxy-7-[3-(N-(2-(3-methyl-phenyl)ethyl)-amino)-propyll-6,7,8,9-tetrahydro-5H-benzocycloheptene, 2 3 -dimethoxy-7-hydroxy-7-[3-(N-(2-(3-methanesulphonyl.
amino-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro.
'I 30 2 3 -dimethoxy-7-hydroxy-7-[3-(N-(2-phenylehyl).amino)..
propyl] 7, 8,9-tetrahydro-5H-benzocycloheptene, 2,3-dimethoxy-7-hydroxy-7-[3- (3-phenyipropyl)arino)-propyl]-6, 7 8 2, 3-dimethoxy-7-hydroxy-7-[ (3-chioro-phenyl) ethyl) -amino) -propyl] heptene, k W Ll L .L LII X 1 represents a hydrogen atom, X 2 represents a hydrogen atom, and X 3 represents a hydrogen atom or a hydroxyl or C 1 3 alkoxy group, or 0 OLE 0* (0 *00000 o 0 00 ~0 o 0 0000 0 0 0 00 0 00 00 4 4 04 15 2, 3-dimethoxy-7-hydroxy-7- (3-acetylaminophenyl) -ethyl) -amino) -propyl] 9-tetrahydro- 2,3-dimethoxy-7-hydroxy-7-[3-(N-(2-(3-amino-phelyl)ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-( 3 3 4 methylenedioxy-phenoxy)-propyl) -amino)-propyl]-6,7,8,9- 2,3-dimethoxy-7-hydroxy-7-[3- (N-methyl-N- (4-fluorophenyl) -ethyl) -amino) -propyll 9-tetrahydro- 2,3-dimethoxy-7-hydroxy-7-[3- (N-methyl-N- (2-(3-methoxyphenyl) -ethyl) -amino) -propyl] 8, 9-tetrahydro- 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(3-(3,4dimethyl-phenoxy) -propyl) -amino) -propyl] 7, 8,9- 2,3-dimethoxy-7-hydroxy-7-[3- (N-methyl-N- (3-methoxyphenoxy) -propyl) -amino) -propyll 7,8, 9-tetrahydrozocycloheptene, 2, -ie h x -y r x -3 -eh lN -3hd oy phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro- 2,3-dimethoxy-7-hydroxy-7-[3- (N-methyl-N- (3-methanesulphonyloxy-phenyl) -ethyl) -amino) -propyl] 8,9- 2, 3-dimethoxy-7-hydroxy-7- [-3-(N-methyl-N- (2-phenylethyl) amino) -propyl] 7,8, -16 2, 3-dimethoxy-7-hydroxy-7-[3- (N-methyl-N- (3-phenyipropyl) amino) -propyl 1-6,7,8, 2, 3-dimethoxy-7-hydroxy-7- (N-methyl-N- (3-methylphenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro- 2, 3-dimethoxy-7-hydroxy-7-[3- (N-methyl-N- (3-methanesuiphonylamino-phenyl) -ethyl) -amino) -propyl] -6,7,8,9- 2, 3-dimethoxy-7-hydroxy-7-[ 3- (N-methyl-N- (2-phenylethyl) amino) -propyl] -6 2,3-dimethoxy-7-hydroxy-7-[3- (N-methyl-N- (3-phenylpropyl)amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, 2,3-dimethoxy-7-hydroxy-7-[3- (N-methyl-N- (3-chlorophenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro- 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3-acetylamino- 2, 3-dimethoxy-7-hydroxy-7-[3- (N-methyl-N- (3-aminophenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro- 2,3-dimethoxy-7-hydroxy-7-[3-(N-ethyl-N-(3-(3,4-methylenedioxyphenoxy) -propyl) -amino) -propyl] 9-tetrahydrozocycloheptene, 2,3-dimethoxy-7-hydroxy-7-[3-(N-ethyl-N-(2-(3-methoxyphenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro- In the compounds of formula I: R, may represent hydrogen, fluorine, chlorine and bromine atoms, or methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, hydroxyl, methoxy, ethoxy, n-propoxy, isopropoxy, nitro, amino, -17- 2,3-dimethoxy-7-hydroxy-7-[3- (N-allyl-N- (3-methoxy- 2, 3-dimethoxy-7-hydroxy-7-[3- (N-allyl-N- (3-(3,4-dimethylphenoxy) -propyl) -amino) -propyl] 7,8, 9-tetrahydro- 2, 3-dimethoxy-7-hydroxy-7-[3- (N-allyl-N- (3-methoxyphenoxy)-propyl)-amino)-propyl]-6,7,8,9-tetrahydro- 7-hydroxy-7-[3- 4-methylenedioxy-phenoxy) propyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, 00 7-hydroxy-7-[3-(N-(2-(4-fluoro-phenyl)-ethyl)-amino)propyl]-6, 7, 8,9-tetrahydro-5H-benzocycloheptene, 00 r'O 0 0 7-hydroxy-7-[3-(N-(2-(3-methoxy-phenyl)-ethyl)-amino)propyl]-6, 7, 8,9-tetrahydro-5H-benzocycloheptene, 2,3-dimethoxy-7-hydroxy-7-[4-(N--(3-(3,4-methylenedioxyphenoxy)-propyl)-amino)-butyl]-6,7,8,9-tetrahydro- 2, 3-dimethoxy-7-hydroxy-7-L4- (3-phenyipropyl) amino)-butyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene, M a yi e h x 7 y r x 7 5 3 m t h x p e y ethy-minho)-7-enty-7-[-(--(-teayeoH-enycl)heptene, 2,3--dimethoxy-7-hydroxy-7-[5-(N-(3-phenylpropyl)- 2,3-dimethoxy-7-hydroxy-7-[5- (N-methyl-N-(3-(3-methoxyphenoxy) -propyl) -amino) -pentyl] 7,8, 9-tetrahydro- SE-ben zocycloheptene, Lit= a IJ~ e. L ~y I fr"- propoxyl 3- phenyipropoxy, 2-hydroxy-eth'xy, 2-hydroxyn-propoxy, 3-hydroxy-n-propdxy, methylsulfonyloxy, ethylsulfonfloxy, isopropylsulfonyl0xy, methoxycarbofloxy, 4A -18 2,3-dimethoxy-7--[4-(N-(3-(3,4-dimethoxy-phenyl)-propyl) amino) -butyl] 2,3-dimethoxy-7-[3- 4-methylenedioxy-phenoxy) propyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one, 2, 3-dimethoxy-7-[3- (4-fluoro-phenyl) -ethyl) amino) -propyll-6, 7, 8,9-tetrahydro-5H-benzocyclohepten- 6-one, 2, 3-dimethoxy-7-[3- (3-methoxy-phenyl) -ethyl) '#tsamino) -propyl] 7,8, 6-one, 00 015 2,3-dimethoxy-7-[3-(N-(3-(3,4-dimethyl-phenoxy)-propyl)amino)-propylll-6,7, 8,9-tetrahydro-5H-benzocyclohepten- 6-one, 2,3-dimethoxy-7-[3-(N-(3-(3-methoxy-phenoxy)-propyl)- 3amino)-propyl]-6,7,8,9-tetrahydro-5H-benzccoetn 6-one, 2,3-dimnethoxy-7-[3-(N-(2-(3-hydroxy-phenyl)-ethyl)- 0 25 amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten- 6-one, 2, 3-dimethoxy-7-[3- C2- (3-methanesulphonyloxy-phenyl) ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten- 6-one, 2 3 -dimethoxy-7-[3-(N-(2-phenylethyl)-amino)-propyl]- 6, 7,8, 9-tetrahydro-5H-ben zocyclohepten-6-one, 2 3 -dimethoxy-7-[3-(N-(3-phenylpropyl)-amino)-propyl]- 6,7,8, 9 -tetrahydro-5H-benzocyclohepten-6-one, -19- 2,3-dimethoxy-7-1i3-(N- (3-methyl-phenyl)-ethyl) amino) -propyll 6-one, 2,3-dimethoxy-7--[3-(N-(2-(3-methanesulphonylaminophenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro- 5H-benzocyclohepten-6-one, 2,3-dimethoxy-7-[3-(N-(2-phenylethyl)-amino)-propyl]- 6 ,7,8,9-tetrahydro-5H-benzocyclohepten-6-one, 2 ,3-dimethoxy-7-[3-(N-(3-phenylpropyl)-amino)-propyl..
6,7,8, 9-tetrahydro-5H-benzocyclohepten-6-one, a o~y a-ne 2,3-dimethoxy-7-[3-(N-(2-(3-clao-phenyl)-ethyl)amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten- 6-one, o a 2 ,3-dimethoxy-7-[3-(N-(2-(3-aeamino-phenyl)-ethyl y..
amino) -propyl] 8, 6-one, 2 ,3-dimethoxy-7-[3-(N-met-( amin-heny4-ethyl)-dixy phnx)oy)amino)-propyl-6,7,8,9-tetrahydro-5-ezccheen ylhptn6oe 2 3 -dirnethoxy-7-[3-(N-methyl-N-(2-(34-leto-hyendioxethnx)yl)-amno)-propyl]-6,7,8,9-tetrahydroezoyco 5Hbnylhepten-6-one, 2 ,3-dimethoxy-7-[3-(N-methyl-N-(2-(3-metuoo-phenyl).
ethyl) -amino) -propyll 7, 8,9-tetrahydro-5H-benzocyclohepten-6-one, 20 2,3-dimethoxy-7-13- (N-methyl-N- (3.-(3,4-diniethyl-phenoxy) propyl)-amino)-propylil-6,7,8,9-tetrahydro-5H-benzocyclohepten- 6-one, 2, 3-dimethoxy-7-[3- (N-methyl-N- (3-methoxy-phenoxy) propyl) -amino) -propyl] 8, hepten-6 -one, 2, 3-dimethoxy-7-[3- (N-methyl-N- (3-hydroxy-phenyl) ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5HI-benzocyclohepten-6-one, 2,3-dimethoxy-7-[3- (N-methyl-N-(2- (3-methanesuiphonyloxy-phenyl) -ethyl) -amino) -propyl] 8, 9-tetrahydro- 5H-benzocyclohepten-6-one, 0 0 0 0 2,3-dimethoxy-7-[3-(N-methyl-N-(2-phenylethyl)-amino)- 0 0I~ 0propyl] 7, 8,9-tetrahydro-5H-benzocyclohepten-6one, 0 0 0 0 2,3-dimethoxy-7-173-(N-methyl-N-(3-phenylpropyl)-amino)propyl] 7, 8,9-tetrahydro-5H-benzocyclohepten-6- 0 0 one, S0 2,3-dimethoxy-7-[3-(N-methyl-N-(2-(3-methy.-phenyl)ethyl) -amino) -propyl] hepten-6-one, 2,3-dimethoxy-7-[3-(N-methyl-N-(2-(3-methanesulphonylamino-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro- 5H-benzocyclohepten-6-one, 2,3-dimethoxy-7-[3-(N-methyl-N-(2-phenylethyl)-amino)propyl] 7,8, 9-tetrahydro-5H-benzocyclohepten-6one, 2,3-dimethoxy-7-[3- (N-methyl-N-(3--phenylpropyl)-amino)propyl] 7,8, 9-tetrahydro-5H-benzocyclohepten-6one,
R
7 represents a hydrogen atom; and n is 0 or 1; and -21 ethyl)-arnino)-propyll-6,7,8,9-tetrahydro-5H-benzocyclo- 2,3-dimethoxy-7-[3-(N-methyl-N-(2-(3-acetylaminophenyl) -ethyl) -amino) -propyl] 8,9-tetrahydro- Iy 51-benzocyclohepten-6-one, 2,3-dimethoxy-7-[3-(N-methyl-N-(2-(3-amino-phenyl)ethyl)-amino)-propyl-6,7,8,9-tetrahydro-5Hbenzocyco.
hepten-6-one, 2,3-dimethoxy-7-[3-(N-ethyl-N--(3-(3,4-methylenedioxyphenoxy) -propyl) -amino) -propyl] 9-tetrahydro- 5H-benzocyclohepten-6-one, o 2 ,3-dimethoxy-7-[3-(N-ethyl-N-(2-(3-methoxy-phenyl)- 0 ethy1)-amino)-propyl]-6,7,8,9-tetrahydro-H-benzocyco.
0O000 hepten-6 -one, 0 0 0 2 3 -dimethoxy-7-[3-(N-allyl-N-(2-(3-methoxy-phenyl)ethyl) -amino) -propyl] 7,8, o hepten-6-one, o 25 2 3 -dimethoxy-7-[3-(N-aly-N(-(3-(,4dimethylphenoxy).
propyl)-amino)-propyl]-6,7,8,9-tetrahydro-5-benzocyclo.
tepten-6-one, lift 2 ,3-dimethoxy-7-[3-(N--allyl-N-(3-(3-methoxy-phenoxy)propyl) -amino) -propyl] 8,9-tetrahydro-5H-benzocyclohepten-6 -one, 7-hydroxy-7-[ 3- 4-methylenedioxy-phenoxy) propyl)-amino)-propyl] -6,7i,8,9-tetrahydro-5H-benzocyclohepten- 6-one, 7-hydroxy-7-[3- (4-fluo'ro-phenyl) -ethyl.)-amino) propyl] 7, 8,9-tetrahydro-5H-benzocyclohepten-6one, 22 7-hydroxy-7-[3-(N-(2-(3-methoxy-phenyl)-ethyl)-amino)propyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-6one and 2,3-dimethoxy-7-14-(N-(3-(3,4-methylenedioxy-phenoxy)propyl)-amino)-butyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one, the enantiomers, diastereomers and acid addition salts thereof.
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: 00 reacting a compound of formula II
R
1 A 1 R4 b o 201 1 (II) 2V X1 X 1 2 with a compound of formula III Z A 2 R (III) 2 2 4 (in which
R
1
R
2
R
4 Al, A2' X 1
X
2 and X are as hereinbefore defined, one of the groups Z 1 and Z 2 represents an R 3 -NH group, where R3 is as hereinbefore defined, and the other one of the groups Z 1 and Z 2 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);
I
9 I
I
l Wsr.lru~-..-4* a~ 23 (to prepare compounds of formula I in which X 3 represents a hydrogen atom) catalytically hydrogenating a compound of formula IV R R IR2 A 1
-N-A
2
-R
4
(IV)
x x2 X1 X 2 (in which
R
1
R
2
R
3
R
4
X
1
X
2 and A 2 are as hereinbefore defined, and X 4 represents a hydroxyl group and A," "o is a moiety A 1 as hereinbefore defined, or
X
1 and X 4 together represent a carbon-carbon bond oa and is a moiety A 1 as hereinbefore defined, or S' X 4 and together represent a straight chain C3-4 o 20 alkanylylidene group optionally substituted by a 0 Cl-3 alkyl group and in which any ethanylylidene moiety bonded to the benzocycloheptene ring can be 0 replaced by an ethenylylidene moiety); 0 a 0 25 (to prepare compounds of formula I in which X1 and X 3 represent a carbon-carbon bond) 4 1 cleaving off a moiety HZ 3 from a compound of formula V 30 RW R
R
"1 3 RA -N-A 2
-R
4 2 (V) z 3
L
I t I I
I
24 (in which
R
1
R
2
R
3
R
4
A
1 and A 2 are as hereinbefore defined and Z 3 represents a leaving group such as a hydroxyl, alkoxy, acyloxy or alkylsulphonyloxy group); (to prepare compoundsof formula I in which X 3 represents a hydroxyl group) reacting a compound of formula VI
R
(VI)
000000 00000 00 25 M-Al-NR -A 2
-R
4
(VII)
20 in which
R
3 R, A and RA are as hereinbefore defined) with a compound 30 M represents an alkali metal atom or a MgHal group, where Hal represents a chlorine, bromine or iodine atom); e) (to prepare compounds of formula VIII in which 25 M-AI-NR3-A2-R 4
(VII)
(in which I R 3 R' A 1 and A 2 are as hereinbefore defined and I aeaI 30 M represents an alkali metal atom or a MgHal group, where Hal represents a chlorine, bromine or iodine atom); (to prepare compounds of formula I in which R represents an alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulphonylamino, bis(alkylsulphonyl)-amino, N-alkyl-alkylsulphonylamino, alkylmercapto, alkoxy, alkoxycarbonyloxy, hydroxycarbonyl- -j alkoxy, alkoxycarbonylalkoxy, phenylalkoxy, trifluoroor trifluoromethylsulphonyloxY group) reacting a compound of formula VIII
R
3 A 1 -N-A 2R.
4 1
(VIII)
XN 3 (in which Rif, R, Ai, A, X 1 1 X and X are as hereinbefore 2 3 22 3 defined, and R 4 1 represents a group
R
6 n- 0% R 8 wherein R 6 R 7 and n are as hereinbefore defined, and R 8represents a hydroxyl, amino or C 1 3 alkylamino 25 group) with a compound of formula IX z R9(IX) (in which
Z
4 represents a nucleophili(; leaving group such as a halogen atom, for example a chlorine, bromine or iodine atom, ar Rrepresents a C 3 alkyl, C 3 alkanoyl, (C 3 alkoxy) carbonyl, hydroxycarbonyl (C 1 3 alkyl), (C 1 3 alkoxy)carbonyl(C 1 3 alkyl), (C 1 3 alkyl)sulphonyl, phenyl(Cl..
3 alkyl), trifluoromethyl, difluoromethyl or cyano (Cl 1 3 alkyl) group) 26 reducing a compound of formula X R R3 R ,A -N-C-A-R 4 R 2
(X)
x 3 X H (in which
R
2
R
3
R
4 Al X 1 and X 3 are as hereinbefore defined, and
A
2 represents a straight-chained C 1 4 alkylene group which is optionally substituted by a C 1 3 alkyl group); 0"'o 15 (to prepare compounds of formula I in which A 1 So represents a straight-chain C 3 -4 alkylene group optionally substituted by a C 1 _3alkyl group and in which an ethylene moiety bonded to the benzocycloheptene ring may be replaced by an ethenylene moiety) S catalytically hydrogenating a compound of formula XI o o R R .3 *4 AI '-N-A 2
-R
4
R
25 (XI)
X
3 Ri R2' R3' R4' A2' X1, X 2 and X 3 are as hereinbefore defined, and Al' represents a straight-chain C alkylene group optionally substituted by a C 1 3 alkyl group and in which an ethylene moiety bonded to the benzocycloheptene ring is replaced by an ethenylene or ethynylene moiety); eliminating any protective group used to protect a reactive group in any of reaction steps to c 27 0 o0 0 0 o o 0 o0 0 0 0 00 00 00 0
*Q
debenzylating a compound of formula I in which
R
5 represents a benzyloxy group to produce the corresponding hydroxy compound; resolving a compound of formula I which contains at least one chiral centre into its diastereomers or into its enantiomers; and 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.
The reaction of step is conveniently carried out in a solvent, or mixture of solvents, such as acetone, diethyl ether, methylformamide, dimethylformamide, dimethylsulphoxide, benzene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane, or in an excess of the compounds of formulae II and/or III used, and optionally in the presence of an acidbinding 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 25 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 30 leaving group, conveniently at a temperature of between 0 and 150 0 C, preferably at a temperature of between 50 and 120 0 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, in the presence of a tertiary organic base or of an excess of one of the amines of formula II or III used.
heptene, f 28 The catalytic hydrogenation of step 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 between 0 and 80 0 C, but preferably at a temperature between 1U ambient temperature and 60 0
C.
If X 4 represents a hydroxyl group, the catalytic hydrogenation is conveniently carried out in the presence of an acid.
o° oIt is possible in the catalytic hydrogenation for o°o double or triple bonds which are present simultaneously Sto be hydrogenated or, where appropriate, benzyl groups which are present to be eliminated.
0 0 uo The reaction of step is preferably carried out in a solvent such as ethanol, isopropanol, tetrahydrofuran, o,.o dioxane or pyridine, optionally in the presence of an acid-binding agent such as sodium carbonate or 0 0° 25 pyridine, or in the presence of an acid such as hydrochloric acid or sulphuric acid, at a temperature of between 0 and 100 0 C, preferably at a temperature of between 20 and 80 0
C.
In the reagent of formula V, the group Z 3 may conveniently for example have a carbon atom content in any alkyl moiety of 1 to 3.
A mixture of isomers which may be obtained in this way and which consists of a compound of formula I in which X 1 and X 3 together represent a carbon-carbon bond, and of a compound of formula I in which X 3 together with one hydrogen atom of the adjacent saturated i- c 29 carbon atom of the moiety Ai, represents a carboncarbon bond, may subsequently be fractionated by chromatography, for example on aluminium oxide (neutral).
The reaction of step is preferably carried out in a solvent such as diethyl ether, methyl tert.butyl ether, tetrahydrofuran, dioxane, n-hexane or benzene, optionally under inert protective gas such as nitrogen or argon, at a temperature of between 0 and 50 0
C,
but preferably at ambient temperature.
The reaction of step is conveniently carried out in a solvent or mixture of solvents such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile Eo p or dimethylformamide, optionally also in the presence So of an acid-activating agent, or of a dehydrating agent, for example in the presence of ethyl chloroformate, thionyl chloride, phosphorus trichloride, phosphorus O° 20 pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicycloo hexylcarbodiimide/N-hydroxysuccinimide, N,N'-carbonyldiimidazole or N,N'-thionyl diimidazole, and optionally in the presence of an inorganic base such as sodium 0 0 a o carbonate, or of a tertiary organic base such as 0 04 °o 25 triethylamine or pyridine (it also being possible for the two latter simultaneously to act as solvent), at a temperature of between -25 and 250 0 C, but preferably at a temperature of between -10 0 C and the boiling point of the solvent used.
If R 3 in a compound of formula VIII denotes a hydrogen atom, unless the latter is protected during the reaction, e.g. by a customary protective group it will be simultaneously replaced by a corresponding R 9 The reduction of step is preferably carried out with a hydride such as lithium aluminium hydride or diborane or with a complex composed of borane 30 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 0 C, but preferably at a temperature of between 10 and 45 0
C.
The catalytic hydrogenation of step 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 0 C, but preferably at a temperature of between ambient temperature and 60 0
C.
For the preparation of compounds of formula I in 0 which Al contains a double bond, the catalytic hydrogenao 20 tion of a compound of formula XI in which A contains o0 a triple bond is preferably carried out in the presence of Raney nickel or a Lindlar catalyst.
o o Furthermore it is possible in the catalytic hydrogenation .o6 25 for a double bond present in the moiety A 2 to be 0 simultaneously hydrogenated.
In the reactions described above, reactive groups, 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.
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.
c~ I ;i 31 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 0 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 0 C, but preferably at ambient temperature, and under a hydrogen pressure S'o of 1 to 7 bar, but preferably of 3 to 5 bar.
0 0 If a compound of formula I in which R 5 represents o <o 20 a benzyloxy group is obtained according to the invention, Jo, this can be converted by debenzylation into the corresponding hydroxyl compound.
4 The subsequent debenzylation is preferably carried 25 out in a solvent such as water, water/ethanol, methanol, 44 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 0 C, preferably at ambient temperature.
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 L j -ii i ~.i 32 tartaric acid, D- or L-diacetyl tartaric acid, Dor L-tartaric acid, D- or L-lactic acid, D- or Lcamphoric acid, D- or L-dibenzoyl tartaric acid, D- or L-camphorsulphonic acid or D- or L-camphanic acid.
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, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid, fumaric acid and oxalic acid.
n The compounds of formulae II to XI used as starting materials are in part known from the literature, 0 a otherwise they can be obtained by processes known 0 0 .o 20 per se.
For example, a starting compound of formula II may be obtained by reaction of a corresponding benzocyclo- 0a 4 hepten-7-one with an appropriate organometallic compound o G a1 25 and, where appropriate, subsequent dehydration and/or hydrogenation. A pyranyl-2-oxy compound which is 3 obtained in this way can, where appropriate, subsequently be converted into a compound of formula II in which
Z
1 represents a halogen atom.
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.
As already mentioned herinbefore the new compounds of formula I and the physiologically acceptable acid addition salts thereof have valuable pharmacological 1~ I 1 33 properties, in particular a heart rate lowering, blood pressure lowering, Ca -antagonist and/or antithrombotic effect, an antiischaemic effect on the heart, and an effect of reducing the 0 2 -requirement of the heart, while the central side effects are slight.
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.
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.
S° 20 In a still further aspect, the invention provides 0 the use of a compound of formula I or a physiologically S° 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, thrombosis or ischaemia of the heart.
In a yet still further aspect, the invention provides a method of treatment of the human or 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.
The compounds A 2,3-dimethoxy-7-[3-(N-methyl-N-(2-(3,4-dimethoxyphenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro- L_ i i one, 34 B 2,3-dimethoxy-[3-(N-methyl-N-(2-(4-methoxyphenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro- C 2,3-dimethoxy-7-[3-(N-methyl-N-(2-(3-methoxyphenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro- D 2,3-dimethoxy-7-ydroxy-7-[3-(N-methyl-N-(2- (3-methoxy-phenyl)-ethyl)-amino)-propyl]-6,7,8,9- 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 F 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2r00 (3-methanesulphonyloxy-phenyl)-ethyl)-amino)propyl]-6,7,8,9-tetrahydro-5H-benzo-cycloheptene 000000 0 o*0 have been investigated for their biological properties, 0c no for example, as follows: Effect on the heart rate of rats S0 0 The effect of the substances A-F on the heart rate was investigated for each dose on two rats with a 0 mean weight of 250-300 g. For this purpose, the rats were anaesthetised with pentobarbitone (50 mg/kg i.p. and 10 mg/kg The substances to be investigated were injected in aqueous solution into the jugular vein (0.1 ml/100 g).
The blood pressure was measured via a cannula in a carotid artery, and the heart rate was recorded from a ECG recorded with needle electrodes (lead II or III). The heart rate of the animals in the control period was between 350 and 400 beats/minute (bpm).
-i one, The results obtained are set forth in the Table below: Substance Dose Change of heart rate measured [mg/kg] minutes after administration of substance [bpm] 0 00 00 0 o 00 0 0 0 0 00 0 0 Ct~ 4 0 0 0 04 00 0 0 0 0 0 A 5.0 -173 B 5.0 -170 C 5.0 -180 D 5.0 -155 E 5.0 -167 F 5.0 -130 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.
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.
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 u ule atom, or a methanesulphonyloxy, P-toluenesulphonyloxy or ethoxysulphonyloxy group); -36inert excipients and/or diluents, for example with maize starch, lactose, sucrose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, 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.
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): 0 0 0 00 0 0 0 0 o0 00 0 0 0 0 0 0 0 4 -1 I 37 Example A N-Benzyl-N-methyl-propargylamine 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 0
C,
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 in vacuo and distilled.
Yield: 74.4 g (78% of theory), B.P. 15-20 mm: 108-115 0
C.
Example B 9909 o r o oo o D o 90900 0 o 90O °0 0 25 I r 3 0u Q 0 0 a o d °25 0 69 i 2,3-Dimethoxy-7-hydroxy-7-(3-(N-benzyl-N-methyl-amino)propyn-1-yl)-6,7,8,9-tetrahydro-5H-benzocycloheptene 170 ml of tetrahydrofuran are added dropwise at 15 0
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 0
C
a solution of 74.2 g (0.467 mol) of N-benzyl-N-methylpropargylamine 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 0
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, 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) 38 using methylene chloride and subsequently using increasing proportions of ethanol (up to Yield: 127 g (90% of theory), R F: 0.2 (aluminium oxide, mobile phase: 2% ethanol in methylene chloride).
Example C 2, 3-Dimethoxy-7-iiydroxy-7- (N-benzyl-N--methyl-amino) propyl) 8, 24.2 g (0.064 mol) of 2,3-dimethoxy-7-hydroxy-7-(3- (N-benzyl-N-methyl-amino) -propyn-l-yl) 8, 9-tetrahydroare 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 hours. After filtration and evaporation in 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 4 Yield: 24 g (98% of theory), R F: 0.65 (aluminium oxide, mobile phase: 3% ethanol o in methylene chloride).
44 Example D 4 4 S Mixture of the isomers 2, 3-dimethoxy-7- (N-benzyl-N--methyl-amino) -propyl) 8,9-dihydro-5H-benzocycloheptene and 2, 3-dimethoxy-7- (N-benzyl-N-methyl-amino) -propylidene) 6, 7, 8,9-tetrahydro-5H-benzocycloheptene 23.8 g (0.062 mol) of 2,3-dimethoxy-7-hydroxy-7-(3- (N-benzyl-N-methyl-amino) -propyl) -6 8,9-tetrahydroand 5.5 g (0.029 mol) of p-toluene- ~Wcnr; rr~ 39 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.
Yield: 18.3 g (80% of theory), R 0.87-0.92 (aluminium oxide, mobile phase: cyclohexane 50% ethyl acetate).
Example E 2,3-Dimethoxy-7-(3-(N-methyl-amino)-propyl)-6,7,8,9- ,O°o 8.3 g (0.0227 mol) of a mixture of the isomers 2,3no"o 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)-6,7,8,9tetrahydro-5H-benzocycloheptene are hydrogenated So in 150 ml of glacial acetic acid in the presence of 1 g of 10% palladium on active charcoal at 50 0
C
and under 2 bar of hydrogen for 4 hours. The filtrate S 25 is evaporated down in vacuo and then dissolved in 0 00 oo methylene chloride, the solution is washed 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 aluminium oxide (neutral, activity II--III) o using methylene chloride and increasing proportions of ethanol (up to Yield: 2.27 g (36.0% of theory), R 0.25 (aluminium oxide, mobile phase: 10% ethanol in methylene chloride).
a reactive group in any of reaction steps to Example F 2, 3-Dimethoxy-7-hydroxy-7- (N-methyl-amino) -propyl) 6,7,8, 8.15 g (0.0215 mol) of 2,3-dimethoxy-7-hydroxy-7- -benzyl-N-methyl-amino)-propyn-l-yl)- 6 7 ,8, 9 tr- ahydro-5H-benzocycloheptene are hydrogenated in 120 ml of ethanol in the presence of 2 g of palladium on active charcoal at ambient temperature and under 5 bar of hydrogen for 7 hours. The filtrate is evaporated down in 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 Yield: 4.55 g (72.1% of theory), Melting point: 94-96'C.
Example G 0 0~0 00 2,3-Dimethoxy-7-hydroxy-7- (pyranyl-2--oxy)-propyn- 0 l-yl)-6,7,8,9-tetahydro-5H-benzocycloheptene Prepared from 2,3-dimethoxy-6,7,8,9-tetrahydro-5Hbenzocyclohepten-7-one and 3-(pyranyl--2-oxy)-propyne .0,00analogously to Example B.
Yield: 96.5% of theory, o 0.67 (aluminium oxide, mobile phase: ethyl acetate).
Example H 2,3-Dimethoxy-7-methoxy-7- (pyranyl-2-oxy)-propyn- 1-yl) 8, 4.7 g (13 mmol) of 2,3-dimethoxy-7-hydroxy-7-(3-(pyranyldissolved in 80 ml of tetrahydrofuran, are added dropwise at -30*C to a solution of 8.7 ml (13.9 mmol) *"jm 'uim~ lrOl- Pi i ur i li~l ui Wir- uu ^rm jyn. 41 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 0 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 0 C for one hour and at 50 0 C for one hour. It is poured onto saturated sodium chloride solution and extracted with diethyl ether. The organic phase is washed with water, 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 Yield: 3.5 g (72.0% of theory), Melting point: 67-72 0
C.
nope o e c 0 00 Example I
O
o 0 j 00 sod Io
I
20 2,3-Dimethoxy-7-methoxy-7-(3-chloro-propyn-l-yl)- 6,7,8,9-tetrahydro-5H-benzocycloheptene A solution of 3.25 g (8.68 mmol) of 2,3-dimethoxy- 7-methoxy-7-(3-(pyranyl-2-oxy)-propyn-1-yl)-6,7,8,9tetrahydro-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 in vacuo is purified on 350 g of aluminium oxide (neutral, activity II-III) using methylene chloride and 50% cyclohexane.
Yield: 2.0 g (74.6% of theory), Melting point: 66-70 0
C.
Example J 2,3-Dimethoxy-7-(3-(pyranyl-2-oxy)-propyn-1-yl) 8,9-dihydro-5H-benzocvcloheptene -42- Prepared from 2,3-dimethoxy-7-hydroxy-7- (pyranyl- 2-oxy) -propyn-l-yl) heptene and methanesuiphonyl chloride in pyridine at 45 0
C.
Yield: 68.2% of theory, RF:0.62 (aluminium oxide, mobile phase: methylene chloride) Example K 2, 3-Dimethoxy-6, 7-epoxy-7- (pyranyl-2-oxy) -propynl-yl) -6,7,8,9-tetrahydro--5H-benzocycloheptene 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- 2--oxy)-propyn---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 0 25 product is purified on 1600 g of aluminium oxide 0 (neutral, activity II-III) using methylene chloride.
Yield: 9.3 g (33% of theory), R f: 0.48 (aluminium oxide, mobile phase: methylene chloride) 0 30 Example L 2, 3-Dimethoxy-7- (pyranyl-2-oxy) -propyn-1-yl) 6.7,8, 9-tetrahydro-511-benzocyclohep2ten-6-one 9.25 g (25.8 mmol) of 2,3-dimethoxy-6,7-epoxy-7- (pyranyl-2-oxy) -propyn-l-*yl) 9-tetrahydroare dissolved in 700 ml of -4 43 toluene and stirred with 2 g (10.5 mmol) of p-toluenesulphonic 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 in vacuo, and the crude product is purified on 1000 g of aluminium oxide (neutral, activity II-III) using cyclohexane and methylene chloride (50/50).
Yield: 1.9 g (20.5% of theory), R f: 0.64 (aluminium oxide, mobile phase: methylene chloride and 3% ethanol) 200 00 .0 0 04 0 0. Ot00 0 0 00 0 Example M 2, 3-Dimethoxy-7- (3-methanesulphonyloxy-propyn-lyl) 7,8, 9 -tetrahydro-5H-benzocyclohepten-6-one Prepared from 2,3-dimethoxy-7- (pyranyl-2-oxy) propyn-l-yl) 8, 6-one and methanesulphonyl chloride in pyridine at 45 0
C.
Yield: 12.7% of theory.
Example N 2, 3-Dimethoxy-7-[3- (N-methyl-N-(2- 4-dimethoxyphenyl) -ethyl) -amino) -propyn-1-yll 7, 8,9-tetrahydro- 5H--benzocyclohepteri-6-one kf.ftk loam 30 Prepared from 2,3-dimethoxy-7- (3-methanesuiphonyloxypropyn-1-yl) 6 7 ,8, 9 6-one and two equivalents of N-methyl-N-(2-(3,4dimethoxy-phenyl)-ethyl)-amine at 80 0
C.
Yield: 7.0% of theory.
S- 44 Example 1 S2,3-Dimethoxy-7-[3-(N-methyl-N-(3-phenyl-propyl)amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride 3.2 g (0.0079 mol) of 2,3-dimethoxy-7-hydroxy-7- S(3-(N-cinnamyl-N-methyl-amino)-propyn-l-yl)-6, 7 8 9 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 0 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 oBoo phase is dried over magnesium sulphate, and the o crude product obtained by evaporation down in vacuo o is purified on 280 g of aluminium oxide (neutral, 20 activity II-III) using methylene chloride. The hydrochloride is subsequently precipitated using o ethyl acetate/ethereal hydrochloric acid.
Yield: 1.77 g (51.9% of theory), Melting point: 159-160.5 0
C
S 25 Calculated: C 72.28 H 8.87 N 3.24 Cl 8.21 Found: 72.40 8.82 3.19 8.36 Example 2 2,3-Dimethoxy-7-[3-(N-methyl-N-(2-(3,4-dimethoxyphenyl)-ethyl)-amino)-propyn-1-yl]-8,9-dihydro- 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- (3,4-dimethoxy-phenyl)-ethyl)-amino)-propyn-1-yl]- 6,7,8,9-tetrahydro-5H-benzocycloheptene in 15 ml of pyridine, and the mixture is then stirred at 0 C for 2 hours. The crude product obtained by evaporation down in 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, activity II-III) using methylene chloride and increasing proportions of ethanol (up to Yield: 0.66 g (60.6% of theory), Calculated: C 74.45 H 7.64 N 3.22 Found: 74.30 7.49 3.02 Example 3 2,3-Dimethoxy-7-hydroxy-7-[3-(N-cinnamyl-N-methyla o amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride 1.0 g (0.003 mol) of 2,3-dimethoxy-7-hydroxy-7- S" [3-(N-methyl-amino)-propyl]-6,7,8,9-tetrahydro- 0.5 g (0.003 mol) of cinnamyl chloride and 0.34 g (0.003 mol) of triethylamine are heated at 80 0 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 in 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.
Yield: 300 mg (24% cf theory), Melting point: 234 0
C
Calculated: C 70.01 H 8.14 N 3.14 Cl 7.95 Found: 69.86 8.25 3.16 8.00 46 Example 4 2,3-Dimethoxy-7-hydroxy-7-[3- (N-methyl-N-(3-(4bromo-phenyl)-propyl)-amino)-propyl]-6,7,8,9-tetrahydro- 5H--benzocycloheptene hydrochloride Prepared from 3- (4-bromo-phenyl)-1-bromo-propane and 2,3-dimethoxy-7-hydroxy-7-113-(N-methyl-amino)propyl] 7, 8,9-tetrahydro-5H-benzocycloheptene an alogousy to Example 3.
Yield: 25% of theory, Melting point: 174 0
C
Calculated: C 59.26 H 7.08 N 2.66 Cl 6.73 Br 15.17 Found: 60.04 7.18 2.78 6.43 14.94 Example 4 Do p '4 CCCI 0 41.) 0
C.
0 1.' 4 CC CCC' 0)4 Cl p PC. r.c, 4 o 4 CC CC CC 4 Cl 1.14 4 C, 4 44 44 CC 2, 3-Dimethoxy-7-methoxy-7-[3- (N-methyl-N- (3,4dimethoxy-phenyl) -ethyl) -amino) -propyn-l-yl] 8,9- 20 1.75 g (5.67 mmol) of 2,3-dimethoxy-7-methoxy-7- (3-chloro-propyn-l-yl) 7,8, heptene and 2.21 g (11.3 mmol) of N-methyl-2-(3,4- 25 dimethoxy-phenyl)-ethylamine are heated at for 1.5 hours. The cooled crude product is purified on 400 g of aluminium oxide (neutral, activity II-III) using methylene chloride and increasing proportions of ethanol (up to Yield: 2.4 g (90.6% of theory), Melting point: 67-70 0
C,
Calculated: C 71.92 HI 7.98 N 3.00 Found: 71.80 7.88 3.00 -47 Examp Le 6 0 08 08 8 8 8 88 8 86.8888 6 8 888418 18 6. 6.
2, 3-Dimethoxy-7-hydroxy-7-[3- (N-methyl-N- (3trifluoromethanesulphonyloxy-phenyl) -ethyl) -amino) 7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride g (0.0024 mol) of 2,3-dimethoxy-7-hydroxy-7- (N-methyl-N- (3-hydroxy-phenyl) -ethyl) -amino) propyl]-6,7,8,9-tetrahydro-5-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 in 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.
20 Yield: 490 mg (97% of theory), Melting point: 160'C, Calculated: C 53.65 H 6.06 N 2.41 Cl 6.09 S 5.51 Found: 53.53 6.08 2.55 6. 28 5.80 Example 7 a) N-(3-(2,3-Dimethoxy-7-hydroxy-6,7,8,9-tetrahydrozocyclohepten-7-yl) -propyl) -N-methyl-3 ,4dimethoxy-cinnamide 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 0 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 9-te-trahydro-SIJ-benzocycloheptene, 48and 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.
Yield: 1.3 g (45% of theory), Melting point: 145-146 0
C,
RF: 0.6 (aluminium oxide, mobile phase: 5% ethanol in methylene chloride).
b) 2,3-Dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(3,4dimethoxy-cinnamyl)-amino)-propyl]-6,7,8,9-tetrahydrohydrochloride n o 1.3 g (0.0027 mol) of N-(3-(2,3-dimethoxy-7-hydroxy- 0.o 6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-propyl)- N-methyl-3,4-dimethoxy-cinnamide, dissolved in S° 10 ml of dry tetrahydrofuran, are added dropwise S 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 Oo 25 mixture is cooled in ice and 0.1 ml of water, 0.1 ml °oo of 15% sodium hydroxide solution and 0.3 ml of o water are successively added dropwise. The precipitate is suction filtered and washed with tetrahydrofuran, and the filtrate is evaporated down in vacuo.
The crude product is purified on 160 g of aluminium Soxide (neutral, activity II-III) using methylene chloride, and then the hydrochloride is precipitated using ethereal hydrochloric acid in acetone.
Yield: 80 mg of theory), Melting point: 199 0
C,
Calculated: C 66.45 H 7.97 N 2.77 Cl 7.01 Found: 66.30 8.81 2.89 7.05 tA~t..J V u i i lu I*L VV.A. S-L 49 Example 8 2,3-Dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3,4dimethoxy-phenyl)-ethyl)-amino)-propyn-1-yl]-6,7,8,9- 3.8 ml of tetrahydrofuran are added dropwise at 0 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 0 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 0o are added dropwise. After 30 minutes at about 0 C, 15 ml of 10% ammonium chloride solution are added, the mixture is extracted with diethyl ether, 0 and is washed with 50% saturated potassium carbonate solution and with water. The organic phase is dried over magnesium sulphate and evaporated down o in vacuo. The resulting crude product is purified 0 25 on 400 g of aluminium oxide (neutral, activity So II-III) using methylene chloride and, subsequently, increasing proportions of ethanol (up to 3%) Yield: 2.27 g (59.0% of theory), Melting point: 114-117 0
C,
Calculated: C 71.50 H 7.78 N 3.09 Found: 71.40 7.55 2.86 Example 9 2,3-Dimethoxy-7-hydroxy-7-[3-((N-cinnamyl-N-methyl)amino)-propyn-l-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride Prepared from (N-cinnamyl-N-methyl-amino) ]-prop- I l-yne and 2, 3-dimethoxy-6, 7, 8,9-tetrahydro-5H-benzocyclohepten-7-one analogously to Example 8.
Yield: 39% of theory, Melting point: 214'C, Calculated: C 70.65 H 7.29 N 3.16 Cl 8.02 Found: 70.53 7.43 2.98 8.28 Example 00 0 00.000 *0 0 0 0. 0 0 2,3-Dimethoxy-7-hydroxy-7-173-(N-methyl-N-(2-(3,5dimethoxy-phenyl) -ethyl) -amino) -propyn--yll-6,7,8,9- Prepared from 2,3-dimethoxy-6,7,8,9-tetrahydro- 5H-benzocyclohepten-7-one and 3-(N-methyl-N-(2- (3,5-dimethoxy-phenyl) -ethyl) -amino) -propyne analogously to Example 8.
Yield: 42.7% of theory, Melting point: 112-113'C, Calculated: C 71.50 H 7.78 N 3.09 Found: 71.30 7.80 2.88 Example 11 2,3-Dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(4benzyloxy-phenyl) -ethyl) -amino) -propyn-1-yl] -6,7,8,9- Prepared from 2,3-dimethoxy-6,7,8,9-tetrahydro- 5H-benzocyclohepten-7-one and 3- (N-methyl-N-(2- (4-benzyloxy-phenyl) -ethyl) -amino) -propyne analogously to Example 8.
Yield: 81-8% of theory, Melting point: 86-88 0
C,
Calculated: C 76.92 H 7.46 N 2.80 Found: 76.76 7.46' 2.81 0 05) o 0 0 00 0 0 0 1 0 0 00 0 00 0 0 0 0 0 04 P0 0 0 0 0 0 0 4 0 040 o a o o o CO D 6 0.
t0 1o r
D
.s 51 Example 12 2,3-Dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(4methoxy-phenyl)-ethyl)-amino)-propyn-l-yl]-6,7,8,9- Prepared from 2,3-dimethoxy-6,7,8,9-tetrahydro- 5H-benzocyclohepten-7-one and 3-(N-methyl-N-(2- (4-methoxy-phenyl)-ethyl)-amino)-propyne analogously to Example 8.
Yield: 64.4% of theory, Melting point: 101-104 0
C,
Calculated: C 73.73 H 7.85 N 3.31 Found: 73.69 8.02 3.55 Example 13 2,3-Dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(4methoxy-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro- 20 5H-benzocycloheptene oxalate 3.3 g (0.008 mol) of 2,3-dimethoxy-7-hydroxy-7- [3-(N-methyl-N-(2-(4-methoxy-phenyl)-ethyl)-amino)propyn-1-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene 25 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, activity II-III) using methylene chloride and increasing proportions of ethanol (up to Subsequently, the oxalate is precipitated with oxalic acid in ethyl acetate/diethyl ether.
52 Yield: 1.64 g (73.9% of theory), Melting point: greater than 40'C (sintering), Calculated: C 64.97 H 7.59 N 2.71 Found: 65.00 7.72 2.52 Example 14 a 0 a a 0 00 0 0 0 a CO 0 3 0 o 0 0 00 0 o 00 0 00 2z3pimethoxy-7-hydroxy-7-[3- (N-methyl-N- hydroxy-phenyl) -ethyl) -amino) -p:ropyll-6,7,8, 9-tetrahydro- 5H-benzocycloheptene oxalate Prepared from 2,3-dimethoxy-7-hydroxy-7-113-(N-methyl- N- (4-benzyloxy-phenyl) -ethyl) -amino) -propyn- 1-yl]-5,6, 8,9-tetrahydro-benzocyuloheptene analogously to Example 13.
Yield: 81.3% of theory, Calculated: C 72.61 H 8.53 N 3.99 Found: 72.49 8.79 3.74 R :0.28 (aluminium oxide, mobile phase: 3% of ethanol in methylene chloride) Example 2, 3-Dimethoxy-7-[3- (N-methyl-N- (4-methoxy-phenyl) 25 ethyl)-amino)-propyl]-6,7,8,9-tetrahydro-5H-belzocycloheptene hydrochloride 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 2,3dimethoxy-7-[3- (N-methyl-N- (4-methoxy-phenyl) ethyl)-amino)-propylidene]-5,6,8,9-tetrahydro-benzocycloheptene analogously to Example 16.
Yield: 55.6% of theory, Melting point: 158-160*C, Calculated: C 69.70 H 8.55 N 3.13 Cl 7.91 Found: 68.95 8.60 3.17 7.40 -53- Example 16 2,3-Dirnethoxy-7-[3- (N-methyl-N- (3,4-dimethoxyphenyl) -ethyl) -amino) -propyl]-6,7, 8, 9-tetrahydro- 5H-benzocycloheptene hydrochloride 1.65 mg (3.75 mmol) of a mixture of the isomers 2,3-dimethoxy-7-[3-(N-methyl-N-(2- 4-dimethoxyphenyl) -ethyl) -amino) -propyl] heptene and 2,3-dimethoxy-7-[3-(N-methyl-N-(2-(3,4dimethoxy-phenyl) -ethyl) -amino) -propylidene] -6,7,8,9are hydrogenated in 20 ml of ethanol in the presence of 0.2 g of palladium on active charcoal at ambient temperature and under 5 bar of hydrogen for 7 hours. The filtrate is evaporated down in. vacuo, and the hydrochloride g is precipitated with acetone/ethereal hydrochloric acid.
4, 0 Yield: 0.85 g (47.5% of theory), o 20 Melting point: 155-.156'C, Calculated: C 67.83 H 8.43 N 2.93 Cl 7.42 Found: 67.85 8.33 2.97 7.76 04,04,Example 17 0 0: K. 25 2,3-Dimethoxy-7-hydroxy-7-[3-(-methyl-N-.(2-(3, dirnethoxy-phenyl)-eth d)-amino)-propyl]-6,7,8,9o Prepared from 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-
N-(
2 3 4 -dimethoxy-phenyl)-ethyl)-amino)-propyn- 1-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene analogously to Example 13.
Yield: 60.6% of theory, Melting point: 91 0
C,
Calculated: C 70.87 H 8.59 N 3.06 Found: 70.87 8.46 2.92 54 Example 18 2, 3-Dimethoxy-7-[3--(N-methyl-N-(2-(3-methoxy-]phenyl)ethyl) -amino) -propyl] heptene hydrochloride Prepared from the mixture of isomers 2,3-dimethoxy- (N-methyl-N- (3-methoxy-phenyl)-ethyl)-amino)propyl]-8 ,9-dilhydro-5H-be nzocycloheptene and 2,3dimethoxy-7-[3- (N-methyl--N- (3-mrethoxy-phenyl) ethyl)-amino)-propylidenejj-5,6,8,9-tetrahydro-benzocycloheptene analogously to Example 16.
Yield: 76.9% of TCheory, melting point: 164-165'C,, Calculated: C 69.70 H 8.55 N 3.13 Cl 7.91 Found: 69.63 8.53 3.11 8.02 00:0 Example 19 2, 3-Dimethoxy-7-[3- (N-methyl-N- (4-hydroxy-phenyl) 00 20 ethyl)-amTIno)-propylll-6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride Prepared from ti-ie mixture of isomers 2,3-dimethoxy- 7-13-(N-methy.-N-(2-(4-hydroxy-phenyl)-ethyl)-amino)propyl]-8,9-dihydro-5H-benzocycloheptene and 2,3dimethoxy-7-[ 3- (N-methyl-N- (4-hydroxy-phenyl) ethyl) -aminio) -propylidene 1-5, 6, 8,9-tetrahydro-benzocycloheptene analogously to Example 16.
Yield: 55.8% of theory, Melting point: 204-206'C, Calculated: C 69.18 H 8.36 N 3.23 Cl 8.17 Found: 68.98 8.57 3.03 8.28 Example 2, 3,7-Trimethoxy-7-[3- (N-methyl-N-(2--(3,4-dimethoxyphenyl) -ethyl) -amino) -propyl] 7, 8,9-tetrahydrohydrochloride 55 Prepared from 2,3,7-trimethoxy-7-[3- (N-methyl-N- 4-dimethoxy-phenyl) -ethyl) -amino) -propynl-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride analogously to Example 13.
Yield: 83.1% of theory, Melting point: 135-137*C, Calculated: C 66.18 H 8.33 N 2.76 Cl 6.98 Found: 66.36 8.18 2.81 6.92 Example 21 2 ,3-Dimethoxy-7-[3-(N-methyl-N-(2-(4-fluoro-phenyl).
ethyl) -amino) -propyl] 8, heptene hydrochloride Prepared from 2, 3-dimethoxy-7- (N-methyl.-amino) propyl) C and 2-(4-fluorophenyl)-ethyl methanesulphonate analogously to Example 3.
Yield: 30.3% of theory, o Melting point: 122-124'C, o o Calculated: C 68.87 H 8.09 N 3.21 Cl 8.13 Found: 68.75 8.18 3.12 8.15 04 25 Example 22 2 ,3-Dimethoxy-7-hydroxy-7-[3-(N-methyl-N o benzyloxy-phenyl) -ethyl) -amino) -propyl] -6,7,8,9hydrochloride Prepared from 2,-iehx--yroy7(-(-ehl amino) -propyl) 8, 9 and 2- (4-ben zyloxy-phenyl) -ethyl methanesulphonate analogously to Example 3.
Yield: 30.1% of theory, Melting point: 170-171*C, Calculated: C 71.18 H 7.84 N 2.59 Cl 6.57 Found: 70.93 7.91 2.57 6.67 -56 Example 23 2,3-Dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(4amino-3, 5-dichioro-phenyl) -ethyl) -amino) -propyl] 56,7, 8, 9-tetrahydro-5H-benzocycloheptene oxalate Prepared from 2,3-dimethoxy-7-hydroxy-7-.(3- (N-methylamino) -propyl) -6 8,9-tetrahydro-5H-benzocycloheptene and 2-(4-amino-3,5-dichloro-phenyl) -ethyl bromide analogously to Example 3.
Yield: 36.8% of theory, Melting point: greater than 75 0 C (decomposition), Calculated: C 56.74 H 6.35 N 4.90 Cl 12.41 Found: 56.57 6.58 4-74 12.59 Example 24 2,3-Dimethoxy-7-hydroxy-7-[3-(N-nethvl-N-(3-.(4- -propyl) -amino) -propyl]- 6,7,8,9-tetrahydro-5H-benzoc yclohe ptene oxalate Prepared from 2,3-dimethoxy-7-hydroxy-7-(3-(N-methylamino) -propyl) -6 8,9-tetrahydro-5H--benzocycloheptene and 3- (4-amino-3, 5-dibromo-phenoxy) -propyl chloride analogously to Example 3.
Yield: 44.9% of theory, Melting point: greater than 80'C (decomposition), oCalculated: C 48.71 R 5.55 N 4.06 Br 23.15 Found: 48.59 5.70 3.91 23.42 Example 2, 3-Dimethoxy-7-hydroxy-7-[ 3- (N-methyl-N- (4cyano-phenyl) -propyl) -amino) -propyl] 9-tetrahydro- Prepared from 2, 3-dimethoxy--7-hydroxy-7-(3- (N-methylamino)-propyl) 6 ,7, 8 9 -57and 3-(4-cyano-phenyl)--propyl bromide analogously to Example 3.
Yield: 86.2% of theory, Melting point: 79-81'C, Calculated: C 74.28 H 8.31 N 6.42 Found: 74.23 8.19 6.52 Example 26 2,3-Dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(4nitro-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro- Prepared from 2,3-dimethoxy--7-hydroxy-7-(3-(N-methylamino)-propyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene and 2-(4-nitro-phenyl)-ethyl bromide analogously to Example 3.
0 00 Yield: 46.3% of theory, Calculated: C 67.85 H 7.74 N 6.33 Found: 67.75 7.98 6.55 RF: 0.25 (aluminium oxide, mobile phase: cyclohexane o 50% ethyl acetate) Example 27 2,3-Dimethoxy-7-[3-(N-methyl-N-(3-(4-amino-3,5dibromo-phenoxy)-propyl)-amino)-propyl]-6,7,8,9hydrochloride Prepared from 2,3-dimethoxy-7-(3-(N-methyl-amino)propyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene mawand 3- (4-amino-3 ,5-dibromo-phenoxy) -l-chloropropane analogously to Example 3.
Yield: 21.8% of theory, Melting point: 80'C (decomposition), 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 -58 Example 28 ,3-Dimethoxy-7-[3- (N-methyl-N- (3-(3,4-methylenedioxyphenoxy)-propyl)-amino)-propylij-6,7,8,9-tetrahydro- 51-benzocycloheptene hydrochloride Prepared from 2, 3-dimethoxy-7- (N-methyl-amino) propyl) 7,8, and 3- 4-methylenedioxy-phenoxy) -1-chioropropane analogously to Example 3.
Yield: 21.1% of theory, Melting point: 146-147'C, Calculated: C 65.90 H 7.78 N 2.85 Cl 7.21 Found: 65.90 7.91 2.70 7.39 Example 29 2, 3-Dimethoxy-7-[3-(N-methyl-N- (3-methyl-phenoxy) propy )-amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocyclo- 2 0 he ptene hydrochloride Prepared from 2,3-dimethoxy-7-(3-(N-methyl-amino)propyl) 8, and 3-(3-methyl-phenoxy) -1-chioropropane analogously to Example 3.
2L Yield: 9.7% of theory, 4. Melting point: 126-127'C, Calculated: C 70.18 H 8.73 N 3.03 Cl 7.67 Found: 69.97 8.81 2.93 7.54 Example 2 ,3-Dimethoxy-7-[3-(N-methyl-N-(2-(4-trifluoronethanesulphoxY-phenyl) -ethyl) -amino) -propyl] -6,7,8,9tetrahydro-5H-benzocycloheptene hydrochloride Prepared from 2,3-dimethoxy-7-[3- (N-methyl-N- (2- (4-hydroxyphenyl) -ethyl) -amino) -propyl] -6,7,8,9- 0020 00 0 0 59 tetrahydro-511-benzocycloheptene and trifluoromethanesuiphonyl chloride analogously to Example 6.
Yield: 76.4% of theory, Melting point: 144-146*C, Calculated: C 55.16 H 6.23 N 2.47 Cl 6.26 Found: 55.16 6.39 2.32 6.15 Example 31 2, 3-Dimethoxy-7-[3- (N-methyl-N- (4-methanesulphonyloxyphenyl) -ethyl) -amino) -propyl] 9-tetrahydrohydrochloride Prepared from 2, 3-dimethoxy-7- (N-methyl-N- (2- (4-hydroxy-phenyl) -ethyl) -amino) -propyl] -6,7,8,9and methanesulphonyl chloride analogously to Example 6.
Yield: 73.2% of theory, Melting point: 162-164'C, Calculated: C 60.98 H 7.48 N 2.74 Cl 6.92 Found: 60.83 7.47 2.63 6.96 Example 32 2, 3-Dimethoxy-7-[ 3- (N-methyl-N- (4-hydroxy-3methoxy-phenyl) -ethyl) -amino) -propyl] 9-tetrahydro- Prepared from 2,3-dimethoxy--7-hydroxy-7-[3-(N-methyl- N- (4-benzyloxy-3-methoxy-phenyl) -ethyl) -amino) propyn-l-yl] 8, analogously to Example 1.
Yield: 67.2% of theory, Melting point: 479C, Calculated: C 73.04 H 8.72 N 3.28 Found: 73.10 8.68 3.51 Example 33 2, 3-Dimethoxy-7-hydroxv-7-[3- (N-methyl-N- (3,4methylenedioxy-phenoxy) -propyl) -amino) -propyn-l- Prepared from 3- (N-methyl-N- 4-methylenedioxyphenoxy) -propyl) -amino) -propyne and 2, 3-dimethoxy- 6 7 8 ,9-tetrahydro-5H-benzocyclohepten-7-one analogously to Example 8.
Yield: 30% of theory, Calculated: C 64.34 H 6.80 N 2.78 Cl 7.03 Found: 64.25 6.79 2.57 7.04 Example 34 2, 3-Dimethoxy-7-hydroxy-7-[3- (N-methyl-N- (3,4methylenedioxy-phenoxy)-propyl)-amino) -propyl]- 6, 7, 8,9-tetrahydr2-5H-benzocycloheptene hydrochloride Prepared from 2 3 -dimethoxy-7-hydroxy-7-[3-(N-methyl- N 3 3 4 -methylenedioxy-phenoxy)-propyl)-amino)propyn-l-yl] 7, 8, 9 analogously to Example 13.
18% of theory, 4 4 Melting point: 167 0
C,
Calculated: C 63.83 H 7.54 N 2.76 Cl 6.98 Found: 63.72 7.66 2.79 7.02 Example ethyl)-amino) -propyne and 2, 3-dimethoxy-6,7, 8,9- -61 tetrahydro-5H-benzocyclohepten-7-one aniogously to Example 8.
Yield: 42% of theory, Melting point: 231*C, Calculated: C 67.03 H 6.98 N 3.13 Cl 7.91 Found: 66.88 7.17 2.98 8.17 Example 36 2,3-Dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(4fluoro-phenyl)-ethyl)-amino)-propyll-6,7,8,9-tetrahydro 51-benzocycloheptene hydrochloride 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 I -Arto Example 13.
Yield: 28% of theory, Melting point: 178*C, Calculated: C 66.43 H 7.58 N 3.10 Cl 7.84 Found: 66.30 7.74 2.94 8.01 2,3-Dimethoxy-7-hydroxy-7-[3--(N-methVl-N-(2-(3methoxy-phenyl)-ethyl)-amino)-propyn-1-yl]-6,7,8,9hydrochloride Prepared from 3- (N-methyl-N- (3-methoxy-phenyl) ethyl)-amino)-propyne and 2,3-dimethoxy-6,7,8,9tetrahydro-5H-benizocyclohepten-7-one analogously to Example 8.
Yield: 40% of theory, Melting point: 187'C, Calculated: C 67.89 H 7.45 N 3.04 Cl 7.71 Found: 67.92 7.61 3.03 7.97 -62 Example 38 2, 3-Dimethoxy-7-hydroxy-7-[3- (N-methyl-N- (3methoxy-phenyl) -ethyl) -amino) -propyl] 8,9-tetrahydro- 5H-benzocycloheptene hydrochloride Prepared from 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl- N- (3-methoxy-phenyl) -ethyl) -amino) -propyn-1yl] 7, 8,9-tetrahydro-5H-benzocycloheptene analogously to Example 13.
Yield: 65% of theory, Melting point: 149-150 0
C,
Calculated: C 67.29 H 8.25 N 3.02 Cl 7.64 Found: 67.44 8.39 3.04 7.76 o 0 Example 39 00 0 2,3-Dimethoxy-7-hydrox-7-[3-(N-methyl-N-(3-(3,4- 000000 o oo dimethyl-phenoxy) -propyl) -amino) -propyn-1-yl] 7, 8,9- 20 o aPrepared from 3- (N-methyl-N- (3,4-dimethyl-phenoxy) propyl)-amino)-propyne and 2,3-dimethoxy-6,7,8,9o 00 tetrahydro-5H-benzocyclohepten-7-one analogously 00 00 25to Example 8.
0 0 Yield: 58% of theory, Melting point: 99-100'C, Calculated: C 74.47 H 8.26 N 3.10 Pound: 74.70 8.23 3.10 4 Example 2,3-Dimethoxy-7-hydroxy-7-13-(N-methyl-N-(3-(3,4dimethyl-phenoxy) -propyl) -amino) -propyl] 7,8,9tetrahydro-5H-benzocycloheptene hydrochloride Prepared from 2, 3-dimethoxy-7-hydroxy-7-[ 3- (N-methyl- N- 4-dimethyl-phenoxy) -propyl) -amino) -propyn- 63 l-yl] 8, 9-tetrahydro-5H-benzoc ycloheptene analogously to Example 13.
Yield: 63% of theory, Melting point: 179*C, Calculated: C 68.34 H 8.60 N 2.85 Cl 7.21 Found: 68.21 8.70 2.85 7.42 Example 41 2,3-Dimethoxy-7-hydroxy-7-[3-(N-methlyl-N-(3-(3methoxy-phenoxy) -propyl) -amino) -propyn-l-yl] 8,9hydrochloride Prepared from 3- (N-methyl-N- (3-methoxy-phenoxy) 00 propyl)-amino)-propyne and 2,3-dimethoxy-6,7,8,9- 00 tetrahydro-5H-benzocyclohepten-7-one analogously 001111 to Example 8.
0 0 Olo ".O0Yield: 28% of theory, 00 Melting point: 168*C, 0 0Calculated: C 66.18 H 2.86 N 7.40 Cl 7.24 Found: 66.01 2.76 7.37 7.31 000 ooExample 42 00 00 04-25 2, 3-Dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(3-(3methoxy-phenoxy) -propyl) -amino) -propyl] 8,9hydrochloride Prepared from 2, 3-dimethoxy-7-hydroxy-7- (N-methyl- N-(3-(3-methoxy-phenoxy)-propyl)-amino)-propynl--yl]-6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride analogously Example 13.
Yield: 41% of theory, Melting point: 168'C, Calculated: C 65.64 H 8.16 N 2.83 Cl 7.18 Found: 65.55 8.02 2.69 7.25 64 Example 43 2,3-Dimethoxy-7-hydroxy-7-[3- (N-methyl-N-(2-(3benzyloxy-phenyl) -ethyl) -amino) -propyn-l-yl] -6,7,8,9tetrahydro-5H-benzocycloheptene hydrochloride Prepared from 3- (N-methyl-N- (3-benzyloxy-phenyl) ethyl)-amino)-propyne and 2,3-dimethoxy-6,7,8,9tetrahydro-5H-benzocyclohepten-7-one analogously to Example 8.
Yield: 36% of theory, Melting point: 188-189'C, Calculated: C 71.69 H 7.14 N 2.61 Cl 6.61 Found: 71.58 7.28 2.61 6.67 000 0Example 44 0 2,3-Dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3- 0 0 enzyloxy-phenyl)-ethyl)-amino)-propen-1-ylJ-6,7,8,9- 0 00 tetrahydro-5H-benzocycloheptene drclie (0002 ol)of 2,3-dimethoxy-7-hydroxy-7propyn-l-yl]-6,7, 8,9-tetrahydro-5-H-benzocycloheptene .25 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 36C g of aluminium oxide (neutral, activity !I-III) using methylene chloride and increasing proportions of ethanol (up to Subsequently the hydrochloride is precipitated in acetone with ethereal hydrochloric acid.
Yield: 180 mg (19% of theory), Melting point: 165-166*C, Calculated: C 71.44 H 7.31 N 2.60 Cl 6.59 Found: 71.36 7.49 2.70 6.77 Example 2, 3-Dimethoxy-7-hydroxy-7 (N-methyl-N- (3hydroxy-phenyl)-ethyl)-amino)-propyl]-6,7, 8,9-tetrahydro- Prepared from 2, 3-dimethoxy-7-hydroxy-7-[3- (N-mtethyl- N- (3-benzyloxy-phenyl) -ethyl) -amino) -propyn- 1-yl]-6,7,8, 9-tetrahydro-5H-benzocycloheptene analogously to Example 13.
Yield: 50% of theory, Calculated: C 72.61 H 8.53 N 3.39 Found: 72.44 8.51 3.29 RF: 0.33 (aluminium oxide, mobile phase: 5% ethanol inmethylene chloride) Example 46 o000 o a 2,3-Dimethoxy-7-hydroxy-7-:[3-(N-methyl-N-(2-(3methanesulohonyloxy-phenyl) -ethyl) -amino) -propyl] 6,7, 8,9-tetrahydro-5H-benzocycloheptene hydrochloride 0 o0 0 Prepared from 2, 3-dimethoxy-7-hydroxy-7- (N-methyl- 0 00 N-(2-(3-hydroxy-phenyl)-ethyl)-amino)-propyl]-6,7,8,9- 0,25 tetrahydro-5H-berizocycloheptene and methanesulphonyl chloride analogously to Example 6.
Yield: 20% of theory, Melting point: 146-148'C, 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 U.09 Example 47 2, 3-Dimethoxy-7-hydroxy-7-[3- (N-methyl-- (2-phenylethyl) amino) -propyn-1-yl] -6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride Prepared from 3-[N-methyl-N- (2-phenylethyl) -amino]propyne and 2,3-dimethoxy-6, 7,8,9-tetrahydro-SE- -66 benzocyclohepten-7-one analogously to Example 8.
Yield: 97% of theory, Melting point: 217*C, Calculated: C 69.83 H 7.50 N 3.26 Cl 8.25 Found: 69.79 7.68 3.17 8.20 Example 48 2,3-Dimethoxy-7 -hydroxy-7-[3-(N-methyl-N---(2-phenylethyl) amino) -propyl] 8, hydrochloride Prepared from 2,3-dirnethoxy-7-hydroxy-7-[3- (N-methyl- N- (2-phenylethyl) -amino) -propyn--l-yl] 8, 9-tetrahydro- 0~01~5H-benzocycloheptene analogously to Example 13.
Yield: 47% of theory, Melting point: 194-195'C, Calculated: C 69.18 H 8.36 N 3.23 Cl 8.17 000Found: 69.00 8.29 3.21 8.25 0 Example 49 0 40 0 2, 3-Direthoxy-7-hydroxy-7-[3- (N-methyl-N- (3-phenylpropyl) amino) -propyn-1-yl] Prepared from 3-(N-methyl-N-(3-phenylpropyl)-amino)propyne and 2,3-dimethoxy-6,7,8,9-tetrahydro-5Hbenzocyclohepten-7-one analogously to Example 8.
Yield: 76% of theory, Melting point: 184-195'C, Calculated: C 70.33 H 7.72 N 3.15 Cl 7.99 Found: 70.26 7.84 3.04 8.08
M
67 Example 2,3-dimethoxy-7-hydroxV-7-[3-(N-mlethyl-N-(3-phenfllpropyl)amino) -propyl] 8, hydrochloride Prepared from 2, 3-dimethoxy-7-hydroxy-7-[ 3- (N-methyl- N- (3-phenyipropyl) -amino) -propyn-l-yl] -6,7,8,9analogously to Example 13.
Yield: 40% of theory, Melting point: 187'C, Calculated: C 69.70 H 8.55 N 3.13 Cl 7.91 Found: 69.65 8.68 2.97 8.06 000~15 0 Example 51 0 2,3-Dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3- 0 0methyl-phenvl) -ethyl) -amino) -propyn-l-yl] 8,9tetrahydro-5H-benzocycloheptene hydrochloride P Prepared from 3- (N-methyl-N- (3-methyl-phenyl) 0 o:ethyl) -amino) -propyne and 2,3-dimethoxy-6,7,8,9tet rahydr o-5H- ben zoc yclohept en-7 -one analogously to Example 8.
0 0 Yield: 57% of theory, Melting point: 185-186'C, Calculated: C 70.33 H 7.72 N 3.15 Cl 7.99 Found: 70.18 7.66 3.07 8.05 Example 52 2, 3-Dimethoxy-7-hydroxy-7-[ 3- (N-methyl-N- (3methyl-phenyl)-ethyl)-amino)-propyl]-6,7,8,9-tetrahydro- 5H-benzocycloheptene hydrochloride Prepared from 2, 3-dimethoxy-7-hydroxy-7- (N-methyl- N- (3-methyl-phenyl) -ethyl) -amino) -propyn-l-yl] -68- 6,7,8, 9-tetrahydro-5H-benzocycloheptene analogously to Example 13.
Yield: 42% of theory, Melting point: 169*C, Calculated: C 69.70 H 8.55 N 3.13 Cl 7.91 Found: 69.56 8.58 3.22 7.94 Example 53 2,3-Dimethoxy-7-[3-(N-m-thyl-N-(2-(3,4-dimethoxVphenyl) -ethyl) -amino) -propyl] 9-tetrahydro- 511-ben zocyclohepten-6-one Prepared from 2,3-dimethoxy-7-[3-(N-methyl-N-(2- 3 4 -dimethoxy-pheny)-ethyl)-amino)propyn1yl..
6,7,8,9-tetrahydro 5H-benzocyclohepten-6-one and hydrogen analogously to Example 13.
Yield: 22.4% of theory -1 IN IR spectrum (KBr): CO 1725 cm (C=O) M:455 o Example 54 2 ,3-Direthoxy-7-[3-(N-methyl-Nl-(2-(4-benzyloxyphenyl)-ethyl)-amino)propyl'6,7,8,9tetrahydrohydrochloride Prepared from 2,3-dimethoxy-7-[3-(N-methy1-amino)propyl] 8, and 2 -(4-benzyloxy-phenyl)-ethyl methanesulphonate analogously to Example 3.
Yield: 47.4% of theory Melting point: 160-161*C.
-69 Example 7-Hydroxy-7--[3-(N-methyl-N-(2-(3,4-dimethoxy-phelyl)ethyl) -amrino) -propyn-l-yl] 8, ~benzocycloheptene Prepared from 3-(N-methyl-N-(2-(3,4-dimethoxy-phelyl)ethyl)-amino)-propyne and 6,7, 8,9-tet'-rahydro-5Hbenzocyclohepten-7-one analogously to Example 8.
Yield: 56.2% of theory, Melting point: 85-89*C.
Example 56 7-H-ydroxy-7--[3- (N-methyl-N-(2- (3,4-dimethoxy-phenyl)ethyl) -amino) -propyl]l-6, 7, 8,9-tetrahydro-5H-benzocycloheptene hydrochloride Prepared from 7-hydroxy-7-[3-(N-methyl-N-(2-(3,4dimethoxy-phenyl)-ethyl)-amino)-propyn-l-yl]- 6 7 8 9 analogously to Example 13.
Yield: 64.6% of theory, Melting point: 147-148'C.
Example 57 (N-Methyl-N- 4-dimethoxy-phenyl) -ethyl) amino) -propyl] hydrochloride Prepared from the mixture of isomers 7-[3-(N-methyl- N- 4-dimethoxy-phenyl) -ethyl) -amino) -propyl] 8, 9-dihydro-5H-benzocycloheptene and 3- (N-methyl- (3,4-dimethoxy-phenyl)-ethyl)-amino)-propylidene]- 5,6,8,9-tetrahydro-benzocycloheptene analogously to Example 16.
Yield: 52.8% of theory, Melting point: 141-142*C.
70 Example I Tablets each containing 10 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 1 tablet contains: Active substance Maize starch Lactose Polyvinylpyrrolidone Magnesium stearate 10.0 mg 57.0 mg 48.0 mg 4.0 mg 1.0 mg 120.0 mg 0 0 o 0 0 0 0 0 0 0 0 0 0 a 0 0 0 0 0000 H' o 4 0 00 0. 0 0 0 i00< 00 44 O O 0 a a 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 0 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.
Example II Coated tablets each containing 5 mg of 2,3-dimethoxy- 7-[3-(N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)amino)-propyll-6,7,8,9-tetrahydro-5H-benzocycloheptene 1 tablet core contains: Active substance 5.0 mg Maize starch 41.5 mg Lactose 30.0 mg Polyvinylpyrrolidone 3.0 mg Magnesium stearate 0.5 mg 80.0 mg 71 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 0 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.
15 Example III o 0 0 o 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-benzocycloheptene o Each ampoule contains: Active substance 5.0 mg SSorbitol 50.0 mg S Water for injections ad 2.0 ml 0 o The active substance is dissolved in water for A injections in a suitable batch vessel, and the e solution is made isotonic with sorbitol.
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.
Example
IV
Suppositories each containing 15 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 72 Each suppository contains: Active substance 0.015 g Hard fat Witepsol H 19 and W 45) 1.685 g 1.700 g The hard fat is melted. Ground active substance is homogeneously dispersed in the melt at 38 0
C.
The mixture is cooled to 35 0 C and poured into slightly precooled suppository moulds.
Example V Dropping solution containing 10 mg of 2,3-dimethoxy- 5 7-[3-(N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)- Oo 0 amino)-propyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene 100 ml of solution contain: S° Active substance 0.2 g 20 Hydroxyethylcellulose 0.15 g Tartaric acid 0.1 g Sorbitol solution, 70% dry matter 30.0 g SGlycerol 10.0 g q Benzoic acid 0.15 g o 1,25 Distilled water ad 100 ml Distilled water is heated to 70 0 C. It is stirred 9 while hydroxyethylcellulose, benzoic acid and tartaric Sacid 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.
I

Claims (3)

1. Compounds of formula I (wherein -s 0 0 0 090 0a 0 0 00' 04 0 0l X 1 represents a hydrogen atom, X 2 represents a hydrogen atom, and X 3 represents a hydrogen atom or a hydroxyl or a Cl_ 3 alkoxy group, or X 1 and X 3 together represent a carbon-carbon bond and X 2 represents a hydrogen atom, or X 1 and X 2 together with the intervening carbon atom, represent a carbonyl group and X 3 represents a hydrogen atom; Al represents a straight-chain C3_ 4 alkylene group optionally substituted by C 1 3 alkyl group and in which any ethylene moiety bonded to the benzocyclo- heptene ring can be replaced by an ethenylene or ethynylene moiety; A 2 represents a straight-chain C2- 5 alkylene group optionally substituted by a C 1 3 alkyl group and in which any ethylene moiety bonded to a radical R 4 wherein n is zero can be replaced by an ethenylene moiety; R 1 represents a hydrogen or a halogen atom or a trifluoromethyl, nitro, amino, C-3alkylamino, di(C 1 _3alkyl)amino, C1-3 alkyl, hydroxyl, C 1 3 alkoxy, or phenyl(C 1 3 alkoxy) group, and
74- R 2 represents a hydrogen or halogen atom or a hydroxyl, C 1 3 alkoxy, or phenyl(C 1 3 alkoxy) or C 1 3 alkyl group, or R, and R2together represent a C- lyeeix group; Rrepresents a hydrogen atom, a C13alkyl group or a C 3 5 alkenyl group; R 4 represents a group R -to) n-. R *7 n is 0 or 1; R 5 represents a hydrogen or halogen atom or a C 1 3 a 0o 013 00,3alkyl, nitro, amino, C 1 3 alkylamino, di(C 1 3 alkyl) amino, C 2 3 alkanoylamino, (C 1 3 alkoxy)carbonyl- 0amino, (C 1 alkyl)sulfonylamino, bis(C 1 alkylsulfonyl)- 1- 1- amino, N-(C 1 3 alkyl)- (C 1 3 alkyl)sulfonylamino, cyano, (C 13alkyl)mercapto, (C 1 3 alkyl)sulfinyl or (C 1 3 alkyl)sulfonyl group or a hydroxyl group optionally substituted by a C 1 alkyl, phenyl(C 1 alkyl) 2-hydroxyethyl, 3-hydroxy-n-propyl, 2-hydroxy- n-propyl, (C 1 alkyl)sulfonyl, cyano(C 3 alkyl), (C 3 alkoxy)carbonyl, hydroxycarbonyl(C 1 alkyl), (C -3alkoycrol(1- alkyl) trifluoromethyl, difluoromethyl or trif'Luoromethylsulfonyl group, and R 6 represents a hydrogen or halogen atom or a C 1 3 alkyl, hydroxyl, C 3 alkoxy, cyano or trifluoromethyl group, 75 or R 5 and R 6 together represent a C 1 2 alkylenedioxy group; and R 7 represents a hydrogen or halogen atom or a C 1 3 alkyl or C 1 3 alkoxy group) the enantiomers theret, the diastereomers thereof and the acid addition salts thereof. 2. Compounds as claimed in claim 1 being compounds of formula I wherein X 1 represents a hydrogen atom, X 2 represents a hydrogen atom and X 3 represents a hydrogen atom or a hydroxyl or methoxy group, or o X 1 and X 3 together represent a carbon-carbon bond S"oo' and X 2 represents a hydrogen atom, or o 0o0 X 1 and X 2 together with a intervening carbon atom, o .o represent a carbonyl group and X 3 represents a o hydrogen atom; o A1 represents an n-propylene group in which an 0 o ethylene moiety bonded to the cycloheptene ring can be replaced by an ethenylene or ethynylene ".0o moiety; A A 2 represents an ethylene or n-propylene group or an n-propylene group in which an ethylene moiety I a bonded to a group R 4 wherein n is zero is replaced by an ethenylene moiety; R 1 represents a hydrogen atom or a methyl or methoxy group; R 2 represents a hydrogen atom or a methyl or methoxy group; lap i--e 1 Y~ 1 it .~II_ 76 R 3 represents a methyl group; n is 0 or 1; R 5 represents a hydrogen, fluorine, chlorine or bromine atom or a hydroxyl, methoxy, cyano, methyl, nitro, amino, methylsulphonyloxy, trifluoromethyl- sulphonyloxy or benzyloxy group; R 6 represents a hydrogen, chlorine or bromine atom or a methoxy group; and R 7 represents a hydrogen, chlorine or bromine atom; and the enantiomers thereof, the diastereomers thereof, and the acid addition salts thereof. 3. Compounds as claimed in either one of claims 1 and 2 being compounds of formula I *o «o wherein: X 1 and X 2 represent hydrogen atoms and X 3 represents S0 a hydrogen atom or a hydroxyl group, or 0 0 t X 1 and X 3 together represent a carbon-carbon bond 0"44 and X 2 represents a hydrogen atom, or X 1 and X2, together with the intervening carbon atom, represent a carbonyl group and X 3 represents Ssa a hydrogen atom; R 1 represents a methoxy group; R 2 represents a methoxy group; R 3 represents a methyl group; A 1 represents an n-propylene group; 77 *2 represents an ethylene or n-propylene group; *represents a methoxy or mehlupoyoygroup; *6 represents a hydrogen atom or a methoxy group; R represents a hydrogen atom; and n is 0 or 1; and the enantiomers thereof, the diastereomers thereof, and the acid addition salts thereof. 4. A compound as claimed in any one of claims 1 to 3 being: 2,3-dimethoxy-7-[3- (N-methyl-N- (3,4-dimethoxy- phenyl) -ethyl) -amino) -propyll 8, 9-tetrahydro- zocycloheptene, 2, 3-dimethoxy-7-[3- (N-methyl-N- (4-methoxy-phenyl) ethyl) -amino) -propyl] 7, 8 a; heptene, 2, 3-dimethoxy-7-[3- (N-methyl-N- (3-methoxy-phenyl) 4 ethyl)-amino).-propyl]-6,7,8,9-tetrahydro-5H-benzocyclo- heptene, 2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3- methoxy-phenyl) -ethyl) -amino) -propyl] 7,8, 9-tetrahydro- 2, 3-dimethoxy-7-hydroxy-7-[3- (N-methyl-N- (3- methoxy-phenoxy) -propyl) -amino) -propyl] -6,7,8,9- or 2, 3-dimethoxy-7-hydroxy-7- [3 (N-methyl-N- (3- methanesulphonyloxy-phenyl) -ethyl) -amino) -propyl] 6, 7, 8,9-tetrahydro-5H-benzocycloheptene, propyne and 2,3-dimethoxy-6,7,8,9-tetrahydro-5H- i 78 or an the enantiomer thereof, a diastereomer thereof or an acid addition salt thereof. 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- or an enantiomer thereof, a diastereomer thereof, or an acid addition salt thereof. 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. 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. 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: reacting a compound of formula II t R 1 R A2~ A 2z R 1 1 2X3 j T 3 (II) X 1 X 2 with a compound of formula III Z2 A R (III) 2 2 4 (in which R 1 R 2 R 4 A 2 X 1 X 2 and X3 are as defined in any one of claims 1 to 111i r- i i 79 one of the groups Z 1 and Z 2 represents an R 3 -NH group, where R 3 is as defined in any one of claims 1 to 5, and the other one of the groups Z 1 and Z 2 represents a nucleophilic leaving group); (to prepare compounds of formula I in which X 3 represents a hydrogen atom) catalytically hydrogenating a compound of formula IV R A -N-A2-R X 4 (IV) X 1 X 2 (in which R1, R 2 R 3 R 4 X1' X 2 and A 2 are as defined in any one of claims 1 to 5, and X 4 represents a hydroxyl group and Al" represents a moiety A 1 as defined in any one of claims 1 to or X 1 and X 4 together represent a carbon-carbon bond and Al" represents a moiety A 1 as defined in any one of claims 1 to 5, or X 4 and Al" together represent a straight-chain C 3 -4 alkanylylidene group optionally substituted by a C-_ 3 alkyl group and in which any ethanylylidene moiety bonded to the benzocycloheptene ring can be replaced by an ethenylylidene moiety); (to prepare compounds of formula I in which X 1 and X 3 together represent a carbon- carbon bond) eliminating a moiety HZ 3 from a compound of formula V ~IE~assa~a~ 80 R R 3 (V) A 3-N-A 2 -R 4 R 2 (in which R 1 R 2 R3' R 4 A 1 and A 2 are as defined in any one of claims 1 to 5, and Z 3 represents a leaving group); (to prepare compound of formula I in which X 3 represents a hydroxyl group) reacting a compound of formula VI R 1 1 and R2 are as defined in any one of claims 1 to 5) with a compound of formula VII M-A0 0-NR -A -R 0 o (VII) (in which R RV Aand A2 are as defined in any one of claims 1 thy~ claims 1 to 5, and M represents an alkali metal atom or an MgHal group, where Hal represents a chlorine, bromine or iodine atom); (e to 5) (to prepare compounds of formula I in which represents an alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulphonylamino, bis(alkyl- sulphonyl)amino, N-alkyl-alkylsulphonylamino alkyl (VII) (in which "i R 3 c R 4 A 1 and A 2 are as defined in any one of claims 1 to 5, and M represents an alkali metal atom or an MgHal group, where Hal represents a chlorine, bromine or iodine atom); (to prepare compounds of formula I in which R 5 represents an alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulphonylamino, bis (alkyl- sulphonyl)amino, N-alkyl-alkylsulphonylamino, alkyl- 81 mercapto, alkoxy, alkoxycarbonyloxy, hydroxycarbonyloxy, alkoxycarbonylalkoxy, phenylalkoxy, trifluoromethoxy, difluoromethoxy, cyanoalkoxy, alkylsuiphonyloxy or trifluoromethylsulphonyloxy group) reacting a compound of formula VIII R, R3 A 1 -N-A 2 -R 4 R 2(VIII) 3 (in which S00:00 Rl, R R A, Xl' X 2 and X 3 are as defined 0 in any one of claims 1 to 5, and 0. 4 represents a group 0 R a R 6 0 000 0. 00 R RR *a0 R6' R 7 and n are as defined in any one of claims 0 1 to 5, and R 8 represents a hydroxyl, amino or C 1 3 alkylamino group) with a compound of formula IX Q Z 4-R (IX) (in which Z 4 represents a nucleophilic leaving group, and R 9 represents a C 1 3 alkyl, C 2 3 alkanoyl, (C 1 3 alkoxy)carbonyl, hydroxycarbony),(C 1 3 alkyl), (C]I. 3 alkoxy)carbonyl(C 1 3 alkyl), (C 1 3 alkyl)sulphonyl, phenyl (C 1 3 alkyl1), trifluoromethyl, difluoromethyl or cyano(C 1 3 alkyl) group); IvIelLIlly PUILIL; Lq-L--Lq4 I
82- reducing a compound of formula X R R3 A 1 -N-C-A z R 4 R2 L 1 4 (X) x 3 X 1 H (in which R 1 R 2 R 3 R 4 X 1 and X3 are as defined in any one of claims 1 to 5, and A 2 represents a straight-chained C 1 4 alkylene group optionally substituted by a C 1 3 alkyl group); n (to prepare compounds of formula I in which a 0 A1 represents a straight-chain C3_ 4 alkylene group optionally substituted by a C-_ 3 alkyl group and in which an ethylene moiety bonded to the benzocyclo- oo heptene ring may be replaced by an ethenylene moiety) catalytically hydrogenating a compound of formula XI o o R R s a 1 1 R A I -N-A2-R4 (XI) 44 *2 3 Xl X2 ago@ (in which R 1 ,R 2 R 3 R 4 A 2 X 1 X 2 and X 3 are as defined in any one of claims 1 to 5, and A 1 represents a straight-chain C3_ 4 alkylene group optionally substituted by a C 1 3 alkyl group and in which an ethylene moiety bonded to the benzocyclo- heptene ring is replaced by an ethenylene or ethynylene moiety); -83- eliminating any protective group used to protect a reactive group in any of reaction steps to debenzylating a compound of formula I in which R 5 represents a benzyloxy group to produce the corresponding hydroxy compound; resolving a compound of formula I which contains at least one chiral centre into its diastereomers or into its enantiomers; and 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. 9. A process as claimed in claim 8 wherein the reaction is carried out in a solvent. 0 Q 0ao o 0 e" 0 e 10. A process as claimed in either one of claims 8 and 9 wherein the reaction of step is carried out in the presence of an acid-binding agent. 0 i) o° 11. A process as claimed in either of claims 8 and 9 wherein the reaction of step is carried out at a temperature of between 0 and 150 0 C. S12. A process as claimed in either one of claims k" 8 and 9 wherein the catalytic hydrogenation of step or is carried out in the presence of platinum, palladium/charcoal or Raney nickel. 13. A process as claimed in either one of claims 8 and 9 wherein the catalytic hydrogenation of step is carried out in the presence of an acid. CzILL.LII) -PLUPyLJ- -0 1 -LeranyarO-bH-ben zOcclOheptene lll IllI.. i- -84 14. A process as claimed in either one of claims 8 and 9 wherein the catalytic hydrogenation of step or is carried out at a temperature of between 0 and 80 0 C. A process as claimed in either one of claims 8 and 9 wherein the reaction of step is carried out in the presence of an acid-binding agent or an acid. 16. A process as claimed in either one of claims 8 and 9 wherein the reaction of step is carried out at a temperature of between 0 and 100 0 C. a a 17. A process as claimed in any one of claims So 8, 9, 15 and 16 wherein a resulting mixture of isomers is fractionated by chromatography. 18. A process as claimed in either one of claims 8 and 9 wherein the reaction of step is carried out under an inert gas and at a temperature of between 0 and 50 0 C. j 19. A process as claimed in either one of claims I s 8 and 9 wherein the reaction of step is carried out in the presence of an acid-activating agent or a water-abstracting agent., A process as claimed in either one of claims 8 and 9 wherein the reaction of step is carried out at a temperature of between -25 and +250 0 C. 21. A process as claimed in either one of claims 8 and 9 wherein the reduction of step is carried out with a metal hydride or with a complex of borane and a thioether. I 85 22. A process as claimed in either one of claims 8 and 9 wherein the reduction of step is carried out at a temperature of between 0 and 23. A process as claimed in any one of claims 8 to 22 wherein the subsequent elimination in step of a protective group is by hydrolysis, or where the protective group is a benzyl group by hydrogenolysis. 24. The use of a compound of formula I as claimed in any one of claims 1 to 5 or of a physiologically "S 8 acceptable acid addition salt thereof for the 0 0000o manufacture of a pharmaceutical agent for the treatment o0oo of the human or non-human animal body to combat ischaemic heart disorders or sinus tachycardias. A method of treatment of the human or non-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. 0o 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. DATED this 17th day of April 1991 DR KARL THOMAE GMBH By his Patent Attorneys CALLINAN LAWRIE
AU31189/89A 1988-03-10 1989-03-10 Benzocycloheptene derivatives Ceased AU612471B2 (en)

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DE3807813A DE3807813A1 (en) 1988-03-10 1988-03-10 NEW BENZOCYCLOHEPEN DERIVATIVES, MEDICAMENTS CONTAINING SUCH COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF
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US7709478B2 (en) 2001-02-13 2010-05-04 Sanofi-Aventis Deutschland Gmbh Acylated 6,7,8,9-tetrahydro-5H-benzocycloheptenyl amines and their use as pharmaceutical agents

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SE467076B (en) * 1989-06-16 1992-05-18 Gunnar Martin Natanael Staalma SET AND DEVICE FOR THEORETARY PROOF
SE9103745D0 (en) * 1991-12-18 1991-12-18 Wikstroem Haakan ARYL-TRIFLATES AND RELATED COMPOUNDS
EP0920306A2 (en) 1996-07-12 1999-06-09 Leukosite, Inc. Chemokine receptor antagonists and methods of use therefor
DE69839305T2 (en) 1997-02-27 2009-04-09 Takeda Pharmaceutical Co. Ltd. AMIN DERIVATIVES, THEIR PREPARATION AND USE AS INHIBITORS OF THE PRODUCTION OF AMYLOID BETA
ATE413379T1 (en) 2000-04-03 2008-11-15 Takeda Pharmaceutical METHOD FOR PRODUCING AMINE DERIVATIVES
KR100891599B1 (en) * 2003-08-29 2009-04-08 미쓰이 가가쿠 가부시키가이샤 Insecticide for agricultural or horticultural use and method of use thereof
AU2009323259A1 (en) * 2008-12-05 2011-06-23 Astellas Pharma Inc. 2H-chromene compound and derivative thereof
JP6088595B2 (en) 2015-07-24 2017-03-01 ファナック株式会社 Machine tool, partition device, and robot system including partition member that shields part of opening of cover

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US7709478B2 (en) 2001-02-13 2010-05-04 Sanofi-Aventis Deutschland Gmbh Acylated 6,7,8,9-tetrahydro-5H-benzocycloheptenyl amines and their use as pharmaceutical agents

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PH26473A (en) 1992-07-23
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KR890014446A (en) 1989-10-23

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