PH26473A - New benzocycloheptene derivatives and pharmaceuticals containing these compounds - Google Patents

New benzocycloheptene derivatives and pharmaceuticals containing these compounds Download PDF

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PH26473A
PH26473A PH38311A PH38311A PH26473A PH 26473 A PH26473 A PH 26473A PH 38311 A PH38311 A PH 38311A PH 38311 A PH38311 A PH 38311A PH 26473 A PH26473 A PH 26473A
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amino
dimethoxy
methyl
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PH38311A
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Manfred Dr Psiorz
Manfred Dr Reiffen
Andreas Dr Bomhard
Volker Dr Trach
Joachim Dr Heider
Jurgen Dr Dammgen
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Lillie Christian Dr
Kobinger Walter Prof Dr
Thomae Gmbh Dr K
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    • 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
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
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    • 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
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    • 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
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
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    • 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
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    • 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
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    • 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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Description

Mi to i
CL
; wo = i
New_Benzocvcloheptene derivatives. pharmageuticalg containing these compounds. and processes for the preparation thereof.
KEP-A-0177960 describes tetrahydronaphthalenes which are substituted in the 2-position by a hydroxyl . group which is optionally substituted by an acyl radical. These compounds have a pronounced calcium- antagonistic effect and can therefore be used as pharmaceuticals, in particular for combatting and : 190 preventing angina pectoris, ischaemia, arrythmias
M and high blood pressure.
It has now been found, surprisingly, that the new benzocycloheptene derivatives of the formula
R
R 3 n (1) : 1= F=AmRy,
R, « 3 x,
Xy 156 the enantiomers thereof, the diastereomers thereof, . and the acid additions salts thereof, end in particular the physiologically tolerable acid addition salts thereof with inorganic or organic acids, have other valuable pharmacological properties, in particular a heart rate lowering effect and a reduction in the Oy requirement of the heart.
Thus the present invention relates to the new benzocycloheptene derivatives of the above formula 1, the enantiomers thereof, the diastereomers thereof, the acid addition salts thereof, especially for pharmaceutical use the physiologically tolerable acid addition salts with organic or inorganic acids, to processes for their preparation, and to 5 pharmaceuticals containing these compounds.
The unsaturated compounds of formula 1 also serve as intermediates for the preparation of the saturated compounds of formula I.
In the above general formula I xy denotes a hydrogen atom, X denotes a hydrogen . atom, and Xg denotes a hydrogen atom, a hydroxyl or alkoxy group having 1 to 3 carbon atoms or
Xq and Xq together denote another carbon-carbon bond, and Xo denotes a hydrogen atom, or
X41 and Xx, together with the carbon atom located . between them, denote a carbonyl group, and X3 denotes a hydrogen atom,
Aq denotes a straight chain alkylene group which has 3 or 4 carbon atoms and is optionally substituted by an alkyl) group having 1 to 3 carbon atoms and in which an ethylene group which is present in the moiety A; and is linked to the benzocycloheptene ring can be replaced by an ethenylene or ethynylene group,
Ay denotes a straight chain alkylene group which has 2 to 5 carbon atoms and is optionally substituted by an alkyl group having 1 to 3 carbon atoms and in which, if n represents the number ©, an ethylene group which is present in the moiety ay and which is 5 linked to the radical Ry can be replaced by an ethenylene group, t
Ry denotes a hydrogen or halogen atom, a trifluoromethyl, nitro, amino, alkylamino, dialkylamino, alkyl, hydroxyl, alkoxy, or ‘ phenylalkoxy group, ‘ Roy denotes a hydrogen atom or halogen atom, a hydroxyl, alkoxy, phenylalkoxy or alkyl group, or
Ry and R, together denote an alkylenedioxy group having 1 or 2 carbon atoms, . Rg denotes a hydrogen atom, an alkyl group or an alkenyl group having 3 to 5 carbon atoms, and
R4 denotes a group of the formula
Bs
Rg -(0)
Ra where n denotes the number @ or 1,
Rg denotes a hydrogen or halogen atom, an alkyl, © nitro, amino, alkylamino, dialkylsmino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, bis(alkylsulfonyl)- amino, N-alkyl-alkylsulfonylamino, cyano, alkylmercapto, alkylsulfinyl or alkylsulfonyl group or a hydroxyl group which is optionally substituted by an alkyl, phenylalkyl, 2-hydroxyethyl, 3-hydroxy- n-propyl, 2-hydroxy-n-propyl, alkylsulfonyl, cyanoalkyl, alkoxycarbonyl, hydroxycarbonylalkyl, ’ alkoxycarbonylalkyl, trifluoromethyl, difluoromethyl
Ee or trifluoromethylsulfonyl group,
Rg denotes a hydrogen or halogen atom, an alkyl, hydroxyl, alkoxy, cyano or trifluoromethyl group or
Rg and Rg together denote an alkylenedioxy group } having 1 or 2 carbon atoms and
Ry denotes a hydrogen or halogen atom, an alkyl or - 20 alkoxy group, wherein the above mentioned alkyl or alkoxy groups may each contain 1 to 3 carbon atoms and the above mentioned alkanoyl groups may each contain 2 or 3 carbon atoms.
Examples of suitable meanings for the definitions of the groups mentioned hereinbefore are for Ry hydrogen, fluorine, chlorine or bromine atoms or methyl, ethyl, n-propyl, isopropyl,
trifluoromethyl, hydroxyl, methoxy, ethoxy, n- propoxy, isopropoxy, nitro, amino, methylamino, ethylamino, n-propylamino, isopropylamino, dimethylamino, diethylamino, di-—n-propylamino, diisopropylamino, methyl-ethylamino, methyl-n-
19 propylamino, methyl-isopropylamino, ethyl-n-propyl-
\ amino, benzyloxy, l1l-phenylethoxy, 1-phenylpropoxy, ~ 2-phenylethoxy or 3-pheny 1 propoxy groups, - for Ry hydrogen, chlorine or bromine atoms or methyl, ethyl, n-propyl, isopropyl, hydroxyl,
methoxy, ethoxy, n-propoxy, isopropoxy, benzyloxy, 1-phenylethoxy, 2-phenylethoxy, 2-phenylpropoxy, or 3-phenylpropoxy groups, or, together with Ry methylenedioxy or ethylenedioxy groups, for Ry hydrogen atom or methyl, ethyl, n-propyl,
isopropyl, allyl, crotyl, or n-penten-2-yl groups, for Rg hydrogen, fluorine, chlorine, bromine or iodine atoms or methyl, ethyl, n-propyl, isopropyl,
} hydroxyl, methoxy, ethoxy, n-propoxy, isopropoxy, amino, methylamine, ethylamino, n-propylamino,
isopropylamino, dimethylamino, diethylamino, di-n- propylamino, diisopropylamino, methyl-ethylamino,
methyl-n-propylamino, methyl-isopropylamino, ethyl - n-propylamino, acetylamino, propionylamino, methoxycarbonylamino, ethoxycarbonylamino, n-pro- poxycarbonylamino, methylfulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, bis(methylsulfonyl amino, bis(ethylsulfonyl)amino,
N-methyl-methylsulfonylamino, cyano, methylmercapto, ethylmercapto, n-propylmercapto, methylsulfinyl, ethylsulfinyl, isopropylsulfinyl, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, benzyloxy, 1- phenylethoxy, 2-phenylethoxy, 2-phenylpropoxy, 3- rhenylpropoxy, 2-hydraxy-ethoxy, 2-hydroxy-n- propoxy, 3-hydroxy-n-propoxy, methylsulfonyloxy, ethylsulfonyloxy, isopropylsulfonyloxy, methoxy- carbonyloxy, ethoxycarbonyloxy, isopropoxycarbonyl- . oxy, hydroxycarbonylmethoxy, 2-(hydroxycarbonyl)- ethoxy, methoxycarbonylmethoxy, ethoxycarbonyl- methoxy, isopropoxycarbonylmethoxy, 2-{(methoxycar- bonyl )-ethoxy, 2- (n-propoxycarbonyl)-ethoxy, cyano- ’ 20 methoxy, 2-cyanoethoxy, 3-cyano-n-propoxy, difluoro- methoxy, trifluoromethoxy or nitro groups, for Rg hydrogen, chlorine or bromine atoms or : methyl, ethyl, n-propyl, isoprovyl, hydroxyl, methoxy, ethoxy, n-propoxry, isopropoxy, cyano or trifluoromethyl groups, or for Rp and Rg together methylenedioxy or ethyvlenedioxy groups,
for Ry; hydrogen atom or hydroxyl, methoxy, ethoxy, n-propoxy or isopropoxy groups, for Ay n-propylene, l-methyl-n-propylene, 2-methyl- n-propylene, 3-methyl-n-propylene, l-ethyl-n- propylene, 2-n-propyl-n-propylene, 3-ethyl-n- propylene, n-butylene, 1-methyl-n-butylene, l-ethyl- n-butylene, prop-l-enylene, n-but-1i-enylene, 1- ’ methyl-prop-l-enylene, 2-methyl-prop-1l-enylene, 3- methyl-prop-1--enylene, prop-1-ynylene, 3-methyl- prop—-l-ynylene or n-but-ynylene groups and for Ay ethylene, l-methyl-ethyvlene, 1l-ethyl-ethyl- ene, 1-propyl-ethylene, 2-methyl-ethylene, 2-ethyl- ethylene, n-propylene, n-butylene, n-pentylene, 1- methyl-n-propylene, l1-methyl-n-butylene, l-ethyl-n- propylene, 2-ethyl-n-propylene, 1l-ethyl-n-butylene, prop-l-enylene, n-but-l-enylene, n-pent-l-enylene, : 1-methyl-prop-1-enylene, 2-methyl-prop-l1-enylene, 3- methyl-prop—-1-enylene, 4-methyl-n-but-l-enylene or 5-methyl-n-pent—-l1-enylene groups.
In addition to the compounds mentioned in the
Examples, the following compounds which are covered by the above mentioned formula 1 may also be . mentioned by way of example: 2,3-dimethoxy-7-hydroxy-7-{3-(N-(2-(3,4-dimethoxy- phenyl )-ethyl)-amino)-propyn-1-y11-6,7,8,9-tetra- hydro-5H-benzocycloheptene,
2,3 -dimethoxy-7-hydroxy-7-[3-( (N-cinnamyl-N-methyl )- amino )-propyn-1-y11-6,7,8,9-tetrahydro-5H- benzocycloheptene, 2,3-dimethoxy-7-hydroxy-7-{3-(N-(2-(4-benzyloxy-
phenyl)-ethyl)-~amino)-propyn-1-y11-6,7,8,9-tetrahydro-5H- benzocycloheptene, 2,3-dimethoxy-7-hydroxy—-7-{3-(N-(2-(4-methoxy-phenyl)- ethyl )-amino)-propyn-1-y11-6,7,8,9-tetrahydro-5H- benzocycloheptene,
\
2,3-dimethoxy-7-hydroxy—7-{3-(N-(2-(3-methoxy-phenyl)- ethyl )-amino)-propyn-1-y13-6,7,8,9-tetrahydro-5H- benzocycloheptene,
. 2,3-dimethoxy-7-hydroxy-7-13-(N-(3-(3,4-dimethyl- phenoxy )-propyl)-amino )-propyn-1-y11-6,7,8,9-tetra- : 15 hydro-5H-benzocycloheptene, 2,3-dimethoxy-7-hydroxy-7-{3-(N-(3-(3-methoxy- phenoxy )-propyl)-amino)-propyn-1-y11-6,7,8,9-tetra- hydro-5H-benzocycloheptene, 2.3-dimethoxy-7-hydroxy-7-13-(N-(2-(3-benzyloxy- . 29 phenyl )-ethyl)-amino)-propyn-1-y11-6,7,8,9-tetra—- hydro-5H-benzocycloheptene, 2,3-dimethoxy-7-hydroxy-7-[3-(N-(2-(3-benzyloxy- phenyl)-ethyl)-amino)-propyn-1-y11-6,7,8,9-tetra- hydro-5H-benzocyc loheptene,
2,3 -dimethoxy-7-hydroxy-7-13-(N-(2~-phenylethyl)- amino )-propyn-1-v11-6,7,8,9-tetrahydro-5H- benzocycloheptene, 2, 3-dimethoxy-7-hydroxy-7—-[3-(N-(3-phenylpropyl)- amino )-propyn—-1-y11-6,7,8,9-tetrahydro-5H- benzocyc loheptene, 2,3—-dimethoxy-7-hydroxy-7-1{3-(N-(2-(3-methyl-phenyl)- ’ ethyl )-amino)-propyn-1i-y11-6,7,8,9-tetrahydro-5H- benzocycloheptene,
N
2,3-dimethoxy-7-methoxy-7-{3-(N-methyl-N-(2-(3, 4- a dimethoxy-vhenyl )-ethyl })-amino)-propyn-t-y11-6,7,8,9- tetrahydro-bH-benzocycloheptene, 2,3-dimethoxy-7-hydroxy-7—-{3-(N-methyl-N~-(2-(3, 4- dimethoxy-phenyvl )-ethyl )-amino)-propyn-1-y11-6,7,8,9- : 15 tetrahydro-5H-benzocycloheptene, 2,3—-dimethoxy-7-hydroxy-7-13-( (N-cinnamyl-N-methyl )- amino )-propyn-1-y11-6,7,.8,9-tetrahydro~5H- benzocycloheptene, 2,3-dimethoxy-7-hydroxy-7-{3-(N-methyl-N-(2-(3,5- dimethoxy-phenyl)-ethyl)-amino)-propyn-1-y11-6,7,8,9- tetrahydro-5H-benzocycloheptene, 2,3-dimethoxy-7-hydroxy-7-[3—-(N-methyl-N-(2-(4- benzyloxy-phenyl )-ethyl)-amino)-propyn-1-y11-6,7,8,9- tetrahydro-5H-benzocycloheptene,
2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(4- methoxy-phenyl )-ethyl)-amino)-propyn-1-y11-6,7,8,9- tetrahydro-5H-benzocycloheptene,
2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3-
methoxy-phenyl )-ethyl)-amino)-propyn—-1-y11-8,7,8,9- tetrahydro-5H-benzocycloheptene, 2,3-dimethoxy-7-hydroxy-7-13-(N-methyl1-N-(2-(3, 4 dimethyl-phenoxy )-propyl )-amino)-propyn-1-y11-6,7,8,9- tetrahydro-5H-benzocycloheptene, ° -
2,3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(3-(3- methoxy-phenoxy )-ethyl )-amino )-propyn-1-y11-6,7,8,9- tetrahydro-5H-benzocycloheptene, 2,3-dimethoxy-7-hydroxy-7-{3-(N-methyl-N-(2-(3~ benzyloxy-phenyl )-ethyl)-amino)-propyn-1-y11-6,7,8,9-
’ 15 tetrahydro-5H-benzocycloheptene, 2, 3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3- benzyloxy-phenyl)-ethyl)-amino)-propen-1-yl11-6,7,8,9- tetrahydro-5H-benzocycloheptene, 2,3-dimethoxy-7-hydroxy-7-(3-(N-methyl-N-(2-
phenylethyl )-amino)-propyn-1-y11-6,7,8,9-tetrahydro- 5H-benzocycloheptene, 2, 3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(3-phenyl- ‘propyl)—amino)-propyn-1-y11-6,7,8,9-tetrahydro-5H- benzocycloheptene,
2,3-dimethoxy-7-hydroxy-7-f3-(N-methyl-N—(2-(3- methylphenyl)-ethyl)-amino)-propyn-1-y11-6,7,8,9- tetrahydro-5H-benzocycloheptene, 2,3-dimethoxy-7-hydroxy-7-13-(N-ethyl-N-(2-(3, 4- dimethoxy-phenyl)-ethyl)-amino)-propyn-1-y11-6,7,8,9- tetrahydro-5H-benzocycloheptene, 2,3-dimethoxy-7-hydroxy-7-{3-(N-ethy1-N-(2-(3, 4- dimethoxy-phenyl)-ethyl)-amino)-propyn-1-y11-6,7,8,9- tetrahydro-5H-benzocycloheptene, ’ 7-methoxy-7-[3-(N-(2-(3,4-dimethoxy-phenyl )- ethyl)-amino )-propyn-1-y11-6,7, 8, 9- tetrahydro—5H— benzocycloheptene, 7-hydroxy-7-[3-(N-(2-(3, 4-dimethoxy-phenyl )—~ ethyl)-amino)-propyn-1-y11-6,7,8,9-tetrahydro-5H- benzocycloheptene, 7-hydroxy-7-13-(N-(2-(4-benzyloxy-phenyl )-ethyl)- amino )-propyn-1-y11-6,7,8,9-tetrahydro-5H-benzo- cycloheptene, 7-hydroxy~7-[3-(N-(2-(4-methoxy-phenyl )-ethyl )- amino)-propyn-1-y11-6,7,8,9-tetrahydro-5H-benzo- cycloheptene,
T-hydroxy-7-[3-(N-(2-(3-methoxy-phenyl )-ethyl)- amino )-propyn—-1-y11-6,7,8,9-tetrahydro-5H-benzo- cycloheptene,
7 -hydroxy-7-13-(N-(3-(3,4-dimethy1-phenoxy)-propyl)- amino )-propyn-1-y11-8,7,8,9-tetrahydro-5H-benzo- cycloheptene,
7-hydroxy-7-[ 3-(N-(3-(3-methoxy-phenoxy)-propyl )-
amino )-propyn-1-y11-6,7,8,9-tetrahydro-5H-benzo- cycloheptene, 7-hydroxy-7—-[3-(N-(2-(3-benzyloxy-phenyl)-ethyl)- amino )-propyn-1-y11-6,7,8,9-tetrahydro-5H-benzo- cycloheptene,
7-hydroxy-7-13-(N- (2- (3-benzyloxy-phenyl)-ethyl)-
amino )-propen-1-y11-6,7.,8,9-tetrahydro-5H-benzo- cycloheptene, 7-hydroxy—7-[3-(N-(2-phenylethyl)-amino)-propyn-1- } y11-6,7,8,9-tetrahydro-5H-benzocycloheptene,
7-hydroxy-7-13-(N-(3-phenylethyl)-amino)-propyn-1- y11-6,7,8,9-tetrahydro-5H-benzocycloheptene, 7-hydroxy-7-{3-(N-(2-(3-methyl-phenyl)-ethyl)- amino )-propyn-1-y11-6,7,8,9-tetrahydro-bi-benzo- cycloheptene,
© 20 7-methoxy-7~-{3- (N-methyl-N-(2-(3, 4-dimethoxy-phenyl)- ethyl )-amino)-propyn-1-y11-6,7,8,9-tet.rahydro-5H- . benzocycloheptene,
7T-hydroxy-7-1[3-(N-methyl-N-(2-(3,4-dimethoxy-phenyl)- ethyl )-amino)-propyn—-1-y11-6,7,8,9-tetrahydro-5H- benzocycloheptene,
T-hydroxy-7-[3-(N-cinnamyl-N-methyl )-amino )-propyn- 1-v11-6,7,8,9-tetrahydro-5H-benzocycloheptene, 7-hydroxy-7-13-(N-methyl-N-(2-(3,5-dimethoxy-phenyl )- ethyl )-amino)-propyn-1-v11-6,7,8,9-tetrahydro-5H- benzocycloheptene,
T-hydroxy-7-[3-(N-methyl-N-(2-(4-benzyloxy-phenyl )- ethyl)-amino)-propyn-1-y11-6,7,8,9-tetrahydro-5H- benzocycloheptene, t 7-hydroxy—-7—-[3-(N-methyl-N-(2-(3-methoxy-phenyl)—- ethyl )-amino)-propyn-1-y11-6,7,8,9-tetrahydro-5H- benzocycloheptene, 7-hydroxy-T7-[{3- (N-methyl-N-(2-(3-methoxy-phenyl)- } ethyl)-amino)-propyn-1-y11-6,7,8,9-tetrahydro-bH- benzocycloheptene,
T-hydroxy-7-13-(N-methyl-N-(3-(3,4-dimethyl-phenoxy)- propyl )-amino)-propyn-1-y11-6,7,8,9-tetrahydro-5H- benzocycloheptene, 7-hydroxy-7-[3-(N-methyl-N-(3-(3-methoxy-phenoxy)- propyl )-amino)-propyn-1-y11-6,7,8,9-tetrahydro-5H- benzocycloheptene,
7 -hydroxy-7-[3-(N-methy 1-N-(2-(3-benzyloxy-phenyl)- ethyl )-amino)-propyn-1-y11-6,7,8,9-tetrahydro-5H- : benzocycloheptene, 7-hydroxy-7-[ 3- (N-methyl-N-(2-(3-benzyloxy-phenyl)- ethyl)-amino)-propen-1-yl11-6,7,8,9-tetrahydro-5H- benzocycloheptene, 7-hydroxy-7-[3-(N-methyl-N-(2-phenylethyl)~amino)}- propyn-1-y11-6,7,8,9-tetrahydro-5H-benzocycloheptene, ’ 7-hydroxy-7-[3-(N-methyl-N-(3-phenylpropyl)-amino)-
S propyn-1-y11-6,7,8,9-tetrahydro-5Hi-benzocycloheptene, 7-hydroxy-7-13-(N-methyl-N-(2-(3-methyl-phenyl)- ethyl )-amino)-propyn—1-y11-6,7,8,9-tetrahydro-5H- benzocycloheptene, : 7-hydroxy-7-f 3- (N-methyl1-N-(2-(3-methoxy-phenyl)- ethyl)-amino)-propyn-1-y11-6,7,8,8-tetrahydro—6H- . benzocycloheptene, 7-methoxy-T7-[3-(N-allyl-N-(2-(3,4-dimethoxy-phenyl)}- ethyl)-amino)-propyn-1-y11-6,7,8,9-tetrahydro-6H- benzocycloheptene, 7—-hydroxy-T-[3-(N-allyl-N-(2-(3,4-dimethoxy-phenyl)- ethyl )-amino )-propyn-1-y11-6,7,8,9-tetrahydro-5H- benzocycloheptene, oo 15
2,3-dimethoxy-7-hydroxy-7-[3-(N-(3-(3, 4-methylene— dioxy-phenoxy)-propyl)-amino)-propyl]-6,7,8,9— tetrahydro-5H-benzocycloheptene, 2,3-dimethoxy-7-hydroxy-7-[3-(N-(2-(4-fluoro-
phenyl)-ethyl)-amino)-propyl1-6,7,8,9-tetrahydro— 5H-benzocycloheptene, 2,3-dimethoxy-7-hydroxy-7-I 3- (N- (2-(3-methoxy- phenyl )-ethyl-amino)-propyl1-6,7,8,9-tetrahydro-5H— benzocycloheptene,
2,3-dimethoxy-7-hydroxy-7-13-(N-(3-(3,4-dimethyl- phenoxy )-propyl )-amino) propyl 1-6,7,8,9- tetrahydro-
5H-benzocycloheptene, ] 2,3-dimethoxy-7-hydroxy-7-[3-(N-(3-(3-methoxy- phenoxy-propyl)-amino)-propyl1-6,7,8,9-tetrahydro-
5H-benzocycloheptene, 2,3-dimethoxy-7-hydroxy—-7-[ 3~(N-(2-(3-hydroxy- phenyl-ethyl)-amino)-propyl11-6,7,8,9-tetrahydro- 5H-benzocycloheptene, ’ 2,3-dimethoxy-7-hydroxy-7-[ 3-(N-(2- (3-methane-
sulfonyl-oxyphenyl)-ethyl-amino)-propyl1-6,7,8,9-
tetrahydro-5H-benzocycloheptene,
: 2,3-dimethoxy-7-hydroxy-7-(3- (N-(2-phenylethyl- amino )-propyl]-6,7,8,9-tetrahydro-5H-benzocyclo- Co heptene,
2,3-dimethoxy-7-hydroxy-7-{3-(N-(3-phenylpropyl—-
: amino )-propyl]-8,7,8,9-tetrahydro-5H-benzocyclo- heptene, 2,3-dimethoxy-7-hydroxy-7-1 3—(N-(3-methyl-phenyl)- nL ethyl )-amino)-propyl1-6,7,8,9-tetrahydro-5H-benzo- cycloheptene, 2,3-dimethoxy-7-hydroxy-7-{3-(N-(3-methanesulphonyl- amino-phenyl )-ethyl)-amino)-propyl}1-6,7,8,9- tetrahydro-5H-benzocycloheptene,
2,3-dimethoxy-7-hydroxy-7-[3-(N-(2-phenylethyl)- amino )-propyl1-6,7,8,9-tetrahydro-5H-benzocyclo- heptene, 2,3-dimethoxy-7-hydroxy-7-[3-(N-(3-phenylpropyl)- amino )-propyl]1-6,7,8,9-tetrahydro-5H-benzocyclo-
heptene, 2,3-dimethoxy-7-hydroxy-7-[3-(N-(3-chloro-phenyl)- ethyl)-amino)-propyl]1-6,7,8,9-tetrahydro-5H-benzo-
cycloheptene, 2,3-dimethoxy-7-hydroxy-7-[(3-(N-(2-(3-acetylamino)- .
phenyl )-ethyl)—amino)-propyl1-6,7,8,9-tetrahydro- 5H-benzocycloheptene, .
2, 3-dimethoxy-7-hydroxy-7-I 3- (N-(2-(3-amino-phenyl)- ethyl )-amino)-propyl}-6,7,8,9-tetrahydro-5H-benzo- cycloheptene,
2,3-dimethoxy-7-hydroxy-7-13-(N-methyl1-N-(3-(3,4- methylenedioxy-phenoxy)-propyl )-amino)-propyl]- 6,7,8,9-tetrahydro-5H-benzocycloheptene, 2,3-dimethoxy-7-hydroxy-7-[3—-(N-methyl-N-(2-(4-
fluoro-phenyl )-ethyl )-amino)-propyl11-6,7,8,9-
’ tetrahydro-5H-benzocycloheptene, 2,3-dimethoxy-7-hydroxy~-7-F3- (N-methyl -N-(2Z2-(3- methoxy-phenyl)-ethyl)-amino)-propyl1-6,7,8,9- tetrahydro-5H-benzocycloheptene,
.
2,3-dimethoxy-7-hydroxy-7-[3- (N-methy1-N-(3-(3, 4~- dimethyl-phenoxy )-propyl)-amino)-propyl 1-6,7,8,9- tetrahydro-5H-benzocycloheptene, 2,3-dimethoxy-7-hydroxy-7-13-(N-methy1-N-(3-(3- methoxy-phenoxy )-propyl )-amino)-propyl 1-6,7,8,9-
tetrahydro-5H-benzocycloheptene, 2,3-dimethoxy-7-hydroxy-7-13-(N-methyl-N-{2-(3- hydroxy-phenyl )-ethyl )-amino)-propyl1-6,7.,8,9- tetrahydro-5H-benzocycloheptene, 2,3-dimethoxy-7-hydroxy-7-I3-(N-methy1-N-(2-(3-
methane-sulphonyloxy-phenyl )-ethyl)-amino)-propyl ]- 8,7,8,9-tetrahydro-bH-benzocycloheptene, 2,3-dimethoxy-7-hydroxy-7-f3- (N-methy1l-N-(2-phenyl--
ethyl) -amino)-propyl1-6,7,8,9-tetrahyvdro-5H-benzo- cycloheptene, 1R
2, 3-dimethoxy-7-hydroxy-7-[3-(N-methy1l-N-(3- phenylpropyl)-amino)-propyl1-6,7,8,9-tetrahydro- 5H-benzocycloheptene, 2,3-dimethoxy—-7-hydroxy-7—-[3-(N-methyl-N-(2-(3- .
methyl-phenyl)-ethyl)-amino)-propoyl1-6,7,8,9- tetrahydro-5H-benzocycloheptene,
2, 3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3- methane-sul phony lamino-phenyl)-ethyl)-amino)- propyl 1-6,7,8,9-tetrahydro-5H-benzocycloheptene,
2, 3-dimethoxy-7-hydroxy-7-(3-(N-methyl-N-(2- phenylethyl)-amino)-propyl1-6,7,8,9-tetrahydro- 5H-benzocycloheptene,
2, 3-dimethoxy-7-hydroxy-7-{3-(N-methyl-N-(3- phenylpropyl)-amino)-propyl1-6,7,8,9-tetrahydro-
5H-benzocycloheptene,
2, 3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3- chloro-phenyl )-ethyl)-amino)-propyl1-6,7,8,9~ tetrahydro-5H-benzocycloheptene,
2, 3-dimethoxy-7-hydroxy-7-[3-(N-methyl-N-(2-(3-
acetylamino-phenyl)-ethyl)-amino)-propyl 1-6,7,8,9- tetrahydro-5H-benzocycloheptene,
‘2, 3-dimethoxy-7-hydroxy-7-[3- (N-methyl-N-(2-(3- amino-phenyl)-ethyl)-amino)-propyl1-6,7,8,.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-tetrahydro-5H-benzocycloheptene, 2,3-dimethoxy-7-hydroxy-7-(3-(N-ethyl-N-(2-(3- methoxy-prhenyl )-ethyl)-amino)-propy11-6,7,8,9- ‘ tetrahydro-5H-benzocycloheptene, 2,3—-dimethoxy-7-hydroxy-7-[3-(N-allyl-N-(2-(3- methoxy-phenyl )-ethyl )-amino)-propyl1-6,7,8,9- tetrashydro-5H-benzocycloheptene, )) ‘ 10 2,3-dimethoxy-7-hydroxy—-7-{3-(N-allyl-N-(3-(3,4- dimethyl-phenoxy )-propyl )-amino)-propyl1-6,7.8,9- tetrahydro-bH-benzocycloheptene, 2,3-dimethoxy-7-hydroxy-7-{3-(N-allyl-N-(3-(3- methoxy-phenoxy )-propyl )-amino)-propyl1-6,7,8,9- tetrahydro-bH-benzocycloheptene,
T-hydroxy-7-13-(N-(3-(3,4-methylenedioxy-phenoxy)- propyl )-amino)-propyll1-6,7,8,9-tetrahydro-5H- benzocycloheptene,
T-hydroxy-7-{3-(N-(2-(4—f luoro-phenyl )-ethyl)- amino )-propyll1-6,7,8,9-tetrahydro-5H-benzocyclo- . heptene, ’ T-hydroxy-7-[3—(N-(2-(3-methoxy-phenyl )-ethyl)- amino )-propyl]1-6,7.8,9-tetrahydro-5H-benzocyclo- heptene,
2,3 -dimethoxy-7-hydroxy-7-14-(N-(3-(3,4-methylene- dioxy-phenoxy)-propyl )-amino)-butyl11-68,7,8,9- - tetrahydro-5H-benzocycloheptens, 2,3-dimethoxy-7-hydroxy-7—-{4—-(N-{(3-phenylpropyl)- amino )-butyl}-6,7,8,9-tetrahydro-5H-benzocyclo- heptene, 2,3-dimethoxy-7-hydroxy-7-[5-(N-(2-(3-methoxy-pheny)- ethyl)-amino)-pentyl1-6,7,8,9-tetrahydro-5H- benzocycloheptene, 2,3-dimethoxy-7-hydroxy-7-{5-(N-(3-phenypropyl)- amino )-pentyl1-6,7,8,9-tetrahydro-5H-benzocyclo- heptene, 2, 3-dimethoxy-7-hydroxy-7-F5- (N-methyl-N-(3-(3- : methoxy-phenoxy )-propyl )-amino)-pentyl1-68,7,8,9- no 15 tetrahydro-5H-benzocycloheptene, 2,3-dimethoxy-7-{4-(N-(3-(3, 4-dimethoxy—-phenyl)- propyl )-amino)-butyl1-6,7,8,9-tetrahydro-5H- - benzocycloheptene, 2,3-dimethoxy-7-[3-(N-(3-(3,4-methylenedioxy- phenoxy )-propyl )-amino)-propyl1-6,7,8,8-tetrahydro-
BH-benzocycloheptene-6-one, 2, 3-dimethoxy—7-[3~(N-(2-(4-fluoro-phenyl)- ethyl )-amino)-propyl1-6,7,8,9-tetrahydro-5H- benzocycloheptene-6-one,
2,3-dimethoxy-7-[3-(N-(2-(3-methoxy-phenyl)- ethyl )-amino)-propyl1-6,7,8,9-tetrahydro-5H- benzocycloheptene-6-one, 2,3-dimethoxy~-7-{3-(N-(3-(3,4-dimethyl-phenoxy)-
propyl )-amino)-propyll}-6,7,8,9-tetrahydro-5H- benzocycloheptene-6-one, 2,3-dimethoxy-7-{3-(N-(3-(3-methoxy-phenoxy)- propyl )-amino)-propyl1-6,7,8,9-tetrahydro-bH- benzocycloheptene-6-one,
\
2,3-dimethoxy-7-{3-(N-(2-(3-hydroxy-phenyl )-ethyl)- amino)-propyl1-6,7,8,9-tetrahydro-5H-benzocyclo- heptene-6-one, 2,3-dimethoxy-7-[3-(N-(2-({3-methanesulphonyloxy- phenyl )-ethyl )-amino)-propyl1-6,7,8,9-tetrahydro-5H-
benzocycloheptene-68-one, 2,3~dimethoxy-7-13—- (N-(2-phenylethyl )-amino)-propyl]1- 6,7,8,9-tetrahydro-5H-benzocycloheptene-6-one, } 2,3-dimethoxy-7-(3-(N~(3-phenylpropyl )-amino)-propyl}l- 6,7,8,9-tetrahydro-5H-benzocycloheptene-8-one,
2,3-dimethoxy-7-[3-(N-(2-(3-methyl-phenyl )-ethyl)- amino )-propyl1-6,7,8,9-tetrahydro-5H-benzocyclo-
} heptene-6-one, i
. 2.3 -dimethoxy—7-I 3- (N-( 2-( 3-methanesul phony Lamino- . phenyl )-ethyl)-amino)-propyl11-6,7,8,9-tetrahydro-5H- benzocycloheptene—6-one, 2,3-dimethoxy-7-13-(N-(2-phenylethyl)-amino)-propyl]-
6,7,8,9-tetrahydro-5H-benzocycloheptene—-6-one, 2.3-dimethoxy-7-f3-(N-(3-phenylpropyl)-amino)-propyll- 6,7,8,9-tetrahydro-5H-benzocycloheptene-6-one, 2.3-dimethoxy-7-{3-(N-(2-(3-chloro-phenyl)-ethyl)- amino )-propyl1-8,7,8,9-tetrahydro-5H-benzocyclo-
heptene-8-one, oe 2,3-dimethoxy-7-[3-(N-(2-(3-acethylamino-phenyl)- ethyl)-amino)-propyl1-6,7,8,9-tetrahydro-5H- benzocycloheptene-6-one, 2,3-dimethoxy-7-f3-(N-(2-(3-amino-phenyl)-ethyl)-
amino )-propyl}-6,7,8,9-tetrshydro-5H-benzocyclo- heptene-6-one, 2,3-dimethoxy-7-13- (N-methyl-N-(3-(3,4-methylene- dioxy-phenoxy )-propyl)-amino)-propyl1-6,7,8,9- tetrahydro-5H-benzocycloheptene-6-one,
2,3-dimethoxy-7-[3-(N-methyl-N-(2-(4-fluoro-phenyl)-
. ethyl )-amino)-propyl1-6,7,8,9-tetrahydro-5H- benzocycloheptene-6-one,
2,3 -dimethoxy-7-13-(N-methyl1-N-(2~(3-methoxy— phenyl )-ethyl)-amino)-propyl1-6,7,8,9-tetrahydro- 5H-benzocycloheptene—-6-one, 2,3-dimethoxy-7-[3-(N-methyl-N-(3-(3,4-dimethyl-
phenoxy )-propyl )-amino)-propyl1-6,7,8,9-tetrahydro— 5H-benzocycloheptene-6-one, 2,3-dimethoxy-7-{3-(N-methyl-N-(3-(3-methoxy- ’ phenoxy-propyl)—amino)-propyl1-6,7,8,9-tetrahydro-5H- benzocycloheptene—-6-one,
2,3-dimethoxy-7-[3-(N-methyl-N-(2—(3-hydroxy-phenyl )- ethyl)-amino)-propyl1-8,7,8,9-tetrahydro-5H-benzo- cycloheptene-6-one, 2,3-dimethoxy—-7-[3—-(N-methy1l-N-(2-(3-methanesulphon- vl-oxy-phenyl )-ethyl)-amino)-propyl1-6,7,8,9-
tetrahydro-5H-benzocycloheptene-6-one, 2,3-dimethoxy-7-I3—(N-methyl-N-(2~-phenyvlethyl )- amino )-propyl1-6,7,8,9-tetrahydro-5H-benzocyclo- heptene-6-one, 2,3-dimethoxy-7-{3-(N-methyl-N-(3-phenylpropyl )-
amino )-propyl}-6,7,8,9-tetrahydro-5H-benzocyclo~ heptene-6-one,
‘ 2,3-dimethoxy-7-13-(N-methyl-N-(2-(3-methyl- phenyl-ethyl)-amino)-propyl]1-6,7,8,9-tetrahydro-5H- benzocycloheptene—-6-one,
2,3-dimethoxy—-7-[3-(N-methy1-N-(2-(3-methane- sulphonylamino-phenyl)-ethyl)-amino)-propyl]}- 6,7,8,9-tetrahydro-5H-benzocycloheptene-8-one, 2, 3-dimethoxy-7-I 3-(N-methy1l-N-(2-phenylethyl)- amino )-propyll-6,7,8,9-tetrahydro-5H-benzocyclo- heptene—68-one, 2,3-dimethoxy-7-[3-(N-methy 1-N-(3-phenylpropyl)- amino )-propyl1-6,7,8,9-tetrahydro-5H-benzocyclo- heptene-6-one, 19 2, 3-dimethoxy-7-[3-(N-methy1l-N-(2-(3-chloro- phenyl )-ethyl)-amino)-propyl1-6,7,8,9-tetrahydro-
S5H-benzocycloheptene-6-one, 2, 3-dimethoxy-7-[ 3-(N-methyl-N-(2-(3-acetylamino- phenyl )-ethyl)-amino)-propyl1-6,7,8,9-tetrahydro- 5H-benzocycloheptene-6-one, 2, 3-dimethoxy-7-[ 3- (N-methyl-N-(2-(3-amino-phenyl)- ethyl )-amino)-propyl1-6,7,8,9-tetrahydro-5H-benzo- cycloheptene-6-one, 2,3-dimethoxy-7-[3-(N-ethyl-N-(3-(3,4-methylene— dioxy-phenoxy)-propyl )-amino)-propyl1-6,7,8,9- : tetrashydro-5H-benzocycloheptene-6-one, 2,3-dimethoxy-7-13-(N-ethy1-N-(2-(3-methoxy- phenyl )-ethyl)-amino)-propyl1-6,7,8,9-tetrahydro-
S5H-benzocycloheptene-6-one,
2,3-dimethoxy-7-13-(N-allyl-N-(2-(3-methoxy-phenyl )- ethyl )-amino)-propyl1-6,7,8,9-tetrahydro-5H-benzo- cycloheptene—-6-one, 2,3-dimethoxy-7-13-(N-allyl-N-(3-(3,4-dimethyl- phenoxy )-propyl)-amino)-propyl}-6,7,8,9-tetrahydro- 5H-benzocycloheptene-6-one, 2,3-dimethoxy-7-f3-(N-allyl-N-(3-(3-methoxy- phenoxy }-propyl )-amino)-propyl1-6,7,8,9-tetrahydro- . 5H-benzocycloheptene-8-one, 5
T-hydroxy-7-{3-(N-(3-(3, 4-methylenedioxy-phenoxy)—- propyl)-amino)-propyl]1-6,7,8,9-tetrahydro-5H-benzo- cycloheptene—-6-one,
T-hydroxy-7-[3-(N-{(2—-(4-fluoro-phenyl)-ethyl)- amino )-propyl])-6,7,8,9-tetrahydro-5H-benzocyclo- heptene-6-one,
T-hydroxy-7-[3-(N-(2-(3-methoxy-phenyl )-ethyl)- amino )-propyl1-6,7,8,9-tetrahydro-5H-benzocyclo- _ heptene-8-one, and 2,3-dimethoxy-7-[4-(N-(3-(3,4-nethylenedioxy- phenoxy )-propyl )-amino})-butyl3}-6,7,8,9-tetrahydro-
S5H-benzocyclohepten-6-one,
Co the enantiomers thereof, the diastereomers thereof, and the acid addition salts thereof.
Preferred compounds of the above formula I are, oo however, those in which xy denotes a hydrogen atom, Xo denotes a hydrogen atom and X3 denotes a hydrogen atom, a hydroxyl or methoxy group or, xX; and X45 together denote a further carbon-carbon bond, and Xo; denotes a hydrogen atom, or x and Xo, together with the carbon atom located . between them, denote a carbonyl group, and Xg denotes a hydrogen atom,
Ay denotes an n-propylene group in which the ethylene group which is linked to the cycloheptene ring can be replaced by an ethenylene group or ethynylene group,
Ag denotes an ethylene or n-propylene group or an n— propylene group in which, if n represents the number . 9, an ethylene group which is present in the moiety
Ay and which is linked to the radical R4 is replaced by an ethenylene group,
Ry denotes a hydrogen atom, a methyl or methoxy group,
Roy denotes a hydrogen atom, a methyl or a methoxy group,
Rg denotes the methyl group,
n denotes a nimber © or i. .
I; denotes a hydrogen, fluorine, chlorine or bromine atom, a hydroxyl, methoxy, cyano, methyl, nitro, amino, methylsulphonyloxy, trifluoromethylsulphonyl-
Oxy or benzyloxy group,
Rg denotes a hydrogen, chlorine or bromine atom or a methoxy group, and
Ry denotes a hydrogen, chlorine or bromine atom, the enantiomers thereof, the diastereomers thereof, and the acid addition salts thereof.
Particular preferred compounds of the formula I are those in which
Xy denotes a hydrogen atom, Xo denotes a hydrogen atom, and X3 denotes a hydrogen atom or a hydroxyl 15H group, or xX and Xg together denote a further carbon-carbon bond, and xX, denotes a hydrogen atom, or
Xy and Xx, together with the carbon atom located between them, denote a carbonyl group, and x3 denotes a hydrogen atom, ’ Ry denotes a methoxy group,
R, denotes a methoxy group,
Rg denotes a methyl group,
Ay denotes an n-propylene group.
A, denotes an ethylene or n-propylene group,
Re, denotes a methoxy or methylsulphonyloxy group,
Rg denotes a hydrogen atom or a methoxy group,
Ra denotes a hydrogen atom, and n denotes the number @ ovr 1, ’ the enantiomers thereof, the diastereomers thereof, and the acid addition salts thereof.
N
The new compounds according may be obtained according to the invention by the following processes: ’ a) reaction of a compound of formula
R
0 — Ay-24 2 X (II) s 3
X, . Xy with a compound of formula
Zo = An - Ry (111)
in which
Ry, Ry, Ry» Aq, A, and Xy to X3 are as hereinbefore defined, one of the groups Zy or Xx, represents an Rg3-NH group, where Rg is as hereinbefore defined, and the other one of the groups zy or zy represents a nucleovhilic leaving group such as a halogen atom or a sulphonyloxy group, for example a chlorine, bromine or iodine atom, or a methanesulphonyloxy, p-toluene- sulphonyloxy or ethoxygulphonyloxy group.
The reaction is conveninently carried out in a solvent or solvent mixture, such as acetone, diethyl ether, methylformamide, dimethyl formamide, ’ dimethylsulphoxide, benzene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran, dioxane or in an excess of the compounds of formulae I1 and/or
III used, and optionally in the presence of an acid- binding agent, for example, an alcocholate such as . potassium tert._butylate, 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, carbonate, ’ an alkali metal amide such as sodium amide, an alkali metal hydride such as sodium hydride, a tertiary organic base such as triethylamine or pyridine, it also being possible for the latter simultaneously to act as solvent, or of a reaction accelerator such as potassium iodide, depending on the reactivity of the nucleophilically replaceable group, conveniently at temperatures between © and 150°c¢, preferably at temperatures of between 59 and 120°C, for example at the boiling point of the solvent used. However, the reaction can 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 the formula Il or 11] used. .. b) For the preparation of compounds of formula I in which X35 represents a hydrogen atom:
Catalytic hydrogenation of a compound of formula
R
A |’
A ~N-A-R,
R, LK (1V)
X,,
Xa 1 in which
Ry to Ry, Xs i, ay and Ay are as hereinbefore defined but where
Xs must represent a hydroxyl group, or
Xy and X4 together must represent a further carbon- carbon bond, or
X45 together with one hydrogen atom of the adjacent saturated carbon atom of the moiety Ay, must represent a carbon-carbon bond.
The catalytic hydrogenation is preferably carried 190 out in a solvent such as methanol, ethanol, glacial
IE 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 temperatures between @ to 80°C, but preferably at temperatures between ambient temperature and 60°C. 1f Xy denotes a hydroxyl group, the catalytic hydrogenation is carried out in the presence of an . acid.
It is possible in the catalytic hydrogenation for . double or triple bonds which are present simultaneously to be hydrogenated or, where appropriate, benzyl groups which are present to eliminated. c) For the preparation of compounds of formula I in which Xy and Xg represent a further carbon-carbon bond:
Cleavage of a moiety HZ 4 from a compound of the formula 3 12
A,~N-A-R, Vv)
Rj 2 3 . in which
Ry to Ry, Ay and A, are as hereinbefore defined and
Z3 represents a group which can be split off, such . as a hydroxyl, alkoxy, acyloxy or alkylsulphonyloxy group.
The reaction is preferably carried out in a solvent such as ethanol, isopropanol, tetrahydrofuran,
dioxane or pyridine, optionally in the presence of an acid-binding agent such as sodium carbonate or pyridine, or in the presence of an acid such as hydrochloric acid or sulphuric acid, at temperatures between © and 100°C, preferably at temperatures between 20 and 80°C.
A mixture of isomers which may be obtained in this way and which consists of a compound of formula I in which xy and Xg together represent a further carbon- ie carbon bond, and of a compound of formula I in which .
X3, together with one hydrogen atom of the adjacent saturated carbon atom Of the moiety Ay, represents a carbon-carbon bond, is subsequently fractionated by : , chromatography, for example on aluminium oxide (neutral). d) For the preparation of compounds of formula I in which X35 represents the hydroxyl group:
Reaction of a compound of formula
Ry = 0 : i. ] ) (V1) 29 in which
RH, and R, are as hereinbefore defined, with a compound of formula
Me-A|-NRg-8.,-Ry (VIL) in which
R3, R4, Ay and A, are as hereinbefore defined and Me represents an alkali metal atom or a MgHal group, where Hal denotes a chlorine, bromine or iodine atom. 5
The reaction is preterably carried out in a solvent 190 such as diethyl ether, methyl-tert.butyl ether, tetrahydrofuran, dioxane, n-hexane or benzene, optionally under protective gas such as nitrogen or .argon, at temperatures between 0 and 50°¢, but preferably at ambient temperature. e) For the preparation of compounds of formula in which Ry represente an alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulphonyl- amino, bia(alkylsulphonyl)-amino, N-alkyl-alkyl- _ sulphonylamino, alkylmercapto, alkoxy, alkoxy- carbonyloxy, hydroxycarbonylalkoxy, alkoxycar- } bonylalkoxy, vhenylalkoxy, trifluoromethoxy, . difluoromethoxy, cyanoalkoxy, alkylsulphonyloxy or trifluoromethylsulphonyloxy group:
Reaction of a compound of formula
R . we Nee -— t a A, N A, R, 2
Xs
X
2 x \ in which
Ry to Rg, Ay, Ag and Xy to Xq are as hereinbefore defined, and Ry” represents a group of formula
Rg
R
7 -(0)
Rg where Rg» R, and n are as hereinbefore defined, and
Rg represents a hydroxyl, amino or alkylamino group having 1 to 3 carbon atoms, with a compound of formula 24 - Rg (TX)
in which Co
Zy4 denotes a nucleophilic leaving group such as a halogen atom, for example a chlorine, bromine or iodine atom, and .
Rg denotes an alkyl, alkanoyl, alkoxycarbony. hydroxycarbonylalkyl, alkoxycarbonylalkyl, : alkylsulphonyl, phenylalkyl, trifluoromethyl, difluoromethyl or cyanoalkyl group, wherein the above-mentioned alkyl and alkoxy moleties may each contain 1 to 3 carbon atoms and the alkanoyl moiety way contain 2 or 3 carxbon atoms.
The reaction is conveniently carried out in a solvent or solvent mixture such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, ae acetonitrile or dimethylformamide, optionally also in the presence of an acid activating agent, or of a dehydrating agent, for example in the presence of ethyl! chloroformate, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N,N -dicyclo- hexylcarbodiimide, N,N"-dicyclohexylcarbodiimide/N- hydroxysuccinimide, N,N’-carbonyldiimidazole or
N,N“ ~thionyl diimidazole, and optionally in the presence of an inorganic base such as sodium carbonate, or of a tertiary organic base such as triethylamine or pyridine, it also being possible for the two latter simultaneously to act as solvent,
at temperatures between -25 and 250°C, but preferably at temperatures between -10°C and the boiling point of the solvent used.
If Rg in a compound of formula VIII denotes a " hydrogen atom, unless the latter is protected during the reaction by a customary protective group it will be simultaneously replaced by a corresponding Ry. £) Reduction of a compound of formula \
R I’ - -— —- !.. o A, N A, Ry, 2
X
3
H
X
1 (X) in which
Ry to Ry. A, xy and X3 are as hereinbefore defined, and
Ay” represents a straight-chained alkylene group which has 2 to 4 carbon atoms and is optionally substituted by an alkyl group having 1 to 3 carbon atoms, and in which a methylene group tinked to the nitrogen atom of the R3-N group is replaced by a carbonyl group.
The reduction is preferably carried out with a metal : hydride sich as Lithium aluminium hydride or diborane or with a complex composed of borane and a thioether, for example with borane/dimethylsulphide complex, in a suitable solvent such as diethyl ether or tetrahydrofuran, at temperatures between © aud :
Ae°C, but preferably at temperatures between 19 and 45°C. eg) For the preparation of compounds of formula J in which A; represents a straight chain alkylene group which has 3 or 4 carbon atoms and is optionally substituted by an alkyl group having 1 to ] 3 carbon atoms, and in which an ethylene group linked to the benzocycloheptene ring can be replaced by an ethenylene group:
Catalytic hydrogenation of a compound oft formula 1 3 (X1) 2
Xs
X Ya 1 in which
Ry to Ry, A, and x to Rg are as hereinbefore defined, and Ay represents a straight chain alkylene group which has 3 or 4 carbon atoms and is optionally substituted by an alky! group having | to 3 carbon atoms, and in which an ethylene group which is present in the moiety ay’ and is linked to the benzocycloheptene ring is replaced by an ethepvlene or ethynylene group. ‘Ihe catalytic hydrogenation is preferably carried out in a solvent such na wethanol, ethanol, glacial acetic acid, ethyl acetate or dimethyltormomide, using hydrogen at a hydrogen pressure ot 1 to 5H har, preferably of | to 4 bar, in the presence of a hydrogenation catalyst such as platinum, palladium/charconl or Roney mickal, optionally in the presence of an acid such as perchloric acid, at temperatures between © to 807C., but preferably at temperatures oi between ambient temperature and 60°C. :
For the preparstion of compounds of formula [| in which Ay contains a double bond, the catalytic hydrogenation of a compound of formula Xl in which
A” contains a triple bond is preferably carried out in the presence of Raney nickel or a Lindlar catalyst.
Furthermore it is possible in the catalytic hydrogenation for a deuble bond present in the molety Ay to be 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 eliminated again after the reaction. :
Examples of protective groups suitable for a hydroxyl group are trimethylsilyl. acetyl, benzoyl, benzyl or tetrahydropyranyl groups, and examples of protective groups suitable for an imino or amino group are acetyl, benzoyl, ethoxycarbonyl or benzyl } groups.
The subsequent elimination, where appropriate, of a protective group which is used is preferably carried out 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 metal base such as sodium hydroxide or potassium hydroxide, at temperatures between © and 100°C, preferably at the boiling point of the reaction mixture. However, a benzyl group is preferably 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 methenol, ethanol, ethyl acetate or glacial . acetic acid, optionally with the addition of an acid such as hydrochloric acid, at temperatures between © and 50°C, but preferably at ambient temperature, and under a hydrogen pressure of 1 to 7 bar, but preferably of 3 to 5 bar. 1f a compound of the formula | in which Rg represents a benzyloxy group is obtained according to the invention, this can be converted by debenzylation into the corresponding hydroxyl compound.
The subsequent. debenzylation is preferably carried out in a solvent such as water, water/ethanol, methanol, glacial acetic acid, ethyl acetate or dimethylformamide, conveniently with hydrogen in the presence of an hydrogenation catalyst such as Raney nickel, platinum or palladium/charcoal, at . temperatures betwen @ and 950°C, preferably at ambient temperature.
The resulting compounds of the formula 1 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 vhase or by crystallisation using optically active acids, for example using D- or L-monomethyl tartaric acid, D- or LL-diacetyl tartaric acid, D- or L-tartaric acid,
P—- or L-lactic acid, D- or L-camphoric acid, - or }
L-dibenzoyl tartaric acid, D- or L-camphorsulphonic acid or D- or L-camphanic acid. :
The resulting compounds otf the formula 1 can furthermore be converted into their acid addition salts, in particular tor their pharmaceutical use oe into their physiologically tolerable acid addition salts with inorganic or organic acids. Examples of acids suitable in this connection are hydrochiorie acid, hydrobromic acid, sulphuric acid, phosphoric acld, acetic acid, lactic acid, cltric acid, tartaric acid, succinic acid, maleic acid, ftumaric acid or oxalic acid.
The compounds oft formulae 11 to XI used ans starting materials are in part known trom the literature, or 4:3
‘ ¢ to they can be obtained by processes known ver ae.
For example, a starting compound of formula ll is obtained by reaction of a corresponding benzocyclohepten-7-one with an appropriate organometallic compound and, where appropriate, subsequent dehydration and/or hydrogenation. A pyranyl-2-oxy compound which is obtained in this way can, where appropriate, subsequently be converted into a compound of formula 11 in which Z; represents a halogen atom. \
A compound of the forgula IV, V, VIII, X or XI used as starting material is obtained by reaction of a corresponding benzocycloheptene derivative with an appropriate alkyl halide or alkylamine.
As already mentioned in the introduction, the new compounds of formula I and the physiologically tolerable acid addition salts thereof with inorganic ] or organic acids have valuable pharmacological ‘vroperties, in particular, while the central side ] . 20 effects are slight, a heart rate lowering, blood pressure lowering, catt- antagonist and/or - antithrombotic effect and an antiischaemic effect on the heart, and an effect of reducing the 0, ‘ requirement of the heart.
: vo.
The compounds
A = 2,3-dimethoxy-7-13-(N-methyl-N-(2-(3,4-di- methoxy-phenyl)-ethyl)-amino l-propyl1-6,7,8,9- tetrahydro-5-benzocyloheptene,
B = 2,3-dimethoxy-7-{3-(N-methyl-N-(2-(3-methoxy- phenyl )-ethyl )-amino )-propyl}]-6,7,8,9-tetra- hydro-5-benzocyloheptene, ’
C = 2,3-dimethoxy-7-[3-(N-methyl-N-(2-(3-methoxy— phenyl )-ethyl)-amino }l-propyl1-6,7.,8,9-
Sy tetrahydro-5-benzocyloheptene, “>
Db = 2,3-dimethoxy-7-hydroxy-7-(3-(N-methyl-N-(2-(3- methoxy-phenyl )-ethyl )~aminol-propyl1l1-6,7,8,9- tetrahydro-5-benzocyloheptene,
E = 2,3-dimethoxy-7-hydroxy-7-{3-(N-methyl-N-(3-(3- methoxy-phenoxy )-propyl )-amino ]l-propyl11-6,7,8,9- . tetrahydro-5-benzocyloheptene,
F = 2,3-dimethoxy-7-hydroxy-7-{3—-(N-methyl-N-(2-(3- methanesulphonyloxy-phenyl)-ethyl )-aminol-propyl ]- 8,7,8,9-tetrahydro-5-benzocyloheptene © 20 have been investigated for their biological properties, for example, as follows:
Effect on the heart rate or rats
The effect on the heart rate of the substances to be investigated was investigated for each dose on two rats with a mean weight of 250-300 g. For this purpose, the rats were anaesthetised with pentobarbitone (50 mg/kg 1.p. and 10 mg/kg s.c.).
The substances to be investigated were injected in aqueous solution into the jugular vein (0.1 wml/100 g).
The blood pressure was measured via a cannula in a carotid arterv, and the heart rate was recorded from a KCG recorded with needle electrodes (lead II or le III). The heart rate of the animals in the control veriod was between 350 and 400 beats/minute (bpm).
The Table below contains the findings:
Substance: Dose : lowering of heart rate measured :twg/ke] : 5 minutes after administration : : of substance [bpm]
A : Ho : ~-173
HR : bho : ~-170 ¢ : 5.0 -1R0
D : h.O z —-156
RK : 5.0: -167 of : hoe : -130
The compounds prepared according to the invention have no toxic side effects whatever at therapeutic doses. ‘Thus, for example, with an intravenous administration of substance A to IF, even at a high dose ot 10 mg/kg. to mice 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 treatment and prophylaxis of ischaemic heart disorders, for example for the treatment and prophylaxis of mycardial infarct, and for the treatment of sinus tachycardias.
The dosage required to achieve an appropriate effect is conveniently once or twice a day 0.93 to 0.4 ng/kg of bodyweight, preferably 0.07 to 0.25 ng/kg of bodyweight. For this purpose, the compounds of } formula I prepared according to the invention, as well as the physiologically tolerable acid addition - salts thereof with inorganic or organic acids, can be incorporated into customary pharmaceutical preparations such as tablets, coated tablets, capsules, powders, suspensions, drops, ampoules, syrups or suppositories, optionally in combination 29 with other active substances, together with one or more customary inert 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-contalning substances such as hard fat or suitable mixtures thereof.
The Examples which follow are intended to explain the invention in detail:
Example A
N-Benzvl-N-methyvl-propargyvlamine 45.4 wl] (9.6 mol) of propargyl! bromide are added over 45 minutes to a solution of 78.9 wl (¥.6 mol) of N-methyl-benzylamine and B3.8 ml (0.6 mol) of triethylamine in 500 ml of diethyl ether at 22°C, while cooling in ice. After 2 hours at room temperature, the mixture is extracted with 500 ml of water, and the organic phase is dried over magnegium sulphate, evaporated down in vacuo and distilled.
Yield: 74.4 g (78% of theory),
B.P. 15-20 mm: 108-115°C.
Example B
Z.39-Dimethoxv-7-hvdroxy-7-(3-(N-benzvl-N-methyl— amino )-propyn-1-v1)-6.7.8.9-tetrahydro-5H~benzo- cvcloheptene 179 ml of tetrahydrofuran are added dropwise at 15°C . to a solution of ethyl magnesium bromide in 80 ml of diethyl ether freshly prepared from 11.4 g (9.467 ’ mol) of magnesium in 40 ml of diethyl ether and 34.3 ml (0.467 mol) of ethyl bromide. Subsequently, at
20-37°C a solution of 74.2 g (0.467 mol) of N- benzyl-N-methyl-propargylamine in 80 ml of tetrahydrofuran is added dropwise. After the evolution of ethane has ceased, 82.2 g (0.373 mol) oo of 2,3-dimethoxy-6,7,8,9-tetrahydro-5H- benzycycloheptene-7-one in 160 ml of tetrahydrofuran are added dropwise. After 39 minutes at about 30°C, 100 ml of 10% ammonium chloride solution are added, the mixutre is extracted with diethyl ether, and washed with 50% saturated potassium carbonate solution and with water. The organic phase is separated off, dried gver magnesium sulphate and evaporated down in vacuo. The resulting crude product is purified on 3 kg of aluminium oxide (neutral, activity II-III) using methylene chloride and subsequently using increasing proportions of ethanol (up to 1%).
Yield: 127 g (99% of theory),
Rp: ©.2 (aluminium oxide, mobile phase: 2X ethanol in methylene chloride).
Example C : 2.3-Dimethoxy-7-hvdroxy-7-(3-(N-benzvl-N-methyv]l- amino)-propyl)-6.7.8,9-tetrahvdro-5H- © 25 benzocvcloheptene ' 24.2 g (0.064 mol) of 2,3-dimethoxy-7-hydroxy—-7-(3- (N-benzyl-N-methyl-amino)-propyn-1-y1)-6,7,8,9- ’
tetrahydro-5H-benzocycloheptene are hydrogenated in 300 ml of methanol in the presence of 4 g of Raney nickel at ambient temperature and under 5 bar of hydrogen for 20 hours. After filtration and evaporation in vacuo, the crude product is purified on 1600 g of aluminium oxide (neutral, activity I11- 111) using methylene chloride and increasing proportions of ethanol (up to 3%).
Yield: 24 g (98% of theory),
Rp: 0.65 (aluminium oxide, mobile phase: 3% ethanol ‘in methylene chloride).
Example D
Mixture of the isomers 2, 3-dimethoxy—7-(3— (N-benzyl-N-methyl-amino)-propyl)- : 8,9-dihydro-5H-benzocycloheptene and 2, 3-dimethoxy—T7-(3-(N-benzyl-N-methyl-smino)-propyl- idene)-6.7.8.9-tetrahvdro-5H-benzocveloheptene 23.8 g (0.062 mol) of 2, 3-dime thoxy-7-hydroxy-7-(3- (N-benzyl-N-methy l-amino)-propyl)-6,7,8,9-tetrahy— dro-5H-benzocycloheptene and 5.5 g (0.029 mol) of p-toluenesulphonic acid hydrate in 600 ml of toluene ’ are boiled under a water peparator 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),
Rp: 0.87-0.92 (aluminium oxide, moblle phase: cyclohexane + 50% ethyl acetate).
Example E 2.3-Dimethoxy-7-(3-(N-methvl-amino)-propyvl)-6.7.8,.9- tetrahvdro-5H-benzocvcloheptene ] 8.3 g (90.0227 mol) of a mixture of the isomers 2,3- 190 dimethoxy-7-(3-(N-benzyl-N-methyl-amino)-propyl)- 8,9-dihydro-5H-benzocycloheptene and 2,3-dimethoxy-
T-(3-(N-benzyl-N-methylamino)-propylidene)-6,7,8,9- tetrahydro-5H-benzocycloheptene are hydrogenated in 150 ml of glacial acetic acid in the presence of 1 g of 10% palladium on active charcoal at 50°C and under 2 bar of hydrogen for 4 hours. The filtrate is evaporated down in vacuo and then dissolved in methylene chloride, the solution is washed with saturated sodium hydrogencarbonate 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-I11) using methylene chloride and increasing proportions of ethanol (up to 15%).
Yield: 2.27 g (36.0% of theory),
$ : }
Rp: 2.25 (aluminium oxide, mobile phase: 10% ethanol in methylene chloride). ’
Example F 2.3-Dimethoxy-7-hvdroxv-7-(3-(N-methvl-amino)- propyvl)-6.7.8.9-tetrahvdro-5H-benzovevaloheptene 8.15 g (0.0215 mol) of 2,3-dimethoxy-7-hydroxy-7-(3- (N-benzyl-N-methyl-amino)-propyn-1-y1)-6,7,8,9- tetrahydro-5H-benzocycloheptene are hydrogenated in 120 ml of ethanol in the presence of 2 g of 10% 19 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 10X).
Yield: 4.55 g (72.1% of theory),
Melting point: 94-96°C.
Example G : 2.3-Dimethoxy-7-hydroxy-7-(3-pyranvl-2-oxv)- propyn-1-v1)-6.7.8.9-tetrahvdro-5H- : benzocycloheptene
Prepared from 2,3-dimethoxy~8,7,8,9-tetrahydro-5H- benzocyclohepten-7-one and 3-(pyranyl-2-oxy)-propyne analogously to Example B.
Yield: 96.5% theory,
Rg: 0.67 (aluminium oxide, mobile phase: ethyl acetate).
Example H 2.3-Dimethoxy-7-methoxy-7-(3-(pyvranvl-2-oxyv)- propvn-1-v11-6,7,.8.9-tetrahvdro-5l-benzocycloheptene 4.7 g (13 mmol) of 2,3-dimethoxy-7-hydroxy—-7-(3- (pyranyl-2-oxy)-propyn-1-y1)-6,7,8,9-tetrahydro-5H4- benzocycloheptene, dissolved in 80 ml of tetrahydrofuran, are added dropwise at -30°C to a solution of 8.7 ml (13.9 mmol) of n-butyl lithium in n-hexane (about 15% strength) and 9.6 ml of tetrahydrofuran. 10 minutes later, 41.4 ml of dimethylsulphoxide are added dropwise at -25°C and, a further 8 minutes later, 1.22 ml (19.6 mmol) of x 15 methyl iodide are added dropwise. The mixture is then stirred at -15°C for one hour and at 50°C for one hour. It is poured onto saturated sodium chloride solution and extracted with diethyl ether.
The organic phase is washed with water, dried over magnesium sulphate and evaporated down in vacuo.
The resulting crude product is purified on 40@ g of . aluminium oxide (neutral, activity II-III) using methylene chloride and increasing proportions of ’ ethanol (up to 3%).
Yield: 3.5 g (72.0X of theory),
Melting point: 67-72°C.
Example 1 2. 3-Dimethoxy-7-methoxy-7-(3-chloro-propvn-l-vl)= 6.7.8.9-tetrahvdro-bH-benzocveloheptene
A solution of 3.25 g (B.68 mmol) of 2,3-dimethoxy-7- methoxy—T7- (3-pyranyl-2-oxy)-propyn-1-y1)-6,7,8,9- tetrahydro-6H-benzocycloheptene and 86 ml (82 mmol) : of thionyl chloride in 39 ml of chloroform is refluxed for 1 hour. The crude product obtained by evaporation down in vacuo is purified on 35@ g of aluminium oxide (neutral, activity II-111) using ‘ methylene chloride and 50% cyclohexane. . Yield: 2.0 g (74.6% of theory),
Melting point: 66.70°C.
Example J 2.3-Dimethoxy-7-(3-pvranyl-2-oxv)-propyn=1-vl}= 8.9-dihvdro-5H-benzocvcloheptene
Prepared from 2 ,3-dimethoxy—-7-hydroxy-T-(3-(pyranyl- i 2-oxy )-propyn-1-y1)-6,7,8,9-tetrahydro-5H- benzocycloheptene and methanesulphonyl chloride in ’ pyridine at 45°C.
Yield: 68.2% of theory, ’ ’ Rp: ‘0.62 (aluminium oxide, mobile phase: methylene " chloride)
Example K 2.3-Dimethoxyv-6,7-epoxyv-7-(3-pyranyl-2-oxyv)-propyn— 1-v1)-6.7.8,9-tetrahvdro-5H-benzocycloheptene 36.6 g (9.2 mol) of m-chloroperoxybenzoic acid, dissolved in 1000 ml of chloroform, are added to 27
Eg (0.078 mol) of 2,3-dimethoxy-7-(3-(pyranyl-2-oxy)- propyn-1-yl)-8,9-dihydro—-5H-benzocycloheptene, dissolved in 800 ml of chloroform, and the mixture is stirred at ambient temperature for 14 hours. The 19 remaining peroxide is decomposed using 400 ml of 10% hydrogen 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 156 vacuo. The crude product is purified on 1600 g of aluminium oxide (neutral, activity II-III) using methylene chloride.
Yield: 9.3 g (33% of theory),
Rg: 0.48 (aluminium oxide, mobile phase: methylene chloride)
Example L 2.3-Dimethoxyv-7—-(3-(pyvranvl-2-oxv)-propyn-1-vl )- 8.7.8.9-tetrahyvdro-5H-benzocvclohepten-6-one 9.25 g (25.8 mmol) of 2,3-dimethoxy-6,7-epoxy-7-(3- (pyranyl-2-oxy)-propyn-1-y1)-6,7,8,9-tetrahydro-5H-
benzocycloheptene are dissolved in 700 ml of toluene and stirred with 2 g (10.5 mmol) of p-toluene- sulphonic acid hydrate at ambient temperature for 13 hours. After extraction with saturated sodium hydrogen carbonate solution, it is dried over magnesium sulphate and evaporated down in vacuo, and the crude product is purified on 1000 g of aluminium oxide (neutral, activity II-III) using cyvclohexane and methylene chloride (50/50).
Yield: 1.9 g (20.5X of theory),
Rg: 0.64 (aluminium oxide, mobile phase: methylene chloride and 3% ethanol)
Example M 2.3-Dimethoxv-7-(3-methanesgulrhonvioxy-propvn-1- ¥1)-6,7.8,9-tetrahvdro-5H-benzocvclohepten—6-one
Prepared from 2,3-dimethoxy-7-(3-(pyranyl-2-oxy)- propyn-1-v1)-6,7,8,9-tetrahydro-bH-benzocyc lohepten— 6-one and methanesulphonyl chloride in pyridine at 45°C.
Yield: 12.7% of theory.
Example N 2,3-Dimethoxy-7-[3-(N-methyl-N-(2-(3.4-dimethoxv- phenvl)-ethvl)-amino)-propyn-1-v11-6.7.8.9-tetrahv- dro-SH-benzocvclohepten-6-one
Prepared from 2,3~dimethoxy-7-(3-methanesulphonyl- oxy-propyn-1-y1)-6,7,8,9-tetrahydro-5H-benzocyclo- hepten-6-one and two equivalents of N-methyl-N-(2- (3,4-dimethoxy-phenyl)-ethyl)-amine at 8@°C.
Yield: 7.0% of theory.
Example 1 2.3-Dimethoxy-7-f3-(N-methyvl-N-~(3-phenyl-propvl}- amino )-propvl1-6.7,8.9-tetrahvdro-5H-benzocvclo- heptene-hvdrochloride 3.2 g (0.9979 mol) of 2,3-dimethoxy-7-hydroxy-7-(3- {N-cinnamyl-N-methyl-amino)-propyn-1-y1)-6,7,8,9- tetrahydro-bH-benzocycloheptene are hydrogenated in 40 ml of glacial acetic acid and 2 ml of perchloric acid in the presence of 0.5 g of 10X palladium on active charcoal at 60°C and under 3.5 bar of . hydrogen for 2 hours. The filtrate is evaporated down in vacuo, the residue is dissolved in methylene chloride and the solution is washed with saturated sodium hydrogen carbonate solution. The organic : phase is dried over magneisum sulphate, and the crude product obtained by evaporation down in vacuo is purified on 280 g of aluminium oxide (neutral, ] activity II-III) using methylene chloride. The hydrochloride is subsequently precipitated using ethyl acetate/ethereal hydrochloric acid.
Yield: 1.77 g (51.9% of theory),
Melting point: 159-160°C
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-methy1-N-(2-(3.4-dimethoxy— phenvl)-ethvl)-amino)-propyn-1-vl1-8.9-dihvdro-
SH-benzocvcloheptene 9.2 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-7-13- (N-methyl-N-(2- (3,4-dimethoxy-phenyl)-ethyl )-amino)-propyn-1- v131-6,7,8,89-tetrahydro-5H-benzocycloheptene in 15 ml of pyridine, and the mixture is then stirred at 45°¢C for 2 hours. The crude product obtained by evaporation down in vacuo is dissolved in methylene chloride/water and the organic phase is dried over } magnesium sulphate, evaporated down in vacua and purified on 100 g of aluminium oxide (neutral, activity 11-111) using methylene chloride and increasing proportions of ethanol (up to 1%).
Yield: ©.66 g (60.6% of theory),
Calculated: C 74.45 H 7.64 N 3.22
Found: 74.30 7.49 3.02 5A
Example 3 2.3-Dimethoxy-"1-hydrozy=7-13-(N=cinnamyl-N-methyl- amino )-propyl 1-6.7,8.9-tetrahvdro-5i-benzocyc Lo- heptene hvdrochloride 1.9 g (0.003 mol) of 2,3-Dimethoxy-7-hydroxy-7-13- (N-methyl-amino)-propyl1-6,7,8,9-tetrahydro-5H- benzocycloheptene, 0.5 g (0.003 mol) of cinnamyl chloride and 0.34 g (0.003 mol) of triethylamine are heated at 80°C for 1 hour. 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 vo evaporated down in vacug. 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: 309 mg (24% of theory),
Melting point: 234°C
Calculated: C 76.61 H 8.14 N 3.14 C1 7.95
Found: 69.86 8.25 3.16 8.00
Example 4 2.3-Dimethoxv-T-hvdroxv-7T-[3-(N-methyl-N-(3(4- - - bromo-rhenyl)-propyl1-6.7.8.9-tetrahvdro-5H- benzocyeloheptene hydrochloride
Prepared from 3-(4-bromo-phenyl)-1-bromo-propane and 2,3-Dimethoxy-7-hydroxy-7-[{3-(N-methyl-amino)- propyl1-6,7,8,9-tet.rahvdro-5H-benzocycloheptene analogously to Example 3.
Yield: 25% of theory,
Melting pint: 174°C
Calculated: CC 59.26" 'H 7.08 N 2.668 Cl 6.73 Br 15.17
Found: 60.04 7.18 2.78 6.43 14.94
Example 5 2. 3-Dimethoxyv-7-methoxy-7-[3-(N-methvl-N-(2-(3,4- dimethoxy-phenvl)-ethyl)-amino)-propyn-l-yl11-6.7.8.9- tetrahvdro-bH-benzocycloheptene 1.75 g (5.67 mmol) of 2,3-dimethoxy-7T-methoxy-7-(3- chloro-propyn-1-y11-6,7,8,9-tetrahydro-5H-benzocyclo- heptene and 2.21 g (11.3 mmol) of N-methyl-2-(3,4- . 29 dimethoxy-phenyl)-ethylamine are heated at 95°C for 1.5 hours. The cooled crude product is purified on 400 g of aluminium oxide (neutral, activity I11-]I11) using methylene chloride and increasing proportions of ethanol (vp to 1%).
Yield: 2.4 (90.6% of theory),
Calculated: Cl 71.92 H 7.98 N 3.00
Found: 71.80 7.88 3.00
Example 6 2.3-Dimethoxv-T-hvdroxy-7-13-(N-methyvl-N-(2-(3- trifluoromethanesulehonyloxv-phenvl)-ethyl)-amino)- propyl1-6.7.8.9-tetrahvdro-bli-benzocycloheptene hydrochloride 1.9 g (0.0024 mol) of 2,3-dimethoxy-7-hydroxy-7-[3- (N-methy 1-N- ( 2- ( 3-hydroxy-phenyl)-ethy 1) amino )- propyl 1-6,7,8,9-tetrahydro-5H-benzocycloheptene and 0.5 g (9.9948 mol) of triethylamine are dissolved in . 20 ml of methylene chloride, and 8.59 g (9.0035 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-11I) using methylene chloride, and the hydrochloride is precipitated with ethereal hydrochloric acid in acetone.
Yield: 490 mg (97% of theory),
Melting point: 160°C,
Calculated: C 563.65 H 6.06 N 2.41 Cl 6.909 § 5.51
Found: 53.53 6.08 2.55 6.28 5.80
Example 7 a) N-(3-(2.3-Dimethoxv-7-hvdroxy-6.7.8.9-tetrahvdro-
SH-benzocyclohepten-7-vl)-propyl)-N-methvl-3.4- dimethoxy-cinnamide 1.2 g (90.006 mol) of 3,4-dimethoxy-cinnamic acid are suspended in 60 wml of ethyl acetate, 1.0 g (90.008 mol) N,N” -carbonyldiimidazole is added, and the mixture is stirred at 40°C for 15 minutes. To this suspension are added dropwise 2.0 g (0.086 mol) of 2,3-dimethoxy-7-hydroxy—-{ 3— (N-methyl-amino )-propyl ]- 6,7,8,9-tetrahydro-5Hi-benzocyc loheptene, and the mixture is refluxed fdr 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-1I11) using methylene chloride.
Yield: 1.3 g (45% of theory),
Melting point: 145-146°C,
Rp: ©.6 (aluminium oxide, mobile phase: 5% ethanol in methylene chloride). b)__2.3-Dimethoxv-7-hydroxy-7-{3-(N-methyl-N-(3.4- dimethoxy-cinnamyl)-amino)-propyl1-6.7.8.9- tetrahvdro-bH-benzocveloheptena hydrochloride
1.3 g (0.0027 mol) of N-(3-(2, 3-Dimethoxy-7-hydroxy- 8,7,8,9-tetrahydro-5H-benzocycloheptene-7-y1)- propyl)-N-methyl-3, 4-dimethoxy-cinnamide, dissolved in 1@ ml of dry tetrahydrofuran, are added dropwise at 59C to 0.11 g (0.903 mol) of lithium aluminium hydride in 15 ml of dry tetrahydrofuran. After stirring at ambient temperature for 19 hours, the mixture is cooled in ice and 9.1 ml of water, 0.1 mi of 15% sodium hydroxide solution and 8.3 ml of water are successively added dropwise. The precipitate is suction filtered and washed with tetrahydrofuran, and the filtrate is evaporated down in vacuo. The crude product is purified on 169 g of aluminium oxide (neutral, activity II-I11) using methylene chloride, and then the hydrochloride is precipitated using ethereal hydrochloric acid in acetone.
Yield: 80 mg (8X of theory),
Melting point: 199°C,
Calculated: C 66.45 H 7.97 N 2.77 Cl 7.01
Found: 66.30 8.81 2.89 7.065
Example 8 } 2.3-Dimethoxy-T-hydroxy-7-13-(N-methyl-N-(2- (3,4 dimethoxv-phenvl)-ethyl)-amine)-propyn-1-yii- . 6.7.8.9-tetrahvdro-5H-benzocycloheptene 3.8 ml of tetrahydrofuran are added dropwise at 159C to a solution of ethyl magnesium bromide freshly prepared from 0.26 g (19.6 mmol) of magnesium in 2 ml of diethyl ether and @.85 ml (10.6 mmol) of ethyl bromide in LIL 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 mi of tetrahydrofuran is added dropwise at 20-27°C.
After the evolution of ethane has ceased, 1.87 g (8.5 mmol) of 2,3-dimethoxy-6,7,8,9-tetrahydro-5H- benzocyclohepten-7-one in 4 ml of tetrahydrofuran 19 are added dropwise. After 30 minutes at about 30°C, ml of 10% ammonium chloride solution are added, the mixture is extracted with diethyl ether, and is washed with 50% saturated potassium carbonated solution and with water. The organic phase is dried 15 over magnesium sulphate and evaporated down in no vacug. The resulting crude product is purified on 400 g of aluminium oxide (neutral, activity 11-111) using methylene chloride and, subsequently, increasing proportions of ethanol (up to 3%).
Yield: 2.27 g (59.0% of theory),
Melting point: 114-117°C,
Calculated: C 71.56 H 7.78 N 3.09 : Found: 71.40 7.55 2.88
Example 9 2.3-Dimethoxyv-7-hvdroxy-7-I3-(N-ci nnamyl-N-methyl- amino)-propyn-1-v11-6.7.8.9-tetrahvdro-5H- benzocycloheptene hvdrochloride
Prepared from 3-[(N-cinnamyl-N-methyl-amino) ]-prop- 1-yne and 2,3-dimethoxy-6,7,8,9-tetrahydro-5H— benzocyclohepten-7-one analogously to Example 8B. ’
Yield: 39% of theory,
Melting, point: 214°C,
Calculated: CC 70.65 H 7.29 N 3.18 C1 8.92
Found: 70.53 7.43 2.98 8.28
Example 10 2.3-Dimethoxv-7-hvdroxy-7-13-(N-methyl-N-(2-(3,5- dimethoxv-phenyl)-ethyl)-amino)-propvn-1-vl1- 8.7.8.9-tetrahvdro-bH-benzocycloheptene
Prepared from 2,3-dimethoxy-6,7,8,9-tetrahydro-5H- benzocyclohepten—-7-one and 3-(N-methyl-N-(2-(3,56- dimethoxy-phenyl)-ethyl)-amino )-propyne analogously to Example 8.
Yield: 42.7% of theory,
Melting point: 112-113°C,
Calculated: C 71.506 H 7.78 N 3.09
Found: 71.30 7.80 2.88
Example 11 2,3-Dimethoxy-7-hvdroxy-7-{3-(N-methyl-N-(2-(4-— benzyloxv-phenvll-ethvl)-amino)-propvn-1l-vi1- 6.7.8.9-tetrahvdro-5H-benzocycloheptene
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°C,
Calculated: CC 76.92-"H 7.46 N 2.80
Found: 76.76 7.46 2.81
Example 12 wmethoxv-phenyl )-ethyl}-amino)-propyn-l-vii1- 6.7.8.9-tetrahydro-5H-benzocycloheptene
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 8B.
Yield: 64.4% of theory, . Melting point: 1@1-104°C,
Calculated: C 73.73 H 7.85 N 3.31
Found: 73.69 8.02 3.656
Example 13 2.3-Dimethoxy=-7-hvdroxv-7-[3- (N-methyl -N-(2-(4- methoxy-phenvl )-ethvl)-amino)-propyl 1~6.7.8.9- tetrahvdro-5H-benzocycloheptene oxalate 3.3 g (0.908 mol) of 2,3-dimethoxy-7-hydroxy-7-[ 3- (N-methy 1-N-(2-(4-methoxy-phenyl )-ethyl)-amino )- propyn-1-y11-6,7,8,9-tetrahydro-5H-benzocycloheptene are hydrogenated in 40 ml of glacial acetic acid in the presence o 0.3 8 of 10X palladium on active 190 charcoal at ambient temperature and under 1 bar of hydrogen or 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 hydrogencarbonate 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 15%).
Subsequently, the oxalate is precipitated with oxalic acid in ethyl acetate/diether ether.
Yield: 1.64 g (73.9% of theory),
Melting point: greated than 40°C (sintering), . Calculated: C 64.97 H 7.59 N 2.71
Found: 65.00 7.72 2.52
Example 14 : 2,3-Dimethoxy-71-hvdroxy-7-{ 3-(N-wethy l-N-(2-(4- hvdroxv-phenvl)-ethvl)-amino)-propyl1-6.7.8.9- tetrahvdro-bH-benzocvcloheptene oxalate
Prepared from 2,3-dimethoxy-7-hydroxy-7-{3-(N-methyl-
N-(2-(4-benzyloxy-phenyl)-ethyl)-amino)-propyn-1- v1]-5,6,8,9-tetrahydro-benzocycloheptene analogously to Example 13.
Yield: 81.3% of theory,
Calculated: C 72.61 H 8.53 N 3.99
Found: 12.49 8.79 3.74
Ry. 9.28 (aluminium oxide, mobile phase: 3% of ethanol in methylene chloride) :
Example 15 2,3-Dimethoxy—-7-{3-(N-methyl-N-(2-(4-methoxy- phenyl)-ethyl)-amine)-propyvl1-6.7.8.9-tetrahvdro-
HH-benzocve loheptene hvdrochloride
Prepared from the mixture of the isomers 2,3- dimethoxy-7-{3-(N-methyl-N-(2-(4-methoxy-phenyl)- ethyl )-amino)-propyl 1-8, 9-dihydro-benzocycloheptene and 2,3-dimethoxy-7-13~-(N-methyl-N-(2-(4-methoxy- . phenyl )-ethyl)-amino)-propylidene}-5,6,8,9- tetrahydro-benzocycloheptene analogously to Example 18. s15]
Yield: 55.6% of theory, "Melting point: 158-160°C,
Calculated: C 69.76 H B.56 N 3.13 Cl 7.91
Found: 68.95 8.60 3.17 7.40
Example 16 2.3-Dimethoxy-7-[3-(N-methyl-N-(2-(3,4-dimethoxy— phenvl)-ethyl)-amino)-propyl1-6,7.8.9-tetrahvdro—
SH-benzocycloheptene hydrochloride 1.65 mg (3.75 mmol) of a mixture of the isomers
LL 10 2,3-dinethoxy-7-[3-(N-mothy1-N- (2-(3, 4-dimethoxy—phonyl)- ethyl)-amino)-propyl 1-8, 9-dihydro-5H-benzocyc lo heptene and 2,3-dimethoxy-7-[3-(N-methyl-N-(2-(3, 4- dimethoxy-phenyl)-ethyl)-amino )-propylidene }- 6,7,8,9-tetrahydro-5H-benzocyc loheptene are hydrogenated in 20 ml of ethanol in the presence of 0.2 g of 10% palladium on active charcoal at ambient temperature and under 5 bar of hydrogen for 7 hours.
The filtrate is evaporated down in vacua, and the hydrochloride is precipitated with acetone/ethereal hydrochloric acid.
Yield: ©.85 g (47.5% of theory),
Melting point: 1655-166°C,
Calculated: C 67.83 H B8.43 N 2.93 Cl 7.42
Found: 87.85 8.33 2.97 7.76
Example 17
BE : 2, 3-dimethoxy-7-hydroxy—7-13—(N-methyl-N-(2-(3,4- dimethoxy-phenvl)-ethyl)-amino)-propyl1-6,7,.8.9- . tetrahvdro-5i-benzocvcloheptene .
Prepared from 2, 3-dimethoxy-7-hydroxy-7-[3-(N-methyl-
N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino)-propyn—1- v11-6,7,8,9-tetrahydro-5H-benzocycloheptene analogously to Example 13.
Yield: 60.6% of theory,
Melting point: 91°C,
Calculated: C 70.87 H 8.59 N 3.08 ' found: 70.87 8.48 2.92
Example 18 2.3-Dimethoxy-7-[3-(N-methyl-N-(2-(J-methoxy— pbenvl)-ethyl)-amino)-propyl1-6.7.8,.9-tetrahydro- 5H-benzocycloheptene hvdrochloride
Prepared from the mixture of isomers 2,3-dimethoxy- : 7-[{3- (N-methyl-N-(2-(3-methoxy-phenyl)-ethyl)- amino )-propyl }-8,9-dihydro-5H-benzocycloheptene and 2,3-dimethoxy-7-[3- (N-methyl-N-(2-(3-methoxy- phenyl)-ethyl)-amino)-propylidene}-5,6,8,9- . tetrahydro-5H-benzocycloheptene analogously to
Example 16.
Yield: 76.9% of theory, . 25 Melting point: 164-1685°C,
Calculated: C 689.706 H A.55 N 3.13 CI T.91
Found: 69.63 8.53 3.11 8.02
Example 19 2.3-Dimethoxy-7-13-(N-methyl-N-(2-(4-hydraoxy- b ehenvl)-ethyl })-amina)-propyl 1-6,7.8.9-tetrahydro-
SH-benzocycloheptene hydrochloride
Prepared from the mixture ot isomers 2,3-dimethoxy- 7-[3-(N-methy1-N-(2-(4-hydroxy- phenyl )-athyl )- amino )-propyl |-8, 9-dihydro-5il-benzocyc loheptene and \ . 2,3-dimethoxy-7-13-(N-methy}-N-(2-(4-hydroxy-phenyl )- ethyl)-amino)-propylidenel-5,6,8,9-tetrahydro- benzocycloheptene analogously to Example 16.
Yield: 55.8% of theory,
Melting point: 204-208°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¢ 2.3, 1-Trimethoxy-7-{3- (N-methyl -N-(2-(3,4-dimethoxy- rhenvl)-ethyl)-amino)-propyl 1-6,7,8.9-tetrahvdro- aH-benzocycloheptene hydrochloride
Prepared from 2,3, 7-trimethoxy-7-13-(N-methyl1-N-(2- ’ (3,4-dimethoxy-phenyl })-ethy!)-amino)-propyn-1-y1 |- 6,7,8,9-tetrahydro-5H-benzocyc loheptene 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 ethyl)-amino)-propvl1-6.7.8.9-tetrahvdro-5H-benzo- cyvcloheptene hvdrochloride
Prepared from 2,3-dimethoxy-7-(3-(N-methyl-amino)- propyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene and . 2-(4-fluorophenyl)-ethyl me thanesulphonate analogously to Example 3.
Yield: 308.3% of theory,
Melting point: 122-124°C,
Calculated: C 68.87 H 8.09 N 3.21 Cl 8.13
Found: 68.75 8.18 3.12 8.15
Example 22 2.3-Dimethoxv-7-hvdroxy-7-I3-(N-methyl-N-(2-(4- benzyloxy-phenvl)-ethvl)-amino)-propyl1-6.7.8.9- tetrahvdro-5SH-benzocyvcloheptene hydrochloride
Prepared from 2,3-dimethoxy-7-hydroxy-7-(3-(N- methyl-amino)-propyl)-6,7,8,9-tetrahydro-bH- benzocycloheptene and 2-(4-benzyloxy-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: 79.93 7.91 2.57 6.67
Example 23 2.39-Dimethoxv-7-hyvdroxy-7-{3-(N-methyl-N-(2-(4- amine-3.,5-dichloro-phenyl)-ethvl)-amino)-propyl I- 6.7.8.9-tetrahvdro-5H-benzocveloheptene oxalate
Prepared from 2,3-dimethoxy—-7-hydroxy-7-{3- (N- 190 methyl-amino)~propyl)-6,7,8,9-tetrahydro—5H- benzocycloheptene and ‘2-(4-amino-3,6-dichloro— phenyl )-ethyl bromide analogously to Example 3.
Yield: 36.8% of theory,
Melting point: greater than 75°C (decompostion),
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-Dimethoxv-7-hvdroxy-7-{3-(N-methyl-N-(3-(4- amino-3.5-dibromo-phenoxy)-propyl )-amino)-propyli- 6.7.8.9-tetrahvdro-bH-benzocveloheptene oxalate
Prepared from 2,3-dimethoxy-7-hydroxy-7-(3-(N- . methyl-amino)-propyl)-6,7,8,9-tetrahydro-5H- benzocycloheptene and 3-(4-amino-3,5-dibromo- phenoxy )-propyl chloride analogously to Example 3.
Yield: 44.9% of theory,
Melting poinlL: greater than 00°C (decomposition),
Calculated: © A43.71 I H.5H N 4.656 Br 23.15
Found: 48.59 5.70 3.91 23.42 aS) Rxample. 25 2.3: Dime thoxy 7 hydroxy.-7--[J- (N-methyl -N--(3-{4- cyvano-phenyl)- propyl)oamiue)-propyl1-6,7,.8,9- tetrabydro: HII benzocyveloheptene
Prepared from 2.3 dimethoxy 7 hydroxy-7--(3-(N- methyl amine) propyl) 6,7,8,9 tetrahydro 5H - benzoeye loheptone and 3 (1 cyano phenyl) propyl bromide analogously to Example JO.
Yield: 806.2% of theory,
Melting point: 79-81°C,
Calculated: © 74.28 11 8.31 N 6.42
Found: TA.23 8.19 6.52
Izample 206 2. Dimethoxy: 7 hyvdroxy-7 [J-(N-methvl-N-(2-(4-- nitro-phenyl): ethyl) -aminol)-propvl | 6,7.8,9= tetrahydro-dil-benzocyvcloheptene
Prepared from 2,3-dimethoxy-7--hydroxy -7-(3-(N- ’ methyl amino) propyl) 6,7,8,9 tetrahydro -HH benzocyclohepteone and 2 (4 nitro phenyl) ethyl bromide analogously to Ixample 3.
BAD ORIGINAL
Yield: 46.3% of theory,
Calculated: C 67.85 H 7.74 N 6.33
Found: 87.7H 7.98 6.55
Rg: 0.25 (aluminium oxide, mobile phase: cyclohexane + 50% ethyl acetate)
Example 27 2.3-Dimethoxy-7-{3-(N-methyvl-N-(3-(4-amino-3.5- dibromo-phenoxv)-propvl)-amino)-propyvl 1- 6.7.8,9-tetrahvdro-SH-benzocycloheptene hvdrochloride \
Prepared from 2,3-dimethoxy-7-(3-(N-methyl-amino)- propyl )}-6,7,8,9-tetrahydro-5H-benzocyc loheptene and 3-(4-amino-3, 5-dibromo-phenoxy )-1-chloropropane analogously to Example 3.
Yield: 21.8% of theory, ’
Melting point: 80°C (decomposition),
Calculated: C 506.30 H 6.01 N 4.51 Cl 5.71 Br 25.74
Found: 50.21 6.00 4.49 5.65 26.48
Example 28 2,3-Dimethoxyv-7-1{3-(N-methvl-N-(3-(3.4-methyl- : enedioxy-phenoxy)-propyvl)-amino)-propyvl 1-6.7.8,9- tetrahvdro-5H-benzocvcloheptene hydrochloride
Prepared from 2,3-dimethoxy-7-(3-(N-methyl-amino)- propyl )-6,7,8,9-tetrahydro-5H-benzocycloheptene and
AL
HQ a 75
3 (3,4 methylenedioxy: phenoxy) 1 chloropropane analogously Lo Example 3.
Yield: 21.1% of theory,
Melbing point: 146- 147°C,
Calculated: ©€ 65.90 [1 7.78 N 2.845 C1 7.21 Co
Found: 65.90 7.91 2.79 7.39 zample 29 2x Dimethory: 7-13 (N-methyl N-G3-(3- methyl - phenozry). propy Ll -amino)-propyv11:-6,7.8.9-tetra- 5 19 hydro Hl benzocyelohepi.ene. hydrochloride
Prepared from 2,3 -dimethoxy-7--(3- (N-methyl -N-amino) propyl) -6,7,8,9 tetrahydro- 51- benzoecycloheptene and 3 (3-methyl- phenoxy) -l-chloropropane analogously Lo
Txample 3.
Yield: 9.7% of theory,
Melting point: 126 127°C,
Caleulated: ©€ 70.1B HI 8.73 N 3.63 Cl T7T.67
Found: 69.97 8.81 2.93 7.54 lLxample_ JQ
Jai -Dimelhoxy 713. LN: (methyl MN. _(Z-(A-tea fluocome thang: } sulrhosy phenyvl)-ebhyv]ll-aninel -propyll1-6.7,0,9-- tetrahvdrao--hHllt benzocloheptene_ hydrochloride =n
Prepared from 2,3-dimethoxy-7-/3-(N-methyl-N-(2- (4-hydroxyphenyl)-ethyl)-amino)-propyl7-6,7,8, 9+ tetrahydro-5H-venzocycloheptene and trifluoro- methanesulphonyl 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
Zxample 31 2,3-Dimethoxy=-7=/3=(N-methyl-N-(2-(4-methanesul- phongloxy-phenyl)-ethyl damino)-propyl/=6,7,8,9~ tetrahydro-5H-benzocycloheptene hydrochloride
Prepared from 2,3-dimethoxy-T7-/3-(N-methyl-N-(2- (4-hydroxy-phenyl)-ethyl)-amino=propyl/-6,7,8,9- tetrahydro-5H-benzocycloheptene and methane- sulphonyl chloride analogously to Example 6,
Yield: 73.2% of theory,
Melting point: 162-164°¢, - 20 Calculated: C 60.98 H 7.48 N 2,74 Cl 6,92 . Found: 60.83% TedT 2.63 6.96
Example 32 2, 3=Dimethoxy=T7=/3=(N-methyl~N-(2-(4-hydroxy=3- methoxy-phenyl)-ethyl)-aminc}-propyl/=6,7,8,9=- tetrahydro-5H-benzocycloheptene
Prepared from 2,3-dimethoxy-7-hydroxy-7-/3- (N= methyl-N-(2~(4-benzyloxy-3~methoxy-phenyl)~ethyl)- amino)-propyn-1-y1/$6,7,8,9-tetrahydro-5H-benzo- cycloheptene analogously to Example 1.
Yield: 67.2% of theory,
Melting point: 47°%c,
Calculated: C¢ 73,04 H 8,72 N 3.28 :
Found: 75.10 8.68 3.51
Example 33 5 2,3-Dimethoxy-7=hydroxy=~J=/3- (N-methyl -N=(3=(3,4~ me thylenedioxy-phenoxy)-propyl)-amino)-propyn-1- y17/-6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride
Prepared from 3-(N-methyl-N-(3-(3,4-methylenedioxy- i 15 phenoxy )-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 C1 17.03
Found : 64.25 6.79 2.57 7.04
Example 34 2,3-Dimethoxy=T-hydroxy="1=-/3~(N-methyl-N=(3- - methylenedioxy-phenoxy)-propyl)-amino)-propyl/- 6,7,8,9~-tetrahydro-5H-benzocycloheptene hydrochloride
Prepared from 2,3-dimethoxy-7-hydroxy-7-/3-(N- methyl-N-(3-(3,4-methylenedioxy-phenoxy)-propyl)- amino)-propyn-l1-yl/-6,7,8,9~-tetrahydro-5H-benzo- cycloheptene analogously to Example 13,
Yield: 18% of theory,
Melting point: 167°¢,
Calculated: C 63.83 H 7.54 N 2.76 Cl 6.98
Found: 63.72 7.66 2.779 7.02
Example 35 _ 2,3-Dimethoxy-T-hydroxy-7-/3-(N-methyl-N-(2-(4- fluoro-phenyl)-ethyl )-amino)-propyn-1-yl7 -6,7,8,9= tetrahydro-5H-benzocycloheptene hydrochloride
Prepared from 3-(N-methyl-N-(2-(4-fluoro-phenyl)- ethyl )-amino)-propyne and 2,3-dimethoxy-6,7,8,9- tetrahydro-SH-benzocyclohepten-7-one analogously to bxample 8.
Yield: 42% of theory,
Melting point: 231°,
Calculated: ¢ 67.03 H 6,98 N 3.13 (Cl 7.91
Found: 66.88 T.17 2.98 8,17
Example 36 2,3-Dimethoxy-T-hydroxy=-T=/3-(N-methyl-H-(2-(4~ fluoro-phenyl)-ethyl)-amino)-propyl/-6 8,9~ tetrahydro-5H-benzocycloheptene hydrochloride
Prepared from 2, 3-dime thoxy-7~hydroxy-B(N-methyl-
N-(2-(4~fluoro-phenyl)-ethyl)-amino)-propyn-l-yl/- 6,7,8,9-tetrahydro-5H~-benzocycloheptene analogously to Example 13.
Yield: 28% of theory,
Melting point: 178°C,
Calculated: C 66.43 H 7.58 WN 3,10 C1 7.84
Example 37 “ 19 2,3=Dimethoxy-T=hydroxy=7=/3=(N-methyl—N=(2-(3~- me thoxy-phenyl)=-ethyl)=amino)-propyn-1-y17-6,7,8, = tetrahydro-5H-benzocycloheptene hydrochloride
Prepared from 3-(N-methyl-N-(2-(3-methoxy-phenylsy- ethyl)-amino)-propyne and 2,3-dimethoxy-6,7,8,9~ tetrahydro-5H-benzocyclohepten-7-one analogously to Example 8.
Yield: 40% of theory,
Melting point: 187°C,
Calculated: C 67.89 H 7.45 N 3.04 C1 7.71
Found: 67.92 7.61 3.03 7.97
Example 38 2, 3-Dimethoxy=-T-hydroxy=7=-/3-(N-methyl=N=-(2=(3- methoxy-phenyl)-ethyl)-amino)-propyl/-6 8,9~ tetrahydro-5H-benzocycloheptene hydrochloride
Prepared from 2,3-dimethoxy-7-hydroxy-7-/3-(N- methyl-N-(2-(3-methoxy~phenyl)~ethyl)-amino}- propyn-1-yl1/-6,7,8,9~tetrahydro-5H-benzocyclo~ heptene analogously to sxample 13,
Yield: 65% of theory,
Melting point: 149-150°¢c,
Calculated: 67,29 H 8,25 N 3,02 Cl 7.64
Found ; 67.44 8,39 3.04 7.76
Example 33 \ 2,3-Dimethoxy-7-hydroxy-7-/3-(N-methyl-N-(3-(3,4~ dimethyl-phenoxy)-propyl)-amino)-propyn=1-y17- 6,7,8,9~tetrahydro-5H~-benzocycloheptene
Prepared from 3-(N-methyl-N-(3-(3,4-dimethyl- phenoxy )-propyl)-amino)-propyne and 2,3=-dimethoxy- 6,7,8,9-tetrahydrg~5H-benzocycloheptene-7-One analogously to Example 8.
Yield: 58% of theory,
Melting point: 99-100°¢,
Calculated: C 74.47 H 8,26 N 3.10
Found 74,70 8,23 3,10
Example 40 2,3-Dimethoxy-7-hydroxy=7=/3~(N-methyl-N-(3= - >” dimethyl-phenoxy)-propyl)-amino)-propyl/~6,7,8,9=- tetrahydro-5H-benzocycloheptene hydrochloride
Prepared from 2,3-dimethoxy-7-hydroxy=7=/3-(N- methyl-N~-(3-(3,4-dimethyl-phenoxy)-propyl)-amino)- propyn-1-y1/-6,7,8,9~tetrahydro-5H-benzocycloheptene analogously to Example 13.
Yield: 63% of theory,
Melting point: 179°C,
Calculated: CC 68.34 H 8,60 N 2,85 (C1 7.21
Found: 68,21 8,70 2.85 7.42
Lxample 41 2,3-Dimethoxy-7-hydroxy=-7=/3=(N-methyl-N-(3-(3~ methoxy-phenoxy)-propyl)-amino)-propyn-l-yl/- 6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride
Prepared trom 3«(N-methyl-N-(3-(3-methoxy-phenoxy)- propyl)-amino)-propyne and 2,3-dimethoxy-6,7,8,9- tetrahydro-5H-benzocytlohepten-T7-one analogously to Example 8.
Yield; 28% of theory,
Melting point: 168°C,
Calculated : CU 66.18 H 2.86 N 7,40 C1 7.24
Found: 66,01 2.76 Te37 7.31
Example 42 } 24 3-Dimethoxy-7-hydroxy=7=~/3=(N-methyl-N-(3-(3- me thoxy-phenoxy}-propyl)-amino)~propyl/=6,7,8,9~ tetrahydro-5H-bengocycloheptene hydrochloride
Prepared from 2, 5-dimethoxy-7-hydroxy-7-/3-(N- methyl-N-(3-(3-methoxy-phenoxy)-propyl)-amino)- propyn-1-yl/-6,7,8,9-tetrahydro-5H-benzocyclo- heptene hydrochloride analogously to Example 13.
Yield: 41% of theory,
Melting point: 168°C,
Qalculated: C 65.64 H 8,16 N 2.83 Cl 17.18
Found: 65.55 8.02 2.69 Te25 rxample 43 \ 2,3-Dimethoxy-7-hydroxy~T7=/3- (N-methyl~N=(2=(3= benzyloxy-phenyl)-ethyl)-amino)¥propyn-i-yi7/- 6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride
Prepared from 3-(N-methyl-N-(2-(3-benzyloxy-phenyl)- ethyl )-amino)-propyne and 2,3-dimethoxy-6,7,8,9- tetrahydro-5H-benzocyclohepten-7-one analogously to Example 8.
Yield: 36% of theory,
Melting point: 188-189°cC,
Calculated: C¢ 71.69 H 7.14 N 2,61 Cl 6.61
Found: 71.58 7.28 2.61 6.67
Example 44 2,3-Dimethoxy-7-hydroxy=-7=/3=(N-methyl-N-(2=(3~ benzyloxy-phenyl)-ethyl)-amino)-propen=1-y1/-6,7,8,9- tetrahydro-5H-bengocycloheptene hydrochloride
1.0 g (0.002)mol) of 2,3-dimethoxy-T7-hydroxy-T- [3 (N-methyl-N-(2-(3-benzyloxy-phenyl)-ethyl)- amino)-propyn-1-yl/-6,7,8,9-tetrahydro-5H-benzo- cycloheptene is hydrogenated in 15 ml of ethanol in the presence of 0,15 g of Raney nickel at ambient temperature and under 1 bar of hydrogen for 3.5 hours. After filtration and evaporation down in vacuo, the crude product is purified on 360 g of aluminium oxide (neutral, activity II=-
III) using methylene chloride and increasing proportions of ethanol (up to 2%). Subsequently the hydrochloride is precipitated in acetone with ethereal hydrochloric acid. -
Yield: 180 mg (19% of theory),
Melting point: 165-166°C,
Calculated: C 71.44 H 7.31 ©§ 2,60 Cl 6.59
Found: 71.36 7.49 2.70 6.77 bxample 45 2, 3=Dimethoxy-7-hydroxy=-7-/3=(N-methyl-N-(2=-(3~ hydroxy-phenyl)-ethyl)-amino)-propyl/-6,7,8,9= tetrahydro-5H-benzocycloheptene
Prepared from 2, 3=-dimethoxy=-7-hydroxy~7-/3~(N- methyl-N-(2~-(3-benzyloxy-phenyl)-ethyl)-amino)- propyn-l-yl7~6,7,8,9~-tetrahydro-5i-benzocyclo~ heptene 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
Rp: 0.33 (aluminium oxide, mobile phase: 5% ethanol in methylene chloride) bxample 46 2,3-Dimethoxy-7-hydroxy-7=-/3=(N-methyl-N-(2~(3~ methanesulphonyloxy-phenyl)=ethyl)=amino)-propyl/=
LL 6,7,8,9-tetrahydro-5H~benzocycloheptene hydrochlo- ride .
Prepared from 2,3-dimethoxy-7-hydroxy-7-/3-(N- methyl=-N-(2-(3-hydroxy-phenyl)-ethyl)-amino)- propyl/-6,7,8,9-tetrahydro-5H-benzocycloheptene and methanesulphonyl chloride analogously to Example 6,
Yield: 20% of theory,
Melting point: 146-148°¢,
Calculated: C 59.13 H 7.25 N 2.65 CL 6.71 S 6,07
Found: 58.97 Te 38 2.64 6.63 6.09
Lxample 47 243=-Dimethoxy-T-hydroxy-T1-=/5~(N-methyl-N-(2- phenylethyl)-amino)-propyl-1-y17-6,7,8,9-tetrahydro-
S5H-benzocycloheptene hydrochloride trepared from 3-/N-methyl-N-(2-phenylethyl)-amino/- propyne and 2,3-dimethoxy-6,7,8,9-tetrahydro-5H- benzocyclohepten-7-one analogously to Example 8,
Yield: 97% of theory,
Melting point: 217%¢,
Calculated: C 69.83 H 7,50 N 3,26 Cl 8.25 : Found: 69.79 7.68 3.17 18.20
Example 48 2,3-Dimethoxy~7-hydroxy-#/3- (N-methyl-N-(2-phenyl= ethyl)-amino-propyl/-6,7,8,9~tetrahydro-5H-benzo=_ cycloheptene hydrochloride
Prepared from 2,3-dimethoxy-7-hydroxy-7-/3-(N- 5 me thyl-N-(2-phenylethyl)-amino)-propyn-l-y1/- 6,7,8,9-tetrahydro-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
Found: 69.00 8,29 3.21 8.25
Lxample 49 2,3-Dimethoxy-7-hydroxy-7-/3~(N-methyl-N-(3~phenyl- propyl)-amino)-propyn-1-y1/-6 7,8,9~tetrahydro~N
S5H-benzocycloheptene hydrochloride
Prepared from %- (N-methyl-N«(3-phenylpropyl)- amino)-propyne and 2,3-dimethoxy-6,7,8,9~-tetrahydro- 5i-benzocyclohepten-7-one analogously to Example 8, i 66
Yield: 76% of theory,
Melting point: 184-195°¢,
Calculated: C 70,33 H 7.72 N 3,15 C1 7.99
Found: 70.26 7.84 3.04 5.08
Example 50 2,3-Dimethoxy-7-hydroxy=7-/3=(N-methyl-N-(3-phenyl- propyl-amino)-propyl/-6,7,8,9-tetrahydro-5H-bengo~ cycloheptene hydrochloride
Prepared from 2,3-dimethoxy-7-hydroxy-7-/3-(N- me thyl-N-(3-phenylpropyl)-amino)-propyn-l-yl7- 6,7,8,9-tetrahydro-5H-benzocycloheptene analogously to Example 13.
Yield: 40% of theory,
Melting point: 187°C,
Calculated: U 69.70 H 8.55 N 3,13 CL 7.91
Found: 69.65 8.68 2.97 8,06
Example 51 2, 3-Dimethoxy-7-hydroxy=T7=/%~(N-methyl=N=(2=(3= methyl-phenyl)-ethyl)-amino)-propyn-l-yl/-6 8,9~ tetrahydro-5H-benzocycloheptene hydrochloride
Prepared from 3-(N-methyl-N-(2-(3-methyl-phenyl)- : ethyl)-amino)-propyne and 2,3-dimethoxy-6,7,8,9- tetrahydro-5H-benzocyclohepten-T7-one analogously to Example 8,
Yield: 57% of theory,
Melting point: 185-186°C,
Calculated: Cc 70.33 H Ta72 N 3615 Cl 7.99
Found: 70,18 7.66 5.07 8.05
Example 52 2,3-Dimethoxy-7-hydroxy=7-/3-N-methyl—-N-(2-(3- methyl-phenyl)-ethyl)-amino)-propyl/-6,7,8,9=-tetra- hydro=-5li-benzocycloheptene hydrochloride
Prepared from 2,3-dimethoxy-7-hydroxy=-T7-/%-(N- methyl-N-(2-(3~methyl-phenyl)-ethyl)-amino)-propyn=- 1-yl7-6,7,8,9=tetrahydro~5H-benzocycloheptene analogously to Example 13.
Yield: 42% of theory,
Melting point: 169°C, : 15 Calculated: C 69.70 H 8.55 N 3.13 (C1 7.91
Found: 69,56 8,58 3,22 7.94
Example 53 2,3-Ppimethoxy-T7=/3=(N-methyl-N-(2-(3,4~dimethoxy= peenyl)-ethyl)-amino)-propyl/-6,7,8,9-tetrahydro-
S5H-benzocyclohepten-6-one
Prepared from 2,3-dimethoxy-7-/5-(N-methyl-N-(2- : (3,4-dimethoxy-phenyl)-ethyl)-amino)-propyn-1- yl7-6,7,8,9-tetrahydro-5i-benzocyclohepten-6-one and hydrogen analogously to Example 13,
Yield: 22.4% of theory .
IR spectrum (KBr): CO 1725 emt a : 455 : bxample 54 2,3-Dimethoxy=7-/3=(N-methyl-N-(2~-(4-benzyloxy= phenyl)-ethyl)-amino)-propyl/-6,7,8,9-tetrahydro- 5H-benzocycloheptene hydrochloride
Prepared from 2,3-dimethoxy-7-/3-(N-methyl-aminoj- propyl/-6,7,8,9-tetrahydro-5H-benzocycloheptene and 2- (4=-venzyloxy-phenyl j-ethyl methanesulphonate analogously to Example ‘3.
Yield: 47.4% of theory
Melting point: 160-161°C.
Example 55
T-Hydroxy-T=43=(N-methyl-N=(2-(3,4-dimethoxy=- phenyl)=-ethyl)-amino)-propyn=1l=-y1/-6,7,8,9=tetra- hydro-5H=-benzocycloheptelie }
Prepared from 3-(N-methyl-N-(2-(3,4-dimethoxy=- phenyl)-ethyl)-amino)-propyne and 6,%,8,3-tetrahydro- 5H-benzocyclohepten-T7-one analogously to Example 8,
Yield: 56.20 of theory,
Melting point: 85-89°C.
ikxample 56 7-Hydroxy=-T=/3=(N-methyl-N-(2-(3,4~-dimethoxy-_ phenyl)-ethyl}-amino)-propyl7-6,7,8,9=-tetrahydro= } 5H-benzocy¥cloheptene hydrochloride
Prepared from 7-hydroxy=T-/3~(N-methyl-N-(2-(3,4- dimethoxy-phenyl)-ethyl)-amino)-propyn-1-y1/- ~ 6,17,8,9-tetrahydro-5H-benzocycloheptene analgously to Example 13.
Yield: 64.6% of theory,
Melting point: 147-148°C.
Example 57 7-/3- (N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)- amino)-propyl7-6,7,8,9-tetrahydro-5H-benzocycloheptene ) hydrochloride
Prepared from the mixture of isomers T-/3-(N-methyl-
N-(2-(3, 4-dimethoxy-phenyl)-ethyl)-amino)-propyl/- 8,9~dihydro-5H-benzocycloheptene and 7-/3- (N- methyl-f-(2~(3, 4-dimethoxy-phenyl)=-ethyl}-amino)- propylidene7-5,6,89-tetrahydro-bengocycloheptene } 20 analogously to Example 16.
Yield: 52.8% of theory,
Melting point: 141-142°C,
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-benzocyclo=_ heptene
Composition: 1 tablet contains:
Active substance 10.0 mg
Maize starch 57.0 mg
Lactose 48.0 mg
Polyvinylpyrrolidone 4.0 mg
Magnesium stearate - 1.0 mg 120.0 mg
Production process
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 andis dried at about ¢s°C. The dry granules are pressed through a screen with a mesh size of 1,0 mm and are mixed with magnesium stearate. <1he finished mixture is compressed to tablets in a tabletting machine with dies which have a diameter of 7 mm and are provided with a dividing notch,
Tablet weight: 120 mg
Example II
Coated tablets each containing 5 mg of 2,3-dimethoxy- 7-/3-(N-methyl=N=-(2-(3, 4-dimethoxy-phenyl )~ethyl)- amino )-propyl/-6,7,8,9-tetrahydro-5H-benzocyclo-hep~- tene
Lactose 30,0 mg
Polyvinylpyrrolidone 3.0 mg :
Magnesium stearate 0.5 mg 80.0 mg
Production process
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%, and the granules are subsequently pressed through the same screen.
After magnesium stearate has been mixed.in, bicon- vex tablet cores with a diameter of 6 mm are com- pressed 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.
Coated tablet weight: 130 mg
Example 1I1 }
Ampoules each containing 5 mg of 2,3-dimethoxy=-
T=/3-(N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)~ amino)-propyl/-6,7,8,9-tetrahydro-5H-benzocyclohep~ > tene 1 ampoule contains:
Active substance 5.0 mg
Sorbitol 50.0 mg
Water for injections ad 2,0 ml
Production process
The active substance is dissolved in water for injections in a suitable batch vessel, and the : solution is made isotonic with sorbitol, After filtration through a membrane filter, the solution is dispensed under an atmosphere of N, into cleaned and sterilised ampoules and is autoclaved for 20 minutes a stream of steam. bxample 1V
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 -tetrahydro-5H-bengocyclo- . heptene :
1 suppository contains:
Active substance 0.015 g
Hard fat (e.g. Witepsol H 19 and W 45) 1,685 g 1.700 g
Production process
The hard fat is melted. The ground active substance is homogeneously dispersed in the melt at 38°¢,
The mixture is cooled to 35%¢ and poured into slightly precooled suppository moulds.
N
Example V ye
Dropping solution containing 10 mg of 2,3-dimethoxy- 71=/3=(N-methyl-N-(2-(3,4~dimethoxy-phenyl)~ethyl)= amino )-propyl7-6,7,8,9-tetrahydro-5H-benzocyclo= heptlene 100 ml of solution contain
Active substance 0.2 g
Hydroxyethyl cellulose 0.15 ¢g
Tartaric acid - 0.1 g
Sorbitol solution, 70% dry matter 30.0 g } Glycerol 10.0 g
Benzoic acid 0.15 g : Distilled water ad 100 ml
Production process Co
Distilled water is heated to 70°C. It is stirred } while hydroxyethyl cellulose, benzoic acid and tartaric acid are dissolved in it. It is cooled to ambient temperature and, during this, the glycerol and the sorbitol solution are added while stirring. The active substance 1s added at ambient temperature, and the mixture is stirred until dissolution is complete. The solution is sub- sequently degassed by evcuation under stirring.

Claims (8)

  1. We claim:
    l., A compound of the formula By is A -N-4,-R, (1) R, | . 3 X 1 2 \ in which xy denotes a hydrogen atom, X, denotes a hydrogen atom, and Xs denotes a hydrogen atom, a hydroxyl or alkoxy group having 1 to 3 carbon atoms, or Xy and Xs together denote a further carbon-carbon bond, and X5 denotes a hydrogen atom, Ay denotes a straight chain alkylene group which has “3 or 4 carbon atoms and is optionally substituted by an alkyl group having 1 to 3 carbon atoms and in which an ethylene group } which is present in the moiety A; and is linked to the benzocycloheptene ring can be replaced by an ethenylene or ethynylene group,
    A, denotes a straight chain alkylene group which has 2 to 5 carbon atoms and is optionally substituted by an alkyl group having 1 to 3 carbon atoms and in which, if n represents the number O, an ethylene group which is present in the moiety A, and which is linked to the radical R, can be replaced by an ethenylene group, ’ Ry denotes a hydrogen atom or an alkoxy group having 1 to 3 carbon atoms, 5 R, denotes a hydrogen atom or an alkoxy group having 1 to 3 carbon atoms, R3 denotes a hydrogen atom or an alkyl group having 1 to 3 carbon atoms and Ry denotes a group of the formula Rs Re -(0), Ry } where n denotes the number O or 1, Rg denotes a hydrogen or fluorine atom, an alkyl, nitro, amino, alkylamino, dialkylamino, alkanoyl- amino, cyano or alkylsulfonyl group or a hydroxyl
    ] group which is optionally substituted by an alkyl, benzyl, alkylsulfonyl or trifluro- methylsulfonyl group, Reg denotes a hydrogen or halogen atom, an alkyl, hydroxy, alkexy, cyano or trifluoromethyl group or Rg and Re together denote an alkylenedioxy group having 1 or 2 carbon atoms and Ro denotes a hydrogen or halogen atom, an alkyl or alkoxy group, wherein the above mentioned alkyl or alkoxy groups of the radicals Rg to R, may each contain 1 to 3 carbon atoms and the above mentioned alkanoyl groups of the radical . Rg may contain 2 or 3 carbon atoms, the enantiomers thereof, the diastereomers thereof, or a pharmaceutically acceptable acid addition salt thereof,
  2. 2. A compound of formula 1, according to claim I, in which xy denotes a hydrogen atom, Xs, denotes a hydrogen atom and .
  3. Xs denotes a hydrogen atom, a hydroxyl or methoxy : group or X, and Xg together denote a further carbon-carbon bond, and xX, denotes a hydrogen atom,
  4. A denotes an an-propylene group in which the ethylene group which is linked to the cyclo~- heptene ring can be replaced by an ethenylene or ethynylene group, A, denotes an ethylene or n-propylene group or an n-propylene group in which, if n represents the number 0, an ethylene group which is present in the moiety A, and which is linked to the group R, is replaced by an ethenylene group, Ry denates a hydrogen atom or a methoxy group, R, denotes a hydrogen atom or a methoxy group, Ry denotes the methyl group, n denotes the number O or 1, Rg denotes a hydrogen or fluorine atom, a hydroxyl, methoxy, cyano, methyl, nitro, amino, methyl- sulphonyloxy, trifluoromethylsulphonyloxy or benzyloxy group, Reg denotes a hydrogen, chlorine or bromine atom : or a methoxy group, and Ry denotes a hydrogen, chlorine or bromine atom, the enantiomers thereof, the diastereomers thereof, or a pharmaceutically acceptable acid addition salt thereof. ;
  5. 3, A compound formula I, according to claim I, in which x denotes a hydrogen atom, x, denotes a hydrogen atom, and X3 denotes a hydrogen atom or a hydroxyl group, or Xy and Xs together denote a further carbon-carbon bond, and xX, denotes a hydrogen atom, Ry denotes a methoxy group, R, denotes a methoxy.group, Ry denotes a methyl group, Ay denotes an n-propylene group, A, denotes an ethylene or n-propylene group, Rg denotes a methoxy or methylsulphonyloxy group, Rg denotes a hydrogen atom or a methoxy group, Ro denotes a hydrogen atom, and n denotes the number O or 1, the enantiomers thereof, the diastereomers thereof, or a pharmaceutically accepthble acid addition salt thereof.
  6. 4, 2,3-Dimethoxy-T7-/3-(N-methyl-N-(2-(3,4-dimethoxy- : phenyl-ethyl)-amino)-propyl/-6,7,8,9-tetrahydro= 5H-benzocycloheptene, or a pharmaceutically acceptable acid addition salt thereof, 5, 2,3-Dimethoxy=7-hydroxy=7-/3-(N-methyl-N-(2- (3-methexy-phenyl-ethyl)-amino-propyl/-6,7,8,9- tetrahydro-5H-benzocycloheptene, or a pharma- ceutically acceptable acid addition salt thereof. ) 10 6. 2, 3-Dimethoxy-7-hydroxy-7-/=3-N-methyl-N-(3-(3- methoxy-phenoxy )-prophyl)-amino-prophyl)-6,7,8,9- tetrahydro-SH-benzocycloheptene, or a pharma- ceutically acceptable acid addition salt thereof.
  7. 7. 2,3-Dimethoxy-7-/3-(N-methyl-N=-(2-(3~methoxy- phenyl )~ethyl)-amino)-prophyl/-6,7,8,9-tetra- hydro-5H-benzocloheptene, or a pharmaceutically acceptable acid addition salt thereof, Te
  8. 8. A pharmaceutical composition suitable for the treatment or prophylaxis of ischaemic heart disorders, and for the treatment of sinus tachycardias, comprising a therapeutic amount of a compound formula 1, according to claim 1, and a pharmaceutically acceptable carrier,
PH38311A 1988-03-10 1989-03-10 New benzocycloheptene derivatives and pharmaceuticals containing these compounds PH26473A (en)

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