US4469695A
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2-(4-Hydroxyalkyl-1-piperazinyl)-2,4,6-cycloheptatrien-1-one derivatives
Assignee: Wyeth Canada Inc
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Filing: 1980-02-25
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Granted: 1984-09-04
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Expires: 2000-02-25
Abstract
Abstract 2-(4-Hydroxyalkyl-1-piperazinyl)-2,4,6-cycloheptatrien-1-one derivatives, therapeutically acceptable acid addition salts thereof, processes for their preparation, methods of using the derivatives and pharmaceutical compositions of the derivatives are disclosed. The derivatives exhibit dopamine-receptor stimulating activity in a mammal and are useful for treating hyperprolactinemia, galactorrhea, amenorrhea, impotence, Parkinsonism, diabetes, acromegaly, hypertension and other central nervous system disorders.
Inventors
- 👤 Jehan F. Bagli
- 👤 Tibor Bogri
- 👤 Katherine Voith
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-29 08:56
CPC Classifications
C; C07; C07D; C07D209/00; C07D209/02; C07D209/44; C07D209/48; A; A61; A61P; A61P25/00; A61P25/02; A61P43/00; C07D209/04; C07D209/10; C07D209/14; C07D209/16; C07D233/00; C07D233/54; C07D233/64; C07D233/66; C07D233/72; C07D233/76; C07D263/00; C07D263/02; C07D263/08; C07D263/10; C07D263/14; C07D295/00; C07D295/04; C07D295/10; C07D295/112; C07D295/116; C07D295/12; C07D295/125; C07D295/13; C07D295/14; C07D295/145; C07D295/15; C07D295/16; C07D295/18; C07D295/182; C07D295/185
Claims Analysis
Total Claims: 40
Claim 1
Independent Claim
140 words
A compound of the formula ##STR12## in which Alk is a trivalent alkylene having one to six carbon atoms; R 1 is hydrogen or lower alkyl having one to three carbon atoms; R 2 and R 3 each is hydrogen or lower alkyl having one to three carbon atoms; R 4 is hydrogen, phenyl, hydroxy, phenoxy, phenyl mono-, di- or trisubstituted with methylsulfonylamino, lower alkyl, halo, lower alkoxy, hydroxy or trifluoromethyl, or phenoxy mono-, di- or trisubstituted with lower alkyl, halo, lower alkoxy, hydroxy or trifluoromethyl; and R 5 represents a substituent at positions 3,4,5,6 or 7 of the 2,4,6-cycloheptatrien-1-one ring and is selected from hydrogen, halo, lower alkyl, lower alkoxy, trifluoromethyl, or 1-oxo(lower)alkylamino; with the proviso that when R 4 is hydroxy, the hydroxy groups are joined to different carbon atoms; or a therapeutically acceptable acid addition salt thereof.
Claim 2
Dependent Claim
140 words
A compound of the formula ##STR12## in which Alk is a trivalent alkylene having one to six carbon atoms; R 1 is hydrogen or lower alkyl having one to three carbon atoms; R 2 and R 3 each is hydrogen or lower alkyl having one to three carbon atoms; R 4 is hydrogen, phenyl, hydroxy, phenoxy, phenyl mono-, di- or trisubstituted with methylsulfonylamino, lower alkyl, halo, lower alkoxy, hydroxy or trifluoromethyl, or phenoxy mono-, di- or trisubstituted with lower alkyl, halo, lower alkoxy, hydroxy or trifluoromethyl; and R 5 represents a substituent at positions 3,4,5,6 or 7 of the 2,4,6-cycloheptatrien-1-one ring and is selected from hydrogen, halo, lower alkyl, lower alkoxy, trifluoromethyl, or 1-oxo(lower)alkylamino; with the proviso that when R 4 is hydroxy, the hydroxy groups are joined to different carbon atoms; or a therapeutically acceptable acid addition salt thereof.
Claim 3
Dependent Claim
93 words
A compound of claim 1 in which R 1 is hydrogen or methyl; R 2 and R 3 each is hydrogen or lower alkyl having one to three carbon atoms, R 4 is hydrogen, phenyl, hydroxy, phenoxy, phenyl mono-, di- or trisubstituted with methylsulfonylamino, lower alkoxy or hydroxy, or phenoxy mono-, di- or trisubstituted with lower alkyl or halo; and R 5 represents a substituent at position 7 of the 2,4,6-cycloheptatrien-1-one ring and is selected from hydrogen, halo, lower alkyl, lower alkoxy, trifluoromethyl, or 1-oxo(lower)alkylamino; or a therapeutically acceptable acid addition salt thereof.
Claim 4
Dependent Claim
91 words
A compound of claim 1 in which Alk is a trivalent alkylene having one to three carbon atoms; R 1 is hydrogen; R 2 and R 3 each is hydrogen or lower alkyl having one to three carbon atoms; R 4 is hydrogen, phenyl, hydroxy, phenoxy, phenyl mono-, di- or trisubstituted with lower alkoxy or hydroxy, or phenoxy monosubstituted with lower alkyl; or halo; R 5 represents a substituent at position 7 of the 2,4,6-cycloheptatrien-1-one ring and is selected from hydrogen or bromo; or a therapeutically acceptable acid addition salt thereof.
Claim 5
Dependent Claim
63 words
A compound of claim 1 in which Alk is CH; R 1 , R 2 and R 5 are hydrogen; R 3 is hydrogen or lower alkyl having one to three carbon atoms; and R 4 is phenyl or phenyl mono-, di- or trisubstituted at positions 3, 4 or 5 with lower alkoxy or hydroxy; or a therapeutically acceptable acid addition salt thereof.
Claim 6
Dependent Claim
27 words
4-(2-Oxo-3,5,7-cycloheptatrien-1-yl)-1-piperazine-ethanol, a compound of claim 1 wherein R 1 , R 2 , R 3 , R 4 and R 5 are hydrogen and Alk is CH.
Claim 7
Dependent Claim
29 words
2-[4-(3-Hydroxypropyl)-1-piperazinyl]-2,4,6-cycloheptatrien-1-one, a compound of claim 1 wherein R 1 , R 2 , R 3 , R 4 and R 5 are hydrogen and Alk is CH 2 CH.
Claim 8
Dependent Claim
28 words
2-[4-[2-Hydroxy-2-(3,4-dimethoxyphenyl)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one, a compound of claim 1 wherein R 1 , R 2 , R 3 and R 5 are hydrogen; R 4 is 3,4-dimethoxyphenyl; and Alk is CH.
Claim 9
Dependent Claim
13 words
(+)-2-[4-[2-Hydroxy-2-(3,4-dimethoxyphenyl)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one having [α] D 25 +11.7° (c=1, dimethylformamide), a compound of claim 7.
Claim 10
Dependent Claim
13 words
(-)-2-[4-[2-Hydroxy-2-(3,4-dimethoxyphenyl)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one having [α] D 25 -12.0° (c=1, dimethylformamide), a compound of claim 7.
Claim 11
Dependent Claim
27 words
2-[4-[2-Hydroxy-2-[4-(methylsulfonylamino)phenyl]ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one, a compound of claim 1 wherein R 1 R 2 , R 3 and R 5 are hydrogen; R 4 is 4-(methylsulfonylamino)phenyl; and Alk is CH.
Claim 12
Dependent Claim
30 words
2-[4-[3-[4-(1,1-Dimethylethyl)phenoxy]-2-hydroxypropyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one, a compound of claim 1 wherein R 1 , R 2 , R 3 and R 5 are hydrogen; R 4 is 4-(1,1-dimethylethyl)phenoxy; and Alk is CHCH 2 .
Claim 13
Dependent Claim
30 words
2-[4-[3-(4-Chlorophenoxy)-2-hydroxypropyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one, a compound of claim 1 wherein R 1 , R 2 , R 3 and R 5 are hydrogen; R 4 is 4-chlorophenoxy; and Alk is CHCH 2 .
Claim 14
Dependent Claim
28 words
2-[4-(2-Hydroxyethyl)-3-methyl-1-piperazinyl]-2,4,6-cycloheptatrien-1-one, a compound of claim 1 wherein R 1 is 3-methyl; R 2 , R 3 , R 4 and R 5 are hydrogen; and Alk is CH.
Claim 15
Dependent Claim
29 words
2-[4-(2-Hydroxypropyl)-1-piperazinyl]-2,4,6-cycloheptatrien-1-one, a compound of claim 1 wherein R 1 , R 2 , R 3 , R 4 and R 5 are hydrogen; and Alk is CHCH 3 .
Claim 16
Dependent Claim
28 words
2-[4-[2-Hydroxy-2-(3,4,5-trimethoxyphenyl)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one, a compound of claim 1 wherein R 1 , R 2 , R 3 and R 5 are hydrogen; R 4 is 3,4,5-trimethoxyphenyl; and Alk is CH.
Claim 17
Dependent Claim
36 words
2-[4-[2-Hydroxy-2-(3,4-dimethoxyphenyl)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one hydrochloride, a compound of claim 1 wherein R 1 , R 2 , R 3 and R 5 are hydrogen; R 4 is 3,4-dimethoxyphenyl; and Alk is CH, and acid addition salt is the hydrochloride.
Claim 18
Dependent Claim
28 words
2-[4-(2-Hydroxy-2-phenylethyl)-1-piperazinyl]-2,4,6-cycloheptatrien-1-one, a compound of claim 1 wherein R 1 , R 2 , R 3 and R 5 are hydrogen; R 4 is phenyl; and Alk is CH.
Claim 19
Dependent Claim
29 words
2-[4-[2-Hydroxy-1-methyl-2-(3,4-dimethoxyphenyl)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one, a compound of claim 1 wherein R 1 , R 2 and R 5 are hydrogen; R 3 is methyl; R 4 is 3,4-dimethoxyphenyl; and Alk is CH.
Claim 20
Dependent Claim
10 words
2-[4-[2-Hydroxy-1-methyl-2-(3,4-dimethoxyphenyl)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one, having mp 133°-135° C., a compound of claim 18.
Claim 21
Dependent Claim
14 words
2-[4-[2-Hydroxy-1-methyl-2-(3,4-dimethoxyphenyl)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one, the maleate salt thereof having mp 165°-168° C., a compound of claim 18.
Claim 22
Dependent Claim
13 words
(+)-2-[4-[2-Hydroxy-1-methyl-2-(3,4-dimethoxyphenyl)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one, having [α] D 25 +84.2° (c=1, dimethylformamide), a compound of claim 20.
Claim 23
Dependent Claim
13 words
(-)-2-[4-[2-Hydroxy-1-methyl-2-(3,4-dimethoxyphenyl)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one, having [α] D 25 -82.5° (c=1, dimethylformamide), a compound of claim 20.
Claim 24
Dependent Claim
28 words
2-[4-[1-(Hydroxymethyl)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one, a compound of claim 1 wherein R 1 , R 3 , R 4 and R 5 are hydrogen; R 2 is methyl; and Alk is CH.
Claim 25
Dependent Claim
30 words
2-[4-(2-Hydroxy-1-methylpropyl)-1-piperazinyl]-2,4,6-cycloheptatrien-1-one, a compound of claim 1 wherein R 1 , R 2 , R 4 and R 5 are hydrogen; R 3 is methyl; and Alk is CHCH 3 .
Claim 26
Dependent Claim
28 words
2-[4-[2-Hydroxy-2-(4-methoxyphenyl)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one, a compound of claim 1 wherein R 1 , R 2 , R 3 and R 5 are hydrogen; R 4 is 4-methoxyphenyl; and Alk is CH.
Claim 27
Dependent Claim
28 words
2-[4-[2-Hydroxy-2-(4-fluorophenyl)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one, a compound of claim 1 wherein R 1 , R 2 , R 3 and R 5 are hydrogen; R 4 is 4-fluorophenyl; and Alk is CH.
Claim 28
Dependent Claim
30 words
2-[4-(2,3-Dihydroxypropyl)-1-piperazinyl]-2,4,6-cycloheptatrien-1-one, a compound of claim 1 wherein R 1 , R 2 , R 3 and R 5 are hydrogen; R 4 is hydroxy; and Alk is CHCH 2 .
Claim 29
Dependent Claim
28 words
2-[4-[2-Hydroxy-2-(3-methoxyphenyl)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one, a compound of claim 1 wherein R 1 , R 2 , R 3 and R 5 are hydrogen; R 4 is 3-methoxyphenyl; and Alk is CH.
Claim 30
Dependent Claim
28 words
2-[4-[2-Hydroxy-2-(4-hydroxy-3-methoxyphenyl)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one, a compound of claim 1 wherein R 1 , R 2 , R 3 and R 5 are hydrogen; R 4 is 4-hydroxy-3-methoxyphenyl; and Alk is CH.
Claim 31
Dependent Claim
120 words
A pharmaceutical composition, for stimulating dopamine receptors in a mammal in need thereof, which comprises an effective dopamine receptor stimulating amount of a compound of the formula ##STR13## in which Alk is a trivalent alkylene having one to three carbon atoms; R 1 is hydrogen; R 2 and R 3 each is hydogen or lower alkyl having one to three carbon atoms; R 4 is hydrogen, phenyl, hydroxy, phenoxy, phenyl mono-, di- or trisubstituted with lower alkoxy or hydroxy, or phenoxy monosubstituted with lower alkyl or halo; R 5 represents a substituent at position 7 of the 2,4,6-cycloheptatrien-1-one ring and is selected from hydrogen or bromo; or a therapeutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier therefor.
Claim 32
Dependent Claim
120 words
A pharmaceutical composition, for stimulating dopamine receptors in a mammal in need thereof, which comprises an effective dopamine receptor stimulating amount of a compound of the formula ##STR13## in which Alk is a trivalent alkylene having one to three carbon atoms; R 1 is hydrogen; R 2 and R 3 each is hydogen or lower alkyl having one to three carbon atoms; R 4 is hydrogen, phenyl, hydroxy, phenoxy, phenyl mono-, di- or trisubstituted with lower alkoxy or hydroxy, or phenoxy monosubstituted with lower alkyl or halo; R 5 represents a substituent at position 7 of the 2,4,6-cycloheptatrien-1-one ring and is selected from hydrogen or bromo; or a therapeutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier therefor.
Claim 33
Dependent Claim
128 words
A pharmaceutical composition, for stimulating dopamine receptors in a mammal in need thereof, comprising an effective dopamine receptor stimulating amount of a compound of the formula ##STR14## which Alk is a trivalent alkylene having one to three carbon atoms; R 1 is hydrogen; R 2 and R 3 each is hydrogen or lower alkyl having one to three carbon atoms; R 4 is hydrogen, phenyl, hydroxy, phenoxy, phenyl mono-, di- or trisubstituted with lower alkoxy or hydroxy, or phenoxy monosubstituted with lower alkyl or halo; R 5 represents a substituent at position 7 of the 2,4,6-cycloheptatrien-1-one ring and is selected from hydrogen or bromo; or a therapeutically acceptable acid addition salt thereof, and an agent selected from bromocriptine, lergotrile, levodopa, combination of levodopa and carbidopa, L-prolyl-L-leucylglycinamide and L-prolyl-N-methyl-D-leucylglycinamide.
Claim 34
Dependent Claim
128 words
A pharmaceutical composition, for stimulating dopamine receptors in a mammal in need thereof, comprising an effective dopamine receptor stimulating amount of a compound of the formula ##STR14## which Alk is a trivalent alkylene having one to three carbon atoms; R 1 is hydrogen; R 2 and R 3 each is hydrogen or lower alkyl having one to three carbon atoms; R 4 is hydrogen, phenyl, hydroxy, phenoxy, phenyl mono-, di- or trisubstituted with lower alkoxy or hydroxy, or phenoxy monosubstituted with lower alkyl or halo; R 5 represents a substituent at position 7 of the 2,4,6-cycloheptatrien-1-one ring and is selected from hydrogen or bromo; or a therapeutically acceptable acid addition salt thereof, and an agent selected from bromocriptine, lergotrile, levodopa, combination of levodopa and carbidopa, L-prolyl-L-leucylglycinamide and L-prolyl-N-methyl-D-leucylglycinamide.
Claim 35
Dependent Claim
25 words
The pharmaceutical composition of claim 30 or 31 wherein said compound is selected from 2-[4-[2-hydroxy-1-methyl-2-(3,4-dimethoxyphenyl)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one and 2-[4-[2-hydroxy-2-(3,4-dimethoxyphenyl)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one, or a therapeutically acceptable acid addition salt thereof.
Claim 36
Dependent Claim
52 words
A method of stimulating dopamine receptors in a mammal in need thereof, which comprises administering to said mammal an effective dopamine receptor stimulating amount of a composition of claim 30, in combination with an effective amount of an agent selected from bromocriptine lergotrile, levodopa, combination of levodopa and carbidopa, L-prolyl-L-leucylglycinamide and L-prolyl-N-methyl-D-leucylglycinamide.
Claim 37
Dependent Claim
33 words
The method of treating disorders in a mammal, which disorders respond to dopamine-receptor stimulation, which method comprises administering to said mammal an effective dopamine receptor stimulating amount of a composition of claim 30.
Claim 38
Dependent Claim
30 words
A method of stimulating dopamine receptors in a mammal in need thereof, which comprises administering to said mammal an effective dopamine receptor stimulating amount of a composition of claim 30.
Claim 39
Dependent Claim
19 words
The method of claim 33 wherein the composition of claim 44, and said agent are administered sequentially or simultaneously.
Claim 40
Dependent Claim
24 words
The method of claim 35 wherein the composition contains a compound selected from 2-[4-[2-hydroxy-1-methyl-2-(3,4-dimethoxyphenyl)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one and 2-[4-[2-hydroxy-2-(3,4-dimethoxyphenyl)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one, or a therapeutically acceptable acid addition salt thereof.
References Cited (Backward Citations)
No citation records indexed.
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