CA1257273A - Indole derivatives - Google Patents
Indole derivativesInfo
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- CA1257273A CA1257273A CA000445776A CA445776A CA1257273A CA 1257273 A CA1257273 A CA 1257273A CA 000445776 A CA000445776 A CA 000445776A CA 445776 A CA445776 A CA 445776A CA 1257273 A CA1257273 A CA 1257273A
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- indolyl
- indole
- butyl
- alkyl
- piperidyl
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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Abstract
"INDOLE DERIVATIVE"
Abstract Indole derivatives of the general formula I
I
in which Ind is a 3-indolyl radical which can be substituted once or twice by alkyl, O-alkyl, S-alkyl, SO-alkyl, SO2-alkyl, OH, F, Cl, Br, CF3 and/or CN or by a methylenedioxy group, A is -(CH2)n-, n is 3, 4 or 5, Ar is a phenyl group which is unsubstituted or is substituted once or twice by alkyl, O-alkyl, S-alkyl, SO-alkyl, SO2-alkyl, OH, F, Cl, Br, CF3 and/or CN or by a methylenedioxy group, and the two radicals L are each H or together are a C-C bond, and in which the alkyl groups each have 1 - 4 C atoms, and their physiologically acceptable acid addition salts, exhibit effects on the central nervous system.
Abstract Indole derivatives of the general formula I
I
in which Ind is a 3-indolyl radical which can be substituted once or twice by alkyl, O-alkyl, S-alkyl, SO-alkyl, SO2-alkyl, OH, F, Cl, Br, CF3 and/or CN or by a methylenedioxy group, A is -(CH2)n-, n is 3, 4 or 5, Ar is a phenyl group which is unsubstituted or is substituted once or twice by alkyl, O-alkyl, S-alkyl, SO-alkyl, SO2-alkyl, OH, F, Cl, Br, CF3 and/or CN or by a methylenedioxy group, and the two radicals L are each H or together are a C-C bond, and in which the alkyl groups each have 1 - 4 C atoms, and their physiologically acceptable acid addition salts, exhibit effects on the central nervous system.
Description
~2S727~
This invention relates to new indole derivatives having valuable pharmacological properties.
It is an object of this invention to provide new compounds having useful pharmacological proper-ties.
These objects have been achieved by providing indole derivatives of the general formula I
Ind-A-N ~--L
~ Ar ~257273 in which Ind is a 3-indolyl radical which can ~e substituted once or twice by alkyl, O-alkyl, S-alkyl, SO-alkyl, SO2-alkyl, OH, F, Cl, Br, CF3 and/or CN or by a methylenedioxy group, A is ~(CH2)n~, n is 3, 4 or 5, Ar is a phenyl group which is unsubstituted or is substituted once or twice by alkyl, O-alkyl, S-alkyl, SO-alkyl, SO2-alkyl, OH, F, Cl, Br, CF3 and/or CN or by a me-thylenedioxy group, and the two radicals L are each H or together are a C-C bond, and in which the alkyl groups each have l - 4 C atoms, and their physiologically acceptable acid addition salts.
In the following text, for reasons of simplicity, the group -N ~ L is denoted "Q", so that the formula I can also be written in the form Ind-A-Q-Ar.
It was found that the compounds of the formula I
and their physiologic~lly acceptable acid addition salts have valuable pharmacological properties. Thus, in particular, they exhibit effects on the central nervous system, especially dopamine-stimulating (anti-parkinsonism) effects.
Specifically, the compounds of the formula I induce contralateral turning behavior in rats with ~;Z 57:273 hemiparkinsonism (which may be demonstrated by the method of Ungerstedt et al., Brain Res. 24, (1970), 485-493) and they inhibit the binding of tritiated dopamine agonists and antagonists to striatal receptors (which may be demonstrated by the method of Schwarcz et al., J. Neurochemistry, 34, (1980), 772-773 and Creese et al., European J. Pharmacol., 46, (1977), 377-381). In addition, the compounds inhibit the linguomandibular reflex in the anaesthetized rat (which may be demonstrated by methods derived from Barnett et al., European J. Pharmacol. 21, (1973), 178-182, and from Ilhan et al., European J. Pharmacol. 33, (1975) 61-64). Moreover, analgesic effects occur.
Thus, compounds of the formula I and their physiologically acceptable acid addition salts can be used as active compounds in medicaments and also as intermediate products for the preparation of other active compounds in medicaments.
The invention relates to the indole derivatives of the formula I and their physiologically acceptable acid addition salts.
In the radicals Ind and Ar, alkyl is preferably methyl, but is also ethyl, n-propyl, isopropyl, n-butyl, lZ~q~73 isobutyl, sec.-butyl or tert.-butyl. O-Alkyl is preferably methoxy, but also ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy or tert.-butoxy. S-Alkyl is preferably methylthio, but is also ethylthio, n-propylthio, i~opropylthio, n-butylthio, isobutylthio, sec.-butylthio or tert.-butylthio. SO-Alkyl is preferably methylsulfinyl, but is also ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, isobutylsulfinyl, sec.-butylsulfi~yl or tert.-butylsulfinyl. SO2-Alkyl is preferably methylsulfonyl, but is also ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n~butylsulfonyl, isobutylsulfonyl, sec.-butylsulfonyl or tert.-butylsulfonyl.
The radical Ind is, in particular, an unsubstituted 3-indolyl radical. However, if Ind is a substituted 3-indolyl radical, then it is preferably substituted once, in particular in the 2-, 5- or 6-position. Substitution in the 1-, 4- or 7-position is also possible. Preferred disubstituted 3-indolyl radicals are substituted in the 5,6-positions; disubstitution is also possible in the 1,2-, 1,4-, 1,5-, 1,6-, 1,7-, 2,4-, 2,5-, 2,6-, 2,7-, 4,5-, 4,6-, 4,7-, 5,7- or 6,7-positions. In all these cases the substituents can be identical or different.
~pecifically, the preferred substituents in the benzene ring of the Ind radical are methyl, ethyl, methoxy, ethoxy, methylthio, ethylthio, OH, F, Cl, Br, CF3 and CN.
Accordingly, some preferred meanings of the Ind radical are 3-indolyl, but also 1-, 2-, 4- r 5-, 6- or 7- methyl-3-~L257273 indolyl, 1-, 2-, 4-, 5-, 6- or 7-ethyl-3-indolyl, 4-, 5-, 6-or 7-methoxy-3-indolyl, 4-, 5-, 6- or 7-ethoxy-3-indolyl, 4-, 5-, 6- or 7-methylthio-3-indolyl, 4-, 5-, 6- or 7-ethylthio 3-indolyl, 4-, 5-, 6- or 7-methylsulfinyl-3-indolyl, 4-, 5-, 6- or 7-methylsulfonyl-3-indolyl, 4-, 5-, 6- or 7-hydroxy-3-indolyl, 4-, 5-, 6- or 7-fluoro-3-indolyl, 4-, 5-, 6- or 7-chloro-3-indolyl, 4-, 5-, 6- or 7-bromo-3-indolyl, 4-, 5-, 6-or 7-trifllloromethyl-3-indolyl, 4-, 5-, 6- or 7-cyano-3-indolyl, 1,2-, 1,4-, 1,5-, 1,6-, 1,7-, 2,4-, 2,5-, 2,6-,
This invention relates to new indole derivatives having valuable pharmacological properties.
It is an object of this invention to provide new compounds having useful pharmacological proper-ties.
These objects have been achieved by providing indole derivatives of the general formula I
Ind-A-N ~--L
~ Ar ~257273 in which Ind is a 3-indolyl radical which can ~e substituted once or twice by alkyl, O-alkyl, S-alkyl, SO-alkyl, SO2-alkyl, OH, F, Cl, Br, CF3 and/or CN or by a methylenedioxy group, A is ~(CH2)n~, n is 3, 4 or 5, Ar is a phenyl group which is unsubstituted or is substituted once or twice by alkyl, O-alkyl, S-alkyl, SO-alkyl, SO2-alkyl, OH, F, Cl, Br, CF3 and/or CN or by a me-thylenedioxy group, and the two radicals L are each H or together are a C-C bond, and in which the alkyl groups each have l - 4 C atoms, and their physiologically acceptable acid addition salts.
In the following text, for reasons of simplicity, the group -N ~ L is denoted "Q", so that the formula I can also be written in the form Ind-A-Q-Ar.
It was found that the compounds of the formula I
and their physiologic~lly acceptable acid addition salts have valuable pharmacological properties. Thus, in particular, they exhibit effects on the central nervous system, especially dopamine-stimulating (anti-parkinsonism) effects.
Specifically, the compounds of the formula I induce contralateral turning behavior in rats with ~;Z 57:273 hemiparkinsonism (which may be demonstrated by the method of Ungerstedt et al., Brain Res. 24, (1970), 485-493) and they inhibit the binding of tritiated dopamine agonists and antagonists to striatal receptors (which may be demonstrated by the method of Schwarcz et al., J. Neurochemistry, 34, (1980), 772-773 and Creese et al., European J. Pharmacol., 46, (1977), 377-381). In addition, the compounds inhibit the linguomandibular reflex in the anaesthetized rat (which may be demonstrated by methods derived from Barnett et al., European J. Pharmacol. 21, (1973), 178-182, and from Ilhan et al., European J. Pharmacol. 33, (1975) 61-64). Moreover, analgesic effects occur.
Thus, compounds of the formula I and their physiologically acceptable acid addition salts can be used as active compounds in medicaments and also as intermediate products for the preparation of other active compounds in medicaments.
The invention relates to the indole derivatives of the formula I and their physiologically acceptable acid addition salts.
In the radicals Ind and Ar, alkyl is preferably methyl, but is also ethyl, n-propyl, isopropyl, n-butyl, lZ~q~73 isobutyl, sec.-butyl or tert.-butyl. O-Alkyl is preferably methoxy, but also ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy or tert.-butoxy. S-Alkyl is preferably methylthio, but is also ethylthio, n-propylthio, i~opropylthio, n-butylthio, isobutylthio, sec.-butylthio or tert.-butylthio. SO-Alkyl is preferably methylsulfinyl, but is also ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, isobutylsulfinyl, sec.-butylsulfi~yl or tert.-butylsulfinyl. SO2-Alkyl is preferably methylsulfonyl, but is also ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n~butylsulfonyl, isobutylsulfonyl, sec.-butylsulfonyl or tert.-butylsulfonyl.
The radical Ind is, in particular, an unsubstituted 3-indolyl radical. However, if Ind is a substituted 3-indolyl radical, then it is preferably substituted once, in particular in the 2-, 5- or 6-position. Substitution in the 1-, 4- or 7-position is also possible. Preferred disubstituted 3-indolyl radicals are substituted in the 5,6-positions; disubstitution is also possible in the 1,2-, 1,4-, 1,5-, 1,6-, 1,7-, 2,4-, 2,5-, 2,6-, 2,7-, 4,5-, 4,6-, 4,7-, 5,7- or 6,7-positions. In all these cases the substituents can be identical or different.
~pecifically, the preferred substituents in the benzene ring of the Ind radical are methyl, ethyl, methoxy, ethoxy, methylthio, ethylthio, OH, F, Cl, Br, CF3 and CN.
Accordingly, some preferred meanings of the Ind radical are 3-indolyl, but also 1-, 2-, 4- r 5-, 6- or 7- methyl-3-~L257273 indolyl, 1-, 2-, 4-, 5-, 6- or 7-ethyl-3-indolyl, 4-, 5-, 6-or 7-methoxy-3-indolyl, 4-, 5-, 6- or 7-ethoxy-3-indolyl, 4-, 5-, 6- or 7-methylthio-3-indolyl, 4-, 5-, 6- or 7-ethylthio 3-indolyl, 4-, 5-, 6- or 7-methylsulfinyl-3-indolyl, 4-, 5-, 6- or 7-methylsulfonyl-3-indolyl, 4-, 5-, 6- or 7-hydroxy-3-indolyl, 4-, 5-, 6- or 7-fluoro-3-indolyl, 4-, 5-, 6- or 7-chloro-3-indolyl, 4-, 5-, 6- or 7-bromo-3-indolyl, 4-, 5-, 6-or 7-trifllloromethyl-3-indolyl, 4-, 5-, 6- or 7-cyano-3-indolyl, 1,2-, 1,4-, 1,5-, 1,6-, 1,7-, 2,4-, 2,5-, 2,6-,
2,7-, 4,5-, 4,6-, 4,7-, 5,6-, 5,7- or 6,7-dimethyl-3-indolyl, l-methyl-4-, -5-, -6- or -7-methoxy-3-indolyl, 1-methyl-4-, -5-, -6- or -7-methylthio-3-indolyl, 1-methyl-4-, -5-, -6- or -7-fluoro-3-indolyl, 1-methy1-4-, -5-, -6- or -7-chloro-3-indolyl, l-methyl-4-, -5-, -6- or -7-bromo-3-indolyl, 1-methyl-4-, -5-, -6- or -7-trifluoromethyl-3-indolyl, 1-methyl-4-, -5-, -6- or -7-cyano-3-indolyl, 2-methyl-4-, -5-, -6- or -7-methoxy-3-indolyl, 2-methyl-4-, -5-, -6- or -7-methylthio-3-indolyl, 2-methyl-4-, -5-, -6-, or -7-fluoro-3-indolyl, 2-methyl-4-, -5-, -6- or -7-chloro-3-indolyl, 2-methyl-4-, -5-, -6- or -7-bromo-3-indolyl, 2-methyl-4-, -5-, -6- or -7-trifluoromethyl-3-indolyl, 2-methyl-4-, -5-, -6- or -7-cyano-3-indolyl, 4-methyl-5-fluoro-3-indolyl, 5-fluoro-6-or -7-methyl-3-indolyl, 4-methyl-5-chloro-3-indolyl, 4-chloro-5-methyl-3-indolyl, 5-methyl-6- or -7-chloro-3-indolyl, 5-chloro-6- or -7-methyl-3-indolyl, 4,5-, 4,6-, 4,7-, 5,6-, 5,7- or 6,7-dimethoxy-3-indolyl, 4,5-, 4,6-, 4,7-, 5,6-, 5,7- or 6,7-dichloro-3-indolyl, 4-trifluoromethyl-5-, -6- or -7-chloro-3-indolyl.
~572'73 The parameter n is prefera~ly 4. The group A is thus preferably -~CH2)4-.
The radical Ar is preferably substituted phenyl, preferably substituted once. However, the phenyl group can also be unsubstituted or substituted twice, it being possible for the subs~ituents to be identical or different. Preferred substituents on the phenyl group are OH, also methyl, methoxy, F, Cl, Br or trifluoromethyl. Specifically, Ar is preferably m-hydroxyphenyl, also preferably o- or p-hydroxyphenyl as well as phenyl, also o-, m- or p-fluorophenyl, o-, m- or p-chlorophenyl, o-, m- or p-bromophenyl, o-, m- or p-tolyl, o-, m- or p-methoxyphenyl, o-, m- or p-trifluoromethylphenyl, but also, for example, o-, m- o~ p-ethylphenyl, o-, m- or p-n-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-n-butylphenyl, o-, m- or p-isobutylphenyl, o-, m- or p-ethoxyphenyl, also dihalogenophenyl such as 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6~, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-di-bromophenyl, 2-fluoro-4-chlorophenyl, 2-bromo-4-chloro-phenyl; dimethylphenyl, such as 2,3-, 2,4-, 2,5-, 2,6-, 3,4-or 3,5-dimethylphenyl; dimethoxyphenyl, such as 2,3-, 2,4-, 2,5-, 2, 6-, 3,4- o r 3,5-dimethoxyphenyl; or methylchlorophenyl, such as 2-methyl-4-chlorophenyl.
Accordingly, the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the meanings indicated above, in particular one of the preferred meanings indicated above.
~257;Z73 Some preferred ~roups of compounds can be expressed by the following part formulae Ia to In which correspond to the formula I and wherein the radicals and parameters which are not specified have the meaning indicated for formula I, but wherein in Ia, Ind is 3-indolyl, methyl-3-indolyl, dimethyl-
~572'73 The parameter n is prefera~ly 4. The group A is thus preferably -~CH2)4-.
The radical Ar is preferably substituted phenyl, preferably substituted once. However, the phenyl group can also be unsubstituted or substituted twice, it being possible for the subs~ituents to be identical or different. Preferred substituents on the phenyl group are OH, also methyl, methoxy, F, Cl, Br or trifluoromethyl. Specifically, Ar is preferably m-hydroxyphenyl, also preferably o- or p-hydroxyphenyl as well as phenyl, also o-, m- or p-fluorophenyl, o-, m- or p-chlorophenyl, o-, m- or p-bromophenyl, o-, m- or p-tolyl, o-, m- or p-methoxyphenyl, o-, m- or p-trifluoromethylphenyl, but also, for example, o-, m- o~ p-ethylphenyl, o-, m- or p-n-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-n-butylphenyl, o-, m- or p-isobutylphenyl, o-, m- or p-ethoxyphenyl, also dihalogenophenyl such as 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6~, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-di-bromophenyl, 2-fluoro-4-chlorophenyl, 2-bromo-4-chloro-phenyl; dimethylphenyl, such as 2,3-, 2,4-, 2,5-, 2,6-, 3,4-or 3,5-dimethylphenyl; dimethoxyphenyl, such as 2,3-, 2,4-, 2,5-, 2, 6-, 3,4- o r 3,5-dimethoxyphenyl; or methylchlorophenyl, such as 2-methyl-4-chlorophenyl.
Accordingly, the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the meanings indicated above, in particular one of the preferred meanings indicated above.
~257;Z73 Some preferred ~roups of compounds can be expressed by the following part formulae Ia to In which correspond to the formula I and wherein the radicals and parameters which are not specified have the meaning indicated for formula I, but wherein in Ia, Ind is 3-indolyl, methyl-3-indolyl, dimethyl-
3-indolyl, methoxy-3-indolyl, dimethoxy-3-indolyl, hydroxy-3-indolyl, dihydroxy-3-indolyl, fluoro-3-indolyl, chloro-3-indolyl, dichloro-3-indolyl, bromo-3-indolyl, cyano-3-indolyl or methylenedioxy-3-indolyl, the substituents preferably being in the 5- and/or 6-positions;
in Ib, Ind is 3-indolyl, 5- or 6-methyl-3-indolyl, 5,6-dimethyl-3-indolyl, 5- or 6-methoxy-3-indolyl, 5,6-dimethoxy-3-indolyl or 5-cyano-3-indolyl;
in Ic, Ind is 3-indolyl;
in Id, A is -(CH2)4-;
in Ie, Ar is hydroxyphenyl, phenyl, tolyl, methoxyphenyl, fluorophenyl, chlorophenyl, trifluoromethylphenyl or dimethoxyphenyl;
In If, Ar is hydroxyphenyl;
in Ig, Ar is phenyl;
in Ih, Ind is 3-indolyl or 5-methoxy-3-indolyl and Ar is hydroxyphenyl, phenyl, tolyl, methoxyphenyl, fluorophenyl, chlorophenyl, trifluoromethylphenyl or dimethoxyphenyl;
in Ij, Ind is 3-indolyl, A is -(CH2)4-, and Ar is 3- or 4-hydroxyphenyl, phenyl, 3- or 4-methoxyphenyl or 3,4-dimethoxypheryl;
in Ik, Ind is 3-indolyl, A is -(CH2)4-, and Ar is 3-hydroxyphenyl or phenyl;
~257273;
in Il, Ind, A, n and Ar have the meaning indicated for formula I, but Ind is an unsubstituted 3-indolyl radical or a 3-indolyl radical substituted once or twice by O-alkyl, OH, F, Cl, Br and/or CF3 only when, simultaneously, Ar is a phenyl group which is unsubstituted in the 3-position, or is a phenyl group which is substituted in the 3-position by alkyl, S-alkyl, SO-alkyl, SO2-alkyl, F, Cl, Br, CF3 or CN and can be substituted additionally in one o~ the remaining positions by alkyl, O-alkyl, S-alkyl, SO-alkyl, SO2-alkyl, OH, F, Cl, Br, CF3 or CN, or is a methylenedioxyphenyl group, and/or the two radicals L together are a C-C bond;
in Im, Ar is phenyl, 4-hydroxyphenyl or ~-methoxyphenyl;
in In, the two radicals L together are a C-C bond;
in Io, Ar is phenyl or phenyl substituted by alkyl, S-alkyl, SO-alkyl, SO2-alkyl, F, Cl, Br, CF3 and/or CN or by a methylenedioxy group;
in Ip, Ind is 3-indolyl substituted by alkyl, S-alkyl, SO-alkyl, SO2-alkyl, and/or CN or by a methylenedioxy group.
~25727:3 The compounds of the formula I can have one or more asymmetric carbon a~oms. Thus they can exist as racemates and, if several asymmetric carbon atoms are present, they can also exist as mixtures of several racemates and in various optically active forms.
The invention also relates to a process for the preparation of the compounds of the formula I and their physiologically acceptable acid addition salts, which is characterized in that a compound of the general formula II
Ind-A-X1 II
in which xl is X or NH~ and X is Cl, Br, I, OH or a reactive derivative of an OH group, and Ind and A have the indicated meanings, is reacted with a compound of the general formula III
X2C~2_CH2 \
CHL III
X3-CH2-CArL
in which x2 and X3 can be identical or different andt if xl is NH2, are each X, but otherwise are together NH, and Ar and L have the indicated meanings, or in that a compound which other~ise corresponds to the formula I, but contains one or more reducible group(s) and/or one or more additional C-C
and/or C-N bond(s) in place of one or more hydro~en atoms, is treated with a reducing agent, or in that a compound which otherwise corresponds to the formula I, but contains one or more group(s) which can be eliminated by solvolysis in place of one or more hydrogen atoms, is treated with a solvolyzing agent, or in ~hat, to prepare a compound of the formula I
:~2572~73 in which the two radicals L are together a C-C bond, a compound of the formula IV
Ind-A- ~ E IV
~ Ar in which one radical E is X, CN or NH2, the other radical E
is H, and Ind, A, Ar and X have the indicated meanings, is treated with an agent which eliminates HE, and/or in that, where appropriate, in a compound of the formula I, a thioether group is oxidized to an SO group or SO2 group, or an SO group is oxidized to an SO2 group, and/or an alkoxy group is cleaved with the formation of an OH group, and/or in that a base of the formula I obtained is converted into one of its physiologically acceptable acid addition salts by treatment with an acid.
The preparation of the compounds of the formula I
is otherwise carried out by methods known per se as are described in the literature (for example in the standard works, such as Houben-Weyl, Methoden der Organischen Chemie (Nethods of Organic Chemistry), Georg-Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York), namely under reaction conditions as are known and suitable for the reactions mentioned. Use can also be made in these prepar~tions of variants known per se which are not mentioned in more detail here.
The starting materials can, if desired, also be formed in situ in such a manner that they are not isolated ~257273 from the reaction mixture but are immediately reacted further to give the compounds of the formula I.
In the indole derivatives of the formula II, xl is preferably ~; accordingly, in the compounds of the formula III, x2 and X3 together are preferably NH. The radical X is preferably Cl or Br; however, it can also be I, OH or a reactive derivative of an OH group, in particular alk~lsulf~nyloxy having 1 - 6 ( for example methanesulfonyloxy) or arylsulfonyloxy having 6 - 10 C atoms ( for example benzenesulfonyloxy, p-toluenesulfonyloxy, 1- or 2-naphthalenesulfonyloxy) .
Accordingly, the indole derivatives of the formula I can be obtained, in particular, by reaction of the compounds of the formulae Ind-A-Cl or Ind-A-Br with compounds of the formula III, wherein X2 and X3 together are an NH
group (denoted IIIa in the following text).
Some of the compounds of the formula II and III are known; the unknown compounds of these formulae II and III can be easily prepared in analogy to the known compounds. Thus, some of the compounds of the formula II are known from German Of fenlegungsschrift 2, 827, 874 .
Alcohols of the formula Ind-A-OH can be obtained, for example, by reduction o~ the corresponding carboxylic acids or their esters. Treatment with thionyl chloride, hydrogen bromide, phosphorus tribromide or similar halogen compounds proYides the corresponding halides of the formula Ind-A-Hal (wherein ~al is Cl, Br or I ) . The corresponding sulfonyloxy compounds can be obtained form the alcohols Ind-A-OH by reaction with the corresponding sulfonyl chlorides.
12 - ~25727~
The iodine compounds of the formula Ind-A-I, for example 3-(4-iodobutyl)indole are obtained, for example, by the action of potassium iodide on the pertinent p-toluenesulfonic esters. The amines of the formula Ind-A-NH2 can be obtained, for example, from the halides with potassium phthalimide or by reduction of the corresponding nitriles.
The piperidine derivatives IIIa can be obtained, for example, by reaction of 3-piperidone with organo-metallic compounds of the formula M-Ar (in which M is an Li atom or Mg~al), subsequent hydrolysis to give the corresponding 3-Ar-3-hydroxypiperidines and, if desired, subsequent hydration to give 3-Ar-3,4-dehydropiperidines. Compounds of the formula III (X2 and X3 each being X) can be prepared, for example, by reduction of 2-Ar-glutaric esters to give 2-Ar-1,5-pentanediols and, if appropriate, subse~uent reaction with SOCl2 or PBr3.
The reaction of the compounds II and III takes place by methods as are known from the literature for the alkylation of amines. It is possible to fuse -the components together in the absence of a solvent, if appropriate in a closed tube or in an autoclave. However, it is also possible to react the compounds in the presence of an inert solvent.
Examples of suitable solvents are hydrocarbons, such as ~enzene, toluene or xylene; ketones, such as acetone or butanone; alcohols, such as methanol, ethanol, isopropanol or n-butanol; ethers, such as tetrahydrofuran (THF) or dioxane;
amides, such as dimethylformamide (DMF) or N-methylpyrrolidone; nitriles, such as acetonitrile, and, ~Z5~2~73 if appropriate, mixtures of these solvents with one anoth4er or mixtures with water. The addition of an acid-binding agent, for example an aikali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or another weak acid salt of the alkali metals or alkaline earth metals, preferably o~
potassium, sodium or calcium, or the addition of an organic base, such as triethylamine, dimethylaniline, pyridine or quinoline or an excess of the amine component Ind-A-NH2 or the piperidine derivative of the formula IIIa can be advantageous. The reaction time depends on the conditions used and is between a few minutes and 14 days, and the reaction temperature is between about 0 and 150, normally between 20 and 130.
Furthermore, it is possible to obtain a compound of the formula I by treating a precursor which, in place of hydrogen atoms, contains one or more reducible group(s) and/or one or more additional C-C and/or C-N bond(s) with reducing agents, preferably at temperatures between -80 and +250 in the presence of at least one inert solvent.
Reducible groups (replaceable by hydrogen) are, in particular, oxygen in a carbonyl group, hydroxyl, arylsulfonyloxy (for example p-toluenesulfonyloxy), N-benzenesulfonyl, N-benzyl or O-benzyl).
It is possible in principle to convert compounds which contain only one of the abovementioned groups or additional bonds or those compounds which contain together two or more of the abovementioned groups or additional bonds into a compound of the formula I by reduction. Nascent ~25q2~3 hydrogen or complex metal hydrides, but also reduction by the - method of Wolff-Kishner, is preferably used for this purpose.
Preferred starting materials for the reduction correspond to the formula V
Ind'-G-Q'-Ar' Y
in which Ind' is a 3-indolyl radical which can be substituted once or twice by alkyl, O-alkyl, S-alkyl, SO-alkyl, SO2-alkyl, OH, F, Cl, Br, CF3, CN and/or O-benzyl or by a methylenedioxy group and/or by an arylsulfonyl group or a benzyl group in the l-position, G is a -(CH2)n- chain in which, however, one or more -CH2- group~s) can be replaced by -CO-, and/or one or more hydrogen atoms can be replaced by OH
groups, Q' is Q or -N ~ ~n~
An~ is an anion of a strong acid, and Ar' is a phenyl which is unsubstituted or substituted once or twice by alkyl, O-alkyl, S-alkyl, SO-alkyl, SO2-alkyl, OH, F, Cl, Br, CF3, CN
and/or O-benzyl or by a methylenedioxy group, but in which it is not possible at the same time for Ind' to be Ind, G to be A, Q' to be Q and Ar' to be Ar.
G in the compounds of the formula V is preferably -CH2CH2CO-, -(CH2)3-CO- or -(CH2)4-cO-~
Compounds of the formula V can be prepared, for example, by reaction of 3-Ar'-1,2,3,6-tetrahydropyridines, 3-Ar'-piperidines or 3-Ar'-pyridines with compounds of the formula VI
- 15 - ~25727~3 Ind'-G-Xl VI
in which Ar', Ind', G and xl have the meanings indicated above, under the conditions indicated above for the reaction of II with III. Amides of the formula V [G = -(CH2)n_1-CO-, Q' = Q] can be obtained, for example, from the free carboxylic acids of the formula Ind'-(CH2)n_1-COOH and amines of the ~ormula IIIa, preferably in the presence of a dehydrating agent, for example carbonyldiimidazole or dicyclohexylcarbodiimide, in an inert solvent, preferably THF.
If nascent hydrogen is used as the reducing agent, this can be produced by, for example, treatment of metals with weak acids or with bases. Thus, for example, a mixture of zinc with alkali metal hydroxide solution or of iron with acetic acid can be used. It is also suitable to use sodium or another alkali metal in an alcohol, such as ethanol, isopropanol, butanol, amyl or isoamyl alcohol or phenol. It is also possible to use an aluminum/nickel alloy in an aqueous alkaline solution, optionally with the addition of ethanol. Sodium amalgam or aluminum amalgam in aqueous alcoholic or aqueous solution are also suitable to produce nascent hydrogen. The reaction can also be carried out in heterogeneous phases, it being preferable to use an aqueous and a benzene or toluene phase.
Moreover, it is possible to use with particular advantage complex metal hydrides, such as LiAlH4, NaBH4, diisobutylaluminum hydride or NaAl(OCH2CH2OCH3)2H2 and diborane, as the reducing agent, if desired with the addition of catalysts, such as BF3, AlC13 or LiBr.
~2S72~73 Solvents which are particularly suit~ble for this purpose are ethers, such as diethyl ether, di-n-butyl ether, THF, dioxane, diglyme or 1,2-dimethoxyethane, and h~drocarbons, such as benzene. For reduction with NaBH4, alcohols, such as methanol or ethanol, but also water and aqueous alcohols, are primarily suitable as the solvent.
Reduction by these methods is preferably carried out at emperatures between -80 and +150, in particular between about 0 and about 100.
It is also possible particularly advantageously to reduce -CO- groups in amides (for example those of the formula V in which G is -(CH2)n_l-CO- and Q' is Q) with LiAlH4 in THF at temperatures between 0 and 66 to give CH2 groups. During this, arylsulfonyl protective groups located in the 1-position of the indole ring can simultaneously be reductively split off.
It is possible to reduce the pyridinium salts of the formula V (wherein Q' is -N ~
Ane and An is preferably Cl or Br) to give compounds of the formula I, for example, using NaBH4 in water, methanol or ethanol or in mixtures of these solvents, with the addition, if desired, of a base, such as NaOH, at temperatures between about 0 and 80.
N-Benzyl groups can be reductively split off using sodium in liquid ammonia.
Moreover, it is possible to reduce one or more carbonyl groups to CH2 groups by the method of Wolff-~25~2'7~
Kishner, for example, by treatment with anhydrous hydrazine in absolute ethanol under pressure at temperatures between about l50 and 250.
Sodium alcoholate is advantageously used as a catalyst. The reduction can also be modified by the method of Huang-Minlon by carrying out the reaction with hydrazine hydrate in a high-boiling solvent which is miscible with water, such as diethylene glycol or triethylene glycol, in the presence of alkali, such as sodium hydroxide. As a rule, the reaction mixture is boiled for about 3-4 hours. The water is then distilled off and the hydrazone formed is decomposed at temperatures up to about ~00. The Wolff-Kishner reduction can also be carried out with hydrazine in dimethyl sulfoxide at room temperature.
Compounds which o-therwise correspond to formula I
but, in place of one or more H atoms, contain one or more group(s) which can be split off by solvolysis can be solvolyzed, in particular hydrolyzed/ to give compounds of the formula I. The starting materials for the solvolysis can be obtained, for example, by reaction of IIIa with compounds which correspond to the formula II (Xl = X) but, in place of one or more H atoms, contain one or more group(s) which can be split off by solvolysis. Thus, l-acylindole derivatives (corresponding to the formula I but containing an acyl group, preferably an alkanoyl, alkylsulfonyl or arylsulfonyl group each having up to lO C atoms, such as methane-, banzene- or p-toluene-sulfonyl in the l-position of the Ind radical) can be hydrolyzed to give the corresponding IL2~;7273 indole derivatives which are unsubs-tituted in the 1-position of the indole ring, for example, in acid, but better in neutral or alkaline medium at temperatures between 0 and 200. Sodium, potassium or calcium hydroxide, sodium or potassium carbonate or ammonia are preferably used as the basic catalysts. The solvents which are preferably chosen are water, lower alcohols, such as methanol or ethanol, ethers, such as THF or dioxane, sulfones, such as tetramethylenesulfone or their mixtures. Hydrolysis can even take place just on treatment with water alone, in particular at the boiling point.
Moreover, compounds of the formula I can be obtained by splitting off HE from compounds of the formu~a IV
to form a double bond. According to the definition of E, this can comprise, for example, splitting off hydrogen halide, water (dehydration), a carboxylic acid or another acid, ammonia or HCN. The starting materials of the formula IV can be obtained, for example, by reaction of II (X1 = X) with a compound of the formula VII
HN ~ E VII
E Ar in which E and Ar have the indicated meanings.
If one of the radicals E is Hal, this substituent can easily be eliminated under basic reaction conditions.
The following can be used as bases: alkali metal hydroxides, ~2s~2q3 alkali metal carbonates, alcoholates, such as, for example, potassium tert.-butylate, amines, such as, for example, dimethylaniline, pyridine, collidine or quinoline; the solvent used îs, for example, benzene, toluene, cyclohexane, methanol, dioxane, THF or tert.-butanol. The amines used as bases can also be employed in excess as the solvent. If one of the radicals E is an OH group, then acids, such as acetic acid, hydrochloric acid or mixtures of the two, are preferably used as the agent to split off water. The addition of a solvent (for example water or ethanol) can be ad~antageous. The elimination of acyl, alkylsulfonyl and alkoxysulfonyloxy or amino radicals can be carried out under similar conditions. An elimination of sulfonic acid radicals, for example mesylates or tosylates, takes place under mild conditions by boiling in DMF or dimethyl sulfoxide with alkali metal carbonates, for example Li2CO3 or with potassium acetate. Ammonia can be split off by just heating the salts of the corresponding amino compounds (especially the 3-amino derivatives). In a similar manner, HCN can be split off from compounds of the formula IV (one group E = CN) by heating. The elimination of HE from IV generally takes place at temperatures between about 0 and about 250, pre~erably between 50 and 200.
Furthermore, the thioether group in a thioether of the formula I can be oxidized to a SO group or to an SO2 group, or the SO group in a sulfoxide of the formula I can be oxidized to an SO2 group. The thioether or sulfoxide groups to be oxidized can be present as substituents in the radical ~257273 Ind and/or in the radical Ar. If the intention is to obtain the sulfoxides, then the oxidation is carried out, for example, with hydrogen peroxide, peracids, such as m-chloroperbenzoic acid, Cr(VI) compounds, such as chromic acid, KMnO4, l-chlorobenzotriazole, Ce(IV) compounds, such as (NH4)2Ce(NO3)6, negatively substituted aromatic diazonium salts, such as o- or p-nitrophenyldiazonium chloride, or electrolytically under relatively mild conditions and at relatively low temperatures (about -80 to -~100). If, on the other hand, the intention is to obtain the sulfones (from the thioethers or the sulfoxides), then the same oxidizing agents are used under more forcing conditions and/or in excess and, as a rule, at higher temperatures. It is possible in these reactions for the customary inert solvents to be present or absent. Examples of suitable inert solvents are water, aqueous mineral acids, aqueous al~ali metal hydroxide solutions, lower alcohols, such as methanol or ethanol, esters, such as ethyl acetate, ketones, such as acetone, lower carboxylic acids, such as acetic acid, nitriles, such as acetonitrile, hydrocarbons, such as benzene, and chlorinated hydrocarbons, such as chloroform or CCl~. A
preferred oxidizing agent is 30% aqueous hydrogen peroxide.
On using the calculated amount in solvents such as acetic acid, acetone, methanol, ethanol or aqueous sodium hydroxide ~olution at temperatures between -20 and 100, this leads to the sulfoxides, while in excess at higher temperatures, preferably in acetic acid or in a mixture of acetic acid and acetic anhydridel this leads to the sulfones.
~:~S72~73 Ethers of the formula I in which the radicals Ind and/or Ar are substituted once or twice by O-alkyl can be cleaved by methods which are known from the literature, the corresponding hydroxyl derivatives being produced. For example, the ethers can be cleaved by treatment with HBr or ~I in aqueous or acetic acid solution, by heating with Lewis acids, such as AlC13 or boron trihalides, or by fusing with pyridine or aniline hydrohalides, preferably pyridine hydrochloride, at about 150 - 250. Reductive cleavage with diisobutylaluminium hydride (for method, compare Synthesis 1975, 617) is particularly mild.
A base of the formula I which has been obtained can be converted into -the relevant acid addition salt using an acid. Acids which provide physiologically acceptable salts are suitable for this reaction. Thus, inorganic acids can be used, for example, sulfuric acid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid, phosphoric acids, such as orthophosphoric acid, nitric acid, sulfamic acid, but also organic acids, specifically aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic~ sulfonic or sulfuric acids, such as formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2-phenylpropionic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, iso-- ~257273 nicotinic acid, methane- or ethanesulfonic acid, ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzene-sulfonic acid, p-toluenesulfonic acid, naphthalenemono-sulfonic acids and naphthalenedisulfonic acids and lauryl sul~uric acid.
It is possible, if desired, to liberate the free bases of the formula I from their salts by treatment with strong bases, such as sodium or potassium hydroxide or sodium or potassium carbonate.
The invention also relates to the use of the compounds of the formula I and their physiologically acceptable salts for the preparation of pharmaceutical formulations, in particular by non-chemical means. For this purpose, it is possible to convert them into a suitable dosage form together with at least one vehicle or auxiliary and, where appropriate, combined with one or more other active compound(s).
The invention also relates to agents, especially pharmaceutical formulations, containing at least one compound of the formula I and/or one of its physiologically acceptable salts. These formulations can be employed as medicaments in human or veterinary medicine. Suitable vehicles are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical administration and which do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatine, carbohydrates, such as lactose or starch, magnesium stearate, talc and vaseline. In particular, tablets, coated tablets, capsules, syrups, liquids, drops or suppositories ~257273 are used for enteral administration, solutions, preferably oily or aqueous solutions, but also suspensions, emulsions or implants are used for parenteral administration, and ointments, creams or powders are used ~or topical application. It is also possible to freeze-dry the new compounds and use the lyophilizates obtained, for example, for the preparation of products ~or injection.
The indicated formulations can be sterilized and/or contain auxiliaries, such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts to modify the osmotic pressure, buffer substances, dyes, flavorings and/or aromatic substances. If desired, t~ley can also contain one or more other active compounds, for example one or more vitamins.
The invention also relates to the use of the compounds of the formula I and their physiologically acceptable salts for the therapeutic treatment of the human or animal body and for the control of illnesses, especially of parkinsonism, of extrapyramidal disturbances associated with neuroleptic therapy, of depression and/or psychosis and of side effects of treatment for hypertension (for example with ~-methyldopa). The compounds can also be used in endocrinology and gynecology, for example for the therapy of acromegaly, hypogonadism, secondary amenorrhoea, premenstrual syndrome, undesired puerperal lactation and generally as prolactin inhibitors, also for the therapy of cerebral disturbances (for example migraine) and especially geriatrics, similar to certain ergot alkaloids.
~257:27 For these purposes, as a rule the substances according to the invention are administer~d in analogy to known and commercially available products (for example bromocriptine and dihydroergocornine), preferably in doses between about 0.2 and 500 mg, in particular between 0.2 and 50 mg per dosage unit. The daily dose is preferably between about 0.001 and 10 mg/kg of body weight. In this con-text, the low doses (about 0.2 to l mg per dosage unit; about 0.001 to 0.005 mg/kg of body weight) are particularly suitable for use as agents for migraine; doses between 10 and 50 mg per dosage unit are preferred for the other indications.
Preferred dose ranges for specific indications are as follows: parkinsonism 1 to 200, preferably 40 to 100;
dyskinesia 40 to 100; psychosis, for example schizophrenia, 2 to 20; acromegaly 2 to 50 mg per dosage unit. However, the specific dose for each particular patient depends on a wide variety of factors, for example on the efficacy of the specific compound employed, on the age, body weight, general state of health, sex, on the diet, on the timing and mode of administration, on the rate of excretion, and on medicaments used in combination and the severity of the particular disorder to which the therapy is applied. Oral administration is preferred.
~257273 The chemical reactions described above are generally disclosed in terms of their broadest application to the preparation of the compounds of this invention.
Occasionally, the reactions may not be applicable as described to each compound included within the disclosed scope. The compounds for which this occurs will be readily recognized by those skilled in the art. In all such cases, either the reactions can be successfully performed b~
conventional modifications known to those skilled in the art, e.g., by appropriate protection of inter~ering groups, by changing to alternative conventional reagents, by routine modification of reaction conditions, etc., or other reactions disclosed herein or otherwise conventional, will be applicable to the preparation of the corresponding compounds of this invention. In all preparative methods, all starting materials are known or readily preparable from known starting materials.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest e~tent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative. In the following ;72'73 examples, all temperatures are set forth uncorrected in degrees Celsius; unless otherwise indicated, all parts and percentages are by weight.
In the examples below, "usual work-up " denotes:
Water is added if necessary, the mixture is extracted with an organic solvent, such as toluene, chloroform or dichloromethane, the phases are separated, the organic phase is dried over sodium sulfate, filtered, evaporated and the product is purif ied by chromatography and/or crystallisation. Temperatures are reported in degrees centigrade, and Rf values are on silica gel ( toluene/triethylamine 8: 2 unless otherwise indicated ) .
~2s72q3 Example 1 A solution of 2 . 08 g of 3- ( 4-chlorobutyl ) indole [ or 2 . 52 g of 3- ( 4-bromobutyl ) indole I and 1 . 6 g of 3-phenyl -1, 2, 3, 6-tetrahydropyridine in lO ml o~ acetonitrile is stirred at 20 for 12 hours, worked up as usual and 3-[4-(3-phenyl-1, 2, 3, 6-tetrahydropyridyl ) butyl ] indole is obtained .
Hydrochloride, m.p. 209-212.
~n analogy, the following are obtained from the appropriate chloro- or bromoalkylindoles with the appropriate 3-aryl-1, 2, 3, 6-tetrahydropyridines or -piperidines: 3- [ 3- ( 3-phenyl-1, 2, 3, 6-te trahydropyridyl ) propyl ] indole, hydrochloride, m.p. 175-177 3 - [ 3 - ( 3 -m-methoxyphenyl- 1, 2, 3, 6 -tetrahydropyridyl ) propyl ] -indole 3- [ 3 - ( 3 -p-methoxyphenyl- 1, 2, 3, 6-tetrahydropyridyl ) -propyl ] -indole 3 - [ 3 - ( 3-m-hydroxyphenyl -1, 2, 3, 6 -tetrahydropyridyl ) propyl ] -indole 3- [ 3- ( 3-p-hydroxyphenyl-1, 2, 3, 6-tetrahydropyridyl)propyl] -indole 3- [ 4- ( 3-phenyl-1, 2, 3, 6 -tetrahydropyridyl ) butyl ] -2-methyl-indole 3- [ 4 - ( 3 -phenyl -1, 2, 3, 6 -tetrahydropyridyl ) butyl ] -5-methoxy-indole 3 - [ 4 - ( 3-phenyl -1, 2, 3, 6 -tetrahydropyridyl ) butyl ] -6-methoxy-indole 3- [ 4 - ( 3 -phenyl -1, 2, 3, 6 -tetrahydropyridyl ) butyl ] -4-hydroxy-indole - 28 - ~2572'73 3-[4-(3-phenyl-1,2,3,6-tetrahydropyridyl)butyl]-5-hydroxy-indole 3-r4~(3-phenyl-1,2,3,6-tetrahydropyridyl)butyl]-6-hydroxy-indole 3-[4-(3-phenyl-ll2~3/6-tetrahydropyridyl)butyl]-5-~luor indole 3-[4-(3-phenyl-1,2,3,6-tetrahydropyridyl)butyl]-5-chloro-indole 3-[4-(3-phenyl-1,2,3,6-tetrahydropyridyl)butyl]-7-bromo-indole 3-[4-(3-phenyl-1,2,3,6-tetrahydropyridyl)butyl]-5-cyano-indole 3-~4-(3-phenyl-1,2,3,6-tetrahydropyridyl)butyl]-5,6-methyl-lenedioxyindole 3-[4-(3-phenyl-1,2,3,6-tetrahydropyridyl)butyl]-5,6-di-methylindole 3-[4-(3-phenyl-1,2,3,6-tetrahydropyridyl)butyl]-5,6-di-methoxyindole 3-[4-(3-phenyl-1,2,3,6-tetrahydropyridyl~butyl]-5,6-di-chloroindole 3-[4-(3-o-tolyl-1,2,3,6-tetrahydropyridyl)butyl]indole 3-~4-(3-m-tolyl-1,2,3,6-tetrahydropyridyl)butyl]indole 3-[4-(3-p-tolyl-1,2,3,6-tetrahydropyridyl)butyl]indole 3-[4-(3 o-methoxyphenyl-1,2,3,6-tetrahydropyridyl)butyl]-indole 3-~4-(3-m-methoxyphenyl-1,2~3,6-tetrahydropyridyl)butyl]-indole, R~ 0.42 3-[4-(3-p-methoxyphenyl-1,2,3,6-tetrahydropyridyl)-butyl]-indole ~257:~'73 3-[4~(3-o-methoxyphenyl-1,2,3,6-tetrahydropyridyl)butyl]-indole 3-[4-(3-m-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)butyl]-indole, Rf 0.32 (CH2Cl2/methanol 9:1) 3-[4-(3-p-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)butyl]-indole 3-[4-(3-o-~luorophenyl-1,2,3,6-tetrahydropyridyl)butyl]-indole 3-[4-(3-m-fluorophenyl-1,2,3,6-tetrahydropyridyl)butyl]-indole 3-[4-(3-p-~luorophenyl-1,2,3,6-tetrahydropyridyl)butyl]-indole 3-[4-(3-o-chlorophenyl-1,2,3,6-tetrahydropyridyl)butyl]-indole 3-[4-(3-m-chlorophenyl-1,2,3,6-tetrahydropyridyl)butyl]-indole 3-[4-(3-p-chlorophenyl-1,2,3,6-tetrahydropyridyl)butyl]-indole 3-[4-(3-p-bromophenyl-1,2,3,6-tetrahydropyridyl)butyl]-indole 3-[4-(3-m-trifluoromethylphenyl-l~2~3~6-tetrahydropyridyl) butyl]indole 3-[4-~3-p-cyanophenyl-1,2,3,6-tetrahydropridyl)butyl]-indole 3-[4-(3-(3,4-dimethoxyphenyl)-1,2,3,6-tetrahydropyridyl)-butyl]indole, Rf 0.48 (CH2Cl2/CH3OH 9:1) 3-[4-(3-(3,4-methylenedioxyphenyl)-1,2,3,6-tetrahydro~
pyridyl)butyl]indole 3-[4-(3-(4-chloro-3-tri~luoromethylphenyl)-1,2,3,6-tetra-hydropyridyl)butyl]indole ~l257273 3-~4-(3-m-methoxyphenyl-1,2,3,6-tetrahydropyridyl)butyl]-5-methoxyindole 3 - [ 4 - ( 3-m-methoxypheny~ 2 ~ 3 ~ 6-tetrahydropyridyl )butyl ] -6 methoxyindole 3-[4-(3-m-methoxyphenyl-1,2,3,6-tetrahydropyridyl)butyl]-5,6-dimethoxyindole 3-[4-(3-m-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)butyl]-5-hydroxyindole 3-[4-(3-m-hydroxyphenyl-1,2,3,6-tetrahydropridyl)butyl]-6-hydroxyindole 3-[5-(3-phenyl-1,2,3,6-tetrahydropyridyl)pentyl]indole, hydrochloride, m.p. 114-116 3-[5-(3-m-methoxyphenyl-1,2,3,6-tetrahydropyridyl)pentyl]-indole 3-~5-(3-p-methoxyphenyl-l~2~3~6-tetrahydropyridyl)pentyl]
i~dole 3-~5-(3-m-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)pentyl]-indole 3-[5-(3-p-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)pentyl]-indole 3-[3-(3-phenyl-1-piperidyl)propyl]indole 3-[3-(3-m-methoxyphenyl-1-piperidyl)propyl]indole 3-[3-(3-p-methoxyphenyl-1-piperidyl)propyl]indole 3-[3-(3-m-hydroxyphenyl-1-piperidyl)propyl]indole 3- L 3-(3-p-hydroxyphenyl-1-piperidyl)propyl]indole 3-[4-(3-phenyl-1-piperidyl)butyl]indole, hydrochloride, m.p.
3-[4-(3-phenyl-1-piperidyl)butyl]-2-methylindole ~257;~73 3-[4-(3-phenyl-1-piperidyllbutyl]-5-methoxyindole 3-[4-(3-phenyl-1-piperidyl)butyl]-6-methoxyindole 3-[4-(3-phenyl-1-piperidyl)butyl]-4-hydroxyindole 3-[4-(3-phe.nyl-1-piperidyl)butyl]-5-hydroxyindole 3-[4-(3-phenyl-1-piperidyl)butyl]-6-hydroxyindole 3-[4-(3-phenyl-1-piperidyl)butyl~-5-fluoroindole 3-[4-(3-phenyl-l-piperidyl)butyl]-5-chloroindole 3-[4-(3-phenyl~l-piperidyl)butyl]-7-bromoindole 3-[4-(3-phenyl-1-piperidyl)butyl]-5-cyanoindole 3-[4-(3-phenyl-1-piperidyl)butyl]-5,6-methylenedioxyindole 3-[4-(3-phenyl-1-piperidyl)butyl]-5,6-dimethylindole 3-[4-(3-phenyl-1-piperidyl)butyl]-5,6-dimethoxyindole 3-[4-(3-phenyl-1-piperidyl)butyl]-5,6-dichloroindole 3~ r 4-(3-o-tolyl-1-piperidyl)butyl]indole 3-[4-(3-m-tolyl-1-piperidyl)butyl]indole 3-[4-(3-p-tolyl-1-piperidyl)butyl]indole 3-[4-(3-o-methoxyphenyl-1-piperidyl)butyl]indole 3-[4-(3-m-methoxyphenyl-1-piperidyl)butyl]indole, Rf ~.41 3-[4-(3-p-methoxyphenyl-l~piperidyl)butyl]indole, hydro-chloride, m.p. 184-185 3-[4-(3-o-hydroxyphenyl-1-piperidyl)butyl]indole 3-[4-(3-m-hydroxyphenyl-1-piperidyl)butyl]indole, m.p. 135-143 (decomposition) 3-[4-(3-p-hydroxyphenyl-1-piperidyl)butyl]indola 3-[4-(3-o-fluorophenyl-1 piperidyl)butyl]indole 3-[4-(3-m-fluorophenyl-1-piperidyl)butyl]indole 3-[4-(3-p-~luorophenyl-1-piperidyl)butyl~indole 3-[4~(3-o-chlorophenyl-1-piperidyl)butyl]indole 3-[4-(3-m-chlorophenyl-l-piperidyl)butyl]indole 3-[4-(3-p-chlorophenyl-1-piperidyl)butyl]indole 3-[4-(3-p-bromophenyl-l-piperidyl)butyl]indol0 3-[4-(3-m-trifluoromethylphenyl-l-piperidyl)butyl]indole 3-[4-(3-p-cyanophenyl-1-piperidyl)butyl]indole 3-[4-(3-(3,4-dimethoxyphenyl)-1-piperidyl)butyl]indole, hydrochloride, m.p. 177.5-178.5 3-[4-(3-(3,4-methylenedioxyphenyl)-l-piperidyl)butyl]-indole 3-[4-(3-(4 chloro-3-trifluoromethylphenyl)-1-piperidyl)-butyl]indole 3-[4-(3-m-methoxyphenyl-1-piperidyl)butyl]-5-methoxyindole, hydrochloride, m.p. 102-104 3-[4-(3-p-methoxyphenyl-1-piperidyl)butyl]-5-methoxyindole, m.p. 109 3-[4-(3-methoxyphenyl-l~piperidyl)butyl]-6-methoxyindole, Rf 0.29 (CH2C12/CH3OH 9:1) 3-[4-(3-m-methoxyphenyl-1-piperidyl)bu-tyl]-5,6-dimethoxy-indole 3-[4-(3-m-hydroxyphenyl-1-piperidyl)butyl]-5-hydroxyindole, m.p. 102-104 3-[4-(3-m~hydroxyphenyl-1-piperidyl)butyl]-6-hydroxyindole, Rf 0.76 (CH~Cl2/CH3OH/triethylamine 7:2:1) 3-[4-(3-p-hydroxyphenyl-1-piperidyl)butyl]-5-hydroxyindole, m.p. 182-185 ~572q3 3-[5-~3-phenyl-1-piperidyl)pentyl]indole 3-[5-(3-m-methoxyphenyl-1-piperidyl)pentyl~indole, hydrochloride, m.p. 164.5 - 165.5 3-[5-(3-p-methoxyphenyl-1-piperidyl)pentyl]indole 3-[5-(3-m-hydroxyphenyl-1-piperidyl)pentyl3indole and 3-[5-(3-p-hydroxyphenyl-1-piperidyl)pentyl]indole 3-[4-(3-m-hydroxyphenyl-1-piperidyl)-butyl]-4-hydroxy-7-chloroindole 3-[4-(3-p-hydroxyphenyl-1-piperidyl)-butyl]-4-hydroxy-7-chloroindole Example 2 A mixture of 4.43 g of 3-t4-p-toluenesulfonyloxy-butyl)indole and 3.2 g of 3-phenylpiperidine is heated -~o 130. After the exothermic reaction has subsided and the mixture has cooled down, it is worked up as usual and 3-[4-(3-phenyl-1-piperidyl)butyl]indole hydrochloride, m.p. 180-182 is obtained.
~2S72~:~
In analogy, the following are obtained from the appropriate tosylates:
3-[4-(3-phenyl-1-piperidyl)butyl]-5-butylindole 3-[4-(3-phenyl-1-piperidyl)butyl]-5-ethoxyindole 3-[4-(3-phenyl-1-piperidyl)butyl]-5-butoxyindole 3-[4-(3-phenyl-1-piperidyl)butyl]-5-methylthioindole 3-[4-(3-phenyl-l-piperidyl)butyl]-5-butylthioindole 3-[4-(3-phenyl-l-piperidyl)butyl]-5-methylsulfinylindole and 3-[4-(3-phenyl-1-piperidyl)butyl]-5-methylsulfonylindole.
Example 3 2.99 g of 3-(4-iodobutyl)indole, 1.91 g of 3-m-methoxyphenylpiperidine and 1.5 g of anhydrous potassium carbonate in 25 ml of n-butanol are boiled, with stirring, for 2 hours, the mixture is allowed to cool, worked up as usual and 3-[4-(3-m-methoxyphenyl-1-piperidyl)butyl]-indole, Rf 0.41, is obtained.
In analogy, the following are obtained from the appropriate 3-Ar-piperidines:
3-[4-(3-p-butoxyphenyl-1-piperidyl)butyl]indole 3-[4-(3 p-methylthiophenyl-l-piperidyl)butyl]indole 3-[4-t3-p-butylthiophenyl-1-piperidyl)butyl]indole 3-[4-(3-p-methylsulfinylphenyl-l-piperidyl)butyl]indole and 3-[4-(3-p-methylsulfonylphenyl-l-piperidyl)butyl]indole.
Example 4 A mixture of 1.8~ g of 3-(4-aminobutyl)indole and 2.15 g of 1,5 dichloxo 2-phenylpentane (obtainable by reduction of diethyl 2-phenylpentane-1,5-dioate with ~257zq3 LiAlH4 and subsequent reaction with 5OC12) in 40 ml of acetone and 40 ml of water is boiled for 24 hours and worked up as usual. 3-[4-(3-Phenyl-1-piperidyl)butyl]-indole hydrochloride m.p. 180-182, is obtained.
In analogy, from the appropriate amines and the appropriate 1,5-dichloro-2-Ar-pentanes or ~-pentenes, the other compounds of the formula I indicated in Examples 1, 2 and 3 are obtained.
Example 5 1 g of NaBH4 in 20 ml of water is added, with stirring, to a solution of 4.23 g of 1-~4-(3-indolyl)-butyl]-3-m-hydroxyphenylpyridinium bromide [obtainable from 3-(4-bromobutyl)indole and 3-m-hydroxyphenylpyridineJ in 50 ml of lN NaOH, and the mixture is then stirred at 60C for 3 hours.
After working up as usual, 3-t4-(3-m-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)butyl]indole, ~f 0.32 (CH2C12/methanol 9:1), is obtained.
In analogy, the other tetrahydropyridines of the formula I indicated in Examples 1, 2 and 3 are obtained by reduction of the appropriate pyridinium bromides.
Example 6 A solution of 3.76 of indole-3-butyric 3-m-methoxyphenylpiperidide (Rf 0.86 in CH2C12/CH3OH 9:1;
obtainable from indole-3-butyric acid and 3-m-methoxyphenyl-piperidine in the presence of l,l'-carbonyldiimidazole) in 20 ml of THF is added dropwise, with stirring, to a suspension of 0.38 g of LiAlH4 in 10 ml of THF. After the reaction has subsided, 5 ml of ethyl acetate are added, the mixture is worked up as usual and 3-~4-(3-m-methoxy-phenyl-1-piperidyl)butyl]indole, Rf 0.41, is obtained.
~25'7~7:~
In analogy, from the appropriate amides, for example:
indole-3-propionic 3-phenyl-1,2,3,6-tetrahydropyridide (m.p.
152-154) indole-3-butyric 3-phenyl-1,2,3,6-tetrahydropyridide (Rf 0.44 in toluene/CH30H/triethylamine 7:2:1) indole-3-butyric 3-~-methoxyphenyl-1,2,3,6-tetrahydropyridide (Rf 0.88 in CH2Cl2/CH30H 9:1) indole-3-butyric 3-(3,4-dimethoxyphenyl)-1,2,3,6-tetra-hydropyridide (Rf 0.78 in OEI2Cl2/CH3H 9 1) indole-3-butyric 3-phenylpiperidide (Rf 0.8 in CH2Cl2/CH30H/ethyl acetate 7:2:1) indole-3-butyric 3-m-methoxyphenylpiperidide (Rf 0.86 in CH2Cl2/cH30H 9:1) indole-3-butyric 3-p-methoxyphenylpiperidide (P~f 0.6~ in CHCl3/CH30H/ethyl ac0tate 7:2:1) indole-3-butyric 3-(3,4-dimethoxyphenyl)piperidide (Rf 0.75 in CH2C12/CH30H 9:1) and indole-3-valeric 3-phenyl-1,2,3,6-tetrahydropyridide (m.p.
155-156), the other compounds of the formula I indicated in Examples 1, 2 and 3 are obtained.
Example 7
in Ib, Ind is 3-indolyl, 5- or 6-methyl-3-indolyl, 5,6-dimethyl-3-indolyl, 5- or 6-methoxy-3-indolyl, 5,6-dimethoxy-3-indolyl or 5-cyano-3-indolyl;
in Ic, Ind is 3-indolyl;
in Id, A is -(CH2)4-;
in Ie, Ar is hydroxyphenyl, phenyl, tolyl, methoxyphenyl, fluorophenyl, chlorophenyl, trifluoromethylphenyl or dimethoxyphenyl;
In If, Ar is hydroxyphenyl;
in Ig, Ar is phenyl;
in Ih, Ind is 3-indolyl or 5-methoxy-3-indolyl and Ar is hydroxyphenyl, phenyl, tolyl, methoxyphenyl, fluorophenyl, chlorophenyl, trifluoromethylphenyl or dimethoxyphenyl;
in Ij, Ind is 3-indolyl, A is -(CH2)4-, and Ar is 3- or 4-hydroxyphenyl, phenyl, 3- or 4-methoxyphenyl or 3,4-dimethoxypheryl;
in Ik, Ind is 3-indolyl, A is -(CH2)4-, and Ar is 3-hydroxyphenyl or phenyl;
~257273;
in Il, Ind, A, n and Ar have the meaning indicated for formula I, but Ind is an unsubstituted 3-indolyl radical or a 3-indolyl radical substituted once or twice by O-alkyl, OH, F, Cl, Br and/or CF3 only when, simultaneously, Ar is a phenyl group which is unsubstituted in the 3-position, or is a phenyl group which is substituted in the 3-position by alkyl, S-alkyl, SO-alkyl, SO2-alkyl, F, Cl, Br, CF3 or CN and can be substituted additionally in one o~ the remaining positions by alkyl, O-alkyl, S-alkyl, SO-alkyl, SO2-alkyl, OH, F, Cl, Br, CF3 or CN, or is a methylenedioxyphenyl group, and/or the two radicals L together are a C-C bond;
in Im, Ar is phenyl, 4-hydroxyphenyl or ~-methoxyphenyl;
in In, the two radicals L together are a C-C bond;
in Io, Ar is phenyl or phenyl substituted by alkyl, S-alkyl, SO-alkyl, SO2-alkyl, F, Cl, Br, CF3 and/or CN or by a methylenedioxy group;
in Ip, Ind is 3-indolyl substituted by alkyl, S-alkyl, SO-alkyl, SO2-alkyl, and/or CN or by a methylenedioxy group.
~25727:3 The compounds of the formula I can have one or more asymmetric carbon a~oms. Thus they can exist as racemates and, if several asymmetric carbon atoms are present, they can also exist as mixtures of several racemates and in various optically active forms.
The invention also relates to a process for the preparation of the compounds of the formula I and their physiologically acceptable acid addition salts, which is characterized in that a compound of the general formula II
Ind-A-X1 II
in which xl is X or NH~ and X is Cl, Br, I, OH or a reactive derivative of an OH group, and Ind and A have the indicated meanings, is reacted with a compound of the general formula III
X2C~2_CH2 \
CHL III
X3-CH2-CArL
in which x2 and X3 can be identical or different andt if xl is NH2, are each X, but otherwise are together NH, and Ar and L have the indicated meanings, or in that a compound which other~ise corresponds to the formula I, but contains one or more reducible group(s) and/or one or more additional C-C
and/or C-N bond(s) in place of one or more hydro~en atoms, is treated with a reducing agent, or in that a compound which otherwise corresponds to the formula I, but contains one or more group(s) which can be eliminated by solvolysis in place of one or more hydrogen atoms, is treated with a solvolyzing agent, or in ~hat, to prepare a compound of the formula I
:~2572~73 in which the two radicals L are together a C-C bond, a compound of the formula IV
Ind-A- ~ E IV
~ Ar in which one radical E is X, CN or NH2, the other radical E
is H, and Ind, A, Ar and X have the indicated meanings, is treated with an agent which eliminates HE, and/or in that, where appropriate, in a compound of the formula I, a thioether group is oxidized to an SO group or SO2 group, or an SO group is oxidized to an SO2 group, and/or an alkoxy group is cleaved with the formation of an OH group, and/or in that a base of the formula I obtained is converted into one of its physiologically acceptable acid addition salts by treatment with an acid.
The preparation of the compounds of the formula I
is otherwise carried out by methods known per se as are described in the literature (for example in the standard works, such as Houben-Weyl, Methoden der Organischen Chemie (Nethods of Organic Chemistry), Georg-Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York), namely under reaction conditions as are known and suitable for the reactions mentioned. Use can also be made in these prepar~tions of variants known per se which are not mentioned in more detail here.
The starting materials can, if desired, also be formed in situ in such a manner that they are not isolated ~257273 from the reaction mixture but are immediately reacted further to give the compounds of the formula I.
In the indole derivatives of the formula II, xl is preferably ~; accordingly, in the compounds of the formula III, x2 and X3 together are preferably NH. The radical X is preferably Cl or Br; however, it can also be I, OH or a reactive derivative of an OH group, in particular alk~lsulf~nyloxy having 1 - 6 ( for example methanesulfonyloxy) or arylsulfonyloxy having 6 - 10 C atoms ( for example benzenesulfonyloxy, p-toluenesulfonyloxy, 1- or 2-naphthalenesulfonyloxy) .
Accordingly, the indole derivatives of the formula I can be obtained, in particular, by reaction of the compounds of the formulae Ind-A-Cl or Ind-A-Br with compounds of the formula III, wherein X2 and X3 together are an NH
group (denoted IIIa in the following text).
Some of the compounds of the formula II and III are known; the unknown compounds of these formulae II and III can be easily prepared in analogy to the known compounds. Thus, some of the compounds of the formula II are known from German Of fenlegungsschrift 2, 827, 874 .
Alcohols of the formula Ind-A-OH can be obtained, for example, by reduction o~ the corresponding carboxylic acids or their esters. Treatment with thionyl chloride, hydrogen bromide, phosphorus tribromide or similar halogen compounds proYides the corresponding halides of the formula Ind-A-Hal (wherein ~al is Cl, Br or I ) . The corresponding sulfonyloxy compounds can be obtained form the alcohols Ind-A-OH by reaction with the corresponding sulfonyl chlorides.
12 - ~25727~
The iodine compounds of the formula Ind-A-I, for example 3-(4-iodobutyl)indole are obtained, for example, by the action of potassium iodide on the pertinent p-toluenesulfonic esters. The amines of the formula Ind-A-NH2 can be obtained, for example, from the halides with potassium phthalimide or by reduction of the corresponding nitriles.
The piperidine derivatives IIIa can be obtained, for example, by reaction of 3-piperidone with organo-metallic compounds of the formula M-Ar (in which M is an Li atom or Mg~al), subsequent hydrolysis to give the corresponding 3-Ar-3-hydroxypiperidines and, if desired, subsequent hydration to give 3-Ar-3,4-dehydropiperidines. Compounds of the formula III (X2 and X3 each being X) can be prepared, for example, by reduction of 2-Ar-glutaric esters to give 2-Ar-1,5-pentanediols and, if appropriate, subse~uent reaction with SOCl2 or PBr3.
The reaction of the compounds II and III takes place by methods as are known from the literature for the alkylation of amines. It is possible to fuse -the components together in the absence of a solvent, if appropriate in a closed tube or in an autoclave. However, it is also possible to react the compounds in the presence of an inert solvent.
Examples of suitable solvents are hydrocarbons, such as ~enzene, toluene or xylene; ketones, such as acetone or butanone; alcohols, such as methanol, ethanol, isopropanol or n-butanol; ethers, such as tetrahydrofuran (THF) or dioxane;
amides, such as dimethylformamide (DMF) or N-methylpyrrolidone; nitriles, such as acetonitrile, and, ~Z5~2~73 if appropriate, mixtures of these solvents with one anoth4er or mixtures with water. The addition of an acid-binding agent, for example an aikali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or another weak acid salt of the alkali metals or alkaline earth metals, preferably o~
potassium, sodium or calcium, or the addition of an organic base, such as triethylamine, dimethylaniline, pyridine or quinoline or an excess of the amine component Ind-A-NH2 or the piperidine derivative of the formula IIIa can be advantageous. The reaction time depends on the conditions used and is between a few minutes and 14 days, and the reaction temperature is between about 0 and 150, normally between 20 and 130.
Furthermore, it is possible to obtain a compound of the formula I by treating a precursor which, in place of hydrogen atoms, contains one or more reducible group(s) and/or one or more additional C-C and/or C-N bond(s) with reducing agents, preferably at temperatures between -80 and +250 in the presence of at least one inert solvent.
Reducible groups (replaceable by hydrogen) are, in particular, oxygen in a carbonyl group, hydroxyl, arylsulfonyloxy (for example p-toluenesulfonyloxy), N-benzenesulfonyl, N-benzyl or O-benzyl).
It is possible in principle to convert compounds which contain only one of the abovementioned groups or additional bonds or those compounds which contain together two or more of the abovementioned groups or additional bonds into a compound of the formula I by reduction. Nascent ~25q2~3 hydrogen or complex metal hydrides, but also reduction by the - method of Wolff-Kishner, is preferably used for this purpose.
Preferred starting materials for the reduction correspond to the formula V
Ind'-G-Q'-Ar' Y
in which Ind' is a 3-indolyl radical which can be substituted once or twice by alkyl, O-alkyl, S-alkyl, SO-alkyl, SO2-alkyl, OH, F, Cl, Br, CF3, CN and/or O-benzyl or by a methylenedioxy group and/or by an arylsulfonyl group or a benzyl group in the l-position, G is a -(CH2)n- chain in which, however, one or more -CH2- group~s) can be replaced by -CO-, and/or one or more hydrogen atoms can be replaced by OH
groups, Q' is Q or -N ~ ~n~
An~ is an anion of a strong acid, and Ar' is a phenyl which is unsubstituted or substituted once or twice by alkyl, O-alkyl, S-alkyl, SO-alkyl, SO2-alkyl, OH, F, Cl, Br, CF3, CN
and/or O-benzyl or by a methylenedioxy group, but in which it is not possible at the same time for Ind' to be Ind, G to be A, Q' to be Q and Ar' to be Ar.
G in the compounds of the formula V is preferably -CH2CH2CO-, -(CH2)3-CO- or -(CH2)4-cO-~
Compounds of the formula V can be prepared, for example, by reaction of 3-Ar'-1,2,3,6-tetrahydropyridines, 3-Ar'-piperidines or 3-Ar'-pyridines with compounds of the formula VI
- 15 - ~25727~3 Ind'-G-Xl VI
in which Ar', Ind', G and xl have the meanings indicated above, under the conditions indicated above for the reaction of II with III. Amides of the formula V [G = -(CH2)n_1-CO-, Q' = Q] can be obtained, for example, from the free carboxylic acids of the formula Ind'-(CH2)n_1-COOH and amines of the ~ormula IIIa, preferably in the presence of a dehydrating agent, for example carbonyldiimidazole or dicyclohexylcarbodiimide, in an inert solvent, preferably THF.
If nascent hydrogen is used as the reducing agent, this can be produced by, for example, treatment of metals with weak acids or with bases. Thus, for example, a mixture of zinc with alkali metal hydroxide solution or of iron with acetic acid can be used. It is also suitable to use sodium or another alkali metal in an alcohol, such as ethanol, isopropanol, butanol, amyl or isoamyl alcohol or phenol. It is also possible to use an aluminum/nickel alloy in an aqueous alkaline solution, optionally with the addition of ethanol. Sodium amalgam or aluminum amalgam in aqueous alcoholic or aqueous solution are also suitable to produce nascent hydrogen. The reaction can also be carried out in heterogeneous phases, it being preferable to use an aqueous and a benzene or toluene phase.
Moreover, it is possible to use with particular advantage complex metal hydrides, such as LiAlH4, NaBH4, diisobutylaluminum hydride or NaAl(OCH2CH2OCH3)2H2 and diborane, as the reducing agent, if desired with the addition of catalysts, such as BF3, AlC13 or LiBr.
~2S72~73 Solvents which are particularly suit~ble for this purpose are ethers, such as diethyl ether, di-n-butyl ether, THF, dioxane, diglyme or 1,2-dimethoxyethane, and h~drocarbons, such as benzene. For reduction with NaBH4, alcohols, such as methanol or ethanol, but also water and aqueous alcohols, are primarily suitable as the solvent.
Reduction by these methods is preferably carried out at emperatures between -80 and +150, in particular between about 0 and about 100.
It is also possible particularly advantageously to reduce -CO- groups in amides (for example those of the formula V in which G is -(CH2)n_l-CO- and Q' is Q) with LiAlH4 in THF at temperatures between 0 and 66 to give CH2 groups. During this, arylsulfonyl protective groups located in the 1-position of the indole ring can simultaneously be reductively split off.
It is possible to reduce the pyridinium salts of the formula V (wherein Q' is -N ~
Ane and An is preferably Cl or Br) to give compounds of the formula I, for example, using NaBH4 in water, methanol or ethanol or in mixtures of these solvents, with the addition, if desired, of a base, such as NaOH, at temperatures between about 0 and 80.
N-Benzyl groups can be reductively split off using sodium in liquid ammonia.
Moreover, it is possible to reduce one or more carbonyl groups to CH2 groups by the method of Wolff-~25~2'7~
Kishner, for example, by treatment with anhydrous hydrazine in absolute ethanol under pressure at temperatures between about l50 and 250.
Sodium alcoholate is advantageously used as a catalyst. The reduction can also be modified by the method of Huang-Minlon by carrying out the reaction with hydrazine hydrate in a high-boiling solvent which is miscible with water, such as diethylene glycol or triethylene glycol, in the presence of alkali, such as sodium hydroxide. As a rule, the reaction mixture is boiled for about 3-4 hours. The water is then distilled off and the hydrazone formed is decomposed at temperatures up to about ~00. The Wolff-Kishner reduction can also be carried out with hydrazine in dimethyl sulfoxide at room temperature.
Compounds which o-therwise correspond to formula I
but, in place of one or more H atoms, contain one or more group(s) which can be split off by solvolysis can be solvolyzed, in particular hydrolyzed/ to give compounds of the formula I. The starting materials for the solvolysis can be obtained, for example, by reaction of IIIa with compounds which correspond to the formula II (Xl = X) but, in place of one or more H atoms, contain one or more group(s) which can be split off by solvolysis. Thus, l-acylindole derivatives (corresponding to the formula I but containing an acyl group, preferably an alkanoyl, alkylsulfonyl or arylsulfonyl group each having up to lO C atoms, such as methane-, banzene- or p-toluene-sulfonyl in the l-position of the Ind radical) can be hydrolyzed to give the corresponding IL2~;7273 indole derivatives which are unsubs-tituted in the 1-position of the indole ring, for example, in acid, but better in neutral or alkaline medium at temperatures between 0 and 200. Sodium, potassium or calcium hydroxide, sodium or potassium carbonate or ammonia are preferably used as the basic catalysts. The solvents which are preferably chosen are water, lower alcohols, such as methanol or ethanol, ethers, such as THF or dioxane, sulfones, such as tetramethylenesulfone or their mixtures. Hydrolysis can even take place just on treatment with water alone, in particular at the boiling point.
Moreover, compounds of the formula I can be obtained by splitting off HE from compounds of the formu~a IV
to form a double bond. According to the definition of E, this can comprise, for example, splitting off hydrogen halide, water (dehydration), a carboxylic acid or another acid, ammonia or HCN. The starting materials of the formula IV can be obtained, for example, by reaction of II (X1 = X) with a compound of the formula VII
HN ~ E VII
E Ar in which E and Ar have the indicated meanings.
If one of the radicals E is Hal, this substituent can easily be eliminated under basic reaction conditions.
The following can be used as bases: alkali metal hydroxides, ~2s~2q3 alkali metal carbonates, alcoholates, such as, for example, potassium tert.-butylate, amines, such as, for example, dimethylaniline, pyridine, collidine or quinoline; the solvent used îs, for example, benzene, toluene, cyclohexane, methanol, dioxane, THF or tert.-butanol. The amines used as bases can also be employed in excess as the solvent. If one of the radicals E is an OH group, then acids, such as acetic acid, hydrochloric acid or mixtures of the two, are preferably used as the agent to split off water. The addition of a solvent (for example water or ethanol) can be ad~antageous. The elimination of acyl, alkylsulfonyl and alkoxysulfonyloxy or amino radicals can be carried out under similar conditions. An elimination of sulfonic acid radicals, for example mesylates or tosylates, takes place under mild conditions by boiling in DMF or dimethyl sulfoxide with alkali metal carbonates, for example Li2CO3 or with potassium acetate. Ammonia can be split off by just heating the salts of the corresponding amino compounds (especially the 3-amino derivatives). In a similar manner, HCN can be split off from compounds of the formula IV (one group E = CN) by heating. The elimination of HE from IV generally takes place at temperatures between about 0 and about 250, pre~erably between 50 and 200.
Furthermore, the thioether group in a thioether of the formula I can be oxidized to a SO group or to an SO2 group, or the SO group in a sulfoxide of the formula I can be oxidized to an SO2 group. The thioether or sulfoxide groups to be oxidized can be present as substituents in the radical ~257273 Ind and/or in the radical Ar. If the intention is to obtain the sulfoxides, then the oxidation is carried out, for example, with hydrogen peroxide, peracids, such as m-chloroperbenzoic acid, Cr(VI) compounds, such as chromic acid, KMnO4, l-chlorobenzotriazole, Ce(IV) compounds, such as (NH4)2Ce(NO3)6, negatively substituted aromatic diazonium salts, such as o- or p-nitrophenyldiazonium chloride, or electrolytically under relatively mild conditions and at relatively low temperatures (about -80 to -~100). If, on the other hand, the intention is to obtain the sulfones (from the thioethers or the sulfoxides), then the same oxidizing agents are used under more forcing conditions and/or in excess and, as a rule, at higher temperatures. It is possible in these reactions for the customary inert solvents to be present or absent. Examples of suitable inert solvents are water, aqueous mineral acids, aqueous al~ali metal hydroxide solutions, lower alcohols, such as methanol or ethanol, esters, such as ethyl acetate, ketones, such as acetone, lower carboxylic acids, such as acetic acid, nitriles, such as acetonitrile, hydrocarbons, such as benzene, and chlorinated hydrocarbons, such as chloroform or CCl~. A
preferred oxidizing agent is 30% aqueous hydrogen peroxide.
On using the calculated amount in solvents such as acetic acid, acetone, methanol, ethanol or aqueous sodium hydroxide ~olution at temperatures between -20 and 100, this leads to the sulfoxides, while in excess at higher temperatures, preferably in acetic acid or in a mixture of acetic acid and acetic anhydridel this leads to the sulfones.
~:~S72~73 Ethers of the formula I in which the radicals Ind and/or Ar are substituted once or twice by O-alkyl can be cleaved by methods which are known from the literature, the corresponding hydroxyl derivatives being produced. For example, the ethers can be cleaved by treatment with HBr or ~I in aqueous or acetic acid solution, by heating with Lewis acids, such as AlC13 or boron trihalides, or by fusing with pyridine or aniline hydrohalides, preferably pyridine hydrochloride, at about 150 - 250. Reductive cleavage with diisobutylaluminium hydride (for method, compare Synthesis 1975, 617) is particularly mild.
A base of the formula I which has been obtained can be converted into -the relevant acid addition salt using an acid. Acids which provide physiologically acceptable salts are suitable for this reaction. Thus, inorganic acids can be used, for example, sulfuric acid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid, phosphoric acids, such as orthophosphoric acid, nitric acid, sulfamic acid, but also organic acids, specifically aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic~ sulfonic or sulfuric acids, such as formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2-phenylpropionic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, iso-- ~257273 nicotinic acid, methane- or ethanesulfonic acid, ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzene-sulfonic acid, p-toluenesulfonic acid, naphthalenemono-sulfonic acids and naphthalenedisulfonic acids and lauryl sul~uric acid.
It is possible, if desired, to liberate the free bases of the formula I from their salts by treatment with strong bases, such as sodium or potassium hydroxide or sodium or potassium carbonate.
The invention also relates to the use of the compounds of the formula I and their physiologically acceptable salts for the preparation of pharmaceutical formulations, in particular by non-chemical means. For this purpose, it is possible to convert them into a suitable dosage form together with at least one vehicle or auxiliary and, where appropriate, combined with one or more other active compound(s).
The invention also relates to agents, especially pharmaceutical formulations, containing at least one compound of the formula I and/or one of its physiologically acceptable salts. These formulations can be employed as medicaments in human or veterinary medicine. Suitable vehicles are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical administration and which do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatine, carbohydrates, such as lactose or starch, magnesium stearate, talc and vaseline. In particular, tablets, coated tablets, capsules, syrups, liquids, drops or suppositories ~257273 are used for enteral administration, solutions, preferably oily or aqueous solutions, but also suspensions, emulsions or implants are used for parenteral administration, and ointments, creams or powders are used ~or topical application. It is also possible to freeze-dry the new compounds and use the lyophilizates obtained, for example, for the preparation of products ~or injection.
The indicated formulations can be sterilized and/or contain auxiliaries, such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts to modify the osmotic pressure, buffer substances, dyes, flavorings and/or aromatic substances. If desired, t~ley can also contain one or more other active compounds, for example one or more vitamins.
The invention also relates to the use of the compounds of the formula I and their physiologically acceptable salts for the therapeutic treatment of the human or animal body and for the control of illnesses, especially of parkinsonism, of extrapyramidal disturbances associated with neuroleptic therapy, of depression and/or psychosis and of side effects of treatment for hypertension (for example with ~-methyldopa). The compounds can also be used in endocrinology and gynecology, for example for the therapy of acromegaly, hypogonadism, secondary amenorrhoea, premenstrual syndrome, undesired puerperal lactation and generally as prolactin inhibitors, also for the therapy of cerebral disturbances (for example migraine) and especially geriatrics, similar to certain ergot alkaloids.
~257:27 For these purposes, as a rule the substances according to the invention are administer~d in analogy to known and commercially available products (for example bromocriptine and dihydroergocornine), preferably in doses between about 0.2 and 500 mg, in particular between 0.2 and 50 mg per dosage unit. The daily dose is preferably between about 0.001 and 10 mg/kg of body weight. In this con-text, the low doses (about 0.2 to l mg per dosage unit; about 0.001 to 0.005 mg/kg of body weight) are particularly suitable for use as agents for migraine; doses between 10 and 50 mg per dosage unit are preferred for the other indications.
Preferred dose ranges for specific indications are as follows: parkinsonism 1 to 200, preferably 40 to 100;
dyskinesia 40 to 100; psychosis, for example schizophrenia, 2 to 20; acromegaly 2 to 50 mg per dosage unit. However, the specific dose for each particular patient depends on a wide variety of factors, for example on the efficacy of the specific compound employed, on the age, body weight, general state of health, sex, on the diet, on the timing and mode of administration, on the rate of excretion, and on medicaments used in combination and the severity of the particular disorder to which the therapy is applied. Oral administration is preferred.
~257273 The chemical reactions described above are generally disclosed in terms of their broadest application to the preparation of the compounds of this invention.
Occasionally, the reactions may not be applicable as described to each compound included within the disclosed scope. The compounds for which this occurs will be readily recognized by those skilled in the art. In all such cases, either the reactions can be successfully performed b~
conventional modifications known to those skilled in the art, e.g., by appropriate protection of inter~ering groups, by changing to alternative conventional reagents, by routine modification of reaction conditions, etc., or other reactions disclosed herein or otherwise conventional, will be applicable to the preparation of the corresponding compounds of this invention. In all preparative methods, all starting materials are known or readily preparable from known starting materials.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest e~tent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative. In the following ;72'73 examples, all temperatures are set forth uncorrected in degrees Celsius; unless otherwise indicated, all parts and percentages are by weight.
In the examples below, "usual work-up " denotes:
Water is added if necessary, the mixture is extracted with an organic solvent, such as toluene, chloroform or dichloromethane, the phases are separated, the organic phase is dried over sodium sulfate, filtered, evaporated and the product is purif ied by chromatography and/or crystallisation. Temperatures are reported in degrees centigrade, and Rf values are on silica gel ( toluene/triethylamine 8: 2 unless otherwise indicated ) .
~2s72q3 Example 1 A solution of 2 . 08 g of 3- ( 4-chlorobutyl ) indole [ or 2 . 52 g of 3- ( 4-bromobutyl ) indole I and 1 . 6 g of 3-phenyl -1, 2, 3, 6-tetrahydropyridine in lO ml o~ acetonitrile is stirred at 20 for 12 hours, worked up as usual and 3-[4-(3-phenyl-1, 2, 3, 6-tetrahydropyridyl ) butyl ] indole is obtained .
Hydrochloride, m.p. 209-212.
~n analogy, the following are obtained from the appropriate chloro- or bromoalkylindoles with the appropriate 3-aryl-1, 2, 3, 6-tetrahydropyridines or -piperidines: 3- [ 3- ( 3-phenyl-1, 2, 3, 6-te trahydropyridyl ) propyl ] indole, hydrochloride, m.p. 175-177 3 - [ 3 - ( 3 -m-methoxyphenyl- 1, 2, 3, 6 -tetrahydropyridyl ) propyl ] -indole 3- [ 3 - ( 3 -p-methoxyphenyl- 1, 2, 3, 6-tetrahydropyridyl ) -propyl ] -indole 3 - [ 3 - ( 3-m-hydroxyphenyl -1, 2, 3, 6 -tetrahydropyridyl ) propyl ] -indole 3- [ 3- ( 3-p-hydroxyphenyl-1, 2, 3, 6-tetrahydropyridyl)propyl] -indole 3- [ 4- ( 3-phenyl-1, 2, 3, 6 -tetrahydropyridyl ) butyl ] -2-methyl-indole 3- [ 4 - ( 3 -phenyl -1, 2, 3, 6 -tetrahydropyridyl ) butyl ] -5-methoxy-indole 3 - [ 4 - ( 3-phenyl -1, 2, 3, 6 -tetrahydropyridyl ) butyl ] -6-methoxy-indole 3- [ 4 - ( 3 -phenyl -1, 2, 3, 6 -tetrahydropyridyl ) butyl ] -4-hydroxy-indole - 28 - ~2572'73 3-[4-(3-phenyl-1,2,3,6-tetrahydropyridyl)butyl]-5-hydroxy-indole 3-r4~(3-phenyl-1,2,3,6-tetrahydropyridyl)butyl]-6-hydroxy-indole 3-[4-(3-phenyl-ll2~3/6-tetrahydropyridyl)butyl]-5-~luor indole 3-[4-(3-phenyl-1,2,3,6-tetrahydropyridyl)butyl]-5-chloro-indole 3-[4-(3-phenyl-1,2,3,6-tetrahydropyridyl)butyl]-7-bromo-indole 3-[4-(3-phenyl-1,2,3,6-tetrahydropyridyl)butyl]-5-cyano-indole 3-~4-(3-phenyl-1,2,3,6-tetrahydropyridyl)butyl]-5,6-methyl-lenedioxyindole 3-[4-(3-phenyl-1,2,3,6-tetrahydropyridyl)butyl]-5,6-di-methylindole 3-[4-(3-phenyl-1,2,3,6-tetrahydropyridyl)butyl]-5,6-di-methoxyindole 3-[4-(3-phenyl-1,2,3,6-tetrahydropyridyl~butyl]-5,6-di-chloroindole 3-[4-(3-o-tolyl-1,2,3,6-tetrahydropyridyl)butyl]indole 3-~4-(3-m-tolyl-1,2,3,6-tetrahydropyridyl)butyl]indole 3-[4-(3-p-tolyl-1,2,3,6-tetrahydropyridyl)butyl]indole 3-[4-(3 o-methoxyphenyl-1,2,3,6-tetrahydropyridyl)butyl]-indole 3-~4-(3-m-methoxyphenyl-1,2~3,6-tetrahydropyridyl)butyl]-indole, R~ 0.42 3-[4-(3-p-methoxyphenyl-1,2,3,6-tetrahydropyridyl)-butyl]-indole ~257:~'73 3-[4~(3-o-methoxyphenyl-1,2,3,6-tetrahydropyridyl)butyl]-indole 3-[4-(3-m-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)butyl]-indole, Rf 0.32 (CH2Cl2/methanol 9:1) 3-[4-(3-p-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)butyl]-indole 3-[4-(3-o-~luorophenyl-1,2,3,6-tetrahydropyridyl)butyl]-indole 3-[4-(3-m-fluorophenyl-1,2,3,6-tetrahydropyridyl)butyl]-indole 3-[4-(3-p-~luorophenyl-1,2,3,6-tetrahydropyridyl)butyl]-indole 3-[4-(3-o-chlorophenyl-1,2,3,6-tetrahydropyridyl)butyl]-indole 3-[4-(3-m-chlorophenyl-1,2,3,6-tetrahydropyridyl)butyl]-indole 3-[4-(3-p-chlorophenyl-1,2,3,6-tetrahydropyridyl)butyl]-indole 3-[4-(3-p-bromophenyl-1,2,3,6-tetrahydropyridyl)butyl]-indole 3-[4-(3-m-trifluoromethylphenyl-l~2~3~6-tetrahydropyridyl) butyl]indole 3-[4-~3-p-cyanophenyl-1,2,3,6-tetrahydropridyl)butyl]-indole 3-[4-(3-(3,4-dimethoxyphenyl)-1,2,3,6-tetrahydropyridyl)-butyl]indole, Rf 0.48 (CH2Cl2/CH3OH 9:1) 3-[4-(3-(3,4-methylenedioxyphenyl)-1,2,3,6-tetrahydro~
pyridyl)butyl]indole 3-[4-(3-(4-chloro-3-tri~luoromethylphenyl)-1,2,3,6-tetra-hydropyridyl)butyl]indole ~l257273 3-~4-(3-m-methoxyphenyl-1,2,3,6-tetrahydropyridyl)butyl]-5-methoxyindole 3 - [ 4 - ( 3-m-methoxypheny~ 2 ~ 3 ~ 6-tetrahydropyridyl )butyl ] -6 methoxyindole 3-[4-(3-m-methoxyphenyl-1,2,3,6-tetrahydropyridyl)butyl]-5,6-dimethoxyindole 3-[4-(3-m-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)butyl]-5-hydroxyindole 3-[4-(3-m-hydroxyphenyl-1,2,3,6-tetrahydropridyl)butyl]-6-hydroxyindole 3-[5-(3-phenyl-1,2,3,6-tetrahydropyridyl)pentyl]indole, hydrochloride, m.p. 114-116 3-[5-(3-m-methoxyphenyl-1,2,3,6-tetrahydropyridyl)pentyl]-indole 3-~5-(3-p-methoxyphenyl-l~2~3~6-tetrahydropyridyl)pentyl]
i~dole 3-~5-(3-m-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)pentyl]-indole 3-[5-(3-p-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)pentyl]-indole 3-[3-(3-phenyl-1-piperidyl)propyl]indole 3-[3-(3-m-methoxyphenyl-1-piperidyl)propyl]indole 3-[3-(3-p-methoxyphenyl-1-piperidyl)propyl]indole 3-[3-(3-m-hydroxyphenyl-1-piperidyl)propyl]indole 3- L 3-(3-p-hydroxyphenyl-1-piperidyl)propyl]indole 3-[4-(3-phenyl-1-piperidyl)butyl]indole, hydrochloride, m.p.
3-[4-(3-phenyl-1-piperidyl)butyl]-2-methylindole ~257;~73 3-[4-(3-phenyl-1-piperidyllbutyl]-5-methoxyindole 3-[4-(3-phenyl-1-piperidyl)butyl]-6-methoxyindole 3-[4-(3-phenyl-1-piperidyl)butyl]-4-hydroxyindole 3-[4-(3-phe.nyl-1-piperidyl)butyl]-5-hydroxyindole 3-[4-(3-phenyl-1-piperidyl)butyl]-6-hydroxyindole 3-[4-(3-phenyl-1-piperidyl)butyl~-5-fluoroindole 3-[4-(3-phenyl-l-piperidyl)butyl]-5-chloroindole 3-[4-(3-phenyl~l-piperidyl)butyl]-7-bromoindole 3-[4-(3-phenyl-1-piperidyl)butyl]-5-cyanoindole 3-[4-(3-phenyl-1-piperidyl)butyl]-5,6-methylenedioxyindole 3-[4-(3-phenyl-1-piperidyl)butyl]-5,6-dimethylindole 3-[4-(3-phenyl-1-piperidyl)butyl]-5,6-dimethoxyindole 3-[4-(3-phenyl-1-piperidyl)butyl]-5,6-dichloroindole 3~ r 4-(3-o-tolyl-1-piperidyl)butyl]indole 3-[4-(3-m-tolyl-1-piperidyl)butyl]indole 3-[4-(3-p-tolyl-1-piperidyl)butyl]indole 3-[4-(3-o-methoxyphenyl-1-piperidyl)butyl]indole 3-[4-(3-m-methoxyphenyl-1-piperidyl)butyl]indole, Rf ~.41 3-[4-(3-p-methoxyphenyl-l~piperidyl)butyl]indole, hydro-chloride, m.p. 184-185 3-[4-(3-o-hydroxyphenyl-1-piperidyl)butyl]indole 3-[4-(3-m-hydroxyphenyl-1-piperidyl)butyl]indole, m.p. 135-143 (decomposition) 3-[4-(3-p-hydroxyphenyl-1-piperidyl)butyl]indola 3-[4-(3-o-fluorophenyl-1 piperidyl)butyl]indole 3-[4-(3-m-fluorophenyl-1-piperidyl)butyl]indole 3-[4-(3-p-~luorophenyl-1-piperidyl)butyl~indole 3-[4~(3-o-chlorophenyl-1-piperidyl)butyl]indole 3-[4-(3-m-chlorophenyl-l-piperidyl)butyl]indole 3-[4-(3-p-chlorophenyl-1-piperidyl)butyl]indole 3-[4-(3-p-bromophenyl-l-piperidyl)butyl]indol0 3-[4-(3-m-trifluoromethylphenyl-l-piperidyl)butyl]indole 3-[4-(3-p-cyanophenyl-1-piperidyl)butyl]indole 3-[4-(3-(3,4-dimethoxyphenyl)-1-piperidyl)butyl]indole, hydrochloride, m.p. 177.5-178.5 3-[4-(3-(3,4-methylenedioxyphenyl)-l-piperidyl)butyl]-indole 3-[4-(3-(4 chloro-3-trifluoromethylphenyl)-1-piperidyl)-butyl]indole 3-[4-(3-m-methoxyphenyl-1-piperidyl)butyl]-5-methoxyindole, hydrochloride, m.p. 102-104 3-[4-(3-p-methoxyphenyl-1-piperidyl)butyl]-5-methoxyindole, m.p. 109 3-[4-(3-methoxyphenyl-l~piperidyl)butyl]-6-methoxyindole, Rf 0.29 (CH2C12/CH3OH 9:1) 3-[4-(3-m-methoxyphenyl-1-piperidyl)bu-tyl]-5,6-dimethoxy-indole 3-[4-(3-m-hydroxyphenyl-1-piperidyl)butyl]-5-hydroxyindole, m.p. 102-104 3-[4-(3-m~hydroxyphenyl-1-piperidyl)butyl]-6-hydroxyindole, Rf 0.76 (CH~Cl2/CH3OH/triethylamine 7:2:1) 3-[4-(3-p-hydroxyphenyl-1-piperidyl)butyl]-5-hydroxyindole, m.p. 182-185 ~572q3 3-[5-~3-phenyl-1-piperidyl)pentyl]indole 3-[5-(3-m-methoxyphenyl-1-piperidyl)pentyl~indole, hydrochloride, m.p. 164.5 - 165.5 3-[5-(3-p-methoxyphenyl-1-piperidyl)pentyl]indole 3-[5-(3-m-hydroxyphenyl-1-piperidyl)pentyl3indole and 3-[5-(3-p-hydroxyphenyl-1-piperidyl)pentyl]indole 3-[4-(3-m-hydroxyphenyl-1-piperidyl)-butyl]-4-hydroxy-7-chloroindole 3-[4-(3-p-hydroxyphenyl-1-piperidyl)-butyl]-4-hydroxy-7-chloroindole Example 2 A mixture of 4.43 g of 3-t4-p-toluenesulfonyloxy-butyl)indole and 3.2 g of 3-phenylpiperidine is heated -~o 130. After the exothermic reaction has subsided and the mixture has cooled down, it is worked up as usual and 3-[4-(3-phenyl-1-piperidyl)butyl]indole hydrochloride, m.p. 180-182 is obtained.
~2S72~:~
In analogy, the following are obtained from the appropriate tosylates:
3-[4-(3-phenyl-1-piperidyl)butyl]-5-butylindole 3-[4-(3-phenyl-1-piperidyl)butyl]-5-ethoxyindole 3-[4-(3-phenyl-1-piperidyl)butyl]-5-butoxyindole 3-[4-(3-phenyl-1-piperidyl)butyl]-5-methylthioindole 3-[4-(3-phenyl-l-piperidyl)butyl]-5-butylthioindole 3-[4-(3-phenyl-l-piperidyl)butyl]-5-methylsulfinylindole and 3-[4-(3-phenyl-1-piperidyl)butyl]-5-methylsulfonylindole.
Example 3 2.99 g of 3-(4-iodobutyl)indole, 1.91 g of 3-m-methoxyphenylpiperidine and 1.5 g of anhydrous potassium carbonate in 25 ml of n-butanol are boiled, with stirring, for 2 hours, the mixture is allowed to cool, worked up as usual and 3-[4-(3-m-methoxyphenyl-1-piperidyl)butyl]-indole, Rf 0.41, is obtained.
In analogy, the following are obtained from the appropriate 3-Ar-piperidines:
3-[4-(3-p-butoxyphenyl-1-piperidyl)butyl]indole 3-[4-(3 p-methylthiophenyl-l-piperidyl)butyl]indole 3-[4-t3-p-butylthiophenyl-1-piperidyl)butyl]indole 3-[4-(3-p-methylsulfinylphenyl-l-piperidyl)butyl]indole and 3-[4-(3-p-methylsulfonylphenyl-l-piperidyl)butyl]indole.
Example 4 A mixture of 1.8~ g of 3-(4-aminobutyl)indole and 2.15 g of 1,5 dichloxo 2-phenylpentane (obtainable by reduction of diethyl 2-phenylpentane-1,5-dioate with ~257zq3 LiAlH4 and subsequent reaction with 5OC12) in 40 ml of acetone and 40 ml of water is boiled for 24 hours and worked up as usual. 3-[4-(3-Phenyl-1-piperidyl)butyl]-indole hydrochloride m.p. 180-182, is obtained.
In analogy, from the appropriate amines and the appropriate 1,5-dichloro-2-Ar-pentanes or ~-pentenes, the other compounds of the formula I indicated in Examples 1, 2 and 3 are obtained.
Example 5 1 g of NaBH4 in 20 ml of water is added, with stirring, to a solution of 4.23 g of 1-~4-(3-indolyl)-butyl]-3-m-hydroxyphenylpyridinium bromide [obtainable from 3-(4-bromobutyl)indole and 3-m-hydroxyphenylpyridineJ in 50 ml of lN NaOH, and the mixture is then stirred at 60C for 3 hours.
After working up as usual, 3-t4-(3-m-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)butyl]indole, ~f 0.32 (CH2C12/methanol 9:1), is obtained.
In analogy, the other tetrahydropyridines of the formula I indicated in Examples 1, 2 and 3 are obtained by reduction of the appropriate pyridinium bromides.
Example 6 A solution of 3.76 of indole-3-butyric 3-m-methoxyphenylpiperidide (Rf 0.86 in CH2C12/CH3OH 9:1;
obtainable from indole-3-butyric acid and 3-m-methoxyphenyl-piperidine in the presence of l,l'-carbonyldiimidazole) in 20 ml of THF is added dropwise, with stirring, to a suspension of 0.38 g of LiAlH4 in 10 ml of THF. After the reaction has subsided, 5 ml of ethyl acetate are added, the mixture is worked up as usual and 3-~4-(3-m-methoxy-phenyl-1-piperidyl)butyl]indole, Rf 0.41, is obtained.
~25'7~7:~
In analogy, from the appropriate amides, for example:
indole-3-propionic 3-phenyl-1,2,3,6-tetrahydropyridide (m.p.
152-154) indole-3-butyric 3-phenyl-1,2,3,6-tetrahydropyridide (Rf 0.44 in toluene/CH30H/triethylamine 7:2:1) indole-3-butyric 3-~-methoxyphenyl-1,2,3,6-tetrahydropyridide (Rf 0.88 in CH2Cl2/CH30H 9:1) indole-3-butyric 3-(3,4-dimethoxyphenyl)-1,2,3,6-tetra-hydropyridide (Rf 0.78 in OEI2Cl2/CH3H 9 1) indole-3-butyric 3-phenylpiperidide (Rf 0.8 in CH2Cl2/CH30H/ethyl acetate 7:2:1) indole-3-butyric 3-m-methoxyphenylpiperidide (Rf 0.86 in CH2Cl2/cH30H 9:1) indole-3-butyric 3-p-methoxyphenylpiperidide (P~f 0.6~ in CHCl3/CH30H/ethyl ac0tate 7:2:1) indole-3-butyric 3-(3,4-dimethoxyphenyl)piperidide (Rf 0.75 in CH2C12/CH30H 9:1) and indole-3-valeric 3-phenyl-1,2,3,6-tetrahydropyridide (m.p.
155-156), the other compounds of the formula I indicated in Examples 1, 2 and 3 are obtained.
Example 7
4.88 g of 1-benzenesulfonyl-3-[4-(3-m-hydroxy-phenyl-1-piperidyl)butyl]indole (obtainable from l-ben-zenesulfonyl-3-(4-chlorobutyl)indol~ and 3-m-hydroxyphenyl-piperidine) are boiled with 1 g of ~OH in 7 ml of water and 14 ml of ethanol for 16 hours, the mixture is concentrated, worked up as usual and 3-[4-(3-m-hydroxyphenyl-1-piperidyl)butyl]indole, m.p. 135-143 (decomposition), is obtained.
~ZS~27:~
Example 8 3.80 g of 1-methyl-3-[4-(3-hydroxy-3-phenyl-1-piperidyl)butyl]indole (obtainable by reaction of 1-methyl-3-(4-bromobutyl)indole wi~h 3-piperidone, subsequent reaction with C6HsLi and hydrolysis) are heated with 40 ml of lN
hydrochloric acid at 50 for 2 hours, worked up as usual and 1-methyl-3-[4-(3-phenyl-1,2,3,6-tetrahydropyridyl)butyl]
indole is obtained.
Example 9 6 ml of 30% H22 are added to a boiling solution of 3.78 g of 3-[4-(3-phenyl-1-piperidyl)butyl]-5-methyl-thioindole in 50 ml of ethanol, and the mixture is then boiled for 3 hours. After addition of a further 4 ml of the oxidising agent, the mixture is boiled a further 9 hours, cooled, worked up as usual and 3-[4-(3-phenyl-1-piperidyl) butyl]-5-methylsulfinylindole is obtained.
Example 10 9 ml of 30% H2O2 are added to a solution of 3.78 g of 3-[4-(3-phenyl-1-piperidyl)butyl3-5-methylthioindole in 20 ml of acetic acid, and the mixture is boiled for 90 minutes.
After working up as usual, 3-[4-(3-phenyl-1-piperidyl)butyl]-
~ZS~27:~
Example 8 3.80 g of 1-methyl-3-[4-(3-hydroxy-3-phenyl-1-piperidyl)butyl]indole (obtainable by reaction of 1-methyl-3-(4-bromobutyl)indole wi~h 3-piperidone, subsequent reaction with C6HsLi and hydrolysis) are heated with 40 ml of lN
hydrochloric acid at 50 for 2 hours, worked up as usual and 1-methyl-3-[4-(3-phenyl-1,2,3,6-tetrahydropyridyl)butyl]
indole is obtained.
Example 9 6 ml of 30% H22 are added to a boiling solution of 3.78 g of 3-[4-(3-phenyl-1-piperidyl)butyl]-5-methyl-thioindole in 50 ml of ethanol, and the mixture is then boiled for 3 hours. After addition of a further 4 ml of the oxidising agent, the mixture is boiled a further 9 hours, cooled, worked up as usual and 3-[4-(3-phenyl-1-piperidyl) butyl]-5-methylsulfinylindole is obtained.
Example 10 9 ml of 30% H2O2 are added to a solution of 3.78 g of 3-[4-(3-phenyl-1-piperidyl)butyl3-5-methylthioindole in 20 ml of acetic acid, and the mixture is boiled for 90 minutes.
After working up as usual, 3-[4-(3-phenyl-1-piperidyl)butyl]-
5-methylsulfonylindole is obtained.
Example 11 A mixture of 3.99 g of 3-[4-(3-p-methoxyphenyl-1-piperidyl)butyl3indole hydrochloride and 3.5 g of pyridine hydrochloride is stirred at 160 for 3 hours. Aft~r ` r,7j ~% 5 ~
working up as usual, 3-[4-(3-p-hydroxyphenyl-1-piperidyl)-butyl]indole hydrochloride, m.p. 234-236, is obtained.
Example 12 A solution of 12.3 g of boron tribromide/dimethyl sulfide complex in 50 ml o~ dichloroethane is added dropwise, with stirring, to a solution of 3.62 g of 3-[4-(3-m-methoxyphenyl-l-piperidyl)butyl]indole in 50 ml of 1,2-dichloroethane at 60-80. After cooling down and working up as usual, 3-[4-~3-m-hydroxyphenyl-1-piperidyl)butyl]indole, m.p. 135-143 (decomposition) is obtained.
The examples below relate to pharmaceutical formulations containing amines of the formula I or their acid addition salts:
Example A: Tablets A mixture of 1 kg of 3-[4-(3-m-hydroxyphenyl-1-piperidyl)butyl]indole, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed to form tablets in a customary manner such that each tablet contains 10 mg of active compound.
Example B: Coated Tablets Tablets are formed by compression in analogy to Example A and these are then coated in a customary manner with a coating of sucrose, potato starch, talc, tragacanth and dyestuff.
Example C: Capsules 2 kg of 3-[4~(3-m-hydroxyphenyl-1-piperidyl)-butyl]indole are filled into hard gelatine capsules in a customary manner such that each capsule contains 20 mg of the active compound.
~r ,'.
~ 39 - ~5~2~
Example D: Ampoules A solution of 1 kg of 3-[4-(3-m-hydroxyphenyl-1-piperidyl)butyl]indole hydrochloride in 30 li-tres of double distilled water is sterilized by filtration, filled into ampoules, freeze-dried under sterile conditions and closed sterile. Each ampoule contains 10 mg of active compound.
In analogy, tablets, coated tablets, capsules and ampoules can be obtained which contain one or more of the other active compounds of the formula I and/or their physiologically acceptable acid addition salts.
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
Example 11 A mixture of 3.99 g of 3-[4-(3-p-methoxyphenyl-1-piperidyl)butyl3indole hydrochloride and 3.5 g of pyridine hydrochloride is stirred at 160 for 3 hours. Aft~r ` r,7j ~% 5 ~
working up as usual, 3-[4-(3-p-hydroxyphenyl-1-piperidyl)-butyl]indole hydrochloride, m.p. 234-236, is obtained.
Example 12 A solution of 12.3 g of boron tribromide/dimethyl sulfide complex in 50 ml o~ dichloroethane is added dropwise, with stirring, to a solution of 3.62 g of 3-[4-(3-m-methoxyphenyl-l-piperidyl)butyl]indole in 50 ml of 1,2-dichloroethane at 60-80. After cooling down and working up as usual, 3-[4-~3-m-hydroxyphenyl-1-piperidyl)butyl]indole, m.p. 135-143 (decomposition) is obtained.
The examples below relate to pharmaceutical formulations containing amines of the formula I or their acid addition salts:
Example A: Tablets A mixture of 1 kg of 3-[4-(3-m-hydroxyphenyl-1-piperidyl)butyl]indole, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed to form tablets in a customary manner such that each tablet contains 10 mg of active compound.
Example B: Coated Tablets Tablets are formed by compression in analogy to Example A and these are then coated in a customary manner with a coating of sucrose, potato starch, talc, tragacanth and dyestuff.
Example C: Capsules 2 kg of 3-[4~(3-m-hydroxyphenyl-1-piperidyl)-butyl]indole are filled into hard gelatine capsules in a customary manner such that each capsule contains 20 mg of the active compound.
~r ,'.
~ 39 - ~5~2~
Example D: Ampoules A solution of 1 kg of 3-[4-(3-m-hydroxyphenyl-1-piperidyl)butyl]indole hydrochloride in 30 li-tres of double distilled water is sterilized by filtration, filled into ampoules, freeze-dried under sterile conditions and closed sterile. Each ampoule contains 10 mg of active compound.
In analogy, tablets, coated tablets, capsules and ampoules can be obtained which contain one or more of the other active compounds of the formula I and/or their physiologically acceptable acid addition salts.
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
Claims (11)
1. An indole derivative of the formula wherein Ind is 3-indolyl or 3-indolyl substituted once or twice by alkyl, O-alkyl, S-alkyl, SO-alkyl, SO2-alkyl, OH, F, Cl, Br, CF3 or CN or substituted by methylenedioxy;
A is -(CH2)n-;
n is 3, 4 or 5;
Ar is hydroxyphenyl;
both L's are H or together form a C-C bond;
each alkyl segment is of 1 - 4 C atoms;
or a physiologically acceptable acid addition salt thereof.
A is -(CH2)n-;
n is 3, 4 or 5;
Ar is hydroxyphenyl;
both L's are H or together form a C-C bond;
each alkyl segment is of 1 - 4 C atoms;
or a physiologically acceptable acid addition salt thereof.
2. A compound of claim 1 wherein Ind is 3-indolyl, methyl-3-indolyl, dimethyl-3-indolyl, methoxy-3-indolyl, dimethoxy-3-indolyl, hydroxy-3-indolyl, dihydroxy-3-indolyl, fluoro-3-indolyl, chloro-3-indolyl, dichloro-3-indolyl, bromo-3-indolyl, cyano-3-indolyl or methylenedioxy-3-indolyl and the substituents are in the 5- and/or 6-positions.
3. A compound of claim 1 wherein Ind is 3-indolyl, 5-or 6-methyl-3-indolyl, 5,6-dimethyl-3-indolyl, 5- or 6-methoxy-3-indolyl, 5,6-dimethoxy-3-indolyl or 5-cyano-3-indolyl.
4. A compound of claim 1 wherein Ind is 3-indolyl.
5. A compound of claim 1 wherein A is -(CH2)4- .
6. A compound of claim 1 wherein Ar is hydroxyphenyl.
7. A compound of claim 1 wherein Ind is 3-indolyl or 5-methoxy-3-indolyl and Ar is hydroxyphenyl.
8. A compound of claim 1 wherein Ind is 3-indolyl, A
is -(CH2)4- , and Ar is 3- or 4-hydroxyphenyl.
is -(CH2)4- , and Ar is 3- or 4-hydroxyphenyl.
9. A compound of claim 1 wherein Ind is 3-indolyl, A
is -(CH2)4-, and Ar is 3-hydroxyphenyl.
is -(CH2)4-, and Ar is 3-hydroxyphenyl.
10. 3-[4-(3-m-Hydroxyphenyl-1-piperidyl)butyl]indole, a compound of claim 1.
11. A composition comprising a compound of claim 1 and a physiologically acceptable carrier.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3301758.1 | 1983-01-20 | ||
| DE3301758A DE3301758A1 (en) | 1983-01-20 | 1983-01-20 | INDOLDER DERIVATIVES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1257273A true CA1257273A (en) | 1989-07-11 |
Family
ID=6188727
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000445776A Expired CA1257273A (en) | 1983-01-20 | 1984-01-20 | Indole derivatives |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP0114603B1 (en) |
| JP (1) | JPS59181276A (en) |
| AT (1) | ATE34983T1 (en) |
| AU (1) | AU565894B2 (en) |
| CA (1) | CA1257273A (en) |
| DE (2) | DE3301758A1 (en) |
| ES (1) | ES529013A0 (en) |
| FI (1) | FI840225A (en) |
| HU (1) | HU193196B (en) |
| IL (1) | IL70698A (en) |
| ZA (1) | ZA84424B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3342632A1 (en) * | 1983-11-25 | 1985-06-05 | Merck Patent Gmbh, 6100 Darmstadt | INDOLDER DERIVATIVES |
| DE3604949A1 (en) * | 1986-02-17 | 1987-08-20 | Merck Patent Gmbh | HYDROXYINDOLESTER |
| DE3614758A1 (en) * | 1986-04-30 | 1987-11-05 | Merck Patent Gmbh | INDOLDER DERIVATIVE |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3238215A (en) * | 1963-10-17 | 1966-03-01 | Sterling Drug Inc | 1-[(3-, 2-, and 1-indolyl)-lower-alkyl-, lower-alkenyl-, and lower-alkynyl]piperidines |
| SE307788B (en) * | 1965-04-23 | 1969-01-20 | Yoshitomi Pharmaceutical | |
| US4160862A (en) * | 1972-06-12 | 1979-07-10 | Sterling Drug Inc. | 1-Acyl-3-(amino-lower-alkyl)indoles |
| DE2708913A1 (en) * | 1976-03-04 | 1977-09-08 | Hoechst Ag | BENZOYL PIPERIDYALKYL INDOLES AND RELATED COMPOUNDS |
| EP0007399B1 (en) * | 1978-06-24 | 1982-01-20 | MERCK PATENT GmbH | Indolylalkyl amines, pharmaceutical preparations containing them and process for their manufacture |
| EP0077607A1 (en) * | 1981-09-17 | 1983-04-27 | Beecham Group Plc | N-substituted 3-aryl piperidines and derivatives thereof |
-
1983
- 1983-01-20 DE DE3301758A patent/DE3301758A1/en not_active Withdrawn
-
1984
- 1984-01-03 AU AU23024/84A patent/AU565894B2/en not_active Ceased
- 1984-01-09 DE DE8484100128T patent/DE3471935D1/en not_active Expired
- 1984-01-09 AT AT84100128T patent/ATE34983T1/en active
- 1984-01-09 EP EP84100128A patent/EP0114603B1/en not_active Expired
- 1984-01-16 IL IL70698A patent/IL70698A/en not_active IP Right Cessation
- 1984-01-19 ZA ZA84424A patent/ZA84424B/en unknown
- 1984-01-19 ES ES529013A patent/ES529013A0/en active Granted
- 1984-01-19 HU HU84204A patent/HU193196B/en not_active IP Right Cessation
- 1984-01-19 FI FI840225A patent/FI840225A/en not_active Application Discontinuation
- 1984-01-20 JP JP59007373A patent/JPS59181276A/en active Pending
- 1984-01-20 CA CA000445776A patent/CA1257273A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| DE3471935D1 (en) | 1988-07-14 |
| FI840225A0 (en) | 1984-01-19 |
| ES8503679A1 (en) | 1985-03-01 |
| IL70698A0 (en) | 1984-04-30 |
| FI840225A (en) | 1984-07-21 |
| ATE34983T1 (en) | 1988-06-15 |
| AU2302484A (en) | 1984-07-26 |
| ZA84424B (en) | 1984-09-26 |
| AU565894B2 (en) | 1987-10-01 |
| JPS59181276A (en) | 1984-10-15 |
| IL70698A (en) | 1987-03-31 |
| DE3301758A1 (en) | 1984-07-26 |
| HU193196B (en) | 1987-08-28 |
| EP0114603B1 (en) | 1988-06-08 |
| ES529013A0 (en) | 1985-03-01 |
| EP0114603A1 (en) | 1984-08-01 |
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| MKEX | Expiry |