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HK1058520A - Novel indole derivatives - Google Patents

Novel indole derivatives Download PDF

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Publication number
HK1058520A
HK1058520A HK04101231.3A HK04101231A HK1058520A HK 1058520 A HK1058520 A HK 1058520A HK 04101231 A HK04101231 A HK 04101231A HK 1058520 A HK1058520 A HK 1058520A
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HK
Hong Kong
Prior art keywords
piperazin
indole
phenoxy
propyl
phenylsulfanyl
Prior art date
Application number
HK04101231.3A
Other languages
Chinese (zh)
Inventor
Ruhland Thomas
Krog-Jensen Christian
Rottlander Mario
Mikkelsen Gitte
Andersen Kim
Knud Moltzen Ejner
Original Assignee
H. Lundbeck A/S
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Publication of HK1058520A publication Critical patent/HK1058520A/en

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Description

Novel indole derivatives
The present invention relates to the field of reactions involving 5-HT1A-novel indole derivatives to which the receptor binds efficiently, pharmaceutical compositions containing these compounds and their use in the treatment of certain psychiatric and neurological disorders. Many of the compounds of the invention are also potent serotonin reuptake inhibitors and/or D4Ligands, therefore, are believed to be particularly useful for the treatment of depression and psychosis.
Background
Clinical and pharmacological studies have shown 5-HT1AAgonists and partial agonists are useful for the treatment of a range of affective disorders such as generalized anxiety disorder, panic disorder, obsessive compulsive disorder, depression and aggressive behavior.
5-HT has also been reported1AThe ligands can be used for the treatment of ischemia.
For 5-HT1AAn overview of potential therapeutic targets for antagonists and proposed inhibitors based on preclinical and clinical data is described in Serotonin 1997, vol 2, stage 7 (Schechter et al). It is described that 5-HT1AAntagonists are useful in the treatment of schizophrenia, senile dementia, dementia associated with alzheimer's disease, and combinations with SSRI antidepressants are also useful for the treatment of depression.
5-HT reuptake inhibitors are well known antidepressants and are used in the treatment of panic disorder and social phobia.
Compounds that inhibit serotonin reuptake have been evaluated in several studies with 5-HT1AThe effect of a combination of receptor antagonists (Innis, R.B. et al, Eur.J. Pharmacol.1987, 143, 195-1070, pp. 204; Gartside, S.E., Br.J. Pharmacol.1995, 115, 1064-1070, Blier, P. et al, Trends Pharmacol.Sci.1994, 15, 220). 5-HT was found in these studies1AThe combination of receptor antagonist and serotonin reuptake inhibitor will produce a therapeutic effect more rapidly.
Dopamine D4The receptor being dopamine D2A family of receptors, and such receptors are believed to be responsible for the psychotropic effects of neuroleptic drugs. Dopamine D4Receptors are mainly located in brain regions outside the striatum, which means dopamine D4Receptor ligands have a psychotropic effect and lack extrapyramidal activity.
Thus, dopamine D4Receptor ligands are potential drugs for the treatment of the positive symptoms of psychosis and schizophrenia (positive symptomm), in dopamine D4And compounds having a combined effect on serotonin-containing receptors may have a more beneficial improving effect on negative symptoms (negease symptoms) of schizophrenia such as anxiety and depression, alcohol abuse, impulse control disorders, aggressive behavior, side effects caused by conventional neuroleptics, ischemic conditions, migraine, senile dementia and cardiovascular diseases, and sleep improvement.
Dopamine D3The receptors also belong to dopamine D2Receptor-like family, neuroleptic D3Antagonistic properties may reduce inhibitory symptoms and cognitive deficits and improve the type of side effects of EPS and hormonal changes.
Thus, it is considered to act on 5-HT1ADrugs of receptors, whether agonists or antagonists, in the treatment of psychiatric and neurological disordersHave potential use in therapy and are therefore highly desirable. Moreover, it has potent serotonin reuptake inhibitory activity and/or D4And/or D3Active antagonists may be particularly useful for the treatment of various psychiatric and neurological disorders.
Closely related structures have been previously reported:
WO 9955672 discloses a composition having 5-HT1AReceptors and D2General formula for receptor affinity, which also includes indole derivatives.
EP 900792 discloses a 5-HT1AAnd 5-HT1DAndD2-receptor ligands of the general formula, which also include indole derivatives.
A class of indole derivatives has been found to be 5-HT1AThe ligands are particularly useful.
Furthermore, many of these compounds have been found to have other very beneficial properties, such as potent serotonin reuptake inhibitory activity and/or for D4Affinity of the receptor.
Summary of The Invention
The invention comprises the following contents:
a compound represented by the general formula I, enantiomers thereof and pharmaceutically acceptable acid addition salts thereof
Wherein
X represents O or S;
n is 2, 3, 4, 5, 6, 7, 8, 9 or 10;
m is 2 or 3;
y represents N, C or CH;
the dotted line represents an optional bond;
R1and R1’Independently represent hydrogen or C1-6An alkyl group;
R7、R8、R10、R11and R12Each independently selected from hydrogen, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl radical, C3-8cycloalkyl-C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio, hydroxy, formyl, acyl, amino, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, acylamino, C1-6Alkoxycarbonylamino, aminocarbonylamino, C1-6Alkylamino carbonylamino and di (C)1- 6Alkyl) aminocarbonylamino;
R9represents hydrogen, C1-6An alkyl or acyl group;
R2、R3、R4、R5and R6Independently represent hydrogen, halogen, cyano, nitro, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C1-6Alkylsulfonyl, hydroxy-C1-6Alkyl radical, C1-6Alkoxycarbonyl, acyl, C3-8Cycloalkyl radical, C3-8cycloalkyl-C1-6Alkyl, trifluoromethyl, trifluoromethoxy, NH2、NR13R14Wherein R is13And R14Independently represent hydrogen, C1-6Alkyl radical, C3-8Cycloalkyl or phenyl; or R13And R14Together with the nitrogen atom to which they are attached form a 5 or 6 membered carbocyclic ring optionally containing one further heteroatom.
The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula I as defined above, or a pharmaceutically acceptable acid addition salt or prodrug thereof, in combination with one or more pharmaceutically acceptable carriers or diluents.
The present invention provides the use of a compound of formula I as defined above, or an acid addition salt or prodrug thereof, in the preparation of a medicament for the treatment of a disease or conditionUse in pharmaceutical formulations for the treatment of diseases and disorders associated with 5-HT1aLigands for receptors are related and may be associated with serotonin reuptake and/or dopamine D4Ligand association on the receptor.
The invention also provides a method for producing the same and 5-HT1aLigands for receptors are related and may be associated with serotonin reuptake and/or dopamine D4A method of treating human diseases and disorders associated with ligands at the receptor comprising administering an effective amount of a compound of formula I.
Diseases and disorders treated by administration of the compounds of the present invention are: affective disorders such as generalized anxiety disorder, panic disorder, obsessive compulsive disorder, depression, social phobia, eating disorders and aggressive behavior, neurological disorders such as psychiatric disorders. Detailed description of the invention
A preferred embodiment of the present invention are the compounds of formula I as described above, the enantiomers thereof and the pharmaceutically acceptable acid addition salts thereof, wherein
X represents O or S;
n is 2, 3, 4 or 5;
m is 2 or 3;
y represents N or CH;
R1and R1’Are all hydrogen;
R7、R8、R10、R11and R12One or two of (A) independently represent hydrogen, halogen, CF3CN or C1-6Alkyl, the remainder represent hydrogen;
R9represents hydrogen;
R2、R3、R4、R5and R6Independently represent hydrogen, halogen, C1-6Alkyl radical, C3-8Cycloalkyl radical, C1-6Alkoxy, hydroxy, nitro, CN, CF3、OCF3Acyl, NH2、NR13R14Wherein R is13And R14Independently represent hydrogen, C1-6Alkyl radical, C3-8Cycloalkyl or phenyl; or R13And R14Together with the nitrogen atom, form piperidine, morpholine, piperazine or pyrrolidine.
In another embodiment of the present invention, R in the above-mentioned compounds of formula I1And R1’Is hydrogen.
In another embodiment of the present invention, m in the above compounds of formula I is 2.
In another embodiment of the present invention, n in the above compounds of formula I is 2, 3 or 4.
In another embodiment of the present invention, Y in the above compounds of formula I is N.
In another embodiment of the present invention, the indole in the compounds of formula I above is attached to the Y group at the 4-position.
Another embodiment of the present invention are the compounds of formula I as described above, wherein at least one R is2、R3、R4、R5And R6Represents halogen.
In another embodiment of the invention, at least two R in the compounds of formula I above are2、R3、R4、R5And R6Represents halogen.
In another embodiment of the present invention, at least three R in the compounds of formula I above2、R3、R4、R5And R6Represents halogen.
In another embodiment of the present invention, R in the above-mentioned compounds of formula I2And/or R6Is not hydrogen.
In a preferred embodiment of the present invention, the above compound of formula I is:
4- {4- [3- (2-chloro-phenoxy) -propyl ] -piperazin-1-yl } -1H-indole
4- {4- [3- (2-chloro-phenylsulfanyl) -propyl ] -piperazin-1-yl } -1H-indole
4- {4- [3- (2-bromo-phenylsulfanyl) -propyl ] -piperazin-1-yl } -1H-indole
4- {4- [3- (2-bromo-phenoxy) -propyl ] -piperazin-1-yl } -1H-indole
4- {4- [4- (2-bromo-4-fluoro-phenoxy) -butyl ] -piperazin-1-yl } -1H-indole
4- {4- [4- (2-chloro-6-methyl-thiophenyl) -butyl ] -piperazin-1-yl } -1H-indole
4- {4- [2- (2-chloro-4-fluoro-phenylsulfanyl) -ethyl ] -piperazin-1-yl } -1H-indole
4- {4- [2- (2, 6-dichloro-phenylsulfanyl) -ethyl ] -piperazin-1-yl } -1H-indole
4- {4- [2- (3, 4-dichloro-phenylsulfanyl) -ethyl ] -piperazin-1-yl } -1H-indole
4- {4- [2- (4-fluoro-phenylsulfanyl) -ethyl ] -piperazin-1-yl } -1H-indole
4- {4- [3- (2-chloro-4-fluoro-phenylsulfanyl) -propyl ] -piperazin-1-yl } -1H-indole
4- {4- [4- (2-bromo-4-fluoro-phenoxy) -butyl ] -piperazin-1-yl } -1H-indole
4- {4- [3- (2, 4-difluoro-phenoxy) -propyl ] -piperazin-1-yl } -1H-indole
4- {4- [4- (2, 6-dichloro-phenylsulfanyl) -butyl ] -piperazin-1-yl } -1H-indole
4- {4- [3- (2-chloro-4-fluoro-phenoxy) -propyl ] -piperazin-1-yl } -1H-indole
4- {4- [4- (2-chloro-6-methyl-thiophenyl) -butyl ] -piperazin-1-yl } -1H-indole
4- {4- [4- (2, 6-dichloro-4-fluoro-phenoxy) -butyl ] -piperazin-1-yl } -1H-indole
4- {4- [3- (2-bromo-4, 6-difluoro-phenoxy) -propyl ] -piperazin-1-yl } -1H-indole
4- {4- [3- (2, 6-dichloro-4-fluoro-phenoxy) -propyl ] -piperazin-1-yl } -1H-indole
4- {4- [4- (4-bromo-2, 6-difluoro-phenoxy) -butyl ] -piperazin-1-yl } -1H-indole
4- {4- [4- (2, 6-dibromo-4-fluoro-phenoxy) -butyl ] -piperazin-1-yl } -1H-indole
4- {4- [3- (2, 4, 6-tribromo-phenoxy) -propyl ] -piperazin-1-yl } -1H-indole
4- {4- [3- (4-bromo-2, 6-difluoro-phenoxy) -propyl ] -piperazin-1-yl } -1H-indole
1- (3, 5-difluoro-4- {3- [4- (1H-indol-4-yl) -piperazin-1-yl ] -propoxy } -phenyl) -propan-1-one
3, 5-dibromo-4- {3- [4- (1H-indol-4-yl) -piperazin-1-yl ] -propoxy } -benzonitrile
4- {4- [2- (2-bromo-4, 6-difluoro-phenoxy) -ethyl ] -piperazin-1-yl } -1H-indole
4- {4- [3- (2, 6-dichloro-phenylsulfanyl) -propyl ] -piperazin-1-yl } -1H-indole
4- {4- [2- (2, 6-dimethyl-phenoxy) -ethyl ] -piperazin-1-yl } -1H-indole
4- {4- [4- (2, 6-dimethyl-phenylsulfanyl) -butyl ] -piperazin-1-yl } -1H-indole
4- {4- [2- (2, 4-dimethyl-phenylsulfanyl) -ethyl ] -piperazin-1-yl } -1H-indole
4- {4- [2- (2, 3-dichloro-phenylsulfanyl) -ethyl ] -piperazin-1-yl } -1H-indole
4- {4- [2- (2-allyl-6-chloro-phenoxy) -ethyl ] -piperazin-1-yl } -1H-indole
4- {4- [3- (2-trifluoromethyl-phenylthio) -propyl ] -piperazin-1-yl } -1H-indole
4- {4- [3- (3, 4-dichloro-phenylsulfanyl) -propyl ] -piperazin-1-yl } -1H-indole
4- {4- [4- (2, 4-dimethyl-phenoxy) -butyl ] -piperazin-1-yl } -1H-indole
4- {4- [4- (2-ethyl-phenoxy) -butyl ] -piperazin-1-yl } -1H-indole
4- [4- (4-thiophenyl-butyl) -piperazin-1-yl ] -1H-indole
4- {4- [4- (2-chloro-5-methyl-phenoxy) -butyl ] -piperazin-1-yl } -1H-indole
4- {4- [2- (2, 5-dichloro-phenylsulfanyl) -ethyl ] -piperazin-1-yl } -1H-indole
4- {4- [2- (3-chloro-phenylsulfanyl) -ethyl ] -piperazin-1-yl } -1H-indole
4- {4- [2- (2-chloro-phenylsulfanyl) -ethyl ] -piperazin-1-yl } -1H-indole
4- {4- [3- (3-chloro-phenylsulfanyl) -propyl ] -piperazin-1-yl } -1H-indole
3-chloro-4- {4- [4- (1H-indol-4-yl) -piperazin-1-yl ] -butoxy } -benzonitrile
4- {4- [4- (3-chloro-phenylsulfanyl) -butyl ] -piperazin-1-yl } -1H-indole
4- {4- [4- (2-chloro-phenylsulfanyl) -butyl ] -piperazin-1-yl } -1H-indole
4- {4- [3- (3, 4-dimethyl-phenylsulfanyl) -propyl ] -piperazin-1-yl } -1H-indole
3- {4- [4- (1H-indol-4-yl) -piperazin-1-yl ] -butoxy } -benzonitrile
4- {4- [4- (2, 5-dichloro-phenoxy) -butyl ] -piperazin-1-yl } -1H-indole
4- {4- [4- (3, 4-dimethoxy-phenylsulfanyl) -butyl ] -piperazin-1-yl } -1H-indole
4- {4- [3- (4-trifluoromethyl-phenylthio) -propyl ] -piperazin-1-yl } -1H-indole
4- {4- [3- (4-trifluoromethoxy-phenylthio) -propyl ] -piperazin-1-yl } -1H-indole
4- {4- [3- (3-bromo-phenylsulfanyl) -propyl ] -piperazin-1-yl } -1H-indole
4- {4- [3- (2-isopropyl-phenylsulfanyl) -propyl ] -piperazin-1-yl } -1H-indole
4- {4- [4- (2-methoxy-phenoxy) -butyl ] -piperazin-1-yl } -1H-indole or
4- {4- [4- (2-isopropyl-phenylsulfanyl) -butyl ] -piperazin-1-yl } -1H-indole
Or a pharmaceutically acceptable salt thereof. Definition of substituents etc
Term C1-6Alkyl refers to branched or linear alkyl groups having 1 to 6 (including 1 and 6) carbon atoms, including but not limited to methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-2-propyl, and 2-methyl-1-propyl.
Similarly, C2-6Alkenyl and C2-6Alkynyl denotes such radicals having 2 to 6, including 2 and 6, carbon atoms, respectively, which radicals have at least one double or triple bond, respectively.
Term C1-6Alkoxy radical, C1-6Alkylthio radical, C1-6Alkylsulfonyl radical, C1-6Alkylamino radical, C1-6Alkylcarbonyl, hydroxy-C1-6Alkyl, etc. represent wherein C1-6Alkyl is such a group as defined above.
Term C3-8Cycloalkyl represents a mono or bi-carbocyclic ring having 3 to 8 carbon atoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
The term aryl refers to a carbocyclic aromatic group such as phenyl, naphthyl, especially phenyl. Aryl groups as used herein may be substituted by halogen, nitro, cyano, trifluoromethyl, C1-6Alkyl, hydroxy and C1-6Alkoxy groups are substituted one or more times.
Halogen represents fluorine, chlorine, bromine or iodine.
Acyl as used herein refers to acyl, C1-6Alkylcarbonyl, acylcarbonyl, aryl-C1-6Alkylcarbonyl (wherein aryl is as defined above), C3-8Cycloalkyl carbonyl or C3-8cycloalkyl-C1-6An alkylcarbonyl group.
The term amino, C1-6Alkylamino and C2-12Dialkylamino groups each represent NH2、NH(C1-6Alkyl) (wherein alkyl is as defined above) and N (C)1-6Alkyl radical)2(wherein alkyl is as defined above).
The term acylamino denotes-CO-amino (wherein amino is as defined above).
The term aminocarbonyl refers to the formula-NHCOH, -NHCO-C1-6Alkyl, -NHCO-aryl, -NHCO-C3-8Cycloalkyl, -NHCO-C3-8cycloalkyl-C1-6The group of alkyl groups (wherein alkyl, cycloalkyl and aryl are as defined above).
The term aminocarbonylamino, C1-6Alkylamino carbonylamino and di (C)1-6Alkyl) aminocarbonylamino group of the formula NHCONH2、-NHCONHC1-6Alkyl, NHCON (Di C)1-6Alkyl) groups.
Preferably, the acid addition salts of the present invention are pharmaceutically acceptable salts of the compounds of the present invention with non-toxic acids. Examples of such organic salts are salts with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic and theophylline acetic acids and 8-halotheophyllines (e.g. 8-bromotheophylline). Examples of such inorganic salts are salts with hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid.
In addition, the compounds of the present invention may exist in the form of a non-solvate or a solvate with a pharmaceutically acceptable solvent (e.g., water, ethanol, etc.). For the purposes of the present invention, the solvated forms are generally considered equivalent to the unsolvated forms.
Some of the compounds of the present invention contain chiral centers and these compounds exist as isomers (i.e., enantiomers). The present invention includes all such isomers and any mixtures thereof (including racemic mixtures).
The racemic form can be resolved into the optical antipodes by known methods, for example separation of the diastereomeric salts with an optically active acid and liberation of the optically active amine compound by treatment with a base. Another method for resolving racemates into optical antipodes is based on chromatography on an optically active matrix. The racemic compounds of the present invention can also be decomposed into their optical antipodes, for example by fractional crystallization of salts such as the d-or 1- (tartrate, mandelate or camphorsulfonate) salts. The compounds of the present invention may also be decomposed by forming diastereomeric derivatives.
Other methods of resolving optical isomers known to those skilled in the art may also be used. These methods include those discussed by j.jaques, a.collet and s.wilen in "enertiomers, racemes, and solutions", John Wiley and Sons, New York (1981).
Optically active compounds can also be prepared from optically active starting materials.
Finally, formula (I) includes any tautomeric form of the compounds of the invention.
The compounds of the invention may be prepared by one of the following methods, which comprises:
a) reducing the carbonyl group of the compound of formula (II),
wherein o is 0-8, R1-R12X, Y, m and the dashed lines are as defined above;
b) reducing the carbonyl group of the compound of formula (III),
wherein o is 0-9 and p is 0-4, with the proviso that o + p is not more than 9, R1-R12X, Y, m and the dashed lines are as defined above;
c) alkylating an amine of formula (IV) with a reagent of formula (V),
wherein G is a suitable leaving group such as halogen, mesylate or tosylate; r2-R6X and n are as defined above;
wherein R is1、R7-R12Y, m and the dashed lines are as defined above;
d) reductive alkylation of an amine of formula (VI) with a reagent of formula (VII),wherein R is1-R12Y, X, m and n and the dotted lines are as defined above, B is an aldehyde or carboxylic acid derivative;
e) oxidizing a 2, 3-indoline of formula (VIII)Wherein R is1-R12Y, X, n and m and the dotted lines are as defined above;
f) reducing the double bond of the unsaturated cyclic amine of formula (IX) to give the corresponding saturated derivative,
wherein R is1-R12X, n and m are as defined above;
g) reductive removal of one or more substituents R in the compound of formula (I)1-R3Or R7-R12Wherein one or more of these substituents are selected from chlorine, bromine or iodine;
h) (ii) di-hydrocarbylating the amine of formula (X) with a reagent of formula (XI),
wherein R is1-R12Y, X, n and m are as defined above, G is a suitable leaving group such as halogen, methanesulphonate or toluenesulphonate;
i) dialkylating an amine of formula (XII) with a reagent of formula (XIII),
wherein R is7-R12And m is as defined above, G is a suitable leaving group such as halogen, methanesulfonate or toluenesulfonate,
wherein R is2-R6X and n are as defined above; or
j) With the formula R9-G (wherein G is a suitable leaving group such as halogen, mesylate or tosylate, R9As defined above but not hydrogen) alkylating or acylating the indole nitrogen atom in the compound of formula (XIV),
wherein R is1-R12Y, X, n and m and the dotted line are as defined above, R9Is hydrogen;
k) reduction of a sulfone or sulfoxide of formula (XV)
Wherein R is1-R12Y, m and n are as defined above, with the dotted line being an optional bond;
m) alkylating a compound of formula (XVI) with a suitable derivatising compound comprising a leaving group to form a compound of the invention,
wherein R is2-R6And X is as defined above.
The compounds of formula (I) may be isolated in the form of the free base or a pharmaceutically acceptable salt thereof.
Preferably, the reduction of processes a) and b) is carried out at reflux temperature in the presence of lithium aluminium hydride in an inert organic solvent, such as diethyl ether or tetrahydrofuran.
The alkylation according to process c) is generally carried out in an inert organic solvent, such as a suitable boiling alcohol or ketone, preferably at reflux temperature in the presence of a base (potassium carbonate or triethylamine).
Arylpiperazine derivatives of formula (IV) are commercially available but can also be conveniently prepared from the corresponding arylamine according to the method described by Martin et al, J.Med.chem.1989, 32, 1052, or Kruse et al, Rec.Trav.Chim.Pays-Bas1988, 107. The starting arylamines are commercially available or are well described in the literature.
Aryl tetrahydropyridine derivatives of formula (IV) are known from the literature, see U.S. Pat. No. 2,891,066, McElvain et al J.Amer.chem.Soc.1959, 72, 3134. Conveniently, the corresponding aryl bromide is lithiated with BuLi followed by addition of 1-benzyl-4-piperidone. Subsequent treatment with acid gives the N-benzyl-aryltetrahydropyridine. Removal of the benzyl group by catalytic hydrogenation or by treatment with, for example, ethyl chloroformate gives the corresponding ethyl carbamate, followed by acidic or basic hydrolysis. The starting aryl bromides are either commercially available or well described in the literature.
The reagents of formula (V) are commercially available or can be prepared by literature methods, for example by reduction of the corresponding carboxylic acid derivative to a 2-hydroxyethyl derivative, conversion of the hydroxyl group to the group G by conventional methods, or from the corresponding dihaloalkyl or 1-halohydrin.
The reductive alkylation of process d) is carried out by standard literature methods. The reaction may be carried out in two steps, i.e. coupling of the reagents of formula (IV) and (VII) via carboxylic acid chloride or using a coupling reagent such as dicyclohexylcarbodiimide by standard methods; the resulting amide is then reduced with lithium aluminum hydride. The reaction can also be carried out by a standard one-pot procedure. The carboxylic acids or aldehydes of the formula (VII) are commercially available or described in the literature.
The oxidation of 2, 3-indoline of process e) can conveniently be carried out by treatment with palladium on carbon under reflux of p-xylene or methanol (Aoki et al, J.Am.chem.Soc.1998, 120, 3068-.
The reduction of the double bond of process f) can most conveniently be carried out by hydrogenation in an alcohol in the presence of a noble metal catalyst, such as platinum or palladium.
The removal of the halogen substituents of process g) can conveniently be carried out by catalytic hydrogenation in an alcohol in the presence of a palladium catalyst or by treatment with ammonium formate in an alcohol at elevated temperature in the presence of a palladium catalyst.
The dialkylation of the amines of processes h) and i) can most conveniently be carried out in an inert solvent such as chlorobenzene, toluene, N-methylpyrrolidone, dimethylformamide or acetonitrile at elevated temperature. The reaction may also be carried out in the presence of a base such as potassium carbonate or triethylamine. The starting materials for processes h) and i) are commercially available or can be prepared in a conventional manner from commercially available starting materials.
The N-alkylation of process j) can be carried out in the presence of a base, such as potassium carbonate or triethylamine at reflux temperature, in an inert solvent, such as an alcohol or ketone, at elevated temperature. Alternatively, a phase transfer agent may be used.
The reduction of the sulfones and sulfoxides of process k) can be carried out at room temperature using several commercially available reagents such as titanium tetrachloride and sodium borohydride (S.Kano et al Synthesis 1980, 9, 695-one 697).
The alkylation of commercially available compounds corresponding to formula XVI using process m) can conveniently be carried out in a polar aprotic solvent (e.g. methyl isobutyl ketone, dimethylformamide) with an alkylating agent (e.g. mesylate, halide) bearing a suitable leaving group and a base (e.g. potassium carbonate or the like).
The halogen, methyl or methoxy substituted indoles used in the examples are all commercially available.
The substituted 2- (1-indolyl) acetic acids used in the examples were prepared by conventional methods from the corresponding substituted indoles and ethyl bromoacetate.
The substituted 3- (2-bromoethyl) indoles used in the examples were prepared according to standard literature procedures by reducing the corresponding 2- (1-indolyl) acetate to the alcohol with lithium aluminum hydride, followed by treatment with tetrabromomethane/triphenylphosphine.
The arylpiperazines used in the examples were prepared from the corresponding arylamines according to the method described by Martin et al in J.Med.chem.1989, 32, 1052 or Kruse et al in Rec.Trav.Chim.Pays-Bas1988, 107, 303.
The following examples are intended to further illustrate the invention, but they are not to be considered as limiting.
Examples
The melting points were measured on a Buuchi SMP-20 apparatus, the data measured being uncorrected. Analytical LC-MS data were obtained on a PE Sciex API 150EX instrument equipped with an ion spray source (method D) or heated nebulizer (APCI, methods A and B) and Shimadzu LC-8A/SLC-10A LC system. The LC condition [ 30X 4.6mm YMC ODS-A, particle size 3.5 μm]The elution was carried out as a linear gradient with water/acetonitrile/trifluoroacetic acid (90: 10: 0.05) -water/acetonitrile/trifluoroacetic acid (10: 90: 0.03) at a flow rate of 2 mL/min over 4 minutes. Purity was determined by integration of the UV trace (254 nm). Retention time RtIn minutes.
Mass spectra were obtained by an alternate scanning method to obtain molecular weight information. Molecular ions MH + were obtained at low sharp pore voltages (5-20V) and fragments were obtained at high sharp pore voltages (100V).
Preparative LC-MS-separations were performed on the same instrument. The LC conditions (50X 20mmYMC ODS-A, particle size 5 μm) were A linear gradient elution with water/acetonitrile/trifluoroacetic acid (80: 20: 0.05) -water/acetonitrile/trifluoroacetic acid (10: 90: 0.03) at A flow rate of 22.7 mL/min over 7 minutes. Fractional collection was performed by split-flow MS detection.
1H NMR spectra were recorded at 500.13MHz on a Bruker Avance DRX500 instrument or at 250.13MHz on a Bruker AC250 instrument. Deuterated chloroform (99.8% D) or dimethylsulfoxide (99.9% D) was used as solvent. TMS was used as internal standard. Chemical shift values are expressed in ppm. The following abbreviations are used to represent various NMR signals: s is singlet, d is doublet, t is triplet, q is quartet, qui is quintet, h is heptat, dd is doublet, dt is doublet triplet, dq is doublet quartet, tt is triplet, m is multiplet, b is broad singlet. The NMR signal corresponding to the acidic proton is usually omitted. The water content of the crystalline compound was determined by Karl Fischer titration. Standard work-up procedures refer to extraction with the indicated organic solvent from an appropriate aqueous solvent, and drying of the combined organic extracts (anhydrous MgSO)4Or Na2SO4) Filtration and evaporation of the solvent in vacuo. For column chromatography, Kieselgel type 60, 230-. For ion exchange chromatography, 1g of SCX, Varian MegaBond Elut , Chrompack catalyst No. 220776 was used. The SCX-column was preconditioned with a 10% acetic acid solution in methanol (3mL) prior to use.
Example 1
1a.4- {4- [3- (2-chloro-phenoxy) -propyl ] -piperazin-1-yl } -1H-indole
To a slurry of sodium hydride (47mmol) in tetrahydrofuran (50mL) was added dropwise a solution of 2-chlorophenol (5g) in tetrahydrofuran (25mL) at room temperature. The mixture was stirred for 30 minutes. The reaction mixture was warmed to reflux, after which 2-bromo-1-propanol (3.5mL) in tetrahydrofuran (25mL) was added over 5 minutes. The mixture was refluxed overnight, an additional equivalent of 3-bromo-1-propanol was added, and the mixture was refluxed for an additional 12 hours. The mixture was cooled, brine and ethyl acetate were added and washed with standard procedures. The combined organic phases were dried and evaporated. The crude product 3 is- (2-chlorophenoxy) -1-propanol was dissolved in acetonitrile (500mL), and carbon tetrabromide (38.7g) was added. Triphenylphosphine (25.5g) was added in portions to the cooled (0 ℃) mixture over 30 minutes. The reaction was allowed to proceed at room temperature for 3 hours and then evaporated to give the product as an oil. The crude product was purified by flash chromatography on silica gel (heptane: ethyl acetate: triethylamine/70: 15: 5) to give 3- (2-chlorophenoxy) -1-propyl bromide (10.7 g). A mixture of (1H-indol-4-yl) piperazine (0.77g), potassium carbonate (1.6g), potassium iodide (catalyst) and 3- (2-chlorophenoxy) -1-propyl bromide (1.0g) in methyl isobutyl ketone/dimethylformamide (1/1, 100mL) was heated to 120 ℃. When TLC indicated completion of the reaction (24 hours), the mixture was cooled, filtered and evaporated. The crude product was dissolved in ethyl acetate, washed with standard procedures, then dried, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane: ethyl acetate: triethylamine/55: 43: 2). The collected pure oil was dissolved in ethanol, after which etherified (etheral) hydrogen chloride was added. Filtration gave the title compound (0.3g) as pure crystals. Mp.189-99 ℃.1H NMR(DMSO-d6): 2.30(m, 2H); 3.20-3.45(m, 6H); 3.60-3.75(m, 4H); 4.20(t, 2H); 6.45(m, 1H); 6.55(d, 1H); 6.95-7.05(m, 2H); 7.10-7.20(m, 2H); 7.25-7.35(m, 2H); 7.45(d, 1H); 11.05(b, 1H); 11.20(s, 1H); MS: m/z: 370(MH +), 199, 117. assay C21H24ClN3O: calculated values: c, 54.72; h, 6.14; n, 9.12, found C, 55.20; h, 6.48; and N, 8.45.
Example 2
2a.4- {4- [3- (2-chloro-phenylsulfanyl) -propyl ] -piperazin-1-yl } -1H-indole, 0.75 oxalate
To a slurry of sodium hydride (38mmol) in dimethylformamide was added dropwise a solution of 2-chlorothiophenol (5g) in dimethylformamide (50mL) at room temperature over 15 minutes. The mixture was stirred for 30 minutes. The reaction mixture was added slowly (10 min) to a solution of 1, 3-dibromopropane in dimethylformamide (25mL) at room temperature. The final mixture was stirred for an additional 60 minutes. Quenching the reaction by adding sufficient water to consume excess sodium hydride, etherifyingThe hydrochloric acid was acidified and then evaporated. The crude product was purified by flash chromatography on silica gel (heptane: ethyl acetate: triethylamine/95: 2.5) to give 3- (2-chlorophenylthio) -1-propyl bromide (5.7 g). A mixture of (1H-indol-4-yl) piperazine (1.1g), potassium carbonate (2.3g), potassium iodide (catalyst) and 3- (2-chlorophenylthio) -1-propyl bromide (1.5g) in methyl isobutyl ketone/dimethylformamide (1/1, 100mL) was heated to 120 ℃. When TLC indicated completion of the reaction (24 hours), the mixture was cooled, filtered and evaporated. The crude product was dissolved in ethyl acetate, washed with standard procedures, then dried, filtered and evaporated. The crude product is purified by flash chromatography on silica gel (heptane: ethyl acetate: ethanol: triethylamine/85: 5: 25: 5). The collected pure oil was dissolved in ethanol (150mL), after which oxalic acid was added. Filtration gave the title compound (1.2g) as pure crystals. Mp.182-83 deg.C.1H NMR(DMSO-d6): 1.95(q, 2H); 2.75-3.00(m, 6H); 3.10(t, 2H); 3.15-3.25(m, 4H); 6.40(m, 1H); 6.45(d, 1H); 6.95-7.05(m, 2H); 7.15-7.25(m, 2H); 7.35(t, 1H); 7.40-7.50(m, 2H); 11.05(s, 1H) MS: m/z: 386(MH +), 285, 157, assay C21H24ClN3S: calculated values: c, 59.58; h, 5.68; n, 9.27, found C, 59.28; h, 6.01; n, 9.33.
The following compounds were prepared analogously:
4- {4- [3- (2-bromo-phenylsulfanyl) -propyl ] -piperazin-1-yl } -1H-indole, oxalate
Mp.163-66℃。1H NMR(DMSO-d6): 1.95(q, 2H); 3.00(t, 2H); 3.00-3.15(m, 6H); 3.20-3.35(m, 4H); 6.40(m, 1H); 6.45(d, 1H); 6.95-7.15(m, 3H); 7.25(m, 1H); 7.40(m, 2H); 7.60(d, 1H); 11.05(s, 1H). MS: m/z: 430(MH +), 229, 159. assay C21H24BrN3S: calculated values: c, 53.07; h, 5.05; n, 8.08, found C, 52.83; h, 5.34; and N, 8.14.
2c.4- {4- [3- (2-bromo-phenoxy) -propyl ] -piperazin-1-yl } -1H-indole, hemioxalate salt
Mp.206-8℃。1H NMR(DMSO-d6): 2.05(q, 2H); 2.85-3.05(m, 6H); 3.15-3.30(m, 4H); 4.15(t, 2H); 6.40(m, 1H); 6.45(d, 1H); 6.85-7.10(m, 3H); 7.15(d, 1H); 7.25(m, 1H); 7.35(m, 1H); 7.55(d, 1H); 11.05(s, 1H). MS: m/z: 416, 414(MH +), 258, 199, 159. assay C21H24BrN3S: calculated values: c, 57.51; h, 5.50; n, 9.15, found C, 57.53; h, 5.59; and N, 8.98.
2d.4- {4- [4- (2-bromo-4-fluoro-phenoxy) -butyl ] -piperazin-1-yl } -1H-indole, oxalate
Mp.218-20℃。1H NMR(DMSO-d6): 1.75-1.95(m, 4H); 3.15-3.25(t, 2H); 3.20-3.40(m, 8H); 4.05-4.15(t, 2H); 6.40-6.45(s, 1H); 6.45-6.50(d, 1H); 6.95-7.00(t, 1H); 7.05-7.10(d, 1H); 7.10-7.25(m, 2H); 7.25-7.30(m, 1H); 7.50-7.60(dd, 1H). MS m/z: 446(MH +), 371, 247, 149, assay C22H25BrFN3O: calculated values: c, 53.73; h, 5.08; n, 7.84, found C, 54.77; h, 5.38; and N, 7.60.
2e.4- {4- [4- (2-chloro-6-methyl-phenylthio) -butyl ] -piperazin-1-yl } -1H-indole, oxalate
Mp.199-210℃。1H NMR(DMSO-d6)：1.45-1.60(m，2H)；1.70-1.85(m，2H)；2.55(s，3H)；2.80-2.90(t，2H)；2.95-3.05(t，2H)；3.15-3.40(m，8H)；6.40-6.45(s，1H)；6.45-6.50(d，1H)；6.95-7.05(t，1H)；7.05-7.10(d，1H)；7.25-7.35(m，3H)；7.35-7.45(dd，1H)；11.05-11.15(s，1H).MS m/z：414(MH+)，256，213，149.
Analysis C22H25ClN3S: calculated values: c, 59.56; h, 6.01; n, 8.34, found C, 60.10; h, 6.15; and N, 8.20.
Example 3
4- {4- [2- (2-chloro-4-fluoro-phenylsulfanyl) -ethyl ] -piperazin-1-yl } -1H-indole, 1.25 oxalate
To a mixture of (1H-indol-4-yl) piperazine (2.50g) and triethylamine (3.8g) in anhydrous tetrahydrofuran was added dropwise a solution of chloroacetyl chloride (1.86g) in anhydrous tetrahydrofuran (5mL) at room temperature over 10 minutes. After 40 minutes the reaction was quenched with water and washed with standard procedures (ethyl acetate). Drying and evaporation gave 3.5g of the chloroacetylated derivative. The crude product was used directly in the following step. 2-chloro-4-fluorothiophenol (1.1g) was dissolved in tetrahydrofuran (40mL), and potassium tert-butoxide (0.84g) was added, followed by stirring for 10 minutes. The above mixture was treated dropwise with a solution of the chloroacetylated derivative (1.70g) prepared above in tetrahydrofuran (20 mL). The reaction was allowed to proceed at room temperature for 1 hour, then at reflux for 20 minutes, after which it was cooled and evaporated. The crude mixture was washed with standard procedures (ethyl acetate) and evaporated to give, after purification by flash chromatography on silica gel (heptane: 30-50% ethyl acetate), the pure alkylated product (2.00g), i.e. 1- [ 2-chloro-4-fluorophenylthiomethylcarbonyl ] -4- [ 1H-indol-4-yl ] piperazine.
To a suspension of lithium aluminum hydride (0.34g) in tetrahydrofuran (20mL) was added dropwise aluminum trichloride (0.34g) in cold tetrahydrofuran (10mL) at 0 ℃. The mixture was stirred for 15 minutes, allowed to warm to about 10 ℃ and then a solution of the amido compound prepared above in tetrahydrofuran (20mL) was added. The reaction was complete after 1 hour and concentrated sodium hydroxide (2mL) was added dropwise. A drying agent was added, followed by filtration and evaporation to give the crude target base (1.94 g). A solution of oxalic acid (0.49g) in acetone was added and filtered to give the title compound (1.77g) as pure white crystals. Mp.106-110 deg.C (decomposition).1H NMR(DMSO-d6): 3.10(t, 2H); 3.15(s, 4H); 3.25(s, 4H); 3.35(t, 2H); 5.00-6.00(b, 1H); 6.35(s, 1H); 6.45(d, 1H); 7.00(t, 1H); 7.05(d, 1H); 7.25-7.35(m, 2H); 7.50-7.65(m, 2H). MS m/z: 390(MH +), 161 assay C22H21ClFN3S: calculated values: c, 53.78; h, 4.71; n, 8.36, found C, 53.69; h, 4.99; n, 8.51.
The following compounds were prepared analogously:
4- {4- [2- (2, 6-dichloro-phenylsulfanyl) -ethyl ] -piperazin-1-yl } -1H-indole, oxalate
Mp.130-33 deg.C (decomposition).1H NMR(DMSO-d6): 2.90-3.00(m, 6H); 3.05-3.20(s, 4H); 3.20(t, 2H); 4.40-5.50(b, 1H); 6.35(s, 1H); 6.45(d, 1H); 6.95(t, 1H); 7.05(d, 1H); 7.20(s, 1H); 7.40(t, 1H); 7.60(d, 2H). MS m/z: 406(MH +), 177 analysis C22H21Cl2N3S: calculated values: c, 53.23; h, 4.67; n, 8.46, found C, 53.12; h, 4.90; and N, 8.45.
3c.4- {4- [2- (3, 4-dichloro-phenylsulfanyl) -ethyl ] -piperazin-1-yl } -1H-indole, 0.8 oxalate
Mp.140-41℃。1H NMR(DMSO-d6): 2.90-3.10(m, 6H); 3.15-3.30(s, 4H); 3.30-3.40(t, 2H); 3.60-4.50(b, 1H); 6.35-6.40(s, 1H); 6.45-6.50(d, 1H); 6.95-7.00(t, 1H); 7.05-7.10(d, 1H); 7.25-7.30(s, 1H); 7.35-7.40(d, 1H); 7.55-7.60(d, 1H); 7.15-7.20(s, 2H). MS m/z: 406(MH +), 177 analysis C22H21Cl2N35: calculated values: c, 54.22; h, 4.77; n, 8.78, found C, 54.01; h, 4.92; and N, 8.68.
3d.4- {4- [2- (4-fluoro-phenylsulfanyl) -ethyl ] -piperazin-1-yl } -1H-indole, 0.9 oxalate
Mp.165-67℃。1H NMR(DMSO-d6): 2.60-2.70(m, 6H); 3.10-3.20(m, 6H); 6.35-6.40(s, 1H); 6.40-6.50(d, 1H); 6.90-7.00(t, 1H); 7.00-7.10(d, 1H); 7.10-7.25(m, 3H); 7.40-7.50(m, 2H). MS m/z: 356(MH +), 127. assay C22H21FN3S: calculated values: c, 59.97; h, 5.51; n, 9.63, found C, 59.84; h, 5.58; and N, 9.65.
Example 4
4a.4- {4- [3- (2-chloro-4-fluoro-phenylsulfanyl) -propyl ] -piperazin-1-yl } -1H-indole
To a suspension of sodium hydride (38.4mmol) in ethanol (50mL) was added dropwise a solution of 2-chloro-4-fluoro-thiophenol (5.0g, 30.7mmol) in tetrahydrofuran (50mL) at room temperature (caution: hydrogen generation). The mixture was stirred for a further 30 minutes when no more hydrogen was generated. The solution was then added dropwise (0.3 mL/min) to a solution of 1, 3-dibromopropane (159g, 768mmol) in ethanol (200mL) at 60 ℃ and stirred for 16 h. The mixture was concentrated in vacuo, followed by standard work-up (ethyl acetate) to give an oil. The excess 1, 3-dibromopropane is removed in vacuo (60 ℃ C., 0.01mbar) and the oily residue is purified by flash chromatography on silica gel (eluent: heptane) to give 3- (2-chloro-4-fluorophenylthio) -1-bromopropane (5.2g, 60%) as a colourless oil.
To a solution of 3- (2-chloro-4-fluorophenylthio) -1-bromopropane (35mg, 0.12mmol) and (1H-indol-4-yl) -piperazine (20mg, 0.10mmol) in acetonitrile (2mL) was added cesium carbonate (108mg, 0.33 mmol). The mixture was stirred at 70 ℃ for 16 hours. After 12 h, isocyanomethylpolystyrene (75mg, 0.08mmol) was added and the mixture was slowly cooled to room temperature. The resin was filtered and washed with methanol (1X 1mL) and dichloromethane (1X 1 mL). The combined liquid phases were concentrated in vacuo to give a dark brown oil, which was dissolved in ethyl acetate (3mL) and loaded onto a preconditioned ion exchange column. The column was washed with methanol (4mL) and acetonitrile (4mL), after which the product was eluted with 4N ammonia in methanol (4.5 mL). After removal of the solvent in vacuo, the product was purified by preparative reverse phase HPLC chromatography. The resulting solution was recharged to the preconditioned ion exchange column. The column was washed with methanol (4mL) and acetonitrile (4mL) as described above, after which the product was eluted with 4N ammonia in methanol (4.5 mL). The volatile solvent was evaporated to give the title compound as a yellow oil (30mg, 74. mu. mol, 74%).
LC/MS (m/z)405(MH +), Rt 6.11, purity 91.0%.
The following compounds were prepared analogously:
4b.4- {4- [4- (2-bromo-4-fluoro-phenoxy) -butyl ] -piperazin-1-yl } -1H-indole
LC/MS (m/z)447(MH +), Rt ═ 6.20 (method a), purity 98.8%.
4c.4- {4- [3- (2, 4-difluoro-phenoxy) -propyl ] -piperazin-1-yl } -1H-indole
LC/MS (m/z)372(MH +), Rt ═ 2.20 (method a), purity 88.12%.
4d.4- {4- [4- (2, 6-dichloro-thiophenyl) -butyl ] -piperazin-1-yl } -1H-indole
LC/MS (m/z)436(MH +), Rt ═ 6.53 (method a), purity 80.59%.
4e.4- {4- [3- (2-chloro-4-fluoro-phenoxy) -propyl ] -piperazin-1-yl } -1H-indole
LC/MS (m/z)389(MH +), Rt ═ 6.11 (method a), purity 97.8%.
4f.4- {4- [4- (2-chloro-6-methyl-phenylthio) -butyl ] -piperazin-1-yl } -1H-indole
LC/MS (m/z)415(MH +), Rt ═ 6.58 (method a), purity 70.2%.
4g.4- {4- [4- (2, 6-dichloro-4-fluoro-phenoxy) -butyl ] -piperazin-1-yl } -1H-indole
LC/MS (m/z)437(MH +), Rt ═ 6.02 (method a), purity 95.1%.
4h.4- {4- [3- (2-bromo-4, 6-difluoro-phenoxy) -propyl ] -piperazin-1-yl } -1H-indole
LC/MS (m/z)451(MH +), Rt ═ 5.62 (method a), purity 99.5%.
4i.4- {4- [3- (2, 6-dichloro-4-fluoro-phenoxy) -propyl ] -piperazin-1-yl } -1H-indole
LC/MS (m/z)423(MH +), Rt ═ 6.38 (method a), purity 87.6%.
4j.4- {4- [4- (4-bromo-2, 6-difluoro-phenoxy) -yl ] -piperazin-1-yl } -1H-indole
LC/MS (m/z)465(MH +), Rt ═ 5.74 (method a), purity 95.2%.
4k.4- {4- [4- (2, 6-dibromo-4-fluoro-phenoxy) -butyl ] -piperazin-1-yl } -1H-indole
LC/MS (m/z)526(MH +), Rt ═ 6.18 (method a), purity 100%.
4l.4- {4- [3- (2, 4, 6-tribromo-phenoxy) -propyl ] -piperazin-1-yl } -1H-indole
LC/MS (m/z)573(MH +), Rt ═ 6.40 (method a), purity 99.6%.
4m.4- {4- [3- (4-bromo-2, 6-difluoro-phenoxy) -propyl ] -piperazin-1-yl } -1H-indole
LC/MS (m/z)451(MH +), Rt ═ 2.42 (method a), purity 100%.
4n.1- (3, 5-difluoro-4- {3- [4- (1H-indol-4-yl) -piperazin-1-yl ] -propoxy } -phenyl) propan-1-one
LC/MS (m/z)428(MH +), Rt 5.46 (method a), purity 98.1%.
4o.3, 5-dibromo-4- {3- [4- (1H-indol-4-yl) -piperazin-1-yl ] -propoxy } -benzonitrile
LC/MS (m/z)519(MH +), Rt 5.38 (method a), 84.6% purity.
4p.4- {4- [2- (2-bromo-4, 6-difluoro-phenoxy) -ethyl ] -piperazin-1-yl } -1H-indole
LC/MS (m/z)437(MH +), Rt ═ 5.35 (method a), purity 74.4%.
4q.4- {4- [3- (2, 6-dichloro-thiophenyl) -propyl ] -piperazin-1-yl } -1H-indole
LC/MS (m/z)421(MH +), Rt ═ 2.44 (method a), purity 96.7%.
Example 5
5aa.4- {4- [2- (2, 6-dimethyl-phenoxy) -ethyl ] -piperazin-1-yl } -1H-indole
To a solution of phenol (1.6mmol) in DMF (1.6mL) was added a solution of potassium tert-butoxide (1.6mL, 1.6mmol, 1.0M in tert-butanol). The mixture was stirred at room temperature for 5 minutes. An aliquot (850. mu.L) of the resulting solution was added to a solution of 2-bromo-1, 1-dimethoxyethane (59mg, 0.35mmol) in DMF (0.70 mL). The reaction mixture was warmed to 80 ℃ and stirred for 16 hours. After cooling to room temperature, ethyl acetate (6mL) was added. The organic phase was washed with water (2X 4mL) and dried over sodium sulfate. The volatiles were evaporated in vacuo and the resulting oil was dissolved in a mixture of dioxane and 3M HCl (4mL, dioxane: 3M HCl 8: 1) and heated to 80 ℃ for 1 hour. After cooling to room temperature, ethyl acetate (6mL) was added. The organic phase was washed with water (2X 4mL) and dried over sodium sulfate. The volatiles were evaporated in vacuo and the resulting oil was dissolved in 1, 2-dichloroethane (1.80 mL). An aliquot (600. mu.L) of the resulting solution was added to a solution of 1- [ 1H-indol-4-yl ] piperazine (4.5mg, 22.4. mu. mol) in DMF (60. mu.L), followed by addition of sodium triacetoxyborohydride (30mg, 0.14 mmol). The reaction mixture was shaken at room temperature for 2 hours, a mixture of methanol/water (600. mu.L, methanol: water 9: 1) was added, and the resulting solution was loaded onto a preconditioned ion exchange column. The column was washed with acetonitrile (2.5mL) and methanol (2.5mL), after which the product was eluted with 4N ammonia in methanol (4.5 mL). After removal of the solvent in vacuo, the title compound was obtained as a colorless oil (5.7mg, 16.9. mu. mol, 75%).
LC/MS (m/z)350(MH +), Rt 2.32 (method B), purity 89.5%.
The following compounds were prepared analogously:
5ab.4- {4- [4- (2, 6-dimethyl-phenylsulfanyl) -butyl ] -piperazin-1-yl } -1H-indole
LC/MS (m/z)394(MH +), Rt 2.58 (method B), purity 98.14%.
5ac.4- {4- [2- (2, 4-dimethyl-phenylsulfanyl) -ethyl ] -piperazin-1-yl } -1H-indole
LC/MS (m/z)366(MH +), Rt ═ 2.38 (method a), purity 93.9%.
5ad.4- {4- [2- (2, 3-dichloro-thiophenyl) -ethyl ] -piperazin-1-yl } -1H-indole
LC/MS (m/z)406(MH +), Rt 2.43 (method a), purity 94.09%.
5ae.4- {4- [2- (2-allyl-6-chloro-phenoxy) -ethyl ] -piperazin-1-yl } -1H-indole
LC/MS (m/z)396(MH +), Rt 2.41 (method a), purity 74.45%.
5af.4- {4- [3- (2-trifluoromethyl-phenylthio) -yl ] -piperazin-1-yl } -1H-indole
LC/MS (m/z)420(MH +), Rt ═ 2.48 (method a), purity 80%.
5ag.4- {4- [3- (3, 4-dichloro-phenylsulfanyl) -propyl ] -piperazin-1-yl } -1H-indole
LC/MS (m/z)420(MH +), Rt 2.53 (method a), purity 94.88%.
5ah.4- {4- [4- (2, 4-dimethyl-phenoxy) -butyl ] -piperazin-1-yl } -1H-indole
LC/MS (m/z)378(MH +), Rt ═ 2.47 (method a), purity 76.4%.
5ai.4- {4- [4- (2-ethyl-phenoxy) -butyl ] -piperazin-1-yl } -1H-indole
LC/MS (m/z)378(MH +), Rt 2.48 (method a), purity 76.62%.
5aj.4- [4- (4-thiophenyl-butyl) -piperazin-1-yl ] -1H-indole
LC/MS (m/z)366(MH +), Rt 2.05, purity 89.3%.
5ak.4- {4- [4- (2-chloro-5-methyl-phenoxy) -butyl ] -piperazin-1-yl ] -1H-indole
LC/MS (m/z)398(MH +), Rt 2.24 (method B), purity 84.56%.
5a1.4- {4- [2- (2, 5-dichloro-thiophenyl) -ethyl ] -piperazin-1-yl } -1H-indole
LC/MS (m/z)406(MH +), Rt 2.1 (method B), purity 93.74%.
5am.4- {4- [2- (3-chloro-phenylsulfanyl) -ethyl ] -piperazin-1-yl } -1H-indole
LC/MS (m/z)372(MH +), Rt ═ 2.01 (method B), purity 96.29%.
4- {4- [2- (2-chloro-phenylsulfanyl) -ethyl ] -piperazin-1-yl } -1H-indole
LC/MS (m/z)372(MH +), Rt ═ 1.93 (method B), purity 96.26%.
5ao.4- {4- [3- (3-chloro-phenylsulfanyl) -propyl ] -piperazin-1-yl } -1H-indole
LC/MS (m/z)386(MH +), Rt ═ 2.09 (method B), purity 90.84%.
5 ap.3-chloro-4- {4- [4- (1H-indol-4-yl) -piperazin-1-yl ] -butoxy } -benzonitrile
LC/MS (m/z)409(MH +), Rt ═ 1.93 (method B), purity 86.56%.
5aq.4- {4- [4- (3-chloro-phenylsulfanyl) -butyl ] -piperazin-1-yl } -1H-indole
LC/MS (m/z)400(MH +), Rt 2.23 (method B), purity 84.85%.
5ar.4- {4- [4- (2-chloro-phenylsulfanyl) -butyl ] -piperazin-1-yl } -1H-indole
LC/MS (m/z)400(MH +), Rt 2.14 (method B), purity 84.83%.
5as.4- {4- [3- (3, 4-dimethyl-phenylsulfanyl) -propyl ] -piperazin-1-yl } -1H-indole
LC/MS (m/z)380(MH +), Rt 2.17 (method B), purity 81.48%.
5at.3- {4- [4- (1H-indol-4-yl) -piperazin-1-yl ] -butoxy } -benzonitrile
LC/MS (m/z)375(MH +), Rt ═ 1.83 (method B), purity 78.43%.
5au.4- {4- [4- (2, 5-dichloro-phenoxy) -butyl ] -piperazin-1-yl } -1H-indole
LC/MS (m/z)418(MH +), Rt 2.23 (method B), purity 79.44%.
5ay.4- {4- [4- (3, 4-dimethoxy-phenylthio) -butyl ] -piperazin-1-yl } -1H-indole
LC/MS (m/z)426(MH +), Rt ═ 1.87 (method B), purity 73.1%.
5aw.4- {4- [3- (4-trifluoromethyl-phenylthio) -propyl ] -piperazin-1-yl } -1H-indole
LC/MS (m/z)420(MH +), Rt 2.24 (method B), purity 88.9%.
5ax.4- {4- [3- (4-trifluoromethoxy-phenylthio) -propyl ] -piperazin-1-yl } -1H-indole
LC/MS (m/z)436(MH +), Rt 2.31 (method B), purity 91.57%.
5ay.4- {4- [3- (3-bromo-phenylthio) -propyl ] -piperazin-1-yl } -1H-indole
LC/MS (m/z)430(MH +), Rt ═ 2.15 (method B), purity 91.2%.
5az.4- {4- [3- (2-isopropyl-phenylthio) -propyl ] -piperazin-1-yl } -1H-indole
LC/MS (m/z)394(MH +), Rt 2.32 (method B), purity 82.81%.
5ba.4- {4- [4- (2-methoxy-phenoxy) -butyl ] -piperazin-1-yl } -1H-indole
LC/MS (m/z)380(MH +), Rt ═ 1.79 (method B), purity 93.2%.
5bb.4- {4- [4- (2-isopropyl-phenylthio) -butyl ] -piperazin-1-yl } -1H-indole
LC/MS (m/z)408(MH +), Rt ═ 2.4 (method B), purity 85.1%. Pharmacological testing
The compounds of the invention were tested in a well-known and reliable manner. The test is as follows:
to pair3H-YM-09151-2 and human dopamine D4Inhibition of receptor binding
By this method, the drug pair is tested in vitro3H]YM-09151-2(0.06nM) and human clone dopamine D expressed in CHO-cells4.2Inhibition of receptor membrane binding. The methodAn improved method for NEN Life Science Products, Inc., technical date certificatePC 2533-10/96. Result in IC50Values are listed in table 1 below.
Para 23H]-spiperone with human D3Inhibition of receptor binding
By this method, the drug pair is tested in vitro3H]-Spiroperone (0.3nM) and human clone dopamine D expressed in CHO-cells3Inhibition of receptor membrane binding. The method is an improved method of R.G.MacKenzie et al, Eur.J.Pharm. -mol.Pharm.Sec.1994, 266, 79-85. Result in IC50Values are listed in table 1 below.
Uptake of brain synaptosomes in rats3Inhibition of H-5-HT
In vitro test for drug inhibition using this method3The ability of H-5-HT to accumulate in whole rat brain synaptosomes. The assay is described by Hyttel, j.psychopharmacology 1978, 60, 13.
By measuring the binding of the radioligand to 5-HT as described in the test below1AInhibition of receptor binding to determine the 5-HT of the Compounds of the invention1A-affinity of the receptor.
To pair3H-5-CT and human 5-HT1AInhibition of receptor binding
By this method, drug pairs were tested in vitro for 5-HT1A-agonists3H-5-carboxamido tryptamine(s) ((3H-5-CT) with the cloned human 5-HT 1A-receptor stably expressed in transfected HeLa cells (HA 7). The assay was performed according to Harrington, m.a. et al, modified from the method described in j.pharmacol.exp.ther.1994, 268, 1098. In that3Human 5-HT in the presence of H-5-CT at pH7.71AThe receptor (40. mu.g of cell homogenate) was incubated for 15 minutes at 37 ℃ in 50mM Tris buffer. Nonspecific binding was determined by addition of 10 μ M ergot benzyl ester. The reaction was stopped on a Tomtec Cell Harvester by rapid filtration through a Unifilter GF/B filter. The filter was placed on a Packard Top CoCount in unit. The results obtained are shown in table 1 below.
Compound numbering To pair3Inhibition of H-YM-09151 binding IC50(nM) or inhibition at 100 nM% To pair3Inhibition of H-5-CT binding IC50(nM) or inhibition at 50 nM% Compound numbering To pair3Inhibition of H-YM-09151 binding IC50(nM) or inhibition at 100 nM% To pair3Inhibition of H-5-CT binding IC50(nM) or inhibition at 50 nM%
1 92 12 5ad 4.1 76％
2a 1.1 2.4 5ae 88％ 92％
2b 1.2 2.7 5af 7.2 93％
2d 1.6 6.4 5ag 95％ 93％
2e 2.2 4.5 5ah 90％ 86％
3a 6.6 15 5ai 90％ 93％
4a 0.52 9.3 5aj 100％ 77％
4b 0.66 2.4 5ak 93％ 91％
4c 1.6 5.4 5al 96％ 92％
4d 1.8 7.1 5am 83％ 93％
4e 2.0 4.9 5an 83％ 91％
4f 3.0 5.8 5ao 102％ 100％
4g 4.9 2.4 5ap 106％ 100％
4h 5.4 1.4 5aq 98％ 100％
4i 16 1.0 5ar 98％ 104％
4j 23 17 5as 99％ 103％
4k 26 6.7 5at 95％ 92％
4l 28 1.1 5an 97％ 99％
4m 39 1.0 5av 107％ 69％
4n 230 0.72 5aw 99％ 98％
4o 32 0.72 5ax 98％ 81％
4p 13 36 5ay 105％ 96％
4q 7.2 3.5 5az 94％ 98％
5aa 81％ 78％ 5ba 80％ 83％
5ab 95％ 83％ 5bb 94％ 94％
5ac 83％ 85％
TABLE 1
In vitro evaluation of cloned 5-HT stably expressed in transfected HeLa cells (HA7) with some of the compounds of the invention1A5-HT on the receptor1A-antagonistic activity. In this assay, 5-HT is assessed by measuring the ability of a compound to antagonize 5-HT-induced inhibition of forskolin-induced cAMP accumulation1A-antagonistic activity. The assay was performed according to a modification of the method described in biochem. pharmacol.1993, 45, 375, Pauwels, p.j.
Some compounds of the invention have been tested in vivo on 5-HT in an assay described by S.nchez, C.et al, Eur.J.Pharmacol.1996, 315, page 2451A-the influence of the receptor. In this test, the pass testThe antagonistic activity of the test compound is determined by the ability of the test compound to inhibit 5-HT syndrome induced by 5-MeO-DMT.
Since the compounds of the invention show affinity in said tests, they are considered to be useful in the treatment of affective disorders such as depression, generalized anxiety disorder, panic disorder, obsessive compulsive disorder, social phobia, eating disorders and neurological disorders such as psychiatric disorders.

Claims (16)

1. A compound represented by the general formula I, enantiomers thereof and pharmaceutically acceptable acid addition salts thereof,
wherein
X represents O or S;
n is 2, 3, 4, 5, 6, 7, 8, 9 or 10;
m is 2 or 3;
y represents N, C or CH;
the dotted line represents an optional bond;
R1and R1’Independently represent hydrogen or C1-6An alkyl group;
R7、R8、R10、R11and R12Each independently selected from hydrogen, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl radical, C3-8cycloalkyl-C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio, hydroxy, formyl, acyl, amino, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, acylamino, C1-6Alkoxycarbonylamino, aminocarbonylamino, C1-6Alkylamino carbonylamino and di (C)1-6Alkyl) aminocarbonylamino;
R9represents hydrogen, C1-6An alkyl or acyl group;
R2、R3、R4、R5and R6Independently represent hydrogen, halogen, cyano, nitro, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C1-6Alkylsulfonyl, hydroxy-C1-6Alkyl radical, C1-6Alkoxycarbonyl, acyl, C3-8Cycloalkyl radical, C3-8cycloalkyl-C1-6Alkyl, trifluoromethyl, trifluoromethoxy, NH2、NR13R14Wherein R is13And R14Independently represent hydrogen, C1-6Alkyl radical, C3-8Cycloalkyl or phenyl; or R13And R14Together with the nitrogen atom to which they are attached form a 5 or 6 membered carbocyclic ring optionally containing one further heteroatom.
2. A compound of formula I according to claim 1, the enantiomers thereof and the pharmaceutically acceptable acid addition salts thereof, wherein
X represents O or S;
n is 2, 3, 4 or 5;
m is 2 or 3;
y represents N or CH;
R1and R1’Are all hydrogen;
R7、R8、R10、R11and R12One or two of (A) independently represent hydrogen, halogen, CF3CN or C1-6Alkyl, the remainder represent hydrogen;
R9represents hydrogen;
R2、R3、R4、R5and R6Independently represent hydrogen, halogen, C1-6Alkyl radical, C3-8Cycloalkyl radical, C1-6Alkoxy, hydroxy, nitro, CN, CF3、OCF3Acyl, NH2、NR13R14Wherein R is13And R14Independently represent hydrogen, C1-6Alkyl radical, C3-8Cycloalkyl or phenyl; or R13And R14Together with the nitrogen atom, form piperidine, morpholine, piperazine or pyrrolidine.
3. A compound of formula I according to any one of the preceding claims, wherein R1And R1’Is hydrogen.
4. A compound of formula I according to any one of the preceding claims, wherein m is 2.
5. A compound of formula I according to any one of the preceding claims, wherein n is 2, 3 or 4.
6. A compound of formula I according to any one of the preceding claims, wherein Y is N.
7. A compound of formula I according to any one of the preceding claims, wherein at least one R2、R3、R4、R5And R6Represents halogen.
8. A compound of formula I according to any one of the preceding claims, wherein at least two R2、R3、R4、R5And R6Represents halogen.
9. A compound of formula I according to any one of the preceding claims, wherein at least three R2、R3、R4、R5And R6Represents halogen.
10. A compound of formula I according to any one of the preceding claims, wherein R2And/or R6Is not hydrogen.
11. A compound of formula I according to any one of the preceding claims, wherein the indole is attached to the Y group in the 4-position.
12. A compound of formula I according to claim 1, which is:
4- {4- [3- (2-chloro-phenoxy) -propyl ] -piperazin-1-yl } -1H-indole
4- {4- [3- (2-chloro-phenylsulfanyl) -propyl ] -piperazin-1-yl } -1H-indole
4- {4- [3- (2-bromo-phenylsulfanyl) -propyl ] -piperazin-1-yl } -1H-indole
4- {4- [3- (2-bromo-phenoxy) -propyl ] -piperazin-1-yl } -1H-indole
4- {4- [4- (2-bromo-4-fluoro-phenoxy) -butyl ] -piperazin-1-yl } -1H-indole
4- {4- [4- (2-chloro-6-methyl-thiophenyl) -butyl ] -piperazin-1-yl } -1H-indole
4- {4- [2- (2-chloro-4-fluoro-phenylsulfanyl) -ethyl ] -piperazin-1-yl } -1H-indole
4- {4- [2- (2, 6-dichloro-phenylsulfanyl) -ethyl ] -piperazin-1-yl } -1H-indole
4- {4- [2- (3, 4-dichloro-phenylsulfanyl) -ethyl ] -piperazin-1-yl } -1H-indole
4- {4- [2- (4-fluoro-phenylsulfanyl) -ethyl ] -piperazin-1-yl } -1H-indole
4- {4- [3- (2-chloro-4-fluoro-phenylsulfanyl) -propyl ] -piperazin-1-yl } -1H-indole
4- {4- [4- (2-bromo-4-fluoro-phenoxy) -butyl ] -piperazin-1-yl } -1H-indole
4- {4- [3- (2, 4-difluoro-phenoxy) -propyl ] -piperazin-1-yl } -1H-indole
4- {4- [4- (2, 6-dichloro-phenylsulfanyl) -butyl ] -piperazin-1-yl } -1H-indole
4- {4- [3- (2-chloro-4-fluoro-phenoxy) -propyl ] -piperazin-1-yl } -1H-indole
4- {4- [4- (2-chloro-6-methyl-thiophenyl) -butyl ] -piperazin-1-yl } -1H-indole
4- {4- [4- (2, 6-dichloro-4-fluoro-phenoxy) -butyl ] -piperazin-1-yl } -1H-indole
4- {4- [3- (2-bromo-4, 6-difluoro-phenoxy) -propyl ] -piperazin-1-yl } -1H-indole
4- {4- [3- (2, 6-dichloro-4-fluoro-phenoxy) -propyl ] -piperazin-1-yl } -1H-indole
4- {4- [4- (4-bromo-2, 6-difluoro-phenoxy) -butyl ] -piperazin-1-yl } -1H-indole
4- {4- [4- (2, 6-dibromo-4-fluoro-phenoxy) -butyl ] -piperazin-1-yl } -1H-indole
4- {4- [3- (2, 4, 6-tribromo-phenoxy) -propyl ] -piperazin-1-yl } -1H-indole
4- {4- [3- (4-bromo-2, 6-difluoro-phenoxy) -propyl ] -piperazin-1-yl } -1H-indole
1- (3, 5-difluoro-4- {3- [4- (1H-indol-4-yl) -piperazin-1-yl ] -propoxy } -phenyl) -propan-1-one
3, 5-dibromo-4- {3- [4- (1H-indol-4-yl) -piperazin-1-yl ] -propoxy } -benzonitrile 4- {4- [2- (2-bromo-4, 6-difluoro-phenoxy) -ethyl ] -piperazin-1-yl } -1H-indole 4- {4- [3- (2, 6-dichloro-phenylthio) -propyl ] -piperazin-1-yl } -1H-indole 4- {4- [2- (2, 6-dimethyl-phenoxy) -ethyl ] -piperazin-1-yl } -1H-indole 4- {4- [4- (2, 6-dimethyl-phenylsulfanyl) -butyl ] -piperazin-1-yl } -1H-indole 4- {4- [2- (2, 4-dimethyl-phenylsulfanyl) -ethyl ] -piperazin-1-yl } -1H-indole 4- {4- [2- (2, 3-dichloro-phenylsulfanyl) -ethyl ] -piperazin-1-yl } -1H-indole 4- {4- [2- (2-allyl-6-chloro-phenoxy) -ethyl ] -piperazin-1-yl } -1H-indole 4- {4- [3- (2-trifluoromethyl-phenylsulfanyl) -propyl ] -piperazin-1-yl } -1H- Indole 4- {4- [3- (3, 4-dichloro-phenylthio) -propyl ] -piperazin-1-yl } -1H-indole 4- {4- [4- (2, 4-dimethyl-phenoxy) -butyl ] -piperazin-1-yl } -1H-indole 4- {4- [4- (2-ethyl-phenoxy) -butyl ] -piperazin-1-yl } -1H-indole 4- [4- (4-phenylthio-butyl) -piperazin-1-yl ] -1H-indole 4- {4- [4- (2-chloro-5-methyl-phenoxy) -butyl ] -piperazin-1-yl } -1H-indole 4 H-indole 4- {4- [2- (2, 5-dichloro-thiophenyl) -ethyl ] -piperazin-1-yl } -1H-indole 4- {4- [2- (3-chloro-thiophenyl) -ethyl ] -piperazin-1-yl } -1H-indole 4- {4- [2- (2-chloro-thiophenyl) -ethyl ] -piperazin-1-yl } -1H-indole 4- {4- [3- (3-chloro-thiophenyl) -propyl ] -piperazin-1-yl } -1H-indole 3-chloro-4- {4- [4- (1H-indol-4-yl) -piperazin-1-yl -butoxy } -benzonitrile 4- {4- [4- (3-chloro-phenylsulfanyl) -butyl ] -piperazin-1-yl } -1H-indole 4- {4- [4- (2-chloro-phenylsulfanyl) -butyl ] -piperazin-1-yl } -1H-indole 4- {4- [3- (3, 4-dimethyl-phenylsulfanyl) -propyl ] -piperazin-1-yl } -1H-indole 3- {4- [4- (1H-indol-4-yl) -piperazin-1-yl ] -butoxy } -benzonitrile 4- {4- [4- (2, 5-dichloro-phenoxy) -butyl ] -piperazin-1-yl } -1H-indole 4- {4- [4- (3, 4-dimethoxy-phenylsulfanyl) -butyl ] -piperazin-1-yl } -1H-indole 4- {4- [3- (4-trifluoromethyl-phenylsulfanyl) -propyl ] -piperazin-1-yl } -1H-indole 4- {4- [3- (4-trifluoromethoxy-phenylsulfanyl) -propyl ] -piperazin-1-yl } -1H-indole 4- {4- [3- (3-bromo-phenylsulfanyl) -propyl ] -piperazin-1-yl } -1H-indole 4- {4- [3- (2-isopropyl-phenylthio) -propyl ] -piperazin-1-yl } -1H-indole
4- {4- [4- (2-methoxy-phenoxy) -butyl ] -piperazin-1-yl } -1H-indole or
4- {4- [4- (2-isopropyl-phenylsulfanyl) -butyl ] -piperazin-1-yl } -1H-indole or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition comprising at least one therapeutically effective amount of a compound of formula I according to any one of the preceding claims or a pharmaceutically acceptable acid addition salt thereof or a prodrug thereof, in combination with one or more pharmaceutically acceptable carriers or diluents.
14. Use of a compound of formula I according to any one of claims 1 to 12 or an acid addition salt or a prodrug thereof for the preparation of a pharmaceutical formulation for the treatment of diseases and disorders associated with 5-HT1aLigands for receptors are related and may be associated with serotonin reuptake and/or dopamine D4Ligand association on the receptor.
15. And 5-HT1aLigand-related combination of receptorsAnd may be reuptake with serotonin and/or dopamine D4A method for the treatment of human diseases and disorders related to ligands at the receptors, which method comprises administering an effective amount of a compound of formula I according to any one of claims 1 to 12.
16. The method of claim 15, wherein the disease is: affective disorders such as generalized anxiety disorder, panic disorder, obsessive compulsive disorder, depression, social phobia, eating disorders and neurological disorders such as psychiatric disorders.
HK04101231.3A 1999-12-30 2000-12-29 Novel indole derivatives HK1058520A (en)

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