WO1997000871A1 - Tetrahydro-betacarboline derivatives and their preparation and use - Google Patents

Tetrahydro-betacarboline derivatives and their preparation and use Download PDF

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Publication number
WO1997000871A1
WO1997000871A1 PCT/DK1996/000258 DK9600258W WO9700871A1 WO 1997000871 A1 WO1997000871 A1 WO 1997000871A1 DK 9600258 W DK9600258 W DK 9600258W WO 9700871 A1 WO9700871 A1 WO 9700871A1
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Prior art keywords
compound
disorders
tetrahydro
betacarboline
compound according
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PCT/DK1996/000258
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French (fr)
Inventor
John Bondo Hansen
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Novo Nordisk A/S
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Priority to AU62981/96A priority Critical patent/AU6298196A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to tetrahydro-betacarboiine derivatives, which binds to the 5 HT 2C receptor, a method of preparing the same, pharmaceutical compositions comprising the compounds, and their use in therapy , e.g. in the treatment of central and periferal nervous system disorders.
  • 5-HT neurotransmitter serotonin
  • 5-HT 1A 1 B 1 D 1 E 1 F 5-HT 2A 2B .
  • 5-HT 4 5-HT 5A 5B
  • 5-HT 6 5-HT 6
  • 5-HT 7 receptors nominally as agreed by the IUPHAR Committee on 5-Hydroxytryptamine Receptors.
  • 5-HT 2A and the 5-HT 2C are very similar in terms of their structure, biochemistry and pharmacology.
  • Both receptors belong to the group of G-coupled 7-transmembrane spanning receptors and both use phosphatidylinositol hydrolysis as a second messenger system for signal transduction.
  • the distribution and physiological role of the 5-HT 2A and the 5-HT 2C are markedly different and the discovery of compounds which discriminate between the two receptors is therefor of potential clinical and scientific value.
  • Compounds which selectively modulate the 5-HT 2c receptor can provide treatment for the 5-HT 2C receptor mediated conditions without the sideeffects associated with the 5-HT 2A - or other receptors.
  • Modulators of 5-HT 2C receptors can be used for the treatment of dis ⁇ eases of the central nervous system, e.g. psychiatric and neurological disorders, which can be schizophrenia, anxiety, depression, obsessive- compulsive disorders, panic disorders, Gilles de la Tourette syndrome, Alzheimers disease and migraine headaches.
  • 5-HT 2C receptors of hypothalamus can influence sleep, appetite, thermoregulation, sexual behaviour, motor activity, and neuroendocrine function, and modulators of 5-HT 2C receptors can therefore be used for the treatment of e.g. sleep disorders, eating disorders and sexual dysfunction.
  • 5-HT 2C receptors of the choriod plexus is involved in the regulation of the production of cerebrospinal fluid modulators of 5-HT 2C receptors can be used for the treatment of e.g. brain edema.
  • US 5,300,645 discloses a class of tetrahydro-betacarboiines having a 7- to 12 membered bicyclic carbon ring at the position where the com ⁇ pounds of the present invention have a benzene ring fused with a 5- membered heterocyclic ring.
  • the compounds of the patent are described as modulators of 5-HT 2C receptors.
  • the present invention relates to tetrahydro-betacarboline derivatives of the general formula I
  • R 1 and R 2 independently are hydrogen, C 1-e -alkyl, C 3 . 6 -cycloalkyl, C ⁇ .e-alkoxy, aralkyl, halogen, halogenalkyl, nitro, C ⁇ -alkylthio;
  • R 3 , R 5 and R 6 independently are hydrogen, C-,. 6 -alkyl, C 2 . 6 -alkenyl, or C 3 . 6 - cycloalkyl; and R is
  • A-B-C together with the benzene ring forms a five membered heterocyclic ring comprising one or more nitrogen-, oxygen- or sulphur atoms, and optionally substituted with one or more of hydrogen, halogen, C 1- ⁇ -alkyl, C 2 . 6 -alkenyl, nitro, halogenalkyl or C 3 . 6 -cycloalkyl;
  • R 7 and R 8 independently are hydrogen, halogen, C ⁇ -alkyl C 2 . 6 -alkenyl, nitro, CN, halogenalkyl or C 3 . 6 -cycloalkyl; and pharmaceutically acceptable salts thereof.
  • Physiologically and pharmaceutically acceptable salts of the compounds of the invention include acid addition salts formed with inorganic or organic acids, for example hydrochlorides, hydrobromides, sulphates, nitrates, oxalates, phosphates, tartrates, citrates, fumarates, maieates, succinates, and sulphonates e.g. mesylates. If desirable, selected salts may be subjected to further purification by recrystallization.
  • the invention includes within its scope all optical isomers of compounds of the general formula I, some of which are optically active, and their mixtures including racemic mixtures thereof.
  • C ⁇ -alky refers to a straight or branched, saturated hydrocarbon chain having 1 -6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert. butyl, n- pentyl, neopentyl, n-hexyl, 2,2-dimethylpropyl.
  • C 3 . 6 -cycloalkyl denotes a saturated monocyclic hydrocarbon having 3-6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl.
  • C 1 . 6 -alkoxy refers to a monovalent substituent comprising a C ⁇ -alkyl group linked through an ether oxygen having its free valence bond from the ether oxygen, e.g. methoxy, ethoxy, propoxy, isopropoxy, cyclopropylmethoxy, butoxy, pentoxy.
  • aralkyl refers to an alkyl chain of 1 to 6 carbon atoms substituted with phenyl or naphthyl. Examples of such aralkyl groups are benzyl, phenethyl, 1 -naphthylme- thyl.
  • halogen as used herein means fluorine, chlorine, bromine and iodine.
  • halogenalkyl refers to an alkyl group as defined above containing one or more halogen atoms replacing some or all of the hydrogens thereon, e.g. trifluoromethyl, trifluoroethyl, trichloro- methyl, trichloroethyl, tribromomethyl.
  • C ⁇ -alkylthio refers to a monovalent substituent comprising a C-.g-alkyl group linked through sulfur, e.g. methylthio, ethylthio, propylthio, butylthio, pentylthio.
  • C 2 . e -alkenyl refers to an unsaturated hydrocar ⁇ bon chain having 2-6 carbon atoms and one double bond such as vinyl, 1 -propenyl, allyl, isopropenyl, n-butenyl, n-pentenyl and n-hexenyl.
  • five membered heterocyclic ring refers to a ring containing one or more hetero atoms selected from nitrogen, oxygen and sulphur and having five members, e.g. furan, thiophene, pyrrole, imidazole, isoxazole, isothiazole, thiazole, 2,3-dihydrofuran, 2,3-dihydro- thiophene.
  • R 1 and R 2 are selected from chlorine, bromine, methyl and isopropyl.
  • R 3 , R 5 and R 6 are selected from hydrogen, methyl and allyl.
  • R 7 , R 8 , R 9 and R 10 independently are hydrogen, halogen, C 1-6 - alkyl, nitro, CN or triflouromethyl.
  • Preferred compounds of the invention are:
  • the compounds of the present invention demonstrate high affinity for the 5HT 2C receptor.
  • the invention relates to a compound of the general formula (I) or a pharmaceutically acceptable acid addition salt thereof for use as a therapeutically acceptable substance, preferably for use as a therapeutically acceptable substance in the treatment of dis- eases of the central nervous system, sleep disorders, eating disorders or sexual dysfunctions, all influenced by dysfunctions of the 5HT 2C receptors.
  • the invention also relates to the use of the inventive com ⁇ pounds of formula (I) as medicaments useful for treating diseases of the central nervous system, e.g. psychiatric and neurological disorders, which can be schizophrenia, anxiety, depression, obsessive-compulsive disorders, panic disorders and further diseases related to sleep, appetite, thermoregulation, sexual behaviour, motor activity and neuroendochine function e.g. sleep disorders, eating disorders, sexual dysfunctions or for treating brain edema.
  • diseases of the central nervous system e.g. psychiatric and neurological disorders, which can be schizophrenia, anxiety, depression, obsessive-compulsive disorders, panic disorders and further diseases related to sleep
  • the invention relates to methods of preparing the above mentioned compounds. These methods comprise:
  • R 1 , R 2 , R 3 and R 6 are as defined above, with a compound selected from III or IV
  • R 4 and R 5 are as defined above and CHXY forms an aldehyde or a derivatives thereof capable of reacting like an aldehyde, to form a com ⁇ pound of formula I;
  • R 1 , R 2 , R 3 , R 5 and R 6 are as defined above, with hydrogen in the presence of a catalyst, which can be Pd or Rh on activated carbon , Pt0 2 or RaNi, to form a compound of formula VI
  • R , R 2 , R , R and R are as defined above;
  • R ⁇ R 2 , R 3 , R 5 , R 6 and R 7 are as defined above.
  • the affinity for the 5HT 2C receptor may be determined by radioligand binding assays using 3 [H]-Mesulergine as determined in D. Hoyer, J. Receptor. Res. 8, 59-81 , (1988); D. Hoyer et al, Eur. J. Pharmacol. 1 18, 13-23, (1985); K. D. Bunis et al, J. Pharm. Exp. Ther. 258, 891 896, (1991 ).
  • the 5HT 2C receptor affinity, as determined by IC 50 values were typically in the range of 1 nM to 1 vM.
  • Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • Tablets containing 0.05-500 mg of active ingredient, more specified 0.1 -200 mg or especially 1 -100 mg per tablet are accordingly suitable representative unit dosage forms.
  • the compounds of this invention can thus be used for the formulation of pharmaceutical preparations e.g. for oral and parenteral administration to mammals including humans in accordance with conventional methods of galenic pharmacy.
  • Conventional excipients are such pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral or oral application which do not deleteriously react with the active compound.
  • Such carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellu- lose and polyvinylpyrrolidone.
  • the pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compound.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compound.
  • Ampoules are convenient unit dosage forms.
  • tablets, dragees, or cap ⁇ sules having talc and/or a carbohydrate carrier or binder or the like, the carrier preferably being lactose and/or corn starch and/or potato starch.
  • a syrup, elixir or like can be used when a sweetened vehicle can be employed.
  • the compound of the inven ⁇ tion is dispensed in unit dosage form comprising 0.05-500 mg, more specified 0.1 -200 mg or especially 1 -100 mg, in a pharmaceutically acceptable carrier per unit dosage.
  • a typical tablet which may be prepared by conventional tabletting tech ⁇ niques contains:
  • Benzofuran-7-carbaldehyde (12.1 g, 83 mmol), N-acetylglycine (9.7 g. 83 mmol), sodium acetate (1 1 .28 g, 83 mmol) and acetic anhydride (100 ml) was stirred at 100°C for 8 hours. The mixture was then cooled to room temperature and poured onto ice. A yellow precipitate was iso ⁇ lated, washed with water and ether and dried to give 10.2 g of 4-(7- benzofuranylmethyiene)-2-methyloxazol-5-one M.p. 172.1 -1 73.5°C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Tetrahydro-betacarboline derivatives of formula (I), wherein R?1 and R2¿ independently are hydrogen, alkyl, cycloalkyl, alkoxy, aralkyl, halogen, halogenalkyl, nitro, alkylthio; R?3, R5 and R6¿ independently are hydrogen, alkyl, alkenyl, or cycloalkyl; and R4 is (a), wherein A-B-C together with the benzene ring forms a five-membered heterocyclic ring comprising one or more N-, O- or S- atoms, and optionally substituted; and R?7 and R8¿ independently are hydrogen, halogen, alkyl, alkenyl, nitro, CN, halogenalkyl or cycloalkyl, are useful in the treatment of disorders influenced by dysfunctions of the 5-HT¿2C? receptors.

Description

Tetrahydro-betacarboline Derivatives and their Preparation and Use
The present invention relates to tetrahydro-betacarboiine derivatives, which binds to the 5 HT2C receptor, a method of preparing the same, pharmaceutical compositions comprising the compounds, and their use in therapy , e.g. in the treatment of central and periferal nervous system disorders.
The importance of the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) is emphasized by the large and increasing number of known 5-HT receptors. Presently are described 5-HT1A 1 B 1 D 1 E 1 F, 5-HT2A 2B. 2O 5-HT3, 5-HT4, 5-HT5A 5B, 5-HT6, and 5-HT7 receptors (nomenclature as agreed by the IUPHAR Committee on 5-Hydroxytryptamine Receptors) . Among these receptors the 5-HT2A and the 5-HT2C are very similar in terms of their structure, biochemistry and pharmacology. Both receptors belong to the group of G-coupled 7-transmembrane spanning receptors and both use phosphatidylinositol hydrolysis as a second messenger system for signal transduction. The distribution and physiological role of the 5-HT2A and the 5-HT2C, however are markedly different and the discovery of compounds which discriminate between the two receptors is therefor of potential clinical and scientific value. Compounds which selectively modulate the 5-HT2c receptor can provide treatment for the 5-HT2C receptor mediated conditions without the sideeffects associated with the 5-HT2A- or other receptors.
Modulators of 5-HT2C receptors can be used for the treatment of dis¬ eases of the central nervous system, e.g. psychiatric and neurological disorders, which can be schizophrenia, anxiety, depression, obsessive- compulsive disorders, panic disorders, Gilles de la Tourette syndrome, Alzheimers disease and migraine headaches. 5-HT2C receptors of hypothalamus can influence sleep, appetite, thermoregulation, sexual behaviour, motor activity, and neuroendocrine function, and modulators of 5-HT2C receptors can therefore be used for the treatment of e.g. sleep disorders, eating disorders and sexual dysfunction. Since 5-HT2C receptors of the choriod plexus is involved in the regulation of the production of cerebrospinal fluid modulators of 5-HT2C receptors can be used for the treatment of e.g. brain edema.
US 5,300,645 discloses a class of tetrahydro-betacarboiines having a 7- to 12 membered bicyclic carbon ring at the position where the com¬ pounds of the present invention have a benzene ring fused with a 5- membered heterocyclic ring. The compounds of the patent are described as modulators of 5-HT2C receptors.
The present invention relates to tetrahydro-betacarboline derivatives of the general formula I
Figure imgf000004_0001
wherein R1 and R2 independently are hydrogen, C1-e-alkyl, C3.6-cycloalkyl, Cη.e-alkoxy, aralkyl, halogen, halogenalkyl, nitro, C^-alkylthio;
R3, R5 and R6 independently are hydrogen, C-,.6-alkyl, C2.6-alkenyl, or C3.6- cycloalkyl; and R is
Figure imgf000005_0001
wherein A-B-C together with the benzene ring forms a five membered heterocyclic ring comprising one or more nitrogen-, oxygen- or sulphur atoms, and optionally substituted with one or more of hydrogen, halogen, C1-β-alkyl, C2.6-alkenyl, nitro, halogenalkyl or C3.6-cycloalkyl;
R7 and R8 independently are hydrogen, halogen, C^-alkyl C2.6-alkenyl, nitro, CN, halogenalkyl or C3.6-cycloalkyl; and pharmaceutically acceptable salts thereof.
Physiologically and pharmaceutically acceptable salts of the compounds of the invention include acid addition salts formed with inorganic or organic acids, for example hydrochlorides, hydrobromides, sulphates, nitrates, oxalates, phosphates, tartrates, citrates, fumarates, maieates, succinates, and sulphonates e.g. mesylates. If desirable, selected salts may be subjected to further purification by recrystallization.
The invention includes within its scope all optical isomers of compounds of the general formula I, some of which are optically active, and their mixtures including racemic mixtures thereof.
The term "C^-alky!" as used herein, alone or in combination, refers to a straight or branched, saturated hydrocarbon chain having 1 -6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert. butyl, n- pentyl, neopentyl, n-hexyl, 2,2-dimethylpropyl. The term "C3.6-cycloalkyl" as used herein denotes a saturated monocyclic hydrocarbon having 3-6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl.
The term "C1.6-alkoxy" as used herein, alone or in combination, refers to a monovalent substituent comprising a C^-alkyl group linked through an ether oxygen having its free valence bond from the ether oxygen, e.g. methoxy, ethoxy, propoxy, isopropoxy, cyclopropylmethoxy, butoxy, pentoxy.
The term "aralkyl" as used herein, alone or in combination, refers to an alkyl chain of 1 to 6 carbon atoms substituted with phenyl or naphthyl. Examples of such aralkyl groups are benzyl, phenethyl, 1 -naphthylme- thyl.
The term "halogen" as used herein means fluorine, chlorine, bromine and iodine.
The term "halogenalkyl" as used herein, refers to an alkyl group as defined above containing one or more halogen atoms replacing some or all of the hydrogens thereon, e.g. trifluoromethyl, trifluoroethyl, trichloro- methyl, trichloroethyl, tribromomethyl.
The term "C^-alkylthio" as used herein, refers to a monovalent substituent comprising a C-.g-alkyl group linked through sulfur, e.g. methylthio, ethylthio, propylthio, butylthio, pentylthio.
The term "C2.e-alkenyl" as used herein refers to an unsaturated hydrocar¬ bon chain having 2-6 carbon atoms and one double bond such as vinyl, 1 -propenyl, allyl, isopropenyl, n-butenyl, n-pentenyl and n-hexenyl.
The term "five membered heterocyclic ring" as used herein refers to a ring containing one or more hetero atoms selected from nitrogen, oxygen and sulphur and having five members, e.g. furan, thiophene, pyrrole, imidazole, isoxazole, isothiazole, thiazole, 2,3-dihydrofuran, 2,3-dihydro- thiophene.
In a preferred embodiment of the invention R1 and R2 are selected from chlorine, bromine, methyl and isopropyl.
In another preferred embodiment of the invention R3, R5 and R6 are selected from hydrogen, methyl and allyl.
In yet another preferred embodiment of the invention R4 is selected from:
Figure imgf000007_0001
wherein R7, R8, R9 and R10 independently are hydrogen, halogen, C1-6- alkyl, nitro, CN or triflouromethyl.
Preferred compounds of the invention are:
1 -(7-Benzofuranylmethyl)-1 ,2,3,4-tetrahydro-betacarboline, hydrochloride;
1 -(7-Benzofuranylmethyl)-6-methyl-1 ,2,3,4-tetrahydro-betacarboline, hydrochloride; 1 -(7-Benzofuranylmethyl)-6-chloro-1 ,2,3,4-tetrahydro-betacarboline, hydrochloride;
1 -(2,3-Dihydrobenzofuran-7-ylmethyl)-1 ,2,3,4-tetrahydro-betacarboline, oxalate.
Other preferred compounds of the invention are:
1 -(7-Benzofuranylmethyl)-1 ,2,3,4-tetrahydro-betacarboline;
1 -(7-Benzofuranylmethyl)-6-methyl-1 ,2,3,4-tetrahydro-betacarboline;
1 -(2,3-Dihydrobenzofuran-7-ylmethγl)-6-methyl-1 ,2,3,4-tetrahydro- betacarboline;
1-(1 -(7-Benzofuranyl)ethyl)-1 ,2,3,4-tetrahydro-betacarboline;
1 -{1 -(7-Benzofuranyl)ethyl)-6-methyl-1 ,2,3,4-tetrahydro-betacarboline;
1 -(1 -(2,3-Dihydrobenzofuran-7-yl)ethyl)-6-methyl-1 ,2,3,4-tetrahydro- betacarboline; 1 -(1 -(2,3-Dihydrobenzofuran-7-yl)ethyl)-6-chloro-1 ,2,3,4-tetrahydro- betacarboline;
1 -(1 -(2,3-Dihydrobenzofuran-7-yl)ethyl)-6-isopropyl-1 ,2,3,4-tetrahydro- betacarboliπe;
1 -(5-Bromo-benzofuran-7-ylmethyl)-6-methyl-1 ,2,3,4-tetrahydro-betacar- boline;
1-(5-Chloro-benzofuran-7-ylmethyl)-6-methyl-1 ,2,3,4-tetrahydro-betacar- boline; 1 -(5-Chloro-benzofuran-7-ylmethyl)-6-chloro- 1 ,2,3, 4-tetrahydro-betacar- boline;
1 -(5-Bromo-benzofuran-7-ylmethyl)-6-isopropyl- 1 ,2,3, 4-tetrahydro- betacarboline; 1 -(5-Bromo-benzofuran-7-ylmethyl)-6-isopropyl-9-methyl- 1 ,2,3, 4-tetra- hydro-betacarboline;
1 -(7-Benzothienylmethyl)-1 ,2,3,4-tetrahydro-betacarboline;
1 -(7-Benzothienylmethyl)-6-chloro-1 ,2,3,4-tetrahydro-betacarboline;
1 -(7-Benzothienylmethyl)-6-methyl-1 ,2,3,4-tetrahydro-betacarboline; 1 -(1 -(7-Benzothienyl)ethyl)-6-methyl-1 ,2,3,4-tetrahydro-betacarboline;
1 -(1 -(7-Benzothienyl)ethyl)-6-isopropyl-1 ,2,3,4-tetrahydro-betacarboline;
1 -(7-Benzoxazolylmethyl)-1 ,2,3,4-tetrahydro-betacarboline;
1 -(7-Benzoxazolylmethyl)-6-methyl-1 ,2,3,4-tetrahydro-betacarboline;
1 -(7-Benzoxazolylmethyl)-6-isopropyl-1 ,2,3,4-tetrahydro-betacarboline; 1 -(7-Benzoxazolylmethyl)-6-chloro-1 ,2,3,4-tetrahydro-betacarboline;
1 -(1 -(7-Benzoxazolyl)ethyl)-1 ,2,3,4-tetrahydro-betacarboline;
1 -(1 -(7-Benzoxazolyl)ethyl)-6-chloro-1 ,2,3,4-tetrahydro-betacarboline;
1 -(1 -(7-Benzoxazolyl)ethyl)-6-methyl-1 ,2,3,4-tetrahydro-betacarboline;
1 -( 1 -(7-Benzoxazolyl)ethyl)-6-isopropyl-1 ,2,3,4-tetrahydro-betacarboline;
or pharmaceutically acceptable acid addition salts of these compounds.
The compounds of the present invention demonstrate high affinity for the 5HT2C receptor.
Accordingly, in another aspect the invention relates to a compound of the general formula (I) or a pharmaceutically acceptable acid addition salt thereof for use as a therapeutically acceptable substance, preferably for use as a therapeutically acceptable substance in the treatment of dis- eases of the central nervous system, sleep disorders, eating disorders or sexual dysfunctions, all influenced by dysfunctions of the 5HT2C receptors. Furthermore, the invention also relates to the use of the inventive com¬ pounds of formula (I) as medicaments useful for treating diseases of the central nervous system, e.g. psychiatric and neurological disorders, which can be schizophrenia, anxiety, depression, obsessive-compulsive disorders, panic disorders and further diseases related to sleep, appetite, thermoregulation, sexual behaviour, motor activity and neuroendochine function e.g. sleep disorders, eating disorders, sexual dysfunctions or for treating brain edema.
In yet another aspect, the invention relates to methods of preparing the above mentioned compounds. These methods comprise:
a) reacting a compound of formula II
Figure imgf000010_0001
wherein R1, R2, R3 and R6 are as defined above, with a compound selected from III or IV
Figure imgf000010_0002
wherein R4 and R5 are as defined above and CHXY forms an aldehyde or a derivatives thereof capable of reacting like an aldehyde, to form a com¬ pound of formula I;
b) treating a compound of formula V
Figure imgf000011_0001
wherein R1, R2, R3, R5 and R6 are as defined above, with hydrogen in the presence of a catalyst, which can be Pd or Rh on activated carbon , Pt02 or RaNi, to form a compound of formula VI
Figure imgf000011_0002
wherein R , R2, R , R and R are as defined above;
c) treating a compound of formula VI with an electrophile reagent, by a method described in e.g. J March, Advanced Organic Chemistry, 4. Ed.
(1992), to form a compound of formula Vll
Figure imgf000012_0001
wherein R\ R2, R3, R5, R6 and R7 are as defined above.
The compounds of the present invention have been tested for their affinity for the 5HT2C receptor.
The affinity for the 5HT2C receptor may be determined by radioligand binding assays using 3[H]-Mesulergine as determined in D. Hoyer, J. Receptor. Res. 8, 59-81 , (1988); D. Hoyer et al, Eur. J. Pharmacol. 1 18, 13-23, (1985); K. D. Bunis et al, J. Pharm. Exp. Ther. 258, 891 896, (1991 ).
The 5HT2C receptor affinity, as determined by IC50 values were typically in the range of 1 nM to 1 vM.
The compounds of the invention, together with a conventional adjuvant, carrier or diluent, and if desired a pharmaceutically acceptable acid addi¬ tion salt thereof, may be placed into the form of pharmaceutical compo¬ sitions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs or capsules filled with the same, all for oral use; in the form of suppositories for rectal administration, or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. Tablets containing 0.05-500 mg of active ingredient, more specified 0.1 -200 mg or especially 1 -100 mg per tablet are accordingly suitable representative unit dosage forms.
The compounds of this invention can thus be used for the formulation of pharmaceutical preparations e.g. for oral and parenteral administration to mammals including humans in accordance with conventional methods of galenic pharmacy.
Conventional excipients are such pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral or oral application which do not deleteriously react with the active compound.
Examples of such carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellu- lose and polyvinylpyrrolidone.
The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compound.
For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
Ampoules are convenient unit dosage forms.
For oral applications, particularly suitable are tablets, dragees, or cap¬ sules having talc and/or a carbohydrate carrier or binder or the like, the carrier preferably being lactose and/or corn starch and/or potato starch. A syrup, elixir or like can be used when a sweetened vehicle can be employed. Generally, as to broader ranges, the compound of the inven¬ tion is dispensed in unit dosage form comprising 0.05-500 mg, more specified 0.1 -200 mg or especially 1 -100 mg, in a pharmaceutically acceptable carrier per unit dosage.
A typical tablet which may be prepared by conventional tabletting tech¬ niques contains:
Active compound 1 .0 mg
Lactosum 67.9 mg Ph. Eur AviceIΦ 31 .4 mg
Amberlite0 IRP 88 1 .0 mg
Magnesii stearas 0.25 mg Ph. Eur.
The following non-limitating examples illustrate the invention.
EXAMPLE 1
1 -(7-Benzofuranyl)-1 ,2,3,4-tetrahydro-betacarboline, hydrochloride
Benzofuran-7-carbaldehyde (12.1 g, 83 mmol), N-acetylglycine (9.7 g. 83 mmol), sodium acetate (1 1 .28 g, 83 mmol) and acetic anhydride (100 ml) was stirred at 100°C for 8 hours. The mixture was then cooled to room temperature and poured onto ice. A yellow precipitate was iso¬ lated, washed with water and ether and dried to give 10.2 g of 4-(7- benzofuranylmethyiene)-2-methyloxazol-5-one M.p. 172.1 -1 73.5°C.
4-(7-benzofuranylmethylene)-2-methyloxazol-5-one (6.8 g, 30 mmol) and tryptamine, hydrochloride (3.2 g, 20 mmol) in 200 ml 1 N HCl was refluxed under nitrogen for 20 hours. The mixture was then cooled to 0°C, whereupon the formed precipitate was isolated and washed with 1 N HCl, water, 2-propanol and ether to give 6.8 g of the title compound.
A sample of this product was additionally purified by separation between ethyl acetate and 2 N NaOH. The organic phase was washed with water and saturated sodium chloride, dried over sodium sulfate and concen- trated in vacuo. The resulting oil was taken up in ethanol and hydrogen chloride in ether added to crystallize the title compound. M.p. 240- 241 °C.
EXAMPLE 2
1 -(7-Benzofuranylmethyl)-6-methyl-1 ,2,3,4-tetrahydro-betacarboline, hydrochloride
4-(7-benzofuranylmethylene)-2-methyloxazol-5-one (1 .6 g, 7 mmol) and
5-methyltryptamine, HCl ( 1 g, 4.7 mmol) was refluxed in 25 ml 1 N HCl for 24 hours. The mixture was then cooled to 0°C and filtered to isolate a semicrystalline brown precipitate which was washed with 2-propanol and recrystallized from ethanol to give 120 mg of the title compound . M.p. > 240°C. EXAMPLE 3
1 -(7-Benzofuranylmethyl)-6-chloro-1 ,2,3,4-tetrahydro-betacarboline, hydrochloride
Starting from 4-(7-benzofuranylmethylene)-2-methyioxazol-5-one (1 .6 g, 7 mmol) and 5-chlorotryptamine, HCl (1 .2 g, 5 mmol) the title compound was prepared by the procedure described in example 1 to give 450 mg of the title compound. M.p. > 230°C.
EXAMPLE 4
1 -(2,3-Dihydrobenzofuran-7-ylmethyl)-1 ,2,3,4-tetrahydro-betacarboline, oxalate
1 -{7-Benzofuranyl)-1 ,2,3,4-tetrahydro-betacarboline (0.8 g, 2.6 mmol) was dissolved in 50 ml glacial acetic acid and reduced catalytically using 100 mg 5% Pd on carbon (RT, 30 psi). The mixture was filtered and separated between CH2CI2 and aqueous potassium carbonate (PH = 8) .
The organic phase was dried over magnesium sulfate and concentrated in vacuo to get 500 mg oil, which was taken up in 2 ml dry acetone.
200 mg oxalic acid was added to precipitate the desired compound . Recrystallization from acetone and ethanol gave 400 mg of the title compound. M.p. 235-238°C.

Claims

A compound of the general formula (I)
Figure imgf000017_0001
wherein R1 and R2 independently are hydrogen, C-,.6-alkyl, C3.6-cycloalkyl, C1-6-alkoxy, aralkyl, halogen, halogenalkyl, nitro, C-,.6-alkylthio; R3, R5 and R6 independently are hydrogen, C1-6-alkyl, C2.6-alkenyl, or C3_6- cycloalkyl; and
R is
Figure imgf000017_0002
wherein A-B-C together with the benzene ring forms a five membered heterocyclic ring comprising one or more nitrogen-, oxygen- or sulphur atoms, and optionally substituted with one or more of hydrogen, halogen, C^-alkyl, C2.6-alkenyl, nitro, halogenalkyl or C3.6-cycloalkyl; R7 and R8 independently are hydrogen, halogen, C 6-alkyl C2.6-alkenyl, nitro, CN, halogenalkyl or C3.6-cycloalkyl; and pharmaceutically acceptable salts thereof. 2___ A compound according to claim 1 wherein R1 and R2 are selected from chlorine, bromine, methyl and isopropyl.
3 A compound according to claim 1 wherein R3, R5 and R6 are selected from hydrogen, methyl and allyl.
4,. A compound according to any of the claims 1 -3 wherein R4 is selected from benzofuranyl, 2,3-dihydrobenzofuranyl, 5-bromo-2,3- dihydrobenzofuranyl, 5-chloro-2,3-dihydrobenzofuranyl, 5,6-dichloro-2,3- dihydrobenzofuranyl, benzothienyl, 2,3-dihydrobenzothienyl, benzimida¬ zolyl, 1 ,2-benzisoxazolyl, benzthiazolyl and benzoxazolyl.
EL. A compound according to any of the claims 1-4 which is
1 -(7-Benzofuranylmethyl)-1 ,2,3,4-tetrahydro-betacarboline, hydrochloride,
1 -(7-Benzofuranylmethyl)-6-methyl-1 ,2,3,4-tetrahydro-betacarboline, hydrochloride,
1 -(7-Benzofuranylmethyl)-6-chloro-1 ,2,3,4-tetrahydro-betacarboline, hydrochloride; 1 -(2,3-Dihydrobenzofuran-7-ylmethyl)-1 ,2,3,4-tetrahydro-betacarboline, oxalate.
6^ A compound according to any of the claims 1-5 or a pharma¬ ceutically acceptable salt thereof for use as a therapeutically acceptable substance.
i A compound according to any of the claims 1 -5 or a pharma¬ ceutically acceptable salt thereof for use as a therapeutically acceptable substance in the treatment of central nervous system disorders, sleep disorders, eating disorders and sexual dysfunctions, all influenced by dysfunction of the 5-HT2C receptors. I . A method of preparing a compound according to any of the claims 1 -5, which comprises:
a) reacting a compound of formula II
Figure imgf000019_0001
wherein R1 , R2, R3 and R6 are as defined above with a compound selected from III or IV
Figure imgf000019_0002
wherein R4 and R5 are as defined above and CHXY forms an aldehyde or a derivatives thereof capable of reacting like an aldehyde, to form a com¬ pound of formula I;
b) treating a compound of formula V
Figure imgf000020_0001
wherein R1, R2, R3, R5 and R6 are as defined above, with hydrogen in the presence of a catalyst, which can be Pd or Rh on activated carbon , Pt02 or RaNi, to form a compound of formula VI
Figure imgf000020_0002
wherein R\ R2, R3, R5 and R6 are as defined above;
c) treating a compound of formula VI with an electrophile reagent, by a method described in e.g. J March, Advanced Organic Chemistry, 4. Ed. (1992), to form a compound of formula Vll
Figure imgf000021_0001
wherein R1 , R2, R3, R5, R6 and R7 are as defined above.
9L A pharmaceutical composition comprising a compound accord¬ ing to any of the claims 1 -5 or a pharmaceutically acceptable salt thereof and a therapeutically inert excipient, carrier or diluent.
10. A pharmaceutical composition for the treatment of central nervous system disorders, sleep disorders, eating disorders and sexual dysfunctions, all influenced by dysfunctions of the 5HT2C receptors, which composition comprises a compound according to any of the claims 1 -5 or a pharmaceutically acceptable salt thereof and a thera¬ peutically inert excipient, carrier or diluent.
1 1 . Use of a compound according to any of the claims 1 -5 or a pharmaceutically acceptable salt thereof for the manufacture of a phar¬ maceutical composition for the treatment of central nervous system disorders, sleep disorders, eating disorders and sexual dysfunctions, all influenced by dysfunction of the 5-HT2C receptors.
1_2, A method of treating central nervous system disorders, sleep disorders, eating disorders and sexual dysfunctions, all influenced by dysfunction of the 5-HT2C receptors in a subject in need thereof com- prising administering an effective amount of a compound according to any of the claims 1 -5.
13. A method of treating central nervous system disorders, sleep disorders, eating disorders and sexual dysfunctions, all influenced by dysfunction of the 5-HT2C receptors in a subject in need thereof com¬ prising administering a pharmaceutical composition according to claim 9.
14. A process for the manufacture of a pharmaceutical composi- tion to be used in the treatment of central nervous system disorders, sleep disorders, eating disorders and sexual dysfunctions, all influenced by dysfunction of the 5-HT2C receptors, which process comprising bringing a compound of formula I according to claim 1 and a pharma¬ ceutically acceptable salt thereof into a galenical dosage form.
PCT/DK1996/000258 1995-06-23 1996-06-14 Tetrahydro-betacarboline derivatives and their preparation and use WO1997000871A1 (en)

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Cited By (6)

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Publication number Priority date Publication date Assignee Title
US6780862B2 (en) 2000-12-20 2004-08-24 Bristol-Myers Squibb Pharma Company Aryl and aminoaryl substituted serotonin receptor agonist and antagonist ligands
EP1747779A1 (en) 2005-07-28 2007-01-31 Laboratorios Del Dr. Esteve, S.A. Tetrahydro-b-carbolin-sulfonamide derivatives as 5-HT6 ligands
WO2007016353A2 (en) * 2005-07-28 2007-02-08 Bristol-Myers Squibb Company Substituted tetrahydro-1h-pyrido[4,3,b]indoles as serotonin receptor agonists and antagonists
WO2007028460A1 (en) * 2005-07-28 2007-03-15 Laboratorios Del Dr. Esteve, S.A. TETRAHYDRO-β-CARBOLIN-SULFONAMIDE DERIVATIVES AS 5-HT6 LIGANDS
WO2007016353A3 (en) * 2005-07-28 2007-03-22 Bristol Myers Squibb Co Substituted tetrahydro-1h-pyrido[4,3,b]indoles as serotonin receptor agonists and antagonists
US8263609B2 (en) 2005-07-28 2012-09-11 Laboratorios Del Dr. Esteve, S.A. Tetrahydro-β-carbolin-sulfonamide derivatives as 5-Ht6 ligands

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