CA2238554A1 - Aryloxyalkylamines with serotonin receptor activity - Google Patents
Aryloxyalkylamines with serotonin receptor activity Download PDFInfo
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- CA2238554A1 CA2238554A1 CA 2238554 CA2238554A CA2238554A1 CA 2238554 A1 CA2238554 A1 CA 2238554A1 CA 2238554 CA2238554 CA 2238554 CA 2238554 A CA2238554 A CA 2238554A CA 2238554 A1 CA2238554 A1 CA 2238554A1
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Abstract
Described herein are compounds selective for a 5-HT1D-like receptor, which have the general formula:
(see fig. I) wherein R1 is selected from halo and cycloalkyl;
R2 is selected from halo and H;
R3 is selected from a group of formula III and IV:
(see fig. II) (see fig. III) wherein R4 and R5 are independently selected from H, C1-6alkyl and arylalkyl;
Y is selected from O and CH2;
and m and n are independently 1 or 2.
Also described is the use of these compounds as pharmaceuticals to treat indications where stimulation of 5-HT1D-like receptors is implicated, such as migraine.
(see fig. I) wherein R1 is selected from halo and cycloalkyl;
R2 is selected from halo and H;
R3 is selected from a group of formula III and IV:
(see fig. II) (see fig. III) wherein R4 and R5 are independently selected from H, C1-6alkyl and arylalkyl;
Y is selected from O and CH2;
and m and n are independently 1 or 2.
Also described is the use of these compounds as pharmaceuticals to treat indications where stimulation of 5-HT1D-like receptors is implicated, such as migraine.
Description
CA 02238~4 1998-0~-26 Aryloxyalkylamines with Serotonin Receptor Affinity This invention relates to compounds having CNS activity and to their production and use.
According to one aspect of the invention, there are provided compounds of Formula I and salts, solvates or hydrates thereof:
0~
R2~ 1 1 0 wherein R' is selected from halo and cycloalkyl;
R2 is selected from halo and H;
R3 is selected from a group of formula III and IV:
~--N~ R4s ~ N~mY
wherein R4 and R5 are independently selected from H, Cl 6alkyl and arylalkyl;
Y is selected from O and CH2;
and m and n are independently 1 or 2;
with the provisos that:
One of R4 or R5 is not isopropyl when the other is H, Rl and R2 are both chloro and n is 1;
One of R4 or R5 is not benzyl when the other is methyl, Rl and R2 are both chloro and n is 1;
Rl is not cyclohexyl when R2 is H, R4 and R5 are both ethyl and n is 1 or 2; and CA 02238~4 1998-0~-26 One of R4 or R5 is not 3,4-dichlorobenzyl or 2,5-dichlorobenzyl when the other is H, R' and R2 are both chloro and n is 1.
According to another aspect of the invention, there is provided a pharmaceuticalcomposition comprising a compound of Formula II in an amount effective to stimulate 5-HTlD-like receptors, and a pharmaceutically acceptable carrier:
0~
R2~1 1 1 1 0 wherein R' is selected from halo and cycloalkyl;
R2 is selected from halo and H;
R3 is selected from a group of formula III and IV:
,R4 ,~m N'R5 -~-N~ Y
wherein R4 and Rs are independently selected *om H, Cl 6alkyl and arylalkyl;
Y is selected from O and CH2;
and m and n are independently 1 or 2.
In another aspect ofthe present invention there are provided compositions containing the present compounds for pharmaceutical use to treat CNS conditions where a 5-HT,D-like ligand CA 02238~4 1998-0~-26 is indicated. These and other aspects of the present invention are described in greater detail hereinbelow.
The term "Cl 6alkyl" as used herein means straight and branched chain alkyl radicals containing from one to six carbon atoms and includes methyl, ethyl, propyl, isopropyl, t-butyl and the like.
The term "halo" as used herein means halide and includes fluoro, chloro, bromo and iodo.
The term "arylalkyl" as used herein means a six membered aromatic ring which is attached to a specified node via a C, 3alkylene linker.
The term "cycloalkyl" as used herein means a four to six membered carbocyclic ring.
In embodiments ofthe invention, compounds of Formula I and II include those in which Rl is selected from halo and cycloalkyl. In particular embodiments, Rl is selected from chloro and cyclopentyl. In a preferred embodiment, Rl is chloro.
In another embodiment of the invention, compounds of Formula I and II include those in which R2 is selected from halo and H. In a preferred embodiment, R2 is chloro.
The group R3 can be selected from a group of Formula III and IV. When R3 is a group of formula III, R4 and R5 are independently selected from H, Cl 6alkyl and arylalkyl. In specific embodiments, R4 and R5 are selected from H, methyl, ethyl, n-propyl, phenethyl and benzyl.
When R3 is a group of formula IV, Y is selected from CH2 and O and m and n are 1 or 2.
Preferrably m and n are both 2 when Y is O. When Y is CH2, m and n are preferrably selected to form a 5- or 6-membered ring.
In specific embodiments of the invention, the compounds of Formula I and Formula II
include:
According to one aspect of the invention, there are provided compounds of Formula I and salts, solvates or hydrates thereof:
0~
R2~ 1 1 0 wherein R' is selected from halo and cycloalkyl;
R2 is selected from halo and H;
R3 is selected from a group of formula III and IV:
~--N~ R4s ~ N~mY
wherein R4 and R5 are independently selected from H, Cl 6alkyl and arylalkyl;
Y is selected from O and CH2;
and m and n are independently 1 or 2;
with the provisos that:
One of R4 or R5 is not isopropyl when the other is H, Rl and R2 are both chloro and n is 1;
One of R4 or R5 is not benzyl when the other is methyl, Rl and R2 are both chloro and n is 1;
Rl is not cyclohexyl when R2 is H, R4 and R5 are both ethyl and n is 1 or 2; and CA 02238~4 1998-0~-26 One of R4 or R5 is not 3,4-dichlorobenzyl or 2,5-dichlorobenzyl when the other is H, R' and R2 are both chloro and n is 1.
According to another aspect of the invention, there is provided a pharmaceuticalcomposition comprising a compound of Formula II in an amount effective to stimulate 5-HTlD-like receptors, and a pharmaceutically acceptable carrier:
0~
R2~1 1 1 1 0 wherein R' is selected from halo and cycloalkyl;
R2 is selected from halo and H;
R3 is selected from a group of formula III and IV:
,R4 ,~m N'R5 -~-N~ Y
wherein R4 and Rs are independently selected *om H, Cl 6alkyl and arylalkyl;
Y is selected from O and CH2;
and m and n are independently 1 or 2.
In another aspect ofthe present invention there are provided compositions containing the present compounds for pharmaceutical use to treat CNS conditions where a 5-HT,D-like ligand CA 02238~4 1998-0~-26 is indicated. These and other aspects of the present invention are described in greater detail hereinbelow.
The term "Cl 6alkyl" as used herein means straight and branched chain alkyl radicals containing from one to six carbon atoms and includes methyl, ethyl, propyl, isopropyl, t-butyl and the like.
The term "halo" as used herein means halide and includes fluoro, chloro, bromo and iodo.
The term "arylalkyl" as used herein means a six membered aromatic ring which is attached to a specified node via a C, 3alkylene linker.
The term "cycloalkyl" as used herein means a four to six membered carbocyclic ring.
In embodiments ofthe invention, compounds of Formula I and II include those in which Rl is selected from halo and cycloalkyl. In particular embodiments, Rl is selected from chloro and cyclopentyl. In a preferred embodiment, Rl is chloro.
In another embodiment of the invention, compounds of Formula I and II include those in which R2 is selected from halo and H. In a preferred embodiment, R2 is chloro.
The group R3 can be selected from a group of Formula III and IV. When R3 is a group of formula III, R4 and R5 are independently selected from H, Cl 6alkyl and arylalkyl. In specific embodiments, R4 and R5 are selected from H, methyl, ethyl, n-propyl, phenethyl and benzyl.
When R3 is a group of formula IV, Y is selected from CH2 and O and m and n are 1 or 2.
Preferrably m and n are both 2 when Y is O. When Y is CH2, m and n are preferrably selected to form a 5- or 6-membered ring.
In specific embodiments of the invention, the compounds of Formula I and Formula II
include:
2-(2 ,3 -Dichlorophenoxy)-N-methylethaneamine;
CA 02238~4 1998-0~-26 2-(2,3-Dichlorophenoxy)-N-phenethylethaneamine;
N-Benzyl-2-(2,3 -dichlorophenoxy)ethaneamine;
2-(2,3-Dichlorophenoxy)-N,N-dimethylethaneamine;
4-[2-(2,3-Dichlorophenoxy)ethyl]morpholine;
1-[2-(2,3-Dichlorophenoxy)ethyl]pyrrolidine;
1 -[2-(2,3-Dichlorophenoxy)ethyl]piperidine;
2-(2-Cyclopentylphenoxy)-N-methyl-N-(n-propyl)ethaneatnine; and 3 -(2-Cyclopentylphenoxy)-N-methyl-N-(n-propyl)propaneamine .
Preferred compounds of Formula I and II include:
2-(2 ,3 -Dichlorophenoxy)-N-phenethylethaneamine;
2-(2 ,3 -Dichlorophenoxy)-N,N-dimethylethaneatnine;
N-Benzyl-2-(2,3-dichlorophenoxy)ethaneamine;
2-(2-Cyclopentylphenoxy)-N-methyl-N-(n-propyl)ethaneamine; and 3 -(2-Cyclopentylphenoxy)-N-methyl-N-(n-propyl)propaneamine .
Particularly preferred compounds of Formula I and II include:
2-(2,3-Dichlorophenoxy)-N-phenethyleth~ne:~mine;
3-(2-Cyclopentylphenoxy)-N-methyl-N-(n-propyl)prop:~n~mine; and 2-(2,3 -Dichlorophenoxy)-N,N-dimethylethaneamine.
Acid addition salts of the compound of Formula I and II are most suitably formed from pharmaceutically acceptable acids, and include for example those formed with inorganic acids e.g.
hydrochloric, sulphuric or phosphoric acids and organic acids e.g. succinic, maleic, acetic or fumaric acid. Other non-pharmaceutically acceptable salts e.g. oxalates may be used for example in the isolation of compounds of Formula I and II for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt. Also included within the scope of the invention are solvates and hydrates of ~e invention.
The conversion of a given compound salt to a desired compound salt is achieved by applying standard techniques, in which an aqueous solution ofthe given salt is treated with a solution of base CA 02238~4 1998-0~-26 e.g. sodium carbonate or potassium hydroxide, to liberate the free base which is then extracted into an a~ pliate solvent, such as ether. The free base is then separated from the aqueous portion, dried, and treated with the requisite acid to give the desired salt.
The compounds of the present invention can be prepared by processes analogous to those established in the art. Therefore, in general, a reagent of formula A, wherein R' and R2 are as defined in Formula I and II and Z represents a leaving group such as halo, tosylate or mesylate, (with bromo and tosylate being preferred) is coupled with an excess amount of an amine of formula B or C wherein R4, R5, m, n and Y are as defined in Formula I and II, optionally in the presence of another base in an inert solvent. The temperature of the reaction can be in the range from 30-120 ~C, preferrably 60-110 ~C, and may be done at atmospheric pressure or in a sealed tube. Suitable solvents include dioxane, toluene, benzene and acetonitrile with dioxane and acetonitrile being preferred. Optional bases can be selected from inorganic salts such as sodium or potassium carbonate or tertiary organic amines such as triethylamine or diisopropylethylamine. Potassiumcarbonateispreferred.
O~Z
R1~ ,R4 J~m R2J~d ~R5 H N~,Y
A B C
Reagents of formula A wherein Z is tosylate or mesylate, can be prepared by reacting the corresponding alcohol with p-toluenesulfonyl chloride or methanesulfonyl chloride (respectively) under standard conditions, for example in the presence of triethylamine in methylene chloride. The alcohol can be prepared by reacting thesodium salt of a reagent of formula D with a reagent of formula E in an inert solvent.
Suitable solvents include acetonitrile and acetone with acetonitrile being preferred. The reaction is normally carried out in a sealed tube at temperatures in the range of 80-120 ~C, preferably at around 100 ~C.
CA 02238~4 l998-0~-26 OH
R2~ Br~;OH Br/~; Br D E F
Reagents of formula A wherein Z is halo can be prepared by reacting the sodium salt of a reagent of formula D with, for example, a reagent of formula F as described above for the reaction of reagent D with E.
Reagents B, C, D, E, and F, wherein R', R2, R4, R5, Y, m and n are as defined above are commercially available or can be prepared by processes analogous to those known in the art.
In an embodiment of the invention, the compound is provided in labeled form, such as radiolabeled form, e. g. labeled by incorporation within its structure 3H or 14C
or by conjugation to 1251. In another aspect of the invention, the compounds in labeled form can be used to identify 5-HT,D-like receptor ligands by techniques common in the art. This can be achieved by incubating the receptor or tissue in the presence of a ligand candidate and then incubating the resulting preparation with an equimolaramount of radiolabeled compound of the invention such as 2-(2,3-dichlorophenoxy)-N-phenethylethaneamine. 5-HT,D-like receptor ligands are thus revealed as those that are not significantly displaced by the radiolabeled compound of the present invention.
Alternatively, 5-HT,D-like receptorligand candidates may be identified byfirst incubating a radiolabeled form of a compound of the invention then incubating the resultingpreparation in the presence of the candidate ligand. A more potent 5-HT,D-like receptor ligand will, at equimolar concentration, displace the radiolabeled compound of the invention.
The present compounds are useful as pharmaceuticals for the treatment of various conditions in which the use of a 5-HT,D-like ligand is indicated, such as for the CA 02238~4 1998-0~-26 treatment of migraine, cluster headache and portal tension, a condition characterized by increased portal vein blood flow and typically associated with cirrhosis of the liver.
For use in medicine, the compounds of the present invention can be administered in a standard pharmaceutical composition. The present invention therefore provides, in a further aspect, pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a Formula I or 11 compound or a pharmaceutically acceptable salt, solvate or hydrate thereof, in an amount effective to treat the target indication.
The compounds of the present invention may be administered by any convenient route, for example by oral, parenteral, buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions formulated accordingly.
Compounds of Formula I and 11 and their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, or as solid forms such as tablets, capsules and lozenges. A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable pharmaceutical liquid carrier for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent. A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose. A composition in the form of a capsule can be prepared using routine encapsulation procedures. Forexample, pellets containing the active ingredient can be prepared using standard carriers and then filled into hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier, for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension filled into a soft gelatin capsule.
Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
CA 02238~4 1998-0~-26 Alternatively, the solution can be Iyophilized and then reconstituted with a suitable solvent just prior to administration.
Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device. Altematively, the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas such as compressed air or an organic propellant such as fluorochlorohydrocarbon. The aerosol dosage forms can also take the form of a pump-atomizer.
Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, wherein the active ingredient is formulated with a carrier such as sugar, acacia, tragacanth, or gelatin and glycerine. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.
Preferably, the composition is in unit dose form such as a tablet, capsule or ampoule. Each dosage unit for oral administration contains preferably from 1 to 250 mg (and for parenteral administration contains preferably from 1 to 25 mg) of a compound of Formula I or ll or a pharmaceutically acceptable salt thereof calculated as the free base.
The phammaceuticallyacceptable compounds ofthe invention will normally be administered in a daily dosage regimen (for an adult patient) of, for example, an oral dose of from 1 mg to 500 mg, preferably between 10 mg and 400 mg, e.g., between 10 mg and 250 mg, or an intravenous, subcutaneous or intramuscular dose of between 0.1 mg and 100 mg,preferably between 0.1 mg and 50 mg, e.g., between 1 mg and 25 mg, of a compound of Formula I or ll or a pharmaceutically acceptable salt, solvate or hydrate thereof calculated as the free base, the compound being administered 1 to 4 times per day. Suitably, the CA 02238~4 1998-0~-26 compounds will be administered for a period of continuous therapy, for example for a week or more.
Example 1 (a): 2-(2,3-Dichlorophenoxy)-N-methylethaneamine Hydrochloride s A mixture of 2-(2,3-dichlorophenoxy)ethanol-p-toluenesulfonate (722 mg,2 mmol), methylamine (40% in ethanol, 3 mL) and anhydrous potassium carbonate (280 mg, 2 mmol) in dioxane (20 mL) was heated at reflux for 3 hours. The solvent was removed by evaporation under reduced pressure. The residue was treated with 10% aqueous sodium hydroxide (10 mL) and extracted with ether (3x 20 mL), washed with water (3x 30 mL), dried and filtered. The filtrate was treated with ether saturated with HCI gas and the solid productwas collected byfiltration. Recrystallization from absolute ethanol/anhydrous ether afforded 400 mg (78%) of the title compound. mp 198-200 ~C; 1H NMR (DMSO-d6) d: 2.7 (s, 3H, CH3), 3.2 (t, 2H, CH2), 4.3 (t, 2H, CH2), 7.2 (m, 3H, Ar-H) and 9.4 (bs, 2H, N+H2);
Anal CgH1,CI2NO HCI by C,H,N.
In a like manner, the following additional compounds were prepared:
(b) 2-(2,3-Dichlorophenoxy)-N-phenethylethaneamine Hydrochloride, from phenethylamine amine. 54% yield, mp 192-193 ~C; Anal C16H17CI2NO HCI by C,H,N.
(c) N-Benzyl-2-(2,3-dichlorophenoxy)ethaneamine Hydrochloride, from benzylamine.51 % yield, mp 157-159 ~C; Anal C15H15CI2NO HCI by C,H,N.
(d) 2-(2,3-Dichlorophenoxy)-N,N-dimethylethaneamine Hydrochloride, from dimethylamine. 18% yield, mp 178-179 ~C; Anal C10H13CI2NO HCI by C,H,N.
(e) 4-[2-(2,3-Dichlorophenoxy)ethyl]morpholine, from morpholine. 46% yield, mp 246-248 ~C; Anal C12H15CI2NO2 HCI by C,H,N.
(f) 1 -[2-(2,3-Dichlorophenoxy)ethyl]pyrrolidine, from pyrrolidine. 31 % yield, mp 184-185 ~C; Anal C12H,5CI2NO HCI by C,H,N.
(g) 1 -[2-(2,3-Dichlorophenoxy)ethyl]piperidine, from piperidine. 30% yield, mp 214-215 ~C; Anal C13H17CI2NO HCI by C,H,N.
Example 2(a): 1-Bromo-2-(2-cyclopentylphenoxy)ethane CA 02238C.C.4 1998-0C.-26 Sodium methoxide (25% solution in methanol, 0.69 g, 3.2 mmol) was added to 2-cyclopentylphenol (0.4 g, 2.5 mmol) in methanol (5 mL) and allowed to stand at room temperature for 30 minutes. After removal of the solvent in vacuo, acetonitrile was added to the solid. The sodium-2-cyclopentyl-phenolate in acetonitrile was then added dropwise to 1,2-dibromoethane (2.3 g,12.0 mmol) in a screw-top test tube and the sealed tube was heated at 100 ~C for 12 hours and then 130 ~C for and additional 12 hours. The solvent was removed in vacuo and petroleum ether (bp 60-90 ~C) (5 mL) and aqueous sodiumhydroxide (2N,3 mL) were added to the residue. The aqueous layerwas removed and the organic portion was extracted once more with aqueous sodium hydroxide (2N,3 mL). The petroleum ether portion was dried over magnesium sulfate and solvent removed in vacuo to yield an oil. Kugelhohr distillation of the oil (bp 52-70 ~C, 0.05 mm Hg) yielded 0.23 g (35%) of 1-bromo-2-(2-cyclopentylphenoxy)ethane as a clear oil. 'H NMR (CDCI3, free base) d: 1.3-2.2 (bm,8H, CH2 cyclopentyl),3.2-3.5 (m,1 H, CH),3.6 (t J = 4 Hz,2H, CH2N), 4.3 (t J = 4 Hz, 2H, CH2O) and 6.7-7.3 (m, 4H, ArH).
In a like manner, the following addition compound was prepared:
(b) 1 -Bromo-3-(2-cyclopentylphenoxy)propane, from 1,2-dibromopropane. bp 52-70 ~C
(0.07 mm Hg); 'H NMR (CDCI3, free base) d: 1.3-2.2 (m, 8H, CH2 cyclopentyl),2.2-2.5 (m J=4Hz,2H,CCH2C),3.2-3.5(m,1H,CH),3.6(tJ=4Hz,2H,CH2N),4.1 (tJ=4Hz,2H, CH2O) and 6.7-7.3 (m, 4H, ArH).
Example 3(a): 2-(2-Cyclopentylphenoxy)-N-methyl-N-(n-propyl)ethaneamine Hydrochloride A solution of 1-bromo-2-(2-cyclopentylphenoxy)ethane (Example 2a, 0.23 g, 0.85 mmol) and N-methylpropaneamine (1.0 g,14.0 mmol) were combined in acetonitrile (1 mL) and heated in a sealed tube at 60 ~C for 24 hours. The reaction mixture was allowed to cool and the N-methylpropaneamine and acetonitrile were recovered by distillation. An ethereal solution of the resulting oil was washed with 1 N sodium hydroxide (3x 1 mL), then extracted with hydrochloric acid (3x 10 mL). The combined acidic fractions were basified to pH 12 with a saturated solution of potassium hydroxide and extracted with ether (3x 15 CA 02238~4 1998-0~-26 mL). Thecombinedetherfractionsweredriedovermagnesiumsulfateandthesolventwas evaporated in vacuo. An ethereal solution of the free base was treated with hydrochloric acid in ether until the salt formation ceased. The salt was collected by filtration and recrystallized from 2-butanone to yield the title compound as a white solid (0.1 g, 40%). mp 193-195 ~C; 'H NMR (CDCI3, free base) d: 0.9 (t, 3H, CH3), 1.0-2.5 (m, 12H), 2.8 (t J = 3 Hz, 2H, CH2N), 3.0-3.5 (m, 1 H, CH), 4.1 (t J = 3 Hz, 2H, CH2O), 6.8-7.2 (m, 4H, ArH); IR
(CHCI3): 2959, 2879, 2578, 2475, 1501, 1477, 1452, 1238, 747 cm~'; Anal C17H27NO HCI
by C,H,N.
In a like manner, the following additional compound was prepared:
(b) 3-(2-Cyclopentylphenoxy)-N-methyl-N-(n-propyl)propaneamine Hydrogen Oxalate,from 1-bromo-3-(2-cyclopentylphenoxy)propane (Example2b)and oxalicacid. mp 136-138 ~C; 'H NMR (CDCI3, free base) d: 0.9 (t, 3H, CH3), 1.2 (m, 19H), 3.1-3.5 (m, 1H, CH), 4.0 (t, 2H, CH2O), 6.7-7.3 (m, 4H, ArH); IR (CHCI3): 3443, 3400 (NH+), 2955 (CH), 2500 (NH+), 1609 (COO~), 1245 (ArOC), 723 (ortho disubstituted benzene) cm~'; Anal C18H2gNO C2H2O4 by C,H,N.
CA 02238~4 1998-0~-26 Summary of Exemplified Compounds Example # R' R2 R3 n 1 a Cl Cl -NHCH3 1 b Cl Cl-NHCH2CH2Ph 1 c Cl Cl -NHCH2Ph 1 d Cl Cl -N(CH3)2 1 e Cl Cl ~
--N~O
1 f Cl Cl /~~ 1 _N~,~
1 g Cl Cl --N~,~
3a ~ H _N~CH3 ~r CH3 3b ~ H _N~CH3 2 ~r CH3 Example 4: Agonist Assay The in vitro evaluation of the 5-HT,D-like receptor agonist activity of the compounds of the invention was carried our by testing the extent to which they mimic sumatriptan in contracting the rabbit saphenous vein (Perez, M. et a/. J. Med. Chem.
1995, 38:3602-3607).
CA 02238 7 74 1998 - O, - 26 Tissues were obtained from male New Zealand White rabbits (~3-4 kg) which were sacrificed by an overdose of pentobarbital. The saphenous veins from both the left and right side were cleaned of fat and connective tissue and placed in Krebs solution (118 mM NaCI, 11 mM glucose, 25 mM NaHCO3, 4.7 mM KCI, 2.5 mM
CaCI2 2H20, 1.2 mM KH2PO4, and 1.2 mM MgSO4 7H2O. Ring segments of the vein (4-5mm in length) were cut and the endothelium gently removed. The segments were mounted in 10 mL baths containing Krebs buffer and were constantly aerated with 95%
oxygen/5% carbon dioxide and maintained at 37~C and pH 7.4 in order to record the isometric tension. A resting tension of 2.5 9 was applied and the tissues allowed to equilibrate for 90 minutes, with washing every 15-20 minutes. After the equilibrium period, the rings were depolarized by the addition of two aliquots of KCI (80 mM final concentration) separated by a 20 minute washing period. The tissues were then exposed to prazosin, idazoxan and indomethacin (all 1 mM final concentration) for 30 minutes in order to exclude the actions of a1- and a2-adrenergic receptors and prostaglandin receptors respectively. Cumulative concentration-effect curves were then constructed for sumatriptan and the test compounds. Responses were calculated asa percentage of the maximal contraction evoked by 80 mM KCI. Only one compound was tested per preparation.
The following Table illustrates the in vitro activities for a compound of the invention on the rabbit isolated saphenous vein. EC50 represents the concentration of the compound which causes 50% of the maximum contraction effected by it.
Compound EC~n (mM) sumatriptan 0.22 Example 1b 1.2
CA 02238~4 1998-0~-26 2-(2,3-Dichlorophenoxy)-N-phenethylethaneamine;
N-Benzyl-2-(2,3 -dichlorophenoxy)ethaneamine;
2-(2,3-Dichlorophenoxy)-N,N-dimethylethaneamine;
4-[2-(2,3-Dichlorophenoxy)ethyl]morpholine;
1-[2-(2,3-Dichlorophenoxy)ethyl]pyrrolidine;
1 -[2-(2,3-Dichlorophenoxy)ethyl]piperidine;
2-(2-Cyclopentylphenoxy)-N-methyl-N-(n-propyl)ethaneatnine; and 3 -(2-Cyclopentylphenoxy)-N-methyl-N-(n-propyl)propaneamine .
Preferred compounds of Formula I and II include:
2-(2 ,3 -Dichlorophenoxy)-N-phenethylethaneamine;
2-(2 ,3 -Dichlorophenoxy)-N,N-dimethylethaneatnine;
N-Benzyl-2-(2,3-dichlorophenoxy)ethaneamine;
2-(2-Cyclopentylphenoxy)-N-methyl-N-(n-propyl)ethaneamine; and 3 -(2-Cyclopentylphenoxy)-N-methyl-N-(n-propyl)propaneamine .
Particularly preferred compounds of Formula I and II include:
2-(2,3-Dichlorophenoxy)-N-phenethyleth~ne:~mine;
3-(2-Cyclopentylphenoxy)-N-methyl-N-(n-propyl)prop:~n~mine; and 2-(2,3 -Dichlorophenoxy)-N,N-dimethylethaneamine.
Acid addition salts of the compound of Formula I and II are most suitably formed from pharmaceutically acceptable acids, and include for example those formed with inorganic acids e.g.
hydrochloric, sulphuric or phosphoric acids and organic acids e.g. succinic, maleic, acetic or fumaric acid. Other non-pharmaceutically acceptable salts e.g. oxalates may be used for example in the isolation of compounds of Formula I and II for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt. Also included within the scope of the invention are solvates and hydrates of ~e invention.
The conversion of a given compound salt to a desired compound salt is achieved by applying standard techniques, in which an aqueous solution ofthe given salt is treated with a solution of base CA 02238~4 1998-0~-26 e.g. sodium carbonate or potassium hydroxide, to liberate the free base which is then extracted into an a~ pliate solvent, such as ether. The free base is then separated from the aqueous portion, dried, and treated with the requisite acid to give the desired salt.
The compounds of the present invention can be prepared by processes analogous to those established in the art. Therefore, in general, a reagent of formula A, wherein R' and R2 are as defined in Formula I and II and Z represents a leaving group such as halo, tosylate or mesylate, (with bromo and tosylate being preferred) is coupled with an excess amount of an amine of formula B or C wherein R4, R5, m, n and Y are as defined in Formula I and II, optionally in the presence of another base in an inert solvent. The temperature of the reaction can be in the range from 30-120 ~C, preferrably 60-110 ~C, and may be done at atmospheric pressure or in a sealed tube. Suitable solvents include dioxane, toluene, benzene and acetonitrile with dioxane and acetonitrile being preferred. Optional bases can be selected from inorganic salts such as sodium or potassium carbonate or tertiary organic amines such as triethylamine or diisopropylethylamine. Potassiumcarbonateispreferred.
O~Z
R1~ ,R4 J~m R2J~d ~R5 H N~,Y
A B C
Reagents of formula A wherein Z is tosylate or mesylate, can be prepared by reacting the corresponding alcohol with p-toluenesulfonyl chloride or methanesulfonyl chloride (respectively) under standard conditions, for example in the presence of triethylamine in methylene chloride. The alcohol can be prepared by reacting thesodium salt of a reagent of formula D with a reagent of formula E in an inert solvent.
Suitable solvents include acetonitrile and acetone with acetonitrile being preferred. The reaction is normally carried out in a sealed tube at temperatures in the range of 80-120 ~C, preferably at around 100 ~C.
CA 02238~4 l998-0~-26 OH
R2~ Br~;OH Br/~; Br D E F
Reagents of formula A wherein Z is halo can be prepared by reacting the sodium salt of a reagent of formula D with, for example, a reagent of formula F as described above for the reaction of reagent D with E.
Reagents B, C, D, E, and F, wherein R', R2, R4, R5, Y, m and n are as defined above are commercially available or can be prepared by processes analogous to those known in the art.
In an embodiment of the invention, the compound is provided in labeled form, such as radiolabeled form, e. g. labeled by incorporation within its structure 3H or 14C
or by conjugation to 1251. In another aspect of the invention, the compounds in labeled form can be used to identify 5-HT,D-like receptor ligands by techniques common in the art. This can be achieved by incubating the receptor or tissue in the presence of a ligand candidate and then incubating the resulting preparation with an equimolaramount of radiolabeled compound of the invention such as 2-(2,3-dichlorophenoxy)-N-phenethylethaneamine. 5-HT,D-like receptor ligands are thus revealed as those that are not significantly displaced by the radiolabeled compound of the present invention.
Alternatively, 5-HT,D-like receptorligand candidates may be identified byfirst incubating a radiolabeled form of a compound of the invention then incubating the resultingpreparation in the presence of the candidate ligand. A more potent 5-HT,D-like receptor ligand will, at equimolar concentration, displace the radiolabeled compound of the invention.
The present compounds are useful as pharmaceuticals for the treatment of various conditions in which the use of a 5-HT,D-like ligand is indicated, such as for the CA 02238~4 1998-0~-26 treatment of migraine, cluster headache and portal tension, a condition characterized by increased portal vein blood flow and typically associated with cirrhosis of the liver.
For use in medicine, the compounds of the present invention can be administered in a standard pharmaceutical composition. The present invention therefore provides, in a further aspect, pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a Formula I or 11 compound or a pharmaceutically acceptable salt, solvate or hydrate thereof, in an amount effective to treat the target indication.
The compounds of the present invention may be administered by any convenient route, for example by oral, parenteral, buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions formulated accordingly.
Compounds of Formula I and 11 and their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, or as solid forms such as tablets, capsules and lozenges. A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable pharmaceutical liquid carrier for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent. A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose. A composition in the form of a capsule can be prepared using routine encapsulation procedures. Forexample, pellets containing the active ingredient can be prepared using standard carriers and then filled into hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier, for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension filled into a soft gelatin capsule.
Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
CA 02238~4 1998-0~-26 Alternatively, the solution can be Iyophilized and then reconstituted with a suitable solvent just prior to administration.
Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device. Altematively, the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas such as compressed air or an organic propellant such as fluorochlorohydrocarbon. The aerosol dosage forms can also take the form of a pump-atomizer.
Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, wherein the active ingredient is formulated with a carrier such as sugar, acacia, tragacanth, or gelatin and glycerine. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.
Preferably, the composition is in unit dose form such as a tablet, capsule or ampoule. Each dosage unit for oral administration contains preferably from 1 to 250 mg (and for parenteral administration contains preferably from 1 to 25 mg) of a compound of Formula I or ll or a pharmaceutically acceptable salt thereof calculated as the free base.
The phammaceuticallyacceptable compounds ofthe invention will normally be administered in a daily dosage regimen (for an adult patient) of, for example, an oral dose of from 1 mg to 500 mg, preferably between 10 mg and 400 mg, e.g., between 10 mg and 250 mg, or an intravenous, subcutaneous or intramuscular dose of between 0.1 mg and 100 mg,preferably between 0.1 mg and 50 mg, e.g., between 1 mg and 25 mg, of a compound of Formula I or ll or a pharmaceutically acceptable salt, solvate or hydrate thereof calculated as the free base, the compound being administered 1 to 4 times per day. Suitably, the CA 02238~4 1998-0~-26 compounds will be administered for a period of continuous therapy, for example for a week or more.
Example 1 (a): 2-(2,3-Dichlorophenoxy)-N-methylethaneamine Hydrochloride s A mixture of 2-(2,3-dichlorophenoxy)ethanol-p-toluenesulfonate (722 mg,2 mmol), methylamine (40% in ethanol, 3 mL) and anhydrous potassium carbonate (280 mg, 2 mmol) in dioxane (20 mL) was heated at reflux for 3 hours. The solvent was removed by evaporation under reduced pressure. The residue was treated with 10% aqueous sodium hydroxide (10 mL) and extracted with ether (3x 20 mL), washed with water (3x 30 mL), dried and filtered. The filtrate was treated with ether saturated with HCI gas and the solid productwas collected byfiltration. Recrystallization from absolute ethanol/anhydrous ether afforded 400 mg (78%) of the title compound. mp 198-200 ~C; 1H NMR (DMSO-d6) d: 2.7 (s, 3H, CH3), 3.2 (t, 2H, CH2), 4.3 (t, 2H, CH2), 7.2 (m, 3H, Ar-H) and 9.4 (bs, 2H, N+H2);
Anal CgH1,CI2NO HCI by C,H,N.
In a like manner, the following additional compounds were prepared:
(b) 2-(2,3-Dichlorophenoxy)-N-phenethylethaneamine Hydrochloride, from phenethylamine amine. 54% yield, mp 192-193 ~C; Anal C16H17CI2NO HCI by C,H,N.
(c) N-Benzyl-2-(2,3-dichlorophenoxy)ethaneamine Hydrochloride, from benzylamine.51 % yield, mp 157-159 ~C; Anal C15H15CI2NO HCI by C,H,N.
(d) 2-(2,3-Dichlorophenoxy)-N,N-dimethylethaneamine Hydrochloride, from dimethylamine. 18% yield, mp 178-179 ~C; Anal C10H13CI2NO HCI by C,H,N.
(e) 4-[2-(2,3-Dichlorophenoxy)ethyl]morpholine, from morpholine. 46% yield, mp 246-248 ~C; Anal C12H15CI2NO2 HCI by C,H,N.
(f) 1 -[2-(2,3-Dichlorophenoxy)ethyl]pyrrolidine, from pyrrolidine. 31 % yield, mp 184-185 ~C; Anal C12H,5CI2NO HCI by C,H,N.
(g) 1 -[2-(2,3-Dichlorophenoxy)ethyl]piperidine, from piperidine. 30% yield, mp 214-215 ~C; Anal C13H17CI2NO HCI by C,H,N.
Example 2(a): 1-Bromo-2-(2-cyclopentylphenoxy)ethane CA 02238C.C.4 1998-0C.-26 Sodium methoxide (25% solution in methanol, 0.69 g, 3.2 mmol) was added to 2-cyclopentylphenol (0.4 g, 2.5 mmol) in methanol (5 mL) and allowed to stand at room temperature for 30 minutes. After removal of the solvent in vacuo, acetonitrile was added to the solid. The sodium-2-cyclopentyl-phenolate in acetonitrile was then added dropwise to 1,2-dibromoethane (2.3 g,12.0 mmol) in a screw-top test tube and the sealed tube was heated at 100 ~C for 12 hours and then 130 ~C for and additional 12 hours. The solvent was removed in vacuo and petroleum ether (bp 60-90 ~C) (5 mL) and aqueous sodiumhydroxide (2N,3 mL) were added to the residue. The aqueous layerwas removed and the organic portion was extracted once more with aqueous sodium hydroxide (2N,3 mL). The petroleum ether portion was dried over magnesium sulfate and solvent removed in vacuo to yield an oil. Kugelhohr distillation of the oil (bp 52-70 ~C, 0.05 mm Hg) yielded 0.23 g (35%) of 1-bromo-2-(2-cyclopentylphenoxy)ethane as a clear oil. 'H NMR (CDCI3, free base) d: 1.3-2.2 (bm,8H, CH2 cyclopentyl),3.2-3.5 (m,1 H, CH),3.6 (t J = 4 Hz,2H, CH2N), 4.3 (t J = 4 Hz, 2H, CH2O) and 6.7-7.3 (m, 4H, ArH).
In a like manner, the following addition compound was prepared:
(b) 1 -Bromo-3-(2-cyclopentylphenoxy)propane, from 1,2-dibromopropane. bp 52-70 ~C
(0.07 mm Hg); 'H NMR (CDCI3, free base) d: 1.3-2.2 (m, 8H, CH2 cyclopentyl),2.2-2.5 (m J=4Hz,2H,CCH2C),3.2-3.5(m,1H,CH),3.6(tJ=4Hz,2H,CH2N),4.1 (tJ=4Hz,2H, CH2O) and 6.7-7.3 (m, 4H, ArH).
Example 3(a): 2-(2-Cyclopentylphenoxy)-N-methyl-N-(n-propyl)ethaneamine Hydrochloride A solution of 1-bromo-2-(2-cyclopentylphenoxy)ethane (Example 2a, 0.23 g, 0.85 mmol) and N-methylpropaneamine (1.0 g,14.0 mmol) were combined in acetonitrile (1 mL) and heated in a sealed tube at 60 ~C for 24 hours. The reaction mixture was allowed to cool and the N-methylpropaneamine and acetonitrile were recovered by distillation. An ethereal solution of the resulting oil was washed with 1 N sodium hydroxide (3x 1 mL), then extracted with hydrochloric acid (3x 10 mL). The combined acidic fractions were basified to pH 12 with a saturated solution of potassium hydroxide and extracted with ether (3x 15 CA 02238~4 1998-0~-26 mL). Thecombinedetherfractionsweredriedovermagnesiumsulfateandthesolventwas evaporated in vacuo. An ethereal solution of the free base was treated with hydrochloric acid in ether until the salt formation ceased. The salt was collected by filtration and recrystallized from 2-butanone to yield the title compound as a white solid (0.1 g, 40%). mp 193-195 ~C; 'H NMR (CDCI3, free base) d: 0.9 (t, 3H, CH3), 1.0-2.5 (m, 12H), 2.8 (t J = 3 Hz, 2H, CH2N), 3.0-3.5 (m, 1 H, CH), 4.1 (t J = 3 Hz, 2H, CH2O), 6.8-7.2 (m, 4H, ArH); IR
(CHCI3): 2959, 2879, 2578, 2475, 1501, 1477, 1452, 1238, 747 cm~'; Anal C17H27NO HCI
by C,H,N.
In a like manner, the following additional compound was prepared:
(b) 3-(2-Cyclopentylphenoxy)-N-methyl-N-(n-propyl)propaneamine Hydrogen Oxalate,from 1-bromo-3-(2-cyclopentylphenoxy)propane (Example2b)and oxalicacid. mp 136-138 ~C; 'H NMR (CDCI3, free base) d: 0.9 (t, 3H, CH3), 1.2 (m, 19H), 3.1-3.5 (m, 1H, CH), 4.0 (t, 2H, CH2O), 6.7-7.3 (m, 4H, ArH); IR (CHCI3): 3443, 3400 (NH+), 2955 (CH), 2500 (NH+), 1609 (COO~), 1245 (ArOC), 723 (ortho disubstituted benzene) cm~'; Anal C18H2gNO C2H2O4 by C,H,N.
CA 02238~4 1998-0~-26 Summary of Exemplified Compounds Example # R' R2 R3 n 1 a Cl Cl -NHCH3 1 b Cl Cl-NHCH2CH2Ph 1 c Cl Cl -NHCH2Ph 1 d Cl Cl -N(CH3)2 1 e Cl Cl ~
--N~O
1 f Cl Cl /~~ 1 _N~,~
1 g Cl Cl --N~,~
3a ~ H _N~CH3 ~r CH3 3b ~ H _N~CH3 2 ~r CH3 Example 4: Agonist Assay The in vitro evaluation of the 5-HT,D-like receptor agonist activity of the compounds of the invention was carried our by testing the extent to which they mimic sumatriptan in contracting the rabbit saphenous vein (Perez, M. et a/. J. Med. Chem.
1995, 38:3602-3607).
CA 02238 7 74 1998 - O, - 26 Tissues were obtained from male New Zealand White rabbits (~3-4 kg) which were sacrificed by an overdose of pentobarbital. The saphenous veins from both the left and right side were cleaned of fat and connective tissue and placed in Krebs solution (118 mM NaCI, 11 mM glucose, 25 mM NaHCO3, 4.7 mM KCI, 2.5 mM
CaCI2 2H20, 1.2 mM KH2PO4, and 1.2 mM MgSO4 7H2O. Ring segments of the vein (4-5mm in length) were cut and the endothelium gently removed. The segments were mounted in 10 mL baths containing Krebs buffer and were constantly aerated with 95%
oxygen/5% carbon dioxide and maintained at 37~C and pH 7.4 in order to record the isometric tension. A resting tension of 2.5 9 was applied and the tissues allowed to equilibrate for 90 minutes, with washing every 15-20 minutes. After the equilibrium period, the rings were depolarized by the addition of two aliquots of KCI (80 mM final concentration) separated by a 20 minute washing period. The tissues were then exposed to prazosin, idazoxan and indomethacin (all 1 mM final concentration) for 30 minutes in order to exclude the actions of a1- and a2-adrenergic receptors and prostaglandin receptors respectively. Cumulative concentration-effect curves were then constructed for sumatriptan and the test compounds. Responses were calculated asa percentage of the maximal contraction evoked by 80 mM KCI. Only one compound was tested per preparation.
The following Table illustrates the in vitro activities for a compound of the invention on the rabbit isolated saphenous vein. EC50 represents the concentration of the compound which causes 50% of the maximum contraction effected by it.
Compound EC~n (mM) sumatriptan 0.22 Example 1b 1.2
Claims (20)
1. A compound according to Formula I:
wherein R1 is selected from halo and cycloalkyl;
R2 is selected from halo and H;
R3 is selected from a group of formula III and IV:
wherein R4 and R5 are independently selected from H, C1-6alkyl and arylalkyl;
Y is selected from O and CH2;
and m and n are independently 1 or 2;
with the provisos that:
One of R4 or R5 is not isopropyl when the other is H, R1 and R2 are both chloro and n is 1;
One of R4 or R5 is not benzyl when the other is methyl, R1 and R2 are both chloro and n is 1;
R1 is not cyclohexyl when R2 is H, R4 and R5 are both ethyl and n is 1 or 2; and One of R4 or R5 is not 3,4-dichlorobenzyl or 2,5-dichlorobenzyl when the other is H, R1 and R2 are both chloro and n is 1.
wherein R1 is selected from halo and cycloalkyl;
R2 is selected from halo and H;
R3 is selected from a group of formula III and IV:
wherein R4 and R5 are independently selected from H, C1-6alkyl and arylalkyl;
Y is selected from O and CH2;
and m and n are independently 1 or 2;
with the provisos that:
One of R4 or R5 is not isopropyl when the other is H, R1 and R2 are both chloro and n is 1;
One of R4 or R5 is not benzyl when the other is methyl, R1 and R2 are both chloro and n is 1;
R1 is not cyclohexyl when R2 is H, R4 and R5 are both ethyl and n is 1 or 2; and One of R4 or R5 is not 3,4-dichlorobenzyl or 2,5-dichlorobenzyl when the other is H, R1 and R2 are both chloro and n is 1.
2. A compound according to claim 1, wherein R1 and R2 are both chloro.
3. A compound according to claim 2, wherein R3 is a group of Formula III.
4. A compound according to claim 3, wherein one of R4 and R5 is selected from C1-6alkyl and arylalkyl and the other is H.
5. A compound according to claim 4, wherein one of R4 and R5 is selected from methyl, benzyl and phenethyl and the other is H.
6. A compound according to claim 3, wherein R4 and R5 are both C1-6alkyl.
7. A compound according to claim 2, wherein R3 is a group of Formula IV.
8. A compound according to claim 7, wherein Y is O.
9. A compound according to claim 7, wherein Y is CH2.
10. A compound according to claim 1, wherein R1 is cycloalkyl and R2 is H..
11. A compound according to claim 10, wherein R1 is cyclopentyl.
12. A compound according to claim 11, wherein R3 is a group of Formula III.
13. A compound according to claim 12, wherein R4 and R5 are both C1-6alkyl.
14. A compound according to claim 1, selected from:
2-(2,3-Dichlorophenoxy)-N-methylethaneamine;
2-(2,3-Dichlorophenoxy)-N-phenethylethaneamine;
N-Benzyl-2-(2,3-dichlorophenoxy)ethaneamine;
2-(2,3-Dichlorophenoxy)-N,N-dimethylethaneamine;
4-[2-(2,3-Dichlorophenoxy)ethyl]morpholine;
1-[2-(2,3-Dichlorophenoxy)ethyl]pyrrolidine;
1-[2-(2,3-Dichlorophenoxy)ethyl]piperidine;
2-(2-Cyclopentylphenoxy)-N-methyl-N-(n-propyl)ethaneamine; and 3-(2-Cyclopentylphenoxy)-N-methyl-N-(n-propyl)propaneamine.
2-(2,3-Dichlorophenoxy)-N-methylethaneamine;
2-(2,3-Dichlorophenoxy)-N-phenethylethaneamine;
N-Benzyl-2-(2,3-dichlorophenoxy)ethaneamine;
2-(2,3-Dichlorophenoxy)-N,N-dimethylethaneamine;
4-[2-(2,3-Dichlorophenoxy)ethyl]morpholine;
1-[2-(2,3-Dichlorophenoxy)ethyl]pyrrolidine;
1-[2-(2,3-Dichlorophenoxy)ethyl]piperidine;
2-(2-Cyclopentylphenoxy)-N-methyl-N-(n-propyl)ethaneamine; and 3-(2-Cyclopentylphenoxy)-N-methyl-N-(n-propyl)propaneamine.
15. A compound according to claim 14, selected from:
2-(2,3-Dichlorophenoxy)-N-phenethylethaneamine;
2-(2,3-Dichlorophenoxy)-N,N-dimethylethaneamine;
N-Benzyl-2-(2,3-dichlorophenoxy)ethaneamine;
2-(2-Cyclopentylphenoxy)-N-methyl-N-(n-propyl)ethaneamine; and 3-(2-Cyclopentylphenoxy)-N-methyl-N-(n-propyl)propaneamine.
2-(2,3-Dichlorophenoxy)-N-phenethylethaneamine;
2-(2,3-Dichlorophenoxy)-N,N-dimethylethaneamine;
N-Benzyl-2-(2,3-dichlorophenoxy)ethaneamine;
2-(2-Cyclopentylphenoxy)-N-methyl-N-(n-propyl)ethaneamine; and 3-(2-Cyclopentylphenoxy)-N-methyl-N-(n-propyl)propaneamine.
16. A compound according to claim 15, selected from:
2-(2,3-Dichlorophenoxy)-N-phenethylethaneamine;
3-(2-Cyclopentylphenoxy)-N-methyl-N-(n-propyl)propaneamine; and 2-(2,3-Dichlorophenoxy)-N,N-dimethylethaneamine.
2-(2,3-Dichlorophenoxy)-N-phenethylethaneamine;
3-(2-Cyclopentylphenoxy)-N-methyl-N-(n-propyl)propaneamine; and 2-(2,3-Dichlorophenoxy)-N,N-dimethylethaneamine.
17. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and, in an amount effective to stimulate a 5-HT1D- like receptor, a compound according to Formula II:
wherein R' is selected from halo and cycloalkyl;
R2 is selected from halo and H;
R3 is selected from a group of formula III and IV:
wherein R4 and R5 are independently selected from H, C, 6alkyl and arylalkyl;
Y is selected from O and CH2;
and m and n are independently 1 or 2.
wherein R' is selected from halo and cycloalkyl;
R2 is selected from halo and H;
R3 is selected from a group of formula III and IV:
wherein R4 and R5 are independently selected from H, C, 6alkyl and arylalkyl;
Y is selected from O and CH2;
and m and n are independently 1 or 2.
18. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, in an amount effective to stimulate a 5-HT,D- like receptor, a compound according to claim 14.
19. A method for treating a patient having a medical condition for which a 5-HT,Da receptoragonist is indicated, comprising the step of administering to the patient a pharmaceutical composition as defined in claim 17.
20. A method for treating a patient according to claim 19, wherein the medical condition is migraine.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US86436697A | 1997-05-28 | 1997-05-28 | |
| US08/864,366 | 1997-05-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2238554A1 true CA2238554A1 (en) | 1998-11-28 |
Family
ID=25343115
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2238554 Abandoned CA2238554A1 (en) | 1997-05-28 | 1998-05-26 | Aryloxyalkylamines with serotonin receptor activity |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2238554A1 (en) |
-
1998
- 1998-05-26 CA CA 2238554 patent/CA2238554A1/en not_active Abandoned
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