WO1998047868A1 - Heterocycle-containing urea derivatives as 5ht1a, 5ht1b and 5ht1d receptor antagonists - Google Patents

Heterocycle-containing urea derivatives as 5ht1a, 5ht1b and 5ht1d receptor antagonists Download PDF

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Publication number
WO1998047868A1
WO1998047868A1 PCT/EP1998/002264 EP9802264W WO9847868A1 WO 1998047868 A1 WO1998047868 A1 WO 1998047868A1 EP 9802264 W EP9802264 W EP 9802264W WO 9847868 A1 WO9847868 A1 WO 9847868A1
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formula
dimethylaminoethyl
group
compound
indol
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PCT/EP1998/002264
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French (fr)
Inventor
Laramie Mary Gaster
Paul Adrian Wyman
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Smithkline Beecham Plc
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Priority claimed from GBGB9707875.2A external-priority patent/GB9707875D0/en
Priority claimed from GBGB9801634.8A external-priority patent/GB9801634D0/en
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Publication of WO1998047868A1 publication Critical patent/WO1998047868A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel urea derivatives, processes for their preparation, and pharmaceutical compositions containing them.
  • WO 95/32967 and WO 97/07120 disclose a series of amide derivatives which are said to possess 5HTj rj receptor antagonist activity. These compounds are alleged to be of use in the treatment of various CNS disorders such as depression.
  • EPA 0533266/7/8 disclose a series of benzanilide derivatives which are said to possess 5-HTij) receptor antagonist activity.
  • a structurally distinct class of compounds have now been found to exhibit combined 5HTj j , 5HTI Q and 5HTID receptor antagonist activity. It is expected that such compounds will be useful for the treatment and prophylaxis of various CNS disorders with the advantage of a relatively fast onset of action.
  • the present invention therefore provides a compound of formula (I) or a salt thereof:
  • R a is a group of formula (i)
  • P* is phenyl, bicyclic aryl, a 5 to 7 membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur, or a bicyclic heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur;
  • R 1 is hydrogen, halogen, Cj. ⁇ alkyl, C3_6cycloalkyl, COCi.
  • R 9 , RlO and Rl 1 are independently hydrogen or Ci .galkyl and c is 1 to 4;
  • R2 is hydrogen, halogen, Ci .galkyl, C3_6cycloalkyl, C .gcycloalkenyl, Ci .galkoxy, C ⁇ _ galkanoyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO2R ⁇ , CONR ⁇ R ⁇ ,
  • P ⁇ and P ⁇ are independently phenyl, bicyclic aryl, a 5- to 7- membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur, or a bicyclic heterocyclic group containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur;
  • A is a bond or oxygen, S(O) m where m is 0 to 2, carbonyl, or CH2 or NR 4 where R 4 is hydrogen or Cj.galkyl;
  • R! is as defined above for formula (i) or is a 5 to 7-membered heterocyclic ring, containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur, optionally substituted by C1.5 alkyl, halogen or C1.5 alkanoyl);
  • R2 and R ⁇ are independently hydrogen, halogen, Ci .galkyl, C . ⁇ cycloalkyl,
  • L is a group of formula
  • V is oxygen or sulphur;
  • Q is an optionally substituted 5- to 7- membered carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur;
  • R c and Rd are independently hydrogen or Ci .galkyl;
  • Ry is a 5- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur, or Ry is a group of formula - NR e R ⁇ in which R e and Rf are independently hydrogen, C ⁇ .galkyl, or aralkyl;
  • R D is hydrogen, halogen, hydroxy, C ⁇ galkyl, trifluoromethyl, Cj.galkoxy or aryl; or R D together with G forms a group W as defined above; and n is 1 to 4.
  • Ci _6 lkyl groups whether alone or as part of another group may be straight chain or branched.
  • the term 'acyloxy' is used herein to describe a group -OC(O)C ⁇ .galkyl.
  • 'aryl' is used herein to describe, unless otherwise stated, a group such as phenyl.
  • 'aralkyl' is used herein to describe, unless otherwise stated, a group such as benzyl.
  • the bicyclic aryl group represented by pi, P ⁇ and/or P ⁇ , which may be partially saturated, is preferably naphthyl.
  • bicyclic heterocyclic rings containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur include quinoline, isoquinoline, indole, benzofuran and benzothiophene rings.
  • the heterocyclic groups can be linked to the remainder of the molecule via a carbon atom or, when present, a suitable nitrogen atom.
  • Examples of 5 to 7 membered heterocyclic rings containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur represented by P , P ⁇ and/or P ⁇ include thienyl, furyl, pyrrolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyrimidyl and pyrazinyl, preferably pyridyl.
  • R! is preferably a halogen atom for example, fluorine, chlorine or bromine, and R2 and/or R ⁇ are each preferably hydrogen, halogen for example a chloro group or a Ci . galkyl group for example a methyl group. a and b are each preferably 1 or 2.
  • A is preferably a bond or oxygen.
  • group L as defined above:
  • Y is preferably -NH-.
  • V is preferably oxygen.
  • G is preferably nitrogen and G is preferably a hydrogen atom or together with R D forms group W, preferably -(CH2)2 _ -
  • R D is preferably hydrogen or R together with G forms group W referred to above.
  • Q is a 6-membered carbocyclic ring or a 5- or 6 membered heterocyclic ring containing one or two heteroatoms.
  • Q together with the phenyl group to which it it attached, forms an indole, indoline, benzoxazine benzoxazole, benzopyran, tetrahydroquinoline or tetrahydronaphthalene ring.
  • Suitable optional substituents for the ring Q include groups Rl and R ⁇ as defined above , preferably hydrogen or methyl.
  • the group (CR c Rd) n -Ry can be linked to the group Q via a carbon atom or, when present, a suitable nitrogen atom.
  • R c and R ⁇ are preferably hydrogen.
  • Ry is preferably a pyrrolidinyl group or a dialkylamino (e.g.dimethylamino) group.
  • n is preferably 2.
  • Particularly preferred compounds according to the invention include :-N-(4- bromo-3-methylphenyl)-N'-[3-(2-dimethylaminoethyl)indol-5-yl]urea, N- [3 -(2-dimethy laminoethy l)indol-5 -yl] -N'- [3 -methy l-4-(pyridin-4-yl)phenyl]urea, N-[3-(2-dimethylaminoethyl)indol-5-yl]-N'-[2'-methyl-4'-(5-methyl-l,2,4-oxadiazol-3- yl)-4-biphenyl]urea,
  • Preferred salts of the compounds of formula (I) are pharmaceutically acceptable salts. These include acid addition salts such as hydrochlorides, hydrobromides, phosphates, acetates, fumarates, maleates, tartrates, citrates, oxalates, methanesulphonates and p-toluenesulphonates. Certain compounds of formula (I) are capable of existing in stereoisomeric forms.
  • Ra _ ⁇ _ ( C 0) - L2 (V) in which R a is as defined in formula (I), Y is -CH2" or -O- and ⁇ J- is an appropriate leaving group, with a compovmd of formula (III)
  • reaction in process (a) is conveniently effected in an organic solvent such as dichloromethane.
  • the urea forming agent can be carbonyl diimidazole, triphosgene or phosgene, and carried out in an inert organic solvent such as dimethylformamide, tetrahydrofiiran or dichloromethane at ambient or elevated temperature in the presence of a base such as triethylamine or pyridine.
  • the leaving group L ⁇ may be a halogen e.g. chloro group and the reaction may be carried out in an inert organic solvent such as tetrahydrofiiran or dichloromethane at ambient or elevated temperature in the presence of a base such as triethylamine or pyridine.
  • an inert organic solvent such as tetrahydrofiiran or dichloromethane
  • a base such as triethylamine or pyridine.
  • the leaving group O- may be a halogen e.g. chloro group and the reaction may be carried out in an inert organic solvent such as tetrahydrofuran or dichloromethane at ambient or elevated temperature in the presence of a base such as triethylamine or pyridine.
  • a base such as triethylamine or pyridine.
  • Carboxylic acid groups can be protected as esters.
  • Aldehyde or ketone groups can be protected as acetals, ketals, thioacetals or thioketals. Deprotection is achieved using standard conditions.
  • 5HTj A/IB/ID receptor antagonists are expected to be of use in the treatment of CNS disorders such as mood disorders, including depression, seasonal affective disorder and dysthymia; anxiety disorders, including generalised anxiety, panic disorder, agoraphobia, social phobia, obsessive compulsive disorder and post-traumatic stress disorder; memory disorders, including dementia, amnestic disorders and age-associated memory impairment; disorders of eating behaviours, including anorexia nervosa and bulimia nervosa ;and sleep disorders (including disturbances of Circadian rhythm).
  • CNS disorders include motor disorders such as Parkinson's disease, dementia in Parkinson's disease, neuroleptic- induced Parkinsonism and tardive dyskinesias, as well as other psychiatric disorders.
  • 5HT ⁇ pj ⁇ B/1D receptor antagonists may also be of use in the treatment of endocrine disorders such as hyperprolactinaemia, in the treatment of vasospasm (particularly in the cerebral vasculature) and hypertension, as well as disorders in the gastrointestinal tract where changes in motility and secretion are involved. They may also be of use in the treatment of sexual dysfunction and hypothermia.
  • the present invention also provides a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in the treatment of the aforementioned disorders.
  • the invention provides a method of treating the aforementioned disorders which comprises administering an effective amount to a patient in need of such treatment of a compound of general formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • the invention provides a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in the treatment or prophylaxis of depression. It will be appreciated by those skilled in the art that the compounds according to the invention may advantageously be used in conjunction with one or more other therapeutic agents, for instance, different antidepressant agents.
  • the present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition of the invention which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.
  • Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colorants.
  • fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration.
  • suitable unit doses may be 0.05 to 1000 mg, more suitably 1.0 to 200 mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks or months.
  • suitable unit doses may be 0.05 to 1000 mg, more suitably 1.0 to 200 mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks or months.
  • the following Examples illustrate the preparation of compounds of the invention.
  • the mixture was cooled and a futher 0.02g of the palladium catalyst was added and the mixture heated to reflux for another 2 hours.
  • the mixture was cooled and treated with water (2ml) and ethyl acetate (30ml).
  • the layers were separated and the aqueous phase extracted with ethyl acetate (2x10ml).
  • the organic extracts were combined, dried (MgSO 4 ) and concentrated in vacuo.
  • the residue was purified by flash chromatography on silica gel, eluting with CH 2 Cl 2 /MeOH/NH 4 OH (100:10:1) to afford the title compound as a pale yellow powder (0.15g, 36%).
  • Example 4 N-[3-(2-Dimethylaminoethyl)-lH-indoI-5-yl]-N'-[naphth-l-yl]urea
  • the title compound was prepared from naphth-1-yl isocyanate and 5-amino-3-(2- dirnethylethyl)indole (Syn. Comm. 1993, 23, 65) using a similar procedure to Example 1.
  • Example 6 N-[3-(2-Dimethylaminoethyl)indol-5-yl]naphth-l-ylacetamide The title compound was prepared from naphth- 1 -ylacetic acid and 5-amino-3-(2- dimethylaminoethyl)indole (Syn. Comm. 1993, 23, 65) using a similar procedure to Example 5.
  • the title compound was prepared from 4-phenoxyphenyl isocyanate and 5-amino-3-(2- dimethylaminoethyl)-l-methylindole (D5) using a similar procedure to Example 1.
  • the title compound was prepared from 3-methyl-4-(pyridin-4-yl)phenyl isocyanate (D2) and 6-amino-3,4-dihydro-4-(2-dimethylaminoethyl)-2H-l,4-benzoxazine (D7 in WO 95/32967).
  • the title compound was prepared from 4-phenoxyphenyl isocyanate and 6-amino-3,4- dihydro-4-(2-dimethylaminoethyl)-2H-l,4-benzoxazine (D7 in WO 95/32967).
  • Example 13 The title compound was isolated as the hydrochloride salt as a yellow powder (0.07g).
  • the title compound was prepared from 6-amino-l-(2-dimethylaminoethyl)indole (D2 in WO 95/32967, 0.15g, 0.74 mmole), 4-(pyridin-4-yl)naphth-l -ylamine (D6, 0.18g, 0.8 mmole), triphosgene (0.10g, 0.33 mmole) in dichloromethane (30 ml) following a similar procedure to Example 13. The product was isolated after chromatography on silica gel eluting with 2- 5% MeOH in CH2CI2 (gradient elution) as a cream powder (0.20g).
  • the title compound was prepared from 7-amino-l-(2-dimethylaminoethyl)-l,2,3,4- tetrahydroquinoline (D10, 0.13g, 0.6 mmole), 4-(pyridin-4-yl)naphth-l -ylamine (0.17g, 0.77 mmole), triethylamine (0.14ml, 1.0 mmole) and triphosgene (0.09g, 0.31 mmole) in dichloromethane (50 ml). The title compound was isolated as the hydrochloride salt as a yellow powder (0.17g).
  • 5-HTJA, 5-HTIB and 5-HTJ D Receptor Binding HEK 293 cells expressing 5-HT ⁇ A receptors (4 x lONml) were homogenised in Tris buffer and stored in 1ml aliquots.
  • CHO cells expressing 5-HTJB receptors (4 x 10? cells/ml) were homogenised in Tris buffer and stored in 1.5 ml aliquots.
  • CHO cells expressing 5-HTJD receptors (0.563 x 10 ⁇ /ml) were homogenised in Tris buffer and stored in 1 ml aliquots.
  • Examples 1, 2, 3, 7, 9, 16, 17 and 18 had pKi values >8.0 at 5-HT ⁇ A , 5-HTi ⁇ and 5- HT1 j) receptors.

Abstract

Compounds of formula (I), in which Ra is a group of formula (i) in which P1 is phenyl, bicyclic aryl, a 5- to 7-membered heterocyclic ring or Ra is a group of formula (ii) wherein P?2 and P3¿ are independently phenyl, bicyclic aryl, a 5- to 7-membered heterocyclic ring or a bicyclic heterocyclic group; L is a group of formula -Y-C(=V)-DG- in which Y is -NH-, NR5 where R5 is C¿1-6?alkyl, or Y is -CH2- or -O-; V is oxygen or sulphur; D is nitrogen, carbon or a CH group, G is hydrogen or C1-6alkyl, R?y¿ is a 5- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur, or Ry is a group of formula -NReRf. The compounds have now been found to exhibit combined 5HT¿1A?, 5HT1B and 5HT1D receptor antagonist activity. It is expected that such compounds will be useful for the treatment and prophylaxis of various CNS disorders with the advantage of a relatively fast onset of action.

Description

HETEROCYCLE-CONTAINING UREA DERIVATIVES AS 5HTIA, 5HTIB AND 5HTID RECEPTOR ANTAGONISTS
The present invention relates to novel urea derivatives, processes for their preparation, and pharmaceutical compositions containing them. WO 95/32967 and WO 97/07120 disclose a series of amide derivatives which are said to possess 5HTj rj receptor antagonist activity. These compounds are alleged to be of use in the treatment of various CNS disorders such as depression. EPA 0533266/7/8 disclose a series of benzanilide derivatives which are said to possess 5-HTij) receptor antagonist activity. A structurally distinct class of compounds have now been found to exhibit combined 5HTj j , 5HTI Q and 5HTID receptor antagonist activity. It is expected that such compounds will be useful for the treatment and prophylaxis of various CNS disorders with the advantage of a relatively fast onset of action. In a first aspect, the present invention therefore provides a compound of formula (I) or a salt thereof:
Figure imgf000003_0001
in which Ra is a group of formula (i)
Figure imgf000003_0002
in which P* is phenyl, bicyclic aryl, a 5 to 7 membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur, or a bicyclic heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur; R1 is hydrogen, halogen, Cj.βalkyl, C3_6cycloalkyl, COCi.βalkyl, Cj.galkoxy, hydroxy, hydroxyC \ .galkyl, hydroxyCι _6alkoxy, Cι_6alkoxyCι_6alkoxy, Ci .galkanoyl, nitro, trifluoromethyl, cyano, SR9, SOR9, SO2R9, SO2NR10R! *, CO2R10, CONR10Rπ, CO2NR10R1 1, CONRlO(CH2)cCO2Rn, (CH2)CNR10R1 1, (CH2)cCONRlθRl l, (CH2)cNRlOCORl l, (CH2)cCO2C1.6alkyl, CO2(CH2)cORl0, NR10R1 1 , NR10CO2R1 1, NR10CONR10RH , CR10=NOR1 1 , CNR10=NOR1 1 , where
R9, RlO and Rl 1 are independently hydrogen or Ci .galkyl and c is 1 to 4;
R2 is hydrogen, halogen, Ci .galkyl, C3_6cycloalkyl, C .gcycloalkenyl, Ci .galkoxy, C\_ galkanoyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO2R^, CONR^R^,
NR10R11 where R!0 and R1 1 axe as defined for R1; a is 1, 2 or 3; or Ra is a group of formula (ii)
Figure imgf000004_0001
wherein P^ and P^ are independently phenyl, bicyclic aryl, a 5- to 7- membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur, or a bicyclic heterocyclic group containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur; A is a bond or oxygen, S(O)m where m is 0 to 2, carbonyl, or CH2 or NR4 where R4 is hydrogen or Cj.galkyl;
R! is as defined above for formula (i) or is a 5 to 7-membered heterocyclic ring, containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur, optionally substituted by C1.5 alkyl, halogen or C1.5 alkanoyl); R2 and R^ are independently hydrogen, halogen, Ci .galkyl, C .βcycloalkyl,
C3_6cycloalkenyl, C1 _5alkoxy, Cj.galkanoyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO2R10, CONR^R11, NR10R! 1 where R10 and R11 are as defined for Rl; and a and b are independently 1, 2 or 3;
L is a group of formula
- Y - C (=V) - DG - in which Y is - NH -, NR5 where R5 is C^galkyl, or Y is - CH2 - or - O -;
V is oxygen or sulphur; D is nitrogen, carbon or a CH group, G is hydrogen or C1.galkyl, providing that D is nitrogen or a CH group, or G together with RD forms a group W where W is (CR^Rl7)t where t is 2, 3 or 4 and Rl6 and R^ are independently hydrogen or C^alkyl or W is (CR16R17)U-J where u is 0, 1, 2 or 3 and J is oxygen, sulphur, CR16=CR17, CR16=N, =CR16O, =CR16S or CRlβ-NR1?;
Q is an optionally substituted 5- to 7- membered carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur; Rc and Rd are independently hydrogen or Ci .galkyl;
Ry is a 5- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur, or Ry is a group of formula - NReR^ in which Re and Rf are independently hydrogen, C \ .galkyl, or aralkyl;
RD is hydrogen, halogen, hydroxy, Cμgalkyl, trifluoromethyl, Cj.galkoxy or aryl; or RD together with G forms a group W as defined above; and n is 1 to 4.
Ci _6 lkyl groups whether alone or as part of another group may be straight chain or branched. The term 'acyloxy' is used herein to describe a group -OC(O)Cι .galkyl.
The term 'aryl' is used herein to describe, unless otherwise stated, a group such as phenyl. The term 'aralkyl' is used herein to describe, unless otherwise stated, a group such as benzyl.
The bicyclic aryl group represented by pi, P^ and/or P^, which may be partially saturated, is preferably naphthyl.
Examples of bicyclic heterocyclic rings containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur include quinoline, isoquinoline, indole, benzofuran and benzothiophene rings. The heterocyclic groups can be linked to the remainder of the molecule via a carbon atom or, when present, a suitable nitrogen atom. Examples of 5 to 7 membered heterocyclic rings containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur represented by P , P^ and/or P^, include thienyl, furyl, pyrrolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyrimidyl and pyrazinyl, preferably pyridyl.
R! is preferably a halogen atom for example, fluorine, chlorine or bromine, and R2 and/or R^ are each preferably hydrogen, halogen for example a chloro group or a Ci . galkyl group for example a methyl group. a and b are each preferably 1 or 2.
A is preferably a bond or oxygen. In the group L, as defined above:-
Y is preferably -NH-.
V is preferably oxygen.
D is preferably nitrogen and G is preferably a hydrogen atom or together with RD forms group W, preferably -(CH2)2_-
_ _
RD is preferably hydrogen or R together with G forms group W referred to above.
Suitably Q is a 6-membered carbocyclic ring or a 5- or 6 membered heterocyclic ring containing one or two heteroatoms. Preferably Q, together with the phenyl group to which it it attached, forms an indole, indoline, benzoxazine benzoxazole, benzopyran, tetrahydroquinoline or tetrahydronaphthalene ring. Suitable optional substituents for the ring Q include groups Rl and R^ as defined above , preferably hydrogen or methyl. The group (CRcRd)n-Ry can be linked to the group Q via a carbon atom or, when present, a suitable nitrogen atom.
Rc and R^ are preferably hydrogen.
Ry is preferably a pyrrolidinyl group or a dialkylamino (e.g.dimethylamino) group. n is preferably 2.
Particularly preferred compounds according to the invention include :-N-(4- bromo-3-methylphenyl)-N'-[3-(2-dimethylaminoethyl)indol-5-yl]urea, N- [3 -(2-dimethy laminoethy l)indol-5 -yl] -N'- [3 -methy l-4-(pyridin-4-yl)phenyl]urea, N-[3-(2-dimethylaminoethyl)indol-5-yl]-N'-[2'-methyl-4'-(5-methyl-l,2,4-oxadiazol-3- yl)-4-biphenyl]urea,
N-[3-(2-dimethylaminoethyl)indol-5-yl]-N'-[naphth- 1 -yljurea, 4-bromo-N-[3-(2-dimethylaminoethyl)indol-5-yl]phenylacetamide, N-[3-(2-dimethylaminoethyl)indol-5yl]naphth- 1 -ylacetamide, N-[3-(2-dimethylaminoethyl)indol-5-yl]-N'-[4-phenoxyphenyl]ureaN-[4-bromo-3- methylphenyl]-N'-[3-(2-dimethylaminoethyl)-l-methyl-indol-5-yl]urea,
N-[3-(2-dimethylaminoethyl)indol-5yl]-N'-[4-(pyridin-4-yl)naphthyl-l-yl)]urea, N-[3-(2-dimethylaminoethyl)-l-methyl-indol-5-yl]-N'-[4-phenoxyphenyl]urea, N-[4-(2-Dimethylaminoethyl)-3,4-dihydro-2H-l,4-benzoxazin-6-yl]-N'- [3-methyl-4- (pyridin-4-yl)pheny 1] urea,
N-[4-(2-Dimethylaminoethyl)-3 ,4-dihydro-2H- 1 ,4-benzoxazin-6-yl]-N'-[4- phenoxypheny 1] urea, N-[4-(2-dimethylaminoethyl)-3,4-dihydro-2H- 1 ,4-benzoxazin-6-yl]-N -[4-(pyridin-4- yl)naphth-l-yl]urea,N-[2,3-dichlorophenyl]-N-[4-(2-dimethylaminoethyl)-3,4-dihydro- 2H- 1 ,4-benzoxazin-6-yl]urea,
N-[4-(2-Dimethylaminoethyl)-2H-3-oxo-l,4-benzoxazin-6-yl]-N'-[4-(pyridin-4- yl)naphth- 1 -yljurea, N-[2,3-Dichlorophenyl]-N'-[l-(2-dimethylaminoethyl)indol-6-yl]urea,
N-[l -(2-Dimethylaminoethyl)indol-6-yl]-N'-[4-(pyridin-4-yl)naphth- 1 -yljurea, 2,3-Dihydro-N-[l -(2-dimethylaminoethyl)- lH-indol-5-yl]-N'-[4-(pyridin-yl)- 1 - naphthyl]urea,
N-[2,3-Dichlorophenyl]-N -[l-(2-dimethylaminoethyl)-l,2,3,4-tetrahydroquinolin-7- yljurea,
N-[l-(2-Dimethylaminoethyl-l,2,3,4-tetrahydroquinolin-7-ylJ-N'-[4-(pyridin-4-yl)naphth- 1 -yljurea,
N-[l-(2-Dimethylaminoethyl)-l,2,3,4-tetrahydronaphth-7-yl]-N'-[4-(pyridin-4-yl)naphth- 1 -yljurea or pharmaceutically acceptable salts thereof.
Preferred salts of the compounds of formula (I) are pharmaceutically acceptable salts. These include acid addition salts such as hydrochlorides, hydrobromides, phosphates, acetates, fumarates, maleates, tartrates, citrates, oxalates, methanesulphonates and p-toluenesulphonates. Certain compounds of formula (I) are capable of existing in stereoisomeric forms.
It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and the mixtures thereof including racemates.
Compounds of the invention can be prepared using procedures known in the art. In a further aspect the present invention provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof which comprises: (a) where D is nitrogen and Y is NH, coupling a compound of formula (II):
Ra -NC(=N) (ID in which Ra and V are as defined in formula (I) or a protected derivative thereof with a compound of formula (III).
Figure imgf000008_0001
in which R°, Rc, R^, Ry, G, Q and n are as defined in formula (I), or a protected derivative thereof; or (b) where D is nitrogen and Y is NH or NR^, reacting a compound of formula (IV)
Ra -NH2 or R -NR5H (IV) in which Ra and R^ are as defined in formula (I) with a compound of formula (III) together with an appropriate urea forming agent;
(c) where D is nitrogen, reacting a compound of formula (V)
Ra _γ_ (C=0) - L2 (V) in which Ra is as defined in formula (I), Y is -CH2" or -O- and \J- is an appropriate leaving group, with a compovmd of formula (III)
(d) where D is carbon or CH, reacting a compound of formula (VI)
R -NH2 (VI) in which Ra is as defined in formula (I) with a compound of formula (VII)
Figure imgf000008_0002
in which D is carbon or CH, Rb, RC, Rd? Ry? ? Q Q^ n ^ as defined in formula (I) and L,2 is an appropriate leaving atom and optionally thereafter:
• removing any protecting groups,
• converting a compound of formula (I) into another compound of formula (I),
• forming a pharmaceutically acceptable salt. The reaction in process (a) is conveniently effected in an organic solvent such as dichloromethane.
In process (b) the urea forming agent can be carbonyl diimidazole, triphosgene or phosgene, and carried out in an inert organic solvent such as dimethylformamide, tetrahydrofiiran or dichloromethane at ambient or elevated temperature in the presence of a base such as triethylamine or pyridine.
In process (c) the leaving group L^ may be a halogen e.g. chloro group and the reaction may be carried out in an inert organic solvent such as tetrahydrofiiran or dichloromethane at ambient or elevated temperature in the presence of a base such as triethylamine or pyridine.
In process (d) the leaving group O- may be a halogen e.g. chloro group and the reaction may be carried out in an inert organic solvent such as tetrahydrofuran or dichloromethane at ambient or elevated temperature in the presence of a base such as triethylamine or pyridine. Compounds of formula (I) can be converted into further compounds of formula (I) using standard techniques.
Intermediate compounds of formula (II), (III), (IV), (V), (VI) and (VII) can be prepared using standard procedures known in the art.
It will be appreciated to those skilled in the art that it may be necessary to protect certain reactive substituents during some of the above procedures. Standard protection and deprotection techniques can be used. For example, primary amines can be protected as phthalimide, benzyl, benzyloxycarbonyl or trityl derivatives. These groups can be removed by conventional procedures well known in the art.
Carboxylic acid groups can be protected as esters. Aldehyde or ketone groups can be protected as acetals, ketals, thioacetals or thioketals. Deprotection is achieved using standard conditions.
5HTj A/IB/ID receptor antagonists, and in particular the compounds of the present invention, are expected to be of use in the treatment of CNS disorders such as mood disorders, including depression, seasonal affective disorder and dysthymia; anxiety disorders, including generalised anxiety, panic disorder, agoraphobia, social phobia, obsessive compulsive disorder and post-traumatic stress disorder; memory disorders, including dementia, amnestic disorders and age-associated memory impairment; disorders of eating behaviours, including anorexia nervosa and bulimia nervosa ;and sleep disorders (including disturbances of Circadian rhythm). Other CNS disorders include motor disorders such as Parkinson's disease, dementia in Parkinson's disease, neuroleptic- induced Parkinsonism and tardive dyskinesias, as well as other psychiatric disorders.
5HTι pj\ B/1D receptor antagonists, and in particular compounds of the present invention, may also be of use in the treatment of endocrine disorders such as hyperprolactinaemia, in the treatment of vasospasm (particularly in the cerebral vasculature) and hypertension, as well as disorders in the gastrointestinal tract where changes in motility and secretion are involved. They may also be of use in the treatment of sexual dysfunction and hypothermia. The present invention also provides a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in the treatment of the aforementioned disorders.
In a further aspect the invention provides a method of treating the aforementioned disorders which comprises administering an effective amount to a patient in need of such treatment of a compound of general formula (I) or a pharmaceutically acceptable salt or solvate thereof.
In particular the invention provides a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in the treatment or prophylaxis of depression. It will be appreciated by those skilled in the art that the compounds according to the invention may advantageously be used in conjunction with one or more other therapeutic agents, for instance, different antidepressant agents.
The present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
A pharmaceutical composition of the invention, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.
Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents. The tablets may be coated according to methods well known in normal pharmaceutical practice.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colorants.
For parenteral administration, fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
The composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration.
The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. However, as a general guide suitable unit doses may be 0.05 to 1000 mg, more suitably 1.0 to 200 mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks or months. The following Examples illustrate the preparation of compounds of the invention.
Description 1 2'-Methyl-4'-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-isocyanate A stirred suspension of 2'-methyl-4'-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4- carboxylic acid (3.0g, 0.010 mole, EP 0533268A1) in dichloromethane (80ml) was treated with oxalyl chloride (1.3ml, 0.015 mole) and DMF (1 drop), then stirred at room temp for 4 hours. The resulting solution was concentrated in vacuo to afford the acid chloride as a yellow solid. This was dissolved in dichloromethane (100ml) and cooled to 0°C. To this was added tetrabutylammonium iodide (50mg) followed by a solution of sodium azide (0.91g, 0.014 mole) in water (20ml) and the mixture stirred vigorously for 3 hours. The mixture was then diluted with water (75ml) and the dichloromethane layer separated, dried (Na2SO4) and concentrated in vacuo but not to dryness. The residue was dissolved in toluene (150ml) and heated under reflux with stirring for 1.5 hours. The toluene was removed in vacuo to afford the title compound as a pale orange solid (3.15g, 100%). 1H NMR (250MHz, CDC13) δ (ppm):7.90 (s, IH), 7.85 (dd, IH), 7.25 (d, 2H and d, IH),
7.10 (d, 2H), 2.61 (s, 3H), 2.26 (s, 3H).
Description 2 4-Bromo-3-methylphenyl isocyanate
The title compound was prepared from 4-bromo-3-methylbenzoic acid using a similar procedure to Description 1. 1H NMR (250MHz, CDC13) δ (ppm): 7.54 (d, IH), 7.06 (d, IH), 6.88 (dd, IH), 2.46 (s, 3H).
Description 3 N,N-Dimethyl-l-methyl-5-nitroindole-3-glyoxamide To a stirred suspension of l-methyl-5-nitroindole (8.00g, 45 mmole) and phthalimide
(3.20g, 20% by weight) in anhydrous diethyl ether (150ml) and dichloromethane (150ml) was added dropwise oxalyl chloride (11.9ml, 17.32g, 136 mmole). The mixture was stirred at room temperature under argon for 96 hours, whereafter it was cooled to 5°C and 40% aqueous solution of dimethylamine (100ml) was slowly added. After stirring the mixture at room temperature for 1.5 hours it was filtered and the collected solid washed with water and CH2C12, then dried in vacuo to leave the title compound as a pale yellow solid (9.76g, 78%). 1H NMR (250MHz, d6DMSO) δ (ppm): 8.92 (s, IH), 8.43 (s, IH), 8.20 (dd, IH), 7.82 (d, IH), 3.93 (s, 3H), 2.97 (d, 6H).
Description 4 3-(2-DimethylaminoethyI)-l-methyl-5-nitroindole
To a stirred suspension of sodium borohydride (3.50g, 92 mmole) in anhydrous THF (200ml) at 0°C under argon, was added, in small portions, boron trifluoride diethyl etherate (17.8ml, 140 mmole). The mixture was stirred at 0°C for 15 minutes, and then at room temperature for 0.5h. It was then added, in small portions to a stirred suspension of N,N-dimethyl-l-methyl-5-nitroindole-3-glyoxamide (D3, 9.50g, 35 mmole) in anhydrous THF (200ml) under argon. The resultant suspension was stirred at room temperature for 18 hours, then 20% aqueous potassium carbonate (25ml) was cautiously added, and the mixture extracted with dichloromethane (3x75ml). The combined organic extracts were washed with water and dried (MgSO4) and evaporated under reduced pressure. The residue was suspended in ethanol (200ml) and cesium fluoride (lO.OOg) and potassium carbonate (lO.OOg) were added and the mixture heated to reflux for 16 hours. The cooled mixture was filtered and the filtrate evaporated to dryness under reduced pressure. The product was purified by flash chromatography on silica gel eluting with 5% MeOH in CH2C12 to afford the title compound as a bright yellow solid (3.53g, 41%). Η NMR (250MHz, CDC13) δ (ppm): 8.49 (d, IH), 8.05 (dd, IH), 7.20 (d, IH), 6.98 (s, IH), 3.73 (s, 3H), 2.90 (t, 2H), 2.59 (t, 2H), 2.26 (s, 6H).
Description 5 5-Amino-3-(2-dimethylaminoethyl)-l-methylindole A mixture of 3-(2-dimethylaminoethyl)-l-methyl-5-nitroindole (D4, 3.40g, 13.8 mmole) and 10% palladium on carbon (0.05g) in abs. ethanol (100ml) was shaken under hydrogen (initially at 50psi) for 16 hours. The mixture was filtered, and the filtrate evaporated to dryness to leave the title product as a thick, brown oil (3.02g, 100%). 1H NMR (250MHz, CDC13) δ (ppm):7.26 (d, IH), 7.05 (d, IH), 6.96 (s, IH), 6.86 (dd, IH), 3.83 (s, 3H), 3.05 (t, 2H), 2.79 (t, 3H), 2.50 (s, 6H).
Description 6 4-(Pyridin-4-yl)naphth-l-ylamine A stirred suspension of 4-bromonaphth-l-ylamine (lOg, 45 mmole) in 1,2- dimethoxyethane (400ml) and water (100ml) containing sodium carbonate (14g) was flushed with argon for 0.3h. Tetrakis (triphenylphosphine)palladium (0) (2.75g, 2.4 mmole) was added followed by 4-pyridylboronic acid (5.7g, 46 mmole) and the mixture heated at reflux for 5h. The mixture was concentrated in vacuo to a brown slurry and partitioned between dichloromethane and water. The aqueous was further extracted with dichloromethane and the combined organics dried (Na2SO4) and concentrated in vacuo to a brown solid (13.2g). Purification of the solid by flash chromatography eluting with ethyl acetate afforded the title compound as a yellow crystalline solid (7.8g, 78%). 1H NMR (250MHz, CDC13) δ (ppm): 8.68 (d, 2H), 7.90 (d, 2H), 7.30 (m, 5H), 6.84 (d, IH), 4.32 (s, 2H).
Description 7 l-(Chloroacetyl)-7-nitro-l,2,3,4-tetrahydroquinoline To a stirred solution of 7-nitro- 1,2,3 ,4-tetrahydroquinoline (1.87g, 10.5 mmole) and triethylamine (2.9 ml, 21 mmole) in dichloromethane (40 ml) at 0°C was added, dropwise, chloroacetylchloride (1.3 ml, 16 mmole). After 1 hr at 0°C the mixture was allowed to warm to room temperature.. After 6 hours water (20 ml) was added. The organic phase was separated washed with 2NHC1 (3x25 ml); dried (sodium sulphate) and evaporated to a pale brown oil, which solidified on standing, 2.23g.
Description 8 l-(2-Dimethylamino-l-oxoethyl)-7-nitro-l,2,3,4-tetrahydroquinoline
To a solution of l-(chloroacetyl)-7-nitro-l,2,3,4-tetrahydroquinoline (D7, 2.20g, 8.6 mmole) in dichloromethane (30 ml) was added a 2.0M solution of dimethylamine in methanol (30 ml). After stirring at room temperature for 4 hours the mixture was evaporated to dryness and the residue subjected to flash chromatography on silica gel eluting with MeOH in dichloromethane (l-» 3% MeOH, gradient). The title compound was isolated as a pale buff powder, 1.91g.
Description 9 7-Amino-l-(2-dimethylamino-l-oxoethyl)-l,2,3j4-tetrahydroquinoline A mixture of l-(2-dimethylamino-l-oxoethyl)-l,2,3,4-tetrahydroquinoline (D8, 1.90g, 7.2 mmole) and 10% palladium on carbon (0.25g) in methanol (100 ml) was stirred under hydrogen for 24 hours. The mixture was filtered and evaporated in vacuo to dryness. The residue was purified by flash chromatography on silica gel, eluting with 2% MeOH in CH2CI2. The title compound was isolated as a brown oil, 1.1 Og.
Description 10 7-Amino-l-(2-dimethylaminoethyI)-l,2,3,4-tetrahydroquinoline
To a stirred solution of 7-amino-l-(2-dimethylamino-l-oxoethyl)-l,2,3,4- tetrahydroquinoline (D9, 1.05g, 4.5 mmole) in anhydrous THF (50 ml), cooled to 0°C was added, in portions, lithium aluminium hydride (0.26g, 6.75 mmole). After 1 hour at 0°C the mixture was allowed to warm to room temperature and was then heated to reflux for 2 hours. It was then cooled to 5°C and water (15 ml) slowly added, followed by 2M NaOH (10 ml) and ethylacetate (50 ml). The organic phase was separated, washed with water, dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by flash chromatography on silica gel eluting with CH2Cl2/MeOH NH3(aq) (100:10:1). The title compound was obtained as a brown oil, 0.37g.
Description 11 2-(7-Amino-l,2,3»4-tetrahydronaphth-l-yI)-N,N-dimethyIacetamide
A mixture of 2-(7-nitro-3,4-dihydronaphth-l-yl-N,N-dimethylacetamide (1.90g, 7.3 mmole), 10% palladium on carbon (0.25g), methanol (100 ml) and DMF (10 ml) was shaken under hydrogen at 50 psi and 45°C for 24 hours. The cooled mixture was filtered and evaporated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 2% methanol in dichloromethane. The title compound was obtained as a pale brown oil, 1.32g.
Description 12 7-Amino-l-(2-dimethyIaminoethyl)-l,2,3,4-tetrahydronaphthalene To a stirred solution of 1 -(7-amino- 1 ,2,3,4-tetrahydronaphth- 1 -yl)-N,N- dimethylacetamide (Dl 1, 1.30g, 5.6 mmole) in anhydrous THF (50 ml) at 0°C under argon was added lithium aluminium hydride (0.43g, 11.2 mmole) over 20 minutes. The mixture was stirred at 0°C for 0.5 hour and then allowed to warm to room temperature as was subsequently heated to reflux for 3 hours. It was then cooled to 0°C and treated with water (15 ml) and 2M NaOH (10 ml), and then extracted with ethyl acetate (3 x 25 ml). The combined organic extracts were washed with water and brine, dried (over Na2SO4) and evaporated to dryness in vacuo. The residue was subjected to flash chromatography on silica gel eluting with CH2Cl2/MeOH/NH3 (100:10:1) to give the title compound as a pale brown oil, 0.70g.
Example 1 N-(4-Bromo-3-methylphenyl)-N,-[3-(2-dimethylaminoethyI)indol-5-yI]urea
To a stirred solution of 4-bromo-3-methylphenyl isocyanate (D2, 0.53g, 2.5 mmole) in dichloromethane (20ml) under argon, was added a solution of 5-amino-3-(2- dimethylaminoethyl)indole (0.51g, 2.5 mmole, Syn. Comm. 1993, 23, 65) in dichloromethane (15ml). The reaction mixture was stirred at room temperature for 18 hours. The mixture was filtered and the collected brown solid washed with dichloromethane and dried in vacuo to leave 0.9 lg (88%) of the crude title compound. This was purified by flash chromatography on silica gel eluting with CH2Cl2/MeOH/NH4OH (100:10:1) to afford the title compound as a pale yellow powder (0.72g, 79%). 1H NMR (250MHz,d6DMSO) δ (ppm): 10.54 (s, IH), 8.49 (s, IH), 8.33 (s, IH), 7.51 (s, IH), 7.34 - 7.10 (m, 4H), 6.98 - 6.88 (m, 2H), 2.64 (t, 2H), 2.40 (t, 2H), 2.18 (s, 3H), 2.09 (s, 6H).
Example 2 N-[3-(2-Dimethylaminoethyl)indol-5-yl]-N'-[3-methyl-4-(pyridin-4-yl)phenyl]urea A stirred mixture of N-(4-bromo-3-methylphenyl)-N'-[3-(2-dimethylaminoethyl)indol-5- yljurea (El, 0.42g, l .Ommole), 4-pyridylboronic acid (0.14g, 1.1 mole), anhydrous sodium carbonate (0.37g, 3.5mmole) and tetrakis(triphenylphosphine) palladium (0) (0.02g) in dimethoxyethane (16ml) and water (4ml) was heated to reflux, under argon, for 3 hours. The mixture was cooled and a futher 0.02g of the palladium catalyst was added and the mixture heated to reflux for another 2 hours. The mixture was cooled and treated with water (2ml) and ethyl acetate (30ml). The layers were separated and the aqueous phase extracted with ethyl acetate (2x10ml). The organic extracts were combined, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with CH2Cl2/MeOH/NH4OH (100:10:1) to afford the title compound as a pale yellow powder (0.15g, 36%).
Η NMR (250MHz, d6DMSO) δ (ppm): 10.52 (s, IH), 8.51 (s, IH), 8.43 (d, 2H), 8.32 (s, IH), 7.50 (s, IH), 7.27 (s, IH), 7.22 (d, 2H), 7.06 - 6.87 (m, 5H), 2.66 (t, 2H), 2.42 (t, 2H), 2.33 (CH3 obscurred by DMSO), 2.09 (s, 6H).
Example 3
N-[3-(2-Dimethylaminoethyl)indol-5-yl]-N'-[2'-methyl-4'-(5-methyl-l,2,4-oxadiazol- 3-y I)-4-bipheny 1] urea
The title compound was prepared from 2'-methyl-4'-(5-methyl-l,2,4-oxadiazol-3- yl)biphenyl-4-isocyanate (Dl) and 5-amino-3-(2-dimethylaminoethyl)indole (Syn, Comm., 1993, 23, 65) using a similar procedure to Example 1.
1H NMR (250MHz, d6DMSO) δ (ppm): 10.47 (s, IH), 8.51 (s, IH), 8.30 (s, IH), 7.73 (s, IH), 7.68 (d, IH), 7.47 (s, IH), 7.39 (d, 2H), 7.21 - 7.04 (m, 4H), 6.92 - 6.86 (m, 2H), 2.62 (m, 2H), 2.48 (s, 3H), 2.35 (CH2 obscurred by H2O), 2.16 (s, 3H), 2.03 (s, 6H).
Example 4 N-[3-(2-Dimethylaminoethyl)-lH-indoI-5-yl]-N'-[naphth-l-yl]urea The title compound was prepared from naphth-1-yl isocyanate and 5-amino-3-(2- dirnethylethyl)indole (Syn. Comm. 1993, 23, 65) using a similar procedure to Example 1. 1H NMR (250MHz, d6DMSO) δ (ppm): 10.87 (s, IH), 9.14 (s, IH), 8.93 (s, IH), 8.38 (d, IH), 8.27 (d, IH), 8.11 (d, IH), 7.90 (s, IH), 7.79 - 7.61 (m, 4H), 7.46 (d, IH), 7.30 (m, 2H), 2.97 (m, 2H), 2.77 (m, 2H), 2.41 (s, 6H).
Example 5
4-Bromo-N- [3-(2-dimethylaminoethy I)indol-5-yl] phenylacetamide
A stirred suspension of 4-bromophenylacetic acid (0.35g, l.όmmole) in toluene (20ml) was treated with thionyl chloride (0.35ml) and heated to reflux for lh. The solution was concentrated in vacuo to afford the acid chloride. This was dissolved in dichloromethane (10ml) and slowly added to a stirred solution of 5-amino-3-(2-dimethylaminoethyl)indole (0.30g, 1.5mmole, Syn. Comm. 1993, 23, 65) and triethylamine (0.27ml, 2.0mmole) in dichloromethane (10ml). The reaction mixture was stirred at room temperature for 2 hours, then washed successively with aqueous sodium carbonate solution, water and brine, dried (MgSO4) and concentrated in vacuo to a pale brown solid (0.50g, 83%). Recrystallisation from acetonitrile (5ml) afforded pure title compound (0.15g, 25%). 1H NMR (250MHZ, d6DMSO) δ (ppm): 10.85 (s, IH), 10.12 (s, IH), 7.95 (s, IH), 7.67 (d, 2H), 7.46 (d, 2H), 7.36 (d, 2H), 7.25 (s, IH), 3.75 (s, 2H), 2.92 (t, 2H), 2.64 (t, 2H), 2.36 (s, 6H)
Example 6 N-[3-(2-Dimethylaminoethyl)indol-5-yl]naphth-l-ylacetamide The title compound was prepared from naphth- 1 -ylacetic acid and 5-amino-3-(2- dimethylaminoethyl)indole (Syn. Comm. 1993, 23, 65) using a similar procedure to Example 5.
1H NMR (HC1 salt) (250MHz, d6DMSO) δ (ppm): 10.94 (s, IH), 10.26 (s, IH), 10.17 (br s, IH), 8.23 (d, IH), 7.95 (m, 2H), 7.85 (d, IH), 7.52 (m, 4H), 7.31 - 7.21 (m, 3H), 4.15 (s, 2H), 3.34 (CH2 obscurred by H2O), 3.05 (m, 2H), 2.79 (s, 6H).
Example 7 N-[3-(2-Dimethylaminoethyl)indoI-5-yl]-N,-[4-phenoxyphenyl]urea
The title compound was prepared from 4-phenoxyphenyl isocyanate and 5-amino-3-(2- dimethylaminoethyl)indole (Syn. Comm. 1993, 23, 65) using a similar procedure to Example 1.
1H NMR (250MHz, d6DMSO) δ (ppm): 10.75 (s, IH), 8.66 (s, IH), 8.50 (s, IH), 7.73 (s, IH), 7.58 (d, 3H), 7.47 (t, 2H), 7.30 (d, IH), 7.19 - 7.02 (m, 6H), 2.89 (m, 2H), 2.59 (CH2 obscurred by H2O), 2.31 (s, 6H).
Example 8
N-[4-Bromo-3-methylphenyl]-N'-[3-(2-dimethylaminoethyl)-l-methylindol-5-yl]urea To a stirred solution of triphosgene (0.22g, 0.74 mmole) in dichloromethane (20ml) was added a solution of 4-bromo-3-methylaniline (0.37g, 2.0 mmole) and triethylamine (0.31ml, 2.2 mmole) during 30 minutes. When the addition was complete the mixture was stirred at room temperature for 15 minutes, then a solution of 5-amino-3-(2- dimethylaminoethyl)-l-methylindole (D5, 0.40g, 1.80 mmole) in dichloromethane (10ml) was added. After lh the mixture was washed with aqueous sodium carbonate and water, dried (MgSO4) and evaporated to dryness. The residue was subjected to flash chromatography on silica gel eluting with dichloromethane/ethanol/aq. ammonia (100:8:1) to afford the title compound as a pale buff powder (0.39g, 51%). 1H NMR (250MHz, d6DMSO) δ (ppm): 8.43 (s, IH), 8.30 (s, IH), 7.46 (s, IH), 7.27 (m, 2H), 7.10 (t, 2H), 6.92 (m, 2H), 3.49 (s, 3H), 2.58 (t, 2H), 2.30 (t, 2H), 2.11 (s, 3H), 2.01 (s, 6H).
Example 9 N-[3-(2-Dimethylaminoethyl)indol-5-yl]-N'-[4-(pyridin-4-yI)naphthyl-l-yl) urea The title compound was prepared from 5-amino-3-(2-dimethylaminoethyl)indole (Syn.
Comm., 1993, 23, 65) and 4-(pyridin-4-yl)naphth-l-ylamine (D6) using the procedure described in Example 8.
1H NMR (250MHz, d6DMSO) δ (ppm): 10.76 (s, IH), 9.03 (s, IH), 8.94 (s, IH), 8.78 (d,
2H), 8.36 (m, 2H), 7.93 (d, IH), 7.80 - 7.52 (m, 6H), 7.37 (d, IH), 7.19 (s, 2H), 2.89 (t, 2H), 2.64 (t, 2H), 2.31 (s, 6H).
Example 10 N-[3-(2-Dimethylaminoethyl)-l-methyIindol-5-yl]-N'-[4-phenoxyphenyl]urea
The title compound was prepared from 4-phenoxyphenyl isocyanate and 5-amino-3-(2- dimethylaminoethyl)-l-methylindole (D5) using a similar procedure to Example 1.
1H NMR (250MHz, CDC13) δ (ppm):7.53 (s, IH), 7.32 - 7.26 (m, 5H), 7.15 - 7.05 (m, 2H), 6.96 - 6.91 (m, 5H), 6.65 (s, IH), 6.57 (s, IH), 3.74 (s, 3H), 2.92 (t, 2H), 2.63 (t, 2H), 2.31 (s, 6H).
Example 11
N-[4-(2-DimethyIaminoethyl)-3,4-dihydro-2H-l,4-benzoxazin-6-yl]-N'-[3-methyl-4- (py ridin-4-yl)phenyl] urea
The title compound was prepared from 3-methyl-4-(pyridin-4-yl)phenyl isocyanate (D2) and 6-amino-3,4-dihydro-4-(2-dimethylaminoethyl)-2H-l,4-benzoxazine (D7 in WO 95/32967).
Η NMR (HCl salt) (250MHz, d6 DMSO) δ: 10.27 (s, IH), 9.46 (s, IH), 8.98 (s, IH), 8.68 (d, 2H), 7.84 (d, 2H), 7.33 - 7.12 (m, 3H), 6.75 (s, IH), 6.40 (s, 2H), 3.92 (m, 4H), 3.40 (m, 2H), 3.12 (m, 2H), 2.64 (d, 6H), 2.11 (s, 3H). Example 12
N-[4-(2-Dimethylaminoethyl)-3,4-dihydro-2H-l,4-benzoxazin-6-yl]-N'-[4- phenoxyphenyl] urea
The title compound was prepared from 4-phenoxyphenyl isocyanate and 6-amino-3,4- dihydro-4-(2-dimethylaminoethyl)-2H-l,4-benzoxazine (D7 in WO 95/32967). 1H NMR (250MHz, d6DMSO) δ (ppm): 8.40 (s, IH), 8.18 (s, IH), 7.33 - 7.19 (m, 4H), 6.96 (t, IH), 6.86 - 6.77 (m, 5H), 6.72 (s, 2H), 3.95 (br s, 2H), 2.30 (t, 2H), 2.07 (s, 6H) (note - two -CH2- signals obscurred by H2O signal).
Example 13
N-[4-(2-Dimethylaminoethyl)-3,4-dihydro-2H-l,4-benzoxazin-6-yl]-N-[4-(pyridin-4- y l)naphth- 1 -y 1] urea
To a stirred solution of triphosgene (0.12g. 0.4 mmole) in dichloromethane (15ml) was added dropwise a solution of 4-(pyridin-4-yl)naphth- 1 -ylamine (D6, 0.24g, 1.0 mmole) and triethylamine (0.15ml, 1.1 mmole) in dichloromethane. After 0.5 hour a solution of 6-amino-3,4-dihydro-4-(2-dimethylaminoethyl)-2H-l,4-benzoxazine (0.22g, 1.0 mmole, D7 in WO 95/32967) in dichloromethane (10ml) was added. The resultant solution was left to stand overnight at room temperature, then washed with dilute potassium carbonate solution, dried (MgSO4) and evaporated to dryness. The residue was purified by flash chromatography on silica gel eluting with CH2Cl2/MeOH (100:10:1). The title compound, as the hydrochloride salt, was a bright yellow powder (0.25g, 46%). 1H NMR (HCl salt) (250MHz, d6DMSO) δ (ppm): 10.49 (s, IH), 10.04 (s, IH), 9.60 (s, IH), 8.86 (d, 2H), 8.60 (dd, IH), 8.23 (d, IH), 8.08 (d, 2H), 7.80 (dd, IH), 7.54 (m, 3H), 6.93 (d, IH), 6.61 - 6.48 (m, 2H), 4.02 (br s, 2H), 3.49 (t, 2H), 3.20 (m, 4H), 2.35 (d, 6H).
Example 14
N-[2,3-DichIorophenyl]-N -[4-(2-dimethylaminoethyI)-3.4-dihydro-2H-l,4- benzoxazin-6-y 1] urea To a stirred solution of 6-amino-3,4-dihydro-4-(2-dimethylaminoethyl)-2H-l,4- benzoxazine (0.1 lg, 0.5 mmole, D7 in WO 95/32967) in dichloromethane (10ml) under argon, was added a solution of 2,3-dichlorophenyl isocyanate (0.1 Og, 0.5mmole) in dichloromethane (10ml). After stirring at room temperature for 2 hours the mixture was filtered and the solid washed with CH2C12 to afford the title compound as a colourless powder (0.1 Og, 50%).
1H NMR (250MHz, d6DMSO): 9.07 (s, IH), 8.23 (s, IH), 8.08 (dd, IH), 7.17 (m, 2H),
6.73 (s, IH), 6.47 (s, 2H), 3.98 (t, 2H), 3.23 (m, 4H), 2.31 (t, 2H), 2.08 (s, 6H).
Example 15
N-[4-(2-Dimethylaminoethyl)-2H-3-oxo-l,4-benzoxazin-6-yl]-N'-[4-(pyridin-4- yl)naphth-l-yl]urea
The title compound was prepared from 6-amino-4-(2-dimethylaminoethyl)-2H-l,4- benzoxazin-3(4H)-one (D8 in WO 95/32967, 0.15g, 0.66 mmole), 4-(pyridin-4-yl)naphth-
1 -ylamine (B6, 0.17g, 0.77 mmole) triethylamine (0.14 ml, 1.0 mmole) and triphosgene
(0.09g, 0.31 mmole) in dichloromethane (30 ml) following a similar procedure to
Example 13. The title compound was isolated as the hydrochloride salt as a yellow powder (0.07g). IH NMR (d6DMSO) δ (ppm): 10.38 (s, IH), 10.16 (bs, IH), 9.65 (s, IH), 8.90 (d, 2H),
8.63 (d, IH), 8.27 (d, IH), 8.07 (d, 2H), 7.86 (d, IH), 7.60 (m, 3H), 7.44 (d, IH), 7.05
(dd, IH), 6.93 (d, IH), 4.57 (s, 3H), 4.21 (m, 2H), 3.27 (m, 2H), 2.82 (s, 6H).
Example 16 N-[2,3-Dichlorophenyl]-N'-[l-(2-dimethylaminoethyl)indol-6-yl]urea
To a stirred solution of 6-amino-l-(2-dimethylaminoethyl)indole (D2 in WO 95/32967, 0.15g, 0.74 mmole) in dichloromethane (10 ml) was added a solution of 2,3- dichlorophenyl isocyanate (0.13g, 0.8 mmole) in dichloromethane (3 ml). After 2 hours at room temperature, diethyl ether (10 ml) was added, the mixture was filtered, and then the collected solid washed with diethyl ether and dried to afford the title compound as a colourless powder (0.18g).
IH NMR (CDC13) δ (ppm): 8.28 (dd, IH), 7.68 (m, 3H), 7.54 (d, IH), 7.22-7.08 (m, 3H), 6.90 (dd, IH), 6.47 (d, IH), 4.22 (t, 2H), 2.72 (t, 2H), 2.29 (s, 6H).
Example 17
N-[l-(2-Dimethylaminoethyl)indol-6-yl]-N'-[4-(pyridin-4-yl)naphth-l-yl]urea
The title compound was prepared from 6-amino-l-(2-dimethylaminoethyl)indole (D2 in WO 95/32967, 0.15g, 0.74 mmole), 4-(pyridin-4-yl)naphth-l -ylamine (D6, 0.18g, 0.8 mmole), triphosgene (0.10g, 0.33 mmole) in dichloromethane (30 ml) following a similar procedure to Example 13. The product was isolated after chromatography on silica gel eluting with 2- 5% MeOH in CH2CI2 (gradient elution) as a cream powder (0.20g). 1H NMR (CDCI3) δ (ppm): 8.70 (d, 2H), 8.11-8.03 (m, 4H), 7.92 (s, IH), 7.84 (m, IH), 7.48-7.34 (m, 6H), 7.10 (d, IH), 6.81 (dd, IH), 6.43 (d, IH), 4.15 (t, 2H), 2.66 (t, 2H), 2.24 (s, 6H).
Example 18
2,3-Dihydro-N-[l-(2-dimethylaminoethyl)-lH-indol-5yl]-N'-[4-(pyridin-4-yl)naphth- 1 -yljurea
To a stirred solution of triphosgene (0.09g, 0.31 mmole) in dichloromethane (15 ml) was added dropwise, a solution of 4-(pyridin-4-yl)naphth-l -ylamine (D6, 0.17g, 0.77 mmole) and triethylamine (0.12 ml, 0.83 mmole) in dichloromethane (12 ml). After stirring for 20 minutes at room temperature a solution of 6-amino-2,3-dihydro-l-(2- dimethylaminoethyl)-lH-indole (D4 in WO 95/32967, 0.14g, 0.65 mmole) in dichloromethane (20 ml) was added. After 1 hour at room temperature the mixture was washed with potassium carbonate solution (20 ml), dried cover sodium sulphate and evaporated to dryness. The residue was subjected to flash chromatography on silica gel eluting with CH2Cl2/MeOH/NH3 (100: 10: 1). The purified product was converted to the hydrochloride salt to afford the title compound as a pale yellow-green powder (0.07g). IH NMR (d6DMSO) δ (ppm): 10.26 (s, 2H), 9.85 (s, IH), 9.03 (d, 2H), 8.74 (d, IH), 8.41 (d, IH), 8.24 (d, 2H), 7.97 (d, IH), 7.69 (m, 3H), 7.03 (d, 2H), 6.81 (d, IH), 3.39 (m, 6H), 2.85 (m, 8H)
Example 19
N-[2,3-Dichlorophenyl]-N'-[l-(2-dimethylaminoethyl)-l,2,3,4-tetrahydroquinolin-7- yl] urea
To a stirred solution of 7-amino-l -(2-dimethylaminoethyl)- 1,2,3, 4-tetrahydroquinoline (D10, 0.1 lg, 0.5 mmole) in dichloromethane (10 ml) was added a solution of 2,3- dichlorophenyl isocyanate (0.1 lg, 0.6 mmole) in CH2CI2 (10 ml). After 1 hr at room temperature the mixture was evaporated to dryness and the residue subjected to flash chromatography on silica gel eluting with 10% MeOH in CH2CI2. The product was isolated as the hydrochloride salt as a white powder (0.15g). !H NMR (d6DMSO) δ (ppm): 10.48 (s, IH), 9.70 (s, IH), 8.55 (s, IH), 8.05 (dd, IH), 7.20 (m, 2H), 6.83 (s, IH), 6.73 (d, IH), 6.57 (dd, IH), 3.54 (m, 2H), 3.17 (m, 4H), 2.75 (d, 6H), 2.52 (m, 2H), 1.78 (m, 2H).
Example 20
N-[l-(2-Dimethylaminoethyl)-l,2,3,4-tetrahydroquinoIin-7-yl]-N -[4-(pyridin-4-yI)- naphth-l-yl]urea
The title compound was prepared from 7-amino-l-(2-dimethylaminoethyl)-l,2,3,4- tetrahydroquinoline (D10, 0.13g, 0.6 mmole), 4-(pyridin-4-yl)naphth-l -ylamine (0.17g, 0.77 mmole), triethylamine (0.14ml, 1.0 mmole) and triphosgene (0.09g, 0.31 mmole) in dichloromethane (50 ml). The title compound was isolated as the hydrochloride salt as a yellow powder (0.17g). iH NMR (d6DMSO) δ (ppm): 10.47 (s, IH), 10.14 (s, IH), 9.63 (s, IH), 8.85 (d, 2H), 8.60 (dd, IH), 8.23 (d, IH), 8.07 (d, IH), 7.79 (dd, IH), 7.49 (m, 3H), 6.79 (s, IH), 6.65 (q, 2H), 3.48 (m, 2H), 3.11 (m, 4H), 2.71 (d, 6H), 2.47 (m, 2H), 1.69 (m, 2H).
Example 21
N-[l-(2-Dimethylaminoethyl)-l,2,3,4-tetrahydronaphth-7-ylJ-N'-[4-(pyridin-4- yl)naphth-l-yl] urea The title compound was prepared from 7-amino- 1 -(2-dimethylaminoethyl)- 1,2,3,4- tetrahydronaphthalene (D12, 0.13g, 0.6 mmole), 4-(pyridin-4-yl)naphth-l -ylamine (0.17g, 0.77 mmole), triphosgene (0.09g, 0.31 mmole) and triethylamine (0.14 ml, 1 mmole) in dichloromethane (20 ml). The product was isolated as the hydrochloride salt (0.13g). IH NMR (d6DMSO) δ (ppm): 10.08 (bd, 2H), 9.62 (d, IH), 8.78 (d, 2H), 8.55 (d, IH), 8.19 (d, IH), 7.95 (d, 2H), 7.72 (dd, IH), 7.45 (m, 3H), 7.21 (s, IH), 7.13 (dd, IH), 6.80 (d, IH), 2.97 (m, 2H), 2.68-2.47 (m, 7H), 1.79 (m, 2H), 1.59 (m, 2H), 1.45 (m, 2H).
Pharmacological Data
5-HTJA, 5-HTIB and 5-HTJ D Receptor Binding HEK 293 cells expressing 5-HTι A receptors (4 x lONml) were homogenised in Tris buffer and stored in 1ml aliquots. CHO cells expressing 5-HTJB receptors (4 x 10? cells/ml) were homogenised in Tris buffer and stored in 1.5 ml aliquots. CHO cells expressing 5-HTJD receptors (0.563 x 10^/ml) were homogenised in Tris buffer and stored in 1 ml aliquots.
0.4 ml of a cell suspension was incubated with [^HJ-5-HT (4nM) for 5-HTι g/ι rj receptors and [3HJ-8-OH DP AT (InM) for 5-HTι A receptors in Tris Mg HCl buffer (pH 7.7) and test drug, at 37°C for 45 minutes. Each test drug was tested at 10 concentrations (0.01 mM to 0.3 nM final concentration), with non-specific binding defined using 0.01 mM 5-HT. The total assay volume was 0.5 ml. Incubation was stopped by rapid filtration using a Packard Filtermate (filters pre-soaked in 0.3% polyethylenimine) and radioactivity measured by Topcount scintillation counting. pKi values were calculated from the IC50 generated by an iterative least squares curve fitting programme.
Examples 1, 2, 3, 7, 9, 16, 17 and 18 had pKi values >8.0 at 5-HTιA, 5-HTiβ and 5- HT1 j) receptors.

Claims

1. A compound of formula (I) or a salt thereof:
Figure imgf000025_0001
in which Ra is a group of formula (i)
Figure imgf000025_0002
in which pi is phenyl, bicyclic aryl, a 5 to 7 membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur, or a bicyclic heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur; Rl is hydrogen, halogen, C^alkyl, C3_6cycloalkyl, COCi .galkyl, Cj.galkoxy, hydroxy, hydroxyCι _0'alkyl, hydroxyCi .galkoxy, Ci .galkoxyCi.galkoxy, Ci.galkanoyl, nitro, trifluoromethyl, cyano, SR9, SOR9, SO2R9, SO2NR1 ORI 1 , CO2R1 °, CONR10R! !, CO2NR10R11, CONRlO(CH2)cCO2R1 !, (CH2)CNR10R11, (CH2)cCONRl°R1 1, (CH2)CNR10CORH, (CH2)cCO2Cι.6alkyl, CO2(CH2)cOR10, NR10R11, NR10CO2R1 1, NR1°CONR10R11, CR10=NORH, CNRl0=NORπ, where R9, RIO and Rl are independently hydrogen or Ci .galkyl and c is 1 to 4; R2 is hydrogen, halogen, C \ _6alkyl, C3_6cycloalkyl, C3_6cycloalkenyl, C \ .galkoxy, C 1. 6alkanoyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO2R 0, CONR10R , NRIORI 1 where Rl° and Rl are as defined for R! ; a is 1, 2 or 3; or Ra is a group of formula (ii)
Figure imgf000025_0003
wherein P2 and P-> are independently phenyl, bicyclic aryl, a 5- to 7- membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur, or a bicyclic heterocyclic group containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur; A is a bond or oxygen, S(O)m where m is 0 to 2, carbonyl, or CH2 or NR4 where R4 is hydrogen or C╬╝╬▓alkyl;
R is as defined above for formula (i) or is a 5 to 7-membered heterocyclic ring, containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur, optionally substituted by C\. alkyl, halogen or Ci _g alkanoyl); R2 and R3 are independently hydrogen, halogen, Ci .galkyl, C3_6cycloalkyl,
C3_6cycloalkenyl, Ci .galkoxy, Ci .galkanoyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO2R10, CONR10Rl 1, NR^R11 where R10 and R1 1 are as defined for R ; and a and b are independently 1, 2 or 3;
L is a group of formula
- Y - C (=V) - DG - in which Y is - NH -, NR5 where R5 is C^alkyl, or Y is - CH2 - or - O -;
V is oxygen or sulphur; D is nitrogen, carbon or a CH group, G is hydrogen or Ci .╬▓alkyl, providing that D is nitrogen or a CH group, or G together with Rb forms a group W where W is (CRl 17)t where t is 2, 3 or 4 and Rl6 and R*? are independently hydrogen or Cj.galkyl or W is
(CR16R17)U-J where u is 0, 1, 2 or 3 and J is oxygen, sulphur, CR16=CR17, CR16=N,
=CRl6╬╕, =CR16S or =CR16-NR!7;
Q is an optionally substituted 5- to 7- membered carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur;
Rc and R^ are independently hydrogen or C╬╣ _6alkyl;
R is a 5- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur, or Ry is a group of formula - NReR^ in which
Re and Rf are independently hydrogen, C^.galkyl, or aralkyl;
Rb is hydrogen, halogen, hydroxy, Ci .galkyl, trifluoromethyl, Cj.galkoxy or aryl; or Rb together with G forms a group W as defined above; and n is 1 to 4.
2. A compound according to claim 1 in which R is a halogen atom.
3. A compound according to claim 1 or 2 in which R2 and/or R3 are each hydrogen, halogen or a C 1 _g alkyl group.
4. A compound according to any of the preceding claims in which p and P2 are phenyl or naphthyl.
5. A compound according to any of the preceding claims in which Y is -NH- .
6. A compound according to any of the preceding claims in which D is nitrogen and and G is a hydrogen atom.
7. A compound according to any of the preceding claims in which Q is a 5- or 6- membered ring containing 1 or 2 heteroatoms.
8. A compound according to any of the preceding claims in which Ry is a dialkylamino group.
9. A compound according to claim 1 which is: N-(4-bromo-3-methylphenyl)-N'-[3-(2-dimethylaminoethyl)indol-5-ylJurea, N-[3-(2-dimethylaminoethyl)indol-5-ylJ-N'-[3-methyl-4-(pyridin-4-yl)phenylJurea, N-[3-(2-dimethylaminoethyl)indol-5-ylJ-N'-[2"-methyl-4'-(5-methyl-l,2,4-oxadiazol-3- yl)-4-biphenylJurea,
N-[3-(2-dimethylaminoethyl)indol-5-yl]-N'-[naphth-l-yl]urea, 4-bromo-N-[3-(2-dimethylaminoethyl)indol-5-yl]phenylacetamide, N-[3-(2-dimethylaminoethyl)indol-5yl]naphth-l-ylacetamide, N-[3-(2-dimethylaminoethyl)indol-5-ylJ-N'-[4-phenoxyphenyl]ureaN-[4-bromo-3- methylphenyl]-N'-[3-(2-dimethylaminoethyl)-l-methyl-indol-5-yl]urea,
N-[3-(2-dimethylaminoethyl)indol-5yl]-N'-[4-(pyridin-4-yl)naphthyl-l-yl)Jurea, N-[3-(2-dimethylaminoethyl)-l-methyl-indol-5-ylJ-N'-[4-phenoxyphenyl]urea, N-[4-(2-Dimethylaminoethyl)-3,4-dihydro-2H-l,4-benzoxazin-6-yl]-N'-[3-methyl-4-
(pyridin-4-yl)phenylJurea,
N-[4-(2-Dimethylaminoethyl)-3,4-dihydro-2H-l,4-benzoxazin-6-ylJ-N'-[4- phenoxyphenyljurea, N-[4-(2-dimethylaminoethyl)-3 ,4-dihydro-2H- 1 ,4-benzoxazin-6-ylJ-N-[4-(pyridin-4- yl)naphth-l-yl]urea,N-[2,3-dichlorophenylJ-N-[4-(2-dimethylaminoethyl)-3,4-dihydro-
2H- 1 ,4-benzoxazin-6-ylJurea,
N-[4-(2-Dimethylaminoethyl)-2H-3-oxo-l,4-benzoxazin-6-ylJ-N'-[4-(pyridin-4- yl)naphth- 1 -yljurea, N-[2,3-Dichlorophenyl]-N'-[l -(2-dimethylaminoethyl)indol-6-yl]urea,
N-[l-(2-Dimethylaminoethyl)indol-6-yl]-N'-[4-(pyridin-4-yl)naphth-l-yl]urea,
2,3-Dihydro-N-[l-(2-dimethylaminoethyl)-lH-indol-5-ylJ-N'-[4-(pyridin-yl)-l- naphthyljurea,
N-[2,3-DichlorophenylJ-N'-[l-(2-dimethylaminoethyl)-l,2,3,4-tetrahydroquinolin-7- yljurea,
N-[ 1 -(2-Dimethylaminoethyl- 1 ,2,3 ,4-tetrahydroquinolin-7-yl]-N'- [4-(pyridin-4-yl)naphth-
1 -yljurea,
N-[ 1 -(2-Dimethylaminoethyl)- 1 ,2,3 ,4-tetrahydronaphth-7-ylJ-N'-[4-(pyridin-4-yl)naphth-
1 -yljurea or a pharmaceutically acceptable salt thereof.
10. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 which comprises: (a) where D is nitrogen and Y is NH, coupling a compound of formula (II):
Ra _NC(=V) (II) in which Ra and V are as defined in formula (I) or a protected derivative thereof with a compound of formula (III).
Figure imgf000028_0001
in which Rb, Rc, R^, Ry, G, Q and n are as defined in formula (I), or a protected derivative thereof; or
(b) where D is nitrogen and Y is NH or NR5, reacting a compound of formula (IV)
R -NH2 or R -NR5H (IV) in which Ra and R5 are as defined in formula (I) with a compound of formula (III) together with an appropriate urea forming agent;
(c) where D is nitrogen, reacting a compound of formula (V)
Figure imgf000029_0001
in which Ra is as defined in formula (I),
Y is -CH2" or -O- and L2 is an appropriate leaving group, with a compound of formula
(d) where D is carbon or CH, reacting a compound of formula (VI)
Ra -NH2 (VI) in which Ra is as defined in formula (I) with a compound of formula (VII)
Figure imgf000029_0002
in which D is carbon or CH, Rb, Rc, Rd5 Ry5 G, Q and n are as defined in formula (I) and L2 is an appropriate leaving atom and optionally thereafter: ΓÇó removing any protecting groups,
ΓÇó converting a compound of formula (I) into another compound of formula (I),
ΓÇó forming a pharmaceutically acceptable salt.
11. A compound according to any of claims 1 to 9 for use in therapy.
12. A pharmaceutical composition which comprises a compound according to any of claims 1 to 9 and a pharmaceutically acceptable carrier.
PCT/EP1998/002264 1997-04-18 1998-04-14 Heterocycle-containing urea derivatives as 5ht1a, 5ht1b and 5ht1d receptor antagonists WO1998047868A1 (en)

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WO2000012492A1 (en) * 1998-09-01 2000-03-09 Nissan Chemical Industries, Ltd. Benzoxazine derivatives
WO2000035919A2 (en) * 1998-12-17 2000-06-22 Smithkline Beecham Plc Quinoline derivatives
WO2001032626A1 (en) * 1999-11-05 2001-05-10 Smithkline Beecham P.L.C. Isoquinoline and quinazoline derivatives having a combined 5ht1a, 5ht1b and 5ht1d receptor activity
JP2002539198A (en) * 1999-03-12 2002-11-19 ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド Compounds useful as anti-inflammatory drugs
WO2003015769A1 (en) * 2001-08-17 2003-02-27 Aventis Pharma Deutschland Gmbh Aminoalkyl-substituted aromatic bicyclic compounds, method for the production thereof and their use as medicaments
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US7777040B2 (en) 2005-05-03 2010-08-17 Cgi Pharmaceuticals, Inc. Certain substituted ureas, as modulators of kinase activity
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US9751890B2 (en) 2008-02-28 2017-09-05 Vertex Pharmaceuticals Incorporated Heteroaryl derivatives as CFTR modulators
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4803218A (en) * 1982-09-29 1989-02-07 Mcneilab, Inc. 3-aminoalkyl-1H-indole-5-urea and amide derivatives
WO1993018028A1 (en) * 1992-03-12 1993-09-16 Smithkline Beecham Plc Indole derivatives as 5ht1c antagonists
WO1995032967A1 (en) * 1994-05-28 1995-12-07 Smithkline Beecham Plc Amide derivatives having 5ht1d-antagonist activity
WO1997007120A1 (en) * 1995-08-11 1997-02-27 Smithkline Beecham Plc Biphenyl(thio)amide and biphenylethan(thi)one derivatives, their preparation and their use as 5-ht1d receptor antagonists
EP0768301A1 (en) * 1995-10-10 1997-04-16 Eli Lilly And Company N-(2-substituted-3-(2-aminoethyl)-1H-indol-5-yl)-amides as new 5-HT1F agonists

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4803218A (en) * 1982-09-29 1989-02-07 Mcneilab, Inc. 3-aminoalkyl-1H-indole-5-urea and amide derivatives
WO1993018028A1 (en) * 1992-03-12 1993-09-16 Smithkline Beecham Plc Indole derivatives as 5ht1c antagonists
WO1995032967A1 (en) * 1994-05-28 1995-12-07 Smithkline Beecham Plc Amide derivatives having 5ht1d-antagonist activity
WO1997007120A1 (en) * 1995-08-11 1997-02-27 Smithkline Beecham Plc Biphenyl(thio)amide and biphenylethan(thi)one derivatives, their preparation and their use as 5-ht1d receptor antagonists
EP0768301A1 (en) * 1995-10-10 1997-04-16 Eli Lilly And Company N-(2-substituted-3-(2-aminoethyl)-1H-indol-5-yl)-amides as new 5-HT1F agonists

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WO2000012492A1 (en) * 1998-09-01 2000-03-09 Nissan Chemical Industries, Ltd. Benzoxazine derivatives
WO2000035919A2 (en) * 1998-12-17 2000-06-22 Smithkline Beecham Plc Quinoline derivatives
WO2000035919A3 (en) * 1998-12-17 2000-10-26 Smithkline Beecham Plc Quinoline derivatives
JP2002539198A (en) * 1999-03-12 2002-11-19 ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド Compounds useful as anti-inflammatory drugs
JP4820488B2 (en) * 1999-03-12 2011-11-24 ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド Compounds useful as anti-inflammatory drugs
WO2001032626A1 (en) * 1999-11-05 2001-05-10 Smithkline Beecham P.L.C. Isoquinoline and quinazoline derivatives having a combined 5ht1a, 5ht1b and 5ht1d receptor activity
JP2003513075A (en) * 1999-11-05 2003-04-08 スミスクライン ビーチャム パブリック リミテッド カンパニー Isoquinoline and quinazoline derivatives having complex 5HT1A, 5HT1B and 5HT1D receptor activity
WO2003015769A1 (en) * 2001-08-17 2003-02-27 Aventis Pharma Deutschland Gmbh Aminoalkyl-substituted aromatic bicyclic compounds, method for the production thereof and their use as medicaments
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