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  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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  • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings

Definitions

• the present invention relates to novel quinoline derivatives, processes for their preparation, and pharmaceutical compositions containing them.
• US patent 5,703,072 discloses bicyclic nonane and decane compounds having dopamine receptor affinity which are claimed to be of use in the treatment of schizophrenia.
• WO 98/50358, WO 98/50346, WO 98/47868, WO 98/47885 and WO 98/50343 all disclose a series of novel compounds which are claimed to possess combined 5-HTi A, 5-HTi ⁇ and 5- HTi jj receptor antagonist activity and are useful in the treatment of various CNS disorders.
• WO 97/36867 and WO 98/14433 both disclose a series of lactam derivatives that are claimed to be selective agonist or antagonists of one or both of 5-HTi A and 5-HTI D receptors.
• the present invention therefore provides a compound of formula (I) or a salt thereof:
• P* is phenyl, bicyclic aryl, C ⁇ .gcycloalkyl, 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;
• Ci.galkyl is halogen, Ci.galkyl, C3_6cycloalkyl, C galkoxy, hydroxy, hydroxyCi.galkyl, hydroxyC ⁇ _6alkoxy, C ⁇ galkoxyCi - alkoxy, Ci.galkanoyl, NO , CF3, CN, SR 9 , SOR 9 , SO 2 R 9 , SO NR 10 R 1 1, CO 2 R 10 , CONRIORH , CONRlO(CH 2 ) c CO2R n , (CH 2 ) C NR 10 R 1 1 , (CH 2 ) c CONR 10 Rl l, (CH ⁇ C N ⁇ COR 1 1 , (CH 2 ) c CO 2 C ⁇ .
• 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, O, S(O) n where n is 0 to 2, carbonyl, CH 2 or NR 4 where R 4 is hydrogen or C ⁇ . galkyl;
• R! and R2 are independently as defined above for R in formula (i); and a and b are independently 0, 1, 2 or 3;
• L is a group of formula
• C ⁇ _6alkyl groups whether alone or as part of another group may be straight chain or branched.
• the term 'halogen' is used herein to describe, unless otherwise stated, a group selected from fluorine, chlorine, bromine or iodine.
• the bicyclic aryl group represented by pl, P ⁇ or P ⁇ , which may be partially saturated, is preferably naphthyl. Where used herein the term naphthyl is intended, unless otherwise stated, to denote both naphth-1-yl and naphth-2-yl groups.
• pl When pl is C3_6cycloalkyl preferred examples are cyclopentyl and cyclohexyl.
• pl When pl is a 5 to 7 membered heterocyclic ring suitable examples include 5 or 6 membered heteroaryl rings such as thienyl, furyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyrimidyl, pyrazinyl and pyridyl.
• Non aromatic 5 to 7 membered heterocyclic rings include pyrrolidinyl, piperidinyl or piperazinyl.
• P s a bicyclic heterocyclic ring suitable examples include benzofused rings such as quinolinyl, isoquinolinyl, indolyl, benzofuryl, benzothienyl and benzo[l,3]dioxolyl.
• the heterocyclic and bicyclic heterocyclic groups listed above can be linked to the remainder of the molecule via a carbon atom or, when present, a suitable nitrogen atom.
• pl is phenyl, naphthyl, quinolyl, pyridyl or thienyl.
• R* When a is greater than 1 the groups R* can be the same or different. Preferably a is 0, 1 or 2.
• Preferred R! groups include halogen (particularly chlorine), a C j .galkyl group (particularly methyl), CN, CF3 or a Cj.galkoxy group (particularly methoxy or ethoxy).
• P ⁇ and/or P ⁇ is a 5 to 7 membered heterocyclic ring or a bicyclic heterocyclic group
• suitable examples include those listed for P above.
• P ⁇ is phenyl, naphthyl, pyridyl, thienyl or furyl.
• a preferred substitution arrangement for naphthyl groups is 1,4 or more preferably 1,5, that is to say, a naphth-1-yl group in which the group A is attached at the 4 or 5 position respectively.
• P ⁇ is phenyl, pyridyl, thienyl, pyrazolyl or oxazolyl.
• groups R! and/or R ⁇ respectively can be the same or different.
• Preferred R! and/or R ⁇ groups include halogen (particularly chlorine), a Cj.galkyl group (particularly methyl), CN, CF3 or a Cj.galkoxy group (particularly methoxy or ethoxy).
• A is preferably a bond or oxygen, most preferably a bond.
• L is a group of formula:-
• Y is preferably NH or CH 2
• D is preferably nitrogen
• Rbl is preferably hydrogen or together with G forms a group W referred to above.
• X is preferably a nitrogen atom, and m is preferably 1 or 2, most preferably 1.
• Particularly preferred compounds according to this invention are:- (S)-(-)-N-[4-(Octahydropyrrolo[l,2-a]pyrazin-2-yl)quinolin-6-yl]-3,4-dichlorobenzamide, (S)-(-)-N-[4-(Octahydropyrrolo[l,2- ⁇ ]pyrazin-2-yl)quinolin-6-yl]-3,4-dichlorobenzamide, (S)-(-)-2,3-Dihydro- 1 -[5-(2,6-dimethylpyridin-4-yl)naphth- 1 -ylcarbonyl]-8- (octahydropyrrolo[l,2- ⁇ ]pyrazin-2-yl)pyrrolo[2,3-g-]quinoline,
• 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.
• acid addition salts such as hydrochlorides, hydrobromides, phosphates, acetates, fumarates, maleates, tartrates, citrates, oxalates, methanesulphonates and p- toluenesulphonates.
• R a -NC( O) (IV) in which R a is as defined in formula (I) or a protected derivative thereof, with a compound of formula (V):
• L 1 is COL a and L 2 is NH 2
• L 1 is NH 2
• L 2 is COL a in which L a is an appropriate leaving group.
• one of L and L 2 is an activated carboxylic acid derivative such as an acyl chloride or acid anhydride, and the other is an amine group.
• Activated compounds of formulae (II) and (III) can also be prepared by reaction of the corresponding carboxylic acid with a coupling agent such as dicyclohexylcarbodiimide, carbonyldiimidazole or diphenylphosphorylazide.
• a coupling agent such as dicyclohexylcarbodiimide, carbonyldiimidazole or diphenylphosphorylazide.
• L or O- is a group COL a where L a is halo particularly chloro.
• reaction 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, tetrahydrofuran or dichloromethane at ambient or elevated temperature in the presence of a base such as triethylamine or pyridine.
• the leaving group L ⁇ is 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.
• an inert organic solvent such as tetrahydrofuran or dichloromethane
• a base such as triethylamine or pyridine.
• the leaving group L ⁇ is 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.
• an inert organic solvent such as tetrahydrofuran or dichloromethane
• 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. The involvement of serotonin receptors in a number of pharmacological effects has been reviewed by R. A. Glennon in "Serotonin Receptors: Clinical Implications", Neuroscience and Behavioural Reviews, 1990, J_4, 35 and by L.O.Wilkinson and C.T. Dourish in "Serotonin Receptor Subtypes : Basic and Clinical Aspects" S. Peroutka Ed., John Wiley and Sons, New York, 1991 ⁇ .147.
• Serotonin (5-hydroxytryptamine; 5-HT) receptors have been implicated in a number of pharmacological effects including 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, amnesic disorders and age-associated memory impairment; disorders of eating behaviours, including anorexia nervosa and bulimia nervosa, sleep disorders (including disturbances of Circadian rhythm), motor disorders such as Parkinson's disease, dementia in Parkinson's disease, neuroleptic-induced Parkinsonism and tardive dyskinesias, as well as other psychiatric disorders.
• 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, amnesic disorders and
• Serotonin receptor ligands have been shown to be of use in the treatment of emesis and nausea and may also be of use in endocrine disorders such as hyperlactinaemia, vasospasm (particularly in the cerebral vasculature), cerebellar ataxia and hypertension, as well as disorders of 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.
• WO 95/31988 refers to the use of a 5-HT ⁇ rj receptor antagonist in conjunction with a 5-HT ⁇ A receptor antagonist to treat CNS (central nervous system), endocrine and GI (gastrointestinal) disorders;
• K. Rasmussen Annual Reports in Medicinal Chemistry, (1995) 30, 1) describes the utility of 5-HTj A receptor agonists and partial agonists in the treatment of various CNS disorders;
• P. Trouillas Progress in Brain Research, CI. de Zeeuw, P. Stara and J. Voogd, Eds. 1997, 144, 589) and G. Maura (J. Neurochemistry, 1996, 66, 202) propose that administration of agonist ligands selective for the 5-HT ⁇ A receptor or for both 5-HTi A and 5-HT ID receptors should provide effective treatment for human cerebellar ataxias.
• the present invention also provides a compound of general formula (I) or a pharmaceutically 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 pharmaceutically acceptable salt or solvate thereof for use in the treatment or prophylaxis of depression.
• the affinities of the compounds of this invention for the 5-HT ⁇ A, 5-HTI g and 5-HTiD receptors can be determined by the following radioligand binding assay.
• HEK 293 cells expressing 5-HTJA. receptors (4 x lO ⁇ /ml) are homogenised in Tris buffer and stored in lml aliquots.
• CHO cells expressing 5-HTIJJ receptors (4 x 10? cells/ml) are homogenised in Tris buffer and stored in 1.5 ml aliquots.
• CHO cells expressing 5-HTID receptors (0.563 x 10 ⁇ /ml) are homogenised in Tris buffer and stored in 1 ml aliquots.
• the intrinsic activity of the compounds of this invention can be determined according to the following procedure.
• HEK-293 cell membranes stably expressing human 5-HT 1 A receptors and CHO cell membranes stably expressing human 5-HT ⁇ g receptors are homogenised in HEPES/EDTA buffer and stored in lml aliquots, and [35s]GTP ⁇ S binding studies are carried out essentially as described by Lazareno et al, (Life Sci., 1993, 52, 449) with some minor modifications.
• Membranes from 10 ⁇ cells are pre-incubated at 30°C for 30 min in 20 mM HEPES buffer (pH 7.4) in the presence of MgCl 2 (3 mM), NaCl (100 mM), GDP (10 ⁇ M) and ascorbate (0.2 mM), with or without compounds.
• the reaction is started by the addition of 10 ⁇ l of [35s]GTP ⁇ S (100 pM, assay concentration) followed by a further 30 minutes incubation at 30°C.
• Non-specific binding was determined using non- radiolabelled GTP ⁇ S (20 ⁇ M) added prior to the membranes.
• the reaction is terminated by rapid filtration through Whatman GF/B grade filters followed by 5 x 1 ml washes with ice cold HEPES (20 mM) /MgCl 2 (3 mM) buffer. Radioactivity is measured using liquid scintillation spectrometry. This procedure is hereafter referred to as the [35s]GTP ⁇ S functional assay.
• the compounds of formula (I) show high affinity for the 5-HT ⁇ A, 5-HTi g and 5-HT ⁇ ) receptors.
• the preferred compounds of this invention will display 5-HTJA, 5-HTH3 and 5-HTjr) antagonist activity in vivo and that such compounds will have a rapid onset of action.
• a rapid onset of action is particularly advantageous for antidepressant compounds: by 'rapid onset of action' we mean that a therapeutic response is seen within 7 days from first administration of the compound, as opposed to a period of about 21 days or more which is typical of SSRI's, tricyclic antidepressants and buspirone.
• the compounds according to the invention may advantageously be used in conjunction with one or more other therapeutic agents, for instance, a selective serotonin reuptake inhibitor (SSRI) antidepressant.
• SSRI selective serotonin reuptake inhibitor
• 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.
• the 1,2-dimethoxyethane was removed in vacuo and the residue diluted with 2M NaOH solution and washed with EtOAc.
• the aqueous phase was acidified to pHl with cone. HCl and washed with EtOAc, then adjusted to pH5 with K 2 CO3 and extracted with DCM (3x).
• the DCM extracts were combined, dried (Na SO4) and concentrated in vacuo, giving the title compound as a white solid (1.38 g, 70%).
• the title compound was prepared from 4-bromo-2,5-dimethylpyridine and 5-carboxynaphth-
• Ethyl 5-bromoacetyl-l-naphthoate (D30, 3.50 g, 10.9 mmole) was dissolved in DCM (40 ml) and cooled in an ice bath to ⁇ 5°C. This solution was treated with tetrabutylammonium iodide (0.20 g, 0.54 mmole) and a solution of sodium azide (1.06 g, 16.3 mmole) in water (8 ml) and stirred vigorously for 3 h, while warming to room temperature. Water (30 ml) was added and the organic phase separated, dried (Na SO4) an£ I concentrated carefully in vacuo to approx. 20 ml volume.
• Ethyl 5-aminoacetyl-l-naphthoate hydrochloride (D31, 2.26 g, 7.70 mmole) was suspended with stirring in DCM (60 ml) and treated with triethylamine (1.2 ml, 8.50 mmole) and acetic anhydride (0.86 g, 8.5 mmole). After 18 h, the mixture was concentrated to dryness in vacuo and the residue partitioned between EtOAc and 10% aqueous Na 2 CO3 solution. The organic phase was separated, dried (Na 2 SO4), concentrated to dryness in vacuo and purified by silica gel chromatography, eluting with EtOAc, to afford the title compound as a white solid (1.73 g, 60%).
• Ethyl 5-acetamidoacetyl-l-naphthoate (D33, 1.71 g, 5.72 mmole) was covered with polyphosphoric acid ( ⁇ 48 g) and the resulting viscous mixture was heated with stirring, under argon. On reaching 140°C, the mixture was partially cooled and poured into a beaker of crushed ice ( ⁇ 50 ml) with stirring. Water (50 ml) was added and the solution extracted with EtOAc.
• the title compound was prepared from (S)-(-)-2,3-dihydro-8-(octahydropyrrolo[l,2- ⁇ ]pyrazin-2-yl)pyrrolo[2,3-g]quinoline (D10, 100 mg, 0.34 mmole) and 5-(2,6- dimethylpyridin-4-yl)naphthoyl chloride (D14, 150 mg, 0.51 mmole) using a similar procedure to Example 2, as a cream coloured solid (31 mg, 16%).
• the title compound was prepared from (S)-(-)-2,3-dihydro-8-(octahydropyrrolo[l,2- fl]pyrazin-2-yl)pyrrolo[2,3-g-]quinoline (D10, 85 ⁇ mole), and 2,3-dichlorobenzoic acid (255 ⁇ mole) using a similar procedure to Example 4, as a yellow glass (51%).
• the title compound was prepared from (S)-(-)-2,3-dihydro-8-(octahydropyrrolo[l,2- ⁇ ]pyrazin-2-yl)pyrrolo[2,3-g]quinoline (D10, 85 ⁇ mole) and 4-(5-methyloxazol-2-yl)-l- naphthoic acid (D21, 255 ⁇ mole) using a similar procedure to Example 4, as a brown glass (47%).
• the title compound was prepared from (S)-(-)-2,3-dihydro-8-(octahydropyrrolo[l,2- ⁇ ]pyrazin-2-yl)pyrrolo[2,3-g]quinoline (D10, 85 ⁇ mole), and 5-(5-methylpyridin-2-yl)-l- naphthoic acid (D16, 255 ⁇ mole) using a similar procedure to Example 4.
• the compound was further purified using reverse phase HPLC and isolated as the trifluoroacetate salt, as a pale brown glass (20%).
• the title compound was prepared from (S)-(-)-2,3-dihydro-8-(octahydropyrrolo[l,2- ⁇ ]pyrazin-2-yl)pyrrolo[2,3-g]quinoline (D10, 85 ⁇ mole), and 5-(6-methylpyridin-2-yl)-l- naphthoic acid (D17, 255 ⁇ mole) using a similar procedure to Example 4, as a yellow glass (46%).
• the title compound was prepared from (S)-(-)-2,3-dihydro-8-(octahydropyrrolo[l,2- ⁇ ]pyrazin-2-yl)pyrrolo[2,3- ]quinoline (D10, 85 ⁇ mole), and 5-(3-methylpyridin-2-yl)-l- naphthoic acid (D23, 255 ⁇ mole) using a similar procedure to Example 4, as a pale yellow glass (64%).
• the title compound was prepared from (S)-(-)-2,3-dihydro-8-(octahydropyrrolo[l,2- ⁇ ]pyrazin-2-yl)pyrrolo[2,3- ]quinoline (D10, 85 ⁇ mole), and 5-(2-methyloxazol-5-yl)-l- naphthoic acid (D34, 255 ⁇ mole) using a similar procedure to Example 4, as a yellow glass (36%).
• the title compound was prepared from (S)-(-)-2,3-dihydro-8-(octahydropyrrolo[l,2- ⁇ ]pyrazin-2-yl)pyrrolo[2,3-g]quinoline (D10, 85 ⁇ mole), and 5-(3-methylisoxazol-5-yl)-l- naphthoic acid (D36, 255 ⁇ mole) using a similar procedure to Example 4, as a yellow glass (26%).
• the title compound was prepared from (S)-(-)-2,3-dihydro-8-(octahydropyrrolo[l,2- ⁇ ]pyrazin-2-yl)pyrrolo[2,3-g]quinoline (D10, 170 ⁇ mole), and 2-(4-chlorophenyl)-3- trifluoromethylpyrazole-4-carboxylic acid (250 ⁇ mole) using a similar procedure to Example 4, as a yellow glass (52%).
• the title compound was prepared from (S)-(-)-2,3-dihydro-8-(octahydropyrrolo[l,2- ⁇ ]pyrazin-2-yl)pyrrolo[2,3-g-]quinoline (D10, 170 ⁇ mole), and 5-(2-methyl-5- trifluoromethylpyrazol-3-yl)-thiophen-2-carboxylic acid (250 ⁇ mole) using a similar procedure to Example 4, as a yellow glass (80%).
• Examples E25 - E72 were prepared in parallel using a similar procedure to that described for Example 4.
• the title compound was prepared from (S)-(-)-2,3-dihydro-8-(octahydropyrrolo[l,2- ⁇ ]pyrazin-2-yl)pyrrolo[2,3-g]quinoline (DIO, 85 ⁇ mole), and 5-(5-methyloxazol-2- yl)naphth-l-ylacetic acid (D27, 255 ⁇ mole) using a similar procedure to Example 4, as a pale brown glass (70%).
• Examples E75 - E80 were prepared in parallel using a similar procedure to that as described for Example E74.
• the affinities of the compound of this invention was determined using the radiolabelled binding assay as described above.

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• 1998
  • 1998-12-17 GB GBGB9827882.3A patent/GB9827882D0/en not_active Ceased
• 1999
  • 1999-12-03 PL PL99353156A patent/PL353156A1/xx not_active Application Discontinuation
  • 1999-12-03 KR KR1020017007626A patent/KR20010108028A/ko not_active Application Discontinuation
  • 1999-12-03 CZ CZ20012151A patent/CZ20012151A3/cs unknown
  • 1999-12-03 CN CN99816080A patent/CN1335850A/zh active Pending
  • 1999-12-03 EP EP99964526A patent/EP1140946A2/en not_active Withdrawn
  • 1999-12-03 CA CA002355234A patent/CA2355234A1/en not_active Abandoned
  • 1999-12-03 IL IL14378299A patent/IL143782A0/xx unknown
  • 1999-12-03 WO PCT/EP1999/009564 patent/WO2000035919A2/en not_active Application Discontinuation
  • 1999-12-03 BR BR9916307-1A patent/BR9916307A/pt not_active Application Discontinuation
  • 1999-12-03 JP JP2000588178A patent/JP2002532501A/ja active Pending
  • 1999-12-03 HU HU0104662A patent/HUP0104662A2/hu unknown
  • 1999-12-03 AU AU30360/00A patent/AU3036000A/en not_active Abandoned
  • 1999-12-03 TR TR2001/01764T patent/TR200101764T2/xx unknown
  • 1999-12-17 CO CO99078949A patent/CO5150146A1/es unknown
• 2001
  • 2001-06-15 NO NO20013003A patent/NO20013003L/no not_active Application Discontinuation
• 2002
  • 2002-02-19 HK HK02101212.8A patent/HK1041480A1/zh unknown

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