WO1994022871A1 - THIENO-INDOLE DERIVATIVES AS 5HT2c AND 5HT2b ANTAGONISTS - Google Patents
THIENO-INDOLE DERIVATIVES AS 5HT2c AND 5HT2b ANTAGONISTS Download PDFInfo
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- WO1994022871A1 WO1994022871A1 PCT/EP1994/000917 EP9400917W WO9422871A1 WO 1994022871 A1 WO1994022871 A1 WO 1994022871A1 EP 9400917 W EP9400917 W EP 9400917W WO 9422871 A1 WO9422871 A1 WO 9422871A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
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- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- This invention relates to novel compounds having pharmacological activity, to processes for their preparation, to compositions containing them and to their use in the treatment of mammals.
- WO 92/05170 describes certain urea derivatives which are described as possessing 5HTJC receptor antagonist activity.
- the 5-HTjc receptor has recently been reclassified as the 5HT2C receptor [P. Hartig et al., Trends in Pharmacological Sciences (TIPS) 1993].
- 5HT2C receptor antagonist activity A structurally distinct class of compounds has now been discovered which have been found to have 5HT2C receptor antagonist activity. Certain compounds of the invention also exhibit 5HT2B antagonist activity. 5HT2 /2B receptor antagonists are believed to be of potential use in the treatment of CNS disorders such as anxiety, depression, obsessive compulsive disorders, migraine, anorexia, Alzheimers disease, sleep disorders, bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus.
- CNS disorders such as anxiety, depression, obsessive compulsive disorders, migraine, anorexia, Alzheimers disease, sleep disorders, bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus.
- the present invention provides a compound of formula (I) or a salt thereof:
- P represents a quinoline or isoquinoline residue or a 5- or 6-membered aromatic heterocyclic ring containing up to three heteroatoms selected from nitrogen, oxygen or sulphur,
- R ⁇ is hydrogen, Ci .g alkyl, halogen, OR7 or NRgR where R7, Rg and R9 are independently hydrogen or Cj_6 alkyl; R2 is hydrogen or Cj_6 alkyl; R3 is hydrogen, C ⁇ _6 alkyl, Cj. ⁇ alkoxy, or halogen; R4 is hydrogen or Cj.g alky R5 and Rg are each independently hydrogen or Cj.g alkyl; and n is 2 or 3.
- C ⁇ _6alkyl groups may be straight chained or branched and are preferably C1-.3 alkyl, such as methyl, ethyl, n- and iso- propyl, most preferably methyl.
- Rj is hydrogen, Cj.6alkyl or halogen. Most preferably Rj is hydrogen, methyl or bromo.
- R2 and R3 are hydrogen.
- R5 and Rg are both hydrogen and n is 2, that is to say, the group -(CR5R ⁇ ) n - forms an ethylene linkage.
- the group -(CR5R6) n - can be attached to the 4- or 6-position of the benzothiophene ring.
- the urea moiety can be attached to a carbon or, when available, a nitrogen atom of the ring P, preferably it is attached to a carbon atom.
- Suitable moieties when the ring P is a 5- or 6-membered aromatic heterocyclic ring include pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, isothiazolyl, isoxazolyl, thiadiazolyl and triazolyl.
- P is a quinoline or isoquinoline residue
- the urea moiety can be attached at any position of the ring, preferably to the 4-position.
- P is pyridyl, quinolyl or isothiazolyl.
- the substituent R3 can be attached to any vacant position in the phenyl part of the benzothiophene ring, that is to say, the 4-, 6- or 7-positions of the benzene ring.
- the substituent R4 can be attached to the 2- or 3-positions of the thiophene ring.
- Preferred compounds of formula (I) include;
- the compounds of the formula (I) can form acid addition salts with acids, such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric and methanesulphonic.
- acids such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric and methanesulphonic.
- Certain compounds of formula (I) are capable of existing in stereoisomeric forms including enantiomers and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates.
- the different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis.
- R2 is hydrogen or when Rj is hydroxy or NR Rg and at least one of R7 and Rg are hydrogen
- the compounds of formula (I) may exist tautomerically in more than one form.
- the invention extends to all tautomeric fo ⁇ ns of compounds of formula (I) and mixtures thereof.
- the present invention also provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises
- a and B contain the appropriate functional group(s) necessary to form the moiety -NR2'CO when coupled, wherein R ⁇ is R2 as defined in formula (I) or a group convertible thereto, and the variables Rj', R3', R4', R5' and Rg' arc R , R3, R4, R5 and R , respectively, as defined in formula (I), or groups convertible thereto, and thereafter optionally and as necessary in any appropriate order, converting any R ⁇ R2 * , R3', R4 * , R5' and R(.' when other than Ri, R2, R3. R4, 5 and Rg to R ⁇ , R2, R3, R4, R5 and R6, interconverting R ⁇ , R2, R3, R4, R5 and R6, and forming a pharmaceutically acceptable salt, or
- R R2', R3', R5 , and R ' are as defined in formulae (II) and (HI) and C and D contain the appropriate functional group(s) necessary to form the thiophene ring substituted by R3 1 and R4' as defined in formula (HI), and thereafter optionally and as necessary in any appropriate order, converting any R ⁇ R2', R3', R4 1 , R5' and R6 * when other than Rj, R2, R3, R4, R5 and Rg to Rj, R2, R3, R4, R5 and Rg, interconverting R ⁇ , R2, R3, R4, R5 and R , and forming a pharmaceutically acceptable salt.
- suitable leaving groups L include imidazole, halogen such as chloro or bromo or phenoxy or phenylthio optionally substituted, for example with halogen.
- reaction is suitably ca ⁇ ied out in an inert solvent for example dichloromethane or toluene at ambient temperature.
- reaction is suitably carried out in an inert solvent such as dichloromethane at ambient temperature optionally in the presence of a base, such as triethylamine or in dimethylformamide at ambient or elevated temperature.
- an inert solvent such as dichloromethane at ambient temperature
- a base such as triethylamine or in dimethylformamide at ambient or elevated temperature.
- reaction is suitably carried out in an inert solvent such as toluene at elevated temperature, optionally in the presence of a base.
- Examples of compounds of formula (IV) which can be used in the preparation of benzothiophenes include those where C is SCH2CO2R5 where R5 is C ⁇ _6 alkyl and D is CHO, or C is SCH2CH(OR5)2 and D is hydrogen.
- Suitable examples of groups Rj', R3' and R4 1 groups which are convertible to Rj, R3 and R4 alkyl groups respectively include acyl groups which are introduced conventionally and may be converted to the corresponding alkyl group by conventional reduction, such as using sodium borohydride in an inert solvent followed by hydrogenolysis in an inert solvent. Hydrogen substituents may be obtained from alkoxycarbonyl groups which may be converted to hydrogen by hydrolysis and decarboxylation. When R ⁇ is hydroxy it is preferably protected in the compound of formula (II) as, for example, benzyloxy which is cleaved by hydrogenation.
- Suitable examples of a group R ⁇ which is convertible to R2 include alkoxycarbonyl and benzyl or para-methoxybenzyl which are converted to R2 is hydrogen using conventional conditions.
- R ⁇ , R2, R3 and R4 Interconversions of R ⁇ , R2, R3 and R4 are carried out by conventional procedures.
- R2 is hydrogen it is possible to introduce a Cj_6 alkyl group at the R2 position by conventional alkylation using 1 molar equivalent of a Cj.g alkyl halide and 1 molar equivalent of a suitable base in an inert solvent.
- A is amino, with phosgene or a phosgene equivalent, in the presence of excess base in an inert solvent.
- A is acylazide (i.e. CON3), via the nitrene, by thermal rearrangement using conventional conditions (ref L.S. Trifonov et al, Helv. Chim. Acta 1987 70262).
- iii) A is CONH2, via the nitrene intermediate using conventional conditions.
- phosgene equivalents include carbonyldiimidazole and phenyl chloroformate.
- Compounds of formula (II) in which A is -NR2'COL may be prepared by reacting a compound of formula (II) in which A is -NHR2' with phosgene or a phosgene equivalent, in an inert solvent, at low temperature, if necessary in the presence of one equivalent of a base such as triethylamine.
- Q is CR ⁇ R ⁇ , CR 5 O or CO2R where L is a leaving group and R ⁇ and R*> are as defined in formula (I), m is 1 or 2, R ⁇ ', R4', R5', Rg' and B are as defined in relation to formula (HI) above and R is aryl or alkyl group,
- R3', R5', Rg' and B are as defined in relation to formula (HI) above and C and D are as defined in relation to formula (TV) above.
- the cyclisation of a compound of formula (V) may be suitably carried out in an inert solvent at ambient or elevated temperatures, optionally in the presence of a base. Reduction, if necessary, may be carried out using conventional reduction techniques.
- the cyclisation of a compound of formula (VI) may be suitably carried out using the procedures outlined for the cyclisation of a compound of formula (TV), above.
- salts may be prepared conventionally by reaction with the appropriate acid or acid derivative.
- N-oxides may be formed conventionally by reaction with hydrogen peroxide or percarboxylic acids.
- Compounds of formula (I) and their pharmaceutically acceptable salts have 5HT2Q/2B receptor antagonist activity and are believed to be of potential use in the treatment or prophylaxis of anxiety, depression, migraine, anorexia, obsessive compulsive disorders, Alzheimer's disease, sleep disorders, bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus.
- the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a therapeutic substance, in particular in the treatment or prophylaxisjTof anxiety, depression, migraine, anorexia, obsessive compulsive disorders, Alzheimer's disease, sleep disorders, bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus.
- a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a therapeutic substance, in particular in the treatment or prophylaxisjTof anxiety, depression, migraine, anorexia, obsessive compulsive disorders, Alzheimer's disease, sleep disorders, bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus.
- the invention further provides a method of treatment or prophylaxis of anxiety, depression, migraine, anorexia, obsessive compulsive disorders, Alzheimer's disease, sleep disorders, bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus, in mammals including humans, which comprises administering to the sufferer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
- the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis of anxiety, depression, migraine, anorexia, obsessive compulsive disorders, Alzheimer's disease, sleep disorders, bulimia, panic attacks, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus.
- 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 infusable 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 colourants.
- 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 sterilization 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 0.05 to 20.0 mg, for example 0.2 to 5 mg; and such unit doses may be administered more than once a day, for example two or three a day, so that the total daily dosage is in the range of about 0.01 to 100 mg kg; and such therapy may extend for a number of weeks or months.
- Ethyl 5-nitrobenzo[b]thiophenecarboxylate was prepared and hydrolysed to the corresponding acid as described by S. Rossi and R. Trave (II Farmaco - Ed. Sci., 1960, 15, 396).
- 5-Nitrobenzo[b]thiophenecarboxylic acid (4.32 g, 19.4 mmol) was heated with copper powder (1.2 g, activated by heating for several hours at 160°C in vacuo) in quinoline (25 ml) at 180-190°C for 2h. After cooling, the mixture was diluted with ether and washed thoroughly with 5N hydrochloric acid. The organic phase was dried and evaporated, and the crude product was recrystallised from ether to give the title compound (3.24 g, 77%), m.p. 142-145°C.
- Extracts were combined, washed with sodium bicarbonate (twice) and water, dried and evaporated. The residue was chromatographed on silica gel (120g) eluted with 1:1 petrol/dichloromethane to give the title compound (1.35 g; 47% combined yield from two preparations), m.p. 104-105° C (ether/petrol).
- the diazonium solution/suspension was then added portionwise via a transfer tube to a solution of formaldoxime [formaldoxime prepared from paraformaldehyde (32.5g, 1000 mmoles) and hydroxylamine hydrochloride (74.0g, 1050 mmoles) by heating under reflux in water (400 ml) with sodium acetate trihydrate (150.0g, 1080 mmoles), copper sulphate pentahydrate (16.3g), sodium sulphite (2.2g) and anhydrous sodium acetate (210g, 2560 mmoles) for 20 mins] with vigorous stirring keeping the temperature ⁇ 15° C (Care! reaction froths greatly). The mixture was stirred at ambient temperature for 1 hr and concentrated hydrochloric acid (470ml) was added. The mixture was then heated under reflux for 1 hr.
- formaldoxime prepared from paraformaldehyde (32.5g, 1000 mmoles) and hydroxylamine hydrochloride (74.0g, 1050 mm
- Ethyl-2-mercaptoacetate (20 ml, 182 mmoles) was added to a solution of sodium ethoxide [prepared by treating ethanol (150 ml) with sodium metal (4.3 g, 180 mmoles)] keeping the temperature ⁇ 5° C. After 20 mins ethanol (300 ml) was added followed by 2-bromo-4- methyl-5-nitrobenzene-carboxaldehyde (D7) (44.2g, 180 mmoles) portionwise over 10 mins resulting in a dense yellow precipitate. More ethanol (200 ml) was added and the mixture heated under reflux for 3 hr. The mixture was allowed to cool and the ethanol was removed in vacua. The residue was partitioned between dichloromethane and water, separated, dried (Na2SO4) and evaporated to dryness to give the title compound (46.0g, 96%).
- sodium ethoxide prepared by treating ethanol (150 ml) with sodium metal (4.3 g, 180 mmoles
- the methanesulphonate (D12) (24.0g, 80 mmoles) was hydrogenated at atmospheric pressure and at 50° C for 3 hrs in ethyl acetate (600 ml) with triethylamine (40 ml) over a 10% palladium on charcoal catalyst. The catalyst was then filtered off and d e filtrate washed wid saturated aqueous sodium bicarbonate, dried (Na2SO4) and evaporated to dryness to give the tide compound as an off-white solid (12.7g, 91%)
- Nicotinyl azide (0.06g, 0.4 mmol) in toluene (3ml) was heated under reflux for 1 h, dien cooled. 6,7-Dihydro-5H-thieno[2,3-fjindole (0.07g, 0.4 mmol) in dichloro- methane was added and die mixture was stirred for 1 h at room temperature. A litde petrol was added and die solid product was filtered off, washed widi petrol and dried in vacua to give the tide compound (0.085g, 72%), m.p. 183-185° C.
- Ci6H 13 N3OS requires C, 65.06; H, 4.44; N, 14.23%
- the tide compound was prepared by die metiiod of Example 3 from 2-methyl-4- aminoquinoline (0.46g, 29 mmoles) and 6,7-dihydro-5H-ti ⁇ ieno [2,3-f] indole (D13) (0.5g, 29 mmoles). Recrystallisation from methanol/dichloromethane gave the tide compound as white crystals (0.5 lg, 49%) m.p. 237-8° C.
- the tide compound was prepared by d e metiiod of Example 3 from 4-aminopyridine (0.27 g, 29 mmoles) and 6,7-dihydro-5H-thieno[2,3-f]indole (0.5g, 29 mmoles). Recrystallisation from methanol/dichloromethane gave d e tide compound as light green crystals (0.45g, 53%) m.p. >240° C.
- mCPP m-(chlorophenyl)piperazine
- TFMPP die related drug l-(m- trifluoromethylphenyl)piperazine
- mCPP-induced hypolocomotion was measured in automated locomotion cages of dimensions 56 cm long x 16Vi cm wide x 25 cm high and made of black perspex. Two photobeams traversed die widtii of the cages at either end at ground level. Sequential breaking of these beams allowed d e measurement of cage transits.
- mice Male Sprague Dawley rats (200-250g) (Charles River) were housed in groups of six. They were given drugs orally lh pretest and 40 mins later mCPP (7 mg/kg i.p.). After a further 20 min they were placed in individual automated cages in groups of four under red light in an adjacent room. After 10 min the test was terminated. Reversal of mCPP-induced hypolocomotion was considered as evidence of in vivo central 5-HT2C receptor antagonist properties.
- the compounds of examples 1, 2 and 5 had ID50 values of 1.4 to 9.6 mg/kg p.o. [3H]-mesulergine binding to rat or human 5-HT2C clones expressed in 293 cells in vitro
- 5-HT2C antagonists may have a number of merapeutic indications including die treatment of anxiety, migraine, depression, feeding disorders and obsessive compulsion disorders. (Curzon and Kennett, 1990; Fozard and Gray, 1989) and Alzheimer's Disease (Lawlor, 1989, J. Arch. Gen. Psychiat. Vol. 46 p.542).
- the affinity of test drugs for the 5-HT2C binding site can be determined by assessing their ability to displace [ ⁇ HJ-mesulergine from 5-HT2C clones expressed in 293 cells (Julius et al., 1988). The method employed was similar to that of Pazos et al, 1984.
- the cells suspension (50ml) was incubated widi [ ⁇ HJ-mesulergine (0.5nM) in Tris HCl buffer (pH 7.4) at 37°C for 30 minutes. Non-specific binding was measured in the presence of mianserin (10""M). Ten concentrations of test drug (3 x 10 ⁇ 9 to 10 " M final concentration) were added in a volume of 50ml. The total assay volume was 500ml. Incubation was stopped by rapid filtration using a Brandel cell harvester and radioactivity measured by scintillation counting. The IC50 values were determined using a four parameter logistic program (DeLean 1978) and die pKj (the negative logarithm of the inhibition constant) calculated from the Cheng Prusoff equation where:
- Kd Affinity of mesulergine for 5-HT2C binding sites.
- the compounds of examples 1 to 8 had pKj values from 5 1 to 8-4.
- Rats are trained on a variable interval 30 sec schedule (VI30) to press a lever in order to obtain food reward.
- the 5 min sessions of the VI30 schedule alternate with 2-5 min of a schedule (FR5) in which every 5th lever press is followed by presentation of a food pellet paired wid a 0.5 sec mild footshock.
- the total study lasts approximately 30 mins.
- Rats typically respond widi high rates of lever pressing under die VB0 schedule and low response rates under die FR5 'conflict' session.
- Anxiolytic drugs increase the suppressed response rates of rats in a 'conflict' session.
- Drugs are administered intraperitoneally or orally to groups of 3-8 rats 30 min before testing.
- the results arc expressed as die percentage increase in the square root of the total number of lever presses in the FR5 'conflict' session.
- Square root transformation is necessary to normalise the data for statistical analysis using parametric methods.
- the compounds of Examples 1 and 2 showed a significant increase in responding in the 'conflict' session at dose levels in the range 1 to 2 mg kg p.o.
- the 5-HT receptor in the rat fundic strip has been characterised as 5-HT2B- Hence this tissue may be used to assess the 5-HT2B antagonist properties of compounds.
- rat f indic strips were challenged widi 1 x 10" ⁇ M 5-HT at 15 minute intervals until cumulative concentration-effect curve to the standard agonist 5-HT (1 x 10" ⁇ upwards) was constructed to determine die individual sensitivity of each preparation. A further concentration-effect curve to either 5-HT, or other agonists was constructed no sooner than lh after completion of die previous curve. When necessary tissues were equilibrated widi die antagonists over this one hour period. Antagonists affinities arc expressed as pA2 estimates.
- the compound of Example 2 has a pA2 value of 7.97.
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Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
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EP94912514A EP0691973A1 (en) | 1993-03-29 | 1994-03-22 | THIENO-INDOLE DERIVATIVES AS 5HT2c AND 5HT2b ANTAGONISTS |
JP6521640A JPH08508275A (en) | 1993-03-29 | 1994-03-22 | Thieno-indole derivatives as antagonists of 5HT-lower 2 ▼ -lower c and 5HT-lower 2 ▼ -lower b |
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GB939306460A GB9306460D0 (en) | 1993-03-29 | 1993-03-29 | Novel compounds |
GB9306460.8 | 1993-03-29 |
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WO1994022871A1 true WO1994022871A1 (en) | 1994-10-13 |
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Cited By (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995029177A1 (en) * | 1994-04-23 | 1995-11-02 | Smithkline Beecham P.L.C. | Tricyclic derivatives as 5ht2c and 5ht2b antagonists |
WO1996011929A1 (en) * | 1994-10-12 | 1996-04-25 | Smithkline Beecham Plc | Biheteroaryl-carbonyl and carboxamide derivatives with 5ht 2c/2b antagonists activity |
WO1996023783A1 (en) * | 1995-02-02 | 1996-08-08 | Smithkline Beecham Plc | Indole derivatives as 5-ht receptor antagonist |
WO1996023769A2 (en) * | 1995-02-02 | 1996-08-08 | Smithkline Beecham Plc | Heterocyclic compounds possessing 5ht2c receptor antagonist activity |
WO1997037989A1 (en) * | 1996-04-04 | 1997-10-16 | Smithkline Beecham Plc | Indole derivatives as 5-ht receptor antagonist |
EP0831835A1 (en) * | 1995-06-01 | 1998-04-01 | Eli Lilly And Company | Method for treating anorexia |
WO1999025709A1 (en) * | 1997-11-18 | 1999-05-27 | Smithkline Beecham P.L.C. | Isoquinoline derivatives and their therapeutical use |
KR100470691B1 (en) * | 2000-04-13 | 2005-03-07 | 르 라보레또레 쎄르비에르 | New cyclobutaindolecarboxamide compounds, a process for their preparation and pharmaceutical compositions containing them |
US7030240B2 (en) | 2003-03-31 | 2006-04-18 | Predix Pharmaceuticals Holdings, Inc. | Piperidinylamino-thieno[2,3-d] pyrimidine compounds |
US7407966B2 (en) | 2004-10-07 | 2008-08-05 | Epix Delaware, Inc. | Thienopyridinone compounds and methods of treatment |
US7488736B2 (en) | 2004-05-17 | 2009-02-10 | Epix Delaware, Inc. | Thienopyridinone compounds and methods of treatment |
US7576211B2 (en) | 2004-09-30 | 2009-08-18 | Epix Delaware, Inc. | Synthesis of thienopyridinone compounds and related intermediates |
US7598265B2 (en) | 2004-09-30 | 2009-10-06 | Epix Delaware, Inc. | Compositions and methods for treating CNS disorders |
US7612078B2 (en) | 2003-03-31 | 2009-11-03 | Epix Delaware, Inc. | Piperidinylamino-thieno[2,3-D] pyrimidine compounds |
US8114894B2 (en) | 2008-12-03 | 2012-02-14 | Nanotherapeutics, Inc. | Bicyclic compounds and methods of making and using same |
CN104245691A (en) * | 2012-03-21 | 2014-12-24 | 默克专利股份有限公司 | Process for preparing benzo[1,2-b |
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Cited By (26)
Publication number | Priority date | Publication date | Assignee | Title |
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WO1995029177A1 (en) * | 1994-04-23 | 1995-11-02 | Smithkline Beecham P.L.C. | Tricyclic derivatives as 5ht2c and 5ht2b antagonists |
WO1996011929A1 (en) * | 1994-10-12 | 1996-04-25 | Smithkline Beecham Plc | Biheteroaryl-carbonyl and carboxamide derivatives with 5ht 2c/2b antagonists activity |
US5990133A (en) * | 1995-02-02 | 1999-11-23 | Smithkline Beecham P.L.C. | Indole derivatives as 5-HT receptor antagonist |
WO1996023783A1 (en) * | 1995-02-02 | 1996-08-08 | Smithkline Beecham Plc | Indole derivatives as 5-ht receptor antagonist |
WO1996023769A2 (en) * | 1995-02-02 | 1996-08-08 | Smithkline Beecham Plc | Heterocyclic compounds possessing 5ht2c receptor antagonist activity |
WO1996023769A3 (en) * | 1995-02-02 | 1996-10-24 | Smithkline Beecham Plc | Heterocyclic compounds possessing 5ht2c receptor antagonist activity |
US6638953B2 (en) | 1995-02-02 | 2003-10-28 | Smithkline Beecham P.L.C. | Indole derivatives as 5-HT receptor antagonist |
US6235758B1 (en) * | 1995-02-02 | 2001-05-22 | Smithkline Beecham P.L.C. | Indole derivatives as 5-HT receptor antagonist |
US5972937A (en) * | 1995-02-02 | 1999-10-26 | Smithkline Beecham P.L.C. | Heterocyclic compounds possessing 5HT2C receptor antagonist activity |
EP0831835A1 (en) * | 1995-06-01 | 1998-04-01 | Eli Lilly And Company | Method for treating anorexia |
EP0831835A4 (en) * | 1995-06-01 | 2000-03-01 | Lilly Co Eli | Method for treating anorexia |
US6028085A (en) * | 1996-04-04 | 2000-02-22 | Smithkline Beecham Plc | Indole derivatives as 5-HT receptor antagonist |
WO1997037989A1 (en) * | 1996-04-04 | 1997-10-16 | Smithkline Beecham Plc | Indole derivatives as 5-ht receptor antagonist |
WO1999025709A1 (en) * | 1997-11-18 | 1999-05-27 | Smithkline Beecham P.L.C. | Isoquinoline derivatives and their therapeutical use |
US6274594B1 (en) | 1997-11-18 | 2001-08-14 | Smithkline Beecham P.L.C. | Isoquinoline derivatives and their therapeutical use |
KR100470691B1 (en) * | 2000-04-13 | 2005-03-07 | 르 라보레또레 쎄르비에르 | New cyclobutaindolecarboxamide compounds, a process for their preparation and pharmaceutical compositions containing them |
US7030240B2 (en) | 2003-03-31 | 2006-04-18 | Predix Pharmaceuticals Holdings, Inc. | Piperidinylamino-thieno[2,3-d] pyrimidine compounds |
US7612078B2 (en) | 2003-03-31 | 2009-11-03 | Epix Delaware, Inc. | Piperidinylamino-thieno[2,3-D] pyrimidine compounds |
US7488736B2 (en) | 2004-05-17 | 2009-02-10 | Epix Delaware, Inc. | Thienopyridinone compounds and methods of treatment |
US7982040B2 (en) | 2004-05-17 | 2011-07-19 | Nanotherapeutics, Inc. | Thienopyridinone compounds and methods of treatment |
US7576211B2 (en) | 2004-09-30 | 2009-08-18 | Epix Delaware, Inc. | Synthesis of thienopyridinone compounds and related intermediates |
US7598265B2 (en) | 2004-09-30 | 2009-10-06 | Epix Delaware, Inc. | Compositions and methods for treating CNS disorders |
US7407966B2 (en) | 2004-10-07 | 2008-08-05 | Epix Delaware, Inc. | Thienopyridinone compounds and methods of treatment |
US8114894B2 (en) | 2008-12-03 | 2012-02-14 | Nanotherapeutics, Inc. | Bicyclic compounds and methods of making and using same |
CN104245691A (en) * | 2012-03-21 | 2014-12-24 | 默克专利股份有限公司 | Process for preparing benzo[1,2-b |
US9216994B2 (en) | 2012-03-21 | 2015-12-22 | Merck Patent Gmbh | Process for preparing benzo[1,2-b;4,5-b′]dithiophene-4,8-dicarboxylic acid or its 2,3-dihydro derivative |
Also Published As
Publication number | Publication date |
---|---|
GB9306460D0 (en) | 1993-05-19 |
EP0691973A1 (en) | 1996-01-17 |
JPH08508275A (en) | 1996-09-03 |
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