Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • 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
  • C07D487/04—Ortho-condensed systems

Definitions

• C 1-3 alkyl such as methyl, ethyl, n- and iso- propyl.
• 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.
• Suitable moieties when the ring P is a 5-membered aromatic heterocyclic ring include, for example, isothiazolyl, isoxazolyl, thiadiazolyl and triazolyl.
• Suitable moieties when the ring P is a 6-membered aromatic heterocyclic ring include, for example, pyridyl, pyrimidyl or pyrazinyl.
• the urea moiety can be attached at any position of the ring, preferably to the 4-position.
• the urea moiety can be attached to a carbon or any available nitrogen atom of the ring P, preferably it is attached to a carbon atom.
• Particularly preferred compounds of formula (I) include:
• a and R 6 contain the appropriate functional group(s) necessary to form the moiety, -NR 5' CO when coupled, wherein R 5 ' is R 5 as defined in formula (I) or a group convertible thereto, n is as defined in formula (I), and the variables R 1' ,R 2' , R 3' , R 10' , R 11 ' , R 13' , R 14' , R 4' R 5' and R 7' are R 1 , R 2 , R 3 , R 10 , R 11 , R 13 , R 14 R 4 and R 7 respectively, as defined in formula (I), or groups convertible thereto, and thereafter optionally and as necessary and in any appropriate order, converting any R 1' , R 2' , R 3' , R 10' , R 11' , R 13' , R 14' , R 4' , R 5' and R 7' when other than R 1 , R 2 , R 3 , R 10 , R 11 , R 13 , R 14 , R 4
• R 4' , R 5' , R 7 ', R 13' , and R 14' are as defined in formulae (II) and (III), n is as defined in formula (I), and C and D contain the appropriate functional group(s) necessary to form the indole or indoline ring substituted by R 1' , R 2' , R 3' , R 10' and R 11' as defined in formula (III), and thereafter optionally and as necessary in any appropriate order, converting any R 1' , R 2' , R 3' , R 10' , R 1 1' , R 13' , R 14' , R 4' , R 5' and R 7' when other than R 1 , R 2 , R 3 , R 10 , R 11 , R 13 , R 14 R 4 , R 5 and R 7 , to R 1 , R 2 , R 3 , R 10 , R 1 1 , R 13 , R 14 , R 4 , R 5 and R 7 , interconverting
• R 5' is as defined above and L is a leaving group.
• 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 carried out in an inert solvent such as toluene at elevated temperature, optionally in the presence of a base.
• the product of formula (IV) may then be cyclised as in the Fischer synthesis above.
• Suitable examples of a group R 5' which is convertible to R 5 include
• R 4 halo and R 7 halo may be introduced by selective halogenation of the ring P or indole/indoline ring respectively using conventional conditions.
• N-(1-Acetyl-5-indolinyl)-2-chloro-N-trifluoroacetylallylamine (D12) (7.63 g, 22 mmol) was stirred in polyphosphoric acid (38 g) at 140° C for 1.5h. The mixture was cooled, dispersed in water (200 ml) and extracted with ethyl acetate. The extract was filtered through Kieselguhr, dried (Na2S04) and evaporated to give a dark gum (ca. 3g).
• N-(1-Acetyl-5-indolinyl)-2-chloro-N-methylallylamine (D21) (2.1g, 7.9 mmol) was stirred in polyphosphoric acid (44g) at 140° C for 24h, cooled, dispersed in water (200 ml), and extracted with ethyl acetate. The extract was washed with brine, dried (Na 2 SO 4 ) and evaporated to give a pink solid. Chromatography on silica gel, eluting with 0-20% ethyl acetate in dichloromethane, gave:
• N-(1,2,3,4-Tetrahydro-6-qumolyl)trifluoroacetamide (D26) (5.64g, 23.1 mmol) and acetyl chloride (2.0 ml, 28 mmol) were stirred in dichloromethane (100 ml) as pyridine (2.25 ml, 28 mmol) was added. The mixture was stirred for 0.5h, when water (100 ml) was added. After vigorous stirring for 0.25 h, it was acidified with 5M hydrochloric acid, and separated. The organic portion was washed with brine, dried (Na 2 SO 4 ), and evaporated, giving the title compound (5.24 g, 79%) as a cream solid.
• N-(1-Acetyl-1,2,3,4-tetrahydro-6-quinolyl)trifluoroacetamide (D27) (1.85g, 6.5 mmol) was stirred in ethanol (15 ml), and sodium hydroxide (0.52g, 13.0 mmol) was added in water (3ml). The mixture was stirred at ambient temperature for 0.5 h, and then heated to reflux over 0.25 h. After 0.5 h at reflux, the mixture was cooled, acidified with 5M hydrochloric acid, basified with solid sodium carbonate, diluted with water (100 ml), and extracted with chloroform. The extract was dried (Na 2 SO 4 ) and evaporated to give the title compound (1.38g, >100%) as a brown oil containing residual chloroform (NMR).
• the tide compound was prepared from 5-ethyl-2,3-dihydropyrrolo[2,3-f]indole (D18) and 3-pyridylisocyanate (prepared in situ from nicotinoyl azide) in 58% yield using a procedure similar to that for E1, m.p. 202-203° C.
• the tide compound was prepared from 2-methyl-4-aminoquinoline, 1,1'-carbonyl diimidazole and 5-methyl-(2,3-dihydropyrrolo[2,3-f]indole) (D6), in 57% yield, m.p.>240° C.
• the tide compound was prepared by the method of E23, using 5-amino-3-methylsothiazole hydrochloride (0.60g, 4 mmol), CDI (0.71g, 4.4 mmol), triethylamine (0.56ml, 4 mmol) and dihydropyrroloindole (D6) (0.69g, 4 mmol). Triethylamine was added only with the isothiazole hydrochloride.
• the title compound was prepared from 2-methyl-4-aminopyridine anion (prepared using sodium hydride) 1,1'-carbonyld ⁇ midazole, and 5-methyl-2,3-dihydropyrrolo[2,3-f]indole in dimediylformamide using a procedure similar to that described for Example 5, in 45% yield.
• the mixture may be compressed to tablets, or filled into hard gelatin capsules.
• the tablet may be coated by applying a suspension of film former (e.g. HPM cellulose), pigment (e.g. titanium dioxide) and plasticiser (e.g. diethyl phthalate) and drying the film by evaporation of the solvent
• film former e.g. HPM cellulose
• pigment e.g. titanium dioxide
• plasticiser e.g. diethyl phthalate
• the film coat can comprise 2.0% to 6.0% of the tablet weight preferably about 3.0%.
• the medicinal compound is dispersed or dissolved in the liquid carrier, with a thickening agent added, if required.
• the formulation is then enclosed in a soft gelatin capsule by suitable technology.
• a pharmaceutical composition for parenteral administration may be prepared by combining the following:
• 5-HT 2C antagonists may have a number of therapeutic indications including the 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 cells suspension 400ml was incubated with [ 3 H]-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 -6 M). Ten concentrations of test drug (3 ⁇ 10 -9 to 10 -4 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 IC 50 values were determined using a four parameter logistic program (DeLean 1978) and the pK i (the negative logarithm of the inhibition constant) calculated from the Cheng Prusoff equation where:
• mCPP-induced hypolocomotion was measured in automated locomotion cages of dimensions 56 cm long ⁇ 161 ⁇ 2 cm wide ⁇ 25 cm high and made of black perspex. Two photobeams traversed the wi th of the cages at either end at ground level. Sequential breaking of these beams allowed the measurement of cage transits.
• mice Male Sprague Dawley rats (200-250g) (Charles River) were housed in groups of six. They were given drugs orally 1h 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-HT 2C receptor antagonist properties.
• the compound of Example 2 showed a significant increase in social interaction at doses of 10 mg/kg.
• Rats are trained on a variable interval 30 sec schedule (VT30) to press a lever in order to obtain food reward.
• the 5 min sessions of the Nl 3 0 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 with a 0.5 sec mild footshock.
• the total study lasts approximately 30 mins.
• Rats typically respond with high rates of lever pressing under the VI30 schedule and low response rates under the 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 are expressed as the 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 compound of Example 2 showed a significant increase in responding in the 'conflict' session at dose levels in the range 5 mg/kg p.o.

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• 1993
  • 1993-07-29 EP EP93917699A patent/EP0656003A1/en not_active Ceased
  • 1993-07-29 AU AU47046/93A patent/AU4704693A/en not_active Abandoned
  • 1993-07-29 NZ NZ254785A patent/NZ254785A/en unknown
  • 1993-07-29 CA CA002142721A patent/CA2142721A1/en not_active Abandoned
  • 1993-07-29 JP JP6505828A patent/JPH08500580A/ja active Pending
  • 1993-07-29 WO PCT/EP1993/002031 patent/WO1994004533A1/en not_active Application Discontinuation
  • 1993-08-18 MX MX9305037A patent/MX9305037A/es unknown
  • 1993-08-18 MA MA23262A patent/MA22955A1/fr unknown
  • 1993-08-19 IL IL10673793A patent/IL106737A0/xx unknown
  • 1993-08-19 AP APAP/P/1993/000560A patent/AP9300560A0/en unknown
  • 1993-08-19 TW TW082106679A patent/TW248557B/zh active
  • 1993-08-19 CN CN93116553A patent/CN1086819A/zh active Pending
  • 1993-08-20 SI SI9300438A patent/SI9300438A/sl unknown

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