WO1997008167A1 - 5ht2c and 5ht2b antagonists - Google Patents
5ht2c and 5ht2b antagonists Download PDFInfo
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- WO1997008167A1 WO1997008167A1 PCT/EP1996/003512 EP9603512W WO9708167A1 WO 1997008167 A1 WO1997008167 A1 WO 1997008167A1 EP 9603512 W EP9603512 W EP 9603512W WO 9708167 A1 WO9708167 A1 WO 9708167A1
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- 0 CC1(*C=C2C)*=C(*)C(*)=*C2=C1 Chemical compound CC1(*C=C2C)*=C(*)C(*)=*C2=C1 0.000 description 2
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- 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
- C07D401/14—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 three or more hetero rings
Abstract
Compounds of formula (I) or a salt thereof, wherein R4 is a group of formula (i), a group of formula (ii) or a group of formula (iii) have been found to have 5HT¿2C? receptor antagonist activity. Some or all of the compounds of the invention also exhibit 5HT2B antagonist activity. 5HT2C/2B receptor antagonists are believed to be of potential use in the treatment of CNS disorders.
Description
5HT2C AND 5HT2B ANTAGONISTS
This invention relates to compounds having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of CNS disorders.
WO 94/04533 (SmithKline Beecham pic) describes indole and indoline derivatives which are described as possessing 5HT2C receptor antagonist activity. A structurally distinct class of compounds has now been discovered, which have been found to have 5HT2C receptor antagonist activity. Some or all of the compounds of the invention also exhibit 5HT2B antagonist activity. 5HT2C/2B receptor antagonists are believed to be of potential use in the treatment of CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorders, migraine, Alzheimers disease, sleep disorders, feeding disorders such as anorexia and 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. Compounds of the invention are also expected to be of use in the treatment of certain GI disorders such as IBS as well as micro vascular diseases such as macular oedema and retinopathy.
The present invention therefore provides, in a first aspect, a compound of formula (I) or a salt thereof:
A,B,C and D are all carbon, or one of A,B,C or D is nitrogen and the others are carbon;
E is oxygen, sulphur, CH2 or NR1 where R1 is hydrogen or C1 -6 alkyl;
P is a phenyl or an optionally substituted 5-7-membered heterocyclic ring containing one to three heteroatoms selected from oxygen, nitrogen or sulphur;
R2 and R3 are independently hydrogen, halogen, C1-6 alkyl, C1-6 alkylthio, CF3,
NR9R10 or OR1 1 where R9, R10 and R1 1 are independently hydrogen, C1-6 alkyl or arylC1-6 alkyl; and
R4 is a group of formula (i)
in which:
X and Y are both nitrogen, one is nitrogen and the other is carbon or a CR14 group or one is a CR14 group and the other is carbon or a CR14 group;
R5, R6, R14 and R15 groups are independently hydrogen, C1-6 alkyl optionally substituted by one or more halogen atoms, C2-6 alkenyl, C3-6cycloalkyl,
C3-6cycloalkylC1-6alkoxy, C2-6 alkynyl, C3-6 cycloalkyloxy, C3-6 cycloalkyl-C1-6 alkyl, C1 -6 alkylthio, C3-6 cycloalkylthio, C3-6 cycloalkyl-C1-6 alkylthio,
C1-6alkoxy, hydroxy, halogen, nitro, CF3, C2F5, OCF3, SCF3, SO2CF3, SO2F, formyl, C2-6 alkanoyl, cyano, optionally substituted phenyl or thienyl, NR9R10or
CONR9R10 where R9 and R10 are as defined for R1, CO2R12 where R12 is hydrogen or C1-6 alkyl;
or R5 and R6 form part of an optionally substituted 5-membered carbocyclic or heterocyclic ring;
R7 and R8 are independently hydrogen or C1-6 alkyl; or
R4 is a group of formula (ii):
X and Y are both CR14 groups and R5, R6, R14 and R15 are as defined in formula
(i); and
R13 is hydrogen or C1-6 alkyl, or
in which R5, R6, X and Y are as defined for formula (i) and Z is oxygen, sulphur, CH2 or NR13 where R13 is hydrogen or C1-6 alkyl.
C1-6 Alkyl groups, whether alone or as part of another group, may be straight chain or branched.
Preferably P is pyridyl, in particular a 3-pyridyl or 4-pyridyl group.
Preferably E is NR1 where R1 is hydrogen.
Preferably R2 is hydrogen.
Preferably R4 is a group of formula (i). Preferably X and Y form part of a phenyl ring, that is to say one of X or Y is carbon and the other is a CH group or both of X and Y are CH groups. Most preferably R4 is an indoline ring, that is to say a group of formula (A):
When R5 and R6 form part of an aromatic ring suitable rings include thiophene, furan and pyrrole rings. Preferred R5 and R6 groups, which can be the same or different, include C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, halogen, CF3, and CO2R1 1 where R1 1 is hydrogen or C1-6 alkyl Preferably R5 is trifluoromethyl or chloro and R6 is C1-6alkylthio, C1-6alkyl or C1-6alkoxy.
Particularly preferred compounds of the invention include:
1-(5-(3-Pyridyl)-3-indolylcarbonyl-5-methoxy-6-trifluoromethylindoline,
1-(5-(4-Pyridyl)-3-indolylcarbonyl)-5-methoxy-6-trifluoromethyl indoline,
1-(6-(3-Pyridyl)-3-indolylcarbonyl)-5-methoxy-6-trifluoromethyl indoline,
1-(6-(4-Pyridyl)-3-indolylcarbonyl)-5-methoxy-6-trifluoromethyl indoline, and pharmaceutically acceptable salts thereof.
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. Quaternary salts of intermediate compounds in which P is an
aromatic group such as pyridyl can also be prepared with C1-6alkylating agents, for example methyl iodide, and such salts also form an aspect of the invention.
Compounds of formula (I) may also form N-oxides or solvates such as hydrates, and the invention also extends to these forms. When referred to herein, it is understood that the term 'compound of formula (I)' also includes these forms.
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. The invention also extends to any tautomeric forms 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) the coupling of a compound of formula (II);
with a compound of formula (III);
wherein R1 6 and R17 contain the appropriate functional group(s) necessary to form a bond when coupled, A, B, C, D and P are as defined in formula (I), E is as defined in formula (I) or is a group NR1 ' and the variables, R1 ', R2', R3' and R4' are R1, R2, R3 and R4 respectively, as defined in formula (I), or groups convertible thereto, and thereafter optionally and as necessary and in any appropriate order, converting any R1 ', R2', R3' and R4', when other than R1, R2, R3 and R4 respectively to R1, R2, R3
and R4, interconverting R1, R2, R3 and R4 and forming a pharmaceutically acceptable salt thereof, or
(b) coupling a compound of formula (IV):
wherein P, A, B, C, D, E, R2' and R3' are as defined above and L is a leaving group with a compound of formula (V):
R4'- H (V) wherein R4 is as defined above and thereafter optionally and as necessary and in any appropriate order, converting any R1 ', R2', R3' and R4', when other than R1 , R2, R3 and R4 respectively to R1, R2, R3 and R4, interconverting R1, R2, R3 and R4 and forming a pharmaceutically acceptable salt thereof.
Preferably R17 is a leaving group such as halogen and in particular bromo. Preferably R16 is a boronic acid group. Compounds of formula (II) and (III) are reacted together using standard boronic acid coupling conditions in the presence of an organometallic catalyst. Preferred catalysts are palladium catalysts, in particular tetrakis (triphenylphosphine) palladium(O).
For process (b) L is a leaving group such as halogen, in particular chloro.
Compounds of formula (IV) and (V) can be reacted together using standard reaction conditions known in the art.
R1 to R3 groups can be introduced at any suitable stage in the process, preferably R1 to R3 groups are introduced at an early stage in the process. It should be appreciated that it is preferred that all groups R1 to R3 are introduced before coupling compounds of formula (II) and (III).
Suitable examples of groups R1 ', R2' and R3' which are convertible to R1,
R2 and R3 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.
Interconversions of R1, R2 and R3 are carried out by conventional procedures. For example halo groups can be introduced by selective halogenation of the ring P or the benzene ring of the indoline group using conventional conditions. It should be appreciated that it may be necessary to protect any R1 to R3 hydrogen variables which are not required to be interconverted.
Suitable protecting groups and methods for their attachment and removal are conventional in the art of organic chemistry, such as those described in Greene T.W. 'Protective groups in organic synthesis' New York, Wiley (1981).
Compounds of formula (II), (III), (IV) and (V) may be prepared according to known methods or analogous to known methods.
Novel intermediates of formula (III) and (IV) also form part of the invention. Parmaceutically acceptable 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 5HT2B/2C receptor antagonist activity and are believed to be of potential use for the treatment or prophylasis of CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorders, migraine, Alzheimers disease, sleep disorders, feeding disorders such as anorexia and 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. Compounds of the invention are also expected to be of use in the treatment of certain GI disorders such as IBS as well as microvascular diseases such as macular oedema and retinopathy.
Thus 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 prophylaxis of the above disorders.
The invention further provides a method of treatment or prophylaxis of the above disorders, 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.
In another aspect, 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 the above disorders.
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.
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 sterilization 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 0.05 to 70.0 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 0.5 to 100 mg; and such therapy may extend for a number of weeks or months.
When administered in accordance with the invention, no unacceptable toxicological effects are expected with the compounds of the invention.
The following Descriptions and Examples illustrate the preparation of compounds of the invention.
Description 1
1-Methoxy-4-nitro-2-trifluoromethylbenzene (D1)
Sodium (11.78g, 0.512 mol) was dissolved in dry methanol (1 1) and to the resulting solution was added a solution of 1-chloro-4-nitro-2-trifluoromethyl-benzene (96.22g, 0.427 mol) in methanol (100 ml). The reaction mixture was refluxed for 3 h then cooled and evaporated in vacuo. The residue was partitioned between water (500 ml) and dichloromethane (3 × 400 ml). The combined organic extracts were dried
(Na2SO4) and evaporated to give the title compound (93.76g, 99%) as a white solid.
NMR (CDCI3) δ: 4.05 (3H, s), 7.12 (1H, d), 8.45 (1H, dd), 8.52 (1H, d). Description 2
(5-Methoxy-2-nitro-4-trifluoromethylphenyl)acetonitrile (D2)
A mixture of 1-methoxy-4-nitro 2-trifluoromethylbenzene (D1) (93g, 0.421 mol) and 4-chlorophenoxyacetonitrile (77.55g, 0.463 mol) in dry DMF (500 ml) was added dropwise over 0.75 h to a stirred solution of KOlBu (103.85g, 0.927 mol) in dry DMF (400 ml) at -10° C. After complete addition the resulting purple solution was maintained at -10° C for 1 h then poured into a mixture of ice/water (1.5 1) and 5 M aqueous HCl (1.5 1). The resulting mixture was extracted with dichloromethane (3 × 1 1). The combined extracts were washed with water (3 1), dried (Na2SO4) and evaporated under reduced pressure. The residue was chromatographed on silica using 10-40% ethyl acetate/petroleum ether as eluant to give the crude product which was recrystallised from ethyl acetate/petroleum ether to afford the title compound (85.13g, 78%) as a white solid. Mp 103-104 °C. NMR (CDCI3) δ: 4.10 (3H, s), 4.37 (2H, s), 7.34 (1H, s), 8.53 (1H, s).
Description 3
5-Methoxy-6-trifluoromethylindole (D3) (5-Methoxy-2-nitro-4-trifluoromethylphenyl)acetonitrile (D2) (85g, 0.327 mol) in ethanol/water (9:1, 1.6 1) and glacial acetic acid (16 ml) was hydrogenated over 10% palladium on carbon (50 g) at 50 psi for 0.5 h at room temperature. The reaction mixture was filtered and evaporated in vacuo. The residue was partitioned between
aqueous K2CO3 (1 1) and dichloromethane (2 × 1 1) and the combined organic extract was dried (Na2SO4) and evaporated to afford the title indole (67.63g, 96%) as a grey solid. NMR (CDCI3) δ: 3.94 (3H, s), 6.53 (1H, m), 7.21 (1H, s), 7.32 (1H, m), 7.64 (1H, s), 8.25 (1H, br s).
Description 4
5-Methoxy-6-trifluoromethylindoline (D4)
The indole (D3) (67.63g, 0.315 mol) was treated with sodium cyanoborohydride (40 g, 0.637 mol) in glacial acetic acid (500 ml) using standard procedures to afford the title indoline (67.73%, 99%) as an off-white solid. NMR (CDCI3) δ: 3.07 (2H, t), 3.58 (2H, t), 3.67 (1H, br s), 3.83 (3H, s), 6.83 (1H, s), 6.88 (1H, s).
Description 5
1-(5-Bromo-3-indoIylcarbonyl)-5-methoxy-6-trifluoromethyl indoline (D5)
A solution of 5-bromoindole-3-carboxylic acid (A.S. Katner, Org. Prep. Proced, 1970, 2, 297) (1.13g, 4.7 mmol) in dry tetrahydrofuran (50 mL) was treated with oxalyl chloride (0.43 mL, 5 mmol) and dimethylformamide (5 drops). The mixture was stirred at room temperature for 1 h, then evaporated to dryness. Tetrahydrofuran (25 mL) was added to the residue, followed by 5-methoxy-6-trifluoromethyl indoline (D4, 1.1g, 5 mmol) and triethylamine (0.7 mL, 5 mmol) in tetrahydrofuran (25 mL). The mixture was stirred overnight, then poured into water. The precipitate was filtered off, washed with water and dried. The crude product was chromatographed on silica gel eluted with 3-4% methanol/dichloromethane. Eluted product was triturated with dichloromethane/methanol to give the title compound (0.89g, 43%), Mp.
>250°C.
NMR (d6DMSO) δ: 3.28 (2H, t, J=8), 3.88 (3H, s), 4.97 (2H, t, J=8), 7.26 (1H, s), 7.33 (1H, d, J=8), 7.47 (1H, d, J=8), 8.11 (1H, s), 8.29 (1H, s), 8.41 (1H, s)
MS (API): m/z=439 (MH+, 79Br), 441 (MH+, 81Br)
C19H14N2O2BrF3 requires M+1 = 439 and 441
Description 6
6-Bromo-3-(trichloroacetyl)indole (D6)
A mixture of 6-bromoindole (1.18g, 6.0 mmol), trichloroacetyl chloride (1.0 mL, 9 mmol) and pyridine (0.72 mL, 9 mmol) in dry 1,4-dioxan (12 ml) was stirred overnight at room temperature, then heated at 90°C until the reaction appeared complete by T.L.C. The mixture was poured into water and the precipitate was filtered off, washed with water and dried. The crude product was recrystallised from ethanol/water to give the title compound (1.36g, 66%), Mp. 234-40°C.
NMR (d6DMSO) δ: 7.47 (1H, dd, J=7,1), 7.80 (1H, d, J=1), 8.23 (1H, d, J=7), 8.64 (1H,s), 12.63 (1H, s).
MS (API) m/z=338, 340, 342. 344 ([M-H]-)
Description 7
6-Bromo-3-indolecarboxylic acid (D7)
A solution of trichloroacetylindole (D6, 1.33g, 3.9 mmol) in methanol containing one drop of 60% aqueous potassium hydroxide was heated under reflux for 3h. Dilute (10%) aqueous sodium hydroxide (10 mL) was added and the mixture was heated under reflux for 2.5 h. Most of the solvent was then removed in vacuo and the residue was diluted with water and extracted with dichloromethane. The aqueous phase was then acidified with dilute hydrochloride acid and extracted with
dichloromethane/methanol. This extract was dried and evaporated to give the title-compound (0.79g, 84%).
NMR (d6DMSO) δ: 7.32 (1H, dd, J=7,2), 7.68 (1H, s), 7.95 (1H, d, J=7), 8.04 (1H, d, J=2), 11.93 (1H, s), 12.15 (1H, s).
MS (API): m/z=238 ([M-H]-, 79Br), 240 ([M-H]-, 81Br)
C9H6NO2Br requires M-1 = 238 and 240
Description 8
1-(6-Bromo-3-indolylcarbonyl)-5-methoxy-6-trifluoromethyl indoline (D8)
The title compound was prepared by the method of Description 5, using 6-bromoindolecarboxylic acid (D7, 0.79g, 3.3 mmol). Chromatography on silica gel
eluted with 3-5% methanol/dichloromethane, followed by trituration with
dichloromethane/methanol gave the title compound (0.89g, 61%), Mp. >250° C.
MHR (d6DMSO) δ: 3.27 (2H, t, J=8), 3.88 (3H, s), 4.95 (2H, t, J=8), 7.28 (2H, m), 7.67 (1H, s), 8.05 (1H, d, J=8), 8.08 (1H, s), 8.49 (1H, s), 11.95 (1H, broad).
MS (API): m/z = 439 (MH+, 78Br), 441 (MH+, 81Br)
C19H14N2OBrF3 requires M+1 = 439 and 441 Example 1
1-(5-(3-PyridyI)-3-indolylcarbonyl-5-methoxy-6-trifluoromethyIindoline (El)
A mixture of the 5-bromoindolecarboxamide (D5, 0.30g,0.68 mmol), 3-pyridylboronic acid (Chem Pharm Bull 1983, 31(12) 4573) (86 mg, 0.7 mmol), tetrakis (triphenylphosphine) palladium (23 mg, 0.02 mmol) and sodium carbonate (0.28g, 2.7 mmol) in 1,2-dimethoxyethane (20 ml) and water (2 ml) was heated under reflux overnight. The mixture was then cooled and poured into water. The precipitate was filtered off, washed with water and dried. The residue was chromatographed on silica gel eluted with 4-5% methanol/ dichloromethane to give the title compound (0.21g, 71%), Mp. >250°C.
NMR (d6DMSO) δ : 3.28 (2H, t, J=8), 3.88 (3H, s), 4.48 (2H, t, J=8), 7.27 (1H, s), 7.48 (1H, dd, J=7, 5), 7.56 (1H, d, J=8), 7.62 (1H, d, J=8), 8.08 (1H, d, J=7), 8.11 (1H, d, J=2), 8.39 (1H, s), 8.42 (1H, s), 8.54 (1H, d, J=5), 8.89 (1H, s).
MS (API): Found m/z 438 (MH+)
C24H18N3O2F3 requires M+1 = 438
Example 2
1-(5-(4-Pyridyl)-3-indolylcarbonyl)-5-methoxy-6-trifluoromethyl indoline (E2)
The title compound was prepared by the method of Example 1, using
4-pyridylboronic acid (Rec Trav Chim Pay Bas 1965, 84, 439) (0.10g, 0.81 mmol). Chromatography and recrystallisation from methanol gave the title compound (0.08g, 27%), Mp. >250°C.
NMR (d6DMSO) δ: 3.28 (2H, t, J=8), 3.89 (3H, s), 4.49 (2H, t, J=8), 7.28 (1H, s), 7.62 (1H, d, J=8), 7.67 (1H, d, J=8), 7.72 (2H, d, J=7), 8.13 (1H, s), 8.42 (1H, s), 8.52 (1H, s), 8.61 (2H, d, J=7), 12.03 (1H, s). MS (API) : Found m/z 438 (MH+)
C24H18N8O2F3 requires M+1 = 438
Example 3
1 -(6-(3-Pyridyl)-3-indolylcarbonyI)-5-methoxy-6-trifluoromethyl indoline (E3)
The title compound was prepared by the method of Example 1, using the
6-bromoindolecarboxamide (D8, 0.30g, 0.68 mmol) and 3-pyridylboronic acid (92 mg, 0.75 mmol). Recrystallisation from dichloromethane/methanol gave the title compound (0.15g, 50%), Mp. 242°C (decomp.)
NMR (d6DMSO) δ: 3.28 (2H, t, J=8), 3.88 (3H, s), 4.49 (2H, t, J=8), 7.28 (1H, s), 7.50 (2H, m), 7.79 (1H, s), 8.10 and 8.13 (2H, s+d), 8.21 (1H, d, J=8), 8.42 (1H, s), 8.57 (1H, d, J=5), 8.94 (1H, s), 12.00 (1H, s). MS (API): Found m/z 438 (MH+)
C24H18N3O2F3 requires M+1 = 438
Example 4
1-(6-(4-Pyridyl)-3-indolylcarbonyl)-5-methoxy-6-trifluoromethyl indoline (E4)
The title compound was prepared by the method of Example 1, using the
6-bromoindolecarboxamide (D8, 0.40g, 0.9 mmol) and 4-pyridylboronic acid (0.27g, 2.2 mmol). Chromatography on silica gel, eluted with 3-6%
methanol/dichloromethane gave the title compound (0.17g, 43%), Mp. >250°C.
NMR (d6DMSO/d6-acetone) δ: 3.29 (2H, t, J=8), 3.88 (3H, s), 4.50 (2H, t, J=8), 7.25 (1H, s), 7.61 (1H, d, J=8), 7.75 (2H, d, J=7), 7.88 (1H, s), 8.14 (1H, d, J=2), 8.25 (1H, d, J=8), 8.44 (1H, s), 8.62 (2H, d, J=7), 12.05 (1H, s). MS (API): m/z=438
C24H18N3O2F3 requires M+1 = 438
Found: C, 65.14; H, 4.33; N, 9.49%
C24H18N3O2F3 requires C, 65.90; H, 4.15; N, 9.61% Pharmacological data [3H]-mesulergine binding to rat or human 5-HT2C clones expressed in 293 cells in vitro
Compounds were tested following the procedure outlined in WO 94/04533. The compounds of examples 1 to 4 have pKi values of 7.5 to 8.1.
Claims
Claims: 1. A compound of formula (I) or a salt thereof:
A,B,C and D are all carbon, or one of A,B,C or D is nitrogen and the others are carbon;
E is oxygen, sulphur, CH2 or NR1 where R1 is hydrogen or C1-6 alkyl;
P is a phenyl or an optionally substituted 5-7-membered heterocyclic ring containing one to three heteroatoms selected from oxygen, nitrogen or sulphur;
R2 and R3 are independently hydrogen, halogen, C1 -6 alkyl, C1-6 alkylthio, CF3,
NR9R10 or OR1 1 where R9, R10 and R1 1 are independently hydrogen, C1-6 alkyl oraryl C1-6 alkyl; and
R4 is a group of formula (i)
X and Y are both nitrogen, one is nitrogen and the other is carbon or a CR14 group or one is a CR14 group and the other is carbon or a CR14 group;
R5, R6, R14 and R1 5 groups are independently hydrogen, C1-6 alkyl optionally substituted by one or more halogen atoms, C2-6 alkenyl, C3-6cycloalkyl,
C3-6cycloalkylC1 -6-alkoxy, C2-6 alkynyl, C3-6 cycloalkyloxy, C3-6 cycloalkyl- C1-6 alkyl, C1-6 alkylthio, C3-6 cycloalkylthio, C3-6 cycloalkyl-C1-6 alkylthio,
C1-6alkoxy, hydroxy, halogen, nitro, CF3, C2F5, OCF3, SCF3, SO2CF3, SO2F, formyl, C2-6 alkanoyl, cyano, optionally substituted phenyl or thienyl, NR9R 10 or CONR9R10 where R9 and R10 are as defined for R1, CO2R12 where R12 is hydrogen or C1-6 alkyl;
or R5 and R6 form part of an optionally substituted 5-membered carbocyclic or heterocyclic ring;
R7 and R8 are independently hydrogen or C1-6 alkyl; or
R4 is a group of formula (ii):
in which X and Y are both nitrogen, one is nitrogen and the other is a CR14 group or X and Y are both CR14 groups and R5, R6, R14 and R 15 are as defined in formula (i); and
R13 is hydrogen or C1-6 alkyl, or
R4 is a group of formula (iii):
in which R5, R6, X and Y are as defined for formula (i) and Z is oxygen, sulphur, CH2 or NR13 where R13 is hydrogen or C1-6 alkyl.
2. A compound according to claim 1 in which P is pyridyl.
3. A compound according to claim 1 or 2 in which R1 is hydrogen.
4. A compound according to any one of claims 1 to 3 in which R2 is
hydrogen.
5. A compound according to any one of claims 1 to 4 in which R4 is a group of formula (i).
6. A compound according to any one of claims 1 to 5 in which R5 and R6 are C1-6alkyl and C1-6alkylthio.
7. A compound according to claim 1 which is: 1-(5-(3-Pyridyl)-3-indolylcarbonyl-5-methoxy-6-trifluoromethylindoline,
1-(5-(4-Pyridyl)-3-indolylcarbonyl)-5-methoxy-6-trifluoromethyl indoline,
1-(6-(3-Pyridyl)-3-indolylcarbonyl)-5-methoxy-6-trifluoromethyl indoline,
1-(6-(4-Pyridyl)-3-indolylcarbonyl)-5-methoxy-6-trifluoromethyl indoline, and pharmaceutically acceptable salts thereof.
8. A compound according to any one of claims 1 to 7 for use in therapy.
9. A pharmaceutical composition which comprises a compound according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier or excipient.
10. A process for the preparation of a compound of formula (I) or a
pharmaceutically acceptable salt thereof, which process comprises:
(a) the coupling of a compound of formula (II);
with a compound of formula (III);
wherein R16 and R17 contain the appropriate functional group(s) necessary to form a bond when coupled, A, B, C, D and P are as defined in formula (I), E is as defined in formula (I) or is a group NR1 ' and the variables, R1 ', R2', R3' and R4' are R1, R2, R3 and R4 respectively, as defined in formula (I), or groups convertible thereto, and thereafter optionally and as necessary and in any appropriate order, converting any R1 ', R2', R3' and R4', when other than R1, R2, R3 and R4 respectively to R1, R2, R3 and R4, interconverting R1, R2, R3 and R4 and forming a pharmaceutically acceptable salt thereof, or (b)
coupling a compound of formula (IV): wherein P, A, B, C, D, E, R2' and R3' are as defined above and L is a leaving group with a compound of formula (V):
R4'- H (V) wherein R4' is as defined above and thereafter optionally and as necessary and in any appropriate order, converting any R1 ', R2', R3' and R4', when other than R1, R2, R3 and R4 respectively to R1, R2, R3 and R4, interconverting R1, R2, R3 and R4 and forming a pharmaceutically acceptable salt thereof.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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GB9517559.2 | 1995-08-26 | ||
GBGB9517559.2A GB9517559D0 (en) | 1995-08-26 | 1995-08-26 | Novel compounds |
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WO1997008167A1 true WO1997008167A1 (en) | 1997-03-06 |
Family
ID=10779844
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Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1996/003512 WO1997008167A1 (en) | 1995-08-26 | 1996-08-06 | 5ht2c and 5ht2b antagonists |
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WO1999063996A1 (en) * | 1998-06-08 | 1999-12-16 | Advanced Medicine, Inc. | Multivalent agonists, partial agonists, inverse agonists and antagonists of the 5ht2 receptors |
WO1999064044A1 (en) * | 1998-06-08 | 1999-12-16 | Advanced Medicine, Inc. | Novel therapeutic agents that modulate 5-ht receptors |
WO2000044737A1 (en) * | 1999-01-27 | 2000-08-03 | Eli Lilly And Company | Aminoalkylbenzofurans as serotonin (5-ht(2c)) agonists |
WO2001009111A1 (en) * | 1999-07-29 | 2001-02-08 | Eli Lilly And Company | Benzofurylpiperazines and benzofurylhomopiperazines: serotonin agonists |
WO2001009123A1 (en) * | 1999-07-29 | 2001-02-08 | Eli Lilly And Company | Benzofurylpiperazine serotonin agonists |
WO2002098857A1 (en) * | 2001-06-07 | 2002-12-12 | F. Hoffmann-La Roche Ag | New indole derivatives with 5-ht6 receptor affinity |
WO2005044812A1 (en) * | 2003-10-24 | 2005-05-19 | Wyeth A Corporation Of The State Of Delaware | Dihydrobenzofuranyl alkanamine derivatives as 5ht2c agonists |
US7045545B1 (en) | 1999-01-27 | 2006-05-16 | Eli Lilly And Company | Aminoalkylbenzofurans as serotonin (5-HT(2c)) agonists |
US7091216B2 (en) | 2002-08-02 | 2006-08-15 | Merck & Co., Inc. | Substituted furo[2,3-b]pyridine derivatives |
WO2007030150A1 (en) * | 2005-04-22 | 2007-03-15 | Wyeth | Dihydrobenzofuranyl alkanamine derivatives as 5ht2c agonists |
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US7638530B2 (en) | 2003-04-24 | 2009-12-29 | Merck & Co., Inc. | Inhibitors of Akt activity |
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US7964603B2 (en) | 2007-07-19 | 2011-06-21 | Laboratorios Del Dr. Esteve, S.A. | Substituted tetrahydro-quinoline-sulfonamide compounds, their preparation and use as medicaments |
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US8138210B2 (en) | 2006-07-31 | 2012-03-20 | Laboratorios Del Dr. Esteve, S.A. | Substituted indanyl sulfonamide compounds, their preparation and use as medicaments |
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