WO2005016922A1 - Derives carbazole-2-carboxamides possedant une activite antagoniste du recepteur vanilloide - Google Patents

Derives carbazole-2-carboxamides possedant une activite antagoniste du recepteur vanilloide Download PDF

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Publication number
WO2005016922A1
WO2005016922A1 PCT/EP2004/009082 EP2004009082W WO2005016922A1 WO 2005016922 A1 WO2005016922 A1 WO 2005016922A1 EP 2004009082 W EP2004009082 W EP 2004009082W WO 2005016922 A1 WO2005016922 A1 WO 2005016922A1
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formula
compound
alkyl
pharmaceutically acceptable
solvate
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PCT/EP2004/009082
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English (en)
Inventor
Harshad Kantilal Rami
Mervyn Thompson
Susan Marie Westaway
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Glaxo Group Limited
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Publication of WO2005016922A1 publication Critical patent/WO2005016922A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Vanilloids are a class of natural and synthetic compounds that are characterised by the presence of a vanillyl (4-hydroxy 3-methoxybenzyl) group or a functionally equivalent group.
  • Vanilloid Receptor (VR-1 ) whose function is modulated by such compounds, has been widely studied and is extensively reviewed by Szallasi and Blumberg (The American Society for Pharmacology and
  • Vanilloid compounds of different structures are known in the art, for example those disclosed in European Patent Application Numbers,
  • vanilloid compounds or vanilloid receptor modulators are capsaicin or trans 8-methyl-N- vanillyl-6-nonenamide which is isolated from the pepper plant, capsazepine
  • WO 02/090326, WO 03/022809, WO 03/053945, WO 03/068749 and WO 04/024710; and co-pending International Patent Application Numbers PCT/GB2004/000543, PCT/EP2004/002377, PCT/GB2004/000978 and PCT/EP2004/002376 also describe a variety of compounds having activity as vanilloid receptor antagonists. According to a first aspect of the present invention, there is provided a compound of formula (I),
  • R1 and R2 may be the same or different and represent -H, alkyl, alkoxy, halo, -
  • CF3 cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, aryloxyalkyl, - (CH2) ⁇ OR 6 or -
  • R 3 and R5 which may be the same or different, represent -H, halo, alkyl, alkoxy, cycloalkyl, aralkyl, aralkoxy, cycloalkylalkyl, cycloalkylalkoxy, -CN, -NO2, -OH, -
  • R4 represents -H, alkyl, -(CH2) x OR 8 or-(CH 2 ) x NR6R7;
  • R6 and R may be the same or different and represent H or alkyl or R and R together with the atoms to which they are attached form a Ca-eazacycloalkane, C 3 _ 6 (2-oxo)azacycloalkane ring or C 5 .
  • 8 polymethylene chain optionally interrupted by heteroatoms such as O or -NR 8 ;
  • R 8 represents -H, alkyl or aryl;
  • Ar represents aryl or heteroaryl;
  • x represents an integer 0, 1 , 2, 3, 4, 5 or 6; and
  • Z represents a bond, O, S, NR 8 or CH2.
  • R1 and R2 may be the same or different and represent -H, alkyl such as methyl, alkoxy such as methoxy or-CF ⁇ .
  • R " ! and R2 together with the carbon atoms to which they are attached form a benzothiazole group (when taken together with the phenyl ring), which benzothiazole group may be optionally substituted by an alkyl group, such as methyl.
  • R 8 and R each represent -H.
  • R 4 represents -H, -(CH2)2 ⁇ Me or -(CH2)2-NR 6 R 7 .
  • x represents 0, 1 , 2 or 3.
  • R 8 represents hydrogen, methyl or ethyl.
  • R represents hydrogen, methyl or ethyl.
  • Examples of the C 3 . 6 ring that R 6 and R 7 may independently represent, when taken together with the atoms to which they are attached, include pyrrolidine, morpholine and piperidine.
  • R 8 represents methyl.
  • Z represents a bond.
  • Ar represents phenyl.
  • R1 and R2 may be the same or different and represent -H, alkyl, alkoxy or -CF3; or R1 and R2 together with the carbon atoms to which they are attached form a benzothiazole group (when taken together with the phenyl ring), which benzothiazole group may be optionally substituted by one or more groups selected from alkyl, such as methyl, alkoxy, halo, -CF3, -OH or -NO2; R 3 represents -H, alkyl, -(CH2) ⁇ OR 6 or -(CH 2 ) X NR 4 R5; R 4 and R ⁇ may be the same or different and represent H or alkyl or R 4 and R together with the atoms to which they are attached form a C 3 -eazacycloalkane, C3-6.2-oxo)azacycloalkane ring or C 5 . 8 polymethylene chain optionally interrupted by heteroatoms such as O or -NR 6 ; R6 represents -H, al
  • Preferred compounds according to this invention include Examples 1 - 9 or pharmaceutically acceptable salts or solvates thereof. Particularly preferred compounds according to this invention include Examples 1 - 4 or pharmaceutically acceptable salts or solvates thereof.
  • Certain of the carbon atoms of formula (I) are chirai carbon atoms, and therefore compounds of formula (I) may exist as stereoisomers.
  • the invention extends to all optical isomers such as stereoisomeric forms of the compounds of formula (I) including enantiomers and mixtures thereof, such as racemates.
  • the different stereoisomeric forms may be separated or resolved one from the other by conventional methods or any given isomer may be obtained by conventional stereospecific or asymmetric syntheses.
  • the compounds of formula (I) can form salts, especially pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts are those used conventionally in the art and include those described in J. Pharm. Sci., 1977, 66, 1-19, such as acid addition salts.
  • Suitable pharmaceutically acceptable salts include acid addition salts.
  • Suitable pharmaceutically acceptable acid addition salts include salts with inorganic acids such, for example, as hydrochloric acid, hydrobromic acid, orthophosphoric acid or sulphuric acid, or with organic acids such, for example as methanesulphonic acid, toluenesulphonic acid, acetic acid, propionic acid, lactic acid, citric acid, fumaric acid, malic acid, succinic acid, salicylic acid, maleic acid, glycerophosphoric acid or acetylsalicylic acid.
  • the salts and/or solvates of the compounds of the formula (I) which are not pharmaceutically acceptable may be useful as intermediates in the preparation of pharmaceutically acceptable salts and/or solvates of compounds of formula (I) or the compounds of the formula (I) themselves, and as such form another aspect of the present invention.
  • the compounds of formula (I) may be prepared in crystalline or non-crystalline form, and if crystalline, may be optionally hydrated or solvated.
  • This invention includes in its scope stoichiometric hydrates as well as compounds containing variable amounts of water.
  • Suitable solvates include pharmaceutically acceptable solvates, such as hydrates.
  • Solvates include stoichiometric solvates and non-stoichiometric solvates.
  • alkyl refers to a straight or branched chain saturated aliphatic hydrocarbon radical containing 1 to 12 carbon atoms, suitably 1 to 6 carbon atoms.
  • alkyl groups in particular include methyl ("Me”), ethyl ("Et”), n-propyi (“Pr””), /so-propyl (“Pr””), n-butyl (“Bun”), S ec-butyl ("Bu S "), terf-butyl ("But”), pentyl and hexyl.
  • cycloalkyl refers to a saturated alicyclic hydrocarbon radical containing 3 to 12 carbon atoms, suitably 3 to 6 carbon atoms.
  • alkyl groups may be substituted by one or more groups selected from halo (such as fluoro, chloro, bromo), -CN, -CF3, -OH, -OCF3, C2- 6 alkenyl, C3_ alkynyl, C-j.g alkoxy, aryl and di-C-). ⁇ alkylamino.
  • Alkyl is preferably unsubstituted.
  • alkoxy refers to an alkyl ether radical, wherein the term “alkyl” is defined above.
  • alkoxy groups in particular include methoxy, ethoxy, n-propoxy, /so-propoxy, n-butoxy, /so-butoxy, sec-butoxy and tet -butoxy.
  • alkoxy groups may be substituted by one or more groups selected from halo (such as fluoro, chloro, bromo), -CN, -CF3, -OH, -OCF3, C-j.g alkyl, C2-6 alkenyl, C3-.5 alkynyl, aryl and di-C ⁇ _ ⁇ alkylamino.
  • Alkoxy is preferably unsubstituted.
  • aryl as a group or part of a group refers to a carbocyclic aromatic radical (“Ar").
  • aryl groups are 6 membered monocyclic groups or 8-10 membered fused bicyclic groups (including aromatic systems fused with non-aromatic systems), especially phenyl ("Ph"), biphenyl, indene and naphthyl, particularly phenyl.
  • Aryl and heteroaryl groups contained within moieties R or Ar may optionally be substituted with one or more substituents selected from the list consisting of halo, hydroxy, carbonyl, alkoxy, alkyl, -CF 3 , NR 6 R 7 and -SO 2 R 8 .
  • the term "naphthyl” is used herein to denote, unless otherwise stated, both naphth-1-yl and naphth-2-yl groups.
  • heteroaryl as a group or part of a group refers to a stable 5- 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic aromatic ring (including an aromatic ring system fused with a non- aromatic ring system) which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.
  • heteroaryl groups include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1 ,5,2-dithiazinyl, _ favor-- -- * .
  • PCT/EP2004/009082 PCT/EP2004/009082
  • heterocyclyl and “heterocyclic” as a group or part of a group refer to stable heterocyclic non-aromatic single and fused rings containing one or more heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • a fused heterocyclyl ring system may include carbocyclic rings and need include only one heterocyclic ring.
  • suitable heterocyclyl groups include, but are not limited to, piperazinyl, homopiperazinyl, piperidinyl, pyrrolidinyl and morpholinyl.
  • halo is used herein to describe, unless otherwise stated, a group selected from fluorine (“fluoro”), chlorine (“chloro”), bromine (“bromo”) or iodine ("iodo”).
  • fluorine fluorine
  • chlorine chloro
  • bromine bromine
  • iodine iodo
  • the present invention also provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, which process comprises: (a) reacting a compound of formula (II),
  • R ⁇ and R2 are as defined in relation to formula (I), with a compound of formula (III),
  • R 3 , R 4 and R ⁇ are as defined in relation to formula (I) and thereafter, as necessary, carrying out one or more of the following reactions: (i) converting one compound of formula (I) into another compound of formula (I); (ii) removing any protecting group; (iii) preparing a salt or a solvate of the compound so formed.
  • the reaction between a compound of formula (II) and a compound of formula (III) may be effected using conventional methods for the formation of an amide bond, such as those described in J March, Advanced Organic Chemistry, 4th edition, J Wiley & Sons, 1992, p. 419-421.
  • reaction may be carried out in a solvent such as DCM in the presence of a suitable diimide, such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
  • a suitable diimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
  • Rl and R are as defined in relation to formula (I), with a suitable reducing agent.
  • a suitable reducing agent may be effected by methods well known in the art, such as those described in J March, Advanced Organic Chemistry, 4th edition, J Wiley & Sons, 1992, p. 1216-1218.
  • Suitable reducing agents include (a) iron or zinc metal in hydrochloric acid, or (b) hydrogen in the presence of a suitable catalyst, such as, 5% palladium on charcoal. Reduction using hydrogen may conveniently be performed in a solvent such as methanol or ethanol.
  • Compounds of formula (IV) are commercially available or may be prepared according to literature methods.
  • Compounds of formula (III) may be prepared by hydrolysis of a compound of formula (V),
  • R 3 , R 4 and R ⁇ are as defined in relation to formula (I), in the presence of a suitable base.
  • a suitable base is aqueous sodium hydroxide.
  • a suitable hydrolysis agent is methanol.
  • Compounds of formula (V) may be prepared by reaction of a compound of formula (VI),
  • R 3 and R 5 are as defined in relation to formula (I), with a suitable alkylating agent.
  • the reaction between a compound of formula (VI) with a suitable alkylating agent may be effected by methods well known in the art, such as those described in J March, Advanced Organic Chemistry, 4th edition, J Wiley & Sons, 1992, p411.
  • a suitable alkylating reagent is an alkyl halide.
  • the reaction is performed in the presence of a suitable base, such as, potassium carbonate or caesium carbonate, in a suitable solvent, such as, dimethylformamide.
  • a suitable base such as, potassium carbonate or caesium carbonate
  • Aldehyde or ketone groups can be protected as acetals, ketals, thioacetals or thioketals. Deprotection of such groups is achieved using conventional procedures known in the art. Pharmaceutically acceptable salts may be prepared conventionally by reaction with the appropriate acid or acid derivative.
  • Vanilloid receptor antagonist Vanilloid receptor antagonist
  • V1 Vanilloid receptor antagonist
  • neuropathic pain neuropathic pain
  • postoperative pain postrheumatoid arthritic pain
  • osteoarthritic pain back pain
  • visceral pain cancer pain, algesia, neuralgia, dental pain, headache, migraine, neuropathies, carpal tunnel syndrome, diabetic neuropathy, HIV-related neuropathy, post-herpetic neuralgia, fibromyalgia, neuritis, sciatica, nerve injury, ischaemia, neurodegeneration, stroke, post stroke pain, multiple sclerosis, respiratory diseases, asthma, cough, COPD, broncho constriction, inflammatory disorders, oesophagitis, heart burn, Barrett's metaplasia, dysphagia, gastroeosophageal relux disorder (GERD), stomach
  • the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, for use as an active therapeutic substance, in particular, in the treatment and/or prophylaxis of the Disorders of the Invention.
  • the invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in the treatment or prophylaxis of pain.
  • the invention further provides a method for the treatment or prophylaxis of disorders in which antagonism of the Vanilloid (VR1) receptor is beneficial, in particular the Disorders of the Invention, in mammals including humans, which method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • the invention provides for the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment or prophylaxis of disorders in which antagonism of the Vanilloid (VR1 ) receptor is beneficial, particularly the Disorders of the Invention.
  • a pharmaceutical composition which comprises a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier or excipient therefor.
  • 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, rectal administration or intravesical administration to the bladder and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusable solutions, 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.
  • 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.
  • suitable unit doses may be 0.05 to 1000 mg, more suitably 0.05 to 20, 20 to 250, or 0.1 to 500.0 mg, for example 0.2 to 5 and 0.1 to 250 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 1000 mg; and such therapy may extend for a number of weeks or months. No unacceptable toxicological effects are indicated with compounds of the invention when administered in accordance with the invention.
  • Example 2 ⁇ V-(2-Methylbenzothiazol-5-yl)-9-[2-(4-morpholino)ethyl]-9H-carbazole-2- carboxamide (E2) Using a procedure similar to that of Example 1 , the title compound was prepared from 5-amino-2-methylbenzothiazole dihydrochloride (31 mg) and D3 (50 mg) as a brown gum (31 mg), m/z (ES): MH + 471 , (M-H)" 469.
  • Example 3 ⁇ V-(3-Methoxyphenyl)-9-[2-(methoxy)ethyl]-9H-carbazole-2-carboxamide (E3) Using a procedure similar to that of Example 1 , the title compound was prepared from m-anisidine (38 mg) and D2 (100 mg) as a white solid (32 mg), m/z (ES): MH + 375, (M-H) " 373.
  • Example 4 ⁇ /-[4-Methyl-3-(trifluoromethyl)phenyl]-9-[2-(methoxy)ethyl]-9H-carbazole-2- carboxamide (E4) Using a procedure similar to that of Example 1 , the title compound was prepared from 4-methyl-3-trifluoromethylaniline (43 mg) and D2 (80 mg) as a white solid (96 mg), m/z (ES): MH + 427, (M-H)" 425. Examples 5-9 presented in Table 1 were prepared in accordance with the procedures described herein and similar to those of E1 and E2.
  • the compounds of the invention are vanilloid receptor (VR1) antagonists and hence have useful pharmaceutical properties. Vanilloid receptor (VR1 ) antagonist activity can be confirmed and demonstrated for any particular compound by use of conventional methods, for example those disclosed in standard reference texts such as D. Le Bars, M. Gozarin and S. W. Cadden, Pharmacological Reviews, 2001 , 53(4), 597-652] or such other texts mentioned herein.
  • the screen used for the compounds of this invention was based upon a FLIPR based calcium assay, similar to that described by Smart et al. (British Journal of Pharmacology, 2000, 129, 227-230).
  • Transfected astrocytoma 1321 N1 cells, stably expressing human VR1 were seeded into FLIPR plates at 25,000cells/well (96-well plate) and cultured overnight. The cells were subsequently loaded in medium containing 4 ⁇ M Fluo-3 AM (Molecular Probes) for 2 hours, at room temperature, in the dark. The plates were then washed 4 times with Tyrode containing 1.5mM calcium, without probenecid.
  • the cells were pre-incubated with compound or buffer control at room temperature for 30 minutes. Capsaicin (Sigma) was then added to the cells. Compounds having antagonist activity against the human VR1 were identified by detecting differences in fluorescence when measured after capsaicin addition, compared with no compound buffer controls. Thus, for example, in the buffer control capsaicin addition results in an increase in intracellular calcium concentration resulting in fluorescence. A compound having antagonist activity blocks the capsaicin binding to the receptor, there is no signalling and therefore no increase in intracellular calcium levels and consequently lower fluorescence. pKb values are generated from the IC50 values using the Cheng-Prusoff equation.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé de formule (I), un sel ou un solvate de celui-ci, acceptable au plan pharmaceutique, formule dans laquelle R1, R2, R3, R4 et R5 sont tels que définis dans la spécification. L'invention porte également sur un procédé de préparation desdits composés, sur une composition pharmaceutique comprenant lesdits composés et sur l'utilisation desdits composé et de ladite composition en médecine.
PCT/EP2004/009082 2003-08-14 2004-08-12 Derives carbazole-2-carboxamides possedant une activite antagoniste du recepteur vanilloide WO2005016922A1 (fr)

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US10450270B2 (en) 2013-07-25 2019-10-22 Janssen Sciences Ireland Uc Glyoxamide substituted pyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
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