WO2004016593A1 - Composes diaryle utilises en tant qu'inhibiteurs du recaptage des monoamines - Google Patents
Composes diaryle utilises en tant qu'inhibiteurs du recaptage des monoamines Download PDFInfo
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- WO2004016593A1 WO2004016593A1 PCT/IB2003/003510 IB0303510W WO2004016593A1 WO 2004016593 A1 WO2004016593 A1 WO 2004016593A1 IB 0303510 W IB0303510 W IB 0303510W WO 2004016593 A1 WO2004016593 A1 WO 2004016593A1
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- GBYBMGHIBZVTJD-UHFFFAOYSA-N CN(C)Cc(ccnc1)c1Sc(cc1)ccc1SC Chemical compound CN(C)Cc(ccnc1)c1Sc(cc1)ccc1SC GBYBMGHIBZVTJD-UHFFFAOYSA-N 0.000 description 1
- OTCONLPIZZXXRE-UHFFFAOYSA-N Cc(cc1)ccc1Sc1c(CNC)ccnc1 Chemical compound Cc(cc1)ccc1Sc1c(CNC)ccnc1 OTCONLPIZZXXRE-UHFFFAOYSA-N 0.000 description 1
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
Definitions
- This invention relates to novel compounds which inhibit monoamine re-uptake.
- compounds of the present invention exhibit activity as selective serotonin re-uptake inhibitors (SSRIs) and have utility therefore in a variety of therapeutic areas.
- SSRIs serotonin re-uptake inhibitors
- the compounds of the present invention are useful in the treatment or prevention of a variety of disorders, including those in which the regulation of monoamine transporter function is implicated, such as depression, attention deficit hyperactivity disorder, obsessive-compulsive disorder, post- traumatic stress disorder, substance abuse disorders and sexual dysfunction including premature ejaculation, and to pharmaceutical formulations containing such compounds.
- US 5,190,965 and US 5,430,063 disclose a class of phenoxyphenyl compounds, which are a class of dopamine antagonists.
- WO 93/12080, WO 97/17325 and EP 0,402,097 disclose substituted diphenylsulfides, which are serotonin uptake inhibitors.
- WO 01/72687, WO 00/50380 and WO 01/27068 describe diphenyl ether derivatives, which are selective serotonin re-uptake inhibitors.
- J. Med. Chem 2002, 45(6), 1253-1258 discloses diphenyl sulfides as selective serotonin transporter ligands.
- the invention provides a compound of general formula (I) or pharmaceutically acceptable salts, solvates or polymorphs thereof;
- X is S or CH 2 ;
- L and U which may be the same or different, are -N-, -N + (-O or -C(H)-;
- M and Q which may be the same or different, are -N-, -N + (-0 or -C(R 4 )-; wherein ring A contains 1 or 2 nitrogen atoms, and wherein when L, U, M or Q is -N + (-0 " )-, ring A contains no other nitrogen atom;
- W, Y and Z which may be the same or different, are hydrogen, halogen, C ⁇ -C 6 al yl, CF 3) OCF 3) C ⁇ .C 4 alkylthio or d.C 4 alkoxy; or Y and Z are linked so that, together with the interconnecting atoms, Y and Z form a fused 5 to 7-membered carbocyclic or heterocyclic ring which may be saturated, unsaturated or aromatic, and wherein when Y and Z form a heterocyclic ring, in addition to carbon atoms, the linkage contains one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; and wherein W, Y and Z are not all hydrogen; and each R 4 is independently:
- R 6 , R 7 , R 8 and R 10 which may be the same or different, are hydrogen or C ⁇ -C 6 alkyl optionally substituted independently by one or more R 12 ;
- R 9 is C ⁇ -C 6 alkyl optionally substituted independently by one or more R 12 ;
- R 11 is hydrogen, C ⁇ -C 6 alkyl optionally substituted independently by one or more R 12 , C(0)R 6 , C0 2 R 9 , C(0)NHR 6 or S0 2 NR 6 R 7 ;
- R 12 is fluoro, hydroxy, C0 2 H, C 3- C 6 cycloalkyl, NH 2 , CONH 2 , d-Cealkoxy, C ⁇ .C 6 alkoxycarbonyl or a 5- or 6-membered heterocyclic ring containing
- any alkyl group may be straight or branched and is of 1 to 6 carbon atoms, preferably 1 to 4 and particularly 1 to 3 carbon atoms.
- any heterocyclyl group contains 5 to 7 ring-atoms up to 4 of which may be hetero-atoms such as nitrogen, oxygen and sulfur, and may be saturated, unsaturated or aromatic.
- heterocyclyl groups are furyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, dioxolanyl, oxazolyl, thiazolyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyranyl, pyridyl, piperidinyl, dioxanyl, morpholino, dithianyl, thiomorpholino, pyridazinyl, pyrimidinyl, pyraziny
- heterocyclyl includes fused heterocyclyl groups, for example benzimidazolyl, benzoxazolyl, imidazopyridinyl, benzoxazinyl, benzothiazinyl, oxazolopyridinyl, benzofuranyl, quinolinyl, quinazolinyl, quinoxalinyl, dihydroquinazolinyl, benzothiazolyl, phthalimido, benzofuranyl, benzodiazepinyl, indolyl and isoindolyl.
- heterocyclic should be similarly construed.
- any carbocyclyl group contains 3 to 8 ring-atoms, and may be saturated, unsaturated or aromatic.
- Preferred saturated carbocyclyl groups are cyclopropyl, cyclopentyl or cyclohexyl.
- Preferred unsaturated carbocyclyl groups contain up to 3 double bonds.
- a preferred aromatic carbocyclyl group is phenyl.
- the term carbocylic should be similarly construed.
- carbocyclyl includes any fused combination of carbocyclyl groups, for example naphthyl, phenanthryl, indanyl and indenyl.
- L and U are -CH-.
- W, Y and Z are each independently selected from hydrogen, methyl, ethyl, CF 3 , OCF 3 , C* ⁇ -C 4 alkylthio, methoxy, ethoxy, chloro, fluoro and bromo.
- W and Z are hydrogen.
- Y is methylthio
- M and Q are each independently selected from -N- and -CH-.
- one of M and Q is -N- and the other is -CH-.
- L and U are -CH-, one of M and Q is -N- and the other is -CH-.
- R 1 and R 2 are each independently selected from hydrogen and C C 6 alkyl.
- R 1 is methyl and R 2 is hydrogen or methyl.
- Preferred compounds are:
- substituted means substituted by one or more defined groups.
- groups may be selected from a number of alternatives groups, the selected groups may be the same or different.
- the term independently means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.
- the pharmaceutically or veterinarily acceptable salts of the compounds of formula I which contain a basic centre are, for example, non-toxic acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, with carboxylic acids or with organo-sulfonic acids.
- Examples include the HCI, HBr, HI, sulfate or bisulfate, nitrate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, saccharate, fumarate, maleate, lactate, citrate, tartrate, gluconate, camsylate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and palmoate salts.
- Compounds of formula I can also provide pharmaceutically or veterinarily acceptable metal salts, in particular non-toxic alkali and alkaline earth metal salts, with bases. Examples include the sodium, potassium, aluminium, calcium, magnesium, zinc and diethanolamine salts.
- the pharmaceutically acceptable solvates of the compounds of the invention include the hydrates thereof.
- the compounds of the invention have the advantage that they are selective inhibitors of the re-uptake of serotonin (SRIs) (and so are likely to have reduced side effects), they have a rapid onset of action (making them suitable for administration shortly before an effect is required), they have desirable potency and associated properties.
- SRIs serotonin
- Compounds that selectively inhibit the re-uptake of serotonin, but not noradrenaline or dopamine, are preferred.
- the compounds of the invention may possess one or more chiral centres and so exist in a number of stereoisomeric forms. All stereoisomers and mixtures thereof are included in the scope of the present invention. Racemic compounds may either be separated using preparative HPLC and a column with a chiral stationary phase or resolved to yield individual enantiomers utilising methods known to those skilled in the art. In addition, chiral intermediate compounds may be resolved and used to prepare chiral compounds of the invention.
- the compounds of the invention may exist in one or more tautomeric forms. All tautomers and mixtures thereof are included in the scope of the present invention. For example, a claim to 2-hydroxypyridinyl would also cover its tautomeric form, ⁇ -pyridonyl.
- the invention also includes radiolabelled compounds.
- prodrugs of compounds of the invention are included within the scope of the invention.
- suitable pro-drugs for the compounds of the present invention are described in Drugs of Today, Volume 19, Number 9, 1983, pp 499 - 538 and in Topics in Chemistry, Chapter 31 , pp 306 - 316 and in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference).
- Preferred prodrugs for compounds of the invention include: esters, carbonate esters, hemi-esters, phosphate esters, nitro esters, sulfate esters, sulfoxides, amides, carbamates, azo-compounds, phosphamides, glycosides, ethers, acetals and ketals.
- the present invention covers a process for the preparation of a compound of formula (I) as hereinbefore defined, which comprises reductively aminating a compound of formula (II)
- the reducing agent is a borohydride reducing agent.
- a further aspect of the present invention is a process for the preparation of a compound of formula (I) as hereinbefore defined wherein R 1 and R 2 are hydrogen, which comprises reducing a compound of formula (II) as hereinbefore defined wherein T is -CN.
- the reducing agent is BH 3 .THF or lithium aluminium hydride or hydrogen in the presence of a metal catalyst.
- a further aspect of the present invention is a process for the preparation of a compound of formula (I) as hereinbefore defined which comprises reducing a compound of formula (II) as hereinbefore defined wherein T is -CONR 1 R 2 , and R 1 and R 2 are as hereinbefore defined.
- the reducing agent is BH 3 .THF or lithium aluminium hydride.
- a further aspect of the present invention is a compound of formula (II) as hereinbefore defined wherein T is -CHO, CN or CONR 1 R 2 , and R 1 and R 2 are as hereinbefore defined.
- a further aspect of the present invention is a process for the preparation of a compound of formula (I) as hereinbefore defined which comprises converting one compound of formula (I) into another compound of formula (I) using conventional techniques generally known in the art.
- a further aspect of the present invention is a process for the preparation of a compound of formula (I) as hereinbefore defined which comprises deprotecting a protected compound of formula (I) using conventional techniques generally known in the art.
- Compounds of general formula I may be prepared from compounds of general formula II where T is -CHO, by reaction with an amine of formula HNR 1 R 2 (or a salt thereof), followed by reduction with a hydride reducing agent in a suitable solvent.
- suitable solvents include protic solvents such as ethanol, and sodium borohydride is an appropriate reducing agent.
- tetrahydrofuran/ dichloromethane is a suitable solvent system and sodium triacetoxyborohydride is a suitable reducing agent.
- HNR 1 R 2 such as the hydrochloride or acetate
- an auxiliary base to aid solubility of the HNR 1 R 2 salt, such as triethylamine may optionally be added along with acetic acid.
- Compounds of general formula I may be prepared from compounds of general formula II where T is cyano, by reduction to its corresponding amine of formula -CH 2 NH 2 , using hydride reducing agents such as BH 3 .THF or lithium aluminium hydride or by hydrogenation with a suitable metal catalyst for example Raney Nickel.
- hydride reducing agents such as BH 3 .THF or lithium aluminium hydride or by hydrogenation with a suitable metal catalyst for example Raney Nickel.
- Compounds of general formula I may be prepared from compounds of general formula II where T is -C(0)NR 1 R 2 , by reduction to provide an amine, for example with a hydride reducing agent such as BH 3 .THF or lithium aluminium hydride.
- Compounds of formula II where T is - C(0)NR 1 R 2 may be prepared from the corresponding compounds of formula II where T is -C0 2 H, by treatment with a coupling agent and an amine HNR 1 R 2 in a suitable inert solvent which does not adversely affect the reaction.
- compounds of general formula I having a particular NR 1 R 2 group may be converted into other compounds of general formula I having a different NR 1 R 2 group
- NR 1 R 2 group For example:
- compounds of formula I where M or Q is -C(R 4 )- may be prepared from the corresponding compound of formula I where M or Q is -C(R 4 )- by a variety of methods.
- Compounds of formula I where M or Q is -C(NH 2 )- may be prepared from the corresponding compounds of formula I where M or Q is -C(N0 2 )- by treatment with a reducing agent in a protic solvent at, or above, room temperature.
- Suitable reducing agents include iron powder / calcium chloride
- suitable protic solvents include aqueous ethanol or acetic acid.
- Basic hydrolysis is preferably conducted with a hydroxide salt such as potassium hydroxide in a protic solvent such as t-butanol at elevated temperatures.
- LG is a suitable leaving group such as halogen (F, CI, Br or I) or a sulfonate ester such as trifluoromethanesulfonate or methanesulfonate (preferably LG is F or CI)
- Such coupling reactions may be accomplished by techniques known in the art, such as via reaction with potassium carbonate in a suitable solvent such as dimethylformamide under appropriate reaction conditions such as elevated temperature and in an inert atmosphere.
- Hal is a halogen such as Br or CI (preferably Hal is Br)
- LG is a suitable leaving group such as halogen (F, CI, Br or I) or a sulfonate ester such as trifluoromethanesulfonate or methanesulfonate (preferably LG is CI)
- Such coupling reactions may be accomplished by techniques known in the art, such as via reaction of V with a suitable form of Zinc metal, such as Riecke® Zinc, in a suitable solvent, such as tetrahydrofuran, followed by reaction of the resulting zincate with III in the presence of a suitable catalyst, such as bis(triphenylphosphine)nickel (II) chloride, under appropriate reaction conditions such as under an inert atmosphere.
- a suitable catalyst such as bis(triphenylphosphine)nickel (II) chloride
- the sulfide or zincate coupling may be performed after conversion of the group T to the group -CH 2 NR 1 R 2 .
- the compounds of the invention are useful because they have pharmacological activity in mammals, including humans. More particularly, they are useful in the treatment or prevention of a disorder in which the regulation of monoamine transporter function is implicated.
- Disease states that may be mentioned include hypertension, depression (including depression in cancer patients, depression in Parkinson's patients, postmyocardial infarction depression, subsyndromal symptomatic depression, depression in infertile women, paediatric depression, major depression, single episode depression, recurrent depression, child abuse induced depression, post partum depression and grumpy old man syndrome), generalized anxiety disorder, phobias (including agoraphobia, social phobia and simple phobias), posttraumatic stress syndrome, avoidant personality disorder, sexual dysfunction (including premature ejaculation and male impotence), eating disorders (including anorexia nervosa and bulimia nervosa), obesity, substance abuse disorders (including chemical dependencies such as addictions to alcohol, cocaine, heroin, phenobarbital, nicotine and benzodiazepines), cluster headache,
- Disorders of particular interest include depression, attention deficit hyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress syndrome, substance abuse disorders and sexual dysfunction including male impotence and (in particular) premature ejaculation.
- Premature ejaculation may be defined as persistent or recurrent ejaculation before, upon or shortly after penile penetration of a sexual partner. It may also be defined as ejaculation occurring before the individual wishes [see The Merck Manual', 16 th edition, p 1576, published by Merck Research Laboratories, 1992].
- the invention provides:
- a compound of formula (I), as defined in the first aspect, pharmaceutically acceptable salts, solvates or polymorphs thereof, in the preparation of a medicament for the treatment or prevention of a disorder in which the regulation of monoamine transporter function is implicated for example hypertension, depression, generalized anxiety disorder, phobias, posttraumatic stress syndrome, avoidant personality disorder, sexual dysfunction (e.g. premature ejaculation and male impotence), eating disorders, obesity, substance abuse disorders (e.g.
- a method of treatment or prevention of depression, attention deficit hyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress syndrome, substance abuse disorders and sexual dysfunction including male impotence and (in particular) premature ejaculation which comprises administering a therapeutically effective amount of a compound of formula (I) as defined in the first aspect, pharmaceutically acceptable salts, solvates or polymorphs thereof, to a patient in need of such treatment or prevention.
- a method of increasing ejaculatory latency which comprises the administration of an effective amount of a compound of formula (I) as defined in the first aspect, pharmaceutically acceptable salts, solvates or polymorphs thereof, to a male desiring increased ejaculatory latency.
- a compound of formula (I) as defined in the first aspect pharmaceutically acceptable salts, solvates or polymorphs thereof, for the treatment or prevention of a disorder in which the regulation of monoamine transporter function is implicated, for example depression, attention deficit hyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress syndrome, substance abuse disorders and sexual dysfunction including male impotence and (in particular) premature ejaculation.
- a disorder in which the regulation of monoamine transporter function is implicated for example depression, attention deficit hyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress syndrome, substance abuse disorders and sexual dysfunction including male impotence and (in particular) premature ejaculation.
- the compounds of the invention may be administered alone or as part of a combination therapy. If a combination of active agents are administered, then they may be administered simultaneously, separately or sequentially. In particular, the compounds of the invention may be combined with the following for the treatment of PE:
- Alpha-blockers e.g. phentolamine, doxazasim, tansulosin, terazasin, prazasin and Example 19 of WO9830560;
- apomorphine - teachings on the use of apomorphine as a pharmaceutical may be found in US-A-59451 17; Dopamine D2 agonists (e.g. Premiprixal, Pharmacia Upjohn compound number
- Melanocortin receptor agonists e.g. Melanotan II
- PGE1 receptor agonists e.g. alprostadil
- Mono amine transport inhibitors particularly Noradrenaline Re-uptake Inhibitors
- NRIs Serotonin Re-uptake Inhibitors
- SRIs Serotonin Re-uptake Inhibitors
- DRIs Dopamine Re-uptake Inhibitors
- 5-HTiA antagonists e.g. robalzotan
- 5-HT3 antagonists e.g. ondansetron and granisetron
- PDE inhibitors such as PDE2 (e.g. erythro-9-(2-hydroxyl-3-nonyl)-adenine) and
- Example 100 of EP 0771799-incorporated herein by reference and in particular a PDE5 inhibitor (e.g. sildenafil, 1- ⁇ [3-(3,4-dihydro-5-methyl-4-oxo-7- propylimidazo[5,1-f]-as-trazin-2-yl)-4-ethoxyphenyl]sulfonyl ⁇ -4-ethylpiperazine i.e. vardenafil / Bayer BA 38-9456 or IC351 (see structure below, lcos Lilly)).
- a PDE5 inhibitor e.g. sildenafil, 1- ⁇ [3-(3,4-dihydro-5-methyl-4-oxo-7- propylimidazo[5,1-f]-as-trazin-2-yl)-4-ethoxyphenyl]sulfonyl ⁇ -4-ethylpiperazine i.e. vardenafil / Bayer BA 38-9456 or IC
- the compounds of the invention can be administered alone but in human therapy will generally be administered in admixture with a suitable pharmaceutical excipient, diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice. Accordingly the present invention provides for a composition comprising a compound of formula (I) as disclosed herein, or pharmaceutically acceptable salts, solvates or polymorphs thereof, and a pharmaceutically acceptable diluent or carrier.
- the compounds of the invention can be administered orally, buccally or sublingually in the form of tablets, capsules (including soft gel capsules), ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed-, modified-, sustained-, dual-, controlled-release or pulsatile delivery applications.
- the compounds of the invention may also be administered via intracavernosal injection.
- the compounds of the invention may also be administered via fast dispersing or fast dissolving dosage forms.
- Such tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine, and starch (preferably corn, potato or tapioca starch), disintegrants such as sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.
- excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine, and starch (preferably corn, potato or tapioca starch), disintegrants such as sodium starch glycollate, croscarmellose sodium and certain complex silicates, and
- Solid compositions of a similar type may also be employed as fillers in gelatin capsules.
- Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols.
- the compounds of the invention, and their pharmaceutically acceptable salts may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
- Modified release and pulsatile release dosage forms may contain excipients such as those detailed for immediate release dosage forms together with additional excipients that act as release rate modifiers, these being coated on and/or included in the body of the device.
- Release rate modifiers include, but are not exclusively limited to, hydroxypropylmethyl cellulose, methyl cellulose, sodium carboxymethylcellulose, ethyl cellulose, cellulose acetate, polyethylene oxide, Xanthan gum, Carbomer, ammonio methacrylate copolymer, hydrogenated castor oil, camauba wax, paraffin wax, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, methacrylic acid copolymer and mixtures thereof.
- Modified release and pulsatile release dosage forms may contain one or a combination of release rate modifying excipients.
- Release rate modifying excipients may be present both within the dosage form i.e. within the matrix, and/or on the dosage form, i.e. upon the surface or coating.
- Fast dispersing or dissolving dosage formulations may contain the following ingredients: aspartame, acesulfame potassium, citric acid, croscarmellose sodium, crospovidone, diascorbic acid, ethyl acrylate, ethyl cellulose, gelatin, hydroxypropylmethyl cellulose, magnesium stearate, mannitol, methyl methacrylate, mint flavouring, polyethylene glycol, fumed silica, silicon dioxide, sodium starch glycolate, sodium stearyl fumarate, sorbitol, xylitol.
- dispersing or dissolving as used herein to describe FDDFs are dependent upon the solubility of the drug substance used i.e. where the drug substance is insoluble a fast dispersing dosage form can be prepared and where the drug substance is soluble a fast dissolving dosage form can be prepared.
- the compounds of the invention can also be administered parenterally, for example, intravenously, intra-arterially, intraperitoneally, intrathecally, intraventricularly, intraureth rally, intrasternally, intracranially, intramuscularly or subcutaneously, or they may be administered by infusion techniques.
- parenteral administration they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
- the aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary.
- the preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
- the daily dosage level of the compounds of the invention or salts or solvates thereof will usually be from 10 to 500 mg (in single or divided doses).
- tablets or capsules of the compounds of the invention or salts or solvates thereof may contain from 5 mg to 250 mg of active compound for administration singly or two or more at a time, as appropriate.
- the physician in any event will determine the actual dosage which will be most suitable for any individual patient and it will vary with the age, weight and response of the particular patient.
- the above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of this invention.
- compounds of the invention may be taken as a single dose on an "as required" basis (i.e. as needed or desired).
- a tablet formulation could typically contain between about 0.01 mg and 500mg of a compound according to the present invention (or a salt thereof) whilst tablet fill weights may range from 50mg to 1000mg.
- An example formulation for a 10mg tablet is illustrated:
- the compounds of the invention can also be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray or nebulizer with the use of a suitable propellant, e.g.
- the dosage unit may be determined by providing a valve to deliver a metered amount.
- the pressurised container, pump, spray or nebulizer may contain a solution or suspension of the active compound, e.g.
- Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
- Aerosol or dry powder formulations are preferably arranged so that each metered dose or "puff" contains from 1 to 50 mg of a compound of the invention for delivery to the patient.
- the overall daily dose with an aerosol will be in the range of from 1 to 50 mg which may be administered in a single dose or, more usually, in divided doses throughout the day.
- the compounds of the invention may also be formulated for delivery via an atomiser.
- Formulations for atomiser devices may contain the following ingredients as solubilisers, emulsifiers or suspending agents: water, ethanol, glycerol, propylene glycol, low molecular weight polyethylene glycols, sodium chloride, fluorocarbons, polyethylene glycol ethers, sorbitan trioleate, oleic acid.
- the compounds of the invention can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder.
- the compounds of the invention may also be dermally or transdermally administered, for example, by the use of a skin patch. They may also be administered by the ocular, pulmonary or rectal routes.
- the compounds can be formulated as micronized suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzylalkonium chloride.
- they may be formulated in an ointment such as petrolatum.
- the compounds of the invention can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
- they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters, wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
- the compounds of the invention may also be used in combination with a cyclodextrin.
- Cyclodextrins are known to form inclusion and non-inclusion complexes with drug molecules. Formation of a drug-cyclodextrin complex may modify the solubility, dissolution rate, bioavailability and/or stability property of a drug molecule. Drug-cyclodextrin complexes are generally useful for most dosage forms and administration routes.
- the cyclodextrin may be used as an auxiliary additive, e.g. as a carrier, diluent or solubiliser.
- Alpha-, beta- and gamma-cyclodextrins are most commonly used and suitable examples are described in WO-A-91/11172, WO-A- 94/02518 and WO-A-98/55148.
- the daily dosage levels of the compounds of the invention will be from 0.01 to 30 mg/kg (in single or divided doses) and preferably will be in the range 0.01 to 5 mg/kg.
- tablets will contain 1 mg to 0.4g of compound for administration singly or two or more at a time, as appropriate.
- the physician will in any event determine the actual dosage which will be most suitable for any particular patient and it will vary with the age, weight and response of the particular patient.
- the above dosages are, of course only exemplary of the average case and there may be instances where higher or lower doses are merited, and such are within the scope of the invention.
- Oral administration is preferred. Preferably, administration takes place shortly before an effect is required.
- a compound of the invention or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate or pro-drug thereof, is administered as a suitably acceptable formulation in accordance with normal veterinary practice and the veterinary surgeon will determine the dosing regimen and route of administration which will be most appropriate for a particular animal.
- the invention provides a pharmaceutical formulation containing a compound of formula (I), as defined in the first aspect, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier.
- the aldehyde of Preparation 1 (from 3.5 mmol of 4-chloronicotinaldehyde) was dissolved in an 8M solution of methylamine in EtOH (9 mL, 72 mmol) and the mixture was stirred at room temperature for 1 h. NaBH 4 (190 mg, 5.0 mmol) was added in one portion and stirring was continued overnight. The reaction was quenched by the cautious addition of 2M HCI (20 mL) and stirred for 1 h before being basified to pH 10 with 10% aqueous K 2 C0 3 . The mixture was extracted with EtOAc (200 mL) and the organic layer was dried (MgS0 4 ) and evaporated.
- Formaldehyde (100 ⁇ L, 1.23 mmol) was added to a solution of the amine of Example 1 (112 mg, 0.41 mmol) in CH 2 CI 2 (4 mL) and the mixture was stirred at room temperature for 15 min before the addition of sodium triacetoxyborohydride (348 mg, 1.64 mmol). The reaction was stirred a further 16 h at room temperature and then partitioned between 10% aqueous K 2 C0 3 (30 mL) and EtOAc (50 mL).
- Oxalyl chloride (575 ⁇ L, 6.6 mmol) was added to a suspension of the acid of Preparation 4 (1.3 g, 4.4 mmol) in CH 2 CI 2 (10 mL) containing 2 drops of DMF. The mixture was stirred at room temperature for 1.5 h then evaporated to dryness, suspended in CH2CI2 (10 mL) and re-evaporated. The residue was re- suspended in CH 2 CI 2 (10 mL) and treated with triethylamine (1.84 mL, 13.2 mmol) followed by a 2M solution of methylamine in THF (3.3 mL, 6.6 mmol). The resulting brown mixture was stirred at room temperature for 1 h before the addition of sat.
- Oxalyl chloride (1.01 mL, 11.6 mmol) was added to a suspension of 4- chloronicotinic acid (prepared according to F. Guillier et al. J. Org. Chem. 1995, 60, 292) (1.5 g, 7.7 mmol) in CH 2 CI 2 (15 mL) containing 2 drops of DMF. The mixture was stirred at room temperature for 1 h then evaporated to dryness, suspended in CH 2 CI 2 (10 mL) and re-evaporated.
- Human embryonic kidney cells HEK-293 stably transfected with either the human serotonin transporter (hSERT), noradrenaline transporter (hNET) or dopamine transporter (hDAT) were cultured under standard cell culture techniques (cells were grown at 37°C and 5% C0 2 in DMEM- culture media (supplemented with 10% dialysed foetal calf serum (FCS), 2mM l-glutamine and 250 ⁇ g/ml geneticin)). Cells were harvested for the assay to yield a cell suspension of 750,000 cells/ml.
- hSERT human serotonin transporter
- hNET noradrenaline transporter
- hDAT dopamine transporter
- test compounds were dissolved in 100% DMSO and diluted down in assay buffer to give appropriate test concentrations. Assays were carried out in 96-well filter bottom plates. Cells (7500 cells/assay well) were pre- incubated in standard assay buffer containing either test compound, standard inhibitor or compound vehicle (1% DMSO) for 5 minutes. Reactions were started by addition of either 3 H-Serotonin, 3 H- Noradrenaline or 3 H-Dopamine substrates. All reactions were carried out at room temperature in a shaking incubator. Incubation times were 5 minutes for the hSERT and hDAT assays and 15 minutes for the hNET assay. Reactions were terminated by removal of the reaction mixture using a vacuum manifold followed by rapid washing with ice cold assay buffer. The quantity of 3 H-substrate incorporated into the cells was then quantified.
- Assay plates were dried in a microwave oven, scintillation fluid added, and radioactivity measured. Potency of test compounds was quantified as IC 5 o values (concentration of test compound required to inhibit the specific uptake of radiolabelled substrate into the cells by 50%).
- the compounds of the invention are potent and selective inhibitors of serotonin re-uptake and the compounds of Examples 1 -8 have a serotonin re-uptake inhibition (SRI) IC 50 value of less than or equal to 25nM and are more than 100- fold as potent in the inhibition of serotonin re-uptake than in the inhibition of dopamine re-uptake and noradrenaline re-uptake.
- SRI serotonin re-uptake inhibition
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Abstract
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
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MXPA05001834A MXPA05001834A (es) | 2002-08-16 | 2003-08-04 | Compuestos de diarilo. |
BR0313524-1A BR0313524A (pt) | 2002-08-16 | 2003-08-04 | Compostos de diarila como inibidores de recaptação de mono-amina |
AU2003250467A AU2003250467A1 (en) | 2002-08-16 | 2003-08-04 | Diaryl compounds as monoamine reuptake inhibitors |
JP2004528757A JP2005539029A (ja) | 2002-08-16 | 2003-08-04 | モノアミン再取り込み阻害剤としてのジアリール化合物 |
CA002495409A CA2495409A1 (fr) | 2002-08-16 | 2003-08-04 | Composes diaryle utilises en tant qu'inhibiteurs du recaptage des monoamines |
EP03787960A EP1556353A1 (fr) | 2002-08-16 | 2003-08-04 | Composes diaryle utilises en tant qu'inhibiteurs du recaptage des monoamines |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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GBGB0219154.2A GB0219154D0 (en) | 2002-08-16 | 2002-08-16 | Diaryl compounds |
GB0219154.2 | 2002-08-16 |
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WO2004016593A1 true WO2004016593A1 (fr) | 2004-02-26 |
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PCT/IB2003/003510 WO2004016593A1 (fr) | 2002-08-16 | 2003-08-04 | Composes diaryle utilises en tant qu'inhibiteurs du recaptage des monoamines |
Country Status (8)
Country | Link |
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EP (1) | EP1556353A1 (fr) |
JP (1) | JP2005539029A (fr) |
AU (1) | AU2003250467A1 (fr) |
BR (1) | BR0313524A (fr) |
CA (1) | CA2495409A1 (fr) |
GB (1) | GB0219154D0 (fr) |
MX (1) | MXPA05001834A (fr) |
WO (1) | WO2004016593A1 (fr) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10154988B2 (en) | 2012-11-14 | 2018-12-18 | The Johns Hopkins University | Methods and compositions for treating schizophrenia |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1981001407A1 (fr) * | 1979-11-16 | 1981-05-28 | Astra Laekemedel Ab | Nouveau derive halophenyl-pyridyl-allylamine |
EP0075752A2 (fr) * | 1981-09-28 | 1983-04-06 | Boehringer Ingelheim Kg | 2-Phényl-2-(pyridyloxy)-éthylamines substituées et composés isostériques, procédé pour leur fabrication et leur utilisation |
WO1997017325A1 (fr) * | 1995-11-09 | 1997-05-15 | Farmak A.S. | Derives de n,n-dimethyl-2-(arylthio)benzylamine, leurs sels, procedes de preparation et leur utilisation dans des medicaments pharmaceutiques |
WO2001072687A1 (fr) * | 2000-03-31 | 2001-10-04 | Pfizer Limited | Composes d'ether de diphenyl utiles en therapie |
DE10029371A1 (de) * | 2000-06-20 | 2002-01-03 | Merck Patent Gmbh | Heterocyclische Aminoalkylpyridinderivate als Psychopharmaka |
-
2002
- 2002-08-16 GB GBGB0219154.2A patent/GB0219154D0/en not_active Ceased
-
2003
- 2003-08-04 JP JP2004528757A patent/JP2005539029A/ja active Pending
- 2003-08-04 EP EP03787960A patent/EP1556353A1/fr not_active Withdrawn
- 2003-08-04 CA CA002495409A patent/CA2495409A1/fr not_active Abandoned
- 2003-08-04 BR BR0313524-1A patent/BR0313524A/pt not_active IP Right Cessation
- 2003-08-04 MX MXPA05001834A patent/MXPA05001834A/es unknown
- 2003-08-04 WO PCT/IB2003/003510 patent/WO2004016593A1/fr not_active Application Discontinuation
- 2003-08-04 AU AU2003250467A patent/AU2003250467A1/en not_active Abandoned
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1981001407A1 (fr) * | 1979-11-16 | 1981-05-28 | Astra Laekemedel Ab | Nouveau derive halophenyl-pyridyl-allylamine |
EP0075752A2 (fr) * | 1981-09-28 | 1983-04-06 | Boehringer Ingelheim Kg | 2-Phényl-2-(pyridyloxy)-éthylamines substituées et composés isostériques, procédé pour leur fabrication et leur utilisation |
WO1997017325A1 (fr) * | 1995-11-09 | 1997-05-15 | Farmak A.S. | Derives de n,n-dimethyl-2-(arylthio)benzylamine, leurs sels, procedes de preparation et leur utilisation dans des medicaments pharmaceutiques |
WO2001072687A1 (fr) * | 2000-03-31 | 2001-10-04 | Pfizer Limited | Composes d'ether de diphenyl utiles en therapie |
DE10029371A1 (de) * | 2000-06-20 | 2002-01-03 | Merck Patent Gmbh | Heterocyclische Aminoalkylpyridinderivate als Psychopharmaka |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10154988B2 (en) | 2012-11-14 | 2018-12-18 | The Johns Hopkins University | Methods and compositions for treating schizophrenia |
EP3610890A1 (fr) | 2012-11-14 | 2020-02-19 | The Johns Hopkins University | Procédés et compositions de traitement de la schizophrénie |
US10624875B2 (en) | 2012-11-14 | 2020-04-21 | The Johns Hopkins University | Methods and compositions for treating schizophrenia |
Also Published As
Publication number | Publication date |
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JP2005539029A (ja) | 2005-12-22 |
BR0313524A (pt) | 2005-06-28 |
EP1556353A1 (fr) | 2005-07-27 |
CA2495409A1 (fr) | 2004-02-26 |
AU2003250467A1 (en) | 2004-03-03 |
GB0219154D0 (en) | 2002-09-25 |
MXPA05001834A (es) | 2005-04-19 |
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