WO2006018309A1 - 5-ht7 receptor antagonists - Google Patents
5-ht7 receptor antagonists Download PDFInfo
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- WO2006018309A1 WO2006018309A1 PCT/EP2005/008979 EP2005008979W WO2006018309A1 WO 2006018309 A1 WO2006018309 A1 WO 2006018309A1 EP 2005008979 W EP2005008979 W EP 2005008979W WO 2006018309 A1 WO2006018309 A1 WO 2006018309A1
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
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- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Definitions
- the present invention relates to compounds having pharmacological activity towards the 5-HT7 receptor, and more particularly to some tetrahydroisoquinoline substituted sulfonamide compounds, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy, in particular for the treatment and or prophylaxis of a disease in which 5-HT 7 is involved, such as CNS disorders.
- 5-HT 7 receptors have been cloned from rat, mouse, guinea pig and human cDNA and exhibit a high degree of interspecies homology (approx. 95%), but it is unique in that it has a low sequence homology with other 5-HT receptors (less than 40%). Its expression pattern, in particular structures of the central nervous system (CNS) (highest in hypothalamus (in particular suprachiasmatic nuclei) and thalamus) and other peripheral tissues (spleen, kidney, intestinal, heart and coronary arthery), implicates the 5-HT 7 receptor in a variety of functions and pathologies.
- CNS central nervous system
- the 5-HT 7 receptor has also been related with the pathophysiology of migraine through smooth muscle relaxation of cerebral vessels (Schoeffter, P. et al., 1996, Br J Pharmacol, 1 17:993-994; Terr ⁇ n, J.A., 2002, Eur. J. Pharmacol, 439: 1-1 1 "/s the 5-HT 7 receptor involved in the pathogenesis and prophylactic treatment of migraine? ").
- involvement of 5-HT 7 in intestinal and colon tissue smooth muscle relaxation makes this receptor a target for the treatment of irritable bowel syndrome (De Ponti, F. et al. , 2001, Drugs, 61 :317-332 "'Irritable bowel syndrome. New agents targeting serotonin receptor subtypes ").
- WO 97/48681 discloses sulfonamide derivatives, which are 5-HT 7 receptor antagonists, for the treatment of CNS disorders.
- the sulphur atom is linked to an aromatic group and to a N-containing heterocyclic group, optionally containing a further heteroatom selected from oxygen or sulphur.
- WO 97/29097 describes sulfonamide derivatives for the treatment of disorders in which antagonism of the 5-HT 7 receptor is beneficial.
- the sulphur atom is linked to an aromatic group and to a CpC 6 alkyl substituted N atom.
- WO97/49695 describes further sulfonamide derivatives in which the N linked to the sulphur atom is also fully substituted, for example forming part of a piperidine.
- WO 03/048118 describes another group of 5HT 7 receptor antagonists.
- aryl and heteroaryl sulfonamide derivatives wherein the sulfonamide group is a substituent on a cycloalkane or cycloalkene ring which additionally bears an amino susbtituent.
- the N linked to sulphur atom is fully substituted.
- WO99/24022 discloses tetrahydroisoquinoline derivatives for use against CNS disorders and binding to serotonin receptors, in particular 5-HT 7 .
- WO 00/00472 refers to compounds which are 5-HT7 receptor antagonists.
- the compounds contain a N-containing fused heterocycle such as tetrahydroisoquinoline.
- EP 21580 and EP 76072 describe sulfonamide compounds having antiarrhythmic activity, corresponding to the formula R 2 N(CH 2 ) n -NH-SO 2 Ri, 5-HT 7 activity is not mentioned.
- the compounds display IC-50 values in the nM range (>10 nM) at human 5-HT7 receptors and exhibit at least 30-fold selectivity for these receptors vs 5-HT1A, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT4, 5-HT5A, Dl, D2, D3, D4, adrenergic ⁇ lA, ⁇ l B, ⁇ l B, ⁇ l, and ⁇ 2 receptors.
- the invention is directed to a compound of the formula I:
- W is a susbtituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, susbtituted or unsubstituted cycloalkyl, susbtituted or unsubstituted aryl, susbtituted or unsubstituted heterocyclyl;
- R 8 and R 9 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, halogen; or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.
- W is aromatic, preferably substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, preferably substituted or unsubstituted phenyl Good results were obtained when W is alkyl or halo substituted phenyl.
- R 5 , R 6 and R 7 are H
- Ri and R 4 are also H
- R 2 and R 3 are dlkoxy, in particular methoxy
- the invention is directed to a pharmaceutical composition which comp ⁇ ses a compound as above defined or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.
- the invention is directed to the use of a compound as defined above in the manufacture of a medicament for the treatment of a 5-HT 7 mediated disease or condition, 1 c diseases caused by failures in central and peripheral serotonin-controlling functions, such as pain, sleep disorder, shift worker syndrome, jet lag, depression, seasonal affective disorder, migraine, anxiethy, psychosis, schizophrenia, cognition and memory disorders, neuronal degeneration resulting from ischemic events, cardiovascular diseases such as hypertension, irritable bowel syndrome, inflammatory bowel disease, spastic colon or u ⁇ nary incontinence
- the typical compounds of this invention effectively and selectively module the 5- HT7 receptor activity without inhibition of other 5-HT receptors such as 5-HT1A, 5- HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT4, 5-HT5A, Dl , D2, D3, D4, as well as adrenergic ⁇ lA, ⁇ l B, ⁇ l B, ⁇ l , and ⁇ 2 receptors, Tachykinin NK-I opiate, GABA, estrogen, glutamate, adenosine, nicotinic, muscarinic receptors and calcium, potassium and sodium channels and neurotransmitter transporteis (serotonin, dopamine, norepinephrine, GABA)
- 5-HT1A 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT4, 5-HT5A, Dl , D2, D3, D4, as well as adrenergic ⁇ lA, ⁇ l B, ⁇ l B, ⁇ l
- Alkyl refers to a straight or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, containing no saturation, having one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e. g., methyl, ethyl, n- propyl, i-propyl, n-butyl, t-butyl, n-pentyl, etc.
- Alkyl radicals may be optionally substituted by one or more substituents such as a aryl, halo, hydroxy, alkoxy, carboxy, cyano, carbonyl, acyl, alkoxycarbonyl, amino, nitro, mercapto, alkylthio, etc. If substituted by aryl we have an "Aralkyl” radical, such as benzyl and phenethyl.
- Alkenyl refers to an alkyl radical having at least 2 C atoms and having one or more unsaturated bonds.
- Cycloalkyl refers to a stable 3-to 10-membered monocyclic or bicyclic radical which is saturated or partially saturated, and which consist solely of carbon and hydrogen atoms, such as cyclohexyl or adamantyl. Unless otherwise stated specifically in the specification, the te ⁇ n"cycloalkyl” is meant to include cycloalkyl radicals which are optionally substituted by one or more substituents such as alkyl, halo, hydroxy, amino, cyano, nitro, alkoxy, carboxy, alkoxycarbonyl, etc.
- Aryl refers to single and multiple ring radicals, including multiple ring radicals that contain separate and/or fused aryl groups. Typical aryl groups contain from 1 to 3 separated or fused rings and from 6 to about 18 carbon ring atoms, such as phenyl, naphthyl, indenyl, fenanthryl or anthracyl radical.
- the aryl radical may be optionally substituted by one or more substituents such as hydroxy, mercapto, halo, alkyl, phenyl, alkoxy, haloalkyl, nitro, cyano, dialkylamino, aminoalkyl, acyl, alkoxycarbonyl, etc.
- Heterocyclyl refers to a stable 3-to 15 membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, preferably a 4-to 8-membered ring with one or more heteroatoms, more preferably a 5-or 6-membered ring with one or more heteroatoms.
- the heterocycle may be a monocyclic, bicyclic or tricyclic ring system, which may include fused ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidised; the nitrogen atom may be optionally quaternized ; and the heterocyclyl radical may be partially or fully saturated or aromatic.
- heterocycles include, but are not limited to, azepines, benzimidazole, benzothiazole, furan, isothiazole, imidazole, indole, piperidine, piperazine, purine, quinoline, thiadiazole, tetrahydrofuran, coumarine, morpholine; pyrrole, pyrazole, oxazole, isoxazole, triazole, imidazole, etc.
- Alkoxy refers to a radical of the formula -ORa where Ra is an alkyl radical as defined above, e. g., methoxy, ethoxy, propoxy, etc.
- Alkoxycarbonyl refers to a radical of the formula-C (O) ORa where Ra is an alkyl radical as defined above, e. g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.
- Alkylthio refers to a radical of the formula-SRa where Ra is an alkyl radical as defined above, e. g., methylthio, ethylthio, propylthio, etc.
- Amino refers to a radical of the fo ⁇ nula-NH2, -NHRa or -NRaRb, optionally quaternized.
- Halo or hal refers to bromo, chloro, iodo or fluoro.
- references herein to substituted groups in the compounds of the present invention refer to the specified moiety that may be substituted at one or more available positions by one or more suitable groups, e. g., halogen such as fluoro, chloro, bromo and iodo ; cyano; hydroxyl ; nitro ; azido ; alkanoyl such as a Cl -6 alkanoyl group such as acyl and the like; carboxamido; alkyl groups including those groups having 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms and more preferably 1 -3 carbon atoms; alkenyl and alkynyl groups including groups having one or more unsaturated linkages and from 2 to about 12 carbon or from 2 to about 6 carbon atoms; alkoxy groups having one or more oxygen linkages and from 1 to about 12 carbon atoms or 1 to about 6 carbon atoms; aryloxy such as phenoxy; alkylthio groups including those moieties having one or more suitable
- Particular individual compounds of the invention include the compounds 1-161 in the examples, either as salts or as free bases
- R 2 and R 3 are alkoxy, preferably methoxy and the rest of the substituents of the tetrahydroisoquinoline (Ri and R 4 to R 7 ) are H In this case it appears that the selectivity is improved
- the gtoup W linked to the sulfonamide is aromatic, such as substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, preferably substituted or unsubstituted phenyl
- aromatic such as substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, preferably substituted or unsubstituted phenyl
- W is unsubstituted phenyl, or alkyl, alkoxy or halo substituted phenyl
- halo substituted phenyl having one or more halo substituents being the same or different are preferred
- the compounds of the invention are also meant to include compounds which differ only in the presence of one or more isotopically en ⁇ ched atoms
- compounds having the present structures except for the replacement of a hydrogen by a pidum or t ⁇ tium, or the replacement of a carbon by a 13 C- or 14C- en ⁇ ched carbon or l 5 N-en ⁇ ched nitrogen are within the scope of this invention.
- te ⁇ ii pharmaceutically acceptable salts, solvates, prodrugs
- pharmaceutically acceptable salts, solvates, prodrugs refers to any pha ⁇ naceutically acceptable salt, ester, solvate, or any other compound which, upon administration to the recipient is capable of providing (directly or indirectly) a compound as desc ⁇ bed herein
- non-pharmaceutically acceptable salts also fall within the scope of the invention since those may be useful in the preparation of pha ⁇ naceutically acceptable salts
- the preparation of salts, piodrugs and derivatives can be carried out by methods known in the art
- pha ⁇ naceutically acceptable salts of compounds provided herein arc synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods
- such salts are, for example, prepared by reacting the free acid or base fo ⁇ ns of these compounds with a stoichiometric amount of the approp ⁇ ate base or acid in water or in an organic solvent or in a mixture of the two
- nonaqueous media like ether, ethyl acetate, ethanol, isopropanol or acetonit ⁇ le are preferred.
- the acid addition salts include mineral acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodidc, sulphate, nitrate, phosphate, and organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulphonate and p- tolucnesulphonate
- the alkali addition salts include inoiganic salts such as, for example, sodium, potassium, calcium, ammonium, magnesium, aluminium and lithium salts, and organic alkali salts such as, for example, ethylenediamine, ethanolamine, N,N- dialkylenethanolamine, t ⁇ ethanolamine, glucamine and basic aminoacids salts
- Particularly favored de ⁇ vatives or prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (e g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.
- prodrug is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention.
- de ⁇ vatives would readily occur to those skilled in the art, and include, depending on the functional groups present in the molecule and without limitation, the following de ⁇ vatives of the present compounds, esters, amino acid esters, phosphate esters, metal salts sulfonate esters, carbamates, and amides
- the compounds of the invention may be in crystalline form cither as free compounds or as solvates and it is intended that both fo ⁇ ns are within the scope of the present invention
- Methods of solvation are generally known within the art.
- Suitable solvates are pharmaceutically acceptable solvates.
- the solvate is a hydrate
- the compounds of formula (I) or their salts or solvates are preferably in pharmaceutically acceptable or substantially pure fo ⁇ n.
- pharmaceutically acceptable form is meant, inter alia, having a pharmaceutically acceptable level of pu ⁇ ty excluding normal pharmaceutical additives such as diluents and earners, and including no mate ⁇ al considered toxic at no ⁇ nal dosage levels
- Pu ⁇ ty levels for the drug substance are preferably above 50%, more preferably above 70%, most preferably above 90% In a preferred embodiment it is above 95% of the compound of formula (I), or of its salts, solvates or prodrugs
- the compounds of the present invention represented by the above described formula (I) may include enantiomers depending on the presence of chiral centres or isomers depending on the presence of multiple bonds (e.g. Z, E). The single isomers, enantiomers or diastereoisomers and mixtures thereof fall within the scope of the present invention.
- the compounds of formula (I) defined above can be obtained by available synthetic procedures. For example, they can be prepared by the coupling of a compound of Formula (II):
- reaction of compounds of formulas (II) and (III) is preferably carried out in an aprotic solvent, but not limited to, such as dichloromethane in the presence of an organic base, such as diisopropylethylamine or triethylamine.
- Compounds of Formula (II) can be prepared from compounds of Formula (IV) using the reactions and techniques described below.
- Compounds of Formula (IV) are commercially available or may be prepared according to known methods.
- the amine of Formula (IV) is allowed to react with a commercially available N-(3-halopropyl)phtalimide (1 -1) in the presence of an appropriate base and solvent.
- useful bases include, but are not limited to, metal carbonates such as K 2 CO 3 or Cs 2 CO 3 , metal hydroxides, hindered alkoxides or tertiary organic amines.
- Typical solvents include polar aprotic liquids such as DMF or THF, or protic liquids such as alcohols.
- polar aprotic liquids such as DMF or THF
- protic liquids such as alcohols.
- buthanol or xylene have been previously described (J. Med. Chem. 1996, 39(5), 1125-1 129, J. Med. Chem. 1999, 42(4), 730-741) but the yield is improved, (from 50% to 90%), with the use of ⁇ VV-dimethylformamide and K 2 CO 3 as the base.
- acylation of compounds of Formula (IV) with carboxyethylphtalimides derivatives (2-1 ), instead of the alkylation with ⁇ f-(3-halopropyl)phtalimides (1-1), may be convenient in some cases.
- the base used for acylation could be a tertiary organic amine such as triethylamine or //,./V-diisopropylethylamine and the hydrazinolysis can be performed as cited in Scheme 1.
- X is an OH
- a coupling reagent must be used for the activation of carboxy group.
- a reductive animation with phtalimidoethylaldehydes (3-1 ), following by hydrazinolysis may also be performed.
- Condensation of the amine (IV) with aldehydes 3-1 can be performed in the presence of an hydride, such as sodium triacethoxyborohydride NaBH(OAc) 3 or sodium cyanoborhydride (NaBH 4 CN) (Bioorg. Med. Chem. Lett. 1999, 9, 179-184).
- Phtalimide intermediate 3-2 is treated as is described in Schemes 1 and 2 in order to obtain the desired compound of Formula (II).
- Compounds of Formula (II) can be prepared in a sequential way by treatment of a dialkylating agent (4- 1) with the corresponding amine (IV) in the presence of a base in an appropriate solvent, followed by the alkylation of another amine (4-2).
- useful alkylating agents (4-1 ) are those where Y is a good to excellent leaving group, such as Br, I, aryl or alkylsulfonate, etc. and X is a good leaving group, such as Br or Cl.
- Useful bases include, but are not limited to, metal carbonates such as K 2 CO 3 or Cs 2 CO 3 , metal hydroxides, hindered alkoxides or tertiary organic amines.
- Typical solvents include polar aprotic liquids such as DMF or THF, or protic liquids such as alcohols.
- the rate of the second alkylation may be enhanced, particulary when X is Cl, by the addition of a catalytic amount of an iodide salt, such as NaI or KI.
- the required alkylating agents (4-1) are generally commercially available.
- an acylation with carboxynitriles to form an amide is preferred instead of the alkylation with the corresponding halonitriles (Scheme 6).
- acylation with compounds 6-1 where X is a good leaving group, such as I, Br, aryl or alkylsulphonate, is carried out in the presence of an appropriate base and solvent, which were described in schemes above.
- the reduction of cyano an keto group of 6-2 can be performed simultaneously in the presence of an excess of a reducing agent such as LiAlH 4 or borane.
- a coupling reagent When X is OH, a coupling reagent must also be used for the activation of carboxy group.
- the coupling reagents used are the same as are cited in Scheme 2.
- Scheme 6 is also possible when X is an H.
- Reductive amination is carried out by a condensation of amine of Formula (IV) with aldehyde 6-1 in appropriate base and solvent, to form an imine or enamine intermediate, followed by a reduction with a reducing agent, such an hyd ⁇ de.
- Amines of Formula (IV) may be alkylated with halopropanamides 7- 1 in an appropriate solvent and base, the same as are cited in Schemes above.
- Intermediate (7-2) may be reduced in the presence of an hyd ⁇ de, such as LiAlH 4 or borane.
- reaction products may, if desired, be purified by conventional methods, such as crystallisation, chromatography and trituration.
- these isomers may be separated by conventional techniques suchas preparative chromatography. If there are chiral centers the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
- One preferred pharmaceutically acceptable form is the crystalline form, including such form in pharmaceutical composition.
- the additional ionic and solvent moieties must also be non-toxic.
- the compounds of the invention may present different polymorphic forms, it is intended that the invention encompasses all such forms.
- Another aspect of this invention relates to a method of treating or preventing an 5- HT 7 mediated disease which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition thereof.
- 5-HT 7 mediated diseases that can be treated are diseases caused by failures in central and peripheral serotonin-controlling functions, such as pain, sleep disorder, shift worker syndrome, jet lag, depression, seasonal affective disorder, migraine, anxiethy, psychosis, schizophrenia, cognition and memory disorders, neuronal degeneration resulting from ischemic events, cardiovascular diseases such as hypertension, irritable bowel syndrome, inflammatory bowel disease, spastic colon or urinary incontinence.
- the present invention further provides pharmaceutical compositions comprising a compound of this invention, or a pharmaceutically acceptable salt, derivative, prodrug or stereoisomers thereof together with a pharmaceutically acceptable carrier, adjuvant, or vehicle, for administration to a patient.
- compositions include any solid (tablets, pills, capsules, granules etc.) or liquid (solutions, suspensions or emulsions) composition for oral, topical or parenteral administration.
- the pharmaceutical compositions are in oral form, either solid or liquid.
- Suitable dose forms for oral administration may be tablets, capsules, syrops or solutions and may contain conventional excipients known in the art such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize starch, calcium phosphate, sorbitol or glycine; tabletting lub ⁇ cants, for example magnesium stearate, disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose, or pharmaceutically acceptable wetting agents such as sodium lauryl sulfate
- binding agents for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone
- fillers for example lactose, sugar, maize starch, calcium phosphate, sorbitol or
- the solid oral compositions may be prepared by conventional methods of blending, filling or tabletting Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers Such operations are conventional in the art
- the tablets may for example be prepared by wet or dry granulation and optionally coated according to methods well known in normal pharmaceutical practice, in particular with an ente ⁇ c coating
- the pharmaceutical compositons may also be adapted for parenteral administration, such as ste ⁇ le solutions, suspensions or lyophihzed products in the aprop ⁇ ate unit dosage form
- parenteral administration such as ste ⁇ le solutions, suspensions or lyophihzed products in the aprop ⁇ ate unit dosage form
- Adequate excipients can be used, such as bulking agents, buffe ⁇ ng agents or surfactants
- Administration of the compounds or compositions of the present invention may be by any suitable method, such as intravenous infusion, oral prepaiations, and intraperitoneal and intravenous administration Oral administration is preferred because of the convenience for the patient and the chronic character of the diseases to be treated
- an effective administered amount of a compound of the invention will depend on the relative efficacy of the compound chosen, the seventy of the disorder being treated and the weight of the sufferer
- active compounds will typically be administered once or more times a day for example 1 , 2, 3 or 4 times daily, with typical total daily doses in the range of from 0 1 to 1000 mg/kg/day
- the compounds and compositions of this invention may be used with other drugs to provide a combination therapy
- the other drugs may form part of the same composition, or be provided as a separate composition for administration at the same time or at different time
- the compounds of general formula (I) were prepared by the coupling of a compound of formula (II) with a compound of formula (III) by means of conventional organic chemistry methods known to those skilled in the art.
- Radioligand binding assays were performed using the Cloned Human Serotonin Receptor, Subtype 7 (h5HT 7 ), expressed in CHO cells, coated on Flashplate (Basic FlashPlate Cat.: SMP200) from PerkinElmer (Cat.: 6120512).
- the protocol assay was essentially the recommended protocol in the Technical Data Sheet by PerkinEmer Life and Analytical Sciences.
- the Mass membrane protein/well was typically 12 ⁇ g and the Receptor/well was about 9-10 fmoles.
- the Flashplate were let equilibrate at room temperature for one hour before the addition of the components of the assay mixture.
- the binding buffer was: 50 mM Tris-HCl, pH 7.4, containing 10 mM MgCl 2 , 0.5 mM EDTA and 0.5% BSA.
- the radioligand was [ 125 I]LSD at a final concentration of 0.82 nM.
- Nonspecific binding was determined with 50 ⁇ M of Clozapine.
- the assay volume was 25 ⁇ l.
- TopSeal-A were applied onto Flashplate microplates and they were incubated at room temperature for 240 minutes in darkness. The radioactivity were quantified by liquid scintillation spectrophotometry (Wallac 1450 Microbeta Trilux) with a count delay of 4 minutes prior to counting and a counting time of 30 seconds per well.
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- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Cardiology (AREA)
- Urology & Nephrology (AREA)
- Heart & Thoracic Surgery (AREA)
- Anesthesiology (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2005274261A AU2005274261A1 (en) | 2004-08-18 | 2005-08-18 | 5-HT7 receptor antagonists |
EP05774634A EP1778641A1 (en) | 2004-08-18 | 2005-08-18 | 5-ht7 receptor antagonists |
JP2007526394A JP2008509962A (en) | 2004-08-18 | 2005-08-18 | 5-HT7 receptor antagonist |
MX2007001992A MX2007001992A (en) | 2004-08-18 | 2005-08-18 | 5-ht7 receptor antagonists. |
BRPI0514463-9A BRPI0514463A (en) | 2004-08-18 | 2005-08-18 | 5-ht7 receptor antagonists |
US11/658,923 US8148397B2 (en) | 2004-08-18 | 2005-08-18 | 5-HT7 receptor antagonists |
CA002575785A CA2575785A1 (en) | 2004-08-18 | 2005-08-18 | 5-ht7 receptor antagonists |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP04380172.9 | 2004-08-18 | ||
ESP200402050 | 2004-08-18 | ||
US10/920,671 US7211584B2 (en) | 2004-08-18 | 2004-08-18 | 5-HT7 receptor ligands |
EP04380172A EP1630159A1 (en) | 2004-08-18 | 2004-08-18 | 5-HT7 receptor antagonists |
US10/920,671 | 2004-08-18 | ||
ES200402050A ES2257168B1 (en) | 2004-08-18 | 2004-08-18 | 5-HT7 RECEIVER LIGANDS. |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2006018309A1 true WO2006018309A1 (en) | 2006-02-23 |
Family
ID=35229688
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2005/008979 WO2006018309A1 (en) | 2004-08-18 | 2005-08-18 | 5-ht7 receptor antagonists |
Country Status (11)
Country | Link |
---|---|
US (1) | US8148397B2 (en) |
EP (2) | EP1630159A1 (en) |
JP (1) | JP2008509962A (en) |
KR (1) | KR20070046879A (en) |
CN (1) | CN101014573A (en) |
AU (1) | AU2005274261A1 (en) |
BR (1) | BRPI0514463A (en) |
CA (1) | CA2575785A1 (en) |
ES (1) | ES2257168B1 (en) |
MX (1) | MX2007001992A (en) |
WO (1) | WO2006018309A1 (en) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008000495A1 (en) * | 2006-06-29 | 2008-01-03 | Laboratorios Del Dr. Esteve, S.A | Use of 5-ht7 receptor agonists for the treatment of pain |
WO2009082268A2 (en) | 2007-12-21 | 2009-07-02 | Alla Chem, Llc | LIGANDS OF α-ADRENOCEPTORS AND OF DOPAMINE, HISTAMINE, IMIDAZOLINE AND SEROTONIN RECEPTORS AND THE USE THEREOF |
US7833999B2 (en) | 2004-05-25 | 2010-11-16 | Sanofi-Aventis | Tetrahydroisoquinoline sulfonamide derivatives, the preparation thereof, and the use of the same in therapeutics |
US7872138B2 (en) | 2006-08-07 | 2011-01-18 | Janssen Pharmaceutica Nv | Process for the preparation of substituted-1,2,3,4-tetrahydroisoquinoline derivatives |
JP5336359B2 (en) * | 2007-05-28 | 2013-11-06 | セルダー ファーマ インコーポレイテッド | Tetrahydroisoquinolin-1-one derivative or salt thereof |
US8748615B2 (en) | 2010-03-05 | 2014-06-10 | Sanofi | Process for the preparation of 2-(cyclohexylmethyl)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide |
EP3589626A4 (en) * | 2017-03-03 | 2020-10-14 | National Taiwan University | 8-phenyl-isoquinolines and pharmaceutical composition thereof used in the treatment of irritable bowel syndrome |
US11938134B2 (en) | 2017-03-10 | 2024-03-26 | Eikonizo Therapeutics, Inc. | Metalloenzyme inhibitor compounds |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9140185B2 (en) * | 2009-11-24 | 2015-09-22 | Honeywell International Inc. | Locating mechanism for turbocharger bearing |
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WO1997049695A1 (en) * | 1996-06-25 | 1997-12-31 | Smithkline Beecham P.L.C. | Sulfonamide derivatives as 5ht7 receptor antagonists |
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US5294621A (en) | 1992-10-07 | 1994-03-15 | Ortho Pharmaceutical Corporation | Thieno tetrahydropyridines useful as class III antiarrhythmic agents |
GB9612884D0 (en) | 1996-06-20 | 1996-08-21 | Smithkline Beecham Plc | Novel compounds |
WO1999024022A2 (en) | 1997-11-10 | 1999-05-20 | F. Hoffmann-La Roche Ag | Isoquinoline derivatives for treating disorders associated with 5ht7 receptors |
WO2000000472A1 (en) | 1998-06-30 | 2000-01-06 | Du Pont Pharmaceuticals Company | 5-ht7 receptor antagonists |
GB0128885D0 (en) | 2001-12-03 | 2002-01-23 | Merck Sharp & Dohme | Therapeutic agents |
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2004
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- 2004-08-18 ES ES200402050A patent/ES2257168B1/en not_active Expired - Fee Related
-
2005
- 2005-08-18 EP EP05774634A patent/EP1778641A1/en not_active Withdrawn
- 2005-08-18 BR BRPI0514463-9A patent/BRPI0514463A/en not_active IP Right Cessation
- 2005-08-18 KR KR1020077004113A patent/KR20070046879A/en not_active Application Discontinuation
- 2005-08-18 CA CA002575785A patent/CA2575785A1/en not_active Abandoned
- 2005-08-18 MX MX2007001992A patent/MX2007001992A/en not_active Application Discontinuation
- 2005-08-18 WO PCT/EP2005/008979 patent/WO2006018309A1/en active Application Filing
- 2005-08-18 AU AU2005274261A patent/AU2005274261A1/en not_active Abandoned
- 2005-08-18 JP JP2007526394A patent/JP2008509962A/en active Pending
- 2005-08-18 US US11/658,923 patent/US8148397B2/en not_active Expired - Fee Related
- 2005-08-18 CN CNA2005800278410A patent/CN101014573A/en active Pending
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Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7833999B2 (en) | 2004-05-25 | 2010-11-16 | Sanofi-Aventis | Tetrahydroisoquinoline sulfonamide derivatives, the preparation thereof, and the use of the same in therapeutics |
US8273733B2 (en) | 2004-05-25 | 2012-09-25 | Sanofi | Tetrahydroisoquinoline sulfonamide derivatives, the preparation thereof, and the use of the same in therapeutics |
US8524700B2 (en) | 2004-05-25 | 2013-09-03 | Sanofi | Tetrahydroisoquinoline sulfonamide derivatives, the preparation thereof, and the use of the same in therapeutics |
WO2008000495A1 (en) * | 2006-06-29 | 2008-01-03 | Laboratorios Del Dr. Esteve, S.A | Use of 5-ht7 receptor agonists for the treatment of pain |
EP1875899A1 (en) * | 2006-06-29 | 2008-01-09 | Laboratorios Del Dr. Esteve, S.A. | Use of 5HT7 receptor agonists for the treatment of pain |
US7872138B2 (en) | 2006-08-07 | 2011-01-18 | Janssen Pharmaceutica Nv | Process for the preparation of substituted-1,2,3,4-tetrahydroisoquinoline derivatives |
JP5336359B2 (en) * | 2007-05-28 | 2013-11-06 | セルダー ファーマ インコーポレイテッド | Tetrahydroisoquinolin-1-one derivative or salt thereof |
WO2009082268A2 (en) | 2007-12-21 | 2009-07-02 | Alla Chem, Llc | LIGANDS OF α-ADRENOCEPTORS AND OF DOPAMINE, HISTAMINE, IMIDAZOLINE AND SEROTONIN RECEPTORS AND THE USE THEREOF |
US8748615B2 (en) | 2010-03-05 | 2014-06-10 | Sanofi | Process for the preparation of 2-(cyclohexylmethyl)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide |
US8779145B2 (en) | 2010-03-05 | 2014-07-15 | Sanofi | Process for the preparation of 2-(cyclohexylmethyl)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline |
EP3589626A4 (en) * | 2017-03-03 | 2020-10-14 | National Taiwan University | 8-phenyl-isoquinolines and pharmaceutical composition thereof used in the treatment of irritable bowel syndrome |
US11938134B2 (en) | 2017-03-10 | 2024-03-26 | Eikonizo Therapeutics, Inc. | Metalloenzyme inhibitor compounds |
Also Published As
Publication number | Publication date |
---|---|
ES2257168B1 (en) | 2007-06-01 |
US8148397B2 (en) | 2012-04-03 |
BRPI0514463A (en) | 2008-06-10 |
JP2008509962A (en) | 2008-04-03 |
CA2575785A1 (en) | 2006-02-23 |
US20090088450A1 (en) | 2009-04-02 |
KR20070046879A (en) | 2007-05-03 |
EP1778641A1 (en) | 2007-05-02 |
AU2005274261A1 (en) | 2006-02-23 |
ES2257168A1 (en) | 2006-07-16 |
MX2007001992A (en) | 2007-05-15 |
CN101014573A (en) | 2007-08-08 |
EP1630159A1 (en) | 2006-03-01 |
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