WO2009058810A1 - Procédé de préparation de dérivés de 2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulène substitués - Google Patents

Procédé de préparation de dérivés de 2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulène substitués Download PDF

Info

Publication number
WO2009058810A1
WO2009058810A1 PCT/US2008/081513 US2008081513W WO2009058810A1 WO 2009058810 A1 WO2009058810 A1 WO 2009058810A1 US 2008081513 W US2008081513 W US 2008081513W WO 2009058810 A1 WO2009058810 A1 WO 2009058810A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
yield
group
reacting
Prior art date
Application number
PCT/US2008/081513
Other languages
English (en)
Inventor
Anusuya Choudhury
Kirk Sorgi
Original Assignee
Janssen Pharmaceutica N.V.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Janssen Pharmaceutica N.V. filed Critical Janssen Pharmaceutica N.V.
Publication of WO2009058810A1 publication Critical patent/WO2009058810A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings 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 ring carbon atoms
    • C07D223/08—Oxygen atoms

Definitions

  • the present invention is directed to processes for the preparation of substituted 2,4,5,6,7,8-hexahydro-1 ,2,6-thaza-azulene derivatives, useful for the treatment of disease states mediated by serotonin receptor activity.
  • the compounds are useful for treating or preventing CNS disorders, such as sleep disorders, depression/anxiety, generalized anxiety disorder, schizophrenia, bipolar disorders, psychotic disorders, obsessive-compulsive disorder, mood disorders, post-traumatic stress and other stress-related disorders, migraine, pain, eating disorders, obesity, sexual dysfunction, metabolic disturbances, hormonal imbalance, alcohol abuse, addictive disorders, nausea, inflammation, centrally mediated hypertension, sleep/wake disturbances, jetlag, and circadian rhythm abnormalities.
  • CNS disorders such as sleep disorders, depression/anxiety, generalized anxiety disorder, schizophrenia, bipolar disorders, psychotic disorders, obsessive-compulsive disorder, mood disorders, post-traumatic stress and other stress-related disorders, migraine, pain, eating disorders, obesity, sexual dysfunction, metabolic disturbances, hormonal imbalance, alcohol abuse, addictive disorders, nausea, inflammation, centrally mediated hypertension, sleep/wake disturbances, jetlag, and circadian rhythm abnormalities.
  • the compounds may also be used in the treatment and prevention of hypotension, peripheral vascular disorders, cardiovascular shock, renal disorders, gastric motility, diarrhea, spastic colon, irritable bowel disorders, ischemias, septic shock, urinary incontinence, and other disorders related to the gastrointestinal and vascular systems.
  • the compounds may be used in the treatment or prevention of a range of ocular disorders including glaucoma, optic neuritis, diabetic retinopathy, retinal edema, and age-related macular degeneration.
  • Substituted pyrazoles are important synthetic targets in the pharmaceutical industry, as the pyrazole motif makes of the core structure of numerous biologically active compounds (Elguero, J.; Goya, P.; Jagerovic, N.; Silva, A.M. S. Targets in Heterocyclic Systems 2002, 6, 52-98) including marketed drugs such as sildenafil (Terrett, N. K. et al. Bioorg. Med. Chem. Lett. 1996, 6, 1819-1824) and celecoxib (Penning, T.D. et al. J. Med. Chem. 1997, 40, 1347-1365).
  • Pyrazoles are often prepared by the reaction of hydrazines with 1 ,3-dicarbonyl compounds or their equivalents, such as ⁇ , ⁇ - ethynylketones or esters. These condensation reactions generally result in mixtures of regioisomers, which complicates isolation and purification processes. Cyclization reactions of 1 ,3-dipoles such as deazoalkanes or nitrilimines with olefins has also been used, but these reactions often suffer from low yields and harsh conditions (Elguero, J. Comp. Heterocycl. Chem. 1984, 5,167; Elguero, J. Comp. Heterocycl. Chem. Il 1996, 3, 1-75 and 817- 932, and references cited therein).
  • the present invention is directed to a process for the preparation of a mixture of a compound of formula (I) and a compound of formula (II)
  • q is an integer from 0 to 1 ;
  • ALK is selected from the group consisting of C 1-4 alkyl
  • CYC is selected from the group consisting of hydrogen, Cs-scycloalkyl and aryl;
  • AR is selected from the group consisting of aryl; wherein the aryl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, C 1-4 alkyl, Ci -4 alkoxy, CF 3 and -OCF 3 ; or pharmaceutically acceptable salts thereof; comprising
  • the present invention is further directed to a process for the preparation of a compound of formula (I)
  • q is an integer from 0 to 1 ;
  • ALK is selected from the group consisting of C-
  • CYC is selected from the group consisting of hydrogen, C 3 - 8 cycloalkyl and aryl;
  • AR is selected from the group consisting of aryl; wherein the aryl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, Ci -4 alkyl, Ci -4 alkoxy, CF 3 and -OCF 3 ; or pharmaceutically acceptable salts thereof; comprising
  • the present invention is further directed to a process for the preparation of a compound of formula (II)
  • ALK is selected from the group consisting of Ci -4 alkyl
  • CYC is selected from the group consisting of hydrogen, C 3 - 8 cycloalkyl and aryl;
  • AR is selected from the group consisting of aryl; wherein the aryl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, C 1-4 alkyl, Ci -4 alkoxy, CF 3 and -OCF 3 ; or pharmaceutically acceptable salts thereof; comprising reacting a compound of formula (X), wherein PG 1 is a nitrogen protecting group with a compound of formula (Xl); in an organic solvent; to yield the corresponding compound of formula (XIII);
  • the present invention is directed to a process for the preparation of a compound of formula (I-S)
  • (I-S) also known as 3-(4-fluoro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro- 1 ,2,6-triaza-azulene; comprising
  • the present invention is directed to a process for the preparation of a compound of formula (N-S)
  • PG 1 is a nitrogen protecting group
  • AR is selected from the group consisting of aryl; wherein the aryl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, Ci -4 alkyl, Ci -4 alkoxy, CF 3 and -OCF 3 ; or pharmaceutically acceptable salts thereof.
  • the present invention is directed to compounds of formula (X) wherein AR is selected from the group consisting of 4-chlorophenyl and 4-fluorophenyl and pharmaceutically acceptable salts thereof.
  • the present invention is further directed to processes for the preparation of the compound of formula (X), as described in more detail herein (more particularly, as described in Scheme 4-9 which follow herein).
  • the present invention is directed to processes for the preparation of compounds of formula (X) wherein AR is selected from the group consisting of 4-chlorophenyl and 4-fluorophenyl, and pharmaceutically acceptable salts thereof, as described in more detail in Schemes 5, 7 and 9 which follow herein.
  • the present invention is further directed to a product prepared according to the process described herein.
  • Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the product prepared according to the process described herein.
  • An illustration of the invention is a pharmaceutical composition made by mixing the product prepared according to the process described herein and a pharmaceutically acceptable carrier.
  • Illustrating the invention is a process for making a pharmaceutical composition comprising mixing the product prepared according to the process described herein and a pharmaceutically acceptable carrier.
  • Exemplifying the invention are methods of treating or preventing a disease or condition selected from the group consisting of depression, anxiety, generalized anxiety disorder, schizophrenia, bipolar disorders, psychotic disorders, obsessive-compulsive disorder, mood disorders, post-traumatic stress disorders, sleep disturbances, sexual dysfunction, eating disorders, migraine, addictive disorders, and peripheral vascular disorders comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds prepared according to the processes described herein.
  • Another example of the invention is the use of any of the compounds described herein in the preparation of a medicament for treating or preventing (a) depression, (b) anxiety, (c) generalized anxiety disorder, (d) schizophrenia, (e) bipolar disorders, (f) psychotic disorders, (g) obsessive-compulsive disorder, (h) mood disorders, (i) post-traumatic stress disorders, (j) sleep disturbances, (k) sexual dysfunction, (I) eating disorders, (m) migraine, (n) addictive disorders or (o) peripheral vascular disorders, in a subject in need thereof.
  • the compounds of formula (I) and formula (II) may be used in the treatment or prevention of CNS disorders, such as sleep disorders, depression/anxiety, generalized anxiety disorder, schizophrenia, bipolar disorders, psychotic disorders, obsessive-compulsive disorder, mood disorders, post-traumatic stress and other stress-related disorders, migraine, pain, eating disorders, obesity, sexual dysfunction, metabolic disturbances, hormonal imbalance, alcohol abuse, addictive disorders, nausea, inflammation, centrally mediated hypertension, sleep/wake disturbances, jetlag, and circadian rhythm abnormalities.
  • CNS disorders such as sleep disorders, depression/anxiety, generalized anxiety disorder, schizophrenia, bipolar disorders, psychotic disorders, obsessive-compulsive disorder, mood disorders, post-traumatic stress and other stress-related disorders, migraine, pain, eating disorders, obesity, sexual dysfunction, metabolic disturbances, hormonal imbalance, alcohol abuse, addictive disorders, nausea, inflammation, centrally mediated hypertension, sleep/wake disturbances, jetlag, and circadian rhythm abnormalities.
  • the compounds of formula (I) and formula (II) may also be used in the treatment and prevention of hypotension, peripheral vascular disorders, cardiovascular shock, renal disorders, gastric motility, diarrhea, spastic colon, irritable bowel disorders, ischemias, septic shock, urinary incontinence, and other disorders related to the gastrointestinal and vascular systems.
  • compounds of formula (I) and formula (II) may be used in the treatment or prevention of a range of ocular disorders including glaucoma, optic neuritis, diabetic retinopathy, retinal edema, and age-related macular degeneration.
  • the compounds of formula (I) and formula (II) are 5-HT 7 modulators and many are 5-HT 7 antagonists. As such, the compounds of formula (I) and formula (II) are useful in the treatment of 5-HT 7 -mediated disease states. Where the compounds of formula (I) and formula (II) possess substantial 5-HT 7 antagonist activity, they may be particularly useful in the treatment or prevention of depression/anxiety, sleep/wake disturbances, jetlag, migraine, urinary incontinence, gastric motility, and irritable bowel disorders. Many of the compounds of formula (I) and formula (II) are 5-HT 2 modulators and many are 5-HT 2 antagonists. As such, the compounds of formula (I) and formula (II) are useful in the treatment of 5-HT 2 -mediated diseases and conditions.
  • the compounds of formula (I) and formula (II) possess substantial 5-HT 2 antagonist activity, they may be particularly useful in the treatment or prevention of depression/anxiety, generalized anxiety disorder, schizophrenia, bipolar disorders, psychotic disorders, obsessive-compulsive disorder, mood disorders, post-traumatic stress disorders, sleep disturbances, sexual dysfunction, eating disorders, migraine, addictive disorders, and peripheral vascular disorders.
  • q is 1.
  • ALK is selected from the group consisting of Ci- 3 alkyl. In another embodiment of the present invention, ALK is selected from the group consisting of methyl and isopropyl.
  • CYC is selected from the group consisting of hydrogen, Cs- ⁇ Cycloalkyl and phenyl. In another embodiment of the present invention, CYC is selected from the group consisting of hydrogen, cyclopentyl and phenyl. In another embodiment of the present invention, CYC is selected from the group consisting of hydrogen and phenyl.
  • AR is phenyl, wherein the phenyl is optionally substituted with a substituent selected from the group consisting of halogen, C 1-4 alkyl, Ci -4 alkoxy, CF 3 and -OCF 3 .
  • AR is AR is phenyl, wherein the phenyl is optionally substituted with a substituent selected from the group consisting of halogen, Ci -4 alkyl and CF 3 .
  • AR is AR is phenyl, wherein the phenyl is optionally substituted with a substituent selected from the group consisting of chloro, fluoro, methyl, ethyl and CF 3 .
  • AR is AR is phenyl, wherein the phenyl is optionally substituted with a substituent selected from the group consisting of halogen and Ci -4 alkyl.
  • AR is AR is phenyl, wherein the phenyl is optionally substituted with a substituent selected from the group consisting of halogen.
  • AR is AR is phenyl, wherein the phenyl is optionally substituted with a substituent selected from the group consisting of chloro and fluoro.
  • halogen shall mean chlorine, bromine, fluorine and iodine.
  • alkyl whether used alone or as part of a substituent group, include straight and branched chains.
  • alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t- butyl, pentyl and the like.
  • Si -4 when used with alkyl means a carbon chain composition of 1-4 carbon atoms.
  • alkoxy shall denote an oxygen ether radical of the above described straight or branched chain alkyl groups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the like. Unless otherwise noted, "Ci -4 " when used with alkoxy means an oxygen ether radical of the above described carbon chain composition of 1-4 carbon atoms.
  • aryl shall refer to unsubstituted carbocylic aromatic groups such as phenyl, naphthyl, and the like.
  • C3-8cycloalkyl shall mean any stable 3-8 membered monocyclic, saturated ring system, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • a particular group is "substituted” (e.g., alkkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, etc.), that group may have one or more substituents, preferably from one to five substituents, more preferably from one to three substituents, most preferably from one to two substituents, independently selected from the list of substituents.
  • the compounds according to this invention may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
  • the enantiomer is present at an enantiomeric excess of greater than or equal to about 80%, more preferably, at an enantiomeric excess of greater than or equal to about 90%, more preferably still, at an enantiomeric excess of greater than or equal to about 95%, more preferably still, at an enantiomeric excess of greater than or equal to about 98%, most preferably, at an enantiomeric excess of greater than or equal to about 99%.
  • the diastereomer is present at an diastereomeric excess of greater than or equal to about 80%, more preferably, at an diastereomeric excess of greater than or equal to about 90%, more preferably still, at an diastereomeric excess of greater than or equal to about 95%, more preferably still, at an diastereomeric excess of greater than or equal to about 98%, most preferably, at an diastereomeric excess of greater than or equal to about 99%.
  • crystalline forms for the compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention.
  • some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
  • solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
  • the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment.
  • a "phenylCr C 6 alkylaminocarbonylCrC 6 alkyl" substituent refers to a group of the formula
  • the term "isolated form” shall mean that the compound is present in a form which is separate from any solid mixture with another compound(s), solvent system or biological environment.
  • the compound of formula (I) is prepared as an isolated form.
  • the compound of formula (II) is prepared as an isolated form.
  • the compound of formula (I-S) is prepared as an isolated form.
  • the compound of formula (N-S) is prepared as an isolated form.
  • the term “substantially pure compound” shall mean that the mole percent of impurities in the isolated compound is less than about 5 mole percent, preferably less than about 2 mole percent, more preferably, less than about 0.5 mole percent, most preferably, less than about 0.1 mole percent.
  • (I) is prepared as a substantially pure compound.
  • the compound of formula (II) is prepared as a substantially pure compound.
  • the compound of formula (I-S) is prepared as a substantially pure compound.
  • the compound of formula (N-S) is prepared as a substantially pure compound.
  • the term "substantially free of a corresponding salt form(s)" when used to described the compound of formula (I) shall mean that mole percent of the corresponding salt form(s) in the isolated base of formula (I) is less than about 5 mole percent, preferably less than about 2 mole percent, more preferably, less than about 0.5 mole percent, most preferably less than about 0.1 mole percent.
  • the compound of formula (I) is prepared in a form which is substantially free of a corresponding salt form(s).
  • the compound of formula (I) is prepared in a form which is substantially free of a corresponding salt form(s).
  • (II) is prepared in a form which is substantially free of a corresponding salt form(s).
  • the compound of formula (I-S) is prepared in a form which is substantially free of a corresponding salt form(s).
  • the compound of formula (N-S) is prepared in a form which is substantially free of a corresponding salt form(s).
  • subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. Preferably, the subject has experienced and / or exhibited at least one symptom of the disease or disorder to be treated and / or prevented.
  • therapeutically effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
  • reaction step(s) is performed under suitable conditions, according to known methods, to provide the desired product.
  • reagent or reagent class/type e.g. base, solvent, etc.
  • the individual reagents are independently selected for each reaction step and may be the same of different from each other.
  • the organic or inorganic base selected for the first step may be the same or different than the organic or inorganic base of the second step.
  • the term “leaving group” shall mean a charged or uncharged atom or group which departs during a substitution or displacement reaction. Suitable examples include, but are not limited to, Br, Cl, I, mesylate, tosylate, and the like.
  • the term “nitrogen protecting group” shall mean a group which may be attached to a nitrogen atom to protect said nitrogen atom from participating in a reaction and which may be readily removed following the reaction.
  • Other suitable nitrogen protecting groups may be found in texts such as T.W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons
  • reaction step of the present invention may be carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems.
  • the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers
  • these isomers may be separated by conventional techniques such as preparative chromatography.
  • the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
  • the compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-D-tartahc acid and/or (+)-di-p-toluoyl-L-tartahc acid followed by fractional crystallization and regeneration of the free base.
  • the compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
  • it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 .
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts.”
  • Other salts may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts.
  • alkali metal salts e.g., sodium or potassium salts
  • alkaline earth metal salts e.g., calcium or magnesium salts
  • suitable organic ligands e.g., quaternary ammonium salts.
  • representative pharmaceutically acceptable salts include the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate,
  • acids and bases which may be used in the preparation of pharmaceutically acceptable salts include the following: acids including acetic acid, 2,2-dichloroactic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1 S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuhc acid, ethane-1 ,2- disulfonic acid, ethanesulfonic acid, 2-hydrocy-ethanesulfonic acid, formic acid, fumaric acid, galactahc acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucor
  • the present invention is directed to a process for the preparation of compounds of formula (I), compounds of formula (II) and mixtures thereof, as described in more detail in Scheme 1 below.
  • PG 1 is a suitably selected nitrogen protecting group such as BOC, CBz, benzyl, t
  • the compound of formula (Xl) is added slowly to a mixture of the compound of formula (X) in the selected organic solvent.
  • the compound of formula (I) is the desired product, then the compound of formula (X) is reacted with the compound of formula (Xl), preferably in the presence of less than about 1 molar equivalent of water, more preferably in the presence of between about 0.1 and about 0.25 molar equivalents, more preferably in the presence of about 0.1 molar equivalents.
  • the mixture comprising the compound of formula (XII) and the compound of formula (XIII) is separated according to known methods, for example by column chromatography, selective crystallization, and the like.
  • the mixture of the compound of formula (XII) and the compound of formula (XIII) is de-protected according to known methods, to yield the corresponding compound of formula (I).
  • PG 1 is BOC
  • the compound of formula (XII) is de-protected by reacting with an acid such as HCI, and the like, preferably HCI, in an organic solvent such as IPA, and the like, preferably IPA, to yield a mixture of the corresponding compound of formula (I) and the corresponding compound of formula (II).
  • the mixture comprising the compound of formula (I) and the compound of formula (II) is separated according to known methods, for example by column chromatography, selective crystallization, and the like.
  • the present invention is directed to a process for the preparation of a compound of formula (I-S) as described in more detail in Scheme 2, below.
  • the compound of formula (Xl-S) is added slowly to a mixture of the compound of formula (X-S) in the selected organic solvent.
  • the compound of formula (XII-S) is de-protected according to known methods, to yield the corresponding compound of formula (I-S).
  • PG 1 is BOC
  • the compound of formula (XII-S) is de-protected by reacting with an acid such as HCI, and the like, preferably HCI, in an organic solvent such as IPA, and the like, preferably IPA, to yield the corresponding compound of formula (I-S).
  • the compound of formula (I-S) (as a free base) is preferably isolated according to known methods, for example by filtration.
  • the compound of formula (I-S) is purified according to known methods, for example by recrystallization from a suitably selected organic solvent such as THF, IPA, methanol, ethanol, and the like, more preferably, from IPA.
  • the compound of formula (I-S) is reacted with a suitably selected acid, according to known methods, to yield its corresponding pharmaceutically acceptable salt.
  • the compound of formula (I-S) is reacted with citric acid, wherein the citric acid is preferably present in an amount in the range of from about 0.9 to about 1.5 molar equivalents, more preferably about 1.4 molar equivalents; in an organic solvent or mixture of organic solvents, such as ethanol, methanol, IPA, ethyl acetate, and the like, preferably in a mixture of methanol and ethyl acetate, to yield the corresponding citrate salt of the compound of formula (I-S).
  • the present invention is directed to a process for the preparation of a compound of formula (N-S) as described in more detail in Scheme 3, below.
  • the compound of formula (Xl-T) is added slowly to a mixture of the compound of formula (X-T
  • the compound of formula (XIII-T) is de-protected according to known methods, to yield the corresponding compound of formula (N-S).
  • PG 1 is BOC
  • the compound of formula (XIII-T) is de-protected by reacting with an acid such as HCI, and the like, preferably HCI, in an organic solvent such as IPA, and the like, preferably IPA, to yield the corresponding compound of formula (N-S).
  • the compound of formula (N-S) is preferably isolated according to known methods, for example by filtration.
  • the compound of formula (N-S) is preferably purified according to known methods, for example by column chromatography.
  • the compound of formula (N-S) is reacted with a suitably selected acid, according to known methods to yield its corresponding pharmaceutically acceptable salt.
  • a suitably selected acid for example, the compound of formula (N-S) is reacted with citric acid, in an organic solvent such as methanol, to yield the corresponding citrate salt of the compound of formula (N-S).
  • the present invention is further directed to processes for the preparation of compounds of formula (X) as outlined in Scheme 4, Scheme 6 and Scheme 8, which follow herein.
  • the present invention is directed to processes for the preparation of a compound of formula (X-A)
  • PG 1 is a nitrogen protecting group such as BOC, Cbz, and the like, preferably BOC; and wherein Q is chloro or fluoro, as outlined in Schemes 5, 7 and 9 which follow herein.
  • Q is chloro.
  • Q is fluoro.
  • the compounds of formula (X) may be prepared as outlined in Scheme 4, adapting the procedure as described in Rathke, M.W., et al., J. Org. Chem, (1985), Vol. 50, pp. 2622-2624.
  • an organic base such as pyridine
  • the organic base is preferably present in an amount in the range of from about 0.9 to about 1.25 molar equivalents, more preferably in an amount of about 1 .0 molar equivalents; preferably at a temperature in the range of from about 0 0 C to about room temperature, more preferably at a temperature in the range of from about 0 0 C to about 5°C; to yield the corresponding compound of formula (XVII).
  • the compound of formula (XVII) is reacted with a suitably selected decarboxylating agent such as lithium chloride, sodium chloride, sodium iodide, sodium acetate, and the like, preferably lithium chloride, wherein the decarboxylating agent is preferably present in an amount in the range of from about 1.0 to 1 .25 molar equivalents, more preferably in an amount of about 1 .1.
  • a suitably selected decarboxylating agent such as lithium chloride, sodium chloride, sodium iodide, sodium acetate, and the like, preferably lithium chloride, wherein the decarboxylating agent is preferably present in an amount in the range of from about 1.0 to 1 .25 molar equivalents, more preferably in an amount of about 1 .1.
  • the present invention is directed to a process for the preparation of compounds of formula (X-A)
  • PG 1 is a nitrogen protecting group, preferably BOC; and wherein Q is chloro or fluoro; as outlined in more detail in Scheme 5 below.
  • the compound of formula (XVII-A) is reacted with a suitably selected decarboxylating agent such as lithium chloride, sodium chloride, sodium iodide, sodium acetate, and the like, preferably lithium chloride, wherein the decarboxylating agent is preferably present in an amount in the range of from about 1.0 to 1 .25 molar equivalents, more preferably in an amount of about 1.1.
  • a suitably selected decarboxylating agent such as lithium chloride, sodium chloride, sodium iodide, sodium acetate, and the like, preferably lithium chloride, wherein the decarboxylating agent is preferably present in an amount in the range of from about 1.0 to 1 .25 molar equivalents, more preferably in an amount of about 1.1.
  • the compounds of formula (X) may alternatively be prepared according to the process outlined in Scheme 6, below.
  • a suitably substituted compound of formula (XX) a known compound is protected according to known methods, to yield the corresponding compound of formula (XXI), wherein PG 1 is the corresponding nitrogen protecting group.
  • PG 1 is BOC
  • the compound of formula (XX) is reacted with for example, BOC anhydride in methanol.
  • suitable nitrogen protecting groups include, but are not limited to, CBz, benzyl, trityl, and the like.
  • the compound of formula (XXI) is reacted with a suitably substituted compound of formula (XXII), a known compound or compound prepared by known methods, in the presence of a base such as LDA, lithium t-butoxide, potassium t-butoxide, and the like, preferably LDA; in an organic solvent such as THF, MTBE, dioxane, and the like, preferably THF; preferably at a temperature in the range of from about 0° to about -78°C, more preferably at about -78°C; to yield a mixture of the desired regioisomer, the corresponding compound of formula (X) and the undesired regioisomer, the corresponding compound of formula (XXIII).
  • the compound of formula (X) is isolated according to known methods, for example by column chromatography, selective crystallization, and the like.
  • the present invention is directed to a process for the preparation of a compound of formula (X-A)
  • PG 1 is a nitrogen protecting group, preferably BOC; and wherein Q is chloro or fluoro, as outlined in more detail in Scheme 7 below.
  • Scheme 7 More particularly, a suitably substituted compound of formula (XX-A), a known compound is protected according to known methods, to yield the corresponding compound of formula (XXI-A), wherein PG 1 is the corresponding nitrogen protecting group.
  • PG 1 is BOC
  • the compound of formula (XX-A) is reacted with for example, BOC anhydride in methanol.
  • suitable nitrogen protecting groups include, but are not limited to CBz, benzyl, trityl, and the like.
  • the compound of formula (XXI-A) is reacted with a suitably substituted compound of formula (XXII-A), wherein Q is chloro or fluoro, a known compound or compound prepared by known methods, in the presence of a base such as LDA, lithium t-butoxide, potassium t-butoxide, and the like, preferably LDA; in an organic solvent such as THF, MTBE, dioxane, and the like, preferably THF; preferably at a temperature in the range of from about 0° to about -78°C, more preferably at about -78°C; to yield a mixture of the desired regioisomer, the corresponding compound of formula (X-A) and the undesired regioisomer, the corresponding compound of formula (XXIII-A).
  • a base such as LDA, lithium t-butoxide, potassium t-butoxide, and the like, preferably LDA
  • organic solvent such as THF, MTBE, di
  • the compound of formula (X-A) is isolated according to known methods, for example by column chromatography, selective crystallization, and the like.
  • the compounds of formula (X) may be prepared according to the process as outlined in Scheme 8, below.
  • a suitably substituted compound of formula (XX) a known compound is protected according to known methods, to yield the corresponding compound of formula (XXI), wherein PG 1 is the corresponding nitrogen protecting group.
  • PG 1 is BOC
  • the compound of formula (XX) is reacted with for example, BOC anhydride in methanol.
  • suitable nitrogen protecting groups include, but are not limited to, CBz, benzyl, trityl, and the like.
  • the compound of formula (XXI) is reacted with a suitably substituted compound of formula (XXV), a known compound or compound prepared by known methods, in the presence of a base such as LDA, lithium t-butoxide, potassium t-butoxide, and the like, preferably LDA; in an organic solvent such as THF, MTBE, dioxane, and the like, preferably THF; preferably at a temperature in the range of from about 0° to about -78°C, more preferably at about -78°C; to yield a mixture of the four corresponding isomers, a mixture of the two isomers of formula (XXVII) and the two isomers of formula (XXVIII).
  • a base such as LDA, lithium t-butoxide, potassium t-butoxide, and the like, preferably LDA
  • organic solvent such as THF, MTBE, dioxane, and the like, preferably THF
  • THF preferably at a temperature
  • the mixture of the compounds of formula (XXVI) and the compounds of formula (XXVIII) is reacted with a suitably selected oxidizing agent such as Dess-Martin reagent, Swern oxidizing reagent, and the like; in an organic solvent such as methylene chloride, THF, toluene, and the like; according to known methods, to yield a mixture of the corresponding compound of formula (XXIII) and the corresponding compound of formula (X).
  • a suitably selected oxidizing agent such as Dess-Martin reagent, Swern oxidizing reagent, and the like
  • organic solvent such as methylene chloride, THF, toluene, and the like
  • the compound of formula (X) is isolated according to known methods, for example by column chromatography, selective crystallization, and the like.
  • the present invention is directed to a process for the preparation of a compound of formula (X-A)
  • a suitably substituted compound of formula (XX) a known compound is protected according to known methods, to yield the corresponding compound of formula (XXI), wherein PG 1 is the corresponding nitrogen protecting group.
  • PG 1 is BOC
  • the compound of formula (XX) is reacted with for example, BOC anhydride in methanol.
  • suitable nitrogen protecting groups include, but are not limited to, CBz, benzyl, trityl, and the like.
  • the compound of formula (XXI) is reacted with a suitably substituted compound of formula (XXV-A), wherein Q is chloro or fluoro, a known compound or compound prepared by known methods, in the presence of a base such as LDA, lithium t-butoxide, potassium t-butoxide, and the like, preferably LDA; in an organic solvent such as THF, MTBE, dioxane, and the like, preferably THF; preferably at a temperature in the range of from about 0° to about -78°C, more preferably at about -78°C; to yield a mixture of the four corresponding isomers, a mixture of the two isomers of formula (XXVII-A) and the two isomers of formula (XXVIII-A).
  • a base such as LDA, lithium t-butoxide, potassium t-butoxide, and the like, preferably LDA
  • organic solvent such as THF, MTBE, dioxane, and
  • the mixture of the compounds of formula (XXVII-A) and the compounds of formula (XXVIII-A) is reacted with a suitably selected oxidizing agent such as Dess-Martin reagent, Swern oxidizing reagent, and the like; in an organic solvent such as methylene chloride, THF, toluene, and the like; according to known methods, to yield a mixture of the corresponding compound of formula (XXIII-A) and the corresponding compound of formula (X-A).
  • a suitably selected oxidizing agent such as Dess-Martin reagent, Swern oxidizing reagent, and the like
  • organic solvent such as methylene chloride, THF, toluene, and the like
  • the compound of formula (X-A) is isolated according to known methods, for example by column chromatography, selective crystallization, and the like.
  • the present invention further comprises pharmaceutical compositions containing one or more compounds prepared according to any of the processes described herein with a pharmaceutically acceptable carrier.
  • Pharmaceutical compositions containing one or more of the compounds of the invention described herein as the active ingredient can be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral).
  • suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like;
  • suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.
  • Solid oral preparations may also be coated with substances such as sugars or be enteric-coated so as to modulate major site of absorption.
  • the carrier will usually consist of sterile water and other ingredients may be added to increase solubility or preservation.
  • Injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives.
  • a pharmaceutical carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular.
  • any of the usual pharmaceutical media may be employed.
  • suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like;
  • suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques.
  • the carrier will usually comprise sterile water, through other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included.
  • injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • the pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above.
  • compositions herein will contain, per unit dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, of from about 0.1-1000 mg or any range therein, and may be given at a dosage of from about 0.01-300 mg/kg/day, or any range therein, preferably from about 0.5-50 mg/kg/day, or any range therein.
  • the dosages may be varied depending upon the requirement of the patients, the severity of the condition being treated and the compound being employed. The use of either daily administration or post-periodic dosing may be employed.
  • compositions are in unit dosage forms from such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
  • the composition may be presented in a form suitable for once-weekly or once- monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection.
  • a pharmaceutical carrier e.g.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules.
  • This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.
  • the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include, aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
  • the method of treating disorders described in the present invention may also be carried out using a pharmaceutical composition
  • a pharmaceutical composition comprising any of the compounds as defined herein and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition may contain between about 0.01 mg and 1000 mg of the compound, or any range therein; preferably about 10 to 500 mg of the compound, and may be constituted into any form suitable for the mode of administration selected.
  • Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.
  • compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), granules, and powders, and liquid forms, such as solutions, syrups, elixers, emulsions, and suspensions.
  • forms useful for parenteral administration include sterile solutions, emulsions and suspensions.
  • compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta- lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl- cellulose and the like.
  • suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl- cellulose and the like.
  • sterile suspensions and solutions are desired.
  • Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
  • a pharmaceutical carrier which carrier may take a wide variety of forms depending of the form of preparation desired for administration (e.g. oral or parenteral).
  • Suitable pharmaceutically acceptable carriers are well known in the art.
  • Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever treatment of disorders as described herein is required.
  • the daily dosage of the products may be varied over a wide range from 0.01 to 5000 mg per adult human per day, or any range therein.
  • the compositions are preferably provided in the form of tablets containing, 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250, 500 and 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.01 mg/kg to about 300 mg/kg of body weight per day, or any range therein.
  • the range is from about 0.5 to about 50.0 mg/kg of body weight per day, or any range therein. More preferably, from about 1.0 to about 25.0 mg/kg of body weight per day, or any range therein. More preferably, from about 1.0 to about 10.0 mg/kg of body weight per day, or any range therein.
  • the compounds may be administered on a regimen of 1 to 4 times per day.
  • Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.
  • the resulting mixture was stirred for 15 minutes, then allowed to warm to ambient temperature, where it is stirred for 1 h.
  • the resulting mixture was cooled to 5°C and quenched slowly adding H 2 O (400 mL).
  • H 2 O 400 mL
  • the resulting mixture was stirred overnight at ambient temperature, then cooled to ice bath temperature and quenched with aqueous HCI (140 mL of cone. HCI diluted to 680 ml in H 2 O).
  • the resulting mixture was stirred for 1 h and then extracted with 1 LX2 of ethyl acetate.
  • the resulting mixture was diluted to a total volume of 1440 mL and charged to a 2L reactor.
  • the white solid mixture of regioisomers was charged to a 200 mL 1 N reactor with a magnetic stirring bar and dissolved in a 5.2N HCI/IPA mixture (51.5 mL), with the resulting mixture stirred overnight at ambient temperature.
  • the resulting mixture was concentrated on a rotary evaporator (bath temperature 50 0 C), to yield an easily stirrable oily mass, which was isolated and then dissolved in ethyl acetate (240 mL).
  • the off white solid prepared as in STEP B above was charged to a 500 mL 4N- reactor equipped with air stirrer, thermocouple, nitrogen-inlet and addition funnel. To the reactor was then added methanol (90 mL). To the resulting stirred mixture was added a solution of citric acid in methanol (13. 65 g, 71 mmol in 70 mL of MeOH). The resulting mixture was stirred overnight (total 23 h of stirring). To the resulting mixture was then added ethyl acetate (60 mL) and the mixture stirred at room temperature for 4.5 h.
  • the resulting mixture was then filtered, and the solids and reactor rinsed with a 10:90 mixture of methanol : ethyl acetate (25 mL).
  • the isolated solids were dried in a vacuum oven to yield the title compound.
  • the filtrate was allowed to stand for about 1 month, over which time a dry sticky solid was formed and isolated.
  • the dry sticky solid was slurried in methanol (50 mL) and stirred overnight in a filter flask. The solids were then filtered, and the filter flask and solids washed with a 50:50 mixture of methanol ethyl acetate (10 mL).
  • THF 500 mL
  • TEA 46 g, 455 mmol, 63.4 mL
  • Isopropyl-hydrazine HCI 50 g, 452 mmol
  • the resulting heterogeneous mixture was stirred overnight at ambient temperature, then using a very light house vacuum the resulting mixture was filtered via a sintered funnel.
  • the reactor was rinsed with THF (2X 50 mL) and the rinse was used to wash the filtered solids, lsopropyl hydrazine was isolated.
  • the isopropyl hydrazine was then stored as a solution in THF, at about 0-5 0 C for up to 4 weeks.
  • Example 6 1 -Benzyl-3-(4-chloro-phenyl)-1 ,4,5,6, 7,8-hexahvdro-1 ,2,6-triaza-azulene
  • 100 mg of the compound prepared as in Example 3 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des procédés de préparation de dérivés de 2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulène substitués de formule (I) et (II), utiles pour le traitement de maladies induites par l'activité du récepteur de sérotonine.
PCT/US2008/081513 2007-11-02 2008-10-29 Procédé de préparation de dérivés de 2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulène substitués WO2009058810A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US98478907P 2007-11-02 2007-11-02
US60/984,789 2007-11-02

Publications (1)

Publication Number Publication Date
WO2009058810A1 true WO2009058810A1 (fr) 2009-05-07

Family

ID=40342305

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2008/081513 WO2009058810A1 (fr) 2007-11-02 2008-10-29 Procédé de préparation de dérivés de 2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulène substitués

Country Status (1)

Country Link
WO (1) WO2009058810A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005040169A2 (fr) * 2003-09-17 2005-05-06 Janssen Pharmaceutica, N.V. Composes heterocycliques fusionnes
WO2007131153A2 (fr) * 2006-05-05 2007-11-15 Janssen Pharmaceutica N.V. Procédé de préparation de composés contenant du pyrazole

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005040169A2 (fr) * 2003-09-17 2005-05-06 Janssen Pharmaceutica, N.V. Composes heterocycliques fusionnes
WO2007131153A2 (fr) * 2006-05-05 2007-11-15 Janssen Pharmaceutica N.V. Procédé de préparation de composés contenant du pyrazole

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
MAJEWSKI, M. ET AL., TETRAHEDRON LETTERS, vol. 30, 1989, pages 5681 - 5684, XP002515413 *
RATHKRE M W ET AL: "PROCEDURES FOR THE ACYLATION OF DIETHYL MALONATE AND ETHYL ACETOACETATE WITH ACID CHLORIDES USING TERTIARY AMINE BASES AND MAGNESIUM CHLORIDE", JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY, EASTON.; US, vol. 50, no. 15, 26 July 1985 (1985-07-26), pages 2622 - 2624, XP002040464, ISSN: 0022-3263 *
STREITWIESER A ET AL: "Role of aggregates in Claisen acylation reactions of imidazole, pyrazole, and thioesters with lithium enolates in THF.", ORGANIC LETTERS 15 JUL 1999, vol. 1, no. 1, 15 July 1999 (1999-07-15), pages 145 - 147, XP002515414, ISSN: 1523-7060 *

Similar Documents

Publication Publication Date Title
US6841684B2 (en) Imidiazoles having reduced side effects
ES2216339T3 (es) Derivados sustituidos de imidazol que tienen actividad de tipo agonista hacia los receptores adrenergicos alfa 2b o 2b/2c.
EP0170213B1 (fr) Agents à base de glutarimide ayant des propriétés anxiolytiques et antihypertensives
BRPI0610150A2 (pt) composto, pró-droga, processo para produzir o composto, composição farmacêutica, antagonista do receptor de crf, e, uso do antagonista do receptor de crf
WO2005118573A1 (fr) Nouveaux composes de diazepine utilises comme ligands des recepteurs 1 et/ou 4 de la melanocortine
EA015542B1 (ru) Новые 2-замещённые бензимидазолы в качестве селективных модуляторов рецептора андрогена (sarms)
KR930011038B1 (ko) 테트라하이드로 벤즈이미다졸 유도체 및 이의 제조방법
KR20220141328A (ko) 소분자 sting 길항제
US8673890B2 (en) 2,3-dihydro-1H-isoindol-1-imine derivatives useful as thrombin PAR-1 receptor antagonist
US8067619B2 (en) Coumarin derivatives as ion channel openers
JPH08507498A (ja) 複素環式化合物、それらの使用および製法
WO2010017105A1 (fr) Antagonistes de récepteur d’urotensine ii
US20040039023A1 (en) Therapeutic agents
US8053441B2 (en) Pyrazolylquinazolinones as potassium channel openers
KR100437561B1 (ko) 신규헤테로고리화합물
WO2009058810A1 (fr) Procédé de préparation de dérivés de 2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulène substitués
EP2010509B1 (fr) Derives de 3,4-diamino-3-cyclobutene-1,2-dione en tant qu'agents d'ouverture du canal potassique
HU193305B (en) Process for production of new indolin-derivatives
US7674793B2 (en) Tricyclic dihydropyrazines as potassium channel openers
AU2002254265B2 (en) Imidiazole derivatives and their use as agonists selective at alpha 2B or 2B/2C adrenergic receptors
FR2640975A1 (fr)
CS268187B2 (en) Method of new tetrahydrobenzothiazolo-quinolines production

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08845336

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08845336

Country of ref document: EP

Kind code of ref document: A1