WO2007057742A2 - Nouveaux derives de piperazinone - Google Patents

Nouveaux derives de piperazinone Download PDF

Info

Publication number
WO2007057742A2
WO2007057742A2 PCT/IB2006/003203 IB2006003203W WO2007057742A2 WO 2007057742 A2 WO2007057742 A2 WO 2007057742A2 IB 2006003203 W IB2006003203 W IB 2006003203W WO 2007057742 A2 WO2007057742 A2 WO 2007057742A2
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
compound
phenyl
disorder
ring
Prior art date
Application number
PCT/IB2006/003203
Other languages
English (en)
Other versions
WO2007057742A3 (fr
Inventor
Christopher John Helal
Original Assignee
Pfizer Products Inc.
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 Pfizer Products Inc. filed Critical Pfizer Products Inc.
Publication of WO2007057742A2 publication Critical patent/WO2007057742A2/fr
Publication of WO2007057742A3 publication Critical patent/WO2007057742A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
    • C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention relates to compounds and related pharmaceutical compositions for medicinal uses thereof.
  • the present invention relates to novel piperazinones, intermediates for their preparation, pharmaceutical compositions containing them, and their medicinal use.
  • the compounds of the present invention include selective agonists and antagonists of serotonin 1 (5-HT 1 ) receptors, specifically, of one or both of the 5-HTi A and 5-HT 1B (formerly classified 5- HT 1 D ) receptors. They are useful in treating hypertension, depression and other disorders for which a 5-HT 1 agonist or antagonist is indicated.
  • European Patent Publication 434,561 published June 26, 1991, refers to 7-alkyl alkoxy, and hydroxy substituted-1-(4-substituted-1-piperazinyl)-naphthalenes.
  • the compounds are referred to as 5-HT 1 agonists and antagonists useful for the treatment of migraine, depression, anxiety, schizophrenia, stress and pain.
  • European Patent Publication 343,050 published on Nov. 23, 1989, refers to 7- unsubstituted, halogenated, and methoxy substituted-1-(4-substituted-1-piperazinyl)- naphthalenes as useful 5-HT 1A ligand therapeutics.
  • 5-HT 1 agonists and antagonists in combination with a 5-HT re-uptake inhibitor refers to 7-methoxy-1-(1-piperazinyl)-naphthalene as a useful 5-HT 1 ligand in the article "5-HT 10 Serotonin Receptors", Clinical Drug Res. Dev., 22, 25-36 (1991).
  • Alzheimer's disease Parkinson's disease and Huntington's disease.
  • World Patent Application WO 95/31988 refers to the use of a 5-HT 1 D antagonist in combination with a 5-HT 1A antagonist to treat CNS disorders such as depression, generalized anxiety, panic disorder, agoraphobia, social phobias, obsessive- compulsive disorder, post-traumatic stress disorder, memory disorders, anorexia nervosa and bulimia nervosa, Parkinson's disease, tardive dyskinesias, endocrine disorders such as hyperprolactinaemia, vasospasm (particularly in the cerebral vasculature) and hypertension, disorders of the gastrointestinal tract where changes in motility and secretion are involved, as well as sexual dysfunction.
  • CNS disorders such as depression, generalized anxiety, panic disorder, agoraphobia, social phobias, obsessive- compulsive disorder, post-traumatic stress disorder, memory disorders, anorexia nervosa and bulimia nervosa
  • Parkinson's disease tardive dyskinesias
  • European Patent Publication 666,261 published Aug. 9, 1995 refers to thiazine and thiomorpholine derivatives, which are claimed to be useful for the treatment of cataracts.
  • compositions of the formula (hereinafter, "formula I"):
  • R 1 is G 1 , G 2 , G 3 , G 4 , G 5 , G 6 , or G 7 , wherein
  • Each Ri 3 is, independently, (Ci-C 4 )alkyl, C 3 -C 8 cycloalkyl, or a (Ci-C 4 ) methylene bridge from one of the ring carbons of the piperazine or piperidine ring of G 1 or G 2 , respectively, to the same or another ring carbon or a ring nitrogen of the piperazine or piperidine ring of G 1 or G 2 , respectively, having an available bonding site, or to a ring carbon of R 6 having an available bonding site;
  • E is oxygen, sulfur, SO, or SO 2 ;
  • Each X is independently hydrogen, chloro, fluoro, bromo, iodo, cyano, (C 1 -C 8 )alkyl, hydroxy, trifluoromethyl, (Ci-C 8 )alkoxy, CO 2 Ri O , Or CONR 11 Ri 2 ;
  • t is zero, one, or two;
  • R s is (Ci-C 6 )alkyl, (C 3 -C 8 )cycloalkyl, or phenyl; Yi and Y 2 are independently C-X or N, provided that Y 1 and Y 2 are not simultaneously
  • R 2 is hydrogen, (Ci-C 4 )alkyl, phenyl or naphthyl, wherein said phenyl or naphthyl may optionally be substituted with one or more substituents independently selected from chloro, fluoro, bromo, iodo, (Ci-C 8 )alkyl, (Ci-C ⁇ )alkoxy, trifluoromethyl, cyano and -SO,(Ci-C 8 )alkyl;
  • R 3 is -(CH 2 ) g B, wherein B is hydrogen, phenyl, naphthyl or a 5- to 7-membered heteroaryl ring containing from one to four heteroatoms in the ring selected from oxygen, nitrogen and sulfur, provided that said ring cannot contain two adjacent oxygen atoms or two adjacent sulfur atoms and wherein each of the foregoing phenyl, naphthyl and heteroaryl rings may optionally be substituted with one to three substituents independently selected from fluoro, chloro, bromo, iodo, nitro, trifluoromethyl, cyano, trifluoromethoxy, (C 1 -C 8 )alkyl, (C 1 -C 8 )BIkOXy, (Ci-C f Oalkoxyfd-C ⁇ Jalkyl, hydroxy, COOH, (C r C 8 )hydroxyalkyl-, (C 3 -C 8 )cycloalkyl-, (C 3 -C
  • each said ring may be optionally substituted with one to three substituents independently selected from (a) a lactone formed from -(CH 2 XiOH with an ortho -COOH; (b) -CONR 14 R 15 , wherein R 14 and R 15 are independently selected from (C 1 -C 8 )alkyl, and benzyl, or R 14 and R 15 together with the nitrogen to which they are attached form a 4- to 7-membered heteroalkyl ring that may contain from zero to three heteroatoms selected from nitrogen, sulfur and oxygen in addition to the nitrogen of the -CONR 14 R 15 group, wherein when any of said heteroatoms is nitrogen it can be optionally substituted with (C 1 -C 8 )alkyl or benzyl, provided that said ring cannot contain two adjacent oxygen atoms or two adjacent sulfur atoms; (c) -(CH 2 )VNCOR 16 R 1 / and COR 16 and
  • (C 3 -C 8 )cycloalkyl wherein alkyl or cycloalkyl is optionally substituted with hydroxy, (CrC ⁇ )alkoxy or one to three fluorine atoms, or [(C 1 -C 4 )alkyl]aryl wherein the aryl moiety is phenyl, naphthyl, or heteroaryl-(CH 2 ) q --, wherein the heteroaryl moiety is selected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl and benzisothiazolyl, and wherein said aryl and heteroaryl moieties can optionally be substituted with one or more substituents independently selected from the group consisting of chloro, fluoro, bromo, iodo, hydroxy, ( -C ⁇ alkyl, (d-C ⁇ alkoxy, trifluoromethyl, cyano and SOt(
  • R 6 or R 7 taken together form a 2 to 4 carbon chain; r is zero, one, two, three or four;
  • R 9 is hydrogen, (Ci-C B )alkyl, or (C 3 -C 8 )cycloalkyl; or R 6 and Rg 1 together with the nitrogen atom to which they are attached, form a 5- to 7-membered heteroalkyl ring that can contain from zero to four heteroatoms selected from nitrogen, sulfur and oxygen; p is zero, one, two, or three;
  • Each of R 10 , Rn and Ri 2 is selected, independently, from the radicals set forth in the definition of R 2 ; or R 11 and Ri 2 , together with the nitrogen to which they are attached, form a 5- to 7-membered heteroalkyl ring that can contain from zero to three additional heteroatoms selected from nitrogen, sulfur and oxygen; the broken line indicates optional double bond, provided that when the broken line in G 2 is a double bond that R 8 is absent; and a pharmaceutically acceptable salt thereof.
  • Ri is any one of G 1 , G 2 , G 3 , G 4 , G 5 , G 6 , or G 7 .
  • the following are more specific embodiments of groups G 1 and G 2 .
  • each X is independently any one of the following: hydrogen, chloro, fluoro, bromo, iodo, cyano, (C 1 -CeJaIlCyI, hydroxy, trifluoromethyl, (Ci-C 8 )alkoxy, SO t (C 1 -C 8 JaIlCyI, CO 2 Ri O , or CONRHRI 2 , and preferably each X is independently hydrogen, chloro, fluoro, (d-C 4 )alkyl, trifluoromethyl, or (C 1 -C 4 JaIkOXy.
  • Yi and Y 2 are both C-X, where X may have any definition provided herein.
  • Another embodiment is where only one of Y 1 and Y 2 is C-X and the other is N, where X may have any definition provided herein.
  • R n is independently any one of the following: hydrogen, (C r C 6 )alkyl, C(O)(Ci-C 3 )alkyl, aryl, or SO 2 R 3 , preferably, R n is hydrogen, or (Ci-C 3 )alkyl.
  • W 1 and W 2 are independently H or (C 1 -C 3 JaIkVl 1 preferably independently H or methyl.
  • R 2 is any one of the following: hydrogen, (C 1 -C 4 JaIlCyI, phenyl or naphthyl, wherein said phenyl or naphthyl may optionally be substituted with one or more substituents independently selected from chloro, fluoro, bromo, iodo, (C 1 -C 8 )alkyl, (C 1 -C 8 JaIkOXy, trifluoromethyl, cyano and -SO f (C 1 -C 8 JaIlCyI, preferably, R 2 is hydrogen.
  • R 3 is -(CH 2 ) g B, wherein g is zero, one, two, or three, preferably zero, and wherein B is hydrogen, phenyl, naphthyl or a 5- to 7-membered heteroaryl ring as described in formula I, preferably phenyl or pyridinyl, wherein each of the foregoing phenyl, naphthyl and heteroaryl rings may be unsubstituted or optionally substituted with one to three substituents independently being any one or more or combination of the following: fluoro, chloro, bromo, iodo, nitra, trifluoromethyl, cyano, trifluoramethoxy, (C 1 -C 8 JaIlCyI.
  • the substituents can be in any combination and all from the same substituent group, e.g., all from (C 1 -C 4 )alkyli or from different substituent groups, e.g., one each from (C 3 -C 8 )hydraxycycloalkyl-, (CrC ⁇ Jalkoxy-heterocycloalkyl, and heterocycloalkyl.
  • Yi and Y 2 are both C-X and R n is aryl.
  • Yi and Y 2 are both C-X and R n is hydrogen or (CrC 3 )alkyl
  • R 3 is phenyl or pyridinyl (g is zero and B is phenyl or pyridinyl), optionally substituted with (C 3 -C 8 )hydroxycycloalkyl-, (Ci-C 8 )alkoxy-heterocycloalkyl, and heterocycloalkyl.
  • Another embodiment of the present invention is where only one of Y 1 and Y 2 is C-X, and R n is (Ci-C 6 )alkyl, (C 3 -C 6 )cycloalkyl, C(O)(C 1 -C 3 )alkyl, aryl, OrSO 2 R 8 .
  • the present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula I.
  • the acids that are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1'-methylene-bis- (2-hydroxy-3-naphthoate)]salts.
  • the invention also relates to base addition salts of formula I.
  • the chemical bases that can be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of formula I that are acidic in nature are those that form non-toxic base salts with such compounds.
  • Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g. potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.
  • the compounds of the present invention include all stereoisomers (e.g., cis and trans isomers) and all optical isomers of compounds of the formula I (e.g., R and S enantiomers), as well as racemic, diastereomeric and other mixtures of such isomers.
  • the compounds of the present invention can contain olefin-like double bonds. When such bonds are present, the compounds of the invention exist as cis and trans configurations and as mixtures thereof.
  • alkyl as used herein, includes straight or branched alkyl groups having one to eight carbon atoms.
  • cycloalkyl as used herein includes moieties derived from cyclic hydrocarbons containing from three to eight ring carbon atoms, including cyclic hydrocarbon moieties substituted with straight or branched alkyl moieties.
  • heterocycloalkyl includes a cyclic hydrocarbon in which one or more of the ring carbon atoms has been replaced with a nitrogen, oxygen or sulfur atom or any combination thereof.
  • examples of such groups are oxetanyl, tetrahydrofuranyl, tetrahydropyran, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorphlinyl, piperazinyl, and azapinyl.
  • heteroaryl is intended to include aromatic heterocyclic groups and includes the non-limiting examples thiophenyl, pyridyl, pyrimidyl, pyridazyl, oxazolyl, isooxazolyl, thiazolyl and isothiazolyl, among others.
  • substituents refers to from one to the maximum number of substituents possible based on the number of available bonding sites.
  • alkoxy means “alkyl-O-", wherein “alkyl” is defined as above.
  • halogen includes fluorine, chlorine, bromine, and iodine.
  • the present invention also relates to a pharmaceutical composition or a method for treating any one or more or combination of a disorder or condition selected from hypertension, all forms of depression (e.g., depression in cancer patients, depression in Parkinson's patients, postmyocardial infarction depression, subsyndromal symptomatic depression, depression in infertile women, pediatric depression, major depressive disorder, single episode depression, recurrent depression, child abuse induced depression, post partum depression, dysthymia; mild, moderate, or severe depressions with or without atypical features, melancholic features, psychotic features, catatonic features; seasonal affective disorder, geriatric depression, chronic depression; adjustment disorder with depressed mood or with anxiety and depressed mood; mixed anxiety and depression; substance induced mood disorder; and mood disorder secondary to a general medical condition), bipolar disorder (including in the depressed phase), generalized anxiety disorder, social anxiety, separation anxiety disorder, phobias (e.g., depression
  • the present invention also relates to a pharmaceutical composition or a method for treating a disorder or condition that can be treated by enhancing serotonergic neurotransmission in a mammal, preferably a human, including an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, effective in treating such disorder or condition and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition or a method for treating a disorder or condition that can be treated by enhancing serotonergic neurotransmission in a mammal, preferably a human, including an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, effective in treating such disorder or condition and a pharmaceutically acceptable carrier.
  • disorders and conditions are those enumerated herein, e.g., those enumerated in the immediately preceding paragraph.
  • the present invention also relates to a pharmaceutical composition or a method for treating any one or more or combination of the following a disorder or condition selected from attention-deficit/hyperactivity disorder (ADHD), bipolar disorder, bipolar disorder-depressed phase; mild, moderate, or severe depression with or without atypical features, melancholic features, psychotic features, catatonic features; seasonal affective disorder, postpartum depression, geriatric depression, chronic depression, dysthymia, adjustment disorder with depressed mood, adjustment disorder with anxiety, depressed mood, mixed anxiety and depression, substance induced mood disorder, mood disorder secondary to a general medical condition, social anxiety, separation anxiety disorder, binge eating disorder, dependencies and addictions to marijuana, panic disorder with agoraphobia; autism, pervasive developmental disorder NOS, Asperger's disorder, selective mutism, chronic motor or vocal tic disorder, somatization disorder, insomnia, intermittent explosive disorder, pyromania, pathological gambling, impulse-control disorder, and premenstrual dysphoric disorder, in a mammal,
  • the compounds of the present invention are also useful in the treatment of patients afflicted with two or more of the above disorders. It is not uncommon for certain of the above listed disorders, which can be treated using the novel compounds of the invention, to exist in patients afflicted with one or more other such disorders. For example, depression is often comorbid with anxiety and both can be treated using the compounds or pharmaceutical compositions of the present invention.
  • a further particular advantage of the serotonin 1 (5-HT 1 ) receptor agonist/antagonist compounds of the present invention is that they exhibit pharmacological and therapeutic activity without the delayed onset of action usually associated with selective serotonin reuptake inhibitors.
  • the present invention further relates to a pharmaceutical composition for treating a condition or disorder that can be treated by enhancing serotonergic neurotransmission in a mammal, preferably a human, including: a) a pharmaceutically acceptable carrier; b) an amount of a compound of formula I or a pharmaceutically acceptable salt thereof; and c) an amount of a serotonin re-uptake inhibitor or a pharmaceutically acceptable salt thereof; wherein the amounts of (b) and (c) are together pharmaceutically effective.
  • the present invention also relates to a method for treating a disorder or condition that can be treated by enhancing serotonergic neurotransmission in a mammal, preferably a human, including administering to a mammal requiring such treatment: a) an amount of a compound of the formula I, as described anywhere herein, or a pharmaceutically acceptable salt thereof; and b) an amount of a 5-HT re-uptake inhibitor, preferably sertraline, or a pharmaceutically acceptable salt thereof; wherein the amounts of (a) and (b) are together effective in treating said disorder or condition.
  • the present invention also relates to a method for treating a disorder or condition that can be treated by enhancing serotonergic neurotransmission in a mammal, preferably a human, including administering to the mammal requiring such treatment: a) an amount of a 5-HT 1A antagonist or a pharmaceutically acceptable salt thereof; and b) an amount of a 5-HT 1 B antagonist of formula I or a pharmaceutically acceptable salt thereof; wherein the amounts of (a) and (b) are together effective in treating said disorder or condition.
  • the present invention also relates to a pharmaceutical composition for treating a disorder or condition that can be treated by enhancing serotonergic neurotransmission in a mammal, preferably a human, including: a) an amount of a 5-HT 1A antagonist or a pharmaceutically acceptable salt thereof; and b) an amount of a 5-HT 1 B antagonist of formula I or a pharmaceutically acceptable salt thereof; wherein the amounts of (a) and (b) are together effective in treating said disorder or condition.
  • Treating refers to, and includes, reversing, alleviating, inhibiting the progress of, or preventing, a disease, disorder or condition, or one or more symptoms thereof; and, “treatment” and “therapeutically” refer to the act of treating, as defined above.
  • “Enhanced serotonergic neurotransmission,” as used herein, refers to increasing or improving the neuronal process whereby serotonin is released by a pre-synaptic cell upon excitation and crosses the synapse to stimulate or inhibit the post-synaptic cell.
  • “Chemical dependency,” as used herein, means an abnormal craving or desire for, or an addiction to a drug. Such drugs are generally administered to the affected individual by any of a variety of means of administration, including oral, parenteral, nasal or by inhalation. Examples of chemical dependencies treatable by the methods of the present invention are dependencies on alcohol, nicotine, cocaine, heroin, phenobarbital, and benzodiazepines (e.g., Valium (trademark)). "Treating a chemical dependency,” as used herein, means reducing or alleviating such dependency. Sertraline, (1S-cis)-4-(3,4-dichlorophenyl)-1 ,2,3,4-tetrahydro-N-methyl-1- naphthalenamine, as used herein has the following structural formula:
  • Sertraline hydrochloride is useful as an antidepressant and anorectic agent, and is also useful in the treatment of depression, chemical dependencies, anxiety obsessive compulsive disorders, phobias, panic disorder, post traumatic stress disorder, and premature ejaculation.
  • Sertraline hydrochloride is useful as an antidepressant and anorectic agent, and is also useful in the treatment of depression, chemical dependencies, anxiety obsessive compulsive disorders, phobias, panic disorder, post traumatic stress disorder, and premature ejaculation.
  • Step 1 of Scheme 1 is a coupling reaction between an amine and an aromatic ring.
  • this coupling can be facilitated by use of a transition metal such as palladium and the preferred method is that of Buchwald as described in Buchwald, et al. J. Org. Ch ⁇ m., 2000, 65, pp. 1144-1157 and pp. 1158-1174.
  • a mixture of the 2-Z-benzaldehyde 12 and N-substituted compound of the formula G 1 , G 3 , G 5 , G 6 , or G 7 , such as 1- methylpiperazine, are treated in a solvent selected from toluene, benzene, DME wherein toluene is preferred with a base such as sodium or potassium tert-butoxide, sodium or potassium carbonate, potassium phosphonate preferably sodium tert-butoxide with a palladium source such as tetrakis(triphenylphosphine)palladium, palladium acetate, tris(dibenzyideneacetone)dipalladium, transdichloro-bis(triphenylphospine)palladium or optionally added phosphine ligands where added such as BINAP or triphenylphosphine where palladium acetate and BINAP is preferred at a temperature of about 4O 0 C to 15O
  • Step 2 of Scheme 1 is an aldol condensation. Addition of a solution of 3 and aldehyde 2 in tetrahydrofuran to a solution of a base such as sodium hydride, potassium hydride, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyiamide), or potassium bis(trimethylsilylamide), where sodium bis(trimethylsilyl)amide is preferred, in a solvent such as tetrahydrofuran, at a temperature from about O 0 C to 100 0 C, where 3O 0 C to 8O 0 C is preferred, affords 1b.
  • Step 3 of Scheme 1 is a reduction of a carbon-carbon double bond.
  • Catalytic reduction of the double bond of compound 1b to afford 1a is accomplished in a reaction inert solvent such as a lower alcohol, preferably methanol or ethanol, with a noble metal catalyst, such as platinum or palladium, suspended on a solid support, preferably 10% palladium on carbon, under a hydrogen pressure of about 1 atmosphere to about 5 atmospheres, preferably about 3 atmospheres to about 4 atmospheres, at a temperature of about 10 0 C to about 100 0 C, preferably about 4O 0 C to about 60°C, while shaking the reaction mixture.
  • a reaction inert solvent such as a lower alcohol, preferably methanol or ethanol
  • a noble metal catalyst such as platinum or palladium
  • suspended on a solid support preferably 10% palladium on carbon
  • the double bond can be reduced under transfer hydrogenation conditions where a hydride donor such as cyclohexadiene or ammonium formate is used in place of hydrogen, where ammonium formate is preferred, in a reaction inert solvent such as a lower alcohol, THF, dioxane or ethyl acetate, preferably methanol or ethanol, in the presence of a noble metal catalyst on a solid support such as palladium on carbon (Pd/C), palladium on barium sulfate (Pd/BaSO 4 ), platinum on carbon (Pt/C), or tris(triphenylphosphine) rhodium chloride (Wilkinson's catalyst), preferably about 10% palladium on carbon, at a temperature of about 2O 0 C to 15O 0 C, preferably 4O 0 C to 8O 0 C.
  • a hydride donor such as cyclohexadiene or ammonium formate is used in place of hydrogen, where ammoni
  • the double bond can be reduced with sodium borohydride or sodium cyanoborohydride, with the optional addition of acetic acid, in a solvent such as methanol, water, ethanol, tetrahydrofuran, or any mixture thereof, at a temperature from 0 to 50 0 C.
  • a solvent such as methanol, water, ethanol, tetrahydrofuran, or any mixture thereof, at a temperature from 0 to 50 0 C.
  • the reduction of the carbon-carbon double bond of 1b to produce a compound 1a can be accomplished using alternative procedures known to one skilled in the art; see Larock, R. C. Comprehensive Organic Transformations. VCN Publishers, 1989, for examples.
  • Step 4 of Scheme 1 is an alkylation, acylation, or sulfonylation of the secondary amine of 1a to afford 1c.
  • the alkylation, acylation, and sulfonylation can be carried out according to methods known to one skilled in the art. Such methods can be found in Larock, R. C. Comprehensive Organic Transformations. VCN Publishers, 1989.
  • a cyanoborohydride or sodium triacetoxyborohydride sodium triacetoxyborohydride
  • the acylation of 1a can be effected by treating a mixture of 1a, a base such as sodium hydroxide, in a solvent system such as chloroform-water with an acylating agent including, but not limited to, acid chlorides, acid anhydrides, or other activated carboxylic acid derivatives, where acid anhydrides and acid chlorides are preferred, to afford 1c.
  • an acylating agent including, but not limited to, acid chlorides, acid anhydrides, or other activated carboxylic acid derivatives, where acid anhydrides and acid chlorides are preferred, to afford 1c.
  • the sulfonylation of 1a to can be effected by treating a mixture of 1a, a trialkylamine base, such as triethylamine or diisopropylethylamine, where triethylamine is preferred, in a solvent such as methylene chloride, with an alkylsulfonyl chloride, to afford 1c.
  • a trialkylamine base such as triethylamine or diisopropylethylamine, where triethylamine is preferred
  • a solvent such as methylene chloride
  • Step 1 of Scheme 2 is an acylation reaction.
  • Treatment of a solution of diamine 4 in methylene chloride with an' acylating agent such as O-benzyl-O'-( ⁇ /-succimidyl) carbonate affords 5 (Adamczyk, M.; Fishpaugh, J. R.; Heuser, K. J. Organic Preparations and Procedures Int. 1998, 30, pp. 339-348).
  • Step 2 of Scheme 2 is an alkylation reaction.
  • Step 3 of Scheme 2 is an amine deprotection/cyclization.
  • Step 4 of Scheme 2 is an acylation of an amine.
  • a base such as sodium or potassium carbonate, where sodium carbonate is preferred
  • a solvent system of 2:1 ethylacetate-water at a temperature from about O 0 C to 5O 0 C, where about 2O 0 C to 3O 0 C is preferred, is added to an acylating agent such as methyl chloroformate, ethyl chloroformate, BOC-anhydride, benzyl chloroformate, or allyl chloroformate, where benzyl chloroformate is preferred, to afford 8.
  • an acylating agent such as methyl chloroformate, ethyl chloroformate, BOC-anhydride, benzyl chloroformate, or allyl chloroformate, where benzyl chloroformate is preferred
  • the conversion of 8 to 3, wherein R 3 is an optionally substituted aryl or heteroaryl group as described in the general claims, can be accomplished by treating 8, an aryl or heteroaryl chloride, bromide, iodide, or sulfonate, where the bromide is preferred, a base such as potassium phosphate, potassium carbonate, sodium carbonate, thallium carbonate, cesium carbonate, potassium terf-butoxide, lithium terf-butoxide, or sodium terf-butoxide, where potassium carbonate is preferred, a diamine, such as 1 ,2-ethylenediamine, /V 1 AT- dimethylethylenediamine, ⁇ /, ⁇ /-dimethylethylenediamine, or cis-1 ,2-diaminocyclohexane, where ⁇ /, ⁇ f-dimethylethylenediamine is preferred, cuprous
  • the conversion of 8 to 3, wherein R 3 is an optionally substituted aryl or heteroaryl group as described in the general claims can be accomplished by treating 8 and an aryl or heteroaryl chloride, bromide, iodide, or sulfonate, where the bromide is preferred, with a base such as an alkali metal carbonate, an alkali metal amine base, an alkali metal phosphonate, or an alkali metal alkoxide, where cesium carbonate is preferred, a phosphine ligand, where 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (XANTPHOSTM) is preferred, a palladium species, such as palladium (II) acetate or tris(dibenzylideneacetone)dipalladium (0) or the corresponding chloroform adduct, where tris(dibenzylideneacetone)dipalladium (0) is preferred, in an inert
  • Scheme 3 shows an alternative route to compounds of formula 3.
  • Step 1 of Scheme 3 is a nucleophilic displacement of a carbamate oxygen by an amine nucleophile. Heating a mixture of an aromatic/heteroaromatic amine hydrochloride salt 9 (R 3 -NH 2 HCI) and oxazolidinone in a solvent such as 2-(2-methoxyethoxy)ethanol at a temperature about 165 0 C affords diamine 10.
  • a solvent such as 2-(2-methoxyethoxy)ethanol
  • Step 2 of Scheme 3 is a nitrogen acylation reaction.
  • an acylating reagent such as methyl chloroformate, ethylchloroformate, allylchloroformate, or benzyl chloroformate, where benzylchloroformate is preferred
  • Step 3 of Scheme 3 is a nitrogen acylation reaction.
  • the reaction mixture from Step 2, containing 11 was treated with bromoacetylbromide to afford 12.
  • Step 4 of Scheme 3 is an intramolecular nucleophilic substitution reaction.
  • a base such as sodium hydride, potassium hydride, sodium bis(trimethylsilylamide), or potassium bis(trimethylsilylamide)
  • a base such as sodium hydride, potassium hydride, sodium bis(trimethylsilylamide), or potassium bis(trimethylsilylamide)
  • Step 1 of Scheme 4 is a palladium-catalyzed cross-coupling.
  • Step 2 of Scheme 4 is an aldol condensation. Addition of a solution of 3 and aldehyde 15 in tetrahydrofuran to a solution of a base such as sodium hydride, potassium hydride, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilylamide), or potassium bis(trimethylsilylamide), where sodium bis(trimethylsilyl)amide is preferred, in a solvent such as tetrahydrofuran, at a temperature from about O 0 C to 100 0 C, where 30°C to 80°C is preferred, affords 16.
  • a base such as sodium hydride, potassium hydride, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilylamide), or potassium bis(trimethylsilylamide), where sodium bis(trimethylsilyl)amide is preferred
  • a solvent such as tetrahydrofuran
  • Step 3 of Scheme 4, wherein A -OBenzyl for 16, is a reduction of two carbon- carbon double bonds and removal of a carboxybenzyl (CBz) protecting group.
  • Reduction/deprotection of 16 to afford 1d is accomplished in a reaction inert solvent such as a lower alcohol, preferably methanol or ethanol, with a noble metal catalyst, such as platinum or palladium, suspended on a solid support, preferably 10% palladium on carbon, under a hydrogen pressure of about 1 atmosphere to about 5 atmospheres, preferably about 3 atmospheres to about 4 atmospheres, at a temperature of about 10°C to about 100 0 C, preferably about 40°C to about 60°C, while shaking the reaction mixture.
  • a reaction inert solvent such as a lower alcohol, preferably methanol or ethanol
  • a noble metal catalyst such as platinum or palladium
  • suspended on a solid support preferably 10% palladium on carbon
  • transfer hydrogenation conditions can be utilized where a hydride donor such as cyclohexadiene or ammonium formate is used in place of hydrogen, where ammonium formate is preferred, in a reaction inert solvent such as a lower alcohol, THF, dioxane or ethyl acetate, preferably methanol or ethanol, in the presence of a noble metal catalyst on a solid support such as palladium on carbon (Pd/C), palladium on barium sulfate (Pd/BaSO 4 ), platinum on carbon (Pt/C), or tris(triphenylphosphine) rhodium chloride (Wilkinson's catalyst), preferably about 10% palladium on carbon, at a temperature of about 20 0 C to 15O 0 C, preferably 4O 0 C to 80 0 C.
  • a reaction inert solvent such as a lower alcohol, THF, dioxane or ethyl acetate, preferably methanol or
  • the method used to accomplish this is the same as described in Step 3 of Scheme 4, and results in the conversion of 16 to 17.
  • Step 5 of Scheme 4 is an alkylation, acylation, or sulfonylation of the secondary amine of 17 to afford 18.
  • the alkylation, acylation, and sulfonylation can be carried out according to methods known to one skilled in the art. Such methods can be found in Larock, R. C. Comprehensive Organic Transformations. VCN Publishers, 1989.
  • a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride, where sodium triacetoxyborohydride is preferred
  • the acylation of 17 can be effected by treating a mixture of 17, a base such as sodium hydroxide, in a solvent system such as chloroform-water with an acylating agent including, but not limited to, acid chlorides, acid anhydrides, or other activated carboxylic acid derivatives, where acid anhydrides and acid chlorides are preferred, to afford 18.
  • the suifonylation of 17 to can be effected by treating a mixture of 17, a trialkylamine base, such as triethylamine or diisopropylethylamine, where triethylamine is preferred, in a solvent such as methylene chloride, with an alkylsulfonyl chloride, to afford 18.
  • Step 6 of Scheme 4 is a fe/f-butoxycarbonyl deprotection.
  • a solvent such as dichloromethane or 1 ,4-dioxane
  • an acid such as trifluoroacetic acid or anhydrous hydrogen chloride at a temperature from about -10 0 C to 50 0 C affords 1 e.
  • Step 7 of Scheme 4 is a reductive alkylation.
  • 1e a lower aldehyde or ketone, and an optional acid, such as acetic acid
  • a solvent such as 1 ,2-dichloroethane, methanol, ethanol, water or tetrahydrofuran
  • a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride, where sodium triacetoxyborohydride is preferred, to afford 1f.
  • Step 8 of Scheme 4 is an acylation.
  • Treatment of 17, wherein A -Otert-butyl, with benzyl chloroformate in a solvent such as 1:1 dichloromethane/water with a base such as sodium or potassium carbonate affords 19.
  • Step 9 of Scheme 4 is a terf-butoxycarbonyl deprotection.
  • Treatment of 19 in a solvent such as dichloromethane or 1 ,4-dioxane with an acid such as trifluoroacetic acid or anhydrous hydrogen chloride at a temperature from about -10 0 C to 50 0 C affords 20.
  • Step 10 of Scheme 4 is a reductive alkylation.
  • Treatment of 20 a lower aldehyde or ketone, and an optional acid, such as acetic acid, in a solvent such as 1 ,2-dichloroethane, methanol, ethanol, water or tetrahydrofuran, are treated with a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride, where sodium triacetoxyborohydride is preferred, affords 21.
  • a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride, where sodium triacetoxyborohydride is preferred
  • Step 11 of Scheme 4 is a carboxybenzyl deprotection.
  • Conversion of 21 to afford 1g is accomplished in a reaction inert solvent such as a lower alcohol, preferably methanol or ethanol, with a noble metal catalyst, such as platinum or palladium, suspended on a solid support, preferably 10% palladium on carbon, under a hydrogen pressure of about 1 atmosphere to about 5 atmospheres, preferably about 3 atmospheres to about 4 atmospheres, at a temperature of about 10 0 C to about 100 0 C, preferably about 4O 0 C to about 60°C, while shaking the reaction mixture.
  • a reaction inert solvent such as a lower alcohol, preferably methanol or ethanol
  • a noble metal catalyst such as platinum or palladium
  • suspended on a solid support preferably 10% palladium on carbon
  • transfer hydrogenation conditions can be utilized where a hydride donor such as cyclohexadiene or ammonium formate is used in place of hydrogen, where ammonium formate is preferred, in a reaction inert solvent such as a lower alcohol, THF, dioxane or ethyl acetate, preferably methanol or ethanol, in the presence of a noble metal catalyst on a solid support such as palladium on carbon (Pd/C), palladium on barium sulfate (Pd/BaSO 4 ), platinum on carbon (Pt/C), or tris(triphenylphosphine) rhodium chloride (Wilkinson's catalyst), preferably about 10% palladium on carbon, at a temperature of about 20 0 C to 15O 0 C, preferably 40 0 C to 8O 0 C.
  • a reaction inert solvent such as a lower alcohol, THF, dioxane or ethyl acetate, preferably methanol or
  • hydroxyl groups on aryl or heteroaryl halides can be etherified by standard methods known in the art such as treatment with an alkali metal hydride or alkali metal hydroxide, such as sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, or cesium hydroxide, preferably sodium hydride, in a solvent such as tetrahydrofuran, ⁇ /, ⁇ /-dimethylformamide, or dimethylsulfoxide, preferably tetrahydrofuran, at a temperature from about -20 to 50 0 C, followed by addition of an alkyl halide or tosylate, preferably an alkyl iodide.
  • an alkali metal hydride or alkali metal hydroxide such as sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, or cesium hydroxide, preferably sodium hydride
  • a solvent such as tetrahydrofuran, ⁇ /, ⁇ /-dimethylform
  • the active compounds are useful psychotherapeutics and are potent agonists and/or antagonists of the serotonin 1A (5-HT 1A ) and/or serotonin 1B (5- HT 1 B) receptors.
  • the active compounds are useful in the treatment of hypertension, depression, generalized anxiety disorder, phobias (e.g., agoraphobia, social phobia and simple phobias), posttraumatic stress syndrome, avoidant personality disorder, sexual dysfunction (e.g., premature ejaculation), eating disorders (e.g., anorexia nervosa and bulimia nervosa), obesity, chemical dependencies (e.g., addictions to alcohol, cocaine, heroin, phenolbarbitol, nicotine and benzodiazepines), cluster headache, migraine, pain, Alzheimer's disease, obsessive-compulsive disorder, panic disorder, memory disorders (e.g., dementia, amnestic disorders, and age-related cognitive decline (ARCD)), Parkinson's diseases (e.g., dementia in Parkinson's disease, neuroleptic-induced parkinsonism and tardive dyskinesias), endocrine disorders (e.g., hyperprolactinaemia), vasospasm (particularly in the cerebral vascula
  • the in vitro activity of the compounds of the present invention at the 5-HTi B binding site may be determined according to the following procedure.
  • Bovine caudate tissue is homogenized and suspended in 20 volumes of a buffer containing 50 mM TRIS.hydrochloride (tris[hydroxymethyl]aminomethane hydrochloride) at a pH of 7.7.
  • the homogenate is then centrifuged at 45,000 G for 10 minutes.
  • the supernatant is then discarded and the resulting pellet resuspended in approximately 20 volumes of 50 mM TRIS.hydrochloride buffer at pH 7.7.
  • This suspension is then pre-incubated for 15 minutes at 37°C, after which the suspension is centrifuged again at 45,000 G for 10 minutes and the supernatant discarded.
  • the resulting pellet (approximately 1 gram) is resuspended in 150 ml of a buffer of 15 mM TRIS.hydrochloride containing 0.01 percent ascorbic acid with a final pH of 7.7 and also containing 10 ⁇ M pargyiine and 4 mM calcium chloride (CaCI 2 ).
  • the suspension is kept on ice at least 30 minutes prior to use.
  • the inhibitor, control or vehicle is then incubated according to the following procedure.
  • a 20 percent dimethylsulfoxide (DMSO)/80 percent distilled water solution is added 200 ⁇ l of tritiated 5-hydroxytryptamine (2 nM) in a buffer of 50 mM TRIS.hydrochloride containing 0.01 percent ascorbic acid at pH 7.7 and also containing 10 ⁇ M pargyiine and 4 ⁇ M calcium chloride, plus 100 nM of 8-hydroxy-DPAT (dipropylaminotetraline) and 100 nM of mesulergine.
  • DMSO dimethylsulfoxide
  • distilled water solution is added 200 ⁇ l of tritiated 5-hydroxytryptamine (2 nM) in a buffer of 50 mM TRIS.hydrochloride containing 0.01 percent ascorbic acid at pH 7.7 and also containing 10 ⁇ M pargyiine and 4 ⁇ M calcium chloride, plus 100 nM of 8-hydroxy-DPAT (di
  • the suspension is then incubated in a shaking water bath for 30 minutes at 25°C. After incubation is complete, the suspension is filtered using glass fiber filters (e.g., Whatman GF/BTM filters.). The pellet is then washed three times with 4 ml of a buffer of 50 mM TRIS.hydrochloride at pH 7.7. The pellet is then placed in a scintillation vial with 5 ml of scintillation fluid (Aquasol 2TM) and allowed to sit overnight. The percent inhibition can be calculated for each dose of the compound. An IC 50 value can then be calculated from the percent inhibition values.
  • glass fiber filters e.g., Whatman GF/BTM filters.
  • the activity of the compounds of the present invention for 5-HT 1A binding ability can be determined according to the following procedure. Rat brain cortex tissue is homogenized and divided into samples of 1 gram lots and diluted with 10 volumes of 0.32 M sucrose solution. The suspension is then centrifuged at 900G for 10 minutes and the supernate separated and recentrifuged at 70,000 G for 15 minutes. The supemate is discarded and the pellet re-suspended in 10 volumes of 15 mM TRIS.hydrochloride at pH 7.5. The suspension is allowed to incubate for 15 minutes at 37 0 C. After pre-incubation is complete, the suspension is centrifuged at 70,000 G for 15 minutes and the supernate discarded.
  • tissue pellet is resuspended in a buffer of 50 mM TRIS.hydrochloride at pH 7.7 containing 4 mM of calcium chloride and 0.01 percent ascorbic acid.
  • the tissue is stored at -70° C until ready for an experiment. The tissue can be thawed immediately prior to use, diluted with 10 ⁇ m pargyline and kept on ice.
  • tissue is then incubated according to the following procedure. Fifty microliters of control, inhibitor, or vehicle (1 percent DMSO final concentration) is prepared at various dosages. To this solution is added 200 ⁇ l of tritiated DPAT at a concentration of 1.5 nM in a buffer of 50 mM TRIS.hydrochloride at pH 7.7 containing 4 mM calcium chloride, 0.01 percent ascorbic acid and pargyline. To this solution is then added 750 ⁇ l of tissue and the resulting suspension is vortexed to ensure homogeneity. The suspension is then incubated in a shaking water bath for 30 minutes at 37° C.
  • the solution is then filtered, washed twice with 4 ml of 10 mM TRIS.hydrochloride at pH 7.5 containing 154 mM of sodium chloride.
  • the percent inhibition is calculated for each dose of the compound, control or vehicle.
  • IC 50 values are calculated from the percent inhibition values.
  • the agonist and antagonist activities of the compounds of the invention at 5-HT 1A and 5-HT 1 B receptors can be determined using a single saturating concentration according to the following procedure. Male Hartley guinea pigs are decapitated and 5-HT 1A receptors are dissected out of the hippocampus, while 5-HT 1 B receptors are obtained by slicing at 350 mM on a Mcllwain tissue chopper and dissecting out the substantia nigra from the appropriate slices.
  • the individual tissues are homogenized in 5 mM HEPES buffer containing 1 mM EGTA (pH 7.5) using a hand-held glass-Teflon ® homogenizer and centrifuged at 35,000xg for 10 minutes at 4°C.
  • the pellets are resuspended in 100 mM HEPES buffer containing 1 mM EGTA (pH 7.5) to a final protein concentration of 20 mg (hippocampus) or 5 mg (substantia nigra) of protein per tube.
  • reaction mix in each tube contained 2.0 mM MgCI 2 , 0.5 mM ATP, 1.0 mM cAMP, 0.5 mM IBMX, 10 mM phosphocreatine, 0.31 mg/mL creatine phosphokinase, 100 ⁇ M GTP and 0.5-1 microcuries of [ 32 P]-ATP (30 Ci/mmol: NEG-003-New England Nuclear).
  • Incubation is initiated by the addition of tissue to siliconized microfuge tubes (in triplicate) at 30° C. for 15 minutes.
  • Each tube receives 20 ⁇ L tissue, 10 ⁇ L drug or buffer (at 10x final concentration), 10 ⁇ L 32 nM agonist or buffer (at 10x final concentration), 20 ⁇ L forskolin (3 ⁇ M final concentration) and 40 ⁇ L of the preceding reaction mix. Incubation is terminated by the addition of 100 ⁇ L 2% SDS, 1.3 mM cAMP, 45 mM ATP solution containing 40,000 dpm [ 3 H]-CAMP (30 Ci/mmol: NET- 275 ⁇ New England Nuclear) to monitor the recovery of cAMP from the columns.
  • the reversal of agonist induced inhibition of forskolin-stimulated adenylate cyclase activity is calculated in relation to the 32 nM agonist effect.
  • the compounds of the invention can be tested for in vivo activity for antagonism of 5- HT 1B agonist-induced hypothermia in guinea pigs according to the following procedure.
  • mice Male Hartley guinea pigs from Charles River, weighing 250-275 grams on arrival and 300-600 grams at testing, serve as subjects in the experiment.
  • the guinea pigs are housed under standard laboratory conditions on a 7 a.m. to 7 p.m. lighting schedule for at least seven days prior to experimentation. Food and water are available ad libitum until the time of testing.
  • the compounds of the invention can be administered as solutions in a volume of 1 ml/kg.
  • the vehicle used is varied depending on compound solubility.
  • Test compounds are typically administered either sixty minutes orally (p.o.) or 0 minutes subcutaneously (s.c.) prior to a 5-HT 1B agonist, such as [3-(1-methylpyrrolidin-2-ylmethyl)-1H-indol-5-yl]-(3-nitropyridin-3- yl)-amine, which can be prepared as described in PCT publication WO93/11106, published Jun. 10, 1993 which is administered at a dose of 5.6 mg/kg, s.c.
  • 5-HT 1B agonist such as [3-(1-methylpyrrolidin-2-ylmethyl)-1H-indol-5-yl]-(3-nitropyridin-3- yl)-amine
  • each guinea pig Before a first temperature reading is taken, each guinea pig is placed in a clear plastic shoe box containing wood chips and a metal grid floor and allowed to acclimate to the surroundings for 30 minutes. Animals are then returned to the same shoe box after each temperature reading. Prior to each temperature measurement each animal is firmly held with one hand for a 30-second period. A digital thermometer with a small animal probe is used for temperature measurements. The probe is made of semi-flexible nylon with an epoxy tip. The temperature probe is inserted 6 cm. into the rectum and held there for 30 seconds or until a stable recording is obtained. Temperatures are then recorded.
  • a "pre-drug" baseline temperature reading is made at - 90 minutes, the test compound is given at -60 minutes and an additional -30 minute reading is taken.
  • the 5-HT 1 B agonist is then administered at 0 minutes and temperatures are taken 30, 60, 120 and 240 minutes later.
  • a pre-drug baseline temperature reading is made at -30 minutes.
  • the test compound and 5-HT 1B agonists are given concurrently and temperatures are taken at 30, 60, 120 and 240 minutes later.
  • the active compounds of the invention can be evaluated as anti-migraine agents by testing the extent to which they mimic sumatriptan in contracting the dog isolated saphenous vein strip (P. Humphrey et al., Br. J. Pharmacol., 94, 1128 (1988)). This effect can be blocked by methiothepin, a known serotonin antagonist.
  • Sumatriptan is known to be useful in the treatment of migraine and produces a selective increase in carotid vascular resistance in the anesthetized dog. The pharmacological basis of sumatriptan efficacy has been discussed in W. Fenwick et al., Br. J. Pharmacol., 96, 83 (1989).
  • the serotonin 5-HTi agonist activity can be determined by the in vitro receptor binding assays, as described for the 5-HT 1A receptor using rat cortex as the receptor source and [ 3 H]-8-OH-DPAT as the radioligand (D. Hoyer et al., Eur. J. Pharm., 118, 13 (1985)) and as described for the 5-HT 1B receptor using bovine caudate as the receptor source and [ ⁇ serotonin as the radioligand (R. E. Heuring and S. J. Peroutka, J- N ⁇ urosci ⁇ nce, 7, 894 (1987)).
  • All tested compounds had IC 50 values of 1000 nM or less for the 5HT 1B receptor.
  • the activity of the compounds of the present invention with respect to 5HTi B (formerly 5HT 1 D ) binding ability can be determined using standard radioligand binding assays as described in the literature.
  • the 5-HT 1A affinity can be measured using the procedure of Hoyer et al. (Brain Res., 376, 85 (1986)).
  • the 5-HT 1 D affinity can be measured using the procedure of Heuring and Peroutka ⁇ J. Neurosci., 7, 894 (1987)).
  • the compounds of formula I can advantageously be used in conjunction with one or more other therapeutic agents, for instance, different antidepressant agents such as tricyclic antidepressants (e.g., amitriptyline, dothiepin, doxepin, trimipramine, butripyline, clomipramine, desipramine, imipramine, iprindole, lofepramine, nortriptyline or protriptyline), monoamine oxidase inhibitors (e.g., isocarboxazid, phenelzine or tranylcyclopramine) or 5-HT re-uptake inhibitors (e.g., fluvoxamine, sertraline, fluoxetine or paroxetine), and/or with antiparkinsonian agents such as dopaminergic antiparkinsonian agents (e.g., levodopa, preferably in combination with a peripheral decarboxylase inhibitor e.g., benserazide or carbidopa, or
  • a 5-HT re-uptake inhibitor e.g., fluvoxamine, sertraline, fluoxetine or paroxetine
  • sertraline preferably sertraline
  • a pharmaceutically acceptable salt or polymorph thereof the combination of a compound of formula I with a 5-HT re-uptake inhibitor is referred herein to as "the active combination”
  • the active combination is useful psychotherapeutics and can be used in the treatment or prevention of disorders the treatment or prevention of which is facilitated by enhanced serotonergic neurotransmission (e.g., hypertension, depression, generalized anxiety disorder, phobias, posttraumatic stress syndrome, avoidant personality disorder, sexual dysfunction, eating disorders, obesity, chemical dependencies, cluster headache, migraine, pain, Alzheimer's disease, obsessive-compulsive disorder, panic disorder, memory disorders (e.g., dementia, amnestic disorders, and age-associated memory impairment), Parkinson's diseases e, dementia in Parkinson's disease, neuroleptic-induced Parkinsonism and tardive
  • Serotonin (5-HT) re-uptake inhibitors preferably sertraline
  • U.S. Pat. No. 4,536,518 describes the synthesis, pharmaceutical composition and use of sertraline for depression and is hereby incorporated by reference in its entirety.
  • compositions of the present invention can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers,
  • the active compounds of the invention can be formulated for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous) or rectal administration or in a form suitable for administration by inhalation or insufflation.
  • the pharmaceutical compositions can take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate).
  • binding agents e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g., lactose, microcrystalline cellulose or calcium phosphate
  • lubricants e.g., magnesium stearate, talc or silica
  • disintegrants e.g., potato starch or sodium
  • Liquid preparations for oral administration can take the form of, for example, solutions, syrups or suspensions, or they can be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).
  • suspending agents e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats
  • emulsifying agents e.g., lecithin or acacia
  • non-aqueous vehicles e.g., almond oil, oily esters or ethyl alcohol
  • the composition can take the form of tablets or lozenges formulated in conventional manner.
  • the active compounds of the invention can be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection can be presented in unit dosage form, e.g, in ampules or in multi-dose containers, with an added preservative.
  • the compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulating agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient can be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • the active compounds of the invention can also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a pressurized aerosol the dosage unit can be determined by providing a valve to deliver a metered amount.
  • the pressurized container or nebulizer can contain a solution or suspension of the active compound.
  • Capsules and cartridges for use in an inhaler or insufflator can be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
  • a proposed dose of the active compounds of the invention for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above (e.g., depression) is 0.1 to 200 mg of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day.
  • Aerosol formulations for treatment of the conditions referred to above are preferably arranged so that each metered dose or "puff 1 of aerosol contains 20 ⁇ g to 1000 ⁇ g of the compound of the invention.
  • the overall daily dose with an aerosol can be within the range 100 ⁇ g to 10 mg.
  • Administration can be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1 , 2 or 3 doses each time.
  • an active compound of this invention with a 5-HT re- uptake inhibitor, preferably sertraline, for the treatment of subjects possessing any of the above conditions
  • these compounds can be administered either alone or in combination with pharmaceutically acceptable carriers by either of the routes previously indicated, and that such administration can be carried out in both single and multiple dosages.
  • the active combination can be administered in a wide variety of different dosage forms, i.e., they can be combined with various pharmaceutically-acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, aqueous suspension, injectable solutions, elixirs, syrups, and the like.
  • Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc.
  • oral pharmaceutical formulations can be suitably sweetened and/or flavored by means of various agents of the type commonly employed for such purposes.
  • the compounds of formula I are present in such dosage forms at concentration levels ranging from about 0.5% to about 90% by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage and a 5-HT re-uptake inhibitor, preferably sertraline, is present in such dosage forms at concentration levels ranging from about 0.5% to about 90% by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage.
  • a proposed daily dose of an active compound of this invention in the combination formulation is from about 0.01 mg to about 2000 mg, preferably from about 0.1 mg to about 200 mg of the active ingredient of formula I per unit dose which could be administered, for example, 1 to 4 times per day.
  • Administration can be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1 , 2 or 3 doses each time.
  • a 5-HT re-uptake inhibitor, preferably sertraline in combination with compounds of formula I are readily adapted to therapeutic use as antidepressant agents.
  • these antidepressant compositions containing a 5-HT reuptake inhibitor, preferably sertraline, and a compound of formula I are normally administered in dosages ranging from about 0.01 mg to about 100 mg per kg of body weight per day of a 5- HT re-uptake inhibitor, preferably sertraline, preferably from about 0.1 mg. to about 10 mg per kg of body weight per day of sertraline; with from about 0.001 mg.
  • the compound of the present invention is administered and dosed in accordance with good medical practice, taking into account the clinical condition of the individual patient, the site and method of administration, scheduling of administration, patient age, sex, body weight and other factors known to medical practitioners.
  • the pharmaceutically "effective amount" for purposes herein is thus determined by such considerations as are known in the art. The amount must be effective to achieve improvement including, but not limited to, improved survival rate or more rapid recovery, or improvement or elimination of symptoms and other indicators as are selected as appropriate measures by those skilled in the art.
  • the compound of the present invention can be administered in various ways. It should be noted that it can be administered as the compound and can be administered alone or as an active ingredient in combination with pharmaceutically acceptable carriers, diluents, adjuvants and vehicles.
  • the compounds can be administered orally, subcutaneously or parenterally including intravenous, intraarterial, intramuscular, intraperitoneally, intratonsillar, and intranasal administration as well as intrathecal and infusion techniques. Implants of the compounds are also useful.
  • the patient being treated is a warm-blooded animal and, in particular, mammals including man.
  • the pharmaceutically acceptable carriers, diluents, adjuvants and vehicles as well as implant carriers generally refer to inert, non-toxic solid or liquid fillers, diluents or encapsulating material not reacting with the active ingredients of the invention.
  • the doses can be single doses or multiple doses over a period of several days.
  • the treatment generally has a length proportional to the length of the disease process and drug effectiveness and the patient species being treated.
  • it can generally be formulated in a unit dosage injectable form (solution, suspension, emulsion).
  • the pharmaceutical formulations suitable for injection include sterile aqueous solutions or dispersions and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • the carrier can be a solvent or dispersing medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Nonaqueous vehicles such as cottonseed oil, sesame oil, olive oil, soybean oil, corn oil, sunflower oil, or peanut oil and esters, such as isopropyl myristate, can also be used as solvent systems for compound compositions.
  • various additives which enhance the stability, sterility, and isotonicity of the compositions including antimicrobial preservatives, antioxidants, chelating agents, and buffers, can be added.
  • antibacterial and antifungal agents for example, parabens, chlorobutanol, phenol, sorbic acid, and the like.
  • isotonic agents for example, sugars, sodium chloride, and the like.
  • Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin. According to the present invention, however, any vehicle, diluent, or additive used would have to be compatible with the compounds.
  • Sterile injectable solutions can be prepared by incorporating the compounds utilized in practicing the present invention in the required amount of the appropriate solvent with various of the other ingredients, as desired.
  • a pharmacological formulation of the present invention can be administered to the patient in an injectable formulation containing any compatible carrier, such as various vehicle, adjuvants, additives, and diluents; or the compounds utilized in the present invention can be administered parenterally to the patient in the form of slow-release subcutaneous implants or targeted delivery systems such as monoclonal antibodies, vectored delivery, iontophoretic, polymer matrices, liposomes, and microspheres.
  • any compatible carrier such as various vehicle, adjuvants, additives, and diluents
  • the compounds utilized in the present invention can be administered parenterally to the patient in the form of slow-release subcutaneous implants or targeted delivery systems such as monoclonal antibodies, vectored delivery, iontophoretic, polymer matrices, liposomes, and microspheres.
  • Examples of delivery systems useful in the present invention include: 5,225,182; 5,169,383; 5,167,616; 4,959,217; 4,925,678; 4,487,603; 4,486,194; 4,447,233; 4,447,224; 4,439,196; and 4,475,196.
  • Many other such implants, delivery systems, and modules are well known to those skilled in the art.
  • the above discussion provides a factual basis for the use of the compound and method for prevention of respiratory viral infection.
  • the methods used with a utility of the present invention can be shown by the following non-limiting examples and accompanying figures.
  • N-arylated product copper (I) iodide (0.1 equivalent), potassium carbonate (1.5 equivalents), and N-N'-dimethylethylendiamine (0.1 equivalent) in toluene (5 volumes) containing water
  • Example 16 1 -(4-tert-Butyl-phenyl)-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]-4-propyl-piperazin-2- one.
  • Example 9 (100 mg, 0.24 mmol) and propionaldehyde (17.3 uL, 0.24 mmol) in methanol (2 mL) were stirred for 1.5 hours.
  • Sodium cyanoborohydride (18 mg, 0.285 mmol) and acetic acid (50 uL, 0.8 mmol) were added and the reaction mixture was stirred for 2 hours.
  • the solvent was removed in vacuo and the residue was purified by silica gel chromatography (75:1 chloroform-methanol w/ 1% ammonium hydroxide) to afford 72% yield (79 mg) of the title compound.
  • Example 18 1-(4-tert-Butyl-phenyl)-4-isopropyl-3-[2-(4-methyl-piperazin-1-yl)-benzyl]-piperazin-2- one.
  • 13 C NMR 100 MHz, CDCI 3 ) ⁇ 171.41, 151.92, 149.68, 140.29, 135.38, 131.29, 127.13, 126.28, 125.34, 123.98, 120.21, 63.74, 55.94, 53.03, 50.00, 49.65, 46.39, 41.21, 34.75, 32.97, 31.57, 21.46, 16.57; MS (AP/CI) 463.5 (M+H)+.
  • Example 19 Example 19:

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Neurology (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés, des compositions, des composés médicinaux, des agents psychothérapeutiques et des compositions pharmaceutiques répondant à la formule I, ainsi que des sels pharmaceutiques de ceux-ci, où R1, R2, R3, Rn, chaque X, W1, W2, Y1 et Y2 étant tels que définis dans la description. L’invention concerne des procédés de préparation des composés, des compositions, des composés médicinaux, des agents psychothérapeutiques et des compositions pharmaceutiques de celle-ci. L’invention concerne également des procédés de traitement de divers troubles et maladies au moyen des composés, compositions, composés médicinaux, agents psychothérapeutiques et compositions pharmaceutiques de la présente invention.
PCT/IB2006/003203 2005-11-18 2006-11-06 Nouveaux derives de piperazinone WO2007057742A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US73837605P 2005-11-18 2005-11-18
US60/738,376 2005-11-18

Publications (2)

Publication Number Publication Date
WO2007057742A2 true WO2007057742A2 (fr) 2007-05-24
WO2007057742A3 WO2007057742A3 (fr) 2007-06-07

Family

ID=37911156

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2006/003203 WO2007057742A2 (fr) 2005-11-18 2006-11-06 Nouveaux derives de piperazinone

Country Status (1)

Country Link
WO (1) WO2007057742A2 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9045445B2 (en) 2010-06-04 2015-06-02 Albany Molecular Research, Inc. Glycine transporter-1 inhibitors, methods of making them, and uses thereof
US10154988B2 (en) 2012-11-14 2018-12-18 The Johns Hopkins University Methods and compositions for treating schizophrenia
US10858359B2 (en) 2016-06-07 2020-12-08 Jacobio Pharmaceuticals Co., Ltd. Heterocyclic ring derivatives useful as SHP2 inhibitors
US10988466B2 (en) 2017-03-23 2021-04-27 Jacobio Pharmaceuticals Co., Ltd. Heterocyclic derivatives useful as SHP2 inhibitors
WO2022074103A1 (fr) 2020-10-08 2022-04-14 Leukos Biotech, S.L. Composés puissants et sélectifs utilisés en tant que modulateurs du récepteur de la sérotonine 1b

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998014433A1 (fr) * 1996-09-30 1998-04-09 Pfizer Inc. Lactames et imides heterocycliques d'aralkyle et d'aralkylidene
WO2002046167A1 (fr) * 2000-12-08 2002-06-13 Pfizer Products Inc. Benzyl(idene)-lactames et leur utilisation en tant que ligands du recepteur 5ht1

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998014433A1 (fr) * 1996-09-30 1998-04-09 Pfizer Inc. Lactames et imides heterocycliques d'aralkyle et d'aralkylidene
WO2002046167A1 (fr) * 2000-12-08 2002-06-13 Pfizer Products Inc. Benzyl(idene)-lactames et leur utilisation en tant que ligands du recepteur 5ht1

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9045445B2 (en) 2010-06-04 2015-06-02 Albany Molecular Research, Inc. Glycine transporter-1 inhibitors, methods of making them, and uses thereof
US10154988B2 (en) 2012-11-14 2018-12-18 The Johns Hopkins University Methods and compositions for treating schizophrenia
EP3610890A1 (fr) 2012-11-14 2020-02-19 The Johns Hopkins University Procédés et compositions de traitement de la schizophrénie
US10624875B2 (en) 2012-11-14 2020-04-21 The Johns Hopkins University Methods and compositions for treating schizophrenia
US10858359B2 (en) 2016-06-07 2020-12-08 Jacobio Pharmaceuticals Co., Ltd. Heterocyclic ring derivatives useful as SHP2 inhibitors
US10988466B2 (en) 2017-03-23 2021-04-27 Jacobio Pharmaceuticals Co., Ltd. Heterocyclic derivatives useful as SHP2 inhibitors
WO2022074103A1 (fr) 2020-10-08 2022-04-14 Leukos Biotech, S.L. Composés puissants et sélectifs utilisés en tant que modulateurs du récepteur de la sérotonine 1b

Also Published As

Publication number Publication date
WO2007057742A3 (fr) 2007-06-07

Similar Documents

Publication Publication Date Title
US6924289B2 (en) Benzyl(Idene)-lactam derivatives, their preparation and their use as selective (ANT) agonists of 5-HT1A- and/or 5-HT1D receptors
HRP970540A2 (en) Aralkyl and aralkylidene heterocyclic lactams and imides
US20050245521A1 (en) Novel benayl(idene)-lactam derivatives
JP3026948B2 (ja) アリールアクリルアミド誘導体
WO2002046167A1 (fr) Benzyl(idene)-lactames et leur utilisation en tant que ligands du recepteur 5ht1
AP1175A (en) Azabicyclic 5HT1 receptor ligands.
WO2007057742A2 (fr) Nouveaux derives de piperazinone
EP1140931B1 (fr) Antagonistes du recepteur 5ht1 pour therapie antidepressive
US20050282816A1 (en) Pyrazinylmethyl lactam derivatives
EP1113015B1 (fr) Dérivés de 3-((2-pipérazinyl-phényle)méthyle)-1-(4-(trifluorométhyl)-phényl)-2-pyrrolidinone optiquement actifs utilisés en tant qu'antagonistes sélectifs du recepteurs de 5-HT 1D
US20050227981A1 (en) Aralkyl and aralkylidene heterocyclic lactam and imides
US20050227980A1 (en) Aralkyl and aralkylidene heterocyclic lactam and imides
WO2006106416A1 (fr) Pyridil-lactams et leur utilisation comme ligands de recepteurs 5-ht1

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 06809222

Country of ref document: EP

Kind code of ref document: A2