EP1230225A2 - Derives de pyrimidine substitues en position 4 actifs pharmaceutiquement - Google Patents

Derives de pyrimidine substitues en position 4 actifs pharmaceutiquement

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Publication number
EP1230225A2
EP1230225A2 EP00971987A EP00971987A EP1230225A2 EP 1230225 A2 EP1230225 A2 EP 1230225A2 EP 00971987 A EP00971987 A EP 00971987A EP 00971987 A EP00971987 A EP 00971987A EP 1230225 A2 EP1230225 A2 EP 1230225A2
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EP
European Patent Office
Prior art keywords
alkyl
group
mmol
phenyl
compound
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP00971987A
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German (de)
English (en)
Inventor
Samantha Jayne Ambler
Stephen Richard Baker
Barry Peter Clark
Darrell Stephen Coleman
Robert James Foglesong
John Goldsworthy
Gunnar Erik Junior Jagdmann
Kirk Willis Johnson
Ann Elizabeth Kingston
William Martin Owton
Darryle Darwin Schoepp
Jian Eric Hong
Jeffrey Michael Schkeryantz
Michael Scott Vannieuwenhze
Mohammad Sadegh Zia-Ebrahimi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eli Lilly and Co
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Eli Lilly and Co
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Publication date
Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co
Publication of EP1230225A2 publication Critical patent/EP1230225A2/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to pharmaceutical compounds. More particularly it relates to the use of certain 4-substituted pyrimidine derivatives as mGluRl antagonists, to novel 4-substituted pyrimidine derivatives, to pharmaceutical formulations comprising 4-substituted pyrimidine derivatives, to a process for preparing 4- substituted pyrimidine derivatives and to intermediates useful in the preparation of 4-substituted pyrimidine derivatives .
  • EAA receptors excitatory amino acid receptors
  • Excitatory amino acid receptors are classified into two general types. Receptors that are directly coupled to the opening of cation channels in the cell membrane of the neurons are termed " ionotropic" . This type of receptor has been subdivided into at least three subtypes, which are defined by the depolarizing actions of the selective agonists N-methyl-D-aspartate (NMDA) , ⁇ -amino-3-hydroxy-5- methylisoxazole-4-propionic acid (AMPA) , and kainic acid (KA) .
  • NMDA N-methyl-D-aspartate
  • AMPA ⁇ -amino-3-hydroxy-5- methylisoxazole-4-propionic acid
  • KA kainic acid
  • the second general type of receptor is the G-protein or second messenger-linked "metabotropic" excitatory amino acid receptor.
  • This second type is coupled to multiple second messenger systems that lead to enhanced phosphoinositide hydrolysis, activation of phospholipase D or C, increases or decreases in c-AMP formation, and changes in ion channel function. Schoepp and Conn, Trends in
  • mGluRl metabotropic glutamate receptor
  • the metabotropic glutamate receptors are a highly heterogeneous family of glutamate receptors that are linked to multiple second-messenger pathways. These receptors function to modulate the presynaptic release of glutamate, and the postsynaptic sensitivity of the neuronal cell to glutamate excitation.
  • Compounds which modulate the function of these receptors in particular agonists and antagonists of glutamate, are useful for the treatment of acute and chronic neurodegenerative conditions, and as antiischaemic, antipsychotic, anticonvulsant , analgesic, anxiolytic, antidepressant , and anti-emetic agents.
  • X 1 represents 0 or NH
  • L represents a bond or a (1-6C) alkylene chain optionally interrupted by 0, S, SO, S0 2 or NH and optionally substituted on an alkylene carbon atom by fluoro, hydroxy, (l-4C)alkoxy or oxo;
  • R 1 represents an unsubstituted or substituted carbocyclic or heterocyclic group
  • R 2 represents a hydrogen atom, a halogen atom, a carboxyl group, a cyano group or a group of formula X 2 -R 5 in which X 2 represents a bond, 0, S, SO, S0 2 or NH and R 5 represents (1- 8C) alkyl, (3-10C) cycloalkyl, halo (1-6C) alkyl, hydroxy (1- 6C)alkyl, dihydroxy (1-4C) alkyl, (1-4C) alkoxy (1-4C) lkyl, (1- 4C) alkanoyl ( 1-4C) alkyl , ( 1-4C ) alkanoyloxy ( 1-4C) alkyl , carboxy (1-4C) alkyl, (1-4C) alkylaminocarbonyl (1-4C) alkyl, (1- 4C)alkanoylamino(l-4C) alkyl, (
  • X 1 represents 0 or NH
  • L represents a bond or a (1-6C) alkylene chain optionally interrupted by 0, S, SO, S0 or NH and optionally substituted on an alkylene carbon atom by fluoro, hydroxy,
  • R 1 represents an unsubstituted or substituted carbocyclic or heterocyclic group
  • R 2 represents a hydrogen atom, a halogen atom, a carboxyl group, a cyano group, a SCH 2 CN, or a group of formula X 2 -R 5 in which X 2 represents a bond, 0, S, SO, S0 2 or NH and R 5 represents (1-8C) alkyl, (3-10C) cycloalkyl, halo (1-6C) alkyl, hydroxy (1-6C) alkyl, dihydroxy (1-4C) alkyl, (1-4C) alkoxy (1-
  • the present invention provides a method of antagonizing the action of glutamate at mGluRl receptors in a patient requiring such treatment, which comprises administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof as defined herein.
  • the term --effective amount refers to the amount of a compound of formula I which is effective, upon single or multiple dose administration to a patient, in treating the patient suffering from the named disorder.
  • the particular effective amount or dose of compound administered according to this invention will of course be determined by the particular circumstances surrounding the case, including the compound administered, the route of administration, the particular condition being treated, and similar considerations.
  • the compounds can be administered by a variety of routes including oral, rectal, transder al , subcutaneous, intravenous, intramuscular, or intranasal routes. Alternatively, the compound may be administered by continuous infusion.
  • a typical daily dose will contain from about 0.01 mg/kg to about 100 mg/kg of the active compound of this invention.
  • daily doses will be about 0.05 mg/kg to about 50 mg/kg, more preferably from about 0.1 mg/kg to about 25 mg/kg.
  • the formula I compounds of the present invention are believed, through their action as mGluRl antagonists, to have the ability to treat a variety of neurological disorders in mammals associated with this condition, including acute neurological disorders such as cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord lesions due to trauma or infarction/ischaemia or inflammation, head trauma, perinatal hypoxia, cardiac arrest, and hypoglycemic neuronal damage, and chronic neurological disorders, such as Alzheimer's disease, Huntington's Chorea, inherited ataxias, amyotrophic lateral sclerosis, AIDS-induced dementia, ocular damage and retinopathy, cognitive disorders, Parkinson's Disease, drug- induced Parkinsonism and essential tremor.
  • the present invention also provides methods for treating these disorders which comprises administering to a patient in need thereof an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.
  • the formula I compounds of the present invention are also believed, through their action as mGluRl antagonists, to have the ability to treat a variety of other neurological disorders in mammals that are associated with glutamate dysfunction, including muscular spasms, convulsions (such as epilepsy) , spasticity, migraine (including menstrual migraine) , urinary incontinence, psychosis, (such as schizophrenia or bipolar disorder) , post traumatic stress disorder, depression, drug tolerance and withdrawal (such as alcohol, nicotine, opiates and benzodiazepines) , drug intoxication, metabolic derangement, anxiety and related disorders, emesis, brain edema, tardive dyskinesia and pain.
  • muscular spasms such as epilepsy
  • spasticity migraine (including menstrual migraine)
  • urinary incontinence such as schizophrenia or bipolar disorder
  • psychosis such as schizophrenia or bipolar disorder
  • post traumatic stress disorder depression
  • drug tolerance and withdrawal such as alcohol, nicotine, opiates and benzodiazepines
  • the present invention also provides methods for treating these disorders which comprise administering to a patient in need thereof an effective amount of the compound of formula I, or a pharmaceutically acceptable salt thereof.
  • the forms of pain that may be treated in accordance with the present invention include those arising as a result of central sensitization or peripheral sensitization of pain transmitting pathways .
  • pain include postoperative pain; dental pain; menstrual pain; migraine pain; persistent headaches, such as cluster headache or chronic tension headache; persistent pain states such as fibromyalgia or myofascial pains; neuropathic pain such as painful diabetic neuropathy; trigeminal neuralgia; postherpetic neuralgia; back pain; cancer pain; arthritic pain such as pain due to osteoarthritis or rheumatoid arthritis; bursitis; pain associated with AIDS; visceral pain, such as interstitial cystitis and IBS; pain due to spinal trauma and/or degeneration; post-stroke pain; burn pain; pain associated with muscle, nerve, skin, joint or bone; conditions such as allodynia; hyperalgesia; hypersensitization to pain signals; referred pain; enhanced memory of pain and neuronal mechanisms involved in coping with pain.
  • treating includes prophylaxis of a named condition, and amelioration or elimination of a named condition once the condition has been established.
  • patient for purposes of the present invention is defined as any warm blooded animal such as, but not limited to, a mouse, guinea pig, dog, horse, or human. Preferably, the patient is human.
  • alkyl as used herein means a straight chain or branched alkyl group.
  • values for a (1-8C) alkyl group include (1-6C) alkyl and (1-4C) alkyl such as methyl, ethyl, propyl, isopropyl, butyl and isobutyl .
  • (1-6C) alkylene chain optionally interrupted by O, S, SO, S0 2 or NH and optionally substituted on an alkylene carbon atom by fluoro, hydroxy, (1-4C) alkoxy or oxo refers to a straight chain or branched divalent group in which one, two or more groups in the chain may be replaced by 0, S, SO, S0 2 or NH and in which one or two chain carbon atoms may bear fluoro, hydroxy, (1-4C) alkoxy or oxo.
  • (1-6C) alkylene includes a group of formula C m H 2m - (X 3 ) q - C n H 2n in which X 3 is O, S, SO, S0 2 , NH, CHF, CF 2 , CHOH, CH(0(l-4C)alkyl) or CO, q is 0 or 1, and each of m and n is 0 or an integer of from 1 to 4, provided that when q is 1 and X 3 is 0, S, SO, S0 2 or NH, m is at least 2. Examples of particular values include ethylene, propylene, butylene, methylthioethylene, and methylsulphonylethylene.
  • halo (1-6C) alkyl refers to an alkyl group in which one or more hydrogen atoms have been replaced by a halogen atom or atoms.
  • Examples of a halo (1-6C) alkyl group are trifluoromethyl and fluoroethyl.
  • (1-4C) alkoxy refers to an alkoxy radical made up of an oxygen radical bearing a saturated straight or branched chain hydrocarbon radical of one to four carbon atoms. Included within the scope of this term are methoxy, ethoxy, propoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy and the like.
  • halogen atom refers to a fluorine, chlorine, bromine or iodine atom.
  • unsubstituted or substituted for example in the term unsubstituted or substituted carbocyclic or heterocyclic group or ring, refers to a group that is unsubstituted or substituted by one, two or more substituents, said substituents being selected from atoms and groups which, when present in the compound of formula I, do not prevent the compound of formula I from functioning as a antagonist of mGluRl receptor subtype function.
  • Examples of atoms and groups which may be present in a substituted carbocyclic or heterocyclic group or ring are oxo, methylenedioxy, a halogen atom, a nitro group, a cyano group, a (1-4C) alkyl group, a halo (1-4C) alkyl group, or a group of formula -X-R in which X represents 0, S, SO, S0 , NR Z , CO, COO, OCO, CONH, NHCO, S0 2 NH, or NHS0 2 and R represents a hydrogen atom, a (1-8C) alkyl group, a (3- 10C) cycloalkyl group, a morpholino group, a phenyl group, a phenyl (1-4C) alkyl group or a phenyl (2-4C) alkenyl group in which any phenyl group is unsubstituted or substituted by one or two substituents selected independently from a hal
  • Examples of particular values include chlorine, bromine, methyl, ethyl, methoxy, 2-methyl-3-prop-2-enoyl, morpholinocarbonyl , cyclohexylaminocarbonyl , adamantylaminocarbonyl , benzylaminocarbonyl , and benzyloxycarbonyl .
  • carbocyclic group includes an aromatic group, a non-aromatic group or a non-aromatic group fused with an aromatic group.
  • aromatic group includes phenyl and a polycyclic aromatic carbocyclic ring such as 1-naphthyl or 2-naphthyl .
  • a carbocyclic group that is a non-aromatic group may be, for example a (3-10C) cycloalkyl group or a (3- 10C) cycloalkenyl group.
  • cycloalkyl refers to a monocyclic or polycyclic group. Examples of particular values include cyclopentyl, cyclohexyl, bicyclo [2.2.1] hept-2-yl, bicyclo [3.1. l]hept-2-yl and adamantyl.
  • cycloalkenyl refers to a monocyclic or polycyclic group. Examples of particular values include bicyclo[2.2. l]hept-2-ene-4-yl .
  • a carbocyclic group that is a non-aromatic group fused with an aromatic group may be, for example, a (3- 10C) cycloalkyl group fused with a benzene ring, such as 2,3- dihydro-lH-indenyl or 1, 2 , 3 , 4-tetrahydronaphthyl .
  • Examples of particular values for a carbocyclic group are phenyl, 1-naphthyl, 2-naphthyl, cyclopentyl, cyclohexyl, bicyclo [2.2.
  • heterocyclic group includes a non-aromatic group and a heteroaromatic group.
  • non-aromatic heterocyclic group includes a saturated or partially unsaturated 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, and a bicyclic group consisting of a saturated or partially unsaturated 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring.
  • An example of a non-aromatic heterocyclic group is 1,3-dihydro- 2H-isoindol-2-yl.
  • heteroaromatic group includes an aromatic 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, and a bicyclic group consisting of a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen.
  • heteroaromatic groups are furyl, thiophenyl, oxazolyl, isoxazolyl, thiazoyl, isothiazolyl, imidazolyl, pyrimidyl , benzofuryl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzo- thiazolyl and indolyl .
  • Examples of particular values for an unsubstituted or substituted carbocyclic or heterocyclic group are phenyl, 2- chlorophenyl , 2 , 6-dichlorophenyl, 2-methoxyphenyl, 4- methoxyphenyl , bicyclo [2.2. l]hept-2-yl, (1R, 2R, 3R, 5S) -2 , 6, 6- trimethylbicyclo [3.1. l]hept-2-yl, 2 , 3-dihydro-lH-inden-l-yl and 2 , 3-dihydro-lH-inden-2-yl .
  • X 1 preferably represents NH.
  • L preferably represents a bond or a group of formula C m H 2m -(X 3 ) q -C n H 2n in which X 3 is 0, S, SO, S0 2 , NH, CF 2 , CHOH, CH(0(1-4C) alkyl) or CO, q is 0 or 1, and each of m and n is 0 or an integer of from 1 to 4 , provided that when q is 1 and X 3 is 0, S, SO, S0 2 or NH, m is at least 2.
  • X 3 is S or S0 2 , q is 0 or 1
  • m is 2 and n is 0, 1 or 2.
  • L examples of particular values for L are a bond, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) -, -CH(CH 3 )CH 2 -, - (CH 2 ) 2 SCH 2 - , -(CH 2 ) 2 )S0 2 CH 2 -, -CH(CH 2 CH 3 )CH 2 OCH 2 -, -CH 2 CHF-, -CH 2 CF 2 -,
  • R 1 preferably represents an unsubstituted or substituted carbocyclic group in which the carbocyclic group is selected from an aromatic group, a non-aromatic group and a non-aromatic group fused with an aromatic group.
  • the carbocyclic group is preferably selected from phenyl which is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, a (1-4C) alkyl group and a (1-4C) alkoxy group; (3- 10C) cycloalkyl which is unsubstituted or substituted by from one to three methyl groups; 2 , 3-dihydro-lH-indenyl ; and 1, 2, 3 , 4-tetrahydronaphthyl .
  • R 1 examples of particular values for R 1 are phenyl, 2- chlorophenyl, 3-bromophenyl , 2 , 6-dichlorophenyl, 2-chloro-4- fluorophenyl, 2-methylphenyl, 2-methoxyphenyl, 4- methoxyphenyl , 4-phenylphenyl, cyclohexyl, bicyclo[2.2.1]hept-2-yl, (1R, 2R, 3R, 5S) -2 , 6 , 6- trimethylbicyclo [3.1.1] hept-2-yl, adamantyl, 2 , 3-dihydro-lH- inden-1-yl, 2 , 3-dihydro-lH-inden-2-yl and 1,2,3,4- tetrahydronaphth-1-yl .
  • R 2 preferably represents a hydrogen atom, a halogen atom, a carboxy group, a cyano group, or a (1-8C) alkyl, halo (1-6C) alkyl, ( 1-6C) alkoxy, hydroxy (1-6C) alkoxy, (1- 6C)alkylthio, (1-4C) alkylsulfonyl, (1-4C) alkylamino, halo(l- 4C)alkylthio, hydroxy (1-4C) alkylthio, dihydroxy(l- 4C)alkylthio, (1-4C) alkoxy (1-4C) alkylthio, (1-4C) alkanoyl (1- 4C)alkylthio, (1-4C) alkoxycarbonyl (1-4C) alkylthio, carboxy (1-4C) alkylthio, (1-4C) alkylaminocarbonyl (1- 4C)alkylthio, (1-4C) alkanoylamino (1-4
  • R 2 examples of particular values for R 2 are hydrogen, chlorine, carboxy, cyano, methyl, ethyl, propyl, isopropyl, isobutyl, trifluoromethyl, ethoxy, 2-hydroxyethyl, ethylamino, 2-fluoroethylthio, methylthio, ethylthio, propylthio, isobutylthio, 2-hydroxyethylthio, 2- hydroxypropylthio, 2 , 3-dihydroxypropylthio, 2- methoxyethy1thio, ethanoylmethylthio, 2-methoxycarbonyl- methylthio, 2-carboxymethylthio 2-methylaminosulfonyl) - ethylthio and 2-dimethylaminophosphonyl) ethylthio .
  • R 3 and R 4 together with the carbon atoms to which they are attached form a ring of formula:
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , Z 9 and Z 10 are each selected independently from 0, NR 41 , S, SO and S0 2 ;
  • ,11 represents 0, S, CH 2 or CH 2 CH 2 ;
  • R 21 and R 22 each independently represents a hydrogen atom, a halogen atom, a nitro group, a cyano group, a (1-4C) alkyl group, a halo (1-4C) alkyl group, or a group of formula -X-R 51 in which X 4 represents 0, S, SO, S0 2 , NR 52 , CO, COO, 0C0, C0NH, NHCO, S0 2 NH, or NHS0 2 and R 51 represents a hydrogen atom, a (1-4C) alkyl group, a phenyl group or a phenyl (1-4C) alkyl group in which any phenyl group is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, a (1-4C) alkyl group and a (1-4C) alkoxy group;
  • R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 36 , R 37 and R 38 each independently represents a hydrogen atom, an oxo group, a halogen atom, a (1-4C) alkyl group, (1-4C) alkoxy, a halo(l- 4C) alkyl group, an aryl (1-4C) alkyl group, a (1-4C) alkoxy (1- 4C) alkyl group, a (1-4C) alkylthio group, a (1-
  • R 33 , R 34 and R 35 each independently represents a hydrogen atom, a halogen atom, a (1-4C) alkyl group or a (1-4C) alkoxy group;
  • R 41 represents a (1-6C) alkyl group or a group of formula Y-R a in which Y represents CO, COO or CONH and R a represents (1- 4C) alkyl, phenyl (1-4C) alkyl, phenyl (2-4C) alkenyl, (3- 10C) cycloalkyl, or, when Y is CO, morpholino; and R 52 represents a hydrogen atom, a (1-4C) alkyl group or a phenyl (1-4C) alkyl group.
  • R 51 represents a hydrogen atom, a (1-4C) alkyl group, a phenyl group or a phenyl (1-4C) alkyl group in which any phenyl group is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, a (1-4C) alkyl group and a (1-4C) alkoxy group; and R 52 represents a hydrogen atom, a (l-4C)alkyl group or a phenyl (1-4C) alkyl group; or R 51 and R 52 together with the nitrogen atom to which they are attached form rings of the following structures:
  • Examples of groups of compounds of formula I of particular interest include compounds of formula
  • R 21 and R 22 are a hydrogen atom, a fluorine atom, a chlorine atom, a nitro group, a hydroxyl group, a carboxyl group, a methyl group and a methoxy group.
  • An example of a value for each of R 23 and R 24 is hydrogen. Another example of a value for R 23 is oxo.
  • R 41 examples of values for R 41 are methyl, benzyl, 2- methyl-3-prop-2-enoyl , cyclopentylcarbonyl , cyclohexycarbonyl , morpholinocarbonyl , cyclohexylaminocarbonyl , adamantylaminocarbonyl and benzylaminocarbonyl , benzyloxycarbonyl .
  • R 26 An example of a value for R 26 is hydrogen.
  • R 29 is hydrogen.
  • values for R 34 are hydrogen, chlorine, methyl and ethyl .
  • R 36 An example of a value for R 36 is hydrogen.
  • R 37 An example of a value for R 37 is hydrogen.
  • R 38 An example of a value for R 38 is hydrogen.
  • the present invention includes pharmaceutically acceptable salts of the formula I compounds. These salts can exist in conjunction with the acidic or basic portion of the molecule and can exist as acid addition, primary, secondary, tertiary, or quaternary ammonium, alkali metal, or alkaline earth metal salts.
  • the acid addition salts are prepared by the reaction of an acid with a compound of formula I.
  • the alkali metal and alkaline earth metal salts are generally prepared by the reaction of the hydroxide form of the desired metal salt with a compound of formula I .
  • Acids commonly employed to form such salts include inorganic acids such as hydrochloric, hydrobromic, hydriodic, sulfuric, and phosphoric acid, as well as organic acids such as para-toluenesulfonic, methanesulfonic, oxalic, para-bromophenylsulfonic, carbonic, succinic, citric, benzoic, and acetic acid, and related inorganic and organic acids.
  • inorganic acids such as hydrochloric, hydrobromic, hydriodic, sulfuric, and phosphoric acid
  • organic acids such as para-toluenesulfonic, methanesulfonic, oxalic, para-bromophenylsulfonic, carbonic, succinic, citric, benzoic, and acetic acid, and related inorganic and organic acids.
  • Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, ammonium, monohydrogenphosphate, dihydrogenphosphate, .meta-phosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, hippurate, butyne-1, 4-dioate, hexane-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate,
  • any salt of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole. It is further understood that the above salts may form hydrates or exist in a substantially anhydrous form.
  • the term "stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures which are not interchangeable. The three-dimensional structures are called configurations.
  • the term “enantiomer” refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another.
  • chiral center refers to a carbon atom to which four different groups are attached.
  • diastereomers refers to stereoisomers which are not enantiomers .
  • two diastereomers which have a different configuration at only one chiral center are referred to herein as “epimers”.
  • racemate refers to a mixture of equal parts of enantiomers .
  • enantiomeric enrichment refers to the increase in the amount of one enantiomer as compared to the other.
  • E 1 is the amount of the first enantiomer and E 2 is the amount of the second enantiomer.
  • the initial ratio of the two enantiomers is 50:50, such as is present in a racemic mixture, and an enantiomeric enrichment sufficient to produce a final ratio of 70:30 is achieved
  • the ee with respect to the first enantiomer is 40%.
  • the final ratio is 90:10
  • the ee with respect to the first enantiomer is 80%.
  • An ee of greater than 90% is preferred, an ee of greater than 95% is most preferred and an ee of greater than 99% is most especially preferred.
  • Enantiomeric enrichment is readily determined by one of ordinary skill in the art using standard techniques and procedures, such as gas or high performance liquid chromatography with a chiral column. Choice of the appropriate chiral column, eluent and conditions necessary to effect separation of the enantiomeric pair is well within the knowledge of one of ordinary skill in the art.
  • the specific stereoisomers and enantiomers of compounds of formula I can be prepared by one of ordinary skill in the art utilizing well known techniques and processes, such as those disclosed by J. Jacques, et al . , “Enantiomers, Racemates, and Resolutions” , John Wiley and Sons, Inc., 1981, and E.L. Eliel and S.H. Wilen, "
  • R and S are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center.
  • the term “R” (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group.
  • the term “S” (sinister) refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group.
  • the priority of groups is based upon their atomic number (in order of decreasing atomic number) .
  • a partial list of priorities and a discussion of stereochemistry is contained in "Nomenclature of Organic Compounds: Principles and Practice", (J.H. Fletcher, et al . , eds., 1974) at pages 103- 120.
  • the compounds of formula I may be prepared by a process which comprises (a) reacting a compound of formula
  • Z 2 represents a leaving atom or group with a compound of formula
  • the leaving atom or group represented by Z 1 may be, for example, a halogen atom such as a chlorine atom.
  • the reaction is conveniently performed in the presence of a base, for example an alkali metal carbonate, such as potassium carbonate or a tertiary amine such as triethylamine or diisopropylethylamine, or poly (4- vinylpyridine) .
  • a base for example an alkali metal carbonate, such as potassium carbonate or a tertiary amine such as triethylamine or diisopropylethylamine, or poly (4- vinylpyridine) .
  • the reaction is conveniently conducted at a temperature in the range of from 0 to 120 2 C.
  • Convenient solvents include alcohols, such as ethanol and amides such as N,N-dimethylformamide or N-methylpyrrolidinone .
  • the leaving atom or group represented by Z 2 may be, for example, a halogen atom such as a chlorine atom or an organosulfonyl group such as methanesulfonyl .
  • the reaction is conveniently performed in the presence of a base, for example an alkali metal alkoxide such as potassium t-butoxide.
  • a base salt of the compound of formula V may be used, for example an alkali metal salt such as a sodium or potassium salt.
  • the reaction is conveniently conducted at a temperature in the range of from 0 to 100 9 C.
  • Convenient solvents include amides such as N, N-dimethy1formamide .
  • the rearrangement according to process step (c) is conveniently effected in the presence of an anionic ion exchange resin, such as 550A-OH and at a temperature of from 0 to 120 2 C.
  • anionic ion exchange resin such as 550A-OH
  • Convenient solvents include mixtures of dimethylformamide and alcohols, such as isopropanol.
  • compositions of formula I may be prepared by conventional methods, for example by reaction with an appropriate acid of base.
  • reaction is conveniently performed at a temperature in the range of from 20 to 150 S C.
  • XXII The reaction is conveniently performed at an elevated temperature, for example in the range of from 100 to 220 2 C.
  • compounds of formula XX may be prepared by reacting a compound of formula XXI with a compound of formula
  • R 2 C( NH)NH 2 XXVII or an acid addition salt thereof, such as a hydrochloride or hydrobromide .
  • Convenient solvents include alcohols, such as ethanol . The reaction is conveniently performed at a temperature of from 0 to 100 S C.
  • Convenient solvents include alcohols, such as ethanol .
  • the temperature is conveniently in the range of from 0 to 100 9 C.
  • Compounds of formula XXIX may be prepared by reacting a compound of formula
  • reaction is conveniently performed in the presence of a cationic ion exchange resin, such as 50wx8-100, and at a temperature in the range of from 0 to 120 9 C.
  • a cationic ion exchange resin such as 50wx8-100
  • the present invention provides the novel compounds of formula I disclosed herein and the novel intermediates disclosed herein.
  • the present invention also provides a process for preparing a novel compound of formula I as described hereinabove .
  • the biological activity of the compounds of the present invention may be evaluated by employing a phosphoinositide hydrolysis assay or a calcium mobilization assay.
  • a phosphoinositide hydrolysis assay or a calcium mobilization assay.
  • metalabotropic glutamate receptors are G- protein, or secondary messenger-linked, receptors. As such, these receptors are linked to multiple second messenger systems which enhance phosphoinositide hydrolysis, activation of phospholipase D, increases or decreases in c- AMP formation, and changes in ion channel function. Schoepp and Conn, Trends in Pharmacol . Sci . , 14, 13 (1993).
  • a general description of the phosphoinositide hydrolysis assay is given as follows:
  • mGluRl receptor-expressing cell lines are cultured in DMEM supplemented with 5% heat inactivated fetal calf serum, sodium pyruvate (ImM), glutamine (ImM) , penicillin (lOOU/m ), streptomycin (lOOmg/mL), HEPES (lOmM), geneticin G418 (0.5mg/mL) and hygromycin B (0.2mg/mL). Confluent cultures are passaged weekly.
  • the [3H] -inositol monophosphate (INS PI) fraction is eluted with 0.1M triethyl ammonium bicarbonate buffer and radioactivity measured by liquid scintillation counting. Following the measurement of radioactivity for each fraction eluted, IC50 calculations are made for each test compound examined. The compounds exemplified herein generated IC50 values equal to or less than 10 ⁇ M in the phosphoinositide assay herein described.
  • the biological activity of the compounds of the present invention can be determined employing an assay which monitors intracellular calcium ion concentration in response to metabotropic glutamate receptor activation.
  • Plates containing cells expressing mGluRl are prepared using standard methods well known to those of skill in the art. Reagent plates are prepared containing 160 ⁇ l/well of buffer (1% DMSO or compound in 1%DMS0 buffer) and additional plates are prepared containing 260 ⁇ l/well of 10M glutamate in assay buffer.
  • (b) Calcium Flux Assay Media is removed from the plates containing the cells expressing mGluRl using a hand held aspirator or standard plate washer. 50 ⁇ l of lO ⁇ M Fluo3 Dye is added to each well which in turn will emit fluorescence upon binding to calcium ions. Cells are incubated at room temperature for approximately 90 minutes to allow the Fluo3 Dye to load into the cells. The dye is then aspirated and replaced with 50 ⁇ l of buffer. The plates are placed in a fluorescent light imaging plate reader (FLIPR) such that the plate containing the buffer or compound is to the right of the cell plate, while the plate containing the glutamate is placed to the left of the cell plate.
  • FLIPR fluorescent light imaging plate reader
  • the FLIPR is programmed to take background fluorescence readings for 10 seconds then add buffer or compound to the cell plates. After 3 minutes, the FLIPR adds lOO ⁇ l of lO ⁇ M glutamate to mobilize cellular calcium ion stores and fluorescence is measured for about a minute. Fluorescence values for cells containing buffer are compared relative to cells containing mGluRl antagonist compound. Percent inhibition of mGluRl elicited calcium ion influx, as indexed by fluorescence, is calculated for each compound.
  • test compounds to treat forms of pain may be demonstrated by activity in one or more standard tests, such as the formalin test, the Chung neuropathic pain model and the carrageenan test of inflammatory pain.
  • mice Male Sprague-Dawley rats (200-250g; Charles River, Portage, MI) are housed in group cages and maintained in a constant temperature and a 12h light/12h dark cycle 4-7 days before the studies are performed. Animals have free access to food and water at all times prior to the day of the experiment . Drugs or vehicles are administered intraperitoneally (i.p.) or orally (p.o.) by gavage in a volume of 1 mL/kg.
  • the test is performed in custom-made Plexiglas® boxes 25x25x20x cm in size (according to Shibata et al . , Pain 38; 347-352, 1989, Wheeler-Aceto et al . , Pain, 40; 229-238, 1990) .
  • a mirror placed at the back of the cage allows the unhindered observation of the formalin injected paw. Rats are acclimated individually in the cubicles at least 1 hour prior to the experiment. All testing is conducted between 08:00 and 14:00 h and the testing room temperature is maintained at 21-23°C. Test compounds are administered 30 minutes prior to the formalin injection.
  • Formalin (50 ⁇ l of a 5% solution in saline) is injected subcutaneously into the dorsal lateral surface of the right hind paw with a 27 gauge needle. Observation starts immediately after the formalin injection. Formalin-induced pain is quantified by recording in 5 minute intervals the number of formalin injected paw licking events and the number of seconds each licking event lasts. These recordings are made for 50 minutes after the formalin injection.
  • the total time spent licking and biting the injected paw was demonstrated to be most relevant (Coderre et al . , Eur. J. Neurosci . 6; 1328-1334, 1993; Abbott et al . , Pain, 60; 91-102, 1995) and is chosen for the testing score.
  • the early phase score is the sum of time spent licking in seconds from time 0 to 5 minutes.
  • the late phase is scored in 5 minute blocks from 15 minutes to 40 minutes and is expressed accordingly or also by adding the total number of seconds spent licking from minute 15 to minute 40 of the observation period. Data are presented as means with standard errors of means ( ⁇ SEM) .
  • the present invention provides a method of treating pain, which comprises administering to a patient in need thereof an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof as defined hereinabove .
  • the ability of test compounds to treat migraine may be demonstrated in the following test.
  • Harlan Sprague-Dawley rats (225-325 g) or guinea pigs from Charles River Laboratories (225-325 g) are anesthetized with sodium pentobarbital intraperitoneally (65 mg/kg or 45 mg/kg respectively) and placed in a stereotaxic frame (David Kopf Instruments) with the incisor bar set at -3.5 mm for rats or -4.0 mm for guinea pigs.
  • two pairs of bilateral holes are drilled through the skull (6 mm posterially, 2.0 and 4.0 mm laterally in rats; 4 mm posteriorly and 3.2 and 5.2 mm laterally in guinea pigs, all coordinates referenced to bregma) .
  • Pairs of stainless steel stimulating electrodes, insulated except at the tips are lowered through the holes in both hemispheres to a depth of 9 mm (rats) or 10.5 mm (guinea pigs) from dura.
  • test compound is administered intravenously (i.v.) at a dosing volume of lmL/Kg or, in the alternative, test compound is administered orally (p.o.) via gavage at a volume of
  • a 50 mg/Kg dose of Evans Blue a fluorescent dye, is also injected intravenously.
  • the Evans Blue complexed with proteins in the blood and functions as a marker for protein extravasation.
  • the left trigeminal ganglion is stimulated for 3 minutes at a current intensity of 1.0 mA (5 Hz, 4 msec duration) with a Model 273 potentiostat/ galvanostat (EG&G Princeton Applied Research) .
  • the animals are killed and exsanguinated with 20 mL of saline.
  • the top of the skull is removed to facilitate the collection of the dural membranes .
  • the membrane samples are removed from both hemispheres, rinsed with water, and spread flat on microscopic slides. Once dried, the tissues are coverslipped with a 70% glycerol/water solution.
  • a fluorescence microscope (Zeiss) equipped with a grating monchromator and a spectrophotometer is used to quantify the amount of Evans Blue dye in each sample.
  • An excitation wavelength of approximately 535 nm is utilized and the emission intensity at 600 nm is determined.
  • the microscope is equipped with a motorized stage and also interfaced with a personal computer. This facilitates the computer-controlled movement of the stage with fluorescence measurements at 25 points (500 mm steps) on each dural sample. The mean and standard deviation of the measurements are determined by the computer.
  • the extravasation induced by the electrical stimulation of the trigeminal ganglion is an ipsilateral effect (i.e. occurs only on the side of the dura in which the trigeminal ganglion is stimulated) . This allows the other
  • the present invention provides a method of treating migraine, which comprises administering to a patient in need thereof an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof as defined hereinabove .
  • the compounds (A) to (H) above have all been found to be selective mGluRl antagonists. In particular, all of the compounds have been found to exhibit at least 10 fold selectivity for mGluRl over mGluR5 in the test described hereinabove.
  • the present application contains the first disclosure that a compound which is a selective mGluRl antagonist is useful for the treatment of migraine.
  • the present invention provides a method of treating migraine, which comprises administering to a patient in need of treatment an effective amount of a selective mGluRl antagonist.
  • the selective mGluRl antagonist is preferably at least 10 fold selective for mGluRl over mGluR5 , more preferably at least 100 fold selective.
  • the compounds of the present invention are preferably formulated prior to administration. Therefore, another aspect of the present invention is a pharmaceutical formulation comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present pharmaceutical formulations are prepared by known procedures using well-known and readily available ingredients.
  • the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, and may be in the form of a capsule, sachet, paper, or other container.
  • the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments containing, for example, up to 10% by weight of active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • suitable carriers include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum, acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl and propyl hydroxybenzoates, talc, magnesium stearate, and mineral oil.
  • the formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, or flavoring agents.
  • Formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art .
  • the formulations are preferably formulated in a unit dosage form, each dosage containing from about 5 mg to about 500 mg, more preferably about 25 mg to about 300 mg of the active ingredient.
  • unit dosage form refers to a physically discrete unit suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutically acceptable carrier.
  • Hard gelatin capsules are prepared using the following ingredients :
  • the above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities.
  • Tablets each containing 60 mg of active ingredient are made as follows:
  • the active ingredient, starch, and cellulose are passed through a No . 45 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No . 14 mesh U.S. sieve.
  • the granules so produced are dried at 50 * C and passed through a No . 18 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
  • Flash 40S Flash 40S
  • Flash 40M Flash 40L
  • flash 40S flash 40M
  • Flash 40L flash chromatography cartridges with the corresponding specifications; 7 X 4 cm, 40 g silica gel; 10 X 4 cm, 90 g silica gel; 21 X 4 cm, 120 g silica gel, respectively.
  • Flash 40S flash 40M
  • Flash 40L flash chromatography cartridges with the corresponding specifications; 7 X 4 cm, 40 g silica gel; 10 X 4 cm, 90 g silica gel; 21 X 4 cm, 120 g silica gel, respectively.
  • These cartridges are available from Biotage, a division of Dyax, 1500 Avon Street Extended, Charlottesville, Virginia, 22902.
  • the crude product was purified by flash chromatography on silica (eluent ethyl acetate) to give the free base of the title compound as a white solid.
  • the free base was dissolved in 0.5 molar ethanolic hydrogen chloride and evaporated in vacuo to give the title compound as a light-yellow solid (m.p. 262-4°C) .
  • the residual gum was dissolved in ethyl acetate and washed sequentially with 2M sodium carbonate, water, and then saturated sodium chloride solution. The organic phase was then dried over magnesium sulphate, filtered and the filtrate evaporated in vacuo to give the crude product as a brown solid.
  • the crude product was purified by flash chromatography on silica (eluent n- hexane 50% diethyl ether) to give the product as a yellow solid.
  • the reaction mixture was poured into water (50mL), extracted ethyl acetate (3x) and the combined organic extracts washed with water and saturated sodium chloride solution, dried over magnesium sulphate, filtered and evaporated in vacuo to give the crude product as a yellow gum.
  • the crude product was purified by flash chromatography on silica (eluent diethyl ether) to give the free base of the title compound as a white solid.
  • the free base was dissolved in 0.5M ethanolic hydrogen chloride (2mL) and evaporated in vacuo to give the title compound as a white solid (m.p. 198-200°C) .
  • the combined organic extracts were washed sequentially with water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated in vacuo to give the crude product as a yellow gum.
  • the crude product was purified by flash chromatography on silica (eluent diethyl ether 33% hexane) to give the free base of the title compound as a white solid.
  • the free base was dissolved in 0.5M ethanolic hydrogen chloride and evaporated in vacuo to give the title compound as a white solid (m.p. 198-200°C) .
  • the reaction mixture was filtered, the filtered solid was washed with methanol, and the combined filtrate and washings evaporated in vacuo to give the crude product as an amber oil.
  • the crude product was purified by flash chromatography on silica (eluent diethyl ether) to give the free base of the product as a white glass.
  • the free base was dissolved in absolute ethanol (lOmL) and a 0.5M ethanolic hydrogen chloride solution (528 ⁇ l) was added. The solution was then cooled at 5°C for 16 hours and the crystalline precipitate collected by filtration and dried in vacuo, to yield the title compound as white crystals, (m.p. 202-3°C) .
  • the compounds of Examples 13 to 25 were prepared following the method of Example 12.
  • the amine starting material used in the preparation of the compound of Example 21 was prepared as follows:
  • reaction mixture was then evaporated in vacuo to dryness, re-suspended in saturated sodium chloride solution and neutralized with saturated sodium bicarbonate solution.
  • aqueous phase was then extracted with ethyl acetate (3X) and the combined organic extracts dried over magnesium sulfate, filtered and evaporated in vacuo to give the product as a white gum.
  • the compound of Example 31 was prepared by the method of Example 30.
  • the crude product was purified by flash chromatography on silica (eluent diethyl ether) to give the free base of the product as a yellow foam.
  • the free base was dissolved in 0.5M ethanolic hydrogen chloride (2mL) and then evaporated in vacuo to yield the title compound as a yellow solid (m.p. 227-8°C) .
  • the compound of Example 33 was prepared by the method of Example 32, except that, in step (iv), ethylamine (30% w/w solution in ethanol) and Hunigs base were used in place of sodium ethoxide .
  • Example 43 (i) The product of Example 43 (i) (500mg, 1.45 mmol) was dissolved in N-methylpyrrolidinone (7mL) and stirred at ambient temperature under nitrogen. Potassium- tert-butoxide (500mg, 4.4 mmol) was added followed by 2-mercaptoethanol (lmL) . The mixture was stirred and heated under nitrogen at 85°C for 4 hours. The reaction mixture was poured into aqueous ammonium chloride solution (150mL) and extracted into ethyl acetate. The organic phase was dried (magnesium sulfate), filtered and concentrated under reduced pressure.
  • Example 43 (i) The product of Example 43 (i) (1.2g, 3.36 mmol) was dissolved in N-methylpyrrolidinone (15mL) and stirred at ambient temperature under nitrogen. Potassium- tert-butoxide (560mg, 5 mmol) was added followed by 2-methoxyethanethiol (500mg, 5.4mmol) . The mixture was stirred and heated under nitrogen at 95°C for 48 hours. The reaction mixture was poured into aqueous ammonium chloride solution (150mL) and extracted into ethyl acetate. The organic phase was dried (magnesium sulfate), filtered and concentrated under reduced pressure.
  • N- (2, 3-dihydro -1H-inden-2-yl) -2- (methylsulfonyl) -5 , 6,7,8- tetrahydroquinazolin-4-amine (600mg, 1.75 mmol) was dissolved in N-methylpyrrolidinone (15mL) and stirred at ambient temperature under nitrogen. Potassium- ert-butoxide (560mg, 5 mmol) was added followed by 1-propanethiol (550mg, 7.25mmol) . The mixture was stirred and heated under nitrogen at 90°C for 18 hours. The reaction mixture was poured into aqueous ammonium chloride solution (150mL) and extracted into ethyl acetate.
  • N- (2 , 3-dihydro-lff-inden-2-yl) -2- (methylsulfonyl) -5 , 6 , 7 , 8- tetrahydroquinazolin-4-amine (660mg, 1.85 mmol) was dissolved in N-methylpyrrolidinone (15mL) and stirred at ambient temperature under nitrogen.
  • Potassium- ert-butoxide (265mg, 2.36 mmol) was added followed by l-mercapto-2- propanol (230mg, 2.5mmol) . The mixture was stirred and heated under nitrogen at 90°C for 18 hours.
  • 6-Benzyl-4-chloro-2- (methylthio) -6, 7-dihydro-5ff- pyrrolo [3 , 4-d] pyrimidine 6-Benzyl-2- (methylthio) -3,5,6, 7-tetrahydro-4ff-pyrrolo [3 , 4- d]pyrimidin-4-one (2.3g 8.4mmol) was dissolved in 1,2- dichloroethane (15mL) at ambient temperature under nitrogen, phosphorus oxychloride (20mL) was added and the mixture was heated under reflux under nitrogen overnight. The reaction mixture was concentrated under reduced pressure, taken up in chloroform and washed with cold dilute aqueous sodium hydrogen carbonate solution.
  • a 4mL Reacti-Vial was charged sequentially with a 0.24M solution of potassium tert-butoxide in dry N-methyl pyrrolidinone (0.5mL), a 0.24M solution of methyl thioglycolate in dry N-methyl pyrrolidinone (0.5mL) and a 0.06M solution of N- (2 , 3-dihydro-lH-inden-2-yl) -2- (methylsulfonyl) -5 , 6, 7 , 8-tetrahydroquinazolin-4-amine in dry N-methyl pyrrolidinone (0.5mL) .
  • the Vial was flushed with nitrogen and capped.
  • the contents of the Vial were heated to 80°C and stirred for 64 hours.
  • the Vial was cooled and its contents quenched with saturated aqueous ammonium chloride solution (ImL) .
  • Chloroform (ImL) was added, and the Vial was recapped and agitated vigorously to extract the organic material into the chloroform phase.
  • a 3mL cartridge containing an octadecyl C18 disc was charged with the contents of the Vial . Only the organic phase passed through the disc and this recovered solution was treated with methanol (ImL) .
  • the mixture was then passed through a 3mL cartridge containing 500mg of methanol-conditioned benzenesulfonic acid resin under gravity.
  • the crude product was purified by flash chromatography on silica (eluent 80% hexane / 20% ethyl acetate) to give the title compound as a white solid, (m.p. 132-133.5°C) .
  • N-methylpyrrolidinone (20mL) were heated to 90°C under N 2 for 48 hours.
  • the reaction mixture was allowed to cool to ambient temperature.
  • the reaction mixture was then poured into water and extracted with ethyl acetate.
  • the organic phase was washed with water then brine, then dried with magnesium sulfate, filtered and evaporated in vacuo to give a crude product.
  • the crude product was purified by flash chromatography on silica (eluent 80% hexane / 20% ethyl acetate) to give the title compound, as a cream solid (m.p.
  • 4-chloro-2-methyl-3 ,5,7, 8-tetrahydro-4H-thiino [ 4 , 3-d] - pyrimidine (380mg, 1.9mmol) and 2-aminoindane (303mg, 2.28mmol), Hunigs base (1.22g, 9.5mmol) and dimethylformamide (30mL) were stirred for 96 hours at ambient temperature. This mixture was diluted with ethyl acetate and washed with water then brine.
  • the organic phase was dried with magnesium sulfate, filtered and evaporated in vacuo to give the crude product.
  • the crude product was purified by prep HPLC at 254 nm, (3464.KR100-5C18) (95A/5W/0.2NH 3 ) .
  • the title compound was obtained as a light tan solid, (m.p. 147-149°C) .
  • the aqueous layer was extracted with 3:1 ethyl acetate / isopropyl alcohol containing a little methanol.
  • the combined organic extracts and initial layer were dried with magnesium sulphate, filtered and evaporated in vacuo .
  • the residue solid was triturated from acetonitrile/isopropyl alcohol. A cream solid was obtained, 72lmg .
  • Ethyl l-methyl-4-oxopiperidine-3-carboxylate (1.43g, 8.3lmmol), sodium carbonate (1.76g, 16.6mmol) and 5- ethylthiourea hydrobromide (2.3g, 12.4mmol) in distilled water (40mL) were stirred under nitrogen at ambient temperature for 24 hours. The mixture was saturated with sodium chloride and extracted with dichloromethane. The organic phase was dried with magnesium sulfate, filtered and evaporated in vacuo, to obtain 1.73g of a yellow oil.
  • the crude product was purified by flash chromatography on silica (eluent 20% ethyl acetate / 80% methanol) to give a yellow oil. This was taken up in ethanol (5mL) , and 0.5N ethanolic HCl (2mL) was added followed by diethyl ether (30mL) . A yellow solid crystallized on standing and was collected by filtration to give the title compound m.p. 253- 256°C.
  • Trifluoromethansulfonic anhydride (2.1 mL, 12.7 mmol) is added to a cool (0°C) solution of 2-Methyl-7 , 8-dihydro-5ff- thiopyrano [4, 3-d]pyrimidin-4-ol (2.1 g, 11.5 mmol) and Et 3 N (1.9 mL, 13.8 mmol) in 50 mL CH 2 C1 2 . After 0.5 h the solution is poured into H 2 0 followed by extraction with CH 2 C1 2 (3x75 mL) . The organics are combined, dried (Na 2 S0 ) , filtered and concentrated in vacuo to give the pure triflate.
  • Trifluoromethansulfonic anhydride (0.72 mL, 4.28 mmol) is added to a cool (0°C) solution of 2-Methoxy-7 , 8-dihydro-5ff- thiopyrano [4, 3-d]pyrimidin-4-ol (0.77 g, 3.895 mmol) and Et 3 N (0.65 mL, 4.67 mmol) in 10 mL CH 2 C1 2 . After 1 h the solution is poured into H 2 0 followed by extraction with CH 2 C1 2 (3x25 mL) . The organics are combined, dried (Na 2 S0 4 ) , filtered and concentrated in vacuo to give the triflate.
  • the crude triflate (0.79 g, 2.39 mmol) is dissolved in 10 mL NMP and Hunig's base (0.5 mL, 2.87 mmol) is added followed by 2- (2-chlorophenyl) -ethylamine (0.45 g, 2.87 mmol).
  • the solution is heated to 90°C for lh and poured into H 2 0 (50 mL) and extracted with EtOAc (3x25 mL) .
  • the organics are combined and washed with H 2 0 (4x25 mL) , brine (25 mL) dried with Na 2 S0 and concentrated in vacuo to provide the crude product.
  • 2-Ethyl-2-thiopseudourea hydrobromide (1.1 g, 6.0 mmol) is added to a solution of 1, 1, 4-Trioxo-hexahydro-l ⁇ 6 -thiopyran- 3-carboxylic acid methyl ester (0.8 g, 5.0 mmol) and K 2 C0 3 (3.45 g, 25.0 mmol) in 25 mL MeOH. After 24 hrs at RT the MeOH is removed in vacuo and the crude solid is neutralized
  • Trifluoro-methanesulfonic acid 2-ethylsulfanyl-6 , 6-dioxo- 5,6,7, 8-tetrahydro-6 ⁇ 6 -thiopyrano [4, 3-d]pyrimidin-4-yl ester.
  • Trifluoromethansulfonic anhydride (0.47 mL, 2.81 mmol) is added to a cool (0°C) solution of 2-Ethylsulfanyl-6, 6-dioxo- 5,6,7, 8-tetrahydro-6 ⁇ 6 -thiopyrano[4, 3-d]pyrimidin-4-ol (0.67 g, 2.56 mmol) and Et 3 N (0.43 mL, 3.1 mmol) in 10 mL CH 2 C1 2 . After 1 h the solution is poured into H 2 0 followed by extraction with CH 2 C1 2 (3x15 mL) .
  • Trifluoromethanesulfonic acid 2-ethylsulfanyl-6, 6-dioxo- 5,6,7, 8-tetrahydro-6 ⁇ 6 -thiopyrano [4, 3-d]pyrimidin-4-yl ester (100 mg, 0.25 mmol) is dissolved in 2.0 mL NMP and Hunig's base (0.05 mL, 0.31 mmol) is added followed by 2- (2- chlorophenyl) -ethylamine (48 mg, 0.31 mmol). The solution is heated to 90 °C for 2h and poured into H 2 0 (25 mL) and extracted with EtOAc (3x10 mL) .
  • This compound was synthesized in a manner similar to Example 104, except in place of benzoyl chloride, nicotinoyl chloride (31 mg, 0.17 mmol) was used.
  • The. crude product was purified by flash chromatography on HMDS treated silica gel (10% MeOH/EtOAc) to yield the free base of the title compound.
  • MS (ES) 419 (M + ) The free base is dissolved in a minimum amount of methylene chloride and an excess of a IM solution of HCl in diethyl ether is added. The diethyl ether, methylene chloride and excess HCl are then removed in vacuo to produce the title compound.
  • the free base is dissolved in a minimum amount of methylene chloride and an excess of a IM solution of HCl in diethyl ether is added.
  • the diethyl ether, methylene chloride and excess HCl are then removed in vacuo to produce the title compound.
  • Example 113 4- [2- (2-Chloro-phenyl) -ethylamino] -5,6,7, 8-tetrahydro- quinazoline-2-carboxylic acid (furan-2-ylmethyl) -amide trifluoroacetate .
  • 2-Mercaptoethyl-4-chloropyrido (2 , 3-d) pyrimidine 2-Mercaptoethyl-4-chloropyrido (2 , 3-d) pyrimidine.
  • a mixture of 2-chloro-4-hydroxypyrido (2 , 3-d) pyrimidine (600 mg, 3.30 mmol), sodium ethanethiolate (960 mg, 11.60 mmol), and N, N-dimethylformamide (20 mL) was warmed at 85-95°C for 2 h. The solution was cooled, concentrated, and treated with 5% methanol in methylene chloride (25 mL) . The resulting solid was dissolved in IN HCl ( 50 mL) , concentrated, and filtered with the aid of diethyl ether.
  • the product was the hydrochloride salt of 2-mercaptoethyl-4- hydroxypyrido (2, 3-d) pyrimidine, 1.5 g, and was used as such without further purification.
  • the hydroxypyrimidine thus obtained (1.5 g, 3.30 mmol, containing sodium chloride) was refluxed in phosphorus oxychloride (20 mL) for 3 h.
  • the reaction mixture was cooled, concentrated, and dissolved in chloroform (75 mL) .
  • the solution, containing some undissolved sodium chloride was added slowly to an ice cold solution of saturated sodium bicarbonate (75 mL) , the layers were separated, and the organic was backwashed with chloroform (25 mL) .
  • the intermediate title compound was prepared essentially by the method outlined in JACS, 77, 2256 (1955).
  • 2-Trifluoromethyl-4-hydroxypyrido (2 , 3-d) pyrimidine 2-aminonicotinic acid (2.5 g, 18.1 mmol), 2 , 2 , 2-trifluoroacetamide (6.2 g, 54.8 mmol), and l-methyl-2- pyrrolidinone (30 mL) was refluxed for 18 h. The mixture was cooled and added as such to a flash 65M silica gel cartridge, eluting with 2% methanol in methylene chloride gradually increasing to 5% methanol in methylene chloride. The crude desired was obtained containing l-methyl-2- pyrrolidinone.
  • Methyl 4-oxo-2H-3, 5, 6-trihydropyran-3-carboxylate was added to a lOOmL round bottom flask containing tetrahydro-4H-pyran-4-one (1 mL, 10.8 mmol) and heated at 110°C while a stream of nitrogen was blown over the mixture. After 30 min, 50 mL diethyl ether was added and the stirred vigorously for 30 min. The solids were then filtered and washed with thoroughly with diethyl ether.
  • the reaction mixture was diluted with EtOAc, washed with brine (2x) , dried with Magnesium sulfate, concentrated and purified on a Flash 40S cartridge (30% EtOAC/Hex) .
  • the appropriate fractions were concentrated and charged with 2 mL 0.5M ethanolic HCl and 1 mL methanol to aid solubilization. After one hour at RT the mixture was concentrated and triturated with diethyl ether. The resulting solids were filtered and dried under high vacuum at 60°C overnight to give 44mg (35%) of the title compound.
  • the title compound was synthesized in the same manner as the procedure set forth in example 120, except in the synthesis of its precursor, as described in example 119, instead of S- methyl isothiourea sulfate, 2-ethyl-2-thiopseudo urea HBr was used, and in the synthesis of the precursor following the procedure in example 120, instead of 2(2- chlorophenyl) ethylamine, 2 , 6-dichlorophenethyl amine was used.
  • Benzylethylmalonate, tetrabutylammonium iodide and Cs 2 C0 3 were azeotroped from toluene and dried under high vacuum prior to use.
  • 1- (2 , 2-Dimethyl-l , 1-diphenyl-l-silapropoxy) - 3-bromopropane (315 mg, 0.83mmol) was added to a dry 5mL round bottom flask, equipped with a reflux condenser, containing benzylethylmalonate (185 ⁇ L, 0.83 mmol), Cs 2 C0 3 (406 mg, 1.25mmol) and tetrabutylammonium iodide (lOmg) in anhydrous THF (2mL) and heated at reflux for 18 hrs.
  • 2-ethyl-2-thiopseudourea HBr (4.1g, 22. lmmol) and Hunig's base (7.7 mL, 44.2mmol) were added and the mixture was stirred at RT for 20 hrs to give a mixture of ethyl 5- (2 , 2-dimethyl-l, 1-diphenyl-l-silapropoxy) -2- [N- ( ethylthioiminomethyl ) carbamoyl]pentanoate and 5- [3- (2,2- dimethyl-1, 1-diphenyl-l-silapropoxy) propyl] -2- ethylthiopyrimidine-4, 6-diol within a fairly complex reaction mixture.
  • tert-Butyl 2-ethylthio-4- [ ( trifluoromethyl) sulfonyloxy] - 5,6,7, 8-tetrahydropyridino [4, 3-d] pyrimidine-6-carboxylate (900 mg, 2.1 mmol) was dissolved in dichloromethane. Added MCPBA (70%w/w, l.Og, 4.2 mmol) and stirred at RT for one hour. The mixture was diluted with dichloromethane and washed with brine and water, partitioned and purified on a Flash 40M cartridge to give 876 mg (88%) of the sulfone.
  • the sulfone was dissolved in NMP, added 2- (2-chlorophenyl) ethylamine (311 ⁇ L, 2.2 mmol) and Hunig's base (383 ⁇ L, 2.2 mmol) and stirred at RT for 30 min. The mixture was warmed to 100°C, added KCN (586 mg, 9.0 mmol) and stirred at that temperature forl ⁇ hrs. The mixture was cooled to RT, diluted with EtOAc, washed with brine and dried with Magnesium sulfate. Purified on a Flash 40L cartridge (25% EtOAc/Hexanes) to give 280 mg (38%) of the intermediate title compound.
  • the resulting dark oil was purified by column chromatography on silica gel (eluent ethyl acetate/hexane, 1:3) to give a dark oil which was taken up in ethanol (5 mL) .
  • 0.5M ethanolic HCl (4 mL) was then added followed by diethyl ether (30 mL) .
  • a white solid crystallized on standing and was collected by filtration to give the title compound, melting point 191-193°C.
  • the resulting yellow oil was purified by column chromatography on silica gel (eluent ethyl acetate/hexane, 1:6) to give a clear oil. This was taken up in ethanol (5 mL) , 0.5M ethanolic HCl (2 mL) was then added followed by diethyl ether (30 mL) . A white solid crystallized on standing and was collected by filtration to give the title compound, melting point 185-187°C.
  • the resulting dark oil was purified by column chromatography on silica gel (eluent ethyl acetate /hexane, 1:4) to give 180 mg of a yellow solid.
  • This material was dissolved in dimethylformamide (10 mL) and stirred at ambient temperature under nitrogen. Potassium- ert-butoxide (125 mg, 1.1 mmol) was added followed by mercaptoethanol (0.5 mL) . The mixture was stirred and heated under nitrogen at 85°C for 18 hours. The reaction mixture was poured into aqueous ammonium chloride solution (70 mL) and extracted into ethyl acetate. The organic phase was dried (magnesium sulfate), filtered and concentrated under reduced pressure.
  • the resulting oil was purified by column chromatography on silica gel (eluent ethyl acetate/hexane, 1:1) to give yellow oil. This was taken up in ethanol (5 mL) , 0.5M ethanolic HCl (3 mL) was then added followed by diethyl ether (50 mL) . A white solid crystallized on standing and was collected by filtration to give the title compound, melting point 202- 203°C.
  • the organic phase dried with magnesium sulfate, filtered and evaporated under vacuum to give the crude product.
  • the crude product was purified by flash chromatography on silica (eluent: 10% hexane, 90% ethyl acetate. Then the product was further purified by prep HPLC using KR100-5C18 column, (80% Acetonitrile/ 20% Water/0.2NH3) . A white solid was obtained of the title product (m.p.l98-200°C) .
  • the reaction mixture was cooled down to room temperature and diluted with aqueous ammonium chloride (20 mL) , and extracted with ethyl acetate (20 mL x 2 ) .
  • the combined organic phases were dried with anhydrous magnesium chloride, filtered through a Celite pad and the filtrate evaporated under vacuum.
  • the crude material was purified with flash chromatography on silica (eluent 10% hexane, 90% ethyl acetate).
  • the hydrochloride salt was formed with 0.5 M ethanolic hydrogen chloride to give the title compound as a white solid (m.p.211-213 °C) .
  • N- (4-methoxyphenyl) -2- (methylsulfonyl) -5,6,7,8- tetrahydro-4-quinazolinamine 600 mg, 1.8 mmol
  • potassium cyanide 600 mg
  • a cream solid was obtained as the title compound as a free base (m.p.178-180 °C) .
  • N- (4-methoxyphenyl) -2- (methylsulfonyl) -5,6,7,8- tetrahydro-4-quinazolinamine 500 mg, 1.5 mmol was added to potassium butoxide (500 mg) in l-methyl-2-pyrrolindone (20 mL) and 2-methoxyethanethiol (1.07 g, 11.7 mmol).
  • the procedure was following example 159 (ii), to give the title compound (m.p.172-174°C) .
  • N-bicyclo [2.2. l]hept-2-yl-2- (methylthio) -5 , 6, 7 , 8- tetrahydro-4-quinazolinamine (1.54 g, 5.3 mmol) was reacted as in example 159 (i), to give N-bicyclo [2.2. l]hept-2-yl-2- (methylsulfonyl) -5,6,7, 8-tetrahydro-4-quinazolinamine .
  • N-bicyclo [2, 2, 1] hept-2-yl-2- (ethylsulfonyl) -tetrahydro- 4-quinazolinamine 300 mg, 0.934 mmol was prepared in the similar manner as 159 (i) from the corresponding ethylthio, and then reacted using 2-methoxyethanethiol (670 mg,7.29 mmol), by the method in example 159 (ii), the crude compound was purified by prep HPLC (KR100-5C18) , (80% Acetonitrile /20% Water/0.2% NH 3 ) , the hydrochloride salt was prepared to obtain the title compound (m.p.133-135 °C) . Examples 170 to 172 These were prepared by the method described in example 12
  • the combined organic extracts were washed sequentially with water and saturated sodium chloride solution, then dried over magnesium sulfate, filtered and evaporated in vacuo to give the crude product as a pink oily solid.
  • the crude product was purified by flash chromatography on silica (eluent diethyl ether) to give the free base of the title compound as a white solid.
  • the free base was dissolved in 0.5 molar ethanolic hydrogen chloride and evaporated in vacuo to give the title compound as a white solid (m.p. 240-2°C) .
  • the combined organic extracts were washed sequentially with water and saturated sodium chloride solution, then dried over magnesium sulfate, filtered and evaporated in vacuo to give the crude product as a white oil.
  • the crude product was purified by flash chromatography on silica (eluent diethyl ether) to give the free base of the title compound as a white solid.
  • the free base was dissolved in 0.5 molar ethanolic hydrogen chloride and evaporated in vacuo to give the title compound as a white solid (m.p. 148°C dec.) .
  • Examples 179 to 188 The compound of examples 179 to 188 were prepared following the method of examples 173 and 178. Thiol side chains used in the preparation of some of the examples were prepared as follows:
  • the amine starting material used in the preparation of the compound of example 185 was prepared as follows: (i) 2- (2-Chlorophenyl) -2-methylpropanenitrile To a stirred suspension of 60% sodium hydride (pre-washed with petroleum spirit b.p.40-60°C) (6.1 g, 198 mmol) in dry dimethylformamide (100 mL) under nitrogen and cooled to 5°C was added, dropwise, a solution of (2-chlorophenyl) acetonitrile (10 g, 66 mmol) in dry dimethylformamide (20 mL) . The reaction mixture allowed to warm to ambient temperature and stirred for 45 minutes.
  • reaction mixture was then re-cooled to 5°C and a solution of iodomethane (12.3 mL, 198 mmol) in dry dimethylformamide (20 mL) was added dropwise.
  • the reaction mixture was allowed to warm to ambient temperature and stirred for a further 2 hours.
  • the reaction mixture was quenched with water and extracted with ethyl acetate (3x) .
  • the combined organic extracts were washed sequentially with water (2x) and saturated sodium chloride solution, then dried over magnesium sulfate, filtered and evaporated in vacuo to give the product as a yellow oil.
  • the reaction mixture was cooled to 5°C, cautiously quenched with water (250 mL) , basified with 2 molar sodium hydroxide and extracted with diethyl ether (3x) .
  • the combined organic extracts were washed sequentially with water and saturated sodium chloride solution, then dried over magnesium sulfate, filtered and evaporated in vacuo to give the crude product as a yellow oil.
  • the crude product was purified by fractional distillation to give the product as a clear oil (b.p. 240°C /2.8mbar) .
  • the amine starting material used in the preparation of the compound of example 186 was prepared as follows: (i) 2- (2-chlorophenyl) propanenitrile A mixture of (2-chlorophenyl) acetonitrile (5.0 g, 33 mmol), potassium carbonate (5.0 g, 36.2 mmol) and dimethyl carbonate (53.43 g, 594 mmol) was stirred in a sealed vessel at 180°C for 72 hours. The reaction mixture was allowed to cool, filtered, the filter cake washed with methanol and the combined filtrates and washings evaporated in vacuo to give an oil. The oil was partially dissolved in dichloromethane, the insoluble portion filtered and the filtrates evaporated in vacuo to give the crude product as an amber oil. The crude product was purified by fractional distillation to give the product as a clear oil.
  • the reaction mixture was cooled to 5°C, cautiously quenched with water (250 mL) , basified with 2 molar sodium hydroxide and extracted with diethyl ether (3x) .
  • the combined organic extracts were washed sequentially with water and saturated sodium chloride solution, then dried over magnesium sulfate, filtered and evaporated in vacuo to give the crude product as a yellow oil.
  • the crude product was purified by distillation in a bulb to bulb apparatus to give the product as a clear oil (b.p. 110°C / 2.0mbar) .
  • Example 190 The compound of example 190 was prepared by the method of example 189.

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Abstract

L'invention concerne l'utilisation de certains dérivés de pyrimidine 4-substituée en tant qu'antagonistes de mGluR1, de nouveaux dérivés de pyrimidine 4-substituée, des formulations pharmaceutiques contenant des dérivés de pyrimidine 4-substituée, un procédé de préparation de dérivés de pyrimidine 4-substituée et des intermédiaires utiles dans la préparation de dérivés de pyrimidine 4-substituée.
EP00971987A 1999-11-01 2000-10-19 Derives de pyrimidine substitues en position 4 actifs pharmaceutiquement Withdrawn EP1230225A2 (fr)

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AU1071301A (en) 2001-05-14
PE20010854A1 (es) 2001-08-28
AR026275A1 (es) 2003-02-05

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