WO2007039781A2 - New compounds - Google Patents
New compounds Download PDFInfo
- Publication number
- WO2007039781A2 WO2007039781A2 PCT/HU2006/000087 HU2006000087W WO2007039781A2 WO 2007039781 A2 WO2007039781 A2 WO 2007039781A2 HU 2006000087 W HU2006000087 W HU 2006000087W WO 2007039781 A2 WO2007039781 A2 WO 2007039781A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- oxadiazol
- alkyl
- phenyl
- methanone
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 163
- 238000000034 method Methods 0.000 claims abstract description 51
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 42
- 150000003839 salts Chemical class 0.000 claims abstract description 39
- 108010065028 Metabotropic Glutamate 5 Receptor Proteins 0.000 claims abstract description 34
- 102000012777 Metabotropic Glutamate 5 Receptor Human genes 0.000 claims abstract description 34
- 238000011282 treatment Methods 0.000 claims abstract description 31
- 239000002253 acid Substances 0.000 claims abstract description 30
- 230000001404 mediated effect Effects 0.000 claims abstract description 24
- 230000002265 prevention Effects 0.000 claims abstract description 22
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 20
- 239000001257 hydrogen Substances 0.000 claims abstract description 20
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 18
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 16
- 150000007513 acids Chemical class 0.000 claims abstract description 13
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 13
- 125000005843 halogen group Chemical group 0.000 claims abstract description 13
- 125000003118 aryl group Chemical group 0.000 claims abstract description 12
- 125000002252 acyl group Chemical group 0.000 claims abstract description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- 230000008569 process Effects 0.000 claims abstract description 11
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 10
- 125000004966 cyanoalkyl group Chemical group 0.000 claims abstract description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 10
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 9
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims abstract description 9
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims abstract description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 9
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims abstract description 7
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims abstract description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 38
- 208000035475 disorder Diseases 0.000 claims description 35
- -1 tetrahydrofuryl ,oxotetrahydrofuryl group Chemical group 0.000 claims description 19
- 208000002193 Pain Diseases 0.000 claims description 18
- 239000004480 active ingredient Substances 0.000 claims description 16
- 230000015572 biosynthetic process Effects 0.000 claims description 12
- 238000003786 synthesis reaction Methods 0.000 claims description 12
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 11
- QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical compound C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 claims description 11
- 208000012902 Nervous system disease Diseases 0.000 claims description 9
- 208000025966 Neurological disease Diseases 0.000 claims description 9
- 125000004043 oxo group Chemical group O=* 0.000 claims description 9
- 208000000094 Chronic Pain Diseases 0.000 claims description 7
- 208000005298 acute pain Diseases 0.000 claims description 7
- 230000004064 dysfunction Effects 0.000 claims description 7
- 125000005842 heteroatom Chemical group 0.000 claims description 7
- 230000002232 neuromuscular Effects 0.000 claims description 7
- 208000020016 psychiatric disease Diseases 0.000 claims description 7
- 210000001635 urinary tract Anatomy 0.000 claims description 7
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims description 6
- 230000001684 chronic effect Effects 0.000 claims description 6
- 125000002541 furyl group Chemical group 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 5
- 125000000335 thiazolyl group Chemical group 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- 241000282414 Homo sapiens Species 0.000 claims description 4
- 241000124008 Mammalia Species 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 239000000969 carrier Substances 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 4
- 125000001188 haloalkyl group Chemical group 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- SVDUTEHSNVPABA-UHFFFAOYSA-N [3-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]-cyclobutylmethanone Chemical compound ClC1=CC=CC(C=2N=C(ON=2)C2CN(CCC2)C(=O)C2CCC2)=C1 SVDUTEHSNVPABA-UHFFFAOYSA-N 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- OOINIBJVKPDFHK-UHFFFAOYSA-N 2-methyl-1-[2-[3-(3-methylphenyl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]propan-1-one Chemical compound CC(C)C(=O)N1CCCCC1C1=NC(C=2C=C(C)C=CC=2)=NO1 OOINIBJVKPDFHK-UHFFFAOYSA-N 0.000 claims 1
- UMKYTYRPUAXZHB-UHFFFAOYSA-N [2-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]pyrrolidin-1-yl]-(furan-2-yl)methanone Chemical compound ClC1=CC=CC(C=2N=C(ON=2)C2N(CCC2)C(=O)C=2OC=CC=2)=C1 UMKYTYRPUAXZHB-UHFFFAOYSA-N 0.000 claims 1
- BKCDBAMVMCCPAF-UHFFFAOYSA-N [2-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]pyrrolidin-1-yl]-cycloheptylmethanone Chemical compound ClC1=CC=CC(C=2N=C(ON=2)C2N(CCC2)C(=O)C2CCCCCC2)=C1 BKCDBAMVMCCPAF-UHFFFAOYSA-N 0.000 claims 1
- PFVHJRXWVNVUQZ-UHFFFAOYSA-N [2-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]pyrrolidin-1-yl]-thiophen-2-ylmethanone Chemical compound ClC1=CC=CC(C=2N=C(ON=2)C2N(CCC2)C(=O)C=2SC=CC=2)=C1 PFVHJRXWVNVUQZ-UHFFFAOYSA-N 0.000 claims 1
- WQHXSRFESPDMBW-UHFFFAOYSA-N furan-3-yl-[2-[3-(3-methylphenyl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]methanone Chemical compound CC1=CC=CC(C=2N=C(ON=2)C2N(CCCC2)C(=O)C2=COC=C2)=C1 WQHXSRFESPDMBW-UHFFFAOYSA-N 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 87
- 239000000243 solution Substances 0.000 description 57
- 239000000543 intermediate Substances 0.000 description 50
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- 239000011541 reaction mixture Substances 0.000 description 28
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 26
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 26
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- 102000016193 Metabotropic glutamate receptors Human genes 0.000 description 24
- 108010010914 Metabotropic glutamate receptors Proteins 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 230000004913 activation Effects 0.000 description 17
- 239000002585 base Substances 0.000 description 15
- 229940093499 ethyl acetate Drugs 0.000 description 15
- 235000019439 ethyl acetate Nutrition 0.000 description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
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- 238000002360 preparation method Methods 0.000 description 13
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
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- 239000000375 suspending agent Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 description 1
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical class [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 231100000886 tinnitus Toxicity 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 206010044652 trigeminal neuralgia Diseases 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 208000022934 urinary frequency Diseases 0.000 description 1
- 230000036318 urination frequency Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- 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
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to a new class of compounds, the processes for their preparation, the pharmaceutical formulations containing these compounds, as well as the process of treatments with these compounds.
- a major excitatory neurotransmitter in the mammalian central nervous system is the glutamate molecule, which binds to neurons in the CNS and thereby activating cell surface receptors.
- These receptors can be divided into two major classes, ionotropic and metabotropic glutamate receptors, based on the structural features of the receptor proteins.
- Metabotropic glutamate receptors mGluRs are G protein-coupled receptors that activate a variety of intracellular second messenger systems following the binding of glutamate.
- Activation of mGluRs in intact mammalian neurons elicits one or more of the following responses: activation of phospholipase C; increases in phosphoinositide (PI) hydrolysis; intracellular calcium release; activation of phospholipase D; activation or inhibition of adenyl cyclase; increases or decreases in the formation of cyclic adenosine monophosphate (cAMP); activation of guanylyl cyclase; increases in the formation of cyclic guanosine monophosphate (cGMP); activation of phospholipase A2; increases in arachidonic acid release; and increases or decreases in the activity of voltage- and ligand-gated ion channels.
- PI phosphoinositide
- intracellular calcium release activation of phospholipase D
- activation or inhibition of adenyl cyclase increases or decreases in the formation of cyclic adenosine monophosphate (cAMP
- mGluRl Eight distinct mGluR subtypes, termed mGluRl through mGluR ⁇ , have been identified by molecular cloning. Nakanishi, Neuron 13:1031 (1994), Pin et al., Neuropharmacology 34: (1995), Knopfel et al., J. Med. Chem. 38:1417 (1995). Further receptor diversity occurs via expression of alternatively spliced forms of certain mGluR subtypes. Pin et al., PNAS 89:10331 (1992), Minakami et al., BBRC 199:1136 (1994), JoIy et al., J. Neurosci. 15:3970 (1995). Metabotropic glutamate receptor subtypes may be subdivided into three groups,
- Group I, Group II, and Group III mGluRs based on amino acid sequence homology, the second messenger systems utilized by the receptors, and by their pharmacological characteristics.
- Group I mGluR comprises mGluRl, mGluR5 and their alternatively spliced variants.
- Metabotropic glutamate receptors have been implicated in a number of normal processes in the mammalian CNS. Activation of mGluRs has been shown to be required for induction of hippocampal long-term potentiation and cerebellar long-term depression. Bashir et al., Nature 363:347 (1993), Bortolotto et al., Nature 368:740 (1994), Aiba et al., Cell 79:365 (1994), Aiba et al., Cell 79:377 (1994). A role for mGluR activation in nociception and analgesia also has been demonstrated. Meller et al., Neuroreport 4: 879 (1993), Bordi and Ugolini, Brain Res. 871:223 (1999).
- Group I metabotropic glutamate receptors and mGluR5 in particular, have been suggested to play roles in a variety of pathophysiological processes and disorders affecting the CNS. These include stroke, head trauma, anoxic and ischemic injuries, hypoglycemia, epilepsy, neurodegenerative disorders such as Alzheimer's disease and pain (Schoepp et al., Trends Pharmacol. Sci. 14:13 (1993), Cunningham et al., Life Sci. 54:135 (1994), Hollman et al., Ann. Rev. Neurosci. 17:31 (1994), Pin et al., Neuropharmacology 34:1 (1995), Knopfel et ⁇ L, J. Med. Ckem.
- MGluR5-selective compounds such as 2-methyl-6-(phenylethynyl)- ⁇ yridine (“MPEP") are effective in animal models of mood disorders, including anxiety and depression (W.P.J.M Spooren et al., Br. J. Pharmacol. Exp. Ther., 295:1267-5 1275 (2000); E. Tatarczynska et al Br. J. Pharmacol., 132:1423-1430 (2001); A.
- Y 1 and Y 2 selected from the group consisting of hydrogen, halogen atom; C 1-4 alkyl, C 1-4 alkoxy, cyano and trifluoromethyl group, Q is -CH 2 - group or N; X 1 and X 2 are different and are independently selected from N and O; Z is -(CH 2 )n- group or S; n is 1 or 2;
- R is selected from the group consisting of optionally substituted C 1-7 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 cyanoalkyl, C 1-3 OC 1-3 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, Q ⁇ CNR ⁇ alkyl; an optionally substituted C 3-7 cycloalkyl, aryl, heteroaryl or saturated heterocyclic group; R 1 and R 2 are independently selected from hydrogen, C 1-7 alkyl or C 1-6 alkanoyl group - and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or pharmaceutically acceptable salts thereof formed with acids and bases.
- Another aspect of the present invention provides processes for the synthesis of compounds of formula (I).
- a further aspect of the present invention provides pharmaceutical compositions containing a therapeutically effective amount of a compound of formula (I) or enantiomers or racemates or diastereomers or geometric isomers or salts or hydrates or solvates thereof as active ingredient and pharmaceutically acceptable diluents, excipients and/or inert carriers.
- a further aspect of the present invention provides the use of a compound of formula (I) for the prevention and/or treatment of mgluR5 receptor mediated disorders, particularly neurological disorders, psychiatric disorders, acute and chronic pain and neuromuscular dysfunctions of the lower urinary tract.
- a further aspect of the present invention provides the use of a compound of formula (I) for the manufacture of a medicament for the prevention and/or treatment of mGluR5 receptor- mediated disorders, particularly neurological disorders, psychiatric disorders, acute and chronic pain and neuromuscular dysfunctions of the lower urinary tract.
- a further aspect of the present invention provides methods of prevention and/or treatment of mGluR5 receptor-mediated disorders with a compound of formula (I) 5 which means administering to a mammal to be treated - including human - effective amount/amounts of compounds of formula (I) of the present invention as such or as medicament.
- Y 1 and Y 2 selected from the group consisting of hydrogen, halogen atom; C 1-4 alkyl, C 1-4 alkoxy, cyano and trifiuoromethyl group,
- Q is -CH 2 - group or N; X 1 and X 2 are different and are independently selected from N and O;
- Z is -(CH 2 )n- group or S; n is 1 or 2;
- R is selected from the group consisting of optionally substituted C 1-7 alkyl, C 1-4 haloalkyl, Ci -4 hydroxyalkyl, Ci -4 cyanoalkyl, Ci -3 OC 1-3 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, Co ⁇ CNR ⁇ alkyl; an optionally substituted C 3-7 cycloalkyl, aryl, heteroaryl or saturated heterocyclic group;
- R 1 and R 2 are independently selected from hydrogen, C 1-7 alkyl or C 1-6 alkanoyl group - and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or pharmaceutically acceptable salts thereof formed with acids and bases.
- R 1 and R 2 are independently selected from hydrogen, C 1-7 alkyl or C 1-6 alkanoyl group - and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or pharmaceutically acceptable salts thereof formed with acids and bases.
- Y 1 and Y 2 selected from the group consisting of hydrogen, halogen atom, C 1-4 alkyl,
- Ci -4 alkoxy, cyano and trifiuoromethyl group is -CH 2 - group or N;
- X 1 and X 2 are different and are independently selected from N and O;
- Z is -(CH 2 )n- group or S; n is 1 or 2; R is selected from the group consisting of optionally substituted C 1-7 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 cyanoalkyl, C 1-3 OC 1-3 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, Co ⁇ CNR ⁇ alkyl;
- C 3-7 cycloalkyl group which is optionally substituted by one or more C 1-7 alkyl or oxo group
- aryl group which is optionally substituted by one C 1-7 alkyl or C 2-7 alkynyl group
- R 1 and R 2 are independently selected from hydrogen, C 1-7 alkyl or C 1-6 alkanoyl group - and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or pharmaceutically acceptable salts thereof formed with acids and bases.
- Y 1 and ⁇ Y 2 selected from the group consisting of hydrogen, halogen atom, C 1-4 alkyl, C 1-4 alkoxy, cyano and trifluoromethyl group;
- Q is -CH 2 - group or N
- X 1 and X 2 are different and are independently selected from N and O;
- Z is -(CH 2 )n- group or S; n is 1 or 2; R is selected from the group consisting of optionally substituted C 1-7 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 cyanoalkyl, C 1-3 OC 1-3 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, Co ⁇ CNR ⁇ alkyl;
- C 3-7 cycloalkyl group which is optionally substituted by one or more C 1-7 alkyl group; aryl group, which is optionally substituted by one C 1-7 alkyl or C 2-7 alkynyl group; an optionally substituted heteroaryl ring, wherein said heteroaryl ring is selected from the group of furyl, thiophenyl, pyridyl, oxopyrrolyl, oxothiazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, thiazolyl, thiadiazolyl, izoxazolyl group; 5-6 membered saturated heterocyclyl containing 1-3 heteroatom(s) optionally substituted with Ci_ 6 -alkyl or oxo group;
- R and R are independently selected from hydrogen, C 1-7 alkyl or C 1-6 alkanoyl group - and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or pharmaceutically acceptable salts thereof formed with acids and bases.
- Y 1 and Y 2 selected from the group consisting of hydrogen, halogen atom, C 1-4 alkyl, C 1-4 alkoxy, cyano and trifluoromethyl group;
- Q is -CH 2 - group or N;
- X 1 and X 2 are different and are independently selected from N and O;
- Z is -(CH 2 )n- group or S; n is 1 or 2;
- R is selected from the group consisting of C 1-7 alkyl, C 1-4 haloalkyl, C 1-4 cyanoalkyl, C 1-3 OC 1- 3 alkyl, C 2-7 alkynyl, C 0 . 2 (NR 1 R 2 )alkyl; an optionally substituted heteroaryl ring, wherein said heteroaryl ring is selected from the group of furyl, thiophenyl, pyridyl, thiazolyl, pyrrolyl group; tetrahydrofuryl or oxotetrahydrofuryl group;
- R 1 and R 2 are independently selected from hydrogen, C 1-7 alkyl or C 1-6 alkanoyl group - and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or pharmaceutically acceptable salts thereof formed with acids and bases.
- C 1-6 means a carbon containing linear or branched group having 1, 2, 3, 4, 5 or 6 carbon atoms.
- alkyl as well as other groups having the prefix “alk” such as, for example, alkoxy, alkanoyl, alkenyl, alkynyl and the like, means carbon chains which may be linear or branched or combinations thereof.
- alkyl groups examples include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl and the like.
- alkenyl includes both straight and is branched chain alkenyl groups.
- C 2 - 7 alkenyl refers to an alkenyl group having 2 to 1 carbon atoms and one to three double bonds, and may be, but is not limited to vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, crotyl, pentenyl, isopentenyl or hexenyl.
- alkynyl includes both straight and branched chain alkynyl groups.
- C 2-7 alkynyl refers to a group having 2 to 7 carbon atoms and one or two triple bonds, and may be, but is not limited to ethynyl, propargyl, butynyl, isobutynyl, pentynyl, isopentynyl or hexynyl.
- cycloalkyl refers to an optionally substituted, saturated cyclic hydrocarbon ring system.
- C 3-7 cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
- aryl means an aromatic substituent which is a single ring or multiple rings fused together. When formed of multiple rings, at least one of the constituent rings is aromatic.
- the preferred aryl substituents are phenyl and naphthyl groups.
- hetero unless specifically stated otherwise includes one or more O, S, or
- heterocyclyl and heteroaryl include ring systems that contain one or more O, S, or N atoms in the ring, including mixtures of such atoms.
- the hetero atoms replace ring carbon atoms.
- heteroaryl rings include pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, and tetrazolyl.
- heterocyclyl examples include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, imidazolinyl, pyrolidin-2-one, piperidin 2-one, and thiomorpholinyl groups.
- halogen includes fluorine, chlorine, bromine and iodine atoms.
- halo may be fluoro, chloro, bromo or iodo.
- haloalkyl means an alkyl group as defined above, wherein at least one or up to all of the hydrogen atoms are replaced with a halogen.
- C 1-6 haloalkyl may include, but is not limited to fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, bromopropyl.
- C 1 ⁇ O haloalkyl may include, but is not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy group.
- optionally substituted is intended to include both substituted and unsubstituted groups.
- optionally substituted cycloalkyl could represent a methylcyclohexyl or a cyclohexyl ring.
- pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
- the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases.
- the salts formed with bases especially important are the salts formed with alkali metals, e.g. sodium, potassium, alkali-earth metals, e.g. calcium and magnesium, as well as with ammonia or organic amines.
- the latter bases can have further substituents, e.g. hydroxy or amino groups, which can influence e.g. the solubility and the handling of the product.
- Both organic and inorganic acids can be used for the formation of acid addition salts. Suitable inorganic acids can be e.g. hydrochloric acid, sulfuric acid and phosphoric acid. Representatives of monovalent organic acids can be e.g. formic acid, acetic acid, trifmoroacetic acid, propionic acid, and different butyric acids, valeric acids and capric acids. Representatives of bivalent organic acids can be e.g. oxalic acid, malonic acid, maleic acid, fumaric acid and succinic acid.
- organic acids can also be used, such as hydroxy acids e.g. citric acid, tartaric acid, or aromatic carboxylic acids e.g. benzoic acid or salicylic acid, as well as aliphatic and aromatic sulfonic acids e.g. methanesulfonic acid and p-toluenesulfonic acid.
- hydroxy acids e.g. citric acid, tartaric acid
- aromatic carboxylic acids e.g. benzoic acid or salicylic acid
- aliphatic and aromatic sulfonic acids e.g. methanesulfonic acid and p-toluenesulfonic acid.
- aliphatic and aromatic sulfonic acids e.g. methanesulfonic acid and p-toluenesulfonic acid.
- acid addition salts are pharmaceutically acceptable acid addition salts.
- activated acid means an activated Boc-protected amino acid, N-acylated amino acid or properly substituted benzoic acid which can be activated as follows: i) as an acid chloride formed from the acid using a suitable reagent such as oxalyl chloride or thionyl chloride; ii) as a mixed anhydride formed with alkyl chloroformate; iii) using traditional methods to activate acids in amide coupling reactions such as CDI, EDC, HBTU.
- Compounds described herein can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers.
- the present invention includes all such possible diastereomers as well as their racemic mixtures and their substantially pure enantiomers.
- Especially important compounds of formula (I) of the present invention are the following: ⁇ 4-[3-(3-chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-thiazolidin-3-yl ⁇ -(5-methyl-thiophen-2-yl)- methanone, ⁇ 2-[3-(3-chloro- ⁇ henyl)-[l,2,4]oxadiazol-5-yl]- ⁇ yrrolidin-l-yl ⁇ -(5-methyl-thio ⁇ hen-2-yl)- methanone,
- compositions comprising a compound represented by formula (I) and/or enentiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts thereof as an active ingredient and one or more pharmaceutically acceptable carrier.
- the compounds of formula (I) and/or enentiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts thereof may be administered by any convenient method, for example by oral, parenteral (including subcutaneous, intramuscular, and intravenous), buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly.
- the pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
- the compounds of formula (I) and/or enentiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts thereof which are active when given orally can be formulated as liquids or solids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
- a liquid formulation of the compounds of formula (I) and/or enentiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts thereof generally consist of a suspension or solution of the compound of formula (I) or physiologically acceptable salts thereof in a suitable liquid carrier(s) for example an aqueous solvent, such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil.
- a suitable liquid carrier(s) for example an aqueous solvent, such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil.
- the formulation may also contain a suspending agent, preservative, flavouring or colouring agent.
- a composition in the solid form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.
- suitable pharmaceutical carrier(s) include lactose, terra alba, sucrose, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid etc.
- tablets may be coated by standard aqueous or nonaqueous techniques.
- a tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
- Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent.
- a composition in the solid form of a capsule can be prepared using routine encapsulation procedures.
- pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatine capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatine capsule.
- Typical parenteral compositions consising of a solution or suspension of the compound of formula (I) and/or enentiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts thereof in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
- a sterile aqueous carrier or parenterally acceptable oil for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
- the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
- compositions of the present invention for nasal administration containing a compound of formula (I) and/or enentiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts thereof may conveniently be formulated as aerosols, drops, gels and powders.
- Aerosol formulations of the present invention typically comprise a solution or fine suspension of the compound of formula (I) in a physiologically acceptable aqueous or nonaqueous solvent and are usually presented in a single or multidose quantities in sterile form is a sealed container, which can take the form of a cartridge or refill for use with an atomizing device.
- the sealed container may be a unitary dispensing device, such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once the contents of the container have been exhausted.
- the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas, such as compressed air or an organic propellant, such as a fluorochlorohydrocarbon.
- the aerosol dosages form can also take the form af a pump- atomiser.
- compositions of the present invention containing a compound of formula (I) are suitable for buccal or sublingual administration including tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier, such as sugar and acacia, tragacanth, or gelatine, glycerin etc.
- a carrier such as sugar and acacia, tragacanth, or gelatine, glycerin etc.
- Compositions of the present invention containing a compound of formula (I) and/or enentiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts thereof for rectal administration are conveniently in the form of suppositories containing a conventional suppository base, such as cocoa butter and other materials commonly used in the art.
- compositions of the present invention containing a compound of formula (I) and/or enentiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts thereof for transdermal administration include ointments, gels and patches.
- compositions of the present invention containing a compound of formula (I) and/or enentiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts thereof is preferably in the unit dose form, such as tablet, capsule or ampoule.
- Each dosage unit of the present invention for oral administration contains preferably from 0.1 to 500 mg of a compound of formula (I) and/or enentiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts thereof.
- Each dosage unit of the present invention for parenteral administration contains preferably from 0.1 to 500 mg of a compound of formula (I) and/or enentiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts thereof.
- physiologically acceptable compounds of formula (I) and/or enentiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts thereof can be administered in a daily dosage regimen.
- mGluR5 mediated disorders such as schizophrenia, anxiety, depression, panic, bipolar disorders, and circadian disorders or chronic and acute pain disorders
- the dosage levels from about 0,01 mg/kg to about 140 mg/kg of body weight per day are useful or alternatively about 0.5 mg to about 7 g per patient per day.
- the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
- a formulation intended for the oral administration to humans may conveniently contain from about 0.5 mg to about 5 g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
- Unit dosage forms will generally contain between from about 1 mg to about 1000 mg of the active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 25-300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.
- the compounds of formula (I) of the present invention have been found to exhibit biological activity at mGluR5 receptors and are expected to be useful in the treatment of mGluR5 mediated disorders.
- the compounds according to the present invention or salts thereof exhibit a high degree of potency and selectivity for individual metabotropic glutamate receptor (mGluR) subtypes.
- mGluR metabotropic glutamate receptor
- the compounds according to the present invention that are potent and selective for mGluR5 receptor.
- the compounds of the present invention are expected to be useful in the prevention and/or treatment of conditions associated with excitatory activation of an mGluR5 receptor and for inhibiting neuronal damage caused by excitatory activation of an mGluR5 receptor.
- the compounds may be used to produce an inhibitory effect of mGluR5, in mammals, including man.
- the compounds of the invention are well suited for the prevention and/or treatment of mGluR5 receptor-mediated disorders such as acute and chronic neurological and psychiatric disorders, chronic and acute pain disorders and neuromuscular dysfunctions of the lower urinary tract.
- the dose required for the therapeutic or preventive treatment of a particular disorder will necessarily be varied depending on the host treated and the route of administration.
- the invention relates to compounds of formula (I) as defined hereinbefore, for use in therapy.
- the invention relates to compounds of formula (I) as defined hereinbefore, for use in prevention and/or treatment of mGluR5 receptor-mediated disorders.
- the invention relates to compounds of formula (I) as defined hereinbefore, for use in prevention and/or treatment of neurological disorders.
- the invention relates to compounds of formula (I) as defined hereinbefore, for use in prevention and/or treatment of psychiatric disorders.
- the invention relates to compounds of formula (I) as defined hereinbefore, for use in prevention and/or treatment of chronic and acute pain disorders.
- the invention relates to compounds of formula (I) as defined hereinbefore, for use in prevention and/or treatment of neuromuscular dysfunctions of the lower urinary tract.
- the invention relates to compounds of formula (I) as defined hereinbefore, for use in prevention and/or treatment of pain related to migraine, inflammatory pain, neuropathic pain disorders such as diabetic neuropathies, arthritis and rheumatoid diseases, low back pain, post-operative pain and pain associated with various conditions including angina, in renal or biliary colic, menstruation, migraine and gout.
- the invention relates to compounds of formula (I) as defined hereinbefore, for use in prevention and/or treatment of Alzheimer's disease senile dementia, AIDS-induced dementia Parkinson's disease, amyotrophic lateral sclerosis, Huntington's Chorea, migraine, epilepsy, schizophrenia, depression, anxiety, acute anxiety, obsessive compulsive disorder, ophthalmological disorders such as retinopathies, diabetic retinopathies, glaucoma, auditory neuropathic disorders such as tinnitus, chemotherapy induced neuropathies, post-herpetic neuralgia and trigeminal neuralgia, tolerance, dependency, Fragile X, autism, mental retardation, schizophrenia and Down's Syndrome.
- the invention relates to compounds of formula (I) as defined hereinbefore, for use in prevention and/or treatment of stroke, head trauma, anoxic and ischemic injuries, hypoglycemia, cardiovascular diseases and epilepsy.
- the compounds are also well suited for the treatment of neuromuscular dysfunction of the lower urinary tract, such as urinary urgency, overactive bladder, greater urinary frequency, reduced urinary compliance, cystitis, incontinence, enuresis and dysuria.
- the present invention relates also to the use of a compound of formula (I) as defined hereinbefore, in the manufacture of a medicament for the prevention and/or treatment of mGluR5 receptor-mediated disorders and any disorder listed above.
- the invention also provides a method of treatment and/or prevention of mGluR5 receptor mediated disorders and any disorder listed above, in a patient suffering from, or at risk of, said condition, which comprises administering to the patient an effective amount of a compound of formula (I), as hereinbefore defined.
- the term “therapy” includes treatment as well as prevention, unless there are specific indications to the contrary.
- the terms “therapeutic” and “therapeutically” should be construed accordingly.
- the term “antagonist” means a compound that by any means, partly or completely blocks the transduction pathway leading to the production of a response by the ligand.
- disorder means any condition and disease associated with metabotropic glutamate receptor activity.
- the pharmacological properties of the compounds of the invention were analyzed by determining binding affinity of the compounds to a binding site on mGluR5 receptors and by fluorimetric assays of intracellular calcium concentration to determine functional activity.
- Another aspect of the present invention provides a process for preparing a compound of formula (I) or salt thereof.
- R 5 R 3 or R 4 ' independently
- Amidoximes, compounds of formula (III) can be prepared using synthetic chemical methods well known in the art (see C. Ainsworth et al., J. Med. Chem., 1967, 10, 208-211) by reacting suitable nitriles and hydroxylamine hydrochloride in refluxing methanol or ethanol in the presence of an appropriate base, for example an alkali metal carbonate, such as potassium carbonate or an alkali such as sodium hydroxide.
- an alkali metal carbonate such as potassium carbonate
- alkali such as sodium hydroxide
- Pyridine-2-aldoxime and pyridine-3-aldoxime are commercially available.
- Boc protected piperidine and pyrrolidine-aldoximes can be prepared by the above mentioned procedure using commercially available nitriles.
- Boc protected or N-acylated piperidine and pyrrolidine-nitriles can be prepared from carboxamides under mild conditions (pi. S.N. Banerjee et al. Int. J. Peptid Protein Res. 1979, 14, 234-246).
- the acid (R 5 COOH) can be activated as follows: i) as an acid chloride formed from the acid using a suitable reagent such as oxalyl chloride or thionyl chloride; ii) as a mixed anhydride formed with alkyl chloroformate; iii) using traditional methods to activate acids in amide coupling reactions such as CDI, EDC, HBTU.
- Compounds of formula (V), 3,5-disubstituted-[l,2,4]oxadiazoles can be prepared by cyclocondensation of a compound of formula (IV).
- Preparation of compounds of formula (V) can be carried out by cyclocondensation of O-acylamidoximes (IV) in ether type solvent (preferable THF) in the presence of tetra- butylammonium salt catalyst (TBAF) at room temperature or by heating as it is known from the literature (see: A.R. Gangloff et.al, Tetrahedron Lett., 2001, 42, 1441-43), or in the presence of a catalyst (e.g. CDI) in dimethylformamide (Deegan TX. et al. Bioorg. Med. Chem. Lett., 1999, 9, 209-212).
- a catalyst e.g. CDI
- Compounds of formula (VII) can be obtained by deprotecting compound of formula (VI) by acidic hydrolysis in an appropriate solvent such as ethyl acetate or dioxane saturated with hydrogen chloride gas.
- Compounds of formula (I) can be prepared by acylation (RCOOH) of the secondary amines of general formula (VII).
- Acylation of compounds of formula (VII) can be accomplished with an acid (RCOOH) as a reagent, which is activated by the above mentioned methods, preferably by EDC in the presence of a base such as sodium hydrogencarbonate or TEA.
- the acylation can be carried out with a proper aminocarbamoyl chloride or isocyanide.
- Compounds of general formula (I) can also be prepared by the following method: compounds of formula (Ha) can be prepared from N-acylated amino acids according to the above mentioned procedure. Amidoximes, compounds of formula (Ilia), can be prepared from nitriles of formula (Ila) according to the method described above. Compounds of formula (IVa) can be prepared from compounds of formula (Ilia) by acylation with a properly substituted benzoic acid (R 3 COOH). Cyclocondensation of the above mentioned O- acylamidoximes (FVa) results in compounds of general formula (Ia).
- compounds of general formula (I) can also be prepared by the following method: compounds of formula (IVb) can be prepared by reacting a compound of formula (HIb) and an N-acylated amino acid (R 4 COOH). Cyclocondensation of the above mentioned O- acylamidoximes (IVb) results in compounds of general formula (Ib).
- the final product, compound (I) can be obtained in appropriate purity therefore after concentration of the solution the biological experiments can be carried out without further purification.
- Optical purities of the enantiomers were controlled by HPLC, using DAICEL Chiracel ODH chiral column.
- Eluent a mixture of n-hexane/2-propanol/methanol (90: 5: 5 v/v) containing 0.05 % diethylamine.
- Flow rate 1 ml/min, detection: at 220 nm.
- 1 H NMR spectra were recorded on a Varian Unity Inova 300 or on a Varian Unity Inova 500 spectrometer. Chemical shifts are reported in parts per million relative to TMS as internal standard.
- the reaction mixture was diluted with dichloromethane (10 ml), washed with 1 N aqueous hydrochloric acid (10 ml), water (10 ml) and 5% aqueous sodium hydrogencarbonate solution (10 ml). The organic layer was dried, filtered and concentrated to yield 0.188 g (82 %) of the title compound as oil.
- Boc-thioproline (1.4 g, 6 mmol) was dissolved in dry THF (12 ml), CDI (1.07 g, 6.6 mmol) was added, and the mixture was stirred at 25 0 C for 30 minutes.
- 3-Chloro-N-hydroxy- benzamidine (1.05 g, 6.15 mmol) was added (example 1, intermediate A), the reaction mixture was stirred for 1.5 hours and concentrated. The residue was dissolved in dichloromethane, washed with 1 N aqueous hydrochloric acid and brine. After drying and concentration the isolated O-acylated amidoxime was dissolved in dry THF and TBAF (1.575 g, 6 mmol) was added.
- N-(Furan-2-carbonyl)-pyrrolidine-2-carboxylic acid (0.31 g, 1.5 mmol) (Laduree, D.et al, J.Med.Chem.,1989, 32, 456-461) was dissolved in DMF (3 ml), CDI (0.3 g, 1.65 mmol) was added, and the reaction mixture was stirred at 25 °C for 30 minutes, then 3-chloro- N-hydroxy-benzamidine (0.28 g, 1.65 mmol; Example 1, Intermediate A) was added.
- Boc-D-proline (0.645 g, 3 mmol) was dissolved in 6 ml dry THF and CDI (0.535 g,
- NMM 22 ml, 2 mmol
- isobutyl chloroformate (0.26 ml, 2 mmol) were added at 0 0 C and the reaction mixture was stirred at 0 0 C for half an hour.
- a solution of l-(tert- butoxycarbonyl)-N-hydroxy ⁇ piperidine-2-carboxamidine (Intermediate C; 0.5 g, 2 mmol) in dry DMF was added, and the reaction mixture was stirred for 1 hour, during this time the temperature reached 25 °C.
- TBAF 0.1 g, 0.4 mmol
- nipasol 0.005-0.02 % of nipasol, 0.01-0.5 % of carbopol (polyacrilic acid), 0.1-5 % of 96 % ethanol,
- flavoring agent 20-70 % of sorbitol (70 % aqueous solution) and 30-50 % of distilled water.
- suppositories For each suppository 0.01-15% of active ingredient of formula (I) and 1-20% of lactose were thoroughly mixed, then 50-95% of adeps pro suppository (for example Witepsol 4) was melted, cooled to 35 °C and the mixture of active ingredient and lactose was mixed in it with homogenizator. The obtained mixture was mould in cooled forms.
- adeps pro suppository for example Witepsol 4
- Lyophilized powder ampoule compositions A 5 % solution of mannitol or lactose was made with bidistilled water for injection use, and the solution was filtered so as to have sterile solution.
- a 0.01-5 % solution of the active ingredient of formula (I) was also made with bidistilled water for injection use, and this solution was filtered so as to have sterile solution. These two solutions were mixed under aseptic conditions, filled in 1 ml portions into ampoules, the content of the ampoules was lyophilized, and the ampoules were sealed under nitrogen. The contents of the ampoules were dissolved in sterile water or 0.9 % (physiological) sterile aqueous sodium chloride solution before administration.
- MGluR5 receptor binding was determined according to Gasparini et.al. (Bioorg.
- rat cerebro-cortical membrane preparation was used to determine the binding characteristics of reference compounds and novel compounds to the rat mGluR5.
- the Al 8 cell line expressing hmGluR5a (purchased from Euroscreen) was used to determine binding characteristics of the chemical compounds to the human mGluR5a receptor.
- radioligand [ 3 H]-M-MPEP (2 nM) was used. The nonspecific binding was determined in the presence of 10 ⁇ M M-MPEP. Assessment of functional activity
- Chinese hamster ovary (CHO) cells stably expressing recombinant human mGluR5a (CH0-mGluR5a, purchased from Euroscreen) receptors were cultured in F12 medium containing 10% FCS, 1% antibiotic antimycotic solution, 400 ⁇ g/ml G418, 250 ⁇ g/ml zeocin, 5 ⁇ g/ml puromycin.
- Cells were kept at 37 0 C in a humidified incubator in an atmosphere of 5% C ⁇ 2 /95% air and were passaged three times a week.
- Cells were plated at 2.5-3.5x 10 4 cell/well on standard 96-well microplates, receptor expression was induced by adding 600 ng/ml doxycycline on the next day. The calcium measurements were carried out 16-24 hours after the addition of the inducing agent.
- cytosolic calcium concentration [Ca ]j ) were carried out on primary neocortical cultures, and on CH0-mGluR5a cells stably expressing human mGluR5a receptors.
- assay buffer 145 niM NaCl, 5 niM KCl, 2 mM MgCl 2 , 2 mM CaCl 2 , 10 mM HEPES, 20 mM D
- the assay buffer also contained TTX (0.5 ⁇ M, to suppress spontaneous oscillations of [Ca 2+ ]O- After incubation at 37 °C for 10-20 min. baseline and agonist-evoked changes of [Ca 2+ ]* were measured column by column with a plate reader fluorimeter (FlexStation II, Molecular Devices). Excitation and detection of emission was carried out from the bottom of the plate. The whole measurement process was performed at 37 0 C and was controlled by custom software. Inhibitory potency of the test compounds was assessed by measuring the reduction in the agonist-evoked [Ca 2+ ]j-elevation in the presence of different concentrations of the compounds.
- DHPG was used as agonist for both cultures, the concentration was 20 ⁇ M for the neocortical cultures.
- the EC 8 o-values were derived from daily determined dose-response curves. Fluorescence data were expressed as ⁇ F/F (fluorescence change normalized to baseline).
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Abstract
The present invention relates to new compounds of formula (I) wherein Y1 and Y2 selected from the group consisting of hydrogen, halogen atom; C1-4 alkyl, C1-4 alkoxy, cyano and trifluoromethyl group, Q is -CH- group or N; X1 and X2 are different and are independently selected from N and O; Z is -(CH2)n- group or S; n is 1 or 2; R is selected from the group consisting of optionally substituted C1-7 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, C1-3 OC1-3 alkyl, C2-7 alkenyl, C2-7 alkynyl, C0-2(NR1R2)alkyl; an optionally substituted C3-7 cycloalkyl, aryl, heteroaryl or saturated heterocyclyl; R1 and R2 are independently selected from hydrogen, C1-7 alkyl or C1-6 alkanoyl group - and/or enentiomers and/or racemates and/or diastereomers and/or geometric isomers and/or pharmaceutically acceptable salts thereof formed with acids and bases, to the processes for producing said compounds, to pharmaceutical compositions containing said compounds and to their use in the prevention and/or treatment of mGluR5 receptor-mediated disorders.
Description
NEW COMPOUNDS
FIELD OF THE INVENTION
The present invention relates to a new class of compounds, the processes for their preparation, the pharmaceutical formulations containing these compounds, as well as the process of treatments with these compounds.
BACKGROUND OF THE INVENTION
A major excitatory neurotransmitter in the mammalian central nervous system (CNS) is the glutamate molecule, which binds to neurons in the CNS and thereby activating cell surface receptors. These receptors can be divided into two major classes, ionotropic and metabotropic glutamate receptors, based on the structural features of the receptor proteins. Metabotropic glutamate receptors (mGluRs) are G protein-coupled receptors that activate a variety of intracellular second messenger systems following the binding of glutamate. Activation of mGluRs in intact mammalian neurons elicits one or more of the following responses: activation of phospholipase C; increases in phosphoinositide (PI) hydrolysis; intracellular calcium release; activation of phospholipase D; activation or inhibition of adenyl cyclase; increases or decreases in the formation of cyclic adenosine monophosphate (cAMP); activation of guanylyl cyclase; increases in the formation of cyclic guanosine monophosphate (cGMP); activation of phospholipase A2; increases in arachidonic acid release; and increases or decreases in the activity of voltage- and ligand-gated ion channels. (Schoepp et al, Trends Pharmcol. Sci. 14:13 (1993), Schoepp, Neurochem. Int. 24:439 (1994), Pin et al., Neuropharmacology 34:1 (1995), Bordi and Ugolini, Prog. Neurobiol. 59:55 (1999).
Eight distinct mGluR subtypes, termed mGluRl through mGluRδ, have been identified by molecular cloning. Nakanishi, Neuron 13:1031 (1994), Pin et al., Neuropharmacology 34: (1995), Knopfel et al., J. Med. Chem. 38:1417 (1995). Further receptor diversity occurs via expression of alternatively spliced forms of certain mGluR subtypes. Pin et al., PNAS 89:10331 (1992), Minakami et al., BBRC 199:1136 (1994), JoIy et al., J. Neurosci. 15:3970 (1995).
Metabotropic glutamate receptor subtypes may be subdivided into three groups,
Group I, Group II, and Group III mGluRs, based on amino acid sequence homology, the second messenger systems utilized by the receptors, and by their pharmacological characteristics. Group I mGluR comprises mGluRl, mGluR5 and their alternatively spliced variants.
Attempts at elucidating the physiological roles of Group I mGluRs suggest that activation of these receptors elicits neuronal excitation. Evidence indicates that this excitation is due to direct activation of postsynaptic mGluRs, but it also has been suggested that activation of presynaptic mGluRs occurs, resulting in increased neurotransmitter release. (Pin et al., Neuropharmacology 34:1(1995), Watkins et al., Trends Pharmacol. Sci. 15:33 (1994).
Metabotropic glutamate receptors have been implicated in a number of normal processes in the mammalian CNS. Activation of mGluRs has been shown to be required for induction of hippocampal long-term potentiation and cerebellar long-term depression. Bashir et al., Nature 363:347 (1993), Bortolotto et al., Nature 368:740 (1994), Aiba et al., Cell 79:365 (1994), Aiba et al., Cell 79:377 (1994). A role for mGluR activation in nociception and analgesia also has been demonstrated. Meller et al., Neuroreport 4: 879 (1993), Bordi and Ugolini, Brain Res. 871:223 (1999).
Further, Group I metabotropic glutamate receptors and mGluR5 in particular, have been suggested to play roles in a variety of pathophysiological processes and disorders affecting the CNS. These include stroke, head trauma, anoxic and ischemic injuries, hypoglycemia, epilepsy, neurodegenerative disorders such as Alzheimer's disease and pain (Schoepp et al., Trends Pharmacol. Sci. 14:13 (1993), Cunningham et al., Life Sci. 54:135 (1994), Hollman et al., Ann. Rev. Neurosci. 17:31 (1994), Pin et al., Neuropharmacology 34:1 (1995), Knopfel et άL, J. Med. Ckem. 38:1417 (1995); Spooren et al., Trends Pharmacol. Sci. 22:331 (2001), Gasparini et al. Curr. Opin. Pharmacol. 2:43 (2002), Neugebauer Pain 98:1 (2002)). MGluR5-selective compounds such as 2-methyl-6-(phenylethynyl)-ρyridine ("MPEP") are effective in animal models of mood disorders, including anxiety and depression (W.P.J.M Spooren et al., Br. J. Pharmacol. Exp. Ther., 295:1267-5 1275 (2000); E. Tatarczynska et al Br. J. Pharmacol., 132:1423-1430 (2001); A. Klodzynska et al, Pol. J. Pharmacol., 132:1423-1430 (2001)). Most of the pathology in these conditions is thought to be due to excessive glutamate-induced excitation of CNS neurons. As Group I mGluRs appear to increase glutamate-mediated neuronal excitation via postsynaptic mechanisms and
enhanced presynaptic glutamate release, their activation probably contributes to the pathology. Therefore, selective antagonists of Group I mGluR receptors could be therapeutically beneficial, especially as neuroprotective agents, analgesics or anticonvulsants.
Compounds that have the above mentioned pharmacological activity are described by various researchers.
International Patent Application WO 0112627 describes heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists. They are useful for treating neurological diseases and disorders.
International Patent Application WO 9817652 claims protection for 1,2,4-oxadiazole derivatives, their preparation and their use as neuroprotective agents to treat neurodegenerative diseases and cerebral ischemia. The specified compound is 5-(2-[2-(N5N- dimethylamino)ethoxy]phenyl)-3-ρhenyl-l,2,4-oxadiazole.
International Patent Application WO 04014902 claims novel substituted 1,2,4- oxadiazol-3-yl benzonitrile derivatives, processes for their preparation and their use for the treatment of mGluR5-mediated disorders.
International Patent Application WO 2005044797 relates to new compounds of 3- aryl-[l,2,4]oxadiazol-5-yl-piperidine and related derivatives. Compounds are mGluR5 receptor modulators useful in the treatment of neurological and psychiatric disorders, particularly schizophrenia. However there remains a need for novel compounds and composition that exhibit an activity at metabotropic glutamate receptors (mGluRs), especially at the mGluR5 receptor.
SUMMARY OF THE INVENTION
Compounds of the present invention are represented by formula (I)
(I)
wherein
Y1 and Y2 selected from the group consisting of hydrogen, halogen atom; C1-4 alkyl, C1-4 alkoxy, cyano and trifluoromethyl group, Q is -CH2- group or N; X1 and X2 are different and are independently selected from N and O; Z is -(CH2)n- group or S; n is 1 or 2;
R is selected from the group consisting of optionally substituted C1-7 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, C1-3OC1-3 alkyl, C2-7 alkenyl, C2-7 alkynyl, Q^CNR^alkyl; an optionally substituted C3-7 cycloalkyl, aryl, heteroaryl or saturated heterocyclic group; R1 and R2 are independently selected from hydrogen, C1-7 alkyl or C1-6 alkanoyl group - and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or pharmaceutically acceptable salts thereof formed with acids and bases. Another aspect of the present invention provides processes for the synthesis of compounds of formula (I).
A further aspect of the present invention provides pharmaceutical compositions containing a therapeutically effective amount of a compound of formula (I) or enantiomers or racemates or diastereomers or geometric isomers or salts or hydrates or solvates thereof as active ingredient and pharmaceutically acceptable diluents, excipients and/or inert carriers.
A further aspect of the present invention provides the use of a compound of formula (I) for the prevention and/or treatment of mgluR5 receptor mediated disorders, particularly neurological disorders, psychiatric disorders, acute and chronic pain and neuromuscular dysfunctions of the lower urinary tract. A further aspect of the present invention provides the use of a compound of formula (I) for the manufacture of a medicament for the prevention and/or treatment of mGluR5 receptor- mediated disorders, particularly neurological disorders, psychiatric disorders, acute and chronic pain and neuromuscular dysfunctions of the lower urinary tract.
A further aspect of the present invention provides methods of prevention and/or treatment of mGluR5 receptor-mediated disorders with a compound of formula (I)5 which means administering to a mammal to be treated - including human - effective
amount/amounts of compounds of formula (I) of the present invention as such or as medicament.
These and other aspects of the present invention are described in detail herein.
DETAILED DESCRIPTION OF THE INVENTION
Compounds of the present invention are represented by formula (I)
Y1 and Y2 selected from the group consisting of hydrogen, halogen atom; C1-4 alkyl, C1-4 alkoxy, cyano and trifiuoromethyl group,
Q is -CH2- group or N; X1 and X2 are different and are independently selected from N and O;
Z is -(CH2)n- group or S; n is 1 or 2;
R is selected from the group consisting of optionally substituted C1-7 alkyl, C1-4 haloalkyl, Ci-4 hydroxyalkyl, Ci-4 cyanoalkyl, Ci-3OC1-3 alkyl, C2-7 alkenyl, C2-7 alkynyl, Co^CNR^alkyl; an optionally substituted C3-7 cycloalkyl, aryl, heteroaryl or saturated heterocyclic group;
R1 and R2 are independently selected from hydrogen, C1-7 alkyl or C1-6 alkanoyl group - and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or pharmaceutically acceptable salts thereof formed with acids and bases. In one subset of formula (I) are compounds wherein
Y1 and Y2 selected from the group consisting of hydrogen, halogen atom, C1-4 alkyl,
Ci-4 alkoxy, cyano and trifiuoromethyl group;
Q is -CH2- group or N;
X1 and X2 are different and are independently selected from N and O;
Z is -(CH2)n- group or S; n is 1 or 2; R is selected from the group consisting of optionally substituted C1-7 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, C1-3OC1-3 alkyl, C2-7 alkenyl, C2-7 alkynyl, Co^CNR^alkyl;
C3-7 cycloalkyl group, which is optionally substituted by one or more C1-7 alkyl or oxo group; aryl group, which is optionally substituted by one C1-7 alkyl or C2-7 alkynyl group; heteroaryl group containing 1-3 heteroatoms independently selected from the group of N, O,
S;, which is optionally substituted by one halogen atom, C1-7 alkyl or oxo group;
5-6 membered saturated heterocyclyl containing 1-3 heteroatom(s) optionally substituted with
C1-6 -alkyl or oxo group;
R1 and R2 are independently selected from hydrogen, C1-7 alkyl or C1-6 alkanoyl group - and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or pharmaceutically acceptable salts thereof formed with acids and bases.
In one embodiment within this subset are compounds wherein
Y1 and^ Y2 selected from the group consisting of hydrogen, halogen atom, C1-4 alkyl, C1-4 alkoxy, cyano and trifluoromethyl group;
Q is -CH2- group or N;
X1 and X2 are different and are independently selected from N and O;
Z is -(CH2)n- group or S; n is 1 or 2; R is selected from the group consisting of optionally substituted C1-7 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, C1-3OC1-3 alkyl, C2-7 alkenyl, C2-7 alkynyl, Co^CNR^alkyl;
C3-7 cycloalkyl group, which is optionally substituted by one or more C1-7 alkyl group; aryl group, which is optionally substituted by one C1-7 alkyl or C2-7 alkynyl group; an optionally substituted heteroaryl ring, wherein said heteroaryl ring is selected from the group of furyl, thiophenyl, pyridyl, oxopyrrolyl, oxothiazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, thiazolyl, thiadiazolyl, izoxazolyl group;
5-6 membered saturated heterocyclyl containing 1-3 heteroatom(s) optionally substituted with Ci_6 -alkyl or oxo group;
1 1
R and R are independently selected from hydrogen, C1-7 alkyl or C1-6 alkanoyl group - and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or pharmaceutically acceptable salts thereof formed with acids and bases.
In a second embodiment within this subset are compounds wherein
Y1 and Y2 selected from the group consisting of hydrogen, halogen atom, C1-4 alkyl, C1-4 alkoxy, cyano and trifluoromethyl group; Q is -CH2- group or N;
X1 and X2 are different and are independently selected from N and O;
Z is -(CH2)n- group or S; n is 1 or 2;
R is selected from the group consisting of C1-7 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, C1-3OC1- 3 alkyl, C2-7 alkynyl, C0.2(NR1R2)alkyl; an optionally substituted heteroaryl ring, wherein said heteroaryl ring is selected from the group of furyl, thiophenyl, pyridyl, thiazolyl, pyrrolyl group; tetrahydrofuryl or oxotetrahydrofuryl group;
R1 and R2 are independently selected from hydrogen, C1-7 alkyl or C1-6 alkanoyl group - and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or pharmaceutically acceptable salts thereof formed with acids and bases.
Listed below are definitions of various terms used in the specification and claims to describe the present invention.
For the avoidance of doubt it is to be understood that where in this specification a group is qualified by "hereinbefore defined', "defined hereinbefore1 or "defined above' the said group encompasses the first occurring and broadest definition as well as each and all of the other definitions for that group. For the avoidance of doubt it is to be understood that in this specification "C1-6" means a carbon containing linear or branched group having 1, 2, 3, 4, 5 or 6 carbon atoms.
As used herein the term "alkyl" as well as other groups having the prefix "alk" such as, for example, alkoxy, alkanoyl, alkenyl, alkynyl and the like, means carbon chains which may be linear or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl and the like. In this specification, unless stated otherwise, the term "alkenyl" includes both straight and is branched chain alkenyl groups. The term "C2-7 alkenyl" refers to an alkenyl group having 2 to 1 carbon atoms and one to three double bonds, and may be, but is not limited to vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, crotyl, pentenyl, isopentenyl or hexenyl. In this specification, unless stated otherwise the term "alkynyl" includes both straight and branched chain alkynyl groups. The term "C2-7 alkynyl" refers to a group having 2 to 7 carbon atoms and one or two triple bonds, and may be, but is not limited to ethynyl, propargyl, butynyl, isobutynyl, pentynyl, isopentynyl or hexynyl.
In this specification, unless stated otherwise, the term "cycloalkyl" refers to an optionally substituted, saturated cyclic hydrocarbon ring system. The term C3-7 cycloalkyl" may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
The term "aryl" means an aromatic substituent which is a single ring or multiple rings fused together. When formed of multiple rings, at least one of the constituent rings is aromatic. The preferred aryl substituents are phenyl and naphthyl groups. The term "hetero" unless specifically stated otherwise includes one or more O, S, or
N atoms. For example, heterocyclyl and heteroaryl include ring systems that contain one or more O, S, or N atoms in the ring, including mixtures of such atoms. The hetero atoms replace ring carbon atoms. Examples of heteroaryl rings include pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, and tetrazolyl. Examples of heterocyclyl include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, imidazolinyl, pyrolidin-2-one, piperidin 2-one, and thiomorpholinyl groups. The term "halogen" includes fluorine, chlorine, bromine and iodine atoms.
In this specification, unless stated otherwise, the term "halo" may be fluoro, chloro, bromo or iodo.
In this specification, unless stated otherwise, the term "haloalkyl" means an alkyl group as defined above, wherein at least one or up to all of the hydrogen atoms are replaced with a halogen. The term "C1-6 haloalkyl" may include, but is not limited to fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, bromopropyl. The term "C1^O haloalkyl" may include, but is not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy group.
The term "optionally substituted" is intended to include both substituted and unsubstituted groups. Thus, for example, optionally substituted cycloalkyl could represent a methylcyclohexyl or a cyclohexyl ring. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Among the salts formed with bases especially important are the salts formed with alkali metals, e.g. sodium, potassium, alkali-earth metals, e.g. calcium and magnesium, as well as with ammonia or organic amines. The latter bases can have further substituents, e.g. hydroxy or amino groups, which can influence e.g. the solubility and the handling of the product. Both organic and inorganic acids can be used for the formation of acid addition salts. Suitable inorganic acids can be e.g. hydrochloric acid, sulfuric acid and phosphoric acid. Representatives of monovalent organic acids can be e.g. formic acid, acetic acid, trifmoroacetic acid, propionic acid, and different butyric acids, valeric acids and capric acids. Representatives of bivalent organic acids can be e.g. oxalic acid, malonic acid, maleic acid, fumaric acid and succinic acid. Other organic acids can also be used, such as hydroxy acids e.g. citric acid, tartaric acid, or aromatic carboxylic acids e.g. benzoic acid or salicylic acid, as well as aliphatic and aromatic sulfonic acids e.g. methanesulfonic acid and p-toluenesulfonic acid. Especially valuable group of the acid addition salts is in which the acid component itself does not have therapeutical effect in the applied dose or it does not have unfavorable influence on the effect of the active ingredient. These acid addition salts are pharmaceutically acceptable acid addition salts. The reason why acid addition salts, which do not belong to the pharmaceutically acceptable acid addition salts belong to the present invention is, that in given case they can be advantageous in the purification and isolation of the desired compounds.
The term "activated acid" means an activated Boc-protected amino acid, N-acylated amino acid or properly substituted benzoic acid which can be activated as follows: i) as an acid chloride formed from the acid using a suitable reagent such as oxalyl chloride or thionyl chloride; ii) as a mixed anhydride formed with alkyl chloroformate; iii) using traditional methods to activate acids in amide coupling reactions such as CDI, EDC, HBTU.
Compounds described herein contain one or more double bonds and may thus give rise to cis/trans isomers as well as other conformational isomers. The present invention includes all such possible isomers as well as mixtures of them.
Compounds described herein can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all such possible diastereomers as well as their racemic mixtures and their substantially pure enantiomers. Especially important compounds of formula (I) of the present invention are the following: {4-[3-(3-chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-thiazolidin-3-yl}-(5-methyl-thiophen-2-yl)- methanone, {2-[3-(3-chloro-ρhenyl)-[l,2,4]oxadiazol-5-yl]-ρyrrolidin-l-yl}-(5-methyl-thioρhen-2-yl)- methanone,
{2-[3 -(3 -chloro-phenyl)-[ 1 ,2,4]oxadiazol-5-yl] -piperidin- 1 -yl} -cyclobutyl-methanone, {2-[3-(3-tolyl)-[l,2,4]oxadiazol-5-yl]-piperidin-l-yl}-cyclobutyl-methanone, {2-[3-(3-tolyl)-[l,2,4]oxadiazol-5-yl]-pvrrolidin-l-yl}-(5-methyl-thiophen-2-yl)-methanone, (R) {2-[3-(3-chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-pyrrolidin-l-yl}-(furan-2-yl)-methanone, 3-[3-(3-chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-piperidin-l-carboxylic acid dimethylamide, {2-[3-(3-methoxy-phenyl)-[l,2,4]oxadiazol-5-yl]-piperidin-l-yl}-cyclobutyl-methanone, 2-methoxy-l-[2-(3-m-tolyl-[l,2,4]oxadiazol-5-yl)-pyrrolidin-l-yl]-ethanone, {2-[3-(3-chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-pyrrolidin-l-yl}-(thiophen-2-yl)-methanone, (2-[3-(3-cyano-ρhenyl)-[l,2,4]oxadiazol-5-yl]-piperidin-l-yl}-(5-methyl-thiophen-2-yl)- methanone,
{2-[3-(3-cyano-phenyl)-[l,2,4]oxadiazol-5-yl]-piperidin-l-yl}-cyclobutyl-methanone,
{2-[3-(3-chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-piperidin-l-yl}-(furan-2-yl)-methanone,
{2-[3-(3-tolyl)-[l,2,4]oxadiazol-5-yl]-pyrrolidin-l-yl}-(furan-3-yl)-methanone,
2-methyl-l-[2-(3-m-tolyl-[l,2,4]oxadiazol-5-yl)-piperidin-l-yl]-propan-l-one, {4-[3 -(3 -chloro-phenyl)-[ 1 ,2,4]oxadiazol-5-yl] -thiazolidin-3 -yl} -(furan-2-yl)-methanone, {2-[3-(3-chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-piperidin-l-yl}-cyclopropyl-methanone, {2-[3-(3-tolyl)-[l,2,4]oxadiazol-5-yl]-piperidin-l-yl}-(furan-3-yl)-methanone, {2-[3-(3-cyano-phenyl)-[l,2,4]oxadiazol-5-yl]-piperidin-l-yl}-cycloheptyl-methanone, {2-[3-(3-chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-pyrrolidin-l-yl}-cycloheptyl-methanone, {2-[3-(3-bromo-phenyl)-[l,2,4]oxadiazol-5-yl]-piperidin-l-yl}-cyclobutyl-methanone, {2-[3-(3-cyano-phenyl)-[l,2,4]oxadiazol-5-yl]-ρiperidin-l-yl}-cyclopentyl-methanone, {2-[3-(3-chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-pyrrolidin-l-yl}-(furan-2-yl)-methanone, {2-[3-(3-tolyl)-[l,2,4]oxadiazol-5-yl]-ρiperidin-l-yl}-(furan-2-yl)-methanone, {2-[3-(3-tolyl)-[l,2,4]oxadiazol-5-yl]-piperidin-l-yl}-cyclopentyl-methanone, 2-methyl- 1 - {3 - [3 -(3 -chloro-phenyl)- [1,2,4] oxadiazol-5-yl] -piperidin- 1 -yl} -propan- 1 -one, 1 - {2-[3-(3-chloro-ρhenyl)-[ 1 ,2,4]oxadiazol-5-yl]-piperidin- 1 -yl} -butan- 1 -one, 2-[3-(3-chloro-phenyl)-[l ,2,4]oxadiazol-5-yl]-piperidin-l -carboxylic acid dimethylamide, 2-methoxy- 1 - {2-[3 -(3 -chloro-phenyl)-[ 1 ,2,4] oxadiazol-5-yl] -pyrrolidin- 1 -yl} -ethanone, {3 - [3 -(3 -chloro-phenyl)- [ 1 ,2,4] oxadiazol-5-yl] -piperidin- 1 -yl} -cyclobutyl-methanone, {2- [3 -(3 -methoxy-phenyl)- [ 1,2,4] oxadiazol-5-yl] -piperidin- 1 -yl} -(thiophen-2-yl)-methanone, {2-[3 -(3 -tolyl)-[ 1 ,2,4] oxadiazol-5-yl] -piperidin- 1 -yl} -cyclopropyl-methanone, 2-methyl-l-{2-[3-(3-chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-piperidin-l-yl}-butan-l-one, 4-[3-(3-chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-piperidin-l-carboxylic acid dimethylamide, 3-[5-(3-chloro-phenyl)-[l,2,4]oxadiazol-3-yl]-piperidin-l -carboxylic acid dimethylamide, {2-[5-(3-chloro-phenyl)-[l,2,4]oxadiazol-3-yl]-pyrrolidin-l-yl}-(foran-2-yl)-methanone and salts thereof.
Pharmaceutical formulations
The present invention provides in a further aspect pharmaceutical compositions comprising a compound represented by formula (I) and/or enentiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts thereof as an active ingredient and one or more pharmaceutically acceptable carrier.
The compounds of formula (I) and/or enentiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts thereof may be administered by any
convenient method, for example by oral, parenteral (including subcutaneous, intramuscular, and intravenous), buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly. The pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
The compounds of formula (I) and/or enentiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts thereof which are active when given orally can be formulated as liquids or solids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges. A liquid formulation of the compounds of formula (I) and/or enentiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts thereof generally consist of a suspension or solution of the compound of formula (I) or physiologically acceptable salts thereof in a suitable liquid carrier(s) for example an aqueous solvent, such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil. The formulation may also contain a suspending agent, preservative, flavouring or colouring agent.
A composition in the solid form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid etc. Optionally, tablets may be coated by standard aqueous or nonaqueous techniques.
A tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent.
A composition in the solid form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatine capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatine capsule.
Typical parenteral compositions consising of a solution or suspension of the compound of formula (I) and/or enentiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts thereof in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
Compositions of the present invention for nasal administration containing a compound of formula (I) and/or enentiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts thereof may conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations of the present invention typically comprise a solution or fine suspension of the compound of formula (I) in a physiologically acceptable aqueous or nonaqueous solvent and are usually presented in a single or multidose quantities in sterile form is a sealed container, which can take the form of a cartridge or refill for use with an atomizing device. Alternatively, the sealed container may be a unitary dispensing device, such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once the contents of the container have been exhausted. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas, such as compressed air or an organic propellant, such as a fluorochlorohydrocarbon. The aerosol dosages form can also take the form af a pump- atomiser.
Compositions of the present invention containing a compound of formula (I) are suitable for buccal or sublingual administration including tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier, such as sugar and acacia, tragacanth, or gelatine, glycerin etc. Compositions of the present invention containing a compound of formula (I) and/or enentiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts thereof for rectal administration are conveniently in the form of suppositories containing a conventional suppository base, such as cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in moulds.
Compositions of the present invention containing a compound of formula (I) and/or enentiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts thereof for transdermal administration include ointments, gels and patches.
The compositions of the present invention containing a compound of formula (I) and/or enentiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts thereof is preferably in the unit dose form, such as tablet, capsule or ampoule.
Each dosage unit of the present invention for oral administration contains preferably from 0.1 to 500 mg of a compound of formula (I) and/or enentiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts thereof. Each dosage unit of the present invention for parenteral administration contains preferably from 0.1 to 500 mg of a compound of formula (I) and/or enentiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts thereof.
The physiologically acceptable compounds of formula (I) and/or enentiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts thereof can be administered in a daily dosage regimen. In the treatment of mGluR5 mediated disorders, such as schizophrenia, anxiety, depression, panic, bipolar disorders, and circadian disorders or chronic and acute pain disorders the dosage levels from about 0,01 mg/kg to about 140 mg/kg of body weight per day are useful or alternatively about 0.5 mg to about 7 g per patient per day. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration to humans may conveniently contain from about 0.5 mg to about 5 g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Unit dosage forms will generally contain between from about 1 mg to about 1000 mg of the active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 25-300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.
It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
Medical use
The compounds of formula (I) of the present invention have been found to exhibit biological activity at mGluR5 receptors and are expected to be useful in the treatment of mGluR5 mediated disorders.
It has been found that the compounds according to the present invention or salts thereof, exhibit a high degree of potency and selectivity for individual metabotropic glutamate receptor (mGluR) subtypes. In particular there are compounds according to the present invention that are potent and selective for mGluR5 receptor. Accordingly, the compounds of the present invention are expected to be useful in the prevention and/or treatment of conditions associated with excitatory activation of an mGluR5 receptor and for inhibiting neuronal damage caused by excitatory activation of an mGluR5 receptor. The compounds may be used to produce an inhibitory effect of mGluR5, in mammals, including man. Thus, it is expected that the compounds of the invention are well suited for the prevention and/or treatment of mGluR5 receptor-mediated disorders such as acute and chronic neurological and psychiatric disorders, chronic and acute pain disorders and neuromuscular dysfunctions of the lower urinary tract.
The dose required for the therapeutic or preventive treatment of a particular disorder will necessarily be varied depending on the host treated and the route of administration.
The invention relates to compounds of formula (I) as defined hereinbefore, for use in therapy.
The invention relates to compounds of formula (I) as defined hereinbefore, for use in prevention and/or treatment of mGluR5 receptor-mediated disorders.
The invention relates to compounds of formula (I) as defined hereinbefore, for use in prevention and/or treatment of neurological disorders.
The invention relates to compounds of formula (I) as defined hereinbefore, for use in prevention and/or treatment of psychiatric disorders. The invention relates to compounds of formula (I) as defined hereinbefore, for use in prevention and/or treatment of chronic and acute pain disorders.
The invention relates to compounds of formula (I) as defined hereinbefore, for use in prevention and/or treatment of neuromuscular dysfunctions of the lower urinary tract.
The invention relates to compounds of formula (I) as defined hereinbefore, for use in prevention and/or treatment of pain related to migraine, inflammatory pain, neuropathic pain disorders such as diabetic neuropathies, arthritis and rheumatoid diseases, low back pain, post-operative pain and pain associated with various conditions including angina, in renal or biliary colic, menstruation, migraine and gout.
The invention relates to compounds of formula (I) as defined hereinbefore, for use in prevention and/or treatment of Alzheimer's disease senile dementia, AIDS-induced dementia Parkinson's disease, amyotrophic lateral sclerosis, Huntington's Chorea, migraine, epilepsy, schizophrenia, depression, anxiety, acute anxiety, obsessive compulsive disorder, ophthalmological disorders such as retinopathies, diabetic retinopathies, glaucoma, auditory neuropathic disorders such as tinnitus, chemotherapy induced neuropathies, post-herpetic neuralgia and trigeminal neuralgia, tolerance, dependency, Fragile X, autism, mental retardation, schizophrenia and Down's Syndrome.
The invention relates to compounds of formula (I) as defined hereinbefore, for use in prevention and/or treatment of stroke, head trauma, anoxic and ischemic injuries, hypoglycemia, cardiovascular diseases and epilepsy.
The compounds are also well suited for the treatment of neuromuscular dysfunction of the lower urinary tract, such as urinary urgency, overactive bladder, greater urinary frequency, reduced urinary compliance, cystitis, incontinence, enuresis and dysuria.
The present invention relates also to the use of a compound of formula (I) as defined hereinbefore, in the manufacture of a medicament for the prevention and/or treatment of mGluR5 receptor-mediated disorders and any disorder listed above. The invention also provides a method of treatment and/or prevention of mGluR5 receptor mediated disorders and any disorder listed above, in a patient suffering from, or at risk of, said condition, which comprises administering to the patient an effective amount of a compound of formula (I), as hereinbefore defined. hi the context of the present specification, the term "therapy" includes treatment as well as prevention, unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be construed accordingly.
In this specification, unless stated otherwise, the term "antagonist" means a compound that by any means, partly or completely blocks the transduction pathway leading to the production of a response by the ligand.
The term "disorder", unless stated otherwise, means any condition and disease associated with metabotropic glutamate receptor activity.
Pharmacology
The pharmacological properties of the compounds of the invention were analyzed by determining binding affinity of the compounds to a binding site on mGluR5 receptors and by fluorimetric assays of intracellular calcium concentration to determine functional activity.
Compounds of the invention showed affinity for both rat and human mGluR5 receptors and proved to be functional antagonists, that is to inhibit functional responses elicited by stimulation of mGluR5 receptors. Detailed protocols for testing the compounds of the invention and results for representative compounds are provided below in Pharmacological
Examples.
Methods of preparations
Another aspect of the present invention provides a process for preparing a compound of formula (I) or salt thereof.
Throughout the following description of such processes it is to be understood that, where appropriate, suitable protecting groups will be added to, and subsequently removed from, the various reactants and intermediates in a manner that will be readily understood by one skilled in the art of organic synthesis. Conventional procedures for using such protecting groups as well as examples of suitable protecting groups are described, for example, in "Protective Groups in Organic Synthesis," T. W. Green, P.G.M. Wuts, Wiley-Interscience, New York, 1999.
Unless specified otherwise, Q, Y1 and Y2 , Z, X1 and X2, R, R , R and n, are defined as in formula (I).
Abbreviations
The abbreviations used herein have the following tabulated meanings. Abbreviations not tabulated below have their meanings as commonly used unless specifically stated otherwise.
Boc- tert-butoxycarbonyl-
CDI N,N'-carbonyldiimidazole
EDC l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
HBTU O-(lH-(benztriazol-l-yl)-N,N,N',N'-tetramethyluronium- hexafluorophosphate
NMM N-methylmorpholine
TEA triethylamine
TBAF tetra-n-butylamrnonium fluoride hydrate
DMF N,N-dimethylformamide
THF tetrahydrofuran
General synthesis of3,5-disubstituted—fl,2,4Joxadiazoles:
Compounds of the present invention can be prepared according to the following methods. Unless stated otherwise, the meaning of substituents is as defined above for formula (I) or apparent to one skilled in the art.
Synthesis of compound of formula (V)
a. NH2OH, ethanol, base, reflux,
b. R5COOH, activation, c. TBAF/THF or CDI/DMF 20-100 0C.
R5 = R3 or R4' independently
Amidoximes, compounds of formula (III), can be prepared using synthetic chemical methods well known in the art (see C. Ainsworth et al., J. Med. Chem., 1967, 10, 208-211) by reacting suitable nitriles and hydroxylamine hydrochloride in refluxing methanol or ethanol in the presence of an appropriate base, for example an alkali metal carbonate, such as potassium carbonate or an alkali such as sodium hydroxide.
Pyridine-2-aldoxime and pyridine-3-aldoxime are commercially available. Boc protected piperidine and pyrrolidine-aldoximes can be prepared by the above mentioned procedure using commercially available nitriles. Boc protected or N-acylated piperidine and pyrrolidine-nitriles can be prepared from carboxamides under mild conditions (pi. S.N. Banerjee et al. Int. J. Peptid Protein Res. 1979, 14, 234-246).
Compounds of formula (IV) (O-acylamidoximes) can be prepared by acylation of compound of formula (III) with an activated Boc-protected amino acid, N-acylated amino acid or properly substituted benzoic acid according to well known procedures (see: R.F.
Poulain et al., Tetrahedron Lett., 2001, 42, 1495-1498). The acid (R5COOH) can be activated as follows: i) as an acid chloride formed from the acid using a suitable reagent such as oxalyl chloride or thionyl chloride; ii) as a mixed anhydride formed with alkyl chloroformate; iii) using traditional methods to activate acids in amide coupling reactions such as CDI, EDC, HBTU.
Compounds of formula (V), 3,5-disubstituted-[l,2,4]oxadiazoles can be prepared by cyclocondensation of a compound of formula (IV). Preparation of compounds of formula (V) can be carried out by cyclocondensation of O-acylamidoximes (IV) in ether type solvent (preferable THF) in the presence of tetra-
butylammonium salt catalyst (TBAF) at room temperature or by heating as it is known from the literature (see: A.R. Gangloff et.al, Tetrahedron Lett., 2001, 42, 1441-43), or in the presence of a catalyst (e.g. CDI) in dimethylformamide (Deegan TX. et al. Bioorg. Med. Chem. Lett., 1999, 9, 209-212).
Intermediates of formula (VI),
VI
wherein X1 and X2 are different and are independently selected from N and O, is equivalent with compound of formula (V). This structural formula demonstrates the different situation of the oxadiazole ring.
Compounds of formula (VII) can be obtained by deprotecting compound of formula (VI) by acidic hydrolysis in an appropriate solvent such as ethyl acetate or dioxane saturated with hydrogen chloride gas.
vi vπ
Synthesis of compound (I) by acylation of3,5-disubstituted-[l,2,4]oxadiazoles
A process for the preparation of a compound of formula I
according to claim 1 comprising reacting a compound of formula VII , deprotected 3,5- disubstituted oxadiazoles with an activated acid in presence of a base to give a compound of structural formula I.
VII
Compounds of formula (I) can be prepared by acylation (RCOOH) of the secondary amines of general formula (VII). Acylation of compounds of formula (VII) can be accomplished with an acid (RCOOH) as a reagent, which is activated by the above mentioned methods, preferably by EDC in the presence of a base such as sodium hydrogencarbonate or TEA.
When R = NR1R2, the acylation can be carried out with a proper aminocarbamoyl chloride or isocyanide.
a. NH2OH5 ethanol, base, reflux, b. R3 COOH, activation, c. TBAF/THF or CDI/DMF 20-100 °C.
R" ^O
Compounds of general formula (I) can also be prepared by the following method: compounds of formula (Ha) can be prepared from N-acylated amino acids according to the above mentioned procedure. Amidoximes, compounds of formula (Ilia), can be prepared from nitriles of formula (Ila) according to the method described above. Compounds of formula (IVa) can be prepared from compounds of formula (Ilia) by acylation with a properly substituted benzoic acid (R3 COOH). Cyclocondensation of the above mentioned O- acylamidoximes (FVa) results in compounds of general formula (Ia).
Synthesis of compound Ib
Compounds of general formula (I) can also be prepared by the following method: compounds of formula (IVb) can be prepared by reacting a compound of formula (HIb) and an N-acylated amino acid (R4COOH). Cyclocondensation of the above mentioned O- acylamidoximes (IVb) results in compounds of general formula (Ib).
Compounds of the present invention can also be synthesized by parallel synthesis using the following conditions: Acylation of secondary amines of formula (VII) (piperidine, pyrrolidine) can be carried out using aliphatic, aromatic and heteroaromatic carboxylic acids (RCOOH) with multiple surplus and EDC activator in dichloromethane or dichloromethane/DMF. Purification of the product can be carried out by fluid/fluid extraction (water/ dichloromethane). Basic extraction can be used for purification of carboxylic acids and acidic extraction can be used for the elimination of EDC and secondary amine.
The final product, compound (I), can be obtained in appropriate purity therefore after concentration of the solution the biological experiments can be carried out without further purification.
Compounds of the present invention were characterized by high performance liquid chromatography coupled to mass selective detector (LC/MS) using HP 1100 Binary Gradient chromatography system with Microplate Sampler (Agilent, Waldbronn), controlled by ChemStation software. Detection was carried out by a Hewlett-Packard-type diode array detector, at λ = 240 nm wavelength. Discovery C16-Amide column, 5 cm x 4.6 mm was used, with flow rate = 1 ml/min. All experiments were performed using Hewlett-Packard MSD
(Agilent, Waldbronn) single quadruple spectrometer equipped with electrospray ionisation source to determine the structure. The compounds were characterized by the k' -values (capacity ratio) and by the (M+H)+- values (M: molecule mass).
Optical purities of the enantiomers were controlled by HPLC, using DAICEL Chiracel ODH chiral column. Eluent: a mixture of n-hexane/2-propanol/methanol (90: 5: 5 v/v) containing 0.05 % diethylamine. Flow rate: 1 ml/min, detection: at 220 nm. 1H NMR spectra were recorded on a Varian Unity Inova 300 or on a Varian Unity Inova 500 spectrometer. Chemical shifts are reported in parts per million relative to TMS as internal standard.
The syntheses of compounds and pharmaceutical compositions according to the invention are illustrated by the following not limiting Examples.
Examples All starting materials are either commercially available or can be synthesized by different known methods described in the literature.
Example 1
{2-[3-(3-Tolyl)-[l,2,4]oxadiazoI-5-yl]-piperidin-l-yl}-cyclobutyl-methanone (Table II, Compound 2)
A solution of {2-[3-(3-tolyl)-[l,2,4]oxadiazol-5-yl]-piperidin-l-yl}-cyclobutyl- methanone hydrochloride salt (0.20 g, 0.07 mmol) (see Table I, compound 2), TEA (0.24 ml, 1.7 mmol), EDC (0.20 g, 1.05 mmol), cyclobutanecarboxylic acid (0.14 ml, 1.05 mmol) and dichloromethane was stirred at 25 0C for 3 hours. The reaction mixture was diluted with dichloromethane (10 ml), washed with 1 N aqueous hydrochloric acid (10 ml), water (10 ml) and 5% aqueous sodium hydrogencarbonate solution (10 ml). The organic layer was dried, filtered and concentrated to yield 0.188 g (82 %) of the title compound as oil.
MS: m/e=326 (MH-H)+.
Compounds 3, 4, 5, and 11 in Table II were prepared according to the method described in Example 1 from properly substituted amines of formula (VII) presented in Table I.
Intermediates (A,B,C)
3-Methyl-N-hydroxy-benzamidine (Intermediate A)
A solution of 3-tolunitrile (6.1 ml, 50 mmol) in ethanol (50 ml) and a solution of sodium hydroxide (2.0 g, 50 mmol) in water (50 ml) were mixed and hydroxylamine hydro chloride (3.51 g, 50 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours, then the organic solvent was evaporated in vacuo and the aqueous residue was extracted with dichloromethane (3x40 ml), the organic layer was dried, filtered and concentrated to yield 6.74 g (90%) of the title compound as oil. MS: m/e=151.2 (M+H)+.
3 -mono-, and 3,4-disubstituted benzamidoxim.es (general formula III) were prepared by following the procedure described above.
2-[3-(3-Tolyl)-[l,2,4]oxadiazol-5-yl]-piperidine-l-carboxylic acid tert-butyl ester (Intermediate B)
To a stirred solution of piperidine-l,2-dicarboxylic acid 1-tert-butyl ester (6.90 g, 25 mmol), dry DMF (30 ml) and N-methylmorpholine (NMM, 2.80 ml, 25 mmol) isobutyl chloroformate (3.30 ml, 25 mmol) was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 30 minutes. A solution of 3-methyl-N-hydroxy-benzamidine (Intermediate
A; 3.75 g, 25 mmol) in dry DMF was added to the so obtained mixture and stirring was continued for 30 minutes. Then TBAF (1.6 g, 6 mmol) was added and the reaction mixture stirred at 100 0C for 3 hours. The solution was concentrated in vacuo and the residue was partitioned between water (60 ml) and dichloromethane (80 ml). The aqueous phase was extracted with dichloromethane (2x30 ml), the organic layer was dried and concentrated. The crude product was purified by column chromatography on silica gel (Kieselgel 60, eluent: dichloromethane: methanol = 39:1) to yield 4.91 g (57 %) of the title compound as oil. MS : m/e=344.4 (M+H)+.
Boc protected derivatives of pyrrolidine- [1, 2,4] oxadiazoles and 2-substituted piperidine-[l,2,4]oxadiazoles presented in Table I were prepared by following the procedure described above.
2-[3-(3~Tolyl)-[l,2,4]oxadiazol-5-yl]-piperidine hydrochloride (Intermediate C)
To a solution of 2-[3-(3-tolyl)-[l,2,4]oxadiazol-5-yl]-piperidine-l-carboxylic acid tert-butyl ester (Intermediate B, 4.80 g, 14 mmol) in ethyl acetate (5 ml) ethyl acetate saturated with hydrogen chloride gas (50 ml 2.5 mol/1) was added. The reaction mixture was stirred at room temperature for 3 hours, the precipitated product was filtered off and washed with ether to yield 3.196 g (82 %) of the title compound (compound 2 in Table I). Melting point: 205 -206 °C. MS: m/e=244.3 (M+H)+.
Compounds 1-6 and Compounds 14-16 in Table I were prepared by following the procedure described above.
Table I
Example 2
{4-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]thiazolidin-3-yl}-(5-methyl-thiophen-2-yl)- methanone (Table II, Compound 1)
A mixture of 3-(3-chloro-phenyl)-5-thiazolidin-4-yl-[l,2,4]oxadiazole hydrochloride (Intermediate B; 0.456 g, 1.5 mniol), TEA (0.42 ml, 3 mmol), 5-methyl-tiophen carboxylic acid (0.31 g, 2.2 mmol), HBTU (0.68 g, 1.8 mmol) and DMF (3 ml) was stirred at 25 °C for 48 hours. Then the reaction mixture was diluted with ethyl acetate (40 ml), washed with brine, 1 N aqueous hydrochloric acid and 5% aqueous sodium hydrogencarbonate. After drying and concentration the obtained crude product (0.534 g, 91 %) was crystallized from ethyl acetate.
Melting point: 104-106 0C.
Compound 13 in Table II was prepared according to the method described in
Example 2 using furan-2-carboxylic-acid as starting material.
Intermediates (A,B)for the preparation of compound 1 and 13 in Table II
^[S-β-Chloro-phenyty-ll^^Joxadiazol-S-yll-thiazolidineS-carboxyUc acid tert- butyl ester (Intermediate A)
Boc-thioproline (1.4 g, 6 mmol) was dissolved in dry THF (12 ml), CDI (1.07 g, 6.6 mmol) was added, and the mixture was stirred at 25 0C for 30 minutes. 3-Chloro-N-hydroxy- benzamidine (1.05 g, 6.15 mmol) was added (example 1, intermediate A), the reaction mixture was stirred for 1.5 hours and concentrated. The residue was dissolved in dichloromethane, washed with 1 N aqueous hydrochloric acid and brine. After drying and concentration the isolated O-acylated amidoxime was dissolved in dry THF and TBAF (1.575
g, 6 mmol) was added. The reaction mixture was stirred for 2 hours and THF was evaporated. The residue was dissolved in dichloromethane, washed with aqueous hydrochloric acid and water, then the organic layer was dried and concentrated. The crude product was purified by flash column chromatography on silica gel (Kieselgel 60, eluent: n-hexane: ethyl acetate = 4:1) to yield 1.38 g (63 %) of the title compound as an oil. MS: m/e= = 390.8 (M+ Na)+.
3-(3-Chloro-phenyl)-5-thiazolidin-4-yl-[l,2,4]oxadiazole hydrochloride (Intermediate B)
4-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-thiazolidine-3-carboxylic acid tert- butyl ester (Intermediate A; 1.38 g, 3.7 mmol) was dissolved in dioxane saturated with hydrogen chloride gas (10 ml 6.3 mol/1), the mixture was stirred at room temperature for 30 minutes and diluted with ether (40 ml). The precipitated product was filtered off and washed with ether to yield 1.05g (92 %) of the title compound. Melting point: 164 -166 0C.
Example 3
{2-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-pyrrolidin-l-yl}-(furan-2-yl)-methanone (Table II, Compound 6)
N-(Furan-2-carbonyl)-pyrrolidine-2-carboxylic acid (0.31 g, 1.5 mmol) (Laduree, D.et al, J.Med.Chem.,1989, 32, 456-461) was dissolved in DMF (3 ml), CDI (0.3 g, 1.65 mmol) was added, and the reaction mixture was stirred at 25 °C for 30 minutes, then 3-chloro- N-hydroxy-benzamidine (0.28 g, 1.65 mmol; Example 1, Intermediate A) was added. The reaction mixture was stirred at 25 0C for 2 hours, then CDI (0.3 g, 1.65 mmol) in 2 ml of DMF was added and the reaction mixture was stirred at 115 0C for 2 hours. After concentration the residue was dissolved in dichloromethane, the solution was washed with aqueous hydrochloric acid, sodium hydrogencarbonate solution and water, dried and concentrated. The crude product was purified by flash column chromatography on silica gel (Kieselgel 60, eluent: n-hexane: ethyl-acetate = 1:1). The final product was crystallized with n-hexane to yield 0.22 g (43 %) of the title compound.
Melting point: 95-96 0C.
Example 4
(R)-{2-[3-(3-chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-pyrrolidin-l-yl}-(furan-2-yl)- methanone
(Table II, Compound 9)
A stirred solution of furan-2-carboxyric acid (100 μl, 0.85 mmol) in DMF (3 ml) was cooled to -10 0C, isobutyl chloroformate (115 μl, 0.85 mmol) was added, then a solution of NMM (100 μl, 0,85 mmol) in DMF (1 ml) was added to the reaction mixture dropwise. The solution was stirred at -10 0C for 20 minutes, then added to a solution of (R)-3-(chloro~ phenyl)-5-pyrrolidin-2-yl-[l,2,4]oxadiazole hydrochloride (Intermediate B; 0.2 g, 0.7 mmol) and TEA (0.1 ml, 0.7 mmol) in DMF (2 ml) previously cooled to -10 °C. The reaction mixture was stirred at 0 °C for 30 minutes, then at 25 °C for 2 hours. Then the reaction mixture was diluted with ethyl acetate (25 ml), washed with aqueous hydrochloric acid, aqueous sodium hydrogencarbonate solution and water, the organic layer was dried over sodium sulfate and concentrated. The crude product was purified by flash column chromatography on silica gel (Kieselgel 60, eluent: n-hexane: ethyl acetate = 1:1) to yield 88 mg (37 %) of the title compound as an oil. MS : m/e = 344.3 (M+ H)+.
Optical purity: 99%.
Intermediates (A, B)
(R)-2-f3-(3-Chloro-phenyl)-fl}2,4Joxadiazol-5-ylJ-pyrrolidine-l-carboxylic acid tert-butyl ester (Intermediate A)
Boc-D-proline (0.645 g, 3 mmol) was dissolved in 6 ml dry THF and CDI (0.535 g,
3.3 mmol) was added. The solution was stirred at 25 0C for 30 minutes and 3-chloro-N- hydroxy-benzamidine (0.53 g, 3.1 mmol) was added. The reaction mixture was stirred at room temperature for 1.5 hours, concentrated and the residue was dissolved in dichloromethane. The solution was washed with aqueous hydrochloric acid and brine, dried
and concentrated. The isolated O-acylated amidoxime was mixed with dry THF (12 ml) and TBAF (0.785g, 3 mmol) and stirred for 2 hours. The solvent was evaporated, and the residue was dissolved in dichloromethane, washed with aqueous hydrogen chloride and water, dried and concentrated. The crude product was purified by flash column chromatography on silica gel (Kieselgel 60, eluent: n-hexane: ethyl acetate = 3:1) to yield 0.63 g (60 %) of the title compound as oil.
MS: m/e - 372.4 (M + Na) +.
(R)-3-(Chloro-phenyl)-5-pyrrolidin-2-yl-[l,2,4]oxadiazole hydrochloride (Intermediate B)
(R)-2-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-pyrrolidine-l-carboxylic acid tert-butyl ester (Intermediate A; 0.63 g, 1.8 mmol) was dissolved in dioxane (2 ml) and dioxane saturated with hydrogen chloride gas (8 ml, 6.3 mol/1) was added. The so obtained mixture was stirred for 20 minutes and diluted with ether (50 ml). The precipitated product was filtered off and washed with ether to yield 0.445 g (87 %) of the title compound.
Melting point: 174 -176 0C;
Optical purity: 99 %.
Example 5 {3- [3-(3-Chloro-phenyl)- [1,2,4] oxadiazol-5-yl] -piperidin-l-ylj-cyclobutyl-methanone (Table II, Compound 8)
The title compound was prepared according to method described in Example 1 from the intermediates described in Example 5.
Intermediates (A,B)
S-β-β-Chloro-phenylJ-fl^^Joxadiazol-S-ylJ-piperidine-l-carboxylic acid tert- butyl ester (Intermediate A)
1-Boc-nipecotic acid (1.34 g, 5.8 mmol) was dissolved in dichloromethane (50 ml), cooled to 0 0C, NMM (0.65 ml, 5.8 mmol) and isobutyl chloroformate (0.76 ml, 5.8 mmol)
were added. The reaction mixture was stirred for half an hour and a solution of 3-chloro-N- hydroxy-benzamidine (0.89 g, 5.9 mmol) (Example 1, Intermedier A) in dichloromethane (20 ml) was added dropwise at 0 0C. The reaction mixture was stirred at 0 0C for 1 hour, then the solvent was evaporated in vacuo. The residue was dissolved in THF (75 ml), TBAF (1.51 g, 5.8 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The solvent was evaporated in vacuo, the residue was dissolved in dichloromethane (40 ml) and washed with water (20 ml). After drying the organic layer was concentrated and the residue was purified by column chromatography (Kieselgel 60, eluent: ethyl acetate: n-hexane = 2:3) to yield 1.0 g (48 %) of the title compound. MS: m/e=364 (M+H)+.
Boc protected derivatives of 3-substituted-piperidine-[l,2,4]oxadiazole presented in Table I were prepared by following the procedure described above.
3-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-piperidine hydrochloride (Intermediate B)
The title compound was prepared according to the method described in Example 1 for Intermediate C. The same process was used for the preparation of Compounds 7-13 in Table I.
Example 6
3-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-piperidine-l-carboxylic acid dimethylamide (Table II, Compound 34)
The title compound was prepared according to the method described in Example 9 from Intermediate B in Example 5.
Example 7
4-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-piperidine-l-carboxylic acid dimethylamide (Table II, Compound 15)
The title compound was prepared according to the method described in Example 9 from Intermediate B in Example 5. MS: m/e=335 (M+H)+. Melting point: 92-93 °C
Intermediates (A,B)
^β-β-Chloro-phenyfy-fl^^JoxadiazolS-ylJ-piperidine-l-carboxylic acid tert- butyl ester (Intermediate A)
The title compound was prepared from Boc-4-piρeridine carboxylic acid according to the method described in Example 5 for Intermediate A.
The compound was purified by column chromatography (Kieselgel 60, eluent: ethyl acetate: n-hexane = 1:2).
4-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-piperidine hydrochloride
(Intermediate B)
The title compound (Compound 17 in Table I) was prepared as Intermediate C in
Example 1.
Example 8
{2-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-yl]-pyrrolidin-l-yl}-(furan-2-yl)-methanone (Table II, Compound 10)
3-Chloro-benzoic acid (0.31 g, 2 mmol) was dissolved in dry THF (4 ml) and CDI (0.36 g, 2.2 mmol) was added. The solution was stirred at 25 °C for 30 minutes, then amidoxime (Intermedier C) (0.46 g, 2.05 mmol) was added and the solution was stirred for 1 hour. After concentration the residue was dissolved in dichloromethane, washed with 1 N aqueous hydrochloric acid and brine, dried and concentrated. The isolated O-acylated amidoxime was dissolved in 10 ml dry THF and TBAF (0.52 g, 2 mmol) was added. After
stirring for 2 hours, the THF was evaporated, the residue was dissolved in dichloromethane and the solution was washed with aqueous hydrochloric acid, sodium hydrogencarbonate and water. The organic layer was dried and concentrated, and the crude product was purified by column chromatography on silica gel (Kieselgel 60, eluent: n-hexane: ethyl acetate = 1:1). The product was crystallized with n-hexane to yield 0.4 g (58 %) of the title compound. Melting point: 81-83 °C.
Intermediates (A,B,C):
l-(Furan-2-carbonyl)-pyrrolidine-2-carboxylic acid amide (Intermediate A)
To a stirred solution of prolinamide hydrochloride (1.5 g, 10 mmol) in DMF (10 ml)
2-furan-carboxylic acid pentafluorophenyl ester (2.3 g, 8.3 mmol) and TEA (2.4 ml, 18 mmol) were added. After stirring for 1 hour the reaction mixture was concentrated. The crude product was purified by column chromatography on silica gel (Kieselgel 60, eluent: chloroform:methanol= 9:1) to yield 1.15 g (70 %) of title compound.
Melting point: 169 - 170 0C.
l-(Furan-2-carbonyl)-pyrrolidine-2-carbonitrile (Intermediate B)
A suspension of l-(ruran-2-carbonyl)-pyrrolidine-2-carboxylic acid amide (Intermediate A; 0.936 g, 4.5 mmol) in pyridine (6 ml) was cooled to 0 0C, and a solution of thionyl chloride (0.68 ml, 9 mmol) in pyridine (3 ml) was added drop wise. The reaction mixture was stirred at 25 0C for 45 minutes, then poured onto 60 g crushed ice. The product was extracted with ethyl acetate, the organic layer was washed with water, dried and concentrated to yield 0.77 g (90 %) of the title compound as an oil.
MS: m/e=191.1 (M + H)+.
l-(Furan-2-carbonyl)-N-hydroxy-pyrrolidine-2-carboxamidine (Intermediate C)
l-(Furan-2-carbonyl)-pyrrolidine-2-carbonitrile (Intermediate B; 0.77 g, 4 mmol) and hydroxylamine hydrochloride (0.42 g, 6 mmol) were added to a stirred mixture of ethanol (8 ml) and 1 N aqueous sodium hydroxide (6 ml) and refluxed for 1 hour. The reaction mixture was concentrated and the crude product was purified by column chromatography on silica gel (Kieselgel 60, eluent: chloroform:methanol = 9:1) to yield 0.945 g (85 %) of the title compound.
Melting point: 121-122 °C.
Example 9
3-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-yl]-piperidine-l-carboxylic acid dimethylamide (Table II, Compound 12)
To a stirred solution of 3-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-yl]-piperidine hydrochloride (Intermediate E; 0.3 g, 1 mmol) in dichloromethane (10 ml) trimethylamine
(0.6 ml, 4.3 mmol), dimethylcarbamoyl chloride (0.2 ml, 2.2 mmol) and N5N- dimethylaminopyridine (2 mg) were added. The reaction mixture was stirred for 2 days, diluted with dichloromethane (10 ml) and washed with water (10 ml). The organic layer was dried and concentrated, the crude product was purified by column chromatography on silica gel (Kieselgel 60, eluent: chlorofoπn:methanol = 98:2) to yield 0.24g (72%) of the title compound as an oil.
MS: m/e=335 (M+H)+.
Intermediates (Λ,B,C,D,E)
l-(tert-Butoxycarbonyl)-piperidine-3-carboxylic acid amide (Intermediate A)
To a stirred solution of piperidine-3-carboxylic acid amide (1.28 g, 10 mmol) in methanol (50 ml) triethylamine (1.4 ml, 10 mmol) was added and the mixture was cooled to 0-5 0C. A solution of di-tert-butyl dicarbonate (2.4 g, 11 mmol) in methanol (30 ml) was added and the reaction mixture was kept at room temperature overnight. The mixture was
concentrated in vacuo, then the residue was suspended in 5% sodium hydrogencarbonate solution (30 ml), filtered and washed with water to yield 1.8 g (79 %) of the title compound. Melting point: 174-175 °C
l-(tert-Butoxycarbonyl)-piperidine-3-carbonitrϊle (Intermediate B)
The title compound was prepared according to the method described in Example 8 for Intermediate B from Intermediate A.
MS: m/e=211 (M+H)+-
l-(tert-Butoxycarbonyl)-N-hydroxy-piperidine-2-carboxamidine (Intermediate C)
To a stirred solution of l-(tert-butoxycarbonyl)-piperidine-3-carbonitrile (Intermediate B; 1.1 g, 5.2 mmol) in ethanol (15 ml) hydroxylamine hydrochloride (0.37 g, 5.2 mmol) and a solution of sodium hydroxide (0.22 g, 5.5 mmol) in water (4 ml) were added. The reaction mixture was refluxed for 5 hours and concentrated in vacuo. The residue was dissolved in water (20 ml) and extracted with dichloromethane (2x15 ml). The combined organic layers were dried and concentrated in vacuo to yield 1.2 g (95 %) of the title compound. MS: m/e=244 (M+H)+-
S-fS-β-Chloro-phenyty-ftø^JoxadiazolS-ylJ-piperidine-l-carboxylic acid tert- butyl ester (Intermediate D)
To a stirred solution of 3-chloro-benzoic acid (0.32 g, 2 mmol) in dry DMF (5 ml)
NMM (22 ml, 2 mmol) and isobutyl chloroformate (0.26 ml, 2 mmol) were added at 0 0C and the reaction mixture was stirred at 0 0C for half an hour. Then a solution of l-(tert- butoxycarbonyl)-N-hydroxy~piperidine-2-carboxamidine (Intermediate C; 0.5 g, 2 mmol) in dry DMF was added, and the reaction mixture was stirred for 1 hour, during this time the temperature reached 25 °C. Then TBAF (0.1 g, 0.4 mmol) was added to the solution, and the mixture was stirred at 100 0C for 5 hours. The solution was concentrated in vacuo and the residue was partitioned between water (20 ml) and dichloromethane (20 ml). The aqueous
phase was extracted with dichloromethane (20 ml), the combined organic layers were dried and concentrated. The crude product was purified by column chromatography on silica gel (Kieselgel 60, eluent: chloroformmethanol = 98:2) to yield 0.35 g (49%) of the title compound as an oil. MS:m/e=364 (M+H)+.
3-[5-(3~Chloro~phenyl)-[l,2,4]oxadiazol-3-yl]-piperidine hydrochloride (Intermediate E)
3-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-yl]-piperidine-l-carboxylic acid tert- butyl ester (Intermediate D; 0.35g, 0.96mmol) was mixed with ethyl acetate saturated with hydrogen chloride gas (10 ml), the reaction mixture was stirred at 0 °C for two hours, then concentrated in vacuo to yield 0.3 g (100 %) of the crude title compound, which was used for the preparation of Compound 12 without further purification.
Example 10
General description of the parallel synthesis of the preparation of compound Ib from compound VII:
0.25 M RCOOH and EDC solutions were prepared in dichloromethane. 0.1 M solution of secondary amines (prepared from VII as a free base) were prepared in an appropriate mixture of DMF and dichloromethane. The dichloromethane content of the mixture was less than 70 (v/v) %. To 1.0 ml solution of RCOOH (0.25 mmol) and 2.5 ml solution of EDC (0.25 mmol)
1.0 ml solution of secondary amine (0.10 mmol) was added and the reaction mixture was stirred at room temperature for 72 hours. Dichloromethane (4.0 ml) was added to the reaction mixture and the resulting solution was extracted twice with an aqueous hydrochloric acid solution (6 ml, 1% (m/m), twice with sodium carbonate solution (6 ml 2 % (m/m) and once with ion-exchanged water (6 ml). The organic layer was passed through a column filled with 400 mg isolute®sorbent and the resulting dry dichloromethane solution was concentrated to
dryness (Addition of reagents and the extraction were carried out with Tecan Combitec synthesizer, the samples were concentrated with Savant centrifugal evaporator.)
Example 11 Preparation of pharmaceutical compositions:
a) Tablets:
0.01-50 % of active ingredient of formula (I), 15-50 % of lactose, 15-50 % of potato starch, 5-15 % of polyvinyl pyrrolidone, 1-5 % of talc, 0.01-3 % of magnesium stearate, 1-3 % of colloid silicon dioxide and 2-7 % of ultraamylopectin were mixed, then granulated by wet granulation and pressed to tablets.
b) Dragees, filmcoated tablets: The tablets made according to the method described above were coated by a layer consisting of entero- or gastrosolvent film, or of sugar and talc. The dragees were polished by a mixture of beeswax and carnuba wax. c) Capsules:
0.01-50 % of active ingredient of formula (I), 1-5 % of sodium lauryl sulfate, 15-50 % of starch, 15-50 % of lactose, 1-3 % of colloid silicon dioxide and 0.01-3 % of magnesium stearate were thoroughly mixed, the mixture was passed through a sieve and filled in hard gelatin capsules. d) Suspensions:
Ingredients: 0.01-15 % of active ingredient of formula (I), 0.1-2 % of sodium hydroxide, 0.1-3 % of citric acid, 0.05-0.2 % of nipagin (sodium methyl 4-hydroxybenzoate),
0.005-0.02 % of nipasol, 0.01-0.5 % of carbopol (polyacrilic acid), 0.1-5 % of 96 % ethanol,
0.1-1 % of flavoring agent, 20-70 % of sorbitol (70 % aqueous solution) and 30-50 % of distilled water.
To solution of nipagin and citric acid in 20 ml of distilled water, carbopol was added in small portions under vigorous stirring, and the solution was left to stand for 10-12 h. Then the sodium hydroxide in 1 ml of distilled water, the aqueous solution of sorbitol and finally the ethanolic raspberry flavor were added with stirring. To this carrier the active ingredient
was added in small portions and suspended with an immersing homogenizator. Finally the suspension was filled up to the desired final volume with distilled water and the suspension syrup was passed through a colloid milling equipment. e) Suppositories: For each suppository 0.01-15% of active ingredient of formula (I) and 1-20% of lactose were thoroughly mixed, then 50-95% of adeps pro suppository (for example Witepsol 4) was melted, cooled to 35 °C and the mixture of active ingredient and lactose was mixed in it with homogenizator. The obtained mixture was mould in cooled forms. f) Lyophilized powder ampoule compositions: A 5 % solution of mannitol or lactose was made with bidistilled water for injection use, and the solution was filtered so as to have sterile solution. A 0.01-5 % solution of the active ingredient of formula (I) was also made with bidistilled water for injection use, and this solution was filtered so as to have sterile solution. These two solutions were mixed under aseptic conditions, filled in 1 ml portions into ampoules, the content of the ampoules was lyophilized, and the ampoules were sealed under nitrogen. The contents of the ampoules were dissolved in sterile water or 0.9 % (physiological) sterile aqueous sodium chloride solution before administration.
Pharmacological examples
Methods for testing pharmacological properties of the compounds
MGluR5 receptor binding tests
MGluR5 receptor binding was determined according to Gasparini et.al. (Bioorg.
Med. Chem. Lett. 2000, 12:407-409) with modifications. Based on the high homology between the human and rat mGluR5 receptors, rat cerebro-cortical membrane preparation was used to determine the binding characteristics of reference compounds and novel compounds to the rat mGluR5. The Al 8 cell line expressing hmGluR5a (purchased from Euroscreen) was used to determine binding characteristics of the chemical compounds to the human mGluR5a receptor. As radioligand [3H]-M-MPEP (2 nM) was used. The nonspecific binding was determined in the presence of 10 μM M-MPEP.
Assessment of functional activity
Cell cultures for native rat mGluRS receptors Functional potency at native rat niGluR5 receptors was estimated using primary neocortical cell cultures derived from 17 day old Charles River rat embryos and primary cerebellar cell cultures derived from 4-day old Wistar rats, respectively (for the details on the preparation of neural cell cultures see Johnson, M.I.; Bunge, R.P. (1992): Primary cell cultures of peripheral and central neurons and glia. In: Protocols for Neural Cell Culture, eds: Fedoroff, S.; Richardson A., The Humana Press hie, 51-77.) After isolation the cells were plated onto standard 96-well microplates and the cultures were maintained in an atmosphere of 95% air-5% CO2 at 37 0C. The neocortical and cerebellar cultures were used for the calcium measurements after 5-7 and 3-4 days in vitro, respectively.
Cell cultures for recombinant human mGluR5a receptors
Chinese hamster ovary (CHO) cells stably expressing recombinant human mGluR5a (CH0-mGluR5a, purchased from Euroscreen) receptors were cultured in F12 medium containing 10% FCS, 1% antibiotic antimycotic solution, 400 μg/ml G418, 250 μg/ml zeocin, 5 μg/ml puromycin. Cells were kept at 37 0C in a humidified incubator in an atmosphere of 5% Cθ2/95% air and were passaged three times a week. Cells were plated at 2.5-3.5x 104 cell/well on standard 96-well microplates, receptor expression was induced by adding 600 ng/ml doxycycline on the next day. The calcium measurements were carried out 16-24 hours after the addition of the inducing agent.
Fluorimetric measurement ofcytosolic calcium concentration
Measurements of cytosolic calcium concentration ( [Ca ]j ) were carried out on primary neocortical cultures, and on CH0-mGluR5a cells stably expressing human mGluR5a receptors. Cells were grown in standard 96-well microplates and before the measurement were loaded with a fluorescent Ca2+-sensitive dye, fiuo-4/AM (2 μM): the neural cultures were loaded in their growth medium, CHO-mGluR5a cells were loaded in assay buffer (145 niM NaCl, 5 niM KCl, 2 mM MgCl2, 2 mM CaCl2, 10 mM HEPES, 20 mM D-glucose, 2 mM probenecid, pH=7.4). Loading was done by incubating the cells with 100 μl/well dye solution
at 37 0C in a humidified incubator in an atmosphere of 5% CO2/95% air for 40-120 min. To stop dye loading cells were washed twice with assay buffer. After washing, various concentrations of the test compounds (diluted in assay buffer from a DMSO stock solution, final DMSO concentration was <0.1%) or buffer were added to each well depending on the experimental setup.
In the case of neocortical cultures the assay buffer also contained TTX (0.5 μM, to suppress spontaneous oscillations of [Ca2+]O- After incubation at 37 °C for 10-20 min. baseline and agonist-evoked changes of [Ca2+]* were measured column by column with a plate reader fluorimeter (FlexStation II, Molecular Devices). Excitation and detection of emission was carried out from the bottom of the plate. The whole measurement process was performed at 37 0C and was controlled by custom software. Inhibitory potency of the test compounds was assessed by measuring the reduction in the agonist-evoked [Ca2+]j-elevation in the presence of different concentrations of the compounds.
DHPG was used as agonist for both cultures, the concentration was 20 μM for the neocortical cultures. In the case of CH0-mGluR5a cells DHPG was applied at an EC8O concentration, the EC8o-values were derived from daily determined dose-response curves. Fluorescence data were expressed as ΔF/F (fluorescence change normalized to baseline).
All treatments on a single plate were measured in multiple wells. Data from all wells with the same treatment were averaged and the average values were used for analysis. Inhibitory potency of a compound at a single concentration point was expressed as percent inhibition of the control agonist response. Sigmoidal concentration-inhibition curves were fitted to the data (derived from at least three independent experiments) and IC50-values were determined as the concentration that produces half of the maximal inhibition caused by the compound. Raw fluorescence data were analyzed using Soft Max Pro (Molecular Devices), curve fitting was done with GraphPad Prism.
Results
Compounds of the invention showed affinity for both rat and human mGluR5 receptors and proved to be functional antagonists, that is to inhibit functional responses elicited by stimulation of mGluR5 receptors. Examples of compounds with affinity for rat mGluR5 are given in Table II.
Table IL
* Ki < 50OnM 50OnM < KKl 50OnM *** Ki>1500nM
Claims
1. A compound of formula (I)
(D
- wherein
Y1 and Y2 selected from the group consisting of hydrogen, halogen atom; C1-4 alkyl, C1-4 alkoxy, cyano and trifluoromethyl group, Q is -CH2- group or N;
X1 and X2 are different and are independently selected from N and O;
Z is -(CH2)n- group or S; n is 1 or 2;
R is selected from the group consisting of optionally substituted C1-7 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, C1-3OC1-3 alkyl, C2-7 alkenyl, C2-7 alkynyl, Co^CNR^alkyl; an optionally substituted C3-7 cycloalkyl, aryl, heteroaryl or saturated heterocyclyl;
R1 and R2 are independently selected from hydrogen, C1-7 alkyl or C1-6 alkanoyl group - and/or enentiomers and/or racemates and/or diastereomers and/or geometric isomers and/or pharmaceutically acceptable salts thereof formed with acids and bases.
2. A compound according to claim 1, wherein
Y1 and Y2 selected from the group consisting of hydrogen, halogen atom, C1-4 alkyl, C1-4 alkoxy, cyano and trifluoromethyl group; Q is -CH2- group or N;
X1 and X2 are different and are independently selected from N and O; Z is -(CH2)n- group or S; n is 1 or 2;
R is selected from the group consisting of optionally substituted C1-7 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, Ci-3OC1-3 alkyl, C2-7 alkenyl, C2-7 alkynyl, C0.2(NR1R2)alkyl; C3-7 cycloalkyl group, which is optionally substituted by one or more C1-7 alkyl or oxo group; aryl group, which is optionally substituted by one Ci-7 alkyl or C2-7 alkynyl group; heteroaryl group containing 1-3 heteroatoms independently selected from the group of N, O, S; which is optionally substituted by one halogen atom, C1-7 alkyl or oxo group; 5-6 membered saturated heterocyclyl containing 1-3 heteroatom(s) optionally substituted with C1-6 —alkyl or oxo group;
R1 and R2 are independently selected from hydrogen, C1-7 alkyl or Ci-6 alkanoyl group - and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or pharmaceutically acceptable salts thereof formed with acids and bases.
3. A compound according to claim 1, wherein
Y1 and Y2 selected from the group consisting of hydrogen, halogen atom, C1-4 alkyl, Ci-4 alkoxy, cyano and trifluoromethyl group;
Q is -CH2- group or N; Xi and X2 are different and are independently selected from N and O;
Z is -(CH2)Ii- group or S; n is 1 or 2;
R is selected from the group consisting of optionally substituted Ci-7 alkyl, Ci-4 haloalkyl, Ci-4 hydroxyalkyl, C1-4 cyanoalkyl, C1-3OC1-3 alkyl, C2-7 alkenyl, C2-7 alkynyl, C0-2(NR1RVkYl;
C3-7 cycloalkyl group, which is optionally substituted by one or more C1-7 alkyl or oxo group;
C5-6 aryl group, which is optionally substituted by one Ci-7 alkyl or C2-7 alkynyl group; an optionally substituted heteroaryl ring, wherein said heteroaryl ring is selected from the group of furyl, thiophenyl, pyridyl, oxopyrrolyl, oxothiazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, thiazolyl, thiadiazolyl, izoxazolyl group;
5-6 membered saturated heterocyclic ring containing l-3-heteroatom(s) optionally substituted with Ci-6 -alkyl or oxo group; R and R are independently selected from hydrogen, C1-7 alkyl or Ci-6 alkanoyl group - and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or pharmaceutically acceptable salts thereof formed with acids and bases.
4. A compound according to claim 2, wherein
Yi and Y2 selected from the group consisting of hydrogen, halogen atom, Ci-4 alkyl, Ci-4 alkoxy, cyano and trifluoromethyl group;
Q is -CH2- group or N; Xi and X2 are different and are independently selected from N and O;
Z is -(CH2)n- group or S; n is 1 or 2;
R is selected from the group consisting of C1-7 alkyl, C1-4 haloalkyl, Ci-4 cyanoalkyl, Ci-3OCi-
3 alkyl, C2-7 alkynyl, C0-2(NR1R2)alkyl; tetrahydrofuryl ,oxotetrahydrofuryl group; an optionally substituted heteroaryl ring, wherein said heteroaryl ring is selected from the group of furyl, thiophenyl, pyridyl, thiazolyl, pyrrolyl group;
R1 and R2 are independently selected from hydrogen, Ci-7 alkyl or Ci-6 alkanoyl group — and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or pharmaceutically acceptable salts thereof formed with acids and bases.
5. A compound according to claim 1 selected from the group consisting of:
{4-[3-(3-chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-thiazolidin-3-yl}-(5-methyl-thiophen-2-yl)- methanone, {2-[3-(3-chloro-ρhenyl)-[l,2,4]oxadiazol-5-yl]-ρyrrolidin-l-yl}-(5-methyl-thiophen-2-yl)- methanone,
{2-[3 -(3 -chloro-phenyl)- [ 1 ,2,4]oxadiazol-5-yl]-ρiperidin- 1 -yl} -cyclobutyl-methanone, {2-[3-(3-tolyl)-[l,2,4]oxadiazol-5-yl]-piperidin-l-yl}-cyclobutyl-methanone5 {2-[3-(3-tolyl)-[l,2,4]oxadiazol-5-yl]-pyrrolidin-l-yl}-(5-methyl-thiophen-2-yl)-methanone, (R)-{2-[3-(3-chloro-ρhenyl)-[l,254]oxadiazol-5-yl]-ρyrrolidin-l-yl}-(furan-2-yl)-methanone3 3-[3-(3-chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-piperidin-l-carboxylic acid dimethylamide, {2-[3 -(3 -methoxy-phenyl)-[ 1 ,2,4] oxadiazol-5-yl]-ρiperidin-l -yl} -cyclobutyl-methanone, 2-methoxy-l-[2-(3-m-tolyl-[l,2,4]oxadiazol-5-yl)-pyrrolidin-l-yl]-ethanone, {2-[3 -(3 -chloro-phenyl)- [1,2,4] oxadiazol-5 -yl] -pyrrolidin- 1-yl} -(thiophen-2-yl)-methanone, {2-[3-(3-cyano-ρhenyl)-[l,2,4]oxadiazol-5-yl]-ρiρeridin-l-yl}-(5-methyl-thiophen-2-yl)- methanone, {2-[3-(3-cyano-phenyl)-[l,2,4]oxadiazol-5-yl]-piperidin-l-yl}-cyclobutyl-methanone, {2-[3-(3-chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-piperidin-l-yl}-(furan-2-yl)-methanone, {2- [3 -(3 -tolyl)-[ 1 ,254]oxadiazol-5-yl] -pyrrolidin- 1 -yl} -(furan-3 -yl)-methanone, 2-methyl- 1 -[2-(3 -m-tolyl-[ 1 ,2,4]oxadiazol-5-yl)-piperidin- 1 -yl] -propan- 1 -one, {4-[3-(3-chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-thiazolidin-3-yl}-(furan-2-yl)-metrianone, {2-[3-(3-chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-piperidin-l-yl}-cyclopropyl-methanone, {2-[3 -(3 -tolyl)-[ 1 ,2,4] oxadiazol-5-yl] -piperidin- 1 -yl} -(furan-3 -yl)-methanone, {2-[3-(3-cyano-phenyl)-[l,2,4]oxadiazol-5-yl]-piperidin-l-yl}-cycloheptyl-methanone, {2-[3-(3-chloro-phenyl)-[ 1 ,2,4]oxadiazol-5-yl]-pyrrolidin- 1 -yl} -cycloheptyl-methanone, {2-[3-(3-bromo-phenyl)-[l,2,4]oxadiazol-5-yl]-piρeridin-l-yl}-cyclobutyl-methanone, {2-[3 -(3 ~cyano-phenyl)-[ 1 ,2,4] oxadiazol-5-yl] -piperidin- 1 -yl} -cyclopentyl-methanone, {2-[3 -(3 -chloro-phenyl)- [ 1 ,2,4]oxadiazol-5-yl]-pyrrolidin- 1-yl} -(furan-2-yl)-methanone, {2-[3-(3-tolyl)-[l,2,4]oxadiazol-5-yl]-piperidin-l-yl}-(furan-2-yl)-methanone, {2-[3-(3-tolyl)-[l,2,4]oxadiazol-5-yl]-piperidin-l-yl}-cyclopentyl-methanone, 2-methyl-l-{3-[3-(3-chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-piperidm-l-yl}-propan-l-one, l-{2-[3-(3-chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-piperidin-l-yl}-butan-l-one,
2-[3-(3-chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-piperidin-l-carboxylic acid dimethylamide, 2-methoxy-l-{2-[3-(3-chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-pyrrolidin-l-yl}-ethanone, {3 -[3 -(3 -chloro-phenyl)-[ 1 ,2,4] oxadiazol-5-yl] -piperidin- 1 -yl} -cyclobutyl-methanone, {2-[3-(3-methoxy-phenyl)-[l,2,4]oxadiazol-5-yl]-piperidin-l-yl}-(thiophen-2-yl)-methanone, {2-[3-(3-tolyl)-[l,2,4]oxadiazol-5-yl]-piperidin-l-yl}-cyclopropyl-methanone,
2-methyl-l-{2-[3-(3-chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-ρiperidin-l-yl}-butan-l-one, 4-[3-(3-chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-piperidm-l-carboxylic acid dimethylamide, 3-[5-(3-chloro-phenyl)-[l,2,4]oxadiazol-3-yl]-piperidin-l-carboxylic acid dimethylamide, {2-[5-(3-chloro-phenyl)-[l,2,4]oxadiazol-3-yl]-pyrrolidin-l-yl}-(furan-2-yl)-methanone and salts thereof.
6. A process for the synthesis of a compound of formula (I)
according to claim 1, comprising reacting a compound of formula VII
VII with an activated acid in the presence of a base to give the compound of structural formula I.
7. A pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula (I) as claimed in claim 1 as an active ingredient in association with one or more pharmaceutically acceptable diluents, excipients and/or inert carriers.
8. A pharmaceutical formulation according to claim 7, for use in the prevention and/or treatment of mGluR5 receptor-mediated disorders.
9. A compound according to claim 1, for use in therapy.
10. A compound according to claim 9, for use in the prevention and/or treatment of mGluR5 receptor-mediated disorders.
11. Use of a compound according to claim 1 in the manufacture of a medicament for the prevention and/or treatment of mGluR5 receptor-mediated disorders.
12. Use according to claim 11, wherein said mGluR5 receptor-mediated disorders are psychiatric disorders.
13. Use according to claim 11, wherein said mGluR5 receptor-mediated disorders are neurological disorders.
14. Use according to claim 11, wherein said mGluR5 receptor-mediated disorders are chronic and acute pain.
15. Use according to claim 11, wherein said mGluR5 receptor-mediated disorders are neuromuscular dysfunctions of the lower urinary tract.
16. A method of prevention and/or treatment of mGluR5 receptor-mediated disorders, comprising administering to a mammal in need of such prevention and/or treatment, a therapeutically effective amount of a compound according to claim 1.
17. A method according to claim 16, wherein said mammal is a human.
18. A method according to claim 16, wherein said mGluR5 receptor-mediated disorders are psychiatric disorders.
19. A method according to claim 16, wherein said mGluR5 receptor-mediated disorders are neurological disorders.
20. A method according to claim 16, wherein said mGluR5 receptor-mediated disorders are chronic and acute pain disorders.
21. A method according to claim 16, wherein said mGluR5 receptor-mediated disorders are neuromuscular dysfunctions of the lower urinary tract.
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Cited By (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010084050A2 (en) | 2009-01-13 | 2010-07-29 | Novartis Ag | Quinazolinone derivatives useful as vanilloid antagonists |
US7834039B2 (en) | 2006-12-15 | 2010-11-16 | Abbott Laboratories | Oxadiazole compounds |
WO2011082010A1 (en) * | 2009-12-29 | 2011-07-07 | Eli Lilly And Company | Tetrahydrotriazolopyridine compounds as selective mglu5 receptor potentiators useful for the treatment of schizophrenia |
WO2011092290A1 (en) | 2010-02-01 | 2011-08-04 | Novartis Ag | Pyrazolo[5,1b]oxazole derivatives as crf-1 receptor antagonists |
WO2011092293A2 (en) | 2010-02-01 | 2011-08-04 | Novartis Ag | Cyclohexyl amide derivatives as crf receptor antagonists |
WO2011095450A1 (en) | 2010-02-02 | 2011-08-11 | Novartis Ag | Cyclohexyl amide derivatives as crf receptor antagonists |
EP2421370A1 (en) * | 2009-04-23 | 2012-02-29 | Merck Sharp & Dohme Corp. | 2-alkyl piperidine mglur5 receptor modulators |
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US9403813B2 (en) | 2013-03-12 | 2016-08-02 | Actelion Pharmaceuticals Ltd. | Azetidine amide derivatives as orexin receptor antagonists |
US9421177B2 (en) | 2009-08-14 | 2016-08-23 | University Of Virginia Patent Foundation | Imidamide sphingosine kinase inhibitors |
US9914721B2 (en) | 2013-12-04 | 2018-03-13 | Idorsia Pharmaceuticals Ltd | Use of benzimidazole-proline derivatives |
US10329287B2 (en) | 2012-06-04 | 2019-06-25 | Idorsia Pharmaceuticals Ltd | Benzimidazole-proline derivatives |
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998017652A1 (en) * | 1996-10-18 | 1998-04-30 | Boehringer Ingelheim Pharma Kg | Oxadiazoles, processes for their preparation and their use as medicaments |
WO2000039125A1 (en) * | 1998-12-23 | 2000-07-06 | Pfizer Limited | Piperidines as ccr5 modulators |
WO2002092086A1 (en) * | 2001-03-27 | 2002-11-21 | F. Hoffmann-La Roche Ag | Imidazo (1,2-a)-pyridine derivatives as mglur5 antagonists |
WO2004014902A2 (en) * | 2002-08-09 | 2004-02-19 | Astrazeneca Ab | Compounds having an activity at metabotropic glutamate receptors |
WO2005044797A1 (en) * | 2003-11-06 | 2005-05-19 | Addex Pharmaceuticals Sa | Allosteric modulators of metabotropic glutamate receptors |
-
2005
- 2005-10-05 HU HU0500920A patent/HUP0500920A2/en unknown
-
2006
- 2006-10-05 WO PCT/HU2006/000087 patent/WO2007039781A2/en active Application Filing
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998017652A1 (en) * | 1996-10-18 | 1998-04-30 | Boehringer Ingelheim Pharma Kg | Oxadiazoles, processes for their preparation and their use as medicaments |
WO2000039125A1 (en) * | 1998-12-23 | 2000-07-06 | Pfizer Limited | Piperidines as ccr5 modulators |
WO2002092086A1 (en) * | 2001-03-27 | 2002-11-21 | F. Hoffmann-La Roche Ag | Imidazo (1,2-a)-pyridine derivatives as mglur5 antagonists |
WO2004014902A2 (en) * | 2002-08-09 | 2004-02-19 | Astrazeneca Ab | Compounds having an activity at metabotropic glutamate receptors |
WO2005044797A1 (en) * | 2003-11-06 | 2005-05-19 | Addex Pharmaceuticals Sa | Allosteric modulators of metabotropic glutamate receptors |
Non-Patent Citations (1)
Title |
---|
BING YAN ET AL.: "Quality control on combinatorial chemistry:" JOURNAL OF COMBINATORIAL CHEMISTRY, vol. 5, no. 5, 2003, pages 547-559, XP002413033 * |
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HU0500920D0 (en) | 2005-12-28 |
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