WO2006072828A2 - Heteroaromatic quinoline compounds and their use as pde10 inhibitors - Google Patents
Heteroaromatic quinoline compounds and their use as pde10 inhibitors Download PDFInfo
- Publication number
- WO2006072828A2 WO2006072828A2 PCT/IB2005/003937 IB2005003937W WO2006072828A2 WO 2006072828 A2 WO2006072828 A2 WO 2006072828A2 IB 2005003937 W IB2005003937 W IB 2005003937W WO 2006072828 A2 WO2006072828 A2 WO 2006072828A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pyridin
- methyl
- quinoline
- pyrazol
- phenoxymethyl
- Prior art date
Links
- -1 Heteroaromatic quinoline compounds Chemical class 0.000 title claims description 57
- 239000003112 inhibitor Substances 0.000 title abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 302
- 238000000034 method Methods 0.000 claims abstract description 154
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 41
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 60
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 51
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 45
- 208000035475 disorder Diseases 0.000 claims description 39
- 125000003342 alkenyl group Chemical group 0.000 claims description 36
- 229910052739 hydrogen Inorganic materials 0.000 claims description 34
- 239000001257 hydrogen Substances 0.000 claims description 34
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 33
- 125000000304 alkynyl group Chemical group 0.000 claims description 32
- 125000001188 haloalkyl group Chemical group 0.000 claims description 32
- 125000005842 heteroatom Chemical group 0.000 claims description 29
- 208000028017 Psychotic disease Diseases 0.000 claims description 28
- 229910052757 nitrogen Inorganic materials 0.000 claims description 27
- 150000003839 salts Chemical class 0.000 claims description 27
- 150000002431 hydrogen Chemical class 0.000 claims description 25
- 229910052799 carbon Inorganic materials 0.000 claims description 24
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 23
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 22
- 206010012289 Dementia Diseases 0.000 claims description 21
- AZEXWHKOMMASPA-UHFFFAOYSA-N 2-{[4-(1-methyl-4-pyridin-4-yl-1h-pyrazol-3-yl)phenoxy]methyl}quinoline Chemical compound C=1C=C(OCC=2N=C3C=CC=CC3=CC=2)C=CC=1C1=NN(C)C=C1C1=CC=NC=C1 AZEXWHKOMMASPA-UHFFFAOYSA-N 0.000 claims description 20
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 19
- 230000004770 neurodegeneration Effects 0.000 claims description 19
- 229910052760 oxygen Inorganic materials 0.000 claims description 19
- 239000001301 oxygen Substances 0.000 claims description 19
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 208000024254 Delusional disease Diseases 0.000 claims description 15
- 208000020401 Depressive disease Diseases 0.000 claims description 15
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 150000002367 halogens Chemical class 0.000 claims description 15
- 208000002851 paranoid schizophrenia Diseases 0.000 claims description 15
- 125000001424 substituent group Chemical group 0.000 claims description 15
- 229910052717 sulfur Inorganic materials 0.000 claims description 15
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
- 239000011593 sulfur Substances 0.000 claims description 14
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- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 13
- 125000004414 alkyl thio group Chemical group 0.000 claims description 13
- 230000036651 mood Effects 0.000 claims description 13
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- 231100000393 Substance-induced psychotic disorder Toxicity 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 12
- 125000002950 monocyclic group Chemical group 0.000 claims description 12
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- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 claims description 10
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- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 claims description 10
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- VRWJZGHUCOFGPZ-UHFFFAOYSA-N 2-{[4-(4-pyridin-4-yl-1h-pyrazol-3-yl)phenoxy]methyl}quinoline Chemical compound C=1C=C2C=CC=CC2=NC=1COC(C=C1)=CC=C1C1=NNC=C1C1=CC=NC=C1 VRWJZGHUCOFGPZ-UHFFFAOYSA-N 0.000 claims description 8
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- 101710138657 Neurotoxin Proteins 0.000 claims description 7
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 7
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- 150000003852 triazoles Chemical class 0.000 claims description 7
- FTOVUYIQDPEFAM-UHFFFAOYSA-N 2-[2-[4-(4-pyridin-4-yl-1h-pyrazol-5-yl)phenyl]ethyl]quinoline Chemical compound C=1C=C2C=CC=CC2=NC=1CCC(C=C1)=CC=C1C=1NN=CC=1C1=CC=NC=C1 FTOVUYIQDPEFAM-UHFFFAOYSA-N 0.000 claims description 6
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- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 claims description 5
- JYHUJIBPGPHSOL-UHFFFAOYSA-N 2-[[4-[4-pyridin-4-yl-1-(2,2,2-trifluoroethyl)pyrazol-3-yl]phenoxy]methyl]quinoxaline Chemical compound C=1C=C(OCC=2N=C3C=CC=CC3=NC=2)C=CC=1C1=NN(CC(F)(F)F)C=C1C1=CC=NC=C1 JYHUJIBPGPHSOL-UHFFFAOYSA-N 0.000 claims description 5
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 229940025084 amphetamine Drugs 0.000 claims description 5
- 229960003920 cocaine Drugs 0.000 claims description 5
- 150000002429 hydrazines Chemical class 0.000 claims description 5
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 5
- 231100000572 poisoning Toxicity 0.000 claims description 5
- 230000000607 poisoning effect Effects 0.000 claims description 5
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 4
- NBPVYBUFEQJIJU-UHFFFAOYSA-N 2-[[4-(4-pyridin-4-yl-1,2,4-triazol-3-yl)phenoxy]methyl]quinoline Chemical compound C=1C=C2C=CC=CC2=NC=1COC(C=C1)=CC=C1C1=NN=CN1C1=CC=NC=C1 NBPVYBUFEQJIJU-UHFFFAOYSA-N 0.000 claims description 4
- ITJWXVOIUJXZHN-UHFFFAOYSA-N 2-[[4-(5-methyl-4-pyridin-4-yl-1h-pyrazol-3-yl)phenoxy]methyl]quinoline Chemical compound CC1=NNC(C=2C=CC(OCC=3N=C4C=CC=CC4=CC=3)=CC=2)=C1C1=CC=NC=C1 ITJWXVOIUJXZHN-UHFFFAOYSA-N 0.000 claims description 4
- NOIXNOMHHWGUTG-UHFFFAOYSA-N 2-[[4-[4-pyridin-4-yl-1-(2,2,2-trifluoroethyl)pyrazol-3-yl]phenoxy]methyl]quinoline Chemical compound C=1C=C(OCC=2N=C3C=CC=CC3=CC=2)C=CC=1C1=NN(CC(F)(F)F)C=C1C1=CC=NC=C1 NOIXNOMHHWGUTG-UHFFFAOYSA-N 0.000 claims description 4
- WWQNFLWIICZHER-UHFFFAOYSA-N 4-chloro-2-[[4-(1-methyl-4-pyridin-4-ylpyrazol-3-yl)phenoxy]methyl]quinoline Chemical compound C=1C=C(OCC=2N=C3C=CC=CC3=C(Cl)C=2)C=CC=1C1=NN(C)C=C1C1=CC=NC=C1 WWQNFLWIICZHER-UHFFFAOYSA-N 0.000 claims description 4
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 4
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 4
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- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- 229940005483 opioid analgesics Drugs 0.000 claims description 3
- JTJMJGYZQZDUJJ-UHFFFAOYSA-N phencyclidine Chemical compound C1CCCCN1C1(C=2C=CC=CC=2)CCCCC1 JTJMJGYZQZDUJJ-UHFFFAOYSA-N 0.000 claims description 3
- 229950010883 phencyclidine Drugs 0.000 claims description 3
- OMRQGOHJLIKRNJ-UHFFFAOYSA-N 1-[4-pyridin-4-yl-5-[4-(quinolin-2-ylmethoxy)phenyl]pyrazol-1-yl]propan-2-ol Chemical compound C=1C=C(OCC=2N=C3C=CC=CC3=CC=2)C=CC=1C=1N(CC(O)C)N=CC=1C1=CC=NC=C1 OMRQGOHJLIKRNJ-UHFFFAOYSA-N 0.000 claims description 2
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- 229960001860 salicylate Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
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- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 201000001716 specific phobia Diseases 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 229940071182 stannate Drugs 0.000 description 1
- 125000005402 stannate group Chemical group 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical group 0.000 description 1
- 125000001302 tertiary amino group Chemical group 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 208000016686 tic disease Diseases 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- VWQVUPCCIRVNHF-UHFFFAOYSA-N yttrium atom Chemical compound [Y] VWQVUPCCIRVNHF-UHFFFAOYSA-N 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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- 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
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- the invention pertains to heteroaromatic compounds that serve as effective phosphodiesterase (PDE) inhibitors.
- PDE phosphodiesterase
- the invention also relates to compounds which are selective inhibitors of PDE10.
- the invention further relates to intermediates for preparation of such compounds; pharmaceutical compositions comprising such compounds; and the use of such compounds in methods for treating certain central nervous system (CNS) or other disorders.
- CNS central nervous system
- the invention relates also to methods for treating neurodegenerative and psychiatric disorders, for example psychosis and disorders comprising deficient cognition as a symptom.
- Phosphodiesterases are a class of intracellular enzymes involved in the hydrolysis of the nucleotides cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphates (cGMP) into their respective nucleotide monophosphates.
- the cyclic nucleotides cAMP and cGMP are synthesized by adenylyl and guanylyl cyclases, respectively, and serve as secondary messengers in several cellular pathways.
- the cAMP and cGMP function as intracellular second messengers regulating a vast array of intracellular processes particularly in neurons of the central nervous system. In neurons, this includes the activation of cAMP and cGMP-dependent kinases and subsequent phosphorylation of proteins involved in acute regulation of synaptic transmission as well as in neuronal differentiation and survival.
- the complexity of cyclic nucleotide signaling is indicated by the molecular diversity of the enzymes involved in the synthesis and degradation of cAMP and cGMP. There are at least ten families of adenylyl cyclases, two of guanylyl cyclases, and eleven of phosphodiesterases.
- different types of neurons are known to express multiple isozymes of each of these classes, and there is good evidence for compartmentalization and specificity of function for different isozymes within a given neuron.
- a principal mechanism for regulating cyclic nucleotide signaling is by phosphodiesterase-catalyzed cyclic nucleotide catabolism.
- PDEs encoded by 21 different genes Each gene typically yields multiple splice variants that further contribute to the isozyme diversity.
- the PDE families are distinguished functionally based on cyclic nucleotide substrate specificity, mechanism(s) of regulation, and sensitivity to inhibitors.
- PDEs are differentially expressed throughout the organism, including in the central nervous system. As a result of these distinct enzymatic activities and localization, different PDEs' isozymes can serve distinct physiological functions.
- compounds that can selectively inhibit distinct PDE families or isozymes may offer particular therapeutic effects, fewer side effects, or both.
- PDE10 is identified as a unique family based on primary amino acid sequence and distinct enzymatic activity.
- mouse PDE10A was identified as the first member of the PDE10 family of PDEs (Fujishige et al., J. Biol. Chem. 274:18438- 18445, 1999; Loughney, K. et al., Gene 234:109-117, 1999).
- the murine homologue has also been cloned (Soderling, S. et al., Proc. Natl. Acad. Sci. USA 96:7071-7076, 1999)and N- terminal splice variants of both the rat and human genes have been identified (Kotera, J. et al., Biochem. Biophys. Res. Comm.
- the mouse PDE10A1 is a 779 amino acid protein that hydrolyzes both cAMP and cGMP to AMP and GMP, respectively.
- the approximately 5-fold greater Vmax for cGMP over cAMP has lead to the suggestion that PDE10 is a unique cAMP-inhibited cGMPase (Fujishige et al., J. Biol. Chem. 274:18438-18445, 1999).
- the PDE 10 family of polypeptides shows a lower degree of sequence homology as compared to previously identified PDE families and has been shown to be insensitive to certain inhibitors that are known to be specific for other PDE families.
- PDE10 also is uniquely localized in mammals relative to other PDE families. mRNA for PDE10 is highly expressed only in testis and brain (Fujishige, K. et al., Eur J Biochem. 266:1118-1127, 1999; Soderling, S. et al., Proc. Natl. Acad. Sci. 96:7071-7076, 1999;
- PDE inhibitors A variety of therapeutic uses for PDE inhibitors has been reported including obtrusive lung disease, allergies, hypertension, angina, congestive heart failure, depression and erectile dysfunction (WO 01/41807 A2, incorporated herein by reference).
- United States Patent Application Publication No. 2003/0032579 discloses a method for treating certain neurologic and psychiatric disorders with the selective PDE10 inhibitor papaverine.
- the method relates to psychotic disorders such as schizophrenia, delusional disorders and drug-induced psychosis; to anxiety disorders such as panic and obsessive-compulsive disorder; and to movement disorders including Parkinson's disease and Huntington's disease.
- the present invention provides for compounds of formula I or pharmaceutical salts thereof,
- R 1 is each independently selected from a group consisting of hydrogen, halogen, hydroxyl, cyano, C 1 to C 8 alkyl, C 2 to C 8 alkenyl, C 2 to C 8 alkynyl, Ci to C 8 alkoxy, C 1 to C 8 haloalkyl, C 3 to C 8 cycloalkyl, C 3 to C 8 CyClOaIkVl-C 1 to C 8 alkyl, 4 to 7 membered heterocycloalkyl, C 1 to C 8 alkylthio, -NR 3 R 3 , -0-CF 3 , -S(O) n -R 3 , C(O)-NR 3 R 3 , and C 1 to C 8 alkyl substituted with a heteroatom wherein the heteroatom is selected from a group consisting of nitrogen, oxygen and sulfur and wherein the heteroatom may be further substituted with a substituent selected from a group consisting of hydrogen, Ci to C 8 alkyl, C 3 to C 8 cyclo
- each R 3 is independently selected from a group consisting of hydrogen, C 1 to C 8 alkyl, C 2 to C 8 alkenyl, C 2 to C 8 alkynyl, C 1 to C 8 haloalkyl, C 3 to C 8 cycloalkyl;
- R 2 is selected from the group consisting of hydrogen, C 1 to C 8 alkyl, C 3 to C 8 CyClOaIkVl-C 1 to C 8 alkyl, C 2 to C 8 alkenyl, C 2 to C 8 alkynyl, C 1 to C 8 haloalkyl and C 3 to C 8 cycloalkyl;
- HET 1 is selected from a group consisting of a monocyclic heteroaryl and a bicyclic heteroaryl, wherein the monocyclic and bicyclic heteroaryl may be optionally substituted with at least one R 4 , and;
- R 4 is selected from a group consisting of halogen, hydroxyl, cyano, C 1 to C 8 alkyl, C 2 to C 8 alkenyl, C 2 to C 8 alkynyl, C 1 to C 8 alkoxy, C 3 to C 8 cycloalkyl, C 3 to C 8 cycloalkyl-C ! to C 8 alkyl, C 1 to C 8 alkylthio, and C 1 to C 8 alkyl substituted with a substituent is selected from the group consisting of -OR 8 , -NR 8 R 8 , and -SR 8 , wherein R 8 is independently selected from the group consisting of hydrogen and C 1 to C 8 alkyl
- HET 2 is a monocyclic or bicyclic heteroaryl, wherein the monocyclic and bicyclic heteroaryl optionally substituted with at least one R 5 , with the proviso that HET 2 is not tetrazole;
- R 5 is independently selected from a group consisting of halogen, hydroxyl, cyano, C 1 to C 8 alkyl, C 2 to C 8 alkenyl, C 2 to C 8 alkynyl, C 1 to C 8 alkoxy, C 3 to C 8 cycloalkyl, C 3 to C 8 cycloalkyM ⁇ to C 8 alkyl, C 1 to C 8 alkylthio, -NR 7 R 7 and C 1 to C 8 haloalkyl;
- B 1 and B 2 are adjacent atoms in Het 1 which are independently selected from a group consisting of carbon and nitrogen;
- bond j is a covalent bond between Z and B 2 ;
- bond k is a covalent bond in Het 1 between B 1 and B 2 ;
- X and X 1 are each independently selected from the group consisting of oxygen, sulfur, C(R 2 ) 2 and NR 2 ; provided that at least one of X or X 1 is carbon;
- Y is selected from a group consisting of carbon and nitrogen, provided that when Y is carbon it is substituted with R 6 ; wherein each R 6 is independently selected from a group consisting of hydrogen, halogen, hydroxyl, cyano, C 1 to C 8 alkyl, C 2 to C 8 alkenyl, C 2 to C 8 alkynyl, C 1 to C 8 alkoxy, C 1 to C ⁇ cycl6alky!, C 3 to C 8 cycloalkyl-d to C 8 alkyl, C 1 to C 8 alkylthio, C 1 to C 8 haloalkyl, -NR 7 R 7 ,
- each R 7 is independently selected from the group consisting of hydrogen and C 1 -C 8 alkyl; p is 1 , 2 or 3;n is 0, 1 or 2; and m is 0, 1 or 2.
- the present invention provides for compounds of formula I or pharmaceutical salts thereof;
- R 1 is each independently selected from a group consisting of hydrogen, halogen, hydroxyl, cyano, C 1 to C 8 alkyl, C 2 to C 8 alkenyl, C 2 to C 8 alkynyl, Ci to C 8 alkoxy, C 1 to C 8 haloalkyl, C 3 to C 8 cycloalkyl, C 3 to C 8 cycloalkyl-d to C 8 alkyl, 4 to 7 membered heterocycloalkyl, C 1 to C 8 alkylthio, -NR 3 R 3 , -0-CF 3 , -S(O) n -R 3 , C(O)-NR 3 R 3 , and C 1 to C 8 alkyl substituted with a heteroatom wherein the heteroatom is selected from a group consisting of nitrogen, oxygen and sulfur and wherein the heteroatom may be further substituted with a substituent selected from a group consisting of hydrogen, Ci to C 8 alkyl, C 3 to C 8 cycloalkyl,
- R 2 is selected from the group consisting of hydrogen, C 1 to C 8 alkyl, C 3 to C 8 cycloalkyl- ⁇ to C 8 alkyl, C 2 to C 8 alkenyl, C 2 to C 8 alkynyl C 2 to C 8 alkenyl, C 1 to C 8 haloalkyl and C 3 to C 8 cycloalkyl;
- HET 1 is selected from a group consisting of a monocyclic heteroaryl and a bicyclic heteroaryl, wherein the monocyclic and bicyclic heteroaryl may be optionally substituted with at least one R 4 ;
- R is selected from a group consisting of C 1 to C 8 haloalkyl
- HET 2 is a monocyclic or bicyclic heteroaryl, wherein the monocyclic and bicyclic heteroaryl and may be substituted with at least one R 5
- R 5 is independently selected from a group consisting of halogen, hydroxyl, cyano, C 1 to C 8 alkyl, C 2 to C 8 alkenyl, C 2 to C 8 alkynyl, C 1 to C 8 alkoxy, C 3 to C 8 cycloalkyl, C 3 to C 8 cycloalkyl-C ! to C 8 alkyl, C 1 to C 8 alkylthio, -NR 7 R 7 , and C 1 to C 8 haloalkyl;
- B 1 and B 2 are adjacent atoms in Het 1 which are independently selected from a group consisting of carbon and nitrogen; bond j is a covalent bond between Z and B 2 ; bond k is a bond in Het 1 between B 1 and B 2 ;
- X and X 1 are each independently selected from the group consisting of oxygen, sulfur, C(R 2 ) 2 and NR 2 , provided that at least one of X or X 1 is carbon;
- Y is selected from a group consisting of carbon and nitrogen, provided that when Y is carbon it is substituted with R 6 ; wherein each R 6 is independently selected from a group consisting of hydrogen, halogen, hydroxyl, cyano, C 1 to C 8 alkyl, C 2 to C 8 alkenyl, C 2 to C 8 alkynyl, C 1 to C 8 alkoxy, C 1 to C 8 cycloalkyl, C 3 to C 8 cycloalkyl-C !
- Y is selected from a group consisting of carbon and nitrogen, provided that not more than one Y is nitrogen.
- X 1 is carbon and X is oxygen.
- all Y's are carbon (i.e., the heteroaryl is quinoline).
- the present invention also provides compounds of formula I or pharmaceutical salts thereof, wherein HET 1 is a 5 membered heteroaryl group.
- HET 1 is selected from a group consisting of pyrazole, isoxazole, triazole, oxazole, thiazole and imidazole.
- the present invention also provides subgenera providing for number of ring members for HET 2 of formula I wherein HET 2 is selected from a group consisting of 4-pyridyl, 4- pyridazine and isoxazole. More preferably, HET 2 is 4-pyridyl.
- the invention is directed to a compound of formula l(a)- l(k):
- HET 1 is not tetrazole.
- Compounds of the Formula I may have optical centers and therefore may occur in different enantiomeric and diastereomeric configurations.
- the present invention includes all enantiomers, diastereomers, and other stereoisomers of such compounds of the Formula I, as well as racemic compounds and racemic mixtures and other mixtures of stereoisomers thereof.
- Pharmaceutically acceptable salts of the compounds of Formula I include the acid addition and base salts thereof.
- Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include, but are not limited to, the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mandelates mesylate, methylsulphate, naphthylate, 2- napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate,
- Suitable base salts are formed from bases which form non-toxic salts. Examples include, but are not limited to, the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
- the resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent.
- the degree of ionization in the resulting salt may vary from completely ionised to almost non-ionised.
- the compounds of the invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline.
- the term 'amorphous' refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid.
- a change from solid to liquid properties occurs which is characterised by a change of state, typically second order ('glass transition').
- 'crystalline' refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterised by a phase change, typically first order ('melting point').
- the compounds of the invention may also exist in unsolvated and solvated forms.
- 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
- solvent molecules for example, ethanol.
- 'hydrate' is employed when said solvent is water.
- a currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in
- Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules.
- channel hydrates the water molecules lie in lattice channels where they are next to other water molecules.
- metal-ion coordinated hydrates the water molecules are bonded to the metal iron.
- the complex When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.
- the compounds of the invention may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions.
- the mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution). Mesomorphism arising as the result of a change in temperature is described as
- 'thermotropic' and that resulting from the addition of a second component, such as water or another solvent, is described as 'lyotropic'.
- Compounds that have the potential to form lyotropic mesophases are described as 'amphiphilic' and consist of molecules which possess an ionic (such as -COCTNa + , -COO " K + , or -SO 3 TJa + ) or non-ionic (such as -N ' N + (CH 3 ) 3 ) polar head group.
- an ionic such as -COCTNa + , -COO " K + , or -SO 3 TJa +
- non-ionic such as -N ' N + (CH 3 ) 3
- references to compounds of Formula I include references to salts, solvates, multi-component complexes and liquid crystals thereof and to solvates, multi- component complexes and liquid crystals of salts thereof.
- the compounds of the invention include compounds of Formula I as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically- labeled compounds of Formula I.
- 'prodrugs' of the compounds of Formula I are also within the scope of the invention.
- certain derivatives of compounds of Formula I which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of Formula I having the desired activity, for example, by hydrolytic cleavage.
- Such derivatives are referred to as 'prodrugs'.
- Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (Ed. E. B. Roche, American Pharmaceutical Association).
- Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of Formula I with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).
- prodrugs in accordance with the invention include, but are not limited to, (i) where the compound of Formula I contains a carboxylic acid functionality
- metabolites of compounds of Formula I 1 that is, compounds formed in vivo upon administration of the drug.
- Some examples of metabolites in accordance with the invention include, but are not limited to, (i) where the compound of Formula I contains a methyl group, an hydroxymethyl derivative thereof (-CH 3 -> -CH 2 OH):
- Compounds of Formual I having a nitrogen atom in a tertiary amine functional group may be further substituted with oxygen (i.e., an N-oxide);
- Compounds of Formula I containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of Formula I contains an alkenyl or alkenylene group, geometric cisltrans (or ZJE) isomers are possible. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism in compounds of Formula I containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds that contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
- /-lysine or racemic, for example, dMartrate or oV-arginine.
- Cisltrans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.
- Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).
- racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of
- Formula I contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid.
- the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.
- Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to
- the first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts.
- the second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.
- Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example, Stereochemistry of Organic Compounds by E. L. Eliel and S. H. Wilen (Wiley, 1994).
- the present invention includes all pharmaceutically acceptable isotopically-labelled compounds of Formula I wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.
- isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as
- oxygen such as 15 O, 17 O and 18 O
- phosphorus such as 32 P
- sulphur such as 35 S.
- isotopically-labelled compounds of Formula I for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
- substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
- Isotopically-labeled compounds of Formula I can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically- labeled reagent in place of the non-labeled reagent previously employed.
- solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 O, d 6 -acetone, d 6 - DMSO.
- Specific embodiments of the present invention include the compounds exemplified in the Examples below and their pharmaceutically acceptable salts, complexes, solvates, polymorphs, steroisomers, metabolites, prodrugs, and other derivatives thereof;
- This invention also pertains to a pharmaceutical composition for treatment of certain psychotic disorders and conditions such as schizophrenia, delusional disorders and drug induced psychosis; to anxiety disorders such as panic and obsessive-compulsive disorder; and to movement disorders including Parkinson's disease and Huntington's disease, comprising an amount of a compound of formula I effective in inhibiting PDE 10.
- this invention relates to a pharmaceutical composition for treating psychotic disorders and condition such as schizophrenia, delusional disorders and drug induced psychosis; anxiety disorders such as panic and obsessive-compulsive disorder; and movement disorders including Parkinson's disease and Huntington's disease, comprising an amount of a compound of formula I effective in treating said disorder or condition.
- psychotic disorders and condition such as schizophrenia, delusional disorders and drug induced psychosis
- anxiety disorders such as panic and obsessive-compulsive disorder
- movement disorders including Parkinson's disease and Huntington's disease
- Examples of psychotic disorders that can be treated according to the present invention include, but are not limited to, schizophrenia, for example of the paranoid, disorganized, catatonic, undifferentiated, or residual type; schizophreniform disorder; schizoaffective disorder, for example of the delusional type or the depressive type; delusional disorder; substance-induced psychotic disorder, for example psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type.
- Examples of movement disorders that can be treated according to the present invention include but are not limited to selected from Huntington's disease and dyskinesia associated with dopamine agonist therapy, Parkinson's disease, restless leg syndrome, and essential tremor.
- this invention relates to a method for treating an anxiety disorder or condition in a mammal which method comprises administering to said mammal an amount of a compound of formula I effective in inhibiting PDE 10.
- This invention also provides a method for treating an anxiety disorder or condition in a mammal which method comprises administering to said mammal an amount of a compound of formula I effective in treating said disorder or condition.
- anxiety disorders examples include, but are not limited to, panic disorder; agoraphobia; a specific phobia; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder; acute stress disorder; and generalized anxiety disorder.
- This invention further provides a method of treating a drug addiction, for example an alcohol, amphetamine, cocaine, or opiate addiction, in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula I effective in treating drug addiction.
- a drug addiction for example an alcohol, amphetamine, cocaine, or opiate addiction
- This invention also provides a method of treating a drug addiction, for example an alcohol, amphetamine, cocaine, or opiate addiction, in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula I effective in inhibiting PDE10.
- a "drug addiction”, as used herein, means an abnormal desire for a drug and is generally characterized by motivational disturbances such a compulsion to take the desired drug and episodes of intense drug craving.
- This invention further provides a method of treating a disorder comprising as a symptom a deficiency in attention and/or cognition in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula I effective in treating said disorder.
- This invention also provides a method of treating a disorder or condition comprising as a symptom a deficiency in attention and/or cognition in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula I effective in inhibiting PDE10.
- This invention also provides a method of treating a disorder or condition comprising as a symptom a deficiency in attention and/or cognition in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula I effective in treating said disorder or condition.
- deficiency in attention and/or cognition refers to a subnormal functioning in one or more cognitive aspects such as memory, intellect, or learning and logic ability, in a particular individual relative to other individuals within the same general age population.
- Deficiency in attention and/or cognition also refers to a reduction in any particular individual's functioning in one or more cognitive aspects, for example as occurs in age-related cognitive decline.
- disorders that comprise as a symptom a deficiency in attention and/or cognition are dementia, for example Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia; delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression; attention-deficit/hyperactivity disorder; and age-related cognitive decline.
- dementia for example Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia
- delirium amnestic disorder
- post-traumatic stress disorder mental retardation
- a learning disorder for example reading disorder, mathematics disorder, or a disorder of written expression
- attention-deficit/hyperactivity disorder and age
- This invention also provides a method of treating a mood disorder or mood episode in a mammal, including a human, comprising administering to said mammal an amount of a compound of formula I effective in treating said disorder or episode.
- This invention also provides a method of treating a mood disorder or mood episode in a mammal, including a human, comprising administering to said mammal an amount of a compound of formula I effective in inhibiting PDE10.
- mood disorders and mood episodes that can be treated according to the present invention include, but are not limited to, major depressive episode of the mild, moderate or severe type, a manic or mixed mood episode, a hypomanic mood episode; a depressive episode with atypical features; a depressive episode with melancholic features; a depressive episode with catatonic features; a mood episode with postpartum onset; post- stroke depression; major depressive disorder; dysthymic disorder; minor depressive disorder; premenstrual dysphoric disorder; post-psychotic depressive disorder of schizophrenia; a major depressive disorder superimposed on a psychotic disorder such as delusional disorder or schizophrenia; a bipolar disorder, for example bipolar I disorder, bipolar Il disorder, and cyclothymic disorder.
- This invention further provides a method of treating a neurodegenerative disorder or condition in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula I effective in treating said disorder or condition.
- This invention further provides a method of treating a neurodegenerative disorder or condition in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula I effective in inhibiting PDE10.
- a “neurodegenerative disorder or condition” refers to a disorder or condition that is caused by the dysfunction and/or death of neurons in the central nervous system.
- the treatment of these disorders and conditions can be facilitated by administration of an agent which prevents the dysfunction or death of neurons at risk in these disorders or conditions and/or enhances the function of damaged or healthy neurons in such a way as to compensate for the loss of function caused by the dysfunction or death of at-risk neurons.
- neurotrophic agent refers to a substance or agent that has some or all of these properties.
- neurodegenerative disorders and conditions that can be treated according to the present invention include, but are not limited to, Parkinson's disease; Huntington's disease; dementia, for example Alzheimer's disease, multi-infarct dementia, AIDS-related dementia, and Fronto temperal Dementia; neurodegeneration associated with cerebral trauma; neurodegeneration associated with stroke, neurodegeneration associated with cerebral infarct; hypoglycemia-induced neurodegeneration; neurodegeneration associated with epileptic seizure; neurodegeneration associated with neurotoxin poisoning; and multi-system atrophy.
- Parkinson's disease Huntington's disease
- dementia for example Alzheimer's disease, multi-infarct dementia, AIDS-related dementia, and Fronto temperal Dementia
- neurodegeneration associated with cerebral trauma neurodegeneration associated with stroke, neurodegeneration associated with cerebral infarct
- hypoglycemia-induced neurodegeneration neurodegeneration associated with epileptic seizure
- neurodegeneration associated with neurotoxin poisoning and multi-system atrophy.
- the neurodegenerative disorder or condition comprises neurodegeneration of striatal medium spiny neurons in a mammal, including a human.
- the neurodegenerative disorder or condition is Huntington's disease.
- This invention also provides a pharmaceutical composition for treating psychotic disorders, delusional disorders and drug induced psychosis; anxiety disorders, movement disorders, mood disorders, neurodegenerative disorders, obesity, and drug addiction, comprising an amount of a compound of formula I effective in treating said disorder or condition.
- This invention also provides a method of treating a disorder selected from psychotic disorders, delusional disorders and drug induced psychosis; anxiety disorders, movement disorders, obesity, mood disorders, and neurodegenerative disorders, which method comprises administering an amount of a compound of formula I effective in treating said disorder.
- This invention also provides a method of treating disorders selected from the group consisting of: dementia, Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia; delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression; attention-deficit/hyperactivity disorder; age-related cognitive decline, major depressive episode of the mild, moderate or severe type; a manic or mixed mood episode; a hypomanic mood episode; a depressive episode with atypical features; a depressive episode with melancholic features; a depressive episode with catatonic features; a mood episode with postpartum onset; post-stroke depression; major depressive disorder; dysthymic disorder; minor depressive disorder; premenstrual dysphoric disorder; post-psychotic depressive disorder of schizophrenia; a major depressive disorder
- This invention also provides a method of treating psychotic disorders, delusional disorders and drug induced psychosis; anxiety disorders, movement disorders, mood disorders, neurodegenerative disorders, obesity, and drug addiction which method comprises administering an amount of a compound of formula I effective in inhibiting PDE10.
- alkyl as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched moieties. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, and t-butyl.
- alkenyl as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon double bond wherein alkyl is as defined above. Examples of alkenyl include, but are not limited to, ethenyl and propenyl.
- alkynyl as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon triple bond wherein alkyl is as defined above.
- alkynyl groups include, but are not limited to, ethynyl and 2-propynyl.
- alkoxy as used herein, unless otherwise indicated, as employed herein alone or as part of another group refers to an alkyl, groups linked to an oxygen atom.
- alkylthio as used herein, unless otherwise indicated, employed herein alone or as part of another group includes any of the above alkyl groups linked through a sulfur atom.
- halogen or halo as used herein alone or as part of another group refers to chlorine, bromine, fluorine, and iodine.
- haloalkyl refers to at least one halo group, linked to an alkyl group.
- haloalkyl groups include, but are not limited, to trifluoromethyl, trifluoroethyl, difluoromethyl and fluoromethyl groups.
- cycloalkyl as used herein, unless otherwise indicated, includes non- aromatic saturated cyclic alkyl moieties wherein alkyl is as defined above. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
- aryl as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl, naphthyl, indenyl, and fluorenyl. "Aryl” encompasses fused ring groups wherein at least one ring is aromatic.
- heterocyclic refers to non-aromatic cyclic groups containing one or more heteroatoms, prefereably from one to four heteroatoms, each preferably selected from oxygen, sulfur and nitrogen.
- heterocyclic groups of this invention can also include ring systems substituted with one or more oxo moieties.
- non-aromatic heterocyclic groups are aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, piperazinyl, 1 ,2,3,6-tetrahydropyridinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholino, thiomorpholino, thioxanyl, pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1 ,3- dioxolanyl, pyrazolinyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.
- heteroaryl refers to aromatic groups containing one or more heteroatoms (preferably oxygen, sulfur and nitrogen), preferably from one to four heteroatoms.
- a multicyclic group containing one or more heteroatoms wherein at least one ring of the group is aromatic is a "heteroaryl” group.
- the heteroaryl groups of this invention can also include ring systems substituted with one or more oxo moieties.
- Heteroaryl groups containing a tertiary nitrogen may also be further substituted with oxygen (i.e., an N-oxide).
- heteroaryl groups are pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazoiyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl
- substituents refers to from one to the maximum number of substituents possible based on the number of available bonding sites.
- all the foregoing groups derived from hydrocarbons may have up to about 1 to about 20 carbon atoms (e.g. C 1 -C 2O alkyl, C 2 -C 2O alkenyl, C 3 -C 2O cycloalkyl, 3-20 membered heterocycloalkyl; C 6 -C 20 aryl, 5-20 membered heteroaryl, etc.) or 1 to about 15 carbon atoms (e.g., C 1 -C 15 alkyl, C 2 -C 15 alkenyl, C 3 -C 15 cycloalkyl, 3-15 membered heterocycloalkyl, C 6 -Ci 5 aryl, 5-15 membered heteroaryl, etc.) , or 1 to about 12 carbon atoms, or 1 to about 8 carbon atoms, or 1 to about 6 carbon atoms.
- carbon atoms e.g. C 1 -C 2O alkyl, C 2 -C 2O alkenyl, C 3
- Neurotoxin poisoning refers to poisoning caused by a neurotoxin.
- a neurotoxin is any chemical or substance that can cause neural death and thus neurological damage.
- An example of a neurotoxin is alcohol, which, when abused by a pregnant female, can result in alcohol poisoning and neurological damage known as Fetal Alcohol Syndrome in a newborn.
- neurotoxins include, but are not limited to, kainic acid, domoic acid, and acromelic acid; certain pesticides, such as DDT; certain insecticides, such as organophosphates; volatile organic solvents such as hexacarbons (e.g. toluene); heavy metals (e.g. lead, mercury, arsenic, and phosphorous); aluminum; certain chemicals used as weapons, such as Agent Orange and Nerve Gas; and neurotoxic antineoplastic agents.
- certain pesticides such as DDT
- certain insecticides such as organophosphates
- volatile organic solvents such as hexacarbons (e.g. toluene)
- heavy metals e.g. lead, mercury, arsenic, and phosphorous
- aluminum e.g. lead, mercury, arsenic, and phosphorous
- certain chemicals used as weapons such as Agent Orange and Nerve Gas
- neurotoxic antineoplastic agents include, but are not limited to, kainic acid, do
- selective PDE10 inhibitor refers to a substance, for example an organic molecule, that effectively inhibits an enzyme from the PDE10 family to a greater extent than enzymes from the PDE 1-9 families or PDE11 family.
- a selective PDE10 inhibitor is a substance, for example an organic molecule, having a Kj for inhibition of PDE10 that is less than or about one-tenth the Kj that the substance has for inhibition of any other PDE enzyme.
- the substance inhibits PDE10 activity to the same degree at a concentration of about one-tenth or less than the concentration required for any other PDE enzyme.
- a substance is considered to effectively inhibit PDE10 activity if it has a Kj of less than or about 10 ⁇ M, preferably less than or about 0.1 ⁇ M.
- a "selective PDE10 inhibitor” can be identified, for example, by comparing the ability of a substance to inhibit PDE10 activity to its ability to inhibit PDE enzymes from the other
- PDE families For example, a substance may be assayed for its ability to inhibit PDE10 activity, as well as PDE1A, PDE1 B, PDE1C, PDE2, PDE3A, PDE3B, PDE4A, PDE4B,
- treating refers to reversing, alleviating, or inhibiting the progress of the disorder to which such term applies, or one or more symptoms of the disorder.
- the term also encompasses, depending on the condition of the patient, preventing the disorder, including preventing onset of the disorder or of any symptoms associated therewith, as well as reducing the severity of the disorder or any of its symptoms prior to onset.
- Treating refers also to preventing a recurrence of a disorder.
- treating schizophrenia, or schizophreniform or schizoaffective disorder also encompasses treating one or more symptoms (positive, negative, and other associated features) of said disorders, for example treating, delusions and/or hallucination associated therewith.
- symptoms of schizophrenia and schizophreniform and schizoaffecctive disorders include disorganized speech, affective flattening, alogia, anhedonia, inappropriate affect, dysphoric mood (in the form of, for example, depression, anxiety or anger), and some indications of cognitive dysfunction.
- the term "mammal”, as used herein, refers to any member of the class “Mammalia”, including, but not limited to, humans, dogs, and cats.
- the compound of the invention may be administered either alone or in combination with pharmaceutically acceptable carriers, in either single or multiple doses.
- suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
- the pharmaceutical compositions formed thereby can then be readily administered in a variety of dosage forms such as tablets, powders, lozenges, liquid preparations, syrups, injectable solutions and the like.
- These pharmaceutical compositions can optionally contain additional ingredients such as flavorings, binders, excipients and the like.
- the compound of the invention may be formulated for oral, buccal, intranasal, parenteral (e.g. intravenous, intramuscular or subcutaneous), transdermal (e.g. patch) or rectal administration, or in a form suitable for administration by inhalation or insufflation.
- parenteral e.g. intravenous, intramuscular or subcutaneous
- transdermal e.g. patch
- rectal administration or in a form suitable for administration by inhalation or insufflation.
- the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycolate); or wetting agents (e.g. sodium lauryl sulphate).
- binding agents e.g. pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
- fillers e.g. lactose, microcrystalline cellulose or calcium phosphate
- lubricants e.g. magnesium stearate, talc or silica
- disintegrants e.g. potato starch or sodium starch glycolate
- wetting agents
- Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
- Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters or ethyl alcohol); and preservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid).
- suspending agents e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats
- emulsifying agents e.g. lecithin or acacia
- non-aqueous vehicles e.g. almond oil, oily esters or ethyl alcohol
- preservatives e.g
- the composition may take the form of tablets or lozenges formulated in conventional manner.
- the compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion.
- Formulations for injection may be presented in unit dosage form, e.g. in ampules or in multi-dose containers, with an added preservative. They may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents.
- the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
- a product solution When a product solution is required, it can be made by dissolving the isolated inclusion complex in water (or other aqueous medium) in an amount sufficient to generate a solution of the required strength for oral or parenteral administration to patients.
- the compounds may be formulated for fast dispersing dosage forms (fddf), which are designed to release the active ingredient in the oral cavity. These have often been formulated using rapidly soluble gelatin-based matrices. These dosage forms are well known and can be used to deliver a wide range of drugs.
- Most fast dispersing dosage forms utilize gelatin as a carrier or structure-forming agent. Typically, gelatin is used to give sufficient strength to the dosage form to prevent breakage during removal from packaging, but once placed in the mouth, the gelatin allows immediate dissolution of the dosage form.
- the compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
- the compound of the invention is conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
- a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
- the dosage unit may be determined by providing a valve to deliver a metered amount.
- the pressurized container or nebulizer may contain a solution or suspension of the active compound.
- Aerosol formulations for treatment of the conditions referred to above e.g. migraine
- each metered dose or "puff" of aerosol contains about 20 mg to about 1000 mg of the compound of the invention.
- the overall daily dose with an aerosol will be within the range of about 100 mg to about 10 mg.
- Administration may be several times daily, e.g. 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses each time.
- a proposed daily dose of the compound of the invention for oral, parenteral, rectal or buccal administration to the average adult human for the treatment of the conditions referred to above is from about 0.01 mg to about 2000 mg, preferably from about 0.1 mg to about 200 mg of the active ingredient of formula I per unit dose which could be administered, for example, 1 to 4 times per day.
- Assay methods are available to screen a substance for inhibition of cyclic nucleotide hydrolysis by the PDE 10 and the PDEs from other gene families.
- the cyclic nucleotide substrate concentration used in the assay is 1/3 of the K n , concentration, allowing for comparisons of IC 50 values across the different enzymes.
- PDE activity is measured using a Scintillation Proximity Assay (SPA)-based method as previously described (Fawcett et al., 2000).
- SPA Scintillation Proximity Assay
- PDE inhibitors The effect of PDE inhibitors is determined by assaying a fixed amount of enzyme (PDEs 1-11) in the presence of varying substance concentrations and low substrate, such that the IC 50 approximates the Kj (cGMP or cAMP in a 3:1 ratio unlabelled to [ 3 H]-labeled at a concentration of 1/3 Km). ).
- the final assay volume is made up to 100 ⁇ l with assay buffer [50 mM Tris-HCI pH 7.5, 8.3 mM MgCI 2 , 1 mg/ml bovine serum albumin].
- Reactions are initiated with enzyme, incubated for 30-60 min at 30 0 C to give ⁇ 30% substrate turnover and terminated with 50 ⁇ l yttrium silicate SPA beads (Amersham) (containing 3 mM of the respective unlabelled cyclic nucleotide for PDEs 9 and 11). Plates are re-sealed and shaken for 20 min, after which the beads were allowed to settle for 30 minutes in the dark and then counted on a TopCount plate reader (Packard, Meriden, CT). Radioactivity units can be converted to percent activity of an uninhibited control (100%), plotted against inhibitor concentration and inhibitor IC 50 values can be obtained using the "Fit Curve' Microsoft Excel extension.
- compounds of the present invention were determined to have an IC 50 for inhibiting PDE10 activity of less than about 10 micromolar.
- This invention also pertains to the preparation of compounds of formula I.
- the present invention also provides for methods for the synthesis compounds of formula I.
- the present invention provides for a process for forming the compound of formula I 1 comprising a step of reacting a compound of formula Il
- dimethoxymethyl-dimethyl amine and hydrazine or substituted hydrazine e.g., such as R 20 -NHNH 2 where R 20 is alkyl.
- the present invention also provides for a process for forming the compound of formula I, comprising a step of reacting a compound of formula III
- the present invention also provides for a process for forming the compound of formula I, comprising a step of reacting a compound of formula IV with dimethoxymethyl-dimethyi amine and hydrazine or substituted hydrazine.
- the present invention also provides for a process for forming the compound of formula I, comprising a step of reacting a compound of formula V
- the substituted pyrazole compounds can be prepared by alkylation of the NH pyrazole.
- One set of conditions is the utilization of cesium carbonate as the base with an alkyl halide as the electrophile in a solvent such as dimethyl formamide. Some reactions require heating.
- a variety of heterocycles can be prepared from the enaminone intermediate.
- Pyrimidines can be prepared by heating with substituted formamides in the presence of ethanol and sodium ethoxide.
- Isoxazoles are prepared by heating the enaminone with hydroxyl amine in methanol/acetic acid. Only one isomer in the isoxazole case is formed. By heating with amino pyroles, amino imidazoles or amino triazoles, 6-5 bicyclic systems can be formed.
- a variety of 4-pyridyl heterocyclic replacements can be prepared according to scheme 4.
- Methyl heterocycles such as 3,5-dimethyl isoxazole and methyl pyridazine can be deprotated with lithium diisopropyl amide and added to a Weinreb amide (Weinreb et al, Tet Lett., 1981, 22(39) 3815) to provide the desired ketone.
- Sequential treatment with dimethoxymethyl-dimethyl amine and a hydrazine provides the heterocyclic pyrazoles.
- Pyrimidines and isoxazoles can also be prepared as described in Scheme 3.
- N-pyridyl pyrazoles can be prepared according to Scheme 5.
- the starting ketones are prepared by alkylation of the phenol as depicted in Scheme 1.
- Treatment of the ketone with dimethoxymethyl-dimethyl amine followed by addition of 4-pyridyl hydrazine provides the desired compounds.
- Other heterocyclic replacements for 4-pyridyl can be prepared by using the requisite hydrazine.
- 3-substituted-N-pyridyl pyrazoles can be prepared by literature methods, (see J. Med. Chem. 2004, 47, 2180). Treatment of the acetophenone (prepared according to scheme 1) with sodium methoxide and dimethyl oxalate provides the ester intermediate. Addition of 4-pyridyl hydrazine (see J. Med. Chem. 2002, 45(24) 5397) provides the pyrazole with an ester at the 3-position. This ester can be converted to amides by hydrolysis and coupling with amines. It can be converted to ethers by reduction to the alcohol and alkylation. Amine formation is capable by amide formation followed by reduction or conversion to the aldehyde followed by reductive amination. All of these transformations can be carried out by those skilled in the art of organic chemistry.
- the benzyl intermediates can be prepared by the method shown in scheme 1.
- the benzyl ether can be removed via treatment with hydrogen gas over a palladium catalyst such as palladium on carbon or palladium hydroxide in a variety of solvents.
- the phenol can then be alkylated using a benzylic chloride in acetone heating with potassium carbonate.
- Mitsunobu chemistry (Hughes, D.L., The Mitsunobu Reaction. Organic Reactions. Vol. 42. 1992, New York. 335-656.) can be applied to couple the phenol with alcohols.
- benzylic halides or alcohols are commericially available or are known in the literature.
- General ways to make these intermediates by those skilled in the art are reduction of an ester, acid or aldehyde to form an alcohol.
- One general procedure is the oxidation of a benylic site with selenium dioxide to provide an aldehyde that is subsequentially reduced with sodium borohydride.
- Benzylic halide can be formed vial halogenation (see Syn. Comm. 1995, 25(21) 3427-3434).
- Triazole analogues can be prepared in many ways. One way is depicted in Scheme 9. Treatment of a hydrazide with dimethyl formamide dimethyl acetal to form an intermediate, which is subsequently treated with an amine or aniline with the addition of heat and acetic acid provides the 1 ,2,4 triazoles (see Org. Lett, 2004, 6(17), 2969-2971). The regioisomeric triazoles can be prepared by interchanging the functionality of the starting materials.
- triazole isomers can be prepared according to scheme 10 by starting with the carboxyamides and treating with dimethyl formamide dimethyl acetai followed by the addition of aromatic hydrazines.
- the regioisomeric triazoles can be prepared by interchanging the functionality of the starting materials.
- the inverted ketone isomer can be prepared according to Scheme 11. (Bunting et al. JACS, 1988, 110, 4008.) The starting aldehyde is coupled with a phosphonate to provide the enaminone. The enaminone is hydrolyzed to provide the desired ketone. The ketone can then be utilized according to Scheme 1 ,2 and 3 to provide the desired compounds Scheme 11
- Scheme 12 depicts a method for synthesizing a 4,5-diaryl oxazole.
- 4-benzyloxy-benzaldehyde and 4-methylbenzenesulfinic acid are heated with formamide to generate a substituted formamide as shown.
- This transformation is known in the literature.fJ. Med Chem., 2002, 45, 1697]
- Dehydration of the formamide in a reaction mediated by POCI3 gives a tosylmethyl isocyanate.
- This class of compound can be treated with an aldehyde and a base to yield an oxazole.
- the tosylmethylisocyanate is treated with isonicotinaldehyde and potassium carbonate.
- the product of this reaction is an oxazole possessing a 4-benzyloxyphenyl group at the 4-position of the oxazole ring, and a 4-pyridyl substituent at the 5-position.
- substituents can be substituted with other aryl groups simply by utilizing different aryl-aldehydes for steps one and three of the sequence.
- Cleavage of the benzyloxy group is achieved by the standard method of catalytic hydrogenation, and the resultant phenol is easily alkylated by treatment with an alkyl halide, such as 2-(chloromethyl)quinoline, and cesium fluoride in DMF.
- the method is not limited to the illustrated case as the relative positions of the phenyl and pyridyl rings can be switched, and said rings may comprise a variety of aryl groups displaying various substitution patterns.
- Scheme 13 depicts a method for preparing 4,5-substituted oxazoles possessing alkyl group substitution in the 2-position of the oxazole ring.
- 1-(4-Benzyloxy- phenyl)-2-pyridin-4-yl-ethanone is brominated by treatment with bromine in acetic acid according to traditional methods.
- the resultant ⁇ -bromoketone is then treated with ammonium acetate and sodium acetate in acetic acid, which yields the methyl-substituted oxazole ring as disclosed in the patent literature (WO 9513067).
- the methyl group can be replaced by other alkyl groups.
- substitution of ammonium ethanoate, sodium ethanoate, and ethanoic acid acid would yield ethyl group substitution.
- Cleavage of the benzyloxy group is achieved by the standard method of catalytic hydrogenation, and the resultant phenol is easily alkylated by treatment with an alkyl halide as described above.
- the method is not limited to the illustrated case as the relative positions of the phenyl and pyridyl rings can be switched, and said rings may comprise a variety of aryl groups displaying various substitution patterns.
- Step 1 of Scheme 14 is an imine formation/heterocycle formation.
- a compound of formula 2A wherein R1 is alkyl, benzyl, or allyl is condensed with 4-pyridine carboxaldehyde in solvent such as toluene and is heated to reflux with a Dean-Stark apparatus attached to remove water for about 40 hours.
- the crude imine is mixed with tosylmethylisocyanide and a base such as potassium carbonate, in a solvent mixture of 1 ,2- dimethoxyethane and methanol, and is heated at reflux for about 3 hours to afford 3A.
- Step 2 of Scheme 14 is a phenol dealkylation.
- R1 is methyl
- the dealkylation can be effected with boron tribromide (BBr3) in a non-coordinating solvent such as methylene chloride at about 20-40 0 C for about 3-48 hours, where about 24 hours is preferred to yield 4A.
- R2 is benzyl
- the dealkylation can be effected with in neat trifluoracetic acid with anisole at a temperature of about 75 0 C for about 3-48 hours, where about 24 hours is preferred to yield 4A.
- the dealkylation can be effected with a palladium catalyst, such as dichloropalladium bis(triphenylphosphine) of palladium acetate, where dichloropalladium bis(triphenylphosphine) is preferred, with a reducing agent such as n- butylammonium formate, in a solvent such as tetrahydrofuran, 1 ,2-dichloroethane, methylene chloride, or an alkanol, where 1 ,2-dichloroethane is preferred, in a temperature range from about 2O 0 C to 75 0 C, to yield 4A.
- a palladium catalyst such as dichloropalladium bis(triphenylphosphine) of palladium acetate, where dichloropalladium bis(triphenylphosphine) is preferred, with a reducing agent such as n- butylammonium formate, in a solvent such as tetrahydrofuran,
- Step 3 of Scheme 14 is a phenol alkylation.
- a base such as potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride, or potassium hydride, where cesium carbonate or sodium hydride are preferred
- a solvent such as tetrahydrofuran, 1,2-dimethoxyethane, N
- Step 4 of Scheme 14 is an imidazole deprotonation/electrophilic trapping.
- a base such as lithium diisopropyl amide or lithium 2,2,6,6-tetramethylpiperidine, where lithium diisopropylamide is preferred, in a solvent such as tetrahydrofuran, at a temperature from about -78 0 C to 0 0 C, where about -20 0 C is preferred, for about 5 minutes to 30 minutes, where about 10 minutes is preferred, followed by addition of the desired electrophile R3-I, affords 3B.
- a base such as lithium diisopropyl amide or lithium 2,2,6,6-tetramethylpiperidine, where lithium diisopropylamide is preferred
- a solvent such as tetrahydrofuran
- Step 5 of Scheme 14 is a phenol dealkylation and uses the same methods as described for Step 2 above to produce 4B.
- Step 6 of Scheme 14 is a phenol alkylation and uses the same methods as described for Step 3 above to produce 1 B.
- Step 1 of Scheme 15 is an acylation of an amine to form an amide.
- Compound 2A wherein R1 can be methyl, benzyl, or allyl, is treated with an acid chloride or a carboxylic acid in the presence of a coupling reagent, such as tri-n-propylphosphonic anhydride or dicyclohexyl carbodiimide, where tri-/?-propylphosphonic anhydride is preferred, in the presence of a base such as sodium hydroxide, potassium or sodium carbonate, triethylamine, or diisopropylethylamine, where diisopropylethylamine is preferred, in a solvent system such as water/methylene chloride, water/ethyl acetate, ethyl acetate, tetrahydrofuran, or methylene chloride, where ethyl acetate is preferred, at a temperature from about 0 0 C to 50 0 C, where about 20 0 C to
- Step 2 consists of a chlorination to form an iminochloride, reaction with an amine to form an amidine, followed by treatment with acid to form an imidazole.
- Compound 5A is treated with a chlorinating agent such as PCI 5 /POCI 3 at a temperature of about 120 0 C for about 4 hours.
- the chlorinating agent is removed in vacuo and an excess of 1,1-diethoxy-2- ethylamine in a solvent such as isopropanol is added and the mixture is stirred for about 5-24 hours at about 23 0 C.
- the solvent is removed in vacuo and concentrated hydrochloric acid and isopropanol is added and the mixture is heated to about 90 °C for about 24 hours to yield 6A.
- Step 3 of Scheme 15 is a phenol dealkylation.
- R1 is methyl
- the dealkylation can be effected with boron tribromide (BBr3) in a non-coordinating solvent such as methylene chloride at about 20-40 0 C for about 3-48 hours, where about 24 hours is preferred to yield 7A.
- R2 is benzyl
- the dealkylation can be effected with in neat trifluoracetic acid with anisole at a temperature of about 75 0 C for about 3-48 hours, where about 24 hours is preferred to yield 7A.
- the dealkylation can be effected with a palladium catalyst, such as dichloropalladium bis(triphenylphosphine) of palladium acetate, where dichloropalladium bis(triphenylphosphine) is preferred, with a reducing agent such as n- butylammonium formate, in a solvent such as tetrahydrofuran, 1,2-dichloroethane, methylene chloride, or an alkanol, where 1 ,2-dichloroethane is preferred, in a temperature range from about 20 0 C to 75 0 C, to yield 7A.
- a palladium catalyst such as dichloropalladium bis(triphenylphosphine) of palladium acetate, where dichloropalladium bis(triphenylphosphine) is preferred, with a reducing agent such as n- butylammonium formate, in a solvent such as tetrahydrofuran, 1,2-d
- Step 4 of Scheme 15 is a phenol alkylation.
- a base such as potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride, or potassium hydride, where cesium carbonate is preferred, in a solvent such as tetrahydrofuran, 1 ,2- dimethoxyethane, N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, or dimethylsulfoxide, where dimethylsulfoxide is preferred, at a temperature from about 20 0 C to 70 0 C, where- about 23 0 C is preferred, for about 3-48 hours, where about 24 hours is preferred, affords 1C.
- a base such as potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride, or potassium hydride, where cesium carbonate is preferred
- a solvent such as tetrahydrofuran, 1 ,2- dimethoxyethane, N,N-dimethylformamide, dimethylacetamide, N-methylpyrrol
- the quinolyl benzaldehyde can be coupled with the ketone in the presence of refluxing piperidine to provide the desired olefin.
- Treatment with hydrazine affords the NH- pyrazole.
- This can be further elaborated by treatment with sodium hydride and an electrophile such as methyl iodide to provide substituted pyrazoles.
- the alkyne and iodide can be coupled via a Sonagashira coupling and the methyl ether deprotected with boron tribromide in dichloromethane.
- Alkylation of the phenol with 2-chloromethylquinoline according to the methods described above provides the penultimate intermediate.
- HPLC system 2 used a linear gradient of 3:7 A:B to 95/5 A:B over 15 min.
- Example 25 2- ⁇ 4-[1-Methyl-4-(3-methyl-isoxazol-5-yl)-1H-pyrazol-3-yl]-phenoxymethyl ⁇ -quinoline Following the procedure for the preparation of 2-[4-(1-Methyl-4-pyridin-4-yl-1 H- pyrazol-3-yI)-phenoxymethyl]-quinoline but substituting 3-Dimethylamino-2-(3-methyl- isoxazol-5-yl)-1-[4-(quinolin-2-ylmethoxy)-phenyl]-propenone provided the title compound as a white solid.
- Example 57 2-[4-(5-Pyridin-4-yl-[1,2,4]triazol-1-yl)-phenoxymethyr]-quinoline lsonicatinamide (4.15g) was heated in 35 ml of N,N-Dimethylformamide diethyl acetal at reflux for 3 h. The reaction mixture was cooled to ambient temperature and concentrated to give 5.02g of N-Dimethylaminomethylene-isonicotinamide.
- the middle-polarity substance (235 mg yellow solid), 4-(5-(4- methoxyphenyl)-1 -methyl-1 H-1 ,2,3-triazol-4-yl)pyridine, 1 H NMR (CDCI 3 , 400 mHz) ⁇ 8.49 (d,
- Phosphorus pentachloride (572 mg, 2.75 mmol) was added to a mixture of 4- methoxy-N-(pyridin-4-yl)benzamide (626 mg, 2.75 mmol) in phosphorus oxychloride (3 mL) and the mixture was heated a 105 0 C oil bath for 4h. The mixture was concentrated to dryness. To the residue was added 2,2-dimethoxyethylamine (3.1 g) in methanol, and the mixture was stirred at RT. After more than one hour the mixture was partially concentrated to remove most of the methanol, stirred at RT overnight and concentrated to dryness, lsopropyl alcohol (10 mL) and cone.
- Example 82 88% yield; diagnostic 13 C NMR signals (100 MHz, CDCI 3 ) ⁇ 159.060, 157.078, 150.004, 147.836, 137.689, 137.397, 130.204, 129.934, 129.239, 128.962, 127.968, 127.871 , 127.385, 127.011, 120.886, 119.354, 116.273, 71.975, 14.225; MS (AP/CI) 393.49 (M+H)+.
- Example 84 393.49 (M+H)+.
- Example 82 92% yield; diagnostic 13 C NMR signals (100 MHz, CDCI 3 ) ⁇ 159.090, 157.078, 150.147, 149.930, 147.836, 137.734, 137.405, 130.211 , 129.680, 129.232, 129.127, 128.970, 127.968, 127.886, 127.392, 127.018, 120.961 , 119.354, 116.243, 71.968, 21.090, 12.333; MS (AP/CI) 407.5 (M+H)+. Preparation 87
- reaction mixture was concentrated in vacuo and concentrated hydrochloric acid (36.5%, 25 mL) in isopropanol (15 mL) was added.
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DE602005022115T DE602005022115D1 (en) | 2005-01-07 | 2005-12-22 | HETERO-AROMATIC CHINOLIN COMPOUNDS AND THEIR USE AS PDE10 INHIBITORS |
AT05824101T ATE472543T1 (en) | 2005-01-07 | 2005-12-22 | HETEROAROMATIC QUINOLINE COMPOUNDS AND THEIR USE AS PDE10 INHIBITORS |
MX2007008287A MX2007008287A (en) | 2005-01-07 | 2005-12-22 | Heteroaromatic quinoline compounds and their use as pde10 inhibitors. |
DK05824101.9T DK1841757T3 (en) | 2005-01-07 | 2005-12-22 | Heteroaromatic quinoline compounds and their use as PDE10 inhibitors |
NZ555737A NZ555737A (en) | 2005-01-07 | 2005-12-22 | Heteroaromatic quinoline compounds and their use as PDE10 inhibitors |
EA200701252A EA012211B1 (en) | 2005-01-07 | 2005-12-22 | Heteroaromatic quinoline compounds and their use as pde10 inhibitors |
AU2005323794A AU2005323794B2 (en) | 2005-01-07 | 2005-12-22 | Heteroaromatic quinoline compounds and their use as PDE10 inhibitors |
CA2592986A CA2592986C (en) | 2005-01-07 | 2005-12-22 | Heteroaromatic quinoline compounds |
GEAP200510167A GEP20094623B (en) | 2005-01-07 | 2005-12-22 | Heteroaromatic quinoline compounds and their use as pde10 inhibitors |
PL05824101T PL1841757T3 (en) | 2005-01-07 | 2005-12-22 | Heteroaromatic quinoline compounds and their use as pde10 inhibitors |
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