US20020082423A1 - Pharmaceutical aminophosphonic acid derivatives - Google Patents
Pharmaceutical aminophosphonic acid derivatives Download PDFInfo
- Publication number
- US20020082423A1 US20020082423A1 US09/946,737 US94673701A US2002082423A1 US 20020082423 A1 US20020082423 A1 US 20020082423A1 US 94673701 A US94673701 A US 94673701A US 2002082423 A1 US2002082423 A1 US 2002082423A1
- Authority
- US
- United States
- Prior art keywords
- hydroxy
- compound
- formula
- dimethylpyridyl
- diethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- PTMHPRAIXMAOOB-UHFFFAOYSA-N phosphoramidic acid Chemical class NP(O)(O)=O PTMHPRAIXMAOOB-UHFFFAOYSA-N 0.000 title abstract description 6
- 108010033266 Lipoprotein(a) Proteins 0.000 claims abstract description 6
- 102000057248 Lipoprotein(a) Human genes 0.000 claims abstract 3
- 150000001875 compounds Chemical class 0.000 claims description 84
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 36
- 125000000217 alkyl group Chemical group 0.000 claims description 34
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 31
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 27
- 150000003839 salts Chemical class 0.000 claims description 23
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 claims description 20
- -1 nitro, hydroxy, hydroxymethyl Chemical group 0.000 claims description 20
- 125000004076 pyridyl group Chemical group 0.000 claims description 20
- 125000003545 alkoxy group Chemical group 0.000 claims description 19
- 150000002466 imines Chemical class 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 9
- 230000003247 decreasing effect Effects 0.000 claims description 8
- 108090001030 Lipoproteins Proteins 0.000 claims description 7
- 102000004895 Lipoproteins Human genes 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 6
- 125000001118 alkylidene group Chemical group 0.000 claims description 6
- 229910052796 boron Inorganic materials 0.000 claims description 6
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 201000001320 Atherosclerosis Diseases 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 241000790917 Dioxys <bee> Species 0.000 claims description 3
- 208000007536 Thrombosis Diseases 0.000 claims description 3
- 238000002399 angioplasty Methods 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 208000037803 restenosis Diseases 0.000 claims description 3
- 125000004938 5-pyridyl group Chemical group N1=CC=CC(=C1)* 0.000 claims description 2
- 125000004849 alkoxymethyl group Chemical group 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 2
- 201000010099 disease Diseases 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 229910052751 metal Chemical class 0.000 claims description 2
- 239000002184 metal Chemical class 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 238000006268 reductive amination reaction Methods 0.000 claims description 2
- 125000004665 trialkylsilyl group Chemical class 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims 4
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 claims 2
- 230000000694 effects Effects 0.000 abstract description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 60
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 43
- 239000000203 mixture Substances 0.000 description 39
- 102100040214 Apolipoprotein(a) Human genes 0.000 description 37
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 36
- 101710115418 Apolipoprotein(a) Proteins 0.000 description 33
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 125000003118 aryl group Chemical group 0.000 description 30
- 239000007787 solid Substances 0.000 description 21
- 238000005481 NMR spectroscopy Methods 0.000 description 19
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 19
- 239000002904 solvent Substances 0.000 description 19
- 239000000243 solution Substances 0.000 description 17
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- 238000004440 column chromatography Methods 0.000 description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 15
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 14
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 description 14
- 239000003921 oil Substances 0.000 description 14
- 235000019198 oils Nutrition 0.000 description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- WISXXOGOMDYNSN-UHFFFAOYSA-N 2,6-dimethylpyridin-3-amine Chemical compound CC1=CC=C(N)C(C)=N1 WISXXOGOMDYNSN-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 229910052681 coesite Inorganic materials 0.000 description 9
- 229910052906 cristobalite Inorganic materials 0.000 description 9
- NFORZJQPTUSMRL-UHFFFAOYSA-N dipropan-2-yl hydrogen phosphite Chemical compound CC(C)OP(O)OC(C)C NFORZJQPTUSMRL-UHFFFAOYSA-N 0.000 description 9
- 239000000377 silicon dioxide Substances 0.000 description 9
- 229910052682 stishovite Inorganic materials 0.000 description 9
- 229910052905 tridymite Inorganic materials 0.000 description 9
- 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 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000003208 petroleum Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- MGJSDNCLGHCTIL-UHFFFAOYSA-N 4-hydroxy-3-methoxy-5-methylbenzaldehyde Chemical compound COC1=CC(C=O)=CC(C)=C1O MGJSDNCLGHCTIL-UHFFFAOYSA-N 0.000 description 5
- 0 Cc1cc(C(*)Nc2ccc(C)nc2C)cc(OC)c1OC Chemical compound Cc1cc(C(*)Nc2ccc(C)nc2C)cc(OC)c1OC 0.000 description 5
- DEQHQTVDFZDCLZ-UHFFFAOYSA-N [H]C(C)(NC1=C(C)N=C(C)C=C1)C1=CC(OC)=C(O)C(C)=C1 Chemical compound [H]C(C)(NC1=C(C)N=C(C)C=C1)C1=CC(OC)=C(O)C(C)=C1 DEQHQTVDFZDCLZ-UHFFFAOYSA-N 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 230000003197 catalytic effect Effects 0.000 description 5
- 229960004132 diethyl ether Drugs 0.000 description 5
- 210000003494 hepatocyte Anatomy 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- NVLTWXMZECWWPC-UHFFFAOYSA-N 3-hydroxy-4,5-dimethoxybenzaldehyde Chemical compound COC1=CC(C=O)=CC(O)=C1OC NVLTWXMZECWWPC-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 238000000921 elemental analysis Methods 0.000 description 4
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 238000001665 trituration Methods 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- 241000282567 Macaca fascicularis Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 3
- 235000019502 Orange oil Nutrition 0.000 description 3
- 208000006011 Stroke Diseases 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 208000029078 coronary artery disease Diseases 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 239000010502 orange oil Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- MJVZSRZTBDMYLX-UHFFFAOYSA-N 2,6-dichloropyridin-3-amine Chemical compound NC1=CC=C(Cl)N=C1Cl MJVZSRZTBDMYLX-UHFFFAOYSA-N 0.000 description 2
- UQGXJTFCHIBNLQ-UHFFFAOYSA-N 3,4-dihydroxy-5-methylbenzaldehyde Chemical compound CC1=CC(C=O)=CC(O)=C1O UQGXJTFCHIBNLQ-UHFFFAOYSA-N 0.000 description 2
- JLTXBASHJPWWES-UHFFFAOYSA-N 3,4-dimethoxy-5-methylbenzaldehyde Chemical compound COC1=CC(C=O)=CC(C)=C1OC JLTXBASHJPWWES-UHFFFAOYSA-N 0.000 description 2
- XDOKRVXGCWSNFV-UHFFFAOYSA-N 3-hydroxy-4-methoxy-5-methylbenzaldehyde Chemical compound COC1=C(C)C=C(C=O)C=C1O XDOKRVXGCWSNFV-UHFFFAOYSA-N 0.000 description 2
- UYGBSRJODQHNLQ-UHFFFAOYSA-N 4-hydroxy-3,5-dimethylbenzaldehyde Chemical compound CC1=CC(C=O)=CC(C)=C1O UYGBSRJODQHNLQ-UHFFFAOYSA-N 0.000 description 2
- 108010012927 Apoprotein(a) Proteins 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- ZZDQYQZXKXAOBR-UHFFFAOYSA-N C1=CC=NC=C1.CC.CC.CC.CC.[H]C(CC1=CC(C)=C(OC)C(C)=C1)(N(C)CC)P(C)(C)=O Chemical compound C1=CC=NC=C1.CC.CC.CC.CC.[H]C(CC1=CC(C)=C(OC)C(C)=C1)(N(C)CC)P(C)(C)=O ZZDQYQZXKXAOBR-UHFFFAOYSA-N 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- LERLCRYSRCHIAV-UHFFFAOYSA-N [H]C(C)(NC1=C(C)N=C(C)C=C1)C1=CC(O)=C(OC)C(C)=C1 Chemical compound [H]C(C)(NC1=C(C)N=C(C)C=C1)C1=CC(O)=C(OC)C(C)=C1 LERLCRYSRCHIAV-UHFFFAOYSA-N 0.000 description 2
- AFPKCMAMNNYPGR-UHFFFAOYSA-N [H]C(NC1=C(C)N=C(C)C=C1)(C1=CC(O)=C(OC)C(C)=C1)P(=O)(O)O(CC)CC Chemical compound [H]C(NC1=C(C)N=C(C)C=C1)(C1=CC(O)=C(OC)C(C)=C1)P(=O)(O)O(CC)CC AFPKCMAMNNYPGR-UHFFFAOYSA-N 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- CZHYKKAKFWLGJO-UHFFFAOYSA-N dimethyl phosphite Chemical compound COP([O-])OC CZHYKKAKFWLGJO-UHFFFAOYSA-N 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 238000003821 enantio-separation Methods 0.000 description 2
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- 239000007788 liquid Substances 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- 235000001968 nicotinic acid Nutrition 0.000 description 2
- 229960003512 nicotinic acid Drugs 0.000 description 2
- 239000011664 nicotinic acid Substances 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- MGRVRXRGTBOSHW-UHFFFAOYSA-N (aminomethyl)phosphonic acid Chemical compound NCP(O)(O)=O MGRVRXRGTBOSHW-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- SHCWQWRTKPNTEM-UHFFFAOYSA-N 2,6-dichloro-3-nitropyridine Chemical compound [O-][N+](=O)C1=CC=C(Cl)N=C1Cl SHCWQWRTKPNTEM-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/58—Pyridine rings
Definitions
- the present invention relates to novel aminophosphonate derivatives, processes for their preparations, pharmaceutical compositions containing them and their use in therapy, in particular for lowering lipoprotein(a) in plama and in tissues.
- Lipoprotein(a) is a LDL-like lipoprotein where its major lipoprotein, apoB-100 is covalently linked to an unusual glycoprotein, apoprotein(a). Due to its structural similarity to plasminogen, apo(a) interfers with the normal physiological thrombosis-hemostasis process. The structural feature of Lp(a), where the LDL lipoprotein is linked to apo(a), is thought to be responsible for its atherogenic and thrombolytic activities.
- Elevated levels of Lp(a) have been associated with the development of atherosclerosis, coronary heart disease, myocardial infarction, cerebral infarction, restenosis following balloon angioplasty and stroke.
- a recent epidemiologic study has provided the clinical proof of a positive correlation between plasma Lp(a) concentrations and the incidence of heart disease (see for instance: “Elevated Plasma Lipoprotein(a) and Coronary Heart Disease in Men Aged 55 Years and Younger”; A. G. Bostom, L. A. Cupples, J. L. Jenner, J. M. Ordovas, L. J. Seman, P. W. F. Wilson, E. J. Schaefer and W. P. Castelli; Journal of American Medical Association 1996, 276, p. 544-548).
- X a is H, C (1-8) alkyl, hydroxy or C (1-8) alkoxy
- X b is C (1-8) alkyl or C (1-8) alkoxy
- X c is H, C (1-4) alkyl, or X 3 O and one of the two other substituents X a or X b may form an alkylidene dioxy ring having from 1 to 4 carbon atoms
- R a and R b which may be identical or different, are H or C (1-6) alkyl
- B is CH 2 CH 2 , CH ⁇ CH, or CH 2
- n is zero or 1
- Z is H or a C (1-8) alkyl group
- m is 0 or an integer from 1 to 5
- X d is H, or C (1-8) alkyl, C (1-8) alkoxy or halo
- the pyridyl ring is attached by the ring carbon ⁇ - or ⁇ - to the nitrogen (2- or 3-pyridy
- the present invention provides a compound of the formula (I):
- X 1 and X 2 which may be the same or different, are H, a straight or branched C (1-8) alkyl or C (1-8) alkoxy group, a hydroxy group or a nitro group;
- X 3 is H, a C (1-4) alkyl group, X 3 O and one of the two other substituents X 1 or X 2 may form a C (1-4) alkylidene dioxy ring;
- R 1 and R 2 which may be the same or different, are H, a straight or branched C (1-6) alkyl group;
- B is CH 2 , CH 2 -CH 2 or CH ⁇ CH
- n is zero or 1;
- Z is H, or a straight or branched C (1-8) alkyl group
- m is 0 or an integer from 1 to 5;
- Y 1 , Y 2 , Y 3 and Y 4 which may be the same or different, are H, a straight or branched C (1-8) alkyl or C (1-8) alkoxy group, a cyano, trifluoromethyl, nitro, hydroxy, hydroxymethyl, C (1-4) alkoxymethyl, amino, C (1-4) alkylamino, C (1-4) dialkylamino group, a halogen atom (F, Cl, Br, I), or any two adjacent Y 1 , Y 2 , Y 3 and Y 4 may form an optionally substituted C (1-6) alkylidene or C (1-4) alkylidenedioxy ring, with the proviso that at least two of the Y 1 , Y 2 , Y 3 and Y 4 groups are not H;
- X 1 is H, hydroxy, C (1-4) alkyl or C (1-4) alkoxy, preferably C (1-3) alkyl or C (1-3) alkoxy, more preferably hydrogen, hydroxy, methyl, methoxy or ethoxy.
- X 2 is C (1-4) alkyl or C (1-4) alkoxy, preferably C (1-3) alkyl or C (1-3) alkoxy, more preferably methyl, methoxy or ethoxy.
- X 1 and X 2 is each C (1-4) alkyl, preferably C (1-3) alkyl, or C (1-4) alkoxy; or or one of X 1 and X 2 is C (1-4) alkyl and the other is C (1-4) alkoxy or C (1-3) alkyl; or X 1 is hydroxy and X 2 is C (1-4) alkyl or C (1-4) alkoxy.
- Preferred combinations of X 1 and X 2 include methoxy and methoxy, methoxy and methyl, ethoxy and methyl, methyl or t-butyl and methyl, ethoxy and ethoxy, hydroxy and methyl, and hydroxy and methoxy, respectively.
- X 3 is hydrogen or methyl.
- a particularly preferred phenyl group is 4-hydroxy-3-methoxy-5-methylphenyl.
- (B) n is a direct bond.
- m is zero.
- R 1 and R 2 is each a C (1-3) alkyl group, more preferably, a C 2 or C 3 alkyl group, in particular R 1 and R 2 is ethyl or isopropyl.
- Z is hydrogen
- Y 1 to Y 4 include alkyl, for instance methyl or t-butyl, methoxy, chloro, hydroxy, hydroxymethyl or two adjacent substituents form an optionally substituted alkylidene or alkylidenedioxy ring having from 1 to 6 carbon atoms.
- Y 1 and Y 2 is each methyl, preferably as 2,6-substituents of the pyridyl ring, and Y 3 and Y 4 is each hydrogen,.
- the pyridyl ring is attached by the ring carbon ⁇ - to the nitrogen (3 ⁇ 5-pyridyl).
- a particularly preferred pyridyl ring is (2,6-dimethyl)pyrid-3-yl.
- salts are well known in the art and include inorganic and organic salts, for instance salts with HCl, H 2 SO 4 , oxalic acid, maleic acid, sulfonic acid, etc.
- Preferred compounds of formula (I) include:
- the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in therapy, in particular as an Lp(a) lowering agent.
- Elevated plasma and tissue levels of lipoprotein(a) is associated with accelerated atherosclerosis, abnormal proliferation of smooth muscle cells and increased thrombogenesis and expressed in disease states such as, for instance: coronary heart disease, peripheral artery disease: intermittent claudication, thrombosis, restenosis after angioplasty, extracranial carotid atherosclerosis, stroke and atherosclerosis occuring after heart transplant.
- Compounds of formula (I) may also be useful in treating inflammatory diseases and excessive wound healing.
- the compounds of the present invention will generally be administered in a standard pharmaceutical composition.
- the present invention provides for a pharmaceutical composition comprising a compound of formaula (I) and a pharmaceutically acceptable excipient or carrier.
- Suitable excipients and carriers are well known in the art and will be selected with regard to the intended route of administration and standard pharmaceutical practice.
- the compositions may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsule, ovules or lozenges either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents.
- parenterally may be injected parenterally, for example, intravenously, intramuscularly or subcutaneously.
- parenteral administration they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
- a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
- the choice of form for administration as well as effective dosages will vary depending, inter alia, on the condition being treated. The choice of mode of administration and dosage is within the skill of the art.
- the compounds of formula (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions or as solids for example, tablets, capsules and lozenges.
- a liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavoring or coloring agents.
- suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavoring or coloring agents.
- a composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.
- a composition in the 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 gelatin 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 gelatin capsule.
- suitable pharmaceutical carrier(s) for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
- Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
- a typical suppository formulation comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent such as polymeric glycols, gelatins or cocoa butter or other low melting vegetable or synthetic waxes or fats.
- the composition is in unit dose form such as a tablet or capsule.
- Each dosage unit for oral administration contains preferably from 1 to 250 mg (and for parenteral administration contains preferably from 0.1 to 25 mg) of a compound of the structure (I) or a pharmaceutically acceptable salt thereof calculated as the free base.
- the compounds of the invention will normally be administered to a subject in a daily dosage regimen.
- a daily dosage regimen for an adult patient this may be, for example, an oral dose of between 1 mg and 500 mg, preferably between 1 mg and 250 mg, or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 25 mg, of the compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day.
- compounds of formula (I) in which Z is hydrogen may be prepared by a process which comprises treating an imine of formula (II):
- R 1 and R 2 are as previously defined; or a trialkyl silyl derivative thereof, preferably the trinmethyl silyl phosphite, or a metal thereof, for instance the sodium salt, formed in situ by treatment of the compound of formula (III) with a suitable base, for instance sodium hydride, ethoxide or methoxide.
- a suitable base for instance sodium hydride, ethoxide or methoxide.
- the reaction may be carried out in presence or absence of a catalyst.
- Suitable catalysts incude an arnine such as diethylamine or triethylamine.
- the reaction may be carried out in presence or in absence of a solvent.
- Suitable solvents include petroleum ether, benzene, toluene, diethyl ether, tetrahydrofuiran, 1,2-dimethoxyethane.
- Suitable reaction temperatures are in the range of 30 to 140° C.
- the imine compound of formula (II) may be obtained by condensing an aldehyde compound of formula (IV):
- the condensation may be effected with or without a catalyst in a solvent such as ether, tetrahydrofuiran, benzene, toluene or ethanol.
- a catalyst include molecular sieve, an acid such as glacial acetic acid, p-toluenesulfonic acid, thionyl chloride, titanium tetrachloride, boron trifluoride etherate, or a base such as potassium carbonate.
- the reaction is suitably carried out in the range of 0° C. to the boiling point of the solvent being used. For less reactive amines or aldehydes, the reaction may be usefully carried out in a Dean-Stark apparatus.
- Compounds of formula (I) may also be prepared by a process which comprises treating equimolar amounts of an aldehyde of formula (IV), an amine of formula (V) in which Z, m, Y 1 , Y 2 , Y 3 and Y 4 are as previously described; and a dialkyl phosphite of formula (III), suitably in the presence of p-toluenesulfonic acid as a catalyst, in a hydrocarbon solvent such as petroleum ether, benzene, toluene or xylene, at a temperature between ambient room temperature and the boiling point of the solvent being used, and with concomitant elimination of water, for instance, by using a Dean-Stark apparatus.
- a hydrocarbon solvent such as petroleum ether, benzene, toluene or xylene
- m is an integer from 1 to 5 and Y 1 , Y 2 , Y 3 and Y 4 are as previously defied; under reductive amination conditions.
- Suitable such conditions include carrying out the reaction in the presence of sodium cyanoborohydride in an alcoholic solvent, preferably methanol, at a pH between 3 to 6 and at a temperature between 0° C. and 25° C.
- a compound of formula (VI) may be obtained according to the process previously described for a compound of formula (I) from an aldehyde of formula (IV), an amine of formula (VIII)
- A is a protecting group which can be removed by hydrogenolysis, for instance an ⁇ substituted benzyl or benzyloxycarbonyl and a phosphite of structure (III). This forms an intermediate which is then subjected to hydrogenolysis according to standard conditions, to give a compound of formula (VI).
- aminophosphonate ester of formula (I) have a basic centre and can form salts, for instance with inorganic acids such as HCl, H 2 SO 4 and with organic acids such as oxalic acid, maleic acid, sulfonic acids, etc. All these salts are integral part of this invention.
- Compounds of structure (I) are racemates as they have at least one chiral center which is the carbon atom in position alpha to the phosphonate group.
- the compounds of formula (I) therefore exist in the two enantiomeric forms.
- the racemic mixtures (50% of each enantiomer), the pure enantiomers and other mixtures thereof all form part of the present invention.
- Mixtures of enantiomers, including racemates, may be resolved into its constituent enantiomers according to procedures well known in the art, including for instance, chiral chromatography. Unless otherwise indicated, the physical constants and biological data given for compounds of structure (I) refer to racemates.
- n normal, i is iso, s is secondary and t is tertiary.
- s is secondary and t is tertiary.
- s is singlet
- d is doublet
- dd is double doublet
- t is triplet
- m s multiplet.
- TsOH is p-toluenesulfonic acid monohydrate. The temperatures were recorded in degrees Celsius and the melting points are not corrected.
- Diisopropyl phosphite (5.84 g, 35 mmol) was added to 3.8 g (14 mnmol) of the crude imine dissolved in 40 ml toluene and the mixture was refluxed for 7 h. A further amount of diisopropyl phosphite (2.34 g, 14 mmol) was added and the mixture was refluxed for 2 more hours (total reaction time 9 h).
- This compound may also be prepared in 1,2-dimethoxyethane (DME).
- DME 1,2-dimethoxyethane
- the imine 8.1 g, 0.03 mol
- diisopropyl phosphite 7.5 g, 0.045 mol
- the reaction may be carried out neat (without solvent) in the phosphite reagent.
- diisopropyl phosphite 7.5 g, 0.045 mol
- the oily reaction mixture was diluted in chloroform and extracted with a saturated bicarbonate solution.
- the dried organic phase was concentrated and triturated in petroleum ether to remove the excess of HPO 3 iPr 2 : a pasty solid was obtained.
- Methyl iodide 50 ml, 113.8 g, 0.8 mol was added to a mixture containing 16.6 g (0.1 mol) 4-hydroxy-3-methoxy-5-methyl-benzaldehyde, 55.2 g (0.4 mol) potassium carbonate in 90 ml methyl ethyl ketone and the resulting mixture was refluxed for 5 h.
- the solvent was evaporated on a rotary evaporator and the residue was partitioned between 100 ml H 2 O and 100 ml CH 2 Cl 2 .
- 2,6-Di-tert-butylpyridine-4-carboxaldehyde was obtained by oxidation of 2,6-di-tert-butyl-4-methylpyridine with excess selenium dioxide in acetic acid at reflux temperature.
- Racemic compound (Example 4) was resolved into its two enantiomers by chiral chromatography, using the following conditions:
- injection Volume 500 ul
- each enantiomer fraction was dried on a rotary evaporator. Each fraction has then been resuspended in a few mls ethanol and transferred to a small preweighed vial. The samples were blown to dryness under nitrogen at present prior to measurement of their mass spec and optical rotation.
- Hepatocytes were isolated from livers of adult Cynomolgus monkeys by the two-step collagenase perfusion method according to C. Guguen-Guillouzo and A. Guillouzo “Methods for preparation of adult and fetal hepatocytes” p. 1-12 in “Isolated and Cultured Hepatocytes”, les editions Inserm Paris and John Libbey Eurotext London (1986).
- the viability of cells was determined by Trypan blue staining. The cells were then seeded at a density from 0.7. 10 5 to 1.10 5 viable cells per cm 2 in tissue culture plates in Williams E tissue culture medium containing 10% fetal calf serum. Cells were incubated for 4-6 hours and 24 hours at 37° C. in a CO 2 incubator (5% CO 2 ) in the presence of 20 ⁇ M of the test compounds dissolved in ethanol. Four to six wells were used for each compound. Nicotinic acid and steroid hormones were used as references to validate the assay system since they are known to decrease Lp(a) in man. Control cells were incubated in the presence of ethanol only.
- Lp(a) secreted in culture medium was directly assayed by ELISA using a cormnercially available kit. Cells were washed and lysed as described by A. L. White et al, Journal of Lipid Research vol 34, p. 509-517, (1993) and the cellular content of Lp(a) was assayed as described above.
- Study Protocol Meat cynomolgus monkeys weighing between 3 and 7 kg were divided into groups of 3 to 4 animals each. Prior to treatment their plasma Lp(a) levels were followed over a two-month period to ascertain a constant baseline value. The Lp(a) values measured at Day -7 and Day -1 were comparable and served as predose values. Test compounds were given orally in gelatin capsules by gavage at the dose of 25 mg/kg/day for 4 weeks and Lp(a) was measured at weekly intervals (Day 7, 14, 21 and 28). At the end of the dosing period, animals were maintained for a treatment free period of 4 weeks, whereupon their plasma Lp(a) levels returned to pretreatment levels. This control provided proof that the decrease in Lp(a) measured was caused by the pharmacological activity of the test compounds.
- Results At Days -7, -1, 7, 14, 21 and 28, after an overnight fast blood samples were collected on EDTA and Lp(a) was measured by the highly sensitive and specific ELISA test. Results (mean of 3-4 values of each group ) were expressed as % of predose values. Selected compounds of formula (I) were tested under the experimental conditions to investigate their pharmacological activity in vivo.
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Abstract
Description
- The present invention relates to novel aminophosphonate derivatives, processes for their preparations, pharmaceutical compositions containing them and their use in therapy, in particular for lowering lipoprotein(a) in plama and in tissues.
- Lipoprotein(a) [Lp(a)] is a LDL-like lipoprotein where its major lipoprotein, apoB-100 is covalently linked to an unusual glycoprotein, apoprotein(a). Due to its structural similarity to plasminogen, apo(a) interfers with the normal physiological thrombosis-hemostasis process. The structural feature of Lp(a), where the LDL lipoprotein is linked to apo(a), is thought to be responsible for its atherogenic and thrombolytic activities.
- Elevated levels of Lp(a) have been associated with the development of atherosclerosis, coronary heart disease, myocardial infarction, cerebral infarction, restenosis following balloon angioplasty and stroke. A recent epidemiologic study has provided the clinical proof of a positive correlation between plasma Lp(a) concentrations and the incidence of heart disease (see for instance: “Elevated Plasma Lipoprotein(a) and Coronary Heart Disease in Men Aged 55 Years and Younger”; A. G. Bostom, L. A. Cupples, J. L. Jenner, J. M. Ordovas, L. J. Seman, P. W. F. Wilson, E. J. Schaefer and W. P. Castelli; Journal of American Medical Association 1996, 276, p. 544-548).
- Patients that have Lp(a) levels in excess of 20-30 mg/dl run a significantly increased risk of heart attacks and stroke. An effective therapy for lowering Lp(a) does not exist at present as potent hypocholesterolemic agents such as the HMGCoA reductase inhibitors do not affect Lp(a). Until recently, the only compound shown to lower Lp(a) was niacin. The high doses necessary for activity however entail unacceptable side-effects. There is therefore an unmet therapeutic need for agents that effectively reduce elevated levels of Lp(a).
-
- in which Xa is H, C(1-8)alkyl, hydroxy or C(1-8)alkoxy; Xbis C(1-8)alkyl or C(1-8)alkoxy; Xc is H, C(1-4)alkyl, or X3O and one of the two other substituents Xa or Xb may form an alkylidene dioxy ring having from 1 to 4 carbon atoms; Ra and Rb which may be identical or different, are H or C(1-6)alkyl; B is CH2CH2, CH═CH, or CH2; n is zero or 1; Z is H or a C(1-8)alkyl group; m is 0 or an integer from 1 to 5; Xd is H, or C(1-8)alkyl, C(1-8)alkoxy or halo; and the pyridyl ring is attached by the ring carbon α- or β- to the nitrogen (2- or 3-pyridyl). These have Lp(a) lowering activity. Compounds of formula (A) fall within scope of the generic disclosure of EP-A-0 559 079. This is directed towards aminophosphonates alpha substitued by phenol groups which are said to be of use in decreasing plasma cholesterol and blood peroxides. Compounds of formula (A) are characterised by having either no substituent (Xd is H) or a single substituent on the pyridyl ring. It has now been found that further substitution on the pyridyl ring provides compounds with an improved biological profile.
-
- in which:
- X1 and X2, which may be the same or different, are H, a straight or branched C(1-8)alkyl or C(1-8)alkoxy group, a hydroxy group or a nitro group;
- X3 is H, a C(1-4)alkyl group, X3O and one of the two other substituents X1 or X2 may form a C(1-4)alkylidene dioxy ring;
- R1 and R2, which may be the same or different, are H, a straight or branched C(1-6)alkyl group;
- B is CH2, CH2-CH2 or CH═CH;
- n is zero or 1;
- Z is H, or a straight or branched C(1-8)alkyl group;
- m is 0 or an integer from 1 to 5; and
- Y1, Y2, Y3 and Y4, which may be the same or different, are H, a straight or branched C(1-8)alkyl or C(1-8)alkoxy group, a cyano, trifluoromethyl, nitro, hydroxy, hydroxymethyl, C(1-4)alkoxymethyl, amino, C(1-4)alkylamino, C(1-4)dialkylamino group, a halogen atom (F, Cl, Br, I), or any two adjacent Y1, Y2, Y3 and Y4 may form an optionally substituted C(1-6)alkylidene or C(1-4)alkylidenedioxy ring, with the proviso that at least two of the Y1, Y2, Y3 and Y4 groups are not H;
- or a pharmaceutically acceptable salt thereof.
- Preferably, X1 is H, hydroxy, C(1-4)alkyl or C(1-4)alkoxy, preferably C(1-3)alkyl or C(1-3)alkoxy, more preferably hydrogen, hydroxy, methyl, methoxy or ethoxy.
- Preferably, X2 is C(1-4)alkyl or C(1-4)alkoxy, preferably C(1-3)alkyl or C(1-3)alkoxy, more preferably methyl, methoxy or ethoxy.
- Preferably, X1 and X2 is each C(1-4)alkyl, preferably C(1-3)alkyl, or C(1-4)alkoxy; or or one of X1 and X2 is C(1-4)alkyl and the other is C(1-4)alkoxy or C(1-3)alkyl; or X1 is hydroxy and X2 is C(1-4)alkyl or C(1-4)alkoxy.
- Preferred combinations of X1 and X2 include methoxy and methoxy, methoxy and methyl, ethoxy and methyl, methyl or t-butyl and methyl, ethoxy and ethoxy, hydroxy and methyl, and hydroxy and methoxy, respectively.
- Preferably, X3 is hydrogen or methyl.
- A particularly preferred phenyl group is 4-hydroxy-3-methoxy-5-methylphenyl.
- Preferably, (B)n is a direct bond.
- Preferably, m is zero.
- Preferably, R1 and R2 is each a C(1-3)alkyl group, more preferably, a C2 or C3 alkyl group, in particular R1 and R2 is ethyl or isopropyl.
- Preferably, Z is hydrogen.
- Representative values for Y1 to Y4 include alkyl, for instance methyl or t-butyl, methoxy, chloro, hydroxy, hydroxymethyl or two adjacent substituents form an optionally substituted alkylidene or alkylidenedioxy ring having from 1 to 6 carbon atoms.
- Preferably, Y1 and Y2 is each methyl, preferably as 2,6-substituents of the pyridyl ring, and Y3 and Y4 is each hydrogen,.
- Preferably, the pyridyl ring is attached by the ring carbon β- to the nitrogen (⅗-pyridyl). A particularly preferred pyridyl ring is (2,6-dimethyl)pyrid-3-yl.
- Pharmaceutically acceptable salts are well known in the art and include inorganic and organic salts, for instance salts with HCl, H2SO4, oxalic acid, maleic acid, sulfonic acid, etc.
- Preferred compounds of formula (I) include:
- Diisopropyl α-(4-hydroxy-3-methoxy-5-methylphenyl)-N-[3-(2,6-dimethylpyridyl)]-amino-methylphosphonate; and
- Diethyl α-(4-hydroxy-3-methoxy-5-methylphenyl)-N-[3-(2,6-dimethylpyridyl)]-amino-methylphosphonate;
- and pharmaceutically acceptable salts;
- in particular:
- (+)-diisopropyl α-(4-hydroxy-3-methoxy-5-methylphenyl)-N-[3-(2,6-dimethylpyridyl)]-amino-methylphosphonate; and pharmaceutically acceptable salts thereof, in particular, the hydrochloride salt.
- Compounds of formula (I) are found to be effective in decreasing Lp(a) production by primary cultures of Cynomolgus monkey hepatocytes. The Lp(a) of these primates is similar in immunologic properties to human Lp(a) and occurs in an almost identical frequency distribution of plasma concentrations (see “Plasma Lipoprotein(a) Concentration is Controlled by Apolipoprotein(a) Protein Size and the Abundance of Hepatic Apo(a) mRNA in a Cynomoigus Monkey Model”, N. Azrolan et al, J. Biol. Chem., 266, 13866-13872, 1991). The compounds of formula (I) are thus potentially useful for decreasing Lp(a) in man and thereby providing a therapeutic benefit. Accordingly, in a further aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in therapy, in particular as an Lp(a) lowering agent. Elevated plasma and tissue levels of lipoprotein(a) is associated with accelerated atherosclerosis, abnormal proliferation of smooth muscle cells and increased thrombogenesis and expressed in disease states such as, for instance: coronary heart disease, peripheral artery disease: intermittent claudication, thrombosis, restenosis after angioplasty, extracranial carotid atherosclerosis, stroke and atherosclerosis occuring after heart transplant. Compounds of formula (I) may also be useful in treating inflammatory diseases and excessive wound healing.
- For such therapeutic use, the compounds of the present invention will generally be administered in a standard pharmaceutical composition. Accordingly, in a further aspect, the present invention provides for a pharmaceutical composition comprising a compound of formaula (I) and a pharmaceutically acceptable excipient or carrier. Suitable excipients and carriers are well known in the art and will be selected with regard to the intended route of administration and standard pharmaceutical practice. For example, the compositions may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsule, ovules or lozenges either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. They may be injected parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The choice of form for administration as well as effective dosages will vary depending, inter alia, on the condition being treated. The choice of mode of administration and dosage is within the skill of the art.
- The compounds of formula (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions or as solids for example, tablets, capsules and lozenges. A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavoring or coloring agents. A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose. A composition in the 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 gelatin 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 gelatin capsule. Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt 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. A typical suppository formulation comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent such as polymeric glycols, gelatins or cocoa butter or other low melting vegetable or synthetic waxes or fats.
- Preferably the composition is in unit dose form such as a tablet or capsule. Each dosage unit for oral administration contains preferably from 1 to 250 mg (and for parenteral administration contains preferably from 0.1 to 25 mg) of a compound of the structure (I) or a pharmaceutically acceptable salt thereof calculated as the free base.
- The compounds of the invention will normally be administered to a subject in a daily dosage regimen. For an adult patient this may be, for example, an oral dose of between 1 mg and 500 mg, preferably between 1 mg and 250 mg, or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 25 mg, of the compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day.
- Compounds of formula (I) may be prepared by processes well known in the art, for instance those previously described in WO 97/02037.
-
- in which X1, X2, X3, B, n, m, Y1, Y2, Y3 and Y4 are as previously defined; with a dialkyl phosphite of formula (III):
- H—PO(OR1)(OR2) (III)
- in which R1 and R2 are as previously defined; or a trialkyl silyl derivative thereof, preferably the trinmethyl silyl phosphite, or a metal thereof, for instance the sodium salt, formed in situ by treatment of the compound of formula (III) with a suitable base, for instance sodium hydride, ethoxide or methoxide.
- The reaction may be carried out in presence or absence of a catalyst. Suitable catalysts incude an arnine such as diethylamine or triethylamine. The reaction may be carried out in presence or in absence of a solvent. Suitable solvents include petroleum ether, benzene, toluene, diethyl ether, tetrahydrofuiran, 1,2-dimethoxyethane. Suitable reaction temperatures are in the range of 30 to 140° C.
-
-
- in which Z, m, Y1, Y2, Y3 and Y4 are as previously defined; under imine forming conditions.
- Suitably, the condensation may be effected with or without a catalyst in a solvent such as ether, tetrahydrofuiran, benzene, toluene or ethanol. Suitable catalysts include molecular sieve, an acid such as glacial acetic acid, p-toluenesulfonic acid, thionyl chloride, titanium tetrachloride, boron trifluoride etherate, or a base such as potassium carbonate. The reaction is suitably carried out in the range of 0° C. to the boiling point of the solvent being used. For less reactive amines or aldehydes, the reaction may be usefully carried out in a Dean-Stark apparatus.
- Compounds of formula (I) may also be prepared by a process which comprises treating equimolar amounts of an aldehyde of formula (IV), an amine of formula (V) in which Z, m, Y1, Y2, Y3 and Y4 are as previously described; and a dialkyl phosphite of formula (III), suitably in the presence of p-toluenesulfonic acid as a catalyst, in a hydrocarbon solvent such as petroleum ether, benzene, toluene or xylene, at a temperature between ambient room temperature and the boiling point of the solvent being used, and with concomitant elimination of water, for instance, by using a Dean-Stark apparatus.
-
-
- in which m is an integer from 1 to 5 and Y1, Y2, Y3 and Y4 are as previously defied; under reductive amination conditions.
- Suitable such conditions include carrying out the reaction in the presence of sodium cyanoborohydride in an alcoholic solvent, preferably methanol, at a pH between 3 to 6 and at a temperature between 0° C. and 25° C.
- A compound of formula (VI) may be obtained according to the process previously described for a compound of formula (I) from an aldehyde of formula (IV), an amine of formula (VIII)
- A-NH2 (VIII)
- in which A is a protecting group which can be removed by hydrogenolysis, for instance an α substituted benzyl or benzyloxycarbonyl and a phosphite of structure (III). This forms an intermediate which is then subjected to hydrogenolysis according to standard conditions, to give a compound of formula (VI).
- It will be appreciated that the aminophosphonate ester of formula (I) have a basic centre and can form salts, for instance with inorganic acids such as HCl, H2SO4 and with organic acids such as oxalic acid, maleic acid, sulfonic acids, etc. All these salts are integral part of this invention.
- Compounds of structure (I) are racemates as they have at least one chiral center which is the carbon atom in position alpha to the phosphonate group. The compounds of formula (I) therefore exist in the two enantiomeric forms. The racemic mixtures (50% of each enantiomer), the pure enantiomers and other mixtures thereof all form part of the present invention. Mixtures of enantiomers, including racemates, may be resolved into its constituent enantiomers according to procedures well known in the art, including for instance, chiral chromatography. Unless otherwise indicated, the physical constants and biological data given for compounds of structure (I) refer to racemates.
- The structure of compounds of formula (I) described in the following Examples was established by their infrared (IR), mass (MS) and nuclear magnetic resonance (NMR) spectra. The purity of the compounds was checked by thin layer, gas liquid or high performance liquid chromatography.
- The invention is further described in the following examples which are intended to illustrate the invention without limiting its scope.
- The abbreviations used in this application are the following:
- In the tables, n is normal, i is iso, s is secondary and t is tertiary. In the description of the NMR spectra, respectively ‘s’ is singlet, ‘d’ is doublet, ‘dd’ is double doublet, ‘t’ is triplet and ‘m’ s multiplet. TsOH is p-toluenesulfonic acid monohydrate. The temperatures were recorded in degrees Celsius and the melting points are not corrected.
-
- A mixture of 1.11 g (7.4 mmol) of 4-hydroxy-3,5-dimethylbenzaldehyde, 0.9 g (7.4 mmol) of 3-amino-2,6-dimethylpyridine, 3.05 g (22 mnnol) diethylphosphite and ca 5 mg TsOH dissolved in 20 ml toluene contained in a flask connected to a Dean Stark apparatus was refluxed for 7 h. The solvent and the excess of diethylphosphite were evaporated to give a yellow oil which was purified by column chromatography (SiO2, 95/5 CHCl3/MeOH) to give 0.38 g (21%) of an oil which slowly solidified.
- MS (m/e)=392: M+, 255 (100%): M+—PO3Et2
- NMR (CDCl3):δ=7.0 (d, J=2 Hz, 2 H): aromatic H, substituted phenyl; 6.73 and 6.61 (2m, 1 H each): aromatic H, 3-pyridyl; 5.3 (1 H) : OH: 4.55 (dd, J=7 and 22 Hz, 1 H): CH—PO3Et2; 4.49 (m, 1 H): N—H: 4.18 to 3.65 (m, 4 H): P—O—CH2—CH3; 2.49 and 2.36 (2s, 6 H total): Py-CH3; 2.2 (1s, 6 H): Ph-CH3; 1.29 and 1.15: (2t, J=7 Hz, 6 H total): P—O—CH2—CH3
-
- A mixture of 1.42 g (7.4 mmol) of 3-tert-butyl-4-hydroxy-5-methyl-benzaldehyde, 0.9 g (7.4 mmol) of 3-amino-2,6-dimethylpyridine, 3.05 g (22 mmol) diethylphosphite and ca 5 mg TsOH dissolved in 20 ml toluene contained in a flask connected to a Dean Stark apparatus was refluxed for 7 h. The solvent and the excess of diethylphosphite were evaporated and the residue was purified by column chromatography (SiO2, 95/5 CHCl3/MeOH) and recrystallization to give 0.89 g (21%) of a solid, mp=139-141° C. MS (m/e)=434: M+, 297 (100%): M+-PO3Et2
- NMR (CDCl3):δ=7.15 and 7.02 (2m, 2 H): aromatic H, substituted phenyl; 6.74 and 6.62 (2m, 1 H each): aromatic H, 3-pyridyl; 5.15 (1 H) : OH; 4.59 (dd, J=7 and 23 Hz, 1 H): CH—PO3Et2; 4.47 (m, 1 H): N—H; 4.18 to 3.65 (m, 4 H): P—O—CH2—CH3; 2.49 and 2.36 (2s, 6 H total): Py-CH3; 2.18 (1s, 3 H): Ph-CH3; 1.39 (s, 9 H): t-Bu; 1.29 and 1.13: (2t, J=7 Hz, 6 H total): P—O—CH2-CH3
-
- A mixture of 4.0 g (24 mmol) of 4-hydroxy-3-methoxy-5-methylbenzaldehyde and 2.94 g (24 mmol) of 3-amino-2,6-dimethylpyridine dissolved in 40 ml toluene and a catalytic amount of p-toluenesulfonic acid (ca. 5 mg) contained in a flask connected to a Dean Stark apparatus was refluxed for 7 h. The solution was evaporated to dryness to give 6.5 g (100%) of an orange oil which was used directly for the next step. Diisopropyl phosphite (5.84 g, 35 mmol) was added to 3.8 g (14 mnmol) of the crude imine dissolved in 40 ml toluene and the mixture was refluxed for 7 h. A further amount of diisopropyl phosphite (2.34 g, 14 mmol) was added and the mixture was refluxed for 2 more hours (total reaction time 9 h). The solvent and the excess of diisopropyl phosphite were evaporated and the residue was purified by column chromatography (SiO2, 95/5 CHCl3/MeOH) and recrystallization (petroleum ether/CH2Cl2) to give 1.48 g (24%) of a tan solid, mp=138-139° C. A further recrystallisation from a t-butyl methyl ether/CH2Cl2 mixture yielded a light yellow solid of analytical purity, mp=159-160° C.
Elemental analysis: C22H33N2O5P % Calc. C 60.54 H 7.62 N 6.47 P7.27 % Found C 60.45 H 7.76 N 6.35 P7.09 - NMR (CDCl3):δ=6.80 and 6.73 (2m, 1 H each): aromatic H, 3-pyridyl; 6.6 (m, 2 H): aromatic H, substituted phenyl; 5.7 (1 H) : OH; 4.65 and 4.47(m, 2 H): P—O—CH-Me2; 4.5 (2 overlapped m, 2 H): CH—PO3iPr2 and N—H; 3.85 (s, 3 H): OCH3; 2.50 and 2.37 (2s, 6 H total): Py-CH3; 2.22 (1s, 3 H): Ph-CH3; 1.32, 1.29, 1.23 and 1.01: (4d, J=7 Hz, 12 H total): P—O—CH—(CH3)2
- This compound may also be prepared in 1,2-dimethoxyethane (DME). The imine (8.1 g, 0.03 mol) was dissolved in 10 ml DME and diisopropyl phosphite (7.5 g, 0.045 mol) was added and the resulting mixture was refluxed overnight. DME was evaporated under vacuum to give a material which was purified by column chromatography (95/5 CHCl3/MeOH); the collected fractions gave after trituration in petroleum ether and two recrystallisations in CH2Cl2/MTBE 6.9 g (52%) of pure title compound, mp=159-160° C.
- Alternately the reaction may be carried out neat (without solvent) in the phosphite reagent. To the crude imine (8.1 g, 0.03 mol) was added diisopropyl phosphite (7.5 g, 0.045 mol) and the homogenous brown mixture was heated at 120° C. for 2 hours. The oily reaction mixture was diluted in chloroform and extracted with a saturated bicarbonate solution. The dried organic phase was concentrated and triturated in petroleum ether to remove the excess of HPO3iPr2: a pasty solid was obtained. Column chromatography (95/5 CHCI3/MeOH) and recrystallisation gave 6.5 g (50%) of the title compound, mp=159-160° C.
-
- As described in Example 3, the imine (3.8 g, 14 mmol) obtained by condensing 4-hydroxy-3-methoxy-5-methylbenzaldehyde with 3-amino-2,6-dimethylpyridine was reacted with diethyl phosphite (5.82 g, 42 mmol) in 40 ml toluene at reflux temperature for 9h to give 1.38 g (24%) of the title compound as a white solid, mp=145-147° C.
- MS (m/e)=408: M+, 271 (100%): M+-PO3Et2
- NMR (CDCl3):δ=6.82 and 6.76 (2m, 1 H each): aromatic H, 3-pyridyl; 6.6 (m, 2 H): aromatic H, substituted phenyl; 5.7 (1 H) : OH; 4.62-4.47 (2 overlapped m, 2 H): CH—PO3Et2 and N—H; 4.18 to 3.7 (m, 4 H): P—O—CH2—CH3; 3.86 (s, 3 H): OCH3; 2.52 and 2.39 (2s, 6 H total): Py-CH3; 2.24 (1s, 3 H): Ph-CH3; 1.31 and 1.19: (2t, J=7 Hz, 6 H total): P—O—CH2—CH3
-
- The enantiomers of a racemic mixture were separated by simulated moving bed chromatography using eight columns packed with 30 g of Chiralpak AD and hexane/ethanol (9/1) as the eluent. 42 g of the racemic mixture was processed to give after trituration with diethyl ether 16.1 g of the faster eluting enantiomer ([α]D25 +14.0° (c=1.0 EtOH), mp=123-124° C., optical purity=98.5%) and 15.2 g of the slower eluting enantiomer ([α]D25−13.1° (c=1.0 EtOH), mp=120-122° C., optical purity=97.5%)
- The structures of both enantiomers were confirmed by NMR, IR and MS spectroscopies and elemental analyses.
Elemental analysis: C22H33N2O5P % Calc. C 60.54 H 7.62 N 6.47 (+) Enantiomer C 60.57 H 7.98 N 6.40 (−) Enantiomer C 60.45 H 7.94 N 6.32 -
- (+)Diisopropyl α-(4-hydroxy-3-methoxy-5-methylphenyl)-N-[3-(2,6-dimethylpyridyl)]-amino-methylphosphonate (1.5 g) was dissolved in 30 ml EtOH and cooled in an ice bath. A solution of HCl in Et2O (1 M, 3.45 ml) was added, after stirring for 10 min the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give 1.25 g of a white solid, [α]D25 +45.6° (c=0.535 EtOH), optical purity 99.9%.
-
- (−)Diisopropyl α-(4-hydroxy-3-methoxy-5-methylphenyl)-N-[3-(2,6-dimethylpyridyl)]-amino-methylphosphonate (1.11 g) was dissolved in 25 ml EtOH and cooled in an ice bath. A solution of HCl in Et2O (1 M, 2.54 ml) was added, after stirring for 10 min the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give 0.98 g of a white solid, [α]D25 −39.3° (c=0.595 EtOH), optical purity 94.0%.
-
- Methyl iodide (50 ml, 113.8 g, 0.8 mol) was added to a mixture containing 16.6 g (0.1 mol) 4-hydroxy-3-methoxy-5-methyl-benzaldehyde, 55.2 g (0.4 mol) potassium carbonate in 90 ml methyl ethyl ketone and the resulting mixture was refluxed for 5 h. The solvent was evaporated on a rotary evaporator and the residue was partitioned between 100 ml H2O and 100 ml CH2Cl2. The aqueous phase was further extracted by three 100 ml portions of CH2Cl2, the combined organic phases were dried over MgSO4 and evaporated to give an orange oil weighing 18 g (100%). NMR (CDCl3): α=9.83 (1 H, CHO), 7.3 (2 H, aromatic H), 3.92 and 3.90 (6 H, OMe) and 2.33 (3 H, Me).
- A mixture of 1.62 g (9 mmol) of 3,4-dimethoxy-5-methylbenzaldehyde obtained as described above and 1.1 g (9 mmol) of 3-amino-2,6-dimethylpyridine dissolved in 25 ml toluene and a catalytic amount of p-toluenesulfonic acid (ca. 1 mg) contained in a flask connected to a Dean Stark apparatus was refluxed for 8 h. The solution was evaporated to dryness to give 2.56 g (100%) of an orange oil which was used directly for the next step.
- Diethyl phosphite (3.73 g, 27 mmol) was added to 2.56 g (9 mmol) of the crude imine dissolved in 25 ml toluene and the mixture was refluxed for 8 h. The solvent and the excess of diethyl phosphite were evaporated and the residue was purified by column chromatography (SiO2, 95/5 CHCl3/MeOH) to give 2.7 g (71%) of a yellow oil.
- MS (m/e)=423: M++1, 286 (100%): M++1-PO3Et2
- NMR (CDCl3):δ=6.83 (m, 2 H): aromatic H, substituted phenyl; 6.75 and 6.60 (2d, 1 H each): aromatic H, 3-pyridyl; 4.62-4.47 (2 overlapped m, 2 H): CH—PO3Et2 and N—H; 4.18 to 3.7 (m, 4 H): P—O—CH2—CH3; 3.83 and 3.78 (2s, 6 H): OCH3; 2.51 and 2.39 (2s, 6 H total): Py-CH3; 2.24 (1s, 3 H): Ph-CH3; 1.30 and 1.16: (2t, J=7 Hz, 6 H total): P—O—CH2—CH3
-
- As described in Example 8, the imine (2.56 g, 9 mmol) obtained by condensing 3,4-dimethoxy-5-methylbenzaldehyde with 3-amino-2,6-dimethylpyridine was reacted with diisopropyl phosphite (4.49 g, 27 mmol) in 25 ml toluene at reflux temperature for 9 h to give 2.4 g (59%) of the title compound as a yellow oil, after purification by column chromatography (95/5 CH2Cl2/MeOH).
- MS (m/e)=451: M++1, 286(100%): M+—PO3iPr2
- NMR (CDCl3):δ=6.81 (m, 2 H): aromatic H, substituted phenyl; 6.75 and 6.65 (2m, 1 H each): aromatic H, 3-pyridyl; 4.65 and 4.50(m, 2 H): P—O—CH-Me2; 4.5 (2 overlapped m, 2 H): CH—PO3iPr2 and N—H; 3.82 and 3.76 (2s, 6 H): OCH3; 2.50 and 2.38 (2s, 6 H total): Py-CH3; 2.23 (1s, 3 H): Ph-CH3; 1.32, 1.29, 1.23 and 1.01: (4d, J=7 Hz, 12 H total): P—O—CH—(CH3)2
-
- Anhydrous aluminum chloride(5.3 g, 40 rumol) was suspended under nitrogen in a solution of 4-hydroxy-3-methoxy-5-methylbenzaldehyde (6 g, 36 mmol) in 40 ml dichioromethane. Pyridine (12.8 ml, 160 mmol) was added dropwise while stirring and cooling to maintain the temperature between 30 and 35° C. and the resulting orange solution was heated to reflux for 24 h. After cooling the reaction mixture was hydrolyzed with a 10% HCl solution until pH 1-2. The resulting two phases were separated, the dichloromethane phase was discarded and the aqueous phase was extracted with three 40 ml portions of diethyl ether. Evaporation of the dried ether phase gave 5.5 g (100%) of a beige solid which was identified as 3,4-dihydroxy-5-methylbenzaldehyde.
- Methyl iodide (5.6 ml, 12.83 g, 90 mmol) was added to a mixture of 3,4-dihydroxy-5-methylbenzaldehyde (5.5 g, 36 mmol) and lithium carbonate (6.68 g, 90 mmol) in N,N-dimethylformamide (90 ml) and the resulting mixture was heated to 55° C. for 15 h. Another portion of methyl iodide (2 ml) was added and the mixture was kept at 55° C. for a further 4 h. The reaction mixture was poured into a mixture of 450 ml water and 10 ml 37% HCl, the aqueous phase was extracted with three portions of 150 ml diethyl ether. The solvent was evaporated and the residue was purified by column chromatography to give 2.8 g (47%) of an oil identified as 3-hydroxy-4-methoxy-5-methylbenzaldehyde. MS (m/e)=166 (100%): M+ −Me; NMR (CDCl3):δ=9.85 (1 H, CHO), 7.32-7.28 (2 H, aromatic H), 5.95 (1 H, OH), 3.88 (3 H, OMe) and 2.38 ( 3 H, Me).
- A mixture of 2.0 g (12 mmol) of 3-hydroxy-4-methoxy-5-methylbenzaldehyde obtained as described above and 1.47 g (12 mmol) of 3-amino-2,6-dimethylpyridine dissolved in 25 ml toluene and a catalytic amount of p-toluenesulfonic acid (ca. 1 mg) contained in a flask connected to a Dean Stark apparatus was refluxed for 4 h. The solution was evaporated to dryness to give 3.25 g (100%) of an brown solid which was used directly for the next step.
- Diethyl phosphite (2.48 g, 18 mmol) was added to 1.63 g (6 mmol) of the crude imine dissolved in 25 ml toluene and the mixture was refluxed for 16 h. The solvent and the excess of diethyl phosphite were evaporated and the residue was purified by column chromatography (SiO2, 95/5 CH2Cl2/MeOH) to give 0.9 g (37%) of a white solid, mp=141-142° C. after trituration in t-butyl methyl ether.
- MS (m/e)=409: M++1, 272 (100%): M++1—PO3Et2
- NMR (CDCl3):
- δ=8.0 (broad peak, 1 H): OH; 6.82 and 6.74 (2m, 2 H): aromatic H, substituted phenyl, 6.75 and 6.58 (2m, 1 H each): aromatic H, 3-pyridyl, 4.56 (dd, J=7 and 24 Hz, 1 H) CH—PO3Et2; 4.43 (dd, J=7 and 10 Hz, 1 H): N—H; 4.16 to 3.71 (m, 4 H): P—O—CH2—CH3; 3.80 (s, 3 H): OCH3; 2.39 (1s, 3 H): Ph-CH3; 2.28 (1s, 6 H total): Py-CH3; 1.29 and 1.16: (2t, J=7 Hz, 6 H total): P—O—CH2—CH3
-
- Diisopropyl phosphite (2.48 g, 18 mmol) was added to 1.63 g (6 mmol) of the crude imine dissolved in 25 ml toluene and the mixture was refluxed for 16 h. The solvent and the excess of diisopropyl phosphite were evaporated and the residue was purified by colunn chromatography (SiO2, 95/5 CH2Cl2/MeOH) to give 1.1 g (42%) of a white solid, mp=168-169° C. after trituration in t-butyl methyl ether.
- MS (m/e)=436: M+, 271 (100%): M+—PO3iPr2
- NMR (CDCl3):δ=7.9 (broad peak, 1 H): OH; 6.83 and 6.74 (m, 2 H): aromatic H, substituted phenyl; 6.74 and 6.58 (2d, 1 H each): aromatic H, 3-pyridyl; 4.66 and 4.47 (2m, 2 H): P—O—CH-Me2; 4.54 -4.45 (2 overlapped m, 2 H): CH—PO3iPr2 and N—H; 3.79 (s, 3 H): OCH3; 2.38 (1s, 3 H): Ph-CH3; 2.29 and 2.27 (2s, 6 H total): Py-CH3; 1.31, 1.29, 1.22 and 1.01: (4d, J=7 Hz, 12 H total): P—O—CH—(CH3)2
-
- A mixture of 1.5 g (8 mmol) of 4,5-dimethoxy-3-hydroxybenzaldehyde and 0.98 g (8 mmol) of 3-amino-2,6-dimethylpyridine dissolved in 25 ml toluene and a catalytic amount of p-toluenesulfonic acid (ca. 1 mg) contained in a flask connected to a Dean Stark apparatus was refluxed for 16 h. The solution was evaporated to dryness to give 2.2 g (100%) of an oil which was used directly for the next step.
- Diethyl phosphite (1.66 g, 12 mmol) was added to 1.15 g (4 mmol) of the crude imine dissolved in 25 ml toluene and the mixture was refluxed for 16 h. The solvent and the excess of diethyl phosphite were evaporated and the residue was purified by column chromatography (SiO2, 95/5 CH2Cl2/MeOH) to give 0.52 g (30%) of a white solid, mp=134-136° C.
- MS (m/e)=425: M++1, 288 (100%): M++1 —PO3Et2
- NMR (CDCl3):δ=7.2 (broad peak, 1 H) : OH; 6.76 and 6.60 (2d, 1 H each): aromatic H, 3-pyridyl; 6.64 and 6.57 (m, 2 H): aromatic H, substituted phenyl; 4.57 (dd, J=7 and 24 Hz, 1 H): CH—PO3Et2; 4.47 (dd, 1 H): N—H; 4.18 to 3.76 (m, 4 H): P—O—CH2—CH3; 3.87 and 3.84 (2s, 6 H total): OCH3; 2.39 and 2.38 (2s, 6 H total): Py-CH3; 1.30 and 1.19: (2t, J=7 Hz, 6 H total): P—O—CH2—CH3
-
- As described in Example 12, the imine (1.15 g, 4 mmol) obtained by condensing 4,5-dimethoxy-3-hydroxybenzaldehyde with 3-amino-2,6-dimethylpyridine was reacted with diisopropyl phosphite (2.0 g, 12 mmol) in 25 ml toluene at reflux temperature for 16 h to give 0.5 g (28%) of the title compound as a solid, mp=157-159° C. after purification by column chromatography (95/5 CH2Cl2/MeOH).
- MS (m/e)=452: M+, 287 (100%): M+—PO3iPr2
- NMR (CDCl3):δ=6.9 (broad peak, 1 H): OH; 6.76 and 6.59 (2 d, 1 H each): aromatic H, 3-pyridyl; 6.64 and 6.57 (m, 2 H): aromatic H, substituted phenyl; 4.69 and 4.51 (m, 2 H): P—O—CH-Me2; 4.5 (2 overlapped m, 2 H): CH—PO3iPr2 and N—H; 3.86 and 3.85 (2s, 6 H total): OCH3; 2.41 and 2.38 (2s, 6 H total): Py-CH3; 1.33, 1.29, 1.23 and 1.04: (4d, J=7 Hz, 12 H total): P—O—CH—(CH3)2
-
- 3-Amino-2,6-dichloropyridine (mp=118-120° C.) was obtained in quantitative yield by reacting 3-nitro-2,6-dichloropyridine with a mixture of reduced iron in aqueous acetic acid.
- A mixture of 1.66 g (10 mmol) of 4-hydroxy-3-methoxy-5-methyl-benzaldehyde and 1.63 g (10 mmol) of 3-amino-2,6-dichloropyridine dissolved in 40 ml toluene and a catalytic amount of p-toluenesulfonic acid (ca. 1 mg) contained in a flask connected to a Dean Stark apparatus was refluxed for 16 h.
- Diethyl phosphite (3.45 g, 25 mmol) was added to the toluene solution of the crude imine and the mixture was refluxed for 7 h. The solvent and the excess of diethyl phosphite were evaporated and the residue was purified by column chromatography (SiO2, 95/5 CH2Cl2/MeOH) to give 0.52 g (30%) of a yellow solid.
- MS (m/e)=448: M+(35Cl), 311 (100%): M+(35Cl)—PO3Et2
- NMR (CDCl3):δ=6.98 and 6.72 (2d, 1 H each): aromatic H, 3-pyridyl; 6.77 (m, 2 H): aromatic H, substituted phenyl; 5.71 (1 H) : OH; 5.36 (dd, J=7 and 10 Hz, 1 H): N—H; 4.53 (dd, J=7 and 24 Hz, 1 H): CH—PO3Et2; 4.18 to 3.73 (m, 4 H): P—O—CH2—CH3; 3.86 (s, 3 H): OCH3; 2.23 (1s, 3 H): Ph-CH3; 1.31 and 1.20: (2t, J=7 Hz, 6 H total): P—O—CH2—CH3
-
- The process described in example 14 was followed using diiisopropyl phosphite as reagent to give the title compound as a white solid, mp=124-125° C.
- MS (m/e)=476: M+(35Cl), 311 (100%): M+(35Cl)—PO3iPr2
- NMR (CDCl3):δ=6.98 and 6.72 (2d, 1 H each): aromatic H, 3-pyridyl; 6.77 (m, 2 H): aromatic H, substituted phenyl; 5.71 (1 H) : OH; 5.36 (dd, J=7 and 10 Hz, 1 H): N—H; 4.67 and 4.50 (2m, 2 H total): P—O—CH—Me2; 4.5 (overlapped m, 1 H): CH—PO3iPr2; 3.86 (s, 3 H): OCH3; 2.23 (1s, 3 H): Ph-CH3; 1.34, 1.31, 1.23 and 1.06: (4d, J=7 Hz, 12 H total): P—O—CH—(CH3)2
-
- The imine (0.60 g, 2 mmol) obtained by condensing 3,5-dimethoxy-4-hydroxy-benzaldehyde with 3-amino-2,6-dimethoxypyridine was reacted with diethyl phosphite (0.52 g, 4 mmol) in 25 ml toluene at reflux temperature for 5 h to give 0.34 g (40%) of the title compound as a brown oil, after purification by column chromatography (98/2 CHCl3/MeOH).
- MS (m/e)=456: M+, 319: M+—PO3Et2
- NMR (CDCl3):δ=6.68 (d, J=2 Hz, 2 H): aromatic H, substituted phenyl; 6.56 and 6.07 (2d, J=8 Hz, 2 H): aromatic H, 3-pyridyl; 4.53 (d, J=23 Hz, 1 H): CH—PO3Et2; ca 4.0 (overlapped m): NH; 4.18 to 3.73 (m, 4 H): P—O—CH2—CH3; 3.98 and 3.81 (2s, 3 H each): pyridyl-OCH3; 3.86 (1s, 6 H): phenyl-OCH3; 1.29 and 1.19: (2t, J=7 Hz, 6 H total): P—O—CH2—CH3
-
- 2,6-Di-tert-butylpyridine-4-carboxaldehyde was obtained by oxidation of 2,6-di-tert-butyl-4-methylpyridine with excess selenium dioxide in acetic acid at reflux temperature.
- Diethyl α-(3,5-di-tert-butyl-4-hydroxyphenyl)-aminomethylphosphonate (1.67 g, 4.5 mmol) and 2,6-di-tert-butylpyridine-4-carboxaldehyde(1.8 g, 8.2 mmol) in 25 ml of MeOH were reacted with NaBH3CN (0.85 g, 13 mmol) for 4 h. After neutralisation with diluted HCl the reaction mixture was extracted with CH2Cl2 and purified by column chromatography on silicagel (CH2Cl2/MeOH) to yield 1.1 g (43%) of the title compound; mp=132-137° C.;
- MS (m/e)=573: M+, 436: M+—PO3Et2
- NMR (CDCl3):δ7.19 (d, J=2 Hz, 2 H): aromatic H, phenyl; 7.01 (s, 2 H): aromatic H, 4-picolyl; 5.2 (s, 1 H): OH; 4.15-3.77 (several m, 5 H): P—O—CH2—CH3 and CH—PO3Et2; 3.75 and 3.54 (2d, J=14 Hz): NH—CH2-Py 1.44 and 1.33 (2s, 9 H each): phenyl-tert-butyl and pyridyl-tert-butyl; 1.29 and 1.10 (2t, J=7 Hz, 6 H): P—O—CH2—CH3
-
- Diisopropyl α-(4-hydroxy-3-methoxy-5-methylphenyl)-N-[3-(2,6-dimethylpyridyl)]-amino-methylphosphonate (4.2 g, 9.6 mmol) was suspended in 20 ml diethylether and cooled in an ice bath. A solution of HCl in Et2O (1 M, 17.5 ml) was added, after stirring for 45 min the mixture was evaporated under reduced pressure until constant weight. An amount of 4.1 g (90%) of a yellow solid was obtained.
Elemental analysis: C22H34ClN2O5P % Calc. C 55.87 H 7.25 Cl 7.50N 5.92 P6.55 % Found C 54.01 H 7.42 Cl 7.54N 5.73 P6.22 -
- Racemic compound (Example 4) was resolved into its two enantiomers by chiral chromatography, using the following conditions:
- Column: Chiralpak AD, 250 mm×20 mm i.d
- Mobile Phase: 85/15 Hexane/Ethanol v/v
- Flow Rate: 10 ml/min
- Detection: UV at 215 nm
- Sample Concentration: 50 mg dissolved in 10 ml of 50/50 Hexane/Ethanol v/v
- injection Volume: 500 ul
- Under these conditions, the first elulting enantiomer peak eluted at 14.7 minutes and the second eluting peak eluted at 18.6 minutes. The two peaks were just baseline resolved. The two peaks were collected as separate fractions over a number of injections. A small sample of each enantiomer fraction was removed for chiral analysis to determine the enantiomeric purity of each fraciton. The HPLC conditions used for this chiral analysis were as follows:
- Column: Chiralpak AD, 250 mm×4.6 mm i.d
- Mobile Phase: 85/15 Hexane/Ethanol v/v
- Flow Rate: 1 ml/min
- Detection: UV at 215 nm
- Injection Volume: 20 ul
- Sample Concentration: Unknown—sample of undried peak fraction used.
- Under these conditions the main peak of the first eluting enantiomer fraction eluted at 6.95 minutes. No peak due to the minor enantiomer was observed in this fraction. The main peak of the second eluting enantiomer fraction eluted at 6.85 minutes with a small peak due to the minor enantiomer also observed eluting at 7.1 minutes and representing 0.3% of the total enantiomer peak area.
- The remainder of each enantiomer fraction was dried on a rotary evaporator. Each fraction has then been resuspended in a few mls ethanol and transferred to a small preweighed vial. The samples were blown to dryness under nitrogen at present prior to measurement of their mass spec and optical rotation.
- M+H for each enatiomer=409.1
- First eluting enantiomer: [α]D at 25° C.=+7.93° (c=1.19% EtOH)
- Second eluting enantiomer: [α]D at 25° C. =−8.29° (c=1.09% EtOH)
- Dimethyl α (4-hydroxy-3-methoxy-5-methylphenyl)-N-[3-(2,6-dimethylpyridyl)] amino-methylphosphonate
- Dimethyl phosphite (0.4 g, 3.7 mmol) was added to 0.5 g (1.85 mmol) of the crude imine (obtained as described in example 3) and the mixture was heated to 120° C. for 2 h. The oily reaction mixture was diluted in chloroform and extracted with a saturated bicarbonate solution. The dried organic phase was concentrated and triturated in petroleum ether to remove the excess of dimethyl phosphite. Further purification by column chromatography (SiO2, 95/5 CHCI3/MeOH) and recrystallization (petroleum ether/CH2CI2) gave 0.25 g (34%) of a solid, mp=166-168° C.
- IR (KBr)=3300 cm −1: NH, 1240: P═O, 1030 P—O—C
- Further compounds of formula (I) were prepared by following procedures analogous to those described in the foregoing examples. The are included in the following Table 1, along with the preceding examples. The left hand column refers to a ‘Compound’ rather than the Example number, the same compound numbers being then used in the Biological Data section.
TABLE 1 Aminophosphonates of formula (I) (where n is 0 and R1, R2 are identical) Cpd No Ex No X1 X2 X3 Z R1, R2 mp(° C.) 1 OMe OMe H H 3-(2,6-dimethyl)pyridyl Et 152-154 2 4 OMe Me H H 3-(2,6-dimethyl)pyridyl Et 145-147 3 3 OMe Me H H 3-(2,6-dimethyl)pyridyl iPr 159-160 4 1 Me Me H H 3-(2,6-dimethyl)pyridyl Et solid 5 2 tBu Me H H 3-(2,6-dimethyl)pyridyl Et 139-141 6 OEt Me H H 3-(2,6-dimethyl)pyridyl Et 125-127 7 OEt Me H H 3-(2,6-dimethyl)pyridyl iPr 145-146 8 17 tBu tBu H H Et 132-137 9 tBu tBu H H Et 139-145 10 tBu tBu H H Et 78-90 11 tBu tBu H H Et 172-176 12 8 OMe Me Me H 3-(2,6-dimethyl)pyridyl Et oil 13 9 OMe Me Me H 3-(2,6-dimethyl)pyridyl iPr oil 14 10 OH Me Me H 3-(2,6-dimethyl)pyridyl Et 141-142 15 11 OH Me Me H 3-(2,6-dimethyl)pyridyl iPr 168-169 16 12 OH OMe Me H 3-(2,6-dimethyl)pyridyl Et 134-136 17 13 OH OMe Me H 3-(2,6-dimethyl)pyridyl iPr 157-159 18 14 OMe Me H H 3-(2,6-dichloro)pyridyl Et solid 19 15 OMe Me H H 3-(2,6-dichloro)pyridyl iPr 124-125 20 16 OMe OMe H H 3-(2,6-dimethoxy)pyridyl H oil 21* 5 OMe Me H H 3-(2,6-dimethyl)pyridyl iPr 123-124 22* 5 OMe Me H H 3-(2,6-dimethyl)pyridyl iPr 120-122 23* 19 OMe Me H H 3-(2,6-dimethyl)pyridyl Et ? 24* 19 OMe Me H H 3-(2,6-dimethyl)pyridyl Et ? - * Cpd21−(+) Enantiomer of Cpd 3; Cpd 22−(−) Enantiomer of Cpd 3; Cpd 23−(+) Enantiomer of Cpd 2; Cpd 24−(−) Enantiomer of Cpd 2
- Biological Data
- The compounds of formula (1) were assayed for lowering the production of Lp(a) in primary cultures of Cynomolgus hepatocytes.
- Assay
- Hepatocytes were isolated from livers of adult Cynomolgus monkeys by the two-step collagenase perfusion method according to C. Guguen-Guillouzo and A. Guillouzo “Methods for preparation of adult and fetal hepatocytes” p. 1-12 in “Isolated and Cultured Hepatocytes”, les editions Inserm Paris and John Libbey Eurotext London (1986).
- The viability of cells was determined by Trypan blue staining. The cells were then seeded at a density from 0.7. 105 to 1.105 viable cells per cm2 in tissue culture plates in Williams E tissue culture medium containing 10% fetal calf serum. Cells were incubated for 4-6 hours and 24 hours at 37° C. in a CO2 incubator (5% CO2) in the presence of 20 μM of the test compounds dissolved in ethanol. Four to six wells were used for each compound. Nicotinic acid and steroid hormones were used as references to validate the assay system since they are known to decrease Lp(a) in man. Control cells were incubated in the presence of ethanol only.
- Results
- (a) Lp(a) concentration:
- The amount of Lp(a) secreted in culture medium was directly assayed by ELISA using a cormnercially available kit. Cells were washed and lysed as described by A. L. White et al, Journal of Lipid Research vol 34, p. 509-517, (1993) and the cellular content of Lp(a) was assayed as described above.
- Changes in Lp(a) concentration in culture medium are given as the percentage of values measured for the control plates at 24 h.
- All compounds were tested at 20 μM. Compounds No, 1, 2, 3, 4, 5, 6, 7, 15, 16, 21 and 22 were found to decrease the Lp(a) secretion by 20% to 50%. Compounds 12, 13, 14, 17, 18 and 19 lowered the Lp(a) secretion by 13 to 20%.
- (b) In vivo Results
- Study Protocol—Male cynomolgus monkeys weighing between 3 and 7 kg were divided into groups of 3 to 4 animals each. Prior to treatment their plasma Lp(a) levels were followed over a two-month period to ascertain a constant baseline value. The Lp(a) values measured at Day -7 and Day -1 were comparable and served as predose values. Test compounds were given orally in gelatin capsules by gavage at the dose of 25 mg/kg/day for 4 weeks and Lp(a) was measured at weekly intervals (Day 7, 14, 21 and 28). At the end of the dosing period, animals were maintained for a treatment free period of 4 weeks, whereupon their plasma Lp(a) levels returned to pretreatment levels. This control provided proof that the decrease in Lp(a) measured was caused by the pharmacological activity of the test compounds.
- Results—At Days -7, -1, 7, 14, 21 and 28, after an overnight fast blood samples were collected on EDTA and Lp(a) was measured by the highly sensitive and specific ELISA test. Results (mean of 3-4 values of each group ) were expressed as % of predose values. Selected compounds of formula (I) were tested under the experimental conditions to investigate their pharmacological activity in vivo.
- Compounds No 2, 3 and 6 were tested at 25 mg/kg/day for 28 days and lowered plasma Lp(a) in the range of 15% to 27% (values measured at Day 28, % change from predose values). Compounds 21 and 22 were tested at 50 mg/kg/day for 10 days and decreased plasma Lp(a) in the range of 13 to 39% (values measured at Day 10, % change from predose values).
Claims (23)
1. A compound of structure (I):
in which:
X1 and X2, which may be the same or different, are H, a straight or branched C(1-8)alkyl or C(1-8)alkoxy group, a hydroxy group or a nitro group;
X3 is H, a C(1-4)alkyl group, X3O and one of the two other substituents X1 or X2 may form a C(1-4)alkylidene dioxy ring;
R1 and R2, which may be the same or different, are H, a straight or branched C(1-6)alkyl group;
B is CH2, CH2-CH2 or CH═CH;
n is zero or 1;
Z is H, or a straight or branched C(1-8)alkyl group;
m is 0 or an integer from 1 to 5; and
Y1, Y2, Y3 and Y4, which may be the same or different, are H, a straight or branched C( 1-8)alkyl or C(1-8)alkoxy group, a cyano, trifluoromethyl, nitro, hydroxy, hydroxymethyl, C(1-4)alkoxymethyl, amino, C(1-4)alkylamino, C(1-4)dialkylamino group, a halogen atom (F, Cl, Br, I), or any two adjacent Y1, Y2, Y3 and Y4 may form an optionally substituted C(1-6)alkylidene or C(1-4)alkylidenedioxy ring, with the proviso that at least two of the Y1, Y2, Y3 and Y4 groups are not H;
or a pharmaceutically acceptable salt thereof.
2. A compound as claimed in claim 1 in which X1 is H, hydroxy, C(1-4)alkyl or C(1-4)alkoxy.
3. A compound as claimed in claim 1 or 2 in which X2 is C(1-4)alkyl or C(1-4)alkoxy.
4. A compound as claimed in any one of claims 1 to 3 in which X1 and X2 is each C(1-4)alkyl or C(1-4)alkoxy; or or one of X1 and X2 is C(1-4)alkyl and the other is C(1-4)alkoxy or C(1-3)alkyl; or X1 is hydroxy and X2 is C(1-4)alkyl or C(1-4)alkoxy.
5. A compound as claimed in any one of claims 1 to 4 in which X1 and X2 are methoxy and methoxy, methoxy and methyl, ethoxy and methyl, methyl or t-butyl and methyl, ethoxy and ethoxy, hydroxy and methyl, and hydroxy and methoxy, respectively.
6. A compound as claimed in any one of claims 1 to 5 in which X3 is hydrogen or methyl.
7. A compound as claimed in any one of claims 1 to 6 in which (B)n is a direct bond.
8. A compound as claimed in any one of claims 1 to 7 in which Z is hydrogen.
9. A compound as claimed in any one of claims 1 to 8 in which Y1 and Y2 is each methyl and Y3 and Y4 is each hydrogen..
10. A compound as claimed in claim 9 in which Y1 and Y2 are 2,6-substituents of the pyridyl ring.
11. A compound as claimed in any one of claims 1 to 10 in which the pyridyl ring is attached by the ring carbon β- to the nitrogen (⅗-pyridyl).
12. A compound as claimed in any one of claims 1 to 10 in which m is zero.
13. A compound of formula (I) as defined in claim 1 selected from:
diethyl α-(4-hydroxy-3,5-dimethoxyphenyl)-N-[3-(2,6-dimethylpyridyl)]-aminomethylphosphonate;
diethyl α-(4-hydroxy-3,5-dimethylphenyl)-N-[3-(2,6-dimethylpyridyl)]-aminomethylphosphonate;
diethyl α-(3-tert-butyl-4-hydroxy-3-methylphenyl)-N-[3-(2,6-dimethylpyridyl)]-aminomethylphosphonate;
diethyl α-(3-ethoxy-4-hydroxy-5-methylphenyl)-N-[3-(2,6-dimethylpyridyl)]-aminomethylphosphonate;
diisopropyl α-(3-ethoxy-4-hydroxy-5-methylphenyl)-N-[3-(2,6-dimethylpyridyl)]-aminomethylphosphonate;
diethyl α-(3,5-di-tert-butyl-4-hydroxyphenyl)-N-[4-(2,6-di-tert-butylpicolyl)]-aminomethylphosphonate;
diethyl α-(3,5-di-tert-butyl-4-hydroxyphenyl)-N-[4-(3-hydroxy-5-hydroxymethyl-2-methylpicolyl)]-aminomethylphosphonate;
diethyl α-(3,5-di-tert-butyl-4-hydroxyphenyl)-N-[5-(3,4-O-isopropylidene-3-hydroxy-4-hydroxymethyl-2-methylpicolyl)]-aminomethylphosphonate;
diethyl α-(3,5-di-tert-butyl-4-hydroxyphenyl)-N-[5-(3-hydroxy-4-hydroxymethyl-2-methylpicolyl)]-aminomethylphosphonate;
diethyl α-(3,4-dimethoxy-5-methylphenyl)-N-[3-(2,6-dimethylpyridyl)]-amino-methylphosphonate;
diisopropylα-(3,4-dimethoxy-5-methylphenyl)-N-[3-(2,6-dimethylpyridyl)]-amino-methylphosphonate;
diethyl α-(3-hydroxy-4-methoxy-5-methylphenyl)-N-[3-(2,6-dimethylpyridyl)]-amino-methylphosphonate;
diisopropyl α-(3-hydroxy-4-methoxy-5-methylphenyl)- N-[3-(2,6-dimethylpyridyl)]-amino-methylphosphonate;
diethyl α-(4,5-dimethoxy-3-hydroxyphenyl)-N-[3-(2,6-dimethylpyridyl)]-amino-methylphosphonate;
diisopropyl α-(4,5-dimethoxy-3-hydroxyphenyl)-N-[3-(2,6-dimethylpyridyl)]-amino-methylphosphonate;
diethyl α-(4-hydroxy-3-methoxy-5-methylphenyl)-N-[3-(2,6-dichloropyridyl)]-amino-methylphosphonate;
diisopropyl α-(4-hydroxy-3-methoxy-5-methylphenyl)-N-[3-(2,6-dichloropyridyl)]-amino-methylphosphonate; and
diethyl α-(3,5-dimethoxy-4-hydroxyphenyl)-N-[3-(2,6-dimethoxypyridyl)]-amino-methylphosphonate; or
a pharmaceutically acceptable salt thereof.
14. A compound of formula (I) as defined in claim 1 selected from:
diisopropyl α-(4-hydroxy-3-methoxy-5-methylphenyl)-N-[3-(2,6-dimethylpyridyl)]-aminomethylphosphonate;
(+)diisopropyl α-(4-hydroxy-3-methoxy-5-methylphenyl)-N-[3-(2,6-dimethylpyridyl)]-aminomethylphosphonate;
(-)diisopropyl α-(4-hydroxy-3-methoxy-5-methylphenyl)-N-[3-(2,6-dimethylpyridyl)]-aminomethylphosphonate; or
a pharmaceutically acceptable salt thereof, in particular the hydrochloride salt.
15. A compound of formula (I) as defined in claim 1 selected from:
diethyl α-(4-hydroxy-3-methoxy-5-methylphenyl)-N-[3-(2,6-dimethylpyridyl)]-aminomethylphosphonate;
(+)diethyl α-(4-hydroxy-3-methoxy-5-methylphenyl)-N-[3-(2,6-dimethylpyridyl)]-aminomethylphosphonate; and
(−)diethyl α-(4-hydroxy-3-methoxy-5-methylphenyl)-N-[3-(2,6-dimethylpyridyl)]-aminomethylphosphonate; or
a pharmaceutically acceptable salt thereof, in particular the hydrochloride salt.
16. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 and a pharmaceutically acceptable excipient thereof.
17. A compound of formula (I) as defined in claim 1 , or a pharmaceutically acceptable salt thereof, for use in therapy.
18. The use of a compound of formula (I) as defined in claim 1 , or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in decreasing plasma and tissue lipoprotein(a) levels.
19. A use of a compound of formula (I) as claimed in claim 18 , for the manufacture of a medicament for the treatment of thrombosis by decreasing plasma lipoprotein(a) levels.
20. A use of a compound of formula (I) as claimed in claim 18 , for the manufacture of a medicament for the treatment of restenosis following angioplasty by decreasing plasma lipoprotein(a) levels.
21. A use of a compound of formula (I) as claimed in claim 18 , for the manufacture of a medicament for the treatment of atherosclerosis by decreasing plasma lipoprotein(a) levels.
22. A method of treating a disease associated with elevated plasma and tissue lipoprotein(a) levels which method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) as defined in claim 1 , or a pharmaceutically acceptable salt thereof.
23. A process for preparing a compound of formula (I) as defined in claim 1 which process comprises:
(a) for compounds of formula (I) in which Z is hydrogen, treating an imine of formula (II):
in which X1, X2, X3, B, n, m, Y1, Y2, Y3 and Y4 are as defined in claim 1; with a dialkyl phosphite of formula (III):
H—PO(OR1)(OR2) (III)
in which R1 and R2 are as defined in claim 1; or a trialkyl silyl or metal derivative thereof;
(b) reacting together equimolar amounts of an aldehyde of formula (IV):
in which X1, X2, X3, B and n are as defined in claim 1;
an amine of formula (V):
(c) for compounds of formula (I) in which m is not zero, treating a compound of formula (VI)
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US09/331,385 US6303784B1 (en) | 1996-12-20 | 1997-12-17 | Pharmaceutical aminophosphonic acid derivatives |
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ES2330552T3 (en) | 2000-02-16 | 2009-12-11 | Smithkline Beecham Plc | DERIVATIVES OF PYRIMIDIN-5-ONA AS INHIBITORS OF LDL-PLA2. |
EP1531157B1 (en) * | 2000-02-29 | 2008-03-19 | Medicure International Inc. | Cardioprotective phosphonates |
EP1268498B1 (en) * | 2000-02-29 | 2005-04-13 | Medicure International Inc. | Cardioprotective phosphonates |
US20030114421A1 (en) * | 2000-09-27 | 2003-06-19 | Phan Hieu Trung | Alpha-substituted beta-aminoethyl phosphonate derivatives |
KR100722586B1 (en) * | 2000-09-27 | 2007-05-28 | 일렉스 프로덕츠, 인코포레이티드 | ?-substituted ?-aminoethyl phosphonates |
GB0024808D0 (en) | 2000-10-10 | 2000-11-22 | Smithkline Beecham Plc | Novel compounds |
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AU2003219701A1 (en) * | 2002-02-11 | 2003-09-04 | Ilex Products, Inc. | Alpha-substituted heteroarylalkyl phosphonate derivatives |
US7208481B2 (en) * | 2002-02-19 | 2007-04-24 | Ilex Products, Inc. | Aminodiphosphonate apolipoprotein E modulators |
JP4824968B2 (en) * | 2005-08-18 | 2011-11-30 | 株式会社クレハ | Phosphonic acid derivatives and acid addition salts thereof, and agricultural and horticultural disease control agents using the same |
WO2012076435A1 (en) | 2010-12-06 | 2012-06-14 | Glaxo Group Limited | Pyrimidinone compounds for use in the treatment of diseases or conditions mediated by lp - pla2 |
JP2014521625A (en) | 2011-07-27 | 2014-08-28 | グラクソ グループ リミテッド | Bicyclic pyrimidone compounds |
EP2739627A4 (en) | 2011-07-27 | 2015-01-21 | Glaxo Group Ltd | 2,3-dihydroimidazo[1,2-c]pyrimidin-5(1h)-one compounds use as lp-pla² inhibitors |
BR112014004251A2 (en) | 2011-09-01 | 2017-03-21 | Glaxo Group Ltd | new crystal shape |
RU2015135824A (en) | 2013-01-25 | 2017-03-03 | Глэксосмитклайн Интеллекчуал Проперти Дивелопмент Лимитед | Bicyclic Compounds of Pyrimidone as LP-PLA2 Inhibitors |
BR112015017768A2 (en) | 2013-01-25 | 2017-07-11 | Glaxosmithkline Ip Dev Ltd | compounds |
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WO2016012916A1 (en) | 2014-07-22 | 2016-01-28 | Glaxosmithkline Intellectual Property Development Limited | 1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidine derivatives useful in the treatment of diseases and disorders mediated by lp-pla2 |
WO2016012917A1 (en) | 2014-07-22 | 2016-01-28 | Glaxosmithkline Intellectual Property Development Limited | 1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidine derivatives useful in the treatment of diseases and disorders mediated by lp-pla2 |
MX2022005615A (en) | 2019-11-09 | 2022-07-27 | Shanghai Simr Biotechnology Co Ltd | Tricyclic dihydroimidazopyrimidone derivative, preparation method therefor, pharmaceutical composition and use thereof. |
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