AP778A - Aminophosphonates and pharmaceutical compositions containing them. - Google Patents

Aminophosphonates and pharmaceutical compositions containing them. Download PDF

Info

Publication number: AP778A
Authority: AP; ARIPO
Prior art keywords: diethyl; compound; pyridyl; formula; aminomethylphosphonate
Prior art date: 1995-06-30

Application number

APAP/P/1997/001160A

Other languages

English (en)

Other versions

AP9701160A0 (en

Inventor

Lan Mong Nguyen

Eric Niesor

Craig Leigh Bentzen

Hieu Trung Phan

Vinh Van Diep

Simon Floret

Raymond Azoulay

Alexandre Bulla

Yves Guyon-Gellin

Robert John Ife

Original Assignee

Symphar Sa

Smithkline Beecham Plc

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1995-06-30

Filing date

1996-06-26

Publication date

1999-10-29

1996-06-26 Application filed by Symphar Sa, Smithkline Beecham Plc filed Critical Symphar Sa

1998-01-31 Publication of AP9701160A0 publication Critical patent/AP9701160A0/xx

1999-10-29 Application granted granted Critical

1999-10-29 Publication of AP778A publication Critical patent/AP778A/en

Links

239000008194 pharmaceutical composition Substances 0.000 title claims description 5
PTMHPRAIXMAOOB-UHFFFAOYSA-N phosphoramidic acid Chemical class NP(O)(O)=O PTMHPRAIXMAOOB-UHFFFAOYSA-N 0.000 title abstract description 14
238000000034 method Methods 0.000 claims abstract description 23
102000004895 Lipoproteins Human genes 0.000 claims abstract description 6
108090001030 Lipoproteins Proteins 0.000 claims abstract description 6
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 84
150000001875 compounds Chemical class 0.000 claims description 82
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 60
125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 53
125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 50
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 39
-1 methoxy, methoxy Chemical group 0.000 claims description 30
125000000217 alkyl group Chemical group 0.000 claims description 27
150000002466 imines Chemical class 0.000 claims description 27
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
MGRVRXRGTBOSHW-UHFFFAOYSA-N (aminomethyl)phosphonic acid Chemical compound NCP(O)(O)=O MGRVRXRGTBOSHW-UHFFFAOYSA-N 0.000 claims description 20
229910052739 hydrogen Inorganic materials 0.000 claims description 20
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
239000002904 solvent Substances 0.000 claims description 18
150000003839 salts Chemical class 0.000 claims description 15
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
125000003545 alkoxy group Chemical group 0.000 claims description 14
230000008569 process Effects 0.000 claims description 14
229910052799 carbon Inorganic materials 0.000 claims description 13
108010033266 Lipoprotein(a) Proteins 0.000 claims description 12
238000006243 chemical reaction Methods 0.000 claims description 12
239000001257 hydrogen Substances 0.000 claims description 12
239000003814 drug Substances 0.000 claims description 11
208000037803 restenosis Diseases 0.000 claims description 11
ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 claims description 10
230000003247 decreasing effect Effects 0.000 claims description 10
201000001320 Atherosclerosis Diseases 0.000 claims description 9
208000007536 Thrombosis Diseases 0.000 claims description 9
238000004519 manufacturing process Methods 0.000 claims description 9
238000002399 angioplasty Methods 0.000 claims description 8
239000003054 catalyst Substances 0.000 claims description 7
125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 7
229910052757 nitrogen Inorganic materials 0.000 claims description 7
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 5
125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 5
208000030613 peripheral artery disease Diseases 0.000 claims description 5
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
125000004432 carbon atom Chemical group C* 0.000 claims description 4
239000003937 drug carrier Substances 0.000 claims description 4
125000004076 pyridyl group Chemical group 0.000 claims description 4
238000006268 reductive amination reaction Methods 0.000 claims description 4
230000001476 alcoholic effect Effects 0.000 claims description 3
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
239000000546 pharmaceutical excipient Substances 0.000 claims description 3
BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 3
125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
241000790917 Dioxys <bee> Species 0.000 claims description 2
125000001118 alkylidene group Chemical group 0.000 claims description 2
125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 2
125000001475 halogen functional group Chemical group 0.000 claims description 2
229910052751 metal Chemical class 0.000 claims description 2
239000002184 metal Chemical class 0.000 claims description 2
125000001424 substituent group Chemical group 0.000 claims description 2
125000004665 trialkylsilyl group Chemical class 0.000 claims description 2
125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims 2
102000057248 Lipoprotein(a) Human genes 0.000 claims 1
OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 claims 1
125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 claims 1
238000002560 therapeutic procedure Methods 0.000 claims 1
238000002360 preparation method Methods 0.000 abstract description 4
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 66
102100040214 Apolipoprotein(a) Human genes 0.000 description 62
101710115418 Apolipoprotein(a) Proteins 0.000 description 49
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 42
239000000203 mixture Substances 0.000 description 41
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 39
125000003118 aryl group Chemical group 0.000 description 36
238000005481 NMR spectroscopy Methods 0.000 description 28
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 27
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 24
239000000243 solution Substances 0.000 description 20
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 20
239000007787 solid Substances 0.000 description 19
238000004440 column chromatography Methods 0.000 description 16
CUYKNJBYIJFRCU-UHFFFAOYSA-N 3-aminopyridine Chemical compound NC1=CC=CN=C1 CUYKNJBYIJFRCU-UHFFFAOYSA-N 0.000 description 14
LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 description 13
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
239000003921 oil Substances 0.000 description 12
235000019198 oils Nutrition 0.000 description 12
239000003208 petroleum Substances 0.000 description 11
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
239000000725 suspension Substances 0.000 description 10
238000003556 assay Methods 0.000 description 9
PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 8
230000003197 catalytic effect Effects 0.000 description 8
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 7
150000001299 aldehydes Chemical class 0.000 description 7
NFORZJQPTUSMRL-UHFFFAOYSA-N dipropan-2-yl hydrogen phosphite Chemical compound CC(C)OP(O)OC(C)C NFORZJQPTUSMRL-UHFFFAOYSA-N 0.000 description 7
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
241000282414 Homo sapiens Species 0.000 description 6
241000282567 Macaca fascicularis Species 0.000 description 6
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 6
208000006011 Stroke Diseases 0.000 description 6
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
210000004027 cell Anatomy 0.000 description 6
230000000875 corresponding effect Effects 0.000 description 6
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
229940079593 drug Drugs 0.000 description 6
210000003494 hepatocyte Anatomy 0.000 description 6
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 6
KCDXJAYRVLXPFO-UHFFFAOYSA-N syringaldehyde Chemical compound COC1=CC(C=O)=CC(OC)=C1O KCDXJAYRVLXPFO-UHFFFAOYSA-N 0.000 description 6
COBXDAOIDYGHGK-UHFFFAOYSA-N syringaldehyde Natural products COC1=CC=C(C=O)C(OC)=C1O COBXDAOIDYGHGK-UHFFFAOYSA-N 0.000 description 6
238000012360 testing method Methods 0.000 description 6
210000001519 tissue Anatomy 0.000 description 6
102000007330 LDL Lipoproteins Human genes 0.000 description 5
108010007622 LDL Lipoproteins Proteins 0.000 description 5
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
201000010099 disease Diseases 0.000 description 5
238000000921 elemental analysis Methods 0.000 description 5
239000011541 reaction mixture Substances 0.000 description 5
238000001953 recrystallisation Methods 0.000 description 5
230000001225 therapeutic effect Effects 0.000 description 5
ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 4
125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 4
YGCZTXZTJXYWCO-UHFFFAOYSA-N 3-phenylpropanal Chemical compound O=CCCC1=CC=CC=C1 YGCZTXZTJXYWCO-UHFFFAOYSA-N 0.000 description 4
125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 4
BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
150000001412 amines Chemical class 0.000 description 4
239000002775 capsule Substances 0.000 description 4
208000029078 coronary artery disease Diseases 0.000 description 4
230000000694 effects Effects 0.000 description 4
238000001704 evaporation Methods 0.000 description 4
230000008020 evaporation Effects 0.000 description 4
239000001963 growth medium Substances 0.000 description 4
238000001727 in vivo Methods 0.000 description 4
238000004452 microanalysis Methods 0.000 description 4
229960003512 nicotinic acid Drugs 0.000 description 4
235000001968 nicotinic acid Nutrition 0.000 description 4
239000011664 nicotinic acid Substances 0.000 description 4
230000036470 plasma concentration Effects 0.000 description 4
150000003335 secondary amines Chemical class 0.000 description 4
239000012312 sodium hydride Substances 0.000 description 4
229910000104 sodium hydride Inorganic materials 0.000 description 4
239000007858 starting material Substances 0.000 description 4
239000003826 tablet Substances 0.000 description 4
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
101000889990 Homo sapiens Apolipoprotein(a) Proteins 0.000 description 3
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 description 3
239000002253 acid Substances 0.000 description 3
238000002617 apheresis Methods 0.000 description 3
210000004369 blood Anatomy 0.000 description 3
239000008280 blood Substances 0.000 description 3
230000008859 change Effects 0.000 description 3
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
238000004128 high performance liquid chromatography Methods 0.000 description 3
238000007327 hydrogenolysis reaction Methods 0.000 description 3
229910052943 magnesium sulfate Inorganic materials 0.000 description 3
235000019341 magnesium sulphate Nutrition 0.000 description 3
239000012074 organic phase Substances 0.000 description 3
230000000144 pharmacologic effect Effects 0.000 description 3
229960002965 pravastatin Drugs 0.000 description 3
TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 3
150000003141 primary amines Chemical class 0.000 description 3
FYPMFJGVHOHGLL-UHFFFAOYSA-N probucol Chemical compound C=1C(C(C)(C)C)=C(O)C(C(C)(C)C)=CC=1SC(C)(C)SC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 FYPMFJGVHOHGLL-UHFFFAOYSA-N 0.000 description 3
229960003912 probucol Drugs 0.000 description 3
210000002966 serum Anatomy 0.000 description 3
229910002027 silica gel Inorganic materials 0.000 description 3
239000000741 silica gel Substances 0.000 description 3
229960001866 silicon dioxide Drugs 0.000 description 3
210000000329 smooth muscle myocyte Anatomy 0.000 description 3
238000004611 spectroscopical analysis Methods 0.000 description 3
239000003270 steroid hormone Substances 0.000 description 3
DOZRDZLFLOODMB-UHFFFAOYSA-N 3,5-di-tert-Butyl-4-hydroxybenzaldehyde Chemical compound CC(C)(C)C1=CC(C=O)=CC(C(C)(C)C)=C1O DOZRDZLFLOODMB-UHFFFAOYSA-N 0.000 description 2
MGJSDNCLGHCTIL-UHFFFAOYSA-N 4-hydroxy-3-methoxy-5-methylbenzaldehyde Chemical compound COC1=CC(C=O)=CC(C)=C1O MGJSDNCLGHCTIL-UHFFFAOYSA-N 0.000 description 2
RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 description 2
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-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
239000004215 Carbon black (E152) Substances 0.000 description 2
208000024172 Cardiovascular disease Diseases 0.000 description 2
208000014882 Carotid artery disease Diseases 0.000 description 2
XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
238000002965 ELISA Methods 0.000 description 2
239000004150 EU approved colour Substances 0.000 description 2
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 2
238000010268 HPLC based assay Methods 0.000 description 2
206010022562 Intermittent claudication Diseases 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
241001465754 Metazoa Species 0.000 description 2
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
102000013566 Plasminogen Human genes 0.000 description 2
108010051456 Plasminogen Proteins 0.000 description 2
239000002202 Polyethylene glycol Substances 0.000 description 2
241000288906 Primates Species 0.000 description 2
229920002472 Starch Polymers 0.000 description 2
230000002159 abnormal effect Effects 0.000 description 2
239000003963 antioxidant agent Substances 0.000 description 2
230000003078 antioxidant effect Effects 0.000 description 2
239000002585 base Substances 0.000 description 2
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
230000015572 biosynthetic process Effects 0.000 description 2
238000009835 boiling Methods 0.000 description 2
208000037876 carotid Atherosclerosis Diseases 0.000 description 2
239000000969 carrier Substances 0.000 description 2
230000020411 cell activation Effects 0.000 description 2
230000004663 cell proliferation Effects 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
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
229940125810 compound 20 Drugs 0.000 description 2
238000009833 condensation Methods 0.000 description 2
230000005494 condensation Effects 0.000 description 2
239000006185 dispersion Substances 0.000 description 2
230000008030 elimination Effects 0.000 description 2
238000003379 elimination reaction Methods 0.000 description 2
CBOQJANXLMLOSS-UHFFFAOYSA-N ethyl vanillin Chemical compound CCOC1=CC(C=O)=CC=C1O CBOQJANXLMLOSS-UHFFFAOYSA-N 0.000 description 2
239000000796 flavoring agent Substances 0.000 description 2
238000009472 formulation Methods 0.000 description 2
239000012458 free base Substances 0.000 description 2
239000007903 gelatin capsule Substances 0.000 description 2
JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 2
229930195733 hydrocarbon Natural products 0.000 description 2
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239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 2
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238000000338 in vitro Methods 0.000 description 2
238000011065 in-situ storage Methods 0.000 description 2
208000021156 intermittent vascular claudication Diseases 0.000 description 2
238000010829 isocratic elution Methods 0.000 description 2
239000008101 lactose Substances 0.000 description 2
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
230000014759 maintenance of location Effects 0.000 description 2
230000008018 melting Effects 0.000 description 2
238000002844 melting Methods 0.000 description 2
229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 2
238000007911 parenteral administration Methods 0.000 description 2
UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 2
229920001223 polyethylene glycol Polymers 0.000 description 2
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
230000035755 proliferation Effects 0.000 description 2
QJZUKDFHGGYHMC-UHFFFAOYSA-N pyridine-3-carbaldehyde Chemical compound O=CC1=CC=CN=C1 QJZUKDFHGGYHMC-UHFFFAOYSA-N 0.000 description 2
BGUWFUQJCDRPTL-UHFFFAOYSA-N pyridine-4-carbaldehyde Chemical compound O=CC1=CC=NC=C1 BGUWFUQJCDRPTL-UHFFFAOYSA-N 0.000 description 2
238000012216 screening Methods 0.000 description 2
238000000926 separation method Methods 0.000 description 2
159000000000 sodium salts Chemical class 0.000 description 2
239000008107 starch Substances 0.000 description 2
235000019698 starch Nutrition 0.000 description 2
238000003786 synthesis reaction Methods 0.000 description 2
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
230000002885 thrombogenetic effect Effects 0.000 description 2
230000002537 thrombolytic effect Effects 0.000 description 2
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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
- 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
- C07F9/59—Hydrogenated pyridine rings
- 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
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/582—Recycling of unreacted starting or intermediate materials

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Health & Medical Sciences (AREA)
Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Life Sciences & Earth Sciences (AREA)
General Health & Medical Sciences (AREA)
Animal Behavior & Ethology (AREA)
Pharmacology & Pharmacy (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Medicinal Chemistry (AREA)
Molecular Biology (AREA)
Biochemistry (AREA)
Epidemiology (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Chemical Kinetics & Catalysis (AREA)
General Chemical & Material Sciences (AREA)
Heart & Thoracic Surgery (AREA)
Cardiology (AREA)
Diabetes (AREA)
Hematology (AREA)
Vascular Medicine (AREA)
Urology & Nephrology (AREA)
Obesity (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

APAP/P/1997/001160A 1995-06-30 1996-06-26 Aminophosphonates and pharmaceutical compositions containing them. AP778A (en)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
CH01920/95A CH690264A5 (fr)	1995-06-30	1995-06-30	Dérivés aminophosphonates substitués, leur procédé de préparation et leur utilisation pour la préparation de compositions pharmaceutiques.
PCT/EP1996/002842 WO1997002037A1 (fr)	1995-06-30	1996-06-26	Composes et compositions pharmaceutiques les contenant

Publications (2)

Publication Number	Publication Date
AP9701160A0 AP9701160A0 (en)	1998-01-31
AP778A true AP778A (en)	1999-10-29

Family

ID=4221681

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
APAP/P/1997/001160A AP778A (en)	1995-06-30	1996-06-26	Aminophosphonates and pharmaceutical compositions containing them.

Country Status (27)

Country	Link
US (2)	US6060464A (fr)
EP (1)	EP0835116A1 (fr)
JP (1)	JPH11508576A (fr)
KR (1)	KR19990028542A (fr)
CN (1)	CN1113654C (fr)
AP (1)	AP778A (fr)
AR (1)	AR004498A1 (fr)
AU (1)	AU705206B2 (fr)
BG (1)	BG102215A (fr)
BR (1)	BR9609653A (fr)
CA (1)	CA2225391A1 (fr)
CH (1)	CH690264A5 (fr)
CZ (1)	CZ422097A3 (fr)
EA (1)	EA199800106A1 (fr)
HU (1)	HUP9901684A3 (fr)
IL (1)	IL122717A0 (fr)
MA (1)	MA24340A1 (fr)
MX (1)	MX9800189A (fr)
NO (1)	NO976128L (fr)
NZ (1)	NZ312696A (fr)
OA (1)	OA10554A (fr)
PL (1)	PL187024B1 (fr)
SK (1)	SK178397A3 (fr)
TR (1)	TR199701700T1 (fr)
TW (1)	TW413681B (fr)
WO (1)	WO1997002037A1 (fr)
ZA (1)	ZA965505B (fr)

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US6548084B2 (en)	1995-07-20	2003-04-15	Smithkline Beecham Plc	Controlled release compositions
GB9626615D0 (en)	1996-12-20	1997-02-05	Symphar Sa	Novel compounds
GB9626616D0 (en) *	1996-12-20	1997-02-05	Symphar Sa	Novel compounds
GB9626536D0 (en) *	1996-12-20	1997-02-05	Symphar Sa	Novel compounds
DE19748659A1 (de) *	1997-11-04	1999-05-06	Hoechst Ag	Aminophosphoniumgruppen enthaltende vernetzte Copolymere für medizinische Verwendungen
US6017918A (en) *	1998-08-06	2000-01-25	Warner-Lambert Company	Phenyl glycine compounds and methods of treating atherosclerosis and restenosis
US6284795B1 (en)	1998-09-04	2001-09-04	Warner-Lambert Company	Sulfonamide compounds and methods of treating atherosclerosis and restenosis
WO2001030339A1 (fr)	1999-10-27	2001-05-03	Teva Pharmaceutical Industries, Ltd.	Utilisation de derives de 1-aminoindan pour le traitement de la manie liée à la psychose maniacodépressive
SI1686119T1 (sl)	2000-02-16	2009-12-31	Smithkline Beecham Plc	Derivati pirimidin-5-ona kot inhibitorji ldl-pla2
JP2004513891A (ja) *	2000-09-27	2004-05-13	アイレックス　オンコロジー　リサーチ　エス．エイ．	α−置換β−アミノエチルホスホネート
US20030114421A1 (en) *	2000-09-27	2003-06-19	Phan Hieu Trung	Alpha-substituted beta-aminoethyl phosphonate derivatives
GB0024808D0 (en)	2000-10-10	2000-11-22	Smithkline Beecham Plc	Novel compounds
GB0025849D0 (en) *	2000-10-23	2000-12-06	Smithkline Beecham Plc	Novel compounds
AU2003219701A1 (en) *	2002-02-11	2003-09-04	Ilex Products, Inc.	Alpha-substituted heteroarylalkyl phosphonate derivatives
AU2003228990A1 (en) *	2002-05-11	2003-11-11	Ilex Products, Inc.	Hydroxyphosphonates and phosphonophosphates as apolipoprotein e modulators
MXPA05002331A (es) *	2002-08-30	2005-08-18	Biostratum Inc	Inhibidores de productos terminales de glicacion avanzada post-amadori.
JP5886310B2 (ja)	2010-12-06	2016-03-16	グラクソグループリミテッドＧｌａｘｏＧｒｏｕｐＬｉｍｉｔｅｄ	Ｌｐ−ＰＬＡ２により媒介される疾患または状態の処置における使用のためのピリミジノン化合物
JP2014521625A (ja)	2011-07-27	2014-08-28	グラクソグループリミテッド	二環式ピリミドン化合物
CA2842965A1 (fr)	2011-07-27	2013-01-31	Glaxo Group Limited	Composes 2,3-dihydroimidazo[1,2-c]pyrimidin-5(1h)-one et utilisation en tant qu'inhibiteurs de lp-pla2
EA027972B1 (ru)	2011-09-01	2017-09-29	Глэксо Груп Лимитед	Новая кристаллическая форма
KR20150111356A (ko)	2013-01-25	2015-10-05	글락소스미스클라인 인털렉츄얼 프로퍼티 디벨로프먼트 리미티드	화합물
BR112015017397A2 (pt)	2013-01-25	2017-07-11	Glaxosmithkline Ip Dev Ltd	compostos pirimidona bicíclica como inibidores de lp-pla2
JP6306053B2 (ja)	2013-01-25	2018-04-04	グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドＧｌａｘｏｓｍｉｔｈｋｌｉｎｅＩｎｔｅｌｌｅｃｔｕａｌＰｒｏｐｅｒｔｙＤｅｖｅｌｏｐｍｅｎｔＬｉｍｉｔｅｄ	２，３−ジヒドロイミダゾール［１，２−ｃ］ピリミジン−５（１Ｈ）−オンに基づくリポタンパク質関連ホスホリパーゼＡ２（Ｌｐ−ＰＬＡ２）阻害剤
WO2016012916A1 (fr)	2014-07-22	2016-01-28	Glaxosmithkline Intellectual Property Development Limited	Dérivés 1,2,3,5-tétrahydro-imidazo [1,2-c]pyrimidine utiles pour le traitement de maladies et de troubles médiés par la lp-pla2
WO2016012917A1 (fr)	2014-07-22	2016-01-28	Glaxosmithkline Intellectual Property Development Limited	Dérivés 1,2,3,5-tétrahydro-imidazo [1,2-c]pyrimidine utiles pour le traitement de maladies et de troubles médiés par la lp-pla2
EP4056571A4 (fr)	2019-11-09	2024-01-24	Shanghai Simr Biotechnology Co., Ltd.	Dérivé de dihydroimidazopyrimidone tricyclique, son procédé de préparation, composition pharmaceutique et son utilisation
CN115304620A (zh)	2021-05-07	2022-11-08	上海赛默罗生物科技有限公司	嘧啶酮衍生物、其制备方法、药物组合物和用途

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EP0559079A1 (fr) *	1992-03-05	1993-09-08	Symphar S.A.	Dérivés substitués à d'aminophosphonates, leur procédé de préparation et compositions pharmaceutiques les contenant

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DE4433244A1 (de) *	1994-09-19	1996-03-28	Hoechst Ag	Aminomethylphosphon- und Aminomethylphosphinsäure-Derivate und deren Verwendung zur Behandlung von degenerativen Gelenkserkrankungen

1995
- 1995-06-30 CH CH01920/95A patent/CH690264A5/fr not_active IP Right Cessation
1996
- 1996-06-26 CZ CZ974220A patent/CZ422097A3/cs unknown
- 1996-06-26 HU HU9901684A patent/HUP9901684A3/hu unknown
- 1996-06-26 CN CN96196395A patent/CN1113654C/zh not_active Expired - Fee Related
- 1996-06-26 US US08/973,669 patent/US6060464A/en not_active Expired - Fee Related
- 1996-06-26 TR TR97/01700T patent/TR199701700T1/xx unknown
- 1996-06-26 EP EP96923971A patent/EP0835116A1/fr not_active Withdrawn
- 1996-06-26 EA EA199800106A patent/EA199800106A1/ru unknown
- 1996-06-26 AP APAP/P/1997/001160A patent/AP778A/en active
- 1996-06-26 IL IL12271796A patent/IL122717A0/xx unknown
- 1996-06-26 WO PCT/EP1996/002842 patent/WO1997002037A1/fr not_active Ceased
- 1996-06-26 CA CA002225391A patent/CA2225391A1/fr not_active Abandoned
- 1996-06-26 NZ NZ312696A patent/NZ312696A/en unknown
- 1996-06-26 JP JP9504801A patent/JPH11508576A/ja not_active Withdrawn
- 1996-06-26 KR KR1019970709860A patent/KR19990028542A/ko not_active Withdrawn
- 1996-06-26 SK SK1783-97A patent/SK178397A3/sk unknown
- 1996-06-26 BR BR9609653-5A patent/BR9609653A/pt not_active Application Discontinuation
- 1996-06-26 MX MX9800189A patent/MX9800189A/es unknown
- 1996-06-26 AU AU64185/96A patent/AU705206B2/en not_active Ceased
- 1996-06-26 PL PL96324341A patent/PL187024B1/pl unknown
- 1996-06-28 AR ARP960103399A patent/AR004498A1/es unknown
- 1996-06-28 ZA ZA9605505A patent/ZA965505B/xx unknown
- 1996-06-28 MA MA24297A patent/MA24340A1/fr unknown
- 1996-07-01 TW TW085107922A patent/TW413681B/zh not_active IP Right Cessation
1997
- 1997-12-29 NO NO976128A patent/NO976128L/no not_active Application Discontinuation
- 1997-12-30 OA OA70171A patent/OA10554A/en unknown
1998
- 1998-01-28 BG BG102215A patent/BG102215A/xx unknown
2000
- 2000-04-03 US US09/541,217 patent/US6660724B1/en not_active Expired - Fee Related

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
EP0559079A1 (fr) *	1992-03-05	1993-09-08	Symphar S.A.	Dérivés substitués à d'aminophosphonates, leur procédé de préparation et compositions pharmaceutiques les contenant

Also Published As

Publication number	Publication date
AR004498A1 (es)	1998-12-16
EP0835116A1 (fr)	1998-04-15
SK178397A3 (en)	1998-06-03
TW413681B (en)	2000-12-01
TR199701700T1 (xx)	1998-03-21
CH690264A5 (fr)	2000-06-30
MX9800189A (es)	1998-04-30
AU705206B2 (en)	1999-05-20
HUP9901684A2 (hu)	1999-09-28
NO976128L (no)	1998-02-10
AP9701160A0 (en)	1998-01-31
CN1113654C (zh)	2003-07-09
JPH11508576A (ja)	1999-07-27
US6660724B1 (en)	2003-12-09
AU6418596A (en)	1997-02-05
MA24340A1 (fr)	1998-07-01
BG102215A (en)	1998-09-30
NO976128D0 (no)	1997-12-29
US6060464A (en)	2000-05-09
ZA965505B (en)	1998-03-30
HUP9901684A3 (en)	2000-04-28
IL122717A0 (en)	1998-08-16
WO1997002037A1 (fr)	1997-01-23
BR9609653A (pt)	1999-12-21
KR19990028542A (ko)	1999-04-15
EA199800106A1 (ru)	1998-08-27
CA2225391A1 (fr)	1997-01-23
OA10554A (en)	2002-05-29
PL187024B1 (pl)	2004-04-30
NZ312696A (en)	1999-10-28
CZ422097A3 (cs)	1998-10-14
PL324341A1 (en)	1998-05-25
CN1193913A (zh)	1998-09-23

Publication	Publication Date	Title
AP778A (en)	1999-10-29	Aminophosphonates and pharmaceutical compositions containing them.
MXPA98000189A (en)	1998-04-01	Compounds and pharmaceutical compositions that contains them
EP0946572B1 (fr)	2003-11-26	Derives pharmaceutiques d'acide aminophosphonique
US5424303A (en)	1995-06-13	Substituted aminophosphonate derivatives, process for their preparation and pharmaceutical compositions containing them
WO1998028311A1 (fr)	1998-07-02	Derives pharmaceutiques d'acide aminophosphonique
WO1998028312A1 (fr)	1998-07-02	Derives pharmaceutiques de l'acide aminophosphonique
AU2001294792B2 (en)	2006-12-14	Alpha-substituted beta-aminoethyl phosphonates
US20020111488A1 (en)	2002-08-15	Beta-substitued beta-aminoethyl phosphonate derivatives
JP2005529071A (ja)	2005-09-29	α−置換ヘテロアリールアルキルホスホン酸エステル誘導体
CZ219699A3 (cs)	2000-02-16	Farmaceutické deriváty kyseliny aminofosfonové
JP2005517711A (ja)	2005-06-16	α−置換アリールアルキルホスホン酸エステル誘導体