AP728A - Azetidinone derivatives for the treatment of atherosclerosis. - Google Patents

Azetidinone derivatives for the treatment of atherosclerosis. Download PDF

Info

Publication number: AP728A
Authority: AP; ARIPO
Prior art keywords: oxoazetidin; diastereoisomer; benzylsulphinyl; acetamide; fluorophenyl
Prior art date: 1995-07-01

Application number

APAP/P/1997/001161A

Other languages

English (en)

Other versions

AP9701161A0 (en

Inventor

Dashyant Dhanak

Deirdre Mary Bernadette Hickey

Robert John Ife

Colin Andrew Leach

David Graham Tew

Original Assignee

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.)

1995-07-01

Filing date

1996-06-20

Publication date

1999-01-29

1995-07-01 Priority claimed from GBGB9513442.5A external-priority patent/GB9513442D0/en

1995-07-22 Priority claimed from GBGB9515056.1A external-priority patent/GB9515056D0/en

1995-07-25 Priority claimed from GBGB9515206.2A external-priority patent/GB9515206D0/en

1995-08-18 Priority claimed from GBGB9516985.0A external-priority patent/GB9516985D0/en

1995-12-08 Priority claimed from GBGB9525132.8A external-priority patent/GB9525132D0/en

1996-04-26 Priority claimed from GBGB9608650.9A external-priority patent/GB9608650D0/en

1996-04-26 Priority claimed from GBGB9608651.7A external-priority patent/GB9608651D0/en

1996-06-20 Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc

1998-01-31 Publication of AP9701161A0 publication Critical patent/AP9701161A0/xx

1999-01-29 Application granted granted Critical

1999-01-29 Publication of AP728A publication Critical patent/AP728A/en

Links

MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical class O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 title claims description 55
201000001320 Atherosclerosis Diseases 0.000 title claims description 13
238000000034 method Methods 0.000 claims abstract description 26
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 277
150000001875 compounds Chemical class 0.000 claims description 201
DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 181
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 128
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 109
125000000217 alkyl group Chemical group 0.000 claims description 96
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 76
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 66
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 61
-1 C^gjalkenyl Chemical group 0.000 claims description 52
QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims description 52
238000006243 chemical reaction Methods 0.000 claims description 50
229940080818 propionamide Drugs 0.000 claims description 50
NXFFJDQHYLNEJK-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)methyl]-7-fluoro-5-methylsulfonyl-2,3-dihydro-1h-cyclopenta[b]indol-3-yl]acetic acid Chemical compound C1=2C(S(=O)(=O)C)=CC(F)=CC=2C=2CCC(CC(O)=O)C=2N1CC1=CC=C(Cl)C=C1 NXFFJDQHYLNEJK-UHFFFAOYSA-N 0.000 claims description 46
125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 43
229910052739 hydrogen Inorganic materials 0.000 claims description 43
125000003118 aryl group Chemical group 0.000 claims description 40
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 40
239000001257 hydrogen Substances 0.000 claims description 38
239000002904 solvent Substances 0.000 claims description 23
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 18
125000000753 cycloalkyl group Chemical group 0.000 claims description 18
125000001072 heteroaryl group Chemical group 0.000 claims description 18
125000001424 substituent group Chemical group 0.000 claims description 17
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 15
239000002253 acid Substances 0.000 claims description 13
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
230000002152 alkylating effect Effects 0.000 claims description 11
150000002431 hydrogen Chemical class 0.000 claims description 11
QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 10
125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 10
208000035475 disorder Diseases 0.000 claims description 10
229910052736 halogen Inorganic materials 0.000 claims description 10
150000002367 halogens Chemical class 0.000 claims description 10
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
125000002947 alkylene group Chemical group 0.000 claims description 8
229910052760 oxygen Inorganic materials 0.000 claims description 8
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 7
239000008194 pharmaceutical composition Substances 0.000 claims description 7
229910000104 sodium hydride Inorganic materials 0.000 claims description 7
239000002168 alkylating agent Substances 0.000 claims description 6
229940100198 alkylating agent Drugs 0.000 claims description 6
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
206010012601 diabetes mellitus Diseases 0.000 claims description 6
125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 claims description 6
150000004702 methyl esters Chemical class 0.000 claims description 6
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KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 5
150000001412 amines Chemical class 0.000 claims description 5
239000012312 sodium hydride Substances 0.000 claims description 5
125000003107 substituted aryl group Chemical group 0.000 claims description 5
229910052717 sulfur Inorganic materials 0.000 claims description 5
238000002560 therapeutic procedure Methods 0.000 claims description 5
KJGUACXIBQJPOT-UHFFFAOYSA-N 4-methylsulfanyl-1-(3-phenoxypropyl)azetidin-2-one Chemical compound CSC1CC(=O)N1CCCOC1=CC=CC=C1 KJGUACXIBQJPOT-UHFFFAOYSA-N 0.000 claims description 4
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
208000038016 acute inflammation Diseases 0.000 claims description 4
230000006022 acute inflammation Effects 0.000 claims description 4
150000001336 alkenes Chemical class 0.000 claims description 4
208000037976 chronic inflammation Diseases 0.000 claims description 4
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239000003937 drug carrier Substances 0.000 claims description 4
208000010125 myocardial infarction Diseases 0.000 claims description 4
206010039073 rheumatoid arthritis Diseases 0.000 claims description 4
150000003839 salts Chemical class 0.000 claims description 4
KANZOFLWLNQFCU-UHFFFAOYSA-N 2-(2-oxoazetidin-1-yl)acetamide Chemical compound NC(=O)CN1CCC1=O KANZOFLWLNQFCU-UHFFFAOYSA-N 0.000 claims description 3
208000024827 Alzheimer disease Diseases 0.000 claims description 3
206010002383 Angina Pectoris Diseases 0.000 claims description 3
206010020772 Hypertension Diseases 0.000 claims description 3
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206010063837 Reperfusion injury Diseases 0.000 claims description 3
206010040047 Sepsis Diseases 0.000 claims description 3
210000004556 brain Anatomy 0.000 claims description 3
229910052799 carbon Inorganic materials 0.000 claims description 3
239000003795 chemical substances by application Substances 0.000 claims description 3
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208000028867 ischemia Diseases 0.000 claims description 3
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IWDCAQIALFUKEA-UHFFFAOYSA-N 2-[4-[1-[2-[6-(4-chlorophenyl)hexylamino]-2-oxoethyl]-4-oxoazetidin-2-yl]oxyphenyl]acetic acid Chemical compound C1=CC(CC(=O)O)=CC=C1OC1N(CC(=O)NCCCCCCC=2C=CC(Cl)=CC=2)C(=O)C1 IWDCAQIALFUKEA-UHFFFAOYSA-N 0.000 claims description 2
DOZZSWAOPDYVLH-UHFFFAOYSA-N 2-phenylpropanamide Chemical compound NC(=O)C(C)C1=CC=CC=C1 DOZZSWAOPDYVLH-UHFFFAOYSA-N 0.000 claims description 2
VDTQLZMGFOUHRD-UHFFFAOYSA-N 4-methylsulfinyl-1-(3-phenoxypropyl)azetidin-2-one Chemical compound CS(=O)C1CC(=O)N1CCCOC1=CC=CC=C1 VDTQLZMGFOUHRD-UHFFFAOYSA-N 0.000 claims description 2
AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 2
CBXNYKLIVLKQMR-UHFFFAOYSA-N O=C1[CH-]N=C1 Chemical compound O=C1[CH-]N=C1 CBXNYKLIVLKQMR-UHFFFAOYSA-N 0.000 claims description 2
230000003213 activating effect Effects 0.000 claims description 2
125000003342 alkenyl group Chemical group 0.000 claims description 2
150000001345 alkine derivatives Chemical class 0.000 claims description 2
230000003257 anti-anginal effect Effects 0.000 claims description 2
230000000879 anti-atherosclerotic effect Effects 0.000 claims description 2
230000003178 anti-diabetic effect Effects 0.000 claims description 2
230000001315 anti-hyperlipaemic effect Effects 0.000 claims description 2
239000002260 anti-inflammatory agent Substances 0.000 claims description 2
230000003110 anti-inflammatory effect Effects 0.000 claims description 2
239000003472 antidiabetic agent Substances 0.000 claims description 2
239000002220 antihypertensive agent Substances 0.000 claims description 2
RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 claims description 2
125000002541 furyl group Chemical group 0.000 claims description 2
125000005647 linker group Chemical group 0.000 claims description 2
238000005809 transesterification reaction Methods 0.000 claims description 2
MSNIUNHFZYJZJL-UHFFFAOYSA-N 2-(2-benzylsulfinyl-4-oxoazetidin-1-yl)-n-(6-phenylhex-3-ynyl)acetamide Chemical compound C=1C=CC=CC=1CCC#CCCNC(=O)CN(C(C1)=O)C1S(=O)CC1=CC=CC=C1 MSNIUNHFZYJZJL-UHFFFAOYSA-N 0.000 claims 2
PCGJXELJRQWVDF-UPHRSURJSA-N 2-(2-benzylsulfinyl-4-oxoazetidin-1-yl)-n-[(z)-6-phenylhex-3-enyl]acetamide Chemical compound C=1C=CC=CC=1CC\C=C/CCNC(=O)CN(C(C1)=O)C1S(=O)CC1=CC=CC=C1 PCGJXELJRQWVDF-UPHRSURJSA-N 0.000 claims 2
AAGCFRJQDACTQE-UHFFFAOYSA-N 2-(2-benzylsulfinyl-4-oxoazetidin-1-yl)-n-[2-(2-phenoxyethoxy)ethyl]acetamide Chemical compound C=1C=CC=CC=1OCCOCCNC(=O)CN(C(C1)=O)C1S(=O)CC1=CC=CC=C1 AAGCFRJQDACTQE-UHFFFAOYSA-N 0.000 claims 2
QDBLQPBYMGYBCA-UHFFFAOYSA-N 2-(2-benzylsulfinyl-4-oxoazetidin-1-yl)-n-[2-(3-phenylpropoxy)ethyl]acetamide Chemical compound C=1C=CC=CC=1CCCOCCNC(=O)CN(C(C1)=O)C1S(=O)CC1=CC=CC=C1 QDBLQPBYMGYBCA-UHFFFAOYSA-N 0.000 claims 2
FEZBOGQWUJLPFB-UHFFFAOYSA-N 4-benzylsulfinyl-1-(2-phenylmethoxyethyl)azetidin-2-one Chemical compound O=C1CC(S(=O)CC=2C=CC=CC=2)N1CCOCC1=CC=CC=C1 FEZBOGQWUJLPFB-UHFFFAOYSA-N 0.000 claims 2
DOXLEKNWIBPKPX-UHFFFAOYSA-N 4-benzylsulfinyl-1-(3-phenoxypropyl)azetidin-2-one Chemical compound O=C1CC(S(=O)CC=2C=CC=CC=2)N1CCCOC1=CC=CC=C1 DOXLEKNWIBPKPX-UHFFFAOYSA-N 0.000 claims 2
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims 2
QZPIZMCHVXMVMX-UHFFFAOYSA-N 1-(2-oxo-4-phenylbutyl)-4-phenoxyazetidin-2-one Chemical compound C=1C=CC=CC=1OC1CC(=O)N1CC(=O)CCC1=CC=CC=C1 QZPIZMCHVXMVMX-UHFFFAOYSA-N 0.000 claims 1
FISQIYYHXXWBJD-UHFFFAOYSA-N 2-(2-benzylsulfanyl-4-oxoazetidin-1-yl)-n-(5-phenoxypentyl)acetamide Chemical compound C=1C=CC=CC=1OCCCCCNC(=O)CN(C(C1)=O)C1SCC1=CC=CC=C1 FISQIYYHXXWBJD-UHFFFAOYSA-N 0.000 claims 1
FXMSWZCZTULJOB-UHFFFAOYSA-N 2-(2-benzylsulfanyl-4-oxoazetidin-1-yl)-n-(6-phenylhex-3-ynyl)acetamide Chemical compound C=1C=CC=CC=1CCC#CCCNC(=O)CN(C(C1)=O)C1SCC1=CC=CC=C1 FXMSWZCZTULJOB-UHFFFAOYSA-N 0.000 claims 1
CLVILFNNDYMNMS-UPHRSURJSA-N 2-(2-benzylsulfanyl-4-oxoazetidin-1-yl)-n-[(z)-6-phenylhex-3-enyl]acetamide Chemical compound C=1C=CC=CC=1CC\C=C/CCNC(=O)CN(C(C1)=O)C1SCC1=CC=CC=C1 CLVILFNNDYMNMS-UPHRSURJSA-N 0.000 claims 1
SMDQYYBJAQQJHZ-UHFFFAOYSA-N 2-(2-benzylsulfanyl-4-oxoazetidin-1-yl)-n-[1-(3-chlorophenyl)hex-5-yn-2-yl]acetamide Chemical compound ClC1=CC=CC(CC(CCC#C)NC(=O)CN2C(CC2SCC=2C=CC=CC=2)=O)=C1 SMDQYYBJAQQJHZ-UHFFFAOYSA-N 0.000 claims 1
FWIXKNHMKBRIGY-UHFFFAOYSA-N 2-(2-benzylsulfanyl-4-oxoazetidin-1-yl)-n-[2-(2-phenoxyethoxy)ethyl]acetamide Chemical compound C=1C=CC=CC=1OCCOCCNC(=O)CN(C(C1)=O)C1SCC1=CC=CC=C1 FWIXKNHMKBRIGY-UHFFFAOYSA-N 0.000 claims 1
HTHODRWFKQYIHK-UHFFFAOYSA-N 2-(2-benzylsulfanyl-4-oxoazetidin-1-yl)-n-[2-(3-phenylpropoxy)ethyl]acetamide Chemical compound C=1C=CC=CC=1CCCOCCNC(=O)CN(C(C1)=O)C1SCC1=CC=CC=C1 HTHODRWFKQYIHK-UHFFFAOYSA-N 0.000 claims 1
DBLCUWPDJVJHNN-UHFFFAOYSA-N 2-(2-benzylsulfinyl-4-oxoazetidin-1-yl)-n-(5-phenoxypentyl)acetamide Chemical compound C=1C=CC=CC=1OCCCCCNC(=O)CN(C(C1)=O)C1S(=O)CC1=CC=CC=C1 DBLCUWPDJVJHNN-UHFFFAOYSA-N 0.000 claims 1
XERRQMGCDBVDBG-UHFFFAOYSA-N 2-(2-benzylsulfonyl-4-oxoazetidin-1-yl)-n-(6-phenylhex-3-ynyl)acetamide Chemical compound C=1C=CC=CC=1CCC#CCCNC(=O)CN(C(C1)=O)C1S(=O)(=O)CC1=CC=CC=C1 XERRQMGCDBVDBG-UHFFFAOYSA-N 0.000 claims 1
LZWOZWVTGGMYLR-UHFFFAOYSA-N 2-[3-(4-methylthiophen-2-yl)oxy-2-oxoazetidin-1-yl]-n-(4-phenylhexyl)acetamide Chemical compound C=1C=CC=CC=1C(CC)CCCNC(=O)CN(C1=O)CC1OC1=CC(C)=CS1 LZWOZWVTGGMYLR-UHFFFAOYSA-N 0.000 claims 1
CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 claims 1
101100063435 Caenorhabditis elegans din-1 gene Proteins 0.000 claims 1
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
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125000001033 ether group Chemical group 0.000 claims 1
SNWXOWJZKKRUNQ-UHFFFAOYSA-N ethyl 4-[[1-[2-[6-(4-fluorophenyl)hexoxy]ethyl]-4-oxoazetidin-2-yl]sulfanylmethyl]benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1CSC1N(CCOCCCCCCC=2C=CC(F)=CC=2)C(=O)C1 SNWXOWJZKKRUNQ-UHFFFAOYSA-N 0.000 claims 1
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 claims 1
125000001475 halogen functional group Chemical group 0.000 claims 1
238000010438 heat treatment Methods 0.000 claims 1
VPGKOBARFCBBRO-UHFFFAOYSA-N n-[2-[4-methoxy-2-(4-phenylhexyl)phenoxy]-4-oxoazetidin-1-yl]acetamide Chemical compound C=1C=CC=CC=1C(CC)CCCC1=CC(OC)=CC=C1OC1CC(=O)N1NC(C)=O VPGKOBARFCBBRO-UHFFFAOYSA-N 0.000 claims 1
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238000005481 NMR spectroscopy Methods 0.000 description 166
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 161
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235000019198 oils Nutrition 0.000 description 155
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XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 78
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CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 66
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 63
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JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 18
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OEYMQQDJCUHKQS-UHFFFAOYSA-N (4-oxoazetidin-2-yl) acetate Chemical compound CC(=O)OC1CC(=O)N1 OEYMQQDJCUHKQS-UHFFFAOYSA-N 0.000 description 15
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Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
- C07D205/085—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a nitrogen atom directly attached in position 3
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
- C07D205/09—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a sulfur atom directly attached in position 4
- C07D205/095—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a sulfur atom directly attached in position 4 and with a nitrogen atom directly attached in position 3
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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

APAP/P/1997/001161A 1995-07-01 1996-06-20 Azetidinone derivatives for the treatment of atherosclerosis. AP728A (en)

Applications Claiming Priority (8)

Application Number	Priority Date	Filing Date	Title
GBGB9513442.5A GB9513442D0 (en)	1995-07-01	1995-07-01	Novel compounds
GBGB9515056.1A GB9515056D0 (en)	1995-07-22	1995-07-22	Novel compounds
GBGB9515206.2A GB9515206D0 (en)	1995-07-25	1995-07-25	Novel compounds
GBGB9516985.0A GB9516985D0 (en)	1995-08-18	1995-08-18	Novel compounds
GBGB9525132.8A GB9525132D0 (en)	1995-12-08	1995-12-08	Novel compounds
GBGB9608650.9A GB9608650D0 (en)	1996-04-26	1996-04-26	Novel compounds
GBGB9608651.7A GB9608651D0 (en)	1996-04-26	1996-04-26	Novel compounds
PCT/EP1996/002765 WO1997002242A1 (en)	1995-07-01	1996-06-20	Azetidinone derivatives for the treatment of atherosclerosis

Publications (2)

Publication Number	Publication Date
AP9701161A0 AP9701161A0 (en)	1998-01-31
AP728A true AP728A (en)	1999-01-29

Family

ID=27562921

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
APAP/P/1997/001161A AP728A (en)	1995-07-01	1996-06-20	Azetidinone derivatives for the treatment of atherosclerosis.

Country Status (23)

Country	Link
EP (1)	EP0840725A1 (cs)
JP (1)	JP2002515852A (cs)
KR (1)	KR19990028630A (cs)
CN (1)	CN1197452A (cs)
AP (1)	AP728A (cs)
AU (1)	AU708032B2 (cs)
BG (1)	BG102214A (cs)
BR (1)	BR9609445A (cs)
CA (1)	CA2225627A1 (cs)
CZ (1)	CZ422197A3 (cs)
EA (1)	EA199800109A1 (cs)
HU (1)	HUP9901153A3 (cs)
IL (1)	IL122650A0 (cs)
MA (1)	MA23922A1 (cs)
MX (1)	MX9800186A (cs)
NO (1)	NO976158L (cs)
NZ (1)	NZ311684A (cs)
OA (1)	OA10648A (cs)
PE (1)	PE8998A1 (cs)
PL (1)	PL324240A1 (cs)
SK (1)	SK178497A3 (cs)
TR (1)	TR199701762T1 (cs)
WO (1)	WO1997002242A1 (cs)

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EP0869943A1 (en) *	1995-12-08	1998-10-14	Smithkline Beecham Plc	Monocyclic beta-lactame derivatives for treatment of atherosclerosis
GB9608649D0 (en) *	1996-04-26	1996-07-03	Smithkline Beecham Plc	Novel compounds
IL126696A0 (en) *	1996-04-26	1999-08-17	Smithkline Beecham Plc	Azetidinone derivatives for the treatment of atherosclerosis
DK1263740T3 (da)	2000-02-16	2006-11-13	Smithkline Beecham Plc	Pyrimidin-4-on-derivat som LDL-PLA2-inhibitor
GB0024808D0 (en)	2000-10-10	2000-11-22	Smithkline Beecham Plc	Novel compounds
KR101730290B1 (ko)	2007-05-11	2017-04-25	토마스 제퍼슨 유니버시티	신경변성 질환 및 장애의 치료 및 예방 방법
CN101687009A (zh)	2007-05-11	2010-03-31	宾夕法尼亚大学理事会	治疗皮肤溃疡的方法
US8962633B2 (en)	2007-05-11	2015-02-24	Thomas Jefferson University	Methods of treatment and prevention of metabolic bone diseases and disorders
KR101861883B1 (ko)	2010-12-06	2018-05-28	글락소 그룹 리미티드	Lp-PLA₂에 의해 매개되는 질환 또는 상태의 치료에 사용하기 위한 피리미디논 화합물
ES2847883T3 (es)	2010-12-17	2021-08-04	Glaxo Group Ltd	Uso de inhibidores de LP-PLA2 en el tratamiento y prevención de enfermedades oculares
CN103619831B (zh)	2011-06-27	2016-05-04	中国科学院上海药物研究所	唑类杂环化合物、其制备方法、药物组合物和用途
CA2842965A1 (en)	2011-07-27	2013-01-31	Glaxo Group Limited	2,3-dihydroimidazo[1,2-c] pyrimidin-5(1h)-one compounds use as lp-pla2 inhibitors
AR087309A1 (es)	2011-07-27	2014-03-12	Glaxo Group Ltd	Compuesto heterociclico de anillos condensados sustituido, composicion farmaceutica que lo comprende y su uso para la fabricacion de un medicamento para el tratamiento de enfermedades neurogenerativas y aterosclerosis
EP2948456A4 (en)	2013-01-25	2016-09-14	Glaxosmithkline Ip Dev Ltd	BICYCLIC PYRIMIDONE COMPOUNDS AS LP-PLA2 INHIBITORS
MX2015009633A (es)	2013-01-25	2015-11-30	Glaxosmithkline Ip Dev Ltd	Inhibidores de fosfolipasa a2 asociada con lipoproteinas basados en 2,3-dihidroimidazol[1,2-c] pirimidin-5(1h)-ona.
US9296755B2 (en)	2013-01-25	2016-03-29	Glaxosmithkline Intellectual Property Development Limited	3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one compounds and their therapeutic applications
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
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
EP4056571A4 (en)	2019-11-09	2024-01-24	Shanghai Simr Biotechnology Co., Ltd.	Tricyclic dihydroimidazopyrimidone derivative, preparation method therefor, pharmaceutical composition and use thereof
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
WO2025015951A1 (zh)	2023-07-17	2025-01-23	上海枢境生物科技有限公司	双环[5,6]咪唑嘧啶酮类衍生物、其制备方法和应用

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EP0337549A1 (en) *	1988-04-11	1989-10-18	Merck & Co. Inc.	New substituted azetidinones as anti-inflammatory and antidegenerative agents
EP0481671A1 (en) *	1990-10-15	1992-04-22	Merck & Co. Inc.	New substituted azetidinones as anti-inflammatory and antidegenerative agents

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GB9421816D0 (en) *	1994-10-29	1994-12-14	Smithkline Beecham Plc	Novel compounds
HUT77089A (hu) *	1994-12-22	1998-03-02	Smithkline Beecham Plc.	Atherosclerosis kezelésére alkalmas szubsztituált 2-oxo-azetidinek, eljárás előállításukra és ezeket tartalmazó gyógyszerkészítmények

1996
- 1996-06-20 CN CN96196661A patent/CN1197452A/zh active Pending
- 1996-06-20 KR KR1019970709952A patent/KR19990028630A/ko not_active Withdrawn
- 1996-06-20 JP JP50477297A patent/JP2002515852A/ja active Pending
- 1996-06-20 EP EP96922030A patent/EP0840725A1/en not_active Withdrawn
- 1996-06-20 WO PCT/EP1996/002765 patent/WO1997002242A1/en not_active Ceased
- 1996-06-20 AU AU63050/96A patent/AU708032B2/en not_active Ceased
- 1996-06-20 AP APAP/P/1997/001161A patent/AP728A/en active
- 1996-06-20 IL IL12265096A patent/IL122650A0/xx unknown
- 1996-06-20 CA CA002225627A patent/CA2225627A1/en not_active Abandoned
- 1996-06-20 PL PL96324240A patent/PL324240A1/xx unknown
- 1996-06-20 NZ NZ311684A patent/NZ311684A/xx unknown
- 1996-06-20 EA EA199800109A patent/EA199800109A1/ru unknown
- 1996-06-20 HU HU9901153A patent/HUP9901153A3/hu unknown
- 1996-06-20 BR BR9609445A patent/BR9609445A/pt unknown
- 1996-06-20 SK SK1784-97A patent/SK178497A3/sk unknown
- 1996-06-20 TR TR97/01762T patent/TR199701762T1/xx unknown
- 1996-06-20 CZ CZ974221A patent/CZ422197A3/cs unknown
- 1996-06-28 PE PE1996000496A patent/PE8998A1/es not_active Application Discontinuation
- 1996-06-28 MA MA24298A patent/MA23922A1/fr unknown
1997
- 1997-12-30 NO NO976158A patent/NO976158L/no unknown
- 1997-12-31 OA OA70172A patent/OA10648A/en unknown
1998
- 1998-01-07 MX MX9800186A patent/MX9800186A/es unknown
- 1998-01-28 BG BG102214A patent/BG102214A/xx unknown

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EP0199630A1 (en) *	1985-04-10	1986-10-29	Merck & Co. Inc.	Substituted azetidinones, pharmaceutical compositions containing them, and their use for the manufacture of anti-inflammatory and antidegenerative medicaments
EP0337549A1 (en) *	1988-04-11	1989-10-18	Merck & Co. Inc.	New substituted azetidinones as anti-inflammatory and antidegenerative agents
EP0481671A1 (en) *	1990-10-15	1992-04-22	Merck & Co. Inc.	New substituted azetidinones as anti-inflammatory and antidegenerative agents

Also Published As

Publication number	Publication date
SK178497A3 (en)	1998-07-08
MX9800186A (es)	1998-07-31
OA10648A (en)	2002-09-25
HUP9901153A2 (hu)	1999-08-30
NZ311684A (en)	2000-04-28
PE8998A1 (es)	1998-03-20
TR199701762T1 (xx)	1998-05-21
KR19990028630A (ko)	1999-04-15
PL324240A1 (en)	1998-05-11
IL122650A0 (en)	1998-08-16
CA2225627A1 (en)	1997-01-23
WO1997002242A1 (en)	1997-01-23
AU708032B2 (en)	1999-07-29
NO976158D0 (no)	1997-12-30
BR9609445A (pt)	1999-04-06
JP2002515852A (ja)	2002-05-28
AU6305096A (en)	1997-02-05
BG102214A (en)	1998-08-31
HUP9901153A3 (en)	1999-11-29
EA199800109A1 (ru)	1998-10-29
MA23922A1 (fr)	1996-12-31
EP0840725A1 (en)	1998-05-13
NO976158L (no)	1998-02-25
CZ422197A3 (cs)	1998-06-17
AP9701161A0 (en)	1998-01-31
CN1197452A (zh)	1998-10-28

Publication	Publication Date	Title
AU708032B2 (en)	1999-07-29	Azetidinone derivatives for the treatment of atherosclerosis
JPH11500415A (ja)	1999-01-12	アテローム性動脈硬化症治療用置換アゼチジン−２−オン
US6071899A (en)	2000-06-06	Azetidinone derivatives for the treatment of atherosclerosis
KR840000606B1 (ko)	1984-04-28	2-페넴 화합물의 제조방법
JP2000509049A (ja)	2000-07-18	アテローム性動脈硬化症の治療用アゼチジノン誘導体
JP2000505063A (ja)	2000-04-25	アテローム性動脈硬化症の治療のためのアゼチジノン化合物
JP2000509063A (ja)	2000-07-18	アテローム性動脈硬化症の治療用アゼチジノン誘導体
JP2000502079A (ja)	2000-02-22	アテローム性動脈硬化症の治療のための単環β―ラクタム誘導体
HU194889B (en)	1988-03-28	Process for producing peneme derivatives and pharmaceutical compositions containing them
JPS58134074A (ja)	1983-08-10	抗菌剤、その製法及びそれを含む医薬組成物
JPH06104672B2 (ja)	1994-12-21	ペネム類の製造方法
EP0174561A1 (en)	1986-03-19	7-Oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene derivatives
JPH04364183A (ja)	1992-12-16	フルオロアルキル化カルバペネム中間体
JPH0316357B2 (cs)	1991-03-05
JPH04117382A (ja)	1992-04-17	１―メチルカルバペネム誘導体及びその製法
FR2541279A1 (fr)	1984-08-24	Derives de l'acide 1-aza-7-oxo-bicyclo(3.2.0)-hept-2-ene-2-carboxylique
JPH021474A (ja)	1990-01-05	１β―アルキルカルバペネム合成中間体の製法
JPH0371434B2 (cs)	1991-11-13
KR20000065040A (ko)	2000-11-06	아테롬성동맥경화증치료를위한아제티디논유도체
MXPA98008924A (en)	1999-04-27	Azetidinone derivatives for deeterosclero treatment
LU86410A1 (fr)	1986-11-05	Procede de preparation de carbapenemes