CZ304355B6 - 2-Azabicyklo[3.1.0.]hexan-3-karbonitrilová sloučenina, farmaceutický prostředek a použití - Google Patents

Info

Publication number

CZ304355B6

CZ304355B6 CZ2002-2974A CZ20022974A CZ304355B6 CZ 304355 B6 CZ304355 B6 CZ 304355B6 CZ 20022974 A CZ20022974 A CZ 20022974A CZ 304355 B6 CZ304355 B6 CZ 304355B6

Authority

CZ

Czechia

Prior art keywords

compound

inhibitor

mmol

agent

carbon atoms

Prior art date

2000-03-10

Links

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• 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 13
• -1 2-Azabicyclo [3.1.0]hexane-3-carbonitrile compound Chemical class 0.000 title claims description 120
• 150000001875 compounds Chemical class 0.000 claims abstract description 302
• 239000003112 inhibitor Substances 0.000 claims abstract description 91
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 26
• 201000010099 disease Diseases 0.000 claims abstract description 21
• 239000003814 drug Substances 0.000 claims abstract description 17
• 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 16
• 208000011580 syndromic disease Diseases 0.000 claims abstract description 13
• 208000008589 Obesity Diseases 0.000 claims abstract description 12
• 235000020824 obesity Nutrition 0.000 claims abstract description 12
• 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 11
• 201000001320 Atherosclerosis Diseases 0.000 claims abstract description 9
• 206010060378 Hyperinsulinaemia Diseases 0.000 claims abstract description 8
• 208000022559 Inflammatory bowel disease Diseases 0.000 claims abstract description 8
• 230000003451 hyperinsulinaemic effect Effects 0.000 claims abstract description 8
• 201000008980 hyperinsulinism Diseases 0.000 claims abstract description 8
• 208000002249 Diabetes Complications Diseases 0.000 claims abstract description 7
• 206010012655 Diabetic complications Diseases 0.000 claims abstract description 7
• 230000002519 immonomodulatory effect Effects 0.000 claims abstract description 7
• 230000001684 chronic effect Effects 0.000 claims abstract description 5
• 201000001421 hyperglycemia Diseases 0.000 claims abstract description 5
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 119
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 67
• 239000003795 chemical substances by application Substances 0.000 claims description 59
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 54
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 53
• 125000004432 carbon atom Chemical group C* 0.000 claims description 45
• 125000000217 alkyl group Chemical group 0.000 claims description 42
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 38
• 229910052757 nitrogen Inorganic materials 0.000 claims description 36
• 239000003472 antidiabetic agent Substances 0.000 claims description 28
• 229940125708 antidiabetic agent Drugs 0.000 claims description 25
• 229910052739 hydrogen Inorganic materials 0.000 claims description 20
• 239000001257 hydrogen Substances 0.000 claims description 19
• NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 18
• 125000004414 alkyl thio group Chemical group 0.000 claims description 17
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
• 150000003839 salts Chemical class 0.000 claims description 15
• 125000000304 alkynyl group Chemical group 0.000 claims description 14
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 14
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 14
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 14
• 150000002632 lipids Chemical class 0.000 claims description 13
• DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 claims description 12
• 229910052760 oxygen Inorganic materials 0.000 claims description 12
• 229910052736 halogen Inorganic materials 0.000 claims description 11
• 150000002367 halogens Chemical class 0.000 claims description 11
• 125000005842 heteroatom Chemical group 0.000 claims description 11
• 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 11
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 11
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 10
• 229910052717 sulfur Inorganic materials 0.000 claims description 10
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• 101800000224 Glucagon-like peptide 1 Proteins 0.000 claims description 9
• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 9
• 102000004877 Insulin Human genes 0.000 claims description 9
• 102100031545 Microsomal triglyceride transfer protein large subunit Human genes 0.000 claims description 9
• 102000023984 PPAR alpha Human genes 0.000 claims description 9
• 108010028924 PPAR alpha Proteins 0.000 claims description 9
• 102100040918 Pro-glucagon Human genes 0.000 claims description 9
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 9
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 9
• 150000001602 bicycloalkyls Chemical group 0.000 claims description 9
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 9
• 125000001188 haloalkyl group Chemical group 0.000 claims description 9
• 229940125396 insulin Drugs 0.000 claims description 9
• 239000001301 oxygen Substances 0.000 claims description 9
• 239000011593 sulfur Substances 0.000 claims description 9
• 208000030507 AIDS Diseases 0.000 claims description 8
• 102000000536 PPAR gamma Human genes 0.000 claims description 8
• 108010016731 PPAR gamma Proteins 0.000 claims description 8
• YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 claims description 8
• VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 claims description 8
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
• 238000004519 manufacturing process Methods 0.000 claims description 8
• HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 claims description 8
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
• QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims description 8
• 239000004059 squalene synthase inhibitor Substances 0.000 claims description 8
• 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims description 7
• 108090001061 Insulin Proteins 0.000 claims description 7
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• 208000001132 Osteoporosis Diseases 0.000 claims description 7
• 206010036049 Polycystic ovaries Diseases 0.000 claims description 7
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• 125000005350 hydroxycycloalkyl group Chemical group 0.000 claims description 7
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• ZGGHKIMDNBDHJB-NRFPMOEYSA-M (3R,5S)-fluvastatin sodium Chemical compound [Na+].C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 ZGGHKIMDNBDHJB-NRFPMOEYSA-M 0.000 claims description 6
• XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 claims description 6
• XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 claims description 6
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• PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 claims description 6
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• ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 claims description 6
• 125000004438 haloalkoxy group Chemical group 0.000 claims description 6
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• 125000004949 alkyl amino carbonyl amino group Chemical group 0.000 claims description 5
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• XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 claims description 4
• BOVGTQGAOIONJV-BETUJISGSA-N 1-[(3ar,6as)-3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-2-yl]-3-(4-methylphenyl)sulfonylurea Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1C[C@H]2CCC[C@H]2C1 BOVGTQGAOIONJV-BETUJISGSA-N 0.000 claims description 4
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