DE102004006325A1

DE102004006325A1 - Tetrahydrobenzo[d]azepin-2-on-Derivate und ihre Verwendung

Tetrahydrobenzo[d]azepin-2-on-Derivate und ihre Verwendung Download PDF

Info

Publication number: DE102004006325A1
Authority: DE; Germany
Prior art keywords: alkyl; formula; group; compound; alkoxycarbonyl
Prior art date: 2004-02-10
Legal status : Withdrawn

Application number

DE102004006325A

Other languages

German (de)

English (en)

Inventor

Nils Dr. Griebenow

Timo Dr. Fleßner

Martin Dr. Raabe

Hilmar Dr. Bischoff

Current Assignee

Bayer AG

Original Assignee

Bayer Healthcare AG

Priority date

2004-02-10

Filing date

2004-02-10

Publication date

2005-08-25

2004-02-10 Application filed by Bayer Healthcare AG filed Critical Bayer Healthcare AG

2004-02-10 Priority to DE102004006325A priority Critical patent/DE102004006325A1/de

2005-02-01 Priority to US10/588,862 priority patent/US7662956B2/en

2005-02-01 Priority to CA002554996A priority patent/CA2554996A1/en

2005-02-01 Priority to JP2006552501A priority patent/JP2007522159A/ja

2005-02-01 Priority to DE502005003904T priority patent/DE502005003904D1/de

2005-02-01 Priority to PCT/EP2005/000960 priority patent/WO2005077907A1/de

2005-02-01 Priority to EP05701287A priority patent/EP1716118B1/de

2005-02-01 Priority to ES05701287T priority patent/ES2304682T3/es

2005-08-25 Publication of DE102004006325A1 publication Critical patent/DE102004006325A1/de

Status Withdrawn legal-status Critical Current

Links

208000032928 Dyslipidaemia Diseases 0.000 title claims description 9
208000037803 restenosis Diseases 0.000 title claims description 7
208000028867 ischemia Diseases 0.000 title claims description 6
206010003210 Arteriosclerosis Diseases 0.000 title claims description 5
208000011775 arteriosclerosis disease Diseases 0.000 title claims description 5
150000008038 benzoazepines Chemical class 0.000 title abstract 3
208000017170 Lipid metabolism disease Diseases 0.000 title 1
150000001875 compounds Chemical class 0.000 claims abstract description 142
-1 2,3-ethylenedioxyphenyl Chemical group 0.000 claims abstract description 80
150000003839 salts Chemical class 0.000 claims abstract description 34
239000012453 solvate Substances 0.000 claims abstract description 28
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 19
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 15
239000003814 drug Substances 0.000 claims abstract description 12
125000005842 heteroatom Chemical group 0.000 claims abstract description 11
125000000623 heterocyclic group Chemical group 0.000 claims abstract description 11
239000000126 substance Substances 0.000 claims abstract description 11
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 10
239000003112 inhibitor Substances 0.000 claims abstract description 7
125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 6
238000004519 manufacturing process Methods 0.000 claims abstract description 6
229910052760 oxygen Inorganic materials 0.000 claims abstract description 5
229910052717 sulfur Inorganic materials 0.000 claims abstract description 5
102000007592 Apolipoproteins Human genes 0.000 claims abstract description 4
108010071619 Apolipoproteins Proteins 0.000 claims abstract description 4
125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims abstract description 4
229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims abstract description 4
238000000034 method Methods 0.000 claims description 61
239000001257 hydrogen Substances 0.000 claims description 28
229910052739 hydrogen Inorganic materials 0.000 claims description 28
125000001424 substituent group Chemical group 0.000 claims description 23
239000002904 solvent Substances 0.000 claims description 22
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 21
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 21
241001465754 Metazoa Species 0.000 claims description 18
238000011282 treatment Methods 0.000 claims description 18
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
239000000460 chlorine Chemical group 0.000 claims description 14
150000002431 hydrogen Chemical class 0.000 claims description 14
229910052757 nitrogen Inorganic materials 0.000 claims description 14
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
201000010099 disease Diseases 0.000 claims description 11
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 10
229910052801 chlorine Inorganic materials 0.000 claims description 10
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
229910052736 halogen Inorganic materials 0.000 claims description 9
150000002367 halogens Chemical group 0.000 claims description 9
230000002265 prevention Effects 0.000 claims description 9
125000004093 cyano group Chemical group *C#N 0.000 claims description 8
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229910052731 fluorine Inorganic materials 0.000 claims description 8
239000012442 inert solvent Substances 0.000 claims description 8
238000002360 preparation method Methods 0.000 claims description 8
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
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150000001735 carboxylic acids Chemical class 0.000 claims description 7
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238000011321 prophylaxis Methods 0.000 claims description 7
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125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
125000004043 oxo group Chemical group O=* 0.000 claims description 6
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125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 5
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125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 5
201000001320 Atherosclerosis Diseases 0.000 claims description 5
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 5
239000002253 acid Substances 0.000 claims description 5
239000004480 active ingredient Substances 0.000 claims description 5
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
229910052794 bromium Inorganic materials 0.000 claims description 5
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
239000000546 pharmaceutical excipient Substances 0.000 claims description 5
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
150000007513 acids Chemical class 0.000 claims description 4
230000009435 amidation Effects 0.000 claims description 4
238000007112 amidation reaction Methods 0.000 claims description 4
GKTNLYAAZKKMTQ-UHFFFAOYSA-N n-[bis(dimethylamino)phosphinimyl]-n-methylmethanamine Chemical compound CN(C)P(=N)(N(C)C)N(C)C GKTNLYAAZKKMTQ-UHFFFAOYSA-N 0.000 claims description 4
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
125000004076 pyridyl group Chemical group 0.000 claims description 4
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 3
125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 3
125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 3
125000000041 C6-C10 aryl group Chemical group 0.000 claims description 3
230000003110 anti-inflammatory effect Effects 0.000 claims description 3
239000003963 antioxidant agent Substances 0.000 claims description 3
230000001906 cholesterol absorption Effects 0.000 claims description 3
230000032050 esterification Effects 0.000 claims description 3
238000005886 esterification reaction Methods 0.000 claims description 3
239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 claims description 3
125000001624 naphthyl group Chemical group 0.000 claims description 3
231100000252 nontoxic Toxicity 0.000 claims description 3
230000003000 nontoxic effect Effects 0.000 claims description 3
238000005903 acid hydrolysis reaction Methods 0.000 claims description 2
230000003078 antioxidant effect Effects 0.000 claims description 2
125000001153 fluoro group Chemical group F* 0.000 claims description 2
230000015572 biosynthetic process Effects 0.000 abstract description 15
YYGNTYWPHWGJRM-UHFFFAOYSA-N (6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C YYGNTYWPHWGJRM-UHFFFAOYSA-N 0.000 abstract description 12
BHEOSNUKNHRBNM-UHFFFAOYSA-N Tetramethylsqualene Natural products CC(=C)C(C)CCC(=C)C(C)CCC(C)=CCCC=C(C)CCC(C)C(=C)CCC(C)C(C)=C BHEOSNUKNHRBNM-UHFFFAOYSA-N 0.000 abstract description 12
PRAKJMSDJKAYCZ-UHFFFAOYSA-N dodecahydrosqualene Natural products CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 abstract description 12
229940031439 squalene Drugs 0.000 abstract description 12
TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 abstract description 12
238000003786 synthesis reaction Methods 0.000 abstract description 12
102100037997 Squalene synthase Human genes 0.000 abstract description 11
108010022535 Farnesyl-Diphosphate Farnesyltransferase Proteins 0.000 abstract description 10
230000000694 effects Effects 0.000 abstract description 6
239000004059 squalene synthase inhibitor Substances 0.000 abstract description 4
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230000003228 microsomal effect Effects 0.000 abstract description 2
125000000217 alkyl group Chemical group 0.000 abstract 11
125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 abstract 3
125000005843 halogen group Chemical group 0.000 abstract 2
229940122502 Cholesterol absorption inhibitor Drugs 0.000 abstract 1
229940123239 Cholesterol synthesis inhibitor Drugs 0.000 abstract 1
125000002252 acyl group Chemical group 0.000 abstract 1
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125000000304 alkynyl group Chemical group 0.000 abstract 1
239000002260 anti-inflammatory agent Substances 0.000 abstract 1
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230000002402 anti-lipaemic effect Effects 0.000 abstract 1
125000003118 aryl group Chemical group 0.000 abstract 1
230000002401 inhibitory effect Effects 0.000 abstract 1
230000010534 mechanism of action Effects 0.000 abstract 1
230000003647 oxidation Effects 0.000 abstract 1
238000007254 oxidation reaction Methods 0.000 abstract 1
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 123
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XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 47
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239000003480 eluent Substances 0.000 description 26
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229910052938 sodium sulfate Inorganic materials 0.000 description 23
235000011152 sodium sulphate Nutrition 0.000 description 23
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OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
235000019253 formic acid Nutrition 0.000 description 21
238000006243 chemical reaction Methods 0.000 description 19
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 19
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238000005160 1H NMR spectroscopy Methods 0.000 description 18
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238000004128 high performance liquid chromatography Methods 0.000 description 17
238000002953 preparative HPLC Methods 0.000 description 16
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
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PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 4
GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
JVKUCNQGESRUCL-UHFFFAOYSA-N 2-Hydroxyethyl 12-hydroxyoctadecanoate Chemical compound CCCCCCC(O)CCCCCCCCCCC(=O)OCCO JVKUCNQGESRUCL-UHFFFAOYSA-N 0.000 description 4
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HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
239000002207 metabolite Substances 0.000 description 4
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