CA2490112A1 - Diphenyl azetidinones substituted by acidic groups, method for their production, medicaments containing said compounds and use thereof - Google Patents
Diphenyl azetidinones substituted by acidic groups, method for their production, medicaments containing said compounds and use thereof Download PDFInfo
- Publication number
- CA2490112A1 CA2490112A1 CA002490112A CA2490112A CA2490112A1 CA 2490112 A1 CA2490112 A1 CA 2490112A1 CA 002490112 A CA002490112 A CA 002490112A CA 2490112 A CA2490112 A CA 2490112A CA 2490112 A1 CA2490112 A1 CA 2490112A1
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- phenyl
- cooh
- compounds
- agonists
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 140
- 239000003814 drug Substances 0.000 title claims description 15
- 238000004519 manufacturing process Methods 0.000 title claims description 5
- 238000000034 method Methods 0.000 title description 6
- VDOXIAUNJCHYRC-UHFFFAOYSA-N 1,3-diphenylazetidin-2-one Chemical group O=C1C(C=2C=CC=CC=2)CN1C1=CC=CC=C1 VDOXIAUNJCHYRC-UHFFFAOYSA-N 0.000 title description 4
- 230000002378 acidificating effect Effects 0.000 title description 2
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 86
- 239000000203 mixture Substances 0.000 claims description 40
- 239000000556 agonist Substances 0.000 claims description 34
- 229910052731 fluorine Inorganic materials 0.000 claims description 25
- -1 lipase inhibitors Substances 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 12
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 12
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
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- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 6
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 6
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- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 claims description 4
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- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)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(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 1
- 229960004666 glucagon Drugs 0.000 description 1
- 230000004110 gluconeogenesis Effects 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 230000004190 glucose uptake Effects 0.000 description 1
- 230000004116 glycogenolysis Effects 0.000 description 1
- 235000014168 granola/muesli bars Nutrition 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 150000002440 hydroxy compounds Chemical class 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 230000031891 intestinal absorption Effects 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229940099563 lactobionic acid Drugs 0.000 description 1
- 229940060975 lantus Drugs 0.000 description 1
- 229960003566 lomitapide Drugs 0.000 description 1
- QKVKOFVWUHNEBX-UHFFFAOYSA-N lomitapide mesylate Chemical compound CS(O)(=O)=O.C12=CC=CC=C2C2=CC=CC=C2C1(C(=O)NCC(F)(F)F)CCCCN(CC1)CCC1NC(=O)C1=CC=CC=C1C1=CC=C(C(F)(F)F)C=C1 QKVKOFVWUHNEBX-UHFFFAOYSA-N 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960000299 mazindol Drugs 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 229960001110 miglitol Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- LYAUICDWKQJAGX-UHFFFAOYSA-N n-(7-hydroxy-2,2,4,6-tetramethyl-1,3-dihydroinden-1-yl)-2-[4-(3-methoxyphenyl)piperazin-1-yl]acetamide Chemical compound COC1=CC=CC(N2CCN(CC(=O)NC3C(CC4=C3C(=C(C)C=C4C)O)(C)C)CC2)=C1 LYAUICDWKQJAGX-UHFFFAOYSA-N 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- YDCVQGAUCOROHB-UHFFFAOYSA-N oxadiazolidine-4,5-dione Chemical class O=C1NNOC1=O YDCVQGAUCOROHB-UHFFFAOYSA-N 0.000 description 1
- MHYFEEDKONKGEB-UHFFFAOYSA-N oxathiane 2,2-dioxide Chemical compound O=S1(=O)CCCCO1 MHYFEEDKONKGEB-UHFFFAOYSA-N 0.000 description 1
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- VWMZIGBYZQUQOA-QEEMJVPDSA-N pamaqueside Chemical compound O([C@@H]1[C@@H](CO)O[C@H]([C@@H]([C@H]1O)O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4C[C@H]5[C@@H]([C@]4(CC(=O)[C@@H]3[C@@]2(C)CC1)C)[C@@H]([C@]1(OC[C@H](C)CC1)O5)C)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VWMZIGBYZQUQOA-QEEMJVPDSA-N 0.000 description 1
- 229950005482 pamaqueside Drugs 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 229960003562 phentermine Drugs 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 229940100467 polyvinyl acetate phthalate Drugs 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- ZLMJMSJWJFRBEC-AKLPVKDBSA-N potassium-42 Chemical compound [42K] ZLMJMSJWJFRBEC-AKLPVKDBSA-N 0.000 description 1
- 229960002965 pravastatin Drugs 0.000 description 1
- 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 1
- 238000003825 pressing Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 239000000700 radioactive tracer Substances 0.000 description 1
- 229960000672 rosuvastatin Drugs 0.000 description 1
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 229960002855 simvastatin Drugs 0.000 description 1
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 235000000891 standard diet Nutrition 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- WBWWGRHZICKQGZ-GIHLXUJPSA-N taurocholic acid Chemical compound C([C@@H]1C[C@H]2O)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)[C@H](O)C1 WBWWGRHZICKQGZ-GIHLXUJPSA-N 0.000 description 1
- XBXCNNQPRYLIDE-UHFFFAOYSA-N tert-butylcarbamic acid Chemical compound CC(C)(C)NC(O)=O XBXCNNQPRYLIDE-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 229950004437 tiqueside Drugs 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- SIOVKLKJSOKLIF-HJWRWDBZSA-N trimethylsilyl (1z)-n-trimethylsilylethanimidate Chemical compound C[Si](C)(C)OC(/C)=N\[Si](C)(C)C SIOVKLKJSOKLIF-HJWRWDBZSA-N 0.000 description 1
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- GXPHKUHSUJUWKP-UHFFFAOYSA-N troglitazone Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)COC(C=C1)=CC=C1CC1SC(=O)NC1=O GXPHKUHSUJUWKP-UHFFFAOYSA-N 0.000 description 1
- 229960001641 troglitazone Drugs 0.000 description 1
- GXPHKUHSUJUWKP-NTKDMRAZSA-N troglitazone Natural products C([C@@]1(OC=2C(C)=C(C(=C(C)C=2CC1)O)C)C)OC(C=C1)=CC=C1C[C@H]1SC(=O)NC1=O GXPHKUHSUJUWKP-NTKDMRAZSA-N 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
Classifications
-
- 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
- C07F9/568—Four-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
-
- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Diabetes (AREA)
- Urology & Nephrology (AREA)
- Biochemistry (AREA)
- Obesity (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention relates to compounds of formula (I), in which R1, R2, R3, R4, R5 and R6 are defined as cited, in addition to their physiologically compatible salts. The compounds are suitable for use e.g. as hypolipidaemics.
Description
Description biphenyl azetidinones substituted by acidic groups, method for their production, medicaments containing said compounds and use thereof 5.
The invention relates to acid-group-substituted diphenylazetidinones, to their physiologically acceptable salts and to derivatives having physiological functions.
Diphenylazetidinones (such as, for example, ezetimibe) and their use for treating hyperlipidemia and arteriosclerosis and hypercholesterolemia have already been described [cf. Drugs of the Future 2000, 25(7):679-685) and US 5,756,470].
It was an object of the invention to provide further compounds having a therapeutically utilizable hypolipidemic action. In particular, it was an object to find novel compounds which, compared to the compounds described in the prior art, are absorbed to a very low extent. Very low absorption is to be understood as meaning an intestinal absorption of less than 10%, preferably less than or equal to 5%.
In particular, absorption of the novel compounds must be less than that of ezetimibe.
Pharmaceutically active compounds which are absorbed to a low extent generally have considerably fewer side-effects.
The invention relates to acid-group-substituted diphenylazetidinones, to their physiologically acceptable salts and to derivatives having physiological functions.
Diphenylazetidinones (such as, for example, ezetimibe) and their use for treating hyperlipidemia and arteriosclerosis and hypercholesterolemia have already been described [cf. Drugs of the Future 2000, 25(7):679-685) and US 5,756,470].
It was an object of the invention to provide further compounds having a therapeutically utilizable hypolipidemic action. In particular, it was an object to find novel compounds which, compared to the compounds described in the prior art, are absorbed to a very low extent. Very low absorption is to be understood as meaning an intestinal absorption of less than 10%, preferably less than or equal to 5%.
In particular, absorption of the novel compounds must be less than that of ezetimibe.
Pharmaceutically active compounds which are absorbed to a low extent generally have considerably fewer side-effects.
Accordingly, the invention relates to compounds of the formula I
OH
R6~ .. I
\ a " .R2 N
in which R1, R2, R3, R4, R5, R6 independently of one another are (Co-C3o)-alkylene-(LAG)~, where n may be 1 - 5 and where one or more carbon atoms of the alkylene radical may be replaced by -S(O)~-, where n = 0.-2, -O-, -(C=O)-, -(C=S)-, -CH=CH-, -C=C-, -N((C~-C6)-alkyl)-, -N(phenyl), -N((C1-C6)-alkyl-phenyl)- , -N(CO-(CHZ)~_~o-COOH)- or -NH-;
H, F, CI, Br, I, CF3, N02, N3, CN, COOH, COO(C1-C6)-alkyl, CONH2, CONH(C~-C6)-alkyl, CON[(C~-Cs)-alkyl]2, (C,-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, O-(C~-C6)-alkyl, where one, more or all hydrogens in the alkyl radicals may be replaced by fluorine;
C(=NH)(NH2), P03H2, S03H, S02-NH2, SOZNH(C~-Cs)-alkyl, S02N[(C~-C6)-alkyl]2 , S-(C~-C6)-alkyl, S-(CH2)~-phenyl, SO-(C~-C6)-alkyl, SO-(CH2)~-phenyl, S02-(C~-C6)-alkyl, SOZ-(CH2)~-phenyl, where n may be 0 - 6 and the phenyl radical may be substituted up to two times by F, CI, Br, OH, CF3, N02, CN, OCF3, O-(C~-C6)-alkyl, (C,-C6)-alkyl, NH2;
NH2, NH-(C~-C6)-alkyl, N((C,-C6)-alkyl)2, NH(C1-C7)-acyl, phenyl, O-(CH2)n-phenyl, where n may be 0 - 6, where the phenyl ring may be mono- to trisubstituted by F, CI, Br, l, OH, CF3, N02, CN, OCF3, O-(C~-C6)-alkyl, (C~-C6)-alkyl, NH2, NH(C~=C6)-alkyl, N((C~-C6}-alkyl)2, S02-CH3, COOH, COO-(C~-C6)-alkyl, CONH2;
(LAG)" is -(CHZ)~_~o-S03H, -(CH2)o-~o-P(0)(OH)2, (CH2)o-~o-0-P(0)(OFi)Z, ~ -(CH2)o_~o-COOH and n may be 1 - 5;
where in each case at least one of the radicals R1 to R6 must have the meaning (Co-C3o)-alkylene-(LAG), where n = 1 - 5 and where one or more carbon atoms of the alkylene radical are replaced by -S(O)"-, where n = 0 - 2, -O-, -(C=O)-, -(C=S)-, -CH=CH-, -C=C-, -N((C~-C6)-alkyl)-, -N(phenyl)-, -N((C,-C6)-alkyl-phenyl)-, -N(CO-(CH2)~_~o-COOH)- or -NH-, and their pharmaceutically acceptable salts;
except for the compound 2-{[4-(4-{1-(4-fluorophenylr3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}phenoxy)butyl]methylamino}ethanesulfonic acid and those compounds in which the radicals R1 - R6 have the meaning -O-(CH2)~_~o-COOH, (C~-C6)-alkylene-COOH or -COOH.
Preference is given to compounds of the formula I where at least one of the radicals R1 to R6 has the meaning (Co-C3o)-alkylene-(LAG), where one or more carbon atoms of the alkylene radical may be replaced by -O-, -(C=O)-, -N((C~-C6)-alkyl)-, -N(CO-(CH2)~_,o-COOH)- or -NH-.
Particular preference is given to compounds of the formula I where one of the radicals R1 or R3 has the meaning (Co-C3o)-alkylene-(LAG), where one or more carbon atoms of the alkylene radical may be replaced by -O-, -(C=O)-, -N(CH3)-, or -N H-.
Very particular preference is given to compounds of the formula I where one of the radicals R1 or R3 has the meaning -(CH2)o_~-Y-W-(Co-C25)-alkylene-Y'-W'-(LAG);
where one or more carbon atoms of the alkylene radical may be replaced by oxygen atoms and where Y and W independently of one another may be NH, NCH3, C=O, O, a bond or S(O)S, where n = 0 - 2, and Y' and W' independently of one another may be NH, NCH3, C=O, O, a bond or S(O)~, where n = 0 - 2, or Y-W or Y'-W' in each case together may be a bond.
Preference is furthermore given to compounds of the formula I where the group LAG
is a carboxylic acid radical or a sulfonic acid radical.
Owing to their increased solubility in water, compared to the parent compounds, pharmaceutically acceptable salts are particularly suitable for medical applications.
These salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds according to the invention are salts of inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, sulfonic acid and sulfuric acid, and of organic acids, such as acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isothionic acid, lactic acid, lactobionic acid, malefic acid, malic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid, tartaric acid and trifluoroacetic acid, for example. For medical purposes, very particular preference is given to using the chloride salt.
Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts).
The scope of the invention also includes salts having a pharmaceutically unacceptable anion, which salts may be useful intermediates for preparing or purifying pharmaceutically acceptable salts and/or for use in nontherapeutic, for example in vitro, applications.
Here, the term "derivative having physiological function" refers to any physiologically acceptable derivative of a compound according to the invention, for example an ester, that is able, upon administration to a mammal, for example man, to form such a compound or an active metabolite (directly or indirectly).
A further aspect of this invention are prodrugs of the compounds according to the invention. Such prod rugs can be metabolized in vivo to give a compound according to the invention. These prodrugs may or may not be active in their own right.
OH
R6~ .. I
\ a " .R2 N
in which R1, R2, R3, R4, R5, R6 independently of one another are (Co-C3o)-alkylene-(LAG)~, where n may be 1 - 5 and where one or more carbon atoms of the alkylene radical may be replaced by -S(O)~-, where n = 0.-2, -O-, -(C=O)-, -(C=S)-, -CH=CH-, -C=C-, -N((C~-C6)-alkyl)-, -N(phenyl), -N((C1-C6)-alkyl-phenyl)- , -N(CO-(CHZ)~_~o-COOH)- or -NH-;
H, F, CI, Br, I, CF3, N02, N3, CN, COOH, COO(C1-C6)-alkyl, CONH2, CONH(C~-C6)-alkyl, CON[(C~-Cs)-alkyl]2, (C,-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, O-(C~-C6)-alkyl, where one, more or all hydrogens in the alkyl radicals may be replaced by fluorine;
C(=NH)(NH2), P03H2, S03H, S02-NH2, SOZNH(C~-Cs)-alkyl, S02N[(C~-C6)-alkyl]2 , S-(C~-C6)-alkyl, S-(CH2)~-phenyl, SO-(C~-C6)-alkyl, SO-(CH2)~-phenyl, S02-(C~-C6)-alkyl, SOZ-(CH2)~-phenyl, where n may be 0 - 6 and the phenyl radical may be substituted up to two times by F, CI, Br, OH, CF3, N02, CN, OCF3, O-(C~-C6)-alkyl, (C,-C6)-alkyl, NH2;
NH2, NH-(C~-C6)-alkyl, N((C,-C6)-alkyl)2, NH(C1-C7)-acyl, phenyl, O-(CH2)n-phenyl, where n may be 0 - 6, where the phenyl ring may be mono- to trisubstituted by F, CI, Br, l, OH, CF3, N02, CN, OCF3, O-(C~-C6)-alkyl, (C~-C6)-alkyl, NH2, NH(C~=C6)-alkyl, N((C~-C6}-alkyl)2, S02-CH3, COOH, COO-(C~-C6)-alkyl, CONH2;
(LAG)" is -(CHZ)~_~o-S03H, -(CH2)o-~o-P(0)(OH)2, (CH2)o-~o-0-P(0)(OFi)Z, ~ -(CH2)o_~o-COOH and n may be 1 - 5;
where in each case at least one of the radicals R1 to R6 must have the meaning (Co-C3o)-alkylene-(LAG), where n = 1 - 5 and where one or more carbon atoms of the alkylene radical are replaced by -S(O)"-, where n = 0 - 2, -O-, -(C=O)-, -(C=S)-, -CH=CH-, -C=C-, -N((C~-C6)-alkyl)-, -N(phenyl)-, -N((C,-C6)-alkyl-phenyl)-, -N(CO-(CH2)~_~o-COOH)- or -NH-, and their pharmaceutically acceptable salts;
except for the compound 2-{[4-(4-{1-(4-fluorophenylr3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}phenoxy)butyl]methylamino}ethanesulfonic acid and those compounds in which the radicals R1 - R6 have the meaning -O-(CH2)~_~o-COOH, (C~-C6)-alkylene-COOH or -COOH.
Preference is given to compounds of the formula I where at least one of the radicals R1 to R6 has the meaning (Co-C3o)-alkylene-(LAG), where one or more carbon atoms of the alkylene radical may be replaced by -O-, -(C=O)-, -N((C~-C6)-alkyl)-, -N(CO-(CH2)~_,o-COOH)- or -NH-.
Particular preference is given to compounds of the formula I where one of the radicals R1 or R3 has the meaning (Co-C3o)-alkylene-(LAG), where one or more carbon atoms of the alkylene radical may be replaced by -O-, -(C=O)-, -N(CH3)-, or -N H-.
Very particular preference is given to compounds of the formula I where one of the radicals R1 or R3 has the meaning -(CH2)o_~-Y-W-(Co-C25)-alkylene-Y'-W'-(LAG);
where one or more carbon atoms of the alkylene radical may be replaced by oxygen atoms and where Y and W independently of one another may be NH, NCH3, C=O, O, a bond or S(O)S, where n = 0 - 2, and Y' and W' independently of one another may be NH, NCH3, C=O, O, a bond or S(O)~, where n = 0 - 2, or Y-W or Y'-W' in each case together may be a bond.
Preference is furthermore given to compounds of the formula I where the group LAG
is a carboxylic acid radical or a sulfonic acid radical.
Owing to their increased solubility in water, compared to the parent compounds, pharmaceutically acceptable salts are particularly suitable for medical applications.
These salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds according to the invention are salts of inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, sulfonic acid and sulfuric acid, and of organic acids, such as acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isothionic acid, lactic acid, lactobionic acid, malefic acid, malic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid, tartaric acid and trifluoroacetic acid, for example. For medical purposes, very particular preference is given to using the chloride salt.
Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts).
The scope of the invention also includes salts having a pharmaceutically unacceptable anion, which salts may be useful intermediates for preparing or purifying pharmaceutically acceptable salts and/or for use in nontherapeutic, for example in vitro, applications.
Here, the term "derivative having physiological function" refers to any physiologically acceptable derivative of a compound according to the invention, for example an ester, that is able, upon administration to a mammal, for example man, to form such a compound or an active metabolite (directly or indirectly).
A further aspect of this invention are prodrugs of the compounds according to the invention. Such prod rugs can be metabolized in vivo to give a compound according to the invention. These prodrugs may or may not be active in their own right.
5 ~ The compounds according to the invention can also be present in various polymorphous, forms, for example as amorphous and crystalline polymorphous forms. The scope of the invention includes all polymorphous forms of the compounds according to the invention, which form a further aspect of the invention.
Hereinbelow, all references to "compound(s) of the formula (I)" refer to a compound or compounds of the formula (I) as described above, and to their salts, solvates and derivatives having physiological function, as described herein.
The compounds of the formula I and their pharmaceutically acceptable salts and derivatives having physiological function are ideal medicaments for treating an impaired lipid metabolism, in particular hyperlipidemia. The compounds of the formula I are also suitable for modulating the serum cholesterol concentration and for preventing and treating arteriosclerotic manifestations.
The compounds) of the formula (I) can also be administered in combination with other active compounds.
The amount of a compound of the formula (I) required to achieve the desired biological effect depends on a number of factors, for example on the specific compound chosen, on the intended use, on the mode of administration and on the clinical condition of the patient. In general, the daily dose is in the range from 0.1 mg to 100 mg (typically from 0.1 mg to 50 mg) per day per kilogram of bodyweight, for example 0.1-10 mg/kg/day. Tablets or capsules may contain, for example, from 0.01 to 100 mg, typically from 0.02 to 50 mg. In the case of pharmaceutically acceptable salts, the abovementioned weight data relate to the weight of the diphenyl-azetidinone-ion derived from the salt. For the prophylaxis or therapy of the abovementioned conditions, the compounds of the formula (I) can be used themselves as the compound, but preferably they are present in the form of a pharmaceutical composition with an acceptable carrier. The carrier must of course be acceptable in the sense that it is compatible with the other constituents of the composition and is not harmful to the health of the patient. The carrier can be a solid or a liquid or both and is preferably formulated with the compound as an individual dose, for example as a tablet, which can contain from 0.05% to 95% by weight of the active compound. Further pharmaceutically active substances can also be present, including further compounds of the formula (I). The pharmaceutical compositions according to the invention can be prepared by one of the known pharmaceutical methods, which essentially consist in mixing the constituents with pharmacologically acceptable carriers and/or auxiliaries.
Pharmaceutical compo:>itions according to the invention are those which are suitable for oral or peroraf (e.g. sublingual) administration, although the most suitable manner of administration is dependent in each individual case on the nature and severity of the condition to be treated and on the type of the compound of the formula (I) used in each case. Coated formulations and coated delayed-release formulations are also included in the scope of the invention. Acid-resistant and enteric formulations are preferred. Suitable enteric coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and mEahyl methacrylate.
Suitable pharmaceutical compounds for oral administration can be present in separate units, such as, for example, capsules, cachets, lozenges or tablets, which in each case contain a specific amount of the compound of the formula (I); as a powder or granules; as ~~ solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion. As already mentioned, these compositions can be prepared according to any suitable pharmaceutical method which includes a step in which the active compound and the carrier (which can consist of one or more additional constituents) are brought into contact. In general, the compositions are prepared by uniform and homogeneous mixing of the active compound with a liquid and/or finely divided solid carrier, after which the product, if necessary, is shaped. For example, a tablet can thus be prepared by pressing or shaping a powder or granules of the compound, if appropriate with one or more additional constituents. Pressed tablets can be produced by tableting the compound in free-flowing form, such as, for example, a powder or granules, if appropriate mixed ~ with a binder, lubricant, inert diluent and/or a (number of) surface-active/
dispersing agents) in a suitable machine. Shaped tablets can be produced by shaping the pulverulent compound moistened with an inert liquid diluent in a suitable machine.
Pharmaceutical compositions which are suitable for peroral (sublingual) administration include Lozenges which contain a compound of the formula (I) with a flavoring, customarily sucrose and gum arabic or tragacanth, and pastilles which include the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic.
Suitable other active compounds for the combination preparations are:
all antidiabetics mentioned in Rote Liste 2001, Chapter 12. They can be combined with the compounds of the formula I according to the invention in particular to achieve a synergistically enhanced action. The active compound combination can be administered either by ;separate administration of the active compounds to the patient or in the form of combination preparations comprising a plurality of active compounds in a pharmaceutical preparation.
Antidiabetics include insulin and insulin derivatives, such as, for example, Lantus~ or HMR 1964, GLP-1 derivatives, such as, for example, those disclosed by Novo Nordisk A/S in WO 98/08871, and oral hypoglycemic active compounds.
The oral hypoglycemic active compounds preferably include sulfonylureas, biguadines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, potassium channel openers, such as, for example, those disclosed by Novo Nordisk A/S in WO 97/26265 and WO 99/03861, insulin sensitizers, inhibitors of liver enzymes involved in stimulating gluconeogenesis and/or' glycogenolysis, modulators of glucose uptake, compounds which modulate lipid metabolism, such as antihyperlipidemic active compounds and antilipidemic active compounds, compounds which reduce food intake, PPAR and PXR agonists and active compounds which act on the ATP-dependent potassium channel of the beta cells.
In one embodiment of the invention, the compounds of the formula I are administered in combination with an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atonrastatin, cerivastatin, rosuvastatin.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a cholesterol absorption inhibitor, such as, for example, ezetimibe, tiqueside, pamaqueside.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a PPAR gamma agonist, such as, for example, rosiglitazone, pioglitazone, JTT-501, GI 262570.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a PPAR alpha agonist, such as, for example, GW
9578, GW 7647.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a mixed PPAR alpha/gamma agonist, such as, for example, GW 1536, AVE 8042, AVE 8134, AVE 0847.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a fibrate, such as, for example, fenofibrate, clofibrate, bezafibrate.
In one embodiment of the invention, the compounds of the formula I are administered in combination with an MTP inhibitor, such as, for example, Bay 9952, BMS-201038, R-103757.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a bile acid absorption inhibitor, such as, for ~ example, HMR 1453.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a CETP inhibitor, such as, for example, Bay 194789.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a polymeric bile acid adsorber, such as, for example, cholestyramine, colesolvam.
In one embodiment of the invention, the compounds of the formula I are administered in combination with an LDL receptor inducer, such as, for example, HMR1171, HMR1586.
In one embodiment of the invention, the compounds of the formula I are administered in combination with an ACAT inhibitor, such as, for example, avasimibe.
In one embodiment of the invention, the compounds of the formula I are administered in combination with an antioxidant, such as, for example, OPC-14117.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein lipase inhibitor, such as, for example, NO-1886.
In one embodiment of the invention, the compounds of the formula I are administered in combination with an ATP citrate lyase inhibitor, such as, for example, SB-204990.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a squalene synthetase inhibitor, such as, for example, BMS-188494.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein(a) antagonist, such as, for example, CI-1027 or nicotinic acid.
10 In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipase inhibitor, such as, for example, Orlistat.
In one embodiment of the invention, the compounds of the formula I are administered in combination with insulin.
In one embodiment, the compounds of the formula I are administered in combination with a sulfonylurea, such as, for example, tolbutamide, glibenclamide, glipizide or gliclazide.
In one embodiment, the compounds of the formula I are administered in combination with a biguanide, such as, for example, metformin.
In another embodiment, the compounds of the formula I are administered in combination with a meglitinide, such as, for example, repaglinide.
In one embodiment, the compounds of the formula I are administered in combination with a thiazolidinedione, such as, for example, troglitazone, ciglitazone, pioglitazone, rosiglitazone, or the compounds disclosed by Dr. Reddy's Research Foundation in WO 97/41097, in particular 5-[(4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinyl-methoxy]phenyl]methyl]-2,4-thiazolidinedione.
In one embodiment, the compounds of the formula I are administered in combination with an a-glucosidase inhibitor, such as, for example, miglitol or acarbose.
In one embodiment, the compounds of the formula I are administered in combination with an active compound which acts on the ATP-dependent potassium channel of beta cells, such as, for example, tolbutamide, glibenclamide, glipizide, gliazide or repaglinide.
In one embodiment, the compounds of the formula I are administered in combination with more than one of the abovementioned compounds, for example in combination ~ with a sulfonylurea and metformin, a sulfonylurea and acarbose, repaglinide and metformin, insulin and a sulfonylurea, insulin and metformin, insulin and troglitazon, insulin and lovastatin, etc.
In a further embodiment, the compounds of the formula I are administered in combination with CART agonists, NPY agonists, MC3 and MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, ~i3-agonists, MCH (melanine-concentrating hormone) antagonists, CCK
agonists, serotonin reuptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormone, growth hormone-releasing compounds, TRH agonists, decoupling protein 2 or 3 modulators, leptin agonists, DA agonists (bromocriptine, doprexin), lipase/amylase inhibitors, PPAR modulators, RXR modulators or TR-~ agonists.
In one embodiment of the invention, the further active compound is leptin.
In one embodiment, the further active compound is dexamphetamine or amphetamine.
In one embodiment, the further active compound is fenfluramine or dexfenfluramine.
In another embodiment, the further active compound is sibutrarnine.
In one embodiment, the further active compound is Orlistat.
In one embodiment, the further active compound is mazindol or phentermine.
In one embodiment, the compounds of the formula I are administered in combination with fiber, preferably insoluble fiber, such as, for example, Caromax~. The combination with Caromax~ can be given in one preparation or by separate administration of compounds of the formula I and Caromax~. Here, Caromax~ can also be administered in the form of food, such as, for example, in bakery goods or muesli bars. Compared to the individual active compounds, the combination of compounds of the formula I with Caromax~ is, in addition to an enhanced action, in particular with respect to the lowering of LDL cholesterol, also characterized by its improved tolerability.
It goes without saying that each suitable combination of the compounds according to the invention with one or more of the compounds mentioned above and optionally one or more further pharmacologically active substances is included in the scope of the present invention.
The invention furthermore provides both stereoisomer mixtures of the formula I
and the pure stereoisomers of the formula I, and diastereomer mixtures of the formula I
and the pure diastereomers. The mixtures are separated by chromatographic means.
Preference is given to both racemic and enantiomerically pure compounds of the formula I of the following structure:
OH
R6~
. _' R2 N
Amino protective groups that are preferably used are the benzyloxycarbonyl (Z) radical, which can be removed by catalytic hydrogenation, the 2-(3,5-dimethyloxyphenyl)propyl(2)oxycarbonyl(Ddz) or trityl (Trt) radical, which can be removed by weak acids, the t-butylcarbamate (BOC) radical, which can be removed by 3M hydrochloric acid, and the 9-fluorenylmethyloxycarbonyl (Fmoc) radical, which can be removed using secondary amines.
The invention furthermore relates to a process for preparing diphenylazetidinone derivatives of formula I.
---~ R2 - ,CHZ)x-Y- R11 K5 ~ (CHZ)x ~Y
R4 ' ~ I
II III R4 wJo-2 (CHZ)Z~W,_Y,~(CHZ)Y
~''C 0 - 2 (LAG) Y can be S, O, (C=O), (C=S), CH=CH, C=C, N((C~-C6)-alkyl), N(phenyl), N((C~-C6)-alkyl-phenyl), N(CO-(CHZ)1_~o-COOH) or NH;
R11 can be H or, if Y = (C=O) or (C=S), OH;
W, Y' and W' can, independently of one another and of Y, be -S(O)S-, where n =
2, -O-, -(C=O)-, -(C=S)-, -CH=CH-, -C=C-, -N((C~-C6)-alkyl)-, -N(phenyl), -N((C~-C6)-alkyl-phenyl)-, -N(CO-(CH2)~_~o-COOH)- or -NH- or a bond;
x, y and z independently of one another can be 0 to 10.
In compound II, -(CH2)x-Y-R11 can alternatively also be attached to one of the other two phenyl rings.
The process for preparing compounds of the formula I comprises reacting, for example, an amine or a hydroxy compound of the formula II with an alkylating or acylating agent which, preferably in the omega position, carries a further functionality- if appropriate in protected form. This functionality is (after deprotection) used for attaching (LAG), for example with the formation of ether, amine or amide bonds.
The examples below serve to illustrate the invention in more detail, without limiting the invention to the products and embodiments described in the examples.
Example I
4-{4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-yl]benzylamino~butane-1-sulfonic acid (6):
a) 3-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-pentanoyl]-4-phenyl-oxazolidin-2-one (1 ):
v °
N~O
F
27 g of 3-[5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyloxazolidin-2-one, 13.6 g of tert-butyldimethylsilyl chloride and 10.2 g of imidazole are dissolved in 36 ml of dimethylformamide and stirred at 60°C for 90 min. After the reaction has ended, the mixture is dissolved in ethyl acetate and extracted two times with water. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. This gives 3-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-pentanoyl]-4-phenyloxazolidin-2-one (1 ) of molecular weight 471.65 (C26HaaFN04Si); MS
(ESI):
340.28 (MH+- HOSi(CH3)2C(CH3)3).
b) 4-(5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-1-(4-methoxyphenyl)-(2-oxo- 4-phenyloxazolidine-3-carbonyl)pentylamino]benzonitrile (2):
16.2 g of 3-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-pentanoyl]-4-phenyl-5 ~ oxazolidin-2-one are dissolved in 350 ml of dichloromethane. 19.8 ml of Hunig base and 10.14 g of 4-[(4-methoxyphenylimino)methyl]benzonitrile are added, and the solution is cooled to -10°C. 8.52 ml of trimethylsilyl triflate are added to the cooled solution, and the mixture is stirred at -10°C for 30 min. The solution is then cooled to -30°C, and 44 ml of titanium tetrachloride solution are added. The reaction mixture is 10 stirred at from -30 to -40°C for 2 h. The solution is then allowed to warm to room temperature and the reaction solution is washed successively with 200 ml of 2N
sulfuric acid, 300 ml of 20% strength sodium hydrogen sulfite solution and sat.
sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure, and the residue is purified on silica gel using 15 n-heptane/ethyl acetate 3/1. This gives 4-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluoro-phenyl)-1-(4-methoxyphenyl)-2-(2-oxo-4-phenyloxazolidine-3-carbonyl)pentyl-amino]benzonitrile (2) of molecular weight 707.93 (C4~H46FN305Si); MS (ESI):
590.51 (MH+- C~HsN2).
c) 4-[3-[3-(tert-butyldimethylsilanyloxy)-3-(4-fluorophenyl)propyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzonitrile (3):
13.2 g of 4-[5-(tert-butyldimethylsilanyloxy~)-5-(4-fluorophenyl)-1-(4-methoxyphenyl)-2-(2-oxo-4-phenyloxazolidine-3-carbonyl)pentylamino]benzonitrile are dissolved in 380 ml of methyl tert-butylether, 18.6 ml of N,O-bis(trimethylsilyl)acetamide and 1.86 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran are added and the mixture is stirred at room temperature for 2 h. After the reaction has ended, 10 ml of acetic acid are added, the reaction mixture is concentrated under reduced pressure and the residue is purified on silica gel using toluene/ethyl acetate 50/1.
This gives 4-[3-[3-(tert-butyldimethylsilanyloxy)-3-(4-fluorophenyl)propyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzonitrile (3) of molecular weight 544.75 (C32H37FN2O3S1); MS (ESI): 545.56 (M+H+).
d) 4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]- benzonitrile (4):
3.5 g of 4-[3-[3-(tert-butyldimethylsilanyloxy)-3-(4-fluorophenyl)propyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzonitrile are dissolved in 65 ml of tetrahydrofuran, 0.74 ml of acetic acid and 8.03 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran are added and the mixture is stirred at room temperature for 2 h. Another 4.82 ml of the tetrabutylammonium fluoride solution are then added, and the mixture is stirred at reflux temperature for another 3 h. The cooled reaction mixture is concentrated under reduced pressure and the residue is purified by silica gel chromatography using n-heptane/ethyl acetate 2/1.
This gives 4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzonitrile (4) of molecular weight 430.48 (C26HZSFN20s);
MS
(ESI): 431.24 (M+H+).
e) 1-(4-Aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)-azetidin-2-one (5):
1.22 g of 4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzonitrile are dissolved in 90 ml of ethanol, 10 ml of conc.
ammonia solution and an excess of Raney nickel are added, and the mixture is stirred at 60°C and a hydrogen pressure of 10 bar for 8 h. Overnight, the reaction mixture cools to room temperature, and the next day, the catalyst is removed, the filtrate is concentrated under reduced pressure and the residue is purified by silica gel chromatography using dichloromethane/methanol/ammonia solution 10/1 /0.1.
This gives 1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)-azetidin-2-one (5) of molecular weight 434.51 (C26H2~FN203); MS
(ESI): 418.2 (MH+- NH3).
~ f) 4-{4-(3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxo-azetidin, 1-yl]benzylamino}butane-1-sulfonic acid (6):
At room temperature, 87 mg of the above benzylamine are dissolved in 3 ml of dry acetonitrile, 40 pl of 1,4-butanesultone are added and the mixture is heated under reflux for 12 h. The cooled reaction solution is concentrated under reduced pressure and purified chromatographically (silica gel; dichloromethane/methanol 85/15 +
10%
water). This gives 4-{4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzylamino}butane-1-sulfonic acid (6) of molecular weight 570.69 (C3oH35FN206S); MS (ESI): 553.28 (MH+- H20).
Example II
2-[(4-{4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]phenoxy}butyl)methylamino]ethylsulfonic acid (8):
~O~.N~S~OH
O ~O
130 mg of 3-[3-(4-fluorophenyl)-3-hydroxypropyl]-1-[4-(4-fluorobutoxy)phenyl]-4-(4-methoxyphenyl)azetidin-2-one (7) are dissolved in 6 ml of absolute methanol.
120 mg of N-methyltaurine in 2 ml of water and 60 mg of potassium carbonate are then added. The mixture is stirred at 50°C for 24 h. The reaction mixture is concentrated using a rotary evaporator and the residue is purified by preparative chromatography.
Freeze-drying gives the product (50 mg) as an oil.
C32H39FN20~S ESIMS mlz: 614 (M+) Example III
[2-(4-{4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]phenoxy}butylamino)ethyl]phosphonic acid (9):
F H
O~N~P~OH
O OH
200 mg of 3-[3-(4-fluorophenyl)-3-hydroxypropyl]-1-[4-(4-fluorobutoxy)phenyl]-4-(4-methoxyphenyl)azetidin-2-one (7) are dissolved in 6 ml of absolute methanol.
165 mg .
of 1-aminoethylphosphate and 247 mg of potassium carbonate dissolved in 3 ml of water are then added. The mixture is stirred at 90°C for 8 h. The reaction mixture is concentrated using a rotary evaporator and the residue is purified by preparative chromatography. Freeze-drying gives the product (47 mg) as an oil.
C3,H38FN20~P ESIMS m/z: 600 (M+) Example IV
Phosphoric acid mono-{6-[4-(4-{1-(4-fluorophenyl)-3-[3-(4-fluorofluorophenyl)-hydroxypropyl]-4-oxoazetidin-2-yl}phenoxy)butylamino]hexyl}ester (10):
~H
N
O
O-P-OH
F OH
115 mg of 1-(4-fluorofluorophenyl)-3-[3-(4-fluorofluorophenyl)-3-hydroxypropyl]-4-[4-(2-fluoromethoxyethoxy)phenyl]azetidin-2-one (7) are dissolved in 6 ml of absolute methanol. 130 mg of 6-amino-1-hexyl phosphate in 1.5 ml of water and 107 mg of , potassium carbonate are then added. The mixture is stirred at 70°C
overnight. The reaction mixture is concentrated using a rotary evaporator and the residue is purified by preparative chromatography. Freeze-drying gives the product as an oil.
CsaHasFzN207P ESIMS m/z: 660 (M+) Example V
4-f4-[3-[3-(4-fluorofluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]phenoxy}butane-1-sulfonic acid (12):
V ~/~
~O~S~OH
160 mg of 3-[3-(4-fluorofluorophenyl)-3-hydroxypropyl]-1-(4-hydroxyphenyl)-4-(4-methoxyphenyl)azetidin-2-one (11 ) are dissolved in 4 ml of absolute dimethylformamide.
210 mg of powdered potassium carbonate and 42 mg of 1,4,-butanesultone are added.
The mixture is stirred at room temperature overnight. The reaction solution is concentrated under oil pump vacuum, taken up in dichloromethane and washed 1x with water. The aqueous phase is acidified with 2N hydrochloric acid and extracted 2x with dichloromethane. The combined organic phases are dried over sodium sulfate and concentrated. The residue is chromatographed on a 10 g Si02 cartridge (dichloromethane/
methanol = 5/1 ). The product (72 mg) is obtained as an oil.
C29H3ZFNO~S ESIMS m/z: 557 (M+) Example VI
4-(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-phenoxy)butane-1-sulfonic acid (13):
vs,o OH
r 250 mg of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxy-phenyl)azetidin-2-one (7) are dissolved in 6 ml of absolute dimethylformamide.
337 mg 10 of powdered potassium carbonate and 69 NI of 1,4,-butanesultone are added.
The mixture is stirred at room temperature overnight. The reaction solution is filtered and concentrated under oil pump vacuum. The residue is chromatographed on a 10 g Si02 cartridge (dichloromethane/rnethanol = 5/1 ) and crystallized from diethyl ether. The product (131 mg) is obtained as a solid.
15 C28H29F2NO6S ESIMS m/z: 546 (M+) Example VII
20 3-(4-(1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropylJ-4-oxoazetidin-2-yl}-phenoxy)propan-1-sulfonin acid (14):
O~S-OH
F
25Q mg of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxy-phenyl)azetidin-2-one (7) are dissolved in 6 ml of absolute dimethylformamide.
337 mg of powdered potassium carbonate and 59 NI of 1,3,-propanesultone are added.
The mixture is stirred at room temperature overnight. The reaction solution is filtered and concentrated under oil pump vacuum. The residue is chromatographed on a 10 g Si02 cartridge (dichloromethane/methanol = 5/1 ) and crystallized from diethyl ether. The product (250 mg) is obtained as a solid.
C2~H2~F2NO6S ESIMS m/z: 532 (M+) Example VIII
(4-{1-(4-Fluorophenyf)-3-[3-(4-ffuorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl?-benzylcarbamoyl)methanesulfonic acid (18):
p O~ S-OH
N
F O
/ F
a) 4-[5-(4-Fluorophenyl)-1-(4-fluorophenylamino)-5-hydroxy-2-(2-oxo-4-phenyloxazolidine-3-carbonyl)-pentyl]-benzonitrile (15):
Under argon, 2.5 g of 3-[5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyloxazolidin-2-one are dissolved in 30 ml of dichloromethane, 3.9 g of 4-[(4-fluorophenylimino)-methyl]-benzonitrile are added and the mixture is cooled to -10°C. 6.4 ml of diisopropylethylamine and, over a period of 30 min, 4.05 ml of trimethylsilyl chloride are added to this mixture so that the temperature does not exceed -5°C.
The mixture is stirred at this temperature for 1 additional hour and then cooled to -25°C. 0.8 ml of titanium tetrachloride are then added slowly. The dark mixture is stirred at from -25 to -30°C overnight and then decomposed using 35 ml of a 7 percent strength solution of tartaric acid and then stirred at room temperature for another hour. 15 ml of a 20 percent strength solution of sodium bicarbonate are then added, and the mixture is again stirred for 1 hour. Following phase separation, the organic phase is washed with 30 ml of water, dried over magnesium sulfate and concentrated to about 10 ml. Following the addition of 2 ml of bistrimethylsilylacetamide, the mixture is heated at reflux for 30 min and then concentrated under reduced pressure. The residue is crystallized using ethyl acetatelheptane. The product is filtered off with suction and dried under reduced pressure. This gives the product of molecular weight 653.81 (C37H37F2N3O4S1); MS (ESI+): 654.3 (M+H+), 582.2 (M+H+-Si(CH3)3).
b) {1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzonitrile (16):
2 g of 4-[5-(4-Fluorophenyl)-1-(4-fluorophenylamino)-5-hydroxy-2-(2-oxo-4-phenyl-oxazolidine-3-carbonyl)-pentyl]-benzonitrile (15) are dissolved in 20 ml of methyl-tert-butyl ether and, together with 100 mg of tetrabutylammonium fluoride trihydrate and 1.3 ml of bistrimethylsilyl acetamide, heated at 40°C for about 1 h.
The reaction is monitored by thin-layer chromatography. After the reaction has ended, 0.2 ml of glacial acetic acid is initially added and the mixture is stirred for 30 min and then concentrated. 20 ml of a mixture of isopropanol/2N sulfuric acid = 10:1 are added to the residue, and the mixture is stirred for 1 hour. Following addition of a spatula tip of solid sodium bicarbonate, the mixture is again concentrated under reduced pressure, the residue is taken up in ethyl acetate and the organic phase is washed with water and dried, and the residue is, after removal of the solvent, purified by column ~ chromatography (Si02, CH2C12/methanol = 100:1 ). This gives the product of molecular weight 418.45 (C25H2oF2N202); MS (DCI+): 419 (M+H+).
c) 4-(4-Aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-~ hydroxypropyl]-azetidin-2-one (17):
200 mg of {1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzonitrile (16) are dissolved in 20 ml of ethanol and, with 0.5 ml of conc.
ammonia, hydrogenated over Raney nickel at a hydrogen pressure of 75 bar and at 25°C for 30 hours. The catalyst is filtered off with suction, the mixture is concentrated under reduced pressure and the residue is purified by column filtration (Si02, CH2C12/methanollconc. NH3 = 100:10:1 ). This gives the product of molecular weight 422.5 (C25H22F2N202); MS (DCI+): 423 (M+H+), 405 (M+H+- H20).
d) (4-{1-(4-Fluorophenyl)-3-(3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-yl}-benzylcarbamoyl)methanesulfonic acid (18):
A solution of 120 mg of 4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluoro-phenyl)-3-hydroxypropyl]azetidin-2-one (17), 48 NI of diisopropylethylamine in 1 ml of dimethylformamide is added to a solution of 40 mg of sulfoacetic acid, 110 NI
of diisopropylcarbodiimide, 76 mg of hydroxybenzotriazole in 2 ml of dimethyl-formamide, and the mixture is stirred at room temperature for 12 h. The reaction solution is concentrated and separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1 % trifluoroacetic acid)/acetonitrile (0.1 % trifluoroacetic acid) =
80/20 ->
10/90). This gives the product of molecular weight 544.58 (C2~H26F2N206S~); MS
(ESI) 527.10 (M + H+- H20) Example IX
{4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzylcarbamoyl}methanesulfonic acid (19):
o., / \
OH
F I / ~N \
O I / N IIO
~~'~OH
O O
A solution of 60 mg of 1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxy-propyl]-4-(4-methoxyphenyl)azetidin-2-one (5) in 1 ml of dimethylformamide is added to a solution of 20 mg of sulfoacetic acid, 55 NI of diisopropylcarbodiimide, 38 mg of hydroxybenzotriazole in 1 ml of dimethylformamide, and the mixture is stirred at room temperature for 12 h. The reaction solution is concentrated and separated by HPLC
(Knauer Eurospher-100-10-C18, water (0.1 % trifluoroacetic acid)/acetonitrile (0.1 trifluoroacetic acid) = 80/20 -> 10/90). This gives the product of molecular weight 556.61 (C28H29F~N20~S~); MS (ESI) 539.05 (M + H+- H20) Example X
N-(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzyl)succinaminic acid (20):
OH
O
O
F
F
A solution of 100 mg of 4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluoro-phenyl)-3-hydroxypropyl]azetidin-2-one (17), 33 NI of triethylamine in 2 ml of 5 dimethylformamide is added to a solution of 279 mg of succinic acid, 92 pl of diisopropylcarbodiimide, 80 mg of hydroxybenzotriazole in 2 ml of dimethyl-formamide, and the mixture is stirred at room temperature for 12 h. The reaction solution is concentrated and separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1 % trifluoroacetic acid)/acetonitrile (0.1 % trifluoroacetic acid) =
80/20 ->
10 10/90). This gives the product of molecular weight 522.55 (C2~H26F2N206S~);
MS
(ESI) 545.19 (M + Na+) 15 Example XI
F
{2-[2-({4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzylcarbamoyl}methoxy)ethoxy]ethoxy}acetic acid (21 ):
OH
v ~N ~
O// I / N ~0,~ OH
~O O
IOI ' IO
A solution of 64 mg of 1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxy-propyl]-4-(4-methoxyphenyl)azetidin-2-one (5), 21 NI of triethylamine in 1 ml of dimethylformamide are added to a solution of 327 mg of 3,6,9-trioxaundecanedioic acid, 57 NI of diisopropylcarbodiimide, 50 mg of hydroxybenzotriazole in 2 ml of dimethylformamide, and the mixture is stirred at room temperature for 12 h.
The reaction solution is concentrated and separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1 % trifluoroacetic acid)/acetonitrile (0.1 % trifluoroacetic acid) _ 80/20 -> 10/90). This gives the product of molecular weight 638.70 (C34H3gF~N2Og);
MS (ESI) 639.27 (M + H+) Example XII
4-((3-Carboxypropionyl)-{4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxy-phenyl)-4-oxoazetidin-1-yl]benzyl}amino)-4-oxobutyric acid (22):
H
'O
O
F H
O I~N
O
O
A solution of 70 mg of 1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxy-propyl]-4-(4-methoxyphenyl)azetidin-2-one (5), 23 NI of triethylamine in 1 ml of dimethylformamide is added to a solution of 190 mg of succinic acid, 63 pl of diisopropylcarbodiimide, 55 mg of hydroxybenzotriazole in 2 ml of dimethyl-formamide, and the mixture is stirred at room temperature for 12 h. The reaction solution is concentrated and separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1 % trifluoroacetic acid)/acetonitrile (0.1 % trifluoroacetic acid) =
80/20 ->
10/90). This gives the product of molecular weight 634.4 (C34H35F1N2Og); MS
(ESI-neg.) 633.22 (M - H+) Example XIII
11-{4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzylcarbamoyl}undecanoic acid (23):
F H
N
OH
O
A solution of 70 mg of 1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxy-propyl]-4-(4-methoxyphenyl)azetidin-2-one (5), 23 pl of triethylamine in 1 ml of dimethylformamide is added to a solution of 371 mg of dodecanedioic acid, 63 NI of diisopropylcarbodiimide, 55 mg of hydroxybenzotriazofe in 2 ml of dimethylformamide, and the mixture is stirred at room temperature for 12 h.
The reaction solution is concentrated and separated by HPLC(Knauer Eurospher-100-C18, water (0.1 % trifluoroacetic acid)/acetonitrile (0.1 % trifluoroacetic acid) = 80/20 -> 10/90). This gives the product of molecular weight 646.81 (C38H4~F~N206);
MS
(ESI) 647.35 (M + H+) Table 1: Compounds of the formula I
EX. R1, R2 R3, R5, Mo~ecularMolecular weight weight of the (found) free base or acid (calculated) XIV . ~ para-F, para-F,531.58 532.4 H
,~g~ , H
OH
pare H (MH+) XV " Para-F, para-F,502.54 503.3 H
Para r H (MH+) v,ll , H
~
S~oH
o XVI para-F, H I Para-F,514.58 515.4 N
) H (MH+) , H
para , S~oH
o XVII para-O-CH3, ~p para-F, H s~ 599.68 599.21 "
w~ H (M+) ~N
~
, H
o oH
XVili para-O-CH3, H para-F,739.95 740.42 H
~N~S~ H (MH+) .H
~
~
p OH
XIX para-O-CH3, p para-F,599.60 600.34 H ~
N~
' H (MH+) OH
.H
para ~
"
off XX para-O-CH3, ~ para-F,534.59 534.4 H ~
~~
pare ~N~ H (MH') , H
"
doff _ XXI ~ . H para-F, para-F,578.66 561.25 _ p.,. ~p H
~
OH H (MH+-H20) XXII ~",~~ ,H para-F, para-F,634.77 617.31 OH H
H (MH+-HZO) XXIII para-F, H ~ para-F,585.65 567.70 H
para H (MH+-~H
H~
OH
H20) XXIV para-O-CH3, pare -F, 557.64 55 H ~ Pa ..19 .
H
~S
o H n ff ( ) XXV ~H~ Para-F, para-F,660.70 660.28 ~P H
.~
pua ~
O
~
O
H (M') XXVI para-0-CH3, p~,;,~ para-F,600.62 600.24 H ~N~
~~P
.H
O
~
p H (M') XXVIi para-O-CH3, ~ para-F,614.73 597.32 H
~
\
~5,~
,"
H (M_ H20)~' ~~I~p wn ~N N~II para-F, para-F,-559.64-__-560.4 ," H
H (MH') XXIX N para-F, para-F,545.61 546.3 Iq H
, ," H (MH+) pace ~"~
S.
" o off XXX para-F, para-F,727.91 710.23 H
" H (MH'_ ~H~s~ ,H
0 ~OH
N "~
H pact' H20) XXXI para-O-CH3, para-F,753.93 752.32 H
~ H (M-H+);
."
~
O
H measured H~
~", in negative mode XXXII ~N para-F, para-F,573.62 572.09 H
N .H
~
~
5 H (M-H+);
off measured in negative mode XXXIII~ para-F, para-F,587.67 586.18 H
part ~H HN
~ H H (M-H+);
o H measured in negative mode Using the method described below, the activity of the compounds of the formula I
according to the invention was examined:
Effect on cholesterol absorption + 3H-taurocholic acid excretion using fecal excrement of mice. rats or hamsters 5 NMRI mice, Wistar rats, or Golden Syrian hamsters (in groups of n=4-6) are kept in metabolic cages, where they are fed with a standard diet (Altromin, Lage (Lippe)).
The afternoon prior to the administration of the radioactive tracers ('4C-cholesterol), the feed is removed and the animals are adapted to grates.
10 Additionally, the animals are labeled s.c. with 3H-TCA (taurocholic acid) (for example 1 pCi/mouse up to 5 NCi/rat) 24 hours prior to the peroral administration of the test meal ("C-cholesterol in Intralipid~ 20, Pharmacia-Upjohn).
Cholesterol absorption test: 0.25 mUmouse Intralipid ~ 20 (Pharmacia-Upjohn) 15 ((spiked with 0.25 pCi of '4C-cholesterol in 0.1 mg of cholesterol) is administered perorally by gavage.
Test substances are prepared separately in 0.5% methylcellulose (Sigma)/5%
Solutol (BASF, Ludwigshafen) or a suitable vehicle.
20 The administration volume of the test substance is 0.5 ml/mouse. The test substance is administered immediately prior to the test meal (Intralipid labeled with'4C-cholesterol) (cholesterol absorption test).
The feces are collected over a period of 24 h: fecal elimination of '4C-cholesterol and 25 3H-taurocholic acid (TCA) is determined after 24 hours.
The livers are removed and homogenized, and aliquots are incinerated in an oximate (Model 307, Packard) to determine the amount of '4C-cholesterol which had been taken up/absorbed.
Evaluation:
Feces samples:
The total weight is determined, the sample is made up with water to a defined volume and then homogenized, and an aliquot is evaporated to dryness and incinerated in an oximate (Model 307 from Packard for the incineration of radioactively labeled samples): the amount of radioactive 3H-H20 and '4C-C02 is ~ extrapolated to the amount of 3H-taurocholic acid and '4C-cholesterol, respectively, that is excreted (dual isotope technique). The ED2oo values as dose from a dose-effect curve are interpolated as those doses at which the excretion of TCA or cholesterol is doubled, based on a control group treated at the same time.
Liver samples:
The amount of '4C-cholesterol taken up by the liver is based on the administered dose. The EDSO values are interpolated from a dose-effect curve as the dose at which the uptake of '4C-cholesterol by the liver is halved (50%), based on a control group.
The EDSO values below demonstrate the activity of the compounds of the formula I
according to the invention Example No. EDSO (liver) [mg/mouse]
I 1.0 II > 0.1 IV 0.3 VIII 0.3 IX < 1.0 X < 1.0 XIII < 0.1 XVI I I 0.005 XXI 0.1 XXII 0.1 XXV 0.3 XXVIII 0.3 As can be seen from the table, the compounds of the formula I have very good cholesterol-lowering action.
Bioabsorption:
The bioabsorption of the compounds of the formula I was examined using the Caco cell model (A.R. Hilgers et al., Caco-2 cell monolayers as a model for drug transport across the intestinal mucosa, Pharm. Res. 1990, 7, 902).
From the measured data, it can be seen that the bioabsorption of the compounds of the formula I according to the invention is considerably lower than that of the compounds described in the prior art (reference structure):
OH
OH
,,, -~.
F N
O
F
Reference structure:
Ezetimibe
Hereinbelow, all references to "compound(s) of the formula (I)" refer to a compound or compounds of the formula (I) as described above, and to their salts, solvates and derivatives having physiological function, as described herein.
The compounds of the formula I and their pharmaceutically acceptable salts and derivatives having physiological function are ideal medicaments for treating an impaired lipid metabolism, in particular hyperlipidemia. The compounds of the formula I are also suitable for modulating the serum cholesterol concentration and for preventing and treating arteriosclerotic manifestations.
The compounds) of the formula (I) can also be administered in combination with other active compounds.
The amount of a compound of the formula (I) required to achieve the desired biological effect depends on a number of factors, for example on the specific compound chosen, on the intended use, on the mode of administration and on the clinical condition of the patient. In general, the daily dose is in the range from 0.1 mg to 100 mg (typically from 0.1 mg to 50 mg) per day per kilogram of bodyweight, for example 0.1-10 mg/kg/day. Tablets or capsules may contain, for example, from 0.01 to 100 mg, typically from 0.02 to 50 mg. In the case of pharmaceutically acceptable salts, the abovementioned weight data relate to the weight of the diphenyl-azetidinone-ion derived from the salt. For the prophylaxis or therapy of the abovementioned conditions, the compounds of the formula (I) can be used themselves as the compound, but preferably they are present in the form of a pharmaceutical composition with an acceptable carrier. The carrier must of course be acceptable in the sense that it is compatible with the other constituents of the composition and is not harmful to the health of the patient. The carrier can be a solid or a liquid or both and is preferably formulated with the compound as an individual dose, for example as a tablet, which can contain from 0.05% to 95% by weight of the active compound. Further pharmaceutically active substances can also be present, including further compounds of the formula (I). The pharmaceutical compositions according to the invention can be prepared by one of the known pharmaceutical methods, which essentially consist in mixing the constituents with pharmacologically acceptable carriers and/or auxiliaries.
Pharmaceutical compo:>itions according to the invention are those which are suitable for oral or peroraf (e.g. sublingual) administration, although the most suitable manner of administration is dependent in each individual case on the nature and severity of the condition to be treated and on the type of the compound of the formula (I) used in each case. Coated formulations and coated delayed-release formulations are also included in the scope of the invention. Acid-resistant and enteric formulations are preferred. Suitable enteric coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and mEahyl methacrylate.
Suitable pharmaceutical compounds for oral administration can be present in separate units, such as, for example, capsules, cachets, lozenges or tablets, which in each case contain a specific amount of the compound of the formula (I); as a powder or granules; as ~~ solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion. As already mentioned, these compositions can be prepared according to any suitable pharmaceutical method which includes a step in which the active compound and the carrier (which can consist of one or more additional constituents) are brought into contact. In general, the compositions are prepared by uniform and homogeneous mixing of the active compound with a liquid and/or finely divided solid carrier, after which the product, if necessary, is shaped. For example, a tablet can thus be prepared by pressing or shaping a powder or granules of the compound, if appropriate with one or more additional constituents. Pressed tablets can be produced by tableting the compound in free-flowing form, such as, for example, a powder or granules, if appropriate mixed ~ with a binder, lubricant, inert diluent and/or a (number of) surface-active/
dispersing agents) in a suitable machine. Shaped tablets can be produced by shaping the pulverulent compound moistened with an inert liquid diluent in a suitable machine.
Pharmaceutical compositions which are suitable for peroral (sublingual) administration include Lozenges which contain a compound of the formula (I) with a flavoring, customarily sucrose and gum arabic or tragacanth, and pastilles which include the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic.
Suitable other active compounds for the combination preparations are:
all antidiabetics mentioned in Rote Liste 2001, Chapter 12. They can be combined with the compounds of the formula I according to the invention in particular to achieve a synergistically enhanced action. The active compound combination can be administered either by ;separate administration of the active compounds to the patient or in the form of combination preparations comprising a plurality of active compounds in a pharmaceutical preparation.
Antidiabetics include insulin and insulin derivatives, such as, for example, Lantus~ or HMR 1964, GLP-1 derivatives, such as, for example, those disclosed by Novo Nordisk A/S in WO 98/08871, and oral hypoglycemic active compounds.
The oral hypoglycemic active compounds preferably include sulfonylureas, biguadines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, potassium channel openers, such as, for example, those disclosed by Novo Nordisk A/S in WO 97/26265 and WO 99/03861, insulin sensitizers, inhibitors of liver enzymes involved in stimulating gluconeogenesis and/or' glycogenolysis, modulators of glucose uptake, compounds which modulate lipid metabolism, such as antihyperlipidemic active compounds and antilipidemic active compounds, compounds which reduce food intake, PPAR and PXR agonists and active compounds which act on the ATP-dependent potassium channel of the beta cells.
In one embodiment of the invention, the compounds of the formula I are administered in combination with an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atonrastatin, cerivastatin, rosuvastatin.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a cholesterol absorption inhibitor, such as, for example, ezetimibe, tiqueside, pamaqueside.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a PPAR gamma agonist, such as, for example, rosiglitazone, pioglitazone, JTT-501, GI 262570.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a PPAR alpha agonist, such as, for example, GW
9578, GW 7647.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a mixed PPAR alpha/gamma agonist, such as, for example, GW 1536, AVE 8042, AVE 8134, AVE 0847.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a fibrate, such as, for example, fenofibrate, clofibrate, bezafibrate.
In one embodiment of the invention, the compounds of the formula I are administered in combination with an MTP inhibitor, such as, for example, Bay 9952, BMS-201038, R-103757.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a bile acid absorption inhibitor, such as, for ~ example, HMR 1453.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a CETP inhibitor, such as, for example, Bay 194789.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a polymeric bile acid adsorber, such as, for example, cholestyramine, colesolvam.
In one embodiment of the invention, the compounds of the formula I are administered in combination with an LDL receptor inducer, such as, for example, HMR1171, HMR1586.
In one embodiment of the invention, the compounds of the formula I are administered in combination with an ACAT inhibitor, such as, for example, avasimibe.
In one embodiment of the invention, the compounds of the formula I are administered in combination with an antioxidant, such as, for example, OPC-14117.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein lipase inhibitor, such as, for example, NO-1886.
In one embodiment of the invention, the compounds of the formula I are administered in combination with an ATP citrate lyase inhibitor, such as, for example, SB-204990.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a squalene synthetase inhibitor, such as, for example, BMS-188494.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein(a) antagonist, such as, for example, CI-1027 or nicotinic acid.
10 In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipase inhibitor, such as, for example, Orlistat.
In one embodiment of the invention, the compounds of the formula I are administered in combination with insulin.
In one embodiment, the compounds of the formula I are administered in combination with a sulfonylurea, such as, for example, tolbutamide, glibenclamide, glipizide or gliclazide.
In one embodiment, the compounds of the formula I are administered in combination with a biguanide, such as, for example, metformin.
In another embodiment, the compounds of the formula I are administered in combination with a meglitinide, such as, for example, repaglinide.
In one embodiment, the compounds of the formula I are administered in combination with a thiazolidinedione, such as, for example, troglitazone, ciglitazone, pioglitazone, rosiglitazone, or the compounds disclosed by Dr. Reddy's Research Foundation in WO 97/41097, in particular 5-[(4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinyl-methoxy]phenyl]methyl]-2,4-thiazolidinedione.
In one embodiment, the compounds of the formula I are administered in combination with an a-glucosidase inhibitor, such as, for example, miglitol or acarbose.
In one embodiment, the compounds of the formula I are administered in combination with an active compound which acts on the ATP-dependent potassium channel of beta cells, such as, for example, tolbutamide, glibenclamide, glipizide, gliazide or repaglinide.
In one embodiment, the compounds of the formula I are administered in combination with more than one of the abovementioned compounds, for example in combination ~ with a sulfonylurea and metformin, a sulfonylurea and acarbose, repaglinide and metformin, insulin and a sulfonylurea, insulin and metformin, insulin and troglitazon, insulin and lovastatin, etc.
In a further embodiment, the compounds of the formula I are administered in combination with CART agonists, NPY agonists, MC3 and MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, ~i3-agonists, MCH (melanine-concentrating hormone) antagonists, CCK
agonists, serotonin reuptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormone, growth hormone-releasing compounds, TRH agonists, decoupling protein 2 or 3 modulators, leptin agonists, DA agonists (bromocriptine, doprexin), lipase/amylase inhibitors, PPAR modulators, RXR modulators or TR-~ agonists.
In one embodiment of the invention, the further active compound is leptin.
In one embodiment, the further active compound is dexamphetamine or amphetamine.
In one embodiment, the further active compound is fenfluramine or dexfenfluramine.
In another embodiment, the further active compound is sibutrarnine.
In one embodiment, the further active compound is Orlistat.
In one embodiment, the further active compound is mazindol or phentermine.
In one embodiment, the compounds of the formula I are administered in combination with fiber, preferably insoluble fiber, such as, for example, Caromax~. The combination with Caromax~ can be given in one preparation or by separate administration of compounds of the formula I and Caromax~. Here, Caromax~ can also be administered in the form of food, such as, for example, in bakery goods or muesli bars. Compared to the individual active compounds, the combination of compounds of the formula I with Caromax~ is, in addition to an enhanced action, in particular with respect to the lowering of LDL cholesterol, also characterized by its improved tolerability.
It goes without saying that each suitable combination of the compounds according to the invention with one or more of the compounds mentioned above and optionally one or more further pharmacologically active substances is included in the scope of the present invention.
The invention furthermore provides both stereoisomer mixtures of the formula I
and the pure stereoisomers of the formula I, and diastereomer mixtures of the formula I
and the pure diastereomers. The mixtures are separated by chromatographic means.
Preference is given to both racemic and enantiomerically pure compounds of the formula I of the following structure:
OH
R6~
. _' R2 N
Amino protective groups that are preferably used are the benzyloxycarbonyl (Z) radical, which can be removed by catalytic hydrogenation, the 2-(3,5-dimethyloxyphenyl)propyl(2)oxycarbonyl(Ddz) or trityl (Trt) radical, which can be removed by weak acids, the t-butylcarbamate (BOC) radical, which can be removed by 3M hydrochloric acid, and the 9-fluorenylmethyloxycarbonyl (Fmoc) radical, which can be removed using secondary amines.
The invention furthermore relates to a process for preparing diphenylazetidinone derivatives of formula I.
---~ R2 - ,CHZ)x-Y- R11 K5 ~ (CHZ)x ~Y
R4 ' ~ I
II III R4 wJo-2 (CHZ)Z~W,_Y,~(CHZ)Y
~''C 0 - 2 (LAG) Y can be S, O, (C=O), (C=S), CH=CH, C=C, N((C~-C6)-alkyl), N(phenyl), N((C~-C6)-alkyl-phenyl), N(CO-(CHZ)1_~o-COOH) or NH;
R11 can be H or, if Y = (C=O) or (C=S), OH;
W, Y' and W' can, independently of one another and of Y, be -S(O)S-, where n =
2, -O-, -(C=O)-, -(C=S)-, -CH=CH-, -C=C-, -N((C~-C6)-alkyl)-, -N(phenyl), -N((C~-C6)-alkyl-phenyl)-, -N(CO-(CH2)~_~o-COOH)- or -NH- or a bond;
x, y and z independently of one another can be 0 to 10.
In compound II, -(CH2)x-Y-R11 can alternatively also be attached to one of the other two phenyl rings.
The process for preparing compounds of the formula I comprises reacting, for example, an amine or a hydroxy compound of the formula II with an alkylating or acylating agent which, preferably in the omega position, carries a further functionality- if appropriate in protected form. This functionality is (after deprotection) used for attaching (LAG), for example with the formation of ether, amine or amide bonds.
The examples below serve to illustrate the invention in more detail, without limiting the invention to the products and embodiments described in the examples.
Example I
4-{4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-yl]benzylamino~butane-1-sulfonic acid (6):
a) 3-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-pentanoyl]-4-phenyl-oxazolidin-2-one (1 ):
v °
N~O
F
27 g of 3-[5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyloxazolidin-2-one, 13.6 g of tert-butyldimethylsilyl chloride and 10.2 g of imidazole are dissolved in 36 ml of dimethylformamide and stirred at 60°C for 90 min. After the reaction has ended, the mixture is dissolved in ethyl acetate and extracted two times with water. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. This gives 3-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-pentanoyl]-4-phenyloxazolidin-2-one (1 ) of molecular weight 471.65 (C26HaaFN04Si); MS
(ESI):
340.28 (MH+- HOSi(CH3)2C(CH3)3).
b) 4-(5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-1-(4-methoxyphenyl)-(2-oxo- 4-phenyloxazolidine-3-carbonyl)pentylamino]benzonitrile (2):
16.2 g of 3-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-pentanoyl]-4-phenyl-5 ~ oxazolidin-2-one are dissolved in 350 ml of dichloromethane. 19.8 ml of Hunig base and 10.14 g of 4-[(4-methoxyphenylimino)methyl]benzonitrile are added, and the solution is cooled to -10°C. 8.52 ml of trimethylsilyl triflate are added to the cooled solution, and the mixture is stirred at -10°C for 30 min. The solution is then cooled to -30°C, and 44 ml of titanium tetrachloride solution are added. The reaction mixture is 10 stirred at from -30 to -40°C for 2 h. The solution is then allowed to warm to room temperature and the reaction solution is washed successively with 200 ml of 2N
sulfuric acid, 300 ml of 20% strength sodium hydrogen sulfite solution and sat.
sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure, and the residue is purified on silica gel using 15 n-heptane/ethyl acetate 3/1. This gives 4-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluoro-phenyl)-1-(4-methoxyphenyl)-2-(2-oxo-4-phenyloxazolidine-3-carbonyl)pentyl-amino]benzonitrile (2) of molecular weight 707.93 (C4~H46FN305Si); MS (ESI):
590.51 (MH+- C~HsN2).
c) 4-[3-[3-(tert-butyldimethylsilanyloxy)-3-(4-fluorophenyl)propyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzonitrile (3):
13.2 g of 4-[5-(tert-butyldimethylsilanyloxy~)-5-(4-fluorophenyl)-1-(4-methoxyphenyl)-2-(2-oxo-4-phenyloxazolidine-3-carbonyl)pentylamino]benzonitrile are dissolved in 380 ml of methyl tert-butylether, 18.6 ml of N,O-bis(trimethylsilyl)acetamide and 1.86 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran are added and the mixture is stirred at room temperature for 2 h. After the reaction has ended, 10 ml of acetic acid are added, the reaction mixture is concentrated under reduced pressure and the residue is purified on silica gel using toluene/ethyl acetate 50/1.
This gives 4-[3-[3-(tert-butyldimethylsilanyloxy)-3-(4-fluorophenyl)propyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzonitrile (3) of molecular weight 544.75 (C32H37FN2O3S1); MS (ESI): 545.56 (M+H+).
d) 4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]- benzonitrile (4):
3.5 g of 4-[3-[3-(tert-butyldimethylsilanyloxy)-3-(4-fluorophenyl)propyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzonitrile are dissolved in 65 ml of tetrahydrofuran, 0.74 ml of acetic acid and 8.03 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran are added and the mixture is stirred at room temperature for 2 h. Another 4.82 ml of the tetrabutylammonium fluoride solution are then added, and the mixture is stirred at reflux temperature for another 3 h. The cooled reaction mixture is concentrated under reduced pressure and the residue is purified by silica gel chromatography using n-heptane/ethyl acetate 2/1.
This gives 4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzonitrile (4) of molecular weight 430.48 (C26HZSFN20s);
MS
(ESI): 431.24 (M+H+).
e) 1-(4-Aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)-azetidin-2-one (5):
1.22 g of 4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzonitrile are dissolved in 90 ml of ethanol, 10 ml of conc.
ammonia solution and an excess of Raney nickel are added, and the mixture is stirred at 60°C and a hydrogen pressure of 10 bar for 8 h. Overnight, the reaction mixture cools to room temperature, and the next day, the catalyst is removed, the filtrate is concentrated under reduced pressure and the residue is purified by silica gel chromatography using dichloromethane/methanol/ammonia solution 10/1 /0.1.
This gives 1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)-azetidin-2-one (5) of molecular weight 434.51 (C26H2~FN203); MS
(ESI): 418.2 (MH+- NH3).
~ f) 4-{4-(3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxo-azetidin, 1-yl]benzylamino}butane-1-sulfonic acid (6):
At room temperature, 87 mg of the above benzylamine are dissolved in 3 ml of dry acetonitrile, 40 pl of 1,4-butanesultone are added and the mixture is heated under reflux for 12 h. The cooled reaction solution is concentrated under reduced pressure and purified chromatographically (silica gel; dichloromethane/methanol 85/15 +
10%
water). This gives 4-{4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzylamino}butane-1-sulfonic acid (6) of molecular weight 570.69 (C3oH35FN206S); MS (ESI): 553.28 (MH+- H20).
Example II
2-[(4-{4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]phenoxy}butyl)methylamino]ethylsulfonic acid (8):
~O~.N~S~OH
O ~O
130 mg of 3-[3-(4-fluorophenyl)-3-hydroxypropyl]-1-[4-(4-fluorobutoxy)phenyl]-4-(4-methoxyphenyl)azetidin-2-one (7) are dissolved in 6 ml of absolute methanol.
120 mg of N-methyltaurine in 2 ml of water and 60 mg of potassium carbonate are then added. The mixture is stirred at 50°C for 24 h. The reaction mixture is concentrated using a rotary evaporator and the residue is purified by preparative chromatography.
Freeze-drying gives the product (50 mg) as an oil.
C32H39FN20~S ESIMS mlz: 614 (M+) Example III
[2-(4-{4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]phenoxy}butylamino)ethyl]phosphonic acid (9):
F H
O~N~P~OH
O OH
200 mg of 3-[3-(4-fluorophenyl)-3-hydroxypropyl]-1-[4-(4-fluorobutoxy)phenyl]-4-(4-methoxyphenyl)azetidin-2-one (7) are dissolved in 6 ml of absolute methanol.
165 mg .
of 1-aminoethylphosphate and 247 mg of potassium carbonate dissolved in 3 ml of water are then added. The mixture is stirred at 90°C for 8 h. The reaction mixture is concentrated using a rotary evaporator and the residue is purified by preparative chromatography. Freeze-drying gives the product (47 mg) as an oil.
C3,H38FN20~P ESIMS m/z: 600 (M+) Example IV
Phosphoric acid mono-{6-[4-(4-{1-(4-fluorophenyl)-3-[3-(4-fluorofluorophenyl)-hydroxypropyl]-4-oxoazetidin-2-yl}phenoxy)butylamino]hexyl}ester (10):
~H
N
O
O-P-OH
F OH
115 mg of 1-(4-fluorofluorophenyl)-3-[3-(4-fluorofluorophenyl)-3-hydroxypropyl]-4-[4-(2-fluoromethoxyethoxy)phenyl]azetidin-2-one (7) are dissolved in 6 ml of absolute methanol. 130 mg of 6-amino-1-hexyl phosphate in 1.5 ml of water and 107 mg of , potassium carbonate are then added. The mixture is stirred at 70°C
overnight. The reaction mixture is concentrated using a rotary evaporator and the residue is purified by preparative chromatography. Freeze-drying gives the product as an oil.
CsaHasFzN207P ESIMS m/z: 660 (M+) Example V
4-f4-[3-[3-(4-fluorofluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]phenoxy}butane-1-sulfonic acid (12):
V ~/~
~O~S~OH
160 mg of 3-[3-(4-fluorofluorophenyl)-3-hydroxypropyl]-1-(4-hydroxyphenyl)-4-(4-methoxyphenyl)azetidin-2-one (11 ) are dissolved in 4 ml of absolute dimethylformamide.
210 mg of powdered potassium carbonate and 42 mg of 1,4,-butanesultone are added.
The mixture is stirred at room temperature overnight. The reaction solution is concentrated under oil pump vacuum, taken up in dichloromethane and washed 1x with water. The aqueous phase is acidified with 2N hydrochloric acid and extracted 2x with dichloromethane. The combined organic phases are dried over sodium sulfate and concentrated. The residue is chromatographed on a 10 g Si02 cartridge (dichloromethane/
methanol = 5/1 ). The product (72 mg) is obtained as an oil.
C29H3ZFNO~S ESIMS m/z: 557 (M+) Example VI
4-(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-phenoxy)butane-1-sulfonic acid (13):
vs,o OH
r 250 mg of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxy-phenyl)azetidin-2-one (7) are dissolved in 6 ml of absolute dimethylformamide.
337 mg 10 of powdered potassium carbonate and 69 NI of 1,4,-butanesultone are added.
The mixture is stirred at room temperature overnight. The reaction solution is filtered and concentrated under oil pump vacuum. The residue is chromatographed on a 10 g Si02 cartridge (dichloromethane/rnethanol = 5/1 ) and crystallized from diethyl ether. The product (131 mg) is obtained as a solid.
15 C28H29F2NO6S ESIMS m/z: 546 (M+) Example VII
20 3-(4-(1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropylJ-4-oxoazetidin-2-yl}-phenoxy)propan-1-sulfonin acid (14):
O~S-OH
F
25Q mg of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxy-phenyl)azetidin-2-one (7) are dissolved in 6 ml of absolute dimethylformamide.
337 mg of powdered potassium carbonate and 59 NI of 1,3,-propanesultone are added.
The mixture is stirred at room temperature overnight. The reaction solution is filtered and concentrated under oil pump vacuum. The residue is chromatographed on a 10 g Si02 cartridge (dichloromethane/methanol = 5/1 ) and crystallized from diethyl ether. The product (250 mg) is obtained as a solid.
C2~H2~F2NO6S ESIMS m/z: 532 (M+) Example VIII
(4-{1-(4-Fluorophenyf)-3-[3-(4-ffuorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl?-benzylcarbamoyl)methanesulfonic acid (18):
p O~ S-OH
N
F O
/ F
a) 4-[5-(4-Fluorophenyl)-1-(4-fluorophenylamino)-5-hydroxy-2-(2-oxo-4-phenyloxazolidine-3-carbonyl)-pentyl]-benzonitrile (15):
Under argon, 2.5 g of 3-[5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyloxazolidin-2-one are dissolved in 30 ml of dichloromethane, 3.9 g of 4-[(4-fluorophenylimino)-methyl]-benzonitrile are added and the mixture is cooled to -10°C. 6.4 ml of diisopropylethylamine and, over a period of 30 min, 4.05 ml of trimethylsilyl chloride are added to this mixture so that the temperature does not exceed -5°C.
The mixture is stirred at this temperature for 1 additional hour and then cooled to -25°C. 0.8 ml of titanium tetrachloride are then added slowly. The dark mixture is stirred at from -25 to -30°C overnight and then decomposed using 35 ml of a 7 percent strength solution of tartaric acid and then stirred at room temperature for another hour. 15 ml of a 20 percent strength solution of sodium bicarbonate are then added, and the mixture is again stirred for 1 hour. Following phase separation, the organic phase is washed with 30 ml of water, dried over magnesium sulfate and concentrated to about 10 ml. Following the addition of 2 ml of bistrimethylsilylacetamide, the mixture is heated at reflux for 30 min and then concentrated under reduced pressure. The residue is crystallized using ethyl acetatelheptane. The product is filtered off with suction and dried under reduced pressure. This gives the product of molecular weight 653.81 (C37H37F2N3O4S1); MS (ESI+): 654.3 (M+H+), 582.2 (M+H+-Si(CH3)3).
b) {1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzonitrile (16):
2 g of 4-[5-(4-Fluorophenyl)-1-(4-fluorophenylamino)-5-hydroxy-2-(2-oxo-4-phenyl-oxazolidine-3-carbonyl)-pentyl]-benzonitrile (15) are dissolved in 20 ml of methyl-tert-butyl ether and, together with 100 mg of tetrabutylammonium fluoride trihydrate and 1.3 ml of bistrimethylsilyl acetamide, heated at 40°C for about 1 h.
The reaction is monitored by thin-layer chromatography. After the reaction has ended, 0.2 ml of glacial acetic acid is initially added and the mixture is stirred for 30 min and then concentrated. 20 ml of a mixture of isopropanol/2N sulfuric acid = 10:1 are added to the residue, and the mixture is stirred for 1 hour. Following addition of a spatula tip of solid sodium bicarbonate, the mixture is again concentrated under reduced pressure, the residue is taken up in ethyl acetate and the organic phase is washed with water and dried, and the residue is, after removal of the solvent, purified by column ~ chromatography (Si02, CH2C12/methanol = 100:1 ). This gives the product of molecular weight 418.45 (C25H2oF2N202); MS (DCI+): 419 (M+H+).
c) 4-(4-Aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-~ hydroxypropyl]-azetidin-2-one (17):
200 mg of {1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzonitrile (16) are dissolved in 20 ml of ethanol and, with 0.5 ml of conc.
ammonia, hydrogenated over Raney nickel at a hydrogen pressure of 75 bar and at 25°C for 30 hours. The catalyst is filtered off with suction, the mixture is concentrated under reduced pressure and the residue is purified by column filtration (Si02, CH2C12/methanollconc. NH3 = 100:10:1 ). This gives the product of molecular weight 422.5 (C25H22F2N202); MS (DCI+): 423 (M+H+), 405 (M+H+- H20).
d) (4-{1-(4-Fluorophenyl)-3-(3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-yl}-benzylcarbamoyl)methanesulfonic acid (18):
A solution of 120 mg of 4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluoro-phenyl)-3-hydroxypropyl]azetidin-2-one (17), 48 NI of diisopropylethylamine in 1 ml of dimethylformamide is added to a solution of 40 mg of sulfoacetic acid, 110 NI
of diisopropylcarbodiimide, 76 mg of hydroxybenzotriazole in 2 ml of dimethyl-formamide, and the mixture is stirred at room temperature for 12 h. The reaction solution is concentrated and separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1 % trifluoroacetic acid)/acetonitrile (0.1 % trifluoroacetic acid) =
80/20 ->
10/90). This gives the product of molecular weight 544.58 (C2~H26F2N206S~); MS
(ESI) 527.10 (M + H+- H20) Example IX
{4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzylcarbamoyl}methanesulfonic acid (19):
o., / \
OH
F I / ~N \
O I / N IIO
~~'~OH
O O
A solution of 60 mg of 1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxy-propyl]-4-(4-methoxyphenyl)azetidin-2-one (5) in 1 ml of dimethylformamide is added to a solution of 20 mg of sulfoacetic acid, 55 NI of diisopropylcarbodiimide, 38 mg of hydroxybenzotriazole in 1 ml of dimethylformamide, and the mixture is stirred at room temperature for 12 h. The reaction solution is concentrated and separated by HPLC
(Knauer Eurospher-100-10-C18, water (0.1 % trifluoroacetic acid)/acetonitrile (0.1 trifluoroacetic acid) = 80/20 -> 10/90). This gives the product of molecular weight 556.61 (C28H29F~N20~S~); MS (ESI) 539.05 (M + H+- H20) Example X
N-(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzyl)succinaminic acid (20):
OH
O
O
F
F
A solution of 100 mg of 4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluoro-phenyl)-3-hydroxypropyl]azetidin-2-one (17), 33 NI of triethylamine in 2 ml of 5 dimethylformamide is added to a solution of 279 mg of succinic acid, 92 pl of diisopropylcarbodiimide, 80 mg of hydroxybenzotriazole in 2 ml of dimethyl-formamide, and the mixture is stirred at room temperature for 12 h. The reaction solution is concentrated and separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1 % trifluoroacetic acid)/acetonitrile (0.1 % trifluoroacetic acid) =
80/20 ->
10 10/90). This gives the product of molecular weight 522.55 (C2~H26F2N206S~);
MS
(ESI) 545.19 (M + Na+) 15 Example XI
F
{2-[2-({4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzylcarbamoyl}methoxy)ethoxy]ethoxy}acetic acid (21 ):
OH
v ~N ~
O// I / N ~0,~ OH
~O O
IOI ' IO
A solution of 64 mg of 1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxy-propyl]-4-(4-methoxyphenyl)azetidin-2-one (5), 21 NI of triethylamine in 1 ml of dimethylformamide are added to a solution of 327 mg of 3,6,9-trioxaundecanedioic acid, 57 NI of diisopropylcarbodiimide, 50 mg of hydroxybenzotriazole in 2 ml of dimethylformamide, and the mixture is stirred at room temperature for 12 h.
The reaction solution is concentrated and separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1 % trifluoroacetic acid)/acetonitrile (0.1 % trifluoroacetic acid) _ 80/20 -> 10/90). This gives the product of molecular weight 638.70 (C34H3gF~N2Og);
MS (ESI) 639.27 (M + H+) Example XII
4-((3-Carboxypropionyl)-{4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxy-phenyl)-4-oxoazetidin-1-yl]benzyl}amino)-4-oxobutyric acid (22):
H
'O
O
F H
O I~N
O
O
A solution of 70 mg of 1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxy-propyl]-4-(4-methoxyphenyl)azetidin-2-one (5), 23 NI of triethylamine in 1 ml of dimethylformamide is added to a solution of 190 mg of succinic acid, 63 pl of diisopropylcarbodiimide, 55 mg of hydroxybenzotriazole in 2 ml of dimethyl-formamide, and the mixture is stirred at room temperature for 12 h. The reaction solution is concentrated and separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1 % trifluoroacetic acid)/acetonitrile (0.1 % trifluoroacetic acid) =
80/20 ->
10/90). This gives the product of molecular weight 634.4 (C34H35F1N2Og); MS
(ESI-neg.) 633.22 (M - H+) Example XIII
11-{4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzylcarbamoyl}undecanoic acid (23):
F H
N
OH
O
A solution of 70 mg of 1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxy-propyl]-4-(4-methoxyphenyl)azetidin-2-one (5), 23 pl of triethylamine in 1 ml of dimethylformamide is added to a solution of 371 mg of dodecanedioic acid, 63 NI of diisopropylcarbodiimide, 55 mg of hydroxybenzotriazofe in 2 ml of dimethylformamide, and the mixture is stirred at room temperature for 12 h.
The reaction solution is concentrated and separated by HPLC(Knauer Eurospher-100-C18, water (0.1 % trifluoroacetic acid)/acetonitrile (0.1 % trifluoroacetic acid) = 80/20 -> 10/90). This gives the product of molecular weight 646.81 (C38H4~F~N206);
MS
(ESI) 647.35 (M + H+) Table 1: Compounds of the formula I
EX. R1, R2 R3, R5, Mo~ecularMolecular weight weight of the (found) free base or acid (calculated) XIV . ~ para-F, para-F,531.58 532.4 H
,~g~ , H
OH
pare H (MH+) XV " Para-F, para-F,502.54 503.3 H
Para r H (MH+) v,ll , H
~
S~oH
o XVI para-F, H I Para-F,514.58 515.4 N
) H (MH+) , H
para , S~oH
o XVII para-O-CH3, ~p para-F, H s~ 599.68 599.21 "
w~ H (M+) ~N
~
, H
o oH
XVili para-O-CH3, H para-F,739.95 740.42 H
~N~S~ H (MH+) .H
~
~
p OH
XIX para-O-CH3, p para-F,599.60 600.34 H ~
N~
' H (MH+) OH
.H
para ~
"
off XX para-O-CH3, ~ para-F,534.59 534.4 H ~
~~
pare ~N~ H (MH') , H
"
doff _ XXI ~ . H para-F, para-F,578.66 561.25 _ p.,. ~p H
~
OH H (MH+-H20) XXII ~",~~ ,H para-F, para-F,634.77 617.31 OH H
H (MH+-HZO) XXIII para-F, H ~ para-F,585.65 567.70 H
para H (MH+-~H
H~
OH
H20) XXIV para-O-CH3, pare -F, 557.64 55 H ~ Pa ..19 .
H
~S
o H n ff ( ) XXV ~H~ Para-F, para-F,660.70 660.28 ~P H
.~
pua ~
O
~
O
H (M') XXVI para-0-CH3, p~,;,~ para-F,600.62 600.24 H ~N~
~~P
.H
O
~
p H (M') XXVIi para-O-CH3, ~ para-F,614.73 597.32 H
~
\
~5,~
,"
H (M_ H20)~' ~~I~p wn ~N N~II para-F, para-F,-559.64-__-560.4 ," H
H (MH') XXIX N para-F, para-F,545.61 546.3 Iq H
, ," H (MH+) pace ~"~
S.
" o off XXX para-F, para-F,727.91 710.23 H
" H (MH'_ ~H~s~ ,H
0 ~OH
N "~
H pact' H20) XXXI para-O-CH3, para-F,753.93 752.32 H
~ H (M-H+);
."
~
O
H measured H~
~", in negative mode XXXII ~N para-F, para-F,573.62 572.09 H
N .H
~
~
5 H (M-H+);
off measured in negative mode XXXIII~ para-F, para-F,587.67 586.18 H
part ~H HN
~ H H (M-H+);
o H measured in negative mode Using the method described below, the activity of the compounds of the formula I
according to the invention was examined:
Effect on cholesterol absorption + 3H-taurocholic acid excretion using fecal excrement of mice. rats or hamsters 5 NMRI mice, Wistar rats, or Golden Syrian hamsters (in groups of n=4-6) are kept in metabolic cages, where they are fed with a standard diet (Altromin, Lage (Lippe)).
The afternoon prior to the administration of the radioactive tracers ('4C-cholesterol), the feed is removed and the animals are adapted to grates.
10 Additionally, the animals are labeled s.c. with 3H-TCA (taurocholic acid) (for example 1 pCi/mouse up to 5 NCi/rat) 24 hours prior to the peroral administration of the test meal ("C-cholesterol in Intralipid~ 20, Pharmacia-Upjohn).
Cholesterol absorption test: 0.25 mUmouse Intralipid ~ 20 (Pharmacia-Upjohn) 15 ((spiked with 0.25 pCi of '4C-cholesterol in 0.1 mg of cholesterol) is administered perorally by gavage.
Test substances are prepared separately in 0.5% methylcellulose (Sigma)/5%
Solutol (BASF, Ludwigshafen) or a suitable vehicle.
20 The administration volume of the test substance is 0.5 ml/mouse. The test substance is administered immediately prior to the test meal (Intralipid labeled with'4C-cholesterol) (cholesterol absorption test).
The feces are collected over a period of 24 h: fecal elimination of '4C-cholesterol and 25 3H-taurocholic acid (TCA) is determined after 24 hours.
The livers are removed and homogenized, and aliquots are incinerated in an oximate (Model 307, Packard) to determine the amount of '4C-cholesterol which had been taken up/absorbed.
Evaluation:
Feces samples:
The total weight is determined, the sample is made up with water to a defined volume and then homogenized, and an aliquot is evaporated to dryness and incinerated in an oximate (Model 307 from Packard for the incineration of radioactively labeled samples): the amount of radioactive 3H-H20 and '4C-C02 is ~ extrapolated to the amount of 3H-taurocholic acid and '4C-cholesterol, respectively, that is excreted (dual isotope technique). The ED2oo values as dose from a dose-effect curve are interpolated as those doses at which the excretion of TCA or cholesterol is doubled, based on a control group treated at the same time.
Liver samples:
The amount of '4C-cholesterol taken up by the liver is based on the administered dose. The EDSO values are interpolated from a dose-effect curve as the dose at which the uptake of '4C-cholesterol by the liver is halved (50%), based on a control group.
The EDSO values below demonstrate the activity of the compounds of the formula I
according to the invention Example No. EDSO (liver) [mg/mouse]
I 1.0 II > 0.1 IV 0.3 VIII 0.3 IX < 1.0 X < 1.0 XIII < 0.1 XVI I I 0.005 XXI 0.1 XXII 0.1 XXV 0.3 XXVIII 0.3 As can be seen from the table, the compounds of the formula I have very good cholesterol-lowering action.
Bioabsorption:
The bioabsorption of the compounds of the formula I was examined using the Caco cell model (A.R. Hilgers et al., Caco-2 cell monolayers as a model for drug transport across the intestinal mucosa, Pharm. Res. 1990, 7, 902).
From the measured data, it can be seen that the bioabsorption of the compounds of the formula I according to the invention is considerably lower than that of the compounds described in the prior art (reference structure):
OH
OH
,,, -~.
F N
O
F
Reference structure:
Ezetimibe
Claims (14)
1. A compound of the formula I, in which R1, R2, R3, R4, R5, R6 independently of one another are (C0-C30)-alkylene-(LAG)n, where n may be 1 - 5 and where one or more carbon atoms of the alkylene radical may be replaced by -S(O)n-, where n = 0 -2, -O-, -(C=O)-, -(C=S)-, -CH=CH-, -C=C-, -N((C1-C6)-alkyl)-, -N(phenyl), -N((C1-C6)-alkyl-phenyl)- , -N(CO-(CH2)1-10-COOH)- or -NH-;
H, F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C1-C6)-alkyl, CONH2, CONH(C1-C6)-alkyl, CON[(C1-C6)-alkyl]2, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, O-(C1-C6)-alkyl, where one, more or all hydrogens in the alkyl radicals may be replaced by fluorine;
C(=NH)(NH2), PO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2 , S-(C1-C6)-alkyl, S-(CH2)n-phenyl, SO-(C1-C6)-alkyl, SO-(CH2)n-phenyl, SO2-(C1-C6)-alkyl, SO2-(CH2)n-phenyl, where n = 0 - 6 and the phenyl radical may be substituted up to two times by F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2;
NH2, NH-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NH(C1-C7)-acyl, phenyl, O-(CH2)n-phenyl, where n may be 0 - 6, where the phenyl ring may be mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2-CH3, COOH, COO-(C1-C6)-alkyl, CONH2;
(LAG)n is -(CH2)1-10-SO3H, -(CH2)0-10-P(O)(OH)2, -(CH2)0-10-O-P(O)(OH)2, -(CH2)0-10-COOH and n may be 1 - 5;
where in each case at least one of the radicals R1 to R6 must have the meaning (C0-C30)-alkylene-(LAG)n, where n = 1 - 5 and where one or more carbon atoms of the alkylene radical may be replaced by -S(O)n-, where n = 0 - 2, -O-, -(C=O)-, -(C=S)-, -CH=CH-, -C.ident.C-, -N((C1-C6)-alkyl)-, -N(phenyl)-, -N((C1-C6)-alkyl-phenyl)-, -N(CO-(CH2)1-10-COOH)- or -NH-, and its pharmaceutically acceptable salts;
except for the compound 2-{[4-(4-{1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}phenoxy)butyl]methylamino}ethanesulfonic acid and those compounds in which the radicals R1 - R6 have the meaning -O-(CH2)1-10-COOH, (C1-C6)-alkylene-COOH or -COOH.
H, F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C1-C6)-alkyl, CONH2, CONH(C1-C6)-alkyl, CON[(C1-C6)-alkyl]2, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, O-(C1-C6)-alkyl, where one, more or all hydrogens in the alkyl radicals may be replaced by fluorine;
C(=NH)(NH2), PO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2 , S-(C1-C6)-alkyl, S-(CH2)n-phenyl, SO-(C1-C6)-alkyl, SO-(CH2)n-phenyl, SO2-(C1-C6)-alkyl, SO2-(CH2)n-phenyl, where n = 0 - 6 and the phenyl radical may be substituted up to two times by F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2;
NH2, NH-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NH(C1-C7)-acyl, phenyl, O-(CH2)n-phenyl, where n may be 0 - 6, where the phenyl ring may be mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2-CH3, COOH, COO-(C1-C6)-alkyl, CONH2;
(LAG)n is -(CH2)1-10-SO3H, -(CH2)0-10-P(O)(OH)2, -(CH2)0-10-O-P(O)(OH)2, -(CH2)0-10-COOH and n may be 1 - 5;
where in each case at least one of the radicals R1 to R6 must have the meaning (C0-C30)-alkylene-(LAG)n, where n = 1 - 5 and where one or more carbon atoms of the alkylene radical may be replaced by -S(O)n-, where n = 0 - 2, -O-, -(C=O)-, -(C=S)-, -CH=CH-, -C.ident.C-, -N((C1-C6)-alkyl)-, -N(phenyl)-, -N((C1-C6)-alkyl-phenyl)-, -N(CO-(CH2)1-10-COOH)- or -NH-, and its pharmaceutically acceptable salts;
except for the compound 2-{[4-(4-{1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}phenoxy)butyl]methylamino}ethanesulfonic acid and those compounds in which the radicals R1 - R6 have the meaning -O-(CH2)1-10-COOH, (C1-C6)-alkylene-COOH or -COOH.
2. A compound of the formula I as claimed in claim 1, wherein R2, R4, R5, R6 independently of one another are H, F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C1-C6)-alkyl, CONH2, CONH(C1-C6)-alkyl, CON[(C1-C6)-alkyl]2, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, O-(C1-C6)-alkyl, where one, more or all hydrogens in the alkyl radicals may be replaced by fluorine;
C(=NH)(NH2), PO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2, S-(C1-C6)-alkyl, S-(CH2)n-phenyl, SO-(C1-C6)-alkyl, SO-(CH2)n-phenyl, SO2-(C1-C6)-alkyl, SO2-(CH2)n-phenyl, where n may be 0 - 6 and the phenyl radical may be substituted up to two times by F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2;
NH2, NH-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NH(C1-C7)-acyl, phenyl, O-(CH2)n-phenyl, where n may be 0 - 6, where the phenyl ring may be mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2-CH3, COOH, COO-(C1-C6)-alkyl, CONH2;
R1, R3 independently of one another are (C0-C30)-alkylene-(LAG) and where one or more carbon atoms of the alkylene radical may be replaced by -O-, -(C=O)-, -N(CH3)- or -NH-, H, F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C1-C6)-alkyl, CONH2, CONH(C1-C6)-alkyl, CON[(C1-C6)-alkyl]2, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, O-(C1-C6)-alkyl, where one, more or all hydrogens in the alkyl radicals may be replaced by fluorine;
C(=NH)(NH2), PO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2 , S-(C1-C6)-alkyl, S-(CH2)n-phenyl, SO-(C1-C6)-alkyl, SO-(CH2)n-phenyl, SO2-(C1-C6)-alkyl, SO2-(CH2)n-phenyl, where n may be 0 - 6 and the phenyl radical may be substituted up to two times by F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2;
NH2, NH-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NH(C1-C7)-acyl, phenyl, O-(CH2)n-phenyl, where n may be 0 - 6, where the phenyl ring may be mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2-CH3, COOH, COO-(C1-C6)-alkyl, CONH2;
(LAG) is -(CH2)1-10-SO3H, -(CH2)0-10-P(O)(OH)2, -(CH2)0-10-O-P(O)(OH)2, -(CH2)0-10-COOH;
where in each case at least one of the radicals R1 or R3 must have the meaning (C0-C30)-alkylene-(LAG) and where one or more carbon atoms of the alkylene radical may be replaced by -O-, -(C=O)-, -N(CH3)- or -NH-, and its pharmaceutically acceptable salts;
except, for the compound 2-{[4-(4-{1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}phenoxy)butyl]methylamino}ethanesulfonic acid and those compounds in which the radicals R1 - R6 have the meaning -O-(CH2)1-10-COOH, (C1-C6)-alkylene-COOH or -COOH.
C(=NH)(NH2), PO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2, S-(C1-C6)-alkyl, S-(CH2)n-phenyl, SO-(C1-C6)-alkyl, SO-(CH2)n-phenyl, SO2-(C1-C6)-alkyl, SO2-(CH2)n-phenyl, where n may be 0 - 6 and the phenyl radical may be substituted up to two times by F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2;
NH2, NH-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NH(C1-C7)-acyl, phenyl, O-(CH2)n-phenyl, where n may be 0 - 6, where the phenyl ring may be mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2-CH3, COOH, COO-(C1-C6)-alkyl, CONH2;
R1, R3 independently of one another are (C0-C30)-alkylene-(LAG) and where one or more carbon atoms of the alkylene radical may be replaced by -O-, -(C=O)-, -N(CH3)- or -NH-, H, F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C1-C6)-alkyl, CONH2, CONH(C1-C6)-alkyl, CON[(C1-C6)-alkyl]2, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, O-(C1-C6)-alkyl, where one, more or all hydrogens in the alkyl radicals may be replaced by fluorine;
C(=NH)(NH2), PO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2 , S-(C1-C6)-alkyl, S-(CH2)n-phenyl, SO-(C1-C6)-alkyl, SO-(CH2)n-phenyl, SO2-(C1-C6)-alkyl, SO2-(CH2)n-phenyl, where n may be 0 - 6 and the phenyl radical may be substituted up to two times by F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2;
NH2, NH-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NH(C1-C7)-acyl, phenyl, O-(CH2)n-phenyl, where n may be 0 - 6, where the phenyl ring may be mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2-CH3, COOH, COO-(C1-C6)-alkyl, CONH2;
(LAG) is -(CH2)1-10-SO3H, -(CH2)0-10-P(O)(OH)2, -(CH2)0-10-O-P(O)(OH)2, -(CH2)0-10-COOH;
where in each case at least one of the radicals R1 or R3 must have the meaning (C0-C30)-alkylene-(LAG) and where one or more carbon atoms of the alkylene radical may be replaced by -O-, -(C=O)-, -N(CH3)- or -NH-, and its pharmaceutically acceptable salts;
except, for the compound 2-{[4-(4-{1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}phenoxy)butyl]methylamino}ethanesulfonic acid and those compounds in which the radicals R1 - R6 have the meaning -O-(CH2)1-10-COOH, (C1-C6)-alkylene-COOH or -COOH.
3. A compound of the formula I as claimed in claim 1 or 2, wherein R2, R4, R5, R6 independently of one another are H, F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C1-C6)-alkyl, CONH2, CONH(C1-C6)-alkyl, CON[(C1-C6)-alkyl]2, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, O-(C1-C6)-alkyl, where one, more or all hydrogens in the alkyl radicals may be replaced by fluorine;
C(=NH)(NH2), PO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2, S-(C1-C6)-alkyl, S-(CH2)n-phenyl, SO-(C1-C6)-alkyl, SO-(CH2)n-phenyl, SO2-(C1-C6)-alkyl, SO2-(CH2)n-phenyl, where n may be 0 - 6 and the phenyl radical may be substituted up to two times by F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2;
NH2, NH-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NH(C1-C7)-acyl, phenyl, O-(CH2)n-phenyl, where n may be 0 - 6, where the phenyl ring may be mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2-CH3, COOH, COO-(C1-C6)-alkyl, CONH2;
R1, R3 independently of one another are -(CH2)0-1-Y-W-(C0-C25)-alkylene-Y'-W'-(LAG), where one or more carbon atoms of the alkylene radical may be replaced by -O-;
H, F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C1-C6)-alkyl, CONH2, CONH(C1-C6)-alkyl, CON[(C1-C6)-alkyl]2, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, O-(C1-C6)-alkyl, where one, more or all hydrogens in the alkyl radicals may be replaced by fluorine;
C(=NH)(NH2), PO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2, S-(C1-C6)-alkyl, S-(CH2)n-phenyl, SO-(C1-C6)-alkyl, SO-(CH2)n-phenyl, SO2-(C1-C6)-alkyl, SO2-(CH2)n-phenyl, where n may be 0 - 6 and the phenyl radical may be substituted up to two times by F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2;
NH2, NH-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NH(C1-C7)-acyl, phenyl, O-(CH2)n-phenyl, where n may be 0 - 6, the phenyl ring may be mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2-CH3, COOH, COO-(C1-C6)-alkyl, CONH2;
Y, W, Y' W' independently of one another are NH, NCH3, C=O, O, a bond or S(O)n, where n = 0 - 2;
or Y-W or Y'-W' in each case together are a bond.
(LAG) is -(CH2)1-10-SO3H, -(CH2)0-10-P(O)(OH)2, (CH2)0-10-O-P(O)(OH)2, -(CH2)0-10-COOH;
where in each case at least one of the radicals R1 or R3 must have the meaning -(CH2)0-1-Y-W-(C0-C25)-alkylene-Y'-W'-(LAG), where one or more carbon atoms of the alkylene radical may be replaced by -O-;
and its pharmaceutically acceptable salts;
except for the compound 2-{[4-(4-{1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl)phenoxy)butyl]methylamino}ethanesulfonic acid and those compounds in which the radicals R1 - R6 have the meaning -O-(CH2)1-10-COOH, (C1-C6)-alkylene-COOH or -COOH.
C(=NH)(NH2), PO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2, S-(C1-C6)-alkyl, S-(CH2)n-phenyl, SO-(C1-C6)-alkyl, SO-(CH2)n-phenyl, SO2-(C1-C6)-alkyl, SO2-(CH2)n-phenyl, where n may be 0 - 6 and the phenyl radical may be substituted up to two times by F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2;
NH2, NH-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NH(C1-C7)-acyl, phenyl, O-(CH2)n-phenyl, where n may be 0 - 6, where the phenyl ring may be mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2-CH3, COOH, COO-(C1-C6)-alkyl, CONH2;
R1, R3 independently of one another are -(CH2)0-1-Y-W-(C0-C25)-alkylene-Y'-W'-(LAG), where one or more carbon atoms of the alkylene radical may be replaced by -O-;
H, F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C1-C6)-alkyl, CONH2, CONH(C1-C6)-alkyl, CON[(C1-C6)-alkyl]2, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, O-(C1-C6)-alkyl, where one, more or all hydrogens in the alkyl radicals may be replaced by fluorine;
C(=NH)(NH2), PO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2, S-(C1-C6)-alkyl, S-(CH2)n-phenyl, SO-(C1-C6)-alkyl, SO-(CH2)n-phenyl, SO2-(C1-C6)-alkyl, SO2-(CH2)n-phenyl, where n may be 0 - 6 and the phenyl radical may be substituted up to two times by F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2;
NH2, NH-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NH(C1-C7)-acyl, phenyl, O-(CH2)n-phenyl, where n may be 0 - 6, the phenyl ring may be mono- to trisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2-CH3, COOH, COO-(C1-C6)-alkyl, CONH2;
Y, W, Y' W' independently of one another are NH, NCH3, C=O, O, a bond or S(O)n, where n = 0 - 2;
or Y-W or Y'-W' in each case together are a bond.
(LAG) is -(CH2)1-10-SO3H, -(CH2)0-10-P(O)(OH)2, (CH2)0-10-O-P(O)(OH)2, -(CH2)0-10-COOH;
where in each case at least one of the radicals R1 or R3 must have the meaning -(CH2)0-1-Y-W-(C0-C25)-alkylene-Y'-W'-(LAG), where one or more carbon atoms of the alkylene radical may be replaced by -O-;
and its pharmaceutically acceptable salts;
except for the compound 2-{[4-(4-{1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl)phenoxy)butyl]methylamino}ethanesulfonic acid and those compounds in which the radicals R1 - R6 have the meaning -O-(CH2)1-10-COOH, (C1-C6)-alkylene-COOH or -COOH.
4. A compound of the formula I as claimed in one or more of claims 1 to 3, wherein (LAG) is a carboxylic acid radical or a sulfonic acid radical, and its pharmaceutically acceptable salts.
5. A medicament comprising one or more compounds as claimed in one or more of claims 1 to 4.
6. A medicament comprising one or more compounds as claimed in one or more of claims 1 to 4 and at least one further active compound.
7. The medicament as claimed in claim 6, comprising, as further active compound, one or more compounds which normalize lipid metabolism.
8. The medicament as claimed in claim 6 or 7, which comprises, as further active compound, one or more antidiabetics, hypoglycemically active compounds, HMGCoA reductase inhibitors, cholesterol absorption inhibitors, PPAR gamma agonists, PPAR alpha agonists, PPAR alpha/gamma agonists, fibrates, MTP inhibitors, bile acid absorption inhibitors, CETP inhibitors, polymeric bile acid adsorbers, LDL receptor inducers, ACAT
inhibitors, antioxidants, lipoprotein lipase inhibitors, ATP citrate lyase inhibitors, squalene synthetase inhibitors, lipoprotein(a) antagonists, lipase inhibitors, insulins, sulfonylureas, biguanides, meglitinides, thiazolidinediones, .alpha.-glucosidase inhibitors, active compounds which act on the ATP-dependent potassium channel of the beta cells, CART agonists, NPY agonists, MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, .beta.3 agonists, MSH (melanocyte-stimulating hormone) agonists, CCK agonists, serotonin-reuptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormones, growth hormone-releasing compounds, TRH agonists, decoupling protein 2 or 3 modulators, leptin agonists, DA
agonists (bromocriptine, doprexin), lipase/amylase inhibitors, PPAR
modulators, RXR
modulators or TR-.beta.-agonists or amphetamines.
inhibitors, antioxidants, lipoprotein lipase inhibitors, ATP citrate lyase inhibitors, squalene synthetase inhibitors, lipoprotein(a) antagonists, lipase inhibitors, insulins, sulfonylureas, biguanides, meglitinides, thiazolidinediones, .alpha.-glucosidase inhibitors, active compounds which act on the ATP-dependent potassium channel of the beta cells, CART agonists, NPY agonists, MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, .beta.3 agonists, MSH (melanocyte-stimulating hormone) agonists, CCK agonists, serotonin-reuptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormones, growth hormone-releasing compounds, TRH agonists, decoupling protein 2 or 3 modulators, leptin agonists, DA
agonists (bromocriptine, doprexin), lipase/amylase inhibitors, PPAR
modulators, RXR
modulators or TR-.beta.-agonists or amphetamines.
9. A compound as claimed in one or more of claims 1 to 4 for use as a medicament for the treatment of impaired lipid metabolism.
10. A process for preparing a medicament comprising one or more of the compounds as claimed in one or more of claims 1 to 4, which comprises mixing the active compound with a pharmaceutically acceptable carrier and bringing this mixture into a form suitable for administration.
11. The use of the compounds as claimed in one or more of claims 1 to 4 for preparing a medicament for treating hyperlipidemia.
12. The use of the compounds as claimed in one or more of claims 1 to 4 for preparing a medicament for lowering the serum cholesterol concentration.
13. The use of the compounds as claimed in one or more of claims 1 to 4 for preparing a medicament for treating arteriosclerotic manifestations.
14. The use of the compounds as claimed in one or more of claims 1 to 4 for preparing a medicament for treating insulin resistance.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10227508A DE10227508A1 (en) | 2002-06-19 | 2002-06-19 | Acid group-substituted diphenylazetidinones, processes for their preparation, pharmaceutical compositions containing them and their use |
DE10227508.4 | 2002-06-19 | ||
PCT/EP2003/005816 WO2004000805A1 (en) | 2002-06-19 | 2003-06-04 | Diphenyl azetidinones substituted by acidic groups, method for their production, medicaments containing said compounds and use thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2490112A1 true CA2490112A1 (en) | 2003-12-31 |
Family
ID=29719283
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002490112A Abandoned CA2490112A1 (en) | 2002-06-19 | 2003-06-04 | Diphenyl azetidinones substituted by acidic groups, method for their production, medicaments containing said compounds and use thereof |
Country Status (29)
Country | Link |
---|---|
EP (1) | EP1517891B1 (en) |
JP (1) | JP2005533073A (en) |
KR (1) | KR20050008835A (en) |
CN (1) | CN100467448C (en) |
AR (1) | AR039690A1 (en) |
AU (1) | AU2003238210B2 (en) |
BR (1) | BR0311896A (en) |
CA (1) | CA2490112A1 (en) |
DE (1) | DE10227508A1 (en) |
EC (1) | ECSP045497A (en) |
HK (1) | HK1079511A1 (en) |
HN (1) | HN2003000185A (en) |
HR (1) | HRPK20041201B3 (en) |
IL (1) | IL165789A0 (en) |
MA (1) | MA27206A1 (en) |
MX (1) | MXPA04012093A (en) |
NO (1) | NO20050134L (en) |
OA (1) | OA12869A (en) |
PA (1) | PA8576101A1 (en) |
PE (1) | PE20040564A1 (en) |
PL (1) | PL372700A1 (en) |
RS (1) | RS108404A (en) |
RU (1) | RU2287522C2 (en) |
SV (1) | SV2004001548A (en) |
TN (1) | TNSN04250A1 (en) |
TW (1) | TW200413311A (en) |
UA (1) | UA78577C2 (en) |
UY (1) | UY27853A1 (en) |
WO (1) | WO2004000805A1 (en) |
Families Citing this family (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB0215579D0 (en) | 2002-07-05 | 2002-08-14 | Astrazeneca Ab | Chemical compounds |
BRPI0418004A (en) | 2003-12-23 | 2007-04-17 | Astrazeneca Ab | compound or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, methods for treating or preventing hyperlipidemic conditions, atherosclerosis, alzheimer's disease, and cholesterol-associated tumors, pharmaceutical formulation, combination, and process for preparing a compound or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof |
AR054998A1 (en) | 2004-12-03 | 2007-08-01 | Schering Corp | PIPERAZINAS REPLACED AS AN ANCHANGIST OF CB1, PHARMACEUTICAL COMPOSITION AND USE OF THE COMPOUND FOR THE MANUFACTURE OF MEDICINES |
MX2007012253A (en) * | 2005-04-04 | 2007-12-07 | Univ Pontificia Catolica Chile | The use of ezetimibe in the prevention and treatment of cholesterol gallstones. |
US7635705B2 (en) | 2005-06-20 | 2009-12-22 | Schering Corporation | Heteroatom-linked substituted piperidines and derivatives thereof useful as histamine H3 antagonists |
SA06270191B1 (en) | 2005-06-22 | 2010-03-29 | استرازينيكا ايه بي | Novel 2-Azetidinone Derivatives as Cholesterol Absorption Inhibitors for the Treatment of Hyperlipidaemic Conditions |
AR060623A1 (en) | 2006-04-27 | 2008-07-02 | Astrazeneca Ab | COMPOUNDS DERIVED FROM 2-AZETIDINONE AND A PREPARATION METHOD |
JP5203360B2 (en) * | 2006-06-23 | 2013-06-05 | アボット・ラボラトリーズ | Cyclopropylamine derivatives as histamine H3 receptor modulators |
RU2009108280A (en) | 2006-08-08 | 2010-09-20 | Санофи-Авентис (Fr) | Arylamino-arylalkyl-substituted imidazolidine-2,4-dione, methods for their preparation containing these compounds and their use |
DE102007002260A1 (en) | 2007-01-16 | 2008-07-31 | Sanofi-Aventis | Use of substituted pyranonic acid derivatives for the preparation of medicaments for the treatment of the metabolic syndrome |
EP2025674A1 (en) | 2007-08-15 | 2009-02-18 | sanofi-aventis | Substituted tetra hydro naphthalines, method for their manufacture and their use as drugs |
CN101200443B (en) * | 2007-10-17 | 2011-06-29 | 中国药科大学 | Nitrogen heterocyclic methyl ethyl ketone derivatives, preparation method and medicine combination containing the same |
DE102007054497B3 (en) | 2007-11-13 | 2009-07-23 | Sanofi-Aventis Deutschland Gmbh | New crystalline hydrate form of dodecanedioic acid 4-((2S,3R)-3-((S)-3-(4-fluoro-phenyl)-3-hydroxy-propyl)-2-(4-methoxy-phenyl)-4-oxo-azetidin-1-yl)-benzylamide ((2S,3R,4R,5R)-pentahydroxy-hexyl)-amide useful e.g. to treat hyperlipidemia |
EP2310372B1 (en) | 2008-07-09 | 2012-05-23 | Sanofi | Heterocyclic compounds, processes for their preparation, medicaments comprising these compounds, and the use thereof |
WO2010068601A1 (en) | 2008-12-08 | 2010-06-17 | Sanofi-Aventis | A crystalline heteroaromatic fluoroglycoside hydrate, processes for making, methods of use and pharmaceutical compositions thereof |
US9212175B2 (en) | 2009-03-06 | 2015-12-15 | Lipideon Biotechnology Ag | Pharmaceutical hypocholesterolemic compositions |
CN101993403B (en) | 2009-08-11 | 2012-07-11 | 浙江海正药业股份有限公司 | Azetidinone compound and medical applications thereof |
SG178880A1 (en) | 2009-08-26 | 2012-04-27 | Sanofi Sa | Novel crystalline heteroaromatic fluoroglycoside hydrates, pharmaceuticals comprising these compounds and their use |
US8933024B2 (en) | 2010-06-18 | 2015-01-13 | Sanofi | Azolopyridin-3-one derivatives as inhibitors of lipases and phospholipases |
EP2683700B1 (en) | 2011-03-08 | 2015-02-18 | Sanofi | Tetra-substituted oxathiazine derivatives, method for their preparation, their usage as medicament and medicament containing same and its use |
EP2683705B1 (en) | 2011-03-08 | 2015-04-22 | Sanofi | Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof |
US8828995B2 (en) | 2011-03-08 | 2014-09-09 | Sanofi | Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof |
EP2683699B1 (en) | 2011-03-08 | 2015-06-24 | Sanofi | Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof |
US8901114B2 (en) | 2011-03-08 | 2014-12-02 | Sanofi | Oxathiazine derivatives substituted with carbocycles or heterocycles, method for producing same, drugs containing said compounds, and use thereof |
EP2567959B1 (en) | 2011-09-12 | 2014-04-16 | Sanofi | 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5631365A (en) * | 1993-09-21 | 1997-05-20 | Schering Corporation | Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents |
DE10042447A1 (en) * | 2000-08-29 | 2002-03-28 | Aventis Pharma Gmbh | Vertebrate intestinal protein that absorbs cholesterol and use of this protein to identify inhibitors of intestinal cholesterol transport |
IL156552A0 (en) * | 2000-12-21 | 2004-01-04 | Aventis Pharma Gmbh | Diphenyl azetidinone derivatives, method for the production thereof, medicaments containing these compounds, and their use |
DK1345895T3 (en) * | 2000-12-21 | 2007-05-07 | Sanofi Aventis Deutschland | Hitherto diphenylazetid ions, methods for their preparation, drugs containing these compounds and their use in the treatment of lipid metabolism disorders |
PL362512A1 (en) * | 2000-12-21 | 2004-11-02 | Avantis Pharma Deutschland Gmbh | Diphenyl azetidinone derivatives, method for the production thereof, medicaments containing these compounds, and their use |
-
2002
- 2002-06-19 DE DE10227508A patent/DE10227508A1/en not_active Withdrawn
-
2003
- 2003-04-06 UA UAA200500488A patent/UA78577C2/en unknown
- 2003-06-02 SV SV2003001548A patent/SV2004001548A/en not_active Application Discontinuation
- 2003-06-04 RU RU2005101093/04A patent/RU2287522C2/en not_active IP Right Cessation
- 2003-06-04 KR KR10-2004-7020643A patent/KR20050008835A/en not_active Application Discontinuation
- 2003-06-04 OA OA1200400331A patent/OA12869A/en unknown
- 2003-06-04 JP JP2004514661A patent/JP2005533073A/en not_active Abandoned
- 2003-06-04 WO PCT/EP2003/005816 patent/WO2004000805A1/en active Application Filing
- 2003-06-04 CN CNB038143321A patent/CN100467448C/en not_active Expired - Fee Related
- 2003-06-04 AU AU2003238210A patent/AU2003238210B2/en not_active Ceased
- 2003-06-04 CA CA002490112A patent/CA2490112A1/en not_active Abandoned
- 2003-06-04 BR BR0311896-7A patent/BR0311896A/en not_active IP Right Cessation
- 2003-06-04 MX MXPA04012093A patent/MXPA04012093A/en active IP Right Grant
- 2003-06-04 RS YUP-1084/04A patent/RS108404A/en unknown
- 2003-06-04 EP EP03735535A patent/EP1517891B1/en not_active Expired - Lifetime
- 2003-06-04 PL PL03372700A patent/PL372700A1/en not_active Application Discontinuation
- 2003-06-16 PE PE2003000596A patent/PE20040564A1/en not_active Application Discontinuation
- 2003-06-16 UY UY27853A patent/UY27853A1/en unknown
- 2003-06-17 HN HN2003000185A patent/HN2003000185A/en unknown
- 2003-06-17 TW TW092116321A patent/TW200413311A/en unknown
- 2003-06-17 AR ARP030102144A patent/AR039690A1/en unknown
- 2003-06-18 PA PA20038576101A patent/PA8576101A1/en unknown
-
2004
- 2004-11-16 MA MA27954A patent/MA27206A1/en unknown
- 2004-12-15 IL IL16578904A patent/IL165789A0/en unknown
- 2004-12-16 EC EC2004005497A patent/ECSP045497A/en unknown
- 2004-12-16 TN TNP2004000250A patent/TNSN04250A1/en unknown
- 2004-12-17 HR HR20041201A patent/HRPK20041201B3/en not_active IP Right Cessation
-
2005
- 2005-01-11 NO NO20050134A patent/NO20050134L/en not_active Application Discontinuation
- 2005-12-12 HK HK05111396.2A patent/HK1079511A1/en not_active IP Right Cessation
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Legal Events
Date | Code | Title | Description |
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EEER | Examination request | ||
FZDE | Discontinued |