WO1992003130A1 - Use of aryl hydroxyurea compounds for the treatment of atherosclerosis - Google Patents
Use of aryl hydroxyurea compounds for the treatment of atherosclerosis Download PDFInfo
- Publication number
- WO1992003130A1 WO1992003130A1 PCT/GB1991/001320 GB9101320W WO9203130A1 WO 1992003130 A1 WO1992003130 A1 WO 1992003130A1 GB 9101320 W GB9101320 W GB 9101320W WO 9203130 A1 WO9203130 A1 WO 9203130A1
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- WIPO (PCT)
- Prior art keywords
- alkyl
- formula
- treatment
- prophylaxis
- hydrogen
- Prior art date
Links
- -1 aryl hydroxyurea compounds Chemical class 0.000 title claims abstract description 19
- 238000011282 treatment Methods 0.000 title claims abstract description 19
- 201000001320 Atherosclerosis Diseases 0.000 title claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 40
- 239000003814 drug Substances 0.000 claims abstract description 29
- 125000001424 substituent group Chemical group 0.000 claims abstract description 21
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 15
- 238000012986 modification Methods 0.000 claims abstract description 15
- 230000004048 modification Effects 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 238000011321 prophylaxis Methods 0.000 claims abstract description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 12
- 239000001257 hydrogen Substances 0.000 claims abstract description 12
- 230000005764 inhibitory process Effects 0.000 claims abstract description 12
- 150000002632 lipids Chemical class 0.000 claims abstract description 11
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 10
- 238000004519 manufacturing process Methods 0.000 claims abstract description 10
- 230000001590 oxidative effect Effects 0.000 claims abstract description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 8
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims abstract description 6
- 125000005843 halogen group Chemical group 0.000 claims abstract description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 6
- 125000001544 thienyl group Chemical group 0.000 claims abstract description 6
- 125000004450 alkenylene group Chemical group 0.000 claims abstract description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 3
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 3
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims abstract description 3
- 125000006310 cycloalkyl amino group Chemical group 0.000 claims abstract description 3
- 125000002541 furyl group Chemical group 0.000 claims abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 3
- 125000001041 indolyl group Chemical group 0.000 claims abstract description 3
- 125000001624 naphthyl group Chemical group 0.000 claims abstract description 3
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 3
- 125000005493 quinolyl group Chemical group 0.000 claims abstract description 3
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims abstract 2
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 claims abstract 2
- 238000000034 method Methods 0.000 claims description 8
- 241000124008 Mammalia Species 0.000 claims description 5
- MWLSOWXNZPKENC-UHFFFAOYSA-N zileuton Chemical compound C1=CC=C2SC(C(N(O)C(N)=O)C)=CC2=C1 MWLSOWXNZPKENC-UHFFFAOYSA-N 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000004534 benzothien-2-yl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 238000007911 parenteral administration Methods 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract 1
- 125000006705 (C5-C7) cycloalkyl group Chemical group 0.000 abstract 1
- 102000007330 LDL Lipoproteins Human genes 0.000 description 19
- 108010007622 LDL Lipoproteins Proteins 0.000 description 19
- 239000000243 solution Substances 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 6
- 239000002585 base Substances 0.000 description 5
- 238000005502 peroxidation Methods 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000002835 absorbance Methods 0.000 description 4
- OUUQCZGPVNCOIJ-UHFFFAOYSA-N hydroperoxyl Chemical compound O[O] OUUQCZGPVNCOIJ-UHFFFAOYSA-N 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 229910052802 copper Inorganic materials 0.000 description 3
- 239000010949 copper Substances 0.000 description 3
- 210000002889 endothelial cell Anatomy 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 2
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- 230000002292 Radical scavenging effect Effects 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 150000001993 dienes Chemical class 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229940097156 peroxyl Drugs 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229940069328 povidone Drugs 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002516 radical scavenger Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- JXYWFNAQESKDNC-BTJKTKAUSA-N (z)-4-hydroxy-4-oxobut-2-enoate;2-[(4-methoxyphenyl)methyl-pyridin-2-ylamino]ethyl-dimethylazanium Chemical compound OC(=O)\C=C/C(O)=O.C1=CC(OC)=CC=C1CN(CCN(C)C)C1=CC=CC=N1 JXYWFNAQESKDNC-BTJKTKAUSA-N 0.000 description 1
- 102000011730 Arachidonate 12-Lipoxygenase Human genes 0.000 description 1
- 108010076676 Arachidonate 12-lipoxygenase Proteins 0.000 description 1
- 102000001381 Arachidonate 5-Lipoxygenase Human genes 0.000 description 1
- 108010093579 Arachidonate 5-lipoxygenase Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical class NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 210000002403 aortic endothelial cell Anatomy 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- OYHQOLUKZRVURQ-IXWMQOLASA-N linoleic acid Natural products CCCCC\C=C/C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-IXWMQOLASA-N 0.000 description 1
- 235000020778 linoleic acid Nutrition 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 108091005485 macrophage scavenger receptors Proteins 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000003617 peroxidasic effect Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 102000014452 scavenger receptors Human genes 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
-
- 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
Definitions
- the present invention is concerned with the use of certain aryl hydroxyurea compounds in the manufacture of medicaments for the prophylaxis and treatment of clinical conditions for which inhibition of the oxidative modification of lipids is indicated, for example, atherosclerosis, with the medicaments obtained thereby and with their preparation and use in the prophylaxis and treatment of such conditions.
- European Patent Specification 0279263 describes a novel class of compounds having 5- and/or 12-lipoxygenase inhibiting properties which have potential utility in the treatment of asthma, allergy, arthritis, psoriasis and inflammation.
- EPS 0279263 also have the ability to scavenge the peroxyl radicals implicated in the oxidation of low density lipoprotein (LDL) . It follows that these compounds may be suitable for use in the treatment of conditions for which inhibition of the oxidative modification of lipids is indicated, for example, atherosclerosis.
- LDL low density lipoprotein
- Y is C. 1f . alkylene or C complaint ⁇ n alkenylene
- R is hydrogen, C- , alkyl, amino, C. , alkylamino, di-C- , alkylamino, C,. -. cycloalkylamino, C,. ⁇ cycloalkyl C- , alkyl)- amino, anilino, N-C. , alkylanilino, or a group as defined for Ar above;
- Preferred compounds for use in the manufacture of the medicaments of the invention include those wherein r is benzofur-2-yl or benzothien-2-yl;
- Y is -CH 2 - or -CH(Me)-;
- R is hydrogen and R is C. , alkyl, amino, C- , alkylamino, or di-C. , alkylamino;
- a particularly preferred compound for use in the manufacture of a medicament according to the invention is N-hydroxy-N-(l-benzo[b]thien- 2-ylethyl)urea or a physiologically acceptable base salt or physiologically functional derivative thereof.
- Physiologically acceptable salts for use in the manufacture of the medicaments of the present invention include ammonium salts, alkali metal salts, such as those of sodium and potassium, alkaline earth salts, such as those of calcium and magnesium, salts with organic bases, such as those of dicyclohexylamine and N-methyl-D-glucamine, and salts with amino acids, such as those of arginine and lysine.
- medicaments comprising a compound of formula (I) , at least one pharmaceutically acceptable carrier and, optionally, one or more other therapeutiously active compounds, for use in the prophylaxis and treatment of a condition for which inhibition of the oxidative modification of lipids is indicated, for example, atherosclerosis, and
- a suitable dose for a mammal suffering from, or likely to suffer from, any of the clinical conditions described hereinbefore is in the range O.l ⁇ g to 500mg of compound kg bodyweight.
- the dose is typically in the range 0.5 to 500mg of compound/kg bodyweight, the most preferred dosage being 0.5 to 50mg kg bodyweight, for example, 5 to 25mg kg, administered two or three times daily.
- a medicament according to the invention comprises a compound of formula (I) in association with at least one pharmaceutically acceptable carrier and, optionally, one or more other therapeutically active compounds.
- the carrier must, of course, be compatible with the other ingredients in the medicament and must not be detrimental to the recipient.
- the compound of formula (I) may comprise from 0.1% to 99.9% by weight of the medicament.
- Typical unit doses of a medicament according to the invention contain from O.lmg to lg of the active ingredient.
- Medicaments according to the invention include those in a form suitable for oral, pulmonary, rectal, or parenteral (including subcutaneous, intramuscular and intravenous) administration.
- Medicaments according to the invention may conveniently be presented in unit dosage form and may be prepared l - any method known in the art of pharmacy. All such methods include the step of bringing the compound of formula (I) into association with a carrier which may contain one or more accessory ingredients.
- the medicaments of the invention are prepared by uniformly and intimately bringing the compound of formula (I) into association with a liquid carrier or a finely divided solid carrier, or both, and then, if desired, shaping the product into the required form, for example, by compression or moulding.
- Medicaments according to the invention which are suitable for oral administration may be in the form of discrete units, such as capsules, cachets, tablets, or lozenges, each containing a predetermined amount of the compound of formula (I); in the form of a powder or granules; in the form of a solution or a suspension in an aqueous or non-aqueous liquid; or in the form of an oil-in-water or water-in-oil emulsion.
- the medicament may also be in the form of a bolus, electuary, or paste.
- Medicaments suitable for parenteral administration typically comprise a sterile aqueous preparation of the compound of formula (I) which is preferably isotonic with the blood of the intended recipient.
- medicaments according to the invention may include one or more additional ingredients selected from diluents, buffers, flavouring agents, binders, surface- active agents, thickeners, lubricants, preservatives, anti-oxidants and emulsifying agents.
- the compounds of formula (I) may also be advantageously employed in combination with one or more other therapeutically active compounds selected, for example, from an antibiotic (for example, an anti-bacterial) , anti-fungal, or anti-viral agent, an anti- .stamine (particularly a peripherally-acting anti-histamine) , or a non-steroidal anti-inflamma ⁇ tory drug (NSAID) .
- antibiotic for example, an anti-bacterial
- anti-fungal anti-fungal
- anti-viral agent an anti- .stamine (particularly a peripherally-acting anti-histamine)
- NSAID non-steroidal anti-inflamma ⁇ tory drug
- the “active ingredient” in the following formulations may be any compound of formula (I) as hereinbefore defined.
- the active ingredient is dissolved in half of the Water for Injections and then made up to volume and sterilised by filtration. The resulting solution is distributed into ampoules under aseptic conditions.
- LDL low density lipoprotein
- Addition of copper to human low density lipoprotein (LDL) results in the initiation of a peroxidative reaction. This results in the formation of conjugated dienes in the lipid phase and a consequent increase in UV-absorbance at 234nm.
- Chain-breaking peroxyl radical scavengers inhibit this increase in absorbance at 234nm and this is used as the basis for an assay to estimate the ability of a compound to inhibit the peroxidation of LDL.
- the reaction was initiated by the addition of 10 ⁇ M CuSO ⁇ to a solution of LDL (125 g/ml) in phosphate-buffered saline.
- the test compounds were added as ethanolic solutions while ensuring the ethanol content of the resulting solution did not exceed 1% v/v.
- Cultured endothelial cells can modify low density lipoprotein (LDL) so that It is rapidly taken up by the macrophage scavenger receptor.
- LDL low density lipoprotein
- the modification involves peroxidation of LDL and brings about changes in the physiocochemical properties of LDL including an increase in electrophoretic mobility.
- Peroxyl radical scavengers have been shown to inhibit the endothelial cell modification of LDL as determined by a decrease in the electrophoretic mobility of the sample.
- Porcine aortic endothelial cells at confluence were incubated for 24 hours at 37 C in Hams F10 medium containing 0.2mg/ml of LDL and a range of concentrations of the test compound in ethanolic solution. The ethanol concentration was always 0.5% w/v. At the end of the incubation, the samples were concentrated and changes in the electrophoretic mobility relative to native LDL measured.
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- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Obesity (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention is concerned with the use of a compound of formula (I): Ar-Y-Q, wherein Ar is either (i) furyl, thienyl, thienyl 1,1-dioxide, pyrryl, pyridyl, benzofuryl, benzothienyl, benzothienyl 1,1-dioxide, indolyl, naphthyl, quinolyl, or tetrahydronaphthyl, any of which is optionally substituted by one or more substituents independently selected from C1-4 alkyl (which may itself optionally be substituted by one or more halogen atoms), C1-4 alkoxy, halo, nitro, amino, carboxy, C1-4 alkoxycarbonyl and hydroxy, or (ii) phenyl optionally substituted by one or more substituents independently selected from phenyl (which is itself optionally substituted by one or more substituents independently selected from those optional substituents specified in (i) above) and those specified as optional substituents in (i) above; Y is C1-10 alkylene or C2-10 alkenylene; Q is formula (II), where R1 is hydrogen, C¿1-4? alkyl, a group as defined for Ar above, or a group of formula -N(R?4)R5¿ wherein R4 is hydrogen or C¿1-4? alkyl and R?5¿ is hydrogen, C¿1-4? alkyl, or phenyl optionally substituted by one or more substituents independently selected from those specified as optional substituents in (i) above; and R?2¿ is hydrogen, C¿1-4? alkyl, amino, C1-4 alkylamino, di-C1-4 alkylamino, C5-7 cycloalkylamino, C5-7 cycloalkyl(C1-4 alkyl)-amino, anilino, N-C1-4 alkylanilino, or a group as defined for Ar above; or a physiologically acceptable base salt or physiologically functional derivative thereof; in the manufacture of a medicament for the prophylaxis and treatment of conditions for which inhibition of the oxidative modification of lipids is indicated, for example, atherosclerosis. The medicaments obtained thereby and their preparation and use in the prophylaxis and treatment of the aforementioned conditions are also within the scope of the invention.
Description
USE OF ARYL HYDROXYUREA COMPOUNDS FOR THE TREATMENT
OF ATHEROSCLEROSIS
The present invention is concerned with the use of certain aryl hydroxyurea compounds in the manufacture of medicaments for the prophylaxis and treatment of clinical conditions for which inhibition of the oxidative modification of lipids is indicated, for example, atherosclerosis, with the medicaments obtained thereby and with their preparation and use in the prophylaxis and treatment of such conditions.
European Patent Specification 0279263 describes a novel class of compounds having 5- and/or 12-lipoxygenase inhibiting properties which have potential utility in the treatment of asthma, allergy, arthritis, psoriasis and inflammation.
We have now found that the compounds of EPS 0279263 also have the ability to scavenge the peroxyl radicals implicated in the oxidation of low density lipoprotein (LDL) . It follows that these compounds may be suitable for use in the treatment of conditions for which inhibition of the oxidative modification of lipids is indicated, for example, atherosclerosis.
Ar-Y-Q (I)
wherein
Ar is either
(i) furyl, thienyl, thienyl 1,1-dioxide, pyrryl, pyridyl, benzofuryl, benzothienyl, benzothienyl 1,1-dioxide, indolyl, naphthyl, quinolyl, or tetrahydronaphth l, any of which is optionally substituted by one or more substituents independently selected from C. , alkyl (which may itself optionally be substituted by
one or more halogen atoms), C. , alkoxy, halo, nitro, amino, carboxy, C. , alkoxycarbonyl and hydroxy, or
(ii) phenyl optionally substituted by one or more substituents independently selected from phenyl (which is itself optionally substituted by one or more substituents independently selected from those specified as optional substituents in (i) above) and those, optional substituents specified in (i) above;
Y is C. 1f. alkylene or C„ ιn alkenylene;
as defined for Ar above, or s hydrogen or C. , alkyl and
ionally substituted by one or more substituents independently selected from those specified as optional substituents in (i) above; and
2 R is hydrogen, C- , alkyl, amino, C. , alkylamino, di-C- , alkylamino, C,. -. cycloalkylamino, C,. η cycloalkyl C- , alkyl)- amino, anilino, N-C. , alkylanilino, or a group as defined for Ar above;
or a physiologically acceptable base salt or physiologically functional derivative thereof;
in the manufacture of a medicament for the prophylaxis and treatment of conditions for which inhibition of the oxidative modification of lipids is indicated, for example, atherosclerosis.
Preferred compounds for use in the manufacture of the medicaments of the invention include those wherein
r is benzofur-2-yl or benzothien-2-yl;
Y is -CH2- or -CH(Me)-; and
1 2
Q is as hereinbefore defined, R is hydrogen and R is C. , alkyl, amino, C- , alkylamino, or di-C. , alkylamino;
and physiologically acceptable base salts and physiologically functional derivatives thereof.
A particularly preferred compound for use in the manufacture of a medicament according to the invention is N-hydroxy-N-(l-benzo[b]thien- 2-ylethyl)urea or a physiologically acceptable base salt or physiologically functional derivative thereof.
Physiologically acceptable salts for use in the manufacture of the medicaments of the present invention include ammonium salts, alkali metal salts, such as those of sodium and potassium, alkaline earth salts, such as those of calcium and magnesium, salts with organic bases, such as those of dicyclohexylamine and N-methyl-D-glucamine, and salts with amino acids, such as those of arginine and lysine.
The above compounds of formula (I) and their physiologically acceptable base salts and physiologically functional derivatives are hereinafter referred to as "compounds of formula (I)" in relation to the therapeutic and pharmaceutical aspects of the invention discussed below.
According to further aspects of the invention, there are provided:
(a) medicaments comprising a compound of formula (I) , at least one pharmaceutically acceptable carrier and, optionally, one or more other therapeuti„ally active compounds, for use in the prophylaxis and treatment of a condition for which inhibition of
the oxidative modification of lipids is indicated, for example, atherosclerosis, and
(b) methods for the prophylaxis and treatment of a condition in a mammal, such as a human, for which inhibition of the oxidative modification of lipids is indicated, for example, atherosclerosis, which comprise the administration to said mammal of a therapeutlcally effective amount of a compound of formula (I) as hereinbefore defined.
The amount of a medicament according to the invention required to achieve the desired therapeutic effect will, of course, vary with the particular compound of formula (I) contained therein, the route of administration, the subject under treatment and the particular disorder or disease being treated. A suitable dose for a mammal suffering from, or likely to suffer from, any of the clinical conditions described hereinbefore is in the range O.lμg to 500mg of compound kg bodyweight. In the case of systemic administration, the dose is typically in the range 0.5 to 500mg of compound/kg bodyweight, the most preferred dosage being 0.5 to 50mg kg bodyweight, for example, 5 to 25mg kg, administered two or three times daily.
As indicated, a medicament according to the invention comprises a compound of formula (I) in association with at least one pharmaceutically acceptable carrier and, optionally, one or more other therapeutically active compounds. The carrier must, of course, be compatible with the other ingredients in the medicament and must not be detrimental to the recipient. The compound of formula (I) may comprise from 0.1% to 99.9% by weight of the medicament. Typical unit doses of a medicament according to the invention contain from O.lmg to lg of the active ingredient.
Medicaments according to the invention include those in a form suitable for oral, pulmonary, rectal, or parenteral (including subcutaneous, intramuscular and intravenous) administration.
Medicaments according to the invention may conveniently be presented in unit dosage form and may be prepared l - any method known in the art of pharmacy. All such methods include the step of bringing the compound of formula (I) into association with a carrier which may contain one or more accessory ingredients. In general, the medicaments of the invention are prepared by uniformly and intimately bringing the compound of formula (I) into association with a liquid carrier or a finely divided solid carrier, or both, and then, if desired, shaping the product into the required form, for example, by compression or moulding.
Medicaments according to the invention which are suitable for oral administration may be in the form of discrete units, such as capsules, cachets, tablets, or lozenges, each containing a predetermined amount of the compound of formula (I); in the form of a powder or granules; in the form of a solution or a suspension in an aqueous or non-aqueous liquid; or in the form of an oil-in-water or water-in-oil emulsion. The medicament may also be in the form of a bolus, electuary, or paste.
Medicaments suitable for parenteral administration typically comprise a sterile aqueous preparation of the compound of formula (I) which is preferably isotonic with the blood of the intended recipient.
In addition to the aforementioned ingredients, medicaments according to the invention may include one or more additional ingredients selected from diluents, buffers, flavouring agents, binders, surface- active agents, thickeners, lubricants, preservatives, anti-oxidants and emulsifying agents. The compounds of formula (I) may also be advantageously employed in combination with one or more other therapeutically active compounds selected, for example, from an antibiotic (for example, an anti-bacterial) , anti-fungal, or anti-viral agent, an anti- .stamine (particularly a peripherally-acting anti-histamine) , or a non-steroidal anti-inflamma¬ tory drug (NSAID) .
The compounds of formula (I) and their physiologically acceptable base salts and physiologically functional derivatives for use in the manufacture of the medicaments of the present invention may be prepared by the methods described in EPS 0279263.
For a better understanding of the invention, the following Examples are given by way of illustration.
PHARMACEUTICAL FORMULATION EXAMPLES
The "active ingredient" in the following formulations may be any compound of formula (I) as hereinbefore defined.
Example A: Tablet
Per tablet
Active Ingredient 5.0 mg
Lactose 82.0 mg
Starch 10.0 mg
Povidone 2.0 mg
Magnesium Stearate 1.0 mg
Mix together the active ingredient, lactose and starch. Granulate the powder using a solution of povidone in purified water. Dry the granules, add the magnesium stearate and compress to produce tablets (lOOmg per tablet) .
Example B: Injectable solution
Active Ingredient 10.0 mg
Water for Injections B.P. to 1.0 ml
The active ingredient is dissolved in half of the Water for Injections and then made up to volume and sterilised by filtration. The
resulting solution is distributed into ampoules under aseptic conditions.
BIOLOGICAL ACTIVITY
(i) Peroxyl radical scavenging
The ability of the compounds of the invention to scavenge peroxyl radicals was measured using the method described in Biochem. Pharm. 38, 1465 (1989) wherein the peroxidation of linoleic acid is inhibited. N-Hydroxy-N-(l-benzo[b]thien-2-ylethyl)urea was found to have significant anti-oxidant activity with an apparent rate constant (k „) for peroxyl radical scavenging of 0.11.
AH.
(ii) Inhibition of copper-induced peroxidation of LDL
Addition of copper to human low density lipoprotein (LDL) results in the initiation of a peroxidative reaction. This results in the formation of conjugated dienes in the lipid phase and a consequent increase in UV-absorbance at 234nm. Chain-breaking peroxyl radical scavengers inhibit this increase in absorbance at 234nm and this is used as the basis for an assay to estimate the ability of a compound to inhibit the peroxidation of LDL. The reaction was initiated by the addition of 10μM CuSO^ to a solution of LDL (125 g/ml) in phosphate-buffered saline. The test compounds were added as ethanolic solutions while ensuring the ethanol content of the resulting solution did not exceed 1% v/v. The absorbance at 234nm was monitored continuously with LDL containing 4μM butylated hydroxytoluene (BHT) and no copper as an optical reference. The time taken for the absorbance to increase to 50% of the maximum was measured for each test compound and plotted as a function concentration. From this plot, the concentration of compound needed to delay conjugated diene forma xon by 60 minutes ^βn^ was calculated. N-Hydroxy-N-(l-benzo[b]thien-2-ylethyl)urea was found to significantly inhibit the peroxidation of LDL with an Ifif) value of 40.1μM.
(iii)Inhibition of endothelial cell modification of LDL
Cultured endothelial cells can modify low density lipoprotein (LDL) so that It is rapidly taken up by the macrophage scavenger receptor. The modification involves peroxidation of LDL and brings about changes in the physiocochemical properties of LDL including an increase in electrophoretic mobility. Peroxyl radical scavengers have been shown to inhibit the endothelial cell modification of LDL as determined by a decrease in the electrophoretic mobility of the sample.
Porcine aortic endothelial cells at confluence were incubated for 24 hours at 37 C in Hams F10 medium containing 0.2mg/ml of LDL and a range of concentrations of the test compound in ethanolic solution. The ethanol concentration was always 0.5% w/v. At the end of the incubation, the samples were concentrated and changes in the electrophoretic mobility relative to native LDL measured.
From a plot of concentration against relative electrophoretic mobility, the IC5Q (concentration of test compound required to inhibit LDL modification by 50%) was determined for each sample. N-Hydroxy- N-(l-benzo[b]thien-2-ylethyl)urea was found to significantly inhibit LDL modification with an IC,-n of 0.5μM.
Claims
Use of a compound of formula (I)
Ar-Y-Q (I)
wherein
Ar is either
(i) furyl, thienyl, thienyl 1,1-dioxide, pyrryl, pyridyl, benzofuryl, benzothienyl, benzothienyl 1,1-dioxide, indolyl, naphthyl, quinolyl, or tetrahydronaphthyl, any of which is optionally substituted by one or more substituents independently selected from C. , alkyl (which may itself optionally be substituted by one or more halogen atoms), C. , alkoxy, halo, nitro, amino, carboxy, C. , alkoxycarbonyl and hydroxy, or
(ii) phenyl optionally substituted by one or more substituents independently selected from phenyl (which is itself optionally substituted by one or more substituents independently selected from those specified as optional substituents in (i) above) and those optional substituents specified in (i) above;
Y is C. 10 alkylene or C„ ..„ alkenylene;
Q is
OR1
—N
\C0R2
where R is hydrogen, C. , alkyl, a group as defined for Ar
4 5 4 above, or a group of formula -N(R )R wherein R is hydrogen or
C. , alkyl and R is hydrogen, C. , alkyl, or phenyl optionally substituted by one or more substituents independently selected from those specified as optional substituents in (i) above; and
2
R is hydrogen, C. . alkyl, amino, C. , alkylamino, • di-C. , alkylamino, c- .-7 cycloalkylamino, Cg _ cycloalkyl(C. , alkyl)amino, anilino, N-C. , alkylanilino, or a group as defined for Ar above;
or a physiologically acceptable base salt or physiologically functional derivative thereof;
in the manufacture of a medicament for the prophylaxis and treatment of a condition for which inhibition of the oxidative modification of lipids is indicated.
Use according to Claim 1 wherein the compound of formula (I) is as shown in Claim 1 and
Ar is benzofur-2-yl or benzothien-2-yl;
Y is -CH2- or -CH(Me)-; and
1 2
Q is as shown in Claim 1, R is hydrogen and R is C. alkyl, amino, C- , alkylamino, or di-C. , alkylamino;
or a physiologically acceptable base salt or physiologically functional derivative thereof.
Use according to Claim 2 wherein the compound of formula (I) is N-hydroxy-N-(l-benzo[b]thien-2-ylethyl)urea or a physiologically acceptable base salt or physiologically functional derivative thereof.
4. Use according to any of Claims 1 to 3 wherein said condition is atherosclerosis.
5. A medicament for the prophylaxis and treatment of a condition for which inhibition of the oxidative modification of lipids is indicated which comprises a compound of formula (I) as defined in Claim 1 or 2 or as named in Claim 3 or a physiologically acceptable base salt or pharmaceutically functional derivative thereof, at least one pharmaceutically acceptable carrier and, optionally, one or more other therapeutically active compounds.
6. A medicament according to Claim 5 for the prophylaxis and treatment of atherosclerosis.
7. A medicament according to Claim 5 or 6 which is in a form suitable for oral or parenteral administration.
8. A method of manufacturing a medicament for the prophylaxis and treatment of a condition for which inhibition of the oxidative modification of lipids is indicated which comprises admixing a compound of formula (I) as defined in Claim 1 or 2 or as named in Claim 3, or a physiologically acceptable base salt or physiologically functional derivative thereof, with at least one pharmaceutically acceptable carrier and, optionally, one or more other therapeutically active compounds.
9. A method according to Claim 8 for manufacturing a medicament for the prophylaxis and treatment of atherosclerosis.
10. A method for the prophylaxis and treatment of a condition in a mammal for which inhibition of the oxidative modification of lipids is indicated which comprises the administration to said mammal of a therapeutically effective amount of a compound of formula (I) as defined in Claim 1 or 2 or as named in Claim 3.
11. A method according to Claim 10 for the prophylaxis and treatment of atherosclerosis.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/325,941 US5461072A (en) | 1990-08-02 | 1994-10-17 | Use of aryl hydroxyurea compounds for the treatment of atherosclerosis |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB909017351A GB9017351D0 (en) | 1990-08-08 | 1990-08-08 | Medicaments for treatment of atherosclerosis |
| GB9017351.9 | 1990-08-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1992003130A1 true WO1992003130A1 (en) | 1992-03-05 |
Family
ID=10680330
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/GB1991/001320 WO1992003130A1 (en) | 1990-08-02 | 1991-08-02 | Use of aryl hydroxyurea compounds for the treatment of atherosclerosis |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0543855A1 (en) |
| JP (1) | JPH06500537A (en) |
| GB (1) | GB9017351D0 (en) |
| WO (1) | WO1992003130A1 (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5260316A (en) * | 1991-07-30 | 1993-11-09 | Ciba-Geigy Corporation | Isoquinolyl substituted hydroxylamine derivatives |
| US5334600A (en) * | 1991-07-30 | 1994-08-02 | Ciba-Geigy Corporation | Isoquinolyl substituted hydroxylamine derivatives |
| US5350761A (en) * | 1991-07-30 | 1994-09-27 | Ciba-Geigy Corporation | Indolyl substituted hydroxylamine derivatives |
| WO1994026269A1 (en) * | 1993-05-10 | 1994-11-24 | Sepracor, Inc. | Methods and compositions for treating asthma, atherosclerosis andinflammatory diseases using optically pure (-)-zileuton |
| US5428048A (en) * | 1993-11-08 | 1995-06-27 | American Home Products Corporation | Aryl-N-hydroxyureas as inhibitors of 5-lipoxygenase and anto-arteriosclerotic agents |
| US5459154A (en) * | 1993-11-08 | 1995-10-17 | American Home Products Corporation | N-hydroxyureas as 5-lipoxygenase inhibitors and inhibitors of oxidative modification of low density lipoprotein |
| US5468760A (en) * | 1993-11-08 | 1995-11-21 | American Home Products Corporation | Aralkyl-N-hydroxyureas as inhibitors of 5-lipoxygenase and oxidation of low density lipoprotein |
| WO1998006400A3 (en) * | 1996-08-09 | 1998-03-26 | Biorex Kutato Fejlesztoe Kft | Pharmaceutical products for curing and preventing illnesses connected with the malfunction of vascular endothelial cells |
| EP1448794A4 (en) * | 2001-10-24 | 2005-06-01 | Univ California | IDENTIFICATION OF 5-LIPOXIDASE AS AN IGGENENE PROMOTING ATHEROSCLEROSIS |
| US7361655B2 (en) | 2002-01-11 | 2008-04-22 | Cytrx Corporation | Pharmaceutically effective compounds |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0128374A2 (en) * | 1983-05-12 | 1984-12-19 | Kyowa Hakko Kogyo Co., Ltd. | Preventive and healing composition for diseases due to lipoxygenase metabolic products |
| EP0183159A2 (en) * | 1984-11-28 | 1986-06-04 | Bayer Ag | 1-Heteroaryl-4-aryl-pyrazolin-5-ones for use as medicaments |
| EP0279263A2 (en) * | 1987-02-10 | 1988-08-24 | Abbott Laboratories | Indole, benzofuran, benzothiophene containing lipoxygenase inhibiting compounds |
-
1990
- 1990-08-08 GB GB909017351A patent/GB9017351D0/en active Pending
-
1991
- 1991-08-02 WO PCT/GB1991/001320 patent/WO1992003130A1/en not_active Application Discontinuation
- 1991-08-02 JP JP3513228A patent/JPH06500537A/en active Pending
- 1991-08-02 EP EP91914214A patent/EP0543855A1/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0128374A2 (en) * | 1983-05-12 | 1984-12-19 | Kyowa Hakko Kogyo Co., Ltd. | Preventive and healing composition for diseases due to lipoxygenase metabolic products |
| EP0183159A2 (en) * | 1984-11-28 | 1986-06-04 | Bayer Ag | 1-Heteroaryl-4-aryl-pyrazolin-5-ones for use as medicaments |
| EP0279263A2 (en) * | 1987-02-10 | 1988-08-24 | Abbott Laboratories | Indole, benzofuran, benzothiophene containing lipoxygenase inhibiting compounds |
Non-Patent Citations (2)
| Title |
|---|
| FEBS Letters, volume 245, no. 1,2, March 1989, Elsevier Science Publishers B.V., M.A. Barradas et al.: "Iron chelators inhibit human platelet aggregation, thromboxane A2 synthesis and lipoxygenase activity", pages 105-109, see page 105, column 1, line 17 - column 2, line 10; abstract; page 108, column 2, line 25 - page 109, column 1, line 4 * |
| Medicina Clinica, volume 84, no. 3, 26 January 1985, J. Santafé Oroz et al.: "Terapeutica farmacologica de la arteriosclerosis (II). Nuevas orientaciones", pages 115-122, see page 120, line 64 - page 121, line 24 * |
Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5334600A (en) * | 1991-07-30 | 1994-08-02 | Ciba-Geigy Corporation | Isoquinolyl substituted hydroxylamine derivatives |
| US5350761A (en) * | 1991-07-30 | 1994-09-27 | Ciba-Geigy Corporation | Indolyl substituted hydroxylamine derivatives |
| US5260316A (en) * | 1991-07-30 | 1993-11-09 | Ciba-Geigy Corporation | Isoquinolyl substituted hydroxylamine derivatives |
| US5629337A (en) * | 1993-05-10 | 1997-05-13 | Sepracor, Inc. | Methods for treating asthma using optically pure (-)-zileuton |
| WO1994026269A1 (en) * | 1993-05-10 | 1994-11-24 | Sepracor, Inc. | Methods and compositions for treating asthma, atherosclerosis andinflammatory diseases using optically pure (-)-zileuton |
| US5428048A (en) * | 1993-11-08 | 1995-06-27 | American Home Products Corporation | Aryl-N-hydroxyureas as inhibitors of 5-lipoxygenase and anto-arteriosclerotic agents |
| US5468760A (en) * | 1993-11-08 | 1995-11-21 | American Home Products Corporation | Aralkyl-N-hydroxyureas as inhibitors of 5-lipoxygenase and oxidation of low density lipoprotein |
| US5541205A (en) * | 1993-11-08 | 1996-07-30 | American Home Products Corporation | Aryl-n-hydroxyureas as inhbitors of 5-lipoxygenase and anti-arteriosclerotic agents |
| US5459154A (en) * | 1993-11-08 | 1995-10-17 | American Home Products Corporation | N-hydroxyureas as 5-lipoxygenase inhibitors and inhibitors of oxidative modification of low density lipoprotein |
| WO1998006400A3 (en) * | 1996-08-09 | 1998-03-26 | Biorex Kutato Fejlesztoe Kft | Pharmaceutical products for curing and preventing illnesses connected with the malfunction of vascular endothelial cells |
| US6143741A (en) * | 1996-08-09 | 2000-11-07 | BIOREX Kutato es Fejleszo Rt. | Pharmaceutical products for curing and preventing illnesses connected with the malfunction of vascular endothelial cells |
| EP1448794A4 (en) * | 2001-10-24 | 2005-06-01 | Univ California | IDENTIFICATION OF 5-LIPOXIDASE AS AN IGGENENE PROMOTING ATHEROSCLEROSIS |
| US7241571B2 (en) | 2001-10-24 | 2007-07-10 | The Regents Of The University Of California | Identification of 5-lipoxygenase as a major gene contributing to atherosclerosis |
| AU2002336657B2 (en) * | 2001-10-24 | 2008-01-03 | The Regents Of The University Of California | Identification of 5-lipoxygenase as a major gene contributing to atherosclerosis |
| US7361655B2 (en) | 2002-01-11 | 2008-04-22 | Cytrx Corporation | Pharmaceutically effective compounds |
| US7384936B2 (en) | 2002-01-11 | 2008-06-10 | Cytrx Corporation | Carboxamidine derivatives and their use in the treatment of vascular diseases |
| US7550457B2 (en) | 2002-01-11 | 2009-06-23 | Cytrx Corporation | Pharmaceutically effective compounds |
| US7691849B2 (en) | 2002-01-11 | 2010-04-06 | Cytrx Corporation | Carboxamidine derivatives and their use in the treatment of vascular diseases |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0543855A1 (en) | 1993-06-02 |
| GB9017351D0 (en) | 1990-09-19 |
| JPH06500537A (en) | 1994-01-20 |
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