EP0505467A1 - Pharmacologically active amide carboxylate derivatives - Google Patents
Pharmacologically active amide carboxylate derivativesInfo
- Publication number
- EP0505467A1 EP0505467A1 EP91901593A EP91901593A EP0505467A1 EP 0505467 A1 EP0505467 A1 EP 0505467A1 EP 91901593 A EP91901593 A EP 91901593A EP 91901593 A EP91901593 A EP 91901593A EP 0505467 A1 EP0505467 A1 EP 0505467A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- amino
- enyl
- methyl
- acid
- oxodec
- 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.)
- Withdrawn
Links
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/91—Dibenzofurans; Hydrogenated dibenzofurans
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- 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
- A61K31/16—Amides, e.g. hydroxamic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/49—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a carbon atom of an acyclic unsaturated carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/51—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C235/12—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
- C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
- C07C323/59—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton with acylated amino groups bound to the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/38—One sulfur atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
- C07D333/34—Sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/56—Ring systems containing bridged rings
- C07C2603/58—Ring systems containing bridged rings containing three rings
- C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
- C07C2603/74—Adamantanes
Definitions
- This invention relates to compounds having
- R 1 represents an alkyl or alkenyl C 1-18 group
- R 2 represents an alkyl C 1-18 group optionally
- R 2 represents a group -CH 2 -X-R 4 wherein X represents O or S, and R 4
- alkenyl C 1-18 group optionally substituted by an aryl group
- R 3 represents OH, alkoxy C 1-6 or -NHR 31 , wherein R 31 represents hydrogen, alkyl C 1-6 , OH or
- R 5 represents hydrogen, an aryl group or an alkyl or alkenyl C 1-18 group optionally substituted by an aryl group,
- n 0, 1, 2 or 3
- p 0, 1 or 2
- a compound of formula I as defined above, in the manufacture of a medicament for the treatment or prophylaxis of inflammation.
- Japanese Patent Application No 54-119414 (Fuji) describes the synthesis of ß-aminoacid derivatives having antibiotic properties.
- German Patent Application No 2252882 (Oreal) relates to aminoacid-amine salts containing sulphur which are useful as hair and scalp conditioners.
- R 1 represents methyl
- R 2 is other than an alkyl C 1-18 group or benzyl
- R 1 is other than an alkyl C 1-18 group, optionally substituted by phenyl, or 2-(5-nitro-2-furyl)ethylenyl, and
- R 1 and R 2 do not both represent CH 3 (CH 2 ) 14 -,
- R 1 represents methyl
- R 2 is other than an alkyl C 1-18 group or benzyl or 2-phenylethyl or
- R 1 is other than an alkyl C 1-6 group optionally substituted by phenyl, and
- R 3 is other than hydroxy or methoxy
- R 1 and R 2 do not both represent CH 3 (CH 2 ) 14 -, and
- R 2 is other than n-pentyl.
- the hydrolysis of process a) may be carried out under acid or, preferably, base catalysis.
- Reagents which may be used for the base catalysed hydrolysis include lithium hydroxide and potassium hydroxide.
- the reaction may be carried out in the presence of a co-solvent such as
- reaction of process b) is preferably carried out in an inert solvent such as dichloromethane in the presence of a coupling reagent such as dicyclohexylcarbodiimide with or without 1-hydroxybenzotriazole or other additives.
- a coupling reagent such as dicyclohexylcarbodiimide with or without 1-hydroxybenzotriazole or other additives.
- reaction of process c) is preferably carried out in an inert solvent or mixture of solvents.
- a coupling reagent such as dicyclohexylcarbodiimide may be employed.
- Leaving groups which L may represent in process d) include halide, notably chloride.
- Acid chlorides of formula V may be prepared by treatment of the corresponding acid with for example, thionyl chloride or oxalyl
- the acid chloride is then treated with the amine of formula III in the presence of an inert solvent such as dichloromethane.
- reaction of process e) may be carried out in the presence of a suitable catalyst, eg 10% palladium on carbon.
- a suitable catalyst eg 10% palladium on carbon.
- the reaction may be carried out by hydrolysis using an inorganic base.
- R 3 , R 5 , Y, n, p and q are as first defined above and R 2 represents CH 2 -X-R 4 .
- R 4 represents an aryl group, or an alkyl or alkenyl C 1-18 group optionally substituted by an aryl group.
- novel compounds of formula III may be prepared by reacting a compound of formula VI
- R 4 -X-H VI with the corresponding compound of formula III in which R 2 represents -CH 2 -L in which L is a leaving group, eg a halogen such as iodine.
- R 1 may represents are alkyl or alkenyl C 1-18 , optionally substituted by hydroxy, phenyl or cycloalkyl C 3-6 .
- Alkyl groups which R 1 may represent include both straight and branched chain groups .
- Straight chain alkyl groups include both relatively short chains, eg methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl, and longer chains, eg pentadecyl, hexadecyl and heptadecyl.
- branched chains include both relatively simple groups such as i-propyl, i-butyl, s-butyl and t-butyl, and groups containing larger numbers of carbon atoms, eg
- Alkenyl groups which R 1 may represent may contain up to 3 double bonds. Where there is more than 1 double bond, they may be conjugated or non-conjugated. Examples of such alkenyl groups include 7-heptadecenyl, 9-pentadecenyl and 2-nonenyl.
- Cycloalkyl groups with which the group R 1 may be substituted include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
- substituted include both carbocyclic and heterocyclic groups.
- the groups may contain rings of various numbers of C-atoms and may be fused ring structures.
- Examples of carbocyclic aryl groups are phenyl and naphthyl.
- Heteroaryl groups include nitrogen, oxygen or sulphur heterocycles and may contain one or more heteroatoms.
- heterocycles containing only one heteroatom include pyrrole, furan, thiophen and pyridine.
- Groups containing more than one heteroatom include pyrazole, oxazole, thiazole, triazole, oxadiazole, thiadiazole etc.
- the aryl group may be substituted by a range of
- substituents including halogen, nitro, alkyl C 1-6 , phenyl and phenyl (alkyl C 1-6 ).
- Particularly preferred aryl groups with which R 1 may be substituted are carbocyclic groups, especially phenyl.
- R 2 represents alkyl C 1-18 , it may be
- the preferred aryl groups with which R 2 may be substituted are carbocyclic groups, especially phenyl.
- R 2 may represent include alkyl C 1-18 , more preferably alkyl C 1-6 , optionally substituted by phenyl, and, more preferably, groups of the formula
- alkyl C 1-18 an aryl group or alkyl C 1-18 substituted by an aryl group.
- Alkyl groups which R 2 may represent include similar groups to those which R 1 may represent.
- R 2 represents the group -CH 2 -X-R 4
- R 4 may represent a similar range of long and short, straight or branched alkyl groups.
- Aryl groups which R 4 may represent include
- carbocyclic groups notably phenyl, optionally substituted by, for example, phenyl and phenylmethyl, and fused ring structures such as naphthyl.
- Other aryl groups which R 4 may represent include heterocyclic structures.
- Such heteroaryl groups include nitrogen, oxygen or sulphur heterocycles and may contain one or more heteroatoms.
- heterocycles containing only one heteroatom include pyrrole, furan, thiophen and pyridine.
- Groups containing more than one heteroatom include pyrazole, oxazole, thiazole, triazole, oxadiazole, thiadiazole etc.
- the aryl group may be substituted by a range of
- substituents including halogen, nitro, alkyl C 1-6 , phenyl and phenyl (alkyl C 1-6 ).
- Alkoxy groups which R 3 may represent include
- R 31 preferably
- Aryl groups with which R 4 may be substituted include both carbocyclic and
- R 31 be substituted by a carbocyclic group, especially phenyl.
- R 31 represents alkoxy C 1-6 or, especially, hydroxy.
- R 5 is preferably lower alkyl, say alkyl C 1-6 , or, more preferably, hydrogen.
- Y is preferably CHR 6 in which R 6 is
- n 1 or 2.
- Alkyl groups which R 6 may represent include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl.
- Aryl groups with which R 6 may be substituted include both carbocyclic and heterocyclic groups. It is
- R 6 be substituted by a
- a particularly preferred group of compounds are those in which
- R 1 represents alkyl or alkenyl C 1-18 , optionally substituted by hydroxy, phenyl or cycloalkyl C 3-6 ,
- R 2 represents alkyl C 1-18 , optionally substituted by phenyl, or a group
- alkyl C 1-18 an aryl group or alkyl C 1-18 substituted by an aryl group,
- R 3 represents hydroxy, alkoxy C 1-6 or NHR 31
- R 31 represents hydrogen, alkyl C 1-6 , hydroxy or alkoxy C 1-6 optionally substituted by phenyl, and
- n 0, 1 or 2
- Y represents -CHR 6 -, in which R 6 represents
- Pharmaceutically acceptable derivatives of the compounds of formula I include esters, amides and salts.
- Salts of the compounds of formula I include metal ion salts, eg alkali metal and alkaline earth metal salts, and addition salts with suitable bases, eg suitable amines such as dicyclohexylamine and 1-adamantanamine.
- the compounds of formula I, and pharmaceutically acceptable derivatives thereof, are useful because they possess pharmacological activity in animals.
- the compounds are useful as broad spectrum anti-inflammatory agents as demonstrated in one or more of the following in vitro assay systems:
- 1 4 C-arachidonic acid from mixed micelles Mixed micelles of 1-stearoyl-2-[1- 14 C]-2-arachidonyl-L-3-phosphatidyl choline and deoxycholate are added to a mixture of porcine pancreatic PLA 2 and test compound in buffer solution.
- pancreatic PLA 2 is incubated with 4-hydroxy-3,5-dioxa- 4,9-dioxo-8-thia-4-phosphahexadecan-1-ammonium hydroxide in buffer solution containing the test compound. Cleavage of the thio ester is assayed photometrically after reaction with DTNB (5,5'-dithiobis[2-nitrobenzoic acid]).
- PMN polymorphonuclear leucocytes
- the compounds are indicated for use in the treatment or prophylaxis of inflammatory conditions in mammals including man. Conditions that may be specifically
- osteoarthritis rheumatoid arthritis, rheumatoid spondylitis, gouty arthritis and other arthritic
- inflammatory eye conditions including uveitis and conjunctivitis;
- lung disorders in which inflammation is involved eg asthma, bronchitis, pigeon fancier's disease, farmer's lung, acute respiratory distress syndrome, bacteraemia, endotoxaemia (septic shock) and pancreatitis;
- conditions of the gastrointestinal tract including aphthous ulcers, gingivitis, Crohn's disease (a condition of the small and sometimes also of the large intestine), atrophic gastritis and gastritis varialoforme (conditions of the stomach), ulcerative colitis (a condition of the large and sometimes of the small intestine), coeliac disease (a condition of the small intestine), regional ileitis (a regional inflammatory condition of the terminal ileum), peptic ulceration (a condition of the stomach and duodenum) and irritable bowel syndrome; pyresis, pain; and other conditions associated with inflammation, particularly those in which phospholipid, lipoxygenase and
- the total daily dose is in the range of from 7.0mg to 1,400mg and unit dosage forms suitable for oral administration comprise from 2.0mg to 1,400mg of the compound admixed with a solid or liquid pharmaceutical diluent or carrier.
- the compounds of formula I may be used on their own or in the form of appropriate medicinal preparations for enteral, parenteral or topical administration.
- composition comprising preferably less than 80% and more preferably less than 50% by weight of a compound of formula I, or a pharmaceutically acceptable derivative thereof, with the provisos that
- R 1 represents methyl
- R 2 is other than an alkyl C 1-1 8 group or benzyl
- R 1 is other than an alkyl C 1-18 group, optionally substituted by phenyl, or 2-(5-nitro-2-furyl)ethylenyl, and
- R 1 and R 2 do not both represent CH 3 (CH 2 ) 14 -,
- Such adjuvants, diluents and carriers are for tablets and dragees - lactose, starch, talc, stearic acid;
- compositions in a form suitable for oesophageal administration include tablets, capsules and dragees;
- compositions in a form suitable for administration to the lung include aerosols, particularly pressurised
- compositions in a form suitable for administration to the skin include creams, eg oil-in-water emulsions or water-in-oil emulsions;
- compositions in a form suitable for administration to the eye include drops amd ointments.
- the compounds of formula I have the advantage that they are less toxic, more efficacious, are longer acting, have a broader range of activity, are more potent, produce fewer side effects, are more easily absorbed or have other useful pharmacological properties, than compounds of similar structure.
- step b) A solution of the a , ⁇ -unsaturated ester as prepared in step b) (0.29g) in methanol (50ml) was treated with 10% palladium on charcoal and hydrogenated at atmospheric pressure for 4 hours. The mixture was filtered through hyflo and evaporated to a white solid. Flash chromatography of the solid using ethyl acetate/hexane mixtures afforded the sub-titled compound as a white solid (0.27g, 93%).
- dimethylformamide 25ml was stirred under nitrogen and treated, batchwise, with sodium hydride (0.25g of 80% dispersion in oil) at room temperature. After a further 1 ⁇ 2-hour, a solution of the product of step a) (2.24g) in dry dimethylformamide (15ml) was added over 1 minute. The mixture was stirred for 3 hours, poured onto dilute hydrochloric acid and extracted with ethyl acetate. The organic solution was washed with water, 50% aqueous sodium metabisulphite solution, water and saturated brine, then dried (MgSO 4 ) and the solvent removed by rotary
- the sub-title product was obtained as a yellow solid by treatment of the product of step a) by a procedure analogous to that described in Example 12a).
- the sub-title product was obtained as a gum from the product of step b) by a procedure analogous to that
- triphenylphosphine (0.26g).
- Example 23d The more polar product of Example 23d) (0.31g) was treated analogously to give the other diastereomer as an oil (0. 03g) .
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- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
La présente invention décrit des composés pharmacologiquement actifs, leurs procédés de fabrication, des compositions les renfermant et des méthodes de traitement dans lesquelles ils entrent. Sous son angle le plus large, la présente invention concerne des composés de formule générale (I), dans laquelle R1 représente un groupe alkyle ou alcényle C1-18 éventuellement substitué par un groupe aryle ou hydroxy ou cycloalkyle C3-6; R2 représente un groupe alkyle C1-18 éventuellement substitué par un groupe aryle, ou R2 représente un groupe -CH2-X-R4 dans lequel X représente 0 ou S, et R4 représente de l'hydrogène, un groupe aryle, ou un groupe alkyle ou alcényle C1-18 éventuellement substitué par un groupe aryle; R3 représente OH, un alcoxy C1-16 ou -NHR31, dans lequel R31 représente de l'hydrogène, un alkyle C1-6, OH ou un alcoxy C1-6 éventuellement substitué par un groupe aryle; R5 représente de l'hydrogène, un groupe aryle, alkyle, ou alcényle C1-18 éventuellement substitué par un groupe aryle; n représente 0, 1, 2 ou 3; p représente 0, 1 ou 2; q représente 0 ou 1; y représente un -CH=CH-, 0 ou S, dans lequel R6 représente de l'hydrogène, un groupe aryle ou un alkyle, ou encore un groupe alcényle C1-18 éventuellement substitué par un groupe aryle. On décrit également les dérivés pharmaceutiquement acceptables desdits composés.The present invention describes pharmacologically active compounds, their methods of manufacture, compositions containing them and methods of treatment in which they fall. In its widest angle, the present invention relates to compounds of general formula (I), in which R1 represents a C1-18 alkyl or alkenyl group optionally substituted by an aryl or hydroxy or C3-6 cycloalkyl group; R2 represents an alkyl group C1-18 optionally substituted by an aryl group, or R2 represents a group -CH2-X-R4 in which X represents 0 or S, and R4 represents hydrogen, an aryl group, or an alkyl group or C1-18 alkenyl optionally substituted with an aryl group; R3 represents OH, C1-16 alkoxy or -NHR31, in which R31 represents hydrogen, C1-6 alkyl, OH or C1-6 alkoxy optionally substituted by an aryl group; R5 represents hydrogen, an aryl, alkyl, or C1-18 alkenyl group optionally substituted by an aryl group; n represents 0, 1, 2 or 3; p represents 0, 1 or 2; q represents 0 or 1; y represents a -CH = CH-, 0 or S, in which R6 represents hydrogen, an aryl group or an alkyl, or alternatively a C1-18 alkenyl group optionally substituted by an aryl group. The pharmaceutically acceptable derivatives of said compounds are also described.
Description
Claims
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB898928456A GB8928456D0 (en) | 1989-12-16 | 1989-12-16 | Compounds |
GB8928456 | 1989-12-16 | ||
GB9023645 | 1990-10-31 | ||
GB909023645A GB9023645D0 (en) | 1990-10-31 | 1990-10-31 | Compounds |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0505467A1 true EP0505467A1 (en) | 1992-09-30 |
Family
ID=26296380
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP91901593A Withdrawn EP0505467A1 (en) | 1989-12-16 | 1990-12-12 | Pharmacologically active amide carboxylate derivatives |
Country Status (7)
Country | Link |
---|---|
EP (1) | EP0505467A1 (en) |
JP (1) | JPH05502233A (en) |
CA (1) | CA2072018A1 (en) |
FI (1) | FI922720A0 (en) |
IE (1) | IE904522A1 (en) |
PT (1) | PT96210A (en) |
WO (1) | WO1991008737A2 (en) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5639746A (en) * | 1994-12-29 | 1997-06-17 | The Procter & Gamble Company | Hydroxamic acid-containing inhibitors of matrix metalloproteases |
US5672598A (en) * | 1995-03-21 | 1997-09-30 | The Procter & Gamble Company | Lactam-containing hydroxamic acids |
DE69635048T2 (en) * | 1995-06-12 | 2006-02-16 | G.D. Searle & Co. | MEDIUM, CONTAINING A CYCLOOXYGENASE-2 INHIBITOR AND A 5-LIPOXYGENASE INHIBITOR |
UA59384C2 (en) | 1996-12-20 | 2003-09-15 | Пфайзер, Інк. | Preventing bone mass loss and recovery thereof by means of prostaglandin agonists |
US7253194B2 (en) | 2000-07-24 | 2007-08-07 | The University Of Queensland | Compounds and inhibitors of phospholipases |
AU2002216249A1 (en) * | 2000-12-21 | 2002-07-01 | De Novo Pharmaceuticals Ltd | Antimicrobial agents |
GB0112324D0 (en) * | 2001-05-21 | 2001-07-11 | Croda Int Plc | Compounds |
ES2273560B1 (en) * | 2005-02-25 | 2008-04-01 | Consejo Superior Investig. Cientificas | INHIBITOR COMPOUND OF THE CERAMIDASE ENZYME, SYNTHESIS PROCEDURE, PHARMACEUTICAL COMPOSITION CONTAINING IT AND ITS APPLICATIONS. |
FR2968952A1 (en) * | 2010-12-17 | 2012-06-22 | Oreal | N-ACYL AMINO ACID ESTER AS A SOOTHING AGENT |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BE790592A (en) * | 1971-10-28 | 1973-04-26 | Oreal | |
PH24782A (en) * | 1985-10-24 | 1990-10-30 | Sankyo Co | Composition containing a penem or carbapenem antibiotic and the use of the same |
-
1990
- 1990-12-12 JP JP3501855A patent/JPH05502233A/en active Pending
- 1990-12-12 CA CA002072018A patent/CA2072018A1/en not_active Abandoned
- 1990-12-12 EP EP91901593A patent/EP0505467A1/en not_active Withdrawn
- 1990-12-12 WO PCT/GB1990/001941 patent/WO1991008737A2/en not_active Application Discontinuation
- 1990-12-14 IE IE452290A patent/IE904522A1/en unknown
- 1990-12-14 PT PT96210A patent/PT96210A/en unknown
-
1992
- 1992-06-12 FI FI922720A patent/FI922720A0/en not_active Application Discontinuation
Non-Patent Citations (1)
Title |
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See references of WO9108737A2 * |
Also Published As
Publication number | Publication date |
---|---|
WO1991008737A3 (en) | 1992-04-16 |
WO1991008737A2 (en) | 1991-06-27 |
PT96210A (en) | 1991-09-30 |
IE904522A1 (en) | 1991-06-19 |
FI922720A0 (en) | 1992-06-12 |
CA2072018A1 (en) | 1991-06-17 |
JPH05502233A (en) | 1993-04-22 |
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