EP1146868A1 - Entzündungshemmende mittel - Google Patents
Entzündungshemmende mittelInfo
- Publication number
- EP1146868A1 EP1146868A1 EP00900731A EP00900731A EP1146868A1 EP 1146868 A1 EP1146868 A1 EP 1146868A1 EP 00900731 A EP00900731 A EP 00900731A EP 00900731 A EP00900731 A EP 00900731A EP 1146868 A1 EP1146868 A1 EP 1146868A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- phenyl
- group
- alkenyl
- substituted
- 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- Withdrawn
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Classifications
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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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/223—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of alpha-aminoacids
-
- 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
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- 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]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to the use of certain esters and thioesters for the treatment of diseases responsive to inhibition of intracellular leukotriene-A 4 hydrolase activity.
- the leukotriene cascade of arachadonic acid is a key mechanism in many inflammatory and allergic disease states.
- the dihydroxy fatty acid leukotriene B 4 (LTB 4 ) produced by this cascade, is a key pro-inflammatory mediator.
- LTB 4 stimulates adhesion of circulating neutrophils to vascular endothelium, directs their migration toward sites of inflammation, and induces secretion of further inflammatory mediators.
- LTA 4 -hydrolase (EC 3.3.2.6) is an enzyme that catalyses the final and rate limiting step in the synthesis of LTB 4 . Inhibition of LTA 4 hydrolase selectively blocks the biosynthesis of LTB 4 which may provide an advantage over current inhibitors, such as those of 5-lipoxygenase, that block earlier in the leukotriene cascade and as a result are less selective.
- LTB 4 Disease states associated with elevated levels of LTB 4 , and which are therefore considered to be responsive to inhibition of intracellular leukotriene-A 4 hydrolase activity include asthma, inflammatory bowel disease, psoriasis and arthritis.
- Peptidomimetic compounds such as bestatin, captopril and kelatorphan exhibit LTA 4 hydrolase inhibitory activity against isolated enzyme (T.D. Penning et al, Biorg. Med. Chem. Lett., 1995, 5, p2517-2522).
- LTA 4 hydrolase inhibitory activity against isolated enzyme
- these compounds are unable to effectively penetrate cells and hence have little anti-inflammatory activity. There is therefore a need in the art for compounds which are capable of inhibiting intracellular LTA 4 hydrolase activity.
- esters and thioesters containing an N-formyl hydroxylamine group are capable of inhibiting intracellular LTA 4 hydrolase activity, resulting in efficient attenuation of LTB 4 biosynthesis.
- Those esters and thioesters are therefore of use for the treatment of diseases responsive to such inhibiton, for example inflammatory and allergic conditions including asthma, rheumatoid arthritis, osteoarthritis, multiple sclerosis, ulcerative colitis, contact and atopic dermatitis, psoriasis, inflammatory bowel disease and Crohn's disease.
- This invention is based on the identification of a class of ester and thioester compounds containing an N-formyl hydroxylamine group, which are capable of inhibiting intracellular LTA 4 hydrolase activity, resulting in efficient attenuation of LTB 4 biosynthesis.
- esters and thioesters are therefore of use for the treatment of diseases responsive to such inhibiton, for example inflammatory and allergic conditions including asthma, rheumatoid arthritis, osteoarthritis, multiple sclerosis, ulcerative colitis, contact and atopic dermatitis, psoriasis, inflammatory bowel disease and Crohn's disease.
- ester and thioester compounds in question have certain structural similarities to known MMP inhibitors generically disclosed in the foregoing patent publications. Most of those prior art publications are concerned with amides rather than esters or thioesters group, but a a few (WO 92/09563, WO 95/19965 and WO 95/22966) include within their generic disclosure compounds having a carboxylate ester group in place of the amide group.
- the carboxylate ester compounds with which this invention is concerned thus represent a selection of a notional subclass from the compounds proposed in the art as MMP inhibitors or for other purposes, for a specific and previously unrecognised pharmaceutical utility - inhibiting intracellular LTA 4 hydrolase activity.
- the present invention provides a method for treatment of mammals suffering diseases responsive to inhibition of intracellular leukotriene-A 4 hydrolase activity, comprising administering to the mammal suffering such disease an amount of a compound of general formula (I) or a pharmaceutically acceptable salt hydrate or solvate thereof sufficient to inhibit such activity:
- R is hydrogen or (C,-C 6 )alkyl; R ⁇ is hydrogen; (C C ⁇ )all yl;
- heterocyclyl or substituted heterocyclyl
- n 0, 1 or 2 and B is hydrogen or a (C C 6 ) alkyl, phenyl, substituted phenyl, heterocyclyl substituted heterocyclyl, (C C 6 )acyl, phenacyl or substituted phenacyl group, and A represents (C C 6 )alkylene;
- lower alkyl substituted by carbamoyl, mono(lower alkyl)carbamoyl, di(lower alkyl)carbamoyl, di(lower alkyl)amino, or carboxy-lower alkanoylamino; or
- a cycloalkyl, cycloalkenyl or non-aromatic heterocyclic ring containing up to 3 heteroatoms any of which may be (i) substituted by one or more substituents selected from C C 6 alkyl, C 2 -C 6 alkenyl, halo, cyano ( -CN), -CO 2 H, -CO 2 R, - CONH 2 , -CONHR, -CON(R) 2 , -OH, -OR, oxo-, -SH, -SR, -NHCOR, and - NHCO 2 R wherein R is C C 6 alkyl or benzyl and/or (ii) fused to a cycloalkyl or heterocyclic ring;
- R 3 is the characterising group of a natural or non-natural ⁇ amino acid in which any functional groups may be protected;
- R 4 is an ester or thioester group
- (C,-C 6 )alkyl or "lower alkyl” means a straight or branched chain alkyl moiety having from 1 to 6 carbon atoms, including for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and n-hexyl.
- (C 2 -C 6 )alkenyl means a straight or branched chain alkenyl moiety having from 2 to 6 carbon atoms having at least one double bond of either E or Z stereochemistry where applicable. This term would include, for example, vinyl, allyl, 1- and 2-butenyl and 2-methyl-2-propenyl.
- C 2 -C 6 alkynyl refers to straight chain or branched chain hydrocarbon groups having from two to six carbon atoms and having in addition one triple bond. This term would include for example, ethynyl, 1-propynyl, 1- and 2-butynyl, 2-methyl- 2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl.
- cycloalkyl means a saturated alicyclic moiety having from 3-8 carbon atoms and includes, for example, cyclohexyl, cyclooctyl, cycloheptyl, cyclopentyl, cyclobutyl and cyclopropyl.
- cycloalkenyl means an unsaturated alicyclic moiety having from 4-8 carbon atoms and includes, for example, cyclohexenyl, cyclooctenyl, cycloheptenyl, cyclopentenyl, and cyclobutenyl. In the case of cycloalkenyl rings of from 5-8 carbon atoms, the ring may contain more than one double bond.
- aryl means an unsaturated aromatic carbocyclic group which is moncyclic (eg phenyl) or polycyclic (eg naphthyl).
- heterocyclyl or “heterocyclic” means (i) a 5-7 membered heterocyclic ring containing one or more heteroatoms selected from S, N and O, and optionally fused to a benzene ring, including for example, pyrrolyl, furyl, thienyl, piperidinyl, imidazolyl, oxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrimidinyl, morpholinyl, piperazinyl, indolyl, benzimidazolyl, maleimido, succinimido, phthalimido, 1 ,2-dimethyl-3,5-dioxo-1 ,2,4-triazolidin-4-yl, 3,4,4- trimethyl-2,5-dioxo-1-imidazolidinyl, 2-methyl-3,5-dioxo
- heteroaryl means a 5-7 membered substituted or unsubstituted aromatic heterocycle containing one or more heteroatoms. Illustrative of such rings are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, trizolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl.
- substituted as applied to any moiety herein means substituted with up to four substituents, each of which independently may be (C C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy, mercapto, (C C 6 )alkylthio, amino, halo (including fluoro, chloro, bromo and iodo), nitro, trifluoromethyl, -COOH, -CONH 2 , -CN, -COOR A , -CONHR A or -CONHR A R A wherein R A is a (C r C 6 )alkyl group or the residue of a natural alpha-amino acid.
- side chain of a natural or non-natural alpha-amino acid means the group R 1 in a natural or non-natural amino acid of formula NH 2 -CH(R 1 )-COOH.
- side chains of natural alpha amino acids include those of alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, histidine, 5- hydroxylysine, 4-hydroxyproline, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, ⁇ -aminoadipic acid, ⁇ -amino-n-butyric acid, 3,4-dihydroxyphenylalanine, homoserine, ⁇ - methylserine, omithine, pipecolic acid, and thyroxine.
- Natural alpha-amino acids which contain functional substituents, for example amino, carboxyl, hydroxy, mercapto, guanidyl, imidazolyl, or indolyl groups in their characteristic side chains include arginine, lysine, glutamic acid, aspartic acid, tryptophan, histidine, serine, threonine, tyrosine, and cysteine.
- R 3 in the compounds of the invention is one of those side chains, the functional substituent may optionally be protected.
- side chains of non-natural alpha amino acids include those referred to below in the discussion of suitable R 3 groups for use in compounds of the present invention.
- Salts of the compounds of the invention include physiologically acceptable acid addition salts for example hydrochlorides, hydrobromides, sulphates, methane sulphonates, p-toluenesulphonates, phosphates, acetates, citrates, succinates, lactates, tartrates, fumarates and maleates. Salts may also be formed with bases, for example sodium, potassium, magnesium, and calcium salts.
- R may be, for example, hydrogen, methyl, ethyl, n-propyl, n-butyl, isobutyl, allyl, phenylpropyl, cyclopropylmethyl, phenylprop-2-enyl, thienylsulphanylmethyl, thienylsulphinylmethyl, or thienylsulphonylmethyl; or
- C C 4 alkyl eg methyl, ethyl n-propyl or n-butyl, substituted by a phthalimido, 1 ,2-dimethyl-3,5-dioxo-1 ,2,4-triazolidin-4-yl, 3-methyl-2,5-dioxo-1- imidazolidinyl, 3,4 ,4-trimethyl-2,5-dioxo-1 -imidazolidinyl, 2-methyl-3,5-dioxo- 1 ,2,4-oxadiazol-4-yl, 3-methyl-2,4,5-trioxo-1 -imidazolidinyl, 2,5-dioxo-3- phenyl-1 -imidazolidinyl, 2-oxo-1 -pyrrolidinyl, 2, 5-dioxo-1 -pyrrolidinyl or 2,6- dioxopiperidinyl, 5,5-dimethyl-2,4-dioxo-3
- R ⁇ groups include hydrogen, cyclopropylmethyl, n-propyl, and allyl.
- R 2 may for example be
- Such groups include methyl, ethyl, n- or iso-propyl, n-, iso- or tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-nonyl, n-decyl, prop-2-yn-1-yl, cyclohexylethyl, cyclopentylmethyl, 3-phenylprop-2-yn-1-yl, 3-(2-chlorophenyl)prop- 2-yn-1-yl, benzyl phenylpropyl, 4-chlorophenylpropyl, 4-methylphenylpropyl, 4- methoxyphenylpropyl, phenoxybutyl, 3-(4-pyridylphenyl)propyl-, 3-(4-(4- pyridyl)phenyl)prop-2-yn-1 -yl, 3-(4-phenylphenyl)propyl-
- R 2 groups include benzyl, n-butyl, iso-butyl, n-hexyl, and cyclopentylmethyl
- R 3 may for example be C C 6 alkyl, phenyl, 2,- 3-, or 4-pyridyl, 2- or 3-thienyl, 2,- 3-, or 4-hydroxyphenyl, 2,- 3-, or 4-methoxyphenyl, 2,- 3-, or 4-pyridylmethyl, benzyl, 2,- 3-, or 4-hydroxybenzyl, 2,- 3-, or 4-benzyloxybenzyl, 2,- 3-, or 4-C r C 6 alkoxybenzyl, or benzyloxy(C C 6 alkyl)-.; or
- Alk is a (C C 6 )alkyl or (C 2 -C 6 )alkenyl group optionally interrupted by one or more -O-, or -S- atoms or -N(R 7 )- groups [where R 7 is a hydrogen atom or a (C 1 -C 6 )alkyl group], n is 0 or 1 , and R 6 is an optionally substituted cycloalkyl or cycloalkenyl group; or
- heterocyclic(C C 6 )alkyl group either being unsubstituted or mono- or di- substituted in the heterocyclic ring with halo, nitro, carboxy, (C 1 -C 6 )alkoxy, cyano, (C 1 -C 6 )alkanoyl, trifluoromethyl (C ⁇ C ⁇ alkyl, hydroxy, formyl, amino, (C.,-C 6 )alkylamino, di-(C C 6 )alkylamino, mercapto, (C C 6 )alkylthio, hydroxy(C C 6 )alkyl, mercapto(C C 6 )alkyl or (C C alkylphenylmethyl; or
- each of R a , R b and R c is independently hydrogen, (C 1 -C 6 )alkyl, (C 2 - C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl; or
- R c is hydrogen and R a and R b are independently phenyl or heteroaryl such as pyridyl; or
- R c is hydrogen, (C C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl(C C 6 )alkyl, or (C 3 -C 8 )cycloalkyl, and R a and R b together with the carbon atom to which they are attached form a 3 to 8 membered cycloalkyl or a 5- to 6-membered heterocyclic ring; or
- R a , R b and R c together with the carbon atom to which they are attached form a tricyclic ring (for example adamantyl); or
- R a and R b are each independently (C C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 - C 6 )alkynyl, phenyl(C C 6 )alkyl, or a group as defined for R 0 below other than hydrogen, or R a and R b together with the carbon atom to which they are attached form a cycloalkyl or heterocyclic ring, and R c is hydrogen, -OH, -SH, halogen, -CN, -CO 2 H, (C r C 4 )perfluoroalkyl, - CH 2 OH, -C0 2 (C r C ⁇ )alkyl.
- R 3 groups include benzyl, phenyl, cydohexylmethyl, pyridin-3- ylmethyl, tert-butoxymethyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, 1-benzylthio-1- methylethyl, 1-methylthio-1-methylethyl, and 1 -mercapto- 1-methylethyl.
- R 3 groups include phenyl, benzyl, tert-butoxymethyl, iso-propyl and iso-butyl.
- R 9 groups include methyl, ethyl, n-and iso-propyl, n-, sec- and tert-butyl, 1-ethyl-prop-1-yl, 1-methyl- prop-1-yl, 1-methyl-but-1-yl, cyclopentyl, cyclohexyl, allyl, phenyl, benzyl, 2-, 3- and 4-pyridylmethyl, N-methylpiperidin-4-yl, 1-methylcyclopent-1yl, adamantyl, tetrahydrofuran-3-yl and methoxyethyl.
- Presently preferred R groups are hydrogen and methyl.
- Compounds of the invention may be prepared by deprotecting an O-protected N- formyl-N-hydroxyamino compound of formula (II):
- R 1 ( R 2 , R 3 and R 4 are as defined in general formula (I) and R 25 is a hydroxy protecting group removable to leave a hydroxy group by hydrogenolysis or hydrolysis.
- R 25 is a hydroxy protecting group removable to leave a hydroxy group by hydrogenolysis or hydrolysis.
- Benzyl is a preferred R 25 group for removal by hydrogenolysis
- tetrahydropyranyl is a preferred group for removal by acid hydrolysis.
- Compounds of formula (II) may be prepared by causing an acid of formula (III) or an activated derivative thereof to react with an amine of formula (IV)
- R R 2 , R 3 and R 4 are as defined in general formula (I) except that any substituents in R 1 f R 2 , R 3 and R 4 which are potentially reactive in the coupling reaction may themselves be protected from such reaction, and R 25 is as defined in relation to formula (II) above, and optionally removing protecting groups from R ⁇ R 2 , R 3 and R 4 .
- a compound of general formula (V) may be prepared by reduction of an oxime of general formula (VI)
- Reducing agents include metal hydrides (eg sodium cyanoborohydride in acetic acid, triethylsilane or borane/pyridine) and hydrogenation.
- metal hydrides eg sodium cyanoborohydride in acetic acid, triethylsilane or borane/pyridine
- a compound of general formula (VI) can be prepared by reaction of a ⁇ -keto carbonyl compound of general formula (VII)
- R R 2 , and R 26 are as defined above, with an O-protected hydroxylamine.
- ⁇ -keto carbonyl compounds (VI) may be prepared by acylation of the enolate derived from a carbonyl compound of formula (VII) or (VIIA)
- R is as defined above and Z is a leaving group such as chloro or alkoxy.
- Z is a leaving group such as chloro or alkoxy.
- Another method for the preparation of a compound of general formula (IV) is by Michael addition of a hydroxylamine derivative to an ⁇ , ⁇ -unsaturated carbonyl compounds of general formula (IX)
- R 1 f R 2 , and R 26 are as defined above.
- the ⁇ , ⁇ -unsaturated carbonyl compounds (IX) may be prepared by standard methods.
- the compounds with which the invention is concerned may be prepared for administration by any route consistent with their pharmacokinetic properties.
- Orally administrable compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical, or sterile parenteral solutions or suspensions.
- Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrrolidone; fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate.
- binding agents for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrrolidone
- fillers for example
- Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
- Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
- suspending agents for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats
- emulsifying agents for example lecithin, sorbitan monooleate, or acacia
- non-aqueous vehicles which may include edible oils
- almond oil fractionated coconut oil
- oily esters such as glycerine, propylene
- the drug may be made up into a cream, lotion or ointment.
- Cream or ointment formulations which may be used for the drug are conventional formulations well known in the art, for example as described in standard textbooks of pharmaceutics such as the British Pharmacopoeia.
- the active ingredient may also be administered parenterally in a sterile medium.
- the drug can either be suspended or dissolved in the vehicle.
- adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
- the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
- Example 1 was prepared as outlined in Scheme 1 using procedures described below.
- Reagents and conditions A. (1) EtOH/KOH/H 2 0, reflux 5 hours, (2) piperidine, HCHO, EtOH, reflux 4 hours; B. H 2 NOBzl, 80°C o/n; C. HCOOH, Ac 2 0; D. WSCDI, HOBT, DMF, L-phenylalanine cyclopentyl ester r.t., 18 hours; E. H 2 (g), Pd catalyst, EtOH 90 minutes.
- Diethyl benzylmalonate (100g, 400mmol) was dissolved in ethanol (300mL) and treated with a solution of potassium hydroxide (134.4g, 2.4mol) in water (500mL). The mixture was heated under reflux for 5 hours and then allowed to cool. Ethanol was removed under reduced pressure and the remaining aqueous solution cooled in ice and acidified to pH1 with concentrated HCI. The product was extracted with ethyl acetate (3x200mL). The combined extracts were washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure to yield benzylmalonic acid as a white crystalline solid.
- the solid was taken-up in ethanol (250mL) and treated portionwise with piperidine (33g, 397mmol) followed by an aqueous solution of formaldehyde (37%, 150mL) which resulted in formation of a white precipitate.
- the reaction mixture was heated and treated with methanol (50mL) to give a homogeneous solution. Following dissolution the reaction mixture was heated under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure. The aqueous residue was acidified to pH1 with 1 M HCI and the product extracted with ethyl acetate (3x150mL).
- Diastereoisomer B (42mg), 1 H-NMR; ⁇ (CDCI 3 ), 8.35 and 7.71 (1 H, 2xs), 7.33-7.15 (8H, m), 7.08-6.94 (1 H, bm), 6.83-6.73 (2H, m), 6.20 and 5.94 (2xd), 5.30-5.08 (1 H, m), 4.73-4.64 (1 H, m), 3.85-3.76 (1 H, m), 3.56-3.47 (1 H, m), 3.01-2.68 (5H, m) and 1.91-1.45 (8H, m); 13 C-NMR; ⁇ (CDCI 3 ), 174.2, 172.9, 172.4, 171.8, 138.7, 136.1 , 129.6, 129.3, 129.1 , 128.9, 128.8, 127.6, 127.5, 127.4, 127.3, 127.2, 127.1 , 79.9, 79.2, 53.9, 53.6, 52.3, 50.3, 48.1 , 4
- Example 2 was prepared as outlined in scheme 2 using procedures described below.
- Reagents and conditions A. Sodium hexamethyldisilazide, AcCI, -60°C 3 hours; B. BzlONH 2 HCI, NaOAc, H 2 0/EtOH, 50°C 18 hours; C. AcOH, NaCNBH 3 , 25 hours; D. HCOOH, AcOH, 18 hours; E. LiOH, H 2 0 2 , THF/H 2 0, 4 hours; F. L-Phenylalanine cyclopentyl ester, HOBT, WSCDI, DMF, 48 hours, G. H 2 (g), Pd catalyst, EtOH, 2 hours. (a) 1 -(4S-Benzyl-2-oxo-oxazolidin-3-yl)-2R-isobutyl-butane-1 ,3-dione
- N-[2-(4S-Benzyl-2-oxo-oxazolidine-3S-carbonyl)-1-(R,S),4-dimethyl-pentyl]-N- benzyloxyformamide 7.30g, 16.1 mmol was dissolved in THF (21 OmL) and water (60mL) and cooled to 0°C. Hydrogen peroxide (1.84mL, 30% solution, 64.5mmol) was added dropwise followed by aqueous lithium hydroxide (1.02g in10mL, 24.2mmol) and the solution stirred at 0°C for 4 hours. The reaction mixture was quenched by the addition of sodium nitrite (1.11g, 16mmol).
- Diastereoisomer B (28mg, 8%), 1 H-NMR; ⁇ (methanol-d 4 ), 7.95 (0.4H, s), 7.84 (0.6H, s), 7.26-7.21 (5H, m), 5.13 (0.4H, m), 5.04 (0.6H, m), 4.73-4.66 (0.4H, m), 4.62-4.56 (0.6H, m), 4.42-4.36 (0.4H, m), 3.89-3.78 (0.6H, m), 3.18-2.61 (3H, bm), 1.77-1.44 (10H, m), 1.29-1.11 (3H, m), 1.00-0.87 (7H, m); 13 C-NMR; ⁇ (methanol-d 4 ), 172.7, 138.0, 130.4, 129.5, 127.9, 79.6, 59.0, 53.3, 49.6, 39.9, 38.8, 38.4, 33.5, 33.4, 27.1 , 26.7, 24.7, 24.6, 24.3, 24.1
- Reagents and conditions A. piperidine, HCHO, EtOH, 80°C, o/n; B. 'BuCOCI, Et 3 N then 3-lithio-4-benzyl-5,5-dimethyl-oxazolidin-2-one; C. H 2 NOBzl, room temp., o/n then pTsOH, EtOAc; D. LiOH, aq THF, 0°C; E. H-t-Leu-OcPentyl, HOBt, EDC, DMF; F. HCOBt, THF; G. H 2 , Pd/C, EtOH.
- Step B 4S-Benzyl-3-(2-butyl-acryloyl)-5,5-dimethyl-oxazolidin-2-one
- Step C 4S-Benzyl-3-[2-(benzyloxyamino-methyl)-hexanoyl]-5,5-dimethyl-oxazolidin- 2-one (p-toluenesulfonic acid salt)
- the reaction was acidified to pH4 with 1 M citric acid and the solvents were removed. The residue was partitioned between dichloromethane and 1 M sodium carbonate. The basic aqueous layer was acidified to pH4 with 1 M citric acid and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated to provide the title compound as a colourless oil (7.4g, 73%).
- Step E 2S-[2R-(Benzyloxyamino-methyl)-hexanoylamino]-3,3-dimethyl butyric acid cyclopentyl ester
- Step G 2S- ⁇ 2R-[(Formyl-hydroxy-amino)-methyl]-hexanoylamino ⁇ -3,3-dimethyl butyric acid cyclopentyl ester
- Example 7-10 were prepared by the method of Example 3 by parallel synthesis, using the appropriate amino acid derivative instead of terf-leucine cyclopentyl ester in Step E.
- the products were purified by preparative HPLC:
- Example 11 was prepared by the method of Example 3, by using the appropriate amino acid derivative instead of te/Y-leucine cyclopentyl ester in step E:
- Examples 14 and 15 were prepared from 2R-(.erf-butoxyamino- methyl)-hexanoic acid and the appropriate amino acid derivative by anology with methods described for Example 3:
- the rat basophilic leukaemia cell line RBL-1 was obtained from ATCC or ECACC and cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% foetal bovine serum, non-essential amino acids, sodium pyruvate, penicillin, streptomycin and 2mM glutamine, at 37°C in an atmosphere of 5% CO 2 in air, as recommended by the culture collection.
- DMEM Dulbecco's modified Eagle's medium
- RBL-1 cells were harvested during log growth, washed and resuspended in Hanks Balanced Salt Solution, without calcium chloride and magnesium chloride, supplemented with 10% foetal bovine serum and penicillin, streptomycin, and 2mM glutamine and adjusted to a final cell concentration of 1.25X10 5 cells/ml. Cells incubated in the presence of the appropriate concentration of inhibitor or vehicle for 4.75 hours at 37°C. Cells then transferred to ice for 15 minutes. Cells washed by centrifugation and resuspension in pre-chilled Phosphate Buffered Saline, with calcium chloride and magnesium chloride, supplemented with the appropriate concentration of test sample.
- Treated cells then exposed to 10 ⁇ M A23187 for 15 minutes at 37°C .
- Cells transferred to ice, thereby stopping the reaction.
- Cell free supernatant harvested by centrifugation.
- the levels of leukotriene B 4 then determined in the cell free supernatant using the Leukotriene B 4 [ 3 H] assay system from Amersham Pharmacia Biotech.
- IC 50 value for the compound of example 4 was estimated as 0.7nM and for Kelatorphan as 350nM.
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