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WO1995013266A1 - Acides acylpyrrole-alcanoiques et indole-2-alcanoiques et leurs derives utilises comme inhibiteurs de la phospholipase a¿2? - Google Patents

Acides acylpyrrole-alcanoiques et indole-2-alcanoiques et leurs derives utilises comme inhibiteurs de la phospholipase a¿2? Download PDF

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Publication number
WO1995013266A1
WO1995013266A1 PCT/DE1994/001121 DE9401121W WO9513266A1 WO 1995013266 A1 WO1995013266 A1 WO 1995013266A1 DE 9401121 W DE9401121 W DE 9401121W WO 9513266 A1 WO9513266 A1 WO 9513266A1
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group
pyr
alkyl
aryl
optionally
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PCT/DE1994/001121
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German (de)
English (en)
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Matthias Lehr
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Merckle Gmbh Chem.-Pharm. Fabrik
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Priority to AU76907/94A priority Critical patent/AU7690794A/en
Publication of WO1995013266A1 publication Critical patent/WO1995013266A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/99—Enzyme inactivation by chemical treatment

Definitions

  • the present invention relates to novel acylpyrrolalkanoic acids and indole-2-alkanoic acids and their derivatives which inhibit the enzyme phospholipase A 2 .
  • These compounds are suitable as medicaments for the prevention and for the treatment of diseases which are caused or also caused by an increased activity of this enzyme, such as, for example, inflammation, pain, fever, allergies, asthma, psoriasis and endotoxin shock.
  • the invention further relates to methods for the synthesis of these compounds and pharmaceutical compositions containing these compounds.
  • the phospholipase A 2 hydrolytically cleaves the ester bond in the 2-position of membrane phospholipids, free fatty acids, mainly arachidonic acid, and lysophospholipids being formed.
  • the released arachidonic acid is metabolized to the prostaglandins and thromboxanes via the cyclooxygenase route and to the leukotrienes and other hydroxylated fatty acids via the lipoxygenase routes.
  • the prostaglandins are involved in the development of pain and fever as well as in inflammatory reactions.
  • Leukotrienes are important mediators in inflammatory processes and in anaphylactic and allergic processes (Forth et al., General and Special Pharmacology and Toxicology BI GmbH, Vienna, Zurich, 1987).
  • the lysophospholipids formed by the phospholipase A 2 have cell-damaging properties. Lysophosphatidylserine leads to the release of the histamine involved in allergic processes (Moreno et al., Agents Actions 1992, 36, 258). Lysophosphatidylcholine is also metabolized to the platelet activating factor (PAF), which is also an important mediator, for example in inflammation.
  • PAF platelet activating factor
  • phospholipase A 2 is the key enzyme for the formation of the pathophysiologically important mediators mentioned, these mediator effects can be eliminated by inhibiting the enzyme.
  • German OS 2,302,669 discloses 1-methyl-5- (3-phenylacryloyl) pyrrol-2-yl-formic acid as a compound with an analgesic effect in mice.
  • WO 88-06,885 discloses aminoalkylamides and EP-A-377 539 discloses 4-aryloyl-pyrrol-2-yl-formic acids with phospholipase A 2 inhibiting activity.
  • Indole-2-alkanoic acids as analgesics with prostaglandin and thromboxane inhibitory activity are disclosed in U.S. Patent No. 5,081,145.
  • U.S. Patent No. 5,132,319 describes 1- (hydroxylaminoalkyl) indole derivatives that inhibit leukotriene biosynthesis. As a result, these compounds have an analgesic and anti-inflammatory effect.
  • the (azaarylmethoxy) indoles disclosed in EP-A-535 923 also inhibit leukotriene biosynthesis.
  • the object of the present invention to provide anti-inflammatory drugs and analgesics with a novel quality of action. While the anti-inflammatory and analgesic effects of the currently therapeutically available non-steroidal anti-inflammatory drugs are based on the inhibition of prostaglandin formation due to an inhibition of the enzyme cyclooxygenase, the claimed substances are said to inhibit the enzyme phospholipase A 2 . This not only prevents the biosynthesis of the prostaglandins involved in inflammatory processes and pain, but also the formation of leukotrienes, the platelet activating factor and the lysophospholipids.
  • cytoplasmic phospholipases c-PLA 2 .
  • the compounds according to the invention particularly inhibit c-PLA 2 .
  • the present invention thus relates to pyrrole compounds of the general formula I:
  • R 1 represents a carboxylic acid, carboxamide, carboximide, carboxysulfonimide group
  • the hydrocarbon radical which may be present may contain a hetero atom or a carbonyl group, or a tetrazole, phosphine or sulfonamide group which is optionally bonded via a hydrocarbon radical, the hydrocarbon radical which may be present is a hetero atom or can contain a carbonyl group.
  • R 2 stands for (a) a saturated or unsaturated (C 5-19 alkyl) carbonyl group which may contain one or more heteroatoms and which may be substituted by an optionally substituted aryl group with which Provided that R 2 is not a 3-phenylacryloyl group or a phenylacetyl group; (b) for an optionally substituted arylcarbonyl group, with the proviso that if the pyrrole nitrogen atom bears a hydrogen atom, a C 1-6 alkyl, benzyl or 2-chlorophenyl group, the aryl group has at least one optionally substituted aryl, arylalkyl , Arylalkoxy-, C 7-20 alkyl or C 7-20 alkoxy group is substituted, wherein the alkyl or alkoxy groups can be saturated or unsaturated and optionally interrupted by one or more heteroatoms; or (c) for a saturated or unsaturated alkyl group which may optionally contain one or more heteroatoms
  • R 3 represents a hydrogen atom, a halogen atom, a CF 3 group, a saturated or unsaturated optionally substituted alkyl group, which may optionally contain a hetero atom, or an optionally substituted aryl group.
  • n stands for 3, with the meaning that the pyrrole ring 3 carries identical or different substituents R 3 .
  • Two adjacent radicals R 1-3 together with the carbon or nitrogen atom to which they are attached, can form a 5- to 8-membered ring which can optionally be substituted by 1 to 2 C 1-4 alkyl groups.
  • the Ring closure takes place formally by the substitution of one hydrogen atom in one of the selected radicals by a bond, this bond being able to be inserted both at the end of the radical and at any point before the end of the radical.
  • the present invention further comprises substituted indole compounds of the general formula II:
  • R 4 represents -X, -X-aryl, -CO-R 9 or -CHR 9 -NH-COR 10 , where X is a C 8-20 -alkyl or C 2-20 _ alkenyl or -alkynyl group, which may optionally be interrupted by one or more oxygen atoms, and aryl is an aryl group optionally substituted with 1 to 3 substituents selected from the group R 11 , R 12 and R 13 ; R 9 and R 10 independently of one another represent -W, -aryl or -W-aryl, where W is a C 1-19 -alkyl or C 2-19 -alkenyl or -alkynyl group, which may be substituted by one or more oxygen atoms may be interrupted, and aryl is an aryl group optionally selected from 1 to 3 substituents from the group R 11 , R 12 and R 13 ;
  • R 6 represents a hydrogen atom, a group -Z, -aryl, -Z-aryl or -ZQ, where Z is a C 1-20 alkyl or C 2-20 alkenyl or alkynyl group, which may be replaced by a Oxygen atom may be interrupted, aryl is an aryl group optionally substituted with 1 to 3 substituents selected from the group R 14 , R 15 and R 16 , and Q is selected from:
  • R 7 , R 8 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are independently selected from:
  • R 17 each independently of one another denotes hydrogen, C 1-20 alkyl or C 2-20 alkenyl or alkynyl group, which can optionally be interrupted by an oxygen atom, or - (CH 2 ) t R 20 ;
  • R 18 each independently represents R 17 , -CF 3 , - (CH 2 ) u COOH or - (CH 2 ) u COOR 21 ;
  • R 19 each independently represents R 17 or -CF 3 ;
  • R 20 each independently represents aryl substituted with one or two R 22 groups
  • R 21 are each independently of the other C 1-6 alkyl, benzyl or
  • R 22 each independently of one another hydrogen, halogen,
  • R 23 each independently represents hydrogen or -COR 21 ;
  • r 1 to 20;
  • s and t are each independently 0 to 12; and u is 0 to 4.
  • the present invention further includes pharmaceutically acceptable salts and esters of the compounds described above.
  • the pharmaceutically acceptable salts can be base addition salts. These include salts of the compounds with inorganic bases such as alkali metal hydroxides, alkaline earth metal hydroxides or with organic bases such as mono-, di- or triethanolamine.
  • esters of the compounds include, in particular, physiologically readily hydrolyzable esters, for example alkyl, pivaoxyloxymethyl, Acetoxymethyl, phthalidyl, indanyl and methoxy methylene esters.
  • alkyl used here includes straight-chain, branched or cyclic alkyl groups, such as methyl, ethyl, n- and isopropyl, n-, iso- or t-butyl, n-pentyl, neopentyl, n-undecyl, n- Dodecyl-, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, cyclopentyl, cyclohexyl, cyclododecyl etc.
  • alkenyl encompasses straight-chain, branched or cyclic alkenyl groups, such as ethenyl, propenyl, butenyl, decenyl, heptadecenyl, cyclopentenyl, cyclohexenyl etc.
  • alkynyl encompasses straight-chain or branched alkynyl groups such as ethynyl, propynyl, butynyl, decynyl, heptadecynyl, etc.
  • aryl encompasses aromatic hydrocarbons having 5 to 14 carbon atoms, which may contain a heteroatom such as oxygen, sulfur or nitrogen.
  • phenyl, naphthyl and pyridyl groups are preferred.
  • halogen atom includes fluorine, chlorine, bromine or iodine atom, with fluorine or chlorine atom being particularly preferred.
  • the pyrrole compounds of the general formula I according to the invention preferably contain the radical R 1 -COOR 29 -Y'-COOR 29 , -Tz, -Y'-Tz, -CONHS (O) 2 -R 31 , -Y'-CONHS (O) 2 ⁇ R 31 -NHS (O) 2 -R 31 , -Y'-NHS (O) 2 -R 31 , -S (O) 2 NH-CO-R 31 -Y'-S (O) 2 NH- CO-R 31 , -S (O) 2 -NH-R 29 , -Y'-S (O) 2 -NH-R 29 -CONR 29 R 29 , -Y'-CONR 29 R 29 , -CONHCO-R 29 , -Y'-CONHCO-R 29 -PR 31 R 31 or -Y'-PR 31 R 31 , wherein Y 1 is a C 1-6 alkyl or C 2-8 alken
  • Suitable radicals R 1 for the present invention are, in particular, formic acid, acetic acid, 3-propionic acid, 4-butyric acid, 3- ⁇ -methylpropionic acid, 3-acrylic acid and 5-oxovaleric acid.
  • Formic acid, acetic acid, 3-propionic acid, 3- ⁇ -methylpropionic acid and 4-butyric acid are preferred.
  • R 2 are the groups -CO-R 24 and -CHR 24 -NH-COR 25 , where R 24 and R 25 independently of one another represent -D, -aryl or -D-aryl, where D is a C 5-1 g-alkyl, alkenyl or alkynyl group, which can optionally be interrupted by one or more oxygen atoms and aryl is an aryl group optionally substituted with 1 to 3 substituents selected from the group R 26 , R 27 and R 28 .
  • R 26 , R 27 and R 28 are independently selected from:
  • R 29 in each case independently of one another denotes hydrogen, C 1-20 alkyl or C 2-20 alkenyl or alkynyl group, which can optionally be interrupted by an oxygen atom, or - (CH 2 ) C R 32 .
  • R 30 each independently means R 29 , -CF 3 , - (CH 2 ) d COOH or - (CH-) d COOR 33 .
  • R 31 each independently means R 29 or -CF3.
  • R 32 each independently represents aryl, substituted with one or two R 34 groups.
  • R 33 each independently denotes C 1-6 alkyl, benzyl or phenyl.
  • R 34 each independently represents hydrogen, halogen, C 1-12 alkyl, C 1-12 alkoxy, C 1-12 alkylthio, C 1-12 alkylsulfonyl, C 1-12 alkylcarbonyl, -CF 3 . -CN or -NO 2 .
  • R 35 each independently represents hydrogen or -COR 33 .
  • a is 1 to 20
  • b and c are each independently 0 to 12 and d is 0 to 4.
  • saturated or unsaturated alkylcarbonyl groups represented by R 2 in general formula I (C 5-19 alkyl, alkenyl or alkynyl) carbonyl groups are particularly suitable, which can optionally be interrupted by a hetero atom, in particular an oxygen atom.
  • R 2 can be substituted with an aryl group.
  • This aryl group can optionally contain one or more, in particular one or two, substituents.
  • suitable substituents are radicals from the group consisting of halogen atoms, nitro, trifluoromethyl, C 4-12 alkyl, C 1-12 alkoxy and hydroxyl groups.
  • (C 7-17 alkyl) carbonyl and aryl (C 7-17 alkyl) carbonyl groups are particularly preferred.
  • the radical R 2 in the general formula I is not bound to the pyrrole nitrogen atom.
  • Preferred compounds are those in which R 2 is in the ⁇ position to the radical R 1 .
  • the groups hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, dodecanoyl, hexadecanoyl and octadecanoyl may be mentioned in particular.
  • R 3 preferably represents a hydrogen atom, a halogen atom or a group -E, -aryl, -E-aryl or -E-Q ', where E is a C 1-20 alkyl or C 2-20 alkenyl or Alkynyl group, which can optionally be interrupted by an oxygen atom, aryl is an aryl group optionally substituted with 1 to 3 substituents selected from the group R 36 , R 37 and R 38 , Q 'is selected from one of the groups (5) to ( 24) as defined above for R 26 -R 28 and R 36 , R 37 and R 38 are defined as the groups R 26 -R 28 defined above.
  • Suitable radicals R 3 are in particular a hydrogen atom, a C 1-20 alkyl or C 2-20 alkenyl or alkynyl group, which may be represented by an oxygen atom can be interrupted, or an optionally substituted aryl group.
  • the alkyl, alkenyl or alkynyl group can be selected with a substituent from carboxy, cyano, amide, N, N-di-C 1-4 -alkylamide, in particular N, N-dimethylamide, hydroxy and aryl group be substituted.
  • Both the aryl group representing R 3 and the aryl group which can be a substituent of the alkyl, alkenyl or alkynyl group, can be substituted.
  • 1 or 2 substituents are preferably selected from C 1-4 alkyl, in particular methyl, C 1-4 alkoxy, in particular methoxy, trifluoromethyl, hydroxy, amino, N, N-di-C 1 -4- alkylamino-, especially N, N-dimethylamino-, amino-C 1-4 -alkyl-, especially aminomethyl-, cyano-, amide-, N, N-Di-C 1-4 -alkylamide-, especially N , N-dimethylamide, carboxy, C 1-4 alkylsulfonyl, especially methylsulfonyl and halogen atom.
  • the radicals R 3 are in particular hydrogen, methyl, ethyl, propyl, butyl, pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, dodecyl, pentadecyl, octadecyl, 3-phenylpropyl, 4-methylbenzyl, 4-methoxybenzyl, 4 -Fluorobenzyl, 4-chlorobenzyl, 3-chlorobenzyl, 2-chlorobenzyl, 3,4-dichlorobenzyl, 4-trifluoromethylbenzyl, 4-hydroxybenzyl, 4-aminomethylbenzyl, 4-cyanobenzyl, 4- (N, N-dimethylcarbamoyl) -benzyl, 4-carboxybenzyl, 6-carboxypentyl, 5-cyanopentyl, 5- (N, N-dimethylcarbamoyl) pentyl
  • R 3 each independently represents a hydrogen atom, a C 1-5 alkyl, in particular neopentyl, benzyl or phenyl group. According to the invention, preference is given to those groups for the radicals R 1 , R 2 and R 3 which, if present, contain saturated alkyl groups without heteroatoms.
  • the invention particularly includes compounds of the general formula I ':
  • A represents a C 7-17 alkyl or aryl (C 7-17 alkyl) group with an optionally substituted aryl radical
  • R 3 is in each case selected independently of one another from the group consisting of a hydrogen atom, a methyl, phenyl and benzyl group
  • m is an integer from 0 to 3.
  • R 2 a (C 7 -7 alkyl) carbonyl or aryl (C 7-17 alkyl) carbonyl group and for R 3 each independently contain a hydrogen atom or a methyl or benzyl group.
  • R 1 3-propionic acid and contain for R 2 is a (C 7-17 -alkyl) carbonyl for R 3 is a methyl group.
  • R 1 acetic acid or 3-propionic acid R 2 is a Octadecanoyl distr and R 3 is a hydrogen atom or a methyl or benzyl group.
  • 3- (3,5-dimethyl-4-octadecanoylpyrrol-2-yl) propionic acid which, as the third substituent R 3 on the pyrrole nitrogen atom, has an nC 1-5 alkyl, neopentyl, phenyl or benzyl group. If the compounds also contain amino or dialkylamino groups, the present invention also includes their salts, in particular their hydrochlorides.
  • the substituted indole compounds of the general formula II preferably contain as substituents R 4 , which stands for -X, -X-aryl, -CO-R 9 or -CHR 9 -NH-COR 10 , where X is a C 8-20 -alkyl- or is C 2-20 alkenyl group and aryl is as defined above; and R 9 and R 10 , which independently of one another represent -W, -aryl or -W-aryl, where W is a C 1-19 alkyl or C 2-19 alkenyl group and aryl is as defined above.
  • R 5 preferably represents -COOH, -Y-COOH, -Tz or -Y-Tz, where Y is a C 1-8 alkyl or C 2-8 alkenyl group and is preferably not interrupted by an oxygen atom.
  • Z in R 6 is preferably a C 1-20 alkyl or c 2-20 alkenyl group and the radicals R 7 , R 8 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are preferably independent selected from each other:
  • radicals R 18 , R 19 , R 20 , R 21 , R 22 and R 23 as well as r, s, t and u are as defined above and R 17 each independently represents hydrogen, C 1-20 -alkyl - or C 2-20 alkenyl group or - (CH 2 ) t R 20 .
  • the compound of the general formula II has the radicals R 4 , R 9 and R 10 as defined above as preferred and R 5 as -COOH or -Y-COOH, where Y is a C 1-8 alkyl group is.
  • R 6 preferably represents a hydrogen atom, a group -Z, -aryl, -Z-aryl or -Z-OR 17 , where Z represents a C 1-20 alkyl or C 2-20 alkenyl group.
  • R 7 , R 8 , R 11 , R 12 , R 13 , R! 4 , R 15 and R 16 are independently selected from:
  • R 4 preference is given to those compounds in which R 4 is -CO-R 9 or -CHR 9 -NH-COR 10 .
  • R 4 is a C 8-18 alkanoyl group or an optionally C 6-12 alkoxy-substituted benzoyl, phenylethanoyl or phenylpropanoyl group or in which R 4 is -CHR 9 -NH-COR 10 and R 9 is heptadecyl and R 10 is heptadecyl, 3-phenylpropyl or methyl.
  • R 4 octanoyl, decanoyl, dodecanoyl, tetradecanoyl, octadecanoyl, undec-10-enoyl, 4-hexylbenzoyl, 2-dodecyloxybenzoyl, 3-dodecyloxybenzoyl, 4-dodecyloxybenzoyloyloxybenzoyloyloyloxybenzoyl , 2-decyloxybenzoyl, 10-phenyldecanoyl, 2-decyloxyphenylethanoyl, 4-decyloxyphenylethanoyl, 3- (2-decyloxyphenyl) propanoyl, 3- (3-decyloxyphenyl) propanoyl and 3- (4-decyloxyphenyl) propanoyl.
  • Octadecanoyl is particularly suitable as radical R 4 .
  • Preferred radicals R 5 are formic acid, acetic acid or 3-propionic acid, formic acid being particularly preferred.
  • a hydrogen atom, a methyl, hexyl, dodecyl, octadecyl, optionally substituted propyl or hexyl or optionally substituted benzyl group or a 3-pyridylmethyl group is preferred as the R 6 radical.
  • Halogen preferably chlorine, methyl, carbamoyl, methoxy, cyano, hydroxy, trifluoromethyl, t-butyl, carboxy and their amide and N, N-dimethylamide are particularly suitable as substituents of the benzyl group.
  • Hydroxy, mercapto, amino, carboxy, carbamoyl and phenyl are particularly suitable as substituents of the alkyl groups.
  • R 6 hydrogen, methyl, hexyl, dodecyl, octadecyl, 3-phenylpropyl, benzyl, 4-chlorobenzyl, 4-methylbenzyl, 4-carbamoylbenzyl, 4-methoxybenzyl, 3-pyridylmethyl, 4-cyanobenzyl , 4-hydroxybenzyl, 3-hydroxypropyl, 4-trifluoromethylbenzyl, 3,4-dichlorobenzyl, 4-t-butylbenzyl, 4-carboxybenzyl and their amide and N, N-dimethylamide, 6-hydroxyhexyl, 6-mercaptohexyl, 6-aminohexyl, 5-carboxypentyl and 5-carbamoylpentyl.
  • a hydrogen atom is preferred as the substituent R 7 and a hydrogen atom, a halogen, in particular 4- or 5-chlorine, or an alkoxy, in particular 5-methoxy group, is preferred as the substituent R 8 .
  • R 7 and R 8 represent a hydrogen atom.
  • the compounds according to the invention have proven to be potent phospholipase A 2 inhibitors.
  • the compounds are therefore useful as pharmaceuticals for the prevention and / or treatment of diseases caused by products or By-products of this enzyme are caused or co-caused, such as for the treatment of the rheumatic type and for the prevention and treatment of allergy-induced diseases.
  • the compounds according to the invention thus represent, inter alia, effective analgesics, anti-inflammatory drugs, antipyretics, antiallergics and broncholytics and are useful for thrombosis prophylaxis and for the prophylaxis of anaphylactic shock and for the treatment of dermatological diseases such as psoriasis, urticaria, acute and chronic rashes of allergic and non-allergic genes .
  • the compounds according to the invention can be administered either as individual therapeutic active substances or as mixtures with other therapeutic active substances. They can be administered alone, but in general they are administered in the form of pharmaceutical agents, i.e. as mixtures of the active ingredients with suitable pharmaceutical carriers or diluents.
  • the compounds or agents can be administered orally, parenterally, by inhalation or topically (including dermal, transdermal, buccal and sublingual).
  • Oral agents can, for example, be in the form of tablets or capsules, also in retarded form, and can contain conventional excipients such as binders (e.g. acacia syrup, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone), fillers (e.g. lactose, sugar, corn starch, calcium phosphate, sorbitol or Glycine), lubricants (e.g. magnesium stearate, talc, polyethylene glycol or silicon dioxide), disintegrating agents (e.g. starch) or wetting agents (e.g. sodium lauryl sulfate).
  • binders e.g. acacia syrup, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone
  • fillers e.g. lactose, sugar, corn starch, calcium phosphate, sorbitol or Glycine
  • lubricants e.g. magnesium stearate
  • Oral liquid preparations can be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs or sprays, etc. and may be dry powder for reconstitution with water or other suitable vehicle.
  • Such liquid preparations can contain customary additives, for example suspending agents, flavoring agents, diluents or emulsifiers.
  • Solutions or suspensions with conventional pharmaceutical carriers can be used for parenteral administration.
  • the compounds can be in aqueous or partially aqueous solution which can be used in the form of an aerosol.
  • Agents for topical use can be present, for example, as pharmaceutically acceptable powders, lotions, ointments, creams, gels or as therapeutic systems which contain therapeutically effective amounts of the compounds according to the invention.
  • the dose required depends on the form of the pharmaceutical agent used, the type of application, the severity of the symptoms and the specific subject (human or animal) being treated. Treatment is usually started at a dose below the optimal dose. The dose is then increased until the optimal effect is achieved for the given conditions.
  • the compounds of the invention are best administered in concentrations at which effective effects can be achieved without causing harmful or disadvantageous effects. They can be administered in a single dose or in multiple doses.
  • the effectiveness of the compounds according to the invention can be determined from the inhibition of phospholipase A 2 .
  • the phospholipase A 2 is stimulated with calcium ionophore A23187 in intact cattle thrombocytes, thereby triggering the release of arachidonic acid from the membrane phospholipids.
  • the dual cyclooxygenase / 12-lipoxygenase inhibitor 5, 8, 11, 14-eicotatetraic acid is added. After purification by means of solid phase extraction, the arachidonic acid released is determined by reversed phase HPLC with UV detection.
  • the inhibition of the enzyme by a test substance results from the ratio of the amounts of arachidonic acid formed in the presence or absence of the test substance. Further information on the test system is given in Examples 68 and 107.
  • the present invention further comprises processes for the preparation of the substituted pyrrole compounds according to claim 1 and the substituted indole compounds according to claim 19.
  • the 3,5-dimethyl-4-octadecanoylpyrrol-2-yl-formic acid can be obtained, for example, by saponification of the 3,5-dimethyl4-octadecanoylpyrrol-2-yl-formic acid ester.
  • the corresponding nitrogen-methylated compound can be obtained from the ester in an analogous manner after prior N-alkylation with methyl p-toluenesulfonate (Scheme 1).
  • the homologous N-methylated acetic acid derivative is e.g. from the 3, 5-dimethyl-4-octadecanoylpyrrol-2-yl formic acid as shown in Scheme 2.
  • Dimethylacylpyrroles with a propionic acid or ⁇ -methyl-propionic acid side chain in position 2 of the pyrrole nucleus can be prepared from the corresponding pyrrole unsubstituted in position 2 by Friedel-Crafts alkylation with acrylic acid or ⁇ -methylacrylic acid.
  • the N-methylated acylpyrrole propionic acid can be obtained, for example, from dimethylacylpyrrole by Friedel-Crafts alkylation with methyl acrylate, N-methylation with methyl p-toluenesulfonate and subsequent saponification (Scheme 3).
  • reaction sequence given in Scheme 4 is suitable for the synthesis of analogous compounds with an acrylic acid side chain in position 2 of the pyrrole.
  • 3- (1,3,5-Trimethyl-4-acylpyrrol-2-yl) propionic acids can also be prepared starting from 1,2,4-trimethylpyrrole as an alternative to the method given above (Scheme 3). This is first implemented by Friedel-Crafts alkylation with methyl acrylate to give methyl 3- (1,3,5-trimethylpyrrol-2-yl) propionate, from which the corresponding 4-acyl derivatives are then converted by Friedel-Crafts acylation with carboxylic acid chlorides can be synthesized. Saponification of these compounds gives the desired carboxylic acids (Scheme 7).
  • Acylpyrrole formic acids according to the invention in which positions 3 and 4 are each occupied by a hydrogen atom, can be prepared, for example, from 1-methylpyrrol-2-yl formic acid methyl ester by Friedel-Crafts acylation, for example with octadecanoic acid chloride and subsequent saponification of the acylpyrrole ester obtained (Scheme 8).
  • 1-methylpyrrol-2-ylacetic acid ethyl ester is first acylated using Vilsmeier synthesis.
  • the 1-methyl-5-octadecanoylpyrrol-2-ylacetic acid ethyl ester is also formed.
  • the saponification of the esters therefore also provides a compound according to the invention in which R 1 and R 2 are in the ⁇ position to the pyrrole nitrogen atom.
  • the reaction sequence also given in Scheme 8 is suitable for the synthesis of the homologous propionic acids.
  • Octadecanoic acid chloride AlCl 3 , CH 2 Cl 2 ;
  • Octadecanoic acid dimethylainide, P ⁇ Cl 3 , benzene; (e) 10% aqueous KOH, ethanol; (f) CH 2 CHCOOCH 3 , BF 3 , CH 2 Cl 2 .
  • pyrrole compounds according to the invention with different substituents in the 1-position, one can start from an N-unsubstituted acylpyrrole, such as, for example, 2,4-dimethyl-3-octadecanoylpyrrole (Scheme 16).
  • the first step is to alkylate the pyrrole nitrogen atom. This reaction takes place under, for example Use of the corresponding alkyl halides in the presence of a base, for example alkali metal alcoholate, such as potassium t-butoxide, in an inert solvent, such as DMSO or the like, as usual.
  • a base for example alkali metal alcoholate, such as potassium t-butoxide
  • an inert solvent such as DMSO or the like
  • the alkylation can also be carried out heterogeneously with the corresponding alkyl halides using phase transfer catalysts in the customary manner (see, for example, Wang et al. Can. J. Chem. 1977, 55, 4112-4116).
  • the acid side chain can then be introduced as described in the examples above.
  • Analogous compounds substituted on the phenyl group can be synthesized in a corresponding manner.
  • the starting compounds necessary for this can be obtained like the 2, 2-dimethyl-6-phenyl-2,3-dihydro-1H-pyrrolizine by reaction of 2,4,4-trimethyl-D1-pyrroline with phenyl-substituted ⁇ -bromoacetophenones.
  • acyl radical is first introduced in position 2 of the pyrroles by Vilsmeier synthesis or Friedel-Crafts acylation. By reaction with ethyl diazoacetate and subsequent saponification, if necessary after prior N-alkylation, such acetic acid derivatives can be prepared (Scheme 18).
  • the first step in the preparation of these compounds according to the invention consists in the introduction of the acyl group in position 3 of the pyrroles.
  • the acid side chain on the pyrrole nitrogen is then reacted with bromocarboxylic acid esters, e.g. Benzyl bromoacetate, in the presence of a base, e.g. Potassium t-butoxide, in an inert solvent such as e.g. DMSO, introduced.
  • a base e.g. Potassium t-butoxide
  • an inert solvent such as e.g. DMSO
  • R 1 is in the 2-position and R 2 in the 3-position on the pyrrole ring can be prepared, for example, from ethyl 4,5-dimethylpyrrole-2-carboxylate.
  • this is first converted into the 3-acyl derivatives, for example by Friedel-Crafts acylation with acid chlorides. Saponification of the compounds obtained, if appropriate after prior N-alkylation, gives the desired carboxylic acids (Scheme 21).
  • reaction sequence given in Scheme 22 is suitable for the synthesis of analogous compounds with a propionic acid side chain in position 2 of pyrrole.
  • indole compounds according to the invention can be prepared according to the following methods.
  • Indole-2-carboxylic acid esters 1 can be reacted with carboxylic acids in the presence of trifluoroacetic anhydride and polyphosphoric acid, optionally in a suitable solvent such as CH 2 Cl 2 or nitrobenzene, or with carboxylic acid chlorides according to Friedel-Crafts to give 3-acylindole-2-carboxylic acid esters 2 (see Murakami et al. Chem. Pharm. Bull. 1985, 33, 4707-4716; Murakami et al. Heterocycles 1980, 14, 1939; Murakami et al. Heterocycles 1984, 22, 241-244; Murakami et al. Chem Pharm. Bull.
  • esters can be alkylated to the compounds 4 on the indole nitrogen.
  • the N-alkylation is carried out, for example, as usual using the corresponding alkyl halides in the presence of a base, for example alkali metal alcoholate, such as potassium t-butoxide, in an inert solvent, such as DMSO or the like.
  • the N-alkylation can also be carried out heterogeneously with toluenesulfonic acid alkyl esters or alkyl halides using phase transfer catalysts in an organic solvent, such as ether, with the addition of powdered alkali metal hydroxide, such as sodium hydroxide.
  • the carboxylic acids 3 or 5 according to the invention are obtained from ester 2 or 4 by ester cleavage.
  • the ester cleavage can be carried out hydrolytically, for example with alcoholic potassium hydroxide solution, or in the case of the benzyl esters also hydrogenolytically, for example in THF with hydrogen in the presence of Pd / C. The latter method is particularly indicated if, in addition to this ester group, further hydrolysis-sensitive functions are contained in the compounds.
  • compounds of formula 5 can also be prepared by method 2.
  • the reactions correspond to the reactions of method 1.
  • the indole-2-carboxylic acid esters 1 are first N-alkylated and only then acylated in position 3 of the indole.
  • alkanoic acids 9 or 11 homologous to 3-acylindole-2-carboxylic acids
  • the esters 8 obtained can be alkylated on the indole nitrogen to give the compounds 10.
  • the N-alkylation can be carried out as described in Method 1.
  • the carboxylic acids 9 and 11 according to the invention are obtained from 8 or 10 by ester cleavage.
  • the ester cleavage can be carried out hydrolytically, for example with alcoholic potassium hydroxide solution, or in the case of the benzyl esters also hydrogenolytically, for example in THF with hydrogen in the presence of Pd / C.
  • the latter method is particularly indicated if, besides this ester group, further hydrolysis-sensitive functions are contained in the compounds.
  • 3- (1-Acylaminoalkyl) indole-2-alkanoic acids 15 and 1/7 can be prepared using the reaction sequence shown in Method 5.
  • the starting compounds are the 3-acylindole-2-carboxylic acid esters 2 (see Method 1). These are first reductively aminated at the * keto group; the amination is carried out, for example, by reaction with hydroxylamine hydrochloride, for example in ethanol / pyridine or with Ethanol / BaCO 3 , to the oximes 13 and subsequent reduction of the oximes with zinc in sodium acetate / glacial acetic acid.
  • R 4 is -X or -X- aryl
  • R 4 is -X or -X- aryl
  • the desired indole derivatives 18 are obtained by reducing the keto group, for example with NaBH 4 / BF 3 -ethyl ether complex in a suitable solvent or solvent mixture, such as THF / methyl acetate, and subsequent ester cleavage.
  • a suitable solvent or solvent mixture such as THF / methyl acetate
  • R 5 is -Tz or -Y-Tz
  • R 5 is -COOH or -Y-COOH
  • Tables 1 through 4 show representative compounds of the invention.
  • Toluene is a solution of 137 mg (1.2 mmol) ethyl diazoacetate in 1.5 ml absolute at a bath temperature of 115-120 ° C. Toluene was added in portions of a few drops each with stirring over 30 minutes. A spatula tip of copper powder is added after each addition of ethyl diazoacetate. Then heated for a further 15 min.
  • the product is isolated from the residue by SC (silica gel, 1st petroleum ether / ethyl acetate 8.5 + 1.5, 2nd petroleum ether / ethyl acetate 8 + 2).
  • SC sica gel, 1st petroleum ether / ethyl acetate 8.5 + 1.5, 2nd petroleum ether / ethyl acetate 8 + 2).
  • the oil remaining after concentration of the product fractions crystallizes after a short time.
  • CH 2 Cl 2 is the mixture of 750 mg (5 mmol) succinic acid methyl ester chloride, 693 mg (5.2 mmol) AICI3 and 5 ml absolute at -20 ° C. CH 2 Cl 2 added. The mixture is stirred at -20 ° C. for 1 h and then at room temperature for 1 h. Then water is added and the mixture is extracted twice with CH 2 Cl 2 . The extracts are washed with saturated aqueous NaHCO 3 solution, dried over Na 2 SO 4 and concentrated.
  • the main product is isolated from the residue by SC (silica gel, petroleum ether / CH 2 Cl 2 / ethyl acetate 50 + 90 + 10).
  • SC sica gel, petroleum ether / CH 2 Cl 2 / ethyl acetate 50 + 90 + 10.
  • the product fractions are concentrated to a few ml. After adding petroleum ether, the mixture is concentrated again, the product precipitating.
  • CH 2 Cl 2 is the solution of 300 mg (0.83 mmol) of 2,4-dimethyl-3-octadecanoylpyrrole (see Example 3 A) in 6 ml of absolute at 0 ° C. CH 2 Cl 2 added.
  • the mixture is stirred at room temperature for 24 h. Then water is added and the mixture is extracted twice with ether / CHCl 3 (3 + 1).
  • Petroleum ether / ethyl acetate 1. 9 + 1, 2. 7 + 3) as an oil.
  • Example 14 A 293 mg (1.5 mmol) of methyl 3- (1,3,5-trimethylpyrrol-2-yl) propionate (see Example 14 A) are reacted with 372 mg (1.7 mmol) of dodecanoic acid chloride according to Example 14 B.
  • the product is purified by means of SC (silica gel, petroleum ether / ethyl acetate 1.9 + 1, 2.8 + 2) and recrystallized from ethanol / water.
  • Example 20 100 mg (0.23 mmol) of 1-methyl-5-octadecanoylpyrrol-2-yl-ethyl acetate (see Example 20) are saponified in accordance with Example 14 C. However, the product is precipitated from petroleum ether.
  • Example 22 B 270 mg (0.60 mmol) of ethyl 3- (1-methyl-5-octadecanoylpyrrol-2-yl) propionate (see Example 22 B) are saponified in accordance with Example 14 C. Deviating from this, the carboxylic acid is extracted with ether / CH 2 Cl 2 (3 + 1). The product is precipitated from petroleum ether.
  • the mixture is then filtered off with suction and the filter residue is washed with CH 2 Cl 2 .
  • the filtrates are dried over Na 2 SO 4 , the solvent is distilled off and the resulting 1-methyl-3,5-diethylpyrrole-2,4-dicarboxylic acid dimethyl ester is precipitated from methanol / water and suction filtered.
  • the solid is then portioned to a mixture of 10 ml of water and 29 ml of conc. H 2 SO 4 added.
  • the mixture is heated on the boiling water bath for 1 h, diluted with water after cooling, alkalized with ice-cooling with 50% NaOH solution and extracted twice with ether. After drying over Na 2 SO 4 , the mixture is concentrated and the product is isolated from the residue by distillation (boiling point 87 ° C. at 20 mm Hg).
  • Example 14 C saponified. The product is precipitated from methanol. Yield: 57 mg (68%)

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Abstract

L'invention concerne de nouveaux dérivés de l'acide acylpyrrole-alcanoïque et de l'acide indole-2-alcanoïque, de formule générale (I), ainsi que leurs sels et esters et leur utilisation pharmaceutique. Les composés selon l'invention sont de puissants inhibiteurs de la phospholipase A2 et sont donc utilisables pour la prévention et/ou le traitement d'affections provoquées ou aggravées par une activité accrue de la phospholipase A2, telles que inflammations, douleurs, fièvre, allergies, asthme, psoriasis et choc endotoxinique.
PCT/DE1994/001121 1993-11-12 1994-09-20 Acides acylpyrrole-alcanoiques et indole-2-alcanoiques et leurs derives utilises comme inhibiteurs de la phospholipase a¿2? WO1995013266A1 (fr)

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WO1998005637A1 (fr) * 1996-08-01 1998-02-12 Merckle Gmbh Acides acylpyrroldicarboxyliques et acides acylindoldicarboxyliques et leurs derives utilises en tant qu'inhibiteurs de la phospholipase a2 cytosolique
US6310217B1 (en) 1996-08-01 2001-10-30 Merckle Gmbh Acylpyrroledicarboxylic acids and acylindoledicarboxylic acids and their derivatives as inhibitors of cytosolic phospholipase A2
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US6828344B1 (en) 1998-02-25 2004-12-07 Genetics Institute, Llc Inhibitors of phospholipase enzymes
WO1999043654A3 (fr) * 1998-02-25 1999-10-28 Genetics Inst Inhibiteurs d'enzymes phospholipases
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