CA2098366A1 - Substituted (benzothiazolyl- and quinoxalyl-methoxy) phenyl-acetic acid derivatives - Google Patents
Substituted (benzothiazolyl- and quinoxalyl-methoxy) phenyl-acetic acid derivativesInfo
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- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
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- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
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Abstract
Substituted (benzothiazolyl- and quinoxalyl-methoxy)-phenyl-acetic acid derivatives A b s t r a c t Substituted (benzothiazolyl- and quinoxalyl-methoxy)-phenyl-acetic acid derivatives are prepared either by reaction of heterocyclylmethylhalogen compounds with corresponding phenoxy compounds, either directly or with subsequent alkylation, or by reaction of the hetero-cyclylmethylhalogen compound with phenoxy compounds and subsequent reaction with suitable Grignard compounds. The substituted (benzothiazolyl- and quinoxalyl-methoxy)-phenyl-acetic acid derivatives can be employed as active compounds in medicaments.
Description
The inven~ion relates to substituted (benzothiazolyl- and quinoxalinyl methoxy)phenyl-acetic acid derivatives, to processes for their prepara~ion and to their use in medicaments.
It has already been disclosed that ~-substituted 4-(quin-olin-2-yl-methoxy)phenylacetic acid derivatives have a lipoxygenase inhibiting action [cf. EP 344,519 (US
4,970,215) and EP 339,416].
The present invention relate~ to substituted ~benzo-thiazolyl- and quinoxalyl-methoxy)phenyl-acetic acid derivatives of the general formula (I) A
D ~ N ~ L
in which R
~, B, D, E and L are identic~l or different and represent hy~rogen, hydroxyl, halogent trifluoro-methyl, trifluoromethoxy or carboxyl, or repre~nt straight-chain or branched alkyl having up to 10 carbon a~om~, which i8 optionally sub~ti~uted Le A 29 140 - 1 -- `~ 2 ~ ~ ~ 3 ~ ~
by hydroxyl or halogen, or repres~nt straight-chain or branched alkoxy or alkoxycarbonyl having up to 10 carbon atoms, or represent aryl having 6 to 10 carbon atoms, which i.s optionally su~stituted by halogen, nitro or cyano or by straight-chain or branched alkyl or alkoxy each having up to 8 carbon atoms, G represents a sulphur atom or the group of the formula -N=CH-, R1 represents cycloal~yl having 3 to 12 carbon atom~, or represents ~kraight-chain or branehed alkyl having up ~o 10 carbon atoms, which i8 optionally ~ub~tl-tuted by aryl having 6 to lO carbon atoms, R2 represents hydrogen, or represents a group of the formula -oR4, in which R4 denote~ hydrogen, straight-chain or branched alkyl having up to 8 carbon a~om~, ben~yl or phenyl, R3 repre3ants hydroxyl, ~traight-chaln or branched alkoxy having up to 8 carbon atoms or phenoxy, or repre~ents a group of the formula -NHSo2-R5J
Le A 29 140 - 2 -`
~9~
in which R5 ~denotes s~raight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by phenyl, which can in turn be sub~tituted by straight-chain or branched alkyl having up to 6 carbon atoms or halogen, ~r d~notes phenyl which can optionally be ~ubsti-tuted by halogen or trifluoromethyl or by s~raight-chain or branched alkyl or alkoxy each having up ~o 6 carbon a~o~s and their salt~.
In the context of the present invention, physiologically acceptable ~alts are preferred. Phy~iologically accep-table 8alt9 of the substituted (benzothiazolyl- and quinoxalyl-methoxy)phenyl-acetic acid derivatives c~n be ~alts of the substances according to the invention with mineral acid~, carboxylic acids or sulphonic acids.
Particularly preferred ~alts are, for example, tho~e with hydrochloric acid, hydrobromic acid, sulphuric acid, ~0 . phosphoric acid, methane~ulphonic acidr ethanesulphonic acid, toluenesulphonic acid, benzene~ulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic ~a~id, tartaric acid, ci~ric ac~d, f~maric acid, maleic acid or benzoic acid.
:: :
Salt3 in the context of ~he present invention are addi-tLon-lly metal aalt~, preferably of th- unlval-nt metals, Le A 29 140 - 3 -- ~2~9~3~
and the am~onium salts. Alkali metal salts such as, for example, sodium, potassium and ammonium salts are preferred;
The compounds according to the invention exist in stereo-isomeric forms which behave either as image and mirror .image (enantiomers), or which do not behave as image and mirror image (dias~ereomers). The invention relates both to the antipodes and to the racemic forms as well as to the diastereomer mixtures. Like the diastereomer~, the racemic forms can also be separated in a known manner into the stereoisomerically uniform constituents tcf. E.L. Eliel, Stereochemistry of Carbon Compounds, McGr~w Hill, 1962].
Preferred compounds of the general formula (I) are those in which A, B, D, E and L are identical or different and represent hydrogen, fluorine, chlorine, bromine, trifluoromethoxy or carboxyl, represent straight~chain or branched alkyl having up to 8 carbon atom~, which is optionally ubsti~uted by hydroxyl, fluorine, chlorine or bromine, represent straight-chain or branched aI~oxy or alkoxycarbonyl each having up to 8 carbon atomæ, or repre~ent phenyl which is optionally ~ub~tituted by fluorine, chlorine, bromine, nitro or cyano or by straight-chain or branched alkyl or alkoxy each Le A 29 140 - 4 -3 ~ ~
having up to 6 carbon atom~, G repr~sent~ a sulphur atom or the group of the formula -N=CH-, Rl represents cyclopropyl~ cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, or represent~ straight chain or branched alkyl having up to 8 carbon atoms r which is optionally substi-tuted by phenyl or naphthyl, R2 represents hydrogen or a group of the formula -oR4, in which .
R4 denote~ hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, benzyl or phenyl, R3 represents hydroxyl or s~raight-chain or branched alkoxy having up to 6 carbon atoms, or : represents a.group of the formula ~NHSo2-~5, in which R5 denote~ straight-chain or branched alXyl having up to 6 carbon atom~, which 1 optionally sub~tituted by phenyl which can in turn be sub~tituted by straight-chain or branched alkyl having up to 6 carbon atom~, fluorine, chlorine Le A 29 140 - 5 -;~983~
or bromine, or denotes phenyl which can optionally be substi-tuted by fluorine, chlorine or bromine or by straight-chain or branched alkyl having up to 4 carbon atoms and their ~alts.
Particularly preferred co~pounds of the general formula (I) are those in which A, B, D, E and L are identical or different and represent hydrosen, fluorine, ~hlorine, bromine or traight-chain or branched alXyl or alkoxy each having up to 6 carbon atom~, 15 G represents a sulphur atom or the group of the formula -N=CH-, :: Rl represents cyclopentyl, cyclohexyl or cycloheptyl r or repre~ents:straight-chain or branched al~yl having : 20 up t~ 6 carbon atoms, which is optionally ~ubsti-tuted by phe~yl, R2: represents hydrogen or a group of the foxmula -OR'j Le A 29 140 - 6 -. ' ' , , .
æ~983~
in which R4 denotes hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or phenyl, R3 represents hydroxyl or straight-chain or branched alkoxy having up to 4 carbon atoms, or represents a group of the formula -NHSoz-R5r in which Rs denokes ætraight-chain or branched alkyl having up to 4 carbon atoms, which i6 optionally subs~ituted by phanyl which can in turn be ~u~stituted by straight chain or branched alXyl having up ~o 4 carbon atoms, fluorine or chlorine~
or denotas phenyl which can optionally be substi-tuted by fluorine, chlorine or methyl and their salts.
Very particularly preferred compounds are those in which the radical -CRlR2-~oR3 is in th~ 3- or 4-position relative to the heterocyclylmethoxy radical.
Moreover, a process for the preparation of the compounds of the formula (I) ha~ been found, which is characterised in that Le A 29 140 - 7 -c~9~3~
[A] compounds of the general foxmula (Ia~
A
D ~ N ~ L Rl (Ia) ~ CH- C - R3 in which A, B, D, ~, G, L, Rl and R3 have the meaning mentioned, are prepared by etherifying c~mpounds of the general formula (II~
A
G : ~ (IIj ~: D ~ N l CH2-M
.
:: : :
in which :
: : A,~ B, D, E and G have the meaning mentioned :
10~ ~ and ~ represents halogen, preferably bromine, :
Le A 29 140 - 8 -" ~ ~
either directly with compounds of the general formula (III) R6O L Rl CH-C - R7 (III) o in which ~6 repreæents a typical hydroxyl protective group such as, for example, benzyl or tert-butyl, preferably benzyl, and R7 ropresents Cl-C8-alkoxy, in inert so1vents, i~ appropriate in the pre~ence of ba~e, after removal of the protective group, or initially etherifying in a firs~ step with compounds of the general formula (IIIa) lS ~ CH2~ R7 (IIIa) O
in which Le A 29 140- 9 -2~3~$
R5 and R7 have the meaning mentioned, in inert solvents, if appropriate in the presence of a base, after removal of the protective group and then alkylating in a second step with compounds of the general S formula (IV) Rl-T (IV) in which Rl has th~ meaning mentioned, and : T represents halogen, pre~erably chlorine or bromine, in inert solvents, if appropriate in the presenc~ of a base and in ~he case of the acids (R3 = O~)j hydrolysing the esters by customary methods, and in the case of the sulphonamides (R3 = NHSo2R5), adding an amidation~ starting from th~ corresponding acids, if appropriate after priox activation thereof, by reaction with the re~pective sulphonamines of ~he general formula (VIII) Le A 29 140 - 10 -3 ~ ~
HzN--So2R5 (VIII ~
in inert solvents, if appropriate in the presence of a base and/or auxiliary, . . and in the case of the various esters, optionall~ carry-ing out a transesterification, likewise starting from the activated carboxylic acids, and in the case of the pure enantiomers s~parating the corresponding acida, and introducing or varying the aub~ti~uents A, B, D, and ~, if appropriate, according to cu~tomary methods, lB] :co~pounds of the genoral formula (IIb) ~ G
D ~ N ~ L Rl ~ (IIb) E O ~
~ C ~ 3 OR4 o in which A, B, D, E, G, L, R1, R3 and R4 have the meaning mentioned, Le A 29 140 ~9~3~
are prepared by converting compounds of the general formula (II) initially by reaction with compounds of ~he general formula (V) (V3 O
in which ~, R5 and R7 have the abovementioned meaning to the compounds of the general formula (VI~
A
D ~ N ~ ~ ~ (VI) n which 7 :
A, B, D,:E, G, L and R7 have the abovemen~ionsd meaning, by~theri~ication and in a second step by reducing the product by reaction with Grignard compound3 of the general formula (VII) Le A 29 140- 12 -L~ 3 ~
R1-V (VII) in which Rl has the abovementioned meaning and S V represents the typical Grignard radical W-Z, in which W denotes magnesium or ~inc and Z denotes chlorine, bromine or iodine, or represents lithium, sodium, magnesium~ aluminium or zincl:
: i n inert . olvents, if appropriate in the presence of a base, with removal of the group V, and in the case in which R4 ~ H, etherifying according to cus~o~ary methods .
Le A 29 140 - 13 -2~$3~
and in the case of the acids (R3 = OH) hydrolysing the esters by customary methods, and in the case of the sulphonamides (R3 = NH-So2-R5) adding an amidation, starting from the corresponding acids, if appropriate after prisr activation thereof, by reaction with the respective sulphonamines of the general formula (VIII) H2N-So2-R5 (VIII) in which R5 has the abovementioned meaning, in inert ~olvents, if appropriate in the pre~ence of a ba~e and/or auxiliary, and in the case of the various e~t~rsl optionally carry-ing out a transestarification, likewise starting from the aotivated carboxylic acids, and in the case of the pure enantiomers separating the corresponding enantiomerically pure acids, and introducing or varying the substituent A, B, D, E
and L, if appropriate, according to cuJtomary methods.
: The processes according to the invention can be Le A 29 140 - 14 ~
~9~3~
illustrated by way of example by th~ following reaction scheme:
~A]
~S~CH2 8~
CO2CH~
~ N
Co2H
I,e A 29 140 - 15 -2~9~3~
[A]
0~S~CH2~r HO~0~CH2-CO2CHI
~S~ H3C-(CH2)3-Br 0~0,CH2-C02CH3 ~N CO2H ~ H2N-sO2-cH3 o~~CH3 ~S ~ CO-NH~$02~CH~
(CH2)3-c113 Le A 29 140 - 16 -2~9~3~
[B]
~NlCH2-E1r ~ 1 C02CH~
M~
0~ , ,.. _. ~
~N ~
~
. HO CO2CH3 ' ~
HO CO~H
~he protective groups are removed ~ro~ the corresponding ethers by a customary method, for example by hydrogenoly-tio cleavage of the benzyl ethers in the abovemeneioned ::
Le A 29 140 - 17 -3 ~ ~
inert solvents in the presence of a catalyst using hydrogen gas [cf. additionally Th. Greene: ~Protective Groups in Organic Synthesis~, J. Wiley/Sons, 1981, New York].
Solvents for the etherification can be inert organic solvent which do not change under the reaction condi-tions. These preferably include ethers such as, for ex~mple, dioxane, tetrahydrofuran or diethyl ether, halogenohydrocarbons such as dichloromethane, trichloro-methane, tetrachloromethana, 1,2-dichloroethane or trichloroethylene, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or mineral oil fractions, nitromethane, dimethyl~ormamide, ace~onitrile, acetone or hexamethylpho6phoramide. It is al80 possible to employ mixtures of the solvents.
Bases which can be employed for the etherification are inorganic or organic bases. These preferably include alkali metal hydroxides such as, for example, sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxide~ such as, for example, barium hydroxide, alkali metal carbonates such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates such as calcium carbonate, or organic amines ~trialkyl(C1-C6~-amines) such as triethylamins t or heterocycles such as pyridine, meth~lpiperidine, piperidine or morpholine.
I~ iB also possible to employ alkali metals such as sodium and their hydrides, such as ~odium hydride, as Le A 29 140 - 18 -3 ~ ~
bases;
The ethe~ification is in general carried out in a temperature range from 0C to l150C, preferably from ~10C to +100C.
.The etherification is in general carried out at normal pressure. Howevert it is also possible to carry out the process at reduced pressure ox elevated pressure (for example in a range from 0.5 to 5 bar).
In general, 0.5 to 5, preferably 1 to 2 mol, of halide, relative to 1 mol of the reaction component, are employed. The base is in general employed in an amount ~rom 0.5 to 5 mol, preferably from 1 to 3 mol, relative to the halide.
~ he hydrolysis of the carboxylic acid esters is carried out by customary method~, by treating the esters with customary bases in inert solvents.
. Suitable bases .for the hy.drolysis. are the customary inorganic bases. These preferably include alkali metal hydroxides or alkaline earth metal hydroxides such as, for example, sodium hydroxide, potassium hydroxide or barium hydroxide, ox alkali ~etal carbonates ~uch as sodium carbonate or potassium carbonate or sodium hydrogencarbonate. Sodium hydroxide or pota~ium hydroxide are particularly preferably employed.
Le A 29 140 - 19 -2~9~3~
Suitable solvents for the hydrolysis are water or the organic solvents customary for hydrolysis~ These prefer ably include alcohols such as methanol, ethanol, pro-panol, isopropanol or butanol, or ethers such as tetra-S hydrofuran or dioxane, or dimethylformamide or dLmethylsulphoxide. Alcohols such as methanol, ethanol, propanol or isopropanol are.particularly preferabl~ used. It is also possible to employ mixtures of the solvents mentioned.
The hydrolysis i5 in general carried out in a temperature range from 0C to +100C~ preferably from +20C to ~80C.
In general, the hydrolysis is carried out at normal pres3ure. However, it i8 al80 possible to work at reduced pressure or at elevated pressure (for example from 0.5 to S bar).
When carrying out the hydrolysis, the base is in general employed in an amount from 1 to.3 mol, preferably from 1 to 1.5 mol, rela~ive to 1 mol of the ester. Molar amounts . o..the reactants are particularly.preferably used.
Suitable ~olvents for the reduction are ~he customary organic solvents which do not change under the reaction condition~. The~e preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dLmethyl ether, or hydrocarbon3 such as benzene, toluene, xylene, hexane, cyclohexane, or mineral oil fractions or dimeth-ylformamide. I~ is also possible to use mixtures of the Le A 29 140 - 20 -` 2~3~
~olvents mentioned. Tetrahydrofuran and diethyl ether are preferred.
The reduction is in general carried out in a temperature range from -80C to +30C, preferably at -40C to +25C.
The reduction is in general carried out at normal pressure. However, it is also possible to carry out the process at elevated pressure or at reduced pressure ~or example in a range from 0.5 to 5 bar).
The removal of the group V i5 carried out by the method cu~tomary for Grignard reaction~ using aqueous ammonium chloride ~olu~ion ~cf~ J. March, Advanced Organic Ch~mistry, Second Edition p. 836].
In general, 1 to 3 mol, preferably 1.1 mol, of the Grignard compound~ or of the organometallic compounds of the general formula (VI) are employed, relative ~o 1 mol of the glyo~yl e~ter of the ~eneral formula (V).
: The ~ulphamidation i8 in general carried out in inert solvent~ in the presence of a base and of a dehydrating agent.
Suitable solvent~ in this case are inert oxganic ~o~vents which do not change und~r ~he reaction conditions. The~e include halo~enohydrocarbons ~uch as dichloromethane, trichloromethane,tetrachloromethane,l,2-dichloroethane, trichloroethane, tetrachloroethane, 1,2-dichloroethylene Le A 29 140 - 21 -or trichloroethylene, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane, or mineral oil fraction ; nitromethane, dLmethylformamide, acetonitrile or hexamethylphosphoramide. It is also possible to employ mixtures of the solvents. Dichloromethane is particularly pre~erred.
Suitable ba~e~ for the sulphamidation are the customary ba3ic compounds. These preferably include alkali metal and alkaline earth metal hydro~ides such as lithium hydro~ide, ~odium hydroxide, potassium hydroxide or baxium hydroxide, alkali me~al hydrides such as sodium hydride, alkali metal or alkaline aarth metal carbo~ates such as ~odium carbonate, pota~sium carbonate, or alkali metal alkoxide~ such as, for exampl~, ~odium methoxide or ethoxide, potassium methoxide or ethoxide or potas~Lum tert-butoxide, or organic EmineS such as benzyltrimethyl-ammonium hydroxide, tetrabutyla~monium hydroxide, pyrid-ine, triethylamine or N-methylpiperidlne.
The sulphamidation i8 in general carried out in a temperature range from 0~ to 150C, pre~erably at 25C
to 40C.
The sulphamidation i~ in general carried out at normal pres~ure~ However, i~ i~ al80 possible to carry out the process at reduced pressure or at elevated pre~sure ~for example in a range from 0.5 to 5 bar).
When carrying out the sulphamidation, the ba~e is in Le A 29 140 22 -2~
general employed in an amount from 1 ~o 3 mol, preferably from 1 to 1.5 mol, relative to 1 mol of the carboxylic acid.
Suitable dehydrating reagents are carbodiLmide~, ~uch as, for example, dii~opropyl carbodiLmide, dicyclohexyl carbodiimide or N-t3-dimethylaminopropyl)-N'-ethylcarbo-diimide hydrochloride or carbonyl compounds such as carbonyldiimidazole or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulphonate or propane-phosphonic anhydride or i~obutyl chloroformate or benzo~tria~olyloxy-tris-~dimethyl~mino)phosphonium hexafluoro-phosphate or diphenyl phosphor2midate or methanesulphonyl chloride, if appropriate in the pre~ence of bases such as triethylamine or N-ethyl~orpholine or N-methylpiperidine or dicyclohexylcarbodiimide and ~-hydroxysuccinimide [cf.
J.C. Sheehan, 8.L. Ledîs, J. Am. Chem. Soc. 95, 875 (1973); F.E. Freeman et al., J. Biol. Chem. 225, 507 (1982) and ~.B. Benoton, K. Kluroda, Int. Pept. Prot.
Res. 13, 403 (1979), 17, 187 (1981)].
. -The compounds of: the general formula (II) are mainly known or can be prepared, for example, by halogenating the corresponding methylene function in one of the above~entioned ~ol~en~s, preferably carbon tetrachloride, if appropriate in the pre~ence of a catAlyst, pre~erably AIBN, using halogenating agents, preferably using N-bromosuccinLmide, in a te~perature range from 20C ~o 100C, preferably from 60C to 80C and at normal pressure.
Le A 29 140 - 23 -~9836~
The compounds of the general formulae (III), (IIIa) and (V) are mainly known or can be prepared by a customary method (cf. for this Chem. Commun. 1~72, (11), 668].
The compounds of the general ~ormula (IV) are also known [cf. Beilstein 5.19 / 5.24 / 5.29] or can be prepared by customary methods from the corresponding alcohols or cycloalkanes.
The compound~ of the general formula ~VI) are new and can be prepared by the abov mentioned process.
The compounds of the general formula (VII) are known per se or can be prepared ~y a customary method [cf.
R. Nutzel, ~ouben-Weyl, Methoden der organischen Chemie (Methods of Organic Ch~mistry), 4th ed. vol. 13/2a, 53 ff. (Thieme ~erlag, S~ut~gart~ 1973, M.S. Rharash, O. Reinmuthl Grignard Reactions o~ No~me~allic Compounds, Prentice Hall, New York, 1974; Uhlman ~II, 370; ~ouben-Weyl XIII/2a, 289-302; R.I. Trust, R.E. Ireland, Org.
Synth. 53, 116, (1973); O. &rummitt, E.I. Becker, Ors.
Synth. Coll. Vol. IV, 771 (1963); H. ~dkins, W. Zartman, Org. Synth. Coll. Vol. II, 606 (1943)].
The sulphonsmine~ of the general formula ~VIII) are known or can be prepared by a customary method.
The pure enantiomers of the compounds of the general formula (I) according to the invention ~an he prepared, Le A 29 140 - 24 -2~3~
for example, by separating the corresponding enantio-merically pure acids by a customary method and then reacting ~hem further as mentioned above.
The compounds of the general formula (I) surprisingly S exhibit a high activity as leukotriene synthesis inhi-bitors, in particular after oral administration.
~he compounds according to the invention can be employed as active compounds in medicaments. The substances can act as inhibitors o~ enz~matic reactions in the context of arachidonic acid metabolism, in particular as inhi-bitor~ of 5-lipo~ygenase.
They are thus preferred for the treatment and pre~ention of diseases of the airway~, such a~ allergies/asthma, bronchitis, emphysema, ~hock lung, pulmonary hyper-tension, inflammations/rheumatism and oedema~, gout,thrombo~e and thromboemboli~m3, ischaemias (peripheral, cardiac or cerebral circulatory disorders), cardiac and cerebral infarcts~ cardiac arrhythmia~, angina pectoris, arteriosclerosis, in tissue transplants, dermatoses such as psoriasis, inflammatory dermatoses, for example eczema, dermatophyte infection, infections of the skin by bacteria, metas~a~e and for cytoprotection in the gastrointestinal tract.
p The sub~tituted (benzothiazolyl- and quinoxalin-2-yl-me~hoxy)phen~l acetic acid derivatives according to the invention can be used both in human medicine and in Le A 29 140 - 25 -- ' 2 ~ ~ ~ s~
veterinary medicine.
The pharmacological activity data of the substances according to the invention are determined by the follow-ing method:
As a measure of the S-lipoxygenase inhibition (LOI), the release of the leukotriene B4 (LTB4) from pol~morpho-nuclear human leukocytes (PNN~, was determined after addition of sub~tances and Ca~ ionophore A 23187 by means of "revers~ phase HPLC~ according to Borgeat, P. et al., Proc. Nat. Acad. Sci. 76, 2148-2152 (1979)~
Ex. No. LOI
tmol/l]
9 5.4 x 10-6 2.8 x 1o-7 11 3.1 x 10-7 1.8 x 1o-7 . 17 1.2 x 10-7 18 2.8 x 1o-7 19 1.3 x 10-7 4.4 x 1o-7 23 3.~ x 10-7 24 2.4 x 1o-7 -The present invention also includes pharmaceutical preparations which, in addition to inert, non-toxic, Le A 29 140 - 26 -~ 3 ~ ~23189-7514 pharmaceutically suitable auxiliaries and excipientsl contain one or more compounds of the ~eneral formula (I), or which consist of one or more active compounds of the formula (I), and processes for the production of these preparations.
The active compounds of the formula (I) should be present in these preparations in a concentration from 0.1 to 99.5% by weight, preferably from 0.5 to 95% by weight, of the total mixture.
In addition to the active compounds of the formula (I), the pharmaceutical preparations can also contain other pharma-ceutical active compounds.
The above-mentioned pharmaceutical preparations can be prepared in a customary manner by known methods, for example using the auxiliary(ies) or excipient(s).
In general, it has prouen advantageous to administer the active compound of the formula (I) in total amounts from about 0.01 to about 100 mg~kg, preferably in total amounts from about 1 mg/kg to 50 mg/kg of body weight every 24 hours, if appropriate in the form of several individual doses, to achieve the desired result.
The invention also extends to a commercial package containing, as active pharmaceutical ingredient, a compound of the invention, together with instructions for its use for treatment of any of the above-mentioned indications.
However, it may possibly be advantageous to depart from the amounts mentioned, namely depending on the type and on the body weight of the subject treated, on individual behaviour towards the medicament, the nature and severity 2Q~33~
of the diseasel the type of prepa~ation and admini-stration, and the time or i~terval at which admini-stration ~akes place.
Startinq compounds Example I
Methyl 4-benzylox~phenylacetate ¢ ~
co2CH3 397 g (2.39 mol) of methyl 4-hydroxyphenylacetate and 330 g (2.39 mol) of potassium carbonate are stirred at 25C for 1 h in 2 1 of dimethylformamide. 302 g (2.39 mol) of henzyl chloride are then added and the mixture is heated at 50C for 15 h. Af~er concentra~ing in vacuo, the re~idue is partitioned between water and ethyl acetate, and the organic phase is dried over sodium sulphate and concentrated. The product is recrystallised from methanol.
Yield: 511 g (83% of theory) Melting point: 60C.
The compound~ ~hown in Table 1 are prepared in analogy to the procedure of Example I:
Le A 29 140 - 28 -2~98~6~
Table I:
0` CH2-~ CH2-C02CH3 Ex. No. L m.p.C Yield (~ of theory) II -Cl 72-74 98 III -Br 40 91 Example IV
~ethyl 2-(4-benzyloxyphenyl)-2~cyclopentylacetate ~
co2CH3 : 10~ 256.3 g (1 mol) of the compound rom Example I are dissolved in 1 1 of DMF and the ~olution is added drop-: wise under pro~ective gas at 0C to a ~uspension of 24 g ~1 mQl) of sodium hydride in 100 ml of DMF. ~fter evolu-tio~ of H2 i8 complete, the mixture is stirred at 0C for 152 h. 149 g (1 mol) of cyclopPntyl bromide, disso1ved in 400 ml of DMFj are then added dropwise at the same ;
Le A. 29 140 - 29 -, 2~9~3~
temperature. After addition is complete, the mixture is stirred at room temperature for 15 h. The solvent is removed on ~ rotary evaporator and the residue is treated with hot water (80C). After stirring, the mixture is slowly cooled. The crystallised product is filtered off with suction, washel well with water, dried and recrys-tallised from methanol.
Yield^ 276 g (85% of theory) Melting point: 77-78C (methanol) The compounds shown in Table II are prepared in analogy to the procedure of Example IV:
Table II: ~ L
W` CH2~ R2 ~02CH3 Ex. No- ~ Rl R2 m.p.C/ Yield b.p.(~ of th~y) V ~-(cH2)3-cH3 H 145-15087 0.2 mm VI H ~ H 59 76 VII Cl ~ H 165-17074 0.2 mm Le A 29 140 - 30 -3 ~ ~
Example VIII
Methyl 2-cyclopentyl-2-(4-hydroxyphenyl)acetate HO
co2CH3 65 g (0.2 mol) of the compound from Example IY are dissolved in 100 ml of THF, 200 ml of ethanol and 100 ml of triethylamine. After addition of 1.5 g of palladium catalyst (100% stxength on carbon), ~he mixture is hydrogenated at 3 bar of hydrogen for 2 h. The catalyst is filtered off, tha fil~rate i9 concentrated and the residue is chromatographed on silica gel (eluent: methy-lene chloride).
Yield: 43.7 g ~93% o~ theory) b.p.: 150-153/0.2 mm The compound~ ~hown in Table III are prepared in analogy to th- procedure of Ex~m~le VIII:
Le A 29 140 - 31 -) 3 ~ 6 .
Table III- HO ~ R2 Ex. No. L R1 R2 m.p.C/ Yield b.p. (~ of ~ Y) IX ~(CHz)3-cH3 H 134-138 81 0.2 mm X H: ~ H 80 79 : XI Cl ~ H 155-~60 7 0.~ mm Example XII
~ethyl 2-[3-(benzothiazol~2-yl-methoxy)phenyl]acetate : ~ N ~ CO2C~3 : ~ ~ O~
~: 14.~9 g (0.1 mol) of 2-methylbenzothiazole are brominated in 250 ml of C14 using 19.6 g (0.11 mmol~ of ~S and 0.5 g of AIBN. ~fter reaction : i~ complete,; ~he Le A 29 140 - 32 -~33~
precipitated succinimide is filtered off, the filtrate is concentrated, the residue is taken up in 100 ml of DME
and the ~solution is added to a solution of 16.6 g (O.1 mol) o~ methyl 3-hydroxyphenylacetate, and 13.8 g (0.1 mol) of KzC03, in 250 ml of DMF. The mixture is heated at 50C for 10 h. After cooling, the solvent is evaporated, ~he residue is -partitioned between ethyl acetate/water, the organic phase is concentrated and the residue is chromatographed on silica gel 60 (eluent:
CH2Cl2)-Yield: 11.7 g (37.3% of theory) Melting point: 58-61C (diisopropyl ether) Example ~III
Methyl 2-~3-bromo-4-(quinoxalin-2-yl-methoxy)phenyl]~
aceta~e ~ N ~ Br .~ .
co2CH3 The title compound is prepared in analogy to the procedure of Example XII.
Yield: 4.7 g (94.2% of theory) Melting point: 120 122C (ethyl aceta~e) Le A 29 140 - 33 -3~3 E~ample XIV
Methyl 4-(quinoxalin-2-yl-methoxy)phenylglyoxylate ~XNN~
O~
~0 CO~H3 The ~itle compound i5 prepared in analogy to the proce-dure of Example I.
Yield: 8.0 g (37.7% of theory) ~elting poine: 125C ~methanol) =~e :w Meth~1 4-tbenzothiazol-2-yl-methoxy~phenylglyoxylate , ; 10 ; ~
The title compound i8 prepared in analogy to the proce-dure of Example XIV.
Le A 29 140 - 34 -.
- ~iO9~36~
Yield: 10.3 g (31.4~ of theory) Melting point: 114C (methanol) Preparation Examples Example 1 Methyl 2-t4~(benzothiazol-2-yl-methoxy~phenyl]-2-cyclo-pentylacetate ~S
~ N ~
o~
3.0 g (20 mmol) of 2-mathylbenzothiazole are brominated using 4.0 g (22.5 mmol) of N-bromo-succinimide and 0.3 g of AIBN in 50 ml of CC14. ~fter reaction, the precipitated ~uccinimide is filtered off, the filtrate is concentrated, the re idue i9 taken up in 50 ml of DME and the solution is added to a solution of 4.7 g (20 mmol) of methyl 2-cyclopentyl-2-(4-hydroxyphenyl)acetatel and 2.8 g (20 mmol) of K2CO3, in 100 ml of DMF. The mixture is heated at 50C for 10 h. ~fter cooling, the solvent is evaporated, the residue is partitioned between ethyl acetate/water, the organic phase is concentra~ed, and the Le A 2g 140 - 35 --residue is chromatographed on silica gel 60 (eluent-cyclohexa~e/ethyl acetate 3:1).
Yield: 1.7 g (22.3% of theory) Melting point: 97-98C (diisopropyl ether) S The compounds shown in Table 1 are prepared in analogy to the procedure of Example 1:
Table 1:
~G
~NJ~ L
~C/-~
Ex . No . G L R2 ~.1 R3 o C Y eld g 2 S H H -(CH2)3CH3 -OCH3 65-66 2.6 (14,1) (Diisopropyl ether) 3 -N=CH- H H ~~ -OCH3 9s-g7 5,7(68) (Diisopropyl ~ ether) 4 -N=CI 1- Cl H ~/ -OCH3 98-100 2,3 (90) (Diisopropyl ether) -N=CH- H H ~ -OCH3 108-110 1,7 (93) e~her) .
~ Le A 29 140 ~ 36 -. .
2~9~
~B~
Methyl 2-~3~(benzothiazol-2-yl-methoxy)phenyl]caproate ~ S
"~ co2CH3 O ~ CH3 The title ~ompoun~ is prepared from 10.9 g (0.035 mol) of the compound from Example IX in analogy to ~he procedure of Exa~ple IV.
Yield: 6.4 g (50~ of theory) Melting poin~: 108C (me~hanol) Example 7 Nethyl 2-[3-bromo-4-(guinoxalin-2-yl-methoxy)phenyl]-2-cycloheptylacetate ~ B
~
Le A 29 140 - 37 -2~983~
The title compound i5 prepared in analogy to thë pro-cedure of Example 6.
Y.ield: 2.1 g (40% of theory) Melting point: 132C (methanol) Example 8 2-[~-(Benzothiazol-2-yl-methoxy)phenyl]-2-cyclopentyl-acetate ~S
~ N ~
~
,~
. 1.5 g (3.9 mmol) of methyl 2-t4-~benzothiazol-2-yl-meth-o~y)phenyl]-2-cyclopen~ylacetate are hydrolysed under reflux in 50 ml of methanol and 20 ml of NaOH (1 normal).
After cooling, 20 ml of HCl (1 normal) are added. The product precipitates. After filtering off with suction, it is washed with water, dried and recrystallised ~rom methanol.
Yield: 1.3 g (97% of theory) Melting point: 152-154C (methanol) The compound~ shown in Table 2 are prepared in analogy to the procedure of Example 8:
Le A 29 140 - 38 -209~3~
Table 2:
~G
N J~ L
0~
o~R3 Ex. No. G L R E~.3 m-p- C Yield g ( solvent ) ( % f theory 9 -N=CH- H ~ OH 173-175 3,~ (60) (Diethyl ~ ether~
-N=CH- Cl ,~J OH 101 -t 03 1,7 (78.4) (Di2thyl ~ ether) 11 -N~CH- H JJ OH 163-16~ 1,2 t87) (CH2C12) 12 S H -(CH2)3CH3 OH 117-118 2,1 (67.8) (Methanol) 13 -N=CH- Br - ,~ OH 149 1.3 (51,5) (CH3oH) 14 :S ~ H -(CH2)3-CH3 OH 99-102 ~.9 (95) (CH30H) Le A 29 140 - 39 -.. æo~g~$
Example 15 N-Methylsulphonyl-2-[3-(benzothiazol-2-yl-methoxy)-phenyl]caproamide S
N~ CONHSO2CH3 o~,L ~, ,CH3 1 g ~2.8 mmol) of 2-t3-benzothiazol-2-yl-methoxy)phenyl]-caproic acid, 0.267 g (2.8 mmol) of methanesulphonamide, 0.54 g (2.8 mmolj of N'~ethyl-N~-(3-dimethylaminopropyl)-carbodiimide and 0.45 g (3.7 ~mol) of DMAP are dissol~ed in 30 ml of CH2Cl2 and the solution is stirred at 25C for 15 h. The solvent is evaporated off and the residue is chromatographed on silica gel 60 leluent: CH2Cl2/MeOH
100s5).
Yield: 0.42 g (34.7% of theory) Melting point: 99-101C ~methanol) The compounds shown in Ta~le 3 are prepared in analo~y to the proc dure of Example 15:
Le A 29 140 - 40 -~9~3~ ~
Table 3:
~¢N ~ L
0~
5H-R, Ex. No. L ~l R3 : m.p. ~C Yield g (solvent) (% of theory) ~ `
16 Cl ~/ -NHSO2CH3 163-165 0.3 (34) (Diethyl ~ ethar) 17 Cl ,~/ -NHSO2-CH2-C6Hs 150-152 0,7 (53,6) ~Diethyl ~ ether) 1~ H l~J -NHSO2CH~ 160-162 Q,5 (51,4) (Die~hyl elher) I r~
19 H ~ -NHSO2-CH2-c~Hs 148-150 0,6 (57) (Di~thyl ~ether~
:
~ H : ~ H-so2-(c6H4)-~cH3 137 : 1,3 (92.5) (Die~hyl ethar) ~; ` : :
Le A 29 140 - 41 -~9~3~
Example 21 Methyl 2-t4-(quinoxalin-2-yl-methoxy)phenyl]-2-cyclo-heptylhydroxyacetate ~ N
~ .
H0 CO2C~3 A freshly prepared eth0real Grignard solution from 5.49 g (3.1 mmol) of cycloheptyl bromide and 0.75 g (3.1 mmol) of magnesium is added dropwi~e under protective gas to a cooled solution (0C) of S g (1.55 mmol~ of methyl 2-~4-(quinoxalin-2-yl-m thoxy)phenyl]glyoxylate in 50 ml of THF. After warming to 25C, the reaction mixture is ~tirred overnight and poured into ice-water, acidified with HCl and extracted with eth~1 acetate. ~fter evapora tion, the residue is chromatographed on silica gel 60 (eluent: cyclohexane/ethyl acetate 3:1).
Yield: 2.26 g (34.7~ of theory~
Melting point: 121C (CH30H) The compound~ shown in Table 4 are prepared in analogy to the procedure of Example 21:
.
Le A 29 140 - 42 -~2~9~3~
Table 4:
,~G
~NJ~
~,~,R1 Ex. No. G Rl R3 m.p. C Yield g ( sol~rent ~ ~ % of theory 22 ~ 5 ~J -OC~3 (CH30H) 2.56~ (39.4) ,/~
23 -N=CH-~ ~J ~H 1(CH30H) 1.t (50,7) 24 5 J / -OH 190 1,8 (86,5) :
, :: : ` ::
`:
Le A 29 140 - 43 -.
,
It has already been disclosed that ~-substituted 4-(quin-olin-2-yl-methoxy)phenylacetic acid derivatives have a lipoxygenase inhibiting action [cf. EP 344,519 (US
4,970,215) and EP 339,416].
The present invention relate~ to substituted ~benzo-thiazolyl- and quinoxalyl-methoxy)phenyl-acetic acid derivatives of the general formula (I) A
D ~ N ~ L
in which R
~, B, D, E and L are identic~l or different and represent hy~rogen, hydroxyl, halogent trifluoro-methyl, trifluoromethoxy or carboxyl, or repre~nt straight-chain or branched alkyl having up to 10 carbon a~om~, which i8 optionally sub~ti~uted Le A 29 140 - 1 -- `~ 2 ~ ~ ~ 3 ~ ~
by hydroxyl or halogen, or repres~nt straight-chain or branched alkoxy or alkoxycarbonyl having up to 10 carbon atoms, or represent aryl having 6 to 10 carbon atoms, which i.s optionally su~stituted by halogen, nitro or cyano or by straight-chain or branched alkyl or alkoxy each having up to 8 carbon atoms, G represents a sulphur atom or the group of the formula -N=CH-, R1 represents cycloal~yl having 3 to 12 carbon atom~, or represents ~kraight-chain or branehed alkyl having up ~o 10 carbon atoms, which i8 optionally ~ub~tl-tuted by aryl having 6 to lO carbon atoms, R2 represents hydrogen, or represents a group of the formula -oR4, in which R4 denote~ hydrogen, straight-chain or branched alkyl having up to 8 carbon a~om~, ben~yl or phenyl, R3 repre3ants hydroxyl, ~traight-chaln or branched alkoxy having up to 8 carbon atoms or phenoxy, or repre~ents a group of the formula -NHSo2-R5J
Le A 29 140 - 2 -`
~9~
in which R5 ~denotes s~raight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by phenyl, which can in turn be sub~tituted by straight-chain or branched alkyl having up to 6 carbon atoms or halogen, ~r d~notes phenyl which can optionally be ~ubsti-tuted by halogen or trifluoromethyl or by s~raight-chain or branched alkyl or alkoxy each having up ~o 6 carbon a~o~s and their salt~.
In the context of the present invention, physiologically acceptable ~alts are preferred. Phy~iologically accep-table 8alt9 of the substituted (benzothiazolyl- and quinoxalyl-methoxy)phenyl-acetic acid derivatives c~n be ~alts of the substances according to the invention with mineral acid~, carboxylic acids or sulphonic acids.
Particularly preferred ~alts are, for example, tho~e with hydrochloric acid, hydrobromic acid, sulphuric acid, ~0 . phosphoric acid, methane~ulphonic acidr ethanesulphonic acid, toluenesulphonic acid, benzene~ulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic ~a~id, tartaric acid, ci~ric ac~d, f~maric acid, maleic acid or benzoic acid.
:: :
Salt3 in the context of ~he present invention are addi-tLon-lly metal aalt~, preferably of th- unlval-nt metals, Le A 29 140 - 3 -- ~2~9~3~
and the am~onium salts. Alkali metal salts such as, for example, sodium, potassium and ammonium salts are preferred;
The compounds according to the invention exist in stereo-isomeric forms which behave either as image and mirror .image (enantiomers), or which do not behave as image and mirror image (dias~ereomers). The invention relates both to the antipodes and to the racemic forms as well as to the diastereomer mixtures. Like the diastereomer~, the racemic forms can also be separated in a known manner into the stereoisomerically uniform constituents tcf. E.L. Eliel, Stereochemistry of Carbon Compounds, McGr~w Hill, 1962].
Preferred compounds of the general formula (I) are those in which A, B, D, E and L are identical or different and represent hydrogen, fluorine, chlorine, bromine, trifluoromethoxy or carboxyl, represent straight~chain or branched alkyl having up to 8 carbon atom~, which is optionally ubsti~uted by hydroxyl, fluorine, chlorine or bromine, represent straight-chain or branched aI~oxy or alkoxycarbonyl each having up to 8 carbon atomæ, or repre~ent phenyl which is optionally ~ub~tituted by fluorine, chlorine, bromine, nitro or cyano or by straight-chain or branched alkyl or alkoxy each Le A 29 140 - 4 -3 ~ ~
having up to 6 carbon atom~, G repr~sent~ a sulphur atom or the group of the formula -N=CH-, Rl represents cyclopropyl~ cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, or represent~ straight chain or branched alkyl having up to 8 carbon atoms r which is optionally substi-tuted by phenyl or naphthyl, R2 represents hydrogen or a group of the formula -oR4, in which .
R4 denote~ hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, benzyl or phenyl, R3 represents hydroxyl or s~raight-chain or branched alkoxy having up to 6 carbon atoms, or : represents a.group of the formula ~NHSo2-~5, in which R5 denote~ straight-chain or branched alXyl having up to 6 carbon atom~, which 1 optionally sub~tituted by phenyl which can in turn be sub~tituted by straight-chain or branched alkyl having up to 6 carbon atom~, fluorine, chlorine Le A 29 140 - 5 -;~983~
or bromine, or denotes phenyl which can optionally be substi-tuted by fluorine, chlorine or bromine or by straight-chain or branched alkyl having up to 4 carbon atoms and their ~alts.
Particularly preferred co~pounds of the general formula (I) are those in which A, B, D, E and L are identical or different and represent hydrosen, fluorine, ~hlorine, bromine or traight-chain or branched alXyl or alkoxy each having up to 6 carbon atom~, 15 G represents a sulphur atom or the group of the formula -N=CH-, :: Rl represents cyclopentyl, cyclohexyl or cycloheptyl r or repre~ents:straight-chain or branched al~yl having : 20 up t~ 6 carbon atoms, which is optionally ~ubsti-tuted by phe~yl, R2: represents hydrogen or a group of the foxmula -OR'j Le A 29 140 - 6 -. ' ' , , .
æ~983~
in which R4 denotes hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or phenyl, R3 represents hydroxyl or straight-chain or branched alkoxy having up to 4 carbon atoms, or represents a group of the formula -NHSoz-R5r in which Rs denokes ætraight-chain or branched alkyl having up to 4 carbon atoms, which i6 optionally subs~ituted by phanyl which can in turn be ~u~stituted by straight chain or branched alXyl having up ~o 4 carbon atoms, fluorine or chlorine~
or denotas phenyl which can optionally be substi-tuted by fluorine, chlorine or methyl and their salts.
Very particularly preferred compounds are those in which the radical -CRlR2-~oR3 is in th~ 3- or 4-position relative to the heterocyclylmethoxy radical.
Moreover, a process for the preparation of the compounds of the formula (I) ha~ been found, which is characterised in that Le A 29 140 - 7 -c~9~3~
[A] compounds of the general foxmula (Ia~
A
D ~ N ~ L Rl (Ia) ~ CH- C - R3 in which A, B, D, ~, G, L, Rl and R3 have the meaning mentioned, are prepared by etherifying c~mpounds of the general formula (II~
A
G : ~ (IIj ~: D ~ N l CH2-M
.
:: : :
in which :
: : A,~ B, D, E and G have the meaning mentioned :
10~ ~ and ~ represents halogen, preferably bromine, :
Le A 29 140 - 8 -" ~ ~
either directly with compounds of the general formula (III) R6O L Rl CH-C - R7 (III) o in which ~6 repreæents a typical hydroxyl protective group such as, for example, benzyl or tert-butyl, preferably benzyl, and R7 ropresents Cl-C8-alkoxy, in inert so1vents, i~ appropriate in the pre~ence of ba~e, after removal of the protective group, or initially etherifying in a firs~ step with compounds of the general formula (IIIa) lS ~ CH2~ R7 (IIIa) O
in which Le A 29 140- 9 -2~3~$
R5 and R7 have the meaning mentioned, in inert solvents, if appropriate in the presence of a base, after removal of the protective group and then alkylating in a second step with compounds of the general S formula (IV) Rl-T (IV) in which Rl has th~ meaning mentioned, and : T represents halogen, pre~erably chlorine or bromine, in inert solvents, if appropriate in the presenc~ of a base and in ~he case of the acids (R3 = O~)j hydrolysing the esters by customary methods, and in the case of the sulphonamides (R3 = NHSo2R5), adding an amidation~ starting from th~ corresponding acids, if appropriate after priox activation thereof, by reaction with the re~pective sulphonamines of ~he general formula (VIII) Le A 29 140 - 10 -3 ~ ~
HzN--So2R5 (VIII ~
in inert solvents, if appropriate in the presence of a base and/or auxiliary, . . and in the case of the various esters, optionall~ carry-ing out a transesterification, likewise starting from the activated carboxylic acids, and in the case of the pure enantiomers s~parating the corresponding acida, and introducing or varying the aub~ti~uents A, B, D, and ~, if appropriate, according to cu~tomary methods, lB] :co~pounds of the genoral formula (IIb) ~ G
D ~ N ~ L Rl ~ (IIb) E O ~
~ C ~ 3 OR4 o in which A, B, D, E, G, L, R1, R3 and R4 have the meaning mentioned, Le A 29 140 ~9~3~
are prepared by converting compounds of the general formula (II) initially by reaction with compounds of ~he general formula (V) (V3 O
in which ~, R5 and R7 have the abovementioned meaning to the compounds of the general formula (VI~
A
D ~ N ~ ~ ~ (VI) n which 7 :
A, B, D,:E, G, L and R7 have the abovemen~ionsd meaning, by~theri~ication and in a second step by reducing the product by reaction with Grignard compound3 of the general formula (VII) Le A 29 140- 12 -L~ 3 ~
R1-V (VII) in which Rl has the abovementioned meaning and S V represents the typical Grignard radical W-Z, in which W denotes magnesium or ~inc and Z denotes chlorine, bromine or iodine, or represents lithium, sodium, magnesium~ aluminium or zincl:
: i n inert . olvents, if appropriate in the presence of a base, with removal of the group V, and in the case in which R4 ~ H, etherifying according to cus~o~ary methods .
Le A 29 140 - 13 -2~$3~
and in the case of the acids (R3 = OH) hydrolysing the esters by customary methods, and in the case of the sulphonamides (R3 = NH-So2-R5) adding an amidation, starting from the corresponding acids, if appropriate after prisr activation thereof, by reaction with the respective sulphonamines of the general formula (VIII) H2N-So2-R5 (VIII) in which R5 has the abovementioned meaning, in inert ~olvents, if appropriate in the pre~ence of a ba~e and/or auxiliary, and in the case of the various e~t~rsl optionally carry-ing out a transestarification, likewise starting from the aotivated carboxylic acids, and in the case of the pure enantiomers separating the corresponding enantiomerically pure acids, and introducing or varying the substituent A, B, D, E
and L, if appropriate, according to cuJtomary methods.
: The processes according to the invention can be Le A 29 140 - 14 ~
~9~3~
illustrated by way of example by th~ following reaction scheme:
~A]
~S~CH2 8~
CO2CH~
~ N
Co2H
I,e A 29 140 - 15 -2~9~3~
[A]
0~S~CH2~r HO~0~CH2-CO2CHI
~S~ H3C-(CH2)3-Br 0~0,CH2-C02CH3 ~N CO2H ~ H2N-sO2-cH3 o~~CH3 ~S ~ CO-NH~$02~CH~
(CH2)3-c113 Le A 29 140 - 16 -2~9~3~
[B]
~NlCH2-E1r ~ 1 C02CH~
M~
0~ , ,.. _. ~
~N ~
~
. HO CO2CH3 ' ~
HO CO~H
~he protective groups are removed ~ro~ the corresponding ethers by a customary method, for example by hydrogenoly-tio cleavage of the benzyl ethers in the abovemeneioned ::
Le A 29 140 - 17 -3 ~ ~
inert solvents in the presence of a catalyst using hydrogen gas [cf. additionally Th. Greene: ~Protective Groups in Organic Synthesis~, J. Wiley/Sons, 1981, New York].
Solvents for the etherification can be inert organic solvent which do not change under the reaction condi-tions. These preferably include ethers such as, for ex~mple, dioxane, tetrahydrofuran or diethyl ether, halogenohydrocarbons such as dichloromethane, trichloro-methane, tetrachloromethana, 1,2-dichloroethane or trichloroethylene, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or mineral oil fractions, nitromethane, dimethyl~ormamide, ace~onitrile, acetone or hexamethylpho6phoramide. It is al80 possible to employ mixtures of the solvents.
Bases which can be employed for the etherification are inorganic or organic bases. These preferably include alkali metal hydroxides such as, for example, sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxide~ such as, for example, barium hydroxide, alkali metal carbonates such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates such as calcium carbonate, or organic amines ~trialkyl(C1-C6~-amines) such as triethylamins t or heterocycles such as pyridine, meth~lpiperidine, piperidine or morpholine.
I~ iB also possible to employ alkali metals such as sodium and their hydrides, such as ~odium hydride, as Le A 29 140 - 18 -3 ~ ~
bases;
The ethe~ification is in general carried out in a temperature range from 0C to l150C, preferably from ~10C to +100C.
.The etherification is in general carried out at normal pressure. Howevert it is also possible to carry out the process at reduced pressure ox elevated pressure (for example in a range from 0.5 to 5 bar).
In general, 0.5 to 5, preferably 1 to 2 mol, of halide, relative to 1 mol of the reaction component, are employed. The base is in general employed in an amount ~rom 0.5 to 5 mol, preferably from 1 to 3 mol, relative to the halide.
~ he hydrolysis of the carboxylic acid esters is carried out by customary method~, by treating the esters with customary bases in inert solvents.
. Suitable bases .for the hy.drolysis. are the customary inorganic bases. These preferably include alkali metal hydroxides or alkaline earth metal hydroxides such as, for example, sodium hydroxide, potassium hydroxide or barium hydroxide, ox alkali ~etal carbonates ~uch as sodium carbonate or potassium carbonate or sodium hydrogencarbonate. Sodium hydroxide or pota~ium hydroxide are particularly preferably employed.
Le A 29 140 - 19 -2~9~3~
Suitable solvents for the hydrolysis are water or the organic solvents customary for hydrolysis~ These prefer ably include alcohols such as methanol, ethanol, pro-panol, isopropanol or butanol, or ethers such as tetra-S hydrofuran or dioxane, or dimethylformamide or dLmethylsulphoxide. Alcohols such as methanol, ethanol, propanol or isopropanol are.particularly preferabl~ used. It is also possible to employ mixtures of the solvents mentioned.
The hydrolysis i5 in general carried out in a temperature range from 0C to +100C~ preferably from +20C to ~80C.
In general, the hydrolysis is carried out at normal pres3ure. However, it i8 al80 possible to work at reduced pressure or at elevated pressure (for example from 0.5 to S bar).
When carrying out the hydrolysis, the base is in general employed in an amount from 1 to.3 mol, preferably from 1 to 1.5 mol, rela~ive to 1 mol of the ester. Molar amounts . o..the reactants are particularly.preferably used.
Suitable ~olvents for the reduction are ~he customary organic solvents which do not change under the reaction condition~. The~e preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dLmethyl ether, or hydrocarbon3 such as benzene, toluene, xylene, hexane, cyclohexane, or mineral oil fractions or dimeth-ylformamide. I~ is also possible to use mixtures of the Le A 29 140 - 20 -` 2~3~
~olvents mentioned. Tetrahydrofuran and diethyl ether are preferred.
The reduction is in general carried out in a temperature range from -80C to +30C, preferably at -40C to +25C.
The reduction is in general carried out at normal pressure. However, it is also possible to carry out the process at elevated pressure or at reduced pressure ~or example in a range from 0.5 to 5 bar).
The removal of the group V i5 carried out by the method cu~tomary for Grignard reaction~ using aqueous ammonium chloride ~olu~ion ~cf~ J. March, Advanced Organic Ch~mistry, Second Edition p. 836].
In general, 1 to 3 mol, preferably 1.1 mol, of the Grignard compound~ or of the organometallic compounds of the general formula (VI) are employed, relative ~o 1 mol of the glyo~yl e~ter of the ~eneral formula (V).
: The ~ulphamidation i8 in general carried out in inert solvent~ in the presence of a base and of a dehydrating agent.
Suitable solvent~ in this case are inert oxganic ~o~vents which do not change und~r ~he reaction conditions. The~e include halo~enohydrocarbons ~uch as dichloromethane, trichloromethane,tetrachloromethane,l,2-dichloroethane, trichloroethane, tetrachloroethane, 1,2-dichloroethylene Le A 29 140 - 21 -or trichloroethylene, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane, or mineral oil fraction ; nitromethane, dLmethylformamide, acetonitrile or hexamethylphosphoramide. It is also possible to employ mixtures of the solvents. Dichloromethane is particularly pre~erred.
Suitable ba~e~ for the sulphamidation are the customary ba3ic compounds. These preferably include alkali metal and alkaline earth metal hydro~ides such as lithium hydro~ide, ~odium hydroxide, potassium hydroxide or baxium hydroxide, alkali me~al hydrides such as sodium hydride, alkali metal or alkaline aarth metal carbo~ates such as ~odium carbonate, pota~sium carbonate, or alkali metal alkoxide~ such as, for exampl~, ~odium methoxide or ethoxide, potassium methoxide or ethoxide or potas~Lum tert-butoxide, or organic EmineS such as benzyltrimethyl-ammonium hydroxide, tetrabutyla~monium hydroxide, pyrid-ine, triethylamine or N-methylpiperidlne.
The sulphamidation i8 in general carried out in a temperature range from 0~ to 150C, pre~erably at 25C
to 40C.
The sulphamidation i~ in general carried out at normal pres~ure~ However, i~ i~ al80 possible to carry out the process at reduced pressure or at elevated pre~sure ~for example in a range from 0.5 to 5 bar).
When carrying out the sulphamidation, the ba~e is in Le A 29 140 22 -2~
general employed in an amount from 1 ~o 3 mol, preferably from 1 to 1.5 mol, relative to 1 mol of the carboxylic acid.
Suitable dehydrating reagents are carbodiLmide~, ~uch as, for example, dii~opropyl carbodiLmide, dicyclohexyl carbodiimide or N-t3-dimethylaminopropyl)-N'-ethylcarbo-diimide hydrochloride or carbonyl compounds such as carbonyldiimidazole or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulphonate or propane-phosphonic anhydride or i~obutyl chloroformate or benzo~tria~olyloxy-tris-~dimethyl~mino)phosphonium hexafluoro-phosphate or diphenyl phosphor2midate or methanesulphonyl chloride, if appropriate in the pre~ence of bases such as triethylamine or N-ethyl~orpholine or N-methylpiperidine or dicyclohexylcarbodiimide and ~-hydroxysuccinimide [cf.
J.C. Sheehan, 8.L. Ledîs, J. Am. Chem. Soc. 95, 875 (1973); F.E. Freeman et al., J. Biol. Chem. 225, 507 (1982) and ~.B. Benoton, K. Kluroda, Int. Pept. Prot.
Res. 13, 403 (1979), 17, 187 (1981)].
. -The compounds of: the general formula (II) are mainly known or can be prepared, for example, by halogenating the corresponding methylene function in one of the above~entioned ~ol~en~s, preferably carbon tetrachloride, if appropriate in the pre~ence of a catAlyst, pre~erably AIBN, using halogenating agents, preferably using N-bromosuccinLmide, in a te~perature range from 20C ~o 100C, preferably from 60C to 80C and at normal pressure.
Le A 29 140 - 23 -~9836~
The compounds of the general formulae (III), (IIIa) and (V) are mainly known or can be prepared by a customary method (cf. for this Chem. Commun. 1~72, (11), 668].
The compounds of the general ~ormula (IV) are also known [cf. Beilstein 5.19 / 5.24 / 5.29] or can be prepared by customary methods from the corresponding alcohols or cycloalkanes.
The compound~ of the general formula ~VI) are new and can be prepared by the abov mentioned process.
The compounds of the general formula (VII) are known per se or can be prepared ~y a customary method [cf.
R. Nutzel, ~ouben-Weyl, Methoden der organischen Chemie (Methods of Organic Ch~mistry), 4th ed. vol. 13/2a, 53 ff. (Thieme ~erlag, S~ut~gart~ 1973, M.S. Rharash, O. Reinmuthl Grignard Reactions o~ No~me~allic Compounds, Prentice Hall, New York, 1974; Uhlman ~II, 370; ~ouben-Weyl XIII/2a, 289-302; R.I. Trust, R.E. Ireland, Org.
Synth. 53, 116, (1973); O. &rummitt, E.I. Becker, Ors.
Synth. Coll. Vol. IV, 771 (1963); H. ~dkins, W. Zartman, Org. Synth. Coll. Vol. II, 606 (1943)].
The sulphonsmine~ of the general formula ~VIII) are known or can be prepared by a customary method.
The pure enantiomers of the compounds of the general formula (I) according to the invention ~an he prepared, Le A 29 140 - 24 -2~3~
for example, by separating the corresponding enantio-merically pure acids by a customary method and then reacting ~hem further as mentioned above.
The compounds of the general formula (I) surprisingly S exhibit a high activity as leukotriene synthesis inhi-bitors, in particular after oral administration.
~he compounds according to the invention can be employed as active compounds in medicaments. The substances can act as inhibitors o~ enz~matic reactions in the context of arachidonic acid metabolism, in particular as inhi-bitor~ of 5-lipo~ygenase.
They are thus preferred for the treatment and pre~ention of diseases of the airway~, such a~ allergies/asthma, bronchitis, emphysema, ~hock lung, pulmonary hyper-tension, inflammations/rheumatism and oedema~, gout,thrombo~e and thromboemboli~m3, ischaemias (peripheral, cardiac or cerebral circulatory disorders), cardiac and cerebral infarcts~ cardiac arrhythmia~, angina pectoris, arteriosclerosis, in tissue transplants, dermatoses such as psoriasis, inflammatory dermatoses, for example eczema, dermatophyte infection, infections of the skin by bacteria, metas~a~e and for cytoprotection in the gastrointestinal tract.
p The sub~tituted (benzothiazolyl- and quinoxalin-2-yl-me~hoxy)phen~l acetic acid derivatives according to the invention can be used both in human medicine and in Le A 29 140 - 25 -- ' 2 ~ ~ ~ s~
veterinary medicine.
The pharmacological activity data of the substances according to the invention are determined by the follow-ing method:
As a measure of the S-lipoxygenase inhibition (LOI), the release of the leukotriene B4 (LTB4) from pol~morpho-nuclear human leukocytes (PNN~, was determined after addition of sub~tances and Ca~ ionophore A 23187 by means of "revers~ phase HPLC~ according to Borgeat, P. et al., Proc. Nat. Acad. Sci. 76, 2148-2152 (1979)~
Ex. No. LOI
tmol/l]
9 5.4 x 10-6 2.8 x 1o-7 11 3.1 x 10-7 1.8 x 1o-7 . 17 1.2 x 10-7 18 2.8 x 1o-7 19 1.3 x 10-7 4.4 x 1o-7 23 3.~ x 10-7 24 2.4 x 1o-7 -The present invention also includes pharmaceutical preparations which, in addition to inert, non-toxic, Le A 29 140 - 26 -~ 3 ~ ~23189-7514 pharmaceutically suitable auxiliaries and excipientsl contain one or more compounds of the ~eneral formula (I), or which consist of one or more active compounds of the formula (I), and processes for the production of these preparations.
The active compounds of the formula (I) should be present in these preparations in a concentration from 0.1 to 99.5% by weight, preferably from 0.5 to 95% by weight, of the total mixture.
In addition to the active compounds of the formula (I), the pharmaceutical preparations can also contain other pharma-ceutical active compounds.
The above-mentioned pharmaceutical preparations can be prepared in a customary manner by known methods, for example using the auxiliary(ies) or excipient(s).
In general, it has prouen advantageous to administer the active compound of the formula (I) in total amounts from about 0.01 to about 100 mg~kg, preferably in total amounts from about 1 mg/kg to 50 mg/kg of body weight every 24 hours, if appropriate in the form of several individual doses, to achieve the desired result.
The invention also extends to a commercial package containing, as active pharmaceutical ingredient, a compound of the invention, together with instructions for its use for treatment of any of the above-mentioned indications.
However, it may possibly be advantageous to depart from the amounts mentioned, namely depending on the type and on the body weight of the subject treated, on individual behaviour towards the medicament, the nature and severity 2Q~33~
of the diseasel the type of prepa~ation and admini-stration, and the time or i~terval at which admini-stration ~akes place.
Startinq compounds Example I
Methyl 4-benzylox~phenylacetate ¢ ~
co2CH3 397 g (2.39 mol) of methyl 4-hydroxyphenylacetate and 330 g (2.39 mol) of potassium carbonate are stirred at 25C for 1 h in 2 1 of dimethylformamide. 302 g (2.39 mol) of henzyl chloride are then added and the mixture is heated at 50C for 15 h. Af~er concentra~ing in vacuo, the re~idue is partitioned between water and ethyl acetate, and the organic phase is dried over sodium sulphate and concentrated. The product is recrystallised from methanol.
Yield: 511 g (83% of theory) Melting point: 60C.
The compound~ ~hown in Table 1 are prepared in analogy to the procedure of Example I:
Le A 29 140 - 28 -2~98~6~
Table I:
0` CH2-~ CH2-C02CH3 Ex. No. L m.p.C Yield (~ of theory) II -Cl 72-74 98 III -Br 40 91 Example IV
~ethyl 2-(4-benzyloxyphenyl)-2~cyclopentylacetate ~
co2CH3 : 10~ 256.3 g (1 mol) of the compound rom Example I are dissolved in 1 1 of DMF and the ~olution is added drop-: wise under pro~ective gas at 0C to a ~uspension of 24 g ~1 mQl) of sodium hydride in 100 ml of DMF. ~fter evolu-tio~ of H2 i8 complete, the mixture is stirred at 0C for 152 h. 149 g (1 mol) of cyclopPntyl bromide, disso1ved in 400 ml of DMFj are then added dropwise at the same ;
Le A. 29 140 - 29 -, 2~9~3~
temperature. After addition is complete, the mixture is stirred at room temperature for 15 h. The solvent is removed on ~ rotary evaporator and the residue is treated with hot water (80C). After stirring, the mixture is slowly cooled. The crystallised product is filtered off with suction, washel well with water, dried and recrys-tallised from methanol.
Yield^ 276 g (85% of theory) Melting point: 77-78C (methanol) The compounds shown in Table II are prepared in analogy to the procedure of Example IV:
Table II: ~ L
W` CH2~ R2 ~02CH3 Ex. No- ~ Rl R2 m.p.C/ Yield b.p.(~ of th~y) V ~-(cH2)3-cH3 H 145-15087 0.2 mm VI H ~ H 59 76 VII Cl ~ H 165-17074 0.2 mm Le A 29 140 - 30 -3 ~ ~
Example VIII
Methyl 2-cyclopentyl-2-(4-hydroxyphenyl)acetate HO
co2CH3 65 g (0.2 mol) of the compound from Example IY are dissolved in 100 ml of THF, 200 ml of ethanol and 100 ml of triethylamine. After addition of 1.5 g of palladium catalyst (100% stxength on carbon), ~he mixture is hydrogenated at 3 bar of hydrogen for 2 h. The catalyst is filtered off, tha fil~rate i9 concentrated and the residue is chromatographed on silica gel (eluent: methy-lene chloride).
Yield: 43.7 g ~93% o~ theory) b.p.: 150-153/0.2 mm The compound~ ~hown in Table III are prepared in analogy to th- procedure of Ex~m~le VIII:
Le A 29 140 - 31 -) 3 ~ 6 .
Table III- HO ~ R2 Ex. No. L R1 R2 m.p.C/ Yield b.p. (~ of ~ Y) IX ~(CHz)3-cH3 H 134-138 81 0.2 mm X H: ~ H 80 79 : XI Cl ~ H 155-~60 7 0.~ mm Example XII
~ethyl 2-[3-(benzothiazol~2-yl-methoxy)phenyl]acetate : ~ N ~ CO2C~3 : ~ ~ O~
~: 14.~9 g (0.1 mol) of 2-methylbenzothiazole are brominated in 250 ml of C14 using 19.6 g (0.11 mmol~ of ~S and 0.5 g of AIBN. ~fter reaction : i~ complete,; ~he Le A 29 140 - 32 -~33~
precipitated succinimide is filtered off, the filtrate is concentrated, the residue is taken up in 100 ml of DME
and the ~solution is added to a solution of 16.6 g (O.1 mol) o~ methyl 3-hydroxyphenylacetate, and 13.8 g (0.1 mol) of KzC03, in 250 ml of DMF. The mixture is heated at 50C for 10 h. After cooling, the solvent is evaporated, ~he residue is -partitioned between ethyl acetate/water, the organic phase is concentrated and the residue is chromatographed on silica gel 60 (eluent:
CH2Cl2)-Yield: 11.7 g (37.3% of theory) Melting point: 58-61C (diisopropyl ether) Example ~III
Methyl 2-~3-bromo-4-(quinoxalin-2-yl-methoxy)phenyl]~
aceta~e ~ N ~ Br .~ .
co2CH3 The title compound is prepared in analogy to the procedure of Example XII.
Yield: 4.7 g (94.2% of theory) Melting point: 120 122C (ethyl aceta~e) Le A 29 140 - 33 -3~3 E~ample XIV
Methyl 4-(quinoxalin-2-yl-methoxy)phenylglyoxylate ~XNN~
O~
~0 CO~H3 The ~itle compound i5 prepared in analogy to the proce-dure of Example I.
Yield: 8.0 g (37.7% of theory) ~elting poine: 125C ~methanol) =~e :w Meth~1 4-tbenzothiazol-2-yl-methoxy~phenylglyoxylate , ; 10 ; ~
The title compound i8 prepared in analogy to the proce-dure of Example XIV.
Le A 29 140 - 34 -.
- ~iO9~36~
Yield: 10.3 g (31.4~ of theory) Melting point: 114C (methanol) Preparation Examples Example 1 Methyl 2-t4~(benzothiazol-2-yl-methoxy~phenyl]-2-cyclo-pentylacetate ~S
~ N ~
o~
3.0 g (20 mmol) of 2-mathylbenzothiazole are brominated using 4.0 g (22.5 mmol) of N-bromo-succinimide and 0.3 g of AIBN in 50 ml of CC14. ~fter reaction, the precipitated ~uccinimide is filtered off, the filtrate is concentrated, the re idue i9 taken up in 50 ml of DME and the solution is added to a solution of 4.7 g (20 mmol) of methyl 2-cyclopentyl-2-(4-hydroxyphenyl)acetatel and 2.8 g (20 mmol) of K2CO3, in 100 ml of DMF. The mixture is heated at 50C for 10 h. ~fter cooling, the solvent is evaporated, the residue is partitioned between ethyl acetate/water, the organic phase is concentra~ed, and the Le A 2g 140 - 35 --residue is chromatographed on silica gel 60 (eluent-cyclohexa~e/ethyl acetate 3:1).
Yield: 1.7 g (22.3% of theory) Melting point: 97-98C (diisopropyl ether) S The compounds shown in Table 1 are prepared in analogy to the procedure of Example 1:
Table 1:
~G
~NJ~ L
~C/-~
Ex . No . G L R2 ~.1 R3 o C Y eld g 2 S H H -(CH2)3CH3 -OCH3 65-66 2.6 (14,1) (Diisopropyl ether) 3 -N=CH- H H ~~ -OCH3 9s-g7 5,7(68) (Diisopropyl ~ ether) 4 -N=CI 1- Cl H ~/ -OCH3 98-100 2,3 (90) (Diisopropyl ether) -N=CH- H H ~ -OCH3 108-110 1,7 (93) e~her) .
~ Le A 29 140 ~ 36 -. .
2~9~
~B~
Methyl 2-~3~(benzothiazol-2-yl-methoxy)phenyl]caproate ~ S
"~ co2CH3 O ~ CH3 The title ~ompoun~ is prepared from 10.9 g (0.035 mol) of the compound from Example IX in analogy to ~he procedure of Exa~ple IV.
Yield: 6.4 g (50~ of theory) Melting poin~: 108C (me~hanol) Example 7 Nethyl 2-[3-bromo-4-(guinoxalin-2-yl-methoxy)phenyl]-2-cycloheptylacetate ~ B
~
Le A 29 140 - 37 -2~983~
The title compound i5 prepared in analogy to thë pro-cedure of Example 6.
Y.ield: 2.1 g (40% of theory) Melting point: 132C (methanol) Example 8 2-[~-(Benzothiazol-2-yl-methoxy)phenyl]-2-cyclopentyl-acetate ~S
~ N ~
~
,~
. 1.5 g (3.9 mmol) of methyl 2-t4-~benzothiazol-2-yl-meth-o~y)phenyl]-2-cyclopen~ylacetate are hydrolysed under reflux in 50 ml of methanol and 20 ml of NaOH (1 normal).
After cooling, 20 ml of HCl (1 normal) are added. The product precipitates. After filtering off with suction, it is washed with water, dried and recrystallised ~rom methanol.
Yield: 1.3 g (97% of theory) Melting point: 152-154C (methanol) The compound~ shown in Table 2 are prepared in analogy to the procedure of Example 8:
Le A 29 140 - 38 -209~3~
Table 2:
~G
N J~ L
0~
o~R3 Ex. No. G L R E~.3 m-p- C Yield g ( solvent ) ( % f theory 9 -N=CH- H ~ OH 173-175 3,~ (60) (Diethyl ~ ether~
-N=CH- Cl ,~J OH 101 -t 03 1,7 (78.4) (Di2thyl ~ ether) 11 -N~CH- H JJ OH 163-16~ 1,2 t87) (CH2C12) 12 S H -(CH2)3CH3 OH 117-118 2,1 (67.8) (Methanol) 13 -N=CH- Br - ,~ OH 149 1.3 (51,5) (CH3oH) 14 :S ~ H -(CH2)3-CH3 OH 99-102 ~.9 (95) (CH30H) Le A 29 140 - 39 -.. æo~g~$
Example 15 N-Methylsulphonyl-2-[3-(benzothiazol-2-yl-methoxy)-phenyl]caproamide S
N~ CONHSO2CH3 o~,L ~, ,CH3 1 g ~2.8 mmol) of 2-t3-benzothiazol-2-yl-methoxy)phenyl]-caproic acid, 0.267 g (2.8 mmol) of methanesulphonamide, 0.54 g (2.8 mmolj of N'~ethyl-N~-(3-dimethylaminopropyl)-carbodiimide and 0.45 g (3.7 ~mol) of DMAP are dissol~ed in 30 ml of CH2Cl2 and the solution is stirred at 25C for 15 h. The solvent is evaporated off and the residue is chromatographed on silica gel 60 leluent: CH2Cl2/MeOH
100s5).
Yield: 0.42 g (34.7% of theory) Melting point: 99-101C ~methanol) The compounds shown in Ta~le 3 are prepared in analo~y to the proc dure of Example 15:
Le A 29 140 - 40 -~9~3~ ~
Table 3:
~¢N ~ L
0~
5H-R, Ex. No. L ~l R3 : m.p. ~C Yield g (solvent) (% of theory) ~ `
16 Cl ~/ -NHSO2CH3 163-165 0.3 (34) (Diethyl ~ ethar) 17 Cl ,~/ -NHSO2-CH2-C6Hs 150-152 0,7 (53,6) ~Diethyl ~ ether) 1~ H l~J -NHSO2CH~ 160-162 Q,5 (51,4) (Die~hyl elher) I r~
19 H ~ -NHSO2-CH2-c~Hs 148-150 0,6 (57) (Di~thyl ~ether~
:
~ H : ~ H-so2-(c6H4)-~cH3 137 : 1,3 (92.5) (Die~hyl ethar) ~; ` : :
Le A 29 140 - 41 -~9~3~
Example 21 Methyl 2-t4-(quinoxalin-2-yl-methoxy)phenyl]-2-cyclo-heptylhydroxyacetate ~ N
~ .
H0 CO2C~3 A freshly prepared eth0real Grignard solution from 5.49 g (3.1 mmol) of cycloheptyl bromide and 0.75 g (3.1 mmol) of magnesium is added dropwi~e under protective gas to a cooled solution (0C) of S g (1.55 mmol~ of methyl 2-~4-(quinoxalin-2-yl-m thoxy)phenyl]glyoxylate in 50 ml of THF. After warming to 25C, the reaction mixture is ~tirred overnight and poured into ice-water, acidified with HCl and extracted with eth~1 acetate. ~fter evapora tion, the residue is chromatographed on silica gel 60 (eluent: cyclohexane/ethyl acetate 3:1).
Yield: 2.26 g (34.7~ of theory~
Melting point: 121C (CH30H) The compound~ shown in Table 4 are prepared in analogy to the procedure of Example 21:
.
Le A 29 140 - 42 -~2~9~3~
Table 4:
,~G
~NJ~
~,~,R1 Ex. No. G Rl R3 m.p. C Yield g ( sol~rent ~ ~ % of theory 22 ~ 5 ~J -OC~3 (CH30H) 2.56~ (39.4) ,/~
23 -N=CH-~ ~J ~H 1(CH30H) 1.t (50,7) 24 5 J / -OH 190 1,8 (86,5) :
, :: : ` ::
`:
Le A 29 140 - 43 -.
,
Claims (18)
1. Substituted (benzothiazolyl- and quinoxalyl-meth-oxy)phenyl-acetic acid derivatives of the general formula (I) in which A, B, D, E and L are identical or different and represent hydrogen, hydroxyl, halogen, tri-fluoromethyl, trifluoromethoxy or carboxyl,or represent straight-chain or branched alkyl having up to 10 carbon atoms, which is option-ally substituted by hydroxyl or halogen, or represent straight-chain or branched alkoxy or alkoxycarbonyl haviny up to 10 carbon atoms, or represent aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, nitro or cyano or by straight-chain or branched alkyl or alkoxy each having up to 8 carbon atoms, G represents a sulphur atom or the group of the formula -N=CH-, R1 represents cycloalkyl having 3 to 12 carbon atoms, or represents straight-chain or branched alkyl having up to 10 carbon atoms, which is option-ally-substituted by aryl having 6-to 10 carbon atoms, R2 represents hydrogen, or represents a group of the formula -OR4, in which R4 denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, benzyl or phenyl, R3 represents hydroxyl, straight-chain or branched alkoxy having up to 8 carbon atoms or phenoxy, or represents a group of the formula -NHSO2-R5, in which R5 denotes straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by phenyl, which can in turn be substituted by straight-chain or branched alkyl having up to 6 carbon atoms or halogen, or denotes phenyl which can optionally be substituted by halogen or trifluoromethyl or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms and their salts.
2. Substituted (benzothiazolyl- and quinoxalyl-meth-oxy)phenyl-acetic acid derivatives according to Claim 1, in which A, B, D, E and L are identical or different and represent hydrogen, fluorine, chlorine, brom-ine, trifluoromethoxy or carboxyl, represent straight-chain or branched alkyl having up to 8 carbon atoms, which is option-ally substituted by hydroxyl, fluorine, chlor-ine or bromine, represent straight-chain or branched alkoxy or alkoxycarbonyl each having up to 8 carbon atoms, or represent phenyl which is optionally substi-tuted by fluorine, chlorine, bromine, nitro or cyano or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms, G represents a sulphur atom or the group of the formula -N=CH-, R1 represents cyclopropyl, cyclobutyl, cyclo-pentyl, cyclohexyl, cycloheptyl or cyclooctyl, or represents straight-chain or branched alkyl having up to 8 carbon atoms, which is option-ally substituted by phenyl or naphthyl, R2 represents hydrogen or a group of the formula -OR4, in which R4 denotes hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, benzyl or phenyl, R3 represents hydroxyl or straight-chain or branched alkoxy having up to 6 carbon atoms, or represent a group of the formula -NHSO2-R5, in which R5 denotes straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by phenyl which can in turn be substituted by straight-chain or branched alkyl having up to 6 carbon atoms, fluorine, chlorine or bromine, or denotes phenyl which can optionally be substituted by fluorine, chlorine or bromine or by straight-chain or branched alkyl having up to 4 carbon atoms and their salts.
3. Substituted (benzothiazolyl- and quinoxalyl-meth-oxy)phenyl-acetic acid derivatives according to Claim 1, in which A, B, D, E and L are identical or different and represent hydrogen, fluorine, chlorine, bromine or straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms, G represents a sulphur atom or the group of the formula -N=CH-, R1 represents cyclopentyl, cyclohexyl or cyclo-heptyl, or represents straight-chain or branched alkyl having up to 6 carbon atoms, which is option-ally substituted by phenyl, R2 represents hydrogen or a group of the formula -OR4, in which R4 denotes hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or phenyl, R3 represents hydroxyl or straight-chain or branched alkoxy having up to 4 carbon atoms, or represents a group of the formula -NHSO2-R5, in which R5 denotes straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by phenyl which can in turn be substituted by straight-chain or branched alkyl having up to 4 carbon atoms, fluorine or chlorine, or denotes phenyl which can optionally be substituted by fluorine, chlorine or methyl and their salts.
4. Substituted (benzothiazolyl- and quinoxalyl-methoxy)-phenylacetic acid derivatives according to claim 1, in which the radical -CR1R-COR3 is in the 3- or 4-position relative to the heterocyclylmethoxy radical.
5. The compound 2-cyclopentyl-2-[4-(quinoxalin-2-yl-methoxy)phenyl]-2-acetic acid.
6. Substituted (benzothiazolyl- and quinoxalyl-methoxy)-phenylacetic acid derivatives according to any one of claims 1 to 5 for therapeutic use.
7. A process for preparing a substituted (benzothiazolyl-or quinoxalyl-methoxy)phenylacetic acid derivative of the general formula (I) or a salt thereof, which process comprises [A] to prepare a compound of formula (Ia) (Ia) in which A, B, D, E, G, L, R1 and R3 are as defined in claim 1, (i) etherifying a compound of the general formula (II) (II) in which A, B, D, E and G are as defined in claim 1 and M
represents a halogen, with a compound of the general formula (III) (III) in which L and R1 are as defined in claim 1 and R7 represents C1-C8-alkoxy; or (ii) alkylating a compound of the general formula (IIa) (IIa) in which A, B, D, E, G and L are as defined in claim 1 and R7 represents C1-C8-alkoxy, by reaction with a compound of the general formula (IV) R1-T (IV) in which R1 is as defined in claim 1 and T represents halogen; or [B] to prepare a compound of the general formula (IIb) (IIb) in which A, B, D, E, G, L, R1, R3 and R4 are as defined in claim 1, reducing a compound of the general formula (VI) (VI) in which A, B, D, E, G and L are as defined in claim 1 and R7 represents C1-C8-alkoxy, with a Grignard compound of the general formula (VII) (R1)n-V (VII) in which R1 is as defined in claim 1, V represents a Grignard radical W-Z, in which W denotes magnesium or zinc and Z denotes chlorine, bromine or iodine and n is 1, or V represents lithium, sodium, magnesium, aluminium or zinc and n is equal to the valency of the metal, to obtain a compound of formula (IIb) in which R4 is hydrogen, and, if required, etherifying the obtained compound to yield a compound of formula (IIb) in which R4 is as defined in claim 1, other than hydrogen;
followed, if required, by hydrolysing an obtained compound of formula (I) in which R3 is other than hydrogen to yield a compound of formula (I) in which R3 is hydroxyl; and, if required, by amidating a compound of formula (I) in which R3 is hydroxyl, or an activated derivative thereof, with a compound of the general formula (VIII) H2N-SO2-R5 (VIII) in which R5 is as defined in claim 1, to obtain a compound of formula (I) in which R3 is NH-SO2-R5 and, if required, converting an acid of formula (I) into an ester thereof and, if required, transesterifying an ester of formula (I) and, if required, converting a compound of formula (I) in which A, B, D or E is hydrogen into a compound in which A, B, D or E is as defined in claim 1 other than hydrogen, or varying a substituent A, B, D or E, and, if required, separating compounds of formula (I) into pure enantiomers, and, if required, converting compounds of formula (I) into salts thereof.
represents a halogen, with a compound of the general formula (III) (III) in which L and R1 are as defined in claim 1 and R7 represents C1-C8-alkoxy; or (ii) alkylating a compound of the general formula (IIa) (IIa) in which A, B, D, E, G and L are as defined in claim 1 and R7 represents C1-C8-alkoxy, by reaction with a compound of the general formula (IV) R1-T (IV) in which R1 is as defined in claim 1 and T represents halogen; or [B] to prepare a compound of the general formula (IIb) (IIb) in which A, B, D, E, G, L, R1, R3 and R4 are as defined in claim 1, reducing a compound of the general formula (VI) (VI) in which A, B, D, E, G and L are as defined in claim 1 and R7 represents C1-C8-alkoxy, with a Grignard compound of the general formula (VII) (R1)n-V (VII) in which R1 is as defined in claim 1, V represents a Grignard radical W-Z, in which W denotes magnesium or zinc and Z denotes chlorine, bromine or iodine and n is 1, or V represents lithium, sodium, magnesium, aluminium or zinc and n is equal to the valency of the metal, to obtain a compound of formula (IIb) in which R4 is hydrogen, and, if required, etherifying the obtained compound to yield a compound of formula (IIb) in which R4 is as defined in claim 1, other than hydrogen;
followed, if required, by hydrolysing an obtained compound of formula (I) in which R3 is other than hydrogen to yield a compound of formula (I) in which R3 is hydroxyl; and, if required, by amidating a compound of formula (I) in which R3 is hydroxyl, or an activated derivative thereof, with a compound of the general formula (VIII) H2N-SO2-R5 (VIII) in which R5 is as defined in claim 1, to obtain a compound of formula (I) in which R3 is NH-SO2-R5 and, if required, converting an acid of formula (I) into an ester thereof and, if required, transesterifying an ester of formula (I) and, if required, converting a compound of formula (I) in which A, B, D or E is hydrogen into a compound in which A, B, D or E is as defined in claim 1 other than hydrogen, or varying a substituent A, B, D or E, and, if required, separating compounds of formula (I) into pure enantiomers, and, if required, converting compounds of formula (I) into salts thereof.
8. A process according to claim 7 wherein in process [A](ii) the compound of formula (IIa) is obtained by reacting a compound of the general formula (II) as defined in claim 7 with a compound of the general formula (IIIa) (IIIa) in which R7 is as defined in claim 7.
9. A process according to claim 7 wherein in process [B]
the compound of formula (VI) is obtained by reacting a compound of formula (II) with a compound of the general formula (V) (V) in which L and R7 are as defined in claim 7.
the compound of formula (VI) is obtained by reacting a compound of formula (II) with a compound of the general formula (V) (V) in which L and R7 are as defined in claim 7.
10. A process according to claim 7 wherein in process [A](i) the compound of formula (III) is obtained by removal of a hydroxyl protective group from a corresponding hydroxy-protected compound.
11. A process according to claim 8 wherein in process [A](ii) the compound of formula (IIIa) is obtained by removal of a hydroxyl protective group from a corresponding hydroxy-protected compound.
12. A process according to claim 9 wherein in process [B] the compound of formula (V) is obtained by removal of a hydroxyl protective group from a corresponding hydroxy-protected compound.
13. A process according to claim 10, 11 or 12 wherein the hydroxyl protective group is a benzyl or tert.-butyl group.
14. A medicament which comprises a substituted (benzo-thiazolyl- or quinoxalinyl-methoxy)phenylacetic acid according to any one of claims 1 to 6 or a physiologically acceptable salt thereof, together with a suitable diluent or carrier.
15. A process for preparing a medicament which comprises admixing a substituted (benzothiazolyl- or quinoxalinyl-methoxy)-phenylacetic acid according to any one of claims 1 to 6 or a physiologically acceptable salt thereof with a suitable diluent or carrier.
16. Use of a substituted (benzothiazolyl- or quinoxalinyl-methoxy)phenylacetic acid according to any one of claims 1 to 6 or a physiologically acceptable salt thereof for inhibiting enzymatic reactions in the context of arachidonic acid metabolism.
17. A commercial package containing, as active pharmaceutical ingredient, a substituted (benzothiazolyl- or quinoxalinyl-methoxy)phenylacetic acid according to any one of claims 1 to 6 or a physiologically acceptable salt thereof, together with instructions for its use for inhibiting enzymatic reactions in the context of arachidonic acid metabolism.
18. A compound of the general formula (VI) as defined in claim 7.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4219765.1 | 1992-06-17 | ||
| DE4219765A DE4219765A1 (en) | 1992-06-17 | 1992-06-17 | Substituted (benzothiazolyl and quinoxalyl-methoxy) phenylacetic acid derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2098366A1 true CA2098366A1 (en) | 1993-12-18 |
Family
ID=6461172
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002098366A Abandoned CA2098366A1 (en) | 1992-06-17 | 1993-06-14 | Substituted (benzothiazolyl- and quinoxalyl-methoxy) phenyl-acetic acid derivatives |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP0574774A1 (en) |
| JP (1) | JPH0665214A (en) |
| KR (1) | KR940000436A (en) |
| CN (1) | CN1084166A (en) |
| AU (1) | AU3981793A (en) |
| CA (1) | CA2098366A1 (en) |
| CZ (1) | CZ109593A3 (en) |
| DE (1) | DE4219765A1 (en) |
| FI (1) | FI932743A7 (en) |
| HU (1) | HU9301754D0 (en) |
| IL (1) | IL106011A0 (en) |
| NO (1) | NO932031L (en) |
| SK (1) | SK62293A3 (en) |
| ZA (1) | ZA934264B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5849751A (en) * | 1995-07-10 | 1998-12-15 | Bayer Aktiengesellschaft | Amides and sulphonamides of benzylamines having heterocyclic substituents |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1238307B (en) * | 1989-12-22 | 1993-07-12 | HEAD FOR ENDOTHERMAL ALTERNATIVE ENGINES EQUIPPED WITH AT LEAST ONE VALVE OPERATED BOTH FOR INTAKE AND FOR EXHAUST. | |
| DE4443891A1 (en) * | 1994-12-09 | 1996-06-13 | Bayer Ag | Heterocyclically substituted oxy-phenyl- (phenyl) glycinolamides |
| DE4443892A1 (en) * | 1994-12-09 | 1996-06-13 | Bayer Ag | 4- (Quinolin-2-yl-methoxy) phenyl acetic acid derivatives |
| JP6557588B2 (en) | 2015-12-04 | 2019-08-07 | 株式会社日立ハイテクノロジーズ | Dry etching method |
| CN117159549B (en) * | 2023-10-11 | 2025-02-14 | 中国药科大学 | Application of an ester compound |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4594425A (en) * | 1984-02-09 | 1986-06-10 | American Home Products Corporation | Heterocyclic compounds as antiallergic agents |
| US4675405A (en) * | 1984-09-21 | 1987-06-23 | American Home Products Corporation | Quinoline compounds as antiallergic and antithrombotic agents |
| NZ213986A (en) * | 1984-10-30 | 1989-07-27 | Usv Pharma Corp | Heterocyclic or aromatic compounds, and pharmaceutical compositions containing such |
| JPS62142168A (en) * | 1985-10-16 | 1987-06-25 | Mitsubishi Chem Ind Ltd | Thiazole derivatives and leukotriene anti-inflammatory agents containing them as active ingredients |
| DE3814504A1 (en) * | 1988-04-29 | 1989-11-09 | Bayer Ag | (ALPHA) -SUBSTITUTED 4- (CHINOLIN-2-YL-METHOXY) PHENYL ACETIC ACIDS AND SITES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE IN MEDICAMENTS |
| DE3900261A1 (en) * | 1988-05-31 | 1989-12-07 | Bayer Ag | SUBSTITUTED 4- (CHINOLIN-2-YL-METHOXY) PHENYL-ACETIC ACID DERIVATIVES |
| IE66512B1 (en) * | 1989-02-28 | 1996-01-10 | Ici Plc | Heterocyclic ethers as 5-lipoxygenase inhibitors |
| DE3927931A1 (en) * | 1989-08-24 | 1991-02-28 | Bayer Ag | DISUBSTITUTED (CHINOLIN-2-YL-METHOXY) PHENYL ACETIC DERIVATIVES |
| PT95692A (en) * | 1989-10-27 | 1991-09-13 | American Home Prod | PROCESS FOR THE PREPARATION OF INDOLE-, INDENO-, PYRANOINDOLE- AND TETRA-HYDROCARBAZOLE-ALCANOIC ACID DERIVATIVES, OR WHICH ARE USEFUL AS PLA2 INHIBITORS AND LIPOXIGENASE |
| DE4105551A1 (en) * | 1991-02-22 | 1992-08-27 | Bayer Ag | 2-SUBSTITUTED CHINOLINES, PROCESS FOR THEIR PREPARATION AND THEIR USE IN MEDICINAL PRODUCTS |
| DE4128681A1 (en) * | 1991-08-29 | 1993-03-04 | Bayer Ag | SUBSTITUTED ALMOND ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE IN MEDICINAL PRODUCTS |
| DE4129742A1 (en) * | 1991-09-06 | 1993-03-11 | Bayer Ag | HETEROCYCLICALLY SUBSTITUTED CHINOLYLMETHOXY-PHENYLACETAMIDE |
-
1992
- 1992-06-17 DE DE4219765A patent/DE4219765A1/en not_active Withdrawn
-
1993
- 1993-05-26 AU AU39817/93A patent/AU3981793A/en not_active Abandoned
- 1993-06-03 NO NO932031A patent/NO932031L/en unknown
- 1993-06-04 EP EP93108996A patent/EP0574774A1/en not_active Withdrawn
- 1993-06-07 CZ CZ931095A patent/CZ109593A3/en unknown
- 1993-06-14 IL IL106011A patent/IL106011A0/en unknown
- 1993-06-14 CA CA002098366A patent/CA2098366A1/en not_active Abandoned
- 1993-06-15 FI FI932743A patent/FI932743A7/en unknown
- 1993-06-15 JP JP5168686A patent/JPH0665214A/en active Pending
- 1993-06-16 ZA ZA934264A patent/ZA934264B/en unknown
- 1993-06-16 SK SK622-93A patent/SK62293A3/en unknown
- 1993-06-16 HU HU9301754A patent/HU9301754D0/en unknown
- 1993-06-16 KR KR1019930010947A patent/KR940000436A/en not_active Withdrawn
- 1993-06-17 CN CN93107472A patent/CN1084166A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5849751A (en) * | 1995-07-10 | 1998-12-15 | Bayer Aktiengesellschaft | Amides and sulphonamides of benzylamines having heterocyclic substituents |
Also Published As
| Publication number | Publication date |
|---|---|
| FI932743A0 (en) | 1993-06-15 |
| CZ109593A3 (en) | 1994-01-19 |
| KR940000436A (en) | 1994-01-17 |
| FI932743L (en) | 1993-12-18 |
| FI932743A7 (en) | 1993-12-18 |
| SK62293A3 (en) | 1994-02-02 |
| JPH0665214A (en) | 1994-03-08 |
| AU3981793A (en) | 1993-12-23 |
| CN1084166A (en) | 1994-03-23 |
| IL106011A0 (en) | 1993-10-20 |
| NO932031L (en) | 1993-12-20 |
| HU9301754D0 (en) | 1993-09-28 |
| EP0574774A1 (en) | 1993-12-22 |
| ZA934264B (en) | 1994-01-14 |
| DE4219765A1 (en) | 1993-12-23 |
| NO932031D0 (en) | 1993-06-03 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |