DD208798A5 - PROCESS FOR THE PREPARATION OF PHENOL DERIVATIVES - Google Patents

Abstract

The invention relates to novel phenol derivatives, in particular those of the general formula &, in which R 0 is hydrogen or an acyl radical, R 1 is a carboxy, esterified carboxy or amidated carboxy, R 2 is a hydrogen or an aliphatic radical, R is low 3 represents an amino group disubstituted by two monovalent hydrocarbon radicals or by a divalent hydrocarbon radical and the aromatic ring A may additionally be substituted, i.a. their salts u. Isomers, process for the preparation of compounds of formula (&) and their salts and the like Isomers, such compounds. containing paramazeutische preparations and their uses. as drug active. u./o. to the manufact. pharmaceutical preparations. The connection of the formula (&) are characterized by pronounced anti-inflammatory u. analgesic properties.

Description

Process for the preparation of phenol derivatives Field of application of the invention

The invention relates to a process for the preparation of phenol derivatives having valuable pharmacological properties for use as medicaments, such as anti-inflammatory drugs or anaesthetics.

Characteristic of the known technical solutions

Although the compounds of the formula I fall within the scope of DE-OS 2 012 327, there are no specific compounds specifically disclosed there which have possibly esterified hydroxy in position 2 of the phenyl ring.

Object of the invention

The aim of the invention is the provision of novel phenol derivatives having valuable pharmacological, in particular analgesic and antiinflammatory properties.

Explanation of the essence of the invention

The invention has for its object to find new phenol derivatives with the desired properties and processes for their preparation.

According to the invention, new phenol derivatives of the general formula

-agric 1983 * 074554

«4 4 3 ^ / 8 - la - 61 577/11

07/03/1983

AP C 07 C / 244 347/8

CH

wherein R is hydrogen or an acyl radical, R _{1 is} carboxy, esterified carboxy or amidated carboxy, R _{2 is} hydrogen or an aliphatic radical, R is a di-substituted by two monovalent hydrocarbon radicals or by a divalent hydrocarbon radical and the aromatic Ring A may additionally be substituted, and their salts and isomers, processes for the preparation of compounds of formula (I) and their salts and isomers, pharmaceutical preparations containing such compounds and their use as pharmaceutical active ingredients and / or for the preparation of pharmaceutical preparations.

An aliphatic radical R ₂ is in particular saturated and unsubstituted and is primarily a lower alkyl radical.

An acyl radical is, for example, a lower alkanoyl radical or an aryl-lower alkanoyl radical "such as a mono- or polysubstituted or unsubstituted phenyl-lower alkanoyl radical in the phenyl part, phenyl being ζ. B, by an aliphatic radical such as lower alkyl, lower alkenyl, optionally branched, in particular two carbon atoms bridging, 3- to 4-membered alkylene having 3 to 8 carbon atoms, hydroxy or lower alkyl, lower alkoxy, lower alkylthio, lower alkanesulfinyl, lower alkanesulfonyl, hydroxy, lower alkanoyloxy , Low

2 4 Λ 3 Λ 7 8

• - 2 -

alkanoyl, halogen and / or nitro may be monosubstituted or polysubstituted or unsubstituted. An aryl-lower alkanoyl radical is derived primarily from a phenylalkanecarboxylic acid of the formula (I), where the radicals R ₉ and R and the substituents of the ring A have the meanings given for the compounds of the formula (I), preferably R and R in particular Hydrogen, furthermore lower alkanoyl means.

Esterified carboxy is, for example, carboxy esterified with an aliphatic or aromatic alcohol. As the aliphatic alcohol, for example, a lower alkanol or a e.g. lower alkanol substituted by hydroxy, by lower alkoxy, by lower alkanoyloxy or by aryl, such as substituted or unsubstituted phenyl, wherein phenyl is e.g. by an aliphatic radical, such as lower alkyl, lower alkenyl, optionally branched, in particular two C atoms bridging, 3- to 4-membered alkylene having 3 to C atoms, hydroxy lower alkyl or halo lower alkyl, lower alkoxy, lower alkylthio, lower alkanesulfinyl, lower alkanesulfonyl, hydroxy, lower alkanoyloxy, Lower alkanoyl, halogen and / or nitro may be mono- or polysubstituted or unsubstituted.

As the aromatic alcohol is, for example, substituted or unsubstituted phenol into consideration, wherein phenol e.g. by an aliphatic radical, such as lower alkyl, lower alkenyl, optionally branched, in particular two C atoms bridging, 3- to 4-membered alkylene having 3 to 8 carbon atoms, hydroxy or lower alkyl, lower alkoxy, lower alkylthio, lower alkanesulfinyl, lower alkanesulfonyl, hydroxy, lower alkanoyloxy , Lower alkanoyl, halogen and / or nitro may be monosubstituted or polysubstituted or unsubstituted.

Correspondingly esterified carboxy is e.g. Lower alkoxycarbonyl, hydroxy-lower alkoxycarbony 1, lower alkoxy-lower alkoxycarbony 1, lower alkanoyloxy-lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl or phenoxycarbonyl.

Amidated carboxy has as amino group, for example, a free, mono- or disubstituted amino group. The monosubstituted amino group is exemplified by lower alkyl, in the phenyl portion

Λ 3 Λ 7 8-3-

substituted or unsubstituted phenyl-lower alkyl or monosubstituted by substituted or unsubstituted phenyl. Disubstituted amino is disubstituted, for example, by lower alkyl, substituted by phenyl substituted or unsubstituted phenyl, by substituted or unsubstituted phenyl or by lower alkylene or lower alkenyl or by monoaza, N-alkylated monoaza, by Monoöxa, Mönothia interrupted lower alkylene or lower alkenylene, wherein Lower alkylene or lower alkenylene unbranched or branched and / or may have one or two ortho-annelated benzene systems. Phenyl is e.g. by an aliphatic radical, such as lower alkyl, lower alkenyl, optionally branched, in particular two C-atoms bridging 3- to 4-membered alkylene having 3 to 8 carbon atoms, hydroxy or lower alkyl, lower alkoxy, lower alkylthio, lower alkanesulfinyl, lower alkanesulfonyl, hydroxy, lower alkanoyloxy, Lower alkanoyl, halogen and / or nitro mono- or polysubstituted or unsubstituted. Correspondingly amidated carboxy is e.g. Carbamoyl, N-mono- or Ν, Ν-di-lower alkylcarbamoyl, N-mono- and N, N-di-phenyl-lower alkylcarbamoyl, N-mono- or N, N-diphenylcarbamoyl, lower alkylenecarbamoyl or by monoaza, N'-loweralkylmonoaza, Monooxa or monothia interrupted Niederalkylencarbamoyl, further N-lower alkyl-N-phenyl-lower alkyl, N-phenyl-lower alkyl-N-phenyl, Niederalkenylcarbamoyl.

The aromatic ring A can additionally be bridged by an aliphatic radical such as lower alkyl, hydroxy lower alkyl, lower haloalkyl, lower alkenyl or optionally branched, in particular two adjacent C atoms, 3- to 4-membered alkylene, lower alkoxy, hydroxy, lower alkylthio, lower alkanesulfinyl, lower alkanesulfonyl, Halogen, lower alkanoyloxy, lower alkanoyl and / or nitro mono- or polysubstituted or, except for R, be unsubstituted.

As such, an amino group disubstituted by two monovalent hydrocarbon radicals has monovalent aliphatic radicals, such as lower alkyl radicals, which are unsubstituted or substituted by 3- to 7-membered

2Λ 4 3 Λ 7 8-

cycloalkyl or by aryl, such as unsubstituted or e.g. may be substituted by an aliphatic radical such as lower alkyl, lower alkenyl, lower alkylene, hydroxy lower alkyl, halo lower alkyl, lower alkoxy, lower alkylthio, lower alkanesulfinyl, lower alkanesulfonyl, hydroxy, halogen, lower alkanoyloxy, lower alkanoyl and / or nitro-containing phenyl. As such, an amino group disubstituted by a divalent hydrocarbon radical has a divalent aliphatic radical which may also be interrupted by aza, N-lower alkylaza, oxa or thia, such as lower alkylene, lower alkenylene, lower alkylene each interrupted by aza, N-lower alkylaza, oxa, thia or lower alkenylene, wherein lower alkylene or lower alkenylene can each also be branched. Further, such cyclic amines R may also have one or two ortho-fused benzo systems.

R is preferably di-lower alkylamino, Cycloalkylniederalkylniederalkyl-amino, di-cycloalkyl-lower alkyl-amino, lower alkyl-phenyl-lower alkyl-amino, di-phenyl-lower alkyl-amino, furthermore phenyl-lower alkyl-cycloniederalkylniederalkyl-amino, and in each case 5- to 8-membered lower alkyleneamino, Niederalkenylenamino, Aza-lower alkyleneamino, N'-lower alkylaza-lower alkylene-amino, oxa-lower alkylene-amino, thia-lower alkylene-amino, aza-lower-alkenylene-amino, N'-lower alkylazo-lowerkenylene-amino, oxa-lower-alkenylene-amino or thia-lower-alkenylene-amino, wherein lower alkylene -or. Lower alkenylene-amino may also be branched and corresponding to 4 to 14, preferably 4 to 7 carbon atoms may have.

Examples of such radicals R are: pyrrolidin-1-yl, 2- or 3-pyrrolin-1-yl, pyrrol-1-yl, piperidin-1-yl, azepin-1-yl, imidazolidin-1-yl, 2-, 3- or 4-imidazolin-1-yl, oxazolidin-3-yl, 4-oxazolin-3-yl, thiazolidin-3-yl, 4-thiazolin-3-yl, piperazin-1-yl, morpholine 4-yl, thiomorpholin-4-yl, 3-methyl-imidazolidin-1-yl, 4-methyl-piperazin-1-yl.

Furthermore, R represents lower-alkylene or lower-alkenylene-amino, which has one or two ortho-fused benzene systems, such as indol-1-yl, indolin-1-yl, isoindol-2-yl, isoindolin-2-yl, carbazole-9- yl or β-carbolin-9-yl.

Above and below, organic radicals and compounds designated "lower" are preferably to be understood as meaning those which contain up to and including 7, especially up to and including 4 carbon atoms.

The general definitions used in the present text have the following meanings in the first place:

Lower alkyl is e.g. Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and further includes corresponding pentyl, hexyl or heptyl radicals.

Hydroxy-lower alkyl is e.g. Hydroxymethyl, 2-hydroxyethyl or 2- or 3-hydroxypropyl.

Halo-lower alkyl is e.g. Chloromethyl or trifluoromethyl.

Lower alkenyl is e.g. Vinyl, 1- or 2-propenyl, 1-, 2- or 3-butenyl or butadien-1,3-yl.

3- or 4-membered alkylene is e.g. straight-chain, such as tri- or tetramethylene, or branched, such as 2,4-butylene, 2,4-pentylene or 2-methyl-l, 3-propylene.

Lower alkoxy is e.g. Methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, further corresponding pentyloxy, hexyloxy or Heptyloxyreste.

Lower alkylthio is e.g. Methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, sec-butyl or tert-butylthio.

2U347 8 -

Lower alkanesulfinyl or sulfonyl is e.g. Methane, ethane, n-propane or isopropane-sulfinyl or -sulfonyl.

Halogen is e.g. Halogen of atomic number to and including 35, such as fluorine, chlorine or bromine, and further includes iodine.

Lower alkanoyloxy is e.g. Acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, sec-butyryloxy or tert-butyryloxy.

Lower alkanoyl is e.g. Acetyl, propionyl, butyryl, isobutyryl or tert-butyryl.

3- to 7-membered cycloalkyl is e.g. Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

Lower alkylene is e.g. straight-chain, such as 4- to 7-membered lower alkylene, such as tetra-, penta- or hexamethylene, furthermore heptamethylene or branched, such as 2,3-dimethyl or 2,3-diethyl-l, 4-butylene.

By Aza or '. N-lower alkylaza interrupted lower alkylene is e.g.

4- to 7-membered monoazo or N'-lower alkylmonoaza-lower alkylene, such as 2-aza-tetramethylene, 3-aza-pentamethylene or 3-methylazapentamethylene.

Lower alkylene interrupted by Oxa or Thia is e.g. Monooxa or monothia-lower alkylene, such as 3-oxa: or 3-thia-pentamethylene.

Lower alkenylene has one or more double bonds and is e.g. 4- to 7-membered lower alkenylene, such as but-2-en-l, 4-ylene, butalb, 3-dien-l, 4-ylene, pent-2-en-l, 5-ylene or penta-1,3 -dien-1, 5-ylene, penta-l, 4-dien-l, 5-ylene, hex-3-en-2,5-ylene or hexa-2,4-diene-2,4-ylene.

Lower alkenylene having one or more double bonds interrupted by aza or N-lower alkylaza is e.g. 2-aza-buten-1-ylene, 2

44347 8 -7-

Aza-buten-2-ylene, 2-aza-buten-3-ylene, 2-methyl-aza-buten-3-ylene or 2-aza-butadien-1, 3-ylene.

Salts of compounds of the formula (I) according to the invention are preferably pharmaceutically acceptable salts, such as pharmaceutically acceptable acid addition salts. These are used, for example, with strong inorganic acids, such as mineral acids, e.g. Sulfuric acid, phosphoric acid or hydrohalic acids, with strong organic carboxylic acids, such as lower alkanecarboxylic acids, e.g. Glacial acetic acid, such as optionally unsaturated dicarboxylic acids, e.g. Oxalic, malonic, maleic or fumaric acid, or hydroxycarboxylic acids, e.g. Tartaric acid or citric acid, or with sulfonic acids such as lower alkane or optionally substituted benzenesulfonic acid, e.g. Methane or p-toluenesulfonic acid formed. For example, when R is carboxy, corresponding compounds can form salts with bases. Suitable salts with bases include, for example, corresponding alkali metal or alkaline earth metal salts, e.g. Sodium, potassium or magnesium salts, pharmaceutically acceptable transition metal salts such as zinc or copper salts, or salts with ammonia or organic amines such as cyclic amines such as mono-, di- or tri-lower alkylamines such as hydroxy-lower alkylamines, e.g. Mono-, di- or Trihydroxyniederalkylamine, hydroxy lower alkyl-lower alkyl amines or as Polyhydroxyniederalkylamine. Cyclic amines are e.g. Morpholine, thiomorpholine, piperidine or pyrrolidine. Examples of suitable mono-lower alkylamines are ethyl- or tert-butylamine, as di-lower alkylamines, for example diethyl- or diisoporpylamine, and trin-lower alkylamines, for example trimethyl- or triethylamine. Corresponding hydroxy-lower alkylamines are e.g. Mono-, di- or triethanolamines, and hydroxy-lower alkyl-lower alkylamines are e.g. Ν, Ν-dimethylamino or Ν, Ν-diethylamino-ethanol, furthermore glucosamine as Polyhydroxyniederalkylamin.

Isomeric compounds of the formula (I) are present in particular as structural isomers. For example, compounds of formula (I) have chiral

244347 8

Carbon atoms, they may be present as diastereomers, diastereomer mixtures, racemates or in the form of a pure enantiomer.

The compounds of the formula (I) have valuable pharmacological properties. In particular, they have a pronounced anti-inflammatory effect, which is obtained, for example, by inhibition of the carrageenin-produced paw edema in the rat from a dose of about 0.1 mg / kg po analogously to that of Pasquale et al., Ag. and Actions, 5, (1975), and in the rat adjuvant arthritis model at a dose of about 1.0 mg / kg po analogously to L. Riesterer et al., Pharmacology, 2 ^, 288 (1969). . »Can be proved. From se rdem inhibiting compounds of formula (I) in vitro at a concentration of about 10 pmol / l prostaglandin synthesis from arachidonic acid analogous to that of HL White et al., Prostaglandins, _t l_ 123 (1974), the method described.

Furthermore, the compounds of the formula (I) have a marked antinociceptive activity component, which can be obtained, for example, from the method described by LC Hendershot et al., J. Pharmacol, exp. Therap./ 125 , 237 (1959) described reduction of the phenyl-p-benzoquinone-induced writhing syndrome in the mouse from a dose of about 0.1 mg / kg po.

Furthermore, the compounds of the formula (I) show the ability to absorb from the region of the UV spectrum the epidermis erythreme-producing rays (between 290 and 320 nm), while the substances for the tanning-emitting rays from about 320 to 100 nm are permeable.

As a result, these compounds can be used as anti-inflammatory agents, (peripheral) analgesics and / or sunscreens, e.g. for cosmetic purposes.

244347 8

The invention relates, for example, to compounds of the formula (I)

wherein R is hydrogen, a lower alkanoyl or an aryl lower

alkanoyl radical, R is carboxy, carboxy esterified with an aliphatic or aromatic alcohol, carbamoyl or mono- or disubstituted carbamoyl, R- is a saturated and unsubstituted aliphatic radical, R "is an amino group disubstituted by two monovalent aliphatic radicals or one by one divalent aliphatic radical disubstituted amino group and the aromatic ring A may additionally be monosubstituted or polysubstituted by an aliphatic radical, lower alkoxy, lower alkylthio, lower alkanesulfinyl, lower alkanesulfonyl, hydroxy, halogen, lower alkanoyloxy, lower alkanoyl and / or nitro or, except for R, unsubstituted , and their salts, especially pharmaceutically acceptable salts, and isomers.

The invention relates, for example, to compounds of the formula (I) in which R is hydrogen, lower alkanoyl or phenyl-lower alkanoyl, where the phenyl radical is mono- or polysubstituted by lower alkyl, hydroxy lower alkyl, lower haloalkyl, lower alkenyl, 3- or 4-membered alkylene, lower alkoxy, lower alkylthio, lower alkanesulfinyl, Lower alkanesulfonyl, hydroxy, halogen, lower alkanoyloxy, lower alkanoyl and / or nitro may be substituted or unsubstituted, or phenyl-lower alkanoyl, which is derived from a Phenylalkanniedercarbonsäure the formula (I), wherein the radicals R "and R and the substituents of the ring A, the following R is hydrogen or lower alkanoyl, R is carboxy, lower alkoxycarbonyl, hydroxy-lower alkoxycarbonyl, lower alkanoyloxy-lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl, phenoxycarbonyl, carbamoyl, N-mono-, Ν, Ν-di-lower alkylcarbamoyl, N-mono- or Ν, Ν-di- phenyl-lower alkylcarbamoyl, N-mono-, N, N, di phenyl 'carbamoyl, N-lower alkyl-N-phenyl-lower alkyl-carbamoyl,' 'N-lower-alkyl-N-phenyl-carbamoyl, N-phenyl-lower alkyl-N-phenyl-carbaraoyl, lower alkylene-carbamoyl, lower alkenyl-carbamoyl, by monoaza, N' -

244347 8.

ίο -

Lower alkylenecarbamoyl, lower alkenylenecarbamoyl, where phenyl or phenoxy is in each case monosubstituted or polysubstituted by lower alkyl, hydroxy lower alkyl, lower haloalkyl, lower alkenyl, 3- or 4-membered alkylene, lower alkoxy, lower alkylthio, lower alkanesulfinyl, lower alkanesulfonyl, hydroxy, halogen, Lower alkanoyloxy, lower alkanoyl and / or nitro may be substituted or unsubstituted, and wherein lower alkylene or lower alkenylene may have unbranched or branched and / or one or two ortho-fused benzo systems, R is hydrogen or lower alkyl and R on the one hand Ν, Ν-di-lower alkyl -amino, N-cyclic-lower alkyl-N-lower-alkyl-amino, N-lower-alkyl-N-phenyl-lower alkyl-amino, N, N-di-cycloloweralkyl-lower alkyl-amino, N-cycloloweralkyl-lower alkyl-N-phenyl-lower alkyl-amino or Ν, Ν-di-phenyl-lower alkyl-amino on the other hand, R "is each 5- to 8-membered lower alkylene amine Oj lower alkenylena mino, by monoaza, N'-Niederalkylmonoaza, monooxa or monothia interrupted Niederalkylenamino, by monoaza, N'-Niederalkylmonoaza, monooxa or monothia interrupted Niederalkenylenamino or one or two ortho-fused benzo systems having lower alkylene or lower alkenylene amino, wherein lower alkylene or Lower alkenylene may be unbranched or branched and may have 4 to 14, in particular 4 to 7, carbon atoms and / or one or two ortho-fused benzene systems and phenyl or benzo each one or more times by lower alkyl, hydroxy lower alkyl, halo lower alkyl, lower alkenyl , 3- or 4-membered alkylene, lower alkoxy, lower alkylthio, lower alkanesulfonyl, lower alkanesulfonyl, hydroxy, halogen, lower alkanoyloxy, lower alkanoyl and / or nitro may be substituted or unsubstituted, and the aromatic ring A is mono- or polysubstituted by lower alkyl, hydroxy lower alkyl, halo lower alkyl Lower alkenyl, 3- or 4-membered alkylene, Lower alkoxy, lower alkylthio, lower alkanesulfinyl, lower alkanesulfonyl, hydroxy, halogen, lower alkanoyloxy, lower alkanoyl and / or nitro, or, except R-, may be unsubstituted, and their salts, especially pharmaceutically acceptable salts, and isomers.

244 3 47 8

The invention relates, for example, to compounds of the formula (I) in which R is hydrogen, lower alkanoyloxy or phenyl which is unsubstituted or monosubstituted or polysubstituted by lower alkyl, lower alkoxy, hydroxyl, halogen, lower alkanoyloxy and / or trifluoromethyl, R is carboxy, with a lower alkanol lower alkanol substituted with hydroxy, lower alkoxy, lower alkanoyloxy or unsubstituted or lower alkyl, lower alkoxy, hydroxy, halo, lower alkanoyloxy and / or trifluoromethyl-containing phenyl, with phenol unsubstituted or lower alkyl, lower alkoxy, hydroxy, halo, lower alkanoyloxy and / or trifluoromethyl esterified carboxy, carbamoyl, by lower alkyl, in the phenyl unsubstituted or lower alkyl, lower alkoxy, hydroxy, halogen, lower alkanoyloxy and / or trifluoromethyl having Phenylniederalkyl monosubstituted carbamoyl, by lower alkyl unsubstituie by in the phenyl moiety or lower alkyl, lower alkoxy, hydroxy, halogen, lower alkanoyloxy and / or trifluoromethyl-containing phenyl, alkyl represented by lower alkylene or by monoaza, N-alkylated monoaza, monooxa or monothia interrupted lower alkylene disubstituted carbamoyl, R "is hydrogen or lower alkyl, R _{3 is} a by lower alkyl, by in the cycloalkyl part 3- to 7-membered cycloalkyl-lower alkyl, by in the phenyl unsubstituted or lower alkyl, lower alkoxy, hydroxy, halogen, lower alkanoyloxy and / or trifluoromethyl-containing phenyl, by lower alkylene, by lower alkenylene, by aza, N-lower alkylaza , Oxa or thia is interrupted lower alkylene or lower alkenylene interrupted by aza or N-lower alkylaza is di-substituted amino group and the aromatic ring A may additionally be substituted by lower alkyl, lower alkoxy, hydroxy, halo lower alkanoyloxy, 3- or 4-membered alkylene and / or trifluoromethyl, and their salt e, in particular pharmaceutically acceptable salts, and isomers.

The invention particularly relates to compounds of the formula

/ ν Λ 3 4 7 8

Γ A Π ^ ₁ (i _a))

r / V \ r

3 1o R

wherein R is hydrogen or lower alkanoyl, such as acetyl, R ₁ o 1

Carboxy, lower alkoxycarbonyl such as methoxycarbonyl, lower alkylenecarbamoyl such as pyrrolidinocarbonyl, or oxa-lower alkylene carbamoyl such as 3-oxapentamethylene-carbamoyl; R_ represents hydrogen or lower alkyl such as methyl; R "di-lower alkyl-amino such as dimethylamino, di -cycloalkyl-lower alkylamino such as di-cyclopropylmethylamino, di-phenyl-lower alkyl-amino such as dibenzylamino, each 5- to 8-membered lower alkyleneamino such as pyrrolidin-1-yl, lower alkenyleneamino such as pyrrol-1-yl, monoaza-lower alkylene-amino such as piperazine 1-yl, N'-loweralkylmonoaza-lower alkyleneamino, such as 4-methyl-piperazin-1-yl, monooxanoweralkoxlene-amino, such as morpholinyl-4-yl, monothia-lower-alkyleneamino, such as thiomorpholin-4-yl, monoaza-lower-alkenyleneamino, such as Imidazol-1-yl, or N'-loweralkylmonoaza-loweralkenyleneamino, such as 3-methylimidazol-1-yl, and R, R, R independently

el D C

from each other are hydrogen, lower alkyl, such as methyl, lower alkoxy, such as methoxy, hydroxy, halogen, such as chlorine, lower alkanoyloxy, such as acetyloxy, 3- or 4-membered alkylene, such as tetramethylene, or trifluoromethyl, and their salts, in particular pharmaceutically acceptable salts, and isomers. , ,

The invention relates in particular to compounds of the formula (Ia) in which R is hydrogen or lower alkanoyl, such as acetyl, or phenyl-lower alkanoyl, which is derived from a phenyl-lower alkanecarboxylic acid of the formula (I), where R ", R ₀ , R, R and R are the radicals to-

I 3 a D c

R _{1 is} carboxy, lower alkoxycarbonyl, such as methoxycarbonyl, lower alkanoyloxy-lower alkoxycarbonyl, such as pivaloyloxymethoxycarbonyl, carbamoyl,

24 4 3 Λ 7 8

Ν, Ν-di-phenyl-lower alkyl-carbamoyl, such as Ν, Ν-dibenzylcarbamoyl, lower alkylenecarbamoyl, such as pyrrolidino-carbonyl, or by monooxa interrupted Niederalkylencarbamoyl, such as 4-morpholino-carbonyl, R is hydrogen or lower alkyl, such as methyl, R "on the one hand Ν, Ν-di-phenyl-lower alkyl-amino, such as dibenzylamino, or R" on the other hand each 5- to 8-membered lower alkyleneamino, such as 1-piperidino, lower alkenyleneamino, such as 1-pyrrolyl, interrupted by monooxa lower alkyleneamino, such as 4- Morpholino, or an ortho-fused benzo system having Niederalkylenamino or Niederalkenylenamino, indolin-1-yl or indol-1-yl, and / or ^R _a »Rj ₃ and R are independently hydrogen, lower alkyl, such as methyl, or halogen, such as Chlorine or bromine, and their salts, especially pharmaceutically acceptable salts, and isomers.

The invention relates, in particular, to compounds of the formula (Ia) in which

R is hydrogen or lower alkanoyl, especially with bis and with ο

5 C atoms, such as acetyl, R represents carboxy, lower alkoxycarbonyl, in particular with, to and with 5 C atoms, such as methoxycarbonyl, 5- to 8-membered lower alkylenecarbamoyl, such as pyrrolidinocarbonyl, 5- to 8-membered monooxa-lower alkylenecarbamoyl, such as 3-0xapentamethylenecarbamoyl, R is hydrogen or lower alkyl, in particular with up to and with 4 C atoms, such as methyl, R is di-lower alkylamino, in particular with up to and with 4 C atoms in the alkyl moiety, such as N , N-dimethylamino, 5- to 8-membered lower alkyleneamino such as pyrrolidin-1-yl, 5- to 8-membered lower alkenyleneamino such as pyrrol-1-yl, or 5- to 8-membered monooxa-lower alkyleneamino such as morpholine-4 -yl, and R and R are hydrogen

and R is halogen, in particular to and with atomic number 35, such as b

Chlorine, and their salts, in particular pharmaceutically acceptable salts and isomers.

The invention relates in the first place to compounds of the formula (Ia) in which R is hydrogen or lower alkanoyl with bis and with 5 C atoms, such as acetyl, R is carboxy or lower alkoxycarbonyl

2 / U347 8 -

to and with 5 C atoms, such as methoxycarbonyl, R _{2 is} lower alkyl having up to and including 4 C atoms, such as methyl, R _{3 is} 5- to 7-membered lower alkylene amino, such as pyrrolidin-1-yl, morpholine-4 is -yl or pyrrol-1-yl, R and R are each hydrogen and R 1 is lower alkyl having up to and including 4 C atoms, such as methyl, or halogen to and having atomic number 35, such as chlorine, and their salts, especially pharmaceutically acceptable salts, and isomers.

The invention relates in the first place to compounds of the formula (Ia)

wherein R is lower alkanoyl with bis and with 5 C atoms, such as acetyl, o

R is lower alkoxycarbonyl having up to and including 5 C atoms, such as

Methoxycarbonyl, R 'represents lower alkyl having up to and including 4 C atoms, such as methyl, R is morpholin-4-yl or pyrrol-1-yl,

R and R are hydrogen and R, halogen is bis and with ac 0

Atom number 35, such as chlorine, or lower alkyl with up to and with 4 C atoms, such as methyl, and their salts, in particular pharmaceutically acceptable salts, and isomers.

The invention relates in particular to the novel compounds mentioned in the examples, their salts, especially pharmaceutically acceptable salts, and isomers, and also to the processes for their preparation described in the examples.

The compounds of the present invention are prepared in a manner known per se, for example by reacting compounds of the formula

(II)

wherein X _{1 is} hydrogen, X is different from R, functionally abgeged deltes carboxy and R 'has the meaning of R or wherein

O η

Is hydrogen and together form R ¹ the group C = O

2U3 47 8

or wherein X together with X "form the group = C = 0 or the group = C (Hal)" and each Hal is halogen, and R 'is the

Meaning of R, or their salts with Solvolysemitteln behano

delt and / or, if desired, a salt obtainable according to the process into the free compound or into another salt, a free compound obtainable according to the process into another free compound or into a salt and / or, if desired, a mixture of isomers obtainable according to the process into its components separates.

For example, cyano, anhydridized carboxy, optionally substituted amidino, optionally esterified thiocarboxy, optionally esterified dithiocarboxy, optionally substituted thiocarbamoyl, optionally esterified or anhydridized carboximidoyl, esterified or amidated carboxy R, various esterified or amidated carboxy, other than R different functionally modified carboxy X-, hydroxy or amino substituted carbamoyl, trialkoxy or trihalomethyl.

Anhydridisierte carboxy is, for example, with a mineral acid, such as hydrohalic acid, or with a carboxylic acid, such as an optionally substituted lower alkane or benzoic acid or a carbonyl halide lower alkyl, anhydride carboxy. Examples which may be mentioned are halocarbonyl, such as chlorocarbonyl, lower alkanoyloxycarbonyl, such as acetoxycarbonyl, or lower alkoxycarbonyloxycarbonyl, such as ethoxycarbonyloxycarbonyl.

Optionally substituted amidino is exemplified by an aliphatic, e.g. Lower alkyl radical, substituted amidino such as amidino or lower alkylamidino, e.g. Ethylamidino.

Optionally esterified thiocarboxy or dithiocarboxy has, for example, the alcohol or hydroxy component mentioned in connection with esterified carboxy. Were singled out as

34 7 8

For example, lower alkylthio-carbonyl, such as ethylthio-carbonyl, lower alkoxythiocarbonyl, such as ethoxy-thiocarbonyl, lower alkylthio-thiocarbonyl, such as ethylthio-thiocarbonyl, the respective thiocarboxy and dithiocarboxy.

Optionally substituted thiocarbamoyl may e.g. having the substituents mentioned under amidated carboxy. Examples which may be mentioned are N-mono- or Ν, Ν-di-lower alkylthiocarbamoyl, such as methyl or diethyl-thiocarbamoyl, and also thiocarbamoyl, such as 4-thiomorpholinyl or 4-morpholinyl-thiocarbonyl.

By alkoxy- or halo-carbimidoyl is meant, for example, lower alkoxy »such as ethoxy or chloro-carbimidoyl.

Trihalo or trialkoxymethyl is e.g. Trichloromethyl or Triniederalkoxy-, such as trimethoxymethyl.

Solvolysemittel are, for example, water, the desired esterified carboxy group corresponding alcohols, ammonia or the desired amidated carboxy group corresponding amines.

The treatment with a corresponding Solvolysemittel is optionally carried out in the presence of an acid or base, optionally with cooling or heating, for example between -20 ° and 300 ⁰ C, and if necessary in an inert solvent or diluent. In addition to the Solvolysemitteln can be used as solvent, for example, ethers, such as dioxane or tetrahydrofuran, amides, such as dimethylformamide, or mixtures thereof as a solvent.

Examples of acids include inorganic or organic protic acids, such as mineral acids, e.g. Sulfuric or hydrohalic, for example hydrochloric, such as sulfonic acids, e.g. Lower alkane or optionally substituted benzenesulfonic acids, for example methane or p-toluenesulfonic acid, or such as carboxylic acids, e.g.

2 / U 3 kl 8

Lower alkanecarboxylic acids, for example acetic acid, while as bases, for example, alkali metal hydroxides, e.g. Sodium or potassium hydroxide, can be used.

Compounds of the formula (II) in which X _{1 is} hydrogen, X _{2 is} difunctional carboxy-modified carboxy and R 1 is R and in which X, is hydrogen and X ₂ together with R ^{1 form} the group C = O, For example, are solvolytically converted into corresponding compounds of formula (I). Here, for example, the cyano group, optionally substituted amidino, anhydridized carboxy, optionally esterified thiocarboxy, optionally esterified dithiocarboxy, optionally substituted thiocarbamoyl, optionally esterified or anhydridisierte carboximidoyl, esterified or amidated carboxy Rxverschiedenes esterified carboxy, substituted by hydroxy or amino carbamoyl, Triniederalkoxymethyl, Niederalkoxyhalogenmethyl or trihalomethyl hydrolyzed to carboxy. Cyano, optionally S-esterified thiocarboxy, anhydridized carboxy, esterified or aminated carboxy R other than esterified or amidated

For example, substituted carboxy and hydroxy- or amino-substituted carbamoyl are alcoholysed with an appropriate alcohol to give esterified carboxy and ammonia or aminolyzed cyano and anhydridized carboxy, for example with ammonia or a suitable amine to amidated carboxy. Optionally located on the ring A lower alkanoyloxy radicals or acyloxy radicals -OR can be hydrolyzed, for example, in the course of the hydrolysis to hydroxy.

Lactones of formula (II), i. those compounds of formula (II) wherein X is hydrogen and X together with R 'is the group C = O

1 Δ ο /

are formed, for example, in the presence of an acid or in particular base to such compounds of formula (I) are hydrolyzed, wherein R is carboxy or carboxylate and R Wasserstpff.

24Λ347 8

In a preferred embodiment of the above process, one starts from compounds of the formula (II) in which X is hydrogen

and X together with R 'form the group β = O, and reacts with an alkali metal hydroxide with heating, for example at about 0 ° to about 150 ° C, with hydrolytic cleavage of the lactone ring to give compounds of formula (I) or their salts in which R ^ is carboxy or carboxylate and R is hydrogen. In subsequent optional follow-up reactions, if desired, carboxy R ₁ in amidated or esterified carboxy R and hydroxy -OR in esterified hydroxy

OR, ο

Ketenes of the formula (II), i. such compounds of the formula (II),

where X. and X_ together form the group = C = 0 and R ^{1 is} Il ο

of R can, for example, by addition of water, a ο

suitable alcohol, ammonia or a suitable amine are converted into corresponding compounds of formula (I) or salts thereof.

Compounds of formula (H) wherein X and X ₂ together represent the group

= C (Hal) "and R ^{1 has} the meaning of R can, for example, 2o o

example, by hydrolysis with water, in particular in the presence of an acid such as mineral acid, eg sulfuric acid, optionally with heating, such as in a temperature range between about 50 ° and about 150 ⁰ C, in such compounds of formula (I) wherein R is carboxy, be transferred.

The starting materials of formula (II) or salts thereof, wherein X ₁ is hydrogen, X is other than R. functionally modified carboxy, and R ¹ has the meaning of R, are obtained in ways known per se. For example, one goes from compounds of the formula

I A Il (Ha)

r / V \ r

3 ο

244347 8

or their salts. These are e.g. with halogenating agents, such as N-bromosucciniraid, in the presence of a radical generator, such as benzoyl peroxide or azobisisobutyronitrile, and with heating in an inert solvent, such as benzene, to compounds of the formula

/ \ / ^c V ^Hal

Ϊ Ail (lib),

r / V \ r

3 ο

wherein Hal is halogen, in particular bromine or chlorine, or their salts are reacted. The compounds of formula (lib) thus obtained are obtained by treatment with alkali metal cyanides, e.g. Sodium cyanide, optionally with heating in a suitable solvent, such as dimethyl sulfoxide, converted into the corresponding nitriles. In an optional measure, in the compounds of the formula

A / ^C V ^CN

  Ϊ A M '(lic)

r / V \ _r

3 ο

or salts thereof, the radical R ₀ by reaction with a compound R2-Hal, wherein Hal is halogen, in the presence of a base such as an alkali metal amide or hydride, for example sodium amide or hydride, at low temperatures, for example below 10 ⁰ C, and in a suitable solvent such as dimethylformamide.

The cyano group may now, if desired, be converted into other carboxy groups other than R, for example, optionally substituted amindino, optionally substituted thiocarbamoyl, optionally esterified or anhydridized carboximidoyl or amidated or esterified carboxy-R different amidated or esterified carboxy.

244347 8

For example, from the cyano group, e.g. by treatment with an alcohol in the presence of a strong acid, the corresponding alkoxycarbamidoyl, by treatment with hydrogen peroxide in the presence of a protic acid carbamoyl, by treatment with hydrogen sulphide in the presence of an inorganic base, the corresponding thiocarbamoyl, by reaction with an excess of alcohol in the presence of an acid the corresponding esterified carboxy be made available. Alkoxycarbamidoyl in turn can be used, for example. by treatment with ammonia, a primary or secondary amine e.g. corresponding amidino and when reacted with at least 2 equivalents of an alcohol e.g. corresponding trialkoxymethyl obtained.

In a preferred embodiment leads to lactones of formula (II) wherein X ₁ is hydrogen and X "together with R ^{1 is} the group C = form O and wherein said ring A except R" is unsubstituted or monosubstituted by lower alkyl or polysubstituted or optionally additionally disubstituted by 3- or 4-membered alkylene, and R "is methyl, by reacting compounds of the formula

y ₀

wherein R, R ^ and R are independently hydrogen, lower alkyl or 3- or 4-membered alkylene, reacted with amines of the formula R-H or their acid addition salts.

The reaction takes place, for example, at elevated temperature, e.g. in the melt or at the reflux temperature of the solvent, e.g. in a temperature range from about 80 ° C to about 200 ° C. Suitable inert solvents include, for example, higher boiling hydrocarbons, such as aromatic hydrocarbons, e.g. Benzene, toluene or xylenes. The amines of formula R3-H are especially useful as acid addition salts, e.g. advantageously used as benzoates.

244347 8

For the preparation of compounds of the formula (III) in which R is hydrogen

means, one goes from compounds of the formula

ΐί T A ^ (he)

from which are optionally substituted in the aromatic moiety and wherein A represents the anion of an inorganic or organic acid, and reacts with fumaric acid, maleic acid or maleic anhydride in the presence of a base, suitable bases being inorganic or organic bases. Inorganic bases are, for example, alkali metal hydroxides or hydrides, such as sodium or potassium hydroxide or sodium or potassium hydride. As organic amines, for example, tertiary amines such as trialkylamines, e.g. Triethylamines or tri-n-butylamines, or cyclic amines such as pyridine, picoline, quinoline or lutidine.

The first available in this way free compounds are prepared by treatment with organic or inorganic acids in the salts of the formula

H ⁷ JN)

HOOC-CH-CH-COOH

converted. These are in the further course of the reaction, optionally in the presence of one of the abovementioned bases, with compounds of the formula R -CH = C (R) -CO-CH ₂ -R (Hg) to compounds of

formula

244347 8

/ X

Il

Α ^Θ

-H-COOH

COOH

implemented in the next reaction step by heating, for example to temperatures between 80 and 160 ⁰ C, with decarboxylation in compounds of the formula

CH

^K b I> = 0 (IL i)

be transferred. The thermal conversion of compounds of the formula (Hh) into compounds of the formula (Hi) is described, for example, in an optionally halogenated aromatic solvent, such as benzene, toluene, xylenes or chlorobenzene, or a lower alkanecarboxylic acid, e.g. Glacial acetic acid, performed. Subsequently, the compounds of formula (Hi) are hydrolyzed to compounds of formula (Hd). The hydrolysis is carried out, for example, in an aqueous or aqueous-organic medium. Particularly suitable organic solvents are high-boiling polar solvents, such as ethers, e.g. Dioxane or tetrahydrofuran, N, N-dialkylamides, e.g. Ν, Ν-dimethylformamide or

244347 8

Ν, Ν-dimethylacetamide, or cyclic amides, such as N-methyl-pyrrolidone. The hydrolysis is carried out, for example, with the aid of an inorganic or organic acid, wherein as inorganic acids, mineral acids, such as hydrohalic acid or sulfuric acid, and as organic acids sulfonic acids, such as lower alkane or optionally substituted benzenesulfonic acids, such as methane or p-toluenesulfonic acid, or optionally substituted alkanecarboxylic acids, like glacial acetic acid _{/ come} into consideration.

For the preparation of compounds of the formula (III) in which R is of

substance is different, starting from compounds of formula (lie) and sets them first with compounds of formula (Hg) and then with fumaric acid, maleic acid or especially with maleic anhydride to compounds of formula (Hh), which in turn, as described above , continue to react to the corresponding compounds of formula (Hd).

In a further advantageous procedure, compounds of the formula (II) ## STR8 ## in which X is hydrogen, X "is a functionally modified carboxy other than R ₁ and R 'is the meaning of

has tung by R and wherein R ₀ is hydrogen, by starting from Verbino £

fertilize the formula

ί A M (Hk)

or their salts go out and these with sulfur and a primary or secondary amine, advantageously with morpholine or thio

244347 8

Morpholine, or reacted with Amraoniumpolysulfid under pressure, analogous to the Willgerodt (-Kindler) reaction. In a compound of formula (II) thus obtainable, X represents "substituted carbamoyl other than R", and correspondingly substituted thiocarbamoyl which may be prepared in a manner known per se, e.g. by appropriate solvolysis, can be converted into other functionally different carboxy X different from R.

The novel compounds of formula (I) can be further prepared by reacting in compounds of formula

/ N / ^H - ^R l

j A fl (III)

x / V \ r

3 ο

or salts thereof in which X. is a radical convertible into R, X is converted into R and / or, if desired, a salt obtainable according to the process is converted into the free compound or into another salt, a free compound obtainable according to the invention into another free compound or converted into a salt and / or, if desired, an isomeric mixture obtainable by the process is separated into its components.

An X ~ radical X ~ is, for example, amino or a group of the formula -NH-AX or -NH-AX ₁ , where A. is a divalent hydrocarbon, for example optionally branched lower alkylene, X, hydrogen, 3- to 7-membered cycloalkyl or aryl, such as phenyl which is unsubstituted or substituted by an aliphatic radical, lower alkoxy, lower alkylthio, lower alkanesulfinyl, lower alkanesulfonyl, hydroxy, halogen, lower alkanoyloxy, lower alkanoyl and / or nitro, A "is a divalent hydrocarbon radical which is also substituted by Aza, N-lower alkylaza, oxa or thia may be interrupted, for example lower alkylene, lower alkenylene, by aza, N-lower

24 UA 7 8 -

alkylaza, oxa or thia interrupted lower alkylene or by aza, N-lower alkylaza, oxa or thia interrupted lower alkenylene, wherein lower alkylene or lower alkenylene may each also be branched and further may additionally have one or two ortho-fused benzo systems, and X ,. Hydroxy or reactive esterified hydroxy. By reactive esterified hydroxy X ₁ ^ is exemplified by a strong inorganic mineral acid, such as hydrohalic acid or sulfuric acid, with an organic sulfonic acid, such as lower alkane or optionally substituted benzenesulfonic acid, eg methane or p-toluenesulfonic acid, further with an organic carboxylic acid, such as lower alkanecarboxylic acid, For example, acetic acid, esterified hydroxy, for example, primarily halogen, such as chlorine or bromine, sulfonyloxy, such as p-toluenesulfonyloxy.

The conversion of -NH-AX. in R_ takes place in a conventional manner. For example, corresponding compounds of the formula (III) or salts thereof are reacted with compounds of the formula X, -A-X (IIIa) or salts thereof. In this case, if appropriate, the reaction is carried out in an inert solvent or diluent under protective gas, for example nitrogen, and / or if necessary in the presence of a condensing agent such as an alkali metal or alkaline earth metal hydroxide or carbonate or an alkaline earth metal alcoholate, for example sodium hydroxide, potassium hydrogencarbonate or sodium methoxide, for example a temperature range from about 0 ° to 150 ⁰ C. suitable solvents are for example aliphatic alcohols such as methanol or ethanol, or aromatic hydrocarbons such as benzene or toluene.

The conversion of -NH-A ₂ -X into R takes place in the manner described above.

244347 8-

A radical R, which is a di-substituted by a divalent hydrocarbon radical amino group can also be introduced directly, for example by reacting compounds of formula (III), wherein X "is amino, or their salts with compounds of formula XA -X (HIb ). The procedure is as described above. In these reactions, it is also possible in situ to react compounds of the formula (III) in which X is a group of the formula -NH-AX, which react further under the reaction conditions directly to corresponding compounds of the formula (I).

ι A remainder R ~ can, if this is non-aromatic nature, continue to be introduced directly by means of, for example, compounds of formula (III) wherein X is hydrogen, a metal-containing radical or optionally reactive esterified hydroxy, or the Salts starting and these with compounds of the formula R -X, wherein X, hydrogen, a metal-containing radical or

3 6 o optionally reactive esterified hydroxy, or

their salts are converted.

A metal-containing group is, for example, an alkali metal atom, such as lithium or sodium. Reactive esterified hydroxy, for example, with a mineral, such as hydrohalic acid, or a sulfonic acid, such as optionally substituted benzenesulfonic acid, esterified hydroxy.

In the first place one sets e.g. Compounds of the formula (III) and

R ₀ -X, in which one of the radicals X "and X is an alkali metal atom, ι 3 6 jo

Lithium, and the other halogen, such as bromine represents.

In the event that X is hydrogen and X is hydroxy or

J 6

Halogen, the reaction is carried out in the presence of a Lewis acid. If X is halogen and X, hydrogen, the reaction takes place

JD

in the presence of a condensing agent.,

4 3 Λ 7 8-

For the preparation of starting materials of the formula (III), the procedure is carried out in a manner known per se and cleaved, for example, in compounds of the formula

I A IJ (HIC)

Ac-HN · OR

or their salts, wherein Ac is an acyl radical, such as lower alkanoyl, e.g. Acetyl means acyl Ac in the presence of a base such as an alkali metal hydroxide, e.g. Sodium hydroxide, from. In this case, lower alkanoyloxy groups can be hydrolyzed to hydroxy, which, however, if desired, can be reesterified as usual. In so obtainable compounds of the formula

I Afl (HId)

2 ° ο

or salts thereof, the amino group is benzylated by reaction with benzyl halides, in particular with benzyl chloride. Subsequently, the carbonyl function is reduced, for example with the aid of optionally complex hydrides, e.g. with sodium borohydride.

This results in compounds of the formula

V / v

I A Il \ ._. ^ * 2 2 * ο

or their salts. '

These are reacted, for example, with alkali metal cyanides, such as sodium cyanide, with heating and then solvolysiert the cyano group zuR. In the next reaction step, the benzyl groups are removed by hydrogenolysis in the presence of a hydrogenation catalyst, such as platinum, and the now free amino group is treated by treatment with compounds of the formula X-i.about.Xc (HIf) in the presence of a condensation reaction.

43 4 7 8-

by means of, such as an alkali metal hydroxide, in the radical X "converted, wherein X- of hydrogen, a metal-containing radical or optionally reactive esterified hydroxy is different.

Compounds of the formula (I) in which R is pyrrol-1-yl are obtainable by reacting compounds of the formula (III) in which X "is amino or their salts with 2-butene-1, 4-diol or a reactively esterified derivative thereof in the presence of a protonic acid, such as lower alkanecarboxylic acid, to pyrrolin-1-yl and dehydrated this in the presence of a dehydrogenation catalyst, such as a quinone, eg 2,3-dichloro-5,6-dicyano-p-benzoquinone or tetrachloro-p-benzoquinone, or a selenium derivative, e.g. Selenium dioxide, or an element of the VIII. Subgroup, such as palladium, or by reacting compounds of formula (III), wherein X- is amino, or their salts with a 2,5-di-lower alkoxytetrahydrofuran, such as 2,5-dimethoxy-tetrahydrofuran, eg under heating, treated.

Furthermore, the pyrrole ring R. can be built up, for example, by reacting the amino group X- in compounds of the formula (III) with an optionally reactively esterified derivative of 1,3-butadiene-1,4-diol, e.g. with 1, A-dibromo-1,3-butadiene, if necessary under heating and under protective gas, e.g. Nitrogen, and is reacted in an inert solvent or diluent.

Furthermore, the pyrrole ring R can be constructed analogously to Knorr-Paal by treating the amino group X in compounds of formula (III) with optionally acetalized 1,4-dioxo-butane, under inert conditions, for example under inert gas and heating and in an inert Solvent can be worked.

A further process variant for constructing the pyrrole ring R consists, for example, in the reaction of compounds of the formula (III) in which X- is, for example, the group of the formula -NH-CH =CH-CH =Ch-OH or a reactive esterified form, furthermore tautomeric form thereof, which is optionally acetalated _(in which case the reaction is advantageously carried out under inert conditions and with heating.

Λ 3 Λ 7 8-

Reactive esterified hydroxy in this context means e.g. with a mineral acid such as hydrohalic acid, e.g. Hydrobromic acid, or with a sulfonic acid, such as lower alkane or optionally substituted benzenesulfonic acid, p-toluenesulfonic acid, esterified hydroxy.

Likewise, sufficient nucleophilic amines R "- * H can be introduced directly into those compounds of the formula (III) in which X" is a radical displaceable by R ~. If, for example, X-halogen, in particular chlorine, bromine or iodine, the reaction can be carried out in the presence or absence of a solvent and, depending on the choice of the halogen atom at low temperatures up to the boiling point of the solvent in question. Advantageously, in the adjacent position of X ", there is a substituent with a strong -I or -M effect, such as nitro, halogen or trifluoromethyl. In some cases, it is advantageous to carry out the reaction under pressure or at elevated temperature. Advantageously, the amines are used in excess.

Likewise, sufficient nucleophilic amines R "-H can be introduced directly into those compounds of the formula (III) in which R and X" are each hydrogen. For this, e.g. corresponding compounds of formula (III) first with an oxidizing agent, such as, lead (IV) acetate, e.g. in the presence of a suitable acid, such as glacial acetic acid, and at room temperature, and then treated with corresponding amines of the formula R-H in an inert solvent, such as an ether, e.g. Dioxane, with heating, e.g. at reflux temperature, from which in particular those compounds of formula (I) can result, wherein R is amidated carboxy accordingly.

When these reactions are carried out in the presence of a base, any acyl present such as lower alkanoyloxy can be hydrolyzed to hydroxy and / or esterified or amidated carboxy to carboxy.

In a further procedure, compounds of formula (I) wherein R is hydrogen by reacting with compounds of formula

2U347 8-

(IV),

in which X represents a radical convertible into the group -OR, converts the radical X ₇ into the group -OR and / or, if desired, converts a salt obtainable according to the invention into the free compound or into another salt, a free compound obtainable in accordance with the invention another free compound or converted into a salt and / or, if desired, a mixture of isomers obtainable according to the method is separated into its components.

For example, a remainder X _{7 that} can be converted into the group -OR is one

ο '

Diazonium group with an anion of an inorganic or organic acid as counterion.

The substitution of hydroxy for the diazonium group is carried out in a manner known per se, for example by heating, e.g. at about 100 ° to about 25O ° C, in aqueous solution. Frequently, this reaction is carried out in the presence of acids, such as mineral acids, in particular sulfuric or orthophosphoric acid, and as the counterion, the hydrogen sulfation is preferred. To avoid azo coupling, the phenol formed is continuously removed from the reaction mixture, for example by shaking out with a suitable solvent.

The starting materials of the formula (IV) can be prepared by processes known _per se, for example by reacting compounds of the formula (I). CH

IAM (IVa)

or their salts go out and the amino group optionally protects by introducing a protective group. Suitable protecting groups are, for example, acyl or benzyl groups. Advantageously, the

Amino group, e.g. with benzyl chloride, benzylated. The subsequent halogenation of the methyl group, e.g. the bromination with N-bromosuccinimide in the presence of azobisisobutyronitrile with heating leads to the corresponding compounds of the formula

ΐ Α Π (IVb),

wherein Hal is halogen, in particular bromine or chlorine, and Sch represents an optionally protected amino group. These compounds are then reacted with an alkali metal cyanide, such as sodium cyanide, for example, with heating in dimethylformamide. In the. thus obtainable compounds of the formula

· CH -CN S / 2

I A M (IVc)

• ·

R ζ ^S S ^V Sch

if desired, the radical R- is e.g. by reaction with compounds of the formula R-Hal (IVd) in the presence of a base such as an alkali metal hydride. In the next reaction step, the cyano group is converted by conventional solvolysis in R and then cleaved off the amino protecting group. Advantageously, for example, the benzyl groups protecting the amino groups are hydrogenolysed in the presence of a hydrogenation catalyst, e.g. Palladium, split off. The compounds of the formula obtainable in this way

(IVe)

or their salts are added, for example, at low temperatures with a mineral acid such as sulfuric acid, and aqueous alkali metal such as sodium nitrite solution. The intermediate compounds of the formula (IV), wherein X _{7 is} a diazonium group with a corresponding counterion, as described above, further reacted to compounds of formula (I).

244347 8

A remainder X_ which can be converted into the group OR can furthermore be used e.g.

ο I

etherified hydroxy or of OR different acyloxy mean

Etherified hydroxy represents, for example, hydroxy etherified with an aliphatic alcohol, suitable aliphatic alcohol being, for example, an optionally substituted alkanol, such as lower alkanol. Examples of such ethers are optionally represented by hydroxy, halogen, alkoxy, e.g. Lower alkoxy, carboxy or a functional derivative thereof, nitro, optionally substituted amino, aryl, such as optionally substituted phenyl, alkylthio, alkanesulfinyl, alkanesulfonyl, alkanoyl-substituted alkoxy, as appropriate lower alkoxy.

For example, etherified hydroxy can usually be converted into hydroxy OR by means of ether cleavage, for example by treatment with a strong protic acid, such as hydrohalic acid, for example hydrobromic or hydroiodic acid, or with a suitable Lewis acid, such as a halide of elements of the 3rd main group, eg tribromide. The ether cleavage with a protonic acid is advantageous to O ⁰ C, and also at room temperature, carried out at elevated temperature, for example at about 15Ü ° to 25O ° C, and the cleavage with a Lewis acid advantageously with cooling, eg at about -78 °. Furthermore, corresponding ethers can also be cleaved with the aid of strongly nucleophilic reagents, such as alkali metal lower alkanolates, for example sodium methylate, strong amides, for example methyl or triethylamine, or a thiophenolate, for example sodium p-methylthiophenolate, advantageously working at elevated temperature , The ether cleavage can be carried out, for example, in the presence or absence of a solvent and at temperatures of from about 0 ° to about 25 ° C. Suitable solvents are, for example, halogenated hydrocarbons, such as corresponding halo-lower alkanes, for example methylene chloride, in question.

Acyloxy X ₇ different from acyloxy OR is, for example, aroyloxy, such as optionally substituted alkanoyloxy, where as substituents of

7 8

Aroyloxy, e.g. Benzyloxy e.g. the substituents initially mentioned for phenyl radicals and as substituents of alkanoyloxy, such as lower alkanoyloxy, e.g. Hydroxy, halogen, alkoxy, carboxy or functional derivatives thereof, nitro, optionally substituted amino, aryl, such as optionally substituted phenyl, alkylthio, alkanesulfinyl, alkanesulfonyl or alkanoyloxy come into question.

Corresponding acyloxy X is prepared in a manner known per se, e.g. converted by hydrolysis in hydroxy OR. So will the hydrolysis

for example in the presence of a protic acid such as mineral acid, or advantageously in the presence of a base such as an alkali metal hydroxide or carbonate, optionally with heating and, for example, in an inert solvent or diluent. In this case also functionally modified carboxyl R can be hydrolyzed to carboxy. Hydrolysis of the ester OR ¹ in OH can, for example, the same and performed _s an amide, such as dimethylformamide, and mixtures in a temperature range of about -20 ° to about 300 ⁰ C in an inert solvent such as a lower alkanol, ether, for example dioxane, water become. Under these hydrolysis conditions, R different from carboxy can also be hydrolyzed.

The starting material of formula (IV), wherein X is etherified or

may be different from OR acyloxy, if not known, ο

be prepared according to known methods. For example, starting from a corresponding 3-nitrophenol, etherified, e.g. with the aid of an appropriate alcohol in the presence of a strong mineral acid and with heating, or esterified, e.g. with the help of a corresponding acyl halide, the phenolic OH group. Subsequent reduction of the nitro group, e.g. with hydrogen in the presence of a hydrogenation catalyst, leads to the corresponding amine, which can be converted into R analogously to the manner described above. The compounds of the formula obtainable in this way

I A I! ·

2U347 8

are acylated, for example, with an oxalyl halide derivative in the presence of a Lewis acid, such as aluminum chloride, and the resulting glyoxylic acid derivative analogously to the Wolff-Kishner reaction or the Huang-Minlon method, e.g. with hydrazine in a high boiling solvent in the presence of a base such as sodium hydroxide, and thermally decomposing the hydrazone intermediately formed, wherein the carbonyl group is reduced to the methylene group. Subsequently, optionally by reaction with a halide R "-Hal in the presence of a base, such as sodium amide, the radical R" are introduced.

The compounds of the invention can be further prepared by reacting compounds of the formula

I A Il 10 (V)

or their salts, wherein X and X are each carboxy, and X

ο y lu

the meaning of R ~ has, where X "is the meaning of R and X is of R" and X is hydroxy, functionally modified hydroxy, substituted by a hydrocarbon radical mercapto, or secondary amino, wherein X has the meaning of R and X and X together

ο ι y lu

Oxo, thioxo or optionally substituted hydrazono, or wherein X has the meaning of R and X and X together form the groups = .R ~ or a tautomeric form thereto and R 'is a divalent aliphatic radical, by reduction in corresponding compounds of Converted formula (I) and / or, if desired, a salt obtainable in accordance with the process into the free compound or into another salt, a free compound obtainable according to the process into another free compound or into a salt and / or, if desired, an isomeric compound obtainable according to the process. Mixture separates into its components.

! 44347 8-

Functionally modified hydroxy is, for example, etherified hydroxy, such as with a lower alkanol, e.g. Methanol, etherified hydroxy or reactive esterified hydroxy, e.g. with strong mineral acids ^ with organic sulfonic acids, such as lower alkane or optionally substituted benzenesulfonic acid ^ of organic carboxylic acids, such as lower alkanecarboxylic acid, esterified hydroxy.

Secondary amino is, for example, dialkylamino, such as di-lower alkylamino, or optionally phenyl-substituted di-phenylsulfamoyl, in particular di- (p-toluene) - or di- (p-bromophenyl) -sulfamoyl.

Mercapto substituted by a hydrocarbon radical is, for example, mercapto substituted by an alkyl radical, the alkyl radical itself being optionally substituted by e.g. may be substituted by an aromatic, such as optionally substituted phenyl, such as lower alkylthio, e.g. Methyl or ethylthio, or phenyl-lower alkylthio, e.g. Benzylthio.

Hydrazono may be exemplified by a sulfonyl radical such as optionally substituted phenylsulfonyl radical, e.g. p-toluenesulfonyl, or substituted by an optionally substituted phenyl radical.

A divalent aliphatic radical is e.g. a lower alkylidene or lower alkenylidene residue and as tautomeric form of = R ', e.g.

a corresponding Niederalkehylenrest in question, wherein lower alkenylene has one or more double bonds.

The reduction is carried out in a manner known per se, for example under inert conditions, such as under protective gas, e.g. Nitrogen, in an inert solvent or diluent, optionally under pressure and / or under cooling or heating.

The decarboxylation of compounds of the formula (V) in which X "and X _q each represent carboxy and X has the meaning of R_ is described below

244347 8-

Heating, for example in a temperature range of about 100 ° to about 30O ⁰ C, optionally in the presence of a transition metal or an alloy thereof, for example copper or copper bronze, or an amine such as a basic nitrogen heterocycle, for example pyridine or quinoline, or an alkylamine, such as Triniederalkylamins performed and leads to compounds of formula (I) wherein R- ^ carboxy, or their salts.

The reductive conversion of X into compounds of the formula (V), where X is the meaning of R and X is that of R ₀ , and X is hydroxy,

ο J y l lu

Functionally modified hydroxy, dialkylamino or substituted with a hydrocarbon radical mercapto, especially lower alkylthio, with hydrogen, for example, by hydrogenation in the presence of a hydrogenation catalyst, such as an element of the VIII. Subgroup of the Periodic Table or its derivative, for example oxide, wherein the catalyst optionally on a support material, such as activated carbon or alkaline earth metal carbonate, or sulfate may be applied. The hydrogenation is advantageously under cooling or heating, for example between about -80 ° to about 200 ⁰ C, especially from room temperature to 100 ⁰ C., conveniently in a suitable solvent such as water, a lower alkanol, for example ethanol or isopropanol, an ether such as dioxane, a lower alkanecarboxylic acid, eg acetic acid, or mixtures thereof.

Examples of such catalysts are Raney nickel or palladium / carbon, furthermore platinum, platinum oxide or palladium. If necessary, the hydrogenation is carried out in the presence of an acid or, in particular, a base. Corresponding acids are protic acids, such as mineral acids, e.g. Hydrohalic acids, further carboxylic acids, such as lower alkanecarboxylic acids. Suitable bases are, for example, alkali metal hydroxides, carbonates or acetates, amines, such as lower alkylamines or basic heterocycles, such as pyridine or quinoline.

3 4 7

In corresponding compounds of formula (V) wherein Χ _{χ () is} hydroxy, the hydroxy group may also be hydrogenated by red phosphorus and / or hydroiodic acid with heating, for example, to about 100 to about 25 ° C, preferably with red phosphorus and hydroiodic acid be transferred.

The reductive conversion of hydroxy X, which is esterified with an organic sulfonic acid, such as p-toluenesulfonyloxy, can be carried out, for example, by means of a conventional reducing agent, such as an alkali metal alloy, e.g. Sodium amalgam, in a protic solvent or with an optionally complex hydride, such as hydrides with elements of the 1st and / or 3rd main group, e.g. Lithium borohydride be performed.

Compounds of the formula (V) in which X.sup.1 and X together are oxo or thioxo can be reduced to those compounds of the formula (I) in which R.sup.1 is hydrogen by reacting the oxo or thioxo group, for example analogously to the Clemensen reduction, e.g. with a metal such as, where appropriate, amalgamated zinc, in a protic acid such as mineral acid, e.g. Hydrochloric acid, or in particular according to Wolff-Kishner with hydrazine in an (inert high-boiling) solvent such as an alcohol, optionally under pressure, at a higher temperature and in the presence of a base such as an alkali metal hydroxides, or according to the Huang-Minlon variant in a high-boiling Solvent, such as a corresponding ethylene glycol is reduced. Hydrazine reduction may also be carried out with a base such as an alkali metal alkoxide, e.g. in dimethyl sulfoxide at room temperature.

Also to compounds of formula (I) wherein R is hydrogen, can be obtained by, for example, compounds of formula (V) wherein X and X is optionally substituted hydrazono, in particular p-toluenesulfonylhydrazono, and X is the meaning of R ₁

ο 1

has, with the help of a suitable reducing agent, in particular

244347 8 -

an optionally complex hydride, e.g. a hydride of elements of the 1st and / or 3rd main group, e.g. Sodium borohydride, reduced.

Starting compounds of the formula (V) in which X has the meaning of R

8 1

and X and X together form the group = R 'or a tautomeric form thereof, for example, by catalytic hydrogenation can be converted into those compounds of formula (I), wherein R is different from hydrogen. The hydrogenation can be carried out in a manner known per se in the manner described above using the stated catalysts.

Basically, e.g. the corresponding reduction methods described in Houben-Weyl, Vol. 4 / 1c (1980) and Vol. 4 / ld (1981).

Starting materials of the formula (V) in which X and X _{n in} each case denote carboxy

8 y

th and X has the meaning of R "can be prepared by methods known per se. For example, one goes from compounds of the formula

A / ^CH 3

I A Il (Va)

or their salts and these are reacted with a halogenating agent, e.g. with N-bromosuccinimide in the presence of a free radical generator, such as benzoyl peroxide, at elevated temperature. In the compounds of the formula thus obtainable

_{/% / C} H ₂ -Hal HAI (Vb)

or salts thereof in which Hal is halogen, in particular bromine or chlorine, the halogen atom is substituted by the cyano group by reaction with an alkali metal cyanide, such as sodium cyanide. On-

244347 8

subsequently, the reaction is followed with a dialkyl carbonate, e.g. Diethyl carbonate, in the presence of a base such as an alkali metal, e.g. Sodium, to compounds of the formula

, COOalkyl (Vc),

AlI

wherein alkyl is an alkyl radical corresponding to the dialkyl carbonate, or their salts. If desired, the radical R other than hydrogen is then converted by reaction with compounds of the formula R.-Hal (Vd) in the presence of a base, such as alkali metal alcoholate, e.g. Sodium methylate, introduced. The subsequent hydrolysis of the cyano group and of the alkoxycarbonyl group leads to the desired compounds of the formula (V).

To starting materials of the formula (V), wherein X is the meaning of R and

ο 1

X is of R ", and X is hydroxy or functionally modified hydroxy, for example, by reacting compounds of the formula

HAI. (Ve)

3 * o

or their salts with cyanides, such as sodium cyanide, in the presence of a protic acid, such as hydrochloric acid, to cyanohydrins of the formula

(Vf)

r / V \ r

3 ο

or their salts. In the next reaction step, the solvolysis of the cyano group follows R and, if desired, the esterification or etherification of the hydroxy group or R.

47 8

Corresponding starting materials of the formula (V), wherein X is secondary amino, is obtained for example by reacting compounds of the formula, ·, CHO

I A Il (Vg)

"ΛΛ"

or salts thereof with a solution of ammonium chloride and sodium cyanide or with sodium cyanide and ammonium carbonate followed by hydrolysis of the resulting hydantoin with the aid of an alkali metal hydroxides and optionally subsequent introduction of the different R from hydrogen by reaction with compounds of formula (Vd) in the presence of bases , eg Sodium ethylate in resulting compounds of the formula

> _A > -CN

I A Π (Vh)

or their salts. In the next reaction step, the conversion of the amino groups into a secondary amino group can take place. This is how, for example, by reaction with formic acid / formaldehyde to a dimethylamino group. Finally, the cyano group is converted by solvolysis in a known manner into the radical R.

For the preparation of starting materials of the formula (V), wherein X is the

Meaning of R and X and X together form the group = R 'or a tautomeric form thereof, starting from compounds of formula (Vf) or their salts. These are obtained, for example, with the aid of an acid such as mineral acid, e.g. Sulfuric acid or phosphoric acid or polyphosphoric acid, their salts, such as potassium bisulfate or their anhydrides, e.g. Thionyl chloride, dehydrated to corresponding compounds of formula (V) and the cyano group solvolytically converted into R.

IU3 4 7 8-

Another way of preparing compounds of formula (I) wherein R is carboxy or esterified carboxy is to react in compounds of formula (I)

A II (VI)

or their salts, in which X is an oxidatively convertible radical in R, X oxidatively converted into R- and / or, if desired, a salt obtainable according to the method in the free compound or converted into another salt, a free compound obtainable according to the invention in another free compound or converted into a salt and / or, if desired, an isomer mixture obtainable in accordance with the method is separated into its components.

An oxidatively convertible into R ₁ X radical is for example hydroxymethyl, with a carboxylic acid such as optionally substituted lower alkanecarboxylic acid, for example acetic acid, esterified hydroxymethyl, with an alcohol such as lower alkanol, for example methanol or ethanol, etherified hydroxymethyl, formyl, hydrated or acetalated formyl, or Groups of formulas -CH = CH-X, -CH = C (Ar),

-CH (OH) -CH (OH) -X _1. , -CH (OH) -CO-X _n ., -CH (OH) -CO-OX _1. , -CO-CO-X _1. , 14 14 14 14

-CH (NHJ-CO-X .., -CO-COOH, where X is ₁ for hydrogen, / 14 14

an aliphatic radical, e.g. optionally substituted lower alkyl radical, or an aryl radical, and Ar represents an aryl radical and below this, e.g. an optionally substituted phenyl radical is to be understood.

The oxidation is carried out in a known per se manner using appropriate oxidizing agent in an inert solvent or diluent, and if necessary with cooling or warming, for example from about 0 ° to about 150 ⁰ C.

43 47 8 -

Suitable oxidizing agents are, for example, oxygen, ozone, peroxides, such as hydrogen peroxide, or peroxides of organic carboxylic acids, such as trifluoroperacetic acid or m-chloroperbenzoic acid, oxidizing compounds of transition metals, in particular those having elements of the I., VI., VII. Or VIII. Subgroup of Periodic table, such as copper compounds, eg Copper chromite, such as silver compounds, e.g. Silver (I) oxide or silver picolinate, such as chromium compounds, e.g. Chromyl chloride, chromium trioxide, alkali metal chromates or dichromates, such as potassium dichromate, such as manganese compounds, e.g. Manganese dioxide or alkali metal permanganate, or as halogen-oxygen compounds, e.g. Alkali metal iodates or periodates, such as halogen, e.g. Bromine or chlorine, halogen-oxygen compounds, e.g. Alkali metal hypochlorites, iodates, periodates or periodic acid, nitrogen acids or by anhydrides, e.g. Nitric acid or corresponding anhydrides concentrated sulfuric acid. If necessary, mixtures of oxidizing agents can also be used.

Frequently in the presence of bases such as alkali metal hydroxides or carbonates, e.g. Sodium hydroxide or carbonate, or Like amines, e.g. cyclic amines, e.g. Pyridine, or lower alkylamines, e.g. Triethylamine, or of protic acids, such as mineral acids, e.g. Sulfuric acid or hydrohalic acid, or organic carboxylic acids such as lower alkanecarboxylic acids, e.g. Acetic acid, and optionally worked under cooling or heating.

Suitable solvents or diluents are, for example, water, ethers, such as dioxane or ethylene glycol diethyl ether, ketones, such as acetone, alcohols, such as the lower alkanols methanol or ethanol, amides, such as dimethylformamide, carboxylic acids, such as the lower alkanecarboxylic acid, or mixtures thereof.

Hydroxymethyl or hydroxymethyl X ₁₁ esterified with a carboxylic acid, for example, is oxidized to carboxy with heating with the aid of potassium dichromate in sulfuric acid, the oxidation being carried out via the formyl

> U347

stage runs. Formyl, hydrated or acetalated is converted into carboxy with the aid of silver (I) oxide in sodium hydroxide solution or potassium permanganate in sodium carbonate solution while heating, while the group X ₁₁ : -CH = CH-X ₁ , for example by means of ozone and hydrogen peroxide on the formyl is oxidized to carboxy. Etherified hydroxymethyl, for example, can be converted into esterified carboxy with potassium heenate anion in aqueous pyridine at room temperature.

The formyl group X can advantageously be formed in situ in the course of oxidation reactions or set free from a functionally modified form. The in situ formation of formyl takes place in particular from such radicals X ₁₁ . which are primarily hydroxymethyl or groups of the formulas -CH = CH-X, -CH (OH) -CH (OH) -X or -CH (OH) -CO-X, furthermore -CH = C (Ar) ₂ , Mean -CO-CO-X ₁₄ , -CH (OH) -CO-OX or -CH (NH ") - CO-X. The release of the formyl group X takes place, for example, from one of its acetals or imines, as well as from other formyl masking groups. Acetalized formyl means, for example, with lower alkanols or a lower alkanediol acetalated formyl, such as di-lower alkoxy, eg, dirnethoxy or diethoxymethyl, or lower alkylenedioxy, for example ethylene or trimethylenedioxy-methyl. Furthermore, formyl can be released from the corresponding thioacetals. Imines are, for example, optionally substituted N-benzylimines or N- (2-benzothiazolyl) -imine.

The oxidation of the remaining radicals X to carboxy can advantageously be carried out in situ, frequently via the formyl stage, and are e.g. X ,, -CH (OH) -COO-X ,, -CH = CH-X ,. and

11 14 14

-CH (OH) -CH (OH) -X ₄ eg with the aid of sodium periodate in the presence of catalytic amounts of potassium permanganate, X hydroxymethyl,

-CH (NHj-CO-X,., -CH (OH) -CO-X ₁ and -CO-CO-X _1, for example with the aid of 2 14 14 14

soda-alkaline permanganate solution, potassium dichromate solution of sulfuric acid or concentrated nitric acid, X -CH = C (Ar) ", in which Ar is in each case phenyl, analogous to Barbier-Wieland, e.g. with chromium trioxide in glacial acetic acid, and X-CO-COOH e.g. by treating with con-

244347 8-

centered sulfuric acid or with hydrogen peroxide in dilute sodium hydroxide solution (decarbonylation).

Starting materials of the formula (VI) in which X. Hydroxymethyl, esterified or etherified hydroxymethyl, are obtainable by, for example, compounds of the formula

/ \ / ^C ° - ^C V ^R 2

ί A Tl (Via)

with a mixture of trimethylsulfonium methyl sulfate and sodium methylate, for example, at room temperature in acetonitrile. In the resulting compounds of the formula

A M (VIb)

In the following reaction step, the oxirane ring is opened, for example in the presence of a Lewis acid, such as aluminum chloride, to the compound of the formula (VI) in which X is formyl. In optional additional reactions, if desired, the formyl may be acetalated in a manner known per se or reduced to hydroxymethyl. The hydroxymethyl group, in turn, may be esterified or etherified if desired.

Corresponding starting materials of formula (VI) can also be obtained by, for example, reacting compounds of formula (VIa) with haloacetonitrile, e.g. Chloroacetonitrile, at low temperatures and a base such as an alkali metal alkoxide, e.g. Sodium methylate, treated and the resulting glycidonitrile e.g. with the aid of a base such as an alkali metal hydroxide, e.g. Sodium hydroxide, hydrolyzed with heating. Subsequently, the compounds thus obtained are of the formula

I A N ° (VIc)

r / V \ r

3 ο

under heating, e.g. at the reflux temperature of toluene, decarboxylated to give compounds of formula (VI) wherein X. is formyl. With the help of optional additional measures, the formyl can be acetalated according to a conventional manner or reduced to hydroxylmethyl. The latter in turn can, if desired, be esterified or etherified.

Starting materials of the formula (VI) wherein X represents a group of the formula -CH = CH-X, can be prepared by, e.g. Compounds of the formula

/ V

I A IJ (VId)

R '^ / ^N OCH ₂ -CH = CH-X _U

to high temperatures, e.g. to 25O ° C, heated and then in thus obtainable compounds of the formula

^X 14

/ \ / ^H - ^{CH = CH} 2 ΐ Α Μ (VIe)

R ₃ ⁷ V ^ ₀ H

if desired, convert the hydroxy group into OR, for example by esterification, for example acetylation with acetic anhydride / pyridine, if desired introducing the radical R "by reaction with a compound of the formula R ₉ -H in the presence of a base, for example sodium amide in liquid ammonia. The subsequent oxidation of compounds thus obtainable of the formula

R _? • I

/ \ -C-CH = CH IA il %

^R 3 '

244347 8-

with ozone and a peroxide, e.g. 30% hydrogen peroxide, at room temperature leads to compounds of formula (I) wherein R is carboxy.

For the preparation of compounds of the formula VI in which X is an oxidatively convertible radical in R, * is also starting, for example, of a corresponding formula I salicylic acid derivative and reduces the carboxy group to the hydroxymethyl group, wherein as reducing agent, for example. a complex hydride such as lithium aluminum hydride is used. After substitution of the hydroxy group by a halogen atom, e.g. by treatment with a halogenating reagent such as thionyl chloride, the resulting halomethyl compound is e.g. with a halide of the formula Hal-X. reacted in the presence of magnesium and copper (I) iodide. Preferred compounds of the formula Hal-X are, for example, those in which X represents the group of the formula -CH =CH-X, or -CH =C (Ar). From the compounds of the formula VI which are obtainable in which X is -CH = CH-X, one arrives e.g. by ozonolysis and cleavage of the ozonide by zinc / glacial acetic acid to formyl X or by hydroxylation of the double bond, e.g. with osmium tetroxide, by partial or complete oxidation of the hydroxy compounds to corresponding oxoderivaten or to such compounds, wherein X stands for the following groups:

-CH (OH) -CH (OH) -X _1., -CH (OH) -CO-X _n, or -CO-CO-X _1,. 14 '14 14

The corresponding α-ketocarboxylic acid of the formula VI, ie X ₁ represents the group of the formula -CO-COOH, is obtainable by treating, for example, a salicylic acid derivative corresponding to the formula (I) with phosgene and the resulting acid chloride, for example with copper (I) - or sodium cyanide and the cyano group is hydrolyzed to the carboxy group, after the esterification can also be prepared those compounds of formula VI, wherein X is the group -CO-CO-X, is.

2U3 4 7- 8-

Another procedure for the preparation of compounds of formula (I) is that in a compound of formula

T A Tl (VIII)

<V \ r 3 ο

or a salt thereof in which X is a radical convertible into the group of formula -CH (R) -R, X is converted by rearrangement into the group of formula -CH (R ₉ JR and / or, if desired, a salt obtainable according to the process converted into the free compound or in another salt, a free compound obtainable in accordance with the process is converted into another free compound or into a salt and / or, if desired, an isomer mixture obtainable in accordance with the process is separated into its components.

Compounds of formula (VIII), wherein X - represents the group of formula

-CH (Rj-Ci = NN = NI) -X ₁ . or -CH (Ro) -Ci = N-OH) -X ₁ , and X represents a corresponding 2. Io * · ^io Ib

optionally substituted aliphatic radical, can be rearranged according to the Schmidt or the Beckmann rearrangement in N-monosubstituted carbamoyl (R) compounds of the formula (I). The Schmidt or Beckmann rearrangement takes place in a manner known per se. For example, the azides or oximes in question are treated with acidic catalysts, such as strong protic acids, for example sulfuric acid, inorganic acid halides, for example phosphorus (V) chloride, or sulfonylides, for example benzenesulfonyl chloride, if appropriate in an inert solvent, such as a halogenated hydrocarbon, eg halogen lower alkane chloroform, or an aromatic such as benzene, in a temperature range of about -30 to about 150 ⁰ C.

Compounds of the formula (VIII) in which X is the group of the formula -CH (R ") -CO-CH-N" can be rearranged by analogous methods in accordance with the Wolff rearrangement to give those compounds of the formula (II) in which R is optionally esterified or amidated carboxy. Thus, the reaction is carried out e.g. under heating and / or

244347 8-

Irradiation with high-energy light, for example UV light, and / or in the presence of a catalyst, for example a noble metal or noble metal oxide, such as copper, silver or silver oxide, in an inert solvent, such as an ether, for example dioxane or tetrahydrofuran, through, wherein advantageous in a temperature range of about 0 ° to about 150 ⁰ C is worked. By addition of water, alcohol, ammonia or amine, the reaction can be directed to the formation of free carboxylic acid, esterified or amidated carboxylic acid R.

Compounds of the formula (VIII) in which X is the group of the formula -CO-CH-Hal and Hal is halogen, such as chlorine, bromine and iodine, can be prepared in a manner known per se analogously to the Favorskiy rearrangement into such compounds Convert formula (I), wherein R is carboxy and R is hydrogen. The corresponding rearrangement can be e.g. by heating with strong bases, such as alkali metal hydroxides, or by treatment with Ag (I) compounds, such as silver (I) oxide or silver (I) nitrate with heating in a solvent, such as water and / or lower alkanol.

The oxidative rearrangement of compounds of the formula (VIII) in which X is the group of the formula -CO-CH-R is effected, for example, by with the aid of the oxidizing agent thallium (III) nitrate, preferably in an alcohol such as lower alkanol, optionally in the presence of traces of strong protic acid, such as perchloric acid, or of trimethyl orthoformate is used. Further, an inert solvent such as an optionally halogenated hydrocarbon, e.g. Hexane or chloroform, or an ether, e.g. Dioxane can be used. The oxidizing agent may also be supported on a suitable support material [Lit. J. Am. Chem. Soc. £ 8, 6750 (1976)].

If the reaction is carried out in a lower alkanol, compounds of the formula (I) are obtained, where R is lower alkoxycarbonyl.

The oxidative rearrangement of compounds of the formula (VIII) in which X is the group of the formula -CO-CH-R and R "is hydrogen

represents, analogous to the Willgerodt-Kindler reaction, with aqueous ammonium polysulfide, generally under pressure, or with sulfur and a ¹ primary or tertiary amine in an inert solvent, and optionally carried out under heating. In this case, compounds of formula (I) are obtained, wherein R is amidated carboxy or a corresponding thiocarbamoyl or ammonium carboxylate and R is hydrogen. Suitable solvents are, for example, ethers, such as dioxane or tetrahydrofuran, or lower alkanols, such as ethanol. Advantageously, the reaction is carried out by prolonged boiling under reflux.

The starting materials of the formula (VIII) are known or are prepared by analogous processes.

A general method for preparing compounds of formula (VIII) is e.g. in that one is a compound of the formula

I A Il (Villa)

3 ο

or a salt thereof with a compound of formula HaI-X, wherein Hal is halo, such as chloro or bromo. The reaction takes place e.g. in the presence of a strong acid, such as polyphosphoric acid, or especially in the presence of a Lewis acid, such as aluminum chloride.

A further process variant for the preparation of compounds of formula (I), or their salts or isomers, is that in a compound of formula

I A M (VII),

r / V V

3 ο

wherein X _{13 is} a radical convertible into the group of the formula -CH (R ₂ ) -R (VIIa), or a salt or isomers thereof the radical X _ is converted into the group of the formula (VIIa) and / or, if desired .

244347 8-

a salt obtainable according to the process is converted into the free compound or into another salt, a free compound obtainable according to the process is converted into a salt or into another free compound and / or, if desired, an isomer mixture obtainable in accordance with the process is separated into its components.

A radical X- which can be converted into the group of the formula (VIIa) is, for example, a group of the formula -Mg-Hal or -CH (R) -Mg-Hal, where Hal in each case represents halogen, in particular chlorine or bromine.

In a compound of the formula (VII) in which X represents the group -Mg-Hal, the group of the formula (VIIa) is introduced in a manner known per se. For example, a corresponding compound of the formula (VII) is reacted with a compound of the formula Hal-CH-1 (VIIb) ₁ or a salt thereof, where Hal is halogen. The reaction is carried out, if necessary, with cooling in an inert solvent or diluent, such as an ether, eg lower alkyl ether or cyclic ether, optionally under protective gas, such as nitrogen, preferably at temperatures between about -80 ° and about the boiling temperature of the solvent.

Corresponding starting materials of the formula (VII) in which X is the group -Mg-Hal, or salts or isomers thereof are prepared by methods known per se, for example by reacting compounds of the formula

ΐ A it (VIId)

or their salts with magnesium in an ether, such as tetrahydrofuran. The corresponding compounds of the formula (VIId) are known or are accessible in an analogous manner.

2U347 8

In compounds of formula (VII) wherein X is the group of the formula -CH (R) -Mg-Hal or their salts or isomers, the group of formula (VIIa) wherein R is carboxy may be obtained by treating corresponding compounds of formula (VII) with carbon dioxide. Incidentally, if necessary, with cooling in an inert solvent such as an ether, e.g. a di-lower alkyl ether or a cyclic ether, and optionally under a protective gas, e.g. Nitrogen, worked.

Corresponding starting materials of the formula (VII) in which X - represents the group of the formula -CH (R) -Mg-Hal can be obtained, for example, by dissolving in compounds of the formula

T A H '(VIIe)

r / V \ r

3 ο

or a salt thereof _s the oxo group with a reducing agent, such as an optionally complex hydride, for example Lithiumalluminiumhydrid or sodium borohydride with gentle heating to the hydroxy group. This is subsequently substituted by halogen, for example by treatment with a phosphorus halide, for example phosphorus bromide or chloride, if necessary with cooling, for example at 0 ^° C. A compound of the formula obtainable in this way

(VIIf)

; ^vv

or salts thereof are then reacted with magnesium to give the corresponding compound of formula (VII), in an inert solvent such as an ether, e.g. Dioxane, is being worked on. A compound of the formula (I) obtainable according to the invention can be converted in a manner known per se into another compound of the formula (I).

244347 8-

If the ring A is substituted by lower alkylthio, it can be oxidized in the usual way to corresponding lower alkanesulfinyl or -sulfonyl. Suitable oxidizing agents for the oxidation to the sulfoxide stage include, for example, inorganic peracids, such as peracids of mineral acids, e.g. Periodic acid or persulfuric acid, organic peracids such as corresponding percarboxylic or persulfonic acids, e.g. Performic, peracetic, trifluoroperacetic or

Perbenzoic acid or p-toluenesulfonic acid, or mixtures of hydrogen peroxide and acids, e.g. Mixture of hydrogen peroxide with

Acetic acid, into consideration.

Frequently, the oxidation is carried out in the presence of suitable catalysts, acids suitable as catalysts, such as optionally substituted carboxylic acids, for example acetic acid or trifluoroacetic acid, or transition metal oxides, such as oxides of elements of the VII subgroup, eg vanadium, molybdenum or tungsten oxide are called. The oxidation is carried out under mild conditions, for example at temperatures of about -50 ° to about + 100 ⁰ C, performed.

The oxidation to the sulfone can also be carried out with dinitrogen tetroxide as a catalyst in the presence of oxygen at low temperatures, as well as the direct oxidation of Niederalkylthio to Niederalkansulfonyl. However, this usually involves the use of the oxidizing agent in excess.

If the ring A is substituted by lower alkanesulphinyl or -sulphonyl, this can be reduced by conventional methods to corresponding lower alkylthio, starting from lower alkanesulphonyl derivatives, and also to lower alkanesulphinyl. Suitable reducing agents are, for example, catalytically activated hydrogen, where noble metals or oxides, such as palladium, platinum or rhodium or their oxides, are used, optionally applied to a suitable support material, such as activated carbon or barium sulfate. Furthermore, reducing metal cations, such as tin II, lead II, copper I, manganese II, titanium II, vanadium II, molybdenum III or tungsten III compounds,

Λ 3 Λ 7 8 -

Hydrogen halides, such as hydrochloric, hydrobromic or hydroiodic, hydrides, such as complex metal hydrides, e.g. Lithium aluminum, sodium boron, tributyltin hydride, phosphorus compounds such as phosphorus halides, e.g. Phosphorus trichloride, bromide, phosphorus pentachloride or phosphorus oxychloride, phosphines, such as triphenylphosphine, or phosphorus pentasulfide-pyridine, or sulfur compounds, such as mercaptans, thioacids, such as thiophosphoric acids or dithiocarboxylic acids, dithionite or sulfur-oxygen complexes, such as iodine-pyridine-sulfur dioxide complex in question.

If the aromatic ring has a hydrogen atom as a substituent, it can be replaced by a halogen atom in the usual way with the aid of a halogenating agent.

Thus, the substitution of hydrogen by bromine occurs e.g. by bromination with bromine analogously to "Methods of Organic Chemistry", Houben-Weyl (4th Edition), VoI, 5/4. Pp. 233-249, in an inert solvent. Furthermore, it is possible to brominate with the aid of the following brominating agents: hypobromous acid, acyl hypobromites or other organic bromine compounds, eg. N-bromosuccinimide, N-bromoacetamide, N-bromophthalimide, pyridinium perbromide, dioxane dibromide, 1,3-dibromo-5,5-dimethylhydantoin, 2,4,4,6-tetrabromo-2, S-cyclohexadiene-1-one.

The corresponding chlorination can be carried out, for example, as described in Houben-Weyl (4th Edition), Vol. 5/3, pp. 651-673, advantageously with elemental chlorine, for example in a halogenated hydrocarbon, such as chloroform, and with cooling, eg at about -10 ° to about +10 ⁰ C.

The replacement of hydrogen by iodine can be done, for example, with elemental iodine in the presence of mercury oxide or nitric acid. Instead of elemental iodine, for example, an alkali metal iodide in _; Presence of a thallium (II) difluoroacetate according to Tetrahedron Letters (1969), p. 2427 as iodinating agent.

43 4 7 8

Further, the benzo moiety of the ring system and / or another aromatic ring can be alkylated with, for example, a lower alkanol or a lower alkyl halide or a lower alkyl phosphite in the presence of Lewis acids (Friedel-Crafts alkylation). For example, in a compound of formula (I) wherein an aromatic ring contains bromine, the bromine may be replaced by lower alkyl by reaction with a lower alkyl bromide in the presence of an alkali metal.

If an aromatic ring contains a hydrogen atom as substituent, this can be replaced by an acyl group in a manner known per se. Thus, for example, the insertion of the acyl group analogous to the Friedel-Crafts acylation (cf., GA Olah, Friedel-Crafts and Related Reactions, Vol. I, Interscience, New York, 1963-1965) be carried out »eg by reacting a reactive functional acyl derivative such as a halide or anhydride of an organic carboxylic acid ₅ in the presence of a Lewis acid such as aluminum, antimony (III) - or - (V) -, iron (III) -, zinc (II) chloride or Brotrifluorid.

If the aromatic ring contains hydroxyl as a substituent, this can be etherified in a manner known per se. The reaction with an alcohol component, e.g. with a lower alkanol, such as ethanol, in the presence of acids, e.g. Mineral acid such as sulfuric acid or dehydrating agents such as dicyclohexylcarbodiimide results in lower alkoxy. Conversely, one can cleave ethers into phenols by subjecting the ether cleavage to acids such as mineral acids, e.g. Hydrohalic acid, such as hydrobromic acid, or as Lewis acids, e.g. Halides of elements of the 3rd main group, such as boron tribromide, or by means of pyridine hydrochloride or thiophenol performs.

2U347 8 -

Further, hydroxy can be converted to lower alkanoyloxy, for example, by reaction with a desired lower alkanecarboxylic acid, such as acetic acid, or a reactive derivative thereof, for example in the presence of an acid, such as a protonic acid, e.g. Hydrochloric, hydrobromic, sulfuric, phosphoric or benzenesulfonic acid, in the presence of a Lewis acid, e.g. of boron trifluoride etherate, or in the presence of a water-binding agent such as dicyclohexylcarbodiimide. Conversely, esterified hydroxy, e.g. by base catalysis, to hydroxy solvo-

be lysed.

Free, esterified and amidated carboxy groups R can be converted into each other, for example a free carboxy group in a conventional manner into an esterified carboxyl group R ₁ , preferably by reaction with a corresponding alcohol or a reactive derivative, such as a carboxylic, phosphorous, sulfuric or carbonic acid ester, ζ.Β "a Niederalkancarbonsäureester, Triniederalkylphosphit, Diniederalkylsulfit or the pyrocarbonate, or a mineral acid or sulfonic acid esters, for example the hydrochloric or hydrobromic acid or sulfuric acid, benzenesulfonic toluenesulfonic or Methansulfonsäureeste.r, the corresponding alcohol or an olefin derived therefrom.

The reaction with the corresponding alcohol is advantageously carried out in the presence of an acidic catalyst, such as a protic acid, for example of hydrochloric or hydrobromic, sulfuric, phosphoric, boronic, benzenesulfonic and / or toluenesulfonic acid, or a Lewis acid, z. of boron trifluoride etherate, I _n an inert solvent, in particular an excess of the alcohol employed and, if necessary, by distillation in the presence of a water-binding agent and / or below, for example, azeotropic, removal of water of reaction and / or at elevated temperature.

The reaction with a reactive derivative of the corresponding alcohol can be carried out in a customary manner, starting from a carboxylic, phosphorous, sulfuric or carbonic acid ester, while

For example, in the presence of an acidic catalyst such as one of the foregoing, in an inert solvent such as an aromatic hydrocarbon, e.g. in benzene or toluene, or an excess of the alcohol derivative or alcohol used, if necessary taking, e.g. azeotropic, distilling off the water of reaction. Starting from a mineral acid or sulfonic acid ester, the acid to be esterified is advantageously added in the form of a salt, e.g. sodium, potassium or calcium hydroxide or carbonate, in the presence of a basic condensing agent such as an inorganic base, e.g. sodium or potassium or calcium hydroxide or carbonate, or a tertiary organic nitrogen base, e.g. triethylamine or pyridine, if necessary in an inert solvent such as one of the above tertiary nitrogen bases or a polar solvent, e.g. in dimethylformamide and / or at elevated temperature.

The reaction with an olefin may be carried out, for example, in the presence of an acidic catalyst, e.g. a Lewis acid, e.g. of boron trifluoride,. a sulphonic acid, e.g. of p-toluenesulfonic acid, or especially a basic catalyst, e.g. of sodium or potassium hydroxide, advantageously in an inert solvent such as an ether, e.g. in diethyl ether or tetrahydrofuran.

Further, a free carboxyl group R can be prepared by reacting with ammonia or an amine having at least one hydrogen in the usual manner to dehydrate the intermediate ammonium salt, e.g. by azeotropic distillation with benzene or toluene or dry heating, in an amidated carboxyl group R are transferred.

However, the above-described transformations of free esterified or amidated carboxyl groups R can also be carried out by reacting a compound of the formula I in which R is carboxyl in a conventional manner into a reactive derivative, for example

4 3 Λ 7 8-

by means of a halide of phosphorus or sulfur, for example by means of phosphorus trichloride or bromide, phosphorus pentachloride or thionyl chloride, into an acid halide or by reaction with a corresponding alcohol or amine in a reactive ester, ie esters with electron-attracting structures, such as the ester with phenol, thiophenol _t p Nitrophenol or cyanomethyl alcohol, or a reactive amide, for example the amide derived from imidazole or 3,5-dimethylpyrazole, and the resulting reactive derivative is then converted in a customary manner, for example as described below for the transesterification, transamidation or interconversion of esterified and amidated carboxyl groups R., reacted with a corresponding alcohol, ammonia or the corresponding at least one hydrogen atom-containing amine to the desired group R »

Further, an esterified carboxyl group, R in customary manner, for _£ example, by hydrolysis in the presence of a catalyst, for example a basic or acidic agent, such as a strong base, for example Natriura- or potassium hydroxide, or a mineral acid, for example hydrochloric acid, sulfuric acid or Phosphoric acid to the free carboxyl group R or, for example by reaction with ammonia or the corresponding, having at least one hydrogen atom-containing amine in an amidated carboxyl group R.

An esterified carboxyl group R may further in a conventional manner, for example by reaction with a corresponding metal alkoxide, for example the sodium or potassium alkoxide of the corresponding alcohol, or with this itself in the presence of a catalyst, for example a strong BaSe _5, for example of sodium or potassium hydroxide, or a strong acid, such as a mineral acid, for example of hydrochloric acid, sulfuric acid or phosphoric acid, or an organic sulfonic acid, for example of p-toluene sulfonic acid, or a Lewis acid, for example of boron trifluoride etherate, be converted to another esterified carboxyl group R.

244347 8

An amidated carboxyl group R can be prepared in a conventional manner, for example by hydrolysis in the presence of a catalyst, for example a strong base such as an alkali metal or alkaline earth metal hydroxide or carbonate, for example sodium or potassium hydroxide or carbonate, or a strong acid such as a mineral acid , For example, be converted from hydrochloric acid, sulfuric acid or phosphoric acid in the free carboxyl group R ₁ .

If the compounds of the formula (I) contain unsaturated radicals, such as lower alkenyl or lower _{alkenylene groups} , these can be converted into saturated radicals in a manner known per se. Thus, for example, the hydrogenation of multiple bonds by catalytic hydrogenation in the presence of hydrogenation catalysts, for this purpose, for example, noble metals or their derivatives, eg oxides suitable, such as nickel, Raney nickel, palladium, platinum oxide, optionally on support materials, for example on carbon or calcium carbonate , can be reared. The hydrogenation may preferably be at at pressures between 1 and about 100., And are carried out at temperatures between about -80 ° to about 200 ⁰ C, in particular between room temperature and about 100 ⁰ C. The reaction is conveniently carried out in a solvent such as water, a lower alkanol, for example ethanol, isopropanol or n-butanol, an ether, for example dioxane, or a lower alkanecarboxylic acid, for example acetic acid.

Conversely, in cyclic systems R "one or more multiple bonds can be introduced, for this purpose, suitable dehydrating agents, for example subgroup elements, preferably those of the VIII subgroup of the Periodic Table, e.g. Palladium or platinum, or corresponding noble metal derivatives, e.g. Ruthenium triphenyl phosphide chloride, wherein the agents may be grown on suitable support materials. Other preferred dehydrating agents are, for example, quinones such as p-benzoquinones, e.g. Tetrachloro-p-benzoquinone or 2,3-dichloro-5,6-dicyano-p-benzoquinone, or as anthraquinones, e.g. Phenanthrene-9,10-quinone. Furthermore, N-halosuccinimides,

! U 34 7 8

such as N-chlorosuccinimide, manganese compounds such as barium-manganate or manganese dioxide, and selenium derivatives such as selenium dioxide or diphenylselenium bis-trifluoroacetate.

Salts of compounds of the formula (I) can be prepared in a manner known per se. Thus, for example, acid addition salts of compounds of the formula (I) are obtained by treatment with an acid or a suitable ion exchange reagent. Salts may be converted to the free compounds in a conventional manner, acid addition salts e.g. by treating with a suitable basic agent.

As a result of the close relationship between the new compound in free form and in the form of its salts, the corresponding salts or the free compound are to be understood as meaningful and appropriate in the preceding and following among the free compound or its salts.

The new compound, including its salts, can also be obtained in the form of its hydrates or include other solvents used for crystallization.

The new compounds may, depending on the choice of starting materials and procedures, in the form of one of the possible isomers or mixtures thereof, e.g. depending on the number of asymmetric carbon atoms, as pure optical isomers, such as antipodes, or as mixtures of isomers, such as racemates, diastereoisomer mixtures or racemate mixtures.

Resulting diastereomer mixtures and mixtures of racemates can be separated in a known manner in the pure isomers, diastereomers or racemates due to the physicochemical differences of the constituents, for example by chromatography and / or fractional crystallization. Racemates obtained can furthermore be decomposed by known methods into the optical antipodes, for example by conversion.

2Λ Λ 3 Λ 7 8.

crystallization from an optically active solvent, by means of microorganisms or by conversion into diastereomeric salts or esters, e.g. by reacting an acidic end product with an optically active base forming salts with the racemic acid or an optically active carboxylic acid or a reactive derivative thereof, and separating the diastereomeric mixture thus obtained, e.g. due to their different solubilities, into the diastereomers from which the desired enantiomer can be released by the action of suitable means. Advantageously, one isolates the more effective enantiomer.

The invention also relates to those embodiments of the process according to which one proceeds from a compound obtainable as an intermediate at any stage of the process and performs the missing steps or uses a starting material in the form of a salt or forms in particular under the reaction conditions.

In the process of the present invention, preference is given to using those starting materials which lead to the compounds described at the outset as being particularly valuable. New starting materials, their use, e.g. as active pharmaceutical ingredients, formulation methods and processes for their preparation also form an object of the invention.

The starting materials of the formulas II, III, IV, V, VI, VII and VIII, which are specially developed for the preparation of the compounds according to the invention, the processes for their preparation and their use also form an object of the invention. In particular, compounds of the formula (VI) in which X is optionally esterified or etherified hydroxymethyl or optionally acetalated formyl, processes for their preparation and their use, e.g. as starting materials or active pharmaceutical ingredients, and also pharmaceutical preparations and their preparation constitute a further subject of the invention.

2ΛΛ3Λ7 8-

The pharmaceutical compositions according to the invention containing the compound according to the invention or pharmaceutically acceptable salts thereof are those for topical application, further enteral, such as oral or rectal, and parenteral administration to warm-blooded animals, the pharmacologically active substance is contained alone or together with a pharmaceutically acceptable carrier material. The daily dosage of the drug depends on the age and the individual condition, as well as on the mode of administration.

The new pharmaceutical preparations contain, for example, from about 10% to about 80%, preferably from about 20% to about 60% of the active ingredient. Inventive pharmaceutical preparations for enteral or parenteral administration are, for example, those in dosage unit forms such as dragees, tablets, capsules or suppositories _5, and also ampoules. These are produced in a manner known per se, for example by means of conventional mixing, granulating, coating, solution or lyophilization processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active ingredient with solid carriers, optionally granulating a mixture obtained, and the mixture or granules, if desired or necessary, after addition of suitable excipients, into tablets or dragee cores processed.

Suitable carriers are, in particular, fillers, such as sugars, e.g. Lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, e.g. Tricalcium phosphate or calcium hydrogen phosphate, further binders such as starch pastes, using

e.g. corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and / or polyvinylpyrrolidone, if desired, disintegrants such as the above-mentioned starches, further carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof such as sodium alginate are primarily flow, regulators and lubricants, eg Silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate,

244347 8-

and / or polyethylene glycol. Dragee cores are provided with suitable, possibly gastric juice-resistant coatings, which u.a. concentrated sugar solutions which may contain arabic gum, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, for the preparation of gastric juice-resistant coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. The tablets or dragee coatings may contain dyes or pigments, e.g. for the identification or labeling of different doses of active substance.

Other orally applicable pharmaceutical preparations are gelatine capsules, as well as soft, closed capsules of gelatin and a plasticizer, such as glycerol or sorbitol. The capsules may contain the active ingredient in the form of granules, e.g. in admixture with fillers, such as lactose, binders, such as starches, and / or lubricants, such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredient is preferably dissolved or superseded in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, it also being possible for stabilizers to be added. ,

As rectally applicable pharmaceutical preparations are e.g. Suppositories which consist of a combination of the active ingredient with a suppository base. Suitable suppository masses include e.g. natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. Furthermore, gelatin rectal capsules containing a combination of the active ingredient with a basic bulking agent may also be used. As basic materials there are e.g. liquid triglycerides, polyethylene glycols or paraffinic hydrocarbons in question.

For parenteral administration, aqueous solutions of an active ingredient in water-soluble form, e.g. a water-soluble salt, further suspensions of the active ingredient, such as corresponding oily injection suspensions, whereby suitable lipophilic solvents or vehicles such as fatty oils, e.g. Sesame oil, or synthetic fatty acid esters, e.g. Ethyl oleate or triglycerides used or aqueous injection suspensions containing viscosity increasing agents, e.g. Sodium carboxymethyl cellulose, sorbitol and / or dextran, and optionally also stabilizers.

As topically applicable pharmaceutical preparations are primarily cream, ointments, pastes, foams, tinctures and solutions in question, which contain from about 0.1 to about 5% of the active ingredient.

Creams are oil-in-water emulsions containing more than 50% water. As an oily basis, fatty alcohols are primarily used., E.g. Lauryl, cetyl or stearyl alcohol, fatty acids, e.g. Palmitic or stearic acid, liquid to solid waxes, e.g. Isopropyl myristate, wool waxes or beeswax, and / or hydrocarbons, e.g. Vaseline (petrolatum) or paraffin oil. Suitable emulsifiers are surface-active substances with predominantly hydrophilic properties, such as corresponding nonionic emulsifiers, e.g. Fatty acid esters of polyhydric alcohols or ethylene oxide adducts thereof, such as polyglycerol fatty acid esters or polyoxyethylene sorbitan fatty acid esters (Tweens), also polyoxyethylene fatty alcohol ethers or fatty acid esters, or corresponding ionic emulsifiers, such as alkali metal salts of fatty alcohol sulfates, e.g. Sodium lauryl sulphate, sodium cetyl sulphate or sodium stearyl sulphate, usually in the presence of fatty alcohols, e.g. Cetyl alcohol or stearyl alcohol. Additives to the water phase are u.a. Agents preventing the drying of the cream, e.g. Polyalcohols such as glycerol, sorbitol, propylene glycol and / or polyethylene glycols, preservatives, fragrances, etc.

244347 8

Ointments are water-in-oil emulsions containing up to 70%, but preferably from about 20% to about 50% water or aqueous phases. The fatty phase is primarily hydrocarbons, e.g. Vaseline, paraffin oil and / or hard paraffins in question, the preferably water-binding capacity suitable hydroxy compounds, such as fatty alcohols or esters thereof, e.g. Cetyl alcohol or wool wax alcohols or wool waxes included. Emulsifiers are corresponding lipophilic substances, such as sorbitan fatty acid esters (Spans), e.g. Sorbitan oleate and / or sorbitan isostearate. Additives to the water phase are u.a. Humectants, such as polyalcohols, e.g. Glycerol, propylene glycol, sorbitol and / or polyethylene glycol, as well as preservatives, fragrances, etc.

Fatty ointments are anhydrous and contain, in particular, hydrocarbon, e.g. Paraffin, vaseline and / or liquid paraffins, also natural or partially synthetic fat, e.g. Coconut fatty acid triglyceride, or preferably hardened oils, e.g. hydrogenated peanut or castor oil, also fatty acid partial esters of glycerol, e.g. Glycerol mono- and distearate, as well as e.g. the mentioned in connection with the ointments, the water absorbency enhancing fatty alcohols, emulsifiers and / or additives.

Pastes are cream and ointments with secretion absorbing powder ingredients, such as metal oxides, e.g. Titanium oxide or zinc oxide, further talc and / or aluminum silicates, which have the task to bind existing moisture or secretions.

Foams are e.g. from pressurized containers and are aerosolized liquid oil-in-water emulsions, halogenated hydrocarbons such as chlorofluoro-lower alkanes, e.g. Dichloridfluoromethane and dichlorotetrafluoroethane, be used as blowing agent. As Oülphase u.a. Hydrocarbons, e.g. Paraffin oil, fatty alcohols, e.g. Cetyl alcohol, fatty acid esters, e.g. Isopropyl myristate, and / or other waxes. As emulsifiers u.a. overall

07/03/1983

AP C 07 C / 244 347/8 '4 4 J 4' O - ⁶⁵ - ⁶ * 577/11

mixtures of those having predominantly hydrophilic properties, such as polyoxyethylene sorbitan fatty acid esters (Tweens), and those having predominantly lipophilic properties, such as sorbitan acid ester (Spans). There are also the usual additives, such as preservatives, etc.

Tinctures and solutions usually have an aqueous-ethanolic basis, the u. a. Polyalcohols, ζ, Β. Glycerol, glycols and / or polyethylene glycol, humectants to reduce evaporation, and greasing substances such as fatty acid esters with low polyethylene glycols, d, h, soluble in the aqueous mixture, lipophilic substances as a substitute for the skin with the ethanol extracted fatty substances, and, if necessary, other auxiliaries and additives are added.

The preparation of the topically usable pharmaceutical preparations is carried out in a manner known per se, z. 3. by dissolving or suspending the active ingredient in the base or in a part thereof, if necessary. In the processing of the active ingredient as a solution of this is usually solved by the emulsification in one of the two phases; when processed as a suspension, it is mixed after emulsification with part of the base and then added to the remainder of the formulation.

The dosage of the active ingredient depends on the species of warm-blooded animals, the age and the individual condition as well as the mode of administration. In the normal case, an approximately daily dose of about 100 to about 600 mg, preferably in several equal divided doses, is to be estimated for a warm-blooded animal weighing about 75 kg when administered orally.

2U347 8-

Working Example

07/03/1983

AP C 07 C / 244 347/8

65a - 61 577/11

The following examples illustrate the invention described above; however, they are not intended to limit their scope in any way. Temperatures are given in degrees centigrade.

4 3 kl 8 - «-

Example 1; 5.4 g (0.02 mol) of S-chloro-O-methyl-o-morpholinobenzofuran-2 (3H) -one are dissolved in 50 ml of AO ml in sodium hydroxide solution. After cooling, the mixture is washed with ether and the aqueous phase is then adjusted to pH 2.0 with 1N hydrochloric acid. The resulting OeI is taken up in ether.

After evaporation of the ether, 2- (5-chloro-2-hydroxy-4-morpholino-phenyl) -propionic acid is obtained as colorless crystals of melting point 198 to 200 ° C.

The starting material can be prepared as follows:

A mixture of 341 g (2 mol) of the hydrochloride of imidazo [1,2-a] -pyridine-2- (3H) -one in 700 ml of water is added portionwise with stirring with a hot solution of 80 g (2 mol) of sodium hydroxide solution in 200 ml of water. Subsequently, a solution of 250.7 g (2.16 mol) of maleic acid in 600 ml of water is added dropwise so that the internal temperature of the reaction mixture remains between 40 ° C and 45 ° C. After 30 hours at room temperature (20 to 25 ° C) is cooled to 5 ° C, the precipitate formed filtered off, the filtrate concentrated in vacuo to about half and the precipitated product filtered off with suction. The combined residues are washed with a little cold methanol and dried at 50 ° C in a vacuum. This results in 400 g of 3- (l, 2-dicarboxyethyl) -imidazo [l, 2-a] pyridin-2 (3H) -one of melting point 193 ⁰ C (dec.). The product obtained is concentrated at room temperature for 6 hours with 650 ml of conc. Hydrochloric acid stirred. After cooling to 5 ° C, the precipitate is filtered off, the filtrate concentrated in vacuo to about half and the precipitated product filtered off with suction. The combined residues are washed with acetone and dried at 50 ° C in vacuo. This gives the hydrochloride of 3- (l, 2-dicarboxyethyl) -imidazo [l, 2-a] pyridin-2 (3H) -one of melting point 205 °. C (Zers.).

2 / U347 8-

67 -

A mixture of 114.7 g (0.4 mol) of the hydrochloride of 3- (1,2-dicarboxyethyl) -imidazo [1,2-a] pyridine-2 (3H) -one, 36.4 g (0, 52 mol) of methyl vinyl ketone, 150 ml of methanol and 150 ml of water is stirred for 36 hours at room temperature and then evaporated at about 45 ° C in vacuo to dryness. The crude product obtained is taken up in 300 ml of glacial acetic acid, admixed with 15 g of sodium acetate and boiled until refluxing CO has ended. Subsequently, the solvent is removed in vacuo, the residue is treated with a mixture of 150 ml of 6M sulfuric acid and 150 ml of tetrahydrofuran and kept at 60 ° C for 8 hours. After removal of the tetrahydrofuran in vacuo, the reaction mixture is diluted with water, extracted with methylene chloride and filtered through silica gel distillation of the crude product in a high vacuum (115 ° C to 125 ° C / 8 Pa) gives the 4- methyl-3- (3 oxo-butyl) -maleic anhydride as a spectroscopically uniform pale yellow oil

A mixture of 18.2 g (0.1 mol) of 4-methyl-3- (3-oxobutyl) -maleic anhydride and 22 g (0.105 mol) of morpholinium benzoate in 400 ml of benzene is refluxed for 48 hours on a water separator. The benzene is removed in vacuo, the residue taken up in methylene chloride and the organic phase extracted twice with saturated sodium bicarbonate solution. The crude product remaining after drying and removal of the methylene chloride is chromatographed on silica gel with petroleum ether / ether. It gives pale yellow crystals, which are recrystallized from methylene chloride / ether.

This gives the 3-methyl-6-morpholino-benzofuran-2 (3H) -one of melting point 118 to 121 ° C.

Λ 3 4 7 8

- 68-

To a mixture of 14.7 g (0.063 mol) of S-methyl-o-morpholino-benzofuran-2 (3H) -one in 100 ml of chloroform is added dropwise at 0 to 5 ° C with stirring, a cold solution of chlorine in chloroform, until in the thin-layer chromatogram no starting material is visible anymore. The reaction mixture is diluted with methylene chloride and washed successively with 10% sodium thiosulfate solution, dilute sodium bicarbonate solution and water. The crude product remaining after drying and evaporation of the organic phase is chromatographed on silica gel with petroleum ether / ether. After recrystallization of the pure fractions from ether / petroleum ether gives the S-chloro-ß-methyl-δ-morpholino-benzofuran-2 (3H) -one of melting point 103 to 105 ° C.

Example 2; A mixture of 19.6 g (0.1 mol) of 4-methyl-3- (2-methyl-3-oxobutyl) -maleic anhydride and 21.3 g (0.11 mol) of pyrrolidinium benzoate in 400 ml of benzene is added during 30 hours heated under reflux at the water separator. The benzene is removed in vacuo and the residue partitioned between ether and saturated sodium bicarbonate solution. The crude product remaining after drying and evaporation of the organic phase is chromatographed on silica gel. Elution with petroleum ether / ether and subsequent recrystallization of the pure fractions from ether / petroleum ether gives 3,5-dimethyl-6- (pyrrolidin-lyl) -benzofuran-2 (3H) -one of melting point 67 to 69 ° C. By increasing the flow polarity (Ether / methanol) are obtained from the following fractions 2- [2-hydroxy-5-methyl-4- (pyrrolidin-1-yl) -phenyl] -propionic acid pyrrolidide. Recrystallization from acetone gives pure product of melting point 178 to 180 ° C.

The starting material can be prepared as follows:

A mixture of 172 g (0.6 mol) of hydrochloride of 3- (1,2-dicarboxyethyl) -imidazole [1,2-a] pyridine-2 (3H) -one, 65.5 g (0.78 mol) 3-Methyl-3-buten-2-one, 220 ml of methanol and 220 ml of water is kept for 36 hours

8th-

69 -

stirred at room temperature and then evaporated at about 45 ° C in vacuo to dryness. The crude product obtained is taken up in 400 ml of glacial acetic acid, admixed with 22.5 g of sodium acetate and refluxed until the CO evolution has ended. The solvent is then removed in vacuo, the residue is treated with a mixture of 225 ml of 6 M sulfuric acid and 225 ml of tetrahydrofuran and heated to reflux for 8 hours. After removal of tetrahydrofuran in vacuo, the reaction mixture is diluted with water and extracted with methylene chloride. The crude product remaining after drying and evaporation of the organic phase is chromatographed on silica gel with petroleum ether / ether. The following

-2 Distillation (100 ° C / 8-10 Torr) gives 4-MeI tyl) -maleinsäureanhydrid as pale yellow OeI.

Distillation (100 ° C / 8-10 torr) gives 4-methyl-3- (2-methyl-3-oxobutyl)

Example 3: A mixture of 19.6 g (0.1 mol) of 4-methyl-3- (2-methyl-3-oxobutyl) -maleic anhydride and 23.0 g (0.11 mol) of morpholinium benzoate in 400 ml of benzene heated to reflux for 60 hours on a water separator. The benzene is removed in vacuo and the residue partitioned between methylene chloride and saturated sodium bicarbonate solution. By further procedure as described in Example 2, 3,5-dimethyl-6-morpholino-benzofuran-2 (3H) -one of melting point 108 to 109 ° C and 2- (2-hydroxy-5-methyl-4-morpholino -phenyl) -propionic acid morpholide of melting point 183-185 ° C.

Example 4: To a solution of 0.9 g (0.039 mol) of sodium in 100 ml of methanol is added 9.5 g (0.035 mol) of 5-chloro-3-methyl] -6-morpholino-benzofuran-2 (3H) -one given. After 3 hours at room temperature, evaporated to dryness in vacuo and the residue dissolved in 50 ml of dimethyl sulfoxide. For this purpose, 5.7 g (0.04 mol) of methyl iodide are added dropwise with stirring. After 16 hours at room temperature, the solution is mixed with 300 ml of water and 100 ml of hexane and the precipitate was filtered off. The filtrate is extracted several times with hexane. After evaporation of the hexane, a crystalline backbone is added.

2U347 8

- 70 -

was preserved. The crude crystals are recrystallized from isopropyl ether. There is obtained 2- (5-chloro-2-methoxy-4-morpholino-phenyl) -propionic acid methyl ester as colorless crystals, melting point 88 to 89 ° C.

Example 5: To a solution of 0.5 g of sodium (0.022 mol) in 50 ml of methanol is added 5.4 g (0.02 mol.) Of 5-chloro-3-met: hy: |. 6-morpholinobenzofuran -2 (3H) -one and allowed to stand at room temperature for 3 hours. It is then evaporated to dryness in vacuo, the residue dissolved in cold water and washed with ether. The aqueous phase is made congo-sour with ice-cold cooling with dilute hydrochloric acid and extracted with ether. After evaporation of the ether, colorless crystals are obtained, which are recrystallized from methanol. This gives the 2- (5-chloro-2-hydroxy-4-morpholino-phenyi) -propionic acid methyl ester of melting point 148 to 149 ° C.

Example 6: To a solution of 5.4 g (0.02 mol) of 5-chloro-3-methyl-6-morpholino-benzofuran-2 (3H) -one in 25 ml of ether is added 2.0 g (0.023 mol) Given morpholine. After 3 hours, the precipitate formed is filtered off, whereby colorless crystals, 2- (5-chloro-2-hydroxy-4-morpholino-phenyl) -propionic acid morpholid of melting point 198 to 199 ° C, are obtained. ^c

Example 7 : 6 g of 0.019 mol) of methyl 2- (5-chloro-2-methoxy-4-morpholino-phenyl) -propionate are boiled in 100 ml of 2N hydrochloric acid for 2 hours at reflux. It is then adjusted to pH 2.5 with dilute sodium hydroxide solution and extracted several times with ether. After evaporation of the ether crystals are obtained, which are recrystallized from ethyl acetate / petroleum ether (1: 1). This gives 2- (5-chloro-2-methoxy-4-morpholino-phenyl) -propionic acid as coarse prisms of melting point 164 to 165 ° C.

2Λ Λ3Λ7 8 -

71 -

Example 8: A suspension of 3.0 g (0.01 mol) of methyl 2- (5-chloro-2-hydroxy-4-morpholino-phenyl) -propionate and 0.03 g of 4-dimethylaminopyridine in 30 ml Acetic anhydride are heated to 50 ° C for 5 minutes on the water bath and dissolved. After 1 hour room temperature is evaporated to dryness in vacuo and the residue chromatographed on silica gel with methylene chloride. There are obtained colorless crystals, which are recrystallized from isopropyl ether. This gives the 2- (2-acetoxy-5-chloro-4-morpholino-phenyl) -propionic acid methyl ester of melting point 104 to 105 ° C.

Example 9: A solution of 11.07 g (30 mmol) of 5-chloro-2-methoxy-4- (piperidin-1-yl) phenylthioacetic acid morpholinamide in 120 ml of glacial acetic acid and 30 ml of conc. Hydrochloric acid is refluxed for 22 hours. The reaction mixture is cooled, diluted with water and extracted with methylene chloride. The combined methylene chloride phases are washed with water dried over sodium sulfate and _£ evaporated in a high vacuum rotary evaporator. Chromatography on silica gel with chloroform / methanol (19: 1) gives the 5-chloro-2-methoxy-4- (piperidin-1-yl) -phenylacetic acid, which melts after recrystallization with methylene chloride / hexane at 120 to 122 ° C. ,

ti

In an analogous manner, the 5-chloro-2-methoxy-4- (4-morpholino) phenylacetic acid of melting point 141 to 143 ° C.

The starting material can be prepared as follows:

A solution of 96 g (0.72 mol) of aluminum trichloride in 180 ml of abs _c nitromethane is added under nitrogen atmosphere and ice / methanol cooling to a mixture of 106.2 g (0.60 mol) of 3,4-dichloroanisole [H , Jamarlik et al, Comptes Rendus Acad. Be. Ser. C 273 (25), 1756 (1971)] and 51.1 ml (0.72 mol) of acetyl chloride are added dropwise over about 30 minutes so that the internal temperature range is between 0 and 5 ° C. The mixture is then further stirred for 1 hour at about 4 to 6 ° C, then poured onto ice and extracted with methylene chloride. The organic extracts are washed with water, combined, over sodium sulfate

Λ Λ 3 Λ 7 8-

72 -

dried and evaporated on a vacuum rotary evaporator. After recrystallization from methanol / water, the 4,5-dichloro-2-methoxy-acetophenone of melting point 93 to 95 ° C.

A solution of 76.7 g (0.35 mol) of 4,5-dichloro-2-methoxy-acetophenone in 750 ml of piperidine is kept in an autoclave for 7 hours at 170 ° C. The reaction mixture is evaporated, taken up in ethyl acetate and washed with water. The ethyl acetate extracts are combined, dried over sodium sulfate and evaporated on a vacuum rotary evaporator. The residue is chromatographed on silica gel with methylene chloride. This gives 5-chloro-2-hydroxy-4- (N-piperidino) acetophenone of melting point 68 to 70 ° C.

In an analogous manner, the 5-chloro-2-hydroxy-4- (N-morpholino) ·· acetophenone of melting point 102 to 103 ° Co

A solution of 32.5 g (128 mmol) of 5-chloro-2-hydroxy-4- (N-piperidino) acetophenone and 75 ml (166 mmol) of an approximately 40% methanolic solution of benzyltriethylammonium hydroxide (Triton B) in 65 ml of tetrahydrofuran is cooled to 0 ° C. During about 6 minutes, 14.6 ml (154 mmol) of dimethyl sulfate are added dropwise so that the internal temperature does not rise above 5 ° C. The reaction mixture is stirred for 1 hour at 0 °, then boiled for about 30 minutes under reflux. The reaction mixture is then poured onto 400 ml of water and extracted with ethyl acetate. The combined ethyl acetate phases are washed with water, dried over sodium sulfate and evaporated on a vacuum rotary evaporator. The residue is recrystallized from methylene chloride / hexane to give 5-chloro-2-methoxy-4- (N-piperidino) acetophenone of melting point 119-120 ° C.

In an analogous manner, the 5-chloro-2-methoxy-4- (N-morpholino) acetophenone of melting point 143 to 145 ° C.

2Λ

- 73 -

A solution of 18.2 g (68 mmol) of 5-chloro-2-methoxy-4- (piperidin-1-yl) -acetophenone and 4.36 g (136 mmol) of sulfur in 68 ml of morpholine is heated at 90 ° for 5 hours ° C held. The reaction mixture is cooled, diluted with ethyl acetate and washed with water. The combined ethyl acetate extracts are dried over sodium sulfate and evaporated on a vacuum rotary evaporator. After recrystallization from methylene chloride / methanol, the 5-chloro-2-methoxy-4- (piperidinl-yl) -phenylthioessigsäuremorpholinamid of melting point 137 to 139 ° C.

In an analogous manner, the 5-chloro-2-methoxy-4- (4-morpholino) -phenylthioessigsäuremorpholinamid of melting point 160 to 162.5 ° C.

Example 10: A solution of 8.5 g (30 mmol) of 5-chloro-2-methoxy-4- (4-piperidin-1-yl) phenylacetic acid in 150 ml of 48% hydrobromic acid is refluxed for 15 hours. The reaction mixture is cooled, diluted with water and adjusted to pH 3-4 with saturated sodium bicarbonate solution. It is then extracted with ethyl acetate, the combined organic phases are washed with water, dried over sodium sulfate and evaporated on a high vacuum rotary evaporator. This gives a dark gray foam of 5-chloro-2-hydroxy-4- (piperidin-1-yl) -phenylacetic acid.

Analogously, the 2-hydroxy-4- (4-morpholino) -phenylacetic acid.

Example 11: A solution of 4.03 g (16.0 mmol) of 5-chloro-3-methyl-6- (pyrrolidin-1-yl) -benzofuran-2 (3H) -one in 160 ml of methanol is added under N Atmosphere at room temperature for about 2 minutes with 160 ml of 0.1 N NaOH and stirred for about 60 minutes at room temperature. The solvent is then concentrated and the residue is freeze-dried. There resulted 2- (5-chloro-2-hydroxy-4- (pyrrolidin-1-yl) -phenyl) -propionic acid sodium salt, mp above 200 ° C with decomposition.

In an analogous manner, 2- (5-chloro-2-hydroxy-4-morpholinophenyl) -pro-

4.7. 8th -

74 -

propionic acid sodium salt of melting point above 200 ⁰ C (decomposition).

Example 12: 59 g of 4-methyl-3- (2-methyl-3-oxobutyl) -maleic anhydride and 240 g of dibenzyl ammonium benzoate are refluxed in 1000 ml of benzene with a water separator for 48 hours. It is then evaporated to dryness in vacuo and the residue is chromatographed in methylene chloride on silica gel. The resulting OeI crystallized from isopropyl ether. This gives the 2- (4-dibenzylamino-2-hydroxy-5-methyl-phenyl) -propionic acid dibenzylamide, mp. 140-141 ° C.

The starting material can be prepared as follows:

A mixture of 172 g (0.6 mol) of hydrochloride of 3- (1,2-dicarboxyethyl) -imidazo [1,2-a] pyridine-2 (3H) -one, 65.5 g (0.78 mol) 3-methyl-3-buten-2-one, 220 ml of methanol and 220 ml of water is stirred for 36 hours at room temperature and then evaporated at about 45 ° in vacuo to dryness. The crude product obtained is taken up in 400 ml of glacial acetic acid, admixed with 22.5 g of sodium acetate and refluxed until the CO evolution has ended. The solvent is then removed in vacuo, the residue is treated with a mixture of 225 ml of 6 M sulfuric acid and 225 ml of tetrahydrofuran and heated to reflux for 8 hours. After removal of tetrahydrofuran in vacuo, the reaction mixture is diluted with water and extracted with methylene chloride. The crude product remaining after drying and evaporation of the organic phase is chromatographed on silica gel with petroleum ether / ether. The subsequent distillation

-2 (l00 ° C / 8-10 Torr) gives 4-methyl-3- (2-methyl-3-oxobutyl) -maleic anhydride as a pale yellow oil.

3 Λ 7 8-

75 -

Example 13: 20 g of 2- (4-dibenzylamino-2-hydroxy-5-methylphenyl) -propionic acid dibenzylamide are refluxed in AO ml of 2N hydrochloric acid and 40 ml of glacial acetic acid for 3 hours. It is then evaporated to dryness in vacuo and the residue is partitioned between ether and sodium hydroxide solution. Acidification to pH = 1 with hydrochloric acid and extraction gives the 2- (4-dibenzylamino-2-hydroxy-5-methyl-phenyl) -propionic acid, which is chromatographed on silica gel for purification in methylene chloride, mp. 174-175 ° C. ,

Example 14: 2.3 g (0.01 mol) of 3,5-dimethyl-6- (pyrrol-1-yl) -benzofuran-2 (3H) -one are added with 15 ml of sodium hydroxide solution and 50 ml of ether for 5 minutes shaken. The acid is isolated by adjusting the sodium hydroxide to pH 1 with concentrated hydrochloric acid and extracting with ether.

After recrystallization from isopropyl ether / petroleum ether, the 2- [2-hydroxy-5-methy1-4- (pyrrol-1-yl) -phenyl] -propionic acid, mp. 73-74 °.

The starting material can be obtained, for example, as follows:

A mixture of 19.6 g (0.1 mol) of 4-methyl-3- (2-methyl-3-oxobutyl) -maleic anhydride and 20 g (0.105 mol) of 3-pyrrolinium benzoate in 250 ml of benzene is added during 5 hours heated under reflux at the water separator. The benzene is evaporated in vacuo and the residue partitioned between ether and saturated sodium bicarbonate solution. The crude product remaining after drying and evaporation of the organic phase is chromatographed on silica gel. Elution with diisopropyl ether and subsequent recrystallization

U-3 4 7 8-

76 -

of the pure fractions from isopropyl ether gives the 3,5-dimethyl-6- (pyrrol-1-yl) -3a, 6-dihydro-benzofuran-2 (3H) -one, mp. 116-117 °.

Example 15: A mixture of 9, Og (O, 04 mol) of 3,5-dimethyl-6- (pyrrol-lyl) -benzofuran-2 (3H) -one and 2.4 g (0.045 mol) of sodium methylate in 40 ml Methanol is stirred for 90 minutes at room temperature. The methanol is evaporated in vacuo and the residue dissolved in 100 ml of ether. A solution of 4.5 g (0.057 mol) of acetyl chloride in 25 ml of ether is added dropwise to this solution at 0-5 ° within 30 minutes. It is stirred for 14 hours at room temperature and then washed with water and ice-cold In sodium hydroxide solution. The neutral parts obtained after evaporation of the ether are chromatographed on silica gel with a mixture of methylene chloride / hexane (3: 1). Recrystallization of the eluates from pure hexane gives 2- [2-acetoxy-5-methyl-4- (pyrrol-l-yl) -phenyl] -propionic acid methyl ester, mp 70-71 ° _r.

Example 16: A mixture of 5.5 g (23.8 mmol) of 3,5-dimethyl-6- (pyrrolidin-1-yl) -benzofuran-2 (3H) -one, 1.28 g (23.8 mmol ) Sodium methylate in 40 ml of methanol is stirred for 90 minutes at room temperature. The methanol is removed in vacuo and the residue taken up in 90 ml of tetrahydrofuran. 1.9 ml (26.7 mmol) of acetyl chloride are added dropwise to this mixture at 0-5 ° for 30 minutes. It is stirred for one hour at room temperature, the. Tetrahydrofuran removed in vacuo, the residue taken up in methylene chloride and the organic phase extracted with dilute sodium bicarbonate solution. The crude product obtained after drying and evaporation of the methylene chloride is chromatographed on silica gel with petroleum ether / ether. Distillation of pure fractions in

-2 Kugelrohr 150 ⁰ C / 6 × 10 Torr) to give 2- [2-acetoxy-5-methyl-4- (pyrrolidin-1-yl) -phenyl] -propionsäuremethy! Ester.

Example 17: To a solution of 2.7 g (0.01 mol) of 2- (5-chloro-2-hydroxy-4-morpholino-phenyl) -propan-1-ol in 20 ml of acetone is added with stirring at 15- 2O ° C within 15 minutes, a solution of 3.0 g (0.025

244347 8

- 77 -

Mol) chromic acid added dropwise in 20% sulfuric acid. After addition of 10 ml of methanol is filtered and the filtrate concentrated in vacuo. Now it is adjusted to pH 1-2 with dilute sodium hydroxide solution and extracted several times with ether. After drying and evaporation of the ether, the residue is recrystallized from ether. In this way, 2- (5-chloro-2-hydroxy-4-morpholino-phenyl) -propionic acid of the mp. 198-200 °.

The starting material can be obtained, for example, as follows:

To a suspension of 0.8 g of lithium aluminum hydride (0.02 mol) in 50 ml of abs. Ether under nitrogen atmosphere, stirring and ice cooling at 0-5 ° within 30 minutes 2.7 g (0.01 mol) of 5-chloro-3-methyl-6-morpholino-benzofuran-2 (3H) -one dissolved in 100 ml Section. Ether. The mixture is then stirred for 3 hours at room temperature. By careful dropwise addition of about 10 ml of water under ice cooling, the lithium aluminum complex is decomposed. By means of hydrochloric acid is slightly acidified and extracted 5 times with chloroform. The crude product thus obtained is recrystallized from ethyl acetate. In this way, 2- (5-chloro-2-hydroxy-4-morpholino-phenyl) -propan-l-ol, mp. 176-177 ° isolated.

Example 18: A methanolic solution of 26.9 g (0.10 mol) of 5-chloro-2-methoxy-4-morpholino-acetophenone is added portionwise while stirring with 3.8 g (0.10 mmol) of sodium borohydride and for one hour stirred at room temperature. The methanol is concentrated on a vacuum rotary evaporator and the residue is partitioned between dilute hydrochloric acid and methylene chloride. The organic phases are combined, dried over sodium sulfate and evaporated. The residue is taken up in 60 ml of abs. Methylencblorid and for 2 hours under a nitrogen atmosphere to a mixture of 17.8 g (0.15 mol) of thionyl chloride and 120 ml of abs. Methylene chloride added dropwise. The mixture is then stirred for a further 1 hour, the solvent is concentrated on a vacuum rotary evaporator, and the residue is partitioned between sodium bicarbonate solution and methylene chloride. The organic phases become neutral

2U347 8 -

78 -

washed, combined, dried over sodium sulfate and concentrated. The residue is taken up in 100 ml of abs. Tetrahydrofuran and added to a suspension of 2.4 g (0.10 grams of atom) of magnesium turnings in 20 ml abs. Dropped tetrahydrofuran so that the reaction mixture boils slightly under reflux. The mixture is then boiled for a further 2 hours under reflux. The cooled to room temperature solution is carefully added to about 50 g with abs. Tetrahydrofuran layered dry ice dripped. The reaction mixture is warmed to room temperature, acidified with dilute hydrochloric acid and extracted three times with methylene chloride. The organic phases are washed neutral, combined, dried over sodium sulfate and concentrated on a vacuum rotary evaporator. Recrystallization of the crude product from ethyl acetate / petroleum ether gives 2- (5-chloro-2-methoxy-4-morpholinophenyl) propionic acid of melting point 164-165 °.

Example 19: In a well-vented hood about 27 g (I ₅₁ O mol) of liquid hydrogen cyanide from a pressure bottle with nitrogen in an ice / saline cooled SuIfierkolben. During about 2 minutes, 134.9 g (0.50 mol) of S-chloro-3-methoxy-3-morpholino-acetophenone and 25o mg (2.9 mmol) of piperidine are added. The cyanohydrin formed is diluted after 30 minutes at 0 ° with 100 ml of ether and pressed with nitrogen in 300 ml of concentrated hydrochloric acid, which is cooled with ice / brine and stirred well. The mixture is then saturated with hydrochloric acid gas and then allowed to stand for about 15 hours at room temperature. The crystallized amide is filtered off, washed with water and boiled without purification with 750 ml of 20% aqueous potassium hydroxide solution for 3 hours under reflux. The reaction mixture is cooled, acidified with 6N hydrochloric acid and extracted three times with ether. The ether phases are washed neutral, combined, dried over sodium sulfate and concentrated on a vacuum rotary evaporator. The crude 2-hydroxy-2- [5-chloro-2-methoxy-4-morpholino-phenyl] -propionic acid thus obtained is added portionwise at room temperature to 300 ml of concentrated sulfuric acid. After about 10 minutes of stirring, the reaction mixture

2Λ 43 Λ7 8

- 79 -

Pour 2 kg of ice and extract with ether three times. The ether extracts are washed neutral with water, combined, dried over sodium sulfate and added to the vacuum rotary evaporator. The Rüsskseand is taken up in 700 ml of methanol, treated with 7 g of palladium / carbon and hydrogenated at room temperature. The catalyst is filtered off and the solvent is concentrated on a vacuum rotary evaporator. Recrystallization of the crude product from ethyl acetate / petroleum ether gives 2- (S-chloro-methoxy-morpholino-phenyl) -propionic acid of melting point 164-165 °.

Example 20; A solution of 2.86 g (10.0 mmol) of 5-chloro-2-methoxy-4-morpholino-phenylacetic acid in 50 ml of saturated methanolic hydrochloric acid is refluxed for 12 hours. The reaction mixture is concentrated on a vacuum rotary evaporator and the residue taken up in methylene chloride and washed three times with water. The organic phase is dried over sodium sulfate and concentrated on a vacuum rotary evaporator. The resulting 5-chloro-2-methoxy-4-morpholino-phenylacetic acid methyl ester is added portionwise with vigorous stirring to a mixture of 514 mg (13 mmol) of sodium amide in 60 ml of liquid ammonia. Subsequently, 2.84 g (20 mmol) of methyl iodide are added dropwise. It is stirred for 2 hours' and then evaporated the ammonia. The residue is partitioned between dilute hydrochloric acid and ether. The ether phases are dried over sodium sulphate and evaporated. Recrystallization of the residue from isopropyl ether gives 2- (5-chloro-2-methoxy-4-morpholino-phenyl) -propionic acid methyl ester, mp. 88-89 °.

Example 21: A mixture of 4 g (12.8 mmol) of 5-bromo-3-methyl-6-morpholino-benzofuran-2 (3H) -one, 0.7 g (13 mmol) of freshly prepared sodium methylate in 25 ml of methanol is stirred for 45 minutes at room temperature. The methanol is removed in vacuo and the residue taken up in 50 ml of tetrahydrofuran. To this mixture are added dropwise at 0-5 ° C for 2 hours 1.4 ml (19.7 mmol) of acetyl chloride. After standing at room temperature for 72 hours, the

47 8

80 -

Tetrahydrofuran removed in vacuo and the residue chromatographed on silica gel with petroleum ether / ether. Subsequent recrystallization of the pure fractions from ether / petroleum ether gives 2- (2-acetoxy-5-bromo-4-morpholino-phenyl) -propionic acid methyl ester, mp. 114-115 ° C.

The starting material can be obtained, for example, as follows:

To a mixture of 15 g (0.064 mol) of S-methyl-o-morpholinobenzofuran-2 (3H) -one in 120 ml of chloroform at 0-5 ⁰ C with stirring for one hour, a solution of 11 g (0.069 mol ) Bromine in 50 ml of chloroform. Subsequently, stirring is continued for 30 minutes at room temperature. The reaction mixture is treated with methylene chloride and washed successively with 10% sodium thiosulfate _s dilute Natriurabicarbonatlösung and water. The crude product remaining after drying and evaporation of the organic phase is chromatographed on silica gel with petroleum ether / ether. After recrystallization of the pure fractions from ether / petroleum ether to give the 5-bromo-3-methyl-6 - morpholino-benzofuran-2 (3H) -one of mp. 99-10O ⁰ C.

Example 22: To a solution of 132.9 g (0.759 mol) of 4-methyl-3-nitroanisole in 1.1 liter of methanol is added 12.4 g of palladium on carbon and hydrogenated at room temperature. The catalyst is filtered off and the filtrate is concentrated on a vacuum rotary evaporator. Recrystallization from isopropanol / water gives 3-amino-4-methylanisole, mp. 43-44 °.

A solution of 88.4 g (0.64 mol) of 3-amino-4-methylanisole in 1.4 liters of glacial acetic acid is heated to 106 ° and at this temperature for 30 minutes with 114 g (0.86 mol) of 2 , 5-dimethoxy-tetrahydrofuran. The mixture is then cooled immediately to room temperature and concentrated on a vacuum rotary evaporator. Distillation of the residue in a high vacuum gives the A-methyl-S-ipyrrol-1-yD-anisole, bp. 93-95VO, 4 Torr. R (toluene / ethyl acetate = 10: 1): 0.57.

244347 8-

81 -

A solution of 86.6 g (0.46 mol) of 4-methyl-3- (pyrrol-1-yl) -anisole in 1.5 liters of absolute methylene chloride is cooled to -78 ° with acetone / dry ice. At this temperature, 231.7 g (0.92 mol) of boron tribromide are added dropwise. Subsequently, the cooling bath is removed and the reaction mixture heated to 0 to 5 °, then poured onto 2 liters of ice / water, the methylene chloride phases separated and washed with saturated brine. The aqueous phases are back-extracted twice with methylene chloride. The organic phases are combined, dried over sodium sulfate and concentrated on a vacuum rotary evaporator. Distillation of the residue in a high vacuum gives the 4-methyl-3- (pyrrol-1-yl) -phenol, bp. 1O5-1O7VO, O3 Torr, R (toluene / ethyl acetate = 10: 1): 0.38.

A suspension of 53.4 g (0.31 mol) of 4-methyl-3- (pyrrol-1-yl) -phenol and 53 ₅ g (0.39 mol) of potassium carbonate in 600 ml of absolute acetone are refluxed during 45.7 g (0.39 mol) Crotylbromid added and then boiled for a further 4 hours. The reaction mixture is cooled and diluted with 800 ml of water. The acetone is evaporated on a vacuum rotary evaporator and the residue extracted several times with methylene chloride. The organic phases are washed with water, combined, dried over sodium sulfate and concentrated on a vacuum rotary evaporator. Brief filtration on about 800 g of silica gel with methylene chloride gives 1- [4-methyl-3- (pyrrol-1-yl)] -phenoxy-2-butene as a light yellow oil, R _f (hexane / ether = 9: 1): 0, 45, R (toluene / ethyl acetate = 10; 1): 0.68.

A solution of 60 g (0.26 mol) of l ™ [4-methyl-3- (pyrrol-1-yl)] -phenoxy-2-butene in 170 ml of absolute Ν, Ν-diethylaniline is refluxed for 5 hours cooked. The reaction mixture is cooled, diluted with methylene chloride and acidified with 6N hydrochloric acid. The water phase is separated off and extracted again with methylene chloride. The organic phases are washed neutral, combined, dried over sodium sulfate and concentrated on a vacuum rotary evaporator. Chromatography on silica gel with hexane / ether (9: 1) gives 3- [2-

2-4 Λ 3 4 7 8

- 82 -

Hydroxy-5-methyl-4- (pyrrol-l-yl) -phenyl] -l-butene. R (hexane / ether = 9: 1): 0.17, R (toluene / ethyl acetate = 10: 1): 0.45.

A solution of 26.7 g (0.12 mol) of 3- [2-hydroxy-5-methyl-4- (pyrrol-lyl) -phenyl] -l-butene in 370 ml of acetic anhydride is added with a few drops of pyridine and while Stirred for 2 hours at room temperature. The reaction mixture is poured onto ice and extracted with methylene chloride 3 times. The methylene chloride phases are washed neutral with dilute sodium bicarbonate solution, then with water, combined, dried over sodium sulfate and concentrated on a vacuum rotary evaporator. Filtration on a small silica gel with methylene chloride gives 3- [2-acetoxy-5-methyl-4-pyrrol-1-yl) -phenyl] -1-butene, R (toluene / ethyl acetate = 10: 1): 0.55 ,

A solution of 2 ", 7 g (10 mmol) of 3- [2-acetoxy-5-methyl-4- (pyrrol-1-yl) -phenyl] -l-butene in 40 ml of absolute methylene chloride is extracted with acetone / dry ice cooled to -78 ° and as long as ozone is blown until the blue color no longer disappears, then 2 ml of dimethyl sulphide are added and the cooling bath removed.The reaction mixture is gently concentrated on a vacuum rotary evaporator, the residue is dissolved in 50 ml of ethanol and treated with a solution of 3.7 g (23 mmol) of silver nitrate in 5 ml of water are added dropwise to this mixture over a period of 15 minutes, a solution of 75 ml of 1N potassium hydroxide solution is added, and the heterogeneous mixture is stirred for a further 2 hours.The reaction mixture is filtered and the residue washed with ethanol, the alkaline filtrate is allowed to stand overnight at room temperature and extracted with methylene chloride, the caustic solution is carefully acidified with hydrochloric acid (6n) under cooling, and treated with methylene chloride extracted. The organic phases are washed twice with water, combined, dried over sodium sulfate and concentrated on a vacuum rotary evaporator. Recrystallization from diisopropyl ether / petroleum ether gives 2- [2-hydroxy-5-methyl-4- (pyrrol-1-yl) -phenyl] -propionic acid of mp. 73-74 °.

244347 8

- 83

Example 23 : To 81.1 g (0.5 mol) of 4-methyl-2- (1-methyl-2-propenyl) -phenol at room temperature with stirring for 1 hour 42.6 ml (0.6 mol) of acetyl chloride dripped. Subsequently, the reaction mixture is heated to 100 ° and left for 2 hours at this temperature. After cooling, water is added carefully and extracted with methylene chloride. The organic phase is dried over sodium sulfate and evaporated. Subsequent distillation of the remaining residue (64-7OV4 χ 10 torr) gives 4-methyl-2- (1-methyl-2-propenyl) -phenylacetate as a pale yellow oil.

A mixture of 20.4 (0.1 mol) of 4-methyl-2- (1-methyl-2-propenyl) -phenylacetate and 100 mg (0.4 mmol) of osmium tetroxide in 300 ml of dioxane and 100 ml of water is added during Rested for 30 minutes at room temperature, then added portionwise for 30 minutes with 42.8 g (0.2 mol) of sodium periodate and stirred for one hour. The resulting precipitate is filtered off and washed with dioxane / water (1: 1). The aqueous-organic phase is concentrated in vacuo to about 1 third and extracted with methylene chloride. The oily crude product obtained after drying and removal of the methylene chloride is taken up in 100 ml of acetone and by dropwise addition of a solution of 7.2 g (72 mmol) of chromium trioxide and 6.2 ml of conc. Sulfuric acid oxidized in 40 ml of water. Then 3 ml of methanol and 200 ml of water are added, the acetone is removed in vacuo, the aqueous phase is extracted with ether and the ether solution is extracted 3 times with 10% sodium hydroxide solution. The alkaline aqueous solution is allowed to stand for 3 hours at room temperature, then with conc. Hydrochloric acid to pH 3 and extracted with ether. The OeI obtained after drying and removal of the ether is stirred for 2 hours with 300 ml of saturated methanolic hydrochloric acid. The methanol is then removed in vacuo and the residue is partitioned between ether and dilute sodium bicarbonate solution. The crude product obtained after drying and evaporation of the organic phase is chromatographed on silica gel with methylene chloride. Subsequent recrystallization of the pure fractions from methylene chloride / petroleum ether gives 2- (2-hydroxy-

244347 8-

5-methylphenyl) -propionic acid methyl ester, mp. 104-106 °.

A mixture of 5.8 g (30 mmol) of methyl 2- (2-hydroxy-5-methylphenyl) propionate, 36.5 g (82 mmol) of lead tetraacetate and 150 ml of glacial acetic acid is stirred for 36 hours at room temperature. The glacial acetic acid is removed in vacuo and the residue is mixed with 300 ml of water. The resulting precipitate is filtered off and washed thoroughly with ether. The filtrate is extracted with ether. The combined ether phases are dried over sodium sulfate and evaporated in vacuo. The remaining reddish OeI is taken up in 80 ml of dioxane, admixed with 8.7 ml (106 mmol) of pyrrolidine and boiled under reflux for 5 hours. The dioxane is removed in vacuo and the residue is chromatographed on silica gel with methylene chloride / acetone. Recrystallization of the pure fractions from acetone gives 2- [2-hydroxy-5-methyl-4- (pyrrolidin-1-yl) -phenyl] -propionic acid pyrrolidide, mp 178-180 ".

Example 24; A mixture of 19.6 g (0.1 mole) of 4-methyl-3- (2-methyl-3-oxobutyl) -maleic anhydride and 48.2 g of indolinium benzoate in 52 ml of benzene is refluxed for 6 hours on a water separator. Subsequently, the benzene is evaporated in vacuo and the residue is partitioned between ether and hydrochloric acid. The organic phase is washed with saturated sodium bicarbonate solution and concentrated after drying. The crude 2- [5-methyl-2-hydroxy-4- (indolin-1-yl) -phenyl] -propionic acid indolinylamide thus obtained melts at 176-178 °.

Example 25: 44 g of 2- (4-dibenzylamino-2-hydroxy-5-methylphenyl) -propionic acid dibenzylamide are dissolved in 450 ml of dioxane and mixed with 10 g of palladium on carbon (5%) at room temperature and normal pressure Hydrogen reduced. It is then filtered, the filtrate evaporated to dryness and the residue recrystallized from ethyl acetate. Obtained in this way the 2- (4-amino-2-hydroxy-5-methylphenyl) -propionic acid dibenzylamide, mp. 166-167 °.

2Λ43 Λ7 8-

85 -

3.7 g (0.01 mol) of 2- (4-amino-2-hydroxy-5-methylphenyl) -propionic acid dibenzylamide are suspended in 20 ml of dioxane and stirred at room temperature with 2 ml of 2,5-dimethoxy-tetrahydrofuran and 1.4 ml of 37% hydrochloric acid. After 30 minutes the solvent is removed in vacuo and the residue partitioned between ether and water. The organic phase is washed with saturated sodium bicarbonate solution, dried and evaporated to dryness. The residue is chromatographed on silica gel with methylene chloride. Recrystallization of the pure eluates from isopropyl ether gives 2- [2-hydroxy-5-methyl-4- (pyrrol-1-yl) -phenyl] -propionic acid-dibenzylamide of the mp. 150-151 °.

The starting material can be prepared as follows: 59 g of 4-methyl-3- (2-methyl-3-oxobutyl) maleic anhydride and 240 g of dibenzylammonium benzoate are dissolved in 1000 ml of benzene with a water separator for 48 hours Reflux then boiled is evaporated to dryness in vacuo and the residue chromatographed on silica gel o The resulting OeI crystallized from isopropyl ether. This gives 2- (4-dibenzylamino-2-hydroxy-5-methylphenyl) -propionic acid-dibenzylamide of mp 140-141 °.,

Example 26 Analogously to Example 14, the 2- [2-hydroxy-5-methyl-6- (2,5-dimethyl-pyrrol-1-yl) -phenyl] -propionic acid is obtained.

The starting material can be prepared as follows:

5.3 g (0.03 mol) of 6-amino-3,5-dimethylbenzofuran-2 (3H) -one _s 4.1 g (0.037 mol) of acetonylacetone, 50 ml of benzene and 0.5 ml of glacial acetic acid become 14 Heated under reflux for hours. After cooling, it is washed with water, saturated sodium bicarbonate solution and in hydrochloric acid. Subsequently, the benzene is evaporated in vacuo and the residue is chromatographed over silica gel with methylene chloride. After crystallization of the pure eluates, 3,5-dimethyl-6- (2,5-dimethylpyrrol-1-yl) -benzofuran-2 (3H) -one of mp. 94-95 °.

2U347 8-

86 -

Example 27: 3.0 g (0.01 mol) of 2- (5-chloro-2-methoxy-4-morpholinophenyl) -propionic acid are refluxed in 20 ml of 48% hydrobromic acid for 1 hour. The mixture is then evaporated to dryness in vacuo, the residue dissolved in dilute sodium hydroxide solution, adjusted to pH 1-2 with dilute hydrochloric acid and extracted several times with ether. After drying and evaporation of the ether, the crude acid is obtained, which can be recrystallised from a little ether. In this way, 2- (5-chloro-2-hydroxy-4-morpholino-phenyl) -propionic acid, mp. 198-200 °.

Example 28 Tablets containing 25 mg of active ingredient, for example methyl 2- (5-chloro-2-hydroxy-4-morpholino-phenyl) -propionate or a salt _1, for example the hydrochloride thereof, can be prepared as follows:

Ingredients (for 1000 tablets):

Active ingredient 25.0 g

Lactose 100.7 g

Wheat starch 7.5g

Polyethylene glycol 6000 5.0 g

Talc 5.0 g

Magnesium stearate 1.8 g

demineralised water q.s.

Preparation: All solid ingredients are first driven through a sieve of 0.6 mm mesh size. Then the active ingredient, lactose, talc, magnesium stearate and half of the starch are mixed. The other half of the starch is suspended in 40 ml of water and this suspension is added to a boiling solution of the polyethylene glycol in 100 ml of water. The resulting starch paste is added to the bulk and the mixture is granulated, if necessary with the addition of water. The granules are dried overnight at 35 ° C, driven through a sieve with 1.2 mm mesh size and pressed on both sides concave tablets of about 6 mm in diameter,

2 / U347 8 -

87 -

Example 29 Chewable tablets containing 30 mg of active ingredient, for example 2- (5-chloro-2-hydroxy-4- (pyrrolidin-1-yl) -phenyl) -propionic acid sodium salt or a salt, for example the hydrochloride thereof, can be prepared as follows become:

Composition (for 1000 tablets):

Active ingredient 30.0 g

Mannitol 267.0 g

Lactose 179.5 g

Talc 20.0 g

Glycine 12.5 g

Stearic acid 10.0 g

Saccharin 1.0 g

5% gelatin solution qs _c

/ Preparation: All solid ingredients are first passed through a 0.25 mm mesh screen. The mannitol and lactose are mixed, granulated with the addition of gelatine solution, passed through a sieve of 2 mm mesh size, dried at 50 ^° C. and again forced through a sieve of 1.7 mm mesh size. The active ingredient, the glycine and the saccharin are mixed thoroughly, the mannitol, the lactose granules, the stearic acid and the talcum added, the whole thoroughly mixed and pressed to both sides concave tablets of about 100 mm diameter with breaking groove on the top.

Example 30 Tablets containing 100 mg of active ingredient, for example 2- (5-chloro-2-hydroxy-4-morpholino-phe'nyl) -propionic acid sodium salt or a salt, for example the hydrochloride thereof, can be prepared as follows:

Composition (for 1000 tablets):

Active ingredient 100.0 g

Lactose 248.5 g

3 4 3 Λ 7 8

- 88-

Corn starch 17.5 g Polyethylene glycol 6000 5.0 g

Talc 15.0 g magnesium stearate 4.0 g

demineralised water q.s.

Preparation: The solid ingredients are first forced through a sieve of 0.6 mm mesh size. Then the active ingredient, lactose, talc, magnesium stearate and half of the starch are intimately mixed. The other half of the starch is suspended in 65 ml of water and this suspension is added to a boiling solution of the polyethylene glycol in 260 ml of water. The resulting paste is added to the powdery substances, the whole is mixed and granulated, if necessary with the addition of water. The granules are dried overnight at 35 ° C, driven through a sieve with 1.2 mm mesh size and pressed on both sides concave tablets of about 10 mm diameter with breaking notch on the top,

Claims (28)

invention claim 1. A process for the preparation of phenol derivatives, in particular those of the general formula (D, wherein R is hydrogen or an acyl radical, R ^ carboxy, verester-th carboxy or amidated carboxy, R ₂ is ^F or hydrogen or an aliphatic radical, R ~ represents a di-substituted by two monovalent hydrocarbon radicals, or by a divalent hydrocarbon radical amino group and the aromatic Ring A may additionally be monosubstituted or polysubstituted by aliphatic radicals, hydroxy, lower alkylthio, lower alkanesulfinyl, sulfonyl, halogen, lower alkanoyloxy, lower alkanoyl and / or nitro, and their silanes and isomers; , characterized in that compounds of the formula (II) where X _x , is hydrogen, Xp of R _x . different, functionally modified carboxy and R 'has the meaning of R or wherein X _x . Is hydrogen and Xp together with R form the group ^ C = O, or where X _x together with Xp form the group = C = 0 or the group sC (Hal) ₂ and η η j. i \ M 9. j ϊ> ^ 2U347 07/03/1983 AP C 07 C / 244 347/8 - 90 - 61 577/11 Hal is in each case halogen and R 'has the meaning of R _Q , or the salts thereof are treated with Solvolysemitteln, or in compounds of the formula Il («ι) ^X 3 ^0R O or salts thereof, wherein X represents a convertible into R ₃ radical, X transferred in R _{3 7,} or in compounds of the formula (IV) ₁ wherein X-, one in the group -OR convertible remainder dar-7 o represents the radical X _{7 converted} into the group -0R _Q , or Ver compounds of the formula l0 (V) ^R 3 ^OR o or salts thereof, wherein X _ß and _g are each X is carboxy, and X ₁₀ has the meaning of R _2, wherein X _{Q g} has the meaning of R. X and R ₂ and X ₁₀ is hydroxy, functionally modified hydroxy, by a hydrocarbon radical 244347 07/03/1983 AP C 07 C / 244 347/8 - 91 - 61 577/11 substituted mercapto or secondary amino, wherein Xg has the meaning of R ₁ and X _g and X ₁₀ together oxo, thioxo or optionally substituted hydrazono, or wherein X _{ß has} the meaning of R ₁ and Xq and X ^ ₀ together the groups RX or a tautomeric form thereof is bilcjen and RX is a divalent aliphatic radical, converted by reduction into corresponding compounds of formula (I), or in compounds of the formula ^ • _N / CH-X ₁₁ I A |] (VI) "3 ^0R o or salts thereof in which X _{11 is} an oxidatively convertible radical into R ₁ , X _{11 is} oxidatively converted into R ₁ , or a compound of the formula (VIII) or a salt thereof, wherein X ₁ - is a radical convertible into the group of the formula -GH (Rp) -R ₁ , X _{15 is converted} by rearrangement into the group of the formula -CH (R ₂ JR ₁ , or in a compound of the formula ^X 13 I A H (VII) ^0R o 61 577 11 - 92 - wherein X "- one in the group of the formula -GH (R _O ) -R. (VIIa) 13 2 '1 means convertible radical, or a salt or isomers thereof, the radical X ₁ O is converted into the group of formula (VIIa) and / or, if desired, a salt obtainable according to the invention into the free compound or converted into another salt, a process according to available transferred free compound into a salt or other free compound and / or if desired, a erfindungsgemäß available I3omerengemiach divides its components. 2 «method according to item 1, characterized in that one compounds of formula (II), wherein X _{1 is} hydrogen, Xp of R _{1 is} different functionally modified carboxy and R 'has the meaning of R and wherein XV / asseretoff is and Xp together with R ^ form the group ^ C = O, with a corresponding Solvolysemittel 3Qlvolyaiert. 3. A method for the preparation of compounds of formula I according to item 1, characterized in that a compound of formula II, wherein X _{1 is} hydrogen i3t and X ₂ together with R 'form the group "^ G = O and wherein the ring Λ bi3 R is unsubstituted or monosubstituted or polysubstituted by lower alkyl or is optionally additionally disubstituted by 3- or 4-membered alkylene, R _{2 is} methyl and R is methyl, which is prepared by reacting compounds of the formula R 1 - H (lic), in which IiU has the abovementioned meaning, with compounds of the formula Hb 61 577 11 244347 8 - 93 - (Lib) wherein R _a , R ^ and R _{c are} independently hydrogen, lower alkyl or 3- or 4-membered alkylene, is formed under the reaction conditions. 4. The method according to item 1, characterized by reacting a compound of formula (III), wherein X-, a group of the formula -HH-A ₂ -X ₁ -, wherein X, - OH or reactive, esterified OH, represents, in the A _2, a divalent hydrocarbon radical which may also be interrupted by aza, IJ-Niederalkylaza, oxa or thia, for example lower alkylene, lower alkenylene, lower alkylene interrupted by aza, N-lower alkylaza, oxa or thia or by Aza, N-Hiederalkylaza , Oxa or Thia interrupted aliederalkenylen means, wherein lower alkylene or lower alkenylene may each also be branched and further may additionally in one or two orthoannellierte benzo systems, optionally in the presence of a Ba3e condensed, that one in a compound of formula (III), wherein X, stands for amino, by reaction with a 2,5-di-lower alkoxy-tetrahydrofuran the pyrrole ring R-, introduced or by reaction with 2-butene-1,4-diol or a reactive ver esterified derivative thereof, pyrrolin-1-yl introduced and dehydrated this in Gegenv / kind of a Dehydrierungskataiysators to pyrrol-1-yl R ~ or by reaction with an oxidizing agent and first 61 57711 -93α- closing 1,4-dioxo-butane pyrrol-1-yl R- introduces or by reacting with one in a compound of formula (III) wherein X _{3 is} an R-displaceable group and in the feasible position of X- is a substituent with a strong -I or-M effect Nucleophilic amine Rv-H a corresponding Re3t R ^ einfuhrt directly, or that in a compound of formula (III) wherein Xo and R are each hydrogen, by reaction with an optionally acetylated, with sufficiently nucleophilic amine R ^ -H corresponding radical R 1 is introduced directly. AP C 07 C / 244 347/8 61 577 11 244347 8 - 94 - 5 »method according to item 1, characterized in that in a compound of formula (IV) wherein Xr _{7 is} etherified hydroxy, this is converted by ether cleavage in hydroxy -OR ₀ » A process as claimed in item 1, characterized in that a compound of the formula (V) in which Xg and Xn are each carboxy is decarboxylated, or in a compound of the formula (V) in which X is ₀ hydroxy, functionally modified hydroxy, alkylthio or Dialkylamino means or wherein Xq and X ^ ₀ together oxo, thioxo or hydrazono, with the aid of a reducing agent, the corresponding group of the formula -C - Xq converted into the group of formula ^ CIL (Ro). \ γ Process according to item 1, characterized in that compounds of the formula (VI) in which X.sup.1 is hydroxymethyl, formyl or a group of the formula -CH.dbd.CH-X.sup.1, in which X.sup.1-Z.sup.1 is hydrogen or an aliphatic radical, oxidized with the aid of an oxidizing agent. 8. The method according to items 1 to 7, characterized in that compounds of formula (VIII), wherein X ,., - represents the group of the formula -CO-CHo-Ro and Rp is hydrogen, analogous to Willgerodt-Kindler Rearranges reaction in such compounds of formula (I), wherein R ^ is amidated carboxy or a corresponding ammonium carboxylate and Rp is hydrogen. 07/03/1983 / / O / 7 O AP C 07 C / 244 347/8 L 4 t \ O A / O - 95 - 61 577/11 9. The method according to any one of the items 1 to 8, characterized by reacting compounds of formula (I) wherein R is hydrogen, a lower alkanoyl or Arylniederalkanoylrest, R. carboxy, with an aliphatic or aromatic alcohol esterified carboxy, carbamoyl or R 'represents a saturated and unsubstituted aliphatic radical, R represents an amino group disubstituted by two monovalent aliphatic radicals or an amino group disubstituted by a divalent aliphatic radical and the aromatic ring A additionally by an aliphatic radical, lower alkoxy, Lower alkylthio, lower alkanesulfinyl, lower alkanesulfonyl. Hydroxy, halogen, lower alkanoyloxy, lower alkanoyl and / or nitro mono- or polysubstituted or, except for R ,, may be unsubstituted, and their salts, in particular pharmaceutically acceptable salts, and isomers. 10. The method according to any one of items 1 to 8, characterized by reacting compounds of formula (I) wherein R is hydrogen, lower alkanoyl or Phenylniederalkanoyl, wherein the phenyl radical is mono- or polysubstituted by lower alkyl, hydroxy lower alkyl, halo-lower alkyl, lower alkenyl, May be 3- or 4-membered alkylene, lower alkoxy, lower alkylthio, lower alkanesulfinyl, lower alkanesulfonyl, hydroxy, halogen, lower alkanoyloxy, lower alkanoyl and / or nitro, or unsubstituted or phenyl-lower alkanoyl which is a phenyl-lower alkanecarboxylic acid of the formula (I). 07/03/1983 / O / 7 O AP C 07 C / 244 347/8 AJA / Ο " ⁹⁶ " 61 577/11 wherein R ₂ and R ₃ and the substituents of ring A have the meanings given below and R _{Q is} hydrogen or lower alkanoyl, R _{1 is} carboxy, lower aloxycarbonyl, hydroxy-lower-aloxycarbonyl, lower alkanoyloxy-lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl, phenoxycarbonyl, carbamoyl, N- Mono-, N, N-di-lower alkylcarbamoyl, N-mono- or Ν, Ν-di-phenyl-lower alkylcarbonyl, N-mono-, Ν, Ν-diphenylcarbamoyl, N-lower-alkyl-N-phenyl-lower alkyl-carbamoyl, N-lower-alkyl-N-phenyl -carbamoyl, N-phenyl-lower alkyl-N-phenyl-carbamoyl, lower alkylene-carbamoyl, lower alkenyl-carbamoyl, lower alkylenecarbamoyl, lower alkenylenecarbamoyl, interrupted by monoaza, N "-lower alkylmonoaza, monooxa or monothia, wherein phenyl and phenoxy are each mono- or polysubstituted by lower alkyl , Hydroxy lower alkyl, lower haloalkyl, lower alkenyl, 3- or 4-membered alkylene, lower alkoxy, lower alkylthio, lower alkanesulfinyl, lower alkanesulfonyl, hydroxy, halogen, Lower alkanoyloxy or lower alkenylene may have unbranched or branched and / or one or two ortho-fused benzo systems, R _{2 is} hydrogen or lower alkyl and R, on the one hand Ν, Ν-Di lower alkyl-amino, N-cyclic-lower alkyl-N-lower alkylamino, N-lower-alkyl-N-phenyl-lower alkyl-amino, N, N-di-cycloloweralkyl-lower alkyl-amino, N-cyclo-lower alkyl-N-phenyl-lower alkyl-amino or N, N-diphenyl-lower alkyl-amino; R, on the other hand, each 5 to 8-membered lower alkyleneamino, lower alkenyleneamino, by monoaza, N'-lower alkylmonoaza, AP C 07 C / 244 · 3W8 61 $ ?? 11 - 97 - Monooxa or Monothia interrupted Niederalkylenamino, by Monoaza, N'-Niederalkylmonoaza, Monooxa or Monothia interrupted Niederalkenylenamino or one or two ortho-fused benzo systems having Niederalkylen ~ or Niederalkenylen-amino, wherein Niederalky len or »lower alkenylene be unbranched or branched 4- may contain up to 14, in particular 4 to 7 carbon atoms and / or may have two ortho-fused benzene systems and phenyl or benzo in each case mono- or polysubstituted by lower alkyl, hydroxy lower alkyl, lower haloalkyl, lower alkenyl, 3- or 4-membered alkylene, lower alkoxy, lower alkylthio, substituted lower alkanesulphinyl, lower alkanesulphonyl, hydroxy, Halo.gen, lower alkanoyloxy, lower alkanoyl and / or nitro, or may be unsubstituted, and the aromatic ring A mono- or polysubstituted by lower alkyl, hydroxy-lower alkyl, halo-lower alkyl, lower alkenyl, 3- or alkylene 4gliedriges _t lower alkoxy, lower alkylthio , Lower alkanesulfinyl , Lower alkanesulfonyl, hydroxy, halogen, lower alkanoyloxy, lower alkanoyl and / or nitro, or may be unsubstituted, except for R 1, and their salts, especially pharmaceutically acceptable salts, and isomers. Process according to one of the items 1 to 8, characterized in that compounds of the formula (I) in which R is hydrogen, lower alkanoyl or unsubstituted or more than one phenyl, lower alkoxy, hydroxy, halogen, vinylthioalanoyloxy and / or or trifluoromethyl-substituted phenyl-lower alkanoyl, R, - carboxy, with a lower alkanol, 7.3,1983 AP C 07 C / 244 347/8 - 61 S77 / SL1 a lower alkanol substituted by hydroxy, lower alkoxy, lower alkanoyloxy or phenyl unsubstituted or lower alkyl, lower alkoxy, hydroxy, halo, lower alkanoyloxy and / or trifluoromethyl-containing phenyl, with an unsubstituted or lower alkyl, lower alkoxy. Hydroxy, halogen, lower alkanoyloxy and / or trifluoromethyl-containing phenol esterified carboxy, carbamoyl, by lower alkyl, unsubstituted in the phenyl or lower alkyl, lower alkoxy, hydroxy, halogen, lower alkanoyloxy and / or trifluoromethyl having phenyl lower alkyl monosubstituted carbamoyl, by lower alkyl unsubstituted by in the phenyl part or "Lower alkyl, lower alkoxy, hydroxy, halo, lower alkanoyloxy and / or trifluoromethyl-containing phenyl-lower alkyl, lower alkylene or monoaza, N-alkylated monoaza, monooxa, monothia interrupted lower alkylene disubstituted carbamoyl, R" is hydrogen or lower alkyl, R, a lower alkyl , by in the cycloalkyl part 3- to 7-membered cycloalkyl-lower alkyl, by in the phenyl unsubstituted or lower alkyl, lower alkoxy, hydroxy, halogen, lower alkanoyloxy and / or trifluoromethyl-containing phenyl, by lower alkylene, by lower alkenylene, by aza, N-lower alkylaza, oxa or thia interrupted lower alkylene or lower alkenylene interrupted by aza or N-lower alkylaza disubstituted amino group and the aromatic ring A may additionally be substituted by lower alkyl, lower alkoxy, hydroxy, halogen, lower alkanoyloxy, 3 or 4-membered alkylene and / or trifluoromethyl, and their salts, especially pharmaceutically acceptable salts, and isomers. 244347 07/03/1983 AP C 07 C / 244 347/8 - 99 - '61 577/11 12. Method according to one of the items 1 to 8 _f, characterized in that compounds of the formula " I Λ κ ^K l (Ia), ο 0 wherein R is hydrogen or lower alkanoyl or Phenylniederalkanoyl, which is derived from a Phenylniederalkancarbonsäure of formula (I), wherein the radicals R ₀ . R- .. R. R, and R below 2 3 a * b c R.sup.4 is hydrogen, R.sub.carboxy, niaderalkoxycarbonyl, lower alkanoyloxy-loweralkoxycarbonyl, carbamoyl, Ν, Ν-diphenyl-loweralkylcarbamoyl, loweralkylenecarbamoyl, or loweralkylenecarbamoyl interrupted by monooxa, Rp is hydrogen or loweralkyl, R_ is on the one hand Ν, Ν-diphenyl-lower alkyl -amino or R on the other hand represents in each case 5- to 8-membered lower alkyleneamino, lower alkenylenamino, lower alkyleneamino interrupted by monooxa or lower alkyleneamino or lower alkenylenamino having an ortho-fused benzose system, and / or R, R and R independently of one another represent hydrogen, lower alkyl or halogen, and their salts, especially pharmaceutically acceptable salts, and isomers. 07/03/1983 2 / / O / 7 O AP C 07 C / 244 347/8 4 O 4 / O - 100 - _m 61 577/11 13. Method according to one of the items 1 to 8 _f, characterized in that compounds of the formula (Ia). wherein R is hydrogen or lower alkanoyl, R _{1 is} carboxy, lower alkoxycarbonyl, lower alkylene carbamoyl or oxa-lower alkylene carbamoyl, Rp is hydrogen or lower alkyl, R, di-lower alkyl-amino, dicycloalkyl-lower alkylamino, di-phenyl-lower alkyl-amino, each 5- to S-lower-lower-alkylene-amino , Lower alkenyleneamino, monoaza-lower-alkylene-amino, N'-loweralkylmonoaza-lower-alkyleneamino, monooxo-lower-alkyleneamino, monothio-lower-alkylamino, monoazo-lower-alkenylene-amino or N "-lower-alkyl-mono-alkenoyl, and R, R, R independently of one another are hydrogen, lower-alkyl, lower-alkoxy, hydroxy, halogen, lower alkanoyloxy, 3- or 4-membered alkylene or trifluoromethyl and their salts and isomers, produces 14, Process according to one of the items 1 to 8, characterized in that compounds of the formula (Ia) in which R is hydrogen or lower alkanoyl with up to and with 5 C atoms, R _{1 is} carboxy or lower alkoxycarbonyl with up to and with 5 C Rp represents lower alkyl having up to and including 4 C atoms, R, 5- to 7-membered lower alkyl AP C 07 C / 244 3W8 61 577 11 47 8 - 101 - alkyleneamino, morpholin-4-yl or pyrrol-1-yl. R 1 and R 6 each represent hydrogen and R represents lower alkyl with up to and with 4 C atoms, or halogen up to and with atomic number 351, and their salts, especially pharmaceutically acceptable salts, and isomers. Process according to any one of items 1 to 8, characterized in that 2- (5-chloro-2-hydroxy-4-morpholinophenyl) propionic acid or a salt or isomer thereof is prepared. 16. The method according to any one of items 1 to 8, characterized in that one produces 2- ^ 2 "-hydroxy-5-methyl-4- (pyrrolidin-1-yl) -phenyl7-propionic acid pyrrolidide or a salt or isomer thereof. Process according to any one of items 1 to 8, characterized in that 2- (2-hydroxy-5-methyl-4-morpholino-phenyl) -propionic acid morpholide or a salt or isomer thereof is prepared 18. The method according to any one of the items 1 to 8, characterized by preparing 2- (5-chloro-2-hydroxy-4-morpholinophenyl) -propionate or a salt or isomer thereof. 19. A process according to any of items 1 to 8, characterized in that 2- (5-chloro-2-hydroxy-4-morpholino-phenyl) -propionic acid morpholide or a salt or isomer thereof is prepared. AP C 07 c / 244- 347/8 61 577 11 2U347 8 - 102 - 20. Method according to one of the items 1 to 8, characterized , in that 2- (2-acetoxy-5-chloro-4-morpholino) phenyl) -propionic acid methyl ester or a salt or isomer thereof is prepared. 21. The method according to any one of items 1 to 8, characterized in that one produces 5-chloro-2-hydroxy-4- (piperidin-1-yl) -phenylacetic acid or a salt thereof. 22. A process according to any one of items 1 to 8, characterized in that 2- (5-chloro-2-hydroxy-4- (pyrrolidin-1-yl) -phenyl-propionic acid sodium salt or an isomer thereof is prepared, 23 o Method according to one of the items 1 to 3, characterized in that 2- (5-chloro- 2- hydroxy-4-morpholino-phenyl) -propionic acid sodium salt or an isomer thereof is prepared. 24. The method according to any one of items 1 to 8, characterized by preparing 2- (4-dibenzylamino-2-hydroxy-5-methyl-phenyl) -propionsäibenzylamid or a salt or isomer thereof. A process according to any one of items 1 to 8, characterized in that 2- (4-dibenzylamino-2-hydroxy-5-methyl-phenyl) -propionic acid or a salt or isomer thereof is prepared. 26. The method according to any one of items 1 to 8, characterized by reacting 2- ^ ~ 2-hydroxy-5-methyl-4- (pyrrol-1-yl) -phenyl-7-propionic acid or a salt AP C 07 C / 244 347/8 61 577 11 47 8 - 103 - or I3omere3 thereof. 27. Method according to one of the items 1 to 8, marked; \ '^ net by preparing 2 ~ / 2 * -acetoxy-5-methyl-4: pyrrol-1-yl) phenyl-7-propionate or a salt or isomer thereof. 28. The method according to any one of items 1 to 8, characterized in that one prepares 2- / 2 "-Acetoxy-5-methyl-4- (pyrrolidin-1-yl) -phenyl7-propionate or a salt or isomer thereof. 29. The method according to any one of items 1 to 8, characterized in that one prepares 2 ~ (2-acetoxy-5-bromo-4-morpholinophenyl) -propionsäuremethyle3ter or a salt or isomer thereof » 30. The method according to any one of items 1 to 8, characterized in that one prepares 2- / 2 ~ hydroxy ~ 5-methyl-2- (pyrrolidin-1 ~ yl) ~ phenyl7 ~ propionic acid pyrrolidide or a salt or isomer thereof. A method according to any one of items 1 to 8, characterized by preparing 2- / 5-methyl-2-hydroxy-4- (indolin-1-yl) -phenyl-7-propionic acid indolinyl amide or a salt or isomer thereof. 32. The method according to any one of items 1 to 8, characterized in that one produces 2- / 2 "-hydroxy-5-methy 1-4- (pyrrol-1 yl) -phenyl7-propionic acid dibenzylamide or a salt or isomer thereof.