DE1913742A1 - Tertiary aliphatic amino acids - Google Patents

Description

CIBA AKTIENGESELLSCHAFT, BASEL (SWITZERLAND) .

Case SU 511 / 1-3 / B / E 19 f 37 A 2

Germany

Tertiary aliphatic amino acids. ·

The present invention relates to the preparation of a- (tert-aminophenyl) -aliphatic carboxylic acids of Formula ■

Ή— Hi — C — 0 — OH (I),

wherein R represents hydrogen or a lower alkyl group, Rp is hydrogen or an aliphatic hydrocarbon radical

or cycloaliphatic character _s vie a lower alkyl,. Nisderalkenyl ~ ₅ cycloalkyl, cycloalkenyl, cycloalkyl-lower alkyl or cycloaPfwil'-nisiei ^ iJkylgruppe beaau-'et ^ -i% -ein

"■ '■■' ■. ■ '" Ί

ORIGINAL

Represents phenylene radical, R ^ stands for a lower alkyl, lower alkenyl, hydroxy r-lower alkyl, lower alkoxy-lower alkyl or amino-lower alkyl group and Ru is an optionally substituted hydrocarbon radical of aliphatic, cycloaliphatic or araliphatic character, such as lower alkyl, lower alkenyl, hydroxy -lower alkyl, lower alkoxy-lower alkyl, cycloalkyl, cycloalkenyl, cycloalkyl-lower alkyl., Cycloalkenyl-lower alkyl or aryl-lower alkyl group, where in a tert-amino group of the formula heteroatoms are separated from the nitrogen atom by at least 2 carbon atoms , with the proviso that R ", R ^ and Rj, together contain at least 3 carbon atoms, or functional acid or amino derivatives thereof. ·

The term "lower", when used above, as follows, together with organic radicals, groups or compounds, means that these radicals, groups and compounds contain up to J _s, preferably up to 4 carbon atoms.

A lower alkyl group R to Ru is, for example, a methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-Hexyl, isohexyl, n-heptyl or isoheptyl group .. A lower alkenyl radical is, for example, a vinyl, alkyl, methallyl, 3-butenyl or 1-pentenyl radical. _;

A lower alkoxy-lower alkyl radical R or R ₂ is, for example, a 2-methoxy, 2-ethoxy, 2-n-propyloxy or 2-isopropyloxy-ethyl group or -propyl group or a 3-methoxy- or 3-ethoxypropyl or 4-methoxybutyl group.

An amino-lower alkyl group R- is, for example, an amino-lower alkyl, Lower alkylamino-lower alkyl, di-lower alkylamino-lower alkyl, Niederalkylenamino-lower alkyl- ,, Monoazaniederalkylenamino-lower alkyl-, Monooxa-lower alkyleneamino-lower alkyl or Monothia-lower alkylenamino-lower alkyl, like the u) -amino-, u) -ethylamino-, tJ-dimethylamino-, u> -pyrrolidino-, U-piperidino-, uJ-piperazino-, ς, ί-4-methylpiperazino-, uz-Morphoüno- or uJ-Thiomorpholino-ethyl group, propyl group or butyl group.

A cycloalkyl or cycloalkenyl group R ₂ or R ₂ preferably has 3-7 ring carbon atoms and is optionally substituted by up to 4 lower alkyl groups. Such radicals are, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclo, hexyl or cycloheptyl radicals, which can optionally contain up to 4 methyl groups as substituents, and 2-cyclopropenyl, 1-, 2- or 3-cyclopentenyl, or 1-, 2- or 3-cyclohexenyl radicals, which can optionally have up to 4, preferably up to 2, methyl groups as substituents. A cycloalkyl-lower alkyl or cycloalkenyl-lower alkyl group Rp or R ₂ represents one of the above-mentioned lower alkyl groups

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which preferably contain up to k carbon atoms and which contain one of the above-mentioned cycloalkyl or cycloalkenyl radicals in any position suitable for substitution, preferably on the terminal carbon atom. Such groups are, for example, cyclopropylmethyl, 2-cyclopentylethyl or 3-cyclopentenylmethyl groups.

The phenylene radical Ph, which is the tertiary amino group of the formula (R ^) (Rj,) N- in the 2- or preferably in the 3-position, but mainly contains in the 4-position, is unsubstituted or can optionally in the other positions one or more, preferably one or two, the same or different Carry substituents. These include lower alkyl, e.g. Methyl, ethyl, n-propyl, isopropyl, η-butyl or isobutyl radicals, free, etherified or esterified hydroxyl or mercapto groups, such as lower alkoxy, e.g. methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy or isobutyloxy groups, Lower alkyl mercapto, e.g. methyl mercapto or ethyl mercapto groups, or halogen, e.g. fluorine, chlorine or bromine atoms, trifluoromethyl groups, nitro groups, amino groups, preferably another group of the formula (R ^.) (R ^) N-, such as di-lower alkylamino-, e.g. Dimethylamine-, N-EthyI-N-methylamino-, Diethylamino, di-n-propylamino, diisopropylamino, Di-n-butylamino or diisobutylamino groups, lower alkanoylamino, e.g. acetylamino or pivaloylamino groups, furthermore

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free or functionally modified carboxy groups, such as cyano, Carbamoyl-, di-lower alkyl-carbamoyl-, e.g. dimethylcarbamoyl-, as well as carbo-lower alkoxy, e.g. carbo-methoxy or carbethoxy groups, or free or functionally modified sulfo, such as lower alkylsulfonyl, e.g. methylsulfonyl or ethylsulfonyl, Sulphamoyl or di-lower alkyl-sulphamoyl, e.g. dimethylsulpharaoyl groups.

The phenylene radical Ph preferably represents the 1,3- or 1,4-phenylene radical, as well as a (lower alkyl) -1,3-phenylene- or -1,4-phenylene radical, a (lower alkoxy) -1,3-phenylene or -1,4-phenylene radical, a (mono- or dihalogen) -1,3-phenylene or -1,4-phenylene radical, a (trifluoromethyl) -1. »3-phenylene-- or -1,4-phenylene radical, an (amino) -1,3-phenylene- or -1,4-phenylene radical, or a (di-lower alkyl-amino) -1,3-phenylene or -1,4-phenylene radical ..

An aryl-lower alkyl group R ^. is preferably an optionally substituted phenyl-lower alkyl group in which the aromatic radical can have the substituents mentioned above for the radical Ph and the lower alkyl radical preferably contains up to 4 carbon atoms. Preferred are phenyl (CH) groups in which the phenyl radical For example, it can have the substituents given above for the radical Ph and η stands for an integer from i-4.

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In view of the above, the tertiary amino group of the formula (R ^) (R ₂ I) N- means, for example, N- (N-leather alkyl, lower alkenyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, amino-lower alkyl, lower alkylamino) -lower alkyl, di-lower alkylamino-lower alkyl, lower alkylenamino-lower alkyl, monoaza-lower alkylenamino-lower alkyl, Monooxaniederalkylenamino-lower alkyl or monothia-lower alkylene

lower alkyl) N- (lower alkyl, lower alkenyl, hydroxy-nie-.

deralkyl, lower alkoxy-lower alkyl, cycloalkyl, cycloalkenyl, cycloalkyl-lower alkyl, cycloalkenyl-lower alkyl or phenyl-lower alkyl) amino, in which cycloaliphatic radicals have 3-7 ring members and a phenyl radical has, for example, the substituents indicated for the radical Ph may have, such as N- (methyl, ethyl, n-propyl, isopropyl, allyl, methallyl, 3-butenyl, 2-hydroxyethyl, 2-methoxyethyl, 3-aminopropyl, 2 -Aethylamino-ethyl-, 3-dimethylamino-propyl-, 2-pyrrolidinoethyl, 2-piperazinoethyl or 2-morpholinoethyl) -N- (methyl, ethyl, n-propyl, isopropyl, allyl, methallyl) , 3-butenyl, 2-hydroxyethyl, 2-methoxyethyl, cyclopropyl, cyclopentyl, cyclohexyl, 3-cyclopentenyl, 2-cyclohexenyl, cyclopropylmethyl, 2-cyclopentylethyl, 3-cyclopentenylmethyl, benzyl , 1-phenylethyl, 2-phenylethyl, tolylmethyl, anisylmethyl, chlorophenylethyl, trifluoromethylbenzyl, aminophenylethyl or dimethylaminobenzyl) amino group.

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Functional derivatives of the acids of the formula I are primarily their esters, such as lower alkyl or lower alkenyl esters, Cycloalkyl, cycloalkenyl, cycloalkyl-lower alkyl or cycloalkenyl lower alkyl esters, in which the cycloaliphatic groups contain 3-7 ring members, aryl or aralkyl, e.g. phenyl or phenyl lower alkyl esters, in which the aromatic radicals can have, for example, the substituents given for the group Ph, free or etherified Hydroxy-lower alkyl, e.g. "lower alkoxy-lower alkyl" or cycloalkoxy-lower alkyl esters, in which the cycloalkyl radical contains 3-7 ring members, or tert-amino-lower alkyl esters ^ wherein the tert., - amino group e.g. for a di-lower alkylamino, like dirnethylamino or diethylamino, a lower alkylenamino, such as pyrrolidino or piperidino ,, or a monoaza-lower alkylene, Monooxa-lower alkylene or Monothia-lower alkylene-amino, such as piperazino, 4-lower alkyl piperazino, e.g. 4-methyl piperazino or 4-Aethylpiperazino-, or Morpholino- or thiomorpholino group. In the above esterifying groups the groups preferably have the above meaning; if one of them contains heteroatoms, then are these from each other and from the oxygen atom of the carboxy group by at least 2, primarily by 2-3 carbon atoms separated.

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Further functional derivatives of the acids of the formula I are e.g. optionally substituted amides or Thioamides, such as mono-lower alkyl or di-lower alkyl amides, Phenyl- or phenyl-lower alkyl-amides, in which the aromatic Radicals, for example, have the substituents given for the group Ph can ,, monocyclic lower alkylenamides or monoazaniederalkylen-, Monooxa-lower alkylene or Monothia-lower alkylene amides, also the corresponding thioamides, optionally substituted hydroxyamides (hydroxamic acids), or nitriles, as well as ammonium or metal salts.

Amino derivatives are N-oxides, lower alkyl or phenyl -lower alkyl quaternary ammonium compounds, in which the aromatic ring is e.g. May contain substituents, or acid addition salts.

The compounds of the present invention have valuable pharmacological, especially anti-inflammatory Properties on; based on animal experiments, preferably using mammals, such as rats, as test animals, can be proven. According to e.g. by Winter et al., Proc.Soc.Exptl.Biol. & Med., Vol. Ill, p. 544 (1962), Test method described are the compounds of the present Invention in the form of aqueous solutions or suspensions with the help of gastric tubes to adult, male and female rats at daily doses of from about 0.0001 to about

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0.075 g / kg, preferably from about 0.0005 to about 0.025 g / kg. About one hour later, 0; 0β ml of a 1% aqueous solution of carrageenin is injected into the left hind paw of the test animal. After 3 hours, the volume and / or weight of the edemaic left hind paw are compared with that of the right hind paw. The difference between the two extremities is compared with that in untreated control animals; this comparison serves as a measure of the anti-inflammatory effect of the test compounds. The compounds of the present invention can therefore be used as anti-inflammatory agents in the treatment of arthritic and dermatopathological conditions, and as intermediates in the preparation of other valuable, especially pharmacologically active compounds.

Those compounds of formula 1 are primarily preferred with regard to their anti-inflammatory properties in which R _{1 represents} hydrogen or a lower alkyl group, R "represents hydrogen, a lower alkyl or lower alkenyl group, a 3-7-membered cycloalkyl or cycloalkenyl group stands, as well as a cycloalkyl-lower alkyl or cycloalkenyl-lower alkyl group, in which the cycloaliphatic radical contains 3-7 ring members, ^ Ph denotes an optionally substituted by 1 to 2 lower alkyl, hydroxy, mercapto, _t lower alkoxy ,, Nlederälkylmercapto ,, Trifludrmethyl = *, .. üfi ^ ro-,

908841 / mS ■ '": ■:" ■ ■ - ·

Amino, lower alkanoylamino, carboxy, cyano, carbamoyl, di-lower alkyl-carbamoyl, sulfo, lower alkylsulfonyl, sulfamoyl or di-lower alkyl sulfamoyl groups or halogen atoms or groups of the formula (R - ^) (Ru) N- , such as di-lower alkylamino groups, substituted phenylene radical, R ^ is a lower alkyl, lower alkenyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, amino-lower alkyl, lower alkylamino-lower alkyl, di-lower alkylamino-lower alkyl, lower alkylenamino-lower alkyl, monoaza-lower alkyleneamino-lower alkyl -, Monooxaniederalkylenamino-lower alkyl or monothia-lower alkylene-lower alkyl group, and R ₂ ^ a lower alkyl, lower alkenyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, cycloalkyl, cycloalkenyl, cycloalkyl-lower alkyl, cycloalkenyl-lower alkyl or phenyl -Lower alkyl group in which cycloaliphatic radicals contain 3-7 ring members and a phenyl radical can have, for example, the substituents specified for the radical Ph, where in one (R ^.) (R ₂ ,) N group heteroatoms are separated from the nitrogen atom by at least 2 carbon atoms, with the proviso that the radicals Rp, R ^ and R ₂ together have at least 3 carbon atoms, furthermore the lower alkyl or lower alkenyl esters, 3-7 ring-membered cycloalkyl, cycloalkenyl, cycloalkyl-lower alkyl or cycloalkenyl-lower alkyl esters _a phenyl or phenyl lower alkyl ester, in which the aromatic radical, for example, «through

-009841/1743 .- -. "" ■

the substituents given for the group Ph may be substituted, or hydroxy-lower alkyl, lower alkoxy-lower alkyl, di-lower alkylamino-lower alkyl, lower alkyleneamino-lower alkyl, monoaza-lower alkyleneamino-lower alkyl , Monooxaniederal kyl · · · niederal enaminö-alkyl- or Monothia-niederaikylenamino-lower alkyl, wherein two heteroatoms by at least 1, 2 Kohienstoffatome ä are preferably separated from each other, also their amides, or Mononiederalkyl- Diniederalkylamide, Niederalkylenamide, phenyl or. Phenyl-lower alkylamides, in which the aromatic groups can contain, for example, the substituents given for the radical Ph, or morpho ^ de, ι thioamides, mono-lower alkyl or di-lower alkyl thioamides, Niederaikyl - thioamides, in which the aromatic groups contain, for example, the substituents given for the radical Ph or thiomorphoids, as well as hydroxamic acids, N-oxides, lower alkyl · or (|

Phenyl-lower alkyl-quaternary ammonium compounds, in which the aromatic radical zj.B. may contain the substituents given for the group Ph, or the pharmaceutically acceptable, non-toxic salts of solar compounds. Particularly valuable, primarily because of their anti-inflammatory properties, are the compounds "of the formula I, in which a) represents R, hydrogen or a lower alkyl group, R _? For hydrogen, a lower alkyl or

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a 3-7-membered cycloalkyl group optionally substituted by 1 or 2 lower alkyl groups, Ph is a 1,3- or 1,4-phenylene radical, (lower alkyl) -l, 3-phenylene- or -1,4- phenylene radical, (lower alkoxy) -l, 3-phenylene or -1,4-phenylene radical, (halogen) -1,3-phenylene or -1,4-phenylene radical, (trifluoromethyl) -l, 3-phenylene or ' -1, '4-phenylene radical, or (di-lower alkyl amino) -1,3-phenylene or -1,4-phenylene radical, FL represents a lower alkyl, lower alkenyl, hydroxy-lower alkyl or lower alkoxy-lower alkyl group and R ^ a 3-7-membered cycloalkyl group optionally substituted by one or two lower alkyl radicals or a phenyl-lower alkyl group, in which phenyl can have the substituents indicated for the above-mentioned radical Ph, or in which b) R represents hydrogen or a lower alkyl group, R "represents a 3-7-membered cycloalkyl group which may have up to two _{lower alkyl radicals, and each of the radicals R 1 and R 2 represents} a lower a alkyl group and Ph has the meaning given under a), or in which c) R is hydrogen or a lower alkyl group and each of the radicals Rp, R ₇ . and R ₂ . stands for a lower alkyl radical and Ph has the meaning given under a), or lower alkyl esters, amides, mono-lower alkyl or di-lower alkyl amides, or ammonium, alkali metal or alkaline earth metal salts or pharmaceutically usable, non-toxic acid addition salts of such compounds.

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Particularly noteworthy for their anti-inflammatory properties Properties are compounds of the formula

(Ia)

wherein a) R 'is a hydrogen, a lower alkyl or an unsubstituted, 3-6-membered one Cycloalkyl group means and R

Hydrogen, a lower alkyl, lower alkoxy or trifluoromethyl group or represents a halogen atom, and Ri represents one Lower alkyl and Ri for an unsubstituted, 3-6-membered one Cycloalkyl group or a benzyl group, or in which b) R * is an unsubstituted, j) -6-membered cycloalkyl group

represents, R has the meaning given under a) and each a

the radicals R 'and Ri represents a lower alkyl group, or in which c) each of the groups Rp, R * ^: and Ri represents a lower alkyl group. group, and R. has the meaning given under * a), or the lower alkyl esters, ammonium salts, alkali metal salts or pharmaceutically acceptable ,,, non-toxic acid addition salts thereof. · - · '"■■"' ■■ "-" ^ ■ "" ■■ · - · Particularly, valuable in terms of their anti-

inflammatory properties - si ⁱ Nä- ^; connections of the formdl Ia, in which a.) ■ -Ri.-Was-serstaff ^ 'cxd.er.-ÖlMe-'iyieth-yl ^' - ethyl or Cyclo-

represents propyl group, R represents hydrogen or a chlorine atom

el

stands, R.! denotes a methyl or ethyl group and Ri represents the cyclopentyl or cyclohexyl radical, or in which

b) Ri stands for the cyclopropyl radical, R for hydrogen or £ - a

represents a chlorine atom and each of the groups R 'and Ri represent a methyl or ethyl radical, or in which c) each of the radicals R', Ri and Rl represent a methyl or ethyl group and R represents hydrogen, or the methyl or ethyl esters , Ammonium or alkali metal salts or the pharmaceutically acceptable, non-toxic acid addition salts thereof.

The compounds of the present invention can be prepared by methods known per se, for example by one a) in a compound of the formula

^R 4 ■■ '

(II)

wherein X represents a radical which can be converted into the free or functionally modified grouping of the formula -C (R) (R _p ) -C (= O) -OH, the radical X-. converted into the latter, or b) in a compound of the formula

X ₂ -Ph-CC-OH (III). , ..,. ₍

R ₂
U σ σ η I / I / 4 ι.

ι or in a functional acid derivative thereof, wherein X_ | a radical which can be converted into the group of the formula (R ^ HR ^ N- represents, the remainder Xp is converted into the latter, and, if desired, converting a compound obtained into another compound of the invention.

The radical X ₁ represents, for example, a radical of the formula -C (R) (Rp) -Y ₁ , in which Y, an alkali metal, for example lithium , sodium or potassium, a halogenomagnesium group or a reactive, etherified or esterified hydroxyl group, for example a Lower alkoxy group or a group formed by a strong mineral acid, in particular a hydrogen halide, for example salt or bromine. Hydrogen acid, or a sulfuric acid, or an organic sulfonic acid, such as a lower alkanesulfonic or phenyl sulfonic, for example methanesulfonic, ethanesulfonic or p-toluenesulfonic acid, is an esterified hydroxyl group. Such a starting material is reacted with a reactive derivative of carbonic acid or formic acid, with at most one of the reactants containing a metal atom. The metal or Grignard compounds can be reacted with any suitable, metal-free derivative of carbonic or formic acid, preferably with carbon dioxide or carbon disulfide, but also with a carbonate, e.g. diethyl carbonate or diethyl thiocarbonate, a haloformate> e.g. ethyl chloroformate, tert-butyl ester , -allylester, -2- ,

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methoxyethyl ester, -3-chloropropyl ester, phenyl ester or benzyl ester, with a cyanogen halide, e.g. cyanogen bromide, or with a carbamoyl halide, e.g. diethylcarbamoyl chloride. One reactive esterified hydroxy compound is preferred 'with a metal, such as an alkali metal, e.g. sodium or Potassium cyanide, implemented.

The radical X in a starting material of the formula II can also represent the grouping of the formula -C (R.) (Rp) -Yp, in which Y _{p is} an ammonium group, a hydroxymethyl or borylmethyl group, a formyl group, a l-lower alkenyl group \ represents or lower alkenoyl group, or a carboxycarbonyl group; > In such starting materials, Yp can be converted into a carboxy group using known exchange, oxidation or decarbonylation methods. An ammonium group Yp, for example the trimethylammonium group, can be replaced by a cyano group when the starting material is treated with a metal, such as an alkali metal, for example potassium cyanide. The other groups Yp can, for example, using hydrogen peroxide, heavy metal salts or oxides, for example alkali metal chromates or permanganates, chromium VI or copper (II) salts, for example halides or sulphates, or mercury (II), manganese -IV- or silver oxides, depending on the reagent in safe. or in an alkaline medium, converted into carboxy groups. Decarbonylation of a carboxycarbonyl group Yp is preferably carried out pyrolytically, advantageously in the presence of copper powder. 909841/1743

BATH ORIGINAL

In a starting material of the formula II, X can also be an acetyl group, a halo carbonyl group or a Represent 1-lower alkenyl group. If X stands for the acetyl group, then it can e.g. according to the Willgerodt-Kindler reaction be oxidized with sulfur in the presence of ammonia or a primary or secondary amine, the corresponding Thiocarbamylmethyl grouping is formed. A Starting material in which X, represents a halocarbonyl, e.g., a chlorocarbonyl group, is prepared according to the Arndt-Eistert method treated with an Rp-diazo compound; the thus obtainable diazoketone is made by hydrolysis, alcoholysis, ammonolysis . or aminolysis rearranged. If X, represents a 1-lower alkenyl group, then the corresponding starting material can with Carbon monoxide and water can be reacted under acidic conditions, e.g. in the presence of sulfuric acid.

The group X in a starting material of the formula II can also be a free or functionally modified grouping of the formula-C (R °) (R ₂ ) -CC = O) -OH 'or the formula -CC = Rg) -CC = O ) -OH, in which R, a carboxy or an optionally reactive esterified hydroxyl group, such as a halogen atom, and Rp is a lower alkylidene or, for example, a cycloalkylidene group. These groups are removed or converted using decarboxylation and reduction methods known per se. Pyrolysis, preferably under acidic conditions, is advantageously used as a decarboxylation process

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turns, while the reduction e.g. with catalytically activated or nascent hydrogen, e.g. hydrogen in the presence a nickel, palladium or platinum catalyst, being that of an α-hydroxy acid starting material can also be done with phosphorus and iodine, hydriodic acid or tin (II) chloride.

Furthermore, in a starting material of the formula II, the group X can also represent hydrogen, as well as a metal, such as an alkali metal, for example lithium atom, or a metal group, such as a halogen-magnesium group. Such starting materials can be reacted with a reactive ester of a glycolic acid compound of the formula Y ^ -C (R ₁ ) (Rp) -C (= 0) -0H or a functional derivative such as an ester, an amide or a nitrile thereof. In these compounds, Y ^, stands for a reactive esterified hydroxyl group, such as a halogen, for example chlorine or bromine atom, or an organic sulfonyloxy, for example benzenesulfonyloxy or toluenesulfonyloxy group. The reaction of a starting material in which X is hydrogen can be carried out in the presence of a suitable Lewis acid, for example aluminum chloride.

The group Xp in the starting material of the formula III represents e.g. a reactive esterified hydroxyl group, i.e. a hydroxyl group esterified by a strong acid, e.g., a halogen atom and primarily a fluorine atom;

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by treating the starting material containing such a group with a secondary amine of the formula

) or an alkali metal derivative thereof, X "can be exchanged for the radical -N (R ^) (R _2. ).

The group X - in a starting material of the formula III can also represent a primary or secondary amino group; This can be done by treating the starting material with reactive esterified, ie with strong inorganic or organic acids esterified alcohols of the formula R -, - ΟΗ or R ₁ ^ -OH, for example with aliphatic, cycloaliphatic or araliphatic halides, such as lower alkyl, cycloalkyl or Aryl-lower alkyl halides, for example chlorides, bromides or iodides, can be converted into the group of the formula -N (R ^) (R _2. ). Such an amino group can also be substituted by reductive alkylation, ie reaction with aliphatic or araliphatic aldehydes or ketones in the presence of reducing agents such as formic acid or functional derivatives thereof, or of catalytically activated hydrogen.

Furthermore, X ″ can also be one of the groups of the formula (R-,) (R ₂ ,) N- corresponding. Represent acylamino group, wherein at least one of the radicals R ^. and R ₁ . contains an oxo group in the α-position; the acyl radical can also be an esterified carboxyl, in particular a carbo-lower alkoxy, e.g. carbometh-

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.oxy or carbethoxy group represent. Such a radical can be converted into the group R and / or R ₁ by reduction, for example with selective reducing agents such as borohydride or diborane.

Compounds of the present invention obtainable in this way can be converted into one another in a manner known per se will. For example, free acids can be prepared by treatment with appropriate alcohols in the presence of a strong acid, e.g. Hydrochloric, sulfuric, benzenesulfonic or ρ-toluenesulfonic acid, or esterified with diazo compounds or with thionyl halides, e.g. thionyl chloride, phosphorus halides, e.g. phosphorus tribromide, or phosphorus oxyhalides, e.g. phosphorus oxychloride, be converted into their acid halides. Obtained esters can be hydrolyzed to the free acids or with alcohols in the presence of acidic or alkaline agents, such as mineral acids or complex heavy metal acids, as well as alkali metal carbonates or alcoholates, are transesterified into other esters; by treatment with ammonia or suitable amines esters can be converted into amides.

Acid halides obtained can be mixed with alcohols, ". As well as Ammonia or amines and obtained metal or ammonium salts with aliphatic or araliphatic halides, e.g. Chlorides or bromides, or aliphatic or araliphatic chlorosulfites, thionyl halides, e.g. thionyl chloride,

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Phosphorus pentoxide, phosphorus pentasulphide, phosphorus halides, e.g. phosphorus pentachloride, or phosphorus oxyhalides, e.g. phosphorus oxychlorides or acyl halides, e.g. chlorides, depending on the choice of starting materials and the use of reactants> be converted into esters, halides, anhydrides, amides, thioamides or nitriles.

Amides or thioamides obtained (products of the WiIlgerodt-Kindler reaction) can be used under acidic or alkaline conditions, e.g. by treatment with aqueous mineral and / or carboxylic acids, or alkali metal hydroxides hydrolyzed, as well as alcoholysed or transaminated, further e.g. by treatment with mercury-II-oxide and alky! halides, followed by hydrolysis, be desulfurized. Nitriles obtained can, for example, by treatment with concentrated aqueous or alcoholic acids or alkali metal hydroxides, as well as alkaline hydrogen peroxide hydrolyzed or alcoholized will.

Esters, salts or nitriles obtained which contain at least one hydrogen in the α-position can be used in this Position, e.g. by treating with organic alkali metal compounds, such as phenyllithium, triphenylmethylsodium or Sodium amide or alcoholates, metallized and then with a reactive ester of an alcohol of the formula R, -OH and / or Rp-OH reacted and thus substituted in the α-position.

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Compounds obtained with a primary or secondary amino group can be mixed with a reactive ester a corresponding alcohol, e.g. such as one of the above, reacted or then acylated, e.g. with reactive " functional derivatives of a corresponding acid, such as a Halide, e.g. chloride, or an anhydride. Acyl derivatives obtained can, for example, split using acidic or alkaline hydrolysis agents, phthaloylamino compounds by hydrazinolysis will.

Unsaturated compounds obtained can be obtained by controlled treatment with catalytically activated hydrogen, which is usually unsubstituted aromatic Residues are more easily reduced than corresponding substituted / e.g. halogenated radicals, are hydrogenated.

Compounds obtained can be in the aromatic radical Ph halogenated or nitrated, the latter e.g. by treating with nitric acid and / or nitrate salts under acidic Conditions. Nitro groups can be reduced to amino groups] these can be converted, for example, via the diazonium salts, such as -halides, e.g. in the presence of copper-I halides, convert into halogen atoms. In compounds with phenolic hydroxyl or mercapto groups, these can be e.g. the corresponding phenates with lower alkyl halides, such as chlorides or bromides, sulfates or sulfonates, to be etherified. Phenol ethers obtained can, for example, by treatment with hydrobromic acids and acetic acid, as well as pyri

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Din hydrochloride are split.

A free acid obtained can be converted into a salt in a manner known per se, for example by reaction with an approximately stoichiometric amount of a suitable salt-forming agent such as ammonia, an amine or an alkali metal or alkaline earth metal hydroxide, carbonate or hydrogen carbonate. Salts of this type can be converted into the free acid by treatment with an acid, for example hydrochloric acid, sulfuric acid or acetic acid, until the necessary pH has been reached. \

A compound having a basic group such as an amino group can, for example, by reacting with an inorganic or organic acid or a corresponding anion exchanger and isolating the salt formed Acid addition salts are transferred. An acid addition salt can be treated with a base, e.g. an alkali metal hydroxide, Ammonia or a hydroxyl ion exchanger, can be converted into the free compound. Pharmaceutical Usable, non-toxic addition salts are e.g. those with inorganic acids, such as hydrochloric, hydrogen bromide, Sulfuric, phosphoric, nitric or perchloric acid, or organic acids, in particular organic carboxylic or sulfonic acids, such as ants, vinegar, propion, amber, glycol, milk, apple, wine, lemon, aseorbin, maleic, hydroxymalein, Pyruvine, phenyl vinegar, benzoin, 4-aminobenzoe,

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Anthranil-, ^ -Hydroxybenzoe-, Salicyl-, Aminosalicyl-, Embon- or nicotine, as well as methanesulfone, ethanesulfone, hydroxy ethanesulfone, ethylene sulfone, benzenesulfone, halobenzenesulfone, Toluenesulfonic, naphthalenesulfonic, sulfanil or cyclohexylsulfamic acid, also methionine, tryptophan, Lysine or arginine.

These and other salts, e.g. the picrates, can also be used for cleaning purposes; so can free Acids are converted into their salts, these separated from the raw mixture and then the free compounds from the isolated salts can be obtained. With regard to the close relationships between the new compounds in free form and in ~ _ The form of their salts are in the preceding and in the following under the free compounds or salts appropriate and appropriate optionally 'to understand the corresponding salts or free compounds.

Isomer mixtures obtained can be known per se Way, e.g. by fractional distillation or crystallization and / or by chromatography, into the individual isomers be separated. Racemic products can be resolved into the optical antipodes in a similar manner, e.g. Separation of diastereoisomeric salts, such as fractional crystallization of mixtures of the diastereoisomeric salts with d- or ^ -tartaric acid, or with d-a-phenylethylamine, d-a- (l-naphthyl) -ethylamine or ^ -Cinchonidine, and, if desired,

900841/1743

Release of the free antipodes from the salts.

The above reactions are carried out according to methods known per se, e.g. in the presence or absence of diluents, preferably those that are opposed to the respondents behave inertly and / or be able to dissolve them, if necessary, in the presence of catalysts, condensation or neutralizing agents, in an inert atmosphere, carried out under cooling or heating and / or under increased pressure.

The invention also makes those modifications of the above process, after which a compound formed as an intermediate at any stage is used as a starting material and the remaining stage (s) is carried out with this is (are), or the process is interrupted at any stage, or after which starting materials are formed under the reaction conditions or in the form of salts or reactive Derivatives are used.

According to the method, those are preferably used Starting materials which lead to those compounds of the invention which are described above as being particularly preferred will.

The starting materials used according to the process are known or, if new, can be known per se Manufacture way. So you can get starting materials of the formula II

909841/1743

Compounds of the formula (IU) (R ^) N-Ph-H. According to the Friedel-Crafts method obtained, e.g. by treating them with a halide such as Chloride, an acid of the formula Rp-C (= 0) -OH in the presence a suitable Lewis acid, such as aluminum chloride, or with Hydrochloric acid and formaldehyde, or with phosgene and Treated aluminum chloride. The ketones or acid halides obtained can either be used in the aforementioned Willgerodt-Kindler or Arndt-Eistert reactions, or the ketones can, preferably, to the corresponding alcohols using R-Grignard compounds or sodium borohydride. These alcohols can also by reacting one containing the remainder of the formula (R ^) (Rh) N-Ph Grignard compound with an aldehyde or ketone of the formula R.-C (= 0) -R "can be obtained.

The alcohols thus obtainable can, for example, by treatment with thionyl halides, such as thionyl chloride, or organic sulfonyl halides, such as chlorides, into reactive Esters or, for example, by treatment with a lower alkanol be converted into reactive ethers in the presence of a suitable mineral acid, e.g. with methanol or ethanol in the presence of sulfuric acid; if desired, esters obtained can be prepared, for example, with the aid of alkali metal lower alkanolates be converted into ether. Esters and ethers obtained can, for example, be treated with magnesium, zinc and mercury

909841/1743

and / or alkali metals, and, if desired, metallize Grignard compounds, starting materials having a group Y ₁ can be obtained.

Compounds with a group Y _p can be obtained, for example, if the above-mentioned metal derivatives are treated with formyl and oxalyl halides, e.g. chlorides, furthermore by reacting an above-mentioned ketone of the formula (R ^) (Rk) N-Ph- C (= O) -Rp with an R -halomagnesium compound and dehydrating an alcohol formed, for example by treatment with sulfuric or hydrochloric acid and / or acetic anhydride; a methylene compound obtained can then be reacted with a borane compound or a dilute mineral acid and, if desired, traces of a peroxide, for example benzoyl peroxide, a desired hydroxymethyl or borylmethyl compound being obtained.

Starting materials of the formula II, in which Yp represents a formyl group, can be prepared from ketones of the formula (R-,) (R ₂ ,) N-Ph-C (= 0) -Rp by reaction with dimethylsulfonium methylide or dimethyloxysulfonium methylide (obtained from corresponding trimethylsulfonium salts) and Rearrangement to the aldehydes of the ethylene oxide compounds thus formed can be obtained by treatment with Lewis acids, for example ρ-toluenesulfonic acid or boron trifluoride. These aldehydes can also be used with the

Produce Darzens Reaction by taking the above mentioned ketones

008841/17 * 3

with α-haloalkane or ct-haloalkenecarboxylic acid esters in Presence of alcoholates, such as alkali metal lower alkanolates, e.g. potassium tert-butoxide, treated, the glycidic acid esters obtained saponified and the free acids then rearranged and decarboxylated, preferably in an acidic medium, e.g. Sulfuric acid.

Furthermore, starting materials of the formula II with the free or functionally modified groupings of the formulas -C (R °) (R ₃ ) -C (= 0) -OH and -CC = Rg) -CC = O) -OH according to the

• Friedel-Crafts Method can be obtained by making compounds of formula (R ^) (Rh) N-Ph-H and oxalyl halides, e.g.

'-chloride, used. The phenylglyoxylic acid esters formed are reduced using an Rp Grignard reagent; if desired, the resulting alcohol can be dehydrated will. They can also be obtained after the ando reaction, by mixing mesoxalic acid esters in the presence of tin-IV-chloride attaches to the above-mentioned tert-aniline compounds; the adduct obtained can then either be hydrogenated, the resulting adduct Malonic acid ester metallized and with a reactive Esters of a compound of the formula Rp-OH are reacted or saponified and decarboxylated. The corresponding nitriles can also be obtained from the above Friedel-Craffcs ketones by the cyanohydrin method; if wanted, the products can be hydrolyzed and / or dehydrated.

009841/1741

■■ '■■■' ■■■ · ■. 29 - 1113742

Starting materials of the formula III can be obtained by the process a) described above, using starting materials of the formula II in which the tertiary amino group of the formula (R ^) (R ^) N- can be converted into this Remainder Xp is replaced. An amino group Xp with a hydrogen atom can, if desired, be acylated, for example by treating such a starting material with a corresponding acid halide or anhydride, such as a lower alkane, hydroxy-lower alkane, lower alkoxy-lower alkane, amino-lower alkane, ' cycloaliphatic -substituted lower ^ 'alkane or aryl-lower alkane-carboric acid halide, such as acetic acid, glycolic acid, cyclopentylcarboxylic acid or benzoic acid chloride. ■ '---. ■ "· ^: ■

Intermediates obtained by the above procedures and starting materials can be according to those described for the end materials Procedures can also be converted into one another. ■■

The .pharmakolögisch usable compounds of the vo-rmation contained herein invention may be ^1, for example, 'also be used the preparation of pharmaceutical preparations which they "together or in admixture with inorganic' for containing solid or 'liquid or organic, pharmaceutically acceptable carriers suitable for enteral to .-or pärenteralen administration suitable Such Trägerstof f e ^ sinä- Sübstanzeihi, "the * with äeh ^Ver; ^ bindüngen "the invention not ^r in'fte'aktion tr'et'eh'v like Mäe ¥ y

Gelatin, sugar, such as milk, grape or fruit sugar ^ starches, such as corn ,. Wheat, rice or arrowroot starch, stearic acid and salts thereof, for example magnesium or calcium stearate, talc, vegetable oils and fats, gum, alginic acid, benzyl alcohols, glycols, polyglycols and other known carriers. The preparations can be in solid form, for example as tablets, coated tablets, capsules or suppositories, or in liquid form, for example as solutions, suspensions or emulsions. They can be sterilized and / or auxiliary materials, e.g. Preservatives, stabilizers, wetting agents or emulsifiers ^ solubility promoters. Salts to regulate the _; osmotic pressure and / or buffer included. She. can also contain other therapeutically valuable substances. The present pharmaceutical preparations, which also represent an object of the present invention, are produced in a manner known at .s4.cn and contain from about 0.1 $ to about 75 $ j *, in particular from about. $ 1 to about $ 50 of the. Active ingredient * .-- '. . ν.; -;., - - .. ■ - ■ - - - ■ _ ■ ", -_,, ..... ·

"* ■ - -The: the following examples serve., To. Illustrate the Invention. Temperatures are given in degrees Celsius.

Example 1:

A solution of IO g ¹ I - dimethylamino-phenylacetic acid -ethyl ester hydrochloride in the minimum amount of water is with. a 5-n. aqueous sodium hydroxide solution made basic. The mixture is extracted with ether, the organic extract is dried and filtered and the piltrate is added dropwise with stirring to a mixture of 500 ml of liquid ammonia, 1.26 g of sodium and a crystal of iron (III) nitrate nonahydrate. The mixture is stirred for one hour and then 6.9 g of methyl iodide are added dropwise. After stirring for 2 hours, 7 g of ammonium chloride are added; one lets
evaporate the ammonia and take the residue in a
25% aqueous sodium hydroxide solution, which is refluxed for 24 hours and then adjusted to a pH of about 4.5 with 3N hydrochloric acid. The mixture is with
Ether extracted; the organic extract is dried, j filtered and evaporated, and the residue is recrystallized from a mixture of ether and petroleum ether. The α- (4-dimethylamino-r-phenyl) propionic acid is thus obtained
formula

which melts at 128-130 °.

000041/1741

The starting material can be obtained as follows: A mixture of 50 g of 4-dimethylamino-acetophenone, 150 ml of morpholine, 9 g of sulfur and 2 g of ρ-toluenesulfonic acid is refluxed for 15 hours, then evaporated under reduced pressure and the residue from acetone recrystallized. The 4-dimethylamine-phenylthioacetic acid-morpholide obtained in this way melts at 138-14-0.

A solution of 21 g of 4-dimethylaminophenylthioacetic acid morpholide in 200 ml of concentrated hydrochloric acid is refluxed for 2 hours, then under reduced pressure evaporated. The residue is in 75 ml of a saturated, Ethanolic hydrogen chloride solution added and that The mixture was refluxed for 15 hours, then evaporated under reduced pressure. The residue is in water taken up, the aqueous solution is washed with ether and made basic with an aqueous sodium hydroxide solution and extracted with ether. The organic extract is dried and filtered and the filtrate is treated with gaseous hydrogen chloride. The precipitate obtained is filtered off and the ethyl 4-dimethylaminophenylacetate hydrochloride is obtained, 132-134 °.

41/17 * 3

Example 2;

A mixture of 3> 8 g of α- (4-nitrophenyl) propionic acid, 100 ml of 80% aqueous ethanol, 75 ml of 40% formaldehyde and 1 g of the above palladium-on-carbon catalyst is hydrogenated under normal conditions; after about 2 hours the theoretical amount of hydrogen has been absorbed. The mixture is filtered and the filtrate is evaporated under reduced pressure. The residue is in a 1-n. aqueous sodium hydroxide solution and added with 1-n. Hydrochloric acid adjusted to pH 4.0-4.5, then extracted three times with 200 ml of chloroform each time. The combined organic extracts are dried, filtered and evaporated and the residue is recrystallized from a mixture of methylene chloride and ether. This gives α- (4 ~ dimethylaminophenyl) propionic acid, mp 128-130 ⁰ ; the product is identical to the compound obtainable by the procedure of example 1.

Example 3 »

A solution of 10 g of a- (4-N-acetyl-N-methylaminophenyl) propionic acid ethyl ester in 60 ml of tetrahydrofuran is added dropwise over one hour to 6j ml of a 1-n. Added borohydride solution in tetrahydrofuran, which is kept under a nitrogen atmosphere during the addition

stirred and cooled in an ice bath. The reaction mixture is slowly heated up and refluxed for one hour. After cooling, add 50 ml of a saturated ethanolic hydrogen chloride solution j the mixture is refluxed for one hour, then evaporated under reduced pressure. The residue takes A one in 50 ml of a saturated ethanolic hydrogen chloride, The solution refluxes again for one hour and evaporated under reduced pressure. Take the arrears, it is dissolved in 50 ml of water and the mixture is extracted with ether and methylene chloride. The combined organic extracts are dried, filtered and evaporated and the residue is distilled.-The fraction boiling at 148 ° .Provides ethyl a- (4-N-ethyl-N-methylaminophenyl) propionate the formula

represent.

The starting material can be prepared as follows: · ·

A mixture of 5000 ml of anhydrous ethanol and 1000 g of ^ -amino-phenylacetic acid is stirred and . Refluxing dry gaseous hydrogen chloride

% t

-5t -Jr; "·

passed through for 5½ hours. After stirring for 4 hours and The mixture is boiled at reflux and cooled at 10 for 1 hour filtered. The filter residue is covered with cold absolute Washed ethanol and dissolved in 8000 ml V / water; one gives a 50 $ aqueous sodium hydroxide solution in Add 50 ml portions until the mixture is made basic is. After stirring for one hour at room temperature, the precipitate obtained is filtered off and washed with water and gives the ethyl 4-aminophenylacetate, P. 47-49 °,

A solution of 200 g of 4-aminopheny / acetic acid ethyl ester in 250 ml of Essagsäureanhydrid is for 10 minutes left to stand, poured out into 1500 ml of ice and water. The precipitate obtained is filtered off and, after washing with water, gives the ethyl 4-acetylaminophenylacetate, P. 75-78 °.

A mixture of 170 g of ethyl 4-acetylaminophenylacetate and 2.5 ml of ether is added within 25 minutes and with stirring to a mixture of 20.38 g of sodium, 2000 ml of anhydrous ammonia and a few crystals of ferric nitrate nonahydrate given, followed by a mixture of 120.28 g of methyl iodide and 50 ml of ether; the latter becomes drop by drop added within 20 minutes. After stirring for one hour, 50 g of ammonium chloride are added; the mixture becomes evaporated and the residue taken up in ether and a dilute aqueous sodium hydroxide solution. The basic solution

• solution is extracted with ether; the combined organic solutions are evaporated and the residue is recrystallized from a mixture of ether and petroleum ether. The main product obtained is a- (4-N-acetylaminophenyl) propionic acid ethyl ester, melting point 84 ° -86 °. The organic mother liquor is evaporated and the residue is distilled; the fraction boiling at 123-128 ° / 0.15 mm Hg represents the ethyl α- (4-N-acetyl-N-methylaminophenyl) propionate obtained as a by-product.

Example 4; . - .- ■■

Following the methods illustrated in the examples above, using equivalent amounts of the appropriate Starting substances made the following compounds will:

α- (4-dimethylaminophenyl) -α-vinyl acetic acid; . a-Cyclopropyl-a- (4-diethylaminophenyl) acetic acid; ß-Cyclopropyl-a- (4-di-n-butylaminophenyl) propionic acid; α- [3-di (2-hydroxyethyl) aminophenyl] propionic acid; 4-N-methyl-N-cyclohexyiamino-phenylacetic acid ethyl ester; α- (4 ^ dimethylamino-3-methoxyphenyl) propionic acid; a- (4-sec-butyl-3-diethylaminophenyl) propionic acid; 4-N- (2-methoxyethyl) -N-methylaminophenylacetic acid; '"α- [4-N- (3 -Dimethyl amino -propy I) -N -methyl amino -phenyl J -propion- -

acid; "

Ö0984 1/1743

r- 37 r-

α- (4-N-Benzyl-N-methylamino-3-chlorophenyl) propionic acid;

4-N-allyl-N-methylaminophenylacetic acid;

3-N-Cyclopentyl-N-ethylamino-4-methoxyphenylacetic acid; α- (i | —Di-n-propylamino-3-trifluoromethyl-phenyl) -propionic acid; α- (3-Amino-4-dimethylaminophenyl) propionic acid;

α- (3-acetylamino-4-dimethylaminophenyl) propionic acid; "

4-cyano-3-N-methyl-N- (2-phenylethyl) -amino-phenylacetic acid; α- (3-Chloro-4-dimethylaminophenyl) -a-cyclopentylacetic acid.

Example. 5: - ■ ·.

Tablets, each containing 0.05 g of the active ingredient, are produced as follows:
Composition (for 10,000 ^tablets!):

α- (4-Dimethylaminophenyl) propionic acid 500 g

Milk sugar - I706 g

Corn starch 90 g

Polyethylene Glycol (6000) "90 g

Talc (powder). . 90 g

Magnesium stearate 24 g

purified water 'q.s.

The powdery substances are passed through a sieve with Openings of 0.6 mm driven. The a- (4-dimethylaminophenyl) propionic acid, the milk sugar, the talc, the magnesium stearate and half of the corn starch are mixed in a suitable blender. The other half of the Corn starch is suspended in 45 ml of water and the suspension to the boiling solution of the polyethylene glycol in 180 ml of water given. The paste obtained is used to granulate the powder mixture, adding another if necessary Amount of water added. The granulate is dried for 16 hours at 35 °, through a sieve with openings of 1.7 mm driven and processed into tablets, using concave punches with a diameter of 7 * 1 MQ, their upper ones are provided with a device for embossing a breaking groove.

Example 6;

Tablets, each containing 0.01 g of the active ingredient, are produced as follows:
Composition (for 10,000 tablets):

α- (4-N-Ethyl-N-methylamino-phenyl) -propionic acid ethyl ester 100 g

Milk sugar * 1157 g

Corn starch '75 g

Polyethylene glycol (6000) - 75 g-

909841 / $ 174 '

Talc (powder). 75 g

Magnesium te ar at ... l8 g

purified water q.s.

The granulate is made according to the procedure shown in Example 5 produced through a sieve with openings of 1.7 mm in diameter driven and processed into tablets, using concave punches with a diameter of 6.4 mm, the top of which are provided with a device for embossing a break groove.

909841 / $ 174

Example 7?

A mixture of 5 g of ethyl a- (4-N-ethyl-N-methylaminophenyl) propionate and 100 ml of 50 # aqueous sodium hydroxide is refluxed for 6 hours, cooled and washed with ether, then adjusted to pH 5.5 with hydrochloric acid and extracted with ether. The organic extract is dried and evaporated; the residue is crystallized from hexane and so the; a- (4-N-Ethyl-N-methylaminophenyl) propionic acid the formula

0Ή-COOH

P. 65-67 °.

909841/1743

Claims (4)

Claims; 1, compounds of formula % \ \ ^l Il IF — Ph— CJ-CH-OH (I) wherein R _{1 is} hydrogen or a lower alkyl group and; R _{2 represents} hydrogen or a hydrocarbon radical aliphatic or cycloaliphatic in character, Ph represents a phenylene radical, R represents a Nlederalkyl-, Niederalke-. nyl, hydroxy-lower alkyl, lower alkoxy'-lower alkyl or amino-lower alkyl group and R _{2 is} an optionally substituted hydrocarbon radical aliphatic, cycloaliphatic or araliphatic in character where in a tert -amino group of the formula (R ,) (R ^) N heteroatoms i are separated from the nitrogen atom by at least 2 carbon atoms, with the proviso that _{R? J} R, and Rh together contain at least 3 carbon atoms. 2. Functional acid or amino derivatives of the claim 1 connections shown. 3 · Compounds of the formula I according to claim 1, wherein a) represents R, hydrogen or a lower alkyl group, R "represents hydrogen, a lower alkyl or gin # - if appropriate '9 0 98 ^ 1/174 3 3-7-membered cycloalkyl group substituted by 1 or 2 lower alkyl groups, Ph a 1,3- or 1,4-phenylene radical, (lower alkyl) -1, 3-phenylene or -1,4-phenylene radical, (lower alkoxy) - 1,3-phenylene or -1,4-phenylene radical, (halogen) -1,3-phenylene or -1,4-phenylene radical, (trifluoromethyl) -l, 3-phenylene or -1,4-phenylene radical, or ( Di-lower alkylamino) -1,3-phenylene or -1,4-phenylene radical, PL represents a lower alkyl, lower alkenyl, hydroxy-lower alkyl or lower alkoxy-lower alkyl group and R. is an optionally substituted by 1 or 2 lower alkyl radicals, 3 -7-glie ^dr strength cycloalkyl group or a phenyl-lower alkyl wherein phenyl may have the substituents given for the above-mentioned radical Ph, or in which) R b represents hydrogen or a lower alkyl group, R _p * is an optionally substituted up to 2 lower alkyl groups having, 3 -7-güedrige cycloalkyl group and each of the "radicals R ^ and R ₂ , stands for a lower alkyl group and Ph is the ge under a) ^{given: has} meaning, or in which c) R stands for hydrogen or a lower alkyl group and each of the radicals R-, R ^, and Rh stands for a lower alkyl radical and Ph has the meaning given under a). ■ 4. The lower alkyl esters, amides, mono-lower alkyl or Di-lower alkyl amides, or ammonium, alkali metal or alkaline earth metal salts or pharmaceutically usable, non-toxic acid addition salts of compounds according to claim 3 · 90384 1 / t "7 4 3 ''''" * ^; ' ^ ¹ 5. Compounds of the formula (Ia) where a) R * is a hydrogen, a lower alkyl or an unsubstituted, 3-6-membered cycloalkyl group and R is hydrogen, a lower alkyl, lower alkoxy or trifluoromethyl group or a halogen atom and Rl for a lower alkyl and Ri for an unsubstituted one, 3-6-membered cycloalkyl group or a benzyl group, or in which b) R * is an unsubstituted, 5-6-membered cycloalkyl group represents, R has the meaning given under a) and each a * * the radicals R 'and Ri represent a lower alkyl group, or wherein e) each of the groups Rl, R ^ and Ri represent a lower alkyl group and R has the meaning given under a). el 6. The lower alkyl esters, ammonium salts, alkali metal salts or pharmaceutically acceptable, non-toxic acid addition salts of the compounds according to claim 5 90 9841 / T7 43 7 · Compounds of the formula Ia according to claim 5> wherein a) R 'is hydrogen or a methyl, ethyl or cyclopropyl group R represents hydrogen or a chlorine atom stands, Rl denotes a methyl or ethyl group and Ri denotes the -Cyclopentyl- or Cyclohexylrest, or in which b) Ri stands for the cyclopropyl radical, R for hydrogen or a d. ■ a Is chlorine atom and each of the groups R 'and Ri is a methyl or Represent an ethyl radical, or in which c) each of the radicals Rp, R * and Rl! a methyl or ethyl group and R for j ^ a Hydrogen stands. 8. The methyl or ethyl esters, ammonium or alkali metal salts or the pharmaceutically acceptable, non-toxic ones Acid addition salts of the compounds according to claim 7 9 · et- (4-dimethylaminophenyl) propionic acid. 10. a- (A-N-Aethyl-N-methylamino-phenyl) -propionic acid ethyl ester. 11. Pharmaceutically acceptable salts of the compound of claims 1, 2, 9 and 10. 09.841 / 1743 Hs 12. Pharmaceutical preparations containing compounds of claims 1-11. 13.. Process for the preparation of compounds of formula 3 \, I Η Ν— Ph— C — 0 — OH (I) where R, is hydrogen or a lower alkyl group and R is hydrogen or a hydrocarbon radical of aliphatic or cycloaliphatic character, Ph is a phenylene radical, R ^ is a lower alkyl, lower alkenyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl or amino-lower alkyl group and R ₂ denotes an optionally substituted hydrocarbon radical of aliphatic, cycloaliphatic or araliphatic character, with N heteroatoms being separated from the nitrogen atom by at least 2 carbon atoms _{in a tertiary amino group of the formula (R ^) (R 2 I), with} with the proviso that Rp, R- and R ₂ together contain at least 3 carbon atoms - or functional acid or amino derivatives thereof, characterized in that a) in a compound of the formula 909841W7 * 41 ν ^; ' (II) where X, one modified to the free or functionally Grouping of the formula -C (Rj (R J-C (= 0) -OH) convertible Represents the radical, the radical X, converted into this grouping, or b) in a compound of the formula R, 0
I ¹ Il. X - Ph - C - C - ^ - OH (III) or in a functional acid derivative thereof, wherein Xp a radical which can be converted into the group of the formula (Rj (Ru) N- represents, the remainder X "converted into this, and, if desired, a received "connection into another of those defined above converted, and / or, if desired, a compound obtained into a salt or a salt obtained into the free compound converted, and / or, if desired, separating a mixture of isomers obtained into the individual isomers. 9098 41/1743