PL93900B1 - Method of preparing piperidine derivatives or salts thereof[su593666a3] - Google Patents

Description

The subject of the invention is a process for the preparation of new piperidine derivatives of the general formula I, in which R t is a phenyl group that is once or twice substituted, R2 is a 2-keto-imidazolidinium-1 group, a -2-keto-3-methylimidazolidinium-1 group or the 2-ketosahydropyrimidinyl-1 group, R4 represents a hydrogen atom or a lower alkyl group, and the symbol n represents a number from 1 to 4, and the salts of these compounds. monosubstituted, for example, a phenyl residue substituted with aliphatic hydrocarbyl residues, preferably lower aliphatic hydrocarbyl residues, which may also contain substituents. An example of such optionally substituted lower hydrocarbon aliphatic residues are lower alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycanbonylaminoalkyl, and acetylaminoethenyl groups. The substituent of the phenyl group R! it may be a hydroxyl group, optionally substituted with a particularly etherified lower aliphatic hydrocarbyl radical, which in turn may also be substituted. Examples of such groups are lower alkoxy, alkenyloxy, alkynyloxy, alkoxyalkoxy, alkylthioalkoxy, aralkoxy groups such as phenylalkoxy, e.g. - a lower alkylthio group, acylamino, cyano, amlin, nitro and / or halogen atoms. Further substituents of the phenyl group R 1 may be optionally substituted carbonyl groups, e.g. N, N -alkylenecarbanyl. The substituent for the phenyl group Rj may also be a ureido group, optionally a substituent. Particularly suitable substituents for the phenyl group Rt are optionally substituted carbonyl alkoxycarbonylaminoalkyl groups, lower alkoxy alkoxy, acylaminoethenyl, lower alkylthioxy, alkoxy , especially acylbamino groups, lower alkoxy, alkanyl, alkenyloxy groups and halogen atoms. The lower groups are considered to be residues with up to 7, preferably up to 4 carbon atoms. The lower alkyl group is eg methyl, ethyl, n-propyl groups , isopropyl, straight or branched, butyl, pentyl or hexyl groups, bound at any position. A lower alkoxy group is a group containing up to 7, preferably up to 4, atoms in the alkyl portion. carbon, wherein the alkyl group is as defined above. Examples of such lower alkoxy groups are: methoxy, ethoxy low, n-propoxy, isopropoxy, n-butoxy or n-anyloxy. Two lower alkoxy groups, especially adjacent ones, can be linked to each other to form a lower alkylene dioxyl group, e.g. methylenedioxyl. Examples of lower alkenyl groups are: vinyl, propenyl, allyl or methyl or allyl. Examples of lower alkenyl xyl groups are: allyloxy, methyl allyl xyl or propenyloxy. Lower alkoxyalkyl groups are, for example, those which contain up to 7, preferably up to 4, carbon atoms in the alkyl part, for example methoxymethyl, ethoxymethyl, n -propoxy-methyl, n-butoxymethyl, 2- (n-butoxy) ethylene, 3- (n-propoxy) propyl, especially 2-methoxyethyl. "20 Lower alkoxyalkoxy groups are, for example, those which contain up to 7, preferably up to 4, carbon atoms in the alkyl portion, the alkyl group having the meaning given above. Examples of such groups are: methoxymethoxy, 1-methoxyethoxy, 4-methoxy-nH-butoxy, 3-methoxy-n-butoxy, especially 3-methoxy-n-propoxy, 2-methoxy-n-butoxy, and 2-eltolxy-ethoxy. (The lower alkynyl group is primarily the 30 group. propargyl and lower alkynyloxy group propargyloxy group Alkanoyl groups are primarily lower alkanoyl groups, such as propionyl or butyryl, especially acetyl. there are, for example, those in which the alkyl moiety has the meaning given above, for example ethylthiol, isopropylthiol, nJ-butylthiol and especially methylthiol. For example, groups containing up to 7, preferably up to 4, carbon atoms are present in the alkyl portion. Examples of such groups are: methylthioethyl, 2-ethylthioethyl, 3-methylthio-n-propyl and especially 2-methylthioethyl. andNischranium alkylthoalkoxy groups are, for example, groups having up to 7, preferably up to 4 carbon atoms on the alkyl portion. Examples of such groups are: methylthiomethoxy, 2-ethylthioethokisyl, 3-methylthio-n-propoxyoyl, and in particular 2-meitythylthiioetoxyl. The lower hydroxyalkyl groups are mostly containing not more than 7, preferably at most 4 carbon atoms and whose gjnupa ajLkdljoiwta is meaningful above. Examples of such groups are: 2-hydroxyethyl, 3-hydroxy-n-propyl, and in particular hydroxyimethylol. Among the halogen atoms, fluorine, bromine, and in particular chlorine atoms are included. Haloalkyl groups are e.g. those in which the alkyl moiety is the lower alkyl group Iowa as defined above. Among them, mention may be made of the chloromethyl, 2-chloroethyl, dichloromethyl and, in particular, trifluoromethyl groups. The alkyl substituents of the N-alkylcarbonyl groups are primarily the lower alkyl groups described above. This also applies to the alkyl substituents of the NjN-dialkylcaribanyl groups. A preferred alkyl substituent of the N, N-alkyl group is 1,4-butylene and 1,5-pentylene. Examples of the above groups are: N-methylcarbonyl, N, N-dimethylcaibonyl and piperidinecarbonyl. An optionally substituted urekyl group is one in which the free amino groups are optionally substituted with lower alkyl groups as defined above, e.g. N ', N'-dimethylureido or N', N'-diethylureido. The ureide group may be a substituted divalent group which may contain heteroatoms and / or may also be substituted, preferably lower, straight-chain or a branched alkyl group with 4-6 carbon atoms in the chain in the absence of it. heteroatoms or of 4 or 5 carbon atoms in the case of the presence of heteroatoms in the carbon chain. The heteroatoms can be oxygen, sulfur and nitrogen atoms. Examples of suitable divalent ureido group substituents are: 1,4-butylene-1, 5-pentylene, 1,5-hexylene, 2,5-hexylene, 1,6-hexylene, 1,6-heptylene, 1,6,3-oxypentylene-1,5,3-oxyhexylene-1,6,3-thia-pentylene-yl,! 5,2,4-dimethyl-3-thiapentylene- -1,5,3-azapentylenated , 5, 3-alkylHo-3-azapentylene-1,5. such as S-methyl-S-aisapentien-1- or 3-methyl-3-azahexylene-yl, 6. Suitable ureido groups are also lower N'-alkylureido groups, such as N'-methylureido and N ', N'-dialkylureido groups. Lower alkoxycarbonylaminoalkyl groups are considered to be those in which both alkyl moieties contain 4 carbon atoms. "Examples of such groups are: methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl, 4-methoxycarbonylamino-n-ibutyl, 2-ethoxycarbonylamino-ethylene, 3-ethoxycarbonylamino-n-propyl-methoxy-methyl, especially 2-methoxycarbonylaminomethyl. Bonylamino-n-propyl. Acylamino groups are primarily those in which the acyl moiety is a cycloaliphatic, aromatic, araliphatic and, above all, an aliphatic acyl group. The aliphatic acyl groups of the formula R-CO- are primarily those in which R is a lower alkyl group. Lower alkyl groups are those having a maximum of 7 carbon atoms, e.g. methyl, ethyl, iso, n-propyl groups. and straight-chain and branched in any position butyl, pentyl and hexyl groups. Cycloaliphatic acyl groups of the formula R'-CO-are primarily those in which R 'is a cycloalkyl group, optionally having an alkylated group, preferably having 3—7, especially —7 carbon atoms in the ring. Examples of R 'are: cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl groups. Aromatic, relatively araliphatic acyl groups are, for example, benzoyl, naphthoyl or phenylalkanoyl groups, for example phenylacetyl, α-phenyl and 3-propionyl groups. phenylpropionyl. The abovementioned acyl groups may also be additionally substituted. The substituents of the aromatic and araliphatic acyl groups, preferably in the ring, are, for example, lower alkyl groups, such as the above-mentioned halogen atoms, such as fluorine, bromine and iodine. and in particular chlorine, the trifluoromethyl radical and the lower alkoxy groups. The aromatic and araliphatic groups may be mono-, bi- or multiply substituted. 2Q The preferred acyl group is benzoyl, especially acetyl. The acylaminoethylenes groups are primarily those of formula II, in which R5 is a lower alkyl group with the above meaning, the lower alkoxy group as defined above, or the first -, a secondary or tertiary amino group, preferably an alkyl or dialkylamino group, the alkyl portion of which is as defined above, R6 is a hydrogen atom or a lower alkyl group as defined above, R7 is a hydrogen atom, an alkyl group as defined above, a carboxyl group or an alkoxy group in which the alkoxy moiety is as defined above, and R8 is a hydrogen atom or a lower alkyl group as defined above. The alkyl groups of R4 are primarily as defined above. lower alkyl groups, for example ethyl, n-propyl, isopropyl and especially methyl. The new compounds according to the invention have valuable pharmacological properties. They reduce blood pressure at doses of 1-10 mg / kg, for example administered intravenously, as can be demonstrated in animal studies, for example in drugged cats. In addition, they slow down the heart rate and have a-sympatholytic effect, which can also be demonstrated in animal studies, e.g. in vitro studies at a concentration of 5-3-100 µg / ml in guinea pigs (the Laagondorf preparation) or in studies in vitro at a concentration of 0.1-100 µ / ml in rats (deeply isolated visceral artery). Thus, the new compounds can be used as blood pressure lowering agents, slowing down the heart rate. and working a-sympathologically. Moreover, the new piperidine derivatives may be the starting or intermediate products for the synthesis of other compounds, particularly compounds with medicinal properties. Compounds of formula I are especially valuable compounds according to the invention, in which: a) Ri is phenyl, optionally monosubstituted in o-, z- or p-, R2. '6 is the group 2 -ketoimidazolidine-1, R 4 is hydrogen. b) Rj is lower alkyl, alkoxy, alkenyl, alkenyloxy, halogen, lower chloroalkyl, carbonyl, optionally substituted lower alkyl, lower alkoxycarbonylaminoalkyl, lower alkoxycarbonylaminoalkyl, lower alkoxy * pe acylammonium ethylenyl, lower alkylthioalkoxy, hydroxyl, lower alkanoyl, lower alkoxyalkyl, lower alkynyl, lower alkylthioalkyl, hydroxyalkyl, alkanoyloxy, alkylthio-, amino, acanoyloxy , ureido, an optionally substituted and / or phenyl group on a mono- or doubled-lower alkynyloxy group, R2 is a 2-ketoimidazolidine group, and R4 is a hydrogen atom. c) Rj is a phenyl group, monosubstituted lower alkyl, alkoxy, alkenyl, alkenyloxy, halogen, carbanyl, optionally substituted with lower alkyl groups, lower alkoxy carbonylaminoalkyl, alkoxyalkoxy, alkanoylaminethenylenyl, hydroxy or a lower alkanoyl group, R2 is 2-keto-imidazolidinyl-1 and R4 is hydrogen. d) Rj is monosubstituted phenyl, lower alkyl, alkoxy, alkenyl, alkenyloxy, alkanoylamino, hydroxyl, N-alkylcarbonyl or halogen atom, R2 is 2-ketoimidazolidyntKwa, and H4 is hydrogen altom . e) Rt is phenyl, monosubstituted methyl, allyl, allyloxy, methoxy, hydroxy, acetylamino, propionyl, N-methylcorbanyl or chlorine, R2 is 2-ketoimidazolidine, and R4 is hydrogen. The following compounds according to the invention are especially valuable: 1- {1- [3-piperidyl-4} -dimidiazolidinone-2j 1- {1- [3- (p-acetamidophenoxy) -2-hydroxy-1-propyl] - piperidyl-4} imidazolidinone-2, 1- {1- [3- (acetamidophenoxy) -2-hydroxy-1-propyl] - piperidyl-4} -imidazolidinone-2, 1- {1- [3-piperidyl-4} imddazalidinone-2,1- {1- [3- (o-allylphenoxy) -2-hydroxy-1-propylJ-piperidyl-4} imidazolidinone-2,1- {1- [3- (o-chlorophenoxy) -Z- hydroxy-1-propyl] piperidyl-4} iimMatzol! i & ^ l- {1- [3- (o-methoxyphenoxy) -2-hydroxy-1-propyl] -piperidyl-4} -3-methyl-imidazolidinone- 2,1- {1- [2- (o, p-dimethoxyphenoxy) -2-hydroxy-1-propyl] piperidyl-4} im; idazolidinone-2,1 - {1 - [3 - (2-methoxy -4-dimethylcarbanylphenoxy) -2-hydroxide sy-1-propyl] -piperidyl-4} imidazolidinone-2, 1- {1- [3- (2-chloro-4-acetaminophenoxy) -, 2-hydroxy--1-propyl] piperidyl-4} imidazolidinone -2, T 93 900 8 l- {1- [3- (2,4-dichlorophenoxy) -2-hydroxy-11-propyl] piperidyl-4} imidazolidinone-2, 1- (1- [3- ( pN-methylcarbonylphenoxy) -2-hydroxy-1-propyl] piperidyl-4} -imidazolidinone-2, 1- {1- [3- (o-lnety'lafenac! sy) -2-hydroxy-1-propyl] pi - peridyl-4} and 2-imidazolidinone, in particular 1- {T- [3- (o-methoxyphenoxy) -2-hydroxy-1-propyl] piperidyl-4} imidazolidinone-2. the compound of formula R1-0-CHa-CH (X) -CH2-Z, where X and Z are both epoxy or X is hydroxyl and Z is a reactive hydroxyl group esterified with a strong acid of an organic or inorganic acid, especially a halogenated acid such as hydrochloric, hydrobromic or hydroiodic acid, sulfuric acid or an organic sulfonic acid, especially an aromatic sulfonic acid such as Benzenesulphonic, p-bromoibenzenesulphonic, p-toluenesulphonic is reacted with a compound of formula III by force (where R 2, R 2 and R 4 are as defined above, whereby the reactions are carried out in the presence of a basic condensing agent. of the reaction conditions and starting materials, the end products are obtained in the free form or also within the scope of the invention, acid addition salt form. Thus, for example, basic, neutral or mixed salts are obtained, optionally their half, one, one and a half or polyhydric acid salts. . Optionally, the addition salts of the new compounds obtained according to the invention with acids by known methods are converted into free compounds, for example by means of basic agents such as metal hydroxides or ion exchangers. The aqueous bases are optionally converted into salts with organic or inorganic acids. Acids which give rise to medicinally useful salts are particularly suitable for this purpose. Examples of such acid include: hydrogen halide acids such as hydrochloric acid, sulfuric acid, phosphoric acids, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic and sulfonic acids such as formic, acetic, propionic, amber, glycolic, lactic, apple, tartaric, citric, maleic, hydroxymaleic or pyruvic acid, fumaric acid, benzoic acid, p-aminobenzoic acid, anthranilic acid, p-hydroxybenzoic acid, salicylic acid or p-amino sulfonic acid, ethanesulfonic acid, methanesulfonic acid hydroxyethanesulfonic acid, ethylene sulfonic acid, halobenzene sulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid or sulfanilic acid, methionine, triptophane, lysine or arginine. Conversion of new compounds into these and other salts, for example picrates, is optionally used to purify the obtained free bases. Purification consists of salifying the base, isolating the salt and regenerating the aqueous base. Due to the close relationship of the new compounds in the figure; free and in salt form, when speaking about free compounds, we also mean their salts. The invention also includes those variants of implementation in which one starts from an intermediate compound obtained at any stage of synthesis and performs the missing operations, interrupting the synthesis at any stage, the starting material is obtained under the reaction conditions or in which the reagents are used in the form of appropriate salts. By the method according to the invention it is possible to obtain new compounds by appropriately selecting the starting materials and synthesis conditions, in the optical form antipodes or rechemes, or as long as they have at least two asymmetric atoms, in the form of a mixture of rechemes and / or pure geometric isomers or a mixture of these isomers. The resulting mixture of isomers can be separated into pure geometric isomers using the differences in their physical properties. A known separation method is chromatography on a suitable stationary phase, such as a silicon gel oncone or alumina, deposited with a complex forming compound of heavy metal, e.g. with a silver compound, or the formation of heavy metal addition salts, e.g. silver nitrate complexes, isolation of pure isomers of addition compounds, e.g. by fractionated crystallization, and decomposition of compounds with isolation of pure isomers. Pure isomers, e.g., trans isomers, may be used in the usual manner, e.g. photochemically, e.g. by irradiation with a suitable wavelength, preferably in a suitable solvent such as an aliphatic hydrocarbon or in the presence of a suitable catalyst, convert to isomers of the opposite configuration, for example cis. Racemic mixtures can be separated into pure stereoisomers (diastereoisomers) in a manner known per se, using a variety of physicochemical properties. The resolution can be carried out, for example, by chromatography and / or fractional crystallization. The racernates may also be separated by crystallization from an optically active solvent, with the aid of microorganisms, or by substitution with an optically active acid, which forms salts with a racemic compound, The division of the diaster of isomeric salts, for example, by using the difference in solubility and separating the antipodes. The following acids are particularly suitable for this purpose: D- and L-tartaric, di-o-toluene, apple, almond and camphorsulfonic acid. It is advantageous to isolate the active antipodes L. The aim is to use in the reactions according to the invention such starting materials that lead to the production of particularly desirable or specially described end products. The new compounds obtained by the method according to the invention find application in medicine, e.g. in the form of pharmaceutical preparations, which, in addition to the active ingredient, contain suitable organic or inorganic carriers, either solid or liquid, and which are inert to the active ingredient. Suitable carriers are, for example, water, gelatin, milk sugar, starch, magnesium stearate, vegetable oils, benzyl alcohols, gum, polyalkylene glycols, petroleum jelly, cholesterin and other known drug carriers. The pharmaceutical preparations can be in the form of tablets, dragees, capsules, suppositories, ointments, creams, solutions (for example elixirs or syrups), suspensions or emulsions. Optionally, they may be sterilized and / or contain adjuvants such as preservatives, stabilizers, crosslinkers or emulsifying agents, salts for changing the osmotic pressure or buffers. In addition, they may also contain other healing valuable materials. Preparations which are also used in veterinary medicine are obtained by the usual methods. Preferred are pharmaceutical preparations which, in addition to new phytochemicals, also contain other potent pressure depressants and / or diuretics. The preparations contain mainly compounds of the α-amino- β-hydroxyphenyl propionic acid and β-amino-β-alkoxyphenyl propionic acid type, especially of the hydrazinopyridazine type, and synpatholytic compounds. nylpropionics are especially those having an α-alkyl radical, in particular a methyl radical, such as α-amino-α-methyl-α-methyl-α-4,4-dihydroxyphenyl) propionic acid, optionally soluble in an aqueous solution of hydrochloric acid in the left-handed form. Suitable P-amino- (3-alkoxyphenylpropionic acids) are especially those having a lower alkoxy radical in the alkoxy phenyl moiety of no more than 6, preferably not more than 3 carbon atoms, in particular a methoxy radical, such as β-amino- (3 - '(3,4-dimethoxy-phenyl) propionic acid, possibly in the right form. A suitable hydrazinopyridazine is primarily hydrazinophthalazine, such as 1,4-dihydraziphthalazine, preferably in the form of a salt, e.g. 1-hydrazriophthalazine sulphate. Suitable sympatholytic agents are primarily imidazole derivatives such as 2Hbenzyl-4, i5-imidazoline, preferably in the form of a salt such as hydrochloride or 2 - {[Np-tolyl- (-N-) m-n-hydroxyphenyl] -aminomethyl} imidazoline, preferably in the form of a salt such as hydrochloride or methanesulfonate. Suitable sympathicolytic agents are primarily blood pressure lowering agents. peripheral part of the sympathetic system, e.g. NO-bromobenzyl-N-ethyl-N, N-dimethylammonium p-toluenesulfonate, in particular guanidine derivatives such as 1,2,3,4-hydroisoquinoline-2 carboxamidine, preferably v in the form of a salt, e.g. 7-bromo-1,2,3,4-quaternary sulphate, Mnoline-2-carboxamidine, preferably in the form of a salt, e.g. sulphate, 1-benzyl -2,3-dimethylguanidine, preferably in the form of a salt, e.g. sulphate, and above all (Hl-aza-cyclooctyl) ethylguanidine, preferably in the form of a salt, e.g. sulphate. Suitable diuretics are compounds that increase diuresis, either by renal action or by extrarenal action. on tissue. Compounds which inhibit reabsorption in the distal canal, especially mole-removing agents, and ethacorinic acid 19 and its analogues are particularly suitable. Benzoithiazine derivatives, such as thiazides, hydratiazides, benzenesulfonamides, are particularly suitable. , phenoxyacetic acids, benzofuranocarfoxyl-2 and benzofuran-2,3-dihydrocarboxylic-2-acids, in particular thiazides of formula IV, where R9 is a hydrogen attom or a phenylalkylalkalloyl group and Rio is a halogen atom or trifluoromethyl group. The phenylalkylthioalkyl group R9 is primarily one in which the alkyl component has up to 4, preferably 1, carbon atoms and the phenyl moiety is unsubstituted. An example of such an OK group is the benzylthiomethyl group. The Rio halogen atom may be bromine, iodine, fluorine, and in particular chlorine. , 4-benzothiadiazines, 6-trifluoroimethyl-7-suIliBamylLo-l, ^, 4H-benzothyldiazine 1,1-dioxide and 2-toenzylthiomethyl-6-chloro-7-sulfamyl-1,2,4- Benzothiadiazines. Also particularly suitable are the hydrotiazines of formula 5 in which Rlt is hydrogen or lower alkyl, R12 is hydrogen, loweralkyl, alkenyl, cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, aryl, lower arylalkyl, haloalkyl, alkphthothioalkyl, alkenylthioalkyl, haloalkalthioalkyl, phenylalkylthioalkyl or heterocyclo-, alkylalkyl, Ru is hydrogen altom or, in combination with the substituent, R 2 is a lower alkylene group. and Ri4 represents a halogen atom or a trifluoromethyl group. The lower alkyl group Rn is primarily a group of at most 7, preferably no more than 4, carbon atoms such as ethyl, n-propyl, isopropyl or rectangular groups. it carries or arbitrarily branched butyl, pentyl, hexyl and especially methyl. The lower alkyl group of R 12 is primarily that of R n, especially methyl, ethyl or isobutyl. The lower alkenyl group of Ria is primarily a group of up to 7, preferably not more than 4, carbon atoms, such as allyl. The cycloalkyl group R12 is primarily a 3-8, especially 5-7 carbon atoms in the ring and to 8, especially up to 7, total carbon atoms, such as cyclopentyl or cyclohexyl. The cycloalkenyl group R 2 is primarily a group of $ -8, especially 5 to 7 atoms in carbon in the ring and preferably up to 8, especially up to 7 carbon atoms in total, such as cyclopentyl, cyclohexyl and especially 5-norbornene-2-yl. The cycloalkylalkyl group R12 is primarily a group in which both components are of the above-mentioned groups, in particular the cyclopentylmethyl group. Gmu (the pyridium Rla is primarily all 6 carbon atomic groups such as a phenyl group, optionally substituted lower alkyl group, such as methyl, lower alkoxy, such as methoxy, a halogen atom such as chlorine or a trifluoromethyl group. The aralkyl group IIa is primarily a group in which the alkyl moiety is as defined above and the aryl moiety is a phenyl group, an alkoxy group such as methoxy, a halogen atom such as chlorine or, particularly preferably, an unsubstituted phenyl group, an example of such a group is a benzyl group or a 1-phenylethyl group. two or three halogen atoms, preferably one in which the alkyl moiety is as defined above, in particular a halomethyl group, e.g. trifluoromethyl, chloromethyl or tri-chloromethyl. The alkylthioalkyl group of R12 is primarily a group in which both components alkyl are as defined above, such as methylthiomethyl or 2-methylthioethyl. The alkenylthioalkyl group R12 may contain, for example, one from the above-mentioned lower alkenyl groups. Such a group is, for example, an allylthiomethyl group. The halo-alkytaalMaofwa R12 group is predominantly an alkylthioalkyl group Rt6, substituted with two or three halogen atoms, for example 2,2,2-tri-fluotfoethylthiomethides. The phenylalkylthioalkyl group R 4 is primarily a group in which the alkyl components have the meaning given above, such as the benzylthiomethyl group. ring member, e.g. furyl or pyrrole group, and with an alkyl component having up to 7, preferably up to 4, carbon atoms, such as ethyl, n-propyl, straight or branched butyl, pentyl, hexyl or heptyl groups, i.e. Methyl lower alkylene group consisting of a total of R12 and Ris is primarily a group having up to 7, especially up to 6 carbon atoms and at least 4 carbon atoms in an alkylene chain, such as 1,5-pentylene or 3-pentylene. methyl--1,5-pentylene. The atom of halogen Ri4 is bromine, iodine, fluorine, and especially chlorine. The following compounds of the formula 5 should be mentioned: 3-ethyl 1,1-dioxide, 6-chloro-7- "Sullam" o- -3,4-dihydro-1,2,4-benisothiodiazine, 3-Trichloro-6-chloro-7-sulfanyl-3,4-dihydro-1,2,4H-benzothiadiazine, 1,1-dioxide, 3-Jbenzyl-6-tr65fluoro-dioxide , 4-dihydro-1,2,4-bemzothiadviuazine, 2-methyl-i3- <2, 2,2-trifluoro-ethylthiomethyl) -6-chloro-4-sulfamyl-S 4 -dioxide dihydro-yl ^^ - benzothiazines * 1,1-dioxide 3- (2,2,2-trifluoroethylthio- methyl) ^ 6-chloro-7-sulfanyl-3,4-dihydro-1,2,4- -benzothiadiazines, 1,1-dioxide 3 - <; 5-norbornene--2-yl) -6-chkro-7-sulfol-amyl-3i4-dihydro-1,2,4-benzothiadiazines, 1,1-dioxide methyl-3-chloromethyl-6-chloro TO-7-sulfanyl-34-dihydro-1,2,4-benzothiadiazines, 1,1-dioxide 6-chloro-7-sulfamoyl-3,4-dihydrogen , i2,4-benzothiadiazines, 3-dichloromethyl-6-chloro-7-suIphanyl-3,4-dihydro-yl, 2,4H-benzothiadiazines, 1,1-dioxide, 3-cyclopentylmethyl-6 1,1-dioxide -chloro-7-isulfanyl -3,4-dihydro-1,2,4-ibenzothiadiazine, 1,1-dioxide, 6-trifluoro: methyl-7-sulfa: methyl-3,4-dihydrogen-yl , 2,4-ibenzothiadquuazyn yi 1,1-dioxide 3-isobutyl-6-chloro-7-sulfanyl-3,4-dihydro-1,2,4-benzothiadiazines. Particularly suitable benzenesulfonamides are compounds of formula 6 in which R 15 is halogen , lower alkyl group, or trifluoromethyl group, R18 represents a hydrogen atom, a lower alkyl group, a phenylalkyl group, a phenyl group, an eintual group, and a lower alkoxy group or an amino group, pyrrolidinomethyl, piperidinomethyl, pyrrolidinomethyl, piperazinyl. morpholinomethyl or thiomorpholinomethyl, R17 is a carboxyl group, optionally an N-mono- or N-disubstituted carbamyl group, optionally an N-mono- or N-disubstituted sulfamyl group, an alkyl Iosulforiyl or isoin-dolinyl group or isoin-dolinyl bound to R17l8 , R18 represents a hydrogen atom, a lower alkyl group, an amino group, optionally monosubstituted or di-substituted, and R19 represents a hydrogen atom or a halogen atom. group, especially a methyl group. The aminophenyl group R16 is primarily a monoaminophenyl group, such as p-amino-phenyl. The N-monosubstituted carbamyl group of R17 is primarily R "." andpa N-alkL.01carba.mylo-. in which the alkyl moiety is as defined above, e.g. N-methylcarbamyl or N-amino substituted carbamyl, where the substituted amine moiety is primarily a dichaikylamino group such as dimethylan inn or alkylidene amine, such as pforplMyiiioi, pQpery (dyno or 2 ^ 6-dimieltyrijriiL-peridine. An example of such a group is the N- (2,6-dimethyltipiperidine) group N-disubstituted carbamyl group R17 is primarily an N-dialkylcarbamyl group in which the alkyl radicals have the meaning given above, such as N, N -dimethylcarbamyl. The N-monosubstituted sulfamyl group and R 17 is predominantly a N-alkylsulfamyl group, in which the alkyl group is as defined above, for example, N-methylsulfamyl, N-furfuryl- or N-tetrahydrofurfurylsulfamyl, e.g. N- (2-methyltetrahydrate N- (2-imethyl-4-ke1; tetrahydrofurfuryl) & ulfamyl. The N-disubstituted sulfamyl group of R17 is primarily an N, N-dialkylsulfamyl group in which the groups alkyl are as defined above, for example N, N-dimethylsulamyl, N, N-alkylenesulfamyl in which the alkylene group is as defined above, for example piperidinolysulfamyl, N-alkyl-N-caiboxyalkylsulphamyl group, in the alkyl components of which are as defined above, e.g. N-methyl-N-carbon - xymethylsulfamyl, an N-alkyl-N-furfurysulfamyl group in which the alkyl group is as defined above, for example, N-methyl-N-furfurylsulfamyl or an N-alkyl-N-tetrahydrofurfurylsulfamyl group in which the alkyl group has the meaning given above, e.g. N-methyl-N- (2-methylphthyltrafurfuryl) sulfamyl or N-methyl-N- <2-methyl-4-ketetrahydrofurfuryl) sulfamyl. The alkylsulfonyl group R17 is primarily a group in which the alkyl moiety is as defined above, for example, methylsulfonyl, ethylsulfonyl or n-butylsulfonyl. An example of an isoindolinyl group R17 is the 3-hydroxy-1-ketoisoindolinyl group. Ri7 are primarily carbamyl groups Hn »bonded to the amino group R18 or to the lower alkyl group of R18, such as 1-keto-2-cyclohexyl-2-aza'propylene-1,3 or 1-keto-2,4 1,4-di-azo-3-ethylbutylene. The monosubstituted amino group R 18 is predominantly a lower alkylamino group. the third alkyl group is as defined above, such as methylamino or tetrahydrofurfurylamino, in particular furfurylamine or benzylamino. The disubstituted amino group R18 is predominantly a lower dialkylamine group in which the alkyl components have the meanings given above, for example dimethylamine or di (phenylalkyl) amino, in which the alkyl components have the meanings indicated above, for example dibenzylamine. halogen, R19, is bromine, iodine, fluorine, and in particular chlorine. Among the compounds of formula 6, those in which, R15 is chlorine, R16 is aminophenyl, methyl, and especially hydrogen, R17 is chlorine, are particularly valuable. ¬boxylic, carbamyl, N-methylcarbamyl, N- (2'6-dimethylpyridine) cetbamyl, 3-hydroxy-1-ketoisoindolyl-3 or N-: methyl-N- (2-methyltetrahydrofurfuryl) carbamyl or altogether R18 is lnketo-1-cyclohexyl--2-azapropylene-1, 3 or 1-keto-2,4-diaz-3-ethylbutylene-1,4, R18 is hydrogen or furfurylamino and Ri9 is a hydrogen atom. Of this class of compounds of formula 6, the following should be mentioned: 2-chloro-5-N -methylsulfonamidobenzenesulfonamide, 2HchloroH5-1piperidinesulfonylbenzenesulfonamide, 2-chloro-5 -! (N-carboxymethyl-N-, methyl) sulfonami-dobenzenesulfonamide, * 2-chloro-5- (N-tetrahydrofurfurylsulfonamide) - 2-benzenesulfonamide - 2-benzenesulfonamide) - [N-methyl-iN- (2-methyl-4-ketetrahydrofurfuryl) sulfonamidobenzehsulfonamide. 2-chloro-5-N, N-dimethylsulfonamidobenzenesulfonamide, 2-chloro-S- (N-furfurylsulfonamidobenzenesulfonamide, 4,5-dichloroibenzene-1,3-disulfonamide, 4-chloro-i5-methylbenzene-1, 3-disulfonamide, u 4-chloro-6-arndai (obeozeno-1,3H-di & ullon-2-chloro-5-methylsulfonylbenzenesulfanamide, 2-chloro-5-ethylsulfonylbenzenesulfonamide, 2-chloro-5-n-ibutylsulfonyl-5-methyl-benzenesulfonamide, -ethylsulfonylbenzenesulfonamide, 2Hmethyl-5-methyl-ulfonyitobenzosulfainamide, 2-methyl-5-n-butylsulfonylbenzenesulfonamide, 2-chloro-4- (N, N-dubenzylamino) -5-carboxybenzenesulfonamide, 4-furyl-furylamine acid -5-N (p-aminophenyl) sulfamylbenzoic acid, 2-furfurylamino-4-chloro-5-N [(o-aminophenyl) sulfamyl] sulfamyobenzoic acid, especially 3-sulfamido-4-chlorobenzoic acid, 3-sulfamido -4-chlorobenzamide, 3- (N-methylsulfamyl) -4-chloro-N-methylbenzamide, 1-chloro-4- [N-methyl-N- (2-methyltetrahydrofurfuryl) sulfamyl] benzenesulfonamide, 1, 3-disulfamyl-4-chlorobenzene, 2-c'hloro-5- (3-hydroxy-, 1-ketoisoindolinyl-3-benzenesulfonamide, 2-ethyl-4-keto-6-sulfamyl-7-chloroHl, 2,3,4-tetrahydroquinazoline, (1-keto-2-cyclohekByl-5) -chloro-6-sulfamyl-1,2-dihydroisoindole, 2-chloro-5-IN- (2,6-dimethylpiperidine) carbahiy-lojbenzenesulfonamide, 2-chloro-4-furfurylamino-5-carboxybenzenesulfonamide and 2-chloro -4Hbenzylamino-5-carboxy-benzenesulfonamide. Particularly suitable are phenoxyacetic acids of formula VII in which Rao is lower alkyl, R5 is halogen or lower alkyl and R5 is hydrogen, halogen or loweralkyl M or R21 and Altogether Rfi is 1,3-butadie-syl-yl, the 4th lower alkyl group Rgo is above all having 2-7, especially "2-4 carbon atoms, a group such as one of the above-mentioned groups, preferably a group with an unbranched chain, such as n-propyl, n-butyl, and especially ethyl. The halogen atom of R2i or R22 is bromine, iodine, fluorine, and especially chlorine. The lower alkyl group of R21 or R22 is primarily the group of having up to 7, preferably up to 4, carbon atoms, in particular a methyl group. Suitable compounds of formula 7 are: [2,3-dimethyl-4015 93 900 16 l-4-i (2-methylenabutyryl) phenoxy ] acetic acid, [2-methyl-3-chloro-^ -i (2-methyliiobutyryl) phenoxBy] - acetic acid, [4- {2-methylene butyryl-1H-naphthoxy] -acetate, especially [2J-yni-chnto-W2-methylenebutyrylphenoxy) acetic acid. Especially suitable benzofuranecarboxylic acids - are compounds of formula 8 where sRflg is the lower alkyl group and R24 represents a lower alkyl group or a lower alkoxy group. The lower alkyl group R 5 is above all having 2-7, especially 2-4 carbon atoms, such as one of the above-mentioned, preferably a non-branched chain, such as Like an ethyl group, the lower alkyl group R 4 is primarily a group having up to 7, preferably up to 4, carbon atoms, especially a methyl group. The lower alkoxy group of R24 is above all the group whose alkyl moiety is as defined above (such as methoxy. Suitable compounds of formula 8 are primarily 5- (2-methylenebutyryl) -6-methyl-benzofuran-2-carboxylic acid. , 5-i (2-methylbutyryl) -6-methoxybenzofuran-2-carboxylic acid and, 5- (2-methylenepropionyl) -6-methylbenzofuranecarboxylic acid-i2. Especially suitable benzofurane-2,3-dihydrogen-2-carboxylic acids there are compounds of formula 9, in which R 25 is a hydroxy, alkoxy, cycloalkoxy or arylalkoxy group, R 5 is two hydrogen atoms or a lower alkylidane group, B 6 is a lower alkyl group, R 5 is a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group, and R29 is a hydrogen atom or a lower alkyl group. The alkoxy group R &lt; 1 &gt; is predominantly having 1M18, especially 1-12 carbon atoms, such as one of the above-mentioned and especially methoxy, et Oxyl, n-butoxy, 24-hexyl, and n-decyloxy. The cycloalkoxy group R 1 is primarily having $ -8, especially 5-7 carbon atoms in the ring, such as cyclopentoxy or cyclohexoxy. The arylalkoxy group R is predominantly. all phenylalkoxy groups of which the alkyl moiety is a lower alkyl radical as defined above; An example of such a group is a benzoxy group. A lower alkylidene group R 5 is primarily a group having up to 7, especially up to 4 carbon atoms, such as a methylene or ethylene group. The lower alkyl group R 1 is primarily a group having up to 7, preferably up to 4 carbon atoms, especially a straight chain group such as methyl, n-propyl, n-butyl, especially ethyl. . The lower alkyl group R 8 or R 6 is primarily a group having up to 7, preferably up to 4 carbon atoms, such as one of the above-mentioned, primarily methyl. The lower alkoxy group of R 9 is primarily any group with up to 7, especially up to 4, carbon atoms, such as one of the above-mentioned, primarily methoxy. R is a methylene or ethylidene group, R 27 is a straight chain alkyl group of 1-4 carbon atoms, R 6 is a matyl group, a methoxy group, a chlorine atom, or a fluorine group, and R 5 is a hydrogen atom or a methyl group. such compounds are: 5-i (2-methyleneibutyryl) -5-methyl-2,3-dihydro-2-benzofuranecarboxylic acid, 5- {2-, methylenebutyryl) -6-fluoro-2,3-dihydrobenzofuran carboxylic acid -3, 5-i (2-methylenbutyryl) -6-chloro-2,3-dihydrogen-benzofuran-carboxylic acid-2, 5-i (2-methylenepropionyl-6-methyl-2,3-dihydrogen-benzofuranecarboxylic acid-2 , i5- (2-methylenehexynooyl) -6-methyl-2,3-dihydrobenzofurancarbo, xylic acid, 5- (2-methylenovaleryl) -6- methyl-2,3-dihydrogen benzofuranecanboxylic acid -2, sq as 5- <2-methylenepropionyl) -6-methyl-2,3-idhydrobenzofurancariboxylic-2, 5- {2-ethylidenebutyryl) -6-methyl-2,3-dihydro-2-benzofuranecarboxylic-2-ester 5- <2-methylenebutyryl) -6-methyl-2,3-dihydroTobenzofuran-2-carboxylic acid, ethyl ester of 6- <2-methylenebutyryl) -6-methyl -2,3-dihydro-ibenzofuran-2-carboxylic acid, n-ester 5- <2-Methylenebutyryl) -6-methyl-2,3-dihydrogen-benzofuranecanoic acid-2-butyl, <5- (2-imethylenebutyryl) -6-methyl-2,3-dihydrogen benzofuranecanoic acid hexyl ester -2, 5- &lt; 2-methylbutyryl) -6-.methyl-i2,3-dihydro-benzofurancarboxylic-2-acid n-decyl ester, 5 ^ 2-methylen-butyl) -6-methyl-2-acid cyclopentyl ester 2,3-dihydrogen benzofuran-carboxylic-, cyclohexyl ester of -K2-methylenebutyryl) -6-methyl-l2,3-dihydrogen-benzofuran-2-carboxylic acid, benzyl 45 5- <2-methylenebuty-2-acid benzyl ester) H6-methyl-2 S, 3-dihydrobenzurate carboxylic acid methyl ester - <2-methylenebutyryl-7-methyl-2,3-dihydrobenzofurancarbaxylM2, 5- <2-methyleneQ-butyryl) -6-chloro-7-methyl -2,3-dihydroibenzofuranecarboxylate3O-2, acid methyl ester 5 - (2-Methylene propionyl) -6-methyl-2-dihydro-2-benzofurancarboxylic acid, 57i (2-methylene-valeryl) -6-methyl-2,3-dihydrogen-benzofuranecarboxylic acid methyl ester-2, acid methyl ester (5- (2-methylene-3-methylbutyryl) -6-methyl-2,3-dihydrogen-benzofurah-carboxylic-2, 5- <2-methylenebutyryl acid methyl ester) -6-fluoro-2,3- 2-dihydrogen-benzofurinecarboxylic-2, especially 5- <2-methylenebutyryl) -6.7-1-methyl-2,3-dihydrogen-benzofurin-2-carboxylic acid, 5- <2-methylenor-3-methylbutyryl) -6 -methyl-2,3-dihydrogen benzophonyl-2-carboxylic acid and 5-i (2-methylenebutyryl) "6-chloro-7-methyl-2,3-dihydrogenbenzofurinocartoxy-2- 5-yl-2. v17 Pharmaceutical preparations containing 1- {1- [3r- (n-methoxyphenoxy) -2-hydroxy-1-4-iropyl] piperidyl-4} imddaz <) lidinone, l *. {1- [3 - - (p-allyloxyphenoxy) -2 ^, hycircksy-1-propyio] pi | iery-4-yl-4} imadazolidine EN EN EN EN

Claims (1)

1. Patent claims 40. . A process for the preparation of new piperidine derivatives of the general formula I, in which R is a single or double substituted phenyl group, R2 is igrupe 2-etho-imdazolidinium-1, 2-keto-4 - group. methyl: imdazolidine-1 or 2-keto-sulfhydroxo-pliirinidinyl-1, R4 is a hydrogen atom or a lower alkyl group and n is (Lkttbe 1 ^ 4, orate dcii salt, characterized in that the compound of The formula Ri-O-CH2-50-CH (X) -CHfc-Z is reacted with a compound of formula III, in which formulas X and Z, when combined, represent an 'epoxy group, combined, X represents a hydroxyl group and Z is a reactive esterified PC hydroxyl group, and Ru R 1 and R 4 have the meaning given above, in which the reactions are carried out, optionally in the presence of a condensing agent, and the obtained compound of formula I in free form or in the form of a salt thereof, optionally it is converted into a salt or a free compound, respectively, and the Aulb is obtained, if appropriate, a recema t splits into optical antipodes. i2.- The method according to claims A compound according to claim 1, characterized in that the sulfite compound of formula R 1 -0-CH 2 -CK (X) -CH 2 -Z is used as the suibrant, wherein Z is a hydroxyl group 93 900 29 esterified with a hydrohalic acid or benzenesulfonic acid. 3. The method according to claim 2, characterized in that the starting material is the compound of formula R1-0-CH2-CH (X) -CH2-Z, in which the symbol Z, which is a hydroxyl group esterified with hydrogen halogen acid, is chlorine, bromine or iodine 4. The process according to formula 1, characterized in that the sctTodek toanldensujacy slfcostufle sie zaisalde 6. The method according to claim 1, characterized in that the reactions are carried out in the presence of an excess of a compound of formula 3. A method according to claim 1, characterized by reacting 1- (o-imethoxyphenoxy) -2,3-epoxypyropane with 1- [piperidyl- (4)] - limddazolidinoneim- - (2) to obtain sie l- {l- [3 -hydroxypropyl-l] -p, iperydyl-i (4)} j) midazolidinone- - (2) optionally in the form of a salt. 7. The method according to p. The process of claim 1, wherein the 3- (o-methoxyyphenoxy) -2-hydroxyprcpyl hailogen are reacted with 1- (piperidyl-4-imidazolidinone- (i2) to obtain 1- {1- [3-xy) -2-hydroxypropyl-1] -piperidyl-! (4)} - iimidazolidinone- <2) optionally in the form of a salt thereof. 18. The method according to claim 5 3. The process of claim 1, wherein 3- (o-) methoxytphenoxy) -2-hydroxyipropyl halide is reacted with 1- (piperidyl-4) limidazolidinone- (2) to give 1- {1- [ 3n (o-: methylphenoxy) -2-ihydroxypropyl-'1] -piperidyl-4} -imidazolylcimone- (2), optionally in the form of its salt. 9. The method according to p. A process as claimed in claim 1, characterized in that 1- (o-methylphenoxy) J2,3-epoxypropane, z. l-thpiiperidyl- (4)] -! iimidazolidinone- <2) and receives ll- {l- [3- (o-imiethylphenoxy) -i2-hydroxy-propyl-l] -piperidyl-4} -taidazolidinone- (2), possibly in the form of its salt. 10. Sposcb according to claim The process of claim 1, wherein 1- (o-tolyloxy) -2,3-epoxypropyl is reacted with 1- 20 midine to give 1- [3- and (o-toldloxy) -2-hydroxypropylol ^ - ^ - keto-hexahydro-pyrimidinyl-1) - -piperidine. 93 900 OH I No. R.-O-CHj.-CH-CH, -nO Ce Rr j? 8 "z6r1 R§-CNCC- O Uzor Z Formula 3 H Rrt A / zcr ^ Formula 5 D «R * Clts f- CO -A ^ J-0" CH2- C00H R «j Usor 6 Mzór 7 R ^ -C-CO- ^ CH2 R * \, s- COOH R ^ -C-CO-r ^ **? A £ tf # LZG Z-d No. 2 Order 1962 110 cgz. A4 Price PLN 10 PL PL PL PL PL