DD246109A5 - PROCESS FOR THE PREPARATION OF 3-PHENOXY-1-PIPERIDINCARBONYLAMINO-PROPANOLENE-2 - Google Patents

Abstract

The invention relates to a process for the preparation of 3-phenoxy-1-piperidincarbonylaminoalkylaminopropanol-2, which are processed for use in human medicine and veterinary medicine for therapeutic purposes to preparations. By the process according to the invention, 3-phenoxy-1-piperidinecarbonylaminoalkylaminopropanols-2 are of the general formula I wherein R 1 is a hydrogen atom or an acyl group of the formula (O) pR 4 where p is 0 or 1 and R 4 is an optionally substituted or by at least one heteroatom interrupted aliphatic, cycloaliphatic or aromatic group and wherein Ar is an aromatic or heteroaromatic group and preferably a group of the general formula I a, wherein m is 0 or 1, n is an integer from 1 to 3, wherein n is 2 or 3 when m is 1 and R 2 is a group OR 3, O (CH 2) qOR 3 or a pyrazole group or a group NHCNHR 3 O, where q is 2 or 3 and R 3 is a straight or branched chain alkyl group having 1 to 8 carbon atoms or a cycloalkylalkyl group having 4 to Is 8 carbon atoms and X is N or CR, wherein R is H, CN or OCH3, or pharmaceutically acceptable salts thereof.

Description

in which ρ is 0 or 1 and R ^{4 is} a straight-chain or branched-chain alkyl group having 1 to 20 carbon atoms, a cycloalkyl or cycloalkylalkyl group having 3 to 20 carbon atoms, a phenyl group, a phenoxy group, a phenoxymethyl group, a benzyl group or a phenylethyl group, wherein each group R ⁴ optionally bears a substituent and / or is interrupted by at least one heteroatom.

5. The method according to item 4, characterized in that one uses starting compounds in which R ^{4 is} a straight-chain alkyl group having 1 to 12 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms or a Cycloalkylalkylgruppe having 3 to 12 carbon atoms, each of which optionally one Substituents and / or interrupted by at least one heteroatom, or an optionally substituted phenyl radical, an optionally substituted phenoxy group, an optionally substituted Phenoxymetzhylgruppe, an optionally substituted benzyl radical or an optionally substituted phenylethyl group having up to 12 carbon atoms.

For this 6 pages tables

Field of application of the invention

The 3-phenoxy-1-piperidinecarbonylaminoalkylaminopropanol-2 prepared by the process of the present invention can be processed into ^ -receptor-blocking preparations for use in human and veterinary medicine.

Characteristic of the known technical solutions

Since the early sixties, a large number of / 3 receptor blocking compounds have been developed. These compounds are often categorized into two compound categories, one in which a particular selective activity towards ^ receptors is to be shown, and one in which the activity is substantially non-selective to-receptors. In both categories of compounds with more or less strong own sympathomimetic (/ 3-stimulating) activity there are also compounds which have essentially no such stimulating activity. Many of the compounds so well known, and especially most of the compounds used in medicines, have the general structural formula

OH

wherein R is a branched chain low molecular weight alkyl group, such as the isopropyl group or tertiary butyl or an optionally substituted low molecular weight alkyl group and Ar is an aromatic or heteroaromatic group, typically a phenyl group, in the 4- and / or 2-position with an aliphatic or heteroaliphatic hydrocarbon radical, the itself may be substituted, or optionally substituted by a halogen atom. A change in the group Ar is explained by referring to known compounds such as alprenolol, atenolol, betaxolol, celiprolol, metoprolol, nadolol, oxprenolol, pafenolol, pindolol, propranolol, sotalol and timolol.

Object of the invention

The aim of the invention is the preparation of new compounds for the treatment of low blood pressure, ischemic heart disease, glaucoma and other possible indications where / 3-adrenoceptor blockers have a beneficial effect.

Explanation of the essence of the invention

The object of the invention is a method for producing strong / 3-adrenoceptor blockers which have a very high selectivity for affinity to peripheral / VAdrenozeptoren and a long duration of action. The invention includes the preparation of both compounds with a moderate degree of intrinsic sympathomimetic activity and compounds having no receptor-stimulating effects.

Strong / 3, selective blockers would be beneficial as they cause a lower degree of ft-blocking and thus lower undesirable side effects in higher doses. In some situations, such as bradycardia and cardiac failure prevention, it is believed that a B-selective blocker with a moderate degree of partial agonist activity is therapeutically beneficial.

The compounds prepared according to the invention are S-phenoxy-1-piperidinecarbonylaminoalkylaminopropanols of the general formula

^r ~ \ 1

ArOCH-CHCH-CH NHCH _{0 0} NHCH) -OR, I

OH. O

wherein R ^{1 represents} a hydrogen atom or an acyl group of the general formula

-C (O) R ⁴

Il P, ·

in which ρ is O or 1 and R ^{4 is} an aliphatic, cycloaliphatic or aromatic group, each of which may optionally be substituted and / or interrupted by at least one heteroatom, and Ar may be an aromatic or heteroaromatic group. The compounds wherein R ^{1 is} hydrogen have particularly high and selective affinity for / 3-i receptors. The compounds in which R ^{1 is} an acyl group can produce compounds of the formula I in which R ^{1 is} a hydrogen atom by biological conversion and show after their conversion their activity in the organism. The gist of the invention is in the provision of the side chain

-OCH-CHCH-NHCH-CH-NHCNV-OH ² . 2 2 2 "/

OH O

which may be bonded to various aromatic or heteroaromatic Ar groups useful in known compounds and which may optionally be esterified to the OH group of the piperidine radical. Thus, in formula I Ar is an aromatic or heteroaromatic group as known in the art. Regardless, subclasses of the Ar groups and special Ar groups provide compounds with particularly advantageous properties. In particular, Ar is represented by the formula

la

wherein m is O or 1, η is an integer of 1 to 3, wherein η is 2 or 3 when m is I, and R ^{2 is} a group-OR ³ , a group-O- (CH ₂ ) _q OR ³ , a pyrazole group or a group.

-NHCNHR ³

wherein q is 2-iodo-3 and R ^{3 is a} straight-chain or branched chain alkyl group having 1 to 8 carbon atoms or a cycloalkylalkyl group having 4 to 8 carbon atoms, and X is X or CR wherein R is H, CN or OCH ₃ . In the acyl group

-C (O) R ⁴ POPO

ρ is 0 or 1 and R ^{4 is} an aliphatic, cycloaliphatic or aromatic group such as a straight or branched chain alkyl group having 1 to 20 carbon atoms, a cycloalkyl or a cycloalkylalkyl group having 3 to 20 carbon atoms, a phenyl, phenoxy, phenoxymethyl, Benzyl or phenylethyl group, each of which is optionally substituted and / or optionally interrupted by at least one heteroatom.

Preferred compounds of the invention are those compounds of formula I wherein X is CH, and especially those compounds wherein Ar

o ^x

and (O) _m (CH) _n -R ^{2 means} one of the groups shown below.

' ^CH 3

ch ₂ ch ₂ and ₂ ch

Nh ₃

OCH ₂ CH ₂ OCH ₂

CH ₂ CH ₂ OCH ₀ CH

The compounds of formula I wherein R ^{1 is} a hydrogen atom have the desired affinity for peripheral β- adrenoceptors. Compounds in which R is an acyl group, as well as other prodrugs or precursors to the compounds wherein R ^{1 is} a hydrogen atom which can be obtained in further inventions or by application of general knowledge, show their activity after biological conversion in the living organism in compounds, wherein R ^{1 is} a hydrogen atom, and they may to some extent themselves have such activity.

The compounds of the invention may be used as the bases or pharmaceutically acceptable salts thereof.

Salt-forming acids can be used in the preparation of pharmaceutically acceptable salts of the compounds. These are: hydrohalic acids, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic acids or sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid or pyruvic acid , Phenylacetic acid, benzoic acid, p-aminobenzoic acid, anthranilic acid, p-hydroxybenzoic acid, salicylic acid or p-aminosalicylic acid, pamoic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, ethylene sulfonic acid, halobenzenesulfonic acid, toluenesulfonic acid, naphthylsulfonic acid or sulphanilic acid, methionine, tryptophan, lysine or arginine.

The compounds of the invention can be prepared as indicated below.

For convenience, the part with the formula I

O.

/ - \ ι

NJkOR

designated as R ^N.

In the groups R ^N and Ar, R ¹ , R ² , R ³ , R ⁴ and η are as defined in connection with the indicated formulas.

The compounds of the formula I are obtained by processes as follows:

a) reaction of a compound of the formula

X ¹

Ar-OCH ₂ CHCH ₂ Z

'1 Ha

Ar-OCH ₂ CHCH ₂ X,

wherein X ^{1 is} a hydroxyl group, Z is a hydroxyl group or a reactive esterified hydroxyl group or X ¹ and Z together form an epoxy group, with a compound of the formula

H ₂ NR ^N. , Ill.

When Z is a reactive esterified hydroxyl group, it is especially one with a strong inorganic acid, preferably a hydrohalic acid such as hydrochloric, hydrobromic or hydroiodic acid, further with sulfuric acid or a strong organic sulfonic acid such as methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, 4-bromobenzenesulfonic acid or 4 Toluenesulfonic acid, esterified hydroxyl group. Z is preferably chlorine, bromine, iodine, methanesulfonyl, trifluoromethanesulfonyl or 4-toluenesulfonyl. When using a reactive ester as a starting material, the reaction is preferably carried out in the presence of a basic condensing agent and / or with an excess of an amine Suitable basic condensing agents are, for example, alkali metal hydroxides such as sodium or potassium hydroxide, alkali metal carbonates such as potassium carbonate, and · Ring-closure to an epoxide can be effected as an intermediate reaction using a compound of formula II or IIa wherein Z is a reactive esterified hydroxyl group When both Z and X ^{1 are} -OH, the reaction is carried out in the presence of a metal catalyst such as Raney nickel The reaction is preferably carried out in a solvent which is, for example, an alcohol of 1 to 4 carbon atoms by reacting the reactants in this solvent for sufficient time to produce the desired compound give, in general 3 to 24 h, heated to reflux.

b) reaction of a compound of the formula

Ar-OCH ₂ CHOHCH ₂ NH ₂ , IV

wherein R ¹ and R ^{2 are} as defined above, with a compound of the formula

ZR ^N , V

wherein Z is as defined above.

The reaction is preferably carried out in the presence of a basic condensing agent and / or an excess of an amine. Suitable basic condensing agents are, for. As alkali metal, preferably sodium or potassium alkoxide, or alkali metal carbonates, such as sodium or potassium carbonate.

c) reaction of a compound of the formula

ArOH 'Vl

, with a compound of the formula

x ¹

i 'ν ^v "

Z is -CH ₂ CHCH ₂ -NHR,

wherein X ^{1 is} as defined above and Z ^{1 is} Z as defined above, but Z ¹ is not a hydroxyl group. When a reactive ester is used as the starting material, the compound of formula VI may conveniently be used in the form of its metal phenolate, such as an alkali phenolate, preferably sodium phenolate. The reaction may also be carried out in the presence of an acid-binding agent, preferably a condensing agent capable of forming a salt, such as an alkali alcoholate of the compound of formula VI.

The reaction is preferably carried out in an autoclave heated at 80 to 100 ° C for 1 to 5 hours in an alkanol having 1 to 3 carbon atoms as a solvent.

d) reaction of a compound of the formula

OH

HO- / T) -OCH-CHCH _NHR ^N IX

with a compound of the formula

Z ¹ (CH ₂ I _n -R ² , '' X

wherein Z ^{1 is} as defined above to form a compound of formula I wherein Ar has the formula I a and m is 1. In reaction d, the reactive hydroxyl group is typically activated by a base. The reaction d is preferably carried out in a polar aprotic medium.

e) Reaction of a compound of the formula

OH -

\ XV

wherein η is as defined above and wherein the nitrogen atom adjacent to the propanol may carry a protecting group such as a benzyl group with a compound of the formula

^ VR ¹ , - ^XVI

wherein R ^{1 is} as defined above and Y is an leaving group such as a halogen atom, an alkoxy group, an aryloxy group or an acyloxy group. ⁷

f) cleaving a residue from a compound of formula I above which is additionally substituted with a radical such as a benzyl group or substituted benzyl group on a heteroatom.

g) Conversion of a compound of the formula

OH OCH ₂ CHCH ₂ NHR ^N

XVII

wherein X ^{0 is} a group containing one or more unsaturated carbon-carbon bonds and which is convertible to the group (O) _m (CH ₂ ) _n -R ² by saturation of each of these unsaturated bonds therein

 h) reducing a Schiff base of the formula

OH Ar-OCH ₂ CH-CH = NR ^{N. xvm}

This reduction is carried out in customary manner, for example using a dileil metal hydride, using a hydride, such as a borane, with formic acid or by means of catalytic hydrogenation, such as with hydrogen in the presence of Raney nickel. In the reduction, care must be taken that other groups are not affected, i) reducing the oxo group to a hydroxyl group in a compound of the formula

N xvi

ο "ΑΛΙ

This reduction is usually carried out, especially using a hybrid as mentioned above. The reduction can also be carried out in the presence of chiral ligands and then results in unequal amounts of the enantiomers. The reduction can also be carried out enzymatically, j) reducing an amide carbonyl group in a compound of one of the formulas

OH

I '/ V-N \ 1 XXII

Ar-OCH ₂ CH-C-NHCH ₂ CH ₂ NHC-J

OH. Q

η η

Ar-OCH ₂ CHCH ₂ NHCCH ₂ NHC-N Q ^{nrJ XXI} "

_ 0

The reduction may be carried out according to the method described above using complex metal hydrides such as lithium aluminum hydride or diisobutyl aluminum hydride. Suitably, the reaction takes place in an inert solvent such as an ether, e.g. Diethyl ether or tetrahydrofuran instead. Complex borohydrides can also be used, especially if a selective reaction is desired

k) to form a compound of formula I wherein R ^{1 is an} acyl group

-C (O) .R ⁴ ti P

if the corresponding compound in which R ^{1 is} H is reacted with an acid or an acid derivative of the formula

wherein Z ^{1 is} a hydroxyl group or a reactive group as defined above for a reactive esterified hydroxyl group Z.

Depending on the process conditions and the starting material to obtain the final product either in free form or in the form of its acid addition salt, which lies within the inventive concept. Thus, for example, basic, neutral or mixed salts as well as hemiamino compounds, sesqui- or polyhydrates can be obtained. The acid addition salts of the novel compounds can be converted in a manner known per se into free compounds using, for example, basic agents such as alkali or ion exchangers. On the other hand, the resulting free bases can form salts with organic or inorganic acids. In the preparation of acid addition salts it is preferred to use those acids which form suitable pharmaceutically acceptable salts. Examples of such acids are given above. ^: "

These or other salts of the new compounds, such as picrates, can serve as cleaning agents for the resulting free bases when the free bases are converted to salts, these are separated and the bases are then released from the salts. In view of the close relationship between the novel compounds in free form and in the form of their salts, it will be understood from the above and the following that, if possible and not otherwise expressly stated, reference to the free compound also refers to corresponding salts. When the novel compounds of the invention contain at least one asymmetric carbon atom, the invention includes all possible isomers of the compounds. Thus, depending on the choice of starting materials and process, the novel compounds may be present as optical antipodes or racemates or, if they contain at least two asymmetric carbon atoms, as an isomer mixture (racemate mixture).

Depending on the physico-chemical differences of the compound, the obtained isomer mixtures (racemate mixtures) can be separated into the two stereoisomeric (diastereomeric) pure racemias, for example by chromatography and / or fractional crystallization.

The racemates obtained can be separated by known methods, such as by recrystallization from an optically active solvent, with the aid of microorganisms or by reaction with optically active acids to form salts of the compound and separation of the salts thus obtained, for. Example, with the help of their different solubility in the diastereoisomers, from which the antipodes can be released under the influence of a suitable agent. Useful optically active acids are e.g. the L and D forms of tartaric acids, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid or quinic acid. Preferably, the more active part of the two antipodes is isolated. In addition, one or both of the enantiomers may be obtained by asymmetric reduction of the corresponding keto compound.

Conveniently, such starting materials are used for the processes outlined above, which result in groups of end-products which are primarily particularly desirable, and which lead in particular to the specifically described and preferred end-products.

The starting materials are known or, if they should be new, can be obtained by methods known per se.

In clinical use, the compounds of the invention are normally administered orally, rectally or by injection in the form of a pharmaceutical preparation containing an active compound either as free base or as pharmaceutically acceptable non-toxic acid addition salts such as the hydrochloride, lactate, acetate , Sulfamate or the like, in association with a pharmaceutical carrier.

The carrier material may be a solid, semi-solid or liquid diluent or capsule. These pharmaceutical preparations form a further subject of the invention. Usually, the amount of active compound is between 0.1 and 10% by weight of the preparation, suitably between 0.5 and 20% by weight in preparations for injection and between 2 and 50% by weight in preparations for oral administration.

In the preparation of pharmaceutical preparations containing a compound of the present invention in the form of dosage units for oral administration, the selected compound may be combined with a solid powdered carrier material such as lactose, sucrose, sorbitol, mannitol, starch such as potato starch, corn starch , Amylopectin, cellulose derivatives or gelatin, as well as with a friction reducing agent, such as magnesium stearate, calcium stearate, polyethylene glycol waxes or the like, are mixed and compressed into tablets. When coated tablets or dragees are desired, the core prepared as above may be coated with a concentrated sugar solution, and this solution may contain, for example, gum arabic, gelatin, talc, titanium dioxide or the like. In addition, the tablets can be coated with a lacquer dissolved in a volatile organic solvent or solvent mixture. To this coating, a dye may be added to easily distinguish between tablets having different active compounds or different amounts of the active compound. In the preparation of soft gelatin capsules (pearled closed capsules) consisting of gelatin and, for example, glycerol, or in the preparation of similar closed capsules, the active compound is mixed with a vegetable oil. Hard gelatin capsules may contain granules of the active compound combined with a solid powdered carrier material such as lactose, sucrose, sorbitol, mannitol, starch (such as potato starch, corn starch or amylopectin), cellulose derivatives or gelatin.

Dosage units for rectal administration may be prepared in the form of suppositories containing the active substance in admixture with a neutral fat base, or they may be prepared in the form of gelatin rectal capsules containing the active substance in admixture with a Vegetable oil or paraffin oil. Liquid preparations for oral administration may be in the form of syrups or suspensions, for example, as solutions containing from about 0.2% to about 20% by weight of the active substance described, the remainder being sugar and a mixture ethanol, water, glycerine and propylene glycol. Optionally, such liquid preparations may contain colorants, flavorings, saccharin and carboxymethylcellulose as thickening agents. Solutions for parenteral administration by injection may be prepared as an aqueous solution of a water soluble pharmaceutically acceptable salt of the active compound, preferably at a level of from about 0.1% to about 10% by weight. These solutions may also contain stabilizing and / or buffering agents and may conveniently be provided in ampoules of different dosage units.

The preparation of pharmaceutical tablets for peroral use is carried out by known methods. The daily dose of the active substance varies and depends on the mode of administration, but as a general rule it is 20 to 500 mg per day for peroral administration and 10 to 200 mg per day for intravenous administration. A recommended dose for the treatment of glaucoma is one drop (50 to 100μ, Ι) of a solution containing 1 to 10 mg / ml of active substance once or twice a day in an affected eye.

embodiments

The following explanations explain the principle and the embodiment of the invention, but without limitation to these embodiments. The temperatures are given in celcius degrees. The structures are shown in the attached Tables 1 to 3.

example 1 Preparation of 4-hydroxy-N- (2 - ((2-hydroxy-3- (4- {3- (cyclopropylmethoxy) -phenoxy) -propyl) -amino) -ethyl) -l-

piperidinecarboxamide (method a)

12.9g of the hydrochloride of N ^ -aminoethyl-hydroxypiperidinecarboxamide and 2.3g NaOH were stirred in ethanol (100ml) at 60 ° C for 1h. Thereafter, 6.0 g of SHO-t-cyclopropylmethoxy-propoxy-phenoxy-i -epoxypropane in 50 ml of ethanol was added over 2 hours. The resulting mixture was stirred overnight at 60 ⁰ C, evaporated to dryness, dissolved in CH2Cl2 and extracted three times with water and evaporated to dryness. The residue was chromatographed on 320 g of silica gel 60. The column was first eluted with CH ₂ Cl ₂ / CH ₃ OH mixture (10: 1) and the first 600 ml were discarded. Thereafter, fractions of 100 ml were collected. After 18 fractions, the methanol content in the mobile phase had increased to 25%. Fractions 30-36 contained the desired product. After evaporation, the residue was recrystallized from acetonitrile. Yield 2.5g. Melting point 89 ^° C. (base). The structure was confirmed by using NMR analysis.

Example 2 ~~ -

Preparation of 4-hydroxy-N- (2 - ((2-hydroxy-3- (4- (2- (cyclobutylmethoxy) -ethyl) -phenoxy) -propyl) -amino) -ethyl) -1-

piperidinecarboxamide (method a)

12.77g of the hydrochloride of N, 3'-aminoethyl-hydroxypiperidinecarboxamide and 2.28 NaOH were stirred in ethanol (150ml) for 4h. Thereafter, 5.1 g of 3- (4- (2-cyclobutylmethoxy) ethyl) phenoxy) -1,2-epoxypropane were added. The mixture was stirred at 50 ^° C for three days, filtered, evaporated and chromatographed on silica using methanol / methylene chloride as the mobile phase. In the end, pure methanol was used. Yield 2.54 g, melting point 92 ° C (base). The structure was confirmed by NMR analysis. '

Example 3 Preparation of 4-hydroxy-N- {2 - ((2-hydroxy-3- (4- {2- (2- {2-methylpropoxy) -ethoxy) -ethyl) -phenoxy) -propyl} -amino) -ethyl )-1-

piperidinecarboxamide (method a)

7.6 g of the hydrochloride of N ^ ^ aminoethyl -hydroxypiperidincarboxamid and 1.36 g NaOH were stirred in ethanol for 1 h at 6O ⁰ C. Thereafter, 4.0 g of 3- (4- (2- (2- (2-methylpropoxy) -ethoxy) -ethyl) -phenoxy) -1,2-epoxypropane in 40 ml of ethanol was added over 3 hours. The resulting mixture was 11 h at 6O ⁰ C stirred, evaporated CH ₂ CI _2, washed three times with water, Na ₂ SO ₄ dried, filtered and evaporated. The residue was chromatographed on 320 g of silica gel 60. The column was first eluted with 11 20% CH ₃ OH in CH ₂ Cl ₂ and then with 1140% CH ₃ OH in CH ₂ Cl ₂ . The following 1.41 were collected and evaporated. The residue crystallized when treated with diisopropyl ether. Yield 2.3g. Melting point 81 ^° C. (base). The structure was confirmed by NMR analysis.

Example 4 Preparation of 4-hydroxy-N- (2 - ((2-hydroxy-3- (4- (2- (2-methylpropoxy) -ethyl) -phenoxy) -propyl) -amino) -ethyl) -1-

piperidinecarboxamide (method a)

11.2 g of the hydrochlorides of N, 3-aminoethyl-hydroxypiperidinecarboxamide and 2 g of NaOH were stirred in isopropanol (100 ml) at 50 ° C for 1 h. Thereafter, 5.0 g of 3- (4- (2- (2-methylpropoxy) ethyl) phenoxy) -1,2-epoxypropane in 50 ml of isopropanol was added over 2 hours. The resulting mixture was stirred at 50 ° C overnight, evaporated, dissolved in 2N hydrochloric acid and extracted with ether. The aqueous layer was extracted three times with CH ₂ Cl ₂ , and this organic layer was treated with 10 N NaOH, washed with water, dried over Na ₂ SO ₄ , filtered and evaporated. The residue was chromatographed on 320 g of silica gel 60 according to the procedure of Example 3. Melting point 94 ^° C. (base). Yield 1 g. The structure was confirmed by NMR analysis.

Example 5 Preparation of 4-hydroxy-N- (2 - ((2-hydroxy-3- (4- (2- (cyclopropylmethoxy) -ethoxy) -phenoxy) -propyl) -amino) -ethyl) -1-

piperidinecarboxamide (method 1)

5.2 g of N- (benzyl) -N- (2 - ((2-hydroxy-3- (4- (2-cyclopropylmethoxy) ethoxy) phenoxy) propyl) amino) ethyl) phenoxycarboxamide and 1, 4 g of 4-hydroxypiperidine in 75 ml of toluene was stirred at 80 ⁰ C for 45 h. The reaction mixture was extracted twice with dilute NaOH and washed with water, dried over Na ₂ SO ₄ , filtered and evaporated. The residue was dissolved in 150 ml of ethanol, and after adding the catalyst (Pd / C), the mixture was hydrogenated for ₂ hours (250 ml of H ₂ ). The reaction mixture was filtered and evaporated. The residue was chromatographed in the usual manner using silica and a CH ₃ OH / CH ₂ Cl ₂ mixture. After evaporation of the solvents, the residue was recrystallized from isopropyl ether / methanol mixture (4: 1). Yield 1.42g. Melting point 86 ° C (base). The structure was confirmed by NMR analysis. ·

Example 6 Preparation of 4-hydroxy-N- (2 - ((2-hydroxy-3- (4- (2- (2-methylpropoxy) -ethoxy) -phenoxy) -propyl) -amino) -ethyl) -1-

piperidinecarboxamide (method 1)

10.0 g of N- (benzyl) -N- (2 - ((2-hydroxy-3- (4- (2- (2-methylpropoxy) ethoxy) phenoxy) propyl) amino) ethyl) phenoxycarboxamide and 2.1 g of 4-hydroxypiperidine in 100 ml of toluene was allowed to react at 100 ^° C. for 8 hours. The mixture was then dissolved in CH ₂ Cl ₂ and extracted twice with 2 M NaOH, washed with water, dried and evaporated. The residue was treated with charcoal, filtered and hydrogenated over 5% Pd / C in 300 ml of ethanol. After consumption of 540 ml H ₂ -GaS, the solution was filtered and evaporated. The residue was dissolved in a mixture of isopropanol and ethanol (3: 1), and after filtration, the product crystallized. The product was filtered off. Yield 6.3g. Melting point 101 ^° C. (base). The structure was confirmed by NMR analysis.

Example 7 Preparation of 4-hydroxy-N- (2 - (((S) -2-hydroxy-3- (4-2- (cyciopropylmethoxy) -ethoxy) -phenoxy) -propyl) -amino) -ethyl) -1-

piperidinecarboxamide (method a)

1.47 g of the hydrochloride of N-2-aminoethyl-4-hydroxypiperidinecarboxamide were refluxed in 15 ml of ethanol until a clear solution was obtained. Thereafter, 0.45 ml of 15M NaOH solution was added. Then, 1.26 g of 3- (4- (2- (cyclopropylmethoxy) ethoxy) phenoxy) - (S) -2-hydroxypropyl methanesulfonate in 15 ml of ethanol was added. The reaction mixture was allowed to react for two days at 45 ° C. The mixture was then filtered, evaporated and dissolved in H ₂ O and extracted with CH ₂ Cl ₂ at pH 10. The organic layer was then extracted with water at pH 3 (H ₂ SO ₄ ) and the water phase was extracted with ethyl acetate. The water phase was basified to pH 10 and extracted with methylene chloride, washed with water, dried, filtered and evaporated. Yield 0.7 g. Melting point 83 ^° C. The structure was confirmed by NMR analysis.

Example 8 Preparation of N- (2 - ((3- (4- (2-Amino-2-oxoethyl) -phenoxy) -2-hydroxypropyl) -amino) -ethyl) -4-hydroxy-1-piperidinecarboxamide

(Method a)

8.47 g of the hydrochloride of N-2-aminoethyl-4-hydroxypiperidinecarboxamide and 1.516 g of NaOH were stirred in 200 ml of ethanol for 3 hours. 3.9 g of 3- (4- (carbamoylmethyl) phenoxy) -1,2-epoxypropane were added and the resulting mixture was allowed to three days at 50 to 55 ⁰ C to react. The resulting mixture was filtered and evaporated. The residue was chromatographed on silica with methanol / methylene chloride as the mobile phase in the usual manner, and finally, pure methanol was used as the mobile phase. After evaporation of the solvents, the residue was crystallized from ether. Yield 1.0g. Melting point 105 ^° C. The structure was confirmed by NMR analysis.

Example 9 Preparation of 2-methylpropanoic acid 1 - (((2 - ((2-hydroxy-3- (4- (2- (2-methylpropoxy) -ethoxy) -phenoxy) -propyl) -amino) -ethyl) -

amino) carbonyl) -4-piperidinyl ester (method e)

2.08 g of N-benzyl-N- (2-aminoethyl) -3- (4- (2- (2- (2-methylpropoxy) -ethoxy) -ethyl) -phenoxy) -2-hydroxypropylamine, 1.17 g of 4- (2-Methylpropanoyloxy-piperidinecarbonyl chloride and 1.7 g of potassium carbonate were allowed to react in 30 mL of methylene chloride for two days The mixture was worked up in the usual manner and chromatographed on an Altex column (2.5 x 50 cm) in 1.5 g portions mobile phase was 2.5% methanol in methylene chloride, 1.26 g of pure product were dissolved in 50 ml of ethanol and hydrogenated (Pd / C), the mixture was filtered and evaporated, the residue was extracted from a mixture of ethyl acetate and isopropanol (1 Recrystallized: Yield 0.61 g, melting point 113 ^° C.

Example 10 Preparation of phenoxyethanoic acid 1 - (((2 - ((2-hydroxy-3- (4- (2- (2-methylpropoxy) -ethoxy) -phenoxy) -propyl) -amino) -ethyl) -

amino) carbonyl) -4-piperidinyl ester (method k)

10 g of N- (Benzyl) -N- (2 - ((2-hydroxy-3- (4- (2-methylpropoxy) -ethoxy) -phenoxy) -propyl) -amino) -ethyl) -4-hydroxypiperidinecarboxamide in 100 ml CH ₂ CI ₂ and 2.96 ml of pyridine were heated to reflux, and 3.45 g of phenoxyethanoyl chloride in 25 ml of CH ₂ Cl ₂ were added over 15 min. The reaction was allowed to reflux for 1 h. It was then washed three times with dilute sulfuric acid and then twice with dilute Na ₂ CO ₃ solution. The organic layer was dried, filtered and evaporated. The residue was chromatographed on silica using CH ₂ Cl ₂ containing 2 to 4% CH ₃ OH as the mobile phase. Yield 5.2 g. This product was dissolved in ethanol, treated with charcoal, filtered and hydrogenated over "Pd / C." The substance consumed 190 ml of H _2. The mixture was filtered and evaporated The residue was then purified from a mixture of isopropanol and ethanol (4 Yield: 2.6 g, melting point 87 ^° C. The structure was confirmed by NMR analysis.

Example 11 Preparation of carboxylic acid 1 - (((2 - ((2-hydroxy-3- {4- (2- (2-methylpropoxy) -ethoxy) -phenoxy) -propyl) -amino) -ethyl) -amino} -

carbonyl) -4-piperidinylpheriyl ester (method k)

The title compound was prepared according to Example 10 above using phenyl chloroformate. Yield 0.5 g (from 5.2 g starting material and 1.72 g phenyl chloroformate). Melting point 92 ° C (base). The structure was confirmed by NMR analysis.

Example 12 Preparation of benzenepropanoic acid 1 - (((2-hydroxy-3- (4- (2- (2-methylpropoxy) -ethoxy) -phenoxy) -propyl) -amino) -ethyl) -

amino) carbonyl) -4-piperidinyl ester (method k)

The title compound was prepared according to Example 10 above using 6.5 g of benzyl protected starting material and 2.22 g of 3-phenylpropanoyl chloride as starting materials. Yield 0.5g. Melting point '87 ° C (base). The structure was confirmed by NMR analysis.

Example 13 Preparation of carboxylic acid ethyl-1 - (((2 - ((2-hydroxy-3- (4- (2- (2-methylpropoxy) -ethoxy) -phenoxy) -propyl) -amino) -ethyl) -

amino) carbonyl) -4-piperidinyl ester (method k)

The title compound was prepared according to Example 10 above using 11.1 g of benzyl protected starting material and 2.14 ml of ethyl chloroformate as starting materials. Yield 2.0g. Melting point 87 ^° C. (base). The structure was confirmed by NMR analysis.

Example 14 Preparation of butanoic acid-1 - (((2 - ((2-hydroxy-3- (4- (2- (2-methylpropoxy) -ethoxy) -phenoxy) -propyl) -amino) -ethyl) -amino) -

carbonyl) -4-piperidinyl ester (method k)

The title compound was prepared according to Example 10 above using 7.25 g of benzyl protected starting material and 1.56 g of butanoyl chloride as starting materials. Yield 1.2g. Melting point 81 ^° C. (base). The structure was confirmed by using NMR analysis. ·

Example 15 Preparation of hexanoic acid-1 - (((2 - ((2-hydroxy-3- (4- (2- (2-methylpropoxy) -ethoxy) -phenoxy) -propyl) -amino) -ethyl) -amino) -

carbonyl) -4-piperidinyl ester (method k)

The title compound was prepared according to Example 10 above using 4.0 g of benzyl protected starting material and 1.12 ml of hexanoyl chloride as starting materials. Yield 1.5 g. Melting point 81 ^° C. (base). The structure was confirmed by NMR analysis.

Example 16 Preparation of 4-hydroxy-N- (2 - ((2-hydroxy-3- (4- (2- (2-methylpropoxy) -ethyl) -2-methoxy-phenoxy) -propyl) -amino) -ethyl) -1-

piperidinecarboxamide (method a)

The title compound was prepared according to Example 2 above. Reaction time 12h at 60 ° C. Yield 3.9 g (52%) of an oily product. n _D ²⁰ = 1.5372. The structure was confirmed by NMR analysis.

Example 17

Preparation of 4-hydroxy-N- (2 - ((2-hydroxy-3- (4- (2- (2-methoxy-ethoxy) -ethyl) -phenoxy) -propyl) -amino) -ethyl-1-piperidinecarboxamide ( Method a) ' _r

The title compound was prepared according to Example 16 above. The product was crystallized from diisopropyl ether containing 20% acetonitrile. Yield 1.5g (18.8%). Melting point 76 ° C (base). The structure was confirmed by NMR analysis.

Example 18 Preparation of 4-hydroxy-N- (2 - ((2-hydroxy-3- (4- (2- (2- (cyclobutylmethoxy) -ethoxy) -ethyl) -phenoxy) -propyl) -amino) -ethyl) - 1-

piperidinecarboxamide (method a)

18.6 g of the hydrochloride of N-2-Amin.oethyl-4-hydroxypiperidincarboxamid and 3.0 g NaOH were stirred in ethanol (200ml) for 3 h at 40 ⁰ C. Thereafter, 8.97 g of 3- (4- (2- (cyclobutylmethoxy) -ethoxy) -ethyl) -phenoxy) -1,2-epoxypropane in 50 ml of ethanol were added. The mixture was stirred at 45 ^° C. for three days. It was then filtered, evaporated and dissolved in chloroform. The organic layer was then washed three times with water, dried and evaporated. The residue was out. Ethyl acetate / petroleum ether 40/60 recrystallized. Yield 5.7 g. Melting point 76 ° C (base). The structure was confirmed by NMR analysis.

Example 19

Preparation of 4-hydroxy-N- (2 - ({(R) -2-hydroxy-3- (4- (2- (2-methyl-pentoxy) -ethoxy) -phenoxy) -propyl) -amino) -ethyl) - 1- piperidinecarboxamide (methods e + f)

2.6 g of N-benzyl-N- (2-aminoethyl) -1- (4- (2- (2-methylpropoxy) -ethoxy) -phenoxy-3-aminopropane - '(R) -2-ol and 1.6 g 4-Benzyloxypiperidinecarbonyl chloride was allowed to stand in 25 mL of methylene chloride and 2 mL of triethylamine overnight at room temperature The organic phase was washed with dilute NaOH, dried, filtered and evaporated Yield 3.9 g of an oily product dissolved in ethanol and 2 × HCl ( Pd / C was added and the mixture was hydrogenated, filtered and evaporated The residue was treated with 2M NaOH and extracted with methylene chloride, filtered and evaporated The mixture became 1: 1 The crystals were purified by dissolving in 1 M HCl, washed twice with ether and made alkaline with 1M NaOH, the crystals were filtered off, washed with water and dried, yielding 1.29 g, melting point 93 ° C (Base) The structure was confirmed by NMR analysis.

Example 20 Preparation of 4-hydroxy-N- (2 - (((S) -2-hydroxy-3- (4- (2- (2-methylpropoxy) -ethoxy) -phenoxy) -propyl) -amino) -ethyl) - 1-

piperidinecarboxamide (methods e + f). -. "

The title compound was prepared according to Example 19 above. The product was crystallized from ethyl acetate. Yield 6.5 g (72%). Melting point 94 ^° C. The structure was confirmed by NMR analysis.

Example 21 Preparation of 4-hydroxy-N- (2 - ((2-hydroxy-3- (4- (2-methoxyethyl) -phenoxy) -propyl) amino) -ethyl) -1-piperidinecarboxamide

(Method a)

7.0 g of the hydrochlorides of N, 3-aminoethyl-hydroxypiperidinecarboxamide and 1.2 g of NaOH were stirred in ethanol for 2 h at room temperature. Thereafter, 3.1 g of 3- (4- (2-methoxyethyl) phenoxy) -1,2-epoxypropane in 30 ml of ethanol were added. The mixture was stirred, filtered, and evaporated overnight at 6O ⁰ C. The residue was dissolved in ethyl acetate and extracted with 2 M HCl. The aqueous phase was washed with ethyl acetate. Thereafter, the aqueous phase was brought to pH 7.5 and extracted with CHCl ₃ . The pH was then raised to 10 and the aqueous phase was extracted again with CHCl ₃ . This procedure was repeated three times. The combined chloroform phase was then evaporated. The residue was recrystallized from toluene. Yield 1.5 g. Melting point 74 ° C (base). The structure was confirmed by NMR analysis.

Example 22 Preparation of N- (2 - ((3- (4- (2- (2- (2- (aminocarbonyl) -phenoxy) -ethoxy) -ethyl) -phenoxy) -2-hydroxy-propyl-amino) -ethyl) - 4

hydroxy-1-piperidinecarboxamide (method a)

The title compound was prepared according to Example 2 above. The reaction time was 60 ^° C. for 6 h. The product was crystallized from acetonitrile containing 0.5% methanol. Yield 2.0g (25%). Melting point 110 ^° C. (base). The structure was confirmed by NMR analysis.

Example 23 Preparation of 4-hydroxy-N- (2 - ((2-hydroxy-3- (4- (2- (2-methylpropoxy) -ethyl) -3-cyanophenoxy) -propyl) -amino) -ethyl) -1-

piperidinecarboxamide (method a)

The title compound was prepared according to Example 2 above and on the same scale. Yield 2.7 g of an oily product. n _D ²⁰ = 1.5545. The structure was confirmed by NMR analysis.

Example 24 Preparation of 2-methylpropanoic acid 1 - (((2 - (((S) -2-hydroxy-3- (4- (2- (2-methylpropoxy) -ethoxy) -phenoxy) -propyl) -amino) -

ethyl) -amino) -carbonyl) -4-piperidinyl ester (method e + f)

8.33g N-Benzyl-N- (2-aminoethyl) -1- (4- (2-methylpropoxy) -ethoxy) -phenoxy-3-aminopropane- (S) -2-ol and 4.67g of 4- (1 Methyl ethylcarbonyloxy-1-piperidinecarbonyl chloride and 5.53 g K ₂ CO ₃ were stirred in 50 mL of methylene chloride for two days at room temperature The reaction mixture was washed twice with water and evaporated The residue was chromatographed on 800 g of silica gel Yield 8.05 g, 3.22 of this product were dissolved in 125 ml of ethanol and hydrogenated over 10% Pd / C was hydrogenated. 155 ml of hydrogen was consumed. the mixture was filtered and evaporated and the residue was crystallized twice from ethyl acetate. yield 1.63 g. melting point 84 ⁰ C. The structure was confirmed by NMR analysis.

Example 25 Preparation of 4-hydroxy-N- (2 ((2-hydroxy-3- (4- (2- (2- (2-pyridinyloxy) -ethoxy) -ethyl) -phenoxy) -propyl) -amino) -ethyl) -1-

piperidinecarboxamide (method a)

The title compound was prepared according to Example 18 above. The product was recrystallized from acetonitrile. Yield 1.4g (19.5%). Melting point 75 ° C. The structure was confirmed by NMR analysis.

Example 26 Preparation of 4-hydroxy-N- (2 - ((2-hydroxy-3- (4- (2- (2- (2-cyclopropylmethoxy) ethoxy) ethyl) phenoxy) propyl) amino) ethyl ) -

1-piperidinecarboxamide (method a)

The title compound was prepared according to Example 18 above using 22.4 g of the hydrochloride of N, 3-aminoethyl-hydroxypiperidinecarboxarhide, 4 g NaOH, and 11.1 g of 3- (4- (2- (cyclopropylmethoxy) ethyl). -phenoxy) -1,2-epoxypropane. The product was recrystallized from ethyl acetate. Yield 4g. Melting point 72 ^° C. The structure was confirmed by NMR analysis.

Example 27 Preparation of 4-hydroxy-N- (2 - ((2-hydroxy-3- (4 - ((2- (cyclopropylmethoxy) -ethoxy) -methyl) -pheno) iV) -propyl) -amino) -ethyl) -

1-piperidinecarboxamide (method a)

The title compound was prepared according to Example 22 above. The product was crystallized from diisopropyl ether containing 25% acetonitrile. Yield 1.5g (15.3%). Melting point 72 ^° C. The structure was confirmed by NMR analysis.

Example 28 Preparation of 4-hydroxy-IM- (2 - ((2-hydroxy-3- (4- (2- (1H-pyrazol-1-yl) -ethoxy) -phenoxy) -propyl) -amino) -ethyl) -1 -

piperidinecarboxamide (method a)

The title compound was prepared according to Example 2 above. Yield 1.0g (6%). Melting point 94 ° C. The structure was confirmed by NMR analysis.

Example 29 Preparation of 4-hydroxy-N- (2 - ((2-hydroxy-3- (4- (2 - ((((1-methylethyl) amino) carbonyi-amino) -ethyl) -phenoxy) -propyl) -

amino) -ethyl) -1-piperidinecarboxamide (method a)

The title compound was prepared according to Example 2 above. Yield 3g (43%), recrystallized from ether. Melting point 117 ^° C. The structure was confirmed by NMR analysis.

Example 30 Preparation of cyclohexanecarboxylic acid-1 - ({(2 - (((S) -2-hydroxy-3- (4- (2- (2- (cyclopropylmethoxy) -ethexy) -ethyl) -phenoxy) -

propylo-amino-ethyno-amino-1-carbonyl-M-piperidinyl ester (method e)

The title compound was prepared according to Example 9 above using N-benzyl-N- (2-aminoethyl) -3- (4- (2- (2-cyclopropylmethoxy) ethoxy) ethyl) phenoxy) - 2- (S) -hydroxypropylamine (4.2g) and 4-cyclohexylcarbonyloxypiperidinecarbonyl chloride (2.1g) were prepared as starting materials. Yield 2.9 g of a yellow oil. ¹ HNMR (SOOMHz, CDCl ₃ ) .87.1 2H, 6.8 2H, 5.5 1H, 4.9 1H, 4.1 1H, 3.9 2H, 3.6 8H, 3.3 4H, 3 , 2 3H, 2.8H, 2.3H, 1.9H, 1.8H, 1.7H, 1.6H, 1.4H, 1.25H, 1.05H, 0 , 5 2H, 0.2 2H.

Example 31 Preparation of 2,2-dimethylpropionic acid-1 - (((2 - (((S) -2-hydroxy-3- (4- (2- (2- (cyclopropylmethoxy) -ethoxy) -ethyl) -phenoxy) -

propyl) -amino) -ethyl) -amino) -carbonyl) -4-piperidinyl ester (method e)

The title compound was prepared according to Example 9 above using N-benzyl-N- (2-aminoethyl) -3- (4- (2- (2- (cyclopropylmethoxy) ethoxy) ethyl) phenoxy). -2- (S) -hydroxypropylamine (5.0g) "and 4- (2,2-dimethylpropionyloxy) -piperidinecarbonyl chloride (2.8g) as starting materials Yield 3.0g of a yellow oil, ¹ HNMR (500MHz, CDCl ₃ ). : 87.1 2H, 6.8 2H, 5.35 1H, 4.85 1H, 4.05 1H, 3.9 2H, 3.6 6H, 3.5 2H, 3.25 6H, 3.2 6H , 1.8 2H, 1.6 2H, 1.15 9H, 1.05 1H, 0.5 2H, 0.2 2H.

Example 32 Preparation of phenylacetic acid 1 - (((2 - (((S) -2-hydroxy-3- (4- (2- (2- (cyclopropylmethoxy) ethoxy) ethyl) phenoxy) propyl) -

amino) -ethyl) -amino) carbonyl) -4-piperidinyl ester (method e)

The title compound was prepared according to Example 9 above using N-benzyl-N- (2-aminoethyl) -3- (4- (2- (2- (cyclopropylmethoxy) ethoxy) ethyl) phenoxy). -2- (S) -hydroxypropylamine (4.4g) and 4-benzylcarbonyloxypiperidinecarbonyl chloride (2.8g) as starting materials. Yield 2.6 g of a yellow oil. ¹ HNMR (CDCl 2 BOOMHz): 87.3 2H, 7.25 3H, 7.1 2H, 6.8 2H, 5.55 1H, 4.9 1H, 4.1 1H, 3.9 2H, 3, 6 8H, 3.5 3H, 3.3 4H, 3.15 2H, 2.8 3H, 2.75 3H, 1.75 2H, 1.55 2H, 1.05 1H, 0.5 2H, 0, 2 2H.

Example 33 Preparation of 2,3-dichlorobenzoic acid-1 - (((2 - (((S) -2-hydroxy-3- (4- (2- (2- (cyclopropylmethoxy) -ethoxy) -ethyl) -phenoxy) -

propyl) amino) ethyl) amino) carbonyl) -4-piperidinyl

2.5 g of N- (2-aminoethyl) -3- (4- (2- (2- (cyclopropylmethoxy) ethoxy) ethyl) phenoxy) - (S) -2-hydroxypropylamine, 25 mL of dry THF and 0.92 g Diisopropylethylamine were mixed and 2.39 g of 4- (2,3-dichlorophenylcarbonyloxy) -piperidinecarbonyl chloride were added portionwise with stirring. The mixture was evaporated after three hours of reaction time. The residue was dissolved in a 1: 1 mixture of methylene chloride and ether and washed with water, dried over Na ₂ SO ₄ , filtered and evaporated to dryness. The synthesis was repeated and the combined residues were chromatographed on SiO ₂ with CH ₂ Cl ₂ : MeOH (9: 1) as the mobile phase. Yield 0.9g. ¹ HNMR (CDCl ₃ , 500MHz, HCl SaIz): 87.6 2H, 7.25 1H, 7.05 2H, 6.8 2H, 6.65 1H, 5.2 1H, 4.55 1H, 4, 05 1H, 3.95 1H, 3.7 4H, 3.6 6H, 3.4 3H, 3.3 6H, 2.8 2H, 1.95 2H, 1.8 2H, 1.05 1H, 0, 55 2H, 0.2 2H.

Example 34 Preparation of 4-hydroxy-N- (2 - (((S) -2-hydroxy-3- (4- (2- (2- (2-cyclopropylmethoxy) -ethoxy) -ethyl) -phenoxy) -propyl) - amino) -

ethyl-1-piperidinecarboxamide (method 1)

The title compound was prepared according to Example 5 above using N- (benzyl) -N- (2 - (((S) -2-hydroxy-3- (4- (2- (cyclopropylmethoxy) -ethoxy) -phenoxy) -propyl) -amino) -ethyl) -phenoxycarboxamide (13.0g) and 4-hydroxypiperidine (3.27g) as starting materials. Yield 3.1 g. Melting point 77-78 ° C. The structure was confirmed by NMR analysis.

Example 35 Preparation of hexanoic acid-1 - {((2 - (((S) -2-hydroxy-3- (4- (2- (2- (cyclopropylmethoxy) -ethoxy) -ethyl) -phenoxy) -propyl) -amino) -

ethyl) amino) carbonyl) -4-piperidinyl

The title compound was prepared according to Example 9 above using Ν-ΒβηζγΙ-Ντ (2-

ninoethy!) - 3- (4- (2- (2- (Cyclopropylmethoxy) ethoxy) ethyl) phenoxy) -2- (S) -hydroxypropylamine (4.5g) and 4-hexanoyloxypiperidinecarbonyl chloride (2.64g) as Prepared starting materials. Yield 3.1 g. Melting point 25 ^ 3O ⁰ C. ¹ H NMR (500 MHz, CDCI _3): 67.1 2H, 6.8 2H, 5.25 1H, 4.9 1H, 4.1 1H, 3.95 2H, 8H 3.6 , 3,35 2H, 3,3 2H, 3,2 2H, 2,85 8H, 2,3 2Hi 1,85 2H, 1,6 4H, 1,3 4H, 1,1 1 H, 0,9 3H , 0.5 2H, 0.2 2H.

Example 36 Preparation of 2-Wlethylpropanoic acid-1 - (((2 - (((S) -2-hydroxy-3- (4- (2- (2- (cyclopropylmethoxy) -ethoxy) -ethyl) -phenoxy) -propyl) -

amino) ethyl) -arhino) carbonyl) -4-piperidinyl

The title compound was prepared according to Example 9 above using N-benzyl-N- (2-aminoethyl) -3- (4- (2- (2- (cyclopropylmethoxy) ethoxy) ethyl) phenoxy). -2- (S) -hydroxypropylamin (5 g) and 4- (2-MethylpropionyloxyJ-piperidinecarbonyl chloride (2.6 g) as starting materials yield 2.4 g ¹ HNMR (CDCI _3, 500MHz):.. 67.1 2H, 6, 8 2H, 6.25 1H, 4.9 1H, 4, 0 2H, 3.65 10H, 3.3 4H, 3.15 4H, 2.8H 2, 2.5 1H, 1.85 2H, 1 , 65 2H, 1.15 6H, 0.9 1H, 0.55 2H, 0.2 2H.

Example 37

An injection solution was prepared by reacting 4-hydroxy-N- (2 - ((2-hydroxy-3- (4- (3- (cyclopropylmethoxy) -propyl) -phenoxy) -propyl-aminol-ethyl-i-piperidinecarboxamide hydrochloride (0 , 1 g), sodium chloride (0.8 g) and ascorbic acid (0.1 g) were dissolved in a sufficient amount of distilled water to give 100 ml of solution, and this solution containing 1 mg of active substance per milliliter was filled used by ampoules that have been sterilized.

Example 38

A syrup containing 2% (weight per volume) of active substance was prepared from the following ingredients:

2-methyl-propionic acid 1 - (((2 - ((2-hydroxy-3- (4- (2- (2-methylpropoxy) ethoxy) -phe'noxy) propyl) amino) ethyl) amino) carbonyl) -4-piperidinyl

HCI 2.0 g

Saccharin 0.6 g

Sugar '30.0 g

Glycerin - 5.0 g

Flavor 0.1 g

Ethanol 96% 10.0 ml

Distilled water "to 100.0 ml

Sugar, saccharin and the ammonium salt were dissolved in 60g of warm water. After cooling, glycerin and a solution of flavorants dissolved in ethanol were added. To the mixture was then added water to 100 ml

Example 39

2-methyl-propionic acid 1 - (((2 - ((2-hydroxy-3- (4- (2- (2-methylpropoxy) -ethoxy) phenoxy) propyl) amino) ethyl) amino) carbonyl ) -4-piperidinyl ester hydrochloride (250g) was mixed with lactose (175.8g), potato starch (169.7g) and colloidal silica (32g). The mixture was moistened with 10% gelatin solution and granulated through a 12-mesh sieve. After drying, potato starch (160g), talc (50g) and magnesium stearate (5g) were mixed and the resulting mixture was compressed into tablets (10,000) each containing 25mg of active ingredient. The tablets were sold on the market with a break line to give a dose other than 25 mg, or a multiple thereof, if broken.

Example 40

Granules were prepared from 2-methylpropanoic acid-1 - (((2 - ((2-hydroxy-3- (4- (2- (2-methylpropoxy) -ethoxy) -phenoxy) -propyl) -amino) -ethyl-aminol carbonylM-piperidinyl ester hydrochloride (250g), lactose (175.9g) and an alcoholic solution of polyvinylpyrrolidone (25g) After the drying step, the granules were treated with talc (25g), potato starch (40g) and magnesium stearate (2.50g These tablets were first mixed with a 10% alcoholic solution of Shellack and then with an aqueous solution containing sucrose (45%), gum arabic (5%), gelatin (4%) and dye ( Talc and powdered sugar were used for powdering after the first five coats The coating was then coated with a 66% sugar syrup and polished with a 10% carnauba wax solution in carbon tetrachloride.

Example 41 "

An eye drop solution can be prepared as follows: Active ingredient (e.g., the compound

Example 26) 1-10mg

NaOH, 0.1MorHCl, 0.1M to pH 7.4

Na ₂ HPO ₄ 12.97 mg NaH ₂ PO ₄ - 2 H ₂ O 3.57 mg

Benzalkonium chloride 0.1 mg

For injection useful water ad 1ml

Example 42

An eye drop solution can be prepared as follows:

Active substance (eg the compound

of Example 26) 1-10 mg

NaOH, 0.1 M or HCl, 0.1 M to pH 7.4

NaCI .. 9mg

BenEalkonium chloride 0.1mg

For injection use water ad 1 ml

O S U

table

OCH ₀ CHCH ₀ NHCH ₉ Ch ₀ NHCN 2 | 2 2 2 j,

_χ 0Η

OH

Example m η R isomer

1 O 3 -0-R ⁰

2 0 2 -0-R ³

3 0 2 -0- (CH ₂ ) 0 -R *

4 0 2 -0-R *

- ^CH 2-O

-CH

CH ,. I 3 -CH ₂ CHCH ₃

CH ₃

-CH ₂ CHCH ₃

5 1 2 -0-R *

6 1 2 -0-R '

-CH

CH,

-CH ₂ CHCH ₃

7 1 2 -0-R *

16 0 2 -0-R *

CH ₃ -CH ₂ CHCH ₃

 COCH.

17 0 2 -O- (CH ₂ ) 0 -R ^:

18 0 2 -0- (CH ₂ ) 0-R x ³

19 1 2 -0-R *

20 1 2 -0 -R ^v

-CH-

CH ₀ I 3

-CH ₂ CHCH ₃

-CH ₂ CHCH ₃

21 0 2 -0-R *

CH.

22 0 2 -0- (CH ₂ ) 0-R x ³

CONH

«U« U

Continuation of Table 1

OCH ₀ CHCH _n NHCHOCH ₂ NHCN

Example m η R

q ROH

? 1

^ Isomer

0 2 -O-R CH ₂ CHCH ₃

25 0 2

26 0 2

27 0 1

28 1 2

29 0 2 -NHCNH-R '

Il 0

34 0 2 -0- (CH ₀ )

-O- (CH ₂ ) 0 -R ³

-O- (CH ₂ ) 0-ΙΓ-O- (CH ₂ ) 0 -R ³

-N

I ³ -CHCH

1 Racemate, unless otherwise indicated ² X """" ^ CH, unless stated otherwise

 43-

Table la ·

ArOCH ₀ CHCH ₀ NHCH ₀ CH ₀ NHCN ' ² I ^{2 2 2} Il OH 0

OH

Ex.

Ar

CH ₀ CNH ₀ 2 II 2 0

, CHCH ₉ NHCH ₉ CH ₉ NHCn • 20- OH 0 V_ Table 2 OCH. V-OR ¹ JL / ^CH 3 ο .CH "0CH" CH OCH

CH.

CH-I

-CCHCH.

Il · 0

10

11

-C-O Il 0

12

-CCH ₉ CH ₉ II 2 0

13

-COCH ₉ CH,

Κ ²

14

-CCH ₂ CH ₂ CH ₃

V 43!

Ex.

isomer "

-XA-

Continued Table 2 Ex. R · isomer

CH ₃ 24 -CHCHCH,

I ³

Racemate, if nothing else 'indicated

table

? 4 Ο ί Ο

OCH ₀ CHCH ₀ NHCh ₀ CH ₀ NHCN

OR

.By sp.

isomer "

30

-C Il 0

31 32

CH ₃ -CC-CH, OCH ₃

-CCH,

33

Cl Cl

35

-C (CH) CH

Ji C * τ Ο

36

/ ^Η 3 -CCH

"CH"

-S shape unless otherwise stated

Claims (4)

Invention claim: 1. A process for the preparation of S-phenoxy-i-piperidincarbonylaminoalkylaminopropanolen- ^ the general formula ArOCH-CHCH-NHCH ₀ CH ₀ NHCN - ° ^r1 / I 2, 2 2 2 "/ OH O wherein R ^{1 represents} a hydrogen atom or an acyl group of the formula -ClO) _p R ⁴
Ö in which ρ is 0 or 1 and R ^{4 represents} an optionally substituted or interrupted by at least one heteroatom aliphatic, cycloaliphatic or aromatic group and wherein Ar is an aromatic or heteroaromatic group and preferably a group of the general formula where m is 0 or 1, η is an integer from 1 to 3, where η is 2 or 3 when m is I, and R ^{2 is} a group-0-R ³ , -O- (CH ₂ IqO-) R ³ or a pyrazole group or a group -NHCNHR ³ Il wherein q is 2 or 3 and R ^{3 is} a straight or branched chain alkyl group having 1 to 8 carbon atoms or a cycloalkylalkyl group having 4 to 8 carbon atoms and X is X or CR wherein R is H, CN or OCH ₃ or a pharmaceutically acceptable salt a, such compound, wherein in the formula I, the part r- 'O -CH ₂ CH ₂ -NHC-N VOR as R ^N is designated, characterized in that one a) a compound of the general formula X ¹ Ar-OCH ₂ CHCH ₂ Z
or X ¹ , " ^a wherein X ^{1 represents} a hydroxyl group, Z represents a hydroxyl group or a reactive esterified hydroxyl group. and X ¹ and Z together represent an epoxy group with a compound of the general formula H ₂ NR ^N : IH implements, or b) a compound of the general formula Ar-OCH ₂ CHOHCH ₂ NH ₂ , -IV wherein R ¹ and R ^{2 are} as defined above, with a compound of the general formula ZR ^N , V wherein Z is as defined above, or reacted
c is a compound of the general formula ArOH Vl with a compound of the general formula X ¹
Z ¹ -CH ₂ CHCH ₂ -NHR ^N _/ ^V " wherein X ^{1 is} as defined above and Z ^{1 has} the meaning of Z, but not hydroxyl, is reacted or
d) a compound of the general formula OH H0 ^{E>> -0CH_CHCH_NHR ^N. '* ^V X ^{l 2} with a compound of the general formula Z ¹ (CH ₂ I _n -R ² 'X wherein Z ^{1 is} as defined above, to form a compound of formula I wherein Ar has the meaning of formula I a and ml is reacted or e) a compound of the general formula OH
Ar-OCH ₉ CHCH NH (.CH ₉ ) NH,, ^xv wherein η is as defined above and wherein the nitrogen atom adjacent to the propanol group may carry a protecting group such as a benzyl group, with a compound of the general formula ycn 'ago ^{1 xvi} wherein R ^{1 is} as defined above and Y represents an leaving group such as a halogen atom, an alkoxy group, an aryloxy group or an acyloxy group, or f) of a compound of formula I, which is additionally substituted with a radical, such as a benzyl or substituted benzyl group on a heteroatom, splits off this radical or g) a compound of the general formula OH ¹ N OCH ₂ CHCH ₂ NHR " XVIl wherein X ^{0 represents} a group containing one or more saturated carbon-carbon bonds and is convertible to the group (O) _m (CH ₂ ) _n -R ^2, converts thereto by saturation of any unsaturated bond therein, or h) a Schiff base of the general formula OH 'N XVIII Ar-OCH ₂ CH-CH = NR reduced or i) in a compound of the general formula - _o C-CH ₉ NH-R ¹ * XXI the oxo group is reduced to a hydroxyl group or
j) in a compound of one of the formulas Ar-QCH ₂ CHCH ₂ NHCCH ₂ NHC-N '() ^ OR _XXM OH 0   I Il /> ~~ n \ 1 XXIII Ar-OCH ₀ CH-C-NHCH ₀ CH ₀ NHC- ² ti ^{2 2} reduced an amide carbonyl group or » k) a compound of formula I wherein R ^{1 is} H to form a corresponding compound of formula I wherein R ^{1 is} an acyl group -C (O) R ⁴
"P means with an acid or an acid derivative of the general formula 1 4 Z -C (O) R, XXIV Il P 0 · wherein Z ^{1 is} a hydroxyl group or a reactive group, as described above for the reactive esterified hydroxyl group Z has been defined, implements, implements and optionally in the compounds obtained by these methods substituents, cleaved or reacted and / or converted by these methods compounds into other final products and / or isomer mixtures separated into pure isomers and / or racemates obtained separates into optical antipodes and / or obtained free Converts bases into their pharmaceutically acceptable salts or converts resulting salts to their free bases. 2. The method according to item 1, characterized in that one used starting materials which XCH means. 3. The method according to item 1 or 2, characterized in that one uses starting compounds in which the group one of the groups ^ - <T CH ₂ CH ₂ OCH ₂ CH / ^CH 3 CH _o CH _o 0CH ₉ - \ / OCH ₂ CH ₂ OCH ₂ CH r <\ CH ₃ means. 4. The method according to any one of items 1 to 3, characterized in that one uses starting compounds, wherein R ^{1 is} a hydrogen atom or an acyl group of the general formula -C (O) R ⁴ P
O '·