NO862241L - NEW PARA-SUBSTITUTED 3-PHENOXY-1-PIPERIDINE CARBONYLAMINOALKYLAMINO-PROPANOL-2 COMPOUNDS WITH BETA-RECEPTOR BLOCKING PROPERTIES AND PROCEDURES FOR THEIR PREPARATION. - Google Patents

Abstract

New compounds with the general formula :. wherein R 1 is hydrogen, which compounds have a particularly high and selective affinity for beta receptors. Compounds of formula I wherein R 1 is an acyl group may give compounds of formula. formula (I) Ar is an aromatic or heteroaromatic group, defined by the formula: where m is an integer 0 or 1, n is an integer 1-3, provided that n is an integer 2-3 when 2 3 3 m is 1 and R is a group -OR, -O-ICH 2) OR, a pyrazole group or a group -NH 2 NHR 2 in which groups q is an integer 2-3, and R is a straight or unbranched alkyl group having 1-8 carbon atoms or a cycloalkylalkyl group having 4-8 carbon atoms, and X is N or CR, where R is H, CN or OCH. each said group is optionally substituted or interrupted by heteroatoms. There are also described processes for the preparation of such compounds, pharmaceutical compositions thereof and treatment methods that use such.

Description

The present invention relates to new β-receptor blocking compounds and methods for their production. The new compounds are intended for use in the treatment of hypertension, ischemic heart disease, glaucoma and other possible indications where p<->adrenoceptor blockers have a beneficial effect.

Since the early 1960s, a very large number of β-receptor blocking compounds have been developed. These compounds are often grouped into two compound categories, one where a degree of selective activity on <p>j receptors is shown, and one where the activity is substantially non-selective between P receptors. In both categories there are compounds that have a more or less pronounced intrinsic sympathomimetic (β-stimulating) activity, as well as compounds that essentially lack such stimulating activity. Many of the compounds thus known, and especially most of the compounds that have been developed into approved pharmaceuticals, have the common structure

where R is a branched lower alkyl group such as isopropyl or tert.-butyl, or sometimes a substituted lower alkyl group, and Ar is an aromatic or heteroaromatic group, typically a phenyl group which is substituted in the 4- and/or 2-position with an aliphatic or heteroaliphatic hydrocarbon which may be further substituted and optionally a halogen atom. Variation in the group Ar is illustrated by reference to known compounds such as alprenolol, atenolol, betaxolol, celiprolol, metoprolol, nadolol, oxprenolol, pafenolol, pindolol, propranolol, sotalol and timolol.

The purpose of the present invention is to provide p<->adrenoceptor blockers which are characterized by a very high selectivity with regard to affinity to peripheral<p>j-adrenoceptors and a long duration of action. The invention encompasses both compounds with a moderate degree of intrinsic sympathomimetic activity and compounds without any receptor-stimulating effects.

A highly β-selective blocker would be useful by causing a lesser degree of β-blockade and thus unwanted side effects at higher doses. In some situations such as marked bradycardia and anticipated heart failure, a -selective blocker with a moderate degree of partial agonist activity is thought to be therapeutically beneficial.

According to the present invention, it has been found that compounds with the general formula

where Ri is hydrogen, has particularly high and selective affinity for & i receptors, and that compounds of formula I where R<*> is an acyl group -C(0)pR^ can give compounds of formula I where R<*> is H by bio- o transformation and exercise its activity after being transformed.

The essence of the present invention lies in the provision of the side chain

which can be used on various aromatic or heteroaromatic groups Ar, which are useful in known compounds, and which are optionally esterified at the OH group on the piperidine part. Thus, in formula I, Ar is an aromatic or heteroaromatic group as known in the art. Nevertheless, subclasses of Ar groups as well as specific Ar groups provide compounds with particularly advantageous properties. In particular, Ar is defined by the formula:

where m is an integer 0 or 1, n is an integer from 1 to 3, provided that n is an integer 2 or 3 when m is 1 and R^ is a group -O-R<3>, -0-( CH2)qO-R<3>, a pyrazole group or a group -NHCNHR<3>, where Q is an integer 2 or 3, and R<3> is a residual or branched alkyl group of 1-8 carbon atoms or a cycloalkylalkyl group of 4-8 carbon atoms, and X is N or C-R, where R is H, CN or OCH3.

In the acyl group -C(0)pR<4>p is an integer, 0 or 1, and R4 is an ali- tt 0

phatic, cycloaliphatic or aromatic group such as a straight or branched alkyl group of 1-20 carbon atoms, a cycloalkyl or cycloalkylalkyl group containing 3-20 carbon atoms, a phenyl, phenoxy, phenoxymethyl, benzyl or phenylethyl group, each of the said the groups are optionally substituted and/or each of the said groups is optionally interrupted by heteroatoms.

Preferred compounds in the present invention are those compounds of formula I where X is CH and especially those compounds where Ar is

The compounds of formula I where R 1 is hydrogen have the desired affinity for peripheral P 1 adrenoceptors. Compounds where R^ is an acyl group, as well as other prodrugs or bioprecursors to the compounds where Rj is hydrogen, which can be conceived in further inventions or by using common knowledge in the art, exert their activity after biotransformation in living organisms to compounds where R^ is hydrogen or may to some extent possess such activity in itself.

Compounds of the present invention can 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 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 acid, or pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, anthranilic acid, p-hydroxybenzoic acid, salicylic acid or p-aminosalicylic acid, palmoic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, halobenzenesulfonic acid, toluenesulfonic acid, naphthylsulfonic acid or sulfanilic acid, methionine, tryptophan, lysine or arginine.

The compounds in the present invention can be prepared as indicated below.

For convenience, the part is denoted by formula I

as R<N>.

In the groups R<N>and Ar, R<1>, R<2>, r<3>, r<4>and n are as defined in connection

with the specified formulas.

The compounds of formula I are obtained in accordance with methods such as the following:

a) Reaction of a compound with the formula:

or where X<*> is a hydroxy group, Z is a hydroxy group or a reactive, esterified hydroxy group, or X^ and Z together form an epoxy group, with a compound of the formula:

When Z is a reactive, esterified hydroxy group, it is in particular a hydroxy group esterified with a strong inorganic acid, preferably a hydrohalic acid such as hydrochloric acid, hydrobromic acid or hydroiodic acid, also sulfuric acid or a strong organic sulphonic acid, e.g. methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, 4-bromobenzenesulfonic acid or 4-toluenesulfonic acid. Z is in particular 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 where Ri has the above meaning, and Y is a leaving group such as halogen, alkoxy, aryloxy or acyloxy.

f) Cleavage of a residue from a compound of formula I as indicated above, further substituted with a residue such as a benzyl or •substituted benzyl group at a heteroatom.

g) Transformation of a compound with the formula

where X^ is a group containing one or more carbon-carbon unsaturations and can be converted into the group (O)m(CH2)n-R^ by saturation of each such unsaturation therein.

h) Reduction of a Schiff's base with the formula:

This reduction is carried out in the usual way, e.g. using a di-light metal hydride, using a hydride such as a borane with formic acid, or by means of a catalytic hydrogenation, e.g. with hydrogen in the presence of Raney nickel. During the reduction, it must be ensured that other groups are not affected.

i) Reduction of the oxo group to a hydroxy group in a compound of the formula:

This reduction is carried out in the usual way, especially using a hydride, as mentioned above. The reduction can also be carried out in the presence of chiral ligands, thereby giving rise to different amounts of the enantiomers. The reduction can also be carried out enzymatically.

j) Reduction of an amidic carbonyl group in a compound of one of the formulas

The reduction can be carried out in the manner described above using complex metal hydrides, e.g. lithium aluminum hydride or diisobutyl aluminum hydride. The reaction conveniently takes place in an inert solvent such as an ether, e.g. diethyl ether or tetrahydrofuran. Complex borohydrides can also be used especially when a selective reaction is desired.

k) For the formation of a compound of formula I where R^ is an acyl group -C(0)pR<4>, reaction of the corresponding compound where Ri is H with an acid or an acid derivative of the formula:

where Z<*> is a hydroxy group or a reactive group as defined for a reactive esterified hydroxy group Z above.

1) Reaction of a compound with the formula:

where the nitrogen atom adjacent to the propanol group can carry a protective group, e.g. a benzyl group, and where Y is a leaving group such as halogen, alkoxy, aryloxy or acyloxy, with a compound of the formula:

where Ri has the above meaning.

Depending on the process conditions and the starting material, the end product is obtained either in free form or in the form of its acid addition salt, which is covered by the present invention. Thus, e.g. basic, neutral or mixed salts are obtained, as well as hemiamino, sesqui- or polyhydrates. The acid addition salts of the new compounds can be transferred in a manner known per se to free compounds using e.g. of basic agents, such as alkali or ion exchangers. On the other hand, the free bases obtained can form salts with organic or inorganic acids. In the preparation of the acid addition salts, such acids are preferably used which form suitable pharmaceutically acceptable salts. Examples of such acids are given above.

These or other salts of the new compounds such as e.g. picrates, can serve as cleaning agents for the obtained free bases when the free bases are converted into salts, these are separated, and the bases are then released from the salts again. According to the close relationship between the new compounds in the free form and in the form of their salts, it will be understood from the above that reference to the free compound, if possible and unless otherwise indicated, should also be taken as a reference to the corresponding salts.

Since the compounds in the present invention have at least one asymmetric carbon atom, the invention encompasses all possible isomers of the compounds. The new compounds can thus, depending on the choice of starting materials and method, be present as optical antipodes or racemate, or, if they contain at least two asymmetric carbon atoms, be present as an isomer mixture (racemate mixture).

The obtained isomer mixtures (racemate mixtures) can, depending on physico-chemical component differences, be separated into the two stereoisomeric (diastereoisomeric) pure racemates, e.g. by means of chromatography and/or fractional crystallization.

The racemates obtained can be separated according to known methods, e.g. by means of recrystallization from an optically active solvent, by means of microorganisms or by reaction with optically active acids which form salts of the compound and separation of the salts thus obtained, e.g. by means of the different solubility of the diastereomers, from which the antipodes can be released by means of a suitable agent.

Suitable usable optically active acids are e.g. The L and D forms of tartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid or quinic acid. The most active part of the two antipodes is preferably isolated. Furthermore, one of the two enantiomers can be obtained by asymmetric reduction of the corresponding keto compound.

Such materials are appropriately used in the above-mentioned methods which lead to groups of end products that are primarily desired, and in particular to the specifically described and preferred end products.

The starting materials are known or, if they were to be new, can be obtained according to methods known per se.

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

The carrier may be a solid, semi-solid or liquid diluent or a capsule. These pharmaceutical preparations are also covered by the invention. Generally, the amount of active component 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.

When preparing pharmaceutical preparations containing a compound according to the invention in the form of dosage units for oral administration, the selected compound can be mixed with a solid, powdered carrier such as e.g. lactose, sucrose, sorbitol, mannitol, starch, such as potato starch, corn starch, amylopectin, cellulose derivatives or gelatin, as well as with antifriction agents such as magnesium stearate, calcium stearate, polyethylene glycol wax or the like, and pressed into tablets. If coated tablets are desired, the core prepared above can be coated with a concentrated solution of sugar, which solution can contain e.g. gum arabic, gelatin, talc, titanium dioxide or the like. Furthermore, the tablets can be coated with a varnish dissolved in a slightly volatile organic solvent or mixture of solvents. A dye can be added to this coating to easily distinguish between tablets with different active compounds or with different amounts of the active compounds present.

In the production of soft soft gelatin capsules (bead-shaped, closed capsules) which consist of gelatin and e.g. glycerin or when producing similar closed capsules, the active compound is mixed with a vegetable oil. Hard gelatin capsules may contain granules of the active compound in combination with a solid, powdery carrier such as lactose, sucrose, sorbitol, mannitol, starch (such as potato starch, corn starch or amylopectin), cellulose derivatives or gelatin.

Dosage units for rectal administration can be prepared in the form of suppositories containing the active substance in a mixture with a neutral fatty base, or they can be prepared in the form of gelatin rectal capsules containing the active substance in a mixture with a vegetable oil or paraffin oil.

Liquid preparations for oral administration may be present in the form of syrups or suspensions, e.g. solutions containing from approx. 0.2 to approx. 20% by weight of the active substance described, whereby the rest consists of sugar and a mixture of ethanol, water, glycerol and propylene glycol. If desired, such liquid preparations can contain dyes, flavourings, saccharin and carboxymethyl cellulose as a thickener.

Solutions for parenteral administration by injection can be prepared as an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active compound, preferably in a concentration from about 0.1 to approx. 10% by weight. These solutions may also contain stabilizing agents and/or buffering agents, and may suitably be available in different dosage unit ampoules.

The production of pharmaceutical tablets for oral use is carried out in accordance with known methods.

The daily dose of the active substance varies and depends on the type of administration, but as a general rule it is 20-500 mg/day for oral administration and 10-200 mg/day for intravenous administration. A recommended dosage for the treatment of glaucoma is 1 drop (50-100 IU) once or twice per day. day in an affected eye, of a solution containing 1-10 mg/ml active substance.

The following examples illustrate the invention. Structures are shown in accompanying Tables 1-3.

Example 1

Preparation of 1-piperidinecarboxamide, 4-hydroxy-N-(2-((2-hydroxy-3(4-(3-(cyclopropylmethoxy)propyl)phenoxy)propyl)amino)ethyl)-. (Method a)

12.9 g of the hydrochloride of N-2-aminoethylene-4-hydroxypiperidinecarboxamide and 2.3 NaOH were stirred in ethanol (100 ml) at 60°C for 1 hour. Then 6.0 g of 3-(4-(3-(cyclopropylmethoxy)propyl)phenoxy)-1,2-epoxypropane in 50 ml of ethanol were added over the course of 2 hours. The resulting mixture was stirred overnight at 60°C, evaporated to dryness, dissolved in CH 2 Cl 2 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 a CH 2 Cl 2 /CH 3 OH (10:1) mixture, and the first 600 ml was discarded. Fractions of 100 ml were then 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 recrystallized from acetonitrile. Yield 2.5 g. Melting point 89°C (base). The structure was confirmed using NMR analysis.

Example 2

Preparation of 1-piperidinecarboxamide, 4-hydroxy-N-(2-((2-hydroxy-3-(4-(2-(cyclobutylmethoxy)ethyl)phenoxy)propyl)amino)ethyl)-. (Method a)

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

Example 3

Preparation of 1-piperidinecarboxamide, 4-hydroxy-2-((2-hydroxy-3-(4-(2-(2-(2-methylpropoxy)ethoxy)ethyl)phenoxy)propyl)amino)ethyl)-. (Method a)

7.6 g of the hydrochloride of N-2-aminoethyl-4-hydroxypiperidinecarboxamide and 1.36 g of NaOH were stirred in ethanol for 1 hour at 60°C. Then 4.0 g of 3-(4-(2-(2-(2-methylpropoxy)ethoxy)ethyl)phenoxy)-1,2-epoxypropane in 40 ml of ethanol was added over the course of 3 hours. The resulting mixture was stirred at 60°C for 11 h, evaporated, dissolved in CHq 2 , washed three times with water, dried over Na 2 SO 4 , filtered and evaporated. The residue was chromatographed on 320 g of silica gel 60. The column was eluted with 1 liter of 20% CH3OH in CH2Cl2 and then with 1 liter of 40% CH3OH in CH2Cl2, and the next 1.4 liters were collected and evaporated. The rest

crystallized by treatment with diisopropyl ether. Yield 3.2 g. Melting point 81°C (base). The structure was confirmed using NMR analysis.

Example 4

Preparation of 1-piperidinecarboxamide, 4-hydroxy-N-(2-((2-hydroxy-3-(4-(2-(2-methylpropoxy)ethyl)phenoxy)propyl)amino)ethyl)-. (Method a).

11.2 g of the hydrochloride of N-2-aminoethyl-4-hydroxypiperidinecarboxamide and 2 g of NaOH were stirred in isopropanol (100 ml) for 1 hour at 50°C. Then 5.0 g of 3-(4-(2-(2-methylpropoxy)ethyl)phenoxy)-1,2-epoxypropane in 50 ml of isopropanol was added over the course of 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 3 times with CH 2 Cl 2 , and this organic phase was treated with 1N 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 method in example 3. Yield 1 g. Melting point 94°C (base). The structure was confirmed using NMR analysis.

Example 5

Preparation of 1-piperidinecarboxamide, 4-hydroxy-N-(2-((2-hydroxy-3-(4-(2-(cyclopropylmethoxy)ethoxy)phenoxy)propyl)amino)ethyl) -. (Method 1)

5.2 g N-(benzyl)-N-(2-((2-hydroxy-3-(4-(2-(cyclopropylmethoxy)ethoxy)-phenoxy)propyl)amino)ethyl)phenoxycarboxamide and 1.4 g 4 -hydroxy-piperidine in 75 ml of toluene was stirred at 80°C for 45 hours. 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 addition of the catalyst (Pd/C), the mixture was hydrogenated for 2 hours (250 ml of H2). The reaction mixture was filtered and evaporated. The residue was chromatographed in the usual manner using silica and a CII^OII/CI^C^ mixture. After evaporation of

the solvents, the residue was crystallized from an isopropyl ether/methanol mixture (4:1). Yield 1.42 g. Melting point 86°C (base). The structure was confirmed using NMR analysis.

Example 6

Preparation of 1-piperidinecarboxamide, 4-hydroxy-N-(2-((2-hydroxy-3-(4-(2-(2-methylpropoxy)ethoxy)phenoxy)propyl)amino)ethyl)-. (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-hydroxy-piperidine 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 2M NaOH, washed with water, dried and evaporated. The residue was treated with charcoal, filtered and hydrogenated over 5% Pd/C in 300 1 ethanol. After 540 ml of H 2 ~ gas had been consumed, the solution was filtered and evaporated. The residue was dissolved in a mixture of isopropanol and ethanol (3:1) and after filtration the product was crystallized. The product was filtered off. Yield 6.3 g. Melting point 101°C (baseSe). The structure was confirmed using NMR analysis.

Example 7

Preparation of 1-piperidinecarboxamide, 4-hydroxy-N-(2-(((S)-2-hydroxy-3-(4-(2-(cyclopropylmethoxy)ethoxy)phenoxy)propyl)amino)ethyl)-. (Method

a)

1.47 g of the hydrochloride of N-2-aminoethyl-4-hydroxypiperidinecarboxamide

was refluxed in 15 ml of ethanol until a clear solution was obtained. Then 0.45 ml of 15N NaOH solution was added. Then 1.26 g of 3-(4-(2-(cyclopropylmethoxy)ethoxy)phenoxy)-(S)-2-hydroxypropylmethanesulfonate in 15 ml of ethanol was added. The reaction mixture was allowed to react for 2 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 aqueous phase was extracted with ethyl acetate. The aqueous phase was adjusted 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 using NMR analysis.

Example 8

Preparation of 1-piperidinecarboxamide, N-(2-((3-(4-(2-amino-2-oxoethyl)-phenoxy)-2-hydroxypropyl)amino)ethyl)-4-hydroxy-. (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 was added and the resulting mixture was allowed to react at 50-55°C for 3 days. The resulting mixture was filtered and evaporated. The residue was chromatographed in the usual way on silica with methanol/methylene chloride as mobile phase, and at the end pure methanol was used as mobile phase. After evaporation of the solvents, the residue was crystallized from ether. Yield 1.0 g. Melting point 105°C. The structure was confirmed by NMR analysis.

Example 9

Preparation of 2-methylpropanoic acid, l-(((2-((2-hydroxy-3-(4-(2-(2-methylpropoxy)ethoxy)phenoxy)propyl)amino)ethyl l)amino)carbonyl)-4- piperidinyl ester. (Method e)

2.08 g N-benzyl-N-(aminoethyl)-3-(4-(2-(2-(2-methylpropoxy)ethoxy)ethyl)-phenoxy)-2-hydroxypropylamine, 1.17 g 4-(2 -methylpropanoyloxy)piperidine carbonyl chloride, and 1.7 g of potassium carbonate were allowed to react in 30 ml of methylene chloride for 2 days. The mixture was worked up in the usual way and chromatographed on an Altex column (2.5 x 50 cm) in portions of 1.5 g. The mobile phase was 2.5% methanol in methylene chloride. 1.26 g of pure product was dissolved in 50 ml of ethanol and hydrogenated (Pd/C). The mixture was then filtered and evaporated. The residue was recrystallized from a mixture of ethyl acetate and isopropanol (1:1). 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. 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 Cl 2 and 2 .96 ml of pyridine was refluxed, and 3.45 of phenoxyethanol chloride in 25 ml of CH 2 Cl 2 was added over 15 min. The reaction mixture was allowed to reflux for 1 hour. 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 CH2Cl2 containing 2-4% CH3OH as 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 H2. The mixture was filtered and evaporated. The residue was then crystallized from a mixture of isopropanol and ethanol (4:1). Yield 2.6 g. Melting point 87°C. The structure was confirmed using NMR analysis.

Example 11

Preparation of carboxylic acid, 1-(((2-((2-hydroxy-3-(4-(2-(2-methylpropoxy)ethoxy)phenoxy)propyl)amino)carbonyl)-4-piperidinylphenyl 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, l-(((-2((2-hydroxy3(4- (—(2-methyl-propoxy) ethoxy) phenoxy) propyl) amino) ethyl ) amino) carbonyl)-4-piperidinyl -ester. (method k).

The title compound which was prepared according to Example 10 above using 6.5 g of the benzyl-protected starting material and 2.22 g of 3-phenyl-propanoyl chloride as starting materials. Yield 0.5 g. 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 the benzyl-protected starting material and 2.14 ml of ethyl chloroformate as starting materials. Yield 2.0 g. Melting point 87°C (base). The structure was confirmed using NMR analysis.

Example 14

Preparation of butanoic acid, l-(((2-((2-hydroxy-3-(4-(2-(2-methylpropoxy)-ethoxy)phenoxy)propyl)amino)ethyl)amino)carbonyl) -4-pipe idin yles ter.

(Method k)

The title compound was prepared according to Example 10 above using 7.25 g of the benzyl-protected starting material and 1.56 g of butanoyl chloride as starting materials. Yield 1.2 g. Melting point 81°C (base). The structure was confirmed 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-pipe idin yles ter.

(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 hexanyl chloride as starting materials. Yield 1.5 g. Melting point 81°C (base). The structure was confirmed using NMR analysis.

Example 16

Preparation of 1-piperidinecarboxamide, 4-hydroxy-N-(2-((2-hydroxy-3-(4- (2-(2-methylpropoxy)ethyl)-2-methoxyphenoxy)propyl)amino)ethyl )-.

(Method a)

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

Example 17

Preparation of 1-piperidinecarboxamide, 4-hydroxy-N-(2-((2-hydroxy-3-(4-(2-(2-methoxyethoxy)ethyl)phenoxy)propyl)amino)ethyl)-. (Method a)

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

Example 18

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

(Method a)

18.6 g of the hydrochloride of N-2-aminoethyl-4-hydroxypiperidinecarboxamide and 3.0 g of NaOH were stirred in ethanol (200 ml) for 3 hours at 40°C. Then 8.97 g of 3-(4-(2-(2-(cyclobutylmethoxy)ethoxy)ethyl)phenoxy)-1,2-epoxy-propane in 50 ml of ethanol were added. The mixture was stirred for 3 days at 45°C. 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 recrystallized from ethyl acetate/petrol 40/60. Yield 5.7 g. Melting point 76°C (base). The structure was confirmed using NMR analysis.

Example 19

Preparation of 1-piperidinecarboxamide, 4-hydroxy-N-(2(((R)-2-hydroxy-3-(4-(2-(2-methylpropoxy)ethoxy)phenoxy)propyl)amino)ethyl)-. (Methods e +

f)

2.6 g of N-benzyl-N-(2-aminoethyl)-1-(4-(2-(2-methylpropoxy)epoxy)phenoxy-3-aminopropane-(R)-2-ol and 1.6 g of 4-benzyloxypiperidinecarbonyl chloride was placed in 25 ml of mctylcnklcrid and 2 ml of triethylamine overnight at

room temperature. The organic phase was washed with dilute NaOH, dried, filtered and evaporated. Yield 3.9 gave an oily product which was dissolved in ethanol and 2 M HCl (to pH= 1). 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 was crystallized from a 1:1 mixture of ethyl acetate and diisopropyl ether. The crystals were purified by dissolving in 1M HCl, washed twice with ether, made alkaline with 10M NaOH. The crystals were filtered off, washed with water and dried. Yield 1.29 g. Melting point 93°C (base). The structure was confirmed using NMR analysis.

Example 20

Preparation of 1-piperidinecarboxamide, 4-hydroxy-N-(2-(((S)-2-hydroxy-3-(4-(2-(2-methylpropoxy)ethoxy)phenoxy)propyl)amnino)ethyl)-. (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 using NMR analysis.

Example 21

Preparation of 1-piperidinecarboxamide, 4-hydroxy-N-(2-((2-hydroxy-3-(4-(2-methoxyethyl)phenoxy)propyl)amino)ethyl)-. (Method a)

7.0 g of the hydrochloride of N-2-aminoethyl-4-hydroxypiperidinecarboxamide and 1.2 g of NaOH were stirred in ethanol for 2 hours at room temperature. Then 3.1 g of 3-(4-(2-methoxyethyl)phenoxy)-1,2-epoxypropane in 30 ml was added. The mixture was stirred overnight at 60°C, filtered and evaporated. The residue was dissolved in ethyl acetate and extracted with 2M HCl. The aqueous phase was then adjusted to pH 7.5 and extracted with CHCl 3 . The pH was then raised to 10, and the aqueous phase was again extracted with CHCl3. This method was repeated three times. The combined chloroform fraction was then evaporated. The rest were re-

crystallized from toluene. Yield 1.5 g. Melting point 74°C (base). The structure was confirmed using NMR analysis.

Example 22

Preparation of 1-piperidine carboxamide, N-(2-((3-(4-(2-(2-(2-amino-carbonyl) fe nok sy) et ox y) ethy 1) f en ox y) - 2- hydroxy propyl )amino) -4- - hydroxy-. (Method a)

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

Example 23

Preparation of 1-piperidinecarboxamide, 4-hydroxy-N-(2-((2-hydroxy-3-(4-(2-(2-methylpropoxy)ethyl)-3-cyanophenoxy)propylamino)ethyl)-. (Method

a) The title compound was prepared according to and on the same scale as the example

2 above. Yield 2.7 g of an oily product. n^<0>= 1.5545. The structure was confirmed using NMR analysis.

Example 24

Preparation of 2-methylpropanoic acid, l-(((2-(((S)-2-hydroxy-3-(4-(2-(2-methylprop oxy)ethoxy)phenoxy)prop yl)amino ) ethyl )a min o)carbonyl)-4-piperidinyl ester. (Method e + f)

8.33 g of N-benzyl-N-(2-aminoethyl)-1-(4-(2-methylpropoxy)ethoxy)phenoxy-3-aminopropane-(S)-2-ol and 4.67 g of 4-(l -methylethylcarbonyloxy)piperidinecarbonyl chloride, and 5.53 g of K 2 CO 3 were stirred in 50 ml of methylene chloride for 2 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 g of this product was dissolved in 125 ml of ethanol and hydrogenated over 10% Pd/C. 155 ml of hydrogen were consumed. The mixture was filtered evaporated, and the residue crystallized twice from ethyl acetate. Yield 1.63 g. Melting point 84°C. The structure was confirmed using NMR analysis.

Example 25

Preparation of 1-piperidinecarboxamide, 4-hydroxy-N-(2-((2-hydroxy-3-(4-(2-(2-(2-pyridinyloxy)ethoxy)ethyl)phenoxy)propyl)amino)ethyl) - . (Method

a)

The title compound was prepared according to Example 18 above. The product was

crystallized from acetonitrile. Yield 1.4 g (19.5%). Melting point 75°C. The structure was confirmed using NMR analysis.

Example 26

Preparation of 1-piperidinecarboxamide, 4-hydroxy-N-(2-((2-hydroxy-3-(4-(2-(2 -(2-cyclopropylmethoxy)ethoxy)ethyl)phenoxy)propyl)amino)ethyl )-. (Method a)

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

Example 27

Preparation of 1-piperidinecarboxamide, 4-hydroxy-N-(2-((2-hydroxy-3-(4- ((2 -cyclopropylethoxy)ethoxy)methyl)phenoxy)propyl)amino)ethyl)-. (Method a)

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

Example 28

Preparation of 1-piperidinecarboxamide, 4-hydroxy-N-(2-((2-hydroxy-3-(4-(2-(1H-pyrazol-1-yl)ethoxy)phenoxy)propyl)amino)ethyl)-. (Method a)

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

Example 29

Preparation of 1-piperidinecarboxamide, 4-hydroxy-N-(2-((2-hydroxy-3-(4- (2- ((((1 -methylethyl)amino)carbonyl)amino)ethyl)phenoxy ) propyl) amino) - ethyl) -. (Method a)

The title compound was prepared according to Example 2 above. Yield 3 g (43%), crystallized 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)ethoxy) ethyl )phenoxy)propyl)amino)ethyl)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 (4.2 g) and 4-cyclohexylcarbonyloxy-piperidinecarbonyl chloride (2.1 g) as starting materials. Yield 2.9 g of a yellow oil.<*>HNMR (500 MHz, CDC13). S 7.1 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, 2.8 7H 2.3 1H, 1.9 2H 1.8 2H, 1.7 2H, 1.6 3H, 1.4 2H, 1.25 3H, 1.05 1H, 0.5 2H, 0.2 2H.

Example 31

Preparation of 2,2-dimethylpropionic acid, 1-(((2-(((S)-2-hydroxy-3-(4-(2-(2-(cyclopropyl methoxy) ethoxy) ethyl) phenoxy ) propyl)amino)etyl)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 (5.0 g) and 4-(2,2-dimethylpropionyloxy)piperidinecarbonyl chloride (2.8 g) as starting materials. Yield 3.0 g of a yellow oil.<*>HNMR (500 MHz, CDCl3): S 7.1 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 3.26H, 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^toxy)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 )-hydroxypropylpropylamine (4.4 g) and 4-benzylcarbonyloxypiperidinecarbonyl chloride (2.8 g) and 4-benzylcarbonyloxypiperidinecarbonyl chloride (2.8 g) as starting materials. Yield 2.6 g of a yellow oil.<i>HNMR (CDCl 3 , 500 MHz): S 7.3 2H, 7.25 3H, 7.12H, 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, l-(((2-(((S)-2-hydroxy-3-(4-(2-(2-(cyclopropylmethoxy)ethoxy)ethyl)phenoxy)propylamino) ethyl) amino) carbonyl) - 4-piperidinyl ester.

2.5gN-(2 - aminoethyl )-3-(4-(2-(2-(cyclopropylmethoxy)ethoxy)ethyl)phenoxy) -

(S)-2-Hydroxypropylamine, 25 ml of dry THF and 0.92 g of diisopropylethylamine were mixed and 2.39 g of 4-(2,3-dichlorophenylcarbonyloxy)piperidinecarbonyl chloride was added in portions with stirring. The mixture was evaporated after a reaction time of 3 hours. 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 SiC>2 and CH2Cl2lMeOH 9:1 as mobile phase. Yield 0.9 g.<*>HNMR (CDCl 3 , 500 MHz, HCl salt): S 7.6 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)-hydroxy-3-(4-(2-(2-(2-cyclopropylmethoxy)ethoxy)ethyl)phenoxy)propyl)amino)ethyl. (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 (13.0 g) and 4-hydroxy-piperidine (3.27 g) as starting materials.Yield 3.1 g.M.P. 77-78°C.The structure was confirmed using NMR analysis.

Example 35

Preparation of hexanoic acid, l-(((2-(((S)-2-hydroxy-3-(4-(2-(2-(cyclopropylmethoxy)ethoxy)ethyl)phenoxy)propyl)amino)ethyl) amino)carbonyl)— 4—piperidinyl ester.

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 (4.5 g) and 4-hexanoyloxypiperidinecarbonyl chloride (4.5 g) and 4-hexanoyloxypiperidine carbonyl chloride (2.64 g) as starting material. Yield 3.1 g. Melting point 25-30°C.<*>HNMR (500 MHz, CDC13): s 7.1 2H, 6.8 2H, 5.25 1H, 4.9 1H, 4.1 1H, 3.95 2H, 3.6 8H, 3.35 2H, 3.3 2H, 3.2 2H, 2.85 8H, 2.3 2H, 1.85 2H, 1.6 4H, 1.3 4H, 1.1 1H, 0.9 3H, 0.5 2H, 0.2 2H.

Example 36

Preparation of 2-methylpropanoic acid, 1-(((2-(((S)-2-hydroxy-3-(4-(2-(2-(cyclopropylmethoxy)ethoxy)ethyl)phenoxy)propyl)amino) ethyl)amino)carbonyl)-4-piperidinyl ester.

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 g) and 4-(methylpropionyloxy)-piperidinecarbonyl chloride (2.6 g) as starting material. Yield 2.4 g.<*>HNMR (CDCl3, 500 MHz): S 7.1 2H, 6.8 2H, 6.25 1H, 4.9 1H, 4.0 2H, 3.65 10H, 3, 3 4H, 3.15 4H, 2.8 211, 2.5 111, 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 dissolving 1-piperidinecarboxamide, 4-hydroxy-N-((2-hydroxy-3-(4-(3-(cyclopropylmethoxy)propyl)-phenoxy)propyl)amino)ethyl)hydrochloride (0.1 g) sodium chloride (0.8 g) and ascorbic acid (0.1 g) in a sufficient amount of distilled water to obtain 100 ml of solution. This solution, which contains 1 mg of active substance per each ml, was used for filling ampoules which were sterilized.

Example 38

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

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

Example 39

2-Methylpropanoic acid, 1 - (((2- ((2-hydroxy-3-(4-(2-methylpropoxy)ethoxy)-phenoxy)propyl)amino)carbonyl)-4-piperidinyl ester chloride (250 g) was mixed with lactose (175.8 g), potato starch, 169.7 g and colloidal silicic acid (32 g). The mixture was moistened with a 10% solution of gelatin and was granulated through a 12-mesh sieve. After drying, potato starch (160

g), talc (50 g) and magnesium stearate (5 g) were mixed together, and the mixture thus obtained was pressed into tablets (10,000) containing 25 mg

fabric. The tablets are sold on the market provided with break markings to obtain a dose other than 25 mg or to obtain several such by dividing.

Example 40

Granules were prepared from 2-methylpropanoic acid, 1-(((2-((2-hydroxy-3-(4-(2-(2-methylpropoxy)ethoxy)phenoxy)propyl)amino)ethyl)amino)carbonyl )-4-piperidinyl ester hydrochloride (250 g), lactose (175.9 g) and an alcoholic solution of polyvinylpyrrolidone (25 g). After drying, the granules were mixed with talc (25 g), potato starch (40 g) and magnesium stearate (2.50 g) and pressed into 10,000 biconvex tablets. These tablets are primarily coated with a 10% alcoholic solution of shellac and then with an aqueous solution containing sucrose (45%), gum arabic (5%), gelatin (4%) and dye (0.2%). Talc and powdered sugar were used for powder treatment after the first five coatings. The coating was then coated with a 66% sugar syrup and polished with a 10% solution of carnauba wax in carbon tetrachloride.

Example 41

An eye drop solution can be prepared with the following composition:

Example 42

An eye drop solution can be prepared with the following composition:

Claims (9)

1. Compound, characterized by the formula: where R 1 is hydrogen or an acyl group where p is an integer 0 or 1, and R^ is an aliphatic, cycloaliphatic or aromatic group, optionally substituted and/or interrupted by heteroatoms, and where Ar is an aromatic or heteroaromatic group known per se. 2. Compound according to claim 1, characterized in that Ar is a group where m is an integer, 0 or 1, n is an integer 1-3, provided that n is an integer 2-3 when m is 1 and R <2> is a group -O-R <3> , -0 -(CH <o> )aO-R"3, a pyrazole group or a group Q is an integer 2-3, and R<3> is a straight or branched alkyl group of 1-8 carbon atoms or a cycloalkylalkyl group of 4-8 carbon atoms, and X is N or C-R, where R is H, CN or OCH3, or a pharmaceutically acceptable salt of such a compound . 3. Compound according to claim 2, or a pharmaceutically acceptable salt thereof, characterized in that X is CH. 4. Compound according to claim 3, characterized in that the group 5. Compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, characterized in that R<1> is hydrogen or an acyl group where P is an integer 0 or 1, and R<4> is a straight or branched alkyl group containing 1-20 carbon atoms, a cycloalkyl or cycloalkylalkyl group containing 3-20 carbon atoms, a phenyl-, phenoxy-phenoxymethyl-, benzyl- or phenylethyl group, where each group R4 possibly contains a substituent and/or is interrupted by one or more heteroatoms. 6. Compound according to claim 5, or a pharmaceutically acceptable salt thereof, characterized in that R<4> is a straight-chain alkyl group containing 1-12 carbon atoms, a cycloalkyl group containing 3-7 carbon atoms or a cycloalkylalkyl group containing 3-12 carbon atoms, each of where possible, these optionally contain a substituent and/or are interrupted by one or more heteroatoms, or a substituted phenyl, phenoxy, phenoxymethyl, benzyl or phenylethyl group with up to 12 carbon atoms. 7. Compound according to claims 1-6, characterized in that it is in the form of a substantially pure S-isomer. 8. Procedure for the preparation of a compound with the formula: where R 1 is hydrogen or an acyl group where p is an integer 0 or 1, and R^ is an aliphatic, cycloaliphatic or aromatic group, optionally substituted or interrupted by heteroatoms, and where Ar is an aromatic or heteroaromatic group known per se and preferably a group where m is an integer 0 or 1, n is an integer 1-3 provided that n is an integer 2-3 when m is 1, and R <2> is a group O-R <3> , -0-( CH2 )qO-R <3> or a pyrazole group or a group- NHgNHR3 where q is an integer 2-3, and R <3> is a straight or branched alkyl group with 1-8 carbon atoms, or a cycloalkylalkyl group with 4-8 carbon atoms, and X is N or C-R, where R is H, CN or OCH3, or a pharmaceutically acceptable salt of such a compound, where in the following part of formula I is denoted RN characterized by a) reacting a compound with the formula: or where X <l> is a hydroxy group, Z is a hydroxy group or a reactive, esterified hydroxy group, or X <*> and Z together form an epoxy group, with a compound of the formula: orb) reacts a compound of the formula: where R<1> and R<2> have the meanings given above, with a connection of the formula where Z has the above meaning or c) reacts with a compound of the formula: with a compound of the formula: where X <l> has the above-mentioned meaning, and X^ and X have the above-mentioned meanings, Z^ however being different from hydroxy, ord) reacts with a compound of the formula: with a compound of the formula: where Z <*> has the meaning given above, for the formation of a compound of formula (I) where Ar has formula (Ia) and m is 1, or) reacts a compound of the formula: where n has the meaning given above, and where the nitrogen atom adjacent to the propanol group can carry a protective group, e.g. a benzyl group, with a compound of the formula: where Ri has the meaning given above, and Y is a leaving group such as halogen, alkoxy, an aryloxy group or an acyloxy group, or f) cleaves a residue from a compound of formula (I) above which is further substituted with a residue, such as a benzyl or substituted benzyl group, at a heteroatom, or g) converts a compound of the formula: where X° is a group containing one or more carbon-carbon unsaturations, and can be converted into the group (0)m (CH2 )n -R <2> by saturating each such unsaturation therein, or h) reduces a Schiff's base with the formula ori) reduces the oxo group to a hydroxy group in a compound of the formula: or j) reduces an amidic carbonyl group in a compound with one of the formulas k) for the formation of a compound of formula (I) where R <*> is an acyl group reacts the existing compound where R^ is H with an acid or acid derivative of the formula: where 7^ is a hydroxy group or a reactive group as defined for a reactive esterified hydroxy group Z above, 1) reacts a compound with the formula: where the nitrogen atom adjacent to the propanol group can carry a protecting group, and where Y is a leaving group, with a compound of the formula: where Ri has the above meaning, and, if desired, introduce, cleave off or convert substituents in the compounds with the definition for the end product, or convert obtained compounds into other end products and/or obtained isomeric mixtures are separated into pure isomers, and/or obtained racemates are separated into optical antipodes and/or obtained free bases are converted into their pharmaceutically acceptable salt or obtained salts are converted into their free bases. 9. Method according to claim 8, characterized in that a compound according to any one of claims 2-7 is produced.