NO863078L - NEW CYCLOALIFATIC KETOAMINES. - Google Patents

Description

In German Offenlegungsschrift 29 19 495, compounds with formula are mentioned

wherein X means the group ^CO or )CH(OH),

R 2 means hydrogen, or a C 1 -C 8 alkyl group and R 1 means hydrogen or a hydroxy group, and R 1 means adamantyl

the residue or a saturated or monounsaturated C₁-C₋₋-cycloalkyl residue, this C₋-C₋₋-cycloalkyl residue can also be substituted with a C₋-C₋-alkyl group or a halogen atom. These compounds improve the cerebral or peripheral circulation.

The invention relates to a method for the preparation of new compounds of formula I.

The compounds produced according to the invention are pharmacologically active and cause an improvement in the contractility of the heart, without thereby affecting the frequency and blood pressure.

If the radical R 1 , R 2 and/or R 2 represents a C 2 -C 1 -alkanoyloxy group, the alkanoyl part of this group may be linear or branched. Preferably, it concerns C₁-C₂-alkanoyloxy groups. The residue R^, R2 and R^ may be the same or different. When the radicals R 1 , R 1 > and R 2 are alkanoyloxy groups, they may likewise be the same or different alkanoyloxy groups.

In the manufacturing process indicated, it is often appropriate in the starting materials to protect the phenolic hydroxyl group by protective groups known per se. Often such protecting groups are already necessary for the production of

ing of the output connections themselves. These protective groups are easily cleavable from the final products. It is about either

about easily solvolytically cleavable acyl groups or hydrogenating cleavable groups such as, for example, the benzyl residue. The solvolytic cleavable protective groups are removed, for example, by saponification with diluted mineral acids in a solvent or suspending agent (lower alcohols) at temperatures between 10 and 15 0°C. However, depending on the type of protecting group, the cleavage already takes place during the process reaction. The latter is, for example, the case when the phenolic hydroxy group is protected with a benzyl group or a carbobenzoxy group, and the method contains a hydrogenation step. If the protective group is not removed during the reaction, then a simple post-treatment of the reaction product is necessary, since the removal of the protective groups takes place, for example, under conditions as indicated above.

Protective groups include, for example: benzyl group, a-phenylethyl group, benzyl group substituted in the benzene nucleus, such as, for example, the p-bromo or p-nitrobenzyl group, the carbomethoxy group, the carbobenzthio group, the trifluoroacetyl group, the phthalyl residue, the trityl residue, the p-toluenesulfonyl residue, et al., but in addition simple acyl groups such as the acetyl group, the formyl group or the tert-butylcarboxy group are also suitable here.

Hydroxy groups present in the process products of formula I can be acylated by means of a C 1 -C 4 -alkanoyl group.

This alkylation can take place in inert solution or suspending agents, such as dioxane, dimethylformamide, benzene, toluene,

at temperatures between 0 to 200°C, preferably 20 to 150°C. As an acylating agent, the following are considered: ketenes such as acid halides, (chlorides, bromides, iodides), acid anhydrides or acid esters of aliphatic carboxylic acids with 2-13 C atoms, optionally with the addition of an acid binding agent

such as alkali carbonates, alkali hydroxides, alkali alcoholates or a tertiary amine, for example triethylamine or pyridine. At the same time, pyridine can also be used as a solvent. The esters are particularly those of the above-mentioned carboxylic acids with lower aliphatic alcohols. In the case of acylation, one can also proceed in such a way that one first prepares an alkali compound from the compound to be reacted, by reacting an inert solvent such as dioxane, dimethylformamide, benzene or toluene, with an alkali metal, alkali hydride or alkali amides (especially sodium or sodium compounds) at temperatures between 0 and 150°C and then the acylating agent is added.

C2-C1-alkanoyl groups in the compounds of formula I can again be cleaved off solvolytically, obtaining the corresponding free hydroxy compounds of formula I. This solvolytic cleaving takes place, for example, by saponification with dilute acids, or with the help of basic substances (pot ash, soda, aqueous alkali solution, alcoholic alkali solutions, NH^), at temperatures between 10 and 150°C, especially 20-100°C.

As resolution or suspension agent, for example: Water, lower aliphatic alcohols, cyclic ethers, such as dioxane or tetrahydrofuran, aliphatic ethers, dimethylformamide, etc., as well as mixtures of these agents.

The production of the compounds takes place according to the method described in the claim.

Regarding the procedure:

The manufacturing process is usually carried out in an inert solvent suspension agent at temperatures between 5 and 250°C, preferably 20-150°C, especially 40-90°C. As a solvent, for example: Lower aliphatic alcohols (ethanol, methanol, isopropanol, propanol), saturated alicyclic and cyclic ethers (dioxane, tetrahydrofuran, diethyl ether), lower aliphatic ketones (acetone), lower aliphatic hydrocarbons or halogen hydrocarbons, (benzene, xylene, toluene), glacial acetic acid, water, resp. mixtures of these agents.

The reaction solution resp. the reaction mixture's pH value should be, for example, between 1 and 6, preferably 2-3.

If a compound of formula III is used as starting material, in which E is the group ✓ CH,,, . work is mostly carried out in the lower part of the specified temperature range (5 to 80°C), with lower alcohols, ethers, acetones, dioxanes or chloroform particularly being taken into account here as solvents. Use of a compound III, in which E means hydrogen and the group -CH2~NraRb, work is mostly carried out in a higher temperature range, (80 to 250°C, especially 80 to 150<Q>C, as the solvent in particular is used , alcohol/water or a two-phase system such as water/benzene or water/toluene.

If a starting material of formula III is used, in which E means two hydrogen atoms, work is carried out in particular between 20 and 150°C. As aldehyde-yielding substances, formaldehyde acetal comes into consideration, for example, from which, in the presence of acid, formaldehyde is released as, for example, polyformaldehyde, paraformaldehyde, hexamethylenetetramine. Instead of formaldehyde and the amine of formula II, an oxazolidine with formula prepared in advance from these substances can also be reacted

respectively a mineral acid addition salt (for example hydrochloride, hydrobromide) thereof, with a compound of formula

If oxazolidine derivatives are not used as salt, it is appropriate to work in the presence of an acid (for example 20% alcoholic hydrochloric acid or hydrobromic acid), or in the presence of an acidic anion exchanger.

Instead of the above-mentioned oxazolidines, the corresponding N,N'-methylene-bis-oxazolidine with the following formulas can also be used

wherein R- has the above meaning.

In the case of using an N,N<1->methylene-bis-oxazolidine, the method takes place, for example, by reacting 1 mol of bis-oxazolidines with 2-3 mol, especially 2.3-2.5 mol of the cycloaliphatic ketone in the presence of an acid or an acidic anion exchanger in a solvent, preferably at temperatures between 20 and 15 0°C.

As acids, for the method according to the invention, in particular, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid are mentioned. However, organic acids or acidic ion exchangers can also be used. Examples of organic acids include: Saturated and mono-unsaturated C^-C^-aliphatic mono- and dicarboxylic acids, such as formic acid, acetic acid, propionic acid, oxalic acid, maleic acid, fumaric acid, aromatic carboxylic acids, such as benzoic acid, cj~C4~alkylbenzoic acid , or aliphatic resp. aromatic sulphonic acids, such as methanesulphonic acids, ethanesulphonic acids, benzenesulphonic acids, toluenesulphonic acids, (for example p-toluenesulphonic acid). Mixtures of these acids can also be used. Acidic ion exchangers include, for example, those mentioned in the book by K. Dorfner, Ionenaustauscher, Verlag De Gruyter, 3rd edition, 1970, in volume 1 of Werken Ionenaustauscher von E. Helfferich, Verlag Chemie, 1959 or in Rompps Chemie Lexi-con Volume 3, Pages 1616-1618 (1976). In detail, it concerns, for example, organic ion exchangers, these active, i.e. ion-forming groups are the carboxyl group or an organic acid group such as the sulfonic acid group (SO^H) or the phosphoric acid group, while the high molecular weight skeleton (matrix) consists of an artificial resin (acrylic resin, polystyrene resin, styrene-divinylbenzene copolymer, styrene-acrylic acid copolymer, divinylbenzene polymer, vinylbenzene polymer, condensation products of phenol for formaldehyde).. Furthermore, acidic cellulose, starch and dextran ion exchangers, carbon ion exchangers are taken into account (of sulphonated high-molecular-weight humus coal), as well as acidic inorganic ion exchangers such as zeolites and aluminum silicates.

The preparation of the above-mentioned mono-oxazolidines and bis-oxazolidines is known.

Starting substances with formula III, in which the group -CH=E is the methyl group, can for example be prepared according to the methods mentioned by H. Stetter and R. Hesse, Monatshefte Chemie 98, page 775 ff (1967) by the corresponding mono- or dihydroxy-cyclohexanecarboxylic acid esters. Hereby, these cyclohexane carboxylic acid ethyl esters are first reacted with phenylsulfone methylmagnesium bromide and then split off in the thus formed reaction products with the aluminum amalgam phenylsulfone group. The cleavage of the phenylsulfone group can, for example, occur

proceed according to the following general regulations:

0.11 mol of the corresponding mono- or dihydroxylated 1-phenylsulfone-2-oxo-2-cyclohexyl-ethane in the cyclohexane ring is dissolved in 1,200 ml of tetrahydrofuran to which 10% 1^0 has been added. 30 g of aluminum amalgam is added to this mixture. After the addition is complete, stir for 30 minutes and then boil for 75 minutes under reflux. After the solution has cooled, it is evaporated in a vacuum. The crystalline product formed after evaporation is now extracted 6 times with 100 ml of ether each time. The combined ether extracts are dried over MgSO 4 , filtered and then evaporated. The colorless oil thus formed is then fractionally distilled in vacuum. Starting substances with formula III, in which the group -CH=E is the group -Cr^-Cr^-NR^jy can for example be obtained using the Mannich reaction of ketones with formula III, in which -CH=E is the methyl group, with a lower dialkylamine or a cycloalkylamine in the presence of formaldehyde. Starting substances with formula III in which -CH=E is the group -CH=CH2^ can for example be obtained from ketories with formula III, in which -CH=E is the group -CI^-CI^NR^R by splitting off the amide (for example by steam distillation) or by thermal HCl cleavage of the corresponding cycloaliphatic B-chloro-ethyl ketones (formula III -CH=E = -Cr^Cr^Cl) .

The compounds which contain asymmetric carbon atoms and which usually appear as racemates can be split in a manner known per se, for example by means of an optically active acid into the optically active isomers. However, it is also possible from the beginning to use optically active resp. also diastereomeric starting substances, as the end product is then a correspondingly pure optically active form, resp. diastereomeric configuration. For example, it concerns compounds of norephedrine no and of pseudonorephedrine configuration. Diastereomeric racemates can also occur as two or more asymmetric carbon atoms are present in the compounds produced. Cleavage is possible in the usual way, for example by recrystallization and chromatography as well as the other usual methods, for diastereomer separation. Generally, process products are obtained due to the substituted cyclohexane ring as stereoisomeric mixtures. The process product formed according to example 1 exists, for example, to 87.5% in transform and to 12.5% in cis form. The process product formed according to example 2 is present in 66.6%

in transform, and to 33.3% in the cis form.

Depending on process conditions and starting forms, the final substances with formula I are obtained in free form, or in the form of their salts. The salts of the final substances can be transferred back to the bases in a manner known per se, for example with alkali or ion exchangers. From the latter, salts can be prepared by reaction with organic or inorganic acids, especially those which are suitable for the formation of therapeutically useful salts.

The compounds prepared according to the invention are suitable for the preparation of pharmaceutical compositions. The pharmaceutical compositions or medicines may contain one or more of the compounds according to the invention or also mixtures thereof with other pharmaceutically active substances. For the production of pharmaceutical preparations, the usual pharmaceutical carriers and excipients can be used. The drugs can be used enterally, parenterally, orally or perlingually. For example, administration can take place in the form of tablets, capsules, dragees, drops, ointments, powders, liquids or aerosols. As liquida, it comes e.g. in question: Oily or aqueous solutions or suspensions, emulsions, injectable aqueous or oily solutions or suspensions.

In the examples, resp. from 1-norephedrine. The corresponding d-isomers resp. racemates are obtained when, for example, instead of the levorotatory norephedrine starting compound, a corresponding dextrorotatory form or race food.

It often pays to isolate the process products to transfer most of the immediate reaction product formed as hydrochloride by treatment with, for example, diluted ammonia to the free base, and optionally transfer this again to a salt in the usual way.

The compound according to the invention shows on anesthetized dog (anaesthesia with Pentobarbital), e.g. the following effect: The contractility of the heart muscle is increased, the heart volume is improved, the blood flow in the arteries is increased.

For example, with the above-mentioned experimental method at a dose of 0.3 mg/kg body weight (dog), an inotropy increase of 26% is achieved. The lowest already effective dose in the above-mentioned animal experiment is, for example, 0.1 mg/kg intravenously.

As a general dose range for the effect (animal experiments as above), for example: 0.1-1.0 mg/kg intravenously, especially 0.3 mg/kg.

Indications for the compounds prepared according to the invention may come into consideration: for example myocardial insufficiency.

The acute toxicity of the compound according to the invention

on mice (expressed with the Ld 50/kg method according to Miller and Tainter: Proe. Soc. Exper.Biol. A. Med. 57 (1944) 261) lies, for example, with oral application above 250 mg/kg (e.g. .between 250 and 600 mg/kg).

The drugs can be used in human medicine, veterinary medicine as well as in agriculture alone or in a mixture with other pharmacologically active substances.

Example 1

-/~3-hydroxy-3-phenyl-propyl-(2]_/-</-3-(4-hydroxy-cyclohex-yl)-3-oxo-propyl/-amine

The reaction mixture of 5 g (0.03 mol) 4-hydroxy-1-acetyl-cyclohexane (bp. 3105-106°C), 5.9 g (0.018 mol) €-N,N'-methylene-bis-(4 -methyl-5-phenyl)-oxazolidine (prepared from Å. -norephedrine), 40 ml of isopropanol and 8 ml of 5.1 normal isopropanol in hydrochloric acid are heated for 3 hours with stirring and reflux. The reaction mixture is allowed to stand overnight at room temperature. The crystallized product is suctioned off and washed with isopropanol (5 ml) and 10 ml of acetone. Melting point of the hydrochloride: 196-199°C.

Example 2

-/_ 3-hydroxy-3-phenyl-propyl-(2)_7-Z 3-(3-hydroxy-cyclohexyl)-3-oxo-propyl/-amine

5 g (0.03 g) 3-hydroxy-1-acetyl-cyclohexane (bop «4116-177°C), 5.9 g (0.018 mol) C -N,N<1->methylene-bis-(4 -methyl-5-phenyl)-oxazolidine (produced from -C-norephedrine), 40 ml of isopropanol and 8 ml of 5,1-normal isopropanolic hydrochloric acid are heated for 6 hours under reflux. After complete reflux, the cooled reaction mixture is evaporated in vacuo. The evaporated residue is chromatographed over silica gel. The eluent is dichloromethane/methanol in a ratio of 95:5. The chromatographed product is transferred by mixing with isopropanolic HCl to hydrochloride. Boiling point of the hydrochloride 177-179°C. Example 3 -C-1_ 3-hydroxy-3-phenyl-propyl-{2\J-/_ 3-(3,4-dihydroxy-cyclohexyl)-3-oxo-propyl/-amine

4.6 g (0.03 mol) 3,4-dihydroxy-1-acetyl-cyclohexane, 5.9 g (0.018 mol) -C-N,N'-methylene-bis-(4-methyl-5-phenyl )-oxazolidine (prepared from -6-norephedrine), 40 ml of isopropanol and 8 ml of 5.1 normal isopropanol hydrochloric acid are heated for 6 hours under reflux. It is then allowed to cool and the resulting reaction mixture is evaporated in a vacuum. The evaporated residue is chromatographed over silica gel. Dichloromethane/methanol in a ratio of 90:10 is used as an eluent. The chromatographed product is transferred to hydrochloride. Melting point of the hydrochloride 178-181°C. Nuclear magnetic resonance spectrum in deuterated chloroform 60 megahertz (chemical shift (6) of the hydrogen atom with Spin 1):

6 = 1.1 (doublet of 3 H of the CH3~ group)

6 = 1.2-2.2 (multiple of 6 H of the 3-ring-CH2~ group)

6 = 2.4-2.6 (multiplet of H of ✓CH-CO moieties)

= 3.0 - 4.0 (multiplet of 7 H of the structural part,

-CO-CH2~CH2-NH, -NH-CH-CH3, 2 times /CH^OH). 6 = 5.2 (doublet 1 H . of the structural part -8h-) 6 = 7.4 (multiplet 5 H of the phenyl ring). Example 4 - £-{_ 3-hydroxy-3-(4-benzyloxyphenyl)-propyl-(2]_7-/ 3-(3-hydroxy-cyclohexyl)-3-oxo-propyl-(1]_7_amine).

1.42 g (0.01 mol) of 3-hydroxy-1-acetyl-cyclohexane is heated with 2.8 g of -d-N,N'-methylene-bis-/4-methyl-5-(4-benzyloxyphenyl)-oxazolidine ( produced from ^-4-hydroxynorephedrine). 5 ml of 5.1 normal isopropanolic hydrochloric acid and 40 ml of isopropanol for 6 hours at 70°C. It is then allowed to cool and the resulting reaction mixture is evaporated in a vacuum. The residue is neutralized with aqueous ammonia and the product formed is chromatographed over silica gel. The eluent used is dichloromethane/methanol in a ratio of 85:15. The product formed is transferred in acetone to the oxalic acid salt. Oxalate's melting point: 12 3 - 126°C.

Example 5 (cleavage of a protecting group).

-C-(3-hydroxy-3-(4-hydroxyphenyl)-propyl-(2_)/- 1~ 3-(3-hydroxy-cyclohexyl)-3-oxo-propyl/-amine.

90 mg (0.0002 mol) £ -/~3-hydroxy-3-(4-benzyloxyphenyl)-propyl-(2]_7-^ 3-(3-hydroxy-cyclohexyl)-3-oxo-propyl-(1 ]_7-amine oxalate is dissolved in methanol and mixed with 9 mg of Pd-C

(10%-ig). It is hydrogenated for 1 hour at 1 bar pressure, the catalyst is sucked off, the solution is evaporated. The oil formed is mixed with diethyl ether, the resulting crystals are sucked off and recrystallized from isopropanol/methanol. Melting point of the oxalate: 195-197°C.

Claims (1)

1. Process for the preparation of therapeutically active compounds of formula wherein R^ means hydrogen, a hydroxy group or ■-C^-C^-alkanoyloxy group, R^ means a hydroxy group or a C^-C^ -alkanoyloxy group and R^ means hydrogen, a hydroxy group, a C^-C^ -alkanoyloxy group or a benzyloxy group, and their acid addition salts, characterized in that an amine of the general formula in which R^ has the indicated meaning, is reacted with a compound of the general formula where R^ and R^ have the indicated meanings, and E means a methylene group or a hydrogen atom plus the group -CP^-NRg^ and Ra and Rtø are low molecular weight alkyl residues which may also be attached to a ring, or where E means hydrogen atoms, when working in the presence of formaldehyde or a formaldehyde-releasing substance, the compounds formed are optionally acylated, and/or protective groups present are cleaved off, and the compounds formed are optionally converted into their acid addition salts.