NL7908030A - N-substd. kinicine analogues - useful as cardiovascular medicaments - Google Patents

Abstract

piperidine derivs. of formula (I) and their salts are new. In (I) A is CH2, CHOH or CO, R1 is H, OH or lower alkoxy, R2 is Et or vinyl, R3 is 2-8C alkyl, 1-8C hydroxyalkyl, alkoxyalkyl, alkanoyloxyalkyl, 3-6C cycloalkyl, hydroxy-, alkoxy- or alkanoyloxy-cycloalkyl, cycloalkylalkyl, hydroxy-, alkoxy- or alkanoyloxy-cycloalkylalkyl, CN, cyanoalkyl, alkenyl, alkynyl, tetrahydrofuryl, mono- or dialkylaminoalkyl, opt. substd. phenyl, phenylalkyl or phenylhydroxyalkyl, opt. substd. diphenylalkyl, opt. substd. phenylalkenyl, opt. substd. benzoyl or benzoylalkyl, opt. substd. heteroaryl or heteroarylalkyl, or opt. substd. heteroaroyl or heteroaroylalkyl, with the proviso that R3 is not n-Pr or i-Pr when A is CO, R1 is MeO and R2 is vinyl. (I) have cardiovascular activity, e.g. antithrombotic, vasodilatory and esp. antihypertensive and antiarrhythmic activity.

Description

v ïq U / Jl ACF CHEMIEFARMA NV, Maarssen

Novel quinoline derivatives and pharmaceutical preparations containing such a compound, as well as a method of preparing these compounds.

The invention relates to new quinoline derivatives.

From Ann. Fharm. Fr. 24, 39 (1966), the pharmacodynamic properties of quinicin (formula 2), also called viquidil, are known, in particular the central nervous system action and the hypotensive, vasodilatory and anti-spasmodic action.

British Patent 1,294,538 describes the use of viquidil in the treatment of cerebral vascular disorders and memory disorders in humans.

In Dutch patent application 77.06614, quinoline-10 derivatives of formula 3 are described, wherein R is hydrogen, C 1-6 alkyl or 2 - 4 a ^ enyl and x hydrogen, halogen, C 1-6 alkyl, alkoxy or alkylthio, trifluoromethyl, nitro, hydroxy, or an amino group optionally substituted by one or two C 1-6 alkyl groups, or C 1-6 acyl or alkyl sulfonyl, which compounds have an inhibitory effect on serotonin uptake and anti-arrhythmic activity.

It has been found that quinoline derivatives with a 4-substituent containing an N-substituted piperidyl group have unexpected pharmacological properties, namely beneficial effects on the cardiovascular system, such as anti-hypertensive, anti-thrombotic, vasodilatory and anti-arrhythmic operation.

The compounds are especially valuable for use in drugs with anti-hypertensive and anti-arrhythmic action.

The invention therefore provides compounds of the formula 1 wherein 25 A -CEL-, -CHOH- or -CO-, 1 R hydrogen, hydroxy or lower alkoxy, 2 R ethyl or vinyl, and 3 RC alkyl, C 8 hydroxyalkyl, lower alkoxyalkyl or lower 7908030 ► * 2 alkanoyloxyalkyl, C18 cycloalkyl, hydroxycyeloalkyl, lower alkoxycycloalkyl or lower alkanoyloxyeycloalkyl, cycloalkyl lower alkyl, hydroxy, lower alkoxy or lower alkanoyloxyeycloalkyl lower alkyl; cyano, cyano lower alkyl, lower alkenyl, lower alkynyl, tetrahydro-furyl, mono or. di-lower alkylamino lower alkyl; optionally substituted phenyl, phenyl lower alkyl or phenyl hydroxy lower alkyl, optionally substituted diphenyl lower alkyl, optionally substituted phenyl lower alkenyl, optionally substituted benzoyl or benzoyl lower alkyl, optionally substituted heteroaryl or heteroaryl lower alkyl, or optionally substituted heteroaroyl or heteroaroyl lower alkyl, wherein the substituents in the 3- and 4-positions of the piperidine ring are in the cis position relative to each other, excluding n-butyl and iso-butylkinicin.

15

As usual, the carbon chains of the different groups can be both straight and branched.

The term "lower" is here understood to mean a group with a maximum of 6 carbon atoms.

The term "optionally substituted" with respect to phenyl includes a phenyl group which may be substituted by one, two or three groups selected from lower alkyl, lower alkoxy, halogen or hydroxy (no more than two hydroxy groups).

By the term "optionally substituted", in relation to heteroaryl, is meant a heteroaryl group which may be substituted by one, two or three groups selected from lower alkyl, lower alkoxy or halogen.

A suitable meaning of A is -CI ^ - Another suitable meaning of A is -CHOH-. Also suitable is the meaning A is -CO-. It has been found that the compounds wherein A is -CHOH- are preferred compounds with regard to their therapeutic properties.

r 'in the sense of alkoxy is preferably methoxy. Preferably R * is hydrogen or methoxy. The meaning R is hydrogen is favorable in this regard. Also favorable is the meaning R * is methoxy.

R 35 in the sense of alkyl is preferably ethyl. Other suitable alkyl groups include n-butyl, iso-butyl, n-pentyl, 7908030-4 iso-pentyl, n-hexyl, n-heptyl or n-octyl.

3 R in the sense of cycloalkyl is, for example, cyclopropyl or cyclobutyl.

3

Suitable values for R in the meaning of hydroxyalkyl, hydroxycyeloalkyl or hydroxycycloalkyl lower alkyl include the substituents of the formula - (CH 2) C (0H) R ^ R ^, where η is 0, 1 or 2, 4 5 ^ n R hydrogen or C.. alkyl and R is hydrogen or C., alkyl or wherein 4 5 1-J.

R and R together with the carbon atom to which they are attached are a

Cg_g carbocyclic ring forms. The meaning of 10 I-hydroxy-I-methyl-ethyl is very suitable.

3

Suitable values for R in the sense of alkoxyalkyl, alkoxycycloalkyl or alkoxycycloalkylalkyl include the substituents of the formula - (C 1 -C-CCOR-R-R-R-1) wherein n, R-1 and R ** have the above meanings and R-C. alkyl.

Suitable values for R in the sense of alkanoyloxyalkyl, alkanoyloxycycloalkyl or alkanoyloxycycloalkylalkyl include the substituents of the formula - (CH.) C (0C0R ^) R ^ R ^, where n, R ^ 5 Δn 7 and R the above meanings and R is hydrogen or C.alkyl.

3 R in the sense of lower alkenyl is preferably vinyl.

If R is lower alkynyl, the preferred group is ethynyl.

3

Suitable values for R in the meaning of di-lower alkyl-amino lower alkyl include the substituents of the formula 8 9 8 9

- (C 1 -NR R, wherein n is 0, 1 or 2, R is hydrogen or C 1-4 alkyl and R

C is alkyl.

Suitable values for R in the meaning of optionally substituted phenyl, phenyl lower alkyl or phenylhydroxy lower alkyl include phenyl, benzyl, α-hydroxybenzyl or benzyl which is substituted by 1, 2 or 3 methoxy groups.

3 R in the meaning of optionally substituted diphenyl lower alkyl is preferably 3- (4,4 * -difluorodiphenyl) propyl.

3

A suitable value for R in the meaning of optionally substituted phenyl lower alkenyl is, inter alia, cinnamyl.

3

Suitable values for R in the meaning of optionally substituted benzoyl or benzoyl lower alkyl include benzoyl, fluorobenzoylmethyl, benzoylmethyl, 2-benzoylethyl, 2- (methylbenzoyl) ethyl, 2- (methoxybenzoyl) ethyl, 2- (chlorobenzoyl) ethyl, 2- (fluorobenzoyl) -ethyl and aminobenzoyl. Very useful are the meanings 4-fluorobenzoyl-methyl, 2- (4-methylbenzoyl) ethyl and 2- (4-methoxybenzoyl) ethyl.

7908030 3.

% · * 4

Suitable values for R m meaning heteroaroyl or heteroaroyl lower alkyl include monocyclic heteroaromatic ring systems with one or two heteroatoms, preferably oxygen, nitrogen or sulfur, which ring systems are optionally substituted by a lower alkyl group. Suitable are, inter alia, thienyl and furyl.

A particular group of compounds of formula 1 is the 23 group of formula la, wherein R and R have the aforementioned meanings 2. Of these, the compounds wherein R is ethyl are preferred.

3

The preferred values for R here are 2-benzoylethyl, 2- (4-fluorobenzoyl-ΙΟ ethyl) and 1-hydroxy-1-methyl-ethyl.

Another group of preferred compounds is that of formula 1b, 2 3 'wherein R has the aforementioned meanings and R ethyl) n-butyl, iso-butyl, n-pentyl, iso-pentyl, lower alkoxy lower alkyl, cycloalkyl lower alkyl, di-lower alkylamino is lower alkyl, lower alkenyl, optionally substituted phenyl lower alkyl or optionally substituted benzoyl 2 or benzoyl lower alkyl. In this case R is preferably vinyl. A special 2 3 *

more preferred is the compound of formula Ib wherein R vinyl and R

2 is n-butyl. Also preferred are the compounds wherein R is vinyl 3 'and R is 2-benzoylethyl, 2- (4-fluorobenzoylethyl) or 1-hydroxy-1-methyl-20 ethyl.

A further group of preferred compounds of formula 1 is 2 of formula 1c, wherein R has the aforementioned meanings and 3 "R ethyl, n-butyl, iso-butyl, n-pentyl, iso-pentyl, cyclobutyl, lower alkenyl, optionally substituted phenyl lower alkyl or optionally substituted benzoyl or benzoyl is lower alkyl, wherein R is preferably 2.3 "vinyl. Very suitable are the compounds wherein R is vinyl and R is cyclobutyl, 2-benzoylethyl or 2- (4-fluorobenzoylethyl).

A particular group of preferred compounds of formula 1 is that of formula Id, wherein A has the above meaning, n is one, two or three, R10 is hydrogen, methyl, methoxy or -C (O) R ^, wherein R ^ is an optional substituted phenyl group.

Particularly suitable compounds with anti-hypertensive activity 1 '.2' are those according to formula 1, wherein R is hydrogen or methoxy, R is ethyl or vinyl and Ar is phenyl. thienyl or phenyl substituted by one, two or three groups selected from fluorine, chlorine or methoxy. Very suitable values for Ar include phenyl, fluorophenyl, (chlorophenyl, methoxyphenyl and thienyl). A very suitable value for R 1 is hydrogen, for R 1 ethyl. The preferred values for Ar are phenyl or 4-fluorophenyl, the latter the Most preferred is from the foregoing that it will be appreciated that a particularly suitable anti-hypertensive compound of the invention 1 '2' is the compound of Formula I wherein R is hydrogen, R ethyl and Ar is 4-fluorophenyl.

Particularly suitable compounds with antiarrhythmic 1 "activity are those according to formula 1, wherein R is hydrogen or methoxy 2".

and R is ethyl or vinyl. Very suitable are the connections in which 1 "2"

R is methoxy. Also very suitable are the compounds in which R

is ethyl. From the foregoing, it will be apparent that a particularly suitable antiarrhythmic compound of the invention is the 1 ”2” compound of formula 1f, wherein R is methoxy and R is ethyl.

The compounds of formula 1 described above can exist as free bases or in the form of acid addition salts thereof, for example the salts of mineral acids, such as hydrochloric acid, bromo-hydrochloric acid or sulfuric acid, or of organic acids such as acetic, fumaric or tartaric acid. The acid used must of course be pharmaceutically suitable.

The compounds of formula 1 wherein A has the meaning -CHOH- contain an asymmetric carbon atom so that two stereoisomers can exist, provided that further asymmetric carbon atoms exist in a side chain. One or more asymmetric carbon atoms in the N substituent can result in different diastereoisomeric forms.

The compounds of the invention are obtained in crystalline form. They can also be obtained in the form of solvates such as hydrates.

The compounds of the invention as represented by formula 1 include both the free bases, acid addition salts, racemates, separated optical forms and mixtures thereof.

The invention also relates to a process for preparing compounds of formula 1, wherein 1 2 A) a compound of formula 4, in which A, R and R have the above meanings, is alkylated with a compound of formula 5, wherein R has the above meaning 35 and Y is a nucleophilic leaving group, in particular 7908030 V 6 chlorine, bromine, iodine, aryl, aralkyl or alkyisulfonyloxy and especially mesyloxy or tosyloxy, 1 2 or B) a compound of formula 6 wherein A, R and R have the above meanings is reduced, 5 or C) the above compound of formula 4 is reacted with a 12 epoxide of formula 7 wherein R is C 1 alkyl, lower alkenyl, W 13

lower alkynyl, optionally substituted phenyl lower alkyl and R.

12 13 is hydrogen, or wherein R and R together with the carbon atom to which they are attached form a C 1 -cycloalkyl group, whereby 3 r 2 10 is formed in a compound of formula I, wherein R / is -Cx 'such as defined above, '' 13 / or D) a compound of formula 1 wherein R 1 contains a hydroxyl group is alkylated, 3 or E) a compound of formula 1 wherein R contains a hydroxyl group is acylated.

The reaction according to method A) is preferably carried out by using an equivalent amount or a small excess of the alkylating agent of the formula S. Preferably an acid binding agent is added, which does not react with the alkylating agent. Sterically hindered amines, such as dicyclohexylethylamine, can be used for this purpose, but inorganic bases such as sodium or potassium carbonate, and in particular sodium or potassium bicarbonate, are generally preferred.

The reaction is preferably carried out in an inert organic solvent such as acetone, butanone, methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofuran, dimethyl formamide, dimethyl sulfoxide, dioxane, methylene chloride, chloroform, benzene, toluene, xylene or a mixture of the like solvents. Preference is given to methyl ethyl ketone, dimethylformamide or toluene or mixtures of these solvents.

In general, the reaction can be carried out at a temperature of between 0 ° C and the boiling point of the solvent.

If less reactive alkylating agents are used, the reaction can be accelerated by adding catalytic or equivalent amounts of sodium or potassium iodide.

The reduction according to method B) is preferably carried out with diburane or a complex hydride, such as lithium aluminum hydride.

7908030 7 • *

The hydride is added in equivalent amounts or in excess, preferably up to three times the amount. The reduction is preferably carried out in an inert solvent, preferably in tetrahydrofuran, at a reaction temperature between 0 ° C and the boiling point of the solvent.

It should be noted that some reducing agents are also capable of reducing carbonyl or alcohol groups. In compounds of formula 6, wherein A is -CO- or -CHOH-, these groups are usually converted to methylene groups to give compounds of formula 1, wherein A is -C 2 -.

For example, the compounds of formula 6 can be prepared by acylation of a compound of formula 4 with a compound of formula 8 wherein R has the above meaning 3 and X is halogen or -OCOR.

The acylation of the compounds of formula IV is preferably carried out in the presence of an acid-binding agent, preferably triethylamine or pyridine. Suitable solvents include

chloroform, pyridine or dimethylformamide. Usually the reaction temperature is between 0 ° C and the boiling point of the reaction mixture.

The compounds of formula 6 can also be prepared by reacting a compound of formula 4 and a carboxylic acid of formula 3, wherein R has the above meaning, presence of dicyclohexylcarbodiimide. This acylation is carried out under normal conditions, for example in chloroform as a solvent, after which the reaction product is isolated in the usual manner.

Method B) is advantageous for the preparation of compounds 3 of formula 1 wherein R carries an alkoxy group.

Method C) can be carried out in an inert organic solvent, preferably a lower alcohol of 1 to 5 carbon atoms, or in a mixture of alcohol with dichloromethane. Sometimes it is advantageous to add water to the reaction mixture.

The reaction conditions usually depend on the reactivity of the epoxide. Usually the reaction takes several hours and is preferably carried out at temperatures between 20 ° and 120 ° C. If a volatile epoxide is used, it may be necessary to carry out the reaction in a closed system.

7908030 8

In method D), the hydroxy group is first converted to the corresponding alkali salt, for example with sodium hydride in an aprotic solvent. This salt is then treated with an alkyl halide or an alkyl or aryl sulfone ester, but preferably with an alkyl halide.

Method E) is preferably carried out with an acid chloride or anhydride, as described under Method D).

The starting compounds of formulas 4, 5, 7, 8 and 9 are either known or can be prepared from known compounds in the usual manner.

The reaction products obtained by any of methods A - E can be isolated and purified from the reaction mixture in the usual manner,

In some instances, certain reaction steps can be carried out in a different order or simultaneously or without isolating the intermediates. These possibilities are all included in the invention.

It will be apparent to those skilled in the art that protecting groups can be used at various reaction stages to protect certain reactive functions, in accordance with conventional chemical practice.

Some of the compounds of formula 1 can also be used for the preparation of other compounds of formula 1 and are therefore also suitable as intermediates.

Diastereoisomers can be separated by known techniques based on their different physical and chemical characteristics, for example, by fractional crystallization or column chromatography. These isomeric separations can be carried out after the last step of the relevant synthesis or, if desired, in an earlier phase, after the mixture of diastereoisomers has been formed.

Racemic mixtures can be cleaved into the enantiomers using known racemate cleavage methods, for example, by separation of their salts with suitable optically active acids.

The free bases and acid addition salts of the compounds of formula 1 can be converted into each other by standard methods.

The compounds of formula 1 have pharmacological action.

7908030 * w 9

In particular, they have cardiovascular activity, for example, anti-hypertensive, anti-thrombotic, vasodilatory and anti-arrhythmic activity.

A suitable daily dose (for a 70 kg human) is 1 - 100 mg of a compound of formula 1, which is preferably administered 2-4 times daily in doses of 0.5 - 50 mg or in the form of a retard formulation. Unit packs for oral administration may contain, for example, 0.5, 1, 2.5, 5, 10, 20, 25 or 50 mg of active substance.

The compounds can be administered as a free base or in the form of a pharmaceutically acceptable acid addition salt, which salt has the same order of action as the free base.

The compounds of formula 1 can be mixed with conventional pharmaceutically suitable diluents or carriers.

If desired, other excipients can also be added to allow administration, for example, in the form of tablets, capsules and injection solutions. The compounds can also be administered in combination preparations with other active substances.

The pharmaceutical preparations can be formulated in a conventional manner, for example according to the formulation of other compounds with anti-hypertensive action.

The following examples further illustrate the invention.

25 7908030 10

Example I

N-3-benzoy 1-n-propy 1-hydroc inchonic ine

co-ch2-ch2- ^ \ h co-ch2-ch2 - / \ - (ch2) 3-c O

I I I 2 5 -► [1 C2H5

A solution of 249.3 g (0.75 mol) of hydrocinchonicin.HCl 10 in 2000 ml of water was made alkaline with 4N sodium hydroxide (pH 9-10) and extracted with 1000 ml of toluene. The water layer was separated from the toluene layer and the toluene fraction was dried with molecular sieves (4 lb) and filtered.

To this dried solution, 207 g (1.5 mole) of potassium carbonate and 164.3 g (0.9 mole) of γ-chlorobutyrophenone were added, and this mixture was refluxed with stirring for 24 hours. A precipitate of potassium chloride formed during the reaction. The conversion was monitored by thin layer chromatography (silica gel with chloroform / acetone / diethylamine 5: 4: 1 as the running liquid). After the reaction mixture cooled to room temperature, water was added, the layers were separated and the toluene layer was evaporated under reduced pressure to a volume of about 250 ml. The solution was filtered over a short silica gel column with chloroform as the running liquid. The fractions containing the desired product were evaporated under reduced pressure, leaving the title compound as oil.

Example II

N-3-benzoy1-n-propy1-hydroc inchonic ine fumarate 30

The oil obtained according to Example I was dissolved in acetone, after which fumaric acid was added to the boiling solution until a pH of 6-7 was reached. The solution was cooled to room temperature, where the title compound crystallized.

The salt was recrystallized from acetone / methanol, mp 127-129 ° C. Analysis: Found C 70.96, H 6.81, N 5.01; calculated C 71.13, H6.9I, N 4.92. In the same manner, the following compounds were prepared: 7908030 * * 11 fCH2-CH2y-) H Α-ΟΗ ^ -ΛΛ-Ο r2 ^ * QX - * 0J r2 (+ hx)

Vrb, A R1 R2 Q mp. ° C / salt X (QX) 1 CO H ethyl - (CHj.-CO- ^ 7 (oil) Cl (ir.) \ - / 2 CO H ethyl - (CHj ^ -CO -f ^ 127-129 BF Cl (iierh.) \ = / 3 CO OCHg vinyl - (CH ^ -CO- ^ ^ 117-11-9 BF Cl 4 CHOH H ethyl - (- CH2 ^ 184-186 BO Cl 5 CHOH 0CH3 ethyl - (CH ^ -CO Ό 148-151 BO Cl 6 CH2 H vinyl - (CH2) 3-00- ^ ^ 119-121 BF Cl 7 CH2 H ethyl - (CH2) ^ - 00- ^ ^ 191- 192 BO Cl 8 CH2 0CH3 vinyl - (CH2) 3-C0- ^ ^ 92-94 HC1 Cl 9 CO H ethyl - (CH2) 3-C0- ^ ^ ~ GH3 121-123 BF cl 10 CH2 H vinyl - (CH ^ -CO - ^ "" ^ - CH3 124-126 BF Cl 11 CO H ethyl - (CH2) 3-C0 O OH 175-177 Fu Cl 12 CO S ethyl - (CH ^ -CO- ^ ^> - 0CH3 139 -141 BF Cl 7908030 12 *

Vrb. A R1 R ^ Q mp. ° C salt X

13 CH2 H vinyl - (CH ^ -CO- ^ ^ -0CH3 122-124 BF Cl 14 CO H ethyl - (CH2) 3-C0 O Cl 128-130 BF I Cl 15 CH2 0CH3 vinyl - (CH ^ -CO 1 128-131 biHCl Cl 16 CO H ethyl - (CH ^ -CO O * 143-146 BF Cl 17 CHOH H ethyl - (CH ^ -CO- ^ y — F 186-188 BO Cl 18 CO H ethyl - (CH ^ -CO- ^ Cl 122-124 BF Cl 19 CO H ethyl - (CH ^ -CoJTj) 157-160 BF Cl 20 CO H vinyl - (CH2) 2-CH3 170-172 BO Br 21 CO H ethyl - (CH2) 2-CH3 187-189 BO Br 22 CO OH ethyl - (CH2) 2-CH3 158-159 HC1 Br 23 CO 0CH3 vinyl - (CH ^ -CHj 115-117 BF Br 24 CO 0CH3 ethyl - (CH2) 2-CH3 202-204 BO Br 25 CO OC3H? Ethyl - (CH2) 2-CH3 135-136 BF Br 26 CO ° iC5Hn ethyl. - (CH2) 2-CH3 190-192 BO Br 27 CHOH OCH3 ethyl - (CH2) 2-CH3 124 (d) HG1 Br 28 CH2 H vinyl - (CH2) 2-CH3 236-239 biHCl Br 29 CH2 H ethyl - (CH2) 2-CH3 178-180 HCl Br 30 CH2 OH ethyl - (CH2) 2 -CH3 176-179 HC1 Br 31 CH2 0CH3 ethyl - (CH2) 2-CH3 145-153 BO Br 32 CH2 OC3H7 ethyl - (CH2) 2-CH3 136-138 BO Br 7908030 »f 13

• A

Vrb. A R1 R Q mp. ° C salt X

33 CH2 O-iC ^ Hjj ethyl - (CH2) 2-CH3 158-159 BO Br 34 GO H ethyl - (CH2) 3-CH3 160-162 BF Br 35 CO H ethyl - (CH ^ -CHg 102-104 BF Br 36 CO OCH3 vinyl - (CH2) 4-CH3 142-144 BF Br 37 CHOH H ethyl - (CH ^ -CHg 116-119 BO Br 38 CH2 H vinyl - (CH2) 4-CH3 142-143 BO Br 39 CH2 H ethyl - (CH2) 4-CH3 141-142 BF Br 40 CH2 0CH3 vinyl - (CH2) 4-CH3 80-83 BO Br 41 CH2 0CH3 ethyl - (CH2) 4-CH3 145-147 BO Br 42 CO H ethyl - (CH2) 5-CH3 106-108 BF Br 43 CO H ethyl - (CH2) g-CH3 90-93 BF Br 44 CO H ethyl - (CH2) g-CH3 105-107 BF Br 45 CO 0CH3 vinyl - ( CH2) g-CH3 134-136 BF Br 46 CH2 H vinyl - (CH2) g-CH3 173-174 BO Br 47 CH2 H ethyl - (CH2) g-CH3 124-126 BF Br 48 CH2 OH ethyl - (CH2) g-CH3 156-158 BO Br 49 CH2 0CH3 vinyl - (CH2) g-CH3 135-137 BO Br 50 CO H ethyl -CI ^ -CHCCH ^ 148-150 BF Br 51 CO H ethyl - (CH2) 2-CH (CH3) 2 180-182 BF Br 52 CH2 OCH3 ethyl - (CH2) 2-CH (CH3) 2 134 BO Br 53 CO H ethyl - <CH2) 3-CH (CH3) 2 138-140 BF Br 54 CO OCH3 vinyl - (CH2) 3-CH (CH3) 2 158-160 BF Br

55 CO 0CH3 vinyl -CH ^ CH ^ ^ 183-185 BF I

56 CO H ethyl -CH2-CH2-0CH3 140-142 BF Br 57 CO 0CH3 vinyl -CH2-CH2-OCH3 126-128 BF Br 58 CO H ethyl - (CH2) 4-OCH3 108-110 BF Br 7908030 14 w «

Vrb, A R * Q mp. (° C) salt X

59 CO H ethyl - (CH ^ -CN 149-151 BO Br 60 CO H ethyl -CH2 ~ <^] 201 BO Br 61 CO H ethyl 146 (d) BF Br 62 CO H ethyl - (CH2) 2-N ( CH3) 2 (oil) Cl 63 CO 0CH3 vinyl - (CH2) 2-N (CH3) 2 223-225 biHCl Cl 64 CO H ethyl - (CH2) 2-N (C2H5) 2 175-176 BF Cl 65 CO 0CH3 vinyl -CH2-CH = CH2 97-99 BF Cl 66 CH2 H vinyl -CH2-CH = CH2 146-148 BO Cl 67 CH2 H ethyl -CH2-CH = CH2 170-171 BO Cl 68 CH2 0CH3 vinyl -CH2-CH = CH2 191-193 Pa Cl 69 CH2 0CH3 ethyl -CH2-CH = CH2 145-148 BO Cl 70 CO H ethyl -CH2-CH = CH Ό 153-155 BF Br 71 CO H ethyl -CH2-CSCH _OCH3 203-205 BO Cl 72 CO H ethyl -CH2-CH2- ^ \ -OCH3 170-172 BF Br 73 CO H ethyl -CH2-CH2- ^ \ -OCH- 155-160 (d) Br \ = J Δ BO 2: 3 / _2? H3 v 74 CO H ethyl - (CH ^ -CH-fl ^ 170 HCL C1 75 CO 0CH3 vinyl - (CH ^ -CH-i ^ "" ^^ 185 HC1 Cl 76 CH2 0CH3 vinyl - (CH2) 3- CHW \ -F | 124 (d) HC1 Cl / 2 77 CO H ethyl -CH2-C0 O 358-160 BO Br 78 CO OCH3 vinyl -CH2-C0 Ό 150-152 BO Br

79 CO H ethyl - (CH2) 2 -CO O F I 153-155 BF | Br J

7908030 15

The following abbreviations were used to list the salts in the table: BF = bifumarate BO = bioxalate 5 Fu = fumarate Pa = pamoate

The compounds listed in the table (in Arabic numerals) are just as many examples illustrating the invention. For the sake of clarity, the compounds prepared according to Examples I and II are also shown in the table.

Example LXXX

N-cyclobutylmethyl-desoxokinicin hydrochloride 15 CH0-CH0-CH0 / NH CH9-CH0-CH0 N-CH.-C ^ VVs fci ^ y CH = CH2 J ch-GH2 20 To a suspension of 10.0 g (28 .8 mmol) deoxokinicin. HCl in 125 ml of dichloromethane was added with stirring 58 ml of triethylamine.

8.6 g (86.4 mmol) of cyclobutanecarboxylic acid were dissolved in 60 ml of dichloromethane, after which 10.3 g (86.4 mmol) of thionyl chloride were added dropwise with stirring and the solution was refluxed for 1 hour. After cooling to room temperature, the resulting solution was added dropwise to the above-described solution of deoxokinicin in dichloromethane with stirring and in a nitrogen atmosphere. Subsequently, it was refluxed for 2 hours with stirring. After the reaction mixture had cooled to room temperature, 1000 ml of water was added with stirring.

The layers were separated and the water layer was extracted twice with 50 ml of chloroform. The combined dichloromethane / chloroform extract was shaken twice with 100 ml of water, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was chromatographed on silica gel with chloroform / acetone / diethylamine 5: 4: 1 as the running liquid. The fractions with the acid amide 7908030 16 were collected and evaporated to dryness under reduced pressure. The residue was dissolved in 450 ml of dry tetrahydrofuran and added, with stirring and in a nitrogen atmosphere, to a suspension of 3.2 g (86.4 mmol) of lithium aluminum hydride in 120 ml of dry tetrahydrofuran.

Then stirring was continued for 2 hours at room temperature and refluxed for 1 hour with stirring.

After the solution was cooled to room temperature, 40 ml of ethyl acetate was added dropwise with stirring and cooling in ice / water, followed by 300 ml of a 30% ammonium chloride solution. The organic phase was separated, dried over magnesium sulfate, filtered and evaporated under reduced pressure.

The residue was chromatographed on silica gel using cyclohexane / acetone 8: 1 as the running liquid. The fractions with the N-cyclobutyl-methyl-deoxokinicin were evaporated to dryness under reduced pressure, after which the base with 1 eq. isopropyl alcohol. HCl was converted into the HCl salt. Melting point 140-143 ° C.

Example LXXXI

N- (2-hydroxy-2-methyl) propyl-hydrokinieine bioxalate (formula: see 20 table below)

To a solution of 22 g of hydrokinicin in 80 ml of absolute ethyl alcohol was added 9 ml of 1,2-epoxy-2-methylpropane. The mixture was refluxed for 2 hours, the conversion being followed by thin layer chromatography. After cooling to room temperature, the reaction mixture was evaporated to dryness under reduced pressure.

The residue was purified by preparative high pressure liquid chromatography using ethyl acetate / diethylamine 95: 5 as the running liquid. The fractions containing the purified product were collected and evaporated to dryness under reduced pressure. Then the residue was dissolved in ethyl acetate / methanol. The solution was heated and the base was converted into the bioxalate (1: 1) with an equivalent amount of oxalic acid. Melting point 135-137 ° C.

In addition to the compound described here, the table below lists a number of compounds that were obtained in a corresponding manner: 7908030 17

CO-CH 2 -CHO- (NH CO-CHo-CHO- (N-Q

, V «'Μ V

kJLy c * —► 0285

Vrb. Q mp. (° C) salt 10 81 H -CH2C (OH) (CH3) 2 132-134 bioxalate 82 OCH3 -CH2C (OH) (CH3) 2 135-138 bioxalate 83 H -CH2CH (0H) ^ 163-165 bioxalate 84 H -CH2GH2COH) 157-160 bioxalate 85 H 172-174 bioxalate

OlN

86 H -CH2GH (0H) CH3 188-190 bioxalate

Example LXXXVII

N- (2-methyl-2-propionyloxy) propyl-hydrocinchonicine bifumarate CH, 0 a, __} 3 0 20 / \ il

CO-CH, -CH 3 - (N-GHO-C-O-C-C OHC

C V7 1

N

A mixture of 15.0 g (40 mmol) N- (2-hydroxy-2-methyl) propyl hydrocinchonicine, 4.4 g (48 mmol) propionyl chloride and 5.7 g (56 mmol) triethylamine in 300 ml carbon tetrachloride was refluxed overnight with stirring. After cooling to room temperature, the reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in 100 ml of toluene, extracted successively with 25 ml of water, 25 ml of saturated sodium bicarbonate solution and 25 ml of water, the layers were separated and the organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure.

The residue was dissolved in 50 ml of cyclohexane and chromatographed on a column of silica gel with cyclohexane / acetone 3: 1 as the running liquid. The fraction of the desired product was evaporated to dryness under a third pressure for 7908030, after which the base was dissolved in 25 ml of acetone. 1.6 g of fumaric acid in isopropyl alcohol were added to the solution with heating. The resulting salt was isolated and recrystallized from methanol / ethyl acetate. Melting point 132-134 ° C.

PHARMACOLOGY

Experiment 1 - Effectiveness of some compounds of the invention in rats with spontaneous hypertension

Systolic blood pressure was measured using the modified "tailstroke method" described by I.M. Claxton et al. In Eur. J. Pharmacology 37, 179 (1976). An oscilloscope or W + W BP recorder, model 8002, was used to display the pulses.

Before the rats were placed in small cages in which the experiments were performed, they were first placed in a heated environment at a temperature of 33.5 + 0.5 ° C. Each blood pressure reading was the average of at least 6 readings.

Rats (ages 12-18 weeks) with spontaneous hypertension, where systolic blood pressure was> 170 mercury pressure, were considered hypertensive.

The following table lists the results with some of the compounds of the invention performed according to the method described above. The numbers of the compounds correspond to those of the examples.

Compound dosage Change in systolic blood

No. mg / kg pressure (%) at different times (hours) 1 2 4 6 24 2 100 -20 -27 -17 -15 +3 6 10 0 -2 -14 -15 -7 7 10 -26 -27 -36 - 28 +4 16 10 -28 -30 -38 -30 -7 17 10 -38 -35 -34 -32 +1 37 100 -38 -35 -40 -25 +3 58 100 -7 -13 -20 -13 - 3 81 100 +2 -7 -2 -13 +8 7908030 19

Experiment 2 - Effectiveness of some compounds according to the invention in the electrostimulation test in guinea pigs

Arrhythmia in guinea pigs was induced by electrostimulation of the right heart ventricle. The animals were anesthetized with urethra (1.2 g / kg i.p.) and artificially ventilated before insertion of a needle electrode into the right heart ventricle.

Thirty minutes before stimulation, the various compounds were administered intraduodenally at a dose of 32 mg / kg.

The voltage required for the induction of additional systoles in control animals (n »6) was compared with that for the induction of arrhythmia in the test animals (n * 6).

This method is based on the work of 1, Szekeres and G.J. Papp, Naunyn-Schmiedebergs Arch. exp. Path. Pharmak., 245, 70 (1963).

The table lists the results with some of the compounds of the invention performed according to the method described above.

The numbers of the compounds correspond to those of the examples.

Connection Voltage increase (%)

No, required for the arrhythmia 2 46 27 141 58 18 81 56 7 908 030

Claims (17)

A compound of formula 1, or a salt thereof, wherein A -CH, -, -CHOH- or -CO-, 1 1 R hydrogen, hydroxy or lower alkoxy, 2 5. ethyl or vinyl, and 3 R C2 Q alkyX8 hydroxyalkyl, lower alkoxyalkyl or lower alkanoyloxyalkyl, C18 cycloalkyl, hydroxycycloalkyl, lower alkoxycycloalkyl or lower alkanoyloxycycloalkyl, cycloalkyl lower alkyl, hydroxy, lower alkoxy or lower alkanoyloxy-10 cycloalkyl lower alkyl; cyano, cyano lower alkyl, lower alkenyl, lower alkynyl, tetrahydrofuryl, mono arSi di-lower alkylamino lower alkyl; optionally substituted phenyl, phenyl lower alkyl or phenylhydroxy lower alkyl, optionally substituted diphenyl lower alkyl, optionally substituted phenyl lower alkenyl, optionally substituted benzoyl or benzoyl lower alkyl, optionally substituted heteroaryl or heteroaryl lower alkyl, or optionally substituted heteroaroyl or heteroaroyl lower alkyl wherein the substituents in the 3- and 4-positions of the piperidine ring are in the cis position relative to each other, excluding n-butyl and iso-butylkinicin. A compound according to claim 1, as represented by formula 1a, wherein R and R have the meanings mentioned in claim 1. A compound according to claim 1, as represented by formula 2, wherein R has the meanings mentioned in claim 1 and 3 * R ethyl, n-butyl, iso-butyl, n-pentyl, iso-pentyl, lower alkoxy lower alkyl C 1-4 cycloalkyl lower alkyl, di-lower alkylamino lower alkyl, lower alkenyl, optionally substituted phenyl lower alkyl or optionally substituted benzoyl or benzoyl lower alkyl. . 2 3 * A compound according to claim 3, wherein R is vinyl and R is n-butyl. 2 3 " A compound according to claim 3, wherein R vinyl and R 7908030 * *? 2-benzoylethyl, 2- (4-fluorobenzoylethyl) or 1-hydroxy-1-methyl-ethyl. A compound according to claim 1, as shown 2. 3 "by formula lc, wherein R has the meaning defined in claim 1 and R ethyl, n-butyl, iso-butyl, n-pentyl, iso-pentyl, cyclobutyl, lower alkenyl, optionally substituted phenyl lower alkyl or optionally substituted benzoyl or benzoyl is lower alkyl. 2 3 " A compound according to claim 6, wherein R is vinyl and R is cyclobutyl, 2-benzoylethyl or 2- (4-fluorobenzoylethyl). A compound according to claim 1, as represented by formula 1d, wherein A has the meaning defined in claim 1, η is 1, 2 or 3, is hydrogen, methyl, methoxy or -C (O) R **, wherein R11 is an optionally substituted phenyl group. A compound according to claim 1, as represented by I '2' formula le, wherein R is hydrogen or methoxy, R is ethyl or vinyl and Ar is phenyl, thienyl or phenyl substituted by 1, 2 or 3 groups selected from fluorine , chlorine or methoxy. 1 » R3 -CC-r12 "i is» "0> R13" 3 or D) a compound of formula 1, wherein R contains a hydroxyl group, alkylates, 3 or E) a compound of formula 1, wherein R contains a hydroxyl group, acylates, A compound according to claim 9, wherein R is hydrogen, 2f R ethyl and Ar 4-fluorophenyl. A compound according to claim 1, as represented by I »2" 20 formula If, wherein R is hydrogen or methoxy and R is ethyl or vinyl. 1 " A compound according to claim 11, wherein R is methoxy 2 "and R is ethyl. 13. A pharmaceutical preparation, characterized in that the active ingredient at least comprises a compound of formula 1, wherein A, R, R and R have the meanings set out in claim 1, or a pharmaceutically acceptable salt thereof. , together with a pharmaceutically suitable carrier or suitable diluent. 14. Process for the preparation of a compound of formula 1, as defined in claim 1, characterized in that such a compound is prepared in a manner known for the synthesis of analogous compounds. 15. Process for the preparation of a compound of formula 1, as defined in claim I, characterized in that alkylation of a compound of formula 4, wherein A, R and R have the meanings mentioned in claim I, is alkylated right away . 3 compound of formula 5, wherein R has the meaning defined in claim 1 and Y is a nucleophilic leaving 7908030 ν 'ν group, 1 2 or B) a compound of formula 6, wherein A, R and R have the meanings mentioned in claim 1 or, C) said compound of formula 4 reacts with an epoxide of formula 7, wherein R 1 alkyl, lower alkenyl, lower jo alkynyl, optionally substituted phenyl lower alkyl and R. 12 13 is hydrogen, or wherein R and R together with the carbon atom to which they are attached form a C 1-8 cycloalkyl group to give a compound of formula 1 wherein Process for the preparation of a pharmaceutical preparation, characterized in that at least one compound of formula 1, as defined in claim 1, is used. or a pharmaceutically acceptable salt thereof, in a form suitable for therapeutic purposes. 17. Compounds, pharmaceutical preparations and methods, as described in the description and the examples. 7908030 Formula sheet A - CH9 - CH0 -4 N - CH0 - R3 4 y 1 ^ N CO - CH „- CH9 / NH Λ νγ \ W 2 CH = CH9 kA r ^ N aCH ^ - CH2 - CH2 \ h 3 IRN / "Λ 3 CO - CH2 - CH2 · N - CH2 - ΈΓ γλ y ia / \ 3 · co - ch9 - ch9 4 N - ch9 - R CH3 ° y ^ V ^ S 1b AL J r2 r ~ \ 3" 'aCH9 - CH9 - CH0 - · N - CH0 - RS w,) * 1 «=" "O -" - · '·' · - LIJ c * 1d 79 0 8 0 3 (5 »Formula sheet (continued) CHOH - CH - CH0 VN - CH0 - CH0 - CH0 - CO - Ar "T ^ iTS 1st kA s R, e ^ TT CHOH - CH2 - CH2 -d N - CH2 - CH2 - CH3 r'TjÓ ^ 1f A - CH0 - CH, - Ê NH Λ 'OÓ ^ Y - CH2 - R3 5 A - CH. - CH0 VN - CO - R3 Όό 6 R12 / R \ VA j 7 OR 0 0 XC-R3 8 HO-O-R3 9 7908030