IE83484B1 - New Bi- and tricyclic aminoalcohol esters, their preparation and their use in medicaments - Google Patents

Description

New Bi- and Tricyclic Aminoalcohol Esters, their preparation and their use in medicaments.

The invention relates to new esters of bi— and tricyclic amino alcohols, the preparation of these compounds and their use in pharmaceutical compositions, H The new compounds correspond to the formula ‘ A40-co—z " (I) idmzein .

A _represents a group of the formula in the 3~u form, wherein one of the groups R and R’ denotes methyl, the other denotes methyl, ethyl, n~propyl or i-propyl, If denotes an equivalent of an anion, and Z denotes the group Fg R2+— (III) Rs wherein ~ gfg and R3, which may be identical or different and one of which may also denote H, a) phenyl, furyl, thienyl, C&4—cyc1oa1ky1, pyridyl, Cyqfcycloalkenyl, or ; H b) an aliphatic group having up to 20 carbon atoms V optionally interrupted by oxygen, a phenyl, phenoxy, thienyl, furyl, C&4—cyc1oalkyl or f1uorine—substituted Cb5—a1ky1 group, or the entire group III also represents a tricyclic group of the formula .

B R1 : / —~ ' _ Y or Y R‘ - \ :- O B _—./ (N) (V) or a group of the formula R; (VI) (CH2)q wherein B denotes S or CH=CH, R'1 means the same as ‘IQ and may additionally denote phenyl, thienyl, with furyl, thiazolyl, thiadiazolyl or methoxyphenyl, Y denotes a single bond, an 0- or S-atom or one of the groups —CH2-f. 'CHz"CH2‘«"CH=C'H-I "0CH2" Or ‘SCH2’ and q denotes 1, 2 or 3, ' the proviso that a) Z—CO does not denote the tropic acid _ group if A denotes \\j? + 3 R-N-R‘ 0‘ and R and R‘ denote methyl or R denotes methyl and -—v-~ R‘ denotes ethyl; _ g b) if R1 denotes OH or methyl and one of the groups R2 or R3 denotes thienyl, the other group R2 or R3 cannot simultaneously be thienyl, phenyl, furyl, cyclopentyl or cyclohexyl.

Accordingly, the group A represents, for example, the - groups of-scopine, N-ethylnorscopine, N— A ‘ isopropylnorscopine, 6, 7-dehydrotropine; N-isopropy1- The group Z may have the following meanings, for example, whilst the aromatic groups may also be substituted, e.g. by CH3, OCH3, F or Cl: // \\ HO-C-- HO-C-— HO-C- / 613 49 »4n-isflll _ <::;;E> HO—C- CH —C n-C5H‘Iu < /O /' ”\' H /“H3 ’ . HO - \ / “ =74, @011 395» CH3 OH S . s :_-—/ The quaternary compounds of formula I are particularly suitable for therapeutic use, while the tertiary- compounds are important not only as active substances but also as intermediate products.

The compounds according to the invention are anticholinergics with a potent and=1ong€lasting effect.

At dosages in the microgram range, periods of effect of more than 24 hours are achieved after inhalation.

' Moreover, the toxicity is in the same range as that of the standard commercial product ipratropium bromide, whilst at the same time the therapeutic effect is in some cases significantly greater.

In accordance with their nature as anticholinergics, the new comounds are suitable, for example, for treating chronically obstructive bronchitis and (slight to moderate) asthma and also for treating vagally induced sinus bradycardia. Whereas in diseases of the respiratory tract it is chiefly recommended to V administer the new active substances by inhalation (especially the quaternary compounds), thereby largely eliminating any side effects, the comounds are preferably administered by intravenous or oral route in It has been found to be advantageous that the new compounds have virtually no i the case of sinus bradycardia. effect on gastrointestinal motility.

For use, the compounds according to the invention are processed with known excipients and/or carriers to form conventional galenic preparations, e.g. solutions for inhalation, suspensions in liquefied propellant gases, preparations containing liposomes or proliposomes, injectable solutions, plain or coated tablets, capsules, and powders for inhalation for use in conventional inhalers. _ 7 _ ‘Examples of formulations (amounts given in percent by weight): . ete n aer so Active substance according to the invention 0.005 Sorbitan trioleate ' ' 0.1 Monofluorotrichloromethane and _ 'dif1uorodich1oromethane 2 : 3 «ad 100 The suspension is poured into a conventional aerosol Preferably, 50 pl of suspension are dispensed on each actuation." The active container with a metering valve. substance may also be dispensed in a higher dosage if desired (e.g. 0.02% by weight). . xablets Active substance according to the invention 0.05 Colloidal silica H 0.95 Lactose 4 65.00 Potato starch 28.00 Polyvinylpyrrolidone 3.00 Na-cellulose glycolate 2.00 Magnesium stearate 1.00 The ingredients are processed in the usual way to form tablets weighing 200 mg. _ 3 _ The advantageous properties.of the new compounds are found for example in their inhibition of broncholysis in rabbits (acetylcholine spasm i.v.).

After intravenous administration of the new active substances (dosage 3 pg/kg i.v.) the maximum effect was obtained after 10 to 40 minutes. ’ organs, e.g. on the guinea-pig ileum or rectum, numerous Even on isolated compounds according to the invention were found to have a long duration of activity. " ' ‘j The new compounds may be prepared by methods known per se.

. Preferably an ester of formula Z - CO — OR" (VII), wherein Z is as hereinbefore defined and R" represents a CL,~a1ky1 group, preferably methyl or ethyl, is transesterified, in the presence of a conventional transesterification catalyst, with an aminoalcohol of formula ’ TH———\‘_ H0-CH’ Q'a Qa \(CH2) n ~ wherein m and n are as hereinbefore defined, Q'a (VIII), represents NR‘ or NH, Q3 denotes one of the'double— bonded groups —CH=CH— or and wherein the OH group is in the u or'B position, transesterified in the presence of a conventional transesterification catalyst or l 35 _ 9 - a reactive derivative (R'" represents a readily cleavable group) 2 — co — OR"' . (Ix) of the acid Z-CO-OH, particularly an acid chloride or imidazolide thereof, is reacted with an alcohol of formula VIII, optionally in excess or in the I presence of a tertiary amine such as.triethylamine, and optionally a) if Q‘, represents NR’, the resulting compound is quaternised with a reactive monoderivative X-R of a corresponding alkane (X = leaving group) or b) if Q'a represents NH, the resulting compound is quaternised with a terminally disubstituted alkane X-(C,+-alkylene)—X without intermediate isolation.

Alternatively, starting compounds may be quaternised, in which the starting compound VIII contains R representing a "halo- or hydroxy-substituted alkyl group" instead of R‘ at the nitrogen atom.

The transesterification according to process 1 is carried out with heating in an organic solvent, e.g. toluene, xylene or heptane, or in a melt, using strong rbases such as sodium methoxide, sodium ethoxide, sodium hydride or metallic sodium as catalyst. In order to eliminate the lower alcohol released from the equilibrium, reduced pressure is used, and possibly the alcohol is distilled off azeotropically. The transesterification is carried out at temperatures generhlly not exceeding 95°C. Frequently, trans- esterification proceeds more easily inma melt. The reaction according to process 2 is carried out in an organic solvent or mixture of solvents which is sufficiently inert under the reaction conditions, e.g. -10, __acetone or acetonitrile, at temperatures between about °C and the boiling temerature of the reaction mixture, The free bases may be obtained from acid addition salts of the tertiary amines, if desired, using suitable basic compounds in a manner known per se. The quaternisation is carried out in suitable solvents, e.g, acetonitrile or acetonitrile/methylene chloride, preferably at ambient temperature; the preferredi quaternising reagent is a corresponding alkyl halide, erg. alkyl bromide, or a corresponding sulphonic acid derivative, e.g. a methane- or toluenesulphonic acid derivative. Conversion into the tertiary and then quaternary comound is carried out using suitable 1,4-, 1,5~ or 1,6—dihaloa1kanes without intermediate isolation.

The starting compounds, where they have not already been described, may be obtained analogously to known compounds.

Examples: Methyl di-(2—thienyl)glyco1ate from dimethyl oxalate and 2-thienylmagnesium bromide; Ethyl di—(2—thieny1)glyco1ate from (2-thienyl)g1yoxylic acid and 2-thienyllithium; Ethyl hydroxyphenyl—(2—thienyl)acetate from methyl phenylglyoxylate and 2—thienylmagnesium bromide or from methyl (2-thienyl)glyoxylate and_phenylmagnesium bromide.

Similarly, methyl 2-thienylglyoxylate and cyclohexy1— or cyclopentylmagnesium bromide may be reacted.

(There are also several possible methods of. preparing the aminoalcohols.

Pseudoscopine can be obtained according to M.

Polonovski et a1., Bull. soc. chim; 3;, 79 (1928).

Pseudotropenol can be isolated from the mixture (by fractional crystallisation or distillation) which is - 11 _ —Methyl—6—azabicyc1o[3.2.1]octan—3—a- corresponding methylesters may be prepared in conventional manner via the 2- or 3—fury1g1yoxylic acid obtainable from the starting material. From these methylesters, the corresponding glycolic acid esters may .be obtained as described with the organometallic derivatives of 2- or 3~bromothiophene. The organometallic compounds obtainable from 2-, 3~ or 4~ halopyridine can be reacted with methyl 2- or 3-thienylglyoxylate to obtain the corresponding glycolic acid.esters. .

Thienylglycolic acid esters in which the thiophene ring in the 2- or 3—position contains fluorine may be obtained, for example, starting from 2-fluorothiophene or 3—fluorothiophene (bromination to obtain 2—bromo—3- -f1uoro— or 2—bromo—5—fluorothiophene and, after conversion into corresponding organometallic compounds, reaction with suitable glyoxylic acid esters to obtain the glycolic acid esters. 2~f1uorothiophene and 3—f1uorothiophene may-be reacted analogously to Unterhalt, Arch.Pharm; esters, as described above. .By a suitable choice of components, symmetrically substituted dithienylglycolic acid esters, may. be prepared analogously.

A method analogous to benzoin condensation and benzylic acid rearrangement is also possible.

The acid chlorides required may be obtained from the acids and thionyl chloride whilst the imidazolides may be obtained from the acids and carbonyldiimidazole.

The following.Examples illustrate the invention without restricting it.

Example 1 2, i ac’ co i t r- hr ‘d Benzylic acid scopine ester from a-chlorodiphenyl¥ acetic acid chloride and scopine ‘ .__....._____._-_._—____....._..__._---—-..._—...........__

Claims (8)

Claims

1. The new compounds of formula A ‘ co — z (I) ‘ wherein A A represents a group of the formula or X‘ x’ in the 3-01 form,‘ wherein . one of the groups R and R‘ denotes methyl, the other denotes methyl, ethyl, n-propyl or i—propyl, X" denotes an equivalent of an anion, and Z denotes the group R‘ . R24-— (III) R3 wherein R1 denotes OI-I, methyl or CHZOH, :1}; and R3, which may be identical or different and one of which may also denote H, a) phenyl, furyl, thienyl, C5-,—cycloa1ky1, pyridyl, C5_,—cycloa1kenyl, or" b) an aliphatic group having up to 20 carbon atoms V optionally interrupted by oxygen, a phenyl, ‘1o -32.. PheI10XYz Chi-€I1Y1, fliryl} C5.-,—cyc1oa1ky1 or fluorine-substituted C1_‘—alky1 group, or the entire group III also represents a tricyclic group of the formula with group if A denotes (N) A _ (V) or a group of the formula R‘, (VI) (0 2)., wherein B denotes S or CH=CI-I, R‘, means the same as R1 and may additionally denote phenyl, thienyl, furyl, thiazolyl, thiadiazolyl or methoxyphenyl, Y denotes a single bond, an 0- or S—atom or one of the groups —CH2f, —CHZ-CH2-,-CH‘=CH-, —0CH2— or ~SCH2- and q denotes 1, 2 or 3, ' the proviso that a) Z—C0 does not denote the tropic acid ‘ ‘ 3 R-NfR' 0 and R and R‘ denote methyl or R denotes methyl and a33- R‘ denotes ethyl; b) if R1 denotes OH or methyl and one of the groups F9 or R5 denotes thienyl, the other group Rzcn:}g cannot simultaneously be thienyl, phenyl, fury1, cyclopentyl or cyclohexyl.

2. Use of compounds according to claim 1 or 2, in the manufacture of a medicament for treating respiratory tract diseases and sinus bradycardia.

3. A Pharmaceutical comositions, characterised in that they contain a compound according to claim 1 or 2 together with conventional excipients and/or carriers.

4. Use of compounds according to claim 1 or 2 in the preparation of anticholinergic pharmaceutical compositions.

5. Use of compounds according to claim 1 or 2 in the manufacture of a medicament for treating respiratory tract diseases and sinus,‘ Qmcardia.

6. Compounds according to claimf 1 or 2, substantially as hereinbefore described and/or exemplified.

7. Pharmaceutical compositions according to claim 3, substantially as hereinbefore described.

8. Use according to claim 4 or 5 substantially as hereinbefore described. ‘Tomkins & Co.