CA1267898A

CA1267898A - Substituted benzoic acid alkylene bridged piperidyl amides

Info

Publication number: CA1267898A
Application number: CA000580288A
Authority: CA
Inventors: Peter Donatsch; Gunter Engel; Bruno Hugi; Brian Peter Richardson; Paul Albert Stadler
Original assignee: Sandoz AG
Current assignee: Novartis AG
Priority date: 1982-06-29
Filing date: 1988-10-14
Publication date: 1990-04-17
Anticipated expiration: 2007-04-17
Also published as: CA1257870A; CA1267898C

Abstract

Abstract:

Compounds are described of formula I
A-CO-B-D I
wherein A is a group of formula III

III

wherein R4 to R7 independently are hydrogen, amino, nitro, (C1-4)alkylamino, di(C1-4)alkylamino, halogen, (C1-4)alkoxy, (C1-4)alkyl, (C1-4)-alkanoylamino or pyrrolyl, with the proviso that at least one of R4 and R5 is other than hydrogen, B is -NH- and D is a group of the formula V

V

They exhibit seratonin M receptor antagonist activity.

Description

39~3 SUBSTITU~8D BENZOIC ACID ALRYLEN~ BRIDG~D PIPERIDYL AHID~S

This invention relates to benzoic acid piperidyl amide deriva~ives.
The present inventi:n provides a compound of formula I
A-CO-B-D- I

wherein A is a group of formula II

RJ ~

wherein R4 i9 (Cl_4 )alkylamino, or (Cl_4)alkoxy, R5 is hydrogen, ~6 iS amino, (Cl_4)alkylamino, or di(Cl 9)alkylamino, and : R~ is halogen,~
:
B i s -NH-, and D is a group of formula III

::

39~3

- 2 - 100-5819/III

III

as well as acid addition salts and quaternary ammonium salts thereof.
These are referred to also as compounds of the inventionO

Any alkyl moiety preferably is methyl, ethyl or propyl. Alkoxy is preferably methoxy or ethoxy. Halogen is fluorine" chlorine, bromine or lodlne.
In a group of formula III conveniently R4 is ~Cl_4)alkylamino or (Cl_4)alkoxy;
R5 is hydrogen or halogen; or R6 is hydrogen, amino,nitro,(Cl_4)alkylamino, or di(Cl_4)al~ylamino,halogen or l-pyrrolyl;
convenlently R6 1~ other than hydrogen,halogen or pyrrolyl.

A group of formula III i9 also known as quinuclidinyl. Conveniently this ls 3- or 4-quinuclidinyl and especially 3-quinuclidinyl.

The present invention furthermore provides a process for the production of a compound of a invention ~hich includes the step of condensing an appropriate~benzoic acid or a~reactive acid derivative ~thereof, or a precursor of the acid or derivative, with an appropriate alkylene bridged piperldyl amlne, or a precursor ~hereof, and as neces~ary converting the resultant piperidyl amide, or acid addition salt or quaternary ammonium;salt thereof, into the required piperidyl amide or ac;id addition salt or quaternary ammonium salt thereof and recoverln~ the resultant piperidyl amide as such or as an ~z~

- 3 _ 100-5819/III

acid addition salt or as a quaternary ammoniwm salt thereof.

In particular the present invention provides a process for the production for a compound of formula I as well as acld.addition salts thereof or quaternary ammonium salts thereof which includes the step of a) condensing an appropriate compound of formula IV
A-CO-OH IV

wherein A is as defined above, a reactive derivative thereof, or a precursor of the acid or derivative, with an appropriate compound of formula V
HB-D

wherein B and D are as defined above, or a precursor o the compound, or b) alkylating a compound of formula I having a secondary amio group to produce a compound of formula I with a tertiary amino group, or c) deprotectlng any protected form of a compound of formula I to obtain a compound of formula I, and recovering the resultant compound of formula I as such or as an acid addition salt or as a quaternary ammonium salt thereof.

The condensation process of the invention to obtain amides may be effected in conventional manner for analogous compounds.

For example the carboxylic acid group may be activated in the form of reactive acid derivative.

, f~

~2~ 8

- 4 - 100-5819/III

Suitable reactive acid derivatives may be formsd by reaction with N,N'-carbonyl-diimidazole producing an intermediate carboxylic acid imidazolide, or with N-hydroxy-succinimide. Alternatively an acid chloride may be used, e.g. produced by reaction with oxalyl chloride.

If desired a heterocyclic or tertiary amine, e.g. pyridine or triethylamine, may be present.

Suitable reaction temperatures may be from about -10 to about 10~.If desired however the reaction temperature may be for example up to about 100C, e.g. in boiling methanol or ethanol.

Other suitable inert organic solvents include, e.g. tetrahydrofuran or dimethoxyethane.

The compounds of the invention may be converted into other compounds of the inventlon, e.g. in conventional manner. Some interconversions are exemplified in processes b) and c).

The alkylation reaction of process b) rnay be effected in conventional manner. hny free amino group may be alkylated.

Appropriate alkylation conditions include reaction with an alkyl halide in the presence of a sodium alcoholate. Suitable temperatures may be from about -50 to about -30C.

The deprotection reaction of process c) is specifically suitable for the production of compounds with secondary amino groupS~ or primary amio groups, e-g- R6 = NH2-For example a compound of formula I may be produced in protec~ed form.

The protectin~ group may be spli~ off in conventional manner, e.g. byhydrogenation.

J~

1~i71~
_ 5 - 100-5819/III

Suitably the hydrogena~ion may be effected in the presence of palladium on active charcoal at room temperature or at a slightly elevated temperature. Suitable solvents include acetic acid, ethyl acetate or ethanol.

A primary amino group as R6 may be protected by e.g.
N-benzyloxycarbonyl. This group may be spli~ off by hydrogenation. In the presence of a benzyl group the N-benzyloxycarbonyl group is generally split off first.

Also the amino group may be in the form of a nitro group. This can be selectively reduced in conventional manner, e.g. by iron in hydrochloric acid.

A precursor of a starting material may be employed if desired. Such a precursor may be capable of being converted into the starting materlal in conventional manner, but instead the process of the invention is carried out with the precursor and the other starting material or mateirals or a precursor thereof. The resultant producc is converted into the compound of the invention in conventional manner, e.g. by using the same reaction conditions by which the precursor may be converted into the starting material. Typlcal precursors include protected forms of a starting material, e.g. wherein amino groups are temporarily protected.

The compounds of the invention may be isolated and purified in conventional manner.

Insofar as the production of any starting material is not particularly described herein, it is known, or may be produced in analogous manner to known compounds, in analogous manner to that described herein, e.g.
the examples, or to known procedures for analogous compounds.

Free base forms of compounds of the invention may be converted into salt forms. For example, acid addition salts may be produced in conventional manner by reaceing with a sultable acid, and vice versa.

lZ~

Suitable acids ~or salt formation include hydrochloric acid, malonic acid, hydrobromic acid~maleic acid, malic acid, fumaric acid, methanesulphonic acid, oxalic acid, and tartaric acid. Quaternary ammonium salts of the compounds of the invention may be produced in conventional manner, e.g. by reaction with methyl iodide.

In the following examples all temperatures are in degrees Centigrade and are uncorrected. All n.m.r. spectra values are in ppm (tetramethylsilane = 0 ppm).

cl~ure l-aza-bicyclol2.2.2loctyl - quinuclldinyl In the tables the column heading "Prep" gives the number of the Examples in the A series describing the preparation procesa.

Abbreviations used:-III-I = 5-chloro-2-methoxy-4-methylaminophenyl 1) hydrogen malonate In the following HYFL0 and HYFL0 SUPERCEL are registered Trade Marks.

The title compounds of Examples A-1, A-2 and A-3 are not part of this invention. They are present here to illustrate processes of the present invention.

~.~

1 2~B98 XAMPLE A-1 5-chloro-2-methoxy-4-methylamino-benzoic acid 1-aza-blcyclo[2.2.2]oct-3-yl ester also called 5-chloro-2-methoxy-4-methylamino-benzoic acid quinuclidin-3-~1 ester (process a) a) 12 g N'N-carbonyl-diimidazole are added to a stirred solution of 8 g 5-chloro-4-methylamino-2-methoxy-benzoic acld in 300 ml dry tetrahydrofuran at 20 to 25~. The mixture is stirred under anhydrous conditlons~for 1 hour, and the solvent removed at 35 to 40. The residue is dissolved in methylene chIoride.

The mixture is washed 2 to 3 times with water, dried over magnesium sulphate, filtered and concentrated. The heading compound crystallises from methylene chloride/hexane~ M.pt.
152-154.
.
b) 5-chloro-4-methylamino-2-methoxy-benzoic acid~ za-bicyclo-[2.2.23Oct-3-yI ester .
27 ml n-butyl lithium (1.6 Molar) in hexane is added drop~ise to a stirred solution of 5.56 g 1-aza-bicyclol2.2.2loctan-3-ol (quinuclidinyl-3-ol) in 100 ml absolute tetrahydrofuran at 0 to

5 under dry nitrogen. The mixture i9 stirred for a further 10 to 15 minutes ae 0 to 5 and then a solution o~ 5-chloro-4-methyl-amino-2-methoxy-benzoic acid imidazolide in 100 ml absolute tetra-hydrofuran i9 added. It is stirred for an hour. 5 ml saturated aqueous potassium hydrogen carbonate solution is added and the solution is decanted. The residue is washed twice with tetrahydrofuran. The combined organic phases are dried over magnesium sulphate, filtered and concentrated. The crude product is treated with an equivalent amount of malonic acid to give the heading compound in hydrogen malonate Eorm. M.pt. 170-172 (from acetone).

R~ :

EXAMPLE A-2: 4-amino-5-chloro-Z-methoxy-benzoic acid exo-8-benzyl-.
-8-aza-bicyclo[3.2.1Joct-3-yl ester also called 4-amino-5-chloro-2-methoxy-benzoic acid 8-benzyl-pseudo-nor-tropyl ester (process c) a) 4-(N-benzyloxycarbonyl)amino-2-methoxy-benzoic acid methyl ester A solution of 42.1 g 4-amino-2-methoxy-ben~oic acid methyl ester in 600 ml toluene is boiled under reflux for 2 1~2 hours together with 60 ml chloroformic phenyl ester. The solution is cooled and crystals of the heading compound filtered off. M.pt. 137-138~

b) 4-(N-benzyloxycarbonylamino)-5-chloro-2-methoxy-benzoic acid methyl ester 18 g chlorine gas ~dried over sulphuric acid) is passed through a stirred solution of 61.4 g 4-(N-benzyloxycarbonyl)amino-2-methoxy-benzoic acid methyl ester in 1 litre chloroform at 20 for 20 to 25 minutes. The reaction mixture is concentrated under a vacuum to give the crys~als of the heading compound ~hi~h is reacted further as suFh.
c~ 4-(N-benzyl ~ ~ino~-5-chloro-2-m~ho~y-benzoic _cid 200 ml 2N aqueous sodium hydroxide solution is added dropwise ~o a stirred solution of 72.1 g of the benzoic acid methyl ester produced in step b) in 800 ml dioxane. The mixture ls stirred for 20 hours and the organic solvent removed under a vacuum. The residue is dissolved in water and adjusted to pH~5-6 with 3N
hydrochloric acid. The heading compound is filtered off and wshed with water. M.pt. 18Z-183 (from methanol~.

d) 4-(N-benzyloxycarbonylamino)-5-chloro-2-methoxy-benzoic aeid imidazolide The compound is produced in analogous manner to Example A-la~

S

1;2~7B9~
_ 9 _ 100-5819/III

e) 4-(N-benzyloxycarbonylamino)-5-chloro-2-methoxy-benzoic acid exo-8-ben2yl-8-aza-bicyclo[3.2.lloct--3-yl ester -The compound is produced in analogous manner to Example A-la.

f) 4-amino-5-chloro-2-methoxy-benzoic acid exo-8-benzyl-8-aza-bicclo-[3.2.1loct-3-yl ester 5.4 g 4-(N-benzyloxycarbonylamino)-5-chloro-2-methoxy-benzoic acid exo-8-benæyl-8-aza-bicyclo~3.2.1]oct-3-yl ester in 100 ml ethanol are hydrogenated in the presence of 0.7 g palladium (lOX) on charcoal for 50 minutes at atmospheric pressure taking up one equivalent of hydrogen. The mixture is filtered through a filtering aid (Hyflo Supercel) and the filtrate concentrated. The residue is chromatographed on silicagel with methylene chloride containing 5~ methanol and the heading compound obtained in free base form. M.pt. 241-242 (hydrobromide produced from H~r, ln ethanol).

;`~. i EXAMPLE A-3: 4-amino-5-chloro-2-methoxy-benzoic acid exo-8-aza-._ bicyclo[3.2.1]oct-3-yl est¢r also called 4-amino-S-chloro-2-methoxy-be zoic acid pseudo nor-tropyl ester (process c) 8.4 g 4-(N-benzyloxycarbonylamino)-5-chloro-2-methoxy-benzoic acid exo-8-benzyl-8-aza-bicyclol3.2.1]oct-3-yl ester in 250 ml ethyl acetate or acetic acid are hydrogenated in the presence of 1.2 g 10% palladium on charcoal at atmospheric pre~sure and at 20 to 25 for 2 hours. The mixture is filtered (e.g. through ~yflo), the filtrate is evaporated and the residue dissolved in me~hylene.
chloride.

The organic phase is washed with lN sodium hydroxide and then with water, dried over magnesium sulphate and concentrated. The product is chromatographed through silicagel using methylene chloride + 5Z
methanol and methylene chloride ~ 20X methanol. The title compound is crystallised as the hydrochloride. M.pt. 258-259 (from ethanol).

The following compound of formula I wherein A is a group of formula III and D is a group of formula V, i9 produced:-Example A B D subst. M.pt. Prép.E-1 III-I NH 3 145-147 A-1*
154_156ol ) if desired in boi1~ng ethanol ~2~
~ 100-5819/III

The compounds of the invention exhibit pharmacologically activity and are therefore useful as pharmaceuticals, e.g. for therapy.

In particular the compounds exhibit serotonin M receptor antagonist activity as indicated in standard tests. For example, in one test the action of the co~pounds in inhibi~ing the action of serotonin in reducing the amplitude of the compound action potential from the isolated rabbit vagus nerve was observed according to the principles of Riccioppo Neto, European Journal of Pharmacology (1978~ 49 351-356, under conditions permitting differentation between action potentials generated in myelinated nerve fibres (A fibres) and those generated in small non-myelinated fibres (C fibres) as described by B.Oakley and R.Schater, Experimental Neurobiology, A Laboratory Manual, University of Michigan Press, 1978, p. 85 to 96. Serotonin itself exerts its effect selectively on the C fibres and reduces the amplitude of the action potential in these fibres progressively with dosage. This action of serotonin is not blocked by the known serotonin antagonists, metitepine, methysergide, BOL -148, which have been said to block D
receptors for serotonin, but not M receptors (see Gaddam and Picarellit Brit.,J.Pharmacol. (1957). 12, 323-328). It therefore appears that serotonin reduces the amplitude of the action potential carried by the C fibres through an effect mediated by M receptors for serotonin which are located on these nerve fibres.

The test may be effected by establishing a dose response curve for serotonin (10-7 - 5 x 10-6 M) after setting up the nerve. The serotonin is ~ashed out and when the C fibre action potential has regained its original amplitude the compound of the invention at a set concentration of from about 10-16 M to about 10-6 M is preincubated with the nerve for 30 to 60 minutes. varying concentrations of serotonin (10-7 to 10-4 M) are then applied with the compound of the invention at the concentration as was present during the preincubatlon period.

The M receptor antagonists of the invention either entirely block ~he ., ~7~

- 12 - 100~5819/III

action of serotonin (non-competitive antagonist) or cause a parallel shift of the serotonin/dose response curve to the right ~i.e.
increased concentrations of serotonin were required for effect) (competitive antagonist). The pD'2 or pA2 value may be obtained in the conventional manner.

The serotonin M receptor antagonist activity is also indicated by inhibiting the effect of serotonin on the isolated rabbit heart according to the method of J.R.Fozard and A.T.Moborak Ali, European Journal of Pharmacology, (1978~, 49, 109-112 at concentrations of 10-1l to 10-5 M of the compound of the invention. pD'2 or pA2 values may be calculated in the conventional manner.

The action of the compounds are serotonin M receptor antagonists for the treat~ent of analgesia is confirmed by action in the hot plate test at a dose of from about 0.1 to 100 mg/kg s.c. or p.o.

The serotonin M receptor antagonist activity is further~ore indicated in the cantharidlne blister base test at a concentration of about 10-~M. A blister is produced on the skin of the orearm of human volunteers with cantharidine. ~hen serotonin is applied to the base of such bllsters it produces pain which can be measured, the intensity being proportional to the concentration of serotonin applled. The procedure has been de~cribed by C.A.Keele and D.Armstrong ln Substances producing Pain and Itch, Edward Arnold, London, 1964, p. 30 to 57. This algesic action of serotonin is not inhibited by the serotonin D receptor antagonists such as lysergic acid diethylamide or its bromo derivative and is therefore believed to be mediated by M
receptors.

In the procedure followed the area under the curve instead o~ the peak amplitude is ~easured by a linear integrater coupled to a pain intensity indicator which is operaterd by the volunteer. With increasing concentrations of serotonin a cumulative dose-response curve to serotonin may be obtained. When no fur~her response on increasing the serotonin concentration is obtained, the serotonin is ~¢,~

~%~

., ~
washed off and the blister incubated with physiological buffer solution for at least 40 minutes before the compound of the invention is applied. The test substance is preincubated with the blister base for 30 minutes at a concentration of about 10-8 M before varying concentrations of serotonin are applied. A pA2 value may be obtained in the conventional manner.

The compounds of the invention are therefore be indicated for use as serotonin M receptor antagonists, e.g. for the treatment o~ pain, especially migraine, vascular and cluster headaches and trigeminal neuralgia and also for the treatment of héart circulation disorders "
e.g. for the treatment of sudden death, and as anti-psychotics.

An indicated daily dose is from about 0.5 to 500 mg conveniently administered in divided doses in unit dosage form 2 to 4 times a day containing from about 0.2 to about 250 mg of the compound or in sustained release form.

The compounds of the invention furthermore exhibit anti-arrhythmic activity as indicated by their serotonin M receptor antagonist activity and in standard tests. For example ~he compounds inhibit arrhythmias induced by norepinerphrine in anaesthetized rats.
In this test infusions of norepinerphrine (3 to 10 microgram/animal body weight) are given until an arrhythmic phase as indicated by ECG
measurements lasts longer than 10 seconds duration. After control of 3 consecutive injections of norephinephrine the compound of the invention i5 injected at from about 10 to about 500 microgram/kg animal body weight followed by norephinephrine injections. The arrhythmic phase is reduced, or abolished depending on the dose of test compound.

The compounds are therefore indicated for use as anti-arrhythmic agents. An indicated daily dose is from about 0.5 to about 500 mg conveniently admnistered orally or by injection in divided doses 2 to 4 times a day or in unit dosage form containing from about 0.2 to about 250 mg, or in sustained release form.

~, ~Z~7~

The present invention accordingly provides a compound of the inventlon in pharmaceutically acceptable form, e.g in the free base form, or pharmaceutically acceptable acid addition salt form or quaternary ammonium salt form, for use as a pharmaceutical, particularly for use as a serotonin M antagonist for those diseases where blockage of serotonin M receptors would be expected to have beneficial effects, e.g. as an analgesic agent, especially as an anti-migraine agent and as an anti-arrhythmic agent.

The present invention furthermore provides a compound of the invention for use as an anti-psychotic or in the manufacture of a medicament for use as an anti-psychotic.

The preferred indication is the analgesic indication.

The compounds of the invention may be administered in free base form, or in pharmaceutically acceptable salt form, e.g. suitable acid addition salts and quaternary ammnonium salts. Such salts exhibit the same order of activi~y as the free bases. The present invention accordingly also provides a pharmaceutical composition comprising a compound of the invention, in particular a compound of formula I, an acid addition salt thereof or a quaternary ammonium salt thereof, in association with a pharmaceutical carrier or diluent. Such compositions ~ay be formulated in conventional manner so as to be for example a solution or a tablet.

Claims

CLAIMS:

1. A process for the production of a compound of formula I

A-CO-B-D

wherein A is a group of formula II

II

wherein R4 is (C1-4)alkylamino, or (C1-4)alkoxy, R5 is hydrogen, R6 is amino, (C1-4)alkylamino, or di(C1-4)alkylamino, and R7 is halogen, B is -NH- and D is a group of the formula III
III
as well as acid addition salts and quaternary ammonium salts thereof, which includes the step of a) condensing an appropriate compound of formula IV

A-CO-OH IV

wherein A is as defined above, or a reactive derivative thereof, or a precursor of the acid or derivative, with an appropriate compound of formula V

HB-D V

wherein B and D are as defined above, or a precursor of the compound, or b) alkylating a compound of formula I having a secondary amino group to produce a compound of formula I with a tertiary amino group, or c) deprotecting any protected form of a compound of formula I to obtain a compound of formula I, and recovering the resultant compound of formula I as such or as an acid addition sale or as a quaternary ammonlum salt thereof.

2. A compound of formula I as defined in claim 1, as well as acid addition salts thereof and quaternary ammonium salts thereof.

3. A compound of claim 2 wherein A is 4-amino-5-chloro-2-methoxy-phenyl.

4. A compound of claim 2 wherein A is 5-chloro-2-methoxy-4-methyl-aminophenyl, B is -NH-, and D is 3-quinuclid-inyl as well as acid addition salts and quaternary ammonium salts thereof.

5. A pharmaceutical composition comprising a compound of claim 2, 3 or 4 or a pharmaceutically acceptable acid addition salt or quaternary ammonium salt thereof in association with a pharmaceutical carrier or diluent.

6. A compound of claim 2, 3 or 4 or a pharmaceutically acceptable acid addition salt or quaternary ammonium salt thereof for use as a serotonin M antagonist.

7. Use of a compound of claim 2, 3 or 4 or a pharmaceutically acceptable acid addition salt or quaternary ammonium salt thereof in the manufacture of a medicament for use as a serotonin M antagonist.

8. A compound of claim 2, 3 or 4 or a pharmaceuticalIy acceptable acid addition salt or quaternary ammonium salt thereof for use as an anti-psychotic.

9. Use of a compound of claim 2, 3 or 4 or a pharmaceutically acceptable acid addition salt or quaternary ammonium salt thereof in the manufacture of a medicament for use as an anti-psychotic.