BE897117A - NOVEL PIPERIDINE DERIVATIVES, THEIR PREPARATION AND THEIR USE AS MEDICAMENTS - Google Patents

Description

       

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 formed by
SANDOZ S. A. for New piperidine derivatives, their preparation and their use as medicaments Invention by: Peter Donatsch, Günther Engel,
Bruno Hügi, Brian P. Richardson,
Paul Stadler Claiming priorities for patent applications filed in SWITZERLAND on June 29, 1982 under number 3979/82, on July 13, 1982 under number 4267/82, on November 30, 1982 under number 6950/82, on November 30, 1982 under n 6951/82, December 22, 1982 under n 7494/82, December 22, 1982 under n 7495/82 and March 9, 1983 under 1256/83 in the name of SANDOZ SA

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   The subject of the present invention is derivatives of piperidyl esters and of N-piperidyl amides of benzofque acid, including analogs of benzo acid? as like polycarbocyclic and heterocyclic carboxylic acids.



   The invention also relates to a process for the preparation of the compounds and their use in therapy, as active principles of medicaments.



   The invention relates more particularly to the piperidyl esters and the N-piperidyl amides of di-carbocyclic or heterocyclic carboxylic acids in which the piperidine nucleus contains an alkylene bridge and the piperidylic esters and the N-piperidyl-friend of the aci of the substituted benzofques of which the piperidine nucleus contains an alkylene bridge,
 EMI2.1
 - having the alkylene bridge connecting two carbon atoms of the piperidine nucleus, to be substituted less than the ortho or meta positions of the phenyl ring, - any piperidyl ester of benzofqùe acid not substituted at the two ortho positions, or substituted by a halo- gene or alkyl in at least one of the ortho positions and only with hydrogen or a halogen in the meta and para positions,

   and having the alkylene bridge connecting two carbon atoms of the piperidine ring, having to have an alkylene bridge containing at least 3 carbon atoms,

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 EMI3.1
 - piperidyl ester of benzolque acid having an alkylene bridge connecting a carbon atom of the piperidin nucleus to the nitrogen atom of the same nucleus and having an oxy substituent, having to have at least one substituent other than an oxy substituent or having only two oxy substituents in the benzene ring, - any amide or ester of heterocyclic carboxylic acid whose heterocycle is monocyclic to six.

   links and contains cyclic nitrogen atoms or any heterocyclic carboxylic acid amide
 EMI3.2
 the heterocycle of which contains two oxygen atoms, having to have an alkylene bridge connecting a carbon atom of the piperidine nucleus to the nitrogen atom of the same nucleus, - benzoic acid having to have an alkylene bridge connecting the atom d nitrogen from the piperidine nucleus to a carbon atom from the same nucleus, - any N-piperidyl amide of benzo acid @ which must not contain halogen, hydroxy or alkyl substituents in any one of the ortho positions, and - the 8-aza-bicyclo esters [3. 2. 1Joct-3-yliques not to be derived from a thiophenecarboxylic or naphthalenic acid, and their salts.



   The salts of the periphytic esters and of the
N-piperidyl-amides according to the invention include, for example, acid addition salts and quaternary ammonium salts, for example on the nitrogen atom of piperidine. All these compounds and salts will hereinafter be designated the compounds of the invention.



   The compounds can be substituted at any position. Any substituent should not form a cycle. In a group of compounds, the ester or amide group is attached to a di-carbocyte system.

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 click. In another group of compounds, the ester or amide group is attached to a heterocyclic system, preferably bicyclic and advantageously containing a cyclic heteroatom. Advantageously, the alkylene bridge contains at least three carbon atoms.



  In another group of compounds, the alkylene bridge is attached to the nitrogen atom of the piperidine ring.



   The invention relates more particularly to the compounds of formula 1
 EMI4.1
 in which A represents a group of formula II
 EMI4.2
 in which the free valence is located on one of the two cycles, X signifies -CH2-, -NR3-, -O-, or -S-, R, and R2 each signify, independently of one another, hydrogen, halogen or C1-C4 alkoxy, hydroxy, amino, (C1-C4 alkyl) C1-C4 amino dialkyl) amino, mercapto or alkylthio
Cl-Ce R3 means hydrogen or a C1-C4 'alkyl group
 EMI4.3
 C alkenyl or aralkyl, j b or A represents a group of formula III
 EMI4.4
 

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 EMI5.1
 J in which R4 to R7 mean, independently of one another, hydrogen, a halogen or an amino, nitro, (C1-C4 alkyl) -amino group,

   di- (alkyl in
C1-C4) amino, C1-C4 alkoxy, C1-C4 'alkyl (C1-C4 alkanoyl) amino or pyrrolyl, at least one of the substituents R4 and Rr must have a meaning other than hydrogen, B represents -O- or -NH-, D represents a group of formula IV
 EMI5.2
 in which n signifies 2,3 or 4, and R8 signifies hydrogen or a C1-C7 'alkyl group
 EMI5.3
 C3-C5 alkenyl or aralkyl, or else D represents a group of formula V
 EMI5.4
 D must signify a group of formula V when
A signifies a group of formula III and B signifies -NH, - n must signify 3 or 4.

   when A signifies a group of formula III where either R4 is hydrogen or R4 is halogen or alkyl and R5 to R7 are chosen from hydrogen and halogen, B signifies -O- and D signifies a group of formula IV , - when A signifies a group of formula III and one of the substituents R4 to R7 is an alkoxy and D signifies

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 a group of formula V, one of the other substituents R4 to R7 must have a meaning other than hy-
 EMI6.1
 drogen and alkoxy or only two of the substituents R4 to R7 which must signify an alkoxy, - which must signify A signifies a group of formula III in which R4 is halogen or alkyl, as well as their acid addition salts and their ammonium salts quaternary.



   Any alkyl residue is preferably a methyl, ethyl or propyl group. Alcoxy preferably means methoxy or ethoxy. Aralkyl advantageously means aryl- (C1-C4 alkyl). Alkenyl preferably means allyl or methallyl.



   Any aryl residue preferably means an unsubstituted phenyl group or a phenyl group bearing one or more substituents chosen from halogens, for example fluorine, and hydroxy groups, C1-C4alkyl, for example methyl, and C1- alkoxy. C4 'for example methoxy. The substituted aryl groups are preferably monosubstituted. Aralkyl advantageously means benzyl. Halogen means fluorine, chlorine, bromine or iodine.



   A advantageously signifies a group of formula II.



   The ester or amide group can be attached in position 2,3, 4,5, 6 or 7 of the group of formula II; however, the ester or amide group is preferably attached at the 4 or 5 position. More preferably, the ester or amide group is attached to the ring containing X, especially at the 3 position. The group A is preferably an indolyl residue.



   R1 is fixed in position 4,5, 6 or 7 of the group of formula II, preferably in position 5, and R in position 2 or 3. The invention also comprises

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 tautomeric forms, for example when R2 in the group of formula II means hydroxy or mercapto in position 2.



   R3 advantageously signifies hydrogen or an alkyl group. Advantageously, n signifies 3 or 4, more preferably 3.



   In the group of formula III, the substituents R4 to R7 advantageously have the following meanings:
R4 = halogen, (C1-C4 alkyl) amino or C1-C4 alkoxy 'Rq = H or halogen,
R6 = H, amino, nitro, (C1-C4 alkyl) amino, dialkyl C1-C4) amino, halogen or 1-pyrrolyl,
R7 = H or halogen.



   R6 advantageously has a meaning other than hydrogen, halogen or pyrrolyl.



   In the group of formula III, R7 preferably means a halogen, preferably chlorine or iodine, especially chlorine.



   Other examples of a group of formula III include the 3,5-dimethoxyphenyl, 3,5-dimethylphenyl and especially 3,5-dichlorophenyl group. The group of formula III can also signify a 3-chloro-, 3-methyl- or 3,4,5-trimethoxyphenyl group.



   The group of formula IV can exist in different conformations. For example the cycle at six. links containing the nitrogen atom and the carbon atom to which the residue B is linked, that is to say the piperidine cycle, can exist in the chair or boat conformation or in an intermediate conformation.



   The rest B can have two different configurations depending on whether it is located above or

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 below the plane formed by the carbon atoms of the piperidine cycle, the nitrogen atom being located above the plane and the alkylene bridge below this plane. The remainder B has configuration a when it is located below the plane, on the same side as the alkylene bridge; this corresponds to the endo and also to the configuration of the tropine etc ... The rest B has the configuration ss when it is above the plane, l on the same side as the nitrogen atom; this corresponds to the exo configuration and also to the configuration of pseudotropin etc ... Below, we will use the exo / endo nomenclature. Endo isomers are preferred.



     Rn preferably means an alkyl group, especially methyl.



   The group of formula V is a quinuclidinyl group. Advantageously, it is the 3- or 4quinuclidinyl group, especially 3-quinuclidinyl.



   A group of compounds includes the compounds of formula Ipa
 EMI8.1
 in which
R4pa signifies a halogen or a group (C1-C4 alkyl) - amino or C1-C4 alkoxy '
 EMI8.2
 R signifies R6pa signifies an amino group, (C1-C4 alkyl) amino opa (4 or dialkyl C1-C4) amino, signifies hydrogen, fluorine, chlorine or bromine, and

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   hydrogen, R. means hydrogen or an alkyl group in opa
C1-C7ouaralkyle, as well as their acid addition salts and their quaternary ammonium salts.



   Another group of compounds includes the homotropanyl esters of benzoic acids, in particular the compounds of formula Ipb
 EMI9.1
 in which R4pa, R5pa, R6pa and R8pa have the meanings given above and
R7pb means hydrogen or halogen, as well as their acid addition salts and their quaternary ammonium salts.



   A group of compounds includes the compounds of formula Iqa
 EMI9.2
 in which the ester group is fixed on one or the other of the two cycles, means 2 or 3, and

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 R1, R2, R3 and R8 have the meanings given above, as well as their acid addition salts and their quaternary ammonium salts.



   Another group of compounds includes the tropanyl and homotropanyl esters of indolecarboxylic acids, in particular the compounds of formula
 EMI10.1
 Iqb
 EMI10.2
 in which the ester group is fixed on one or the other of the two cycles,
Rlqb and R2qb mean, independently of each other, hydrogen, halogen or an alkyl group.
 EMI10.3
 CC means hydrogen or a C1-C4 alkyl group 'Cl-C4'R,., Means hydrogen or a C1-C4 alkyl group or aralkyl, and has the meaning given above, as well as their acid addition salts and their quaternary ammonium salts.



   Another group of compounds includes the N-tropanyl-andN-homotrpanyl-amides of indolecarboxylic acids, in particular the compounds of formula Iqc

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 EMI11.1
 in which the carboxamide group is attached to one or the other of the two rings, R2qc has the meaning given above for R2 except a hydroxy or C1-C4 alkoxy group, and
 EMI11.2
 n ',, have the meanings given ready o o
Recently, as well as their acid addition salts and their quaternary ammonium salts.



   Another group of compounds includes
 EMI11.3
 es in particular the compounds of formula Isa
 EMI11.4
 
 EMI11.5
 in which R ,,, are pa pa cations given previously, as well as their acid addition salts and their quaternary ammonium salts.



   Another group of compounds includes

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   N-qunuc1idinyl-amides of benzo acids? ques, in particular the compounds of formula Isb
 EMI12.1
 in which R4pa, R5pa, R6pa and R7pb have the meanings given above, as well as their acid addition salts and their quaternary ammonium salts.



   The invention also comprises a process for the preparation of the compounds of the invention, a process in which a suitable dicarbocyclic or heterocyclic carboxylic acid or a benzo acid? as appropriate, or a reactive acid derivative, or a precursor of the reactive acid or derivative, with an appropriate piperidylamine or piperidinol whose piperidine ring contains an alkylene bridge, or a precursor of these compounds, and, if necessary, we transform the piperidyl ester
 EMI12.2
 or the N-piperidyl-friend or its acid addition salt or its quaternary ammonium salt, in piperidyl ester or in desired N-piperidylamide or in its acid addition salt or its quaternary ammonium salt ,

   and recovering the piperidyl ester or the resulting N-piperidylamide in the form of the free base or in the form of an acid addition salt or a quaternary ammonium salt.

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   More particularly, the invention relates to a process for preparing the compounds of formula I, their acid addition salts and their quaternary ammonium salts, process according to which a) a suitable compound of formula VI is condensed
 EMI13.1
 in which A has the meaning given above, or a reactive derivative of this acid, or a precursor of the acid or of the reactive derivative, with an appropriate compound of formula VII
 EMI13.2
 wherein B and D have the meanings given above, or a precursor of this compound, or b) alkylating a compound of formula 1 having a secondary amino group to obtain a compound of formula I with a tertiary amino group, or c) removes the protective group (s) in a compound of formula 1 in protected form to obtain a compound of formula I, or d)

   subjecting a compound of formula I in which A signifies a group of formula II and R2 signifying hydrogen, to halogenation to obtain the corresponding compound where R2 signifies a halogen, or e) submitting a compound of formula I in which A signifies a group of formula II and R2 signifies a halogen, at an alkoxylation to obtain the corresponding compound where R2 signifies an alkoxy group, and the compound of formula I resulting is recovered in the form of free base or in the form of a salt addition of acid or a quaternary ammonium salt.

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   The condensation according to the invention for preparing the amides and the esters can be carried out according to the conventional methods used for the preparation of analogous compounds.



   The carboxylic group can for example be activated in the form of a reactive derivative, especially for the preparation of amides. Such reactive - suitable acid derivatives may be formed by reaction with the N, N'-carbonyl-diimidazole to form the intermediate imidazolide of the acid, or with the N-hydroxysuccinimide. It is also possible to bring into play an acid chloride, produced for example by reaction with oxalyl chloride.



   For the preparation of the esters, the alcohol can be used, for example in the form of an alkali metal salt, preferably in the form of a lithium salt. Such salts can be prepared according to the usual methods, for example by reaction of n-butyl lithium with alcohol in tetrahydrofuran.



   If desired, one can operate in the presence of a tertiary or heterocyclic amine, such as pyridine or triethylamine, especially for the preparation of amides.



   Suitable reaction temperatures can range from about -10 to about
10. In the case of compounds in which B signifies
NH and D mean a group of formula V, the reaction temperature can range for example up to approximately
 EMI14.1
 0 100, for example in boiling methanol or ethanol.



   Other suitable inert organic solvents include, for example, tetrahydrofuran or dimethoxyethane.

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   In these reactions, the endo or exo configuration of the substituent B in the group of formula IV is assumed to be retained. If desired, the compound of formula VII can be reacted as a mixture of the endo and exo isomers and then isolate the pure endo isomer or the pure exo isomer, for example by chromatography or by crystallization.



   The compounds of the invention can be transformed into other compounds of the invention, for example according to the usual methods. Some of these transformations are illustrated in processes b), c), d) and e).



   The alkylation according to method b) can be carried out in a conventional manner. Any free amino group can be alkyl, especially the compounds of formula II in which X signifies NH. The alkylation can be conveniently carried out with an alkyl halide in the presence of a sodium alcoholate. Suitable temperatures can range from about -500 to about -300.



   The removal of the protective group (s) according to method c) is specifically suitable for the preparation of compounds containing groups
 EMI15.1
 secondary amino, for example R8 = H in the group of formula IV, or primary amino groups, for example Ré = NH 0 2 * One can for example prepare a compound of formula I in protected form, for example RI being 0 replaced by a protecting group for the secondary amino group, such as the benzyl group. The benzyl group can then be removed according to known methods, for example by hydrogenation to give the corresponding compound of formula I

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 EMI16.1
 in which Ro is hydrogen.



  0
The hydrogenation can be carried out suitably in the presence of palladium on activated carbon, at room temperature or at a slightly higher temperature. Suitable solvents include acetic acid, ethyl acetate and ethanol.
 EMI16.2
 A primary amino group such as R6b can be protected, for example, by an N-benzyloxycarbonyl group. This group can then be removed by hydrogenation, in a manner analogous to that indicated above. In the presence of a benzyl group, the benzyloxycarbonyl group is generally removed first, so that this group can be selectively removed.



   The amino group can also be in the form of a nitro group. This nitro group can be selectively reduced according to the usual methods, for example with iron in hydrochloric acid.



   The halogenation according to method d) can be carried out according to conventional methods. N-chlorosuccinimid can lead, for example, to chlorination. Such reactions can be carried out in suspension in chloroform. The reaction with N-iodo-succinimide can also lead to iodization.



   The substitution of a reactive halogen according to process e) can be carried out according to known methods, for example by reaction with an appropriate alcohol, for example at room temperature for at least 10 to 20 hours.



   One can, if desired, use a starting material in the form of a precursor. Such a precursor must be able to be transformed into a starting product according to the usual methods; however, the process of the invention is rather carried out with the precursor and the other starting product or the other products of

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 departure, or its precursors or their precursors. The. resulting product is then transformed into compound of the invention according to the usual methods, for example by using the same reaction conditions as those used to transform the precursor into starting product. Typical precursors include protected forms of a starting material, for example in which the amino groups are provisionally protected.



   The compounds of the invention can then be isolated and purified according to the usual methods.



   When the preparation of a particular starting product will not be described in detail, it will be a known compound or which can be prepared in a manner analogous to known compounds or in a manner analogous to that described in the description, for example. example in the examples, or according to known methods for analogous compounds.



   The compounds of formula VII in which B signifies -NH- and D signifies a group of formula IV in which n signifies 4, are new compounds which are also part of the present invention. These compounds of formula VII can be prepared for example by reduction of the corresponding oxime, in the same way as for the other compounds of formula VII in which B signifies -NH-. The compounds of formula VII in which B signifies -0- can be prepared according to the usual methods, by reduction of the corresponding ketone.



   All the above reductions can be carried out for example by catalytic hydrogenation, for example on platinum (this process being considered to lead essentially to endo isomers),

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 according to the Bouveault et Blanc method, for example with sodium in amyl alcohol or butanol (this process being considered to lead essentially to exo isomers) or by means of aluminum hydride or sodium borohydride (often leading to a mixture of endo and exo isomers).



   Any mixture of the exo and endo forms can be separated by chromatography.



   The free bases of the compounds of the invention can be transformed according to the usual normal methods of adding acids, and vice versa. The acids suitable for the formation of salts include hydrochloric acid, malonic acid, hydrobromic acid, maleic acid. , malic acid, fumaric acid, methanesulfonic acid, oxalic acid and tartaric acid. The quaternary ammonium salts of the compounds of the invention can be prepared according to the usual methods, for example by reaction with methyl iodide.



   The following examples illustrate the present invention without in any way limiting its scope. All temperatures are given in degrees Celsius and are not corrected. All spectrum values
NMR are in ppm (tetramethylsilane = 0 ppm).



  Nomenclature
Endo-8-methyl-8-aza-bicyclo [3. 2. 1Joct-3-yle = tropyle, -tropyle ou a-tropanyl,
 EMI18.1
 Exo-8-methyl-8-aza-bicyclo [3. 2. 1Joct-3-yle = pseudotropyle, 6-tropyle ou -tropanyl, Endo-9-methyl-9-aza-bicyc1o [3.3.1] non-3-y1e = tropanyl or isopel1étiérinyle, Exo-9-methyl-9 -aza-bicyclo [3.3.1] non-3-yle = ss-homotropanyl, a-isopellétiérinyle or pseudopellétiérinyle,

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 EMI19.1
 l-aza-bicyclo [2. 2.2] octyl = compounds of Examples A-2, A-3 and 8-6 were confirmed by X-ray analysis. The configuration of the other compounds is considered to be that of the starting materials of formula VII which have been used pure, unless otherwise indicated.



  In the tables, the column designated "Conf" gives the configuration of group B-D, that is to say endo or exo. The column designated "Prep" indicates the example n in series A describing the preparation process.



  The following abbreviations have been used 111-1 = 5-chloro-2-methoxy-4-methvlaminophenyl III-II = 2-methoxy-4-dimethylaminophenyl III-III = 4-amino-5-chloro-2-methoxyphenyl III-IV = 4-amino-2-methoxyphenyl III-V = 3-iodo-2-methoxy-4-methylaminophenyl III-VI = 5-chloro-2-methoxy-4-dimethylaminophenyl III-VII = 2-chloro-4-aminophenyl III -VIII = 3-iodo-4-amino2-methoxyphenyl III-IX = 2-methoxy-4-methylamino-phenyl III-X = 2-chloro-4-nitrophenyl III-XI = 4-bromo-2-methoxyphenyl III-XII = 3, 5-dichlorophenyl III-XIII = 5-chloro-2-methoxy-4- III-XIV = 2-methoxy-4 (1-pyrrolyl) phenyl 1) hydrogen maleate 2) hydrogen hydrogenate 3) decomposition 4) bis 5) obtained by reduction of the corresponding 4-nitro compound

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   quinuclidinyl.) - hydrobromide 7)

   passing through imidazolide 8) in the proton NMR spectrum, the exo form has at about 5.15 ppm a large multiplet for the hydrogen located on the carbon atom in position 3 and the endo forms a double triplet at 5.1 ppm for the same hydrogen. The exo alcohol is eluted before the endo isomer on silica gel (eluent:
 EMI20.1
 rH g 9) hydrogen oxalate 10) in the presence of triethylamine in place of pyridine.

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    CH2C12 / 5% methanol / 5% NH40H) EXAMPLE A-1, --- N- (endo-9-methyl-9-aza-bicyclo [3. 3.1] non-3-y1) indole- 3-carboxamide or N- (3a-homotropany1) indole-3-carboxamide
 EMI21.1
 (process a) (Compound of formula I, in which A = group of formula II, position 3; R1 = R2 = H; X = NH B = NH = group of formula IV, configuration <x 3 R8 = CH3) a) Chloride of indo-3-carboxylic acid 32.2 g (0.2) dl anhydrous are suspended in 150 ml of anhydrous methylene chloride and, with stirring, is added to 200 in 30 minutes. 26 ml (0.3M) of oxalyl chloride. There is a gas evolution.

   The mixture is stirred for 3 1/2 hours to 200. After adding 150 ml of hexane, the mixture is stirred for a further 20 minutes, the resulting product is filtered off, washed with a mixture of methylene chloride and d hexane 1: 1 and dried. under vacuum at 20; the title compound is thus obtained in the form of beige crystals, which are then used without purification. F = 135-136 (decomposition).
 EMI21.2
 b) 3. or. 3-homotropanone-oxime We spray in a mortar 176 g (2, 15M)
9-methyl-9-aza-bicyclo [sodium acetate and 150 g (2.15 M) of hydroxylamine hydrochloride to obtain a fine paste, extracted with 1 liter of methanol, the salt is filtered off and the solution is treated with 99.5 9 (0.65M) of endo-9methyl-9-aza-bicyclo [3. 3.1] nonan-3-one (3-homotropanone).



  The oxime begins to crystallize after 10 minutes and the mixture is stirred for a further 4 hours to 20. For further processing, the mixture is concentrated in vacuo, the residue is treated with a solution of potassium hydrogen carbonate and extracted with chloroform containing

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 a little isopropanol. The organic phases are combined, the overall phase is washed with a little water, dried with sodium sulphate and concentrated, which gives the title compound.

   F = 126-127 (after crystallization from a mixture of toluene and hexane). c) Endo-9-methyl-9-aza-bicyclo [3. 3. 1] no -3-yl- amine (or 3 &alpha; -amino-homotropane)
A solution of 50.5 ml (0.95M) of sulfuric acid concentrated in 230 ml of anhydrous tetrahydrofuran is added at -100 for 2 hours to a cooled mixture with stirring of 73 g (1.9M) of hydride. aluminum and lithium in 900 ml of anhydrous tetrahydrofuran. The mixture is left to stand overnight. To the mixture stirred at 300, a solution of 80 g of endo-9-methyl-9-aza-bicyclo is added dropwise for 30 minutes [3. 3. 1] nonan-3-oneoxined in 1.4 liters of anhydrous tetrahydrofuran and left to react for a further 3 hours at 40.
 EMI22.1
 



  For the further treatment, the reaction mixture is cooled to 10, 150 ml of water in 150 ml of tetrahydrofuran are carefully added. The mixture is stirred for 1 hour at 300. The resulting precipitate is filtered off and the residue is washed with methylene chloride and ether. The organic phases are collected and the overall phase is distilled, which gives the
 EMI22.2
 0 composed of the title. E = 115-119. (17-18 Torr) -nO = 1, 5066 0 (The reduction essentially gives the endo product.

   A similar reduction in 8-methyl-8-aza-bicyclo [3. 2. 1 J- octan-3-one-oxime gives the product exo). d) N- (endo-9-methyl-9-aza-bicyclo [3 .. 3.1] nj3n-3-y-1) - indole-3-carboxamide
A solution of 15.4 g (O, 1M) is added dropwise at a temperature between -10 and 0

  <Desc / Clms Page number 23>

 of endo-9-methyl-9-aza-bicyclo- [3.3.1] -non-3-yl-amine in 50 ml of anhydrous pyridine in a stirred suspension of 14.5 g (0.08 M) of chloride indole-3-carboxylic acid [obtained in step a] in 50 ml of anhydrous methylene chloride.
 EMI23.1
 



  Heated to 200 resulting yellow suspension and stirred overnight. A 2N aqueous sodium carbonate solution is added for further processing. The mixture is extracted several times with methylene chloride and treated according to the usual methods. The title compound is obtained after 3 crystallizations.



  F = 247-249 (decomposition).



   EXAMPLE A-2
 EMI23.2
 Endo-8-methyl-8-aza-bicyclo indole-3-carboxylate [3. 2. 1] oct-3-yl (process a) (Compound of formula I, in which A = group of formula II in position 3; R = R2 = H; X = NH; 3 = 0; D = group 1 IV , configuration a; n = 2; Rg = CH3)
Treated at a temperature between 00 and 10 6.35 g (45 mM) dlendo-8-methyl-8-aza-bicyclo- [3. 2.



    1] octane-3-ol (tropine) in 20 ml of anhydrous tetrahydrofuran per, 17 ml of a 2 molar solution of butyllithium in hexane. The mixture is stirred for a further 30 minutes. The hexane is removed in vacuo and replaced with a corresponding amount of tetrahydrofuran, which
 EMI23.3
 gives the lithium salt.



  4.8 (9 mM) of indole-3-carboxylic acid chloride in 20 ml of tetrahydrofuran are added to the mixture, and the beige suspension is stirred overnight at 20. The mixture is treated in the usual way by dividing it between methylene chloride and sodium carbonate, which gives the title compound in the raw state

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 EMI24.1
 which is chromatographed on silica gel (250 g), eluting with methylene chloride containing 10% methanol and 0, ammonia. F = 201-202 (after crystallization from a mixture of methylene chloride and ethyl acetate). Hydrochloride, F = 283-2850 (decomposition). Iodomethylate, F = 285-2870 (decomp.).



  It can also be reacted with carbonyl-diimidazole to form imidazolide. The imidazolide can be reacted with the lithium salt mentioned above, at a temperature between 10 and 15, in tetrahydrofuran.



  EXAMPLE A-3 1-methyl-N- 3. 1non-3y1) indole-3-carboxamide or 1-methyl-N- (3 (3a-homotropanyl) indole-3-carboxamide (method b) (compound of formula 1 in which A = group of formula II in position 3; R-) = R2 = HX = NCH B = NH D = group of formula IV, configuration a; n = 3; R8 = CH3).



  A-50 treats dropwise 0, (20mM) of sodium dissolved in 170 ml of anhydrous liquid ammonia with 1.3 ml (22.5mM) of absolute ethanol diluted with a little anhydrous ether. The resulting colorless suspension of sodium ethylate is stirred for 15 minutes to 4, (15 mM) of N- [3. 3. lJ-non-3-yl) indole-3-carboxamide, which gives a clear solution. The mixture is stirred for 10 minutes at -50, 1.25 ml (20 mM) of methyl iodide in 4 ml of anhydrous ether are added.



  The mixture is stirred for another 4 1/2 hours. For further processing, the ammonia is removed in vacuo. The residue is distributed between methylene chloride and water and treated according to the

  <Desc / Clms Page number 25>

 
5% usual methods, which gives a colorless foam which is chromatographed on 120 g of silica gel, eluting with methylene chloride containing 5% methanol and 3% ammonia. F = 210-212 (recrystallization from a mixture of ethyl acetate and fietol). Hydrochloride, F = 295-297 (decomposition).



   The compound can also be prepared in a manner analogous to that described in Example 1, starting from 1-methyl-indole-3-carboxylic acid.



   EXAMPLE A-4
 EMI25.1
 Endo-9-azabicyclo 5-fluoro-1-methyl-indole-3-carboxylate [3. or N-desmethyl-3a-homotropanyl 5-fluoro-1-methyl-indole-3-carboxylate (method c) (compound of formula I, in which A = group II in position 3; Rj = 5-F; R2 = H; X = NCH3; B = -0- group IV, configuration a; n = 3 = H) Hydrogenation is carried out at room temperature and under normal pressure 4, 9 g of 5-fluoro-1-methyl-indole- 3- endo-9-benzyl-9-aza-bicyclo carboxylate [3. 3. 1non-3yle in 200 ml of ethanol in the presence of 1.5 g of palladium
3. 1Jnon-3-yle at 10% on activated carbon. After 45 minutes, the absorption of hydrogen is complete (approximately 230 ml) and the catalyst is separated by filtration. The solvent is removed in vacuo to give the title compound. F = 130-131 (after recrystallization from ethanol containing a little hexane).



   EXAMPLE A-5
 EMI25.2
 2-methoxy-indole-3-carboxylate bicyclo [3. 2. 1Joct-3-yl or 2-methoxy-indole-3-carboxylate of endo-8-methyl-8-aza-tropyl (compound of formula I; A = group II in position 3:

  <Desc / Clms Page number 26>

 
 EMI26.1
 RI = H; R2 = 2-OCH3; X = NH; B = 0 D = group IV, configuration a; n = 2; R8 = CH3).



  68 g (20 mM) of indole-3carboxylate 2 are added to 20 g. 1Joct-3-yl to a suspension with stirring of 4 g (30 mM) of N-chlorosuccinimid in 80 ml of anhydrous chloroform. The mixture is stirred for 3 hours at 20, to give 2-chloroindole-3-carDoxylate 2. 1] oct-3-yl in the form of a clear yellow solution.



  The yellow solution is treated with 10 ml of absolute methanol and left to stand overnight. The usual subsequent treatment by partitioning the mixture between an aqueous solution of IN sodium carbonate and methylene chloride, gives a product in the raw state which is chromatographed on silica gel (30 times the amount) using chloride as eludant. methylene containing 10% methanol and 0.5% ammonia. F 204-206 (after crystallization from ethanol).



  EXAMPLE A-6 Endo-8-methyl-B-azabicyclo- 3-iodo-indole-4-carboxylate [3. 2. 1Joct-3-yle (compound of formula 1, in which A = group of formula II in position 4; Ri = H = 3-1; X = B = -0- D = group IV, configuration a; (process d).



  To a suspension with stirring of 2.48 g (11 mM) of N-iodosuccinimide in 200 ml of anhydrous chloroform, the solution is added dropwise

  <Desc / Clms Page number 27>

 ; 2.84 g (10 mM) indo-8-methyl-8-aza-bicycol indole-4-carboxylate [3. 2. 1] oct-3-y1e. The mixture is stirred for a further 30 minutes at 20, the mixture is distributed between a solution of IN sodium carbonate and methylene chloride and is subjected to further treatment. The title product melts at 163-165 (decomposition) after crystallization from ethanol. The compound can also be prepared from 3-iodo-indole-4-carboxylic acid in a manner analogous to that described in Example 2.



   EXAMPLE A-7
 EMI27.1
 5-chloro-2-methoxy-4-methylamino-benzoate from a-aza-bicyclo [2. 2.2] oct-3-yl or 5-ch1oro-2-methoxy-4-Tiethylamino benzoate of 3-cuinuclidinyl (method a) (compound of formula I in which A = group III; R4 = OCH3; R5 = H ; R6 = NHCH3; R7 = Cl; B = -O-; D = group V in position 3) a) Imidazolide of 5-chloro-4-methylamino-2-methoxy-benzo acid? than
At a temperature between 20 and 25, 12 g of N, N'-carbonyldiimidazole are added to a stirred solution of 8 g of 5-chloro-4-methylamino-2-methoxy-benzoic acid in 300 ml of anhydrous tetrahydrofuran .

   The mixture is stirred for 1 hour under anhydrous conditions, then the solvent is removed at a temperature between 35 and 400. The residue is dissolved in methylene chloride. The mixture is then washed 2 to 3 times with water, dried over magnesium sulfate, filtered and concentrated. The title compound is crystallized from a mixture of methylene chloride and hexane. F = 152-154.

  <Desc / Clms Page number 28>

 
 EMI28.1
 b) 1-aza-bicyclo 5-chloro-4-methylamino-2-methoxy-benzoate [2. 2. 2Joct-3-yle
At a temperature between 0 and 5 and under a dry nitrogen atmosphere, dropwise added
 EMI28.2
 27 ml of n-butyllithium (1.6 molar) in hexane, a stirred solution of 5.56 g of l-aza-bicyclo- [2. 2.



    2 Joctane-3-ol (quinuclidine-3-ol) in 100 ml of anhydrous tetrahydrofuran. The mixture is stirred for a further 10 to 15 minutes at a temperature between 0 and 5, then a solution of imidazolide of 5-ch-1-oro-4-methyl-amino-2-methoxy-benzofque acid is added. in 100 ml of anhydrous tetrahydrofuran. The mixture is stirred for 1 hour.



  5 ml of a saturated aqueous potassium bicarbonate solution are added and the solution is decanted. The residue is washed twice with tetrahydrofuran. The organic phases are combined, the overall phase is dried over magnesium sulphate, filtered and concentrated. The crude product is treated with an equivalent amount of malonic acid to give the title compound hydrognomalonate, F = 170-172 (after crystallization from acetone).



   EXAMPLE A-8
 EMI28.3
 Exo-8-benzyl-8aza-bicyclo 4-amino-5-chloro-2-methoxy-benzoate [3. 2. 1Joct-3-yl or 4-amino-5-chloro-2-methoxy-benzoate of 8-benzyl-pseudo-nor-tropyl (method c) (Compound of formula I, in which A = group III; R4 = OCH3; R5 = H; R6 = NH2; R7 = Cl; B = 0; D = group IV, configuration; n = 2; R8 = benzyl)

  <Desc / Clms Page number 29>

 a) Methyl ester of 4- (N-benzy1oxycarbony1) - amino-2-methoxy-benzofque acid
A solution of 42.1 g of 4-amino-2-methoxy-benzoic acid methyl ester is heated at reflux for 2 1/2 hours, only in 600 ml of toluene with 60 ml of phenyl chloroformate. The solution is cooled and the title compound is filtered off.
 EMI29.1
 



  0 F = 137-138 .b) Methyl ester of 4- (N-benzyloxycarbonylamino) -5-chloro-2-methoxy-benzo @ acid
18 g of chlorine gas (dried over sulfuric acid) are passed through at 200 for 20 to 25 minutes through a stirred solution of 61.4 g of 4- (N-benzyloxycarbonyl) acid methyl ester. amino-2-methoxy-benzolo. eu in 1 liter of chloroform.

   The reaction mixture is concentrated in vacuo to give the title compound which is used as is for the next reaction. c) 4- (N-Benzyloxycarbonylamino) -5-chloro-2-methoxy-benzoic acid
200 ml of a 2N aqueous sodium hydroxide solution are added dropwise to a stirred solution of 72.1 g of the ester obtained in step b) in 800 ml of dioxane. The mixture is stirred for 20 hours and the organic solvent is removed in vacuo. The residue is dissolved in water and the pH is adjusted to 5-6 with 3N hydrochloric acid. The title compound is separated by filtration and washed with water.

   F = 182-183 (after crystallization from methanol).

  <Desc / Clms Page number 30>

 d) 4- (N-Benzyloxycarbonylamino) -5- chloro-2-methoxy-benzo acid imidazolide? than
The compound is prepared in a similar manner to that described in Example A-7a.
 EMI30.1
 e) exo-8-benzyl-8-aza-bicyclo benzoate [3. 2. 1Joct-3-yle The compound is prepared in a similar manner to that described in Example A-7b. f) exc-8-benzyl-8-aza-bicyclo 4-amino-5-chloro-2-methoxy-benzoate [3. 2. 1Joct-3-yle 54 g of exo-8-benzyl-8-aza-bicyclo 4-chloro-2-methoxy-benzoate [3. 2. 1] oct-3-y1e in 100 ml of ethanol are hydrogenated to (N-benzyloxycarbonylamino) -5-chloro-2-methoxy-presence of 0.7 g of 10% palladium on activated carbon for 50 minutes at atmospheric pressure until one equivalent of hydrogen has been absorbed.

   The mixture is filtered through a filtration aid (Hyflo Supercell) and the filtrate is concentrated. The redidu is chromatographed on silica gel with methylene chloride containing 5% methanol; the title compound is obtained in the form of a free base. Hydrobromide, prepared by reaction of the base with HBr in ethanol,
 EMI30.2
 background at 241-242.



  EXAMPLE A-9 4-amino-5-chloro-2-methoxy-benzoate [3. or pseudo nor-tropyl 4-amino-5-chloro-2-methoxy-benzoate (compound of formula I, in which A = group III; R4 = OCH3; Rs = H; R6 = NH2; R7 = Cl; B = 0; D = group IV, configuration; n = 2; R8 = H) [process c)]

  <Desc / Clms Page number 31>

 
 EMI31.1
 8, exo-8-benzyl-8-aza-bicyclo 4-methoxy benzoate 2. 1] oct-
4 g3-yl in 250 μl of ethyl acetate or acetic acid are hydrogenated for 2 hours in the presence of 1.2 g of 10% palladium on activated carbon at atmospheric pressure and at a temperature between 20 and 25.



  The mixture is filtered (for example on Hyflo), the filtrate is evaporated and the residue is dissolved in methylene chloride. The organic phase is washed with IN sodium hydroxide and then with water; the overall phase is then dried over magnesium sulfate and concentrated.



  The product is chromatographed on silica gel using methylene chloride containing 5% methanol and methylene chloride containing 20% methanol.



  The title compound is crystallized as the hydrochloride. F = 258-259 (after crystallization from methanol).



   EXAMPLE A-10 Endo-8-methyl-8-aza-bicyclo indole-4-carboxylate [3. 2. U oct-3-yl or indole-4-tropyl carboxylate
 EMI31.2
 (compound of formula I, in which A = group II in position 4; Rj = R2 R3 =; B = 0; D = group IV, configuration an =; Rg At a temperature between 10 and 15 we treat drop by drop 7 g (50mM) of endo-8-methyl-8- = H; aza-bicycloL3. 2. 1] octane-3-o1 (tropine) in 15 ml of anhydrous tetrahydrofuran per 20 ml (40mM) of 2 molar butyllithium in hexane. 200 is stirred for 30 minutes and then concentrated to one volume.

  <Desc / Clms Page number 32>

 about 10 ml to remove the hexane, which gives the lithium salt. 10 ml of tetrahydrofuran are added.



   4.8 g (30 mM) of anhydrous indole-4-carboxylic acid in 15 ml of anhydrous tetrahydrofuran are treated in portions with 5.85 g (36 mM) of N, N'-carbonyldiimidazole. The mixture is allowed to stand for 90 minutes at 20 and then added dropwise to the lithium salt. The resulting suspension is stirred overnight at 20 and is distributed between chloride
 EMI32.1
 methylene / a little isopropanol and 1N sodium carbonate. The organic phases are washed, the overall phase is dried over sodium sulfate and evaporated, which gives the title compound. F = 220-222 (decomp.) (After crystallization from ethanol).



   EXAMPLE A-11
Indole-9-methyl-9-aza-bicyclo indo-4-carboxylate
 EMI32.2
 [3. 3. 1Jnon-3-yl or indole-4-carboxylate of 3-homotropanyl (Compound of formula 1, in which A = group II in position X = NH = R2 = H; R3 = NH; B = 0 D = IV, configuration a; n = 3; R8 = CH3) (process a) a) At a temperature between 10 and 15, 7, 65 9 (50 mM) of endo-9-methyl-9-aza-bicylo are treated dropwise [3. 3. 1] nonane-3-o1 in 15 ml of 2 molar tetrahydrofuran of butyl lithium in hexane.

   The resulting mixture is stirred for 30 minutes to 20. The hexane is then evaporated and replaced with tetrahydrofuran to give a solution of the lithium salt. b) At room temperature, treatment is carried out with

  <Desc / Clms Page number 33>

 4.8 9 (30 mM) portions of anhydrous indole-4-carboxylic acid in 15 ml of anhydrous tetrahydrof uranium per 5.85 g (36 mM) of; N'-carbonyldiimidazole. At the end of the evolution of gas, the solution is left to stand for 90 minutes at 20 and the lithium salt obtained under a) is added dropwise to it at a temperature between 10 and 15.



  The resulting suspension is stirred for 15 hours to 20 hours and is partitioned between methylene chloride / a little isopropanol and a 1N sodium carbonate solution.
 EMI33.1
 



  The organic phase is washed with water, the overall phase is dried over sodium sulfate and evaporated, which gives the title compound. F. = 189-190 (after crystallization from ethanol).

  <Desc / Clms Page number 34>

 



   EXAMPLES B
The following compounds of formula I were prepared where D is a residue of formula IV:
 EMI34.1
 
 <tb>
 <tb> Example <SEP> A <SEP> B <SEP> n <SEP> R8 <SEP> Conf. <SEP> Point <SEP> Prep.
 <tb> of <SEP> fusion
 <tb> B-1 <SEP> 5-chloroindol-3-yl <SEP> 0 <SEP> 2 <SEP> CH3 <SEP> endo <SEP> 235-237 3) <SEP> 2
 <tb> B-2 <SEP> 4-methoxyindol-3-yl <SEP> 0 <SEP> 2 <SEP> CH3 <SEP> endo <SEP> 193-194 <SEP> 2
 <tb> B-3 <SEP> 5-methoxyindol-3-yl <SEP> 0 <SEP> 2 <SEP> CH3 <SEP> endo <SEP> 214-2160 <SEP> 2 <SEP>
 <tb> B-4 <SEP> 1-methylindol-3-yl <SEP> 0 <SEP> 2 <SEP> CH3 <SEP> endo <SEP> 143-1440 <SEP> 3
 <tb> 8-5 <SEP> indol-3-yl <SEP> 0 <SEP> 2 <SEP> CH3 <SEP> exo <SEP> 239-24003) <SEP> 2
 <tb> 8-6 <SEP> indol-3-yl <SEP> 0 <SEP> 3 <SEP> CH3 <SEP> endo <SEP> 203-2 <SEP> (903)

    <SEP> 2
 <tb> 8-7 <SEP> indol-3-yl <SEP> 0 <SEP> 2 <SEP> n-C3H7 <SEP> endo <SEP> 158-159 <SEP> 2
 <tb> 8-8 <SEP> indol-3 - yl <SEP> 0 <SEP> 2 <SEP> benzyl <SEP> exo <SEP> 164-165 8) <SEP> 2
 <tb> B-9 <SEP> indol-3-yl <SEP> 0 <SEP> 2 <SEP> benzyl <SEP> endo <SEP> 162-16308) <SEP> 2
 <tb> B-10 <SEP> indol-3-yl <SEP> 0 <SEP> 2 <SEP> H <SEP> endo <SEP> 261-26303) <SEP> 8f
 <tb> B-11 <SEP> 5-fluorindol-3-yl <SEP> 0 <SEP> 3 <SEP> H <SEP> endo <SEP> 247-24803) <SEP> 4
 <tb> B-12 <SEP> 1-methylindoxyl <SEP> 0 <SEP> 3 <SEP> H <SEP> endo <SEP> 147-148 <SEP> 4
 <tb> B-13 <SEP> indol-3-yl <SEP> 0 <SEP> 3 <SEP> H <SEP> endo <SEP> 234-235 3) <SEP> 4
 <tb> B-14 <SEP> 5-methylindol-3-yl <SEP> 0 <SEP> 3 <SEP> CH3 <SEP> endo <SEP> 228-230 <SEP> 2
 <tb>
 

  <Desc / Clms Page number 35>

 
 EMI35.1
 
 <tb>
 <tb> Free <SEP> A <SEP> B <SEP> n <SEP> R8 <SEP> Conf.

    <SEP> Point <SEP> from <SEP> Prep.
 <tb> merge
 <tb> B-15 <SEP> 2-methylindol-3-yl <SEP> 0 <SEP> 3 <SEP> CH3 <SEP> endo <SEP> 204-205 <SEP> 2
 <tb> B-16 <SEP> 5-fluoro-1méthylindol-
 <tb> 3-y1 <SEP> 0 <SEP> 3 <SEP> CH3 <SEP> endo <SEP> 107-1080 <SEP> 3 <SEP> or <SEP> 2
 <tb> B-17 <SEP> 5-fluoro-indol-3-yl <SEP> 0 <SEP> 3 <SEP> CH3 <SEP> endo <SEP> 244-24503) <SEP> 2
 <tb> B-18 <SEP> 5-fluoro-1methyl-indol-
 <tb> 3-y1 <SEP> 0 <SEP> 3 <SEP> benzyl <SEP> endo <SEP> 127-128 <SEP> 3
 <tb> B-19 <SEP> 1-methyl-indol-3-yl <SEP> 0 <SEP> 3 <SEP> CH3 <SEP> endo <SEP> 103-104 <SEP> 3
 <tb>
 

  <Desc / Clms Page number 36>

 
 EMI36.1
 
 <tb>
 <tb> Example <SEP> A <SEP> B <SEP> n <SEP> R8 <SEP> Conf.

    <SEP> Point <SEP> from <SEP> Prep.
 <tb> merge
 <tb> B-20 <SEP> 5-methyl-indol-3-yl <SEP> NH <SEP> 3 <SEP> CH3 <SEP> endo <SEP> 265-267 3) <SEP> 1
 <tb> B-21 <SEP> 5-fluoro-indol-3-yl <SEP> NH <SEP> 2 <SEP> CH3 <SEP> endo <SEP> 220-222 <SEP> 1
 <tb> B-22 <SEP> 1-methyl-indol-3-yl <SEP> NH <SEP> 2 <SEP> CH3 <SEP> endo <SEP> 169-1700 <SEP> 3 <SEP> or <SEP> 1 <SEP>
 <tb> B-23 <SEP> 2-methyl-indol-3-yl <SEP> NH <SEP> 2 <SEP> CH3 <SEP> endo <SEP> 196-197 3) <SEP> 1
 <tb> B-24 <SEP> indol-3-yl <SEP> HH <SEP> 2 <SEP> CH3 <SEP> exo <SEP> 261-262)

    <SEP> 1 <SEP>
 <tb> B-25 <SEP> indol-3-yl <SEP> NH <SEP> 2 <SEP> CH3 <SEP> endo <SEP> 205-206 <SEP> 1
 <tb> B-26 <SEP> 5-chloro-indol-3-yl <SEP> NH <SEP> 2 <SEP> CH3 <SEP> endo <SEP> 210-212 <SEP> 1
 <tb> B-27 <SEP> indol-3-yl <SEP> 0 <SEP> 3 <SEP> benzyl <SEP> endo <SEP> 234-235 <SEP> 1
 <tb> 6-28 <SEP> l-methyl-'indol-3-yl <SEP> 0 <SEP> 3 <SEP> benzyl <SEP> endo <SEP> 147-148 <SEP> 2
 <tb> B-29 <SEP> 5-fluoro-indol-3-yl <SEP> 0 <SEP> 3 <SEP> benzyl <SEP> endo <SEP> 193-1940 <SEP> 2
 <tb>
 

  <Desc / Clms Page number 37>

 
 EMI37.1
 
 <tb>
 <tb> Example <SEP> A <SEP> B <SEP> n <SEP> R8 <SEP> Conf.

    <SEP> Point <SEP> from <SEP> Prep.
 <tb> merge
 <tb> B-30 <SEP> benzothien-
 <tb> 3-yl <SEP> 0 <SEP> 3 <SEP> CH3 <SEP> endo <SEP> 129-1300 <SEP> 2
 <tb> B-31 <SEP> benzothien-
 <tb> 3-yl <SEP> NH <SEP> 3 <SEP> CH3 <SEP> endo <SEP> 225-2260 <SEP> 17) <SEP>
 <tb> B-32 <SEP> benzofuran-
 <tb> 3-yl <SEP> NH <SEP> 3 <SEP> CH3 <SEP> endo <SEP> 199-201'1
 <tb> B-33 <SEP> benzofuran-
 <tb> 3-yl <SEP> 0 <SEP> 3 <SEP> CH3 <SEP> endo <SEP> 77-78 <SEP> 2
 <tb> B-34 <SEP> 1 <SEP> (H) <SEP> indén-
 <tb> 3-y1 <SEP> NH <SEP> 3 <SEP> CH3 <SEP> endo <SEP> 181-183 <SEP> 1
 <tb> B-35 <SEP> indol-3-yl <SEP> NH <SEP> 4 <SEP> CH3 <SEP> exo <SEP> 264-266 3) <SEP> 110)
 <tb> B-36 <SEP> indol-3-yl <SEP> 0 <SEP> 4 <SEP> CH3 <SEP> exo <SEP> 264-26703) <SEP> 2
 <tb>
 

  <Desc / Clms Page number 38>

 
EXAMPLES C
The following compounds of formula I have been prepared where 0 is a residue of formula IV:

   
 EMI38.1
 
 <tb>
 <tb> Example <SEP> A <SEP> B <SEP> n <SEP> Rg <SEP> Conf. <SEP> Point <SEP> from <SEP> Prep. <SEP>
 <tb> merge
 <tb> C-1 <SEP> indol-5-yl <SEP> 0 <SEP> 2 <SEP> CH3 <SEP> endo <SEP> 191-193 <SEP> 2
 <tb> C-2 <SEP> indol-5-yl <SEP> 0 <SEP> 3 <SEP> CH3 <SEP> endo <SEP> 148-149 <SEP> 10
 <tb> C-3 <SEP> 3-iodo-indol-5-yl <SEP> 0 <SEP> 3 <SEP> CH3 <SEP> endo <SEP> 172-174 <SEP> 6
 <tb> C-4 <SEP> incol-4-yl <SEP> NH <SEP> 2 <SEP> CH3 <SEP> exo <SEP> 267-26903) <SEP> i
 <tb> C-5 <SEP> indoi-4-yl <SEP> NH <SEP> 2 <SEP> CH3 <SEP> endo <SEP> 221-223 3) <SEP> 1
 <tb> C-6 <SEP> indol-5-yl <SEP> NH <SEP> 2 <SEP> CH3 <SEP> endo <SEP> 220-221 "1 <SEP>
 <tb>
 

  <Desc / Clms Page number 39>

 
EXAMPLES D
Analogously to that described above, the following compounds were prepared in which A is a group of formula III and D is a group of formula IV:

   
 EMI39.1
 
 <tb>
 <tb> Example <SEP> A <SEP> B <SEP> n <SEP> R8 <SEP> Conf. <SEP> Point <SEP> from <SEP> prep. <SEP>
 <tb> merge
 <tb> D-1 <SEP> III-I <SEP> 0 <SEP> 2 <SEP> CH3 <SEP> endo <SEP> 193-195 * 1) <SEP> 7
 <tb> D-2 <SEP> III-II <SEP> 0 <SEP> 2 <SEP> benzyl <SEP> exo <SEP> 112-114 2) <SEP> 7
 <tb> 0-3 <SEP> 111-111 <SEP> 0 <SEP> 2 <SEP> CH3 <SEP> endo <SEP> 154-15502) <SEP> 7
 <tb> D-4 <SEP> III-lII <SEP> 0 <SEP> 2 <SEP> H <SEP> endo <SEP> 168-16902) <SEP> 9 <SEP>
 <tb> 0-5 <SEP> III-IV <SEP> 0 <SEP> 2 <SEP> H <SEP> endo <SEP> 184 <SEP> 18DE1) <SEP> 9
 <tb> D-6 <SEP> III-IV <SEP> 0 <SEP> 2 <SEP> H <SEP> exo <SEP> 166-167 2) <SEP> 9
 <tb> D-7 <SEP> III-IV <SEP> 0 <SEP> 2 <SEP> CH3 <SEP> endo <SEP> 245-246 4) <SEP> 7
 <tb> D-8 <SEP> III-VI <SEP> 0 <SEP> 2 <SEP> CH3 <SEP> in <SEP> do <SEP> 146-147 "2) <SEP> 7
 <tb> D-9 <SEP> III-VII <SEP> 0 <SEP> 2 <SEP> CH3 <SEP> endo <SEP> 210-211 5)

    <SEP> 7
 <tb> D-10 <SEP> III-VIII <SEP> 0 <SEP> 2 <SEP> CH3 <SEP> endo <SEP> 216 6) <SEP> 7
 <tb> D-11 <SEP> III-V <SEP> 0 <SEP> 3 <SEP> CH3 <SEP> endo <SEP> 164-1660 <SEP> 7 <SEP>
 <tb> 0-12 <SEP> III-IX <SEP> 0 <SEP> 3 <SEP> CH3 <SEP> endo <SEP> 163-1640 <SEP> 7
 <tb> D-13 <SEP> III-X <SEP> 0 <SEP> 2 <SEP> CH3 <SEP> endo <SEP> 132-1330 <SEP> 7
 <tb> D-14 <SEP> III-XI <SEP> 0 <SEP> 2 <SEP> CH3 <SEP> endo <SEP> 91-92 <SEP> 7
 <tb> D-15 <SEP> III-XII <SEP> 0 <SEP> 3 <SEP> CH3 <SEP> endo <SEP> 170-171 <SEP> 7 <SEP>
 <tb> D-16 <SEP> III-XIII <SEP> 0 <SEP> 2 <SEP> CH3 <SEP> endo <SEP> 158-1592) <SEP> 7
 <tb> D-17 <SEP> III-XIV <SEP> 0 <SEP> 2 <SEP> CH3 <SEP> endo <SEP> 159-1602) <SEP> 7
 <tb>
 

  <Desc / Clms Page number 40>

 EXAMPLES E
 EMI40.1
 t
The following compounds of formula I were prepared, in which A is a group of formula II or III and D is a group of formula V:

   
 EMI40.2
 
 <tb>
 <tb> Example <SEP> A <SEP> B <SEP> D <SEP> Point <SEP> from <SEP> Prep. <SEP>
 <tb>



  (position) <SEP> fusion
 <tb> E-1 <SEP> indol-3-yl <SEP> 0 <SEP> 3 <SEP> 2] <SEP> 9-221 4) <SEP> 3) <SEP> 7
 <tb> E-2 <SEP> 111-1 <SEP> NH <SEP> 3 <SEP> 145-1470
 <tb> 154-156 <SEP> 2) <SEP> 7 *
 <tb> E-3 <SEP> III-XII <SEP> 0 <SEP> 3 <SEP> 159-160 <SEP> 7
 <tb>
 * if necessary in boiling ethanol

  <Desc / Clms Page number 41>

 Representative formula VII starting materials
 EMI41.1
 
 <tb>
 <tb> EXAMPLE <SEP> n <SEP> R8 <SEP> Conf. <SEP> B <SEP> Characteristics <SEP> Name <SEP> trivial <SEP>
 <tb> a) <SEP> 2 <SEP> CH3 <SEP> endo <SEP> 0 <SEP> F.

    <SEP> = <SEP> 59-61 "tropine <SEP>
 <tb> b) <SEP> 2 <SEP> CH3 <SEP> exo <SEP> 0 <SEP> F <SEP> = <SEP> 105-107 <SEP> pseudotropin
 <tb> c) <SEP> 2 <SEP> CH3 <SEP> endo <SEP> NH <SEP> E <SEP> = <SEP> 82 / 12mmHg <SEP> tropinamine
 <tb> d) <SEP> 2 <SEP> CH3 <SEP> exo <SEP> HH <SEP> E <SEP> = <SEP> 75 / 0.05 <SEP> mmHG <SEP> pseudotropinamine
 <tb> e) <SEP> 3 <SEP> CH3 <SEP> endo <SEP> NH <SEP> E <SEP> = <SEP> 115/17 <SEP> mmHg
 <tb> f) <SEP> 3 <SEP> CH3 <SEP> endo <SEP> OH <SEP> amorphous <SEP> +
 <tb> g) <SEP> 3 <SEP> benzyl <SEP> endo <SEP> OH <SEP> F <SEP> = <SEP> 69-70 +
 <tb> h) <SEP> 2 <SEP> n-C3H7 <SEP> endo <SEP> OH <SEP> oil <SEP> ++ <SEP>
 <tb>
 + prepared by reduction of the ketone with NaBH4 and separation of the isomers ++ prepared by reduction of the ketone with Nab4.



   Main product.

  <Desc / Clms Page number 42>

 
 EMI42.1
 i) 3. 1] dec-8-ylamine (for example B-35) In a manner analogous to that described below in example j), 15 g of sodium are reacted with 9.69 g of acetate. 10-methyl-10-azabicyclo [4. 3. 1] N-methyl-10-aza-bicyclo [4.decane-8-one-oxime [F = 253-253, 5 prepared in a similar manner to that described in Example A-lb], which gives an oil (boiling point = 105 / 0.9 mmHg) after treating. 1ent subsequent according to conventional methods.



     H NMR (200 MHz) 3.27-3.04 (multiplet, 2H, HC- (1) - and H-C (6); 2.59 (singlet, 3H, H-C (II);
 EMI42.2
 2, 01-1, 49 multiplet, 13H 6 x 2H-C and H-C (8); 1.24 (singuet, 2H: interchangeable with 020); 13C NMR (25.2 MHz) 56, 41 (d) doublet), 42, 85 (quartet C-11), 41.44 (doublet), 37.13 (triplet, C-7 and C-9), 32 , 54 (triplet, C-2 and C-5) and 24.88 (triplet C-3 and C-4).

   The product is assumed to have the exo configuration. j) N-. methyl-10-azabicyclo [4.3.1] decane-8-ol (for example B-36)
5 g of pieces of sodium are added to a hot solution of 3.5 g of 8-methyl-10-azabicyclo [4.3.1] decane-8-on in 100mlden-butanolanhydrous. The mixture is heated at reflux for one hour, it is cooled and acidified with concentrated hydrochloric acid to a pH of 2. The mixture is evaporated to dryness, which gives a residue which is taken up in sodium hydroxide. The mixture is extracted with chloroform, dried and distilled: boiling point = 90-95 / 0.025 mm Hg.



     H NMR (200 MHz) 4.07-4, 23 (multiplet, 'HC (8) half width about 20Hz), - 3.63-3.69 (triplet, 0.33 H, J = 7Hz, HO-C - (8) an isomer interchangeable with

  <Desc / Clms Page number 43>

 
 EMI43.1
 D20), 2, 13-1, 38 (multiplet, 12H, 6 x CH2). 13C NMR (25, 2 MHz) 63.10 (doublet C-8), 56, 80 (doublet, C-1 and (C-6), 43, 13 (quartet, NCH3), 36, 30 (triplet C- 7 and C-9), 34.80 (triplet, C-2 and C-5), 25.04 (triplet C-3 and C-4) The product is assumed to have the exo configuration.



   The compounds of the invention are distinguished by interesting pharmacological properties and can therefore be used in therapy as medicaments.



   In particular, the compounds have an antagonist activity of the serotonin M receptors, as appears from the conventional tests. For example, the inhibitory action of the compounds on the action of serotonin was demonstrated by the reduction in the amplitude of the action potential of serotonin in the test carried out on the isolated vagus nerve of rabbits, according to the principle described by Riccioppo Neto, in European Journal of Pharmacology (1978) 49 351-356, under conditions allowing the differentiation between the action potentials produced in myelin nerve fibers (A fibers) and those produced in small amyelin fibers (C fibers), as described by B. Oakley and R. Schater in Experimental Neurobiology, A Laboratory Manual, University of Michigan Press, 1978, p. 85 to 96.

   Serotonin itself exerts its effects selectively on C fibers and gradually reduces the amplitude of the action potential of these fibers depending on the dose. This action of serotonin is not blocked by known serotonin antagonists, such as metiotepine, methysergide and BOL-148 which are considered to be blockers of serotonin D receptors, but not M receptors

  <Desc / Clms Page number 44>

 (see Gaddam and Picarelli, Brit. J. Pharmacol. (1957), 12, 323-328). It therefore seems that serotonin reduces the amplitude of the action potential transmitted by C fibers, which is done by mediating the M serotonin receptors which are located on these nerve fibers.



   The test can be performed by establishing a dose / response curve for serotonin (10-7 - 5 x 10-6M) after preparing the nerve. The serotonin is eliminated by washing and when the action potential of the fiber C has returned to its original amplitude, the compound of the invention is added at a given concentration between 10-16 M and
 EMI44.1
 10-6 M and preincubate with the nerve for 30 to 60 minutes. Various concentrations of serotonin (10-7 to 10-4 M) are then applied with the compound of the invention, the latter being at the same concentration as during the preincubation period.



   The M receptor antagonists of the invention either completely block the action of serotonin (non-competitive antagonist), or cause a parallel shift to the right of the dose / response curve of serotonin, higher concentrations of serotonin being necessary for the effect (competitive antagonist). The pD'2 value or the pA2 value can be obtained according to conventional methods.



   The antagonist activity on the serotonin M receptors can also be demonstrated by the inhibition of the effect exerted by serotonin on the isolated heart of the rabbit, according to the method described by J. R.



  Fozard et al. in European Journal of Pharmacology, (1978) 49, 109-112, at concentrations between

  <Desc / Clms Page number 45>

   10-11 and 10-5 M of compound of the invention. The pD'o or pAo values can be calculated according to conventional methods.



   The action of the compounds as serotonin M receptor antagonists for the treatment of pain was confirmed in mice in the hot plate test, at a dose of between 0.1 and 100 mg / kg administered orally or subcutaneously.



   The antagonistic activity on the serotonin M receptors was also demonstrated in the cantharidic vesicle test at a concentration of approximately 10-PI M. It causes the formation of a vesicle on the skin of the forearm of volunteers with cantharidin. When serotonin is applied to the base of such vesicles it causes pain which can be measured, its intensity being proportional to the concentration of serotonin applied. The process has been described by C. A. Keele and D. Armstrong in Substances producing Pain and Itch, Edward Arnold, London, 1964, p. 30 to 57.

   This algic action of serotonin is not inhibited by serotonin D receptor antagonists, such as lysergic acid diethylamide or its brominated derivative, and is considered to be mediated by M receptors.



   In the method used, the area under the curve, and not the top of the amplitude, was measured with a linear integrator coupled to a pain intensity indicator which was activated by the volunteer. As serotonin concentrations increase, a cumulative dose / response curve for serotonin is obtained. When no other response is obtained by increasing the concentration of

  <Desc / Clms Page number 46>

 
5serotonin, the serotonin is removed by washing and the vesicle is incubated with a physiological buffer solution for at least 40 minutes before applying the compound of the invention, for example the preferred compounds of Examples A-2 or A-3.

   The test substance is preincubated with the base of the vesicle for 30 minutes at a concentration of approximately 10-8 M before applying various concentrations of serotonin. A pA2 value can be obtained according to conventional methods.



   Thanks to these properties, the compounds of the invention can therefore be used therapeutically as medicaments, in particular as antagonists of M serotonin receptors, for example for the treatment of pain, especially migraine, vascular headache and pain vascular of the face and trigeminal neuralgia and also for the treatment of disorders of the cardiac circulation, for example for treatment
 EMI46.1
 risk of sudden death and
For their therapeutic use, the compounds of the invention will be administered at a daily dose of between approximately 0.5 and 500 mg, advantageously in divided doses 2 to 4 times per day in the form of unit doses each containing from 0.2 to 250 mg of active substance, or in a delayed release form.



   In addition, the compounds of the invention exert an antiarrhythmic action, as indicated by their antagonist activity of the serotonin M receptors, and by the standard tests. For example, the compounds inhibit arrhythmias caused by norepinephrine in the anesthetized rat. In this test we inject

  <Desc / Clms Page number 47>

 
 EMI47.1
 aalg luaanad uoLUaAUL, "tV sap sa id -5anbL nb 1fJEf ua uos' sanbj.

   A'jB - Read 6). ue ua6e, ue ua'sanbt.s6Leue ua6e, nb what ua ed'anbLjeu - a full euLUooes EL ap nadaDaj eBenboq a saenbsa suep saLpelew sa Inod euLUooas eL L ap W sjnedaoaj sap saSLuoBBue. nb lupq ua uoLBSL n, jnod jeLnoLjed uemBj. uc es - n,. uLûd np saLqe + daJJ aLBUapnb p Las un, p no apLOe, Lppc. unip ap awl snos aldwaxa Jed'alQefdaJJe ueLuenbt. neoBujjpud snos uoLuaAuL, saL DUOP AUUDDUOD UOLIUAAUL aquasaid 'oepa uot. . jeqj. uoj. snos no.'eALoe sqns ap 6w OS2 La 2'0 UOULAUG arqua UPUaqUOD SaJLeLUn awoJ oJ fJeJ uoL33CuL d no eo aloha jed + uawasna6e + ueAe'6w Za S'o qonb stulwpe uo3s A'jB.

   U) U35e, nb 1ue1 Ua Ln a1g jnod senbLPUL '9JfSUWpe fJUOj a3UwLddns Lnp3J Sa P, - pBJOU 33 3'6 / 6) a Ua sz, AuL, UO * 3UL OR n33SU03 33pUL 0U03. vLoae aL OJ'sapuoJas np W4f ^ e, Xual aseud eL anb / 6 u3peJOu

  <Desc / Clms Page number 48>

 [ap sasodwoo saladministres in the form of a free base, or in the form of a pharmaceutically acceptable salt, for example an acid addition salt or a suitable quaternary ammonium salt. Such salts have the same order of activity as the corresponding free bases.

   Furthermore, the present invention relates to a pharmaceutical composition comprising a compound of the invention, in particular a compound of formula I, in the form of the free base or of an acid addition salt or of an ammonium salt quarternaire pharmaceutically acceptable, in combination with a pharmaceutically acceptable carrier or diluent. Such compositions can be prepared according to the usual methods and can be in the form of solutions, capsules or tablets.



   A group of compounds comprises the compounds of formula I in which A is a group of formula II, in which R 1 and R 2 each represent, independently of one another, hydrogen, a halogen, a C 1 alkyl group -C4, or a Cj-C4 alkoxy group, R2 is in position 4 or 5, R3 represents hydrogen or a C1-C4 alkyl group, the free valence is in position 3,4 or
5; or a group of formula III in which R4 represents hydrogen, a halogen or a C1-C4 alkoxy group;
 EMI48.1
 Rc represents or halogen 6 s'gni-Fie amino, nitro, alkylamin C-j-C4, Cl-C4% -. hydrogen or hydrogen or halogen;

   D is a group of formula IV in which Rg represents hydrogen, a C1-C4 alkyl or benzyl group or a group of formula V in which the free valence is fixed in position 3 and with the conditions indicated for formula I.

  <Desc / Clms Page number 49>

 



   The invention also includes a medicament containing, as active principle, a compound of the invention, in particular a compound of formula I, in the form of a free base or in the form of an acid addition salt or of a pharmaceutically acceptable quaternary ammonium salt.


    

Claims (1)

 CLAIMS 1. Piperidyl esters and N-piperidyl amides of di-carbocyclic or heterocyclic carboxylic acids whose piperidine ring contains an alkylene bridge and piperidylic esters and peridylamines of substituted benz'acids including the piperidine ring contains an alkylene bridge, - any piperidyl ester of benzolque having the alkylene bridge connecting two carbon atoms of the piperidine ring, to be substituted at at least one of the ortho or meta positions of the phenyl ring, - any piperidyl ester of benzo acid? that not substituted for the two ortho positions,  or substituted by a halogen or alkyl at at least one of the orthc positions and only by hydrogen or a halogen at the meta and para positions, and having the alkylene bridge connecting two carbon atoms of the piperidine ring, having to have a alkylene bridge containing at least 3 carbon atoms,  EMI50.1  - piperidyl ester of benzotque acid having an alkylene bridge connecting a carbon atom of the piperidine nucleus to the nitrogen atom of the same nucleus and having an oxy substituent, having to have at least one substituent other than an oxy substituent or having to have only two oxy substituents in the benzene nucleus,  - any heterocyclic carboxylic acid amide or ester whose heterocycle is monocyclic at Schaînons and contains cyclic nitrogen atoms or any heterocyclic carboxylic acid amide whose heterocyclic contains two oxygen atoms, having to have an alkylene bridge connecting a carbon atom of the nucleus pi peri-din to the nitrogen atom of the same nucleus,  <Desc / Clms Page number 51>  - any N-piperidyl-amide of benzo @ acid that must have an alkylene bridge connecting the nitrogen atom of the piperidine nucleus to a carbon atom of the same nucleus, - any N-piperidyl-amide of benzo @ acid that not have halogen, hydroxy or alkyl substituents at any of the ortho positions, and - 8-aza-bicyclo esters [3. 2.  1 [Oct-3-yliques not to be derived from a thiophenecarboxylic or naphthalenic acid.  2. The compounds of formula  EMI51.1  in which A represents a group of formula II  EMI51.2  in which the free valence is located on one of the two cycles,  EMI51.3  X signifies -CH -, - NR -, - O-, R, and R2 each signify, independently of one another, a halogen or a C1-C4 alkoxy group (hydroxyl, C1-C4) amino, C1-C4 dialkyl) amino, mercapto or C1-C4 alkylthio, and R3 or a C1-C4 alkyl, CC-alkenyl, or aralkyl group, or A represents a group of formula III  EMI51.4    <Desc / Clms Page number 52>  in which R4 to Ry mean, independently of each other, hydrogen, a halogen or an amino, nitro, (C1-C4 alkyl) -amino, di- (alkyl in Cl-C4) amino, C-alkoxy, -C4 'C1-C4 alkyl' (C1-C4 alkanoyl) amino or pyrrolyl,  at least one of the substituents R4 and RS must have a meaning other than hydrogen, B represents -O- or -NH-, D represents a group of formula IV  EMI52.1  in which n signifies 2,3 or 4, and R8 signifies hydrogen or a C1-C7 alkyl group, C3-C5 alkenyl or aralkyl, or else D represents a group of formula V  EMI52.2  - D must signify a group of formula V when A signifies a group of formula III and B signifies -NH, n having to signify 3 or 4. when A signifies a group of formula III or either R4;  is hydrogen, either R4 is halogen or alkyl and R5 to R7  <Desc / Clms Page number 53>  are chosen from hydrogen and halogens, B signifies -O- and D signifies a group of formula IV, - when A signifies a group of formula III and one  EMI53.1  substituents R. is an alkoxy and D signifies a group of formula V, one of the other substituents R4 to have a meaning other than hydrogen or alkoxy or only two of the substituents a RyR4 to R7 to signify an alkoxy, - B having to signify -O- when A signifies a group of formula III where R4 is a halogen or alkyl, 3.  A compound according to claim 2, characterized in that aryl signifies an unsubstituted phenyl group or a phenyl group bearing one or more substituents chosen from halogens and C1-C4 alkyl, hydroxy and C1-C4 alkoxy groups, and aralkyl means a C1-C4 alkyl radical substituted by an unsubstituted phenyl group or by a phenyl group carrying one or more substituents chosen from halogens and C1-C4 alkyl, hydroxy and C1-C4 alkoxy groups 4.  A compound according to claim 2, characterized in that it corresponds to the formula Ipa  EMI53.2    <Desc / Clms Page number 54>    EMI54.1  in which R4pa signifies a halogen or a group (a1ky1 in C1-C4) amino or alkoxy in C, R, signifies hydrogen, pa R6pa signifies an amino group, in C1-C4) amino opa '' or dialkyl in Ci- c4) amino, R - signifies fluorine, chlorine or bromine, and signifies hydrogen or an alkyl group in C, -C - or 5. A compound according to claim 2, characterized in that it responds to the Ipb formula  EMI54.2  bp. . -Rgpa <R6pa D in which  EMI54.3  R4pa'RSpa'R6pa in claim 4, and R7pb means hydrogen or halogen. 6. A compound according to claim 2, characterized in that it corresponds to the formula Iqa  EMI54.4  / \. 1 N 1 N 1 in which R3  EMI54.5  the ester group is fixed on one or the other of the two cycles, does not mean 2 or 3, and Ri. R3 and Rg have the meanings given in claim 2.  <Desc / Clms Page number 55>    7. A compound according to claim 2, characterized in that it corresponds to the formula Iqb  EMI55.1  in which the ester group is attached to one or the other of the two rings, Rlqb and R2qb mean, independently of one another, hydrogen, a halogen or a C1-C4 alkyl group, R3qb means hydrogen or a C1-C4 alkyl group, R8qb means hydrogen or a C1-C4 alkyl group, and means 2 or 3.  8. A compound according to claim 2, characterized in that it corresponds to the formula Iqc  EMI55.2  in which the carboxamide group is attached to one or the other of the two rings, and R2qc has the meaning given for R2 in claim 2 except a hydroxy or alkoxy group  <Desc / Clms Page number 56>  in Cl-C4, and only RI, R3 and Rg have the meanings given to  EMI56.1  claims and 7.  9. A compound according to claim 2, characterized in that it corresponds to the formula Isa  EMI56.2  in which R4pa, RSpa'R6pa and R7pb have the meanings given in claims 4 and 5.  10. A compound according to claim 2, characterized in that it corresponds to the formula Isb  EMI56.3  in which R4pa R5pa, R6pa and R7pb have the meanings given in claims 4 and 5.  11. A compound according to claim 2, characterized in that A is a group. of formula II in which R1 and R2 each represent, independently of one another, hydrogen, a halogen, a C1-C4 alkyl group, or a C1-C4 alkoxy group, R2 is in position 4 or 5, R3 represents hydrogen or a C1-C4 alkyl group, the free valence is in position 3, 4 or 5;  or one  <Desc / Clms Page number 57>    EMI57.1  formula III which R4 represents a halogen or a C1-C4, Rc, represents hydrogen or a halogen, R6 means amino, nitro, C1-C4) amino, di (C1-C4 alkyl) ar. lino, halogen or 1-pyrrolyl, R7 hydrogen or halogen and a group of formula IV in which Rû represents hydrogen, a C1-C4 alkyl or benzyl group or a group of formula V in which the free valence is fixed in position 3, with the conditions of formula 1 according to claim 2. 12. Lndole-3-. 8-aza-bicycloL3. 2. 1 Joct-3-yle. 13. L-methyl-N-bicyclo [3. 3. 1 14. The compounds specified in any one of claims 1 to 13, in the form of the free base or of an acid addition salt or of a quaternary ammonium salt. 15. A process for the preparation of the compounds specified in claim 1, their acid addition salts and their quaternary ammonium salts, characterized in that a suitable dicarbocytic or heterocyclic carboxylic acid or an acid is condensed appropriate benzoic acid, or a reactive acid derivative, or an acid or derivative precursor with an appropriate pyperidylamine or piperidinol whose piperidine ring contains an alkylene bridge, or a precursor of these compounds, and, if necessary, the piperidyl ester or the N-piperidyl amide or its acid addition salt or its quaternary ammonium salt is transformed into the piperidyl ester or into the desired N-piperidylamide or into its acid addition salt or its bitter salt  <Desc / Clms Page number 58>  quaternary demonium group,  and recovering the piperidyl ester or the resulting N-piperidylamide in the form of the free base or in the form of an acid addition salt or a quaternary ammonium salt.  16. A process for the preparation of the compounds of formula 1 specified in claim 2, characterized in that a) a suitable compound of formula VI is condensed  EMI58.1  in which A has the meaning given in claim 2, or a reactive derivative of this acid, or a precursor of the acid or of the reactive derivative, with an appropriate compound of formula VII  EMI58.2  wherein B and D have the meanings given in claim 2, or a precursor thereof, or b) alkylating a compound of formula 1 having a secondary amino group to obtain a compound of formula l with a tertiary amino group, or c) the protective group or groups are eliminated in a compound of formula 1 in protected form in order to obtain a compound of formula I, or d)  a compound of formula I in which A signifies a group of formula II and R2 signifies hydrogen is subjected to halogenation to obtain the corresponding compound where R2 signifies a halogen, or  <Desc / Clms Page number 59>    EMI59.1  e) subjecting a compound of formula I in which A signifies a group of formula II and R2 signifying a halogen, to alkylation in order to obtain the corresponding compound where R2 signifies an alkoxy group, and the resulting compound of formula I is recovered in the form free base or in the form of an acid addition salt or a quaternary ammonium salt. 17. The compounds specified in any one of claims 1 to 13, in the form of a free base or an acid addition salt or a pharmaceutically acceptable quaternary ammonium salt, for use as medicines. 18. The compounds specified in any one of claims 1 to 13, in the form of a free base or of an acid addition salt or of a pharmaceutically acceptable quaternary ammonium salt, for the use as antagonists of serotonin M receptors, analgesics, antimigraine or antiarrhythmics. 19. A medicament, characterized in that it contains, as active principle, a compound specified in any one of claims 1 to 13 in the form of the free base or of an acid addition salt or a pharmaceutical quaternary ammonium salt. 20. A pharmaceutical composition, characterized in that it contains as active substance a compound specified in any one of claims 1 to 13 in the form of free base or of an acid addition salt or of a salt quaternary ammonium  <Desc / Clms Page number 60>  pharmaceutically acceptable, in combination with a pharmaceutically acceptable diluent or carrier.  21. A compound of formula VII HB-D (VII) in which C signifies NH and D represents a group of formula IV  EMI60.1    EMI60.2  in e in C-j-Cy, c -C5 under salt quaternary aon'uni salt. 22. Products and processes in substance as with reference