FR2567885A1 - 3-AMINOPROPOXYARYLIC DERIVATIVES, THEIR PREPARATION, THEIR USE AS MEDICAMENTS AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME - Google Patents

Abstract

THE OBJECT OF THE INVENTION IS COMPOUNDS OF FORMULA I (CF DRAWING IN BOPI) IN WHICH AR REPRESENTS AN AROMATIC OR HETEROAROMATIC GROUP, B REPRESENTS AN AMINE REMAINDER, P MEANS 0 OR 1, AND R REPRESENTS AN ALKYL GROUP DISUBSTITED BY AROMATIC REMAINS , HETEROAROMATIC AND OR CYCLOALIPHATIC, AND THEIR PHYSIOLOGICALLY HYDROLYSABLE ESTERS. THESE COMPOUNDS CAN BE USED AS A MEDICINAL PRODUCT, IN PARTICULAR AS CARDIOTONIC AGENTS, AS ANTIARRHYTHMIC AGENTS, AS A AND B-ADRENERGIC BLOCKING AGENTS AND AS CALCIUM ANTAGONISTS.

Description

The subject of the present invention is 3-aminopropoxyaryl derivatives and

  their preparation. The invention also relates to the therapeutic application of these

  compounds as medicaments and pharmaceutical compositions

  containing them. In particular, the invention relates to the compounds of formula I ## STR1 ##

1 -

  Ar wherein Ar represents an aromatic or heteroaromatic residue, B represents a group corresponding to one of the following formulas i), ii), iii) or iv): VW i) - wherein V and W denote hydrogen or together form an additional bond, and R 1 denotes hydrogen, a C 1 -C 4 alkyl group or a phenyl group optionally carrying one or two identical or different substituents selected from halogen atoms having an atomic number of 9 to 35 and the alkyl groups of C 4 and C 1 -C 4 alkoxy, ii) - in which R 1 is -R 1 hydrogen or C 1 -C 4 alkyl, iii) -N- (CH) -N- wherein Rk R 1 n is 2, 3 or 4, Rk is hydrogen or a C1-C4 alkyl group and R1 has the meaning given above for R, and iv) wherein m is 2 or 3, p is 0 or 1, and

  R represents an alkyl group having two

  identical or different selected from aromatic, heteroaromatic and cycloaliphatic residues, with the proviso that when a) Ar means a group of formula A (A)

F 'R'

  Wherein R 'is hydrogen, methyl, hydroxymethyl, carboxy, C 2 -C 5 alkoxycarbonyl, carbamoyl or cyano and R "is hydrogen or methyl, or R' is hydroxy and R" means hydrogen, and that b) p means 1 and B means - a group i ') of formula T wherein R 1 has the meaning given above and VI and W' signify hydrogen or, when R 'signifies a group hydroxy and R "a hydrogen atom, V 'and W' signify hydrogen or together form an additional bond, or - a group ii) or iii) as defined above, or p means O or 1 and B means a group iv ') of formula R is then other than a C 13 -C 17 diphenylalkyl group in which each phenyl ring may optionally carry one or two identical or different substituents chosen from halogens having an atomic number of 9 to 35 and the groups C 1 -C 4 alkyl and C 1 -C 4 alkoxy, and the s physiologically hydrolyzable thereof having the hydroxy group in position 2 of the

  propoxy side chain in esterified form.

  The compounds of formula I and their hydrolysable derivatives will be referred to hereinafter as "the compounds

of the invention ".

  Physiologically hydrolyzable derivatives are derivatives which are cleaved under physiological conditions into corresponding compounds having a hydroxy group at the 2-position of the propoxy side chain. A group of esterified derivatives of the compounds of formula I for example comprises the compounds of formula CORE OCH 2 CHCH 2 -B- (CO) p R (E) Ar in which Ar, B, p and R are as defined above, and Re is C1-C12alkyl, C3-C7cycloalkyl, phenyl, C7-C12phenylalkyl or C7-C12phenyl or phenylalkyl wherein the phenyl ring is monosubstituted with C1-C4alkyl or monosubstituted or disubstituted identically or differently by halogens having an atomic number of 9 to 35, or mono-, di- or

  trisubstituted by C1-C4 alkoxy groups

ticks or different.

  Preferred compounds are those in which the hydroxy group at the 2-position of the side chain

  propoxy is in unesterified form.

  When the compounds of the invention can be represented in a tautomeric form, such

  tautomeric forms are also part of the invention.

  For example, when Ar signifies an indole group substituted in the 2-position by a hydroxy group, the invention

  also includes the oxindole form.

  Compounds of similar structure to the compounds of the present invention are described, for example, in European Patent Application No. 25,111 and in British Patent Application No. 2,091,262, and their equivalents. Such compounds are excluded from the scope of the present invention. The compounds of the present invention are neither specifically described nor suggested

by the documents in question.

  Ar can be monocyclic or polycyclic; it may for example consist of two condensed cycles. It is preferably polycyclic. When Ar is polycyclic and heteroatomic, it preferably means a totally condensed ring system

  unsaturated, containing at least one nitrogen heteroatom.

  Ar can represent for example an indole residue,

  oxindole, 2,1,3-benzoxadiazole, benzimidazole, benzimidine

  dazol-2-one, 2-quinolinone, 1,2-, 3,4-tetrahydro-2-oxoquinoline, carbazole, spiro [cyclohexane-1: 2'-indan] -l-one, phenyl, pyridyl or pyridinone. Ar may be substituted or unsubstituted. Ar is preferably an indole or oxindole residue, especially such a residue in which the propoxy side chain is attached in position

  4; Ar especially means a 2-cyano-1H-indole residue

  4-yl. Another preferred Ar residue is the phenyl residue.

  B preferably means a group iv). Lors-

  whether it means a group i), ii) or iii), it is preferably a group i) or ii). V and W preferably mean hydrogen. Ri, Rj and / or R1 mean

  preferably hydrogen or an alkyl group, especially

  hydrogen. n means preferably 2. Rk means

  preferably hydrogen. m is preferably 2.

  When R 1 and / or R 1 signify an optionally substituted phenyl group, it is preferably an unsubstituted phenyl group. When they mean

  a substituted phenyl group, the latter is preferably mono-

  substituted, especially in position 4, or disubstituted,

especially in position 3 and 4.

  p is preferably 0 when B is a group of formula iv). It means preferably

  1 when B means a group of formula i), ii) or iii).

  R preferably denotes a disubstituted alkyl group, one of the substituents being an aromatic or heteroaromatic residue and the other substituent

  is an aromatic, heteroaromatic or cyclo-

  aliphatic. When Ar signifies an indole residue, at least one of these two residues in R is preferably other than a phenyl group. The residues may be substituted or unsubstituted. R is preferably a disubstituted alkyl group in which both substituents are on the same carbon atom. These substituents are

  preferably fixed on the carbon atom in position u.

  For example, a diphenylalkyl group means

  preferably a diphenylmethyl group.

  An aromatic residue in R is preferably

a phenyl group.

  A heteroaromatic residue in R preferably denotes a pyridinyl, thienyl or furyl group,

  pyrrolyl or imidazolyl, especially thienyl or pyridine

  dinyle. A cycloaliphatic residue in R preferably contains 3 to 7 carbon atoms, preferably 6 or more carbon atoms, and especially means a cyclohexyl group. It may contain heteroatoms, for example an oxygen atom or an oxygen atom.

  and a nitrogen atom in the ring, such as tetrahydro-

pyran or morpholine.

  When a phenyl ring is possibly

  substituted, it is preferably unsubstituted.

  When such a phenyl ring is substituted, it is preferably

  mono. When monosubstituted, the substitute

  killing is preferably in the para position. When disubstituted, the substituents are preferably in the meta and para position. When he is polysubstituted,

  the substituents are preferably identical.

  A preferred group of compounds of the invention comprises the compounds of formula Ia OH OCH (OH) OCH2CHCH2-B- (O) pR (a) Ara wherein Ar is a-phenyl, phenyl monosubstituted with hydroxy benzyloxy, carboxy, alkoxy: C2-C5 carbonyl, trifluoromethyl, acetylmethyl,

  methylsulfonylamino, cyanomethylamino, amino, aceto

  tamido, (1-hydroxymethylcyclohexyl) methyl,

  (1-acetoxymethylcyclohexyl) methyl, 1-dimethyl-

  amino-3-oxo-1-buten-2-yl or 3-cyano 1,2-dihydro-

  6-methyl-2-oxopyridin-5-yl, or a phenyl group disubstituted with nitro, amino, hydroxy or benzyloxy groups, or with a hydroxy group and a cyano group, or with a benzyloxy group and a cyano group, or by an acetyl group and a 2-meo group

  thoxy-ethoxy, or by a groupecyano and a 2-methoxy group

  ethoxy, or with a nitro group and a methyl group,

  an indolyl group, an indolyl monosubstituted group

  killed in position 2 by a methyl group, hydroxyl

  methyl, carboxy, C2-C5 alkoxycarbonyl,

  Bamoyl, cyano or acetyl, an indolyl group monosubstituted at the 3-position by a methyl group

  or cyano, an indolyl group monosubstituted in

  6 by a carboxy or C 2 -C 5 alkoxycarbonyl group, an indolyl group monosubstituted at the 7 position by fluorine or by a (C 1 -C 4) alkoxy-C 1 -C 4 alkyl group, an indolyl group disubstituted at the 1-position by a alkyl group

  C1-C4, C2-C5 alkoxycarbonyl or alkoxycarbonyl-

  C3-C9 bonylalkyl and at the 2-position with a cyano group, or disubstituted at the 2-position and 3-position with cyano groups, or disubstituted at the 2-position with

  methyl, hydroxymethyl, carboxy, alkoxy-

  C2-C5 carbonyl, carbamoyl or cyano and in position 3 with a methyl group, or disubstituted at the 2-position by a cyano group and at the 3-position with a dimethylaminomethyl group,

  an oxindolyl group optionally substituted with

  2 by two methyl groups, a 2,1,3-benzoxadiazol-4-yl group,

  a benzimidazol-4-yl or 2-trifluoromethyl group

  benzimidazol-4-yl, a 1,2-dihydro-2-oxobenzimidazol-4-yl group,

  a group 2 (1H) -quinolinone-4-yl or 1,2,3,4-tetra-

  hydro-2-oxo-quinolin-4-yl, 1-E9H] -carbazol-4-yl or - spiro [cyclohexane-1: 2'-indan] -l-one-4Lyl, B and p have the meanings given above and Ra represents a C 1 -C 5 alkyl group having two identical or different substituents chosen from phenyl, pyridinyl, thienyl, furyl, pyrrolyl, imidazolyl, imidazolyl monosubstituted in the 1-position by a methyl group, C3-cycloalkyl group; C7 and phenyl containing one or two identical or different substituents selected from halogens having an atomic number of 9 to 35 and C1-C4 alkyl, C1-C4 alkoxy, hydroxy, cyano, nitro, amino, C2 alkanoylamino groups; -C5 and trifluoromethyl, with the proviso that when a) Ara means a group of formula A as defined under a) of the condition formulated for compounds of formula I above and that b) p and B are as defined under b) the condition formulated for the compounds of formula I below Essus, Ra is then other than a C13-C17 diphenylalkyl group in which each ring: phenyl may optionally carry one or two identical or different substituents selected from halogens having an atomic number of 9 to 35 and alkyl groups C1 -C4 and C1-C4 alkoxy,

  and their physiologically hydrolysable derivatives correspond to

  respondents. In the formula Ia, Ar preferably represents an optionally substituted indolyl or oxindolyl group, as previously defined, preferably an optionally substituted 4-indolyl or 4-oxindolyl group,

  especially an optionally substituted 4-indolyl group

  kill. Another preferred Ara group is an optionally substituted phenyl group, preferably substituted with a hydroxy group. Ra preferably means an alkyl group disubstituted with optionally substituted phenyl groups, or with an optionally substituted phenyl group and with a pyridinyl group, or with pyridinyl groups, or with a pyridinyl group and a thienyl group, in particular disubstituted by groups. pyridinyl or with a pyridinyl group and a thienyl group. When Ra contains a substituted phenyl residue,

  the latter is preferably substituted by fluorine.

  In a subgroup of compounds of formula I

  and their physiologically hydrolysable derivatives correspond to

  clusters, Ara means a 4-indolyl group

  substituted as defined above.

  A particularly preferred group of compounds of the invention comprises compounds of the formula ## STR2 ##

R1

C) H 1 R

in which

  R1 is hydrogen or methyl, hydroxyl

  methylcarboxy, C2-C5 alkoxycarbonyl, carbamoyl or cyano, and R2 is hydrogen or methyl, or R1 is hydroxy and R2 is hydrogen, and B, p and Ra are as previously defined, with the proviso that when B and p are as defined under b) of the condition formulated for the compounds of formula I above, then Ra is other than a C13-C17 diphenylalkyl group;

  in which each phenyl ring may carry

  one or two identical or different substituents chosen from halogens having an atomic number of 9 to 35 and C 1 -C 4 alkyl and C 1 -C 4 alkoxy groups,

  and their physiologically hydrolysable derivatives correspond to

  respondents. In a subgroup of compounds of formula Ia and Iaa and their corresponding physiologically hydrolysable derivatives, R1 has a meaning other than a hydroxy group. In another subgroup, R1 means a cyano group. In another subgroup, p is O. In another subgroup, B is a group of formula iv) as defined above. In another subgroup, B means a group of formula iv) in which m is 2. In another subgroup, B has a meaning other than a group of formula i)

  above. In another subgroup, p is 1.

  In another subgroup, R has the meaning given above with the proviso that it is other than a C 1 -C 5 alkyl group disubstituted by two phenyl groups

  optionally substituted as above.

  In another subgroup, R represents a C 1 -C 5 alkyl group disubstituted with an optionally substituted phenyl group as defined above and by another group chosen from pyridinyl and thienyl groups,

  furyl, pyrrolyl, imidazolyl, imidazolyl monosubstituted

  killed in position 1 by a methyl and C3-C7 cycloalkyl group. In another subgroup, Ra means a C 1 -C 5 alkyl group having two identical or different substituents selected from pyridinyl, thienyl, furyl, pyrrolyl, imidazolyl, imridazolyl monosubstituted in the 1-position by a methyl group, and C3-cycloalkyl. C7. In another subgroup, Ra means a C 1 -C 5 alkyl group having two identical or different substituents selected from

  pyridinyl, thienyl, furyl, pyrrolyl, imidazo

  lyle, imidazolyl monosubstituted in position 1 by a

  methyl, C3-C7 cycloalkyl and phenyl with

  one substituent or two identical or different substituents chosen from hydroxyl and cyano groups,

  nitro, amino, C2-C5 alkanoylamino and trifluoromethyl.

  In another subgroup, Ra means a C 1 -C 5 alkyl group disubstituted by phenyl groups bearing

  a substituent or two identical or different substituents

  selected from hydroxy, cyano, nitroamino, C 2 -C alkanoylamino and trifluoromethyl, the two phenyl groups being the same or different. In another subgroup, the symbols have the meanings indicated above, in combination

  with each other or all together.

  Another group of compounds of the invention comprises compounds of the formula ## STR1 ##

R2

N R1P

H P

  wherein Rp is hydrogen, methyl, hydroxymethyl, carboxy, C2-C5 alkoxycarbonyl, carbamoyl or cyano, R2p is hydrogen or methyl, pp is 1 and Bp is P - ip) of the formula Where R 1 is as defined above, or - a group ii) or iii) as defined above, or where p is O or 1 and B is a group ivp) of formula, and R is an alkyl group comprising two identical or different substituents chosen from aromatic, heteroaromatic and cycloaliphatic radicals,

  with the proviso that R is other than a diphenyl-

  C13-C7 alkyl wherein each phenyl ring may C13-C17 alkyl wherein each phenyl ring may optionally carry one or two identical or different substituents or substituents selected from halogens having an atomic number of 9 to 35 and C1-6 alkyl groups; -C4 and C1-C4 alkoxy, and their corresponding physiologically hydrolysable derivatives. Another group of compounds of the invention comprises the compounds of formula Ip '

OH

OCH2CHCH2- \ Rp (Ip ') $ - g 2p

H R1P

  wherein R1P, R2p and Rpsont as defined above, and their corresponding physiologically hydrolyzable derivatives. Unless otherwise indicated, the preferred meanings are: - alkyl = methyl or ethyl, especially methyl, - alkoxy = methoxy or ethoxy, especially methoxy, - halogen = chlorine or bromine, especially chlorine, - cycloalkyl = cylopentyl or cyclohexyl , especially cyclohexyl, - alkoxycarbonyl = methoxycarbonyl or ethoxycarbonyl, especially methoxycarbonyl;

  contains more than two carbon atoms

  bone, it is preferably branched in position a relative to the rest

  carbonyl, as in the iso-

  propoxycarbonyl, - alkoxyalkyl = methoxymethyl or 2-methoxyethyl,

  - alkoxycarbonylalkyl = ethoxycarbonylmethyl.

  According to the invention, the compounds of the invention can be obtained according to a process comprising 3-amino-2-oxypropylation of a corresponding compound of formula IV

OH (IV)

  Ar where Ar is as previously defined,

or a precursor of this compound.

  The process can be carried out according to conventional methods for the preparation of compounds

  3-amino-2-oxy-propoxyaryl compounds.

  The choice of the most appropriate variant must take account, of course, of the reactivities of the

substituents present.

  Preferably, a compound of

  formula IV rather than a precursor of this compound.

  A precursor of a compound of formula IV is a compound capable of being converted into a compound of formula IV,

  for example by appropriate acylation or deprotection.

  Thus, for a compound of formula IV having an alkoxycarbonyl group, a precursor is for example a corresponding compound having a carboxy group, and vice versa. For a compound of formula IV having a hydroxy group, a precursor is for example a

  corresponding compound having a benzyloxy group.

  For a cyclic system, a precursor may be

  example the corresponding compound in non-cyclized form.

  For a compound of formula IV having an amino group

  substituted, a precursor may be for example the compound

  corresponding having an unsubstituted amino group.

  For a compound of formula IV having an amino group, a precursor may be for example the corresponding compound

having a nitro group.

  Thus, the method of the invention can be carried out in one or more steps. For example, it is possible to use a compound of formula IV under

  protected form, or introduce a 3-amino-2-oxypropo

  in a protected form, and then carry out, after carrying out the 3-amino-2-oxypropylation, a complementary reaction step, for example the removal of any protecting group present. As an example of a protecting group, mention may be made of benzyl, methyl or tetrahydropyranyl, preferably benzyl. According to one variant of the process of the invention, 3-amino-2-oxypropylation can be carried out in

two main steps.

  In a first step, a -CH2oRx o Rx group means a group capable of reacting with an amine

  primary or secondary to give a 2-amino group

  1-hydroxyethyl is introduced by O-alkylation into a compound of formula IV to give a corresponding compound of formula II OCH2-Rx Ar- (11) Ar

  wherein R and Ar are as defined previously.

  x In a second step, a compound of formula II is reacted with a corresponding compound of formula III H- (CO) pR (II) in which p and R are as defined above, and, if necessary, esterified in a appropriate 2-hydroxy group of the 3aminopropoxy side chain in the resulting compound of formula I. The Oalkylation step may be carried out

  in a manner known for the production of ethersanalogues.

  The compound of formula IV is preferably reacted preferably

in anionic form.

  The amination step may be carried out by conventional methods for the preparation of 3-amino-2-hydroxypropoxyaryl compounds. For example, R can be a group of the formula ## STR2 ## or a derivative of this group, for example a group of the formula -CH (OH) -CH 2 L, where L is chlorine, bromine or a group Ry-SO2-O-, where Ry is phenyl, tolyl or lower alkyl. L especially means chlorine. The reaction is preferably carried out in ethanol or in a suitable ether such as dioxane. If necessary, an excess of the amine can be used as the solvent. The melt reaction can also be carried out in the melt. The reaction is carried out appropriately at temperatures

  from about 20 to about 200 C, preferably

  at the reflux temperature of the reaction mixture

when a solvent is used.

  The optional esterification of the hydroxy group in the propoxy side chain can be carried out according to known methods for the production of analogous esters of 3-amino-2-hydroxypropoxy-aryl compounds, if necessary using selective reactions when other reactive groups are present, as a

amino group.

  The compounds of the invention may exist in free form, that is to say normally in the form of bases, or in the form of salts, for example in the form of acid addition salts. The compounds of the invention in free form can be converted into salts according to the known methods, and vice versa. Suitable acids for the formation of salts include hydrochloric acid, malonic acid and fumaric acid. In the compounds of the invention, the carbon atom located for example in position 2 of the chain

  Lateral propoxy is asymmetrically substituted.

  The compounds can therefore exist in racemic form or in the form of isomeroptics. The preferred optical isomer is one in which the asymmetric carbon atom of the 3-amino-propoxy side chain

  has the S configuration. The optical isomers parti-

  can be obtained by known methods,

  for example using optical starting materials

  active ingredients or by fractional crystallisation of

  diastereoisomeric salts formed with optical acids

actively.

  When R is for example an alkyl group having two different substituents,

  the compounds have another center of asymmetry.

  These compounds can therefore exist in the form of mixtures or in the form of two distinct racemates or in the form of pure enantiomers. The individual diastereoisomers may also be obtained in known manner as described above, for example: 1) by chromatography using optically active adsorbents, for example acyl derivatives of cellulose or polymeric derivatives of amino acids, 2) by fractional crystallization of salts using optically active acids for salt formation, or 3) using a corresponding optically active starting material; in this case, separation can

  be carried out at an intermediate stage.

  When the preparation of the starting materials is not described, these are known or may be prepared according to known methods or as described or analogously to that described in the examples. The following examples illustrate this

  invention without in any way limiting its scope.

  All temperatures are in degrees

  Celsius and are uncorrected data.

Example 1

  (S) -4- [3- [4- (3,3'-dithiénylméthyl) piperazine-l-yl] -2-

  hydroxypropoxy] -lh-indole-2-carbonitrile

  70 g of (S) -4-

  (2,3-epoxypropoxy) -1H-indole-2-carbonitrile and 1.85 g of 1- (3,3'-dithienylmethyl) piperazine. The product is chromatographed on silica gel. The title compound is thus obtained (foam, [a] D0 = 15.4 °, c = 1%

in chloroform).

  The epoxide, used as starting material, is obtained as follows: a) 80 g of (S) -2,2-dimethyl-1,3-dioxolan-4-methanol dissolved in dimethylformamide are reacted at 0 with potassium hydroxide and then

  with benzyl bromide. We get the (S) -4-

  benzyloxymethyl-2,2-dimethyl-1,3-dioxolan (oil

  clear; [a] 20 = +9.6, c = 2% in methanol).

  b) 93.3 g are refluxed for 2 hours.

  the product obtained under (a) in hydrochloric acid

  than aqueous and acetone. We get the (R) -3-

  benzyloxypropane-1,2-diol (colorless oil; [a] D =

-1.2, c = 2% in methanol).

  c) 0 118 g of the product obtained under (b) in pyridine are reacted dropwise with 126.5 g of p-toluenesulfonyl chloride in benzene.

  and the mixture is stirred for 72 hours at room temperature.

  ambient temperature. (S) -1-Benzyloxy-3--

  tosyloxy-2-propanol (oil, [α] 20 = + 8.3 c = 2% in methanol).

  d) 41.5 g of 4-hydroxy-1H = indole-2-carbo-

  xamide with sodium hydride to the corresponding sodium salt and this salt is reacted in dimethylformamide with 87.8 g of the product obtained under c). The mixture is stirred for 40 hours at an oil bath temperature of 100. After treatment and purification by chromatography on silica gel,

  (S) -4- (3-Benzyloxy-2-hydroxypropoxy) -

  1H-indole-2-carboxamide (m.p. 115-117, [α] 20.50),

c = 2% in methanol).

  e) 62.2 g of the product obtained under d) are hydrogenated for 6 hours in methanol in the presence of palladium.

  at 10% on charcoal. The (S) -4- (2,3-dihydroxy-

  propoxy) -1H-indol-2-carboxamide (mp = 183 = 1850; [a] 0 = +6.15, c: 2% in methanol) of) 36.65 g of the product obtained under e) are dissolved in pyridine, reacted for 1 hour between -15 and -5 with a solution of p-toluenesulfonyl chloride in pyridine and stirred

mixing for 3 hours at 0.

  (R) -4- (2-hydroxy-3-tosyloxypro = poxy) -1H-indole-2-carboxamide (mp = 162-168;

  [α] 20 -13.5, c = 2% in methanol).

  1 g) To a solution of 2.76 g of sodium in methanol is added dropwise at 0 and in the space of one and a half hours a solution of 44 g. 2 g of the product obtained under f) in a 1: 1 mixture of methanol and tetrahydrofuran and the mixture is stirred

  for 1 hour. (S) -4- (2,3-epoxypropoxy) -

  1H-indole-2-carboxamide (F = 125-135; [α] 20 = +26,

c = 2% in methanol).

  h) To a suspension of 7.9 g of the product obtained under g) in dioxane and pyridine, a solution of 7.8 ml of trifluoroacetic anhydride in 10 ml is added in the course of one hour. dioxane and the mixture is stirred for another hour. (S) -4- (2,3-epoxypropoxy) -1H-indole-2-carbonitrile 10 is obtained

  (F = 123-215, [α] 20 = + 40.0, c = 1% in methanol).

  The amine used as starting material can be obtained as follows: a) Cooled to -70 8.2 g of 3,3'-dithienylcarbinol

  in methylene chloride and 8.45 g of triethyl

  amine and a solution of

  4.79 g of methanesulfonyl chloride in chlorine

  methylene chloride. After 1 hour, a solution of 6.62 g of Nethoxycarbonylpiperazine in methylene chloride is added, the mixture is stirred for

  1 hour and let the mixture return to room temperature.

  ambient temperature. After chromatography on silica gel,

  4- (3,3'-dithienylmethyl) piperazine-1 is obtained

  ethyl carboxylate in the form of an oil.

  b) 10.35 g of the ester obtained under a) are heated for 2 hours in 60 ml of methanol, 60 ml of dimethylsulfoxide and 120 ml of a 30% aqueous solution of sodium hydroxide. There is thus obtained 1- (3,3'dithienylmethyl) piperazine,

(F = 102-104).

  The compounds of formula I collected

  in the table below, are obtained analogously

  to that described in Example 1 (unless otherwise indicated in the notes following the table), by reacting the corresponding compounds of formula II in which R is x

-CHCH2

0

  with the corresponding compounds of formula III.

* Configura. confi-

  of the C * guratio n bearing the C * Point of 20 Ex. Ar B R OH in the fusion group EaID

No. channel pro- R when

  poxy a center 1. Ar = an indole group of asyme sort 1.1. B = piperazine present

  210) 2-CN-1H-indol-4-yl piperazin-1,4-diyl di (2-thienyl) methyl rac. not. at. foam n.a.

  31) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O di (4-NO 2 -phenyl) rac. n.a. dch 205-208 n.a.

  d 2-Ph'-methyl-43) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O (Phe) (cyclohexyl) -S rac. b foam -17.30 (c = 1% in

CHCH 2 '

  3a2) 2-CN-1H-indol-4-yl CHC 2 R- - O, pene-1 (CHCl 3)

  4a 2-CN-1H-indol-4-yl piperazin-1,4-diyl O (Phe) (cyclohexyl) -Sulfate -

CHCH 2-

3a)

  4b 2-CN-1H-indol-4-yl piperazin-1,4-diyl O (Phe) (cyclohexyl) -Sb foam

CHCH 2-

  2) 2-CN-11-indol-4-ylpiperazin-1,4-diyl-di (4-CN-phenyl) -N naphtin 170172 -2.8 ethyl (c = 2% in

4 CH 3OH)

  64)) 2-CN-1H-indol-4-yl piperazin-1,4-dlyl di (4-NH 2 -phenyl) -N-b.

mthyl

  2-CN-1H-indol-4-yl piperazin-1,4-diyl di (4-MeCONH-phenyl) -N.a.

m4thyl Co oe.

Configura- Confi-

  tion of the C * guratio bearing the C * 20 Ex. Ar B R OH in the group Point of n ° chaine pro R fusion [a poxy a center

asy% of E-

  tris esb 86) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O di (4-pyridinyl) present b foam

7) methyl S n.a.

  2-CN-1H-indol-4-yl piperazin-1,4-diyl O (4-OH-Phe phenyl). rac. rac. b methylated foam 3a)

  9a 2-CN-1H-indol-4-yl piperazin-1,4-diol O (4-OH-Phe) phenyl). S A foam -

  3a) Bmethyl 9b 2-CN-1H-indol-4-yl piperazin-1,4-diyl O (4-OH-Phe) hexyl) o B foam 8) methyl 2-CN-1H-indol-4- piperazin-1,4-diyl O (dicyclohemyl) foam (9)

  2-CN-1H-indol-4-yl p! Zerazin-14-di (4-CF3-Phe'y) s.

  B-methyl-2-CN-1H-indol-4-yl piperazin-1,4-diyl O (Phe) (pyridin-3-methyl-3-yl) methyl 3a

  2-CN-1H-indol-4-yl piperazin-1,4-diyl O (Phe) (pyridin -

  4yl JtbAyl SA b, foam +6.8 14) (c = 1% in 3a) ethanol) 13 2-CN-1Hindol-4-yl piperazin-14, -diyl O Phe) (pyridin-B foam +8.0 4 Y = methyl (c = i% in 6) ethanol) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O di (2-pyridinyl) -Sulfate + 7.30 mfthyl (c = 1% in r oe

CH30H) 'N

ula

Configura- Confi-

  C + 1 in the Ex point group. center

of asyré-

  ______________________________________ is present 14) 14a 2-CN-1H-indol-4-yl piperazin-1,4diyl O (Phe) (pyridin-3-S-racerb foam yl) methyl 3a ) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O (Phe) (pyridin-3-SA foam +4.5 yl) ethyl N ethanol) 3a) 16 2-CN-1H -indol-4-yl piperazin-1,4-diyl O (Phe) (pyridin-3-B foam +3.6 yl) methyl (c-11%)) el Sthanol)

  2-CN-1H-indol-4-yl piperazin-1,4-diyl O (3-thynyl) (b) foam

pyridinyl methyl 3a)

  17a 2-CN-1H-indol-4-yl piperazin-1,4-diyl O (3-thienyl) (4-S) foam

  pyridinyl) methyl 3a) 17b 2-CN-1H-indol-4-yl piperazin-1,4-diyl O (3thienyl) (4-pyridinyl) methyl naphthalene N CO CO 2

Configura- Confi-

of the C * gurati ----

  carrying the C * of the Cl in the group of the R-chain in the case of a point of 20 No. P in the center of fusion [a]

of asym-

  present 188) 2-CN-1H-indol-4-yl piperazin-1,4-diyl dicyclohexyl-naphtylamine 159-8.5 methyl 161 (c = 1%, m.p.

CH 3 OH)

  1b) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O (Phe) (2-thienyl) foam +6.2 nyl) methyl (c = 1X,

CH 3 OH)

  9a 3a) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O (Phe) (2-thisulfate) -

  I nyl) methyl 19b3a) 2-CN-H-indol-4-yl piperazin-1,4-diyl O (Phe) (2-thiolsulfonylmethyl) 2016) 2-CN-1H-indol-4 -yl piperazine-1,4-diyl O (Phe) (3-thiethyl-foam +5.5 nyl) methyl (c = 1%,

CH 3 OH)

  a34) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O (Phe) (3-thi'-M Foam -

  1 nyl) methyl b3a) 2-CN-1H-indl-4-ylpiperazin-1,4-diyl O (Phe) (3-thiolsulfonyl) methylc12) 2-CN-1H-indol- 4-piperazin-1,4-diyl (3-pyridinyl) -Srn. b foam

(3-thienyl) -

  methyl 213a) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O (3-pyridinyl) -AS foam +6.8 (3-thienyl) - (C = 1S, methyl CH 3 OH) 223a) 2-CN 1H-indol-4-yl piperazin-1,4-diyl O (3-pyridinyl) -bosulfate (4-9 = (3-thynyl) - (C 2 R 2 methyl CH 3 O) Co)

ConfiQura- Confi-

  Ex. I * Cguration carrying the C * idu 20 Ex. I Ar B R 0H in the group Point of [a] 0 NO. chalne pro R epoxy fusion that a center

of asym-

  236 is present) 2-CN-1H-indol-4-yl piperazin-1,4-diyl-di (3-pyridinyl) -Submousse +6.20 M.thyi (c = 1%)

CH 3 OH)

  23a13 2-CN-1H-indol-4-yl piperazin-1,4-diyl O (Phe) (1-Me-2-S) bmousse -

  imidazolyl) methy1,24a) 2-CN-1H-indol-4-ylpiperazin-1,4-diyl O (Phe) (i-Me2-Sbmousse +7.00 imidazolyl) ethyl (c = 1%)

CH 3 OH)

  243a) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O (Phe) (1-He-2-Bb foam + 5.2 imidazolyl) methyl (Co1%

CH30H)

  2-CN-1H-indol-5-yl piperazin-1,4-diyl diphenylmethyl rac. n.a. foam n.a.

  b 2-CN-1H-indol-6-yl piperazin-1,4-diyl diphenylmethyl rac. n.a. b 167168 n.a.

o

Configura- Confi-

-. - -tion of C * gurati "-

  carrying the C * b4 OH in the group Ex. pro-chain at point 20 No. Ar Doxy that a] No. Ar BR DOY qcentre fusion

of asym-

trie is present

  2-4-acetyl-1H-indolpiperazin-1,4-diyl diphenylmethyl rac., N.a., b 186188 n.a.

4-yl

  2718) 3-CN-1H-indol-4-yl piperazin-1,4-diyl diphenylnethyl rac. n.a. fu 230-231 n.a.

  2819) 6-COOH-11H-indol-4-piperazin-1,4-diyl-diphenylmethyl rac. n.a. b 145-148 n.a.

  Y1 2920) 6-CO1O4e-1H-indol-piperazin-1,4-diyl-diphenylmethyl rac. n.a. b 110-111 n.a. ro 022) '_Hc20tlt

  27-CH2CH2OEt-1H-piperazin-1,4-diyl diphenyl ethyl rac. n, a, mo 107O110 n.a.

i ndol-4-yl

  3122) 7-CH2CH2ON-1H-piperazin-1,4-diyl diphenylmethyl rac, n.a. hml 105-107 n.a.

/ indol-4-yl

  3223) 2,3-diCN-11H-indol-piperazin-1,4-diyl diphenyloethyl rac, n, a. b. foam n.a.

4-yl

  2-CN-1-Me-1H-indol-piperazin-1,4-diyl O-diphenylmithyl rac. n.a. b 150-152 n.a.

4-yl

  3425) 2-CN-1-CH2COO-piperazin-1,4-diyl diphenylibyl raco n.a. b 142144 n.a.

i ndol-4-yl

  3525) 2-CN-1-COOEt-piperazin-1,4-diyl O-diphenylithyl rac. n.a. b 149151 n.a.

3 indol-4-yl tn

Configura- Confi-

  tion of C * guratior carrying the C * OH in the group of 20 ex. merger No. poxy a center '

of asyWe-

- is

present

  a31 2-CN-3-CH2N1el-piperazin-1,4-diyl diphenylmethyl rac. n / A. ch. 203 n.a.

  1H-Indol-4-ylb 2-CN-3-Me-1H-piperazin-1,4-diyl O (Phe) (pyridin Root b 169-170 Co indol-4-yl 4-yl) methyl

  c3a) 2-CN-3-Me-1H-piperazin-1,4-diyl O (Phe) (pyridin-A foam) -

indol-4-yl 4-yl) nWthyl

  d3ac 2-CN-3-Me-1H-piperazin-1,4-diyl O (Phe) (pyridin-B foam) -

indol-4-yl X 4-yl) methyl

  e41) 1-F-1H-indolpiperazin-1,4-diyl diphenylmethyl rac. n.a. bml 154156 n.a.

4-yl Co co n

Configura- Confi-

  tion of the C * guration bearing the C * of the Point of [a320 ExA.rB CH in the fusion group No. Ar R chalne pro- R-I f P vOxy that a center l '

--_ asyme-

  trie is present. 1.2. = piperidine 36 2-CN-1H-indol-4-yl-O-diphenylmethyl S n.a. bmousse -19.4 (c = 1%, CHCl 3)

  2-CN-1H-indol-4-yl-3o di (4-phenyl) rac. n.a. b 179-181 n.a.

methyl 1.3. B = another group r-1

  382 2-CN-1H-indol-4-yl O diphenylmethyl rac. n.a. foam n.a.

  2-CN-1H-indol-4-yl-CH 2 CH 2 O diphenylmethyl rac. n.a. b 156159 n.a.

28)

    2-CN-1H-indol-4-yl-R-3N (te) -O-diphenyl-ethyl rac. n.a. b 125-1285 n. at.

  4129 2-CN-9H-indol-4-yl -ND -NH-O diphenylmethyl rac. R.a. ml 192-194 n. at.

0 diphnylmty] rc oo zm]] 92o] 94 n.a.

  2-CN-1H-indol-4-yl-N (Me) - cNH-O-diphenylnithyl S n.a. b foam -33. 2o

CHC13)

  42a 2-CN-1H-indol-4-yl -NH-C O-diphenylithyl S n.a. b foam -8.5 (c = 1%, CHC 13) oe #O

- Configura- Conf i-

  C * gurate bearing the C * dZ Ex. Ar R OH in the group P 20 No. Ar BR chalne pro R R-> Point of [alo poxy that a central fusion of asyme-. trie is present 2. Ar.an oxinoole group

  432>) 2,3-dihydro-g-oxo-N <(diphenylthyl b 17172 n.a.

  2,4 2,3-Dihydro-2-oxo-N me. NH - O diphenylmethyl rac. n.a. b 1754017256 n.a.

27) 1H-Indol-4-yl -ND-N

  29) 2,3-Dihydro-2-oxo-N Re) CH 2 CH 2 N -O-diphenylethyl rac. n.a. b 154156 n.a.

1H-indol-4-yl 27)

  2,3-Dihydro-2-oxo-N (<IMe) CH 2 CH 2 N (Me) -diphenylmethyl rac. n.a. b 140142 n.a.

indol-4-yl

  a 2,3-dihydro-2-oxo-NH-N, N-diphenylmethyl rac. n.a. b 106-103 n.a.

1H- i ndol-4-yl / G

  2,3-dihydro-3,3-piperazin-1,4-diyl diphenylmethyl rac. n. zMI 1O8112, n.a.

diMe-2-oxo-LH-

  indol-4-yl 14) 46a 2,3-dihydro-2-oxo-piperazin-1,4-diyl O (Phe) (pyridinrac racyl L 154-155 1H-indol-4-yl 4-yl) methyl 3a) 46b 2,3-Dihydro-2-oxopiperazin-1,4-diyl O (Phe) (3H-allyl foam) 1H-indol-4-yl 4-yl methyl

  46c 2,3-dihydro-2-oxo-piperazin-1,4-diyl O (Phe) (pyridin-S B b mOsse -

  1H-Indol-4-yl 4-yl) Methyl CD Coefficient

Configura- Confi-

  tion of the C * d4 OH in the group

chaSne pro R

  poxy that a point of Ex. center fusion [a] "

No. Ar B p R of Asywé

  sort is _. -______ __ _. ___ _present 3. Ar another group aryb po1yc cigue

  4732) 2,1,3-benzoyl-piperazin-1,4-diyl-diphenylmethyl rac. n.a. b 125126 n.a.

diazol-4-yl 34)

  48α-CF3-benzimid-piperazin-1,4-diyl-diphenyl-ethyl-rac. fu 222 n.a.

azol-4-yl

34) Benzimidazole

  49 4-yl piperazin-1,4-diyl diphenylmetbyl rac. n.a. b 176-178 n.a.

  5034) 1,2-dihydro-2-oxo-piperazin-1,4-diyl-diphenyl-methyl rc. n.a. ch 265-267 n.a.

  benzimidazol-4-yl r3 C n n Co L; Configuration -Configuration of C * guratioq carrying the C * d4 OH in the pro R chain group at 20 Ex. Ar B R POXy a merger [a] o No. center

d.asyce-

_-- trie is present

  2 (1H) -quinolipiperazin-1,4-diyl O diphenylmethyl rac. n.a. fu 214217 na.

none-4-yl (dec.)

  1,2,3,4-tetrapiperazine-1,4-diyl O-diphenylmethyl rac. n.a. fu 218219 n.a.

hydro-2-oxoquino-

l1ine-4-yl r1

  1,2,3,4-tetrahydro-piperazin-1,4-diyl di (4-F-phenyl) rac. nn.a.n.a.

Dro-2-oxoquinomethyl-1-yl-4-yl

  1- [9 N] -carbazol-piperazin-1,4-diyl-diphenyl-ethyl rac. n.a. b 200202 n.a.

4-yl

  piperazin-1,4-diyl-dlphenylmethyl rac. n.a. hfu 169-1700 n.a.

  OCdiphenylmethyl rac. n.a. zml 165-168 n.a.

  57 c - diphenylaithyl rac. n.a. b 201-202 n.a.

kyAPe - NH- ---

e) O Co CDl

  I__ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ _ - - -Co nfiguraConfi- -

of the C * guratioe

wearing the C * b.

  CH in the group chalne pro R at Point of Ex. P Y that a merger [a] 20 center o. Ar Bp Rds

of asywÉ-

  tri is 4. Ar = a phenyl group present

  57a 4-OBz-phenyl piperazin-1,4-diyl-diphenylmethyl rac. n.a. b 106-108 n.a.

  5836) 4-OH-phenyl piperazin-1,4-diyl diphenylmethyl rac. n.a. fu 155159 n.a.

  58a 3-8OZ-phenyl piperazin-1,4-diyl diphenylmethyl rac, n.a. b oil n. at.

  5936) 3-OH-phenyl piperazin-1,4-diyl diphenylmithyl rac. n.a. b 183185 n.a.

  59a 3-COOMe-phenylpiperazin-1,4-diyl diphenylmethylamino. n.a. b oil n.a.

  6035) 3-COOH-phehenyl piperazin-1,4-diyl diphenylmethyl rac. n.a. b 190191 n.a.

  3-CF3-phenylpiperazin-1,4-diyl diphenylrkethyl rac. n.a. fu 180182o a.a.

  6237) 4-MeCOCH 2 -phenylpiperazin-1,4-diyl O-diphenylmethyl rac. n.a. b 108-110 .a.

  62a> 3-NH 2 -phenylpiperazin-1,4-diyldiphenylthyl rac. n.a b oil n.a.

  6339 3-NHSO-2-phenyl piperazin-1,4-diyl-diphenylmethyl rac. n.a. foam n.a.

  6440) 3-NHCH 2 Cl-phenyl piperazin-1,4-diyl diphenyl methyl rac. n.a. bfu 131-133 n.a.

  3-Nicol-phenylpiperazin-1,4-diyldiphenylmethyl rec, n, 1 to 7-119 n.a.

  6611) 2- (1-hydroxy-piperazin-1,4-diyl-diphenyl-ethyl) rac. o.a. fu 154-156 .a.

  6-thylcyclohexyl) piperazin-1,4-diyl diphenylmethyl rac. n / A. 162. 164 n.a.

Methylphenyl o 'Co

Configura- Confi -

  tion of the C * guration bearing the C * of the point of OH in the group fs20 Ex. chalne pro R fusion [(] D Ex. Ar B p R pOxy a center

____ asywé

trie is present

  Piperazin-1,4-diyl diphenylmethyl rac. n.a. foam n.a.

[ORena Me2 J

  68 21) | Plperazin-1,4-diyl diphenyl ethyl rac. a.i. b 177-180i n.-.

me

HI ICN

  68a 3,5-di-OBz-phenyl piperazin-1,4-diyl diphenylmethyl rac. n.a. foam n.a.

926)

  3,6-di-1H-phenyl piperazin-1,4-diyl diphenylthyl rac. n.a. b 193-184 n.a.

  69a 2-CN-4.OBz-phenyl piperazine-1,4-diyl diphenylaethyl rac, n.a. b oil n.a.

  703 2-CNl-4-OH-phenyl piperazin-1,4-diyl-diphenylethyl rac. n / A. fu 196198 n.a.

w CO oe

Configura- Confi-

  tion of the C * guration carrying the C * of the OH in the group chalne pro R at Point [] 20 Ex. ArB P 0 poxy that fusion Ex.Ar center

No. B P R of asyv-

  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _. _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ tr i e e present

  2-acetyl-4-piperazin-1,4-diyl diphenylnethyl rac. n.a. fu 161-163 n.a.

OCH2CH2OMe-phenyl

  2-CN-4-OCH 2 CH 2 O-piperazin-1,4-diyl O-methyl-ethyl rac. n.a. b 107-109 n.a.

phony1 22 c

  2-Me-3-N02-phenylpiperazine-1,4-diyl diphenylmethyl rac., N.a. b 149150 n.a.

  2,3-di-NO2-phenyl piperazin-11,4-diyl diphenylethyl rac. n.a. foam n.a.

  7533) 2,3-di-NH 2 -phenyl piperazin-1,4-diyl-diphenylmethyl rac. n.a, dchl 133- n.a.

    Abbreviations: C * = asymmetric carbon atom rac. = racemic na = not relevant Bz = benzyl Me = methyl Phe = phenyl Et = ethyl bml = bis [maleate] dch = dihydrochloride b = free base fu = fumarate mo = malonate zml = bis [hydrogenaleate] hml = hydrogenomaleate ch = hydrochloride hfu = hydrogenofumarate bfu = bisfumarate tch = trihydrochloride A = in one of two possible stereoisomeric forms B = in one of two possible stereoisomeric forms dec. = decomposition

  Reaction conditions and preparation of international products

  Intermediates 1) 1-bis (4-nitrophenyl) methyl] piperazine is obtained by acetylation of the 1-diphenylmethyl piperazinification of the resulting acetylpiperazine and removal of the acetyl group from the resulting dinitro derivative. 2) 1- [Bis (4-cyanophenyl) methylethyl] piperazine is obtained by reduction of dio (p-cyanophenyl) ketone with NaBH4, mesylation of the resulting alcohol, reaction of the resulting mesylate with N-formylpiperazine and hydrolysis of the derivative of the resulting Nformylpiperazine. 3) 1 - [(2-cyclohexyl-2-phenyl) ethyl] piperazine is obtained by acylation of 1-benzylpiperazine with the

  2-phenyl-2-cyclohexylacetyl chloride, reduced

  of the resulting derivative with LiAlH and N-debenzyla-

  of the resulting derivative by hydrogenation with

palladium on charcoal.

  3a) The corresponding mixture of diastereoisomers of

  formula I is separated into its two optical components-

  pure by chromatography on silica gel.

  4) 1- [bis (4-aminophenyl) methyl] piperazine is obtained

  by reduction of the nitro derivative described under 1).

  ) 1- [bis (4-aminophenyl) methyl] piperazine is obtained

  by acylation of the amino derivative described under 4).

  6) The corresponding 1- [bis (pyridinyl) methyl] piperazine is obtained by reduction of the corresponding dipyridinyl ketone with NaBH 4, mesylation of the resulting alcohol, reaction of the resulting mesylate with Nformylpiperazine and elimination of the formyl group

  from the resulting N-formylpiperazine derivative.

  7) 1 - [(4-Hydroxyphenyl) -phenylmethyl] piperazine is obtained by reduction of phenyl- (p-benzyloxyphenyl) ketone with NaBH4, bromosubstitution by PBr3 of the free hydroxy group in the resulting alcohol,

  reaction of the resulting bromo derivative with benzyl-

  piperazine and removal of L-6-enzyl and benzyloxy from the resulting N-benzylpiperazine derivative by hydrogenation with palladium-on-charcoal. 8) 1- [bis- (cyclohexyl) methyl] piperazine is obtained

  by mesylation of dicyclohexylcarbinol, a reaction

  the resulting mesylate with formylpiperazine and removal of the formyl group from the derivative

  the resulting N-formylpiperazine.

  9) 1- [bis (4-trifluoromethylphenyl) methyl] piperazine is obtained by bromosubstitution with PBr 3 of

  free hydroxy group in di- (p-trifluoromethyl)

  phenyl) carbinol, reaction of the resulting bromo derivative with formylpiperazine and removal of the formyl group from the resulting N-formylpiperazine derivative. The corresponding 1- [bis (thienyl) methyl] piperazine is obtained as described in Example 1, starting from

  of the corresponding di (thienyl) ketone.

  1 11) The title compound is obtained by alkaline hydrolysis

of the compound of Example 67.

  12) 1 - [(3-Pyridinyl) - (3'-thienyl) methyl] piperazine is obtained in a manner analogous to that described

in note 15).

  13) 1 - [(1-methyl-2-imidazolyl) (phenyl) methyl] piperazine is obtained analogously to that described in note 16). Carbinol is prepared by reaction of 2-lithio-1-methylimidazole with benzaldehyde.

  14) The corresponding 1 - [(pyridinyl) (phenyl) methyl] piperazine

  dante is obtained by reaction of the corresponding carbinol

with ethoxycarbonylpiperazine at elevated temperature and hydrolysis of the resulting ethoxycarbonyl compound. 15) 1 - [(4-Pyridinyl) (3'-thienyl) methyl] piperazine is obtained in two stages from the corresponding carbinol as described in Note 8). The

  carbinol is prepared by reaction of 3-thienyl-1

  thium with pyridine-4-carboxaldehyde.

  16) The corresponding 1 - [(phenyl) (thienyl) methyl] piperazine

  dante is obtained by reaction of the corresponding carbinol

  with thionyl chloride, condensation of

  resulting chloride with N-ethoxycarbonylpiperine

  razine and hydrolysis of the ethoxycarbonyl compound

resulting.

  17) The title compound is obtained by reaction of the compound of Example 62 with dimethyl acetal

N, N-dimethylformamide.

  18) 4- (2,3-Epoxypropoxy) -1H-indole-3-carbonitrile

  (F = 125-126) is obtained by reaction of 4- (2,3-

  epoxypropoxy) -H.indole with chloro-isocyanate

  sulfonyl and reaction of the resulting 3-cyano compound

with benzhydrylpiperazine.

  19) Hydrolysis of the compound of Example 29 with an aqueous solution of sodium hydroxide. ) 4-hydroxy-6-methoxycarbonyl-1H-indole (F = 8081) is obtained according to the following reaction sequence: Stobbe condensation of pyrrol-2-carbaldehyde

  with dimethyl succinate, cyclization of the

  resulting positing with acetic anhydride and

  sodium acetate to 4-acetoxy-6-methoxycarbonyl-

  indole and treatment with sodium methoxide in

methanol.

  21) The title compound is obtained by reaction of the compound of Example 67a with cyanoacetamide

in sodium ethoxide.

  22) 4-hydroxy-7- (2-methoxyethyl) -1H-indole (oil) and 4-hydroxy-7 (2-ethoxyethyl) -1H-indole

  (oil) are obtained by formylation of 4-benzyloxy-

  ethyl 1H-indole-2-carboxylate, hydrolysis of the resulting ethyl 4-benzyloxy-7-formyl-1Hindole-2-carboxylate (F = 113-114), decarboxylation of the acid

  4-Benzyloxy-7-formyl-1H-indole-2-carboxylic acid

  both (F = 203-206), reduction by NaB H4 of 4-benzyloxy-7-formyl-1Hindole (F = 1-29-13l1), acetylation of 4-benzyloxy-7-hydroxymethyl-1Hindole

  result (F = 82-84), reaction of 4-benzyloxy-7-

  resulting acetyloxymethyl-1H-indole (F = 70-71)

  with NaC4, hydrolysis of 4-benzyloxy-1H-indole-7-

  acetonitrile (F = 152-154), reduction of the acid

  Resulting 4-benzyloxy-1H-indole-7-acetic acid (F = 133-

  136), corresponding etherification of 4-benzyloxy-

  7- (2-hydroxyethyl) -1H-indole (F = 62-64) with diazomethane or with diazoethane,

  and debenzylation of the resulting ether.

  23) 4- (2,3-Epoxypropoxy) -1H-indole-2,3-dicarbonitrile

  (F = 172-174) is prepared by reaction of 4- (293-

  epoxypropoxy) -1H-indole-2-carbonitrile with iso-

  chlorosulfonyl cyanate in dimethylformamide.

  24) The title compound is obtained by methylation with 4- [3- (4-diphenylmethylpiperazin-1-yl) -2-hydroxypropoxy] 1H-indole-2-carbonitrile dimethyl sulfate with tetrabutylammonium iodide. in a solution of methylene chloride and an aqueous solution

  of sodium hydroxide for 30 minutes and

  trography of the resulting compound on silica gel

  using 5% methanolic methylene chloride

as eluant.

  ) The title compound is obtained by reaction of the

  4- [3- (4-diphenylmethyl-l-yl) -2-hydroxy-

  propoxy] -1H-indole-2-carbonitrile with chloro

  ethyl acetate (example 34) or with the chlorobenzene

ethyl formate (Example 35).

  26) The title compound is obtained by debenzylation

of the compound of Example 68a.

  27) N- (diphenylmethyl) -N, N'-dimethylethylenediamine (oil) is obtained by reaction of MeCON (Me) CH2CH2Cl with i-diphenylmethyl-N-methylamine in dioxane and hydrolysis of the resulting acetamide with

  sodium hydroxide in ethanol.

  28) 4- (N-diphenylmethyl-N-methylamino) = piperidine (F = 116-120) is obtained by hydrogenation of 1-ethoxycarbonyl-4-piperidone on platinum oxide, N-methylation of the resulting amine ( F = 78-80) with formaldehyde in formic acid and hydrolysis of the resulting compound (F = 146-148)

  with potassium hydroxide in ethanol.

  4- (Diphenylmethylamino) piperidine (F = 67-69) is obtained by hydrolysis of the 78-80 amine intermediate amine described in FIG. 28), with

  potassium hydroxide in ethanol.

  ) The title compound is obtained by debenzylation

of the compound of Example 69a.

  31) The title compound is obtained by reaction of the

  4- [3- (4-diphenylmethyl-1-yl) -2-hydroxy-

  propoxy] -1H-indole-2-carbonitrile with the formaldehyde

dehyde and dimethylamine.

  32) 4-hydroxy-2,1,3-benzoxadiazole is obtained by reaction of 2,6-dichloroaniline with hydrogen peroxide, reaction of the resulting 2,6-dichloronitrosobenzene (F = 162-163)

  with sodium azide, reaction of 4-chloro-2,1,3-

  benzoxadiazole (F = 75-79) with the

  sodium methoxide and acid hydrolysis of 4-methoxy-

  Resulting 2,1,3-benzoxadiazole (mp 76-78).

  33) The title compound is obtained by hydrogenation of the compound of Example 74 with palladium on

coal.

  34) The title compound is obtained by cyclization of the compound of Example 75 with, respectively, trifluoroacetic anhydride (Example 48), 4.3

  HC (OEt) 3 (Example 49) or COCl2 (Example 50).

  ) The title compound is obtained by alkaline hydrolysis

of the compound of Example 59a.

  36) The title compound is obtained by debenzylation of the corresponding compound having a benzyl group in place of the hydroxy group (compounds of the examples

57a and 58a).

  37) (4-hydroxybenzyl) methyl ketone is obtained

  by demethylation of (4-methoxybenzyl) -

  methyl ketone with hydrobromic acid.

  38) The title compound is obtained by alkaline hydrolysis

line of the compound of Example 65.

  39) The title compound is obtained by reaction of the

  compound of Example 62a with CH3SO2Cl.

  ) 3-cyanomethylaminophenol (oil) is obtained

  by reaction of 3-aminophenol with chloroacetonitrile

  Trile. 41) The starting material is obtained according to the following reaction sequence 4-fluorophenol Br 2 derivative 2-bromo..dérive benzyloxy, 2-bromo CuCN derivative benzyloxy, 2-cyano _> derivative benzyloxy 2-formyl azide derivative benzyloxy, 2- ( CH =: COOEt) cyclization N 3 -benzyloxy-7-fluoro-1H-indole-2-carboxylate ethyl KOH corresponding acid decarboxylation 7-fluoro-4-benzyloxy-1H-i ndol e debenzylation

  7-fluoro-4-hydroxy-1H-indole> epoxide correspon-

ing

  The compounds of the invention are of interest

  pharmacological properties and can therefore

  to be used in therapeutics as drugs.

  In particular, the compounds of the invention exert a cardiotonic activity, as is apparent from conventional tests. For example, in the normotensive anesthetized dog or Numal [R.Salzmann et al., J. Cardiovasc. Pharm. 7 (1985)], there is an increase in the contractile force of the left ventricle after administration of the compounds of the invention by ... ntravi: s doses included

  between about 0.01 mg / kg and about 2 mg / kg, and after administration

  intraduodenal treatment at doses between

  about 0.02 mg / kg and about 2 mg / kg.

  The method is performed as follows: Dogs of both sexes weighing between 10 and 15 kg are used and are numal anesthetized at a dose of 65 mg / kg intravenously. The animal is

  tied lying on his back on the operating table.

  After having made the usual preparations, a catheter is passed under radiological control.

  heparinized in the right carotid artery until the

  left tricle and record the transmission of

  the pressure with a device Gould Statham P 23 Gb.

  The increase in pressure as a function of time is

  computed and recorded using a physiodifferentiation

  HSE. The increase in pressure in the

  left tricle is a measure of the contractile force of the heart. The amplitude of the differential pressure is indicated in mm Hg / sec. The animals are kept at a constant temperature, with a suitable body temperature of about 36 to 37. After a control period of about 40 minutes, the test substance is injected into the femoral vein and the

  effects produced on the saved or calculated parameters.

  This effect can be confirmed using identical doses in rats anesthetized with Inactin (the method is as described above, but Inactin-anesthetized rats are used instead of Numal-anesthetized dogs) in the decerebrate cat. Opened thoraX according to the method described by R. Salzmann et al. in J. Cardiovasc. Pharm. 7 (1985) with direct measurement of contractile force and on the heart of rabbit batIntn spontaneously presenting acute insufficiency, according to the method described by G. Scholcyaik Gt coll in Naunyn-Schmiedeberg's Arch. Ph. Ariacolo l985). With these compounds, the compounds of the invention can therefore be used in therapy as cardiotonic agents, for example for the treatment of cardiac insufficiency. In this indication, the compounds of the invention have a more balanced activity profile than the compounds because:

  known diotonics of similar structure.

  The preferred compounds for this indication are those of Examples 1, 3, 12, 13, 14, 15, 17, 21, 36,

  38, 43 and 59, especially those of Examples 12 and 21.

  Suitable daily unedose is from about 1 mg to about 500 mg, advantageously administered, for example orally, in divided doses 2 to 4 times daily in unit dosage form each containing from about 0.25 to about 250 mg of substance

  active, or in a form & extended release.

  The compounds of the invention also exert antiarrhythmic activity, as is apparent from conventional assays. For example, on the left atrium of cob3 / e they prolong the functional refractory period to a concentration of about 10'7 M to 10-4 M [R. Hof and G. Scholtysik, J. Cardiovasc. Pharm.

(1983) 176-183] J.

  Thanks to these properties, the compounds of the invention can

  Therefore, they may be used therapeutically as antiarrhythmic agents, for example for the treatment of cardiac rhythm disorders such as supraventricular tachycardia or fibrillation. The compounds of the invention also exert an idrenergic blocking activity, as is apparent from conventional assays. For example, inhibition of α-adrenergic receptors can be observed on segments of the femoral vein of dogs (E. Mueller-Sciweiitt and E. StUrmer, US Pat.

  Br.J.Pharmacol. 51, (1974) 441-446) of a concentration

  bath temperature of about 10-7 M to about 10 5 M.

  Thanks to these properties, the conipovs of the invention can

  Therefore, they may be used in therapies such as α-adrenergic receptor blocking, eg for the prophylaxis and treatment of disorders related to paralyzed bowel motility, such as

paralytic ileus.

  The compounds of the invention also possess an adrenergic receptor blocking activity, as is apparent from conventional assays. For example, on the isolated auricle of the guinea pig, beating spontaneously,

  [AT. Bertholet et al., Postgrad-Med. J. 57, Suppl.

  (1981) 9-17] inhibition of the positive inotropic effect of adrenaline at a bath concentration of about 10-9 M to about 10-6 M.

  Thanks to these properties, the compounds of the invention can

  Therefore, they may be used in therapy as α-adrenergic receptor blocking agents, for example for the prophylaxis and treatment of coronary heart disease such as angina pectoris, conditions resulting from sympathetic overstimulation, such as nervous cardiac disorders. , hypertension,

  myocardial infarction, for the treatment of

  valle of migraine, and for the treatment of glaucoma

and thyrotoxicosis.

  For use as antiarrhythmic agents and α and β-adrenergic receptor blocking agents, the compounds of the invention will be administered at a daily dose of between about 01 mg and about 500 mg, advantageously administered, for example orally, in doses. fractionated 2 to 4 times daily in unit dose form each containing between about 0.025 mg and about 250 mg of active substance,

  or in sustained release form.

  In addition, the compounds of the invention

  characteristic effects of calcium antagonists.

  They exert in fact myorelaxant - pronounced, especially on the smooth muscles, as it appears from the vasodilatation and the fall of the blood pressure in the classic tests. For example, in the microsphere test performed in the anesthetized cat according to the method described by R. Hof et al., In Basic Res. Cardiol. 75, (1980) 747-756 and 76

  (1981) 630-638, and by R. Hof et al, J. Cardiovasc.

  Pharmacol. 4 (1982) 352-362, dilation of the coronary vessels, increase of skeletal muscle blood flow and lowering of blood pressure after administration of the compounds of the invention intravenously at doses between

  about 3 mg / kg and about 300 μg / kg.

  There is also a decrease in blood pressure in the awake spontaneously hypertensive rat according to the method described by M. Gerold et al., In Arzneimittelforsch. 18 (1968) 1285, after administration of the compounds of the invention subcutaneously at doses of from about 1 μg / kg to about

ug / kg.

  Thanks to these properties, the compounds of the invention can be used in therapy as calcium antagonists for the prevention and treatment - coronary insufficiency, for example angina pectoris, - disorders of the cerebral circulation such as cerebrovascular insufficiency , accidents

  such as cerebrovascular attacks

  vascular, and cerebrovascular spasms; - other peripheral circulation disorders, for example in limbs such as intermittent claudication, and smooth muscle spasm, eg colon muscles, and

  - asthma, for example asthma induced by exercise

  cise. For their use as antagonists

  calcium compounds, the compounds of the invention will be administered

  at a daily dose of between about 5 mg and about 500 mg, advantageously administered, for example orally, in divided doses 2 to

  4 times a day as unit doses containing each

  between about 1.25 mg and about 250 mg of substance

  active, or in a sustained release form.

  In general, optical isomers with S-configuration at the 2-position of the propoxy side chain are more active than optical isomers

  having the configuration R, as cardiotomic agents

  antiarrhythmics and receptor blocking

5-adrenergic receptors.

  Preferred compounds as adrenergic receptor blocking agents are those in which substituent B is a radical in which the nitrogen atom attaches to the propoxy side chain.

  is part of a secondary amino group.

  It should be noted that it may be necessary to

  forming a compound having the hydroxy group at the 2-position of the 3-aminopropoxy side chain in the esterified form, to the corresponding unesterified compound, before carrying out the above-mentioned in vitro tests for determining the activity of the compounds

of the invention.

  Of the indicated therapeutic applications

  above for the compounds of the invention, the application

  tion is the use of the compounds of the invention.

  vention as cardiotonic agents.

  The compounds of the invention can be administered in the form of pharmaceutically acceptable salts. Such salts have the same order of activity as the free forms and can be prepared

according to known methods.

  The invention thus relates to the compounds of the invention, in free form or in the form of a pharmaceutically acceptable salt, for use as medicaments, especially as agen tscardiotonic agents, as antiarrhythmic agents, as aadrenergic receptor blocking agents, as blocking agents. 5-adrenergic receptors, and as calcium antagonists. The invention also relates to a medicament comprising, as active substance, a compound of the invention in free form or in the form of a salt.

pharmaceutically acceptable.

  As drugs, the compounds of

  the invention may be used in the form of

  pharmaceutical compositions containing the active substance, in free form or in the form of a pharmaceutically acceptable salt, in combination with a pharmaceutically acceptable carrier or diluent. Such compositions, which are also part of the invention, may for example be in the form of solutions or tablets.

Claims (7)

  1. The compounds of formula I OH! OCH2CHCH2-B .- (CO) pR () Ar wherein Ar represents an aromatic or heteroaromatic residue, B represents a group corresponding to one of the following formulas i), ii), iii) or iv): V i) - Wherein R 1 and W denote hydrogen or together form an additional bond, and R 3 denotes hydrogen, a C 1 -C 4 alkyl group or a phenyl group optionally bearing one or two identical or different substituents selected from halogens. an atomic number of 9 to 35 and the C 1 -C 4 alkyl and C 1 -C 4 alkoxy groups, wherein R 1 is hydrogen or C 1 -C 4 alkyl; Wherein Rk is hydrogen or (C1-C4) alkyl and R1 has the meaning given above for R., and (iv) wherein '(CH2) rm means 2 or 3, p is 0 or 1, and -   R represents an alkyl group having two   identical or different radicals selected from aromatic, heteroaromatic and cycloaliphatic radicals, with the proviso that when a) Ar means a group of formula A R '(A) R '   wherein R 'is hydrogen, methyl, hydroxymethyl, carboxy, C 2 -C 5 alkoxycarbonyl, carbamoyl or cyano and R "is hydrogen or methyl, or R' is hydroxy and R" means hydrogen, and that 3 b) p is 1 and B is - a group i ') of formula V' R. wherein R 1 has the meaning given above and V 'and W' signify hydrogen or, where R 'is hydroxy and R "is hydrogen, V' and W 'are hydrogen or together form an additional bond, or - a group ii) or iii) as defined above, or p is 0 or 1 and B means a group iv ') of the formula -N N -   R is then other than a C 13 -C 17 diphenylalkyl group in which each phenyl ring may optionally carry one or two identical or different substituents chosen from halogens having an atomic number of 9 to 35 and C 1 -C 4 alkyl and alkoxy groups; C1-C4, and the physiologically hydrolysable derivatives of these compounds having the hydroxy group at the 2-position of the propoxy side chain in the esterified form, and the salts of these compounds.   2. A compound according to claim 1, characterized in that it corresponds to the formula ## STR1 ## in which Ara signifies - a phenyl group, a monosubstituted phenyl group.   hydroxy, benzyloxy, carboxy, alkoxy-   C2-C5 carbonyl, trifluoromethyl, acetylmethyl,   methylsulfonylamino, cyanomethylamino, amino, aceto   tamido, (1-hydroxymethylcyclohexyl) methyl,   (1-acetoxymethylcyclohexyl) methyl, 1-dimethyl-   amino-3-oxo-1-buten-2-yl or 3-cyano-1,1,2-dihydro-   6-methyl-2-oxopyridin-5-yl, or a phenyl group disubstituted with nitro, amino, hydroxy or benzyloxy groups, or with a hydroxy group and a cyano group, or with a benzyloxy group and a group   cyano, or by an acetyl group and a 2-group   thoxy-ethoxy, or by a groupecyano and a 2-methoxy group   ethoxy, or with a nitro group and a methyl group,   an indolyl group, an indolyl monosubstituted group   killed in position 2 by a methyl group, hydroxyl   methyl, carboxy, C2-C5 alkoxycarbonyl,   Bamoyl, cyano or acetyl, an indolyl group monosubstituted at the 3-position by a methyl group   or cyano, an indolyl group monosubstituted in   6 by a carboxy or C 2 -C 5 alkoxycarbonyl group, an indolyl group monosubstituted at the 7 position by fluorine or by a (C 1 -C 4) alkoxy-C 1 -C 4 alkyl group, an indolyl group disubstituted at the 1-position by a alkyl group   C1-C5 C1-C4 alkoxycarbonyl or alkoxycarbonyl   C3-C9 bonylalkyl and at the 2-position with a cyano group, or disubstituted at the 2-position and 3-position with cyano groups, or disubstituted at the 2-position with   methyl, hydroxymethyl, carboxy, alkoxy-   C2-C5 carbonyl, carbamoyl or cyano and in position 3 with a methyl group, or disubstituted at the 2-position by a cyano group and at the 3-position with a dimethylaminomethyl group,   an oxindolyl group optionally substituted with   3 by two methyl groups, - a 2,1,3-benzoxadiazol-4-yl group   a benzimidazol-4-yl or 2-trifluoromethyl group   benzimidazol-4-yl, a 1,2-dihydro-2-oxobenzimidazole-4-yl group,   a 2 (1H) -quinolinone-4-yl or 1,2,3,4-tetra-   hydro-2-oxo-quinolin-4-yl, 1- [9H] -carbazol-4-yl or - spiro [cyclohexane-1: 2'-indan] 1-1-yl-4-yl, B and p have the meanings given in claim 1; R represents a C 1 -C 5 alkyl group having two identical or different substituents chosen from phenyl, pyridinyl, thienyl, furyl, pyrrolyl, imidazolyl, imidazolyl monosubstituted in the 1-position by a methyl group, C 3 -C 7 cycloalkyl and phenyl having a substituent or two identical or different substituents selected from halogens having an atomic number of 9 to 35 and C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, cyano, nitro, amino, C 2 -C 5 alkanoylamino and trifluoro-nt groups; hyl, with the proviso read when a) Ara means a group of formula A as defined under a) of the condition formulated in claim 1 for compounds of formula I and b) p and B are as defined under b) of the condition formulated in claim 1 for the compounds of formula I, then R is other than a C13-C7 diphenylalkyl group in which each phenyl ring may optionally bear one or two substituents id entiques or different ones selected from halogens having an atomic number of 9 to 35 and C1-C4 alkyl and C1-C4 alkoxy,   and their physiologically hydrolysable derivatives correspond to   respondents. 3.- A compound according to claim 1, characterized in that it corresponds to the formula Iaa OH OCH2CHCH2-B- (CO) pRa (aa) 2. 2-P_a (Iaa) H in which   R1 is hydrogen or methyl, hydroxyl   methyl, carboxy, C2-C5 alkoxycarbonyl, carbamoyl or cyano, and R2 is hydrogen or methyl, or R1 is hydroxy and R2 is hydrogen, and   B, p and Ra have the meanings given in the claims let2,   with the coniition that when B and p are as defined under b) of the   condition formulated in claim 1. for   Formula I, Ra is then other than a C13-C17 diphenylalkyl group.   in which each phenyl ring may carry   one or two identical or different substituents selected from halogen atoms having an atomic number of 9 to 35 and C 1 -C 4 alkyl and C 1 -C 4 alkoxy groups,   and their physiologically hydrolysable derivatives correspond to   respondents. 4.- A compound according to any one of   claims 1 to 3, characterized in that Ar means a 2-cyano-1H-indol-4-yl group.   5.- A compound according to any one of   Claims 1 to 4A characterized in that it presents itself   as racemic or as enantiomers.   6. A process for the preparation of the compounds specified in claim 1, characterized in that it comprises 3-amino-2-oxypropylation of a corresponding compound of formula IV OH (IV)   Ar in which Ar is as defined in claim 1, or a precursor of this compound.   7. A process for the preparation of a compound according to claim 1, characterized in that a corresponding compound of formula II is reacted. OCH2-R e 2-x (II) Ar   in which Ar has the meaning given to the   1 and R 1 represents a group capable of reacting with a primary or secondary amine to give a 2-amino-1-hydroxyethyl group, with a corresponding compound of the formula III A6781 tererized in that the support surface (21) is fixed of   Adjustable way on the ntcgsxtrémités of both ye s (18).   in which it is possible to use the 4, -   In that the support pad (22) comprises a Y5 dRANGaVe - screw (?) Qopgrant with the sliding axis eeare, it eserie e way) tolimitably adjust the amplitude of its group nyaroxy in position 2 of the lateral chain of motion.   aminopropoxy in the composition of the invention.   ) Clamp conzorme to one that any 8.- Unconpos according to .no.elconu e mor   preceding claims, characterized in   claims there, under form o   (12, 13) show a rain-flow at the axis of each other.   surfaces mV pui u'dtia, 262) facing each other.   9. A molecule, characterized in that it comprises, as active substance, a compound according to   any of claims 1 to 5, in the form of   free or in the form of a pharmaceutically acceptable salt.   10. A pharmaceutical composition, characterized   in the understanding that it comprises as active substance   a compound according to any one of claims 1 to   , in free form or in the form of a pharmaceutically acceptable salt, in association with a vehicle   or pharmaceutically acceptable diluent.