CA2008985A1 - Aminoalkoxyphenyl derivatives, process of preparation and compositions containing the same - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Aminoalkoxyphenyl derivatives useful in the treatment of certain pathological syndromes of the cardiovascu-lar system of formula:

(1) in which :
B represents a -S, SO- or -SO2- group, R1 and R2, which are identical or different, each denote hydrogen, a methyl or ethyl radical or a halogen such as chlorine, bromine or iodine, A denotes a straight- or branched-alkylene radical having from 2 to 5 carbon atoms or a 2-hydroxypro-pylene radical in which the hydroxy is optionally substituted by a lower alkyl radical, Am represents a group ou

Description

20~B9~5 AMINOALKOXYPHENYL DERIVATIVES PROCESS OF PREPARATION
AND COMPOSITIONS CONTAINING THE SA~E

The present invention relates to new carbo-cyclic or heterocyclic derivatives and to a process for preparing them.
More particularly, the invention relates to the novel aminoalkoxyphenyl derivatives represented by the general formula :

Cy-B-~-O-A-Am ( 1 ) R
in which : 2 B represents a -S, -SO- or -SO2- group, R1 and R2, which are identical or different, each denote hydrogen, a methyl or ethyl radical or a halogen such as chlorine, bromine or iodine, A denotes a straight- or branched-alkylene radical having from 2 to 5 carbon atoms or a 2-hydroxypro-pylene radical in which the hydroxy is optionally substituted by a lower alkyl radical, Am represents a group selected from -N-Alk- ~ ~ -R~3 ou -N-Alk-3 R"3 wherein R3, R'3 and R"3, which are identical or different, each denote a halogen such as chlorine or ~romine, a lower alkyl, lower alkoxy or benzyloxy group, R4 denotes hydrogen or an alkyl radical " ~

, , : : :
,-.

:

s Alk denotes a single bond or a straight or branched-alkylene radical having from 1 to 5 carbon atoms.
Cy represents a group of formula :

( C- or ' ~D) (E) R represents hydrogen, an alkyl radical, a cycloakyl radical, a benzyl radical or a phenyl radlcal optio-nally substituted with one or more substituents, which may be identical or different, selected from halogen atoms, for example fluorine, chlorine, bromine atoms and from lower alkyl, lower alkoxy or nitro groups, R5 and R6 are taken together with the carbon atom to which they are attached to form :
- an optionally aromatic mono- or di-cycli.c carbocyclic group haviny from 5 to 10 carbon a~oms and optionally substituted by a R group in the a-POsitiOn with respect to the methyne group, - an optionally aromatic 5-membered heterocyclic group, the heteroatoms or, heterogroups being ~elected from ~he groups 0, S, N,-N-Rg; 0 ànd N; 0 and -N-Rg; S
and N; S and -N-R9; N and N; N and -N-Rg, the hetero-cyclic group being optionally sub~tituted by a R group in the a-position with respect to the methyne group and optionally substituted by one or two groups selected from lower alkyl and phenyl groups, .
' ' ;

2~985 - an optionally aromatic 6- to 10- membered mono- or di-cyclic heterocyclic group, the heteroatoms or heterogroups being selected from the groups O, S, N, -N-Rg; O and N; 0 and -N-Rg; S and N; S and -N-Rg; N
and N; N and -N-Rg, the heterocyclic group being optionally substituted by a ~ group in the a-pOSitiOn with respect to the methyne group, R7 and R8, which are the same or different, each re-present hydrogen, a lower alkyl radical or a phenyl radical or when they are taken together with the carbon atoms to which they are attached represent an optionally aromatic 6-membered carbocyclic ring, Rg represents hydrogen, A lower alkyl radical, a phenyl radical, a benzyl radical or a benzyl radical substituted by a halogen.
In the present context, both in the descrip-tion and in the claims, the following meaning attaches to the terms stated above :
"alkyl" denotes straight- or branched-saturated ali-phatic hydrocarbon residues having up to 8 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, n-heptyl or n-octyl, ~.
"lower alkyl" denotes saturated aliphatic hydrocarbon residues having up to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl or 1-methylpropyl;
"lower alkoxy" denotes a hydroxy group substituted with a lower alkyl group as defined above, "cycloalkyl" denotes an alicyclic ring having from 3 to 6 carbon atoms, such as cyclopropyl or cyclohexyl.
Thus, taking into account the meanings given above :
R can denote, in particular, a methyl, ethyl, n-pro-, `

pyl, isopropyl, n-butyl, isobutyl, tert-butyl, 1-methylpropyl, n-pentyl, neopentyl, phenyl, monofluo-ro-, monochloro- or monobromophenyl, difluoro-, dichloro- or dibromophenyl, monomethyl- or dimethyl-phenyl, or monomethoxy- or dimethoxyphenyl radical, a methylphenyl radical substituted with a halogen atom or a cyclopropyl or cyclohexyl radical, R3, R'3 and R"3 represent, in particular, a methyl or methoxy radical or a chlorine atom, R4 can denote, in particular, a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, n-heptyl or n-octyl radical, A can denote, in particular, a 1,2-ethylene, 1,3-pro-pylene, 2-methyl-1,3-propylene, 1,4-tetramethylene or 1,5-pentamethylene chain, Cy can denote, in particular, a phenyl, cyclohexenyl, indenyl, naphthyl, dihydronaphthyl, pyridyl, dihydro-pyridyl, furyl, dihydrofuryl, thienyl, dihydrothienyl, pyrrolyl, dihydropyrrolyl, pyrazolyl, imidazolyl, py-rimidyl, pyrazinyl, pyridaz.inyl, oxazolyl, isoxazolyl, thiazolyl, benzofuryl, benzothienyl, indolyl, benzimi-dazolyl, benzoxazolyl, quinolinyl, benzisoxazolyl, ci-nnolinyl, quinoxalinyl, quinazolinyl, indolizinyl, thienopyridyl, tetrahydrothienopyridyl, pyrrolopyri-dyl, pyrazolopyridyl, pyrrolopyridazinyl or imidazo-pyridyl, A particularly valuable class of compounds of formula (1) are those in which Cy represents an indolizinyl, benzofuryl, benzothienyl, indolyl, oxazolyl, pyrazo-lyl, phenyl, pyrazolo [1,5-a~ pyridyl or imidazo [1,~-a~ pyridyl.
An other class o~ compounds o~ the invention are those of ~ormula ~1) in which R1 and ~2 each deno-te hydrogen.

- .

. '~: ,, ~ ` :.

Z~ 35 As particularly valuable compounds of formu-la (1), those in which R3, R'3 and R"3 represent me-thoxy can be cited.
Other valuable compounds of formula (1) are those in which R represents an isopropyl or cyclopro-pyl group.
The invention also relates to the pharmaceu-tica].ly acceptable salts of the compounds of formula (1~ formed with an organic or inorganic acid.
As examples of organic salts of this type, there may be mentioned the oxalate, maleate, fumarate, methanesulphonate, benzoate, ascorbate, pamoate, suc-cinate, hexamate, bismethylenesalicylate, ethanedisul-phonate, acetate, propionate, tartrate, salicylate, citrate, gluconate, lactate, malate, cinnamate, man-delate, citraconate, aspartate, palmita~e, strearate, itaconate, glycolatç, p-aminobenzoate, glutamate, ben~enesulphonate and theophylline-acetate, as well as the salts formed with an amino acid such as the lysine or histidine salt.
As exemples of inorganic salts of this type, the hydrochloride, hypobroml~de, sulphate, sulphamate, phosphate and nitrate may be mentioned.
The compounds of formula (1) can exist, in some cases, in the form of optical isomers, in parti-cular as a result of the asymetric carbon present when A represents a 2-hydroxypropylene chain.
The invention relates, at the same time, to all the isomers of the compounds of formula (1), the isomers being considered in the dextrorotatory or laevorotatory form, or in the form of a mixture, for example in the form of a racemic mixture.
It has been found that the aminoalkoxyphenyl derivatives of the invention possess exceptional phar-macological properties, especially calcium transport , .. .~ .~ .
- , . ,, - -': ; `::
, inhibitory properties, as well as bradycardic, hypo-tensive and antiadrenergic properties.
From this viewpoint, the preferred compounds of the invention are those in which B represents a -So2-groUP-These properties are capable of making thecompounds in question very useful in the treatment of certain pathological syndromes of the cardiovascular system, especially in the treatment of angina pecto-ris, hypertension, arrhythmia and cerebral circulatory insufficiency.
In the antitumour field, the compounds of the invention may be useful as potentiators of anti-cancer drugs.
Dependin~ on the administration route selec-ted, the daily dosage fo a human being weighing 60 kg will be between 2 and 500 mg of active principle.
The compounds of the invention may also be employed as the sole ingredient or may be used in combination with an anti~inflammatory agent, for lo-wering and/or controlling the rise in intraocular pressure. In this respect, the compounds of the in-vention may be employed for treating pathological ocular diseases, particularly in the treatment of glaucoma.
Generally, an amount from 5 ng to 0,5 mg of active ingredient will be applied to each eye, the daily frequency of administration depending on the severity of the disease to be treated.
Consequently, the invention also relates to pharmaceutical or veterinary compositions containing, as active principle, at least one aminoalkoxyphenyl derivative of formula t1) or a pharmaceutically ac-ceptable salt of this derivative, in combination with a pharmaceutical vehicle or a suitabl~ excipient.

- . , , . ,: . : : . ,: .
- : :, ~,:. ~ .. :: .

, ,. ,. : ~::-, :- .
, ~ ' ` '.' ' 7 ~ 35 ~ho co~pound~ of formula ~ can be ob~ai~ed :
I. When B re~esents a -S- or -S02- ~roup and A represenes an alkylens radlcal, by conde~ing, in ehe preseuce of an acid accepeor a~d in a polar solvent such as dimethylsulphoxide or an alcohol, for example buta~ol, or a ketone such as methyl ethyl ketone, or a non-polar solvenc such as an aromatic hydrocarbon, for example benzene, toluene or xylene, a 4-alkoxyphenyl derivaeive of general fon~ula:

Rt Cy-3'- ~ -0-A ~ (2) in ~hich 3' represent~ a -S- or -S02- group, Cy, Rl ant R2 hav~ th~ same meaning as abo~e, A repre~ents an alkylene radical a~ defin~t in the formula~1)a~t X repre3ents a halog~n atom, pref~rably bro~ine~ or a~
alkylsulphonyloxy group having fro~ l to 4 carbon atow~ iuch as for example, me~hanesulpho~ylox~, or an a~ylsulphonyloxy group having fro~
6 to lO carbon atom~, such as benzenesulphon~loxy or p~toLue~e~ulphonyloxy, with an amine of general formula:

H - Am ~3) in which Am has ~ ~Ye the 3a~s ~eanin8 a~ above to or~ the deYired aminoalkoxyphenyl derivative of ~or~ul ~ )in the fonm of a free base.
I~ general, the conda~ation in question i~ perfon~ed at a te~perature between roa~-temperaturs and th~ refluxin~ mp~ra~ure of the ~edium, th~ acid acceptor being, ~or exæ~ple, a~ alk~li metal carbonate or hydro~ite or a~ ~xces~ of a~ine of formula (3).

, Tha co~pount~ o formula(2) in que3tiQu can b~ obcained:
a) when X i9 a halogen, by condensation of a 4-hydroxyphenyl derivaeiv2 ~f general or3u1a:
Rl Cy-3'~ OH (4) in which Cy, B', Rl a~d R2 hav~ ~h~ s~m~ m~a~iu8 a~ a~ov~, with a dihaloalka~e of ~en~ral for~ula Hal-~-H~l C~) i~ which A denotes a~ alkyleae radictl a~ dufiu~d il ~h~ formula ~ ) a~d Hal tenote3 a halogen aeo~, preferably bro~in2, thi3 r~action bein8 perfor~¢d unter re~lux in a solvent such as ~athyl ethyl k~tou~
or N,N-timcthylforma~ite and iu th~ pre~oncQ of a ba~ic ag~t ~uch as an aLkali ~cal carbonato, for ~a~ple potas~iu~ carbo~ate, a~
~5 alkali me~al hydrit~ 3uch a3 sotiu~ hydride, a~ alkali metal hydro~ide, for ex ~ple ~odiu~ or potassiu~ hytroxide, or aD alkali me~al alcoholate, for ex~pl~ sotiu~ m~thyla~ or ethylate, b) whe~ X tenot~ as alkylsulphonyloxy or axyl~ulpho~yloxy group~ by coado~s~ti~ o~ ~ hslids of g~eral for~ul~:
Hal-W
i~ ~hlch ~81 ha~ th~ 9a~ ~Ra~ a~ ab~v- a~t W deQo~ a~ alkyl-sulphoayl radic~l h~vir.~ fr~a 1 eo 4 ~arbo~ a~o~s, Ço~ examplo m~thane~ulphoaylt or an ar~lsulphonyl radical havi~s fr 6 to 10 carbo~ atom3, for ~Xa~pl8 ~2~n~ulpho~yl o~ p-~olue~e~ulphon~l, i~ a 901va~e ~hich is a~ acid acc~pto~, for OEx~le pyriti~e, wit~
a 4-hydroxyalkoxy deriva~ivo o ~ al ~on~ul8:

`
'. ' ~

3s Cy~ 0-~

in which Cy, 3', Rl and R2 have ehe sa~e !I!e~ning a~ abov~ and ~ deno~s an alkylenc ratical as tei~sd in for~ula('~).
As regards ehe co~pounts o for~la(6), th~ ca~l b~ pr~par~t by cond~3ing, in a ~ui~abl- solv~ne Ruch a~ N,~ th71~o~ido ~ in th~ prcsl~ncR of a ba~ic a~nt such ~!1 an alk~li mot41 ca~bon~t~, for exasspl~ poeassium carbGn~ea, an al~li mot31 h~rdro~id~ ~uch ~ ~odiu~
or pota3~iu~Y hytroxite, all allu~ tal h~drid~ ~uch a~ sodiu~ h~dri~
or a~ alkali ~tal alcohol&ee, for ex~pl~ sodiu~ ~tb,ylat~ or st~atc, a 4-hydroxyphehyl d~riv~tiva of ~or~ula~4)abovQ ~ith a halo~a~t$d alcohol of general f or~ula:
Hal-~OU ('~) iu ~hich A dauoe2~ an alkylcnQ radic;ll a3 ts~ t iu elll~ fo~ula(1)and Hal ha3 th~ sa~z~men~i~g a~ a~o~.
The a~ines o~ ~ormula (3) are known compounds disclosed in previous publications and susceptible to be prepared by known methods~
Compou~d~ o~ ~o ~ 13(4)~r~ k~o~ produces, fo~ in~tacc~ eho~ co~-pount~ i~ whiCh Cy raprc~t~ a b~a~ofu~yl or ~Qn~oehi~yl group a~t B rl!p~8J~tJ a -S~2- g~oup (US patent n 4,117,128) or in which Cyrepresentq a1-indolizinylgr~up(EhropeanPatent Application n 235,1113.
Th~ othor co~pound~ oÇ çQ~la(~)ca~ b~ prap4ret i~ a g~nar~l proc~u~o, b~ at~pting to th~ t~ at c~pount eh~ ~qthot d~cri~d in th~ ~orQ~ait US p~atQae or th~ h4d3 d~crib~d h~r4us~d~
I3 ~t ca~s, eho~ co6~pou~ts of ~o~ (4) c~ b~ obtaia~t b~r fixing ~ 4-O~protact~ bs~ ulpho~yl o~ phe~ylehio chaia to eh~
r~uir~!d carbocycl~ or h~e~rocycle u~i~g a ~ t~}-Cr3fe3 r~accio~ and d~p~ot~etLn~ e~a oxyge~ i~ eha 4-po~iCio~ o~ th~ b~2 ~ulpb~yl ox ph~ylthig g~oup by m~UQs o cla~ic~l proco~ur~e ~o r~ r~e~
ch- 0~ g~uup.
~ u~r ax~ ~æm~lQ~ o m~t~o~ eo~ u~d fo~ p~ ri~g d~
va~ a o~ ~on~ul~(4):

~ , -. . .: ~ . : . -. . : ~ : , ,:
:i , , .
: - ~ , ;, :
~, . . .
: ~ ; :

.

2~ 5 a) Compounds of formula (4) ln which Cy r~presents a group (D) _________ ~) The compounds of formula(4) in which Cy represents a 2-R-indolizin-3-yl group can be prepared by reacting an i~dolizine derivative of general formNla:
COORt a ~ ~ ~-R (8~ -in which R has tne same mea~ing as above and Rl~ repre~ents a low~r alk~l radical preferably ethyl, with a halide of general formula:
Rl Hal~ OCH3 (g) in which B', R1~ R2 and Hal ha~e the sam~ meaning as above and in the presence o~ a ~riedel -Crafts catalyst such as aluminiu~ chloride to provide a compou~d of general formula:
COORl o -R
~ N ~ -3'- ~ -OCH3 ~1C) in which B', R, Rt, R2 and Rlo have the ~ame meaning a~ above.
The compouad of formula (l~)i5 sub3eq~ently demethylated using a~ etha~ethiol/alu~iniu~ chloride ~ixture to give a 4-m~tho~ypho~yl derivative of ge~eral for~ula:

' -. ~

2~ 85 fO2N

RI_~_ON (11) in which B', R, Rl and R2 h`ave the sama meaning as above which, when heated to aboue 200C provite~ che required compount oÇ forIula (4).
The compounds of formula (~`)are eith~ k~o~n co~pound3 ha~in8 bee~
published i~ J. Che~ Soc. 1962 pp. 2627-2629 or compound~ which can be prepared in accordance with ehe method d~cribed eh~ein.
~) ~ha co~pounds of for~ula t4) in which Cy rcpr~eues a 2-R-i~itazo[1,2-a3 pyrit-3-yl ~roup can be prepared fro~ a 2-R-i~idazo~1,2-a]pyridi~ ~ith a halite of formula (9 )ant in tho pre~encc of a Friedel-Craft3 cataly~t ~uch as aluminium chloride to providQ a co~pou2d of ge~oral formul~ :

~ ~ Q 3 in which B', R, Rl and R2 havc ~he sa~u ~e~ing as abov~.
The co~pound of formul~ (lO i~ su~oq~eutly dem~thylated u~in~ aQ
appropriat~ a~o~t or instance hytro~romic acid or an eehanethiol/aluminium chlorida ~ixture to giv~ the requiret co~pound of for~ula (4).
2~Aryl-i~idazo~192-a]pyridi~e~ are k~o~ fro~ J. Med, Che~. 8, p. 305 (1965). The oth~r 2-R-imitazo[1,2-a]pyridi~e~ ca~ be o~tai~ed i~ accor-dance with th~ m~thod desc~ibed in ths afore~aid reference or using classical procedures.
Alternatively, the co~pounds of forwula (1 ~ caa b~ ob~al~ed fro~ a 2-R-3-halo-imidazo~1,2~a~p~ridiu~ a~d the alkali ~al sale o~ a 4-meth~y terivatiYo of for~ula (1'5~.

3) Th~ compound3 o for~ula (4) iQ ~hlch Cy ~epr~sents a pyridyl or 3-R~

4-pyrityl group cau b~ obtai~d ~y d~e~hylati~ vi~h a~ app~opriaee a8ene ~uch as aqueou~ hydro~ro~ic acit, a 4-w thoxyphe~yl torivaeiv~
of general for~ula :

:

, 9~5 j / ~ g~ ~ 3 OCU ~ -OCH3 (~3) 2 or ~N ( ~3 ) in which B', Rl and R2 have the same meaning as above and R has the same meaning as above with the exception of hydrogen, to provide the required co~pounds of ormula(4~.
The compounds ~ formulae ~ and (~`~/) in which B' repre~ent~
a -S02- group can be prepared by oxidizing a sulfids derivative of general fonmula: Rl ~ 5- < ~ ~ -OC~
(~4~ 2 or ( 14'3 in which Rl and R2 have the same meaning as above a~d R has the sæme meaning as in formula (~3) or (~3'~.
Compounds of for~ula(~4J are know~ having been described i~ US
patent No. 4, 128, 552. The other co~pounds of form~la (~4~can be obtained in accordance with the method described in the aforesaid US pate~t while those compounds o~ formula (~4') cah be preparet from a 3-R-pyridine, in which R is other than hydrogen, by oxidation with hydrogen peroxi~e in acetic acid to provite the correspo~ting 3-R-pyridine-N-oxide which when reacted with a nitric acid/sulphuric acid mixture gives rise to the corresponting 3-R-4-nitro-pyridine N-oxide.
~hiq nitro derivative is ~hen reacted firs with acetyl bromide, then with iron powder in acetic acid ~o giv~ the correspondin~ 3-R-4-bromo-pyridine which, when treatet with a thiophe~ol derivative of general formNla: R
L~ .
M-S- ~ ~ -OCH3 ( ~5) ~2 . ~
; ''~ ' 2~ 8~i in which Rl a~d R2 have the same meaning as above and ~ repreSencs an alkali metal atom such as sodium, provides the required compound of tormula(14 ).
~) The compounds of ~ormula ~4) in which Cy represents a 2-R-quinolin-3-yl group can be prep red by reacting an ~-haloketpne of general formula 2 (16) in which R and Hal have the same meaning a~ above with a metal derivative of general formula :
Rl M-B'- ~ -OTs (~) in which M, B', Rl and R2 have th~ same meani~g a~ above and Ts represents a p-~oluenesulphonyl ~roup, to provide a ketone of general ~or~ula:

R-C-CH2-B'- ~ -OT5 (~) in which B', R, Rl, R2 and Ts have the same meaning a~ above.
This ketone of for~ula f~9) when treated with 2-amino-be~zalde-hyd~ [Helv. Chem. Act. vol. ~VIII, p. l235 (193i)l gives the 4-methoxyphenyl derivative of general formula:

~ B~ OTs ( ~) i~ which B', R, Rl, R2 and ~g have the same ~eanin~ a~ abov~, whieh is sub~equently hydrolysed in ba~ic m~diu~ or in~tauC~ in aqueou~ alkali 2letal hydroxidQ, to provid~ th~ r~quired co~po~ of ~o~ 4~.

~ . ~

3s

5) The co~pounds of ~ormula (4~ in which Cy represents a 3-R-cinnolin-4-yl or 4-R-cinnolin-3-yl group can be obtained by reacting a 3-R-4-halogeno-cinnoline (J. Chem. Soc. 1953, p. 609) with a thiophenol derivative of general formula :

M-B'- ~ -OTs in which ~, R1, R2 and Ts have the sa~e meaning a~ above and B' reprcsents a -S- group to provide the 4-tosylQxyphenyl derivative of general fo~mula :

,~
B'-~/ ~ OTs R R
I ~ 1 11 .
-R R2 ~ -B'- ~ -OTq ~\N~N or ~N~ R2 15 ~ (21) ( 2~

in which R, R1, R2 and Ts have the same meaning as above ant B' repre-`, sents a -S- group.
The 4-~osyloxyphenyl derivative o formula ~ or ~æl'-) is subsequently hydrolysed i~ basic medium or instance in aqueous alkali ~eeal hydroxite 20 to give the required compound of formula (4) in which B' represents a -S-group.
Compount~ of formula ( 2~) in whi~h -OTs is replaced by -OCH3 can also be used. In such case the correspondi~g compound of formula (2~3 or (2l') is demethylated using for instance hydrobromic acid.
The sulphide derivative of form~la t~3) or ~ he~ oxidized with a suitable agent such as h~drogen peroxide in acetic acit or potassium permanganate, provide~ the co2pound of formula~2~) or (~ in which B' represe~ts a -S02- group, which compound after hydroge~ation on a catalyst such a~ palladium charcoal or platinum charcoal gives th~
3~ required compounts o~ ~or~ula (~ which B' repre~ent3 a -S02- group.

, :: .

2~
. 15 Alterna~ively the compounds of formula~4)in question in which B' represents a SO2- group can be obtained from a 3-R-4-halogeno-cinnoline or a 4-R-3-halogeno-cinnoline by reacting with a benzene-sulphonyl derivative o~ general formula (~)in which B' represen~s a -S02- group eo obtain a compound of formula~ or (2t') in which B' represents a -SO2- group which is detosylated as described above to provide the required compound of formula ~
G) The compounds of formula IV in which Cy represents a 6-R-pyrrolo~1,2-bJpyritazin~5-yl group can be prepared by reacting a 3-halo~enomethyl-pyridazine with a metal derivative of formula ~) to provide a pyri-dazine derivative of general formula:

Rl O -cH2-g'- ~ -OTs (2 N ~ R2 in which B', R1, R2 and Ts have ~he same meaning a~ above, which is subsequently reacted with an -haloketone of formula(l6)in the presence of a non-nucleophilic base such as for example 1,8-diazabicyclo~5,4,0]
undec-7-ene to give the pyrrolo n ,2-b~pyridazine derivative of general formula: Rl B' < ~ -OTs ( a3) ~ -R R2 in which B', R, R1, R2 and T~ have the same meaning as ~bove.
The tosyl derivative of formula (~3~ is then hydrolyset in a basic metium for in~tance aqueouq alkali metal hydroYide, to provide the required compount of formula ~
3-Chloromethyl-pyridazine is a knowu compound hsving been publi~h-3~ ed in Khim. Geterot. Sikl. Soe~i~. 39 pp. 412-414 (1970).

:

`

. ....... ............................................................~ 35 ~) The compounds of formulaC4) in which Cy represents a 2-R-pyrazolo [I,S-a]pyrid-l-yl group can be prepared, in accordance with the method described in European patent application No. 121, 197, by treating a 2-R-pyrazolo[1,5-a]pyridine with a halide of formula C9) in the presence of a Friedel-Crafts catalyst such as for example aluminium chloride, to provide the 4-methoxyphenyl derivative of general formula:
B'- ~ -OCH

~ -R R2 (24) ~ N N
~/
in which B', R, Rl and R2 have the same meaning a3 above.
The pyrrolopyridine derivative of formula ~4) i9 then demethyl-ated for instance by using pyridine hydrochloride at 200 - 220C to provide the required compound of formula (4).
&) The compounds of formula C4)in which Cy represent~ a phenyl group can be prepared by reacting benzPne with a halide of formula ~g~ in the presence of a Friedel Craft~ catalyst such as aluminium chloride, to provide the required compound of formulaC4~.
g')The compounds of formula ~4)in which Cy represents a 2-R-phenyl group or a 1-R-2-naphthyl group can be prepared by treating a halide of general formula:
R

" R~- ~ -B'-Hal ~2~) ` 8 in which B', R and Hal have the s~me meaning as above ant R~ and R
each repre~ene hydrogen or are taken together with the carbon a~om to which they are a~tached to form a phenyl group, with a methoxy-phenyl derivative of general formula:

:
.:

-OCH3 C26) in which Rl and R2 have the same meaning as above, in the presencc of a Friedel-Crafts catalyqt such as aluminium chloride, to obtain the compounds of general for~ula:

R R
oca C ~ ~) ~" R 8 - ~;,,1 R2 in which B', R, Rl and R2 have the sane meaning a~ above and R4 and R 8 havs the same mPaning aR in formula ~5~
The compounds of for~ula (2~) are then demethylated u~ing for instance aqueous iodhydric acid to provide the required compound of formula(4).
Compoundq of formula (25~ are kno~n product~ ha~ing been de~-c~ibed i~ C.A. _, 63285 g, o~ can be obtainet in accordance with known procadure~.
Alternatively, compounds of formula (27) in which R7 and R~ cach denote hydrogen and B' represents a -SO2- group can be prepared by trea-tring the alcali metal derivative of a 2-R benzenesulphonate, with a phenyl derivative of formula (26) in the presence of methanesulphonic acid/phosphorous pentoxide, according to the method disclosed in Com-munications, April 1984, p. 323.
According to an other method, the compounds of formula (4) in which Cy represents a 2-napthyl group and B' represents a-S02- group can be obtained by reacting a 2-halogenosulphonyl-naphtalene with a R1R2 phenol derivative.
This sulphonate derivative is s~ uently rearranged in the presence of aluminium chloride to provide a complex which is treated by an acid such as hydrochloridric acid to provide the compound of formula (4).

,. `' ~ ,~

, :

3~5 ~C) The compounds of forDula ~4) in which Cy represent~ an optionally mono-or di-sub~tituted 2-R-4,5-dihydro-furan-3-yl group can be prepared by heating a ketone derivative of forDula C~) with a l,2-dihalogenoethane of ~eneral formula:

Hal-lH-CH-Hal (2 a) R11 1~

in which Rll and Rl~, which are the same or tifferent, each repre3ent hydrogen, a lDwer alkyL radical or ~.~h2nyL radLca~l, in th~ pr~s~ncQ of a basic agent such as an alkali metal carbonate, to obtain a cyclo-propane derivative of general for~ula:

.

~ ', ~ . : :-i,, '' ' ' 1 g . .

f \ C-B'- < ~ 3 -OTs ( 2 ~) Rl~-HC C=O R

in which B'~ R, Rl, R2, R11, Rl~ and Ts have the same meaning a~ above.
The cyclopropane derivative of formula (29) is subsequently heated between 100 and 130C in the presence of a phase transfer cata-lyst such as for instance triphenylpho~phine or tricaprylylmethyl ammonium chloride to provide a 4-tosylo~yphenyl derivative of general formula:

R~ <'~ ~ -OTs ( 3~) in which ~', R, Rl, R2, Rl~, R12 and T~ have the same meaning a5 above and the said 4-tosyloxyphenyl derivat~ve is then detosylated by treat-ment with a basic agent such as an alkali metal hydroxide, to provide the requiret compound of formula(4J~
~0 The compounds of formula ~4)in which Cy represents an op~ionally mono~
or di- 3ubstituted 2-R-furan-3-yl ~roup can be obtained by oxidizing for inRtance with manganese oxide, a 4,5-dihydrofuran derivative of formula C303 to obtain a furan derivative of general formula:

IL ~-b~ -OTs C 3~J

. . . . .,. : . : .

.: . :: : ,. :

: . :: : ~
, .

. . X~9~

. 2~

in ~hich B', R, Rl, R~, R11, Rl~ and Ts have the same meaning as above, which furan derivative is subsequently treated with a basic agent such as an alkali metal hydroxide, to obtain the required compound of formula~4~.
I~)The compounds of formula ~4) in which Cy represents a 2-R-furan-3-yl or 2-R-thien-3-yl or 2-R-pyrrol-3-yl group can be prepared by react-ing a compound of general formula:

H2 ~ -R ~ 32, in which R has the same meanin8 as above and ~ represent~ -0, -S or - N-R~, with a halide of formula ~9~ and in the presence of a Friedel-Cra~ts catalyst such as aluminium chloride to obtain a 4-methoxy deriva~ive of general formula:

-B'- ~ / -OCH3 2 ~ -R ( 3 in which B', R, Rl, R2 and Q have the ~ame meanin~ as above, which i~
subsequently decarbo~ylated by heating ant demethylated with an appro-priate a8ent such as pyridine hydrochloride or aqueou~ hydrobromic acid, to pro~ide the required compound of formula ~4~.
Alternatively~ the co~pounds of formula ~ in which Cy repreRents an optionally sub~tituted 2-R-uran-3-yl group can be prepared by oxidizing, for in~tance with mangane~e oxide, a 4-to3yloxyphenyl derivative of formula C3Q~ ~0 Obeain an optionally sub~titute~ 2-R-3-(4-tosylo~ybenzenesulphonyl)furan terivative ~hich is subsequ~tly treated by a ba~ic mediu~ for instance a~ alkaii me~al hytro~ide, ~o provide the required co~pound of formula(~

::

13j The compounds of formula ~4)in which Cy represents a l-R-imidazol-2 yl or l-R-benzimidazol-2-yl group can be obtained by reacting a l-R-imidazole or l-R-benzimidazole with a halide of for~ula ~9~ in the presence of a Friedel-Cr~fts catalyst such as aluminium chloride, to obt~in a compound of general formula :

R ~ ~1-B ' ~ ~_OCH~ ( ~ 4) in which B', R, Rl and R2 have ~he same meaning as above, R~ and R8 each represent hydrogen or are taken together with the carbon a~om~ to which they are attached to form a phenyl 8roup , which is qubsequently dox~-lated by u$rg an ethancthiol/aluminium chloridc mixture in thc prcscncc of sodium hydride to obtain the required compound of formula (4).
Compounds of formula (34) in which the -OCH3 group is replaced by an -0 benzyl group can also be employed.
In this case, the compounds of formula (34) in question can be de-benzylated by means of hydrogen and an-appropriate catalyst for instance palladium charcoal to obtain the required compound of formula (4).
When R represent~ hydro~en, imidazole or benzi~itazole i9 protected in the l-position with an appropriate N-protec~ing group for instance a benzyl group which can sub~equently be removed, if desiret, using cla~sical procedur@s.

14) The co~pounds of formula ~4)in which C~ represents an optionally substituted 5-R-isoxazol-4-yl derivaeive can be prepared by react-in~ an isoxazole derivative of ~eneral for~ula :
11 ~ -B'-~al C 3 5 N ~ -R

in which B , R, Rl1 and Hal havc thc ~ame meaning as above with a 4-. 22 .
methoxy derivative of for~ulaC2~)in the presence of a Fri2del-Crafts catalyst such as aluminium chloride to obtain the compounds of general formula:

~ 3 -R ~ ~

in which B'~ R, R1, R2 and R1~ have eh~ sama meanin8 as abova, compounds ~hich optionally demethylated by using for instance alu~inium chloride to provide the required compound of formula (4).
Compounds of formula ~35) are kno~n protuct~ havin~ bc2n tes-cribed in Gazz. Chim. Ital. 76, 30 ~1946) while the other co~pou~d~
of for~ula C'~6) can be obtainet ia accordance with the methot tes-cribed ther~in or clas~ical method~.Alt~rna~ively, the co~p~u~d~ o formula (3~ which R1~ r~pr~ ant~
hydrogen and ~' reprQ~ts a -S02- ~roup, can b~ obtaincd in accordanc~
with the mathod tescribet i~ J. Hotoro. Ch~m. 23, 1363 (1986) br reac-ting a 1~(4-~athoxy-banzenesulphonyl)-2-N,N-dLmethyla~ino~th~ne wieh hytroxyla~in-.
Si~ilarly, coOEpou~d~ of for~ula (~6`) i~ which B' r~pr~g22t3 a -SO~-group, R11 is other th~ hydrog~n a~ hich -OC~3 i~ r~plac~d by -O To~pl cu~ b- us~d for obeaining tha corr~poating compounds o for~ (4). Th~Q 3-~ub~titute~ -5-R-4~(4-O-To~yl~-be~z~ne~ulpho~yl i~o~agol~ derivati~s oa~ b~ p~epared ia acrorda~c~ ~ieh tha mQthod d~6crib~ in G~zz. Chi~. Ica}. ~a, 656 (1968) i.~. b~ ~e~ctiag a ~nz~n~ulpho~yl-ke~o~Q a~t a~ h~trox~ie ~cid t~ivativ~.
15) Th~ co~pou~ds o~ for~ul~ (4) i~ which Cy r~pre~ts a 5 R p~ra201-4-yl group caR be p~Qp~rBd by ~etin8 ~ co~pouut o~ g~ l for~ula :
R;

~3 ~2 .. ..
-:: : . . , ia ~hieh B', a, R~, R2 ant ~3 bav~ the same ~anin8 a3 abov~, with hyd~a~ to obtai~ th~ required compound oÇ formula (4).
Th~ compount~ of formula (.~ are compounds which can be preparet in accordance with J~ Heeero. Chem., 23, t363 (~986) i.e. from a N,~-5di~ethylaminoeeh~ne derivative and hydrazine.
Altarnatively the compounds of formula (4) in which Cy represent~
a 5-R~pyrazol-4-yl group can be directly obtained from a compount of 8eneral formula :

TsO- ~ 2 / C~3 10\ C-C~-N \ (3g) ~-C ~3 o in which R ant T~ have ehe qam~ 3~anin8 aa abov~, and h~drazi~e in e~ce3s.
The oo~pound~ of for~ula (h2) ca~ be prepared in accordance with the ~eehod describ~d i~ J. H2tero. Ch~. 23, 1363 (198~) cited above.
16) The co~pouQds of formula (4) in ~bich Cy repr~se~t~ 8 1-Rg -2-R-i~dol-3-yl or l-R~--3-R-intol-2 yl derivativQ can be prep~ret :
a) when Rg represene~ hydrogen, by reacting p-~thoxy~hiophenol sub~titu-ted by R1 a~t R2 group3, ~ith 2-R-iadole or 3-R-iatole in the pr~sence of iodine, to providc a~ indola terivativs o~ goneral formula :

in which R, Rl and R2 havQ ~hQ ~a~2 ~auin8 a~ abov~, which can the~
b~ oxidiz~ with 3-chlorop~rb~20ic acid to provide the ~ulphonyl derivative~ o g~sal ~orlula :

: : ~

2~
9~3~

. ~ R 2 ~ ~C~

H

in which R, R1 and R2 have the 9~me meaning as above.
rhe compounds of for2ulae t39) and (4~) ca2 subsequently be teme-thylaeet using 2-~ercapto~tha~ol in the pr~se~cQ of sodiu~ hytride to provid~ thQ required compoundJ of for~ula (4).
b) whon Rg is other than hydrogen, by ~r~ting a co~pou~t o~ forlul~
(39) or (40) withan iodite of ~ormula Rg -I in which Rg i9 othQr than hydro~en and de~ethyla~i~g tho 1-sub~tituted t~iva~iv~ ~o ob~ai~ed ~ith 2-~ercaptoQthansl in eh~ prQsonc- o~ ~odiu~ h~drit~, :
to provide the requirad co~poundJ o for~ul~ (4).
~5 1~:) The compounds of form~la (4) in which Cy repres~ats a 2-R-5-Rg -4,5,6,7-tetrahydro-thieno~3,2-c]pyrit-3~yl group a~d a~ represe~ts a S02- group can be prepared by reacting a 2~R-5-R9 -4,5,6,7-t~trahydro-thie~o{.3,2-c~
pyridine in which Ag ic oeher eha~ hydrogen with a compound of goneral for~ui M-S03- ~ -0 Bz (4~) R2 ,.

i~ ~hich R1~ R2, U a~d Bz have the sa~ ~a~in~ a~ abov~ ehe pr~o~nc~ o~ ~thauesulphonic aeid/phospho~ou~ p~ntosid~ ~o obtai~ a eetrahydro~hienopyridine of ~eneral for~ula :

Rg .-N~-S52- <~ S03 C~3 in which R, Rl a~t R2 h~v~ the ~a~ ani~8 as a~ov~ a~d R~ has th~

rl ~a~s E~anin~ as abov~ with tho exception o hytrogen.
Th~ compou~tJ of formula (4~) are th2n hytroly~ed iB the presence of a basic agenc such as an alkali metal hydroxide to provide ehe required compounds of formula (4) in which Rg is ocher than hydrogen.
Star e in~ 2R~5~Rg -4,5,6,7-eeerahydro-chieno~3,2-c~pyritineq are known compounts having been tescribed in Heterocycles, 22, 1235 (1984) or can be preparet in accortance with the method tescribed therein.
Ia) The compound3 of for~ula (4) in which Cy represents a 2-R-thieno[3,2-cj pyrid-3-yl ~3~U~ can Je prepared by hydrolising a compound of formula (4~) in which R~ represents a ben2yl or halobenzyl ratical ant further reacting ehe 4-hydroxybenzene~ulphonyl d~rivativQ 30 obtainQd with pallatiu~ charcoal i~ diphcnylQth~r to provitQ th~ required co~po~d of formula (4).
~9~ The compounds of for~ula (4) in which Cy r~p~os~e~ a 5-R thia~ol~4 ~1 group can be prepared by de~thylating a co~pound of ~ ral o~mu1a :

N~ ~ B'~ ~ -OC~3 (43) in which ~1, R, R~ a~d R2 have ehe sa~z m~ani~g as abov~, u3ing hydro-bromic acid in ~cetic acid, to provid~ the required com~ounts of for~u-la (4).
ThG compou~t~ of for~ula (43) ca~ be obtained in accorta~c~ with th~
~ethod t~scribed i~ Tetrah. Lett. 1972, p. 2777 i.e. fre~ a sulphonyl-mc~ ocya~it~ ahd a thio~lycolic acid t~rivaeive.
20) The Compoun~8 of ~or~la (4) in which Cy reprQ3ent~ a 1-R9.-5-~-i~idazol~4-yl group ca~ b~ obtain~d by d2~thylating with 2-morcapto-ethaaol i~ the p~e3ence of s~diu~ hytrid~, a co~pound of general formula :
Rl N~ B'-<~-OC~3 (~) N~
R~g in which B', R, R1, R2 and Rg have the same meaning as above, to provide the required compounds of formula (4).
The compounds of formula (44) can be obtained in accordance with the method described in Tetrahedron Lett. 23, pp. 2373-2374 (1972) i.e. from a sulphonyl-methylisocyanide and an imidazol derivative.

21) The compounds of formula ~4) in which Cy represents an optionally substituted 5-R-4-oxazolyl derivative can he prepared by treating a benzenesulphonylmethyl formamide derivative of general formula :

H3CO- <~ -302-CH2-NH-CH.,o ( 4 5 ) in which R1 and R2 have the same meaning as above with phosphorous oxichloride in the presence of an acid acceptor such as triethylamine for obtaining an isoni-trile of general formula :

H3CO- ~ -S02-CH~-N=C (46) R~

in which R1 and R2 have the same meaning as above.
This isonitrile is subsequently reacted with an acyl-, .

, -x~

halide of general formula :
o Il Hal-C-~ (47) in which Hal and R have the ~ame meaning as aboYe, providing the isoxazole derivative of general formula:

2 ~ OCH3 (48) in which R, R1 and R2 have the same meaning as above, which derivative is subsequently demethylated under reflux in presence of aluminium chloride, providing the required compound of formula (4).

2~) The compounds of formula t4) in which B' represenes a -SO2- group and Cy represents a group of formula (D) in which R; and R6 are caken eogether with ehe carbon acom to which they are a~tach~d eo for~ a non aromatic ~ono- or di-cyclic carbocyclic group having from S to 10 carbon atoms and optionally substituted by a R group in the ~-position with respecc to the methyne group, for inscance a 3-R-inden-2-yl, 2-R-cyclohexen-l-yl or l-R-3,4-dihydro-naphth-2~yl group can be prepared, in accordance with the ~ethod described in J. Org. Che~.
vol. 35, No. 12, pp. 4217-4222 (1970) by heating a compound of general formula :
R
R (49 : . ~
. ~ .:
., ~ , , -28 ~ ~ ~ # ~8 in which ~3 and R~arQ eak-a to8~thQr ~ith th~ carbo~ a~o~ ~o ~hich th-y ar~ aetach~t ~o for~ a group havi~g fro~ 5 eo 10 carbon aeoes ant opCionally substitut~d by a R group in tho ~-po~ition ~ith r~-pect to eh~ me~hyne groupi with a halite of 4-eosyloxvbenzene subs~icu~ed by Rt ang ~2 groups in an appropriate solvene such as benzene and in c~e ?~esence Q~ anhydroua cupric chloride and ~rieehyl~mine, ~o ~bcain a ~-eosyloxyphenyl deriyative of general formula :

( ~ C-S02- ~ -OTs ~C7) ia which Rl, R2 ant T9 h~v~ eh~ ~a~ ~a~i~8 3D abov~ a~t R5 and R6 havo th~ 3aE~ mea~ing a~ in for~ula (3~) ~hich i~ tha d~eo~la~d usi~ an approp~i~t~ a8a~t 3uch as au al~ li mQt~l hytro~id~ to obtain the requir~d compound of for~ula ~4).

b) Co~unda of forE~la ~ ~ in which C~ r~r~sonts a ~ou~ (E).
___ _____..____~____ __________ ___ _______ __ __ ____ Th~ c~ou~d- of for~ula(4) i~ which Cy repr~cne~ a 2-R-i~i~azo1-l-yl or 2-R-hc~zi~ zol-l-yl group ca~ b~ obe~in-t ~y resctia~ a 2-R-i~it~zolc or 2-~-bQnzi~id~xol~ wi~h a h~lid~ o ~or~ul8(9)i~ the pSC~Q~C~ o~ a Fri~d~l-Cr~eD cataly~e such ~ aLu~i~iu~ c~lo~ , to pso~ta ~ co~ound o~ r~l formul~ :
,~ R~-r_____N

2S ~ ) 3'~ ~ -~C~3 ~ .
~ ich 8', R, al 3ssd ~2 ~3~0 e~ s~ in~ ~ 2bo~a ~d R~a~t R 8 ~ch rcp~ C hyd~o~cn or a~ ea~Q~ tog~eh~r ~it~ th~ c~rbo~
a~o~ eo which ehey ar~ at~ac~t Co form a phoayl g~oup.
The co~pouat of fo~ul~ tha~ optionally demethylated using for in~tance hydrobromic acid or pyridine hydrochloride to gi-ve the required compound of formula (4).

According to an alternative method, che co~po~nt~ of for~ula~)in which B repreqene~ a -S- or -S02- group and A repre_en~s an alkylene radical, preferably those in which A represent~ a propylene radical, can also be obtained by reacting, in the pre~ence of a ba9ic a~enc 3uch aa an alkali metal carbonaee, for e~ample pot~sqiu~ carbonate, an alkali metal hytroxits such a~ sotiu~ or pot~iu~ hydroxite, an alkali m~tal hydride such a~ ~odiu~ hydride or au alkali metal alcoholate, for example sodiu~ meehylate or ethylate, a 4-hytroxyphenyl deriv~tive of formula ~) above wieh a compound of general formula:

X-A-a~

in which ~ ha~ th~ aama meaning a~ above and prefera~ly r~pre~ents chlori~e or a ben2enesulphon~ ~ or p-coluenesulphon ~ atical, A represene~ an alkylene radical and Am h~s the 3aDe meaning as a~ove, the reaction takin~ place at a temperature between roo~-temperature ant thc refluxing temperature of the medium and in a polar solvent uch as ~zthyl eehyl ketone or timethylQulphoxide to form the tesired aminoalkoxyphen~l ~e~i-vati~e of formula(1)in the form of the ree base.
Whe~ R4 represe~ta hydrogan, th~ nitroge~ atom i~ prefarably protect-ed by a labile group for in~ea~ce a psotecei~g group which can be elimi-natet in b~sic ~tiu~ for exa~ple ehe ~rtiobutoxycarbonyl (~OC) group.
Tho COmpOUDdJ of for~ula (5~) are protuct~ which are known os which caa ba pr~p~r~d by kno~ m~hots.
Th~ co~pouad~ of fo~ul 41)i~ ~hich Cy represen~s a group (E), A
repre~nt~ a~ alkyl~ne chain and B repr~3e~ a -5- or -S02- group ca~
al~o be pr~p~red by reacting a 2-R-~idazol~ or 2-R-b~nzi~id~zole ~i~h a halite of general for~ula:

R
3~ 31- ~ -O-A-X

,.

.
~:

in whic~ B', Rl, R2, Hal ant ~ have th~ ga~2 ~ea~ing a~ aboYs a~d A
represQnt~ an alkyl~nc chain, in ~ha presence of an acid acc2ptor such a~ criethyla~ine to obtain a co~pount of general formula:

,~ R~- N
~ R B ~ ~N ~¦ R Rl l'- ~ -O-A-X ~5'4) in whlch B', R, Rl, R2 ant X hava eh~ 9a~ a~in8 a~ a~o~, R~ a~d RB
e~ch repre~e~t hydrogQn or ar~ eak~Q eogQeh-r ~ie~ th~ c~bo~ ato~ eo whicb they ar~ aeeached eo for~ ~ ph~nyl group and A r~pr~nts a~
alkylenQ chain, which coEpount is subJaqu~ntly r~act~t with a~ a~in~ of fo D la (3) eo obtai~ th~ requared co~pound of for~ula ~)in th~ form of a frc~ ba~c.
Similarly, th~ co~pounds of formulA(~) in ~hich Cy r~preoe~ts a~
optionally mono- or ti- ~ubotituted 2-R-4,5-dihydro-fura~-3-yl ~roup, A repre~ta ~n alk~la~a chain a~d B repras~nto a -S- or -S02- group, can b~ prepared by hyd~olysing a cyclo~rop~no d~rivativ~ of for~ula C2 9) in th~ p~se~c~ of an aquQou~ alkali ~eal hydro~id~ solution ~o pro~ids a 4-~e~w yph~y1 tsri~ati~ o ~aQrsl formula:

25` ~ R <~> ~

in which B'~ R~ 2' ~ R 8 h3~ th~ ~a~ 8 ~ v8, which i~ th~a r~act~d:

: ' ` ' . ;:
,, - with a dih~loalkane of for~ula(5)a~d the resulting product wi~h en a~ine of forzula(3) - with a compound of general formula (S2) , to provit~ an aminoalkoYy-phenyl derivati~e of general formula:

R~ -HC R~
/ I < ~ -0-A-A~ ~63 ~ 8i HC C~0 R

in which B', R, Rl, R2, R7, R8 and Am . haY~ ehe sa~8 ~eaai~ a~
above and A repre3ent~ an alkylene chain.
The cyclopropane derivative of formula ~ 6) i9 3ubo~quen~1y heaeed between 100 a~t 130C in the prese~c2 of a pha~e transfer cat lyst such a~ for instanc~ triphenylphosphine or tricaprylyl~cthyl a~mo~ium chlorite to provide th@ requiret 2,3-dihytrofuran terivatiYe of for~ula~) in the form of a free ba3~. -II. The compounds of formula (1) in which B represents a -SO- group can be obtained by treating, ~ith an oxidizing agent, ^
a ~ulphid~ of for~ul ~ hich ~ rep~ese~ a -S~ group, chis compouad of for0ul ~)b~ the for~ of the fre~ basa of a ~alt thereof so a~
to o~t~i~ th~ ~equired compo~d i~ the ~on~ oS che free baoe or a salt ther~o.
Wharc th~ r~quir~d co~pou~t i~ provided i~ ehe for~ of a salt~ th~
free ba~e thereo~ ca~ bo r~covexed by treat~ent with a b23ic age~t ~uch as an alkali meeal carbo~te for e~æmplQ potas~iw~ carbouatQ or a~ alkali metal bicarbona~e for e~a~ple sodiu~ bicarbonaeeO
G2ncrally, thQ reactio~ t~kes plac~ i~ waeQr or in a~ ~rgasie ~ol~ent such as ~eth~ chlorida a~d in ~h~ pr~s~cQ of a ~uit~bl~ o~iti~i~g age~ such aa ~or esampl~ ~odiu~ perioda~, pota~3iu~ p~ro~n~a~a~ or 3-chlorop¢rben~oie asi~0 : . ::

-: .
:
,: ~

3~
. 32 D~po~tin~ ou ~ho oxidizi~8 a~Qt used, mlxtur~ of ~ulphoxidns or 3ul-phones can b~ obt~inet. The8e mLxture~ ca~ b~ ~eparated by conventio~al --procetures for inseance by chro~atography, III - The compounds of formula (1) ln which B represents a -S- or -S02- ~roup and A represents an optionally-substituted 2-hydroxy-S propylene chain, can be obtained by reacting under reflux a 4-hydroxy-phenyl darivative of formul~ ~ with an epih210hyd~in. such as epichlorhytri~
or cpibromhydrin iu dextrorotatory or l~vorotaeor~ fon~ or in th~ form of a mixturc of th~ iso~crs, for ex~Eple i~ race~ic for~, ant in thQ presence o~ a b~sic a8~t such as au alk~li ~Rtal c~rbo~st~, fo~ e~c~pl~ pota~siw carbo~Aee, an alk$li ~¢eal hytro~yt~, for ~x3mplc sotiua or potas3iuu hytro~

xid~, dn alk~ otal hydrid~, such a~ sodium hytrid~ or a~ alkali m~t~l al-coholatc, for exa~pL2 ~odiL~ ~aeh~l~eo of ~ehyl~t~, and i~ a pol~r solve~t ~uch as ~ethyl eth~l k~eo~ to give ~h~ osiras~lmatho~r dt~rivaeiva~ o~ g~Qrzl f or;al~la Rl cy-8~ 2-c\H/ 2 (~) in which Cy, B Rl and R2 hav~ th~ 9~ o ~ ~ ing aa abov~.
171~ ox~rs~yl~2tho~c5r deriv~tivee of ~o~la (5~ are eh~ treaect undsr refluæ ~ith aD ~ o~ fomul~ (3) ~ thi~ b~ing p~r~or~t i~ a polar 301Yent ~uch a~ hJl ~th~rl k~to~ or f.n asa ~XCCJ~ of a~n~ of fonDula(3 to giv~ eh~ dR~ir~d cwlpou~d of for~ th~ foml of thR fr~ ~a~o in W~liC~l ~ rcp~o~ 5 2-h~dro~cypropyl~o c~alu wtlich ca~ b~ r2~ct~t, i~ t~ired, with ~ l~q8r ~l~rl hd id~ iB th~ pr~a~s o~ ~ strong bas~ eo provita thQ
ca~p ~ o ~or~ )in eha ~or~ of th~ fr~ ~a~s ~ wbich A rQpr~eQt~ a 2~h~trG~yprop~lo~o ch~n i~ which th~ hyd~o~ sub~itutæd k~ a lo~r alk~l radic21.
I~ ~OE~ C~Q~, b~-pro~uct~ ba for~s~ in p~r~ 1 wit~ the co~pound~
o~ formula C5~ abov~g o~ ehi~ c~ 4-(3-h~1O~2-hydro~ypropo~)b~nzeaa-~u1p~s~1 d~zivativ~s.
On rcactio~ w~t~ th~ a~L~ of for~ul~ C3)~ t~os~ d~ri~aeiq~ vi11 n2~qrth-lc~ giv~ ris~ to th~ d~ir~d co~p~u~d~ of for~ul~ L~ whieh A
r~p~ t~ ~ 2-h~dro~gproprl2~ chal~.

The compounds of formula (1) thereby obtained in the form of the free base can then be converted to pharmaceutically acceptable salts by reaction with a suitable organic or inorganic said, for example oxa-lic, maleic, fumaric, methanesulphonic, benzoic, as-corbic, pamoic, succinic, hexamic, bismethylenesali-cylic, ethanedisulphonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, cinnamic, mandelic, citraconic, aspartic, palmitic, stearic, itaconic, glycolic, p-aminobenzoic, glutamic, benzesulphonic or theophyllineacetic acid or with lysine or histidine.
1 - Phenylalkylamino-alkoxybenzenesulphonyl indolizine derivatives, in which the phenyl group is substituted by one or more substituents identical or different selected from halogen atoms, lower alkyl groups or lower alko~y groups are reported in EP-A-235 111.
However, within the limits of this definition, on-ly 3- or 4-monosubstituted or 3,4-disubstituted phenyl derivatives have been specifically cited and exampli-fied, and more precisely 3-methoxy -or 4-phenyl-or 3,4-dimethoxy-phenyl derivatives.
It has now been surprisingly discovered, that compounds similar to the 3 -or 4- monosubstituted -or 3,4-disubstituted-phenyl derivatives, i.e. 3,5-disubs-tituted or 3,4,5-trisubstituted phenyl derivatives show particularly useful pharmacological properties, because superior to those of the mono-or di-substi-tuted-phenyl derivatives in question.
Thus, the compounds of the invention have been found endowed with calcium transport inhibiting and -and ~- anti-adrenergic activities generally greater than those of the known compounds.

: ~

:
,' - ,' ~
. . ' ~. :

For example, the compounds of the invention have revealed an anti-adrenergic activity rate analogous to that of the known compounds, at doses on average ten fold lower than those of the known compounds.
Furthermore, it ha~ b~en quite surpri~ingly dis-covered ~hat the compounds of the invention show n yiVQ a metabolization rate much faster than that of the previously known compounds.
As has b~n reoor~d i~ dQe~ y R. Ch~rlior in "0ruxelles ~edical", No. 9, So~t~ r 19~9, ~99~
54~-560, i~ is acce~ted ~han an an~ianginal ~ru9 tr~st-~nt should bs caoabl~, in DartiCu~ar, of ane~goni2ing eh~ antiadr~nergic eypQ cardiov3seular r~etion-. rO
this ~nd, ag~nts caDabl~ of blocking thQ ~-r~captor~
h ave bcen ~rooosQd.
Ho~ever, th~ clinical a~Dlication ot SU5~ CO~-~ounds tO ehç tr~at~ent of angina r~m3inQd unsuecQ~tul, v~ry Dro~a~y duQ to th~ tace th~e 3-rec~Deor ant~gon-ists induca only a v~ry oarti~l n~utra~ization of th~
adr~n~rgic ~y3Ca~, eho aeeivit~ o~ th~ B~roc~otor3 boing una~t~cedd.
In tact, tho mo~t und~xira~l~ ha~modyn~ic ~ni-f~tation~ which occur in angin~ P~Ctoris Datiqne~
during rh~ir ~inful aet-ck~ ar~, ~o~t of 3ll, c3r~iae, and consQquQntly involv~ th~ a-r~e~tor~.
~ n oara~l~l, er~e~nt~ h~v- b~n ~ro~os~d ~ith drugs ~hich ar~ ~-adr~n0rgie r~Co~tOr antagoni~
Th~s~ co~ounds, ~hieh ar~ of gsnuin~ clinic~L v~lu~, d~cr~a3~ th~ ateack~ of angin~ by r~ucin~ th~ ~ork ot eh~ hRare by slo~ing th~ h~re rata. Ho~vor~ th~ro i~
no tal~ in eh~ ~ri~h~l art~ri~l r~ t~nc~ Yhieh, an th~ csntrar~, ri~2~ throu~h rolo~30 0- eh~ a-to~ici~.

~-, , 8~

~ h~ r~ treatment; ~nvert~le;s mo~if~ ;om~
haemodynamic oaram~rer5 in a direction ~hich, d~ a funda-mental level, ~e~rac's from tne value of ~nes~ ~ru~s for angina ~ctoris oatiencs in oarticular 3nd heart S ~atient; n 3ener~l.
~ f tne antiadrenergic asoect of 3-blocker5 is considered, it ~ec~mes clear that only the tachycardia and the incre~se in the torc~ and th~ soecd of contrac-tion of ehe heart dre caoa~le of being ncutrali2ed, the lû artcrial hyoereension invo~ving a stimutat;on of th~
~rec~ptors on which ~-antagoni3ts h~ve no aetion.
In f~ct, ~hile th~ cardiovascu~ar di~turbanc~
brought about by the stimulation of ths B-rece~tors are the more harmful to angina oatients, it is non~thetess true that arterial hyDertension also Dlays a not insigni-ficant part.
In addition, blocking the B-recePeors involv~s a risk, deDriving the patient suffering from cardiac insufficiency of a compensatGry mechanism ~hich h~ nor-mally brings into Ptay to l;m;t his circulatory insut-f;c;ency.
This r~fl~x mechanism, the main comPonQnt of ~hich makts use ot th~ Dath~y of the B adren~rg;c sys-tem, leads, ;n Darticular, eo an increasa ;n th~ forc~
and th~ sPced of contraction of the he~rt. In conse-quence, ;f this syste~ is blocked, the patient suff~ring frù~ cardiac insufficiency e~P~riences a ~orsening o~
his tunctional breakdown. It is h@nee logical ~o con-s;der that th~ use of a B-block~r ~hos~ act;on is Dure and comol~te ~ill al~ays involv~ a cardiac ris~.
It henc2 app~ar~ to b~ d~sirable not to s~k compl~te ~- or B-antagoniseic prop~rties, g;v~n th~
clin;c~l s;d~ effeces that thes~ can bring about. It s~ns more log;cal to ai~ to subdue rath~r th~n to ~lim~
inaee th~ card;ovascular disturbances ~hich char~ce~riz~
th~ hyperstimul~tion of the adren~rgic ~yst~ as ~ ~hol~
The compounds of ehe ;nv~ntion me~t this obj~ct-iV2 sinc~ th~y show incon~l~t~ nd B-sYP~ ~nti~dr~n~r-gic prop~rti2s. Thay can henc~ b~ con~id~red, not ~3 :. ~ . . : ,', ;i ~ ,' ~' i .

. ' ', , ~
' ~89~S

3-blockers ~ue ~s ~dren~-ae:e!~ra~rs~ ;nat ~s o ;ay Dartial antagonists of tne Q- ~nd ~-adrenergic roactjonS~
~orentially ~e~oid of ~1' dis~aiant~ges l ste~ dDo~ ar 3-~l~ck~s .
S ;n aa~ition, ~o calciu~ inhibitory comDonent demon,Cra~ed in ehe co~oounds of the invention ~ ac~
dS an e~cep~ional comPlement ~o the Dhar~acological soectrum of their cardiovascular action.
It is known, in ef~Qct, that the transoort of calcium ic;ns is one of tne main CompOnQntS of the action ootential in heart cells and, in consequence, this trans-~ort plays a fundamental Dart in the electrical conduc-tion as well as in the disorders ~hich may occur th~rein (arrhythmia). In ad~i~ion, it is knoun that calcium ions ars involved in the excitation~cùntraction coupling which controls the degree of vasoconstriction in smooth muscle and, in ehe same circùmstances, pLays a critical part in attacks of angina oectoris.
Compounds ~hich are calcium antagonists act at 2û ehe level of the cell membrane by selectively prev~nting calcium from Participating in ths oroc~ss of contraction within tho artori~l cQll.
In fact, it ap~ears increasingly cl~ar, at the present time, that the clinical result3 provid~d by th~
combination of calcium inhibitors and ~ adr~n~rgic inhibitors are beeter than ~hen eash inhibitor is ùsed separately (J.A.M.A. 1~82, 247, pages 1911-1917).
It appoar~, moreoYer, thae no 0-blocker which ex~rt~, in addieion, a significan~ ;nhibitory action in res~ect o~ calcium transDort exists at the pres~nt time.
From this standPoint~ ~he comPounds of th~
invention possessing both an anticalci~m compon~nt and an ~ and B-antiadrenergic com~onent ~ill be o~ funda-mental valu~, since th~y ar~ eap~bl~ of more e~ten3iv~
therapeu~ic aPDlications than 3 separate ~-block~r or a separat~ calsium inhibitor. ~y ~3y of example~ th~ tol-lo~ing may be m~ntioned:

' s . 37 - 2 - isopropyl-lc4-{3-[N-methyl-N-(3J4~5-tr~methoxy- ~-phenethyl)a~ino]
propyloxy~ benzene~ulphonyl]indolizine (S~ 33827) (Ex. 1) - 2-isopropyl-1[4-~ 3-[N-methyl-N-(3,5- dimethoxy- ~ -phenethyl)amino]
propyloxy~ benzenesulphonyl ]indolizine (SR 33 918) (Ex. 12) - 2-isopropyl-1[4-l 3-[N-(3,5-dimethoxy- ~ -phenethyl)amino]propyioxy~
benzenesulphonyl]indolizine (SR 33 815) (Ex. 11) -l-methyl-3-isopropyl-2[4-{ 3-[N-methyl-N- (3,5-dimethoxy-~ -phenethyl) amino]propyloxy~ benzenesulphonyl]indole (SR 33 937) (Ex. 13).
~ o~ev~r, th~ m-jor adv~nt~g~ ot thes~ comoounds ~ill rQsid~ in eh~ t~ct t~-t they may, a~ a resul~ of eh~ir anei calcium af-~ce, b~ us~d in eh~
er~atment of angina ae r~st, a syndrom~ indUCQ~ by th~
aoo~aranc~ ot a s~asm in th~ coronary art~ri~3~ ~hich i~
comaat~d at ores~nt ely comuound5 such a~ ei~t~ v~ra-~amil or nifetiDine in aadition, comoound~ of eh~ inv~tion ~rQ
a~so sho~n to ~ caoable o~ inducing a sub~tan~ia~
incrras~ in the coronary flo~.
The result~ of pharmacological t~t~ o~rtorm~d for th~ ourDos~ of dot~rmining th~ cardiova~eul~r prop-ereies of the comoounds of th~ inv~neion aru r~cord~d belo~
I Calcium inhiiitory proo~rtis~
Th~ Drop~rti~s of inhibiting calciu~ tr~n~DOrt at th~ m~mbran~ l~val shovn by th~ com~ound~ of th~ in-v~ntion ~re demon~tr~t~d by me~uring th~ir anta~onis-tic action ~ith re~et to th- coneractil~ r~sonY~ to PoeDs~iu~-indue~d ci~polari~tion on isola~qd r~t aorta.
It is ~`oll ~seablixh~d th~t th~ d~polari~tion ot ~
smooth mu~cl~ ~mbr~n~ by pot~iu~ rend~r~ tho latt~r p~r~eabl~ to ~er~c~llul~r c~lciu~ and inducu~ ~u~cl~
contr~ction Con~qu~ntlyJ th~ m~Yur~æne ot eho ininibitiQn of the contractil~ r~pOn5Q to dqpol~ri~ation by po~5-silJn~ or th~ ur~ne ot ~ r@l~xation ot eh~ eonic contr~eeion on ~ot~iu~ d~Pol~ri2~tion~ e~n r~pr~

:
:

; ~ .

~u~s - 38 ~

an evaluatio~ of the 2ower of a compound as an inniDico~ O~
~he ~embrane ?ermeability to Ca ions.
rne ~cnnique us~d was as follows :
Ihe aor~a ~as ramoved ~rom ~ale Wis~ar rats weighing approximacely 3008, and cut into strips approximateLy 40 mm long and 3 mm wide.
These ~ragments were placed in a 25-ml isolated organ trough containin~ a modiied Krebs-bicarbonate solution (112 mM ~aCl; 5 m~ ~Cl; 25 mM NaHC03; 1 m~ KH2P04; 1.~ m~
~8S04; 2-5 ~ CaC12; 11.5 m~ glucose, di~illed ~ater to lOOOml) through which a stream of 5-7~ carbo~ dioxide in oxy-gen w~s passed, and maintained at 37C. The preparaeio3 ~as connected eo a fo~ce microsensor ant the contractile responco recorded after amplification on a recorter.
A tension of 2g was applied to the preparaeion. This tension was maintained for 60 minutes in ehe modified Rrebs-bicarbonate solution, and contractions were then inducat by repLacing the Krebs-bicarbonate solution b~ a potassiu~-Kreb~
solution (17 m~ ~aCl; ~00 mM KCl; 25 m~ NaHC03, 1 m~ KH2P04;
1.2 mM ~gS0,,; 2.5 mM CaC12; 11.5 m~ glucose; distilled water to lOOOml). When the contractile response of the preparatio~
had become reprotucible, a given amount of a compou~d of the invention was introducet into the ~ath. Sixty minutes later, a new spasm waa iuducet by poeassium tepolarizatio~.
The results obtainet on the aorra used in the experime~
were then expre~jed as a percentage of r.he maxi~um contrac-tio~al effece before incubation with the test subseance.
By way of ~xamples, the results which follow were obtained, the compounts of formul~(1)being in the form of oxalate, hydro-chloride or methanesulphonate~

Cy-S02- ~ 0-(CH2)3^Am % o~ the maximum contrc ctional _Q~Q~=
Compounc Cy Am lo~8M 10 M 10_loM

I CH3 ~ 3 _ _ Ex. 1 ~ ~ ~-isoC3H7 ~ OCH 21,4 65,7 Ex. 2 ~ ~ -isoC3H7 CH3 OCH3 ~ N _ 1 -N-(CH2)2- ~ -OCH3 21,1 58,5 78,9 : . ,, ~. :: .
, -: . :. .

s % of the maximum ~ompound C~ Am cont ~actiona effect _ lo~8M 10 M lO_loM

_ ~ _ _ 10 ¦ Ex. ~ isoC H7 OCH3 . ~ N ~ . 49 89 Ex.ll ~ -isoC3H7-NH(CH2)2_ ~ 30,3 73,4 _ Ex.12 ~-lsoC H7~g~ CH2)2-~ ~ ~ 21 57~7 ôl Bz a benzyl - . ., ." . _ _ . , . ~

-,, 2~ 3985 By way of comparison, the following results were obtained with known compounds :
Z of the maximum contrac tional ef~ec , S ompound Cy Am . . lo~8M lO M lO_loM
_ - CH3 OCH3 _ _ _ _ .

A ~ -l~oC3H7 -N-(CH2)2- ~ -OCH3 40,1 81,7 I B ~ s~C3 7 ~ ( H2)2 ~ C ~ ~ - oC3 7 ¦-N-(CH2)2- ~ -OCH3 ~ 169, ¦86,5 ,. . . .,.~ ~ : ` :
. . :. .. ~ .
;,-' . ~ ' :

, .

' . ;~, :
, 42 ~ 9~3r~

II. A~tiadrenergic properties The object of this test is to determine the capacity of the compounds of the invention for reducing the increase in epinephrine~induced increase in blood-pressure (anti- effect) and the isoprenaline~induced acceleration in heart rate (anti-B effect), in dogs previously anaesthatized with peneo-barbital and atropinized.
For each dog, the dose of epinephrine (between 3 and 10 ~g/kg) which induced a reprotucible increase in the blood-pressure of approximaeely 133 x 102 Pa and the dose of isoprenaline (1 to 2 ~g/kg) which intuced a reproducible increase in the heart rate of approximately 70 beats/min. were first determined. The dose of epinephrine and of isoprenaline, detenmined in this manner, were injected alternately every ten mi~utes ant9 aSter t~o successive reference responses had been obtaiaed, an amount of the test co~poucd ~as administeret intravenously.
Anti- effect The percentage retuction in the hypertension induced by the tese compound compared with the reference hypertension previously obtained (approximately 100 mm Hg) was recorted.
Anti-3 effect The percentage reduction in the acceleration of the heart raee iaduced by the test compound co~pared with the re4erence tachycardia meacured previously (approximately 70 beats) wa~ recorted.
In both cases, the results of the reductio~ in bloot-pres~ure or the heart rate have been expressed as follows :
+ for a reduction < 50%
++ for a reduction >, 50%
+++ for a reduction sub-total (almost compleee reduction).
The following results were recorded :

, ' .
' : ' 43 2~ S

. ¦ Compoun~ ¦ Dose (mg/kg) ¦antl-~ ¦ anti-~
_ . effect effect Ex. 1 0,055 +++ +++
Ex. 11 0,027 ++ +
0,055 +++ ++~
Ex. 12 0,033 +++ ++
Ex. 13 0,07 +++ ~+

By way of compariqon, the known compounds showed the ~ollowing antiadrenergic effects :

¦ Compo~nd ¦ Dose (mg/kg) ¦ anti-~ ¦ anti-~ ¦
effect effec __ . . _ .. __ ~
A 0.1 +++ +++
C 0 1 +++ ~++

III) TOXICITY
The toxicity of the compounds of the -~n~ntion revealed compatible with their use in therapeutics.

ThQ ~h~rapoueic co~po~itions aecordinQ to th~
inv~n~ion c3n b~ Dre~l~n~d in ~n~ for~ suit~b~ fQP
a~inistration in hu~n or v~tarin~ry th~ra~y. A~
r~rd~ th~ a~inistr~eion unit, ~hi~ e~ln taks th~ for~
of, for ~ pl~, a c~aced- or uncoaeed tablet, hart- or sof t-gela~in capsule, ~ackaged powder, sus~ension or ~yrup for oral adslini~ tra~ion" ~ :~u~oo~ ory ~or ~etsl ad~ini~rztion or ~olution or susD~nsion for par~neQrDl ~d~ini~tr~i0n.
Th~ th~r~utie coRIpo~it;on~ ot th~ inv~n~io may contain" oar adnlinistration unit, ~or ~x~ r tro~
50 to 500 r~9 9~ thQ ~i9ht ot activl~ 9r~ldiont ~or or~
~d-ini~t~tion, fro~ SO to ZOO ~9 of ~C~iv~ di~

. .

: ~ " ' ~
: . :
~. `` : .:', :, ..

t-or rectal admini~eration an~ ~rom 50 to 15~ mg ot ac-~iva ingr2di~nt for par~nt~ral administraeion.
O~o~ndinq on tha administration routr cho~n, thQ therao~u~ical votrrinDry comoo~itions ot th~ inven-S tion ~i~t be oreoar~d by combining at l~st on~ ot th~comoounds ot tormula 1, or ~ non-~o~ic addition salt ot this comoound, ~ith a ~uitab~ ciDiane~ it b~iny oo~-sib~ tor thq ~att~r to consi~t~ tor ~m~, ot Jt l~st ons ingrQdi~nt ~ ct~i tro~ tho tollo~in9 ~ub-~tanccs: lactos~, ~t~rch~ lc, magn~iu~ ~t~r~t~, Polyvinyl~yrrotidon~ ~lginic ~ci~, eolloid~l ~tlic~, distil~d ~eQ~ b~n~yl a~coho~ or t~st~nin~ ag~nt~.
Th~ tollouing non~ iting ~x~ illu~tr~to th~ inv~ntion:

:
:;

E~AMPLE 1 Preparation of 2-isopropyl-1-[4- { 3-[-N-methyl N-t3,4, 5-trimethoxy-~-phenethyl)amino] propyloxy) benzenesulphonyl~ indolizine acid oxalate (SR 33827A) a) 2-isopropyl~ 4-(3-bromo--propoxy)benzenesul-phonyl~indolizine A mixture of 3,15 g (0,01 mol) of 2-isopropyl-1-(4-hydroxy-benzenesulphonyl)indolizine, 40,38 g (0,2 mol; 20,3 ml) of 1,3-dibromo-propane, 1,66 g (0,012 mol.) of potassium carbonate and 20 ml of N,N-dime-thylformamide was heated at 100C and the reaction was controled by thin layer chromatography (solvent) :
dichloromethane/ethyl acetate 95/5).
The reaction was maintained during 50 minutes, and the excess of 1,3-dibromo-propane was evaporated under vacuum.
The residue obtained was ta~en up in ethylaceta-te, washed with diluted sodium hydroxyde and then with water and dried on potassium carbonate. After filtra-tion, the filtrate was poured into water, extracted with ethyl acetate, washed with water and then with a saturated solution o~ sodium chloride.
The obtained residue was dried on sodium sulfate and concentrated.
In this manner, about 4 g of crude 2-isopropyl-1-t4-(3-bromo-propoxy)benzenesulphonyl~ indolizine was obtained and subsequently recrystallized in an ethyl/-hexane mixture.
Yield after recrystallization : 6-7%
M.P : 133~4DC

b) 2-isopropyl-1-[4 -{3-~N-methyl-N-( 314 ~ 5~trime-thoxy-~-phenethyl)amino~propyloxy} benzenesulphonyl]-indolizine acid oxalate .
, . , . , ,. . . .; , .. , . -, .
.

.

0,0025 mol. of 2-isopropyl-1-[4-(3-bromo-propoxy) benzenesulphonyl]indolizine, 0,005 mol. of N-methyl-N-3,4,5-trimethoxy-~-phenethylamine acid 0,010 mol. of potassium carbonate in 5 ml of dimethylsulphoxide were mixed together at room temperature.
The mixture was stirred for 22 hours, while the reaction was controled by thin layer chromatography (solvent : methanol), then the reaction product was poured into water.
The medium was extracted with dichlorome~hane and washed with an saturated aqueous solution of sodium chloride.
The residue was dried on sodium sulphate and con-centrated to obtain about 1,6 g of the crude product which was subsequently purified on a silica column using as eluent a mixture of ethyl acetate/methanol 80/20.
The 2-isopropyl-1[4- ~3-[N-methyl-N (3,9,5-trime-thoxy-~-phenethyl)amino]propyloxy 3 benzenesulphonyl~-indolizine was obtained in the form of a free base.
0,0018 mol. of the obtained base was reacted with 0,0018 mol. of oxalic acid in a mixture of ethylace-tate/ethyl ether.
In this manner, the 2-isopropyl-1l4-~ 3-[N-methyl-N-(3,4,5-trimethoxy-~-phenethyl)amino~propyloxy3 benzenesulphonyl]indolizine acid oxalate was isolated, which could be recrystallized for instance in methanol M.P : 182-183-C (methanol) Preparation of 2-isopropyl-1[4- ~3~[N-methyl-N-(3,4-dimethoxy-5-methyl-~-phenethyl)amino~propyloxy3 benzenesulphonylJindolizine acid oxalate A mixture o~ 0,0126 mol of 2-isopropyl-1 (4-hy-- ~ :

.

, . , ,: , , , , , .:,.

39~;

droxy-benzenesulphonyl)indolizine and 0,0189 mol. of 1-chloro-N-methyl-N-(3,4-dimethoxy-5-methyl-~-phene-thyl)amino]propane in 60 ml of anhydrous dimethylsul-phoxide in the presence of 0,441 mol. of potassium carbonate was strirred for 3 days. After reacting, the medium was poured in a big volume of water, extracted with three fractions each of 100 ml of toluene, washed with water, dried on sodium sulphate, filtered and evaporated to dryness under vacuum.
The product so obtained was stirred in heptane and recrystallized in ethanol. The required compound was obtained in the form of a fre~ base, then the oxalate was formed in boiling ethyl acetate.
In this mann~r, the 2-isopropyl-1[4- r 3-[N-methyl-N-(3,4-dimethoxy-5-methyl-~-phenethyl)amino]propyloxy~
benzenesulphonyl~indolizine was isolated.
M.P : 189-190-C (methanol/ethyl ether) Using the same procedure as that described above, the following compounds were prepared :

2-isopropyl-1-[4-l 3-[N-methyl-N-(3,4, 5-trimetho-xy-~-phenethyl)amino~propyloxy } benzenesulphonyl~-indolizine hydrochloride (SR 33827 B) M.P : 90-110-C (pasty) EXA~PLE 4 2-isopropyl-1-[4- ~3-[N-(3 methoxy-5-methyl-4 ben-zyloxy-~-phenethyl)amino~propyloxy 3 benzenesulpho-nylJindolizine acid oxalate (SR 33964 A) M.P : 165-167-C

E~AMPLE 5 2-i90propyl-1-[4~ ¦ 3-[N-(3~4-dimethoxy-5-meth .- , , .

.

9~S

~-phenethyl)aminoJpropyloxy ~} benzenesulphonyl!-indolizine acid oxalate (SR 33969 A) M.P : 180-183~C (ethyl acetate/methanol) EX~MPLE 6 2-isopropyl-1-[4- ~3-[N-4-methoxy-5-methyl-3-benzy-loxy-~-phenethyl)amino1propyloxy ~ benzenesulpho-nyl3indolizine hydrochloride (SR 33979 A) W.P : 209-210-C (ethylacetate/methanol) 2-isopropyl-3[-4- ~ 3-[N-methyl-N-(3,4,5-trime-thoxy-~-phenethyl) amino3 propyloxy ~ benzenesulphonyl7-benzofuran hydrochloride (SR 34025~) M.P : 138-C (ethyl acetate) 1-methyl-3-isopropyl-2-[4- ~ 3-[N-methyl-N-(3,4,5-trimethoxy-~-phenethyl)amino~propyloxy ~ ben-zenesulphonyllindole hydrochloride (SR 34041 A) M.P : 95-C (ethyl ether) EXAMPLE_9 1-methyl-3-isopropyl 2-l4- ~ 3-[N-methyl-N-(3,4-dimethoxy-5-methyl-~ phenethyl)aminoJ propyloxy3 benzenesulphonyl~indole hydrochloride (SR 34047 A) M.P : 95-C (ethyl ether) EXAMPLE lO
2-isopropyl-3[4- l3-[N-(3,4,5-trimethyl-~-phe-nethyl)amino3propyloxy ~ benzenesulphonyllbenzo~uran hydrochloride (SR 34049 A) M.P : 185-C (m~thyl ethyl ketone) .
-,:: . . ..

:, :~ , ' :

2-isopropyl-1[4- f 3-[N-(3,5-dimethoxy-~-phe-nethyl)amino~propyloxy 3 benzenesulphonyl]indolizine acid oxalate (SR 33815 A) M P : 196-197-C

2-isopropyl-1[4- ~3-[N-methyl-N-(3,5-dimethoxy-~-phenethyl)amino~propyloxy~ benzenesulphonyl~indolizine acid oxalate (SR 33918 A) M P : 169-170-C

1-methyl-3-isopropyl 2-~4-~ 3-[N-methyl-N-~3,5-di-methoxy-~-phenethyl)amino~propyloxy } benzenesulpho-nyl~indole acid oxalate (SR 33937 A) M.P : 156-C (isopropanol/ethanol 1/1) 1-methyl-3-isopropyl-2-[4- ~3-[N-methyl-N-(3,5-di-methoxy-~-phenethyl)amino~prQpyloxy~ benzenesulpho-nyl~indole methanesulphonate (SR 33938 A) (sticky from 50 C) 1-methyl-2-phenyl-3-[4- ~3-[N-methyl-N-(3,4,5-tri-methoxy-~-phenethyl)~mlno~propyloxy3 benzenesulpho-nyl~indole hydrochloride M.P : 116'C (ethyl acetate/ethyl ether) 1-methyl-3-isopropyl-2-[4- ~3-[N-(3,4,5-trimethyl-~-phenethyl)amino~propyloxy~ benzenesulphonyl ~indole hydrochloridride .

, XQ(3~9~35 M.P : 156-C (ethyl acetate/ethyl ether) 2-isopropyl-3-[4- ~ 3-[N-(3,4,5-trimethyl-~-phe-nethyl)aminolpropyloxy 3 benzenesulphonyllbenzofuran hydrochloride M.P : 185-C (methyl-ethyl-k~tone) 2-isopropyl-3-[4-~ 3-[N-methyl-N-(3,4 -dimethoxy-5-methyl-~-phenethyl-)aminolpropyloxy ~ benzenesulpho-nyllbenzofuran fu ~ ate M.P : 109,6-C (ethyl acetate) ~ ~,.
EX~MPLE 19 1-methyl-3-ethyl-2-[4- f 3-~N-methyl-N-(3,4,5-tri-methoxy-~-phenethyl)aminolpropyloxy } benzenesulpho-nylJindole hydrochloride ;,. .-. ~ . ; ~.: .

Claims (21)

51

1 - An aminoalkoxyphenyl derivative of general formu-la :

(1) in which :
B represents a -S, -So- or -SO2- group, R1 and R2, which are identical or different, each denote hydrogen, a methyl or ethyl radical or a halogen such as chlorine, bromine or iodine, A denotes a straight- or branched-alkylene radical having from 2 to 5 carbon atoms or a 2-hydroxypro-pylene radical in which the hydroxy is optionally substituted by a lower alkyl radical, Am represents a group selected from or in which R3, R'3 and R"3, which are identical or different, each denote a halogen such as chlorine or bromine, a lower alkyl, lower alkoxy or benzyloxy group, R4 denotes hydrogen or an alkyl radical Alk denotes a single bond or a straight rr branched-alkylene radical having from 1 to 5 carbon atoms.
Cy represents a group of formula:

ou (D) (E) R represents hydrogen, an alkyl radical, a cycloakyl radical, a benzyl radical or a phenyl radical optio-nally substituted with one or more substituents, which may be identical or different, selected from halogen atoms, for example fluorine, chlorine, bromine atoms and from lower alkyl, lower alkoxy or nitro groups, R5 and R6 are taken together with the carbon atom to which they are attached to form :
- an optionally aromatic mono- or di-cyclic carbocy-clic group having from 5 to 10 carbon atoms and op-tionally substituted by a R group in the .alpha.-position with respect to the methyne group, - an optionally aromatic 5-membered heterocyclic group, the heteroatoms or heterogroups being selected from the groups O, S, N,-N-Rg; O and N; O and -N-Rg; S
and N; S and -N-R9; N and N; N and -N-Rg, the hetero-cyclic group being optionally substituted by a R group in the .alpha.-position with respect to the methyne group and optionally substituted by one or two groups selec-ted from lower alkyl and phenyl groups, - an optionally aromatic 6- to 10- membered mono- or di-cyclic heterocyclic group, the heteroatoms or hete-rogroups being selected from the groups O, S, N, -N-R9; O and N; O and -N-R9; S and N; S and -N-R9; N
and N; N and -N-R9, the heterocyclic group being optionally substituted by a R group in the .alpha.-position with respect to the methyne group, R7 and R8, which are the same or different, each re-present hydrogen, a lower alkyl radical or a phenyl radical or when they are taken together with the carbon atoms to which they are attached represent an optionally aromatic 6-membered carbocyclic ring, Rg represents hydrogen, a lower alkyl radical, a phenyl radical, a benzyl radical or a benzyl radical substituted by a halogen atom and a pharmaceutically acceptable salt thereof.

2 - An aminoalkoxyphenyl derivative according to claim 1 in which Cy represents a phenyl, cyclohexenyl, indenyl, naphthyl, dihydronaphthyl, pyridyl, dihydropyridyl, furyl, dihydrofuryl, thienyl, dihydrothienyl, pyrrolyl, dihydropyrrolyl, pyrazolyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazolyl, isoxazolyl, thiazolyl, benzofuryl, benzothienyl, indolyl, benzimidazolyl, benzoxazolyl, quinolinyl, benzisoxazolyl, cinnolinyl, quinoxalinyl, quinazolinyl, indolizinyl, thienopyridyl, tetrahydro-thienopyridyl, pyrrolopyridyl, pyrazolopyridyl, pyrrolopyridazinyl or imidazopyridyl.

3 - An aminoalkoxyphenyl derivative accor-ding to claim 1 in which Cy represents a indolizinyl, benzofuryl, benzothienyl, indolyl, oxazolyl, pyrazo-lyl, phenyl, pyrazolo[1,5-a]pyridyl or imidazo [1,2-a]
pyridyl.

4 - An aminoalkoxyphenyl derivative accor-ding to claim 1 in which B represents a-SO2- group.

- An aminoalkoxyphenyl derivative accor-ding to claim 1 in which R1 and R2, each represents hydrogen.

6 - An aminoalkoxyphenyl derivative accor-ding to claim 1 in which R3, R'3 and R"3 represent methoxy.

7 - An aminoalkoxyphenyl derivative accor-ding to claim 1 in which R represents isopropyl or cyclopropyl.

8 - An aminoalkoxyphenyl derivative accor-ding to claim 1 in which the pharmaceutically accep-table salt is oxalate, hydrochloride or methanesul-phonate.

9 - An aminoalkoxyphenyl derivative accor-ding to claim 1 which is :
- 2-isopropyl-1-[4- {3-[N-methyl-N-(3,4,5-trimetho-xy-.beta.-phenethyl)amino]prcpyloxy } benzenesulphony]-indolizine - 2-isopropyl-1-[4-{ 3-[N-methyl-N-(3,5-dimethoxy-.beta.-phenethyl)amino]propyloxy} benzenesulphonyl]indolizine - 2-isopropyl-1-[4-{ 3-[N-(3,5-dimethoxy-.beta.-phene-thyl)amino]propyloxy} benzenesulphonyl]indolizine - 1-methyl-3-isopropyl-2-[4- {3-[N-methyl-N-(3,5-dimethoxy-]-phenethyl)amino]propyloxy } benzenesulpho-nyl]indole, and a pharmaceutically acceptable salt thereof.

- Process for preparing an aminoalkoxy-phenyl derivative acording to claim 1 in which A represents an alkylene radical and B represents a-S-or -SO2- group, characterized in that a 4-alkoxyphenyl derivative of general formula in which B' represents a -S- or -SO2- group, Cy, R1 and R2 have the same meaning as in claim 1, A has the same meaning as above and X represents a halogen atom, an alkylsulphonyloxy group having from 1 to 4 carbon atoms or an arylsulphonyloxy group having from 6 to 10 carbon atoms, is condensed in the presence of an acid acceptor in a polar or non-polar solvent at a tempe-taure between the room temperature and the temperature of reflux with an amine of general formula H-Am (3) in which Am has the same meaning as in claim 1 to ob-tain the required compound which is, if desired reac-ted with an organic or inorganic acid to provide a pharmaceutically acceptable salt thereof.

11 - Process for preparing an aminoalkoxy-phenyl derivative according to claim 1 in which A
represents an alkylene radical and B represents a-S-or -SO2- group, characterized in that a 4-hydroxy-phenyl derivative of general formula :

(4) in which B' represents a -S- or -SO2- group and Cy, R1 and R2 have the same meaning as in claim 1 is reacted in the presence of a basic agent, with a compound of general formula :
(52) X-A-Am in which X represents a halogen atom, an alkylsulpho-nyloxy group having from 1 to 4 carbon atoms or an arylsuphonyloxy group having from 6 to 10 carbons atoms, A represents an alkylene radical and Am has the same meaning as in claim 1, the reaction being carried out under reflux and in an appropriate solvent, to ob-tain the required derivative which is, if desired, reacted with an organic or inorganic acid to provide a pharmaceutically acceptable salt thereof.

12 - Process for preparing aminoalkoxyphenyl derivatives according to claim 1 in which A represents an optionally substituted 2-hydroxy propylene radical and B represents a -S- or -SO2- group, characterized in that an oxyranylmethoxy derivative of general formula:

(57) in which B' represents a -S- or -SO2- group and Cy, R1 and R2 have the same meaning as in claim 1, is reacted under reflux with an amine of general formula :
(3) H-Am in which Am has the same meaning as in claim 1, in a polar solvent or with an excess of said amine for obtaining the required compound in which A represents a 2-hydroxy-propylene radical, in the from of a free base, which can be reacted with an alkyl halide having from 1 to 4 carbon atoms, in the presence of a strong base, to provide the required compound in which A
represents a 2-hydroxy-propylene radical wherein the hydroxy is substituted by an alkyl having from 1 to 4 carbon atoms, in the from of a free base, which can, if desired, be reacted with an organic or inorganic acid to provide a pharmaceutically acceptable salt thereof.

13 - Process for preparing aminoalkoxyphenyl derivatives according to claim 1 in which B represents a -SO- group, characterized in that a sulphide of general formula :

in which Cy, R1, R2, A and Am have the same meaning as in claim 1, this sulphide being in the form of a free base or a salt, is reacted with an oxidizing agent, to obtain the required derivative in the form of a free base or a salt which is subsequently reacted with a basic agent to provide the required derivative in the form of a free base, the free base so obtained being, if desired, reacted with an organic or inorganic acid to provide a pharmaceutically acceptable salt of this derivative.

14 - Process according to claim 13, charac-terized in that the oxidizing agent is selected from sodium periodate, potassium permanganate and 3-chlo-ro-perbenzoic acid.

58 - A pharmaceutical or veterinary compo-sition containing, as active principle, at least one aminoalkoxyphenyl derivative according to anyone of claims 1 to 8, in combination with a pharmaceutical vehicle or a suitable excipient.

16 - A pharmaceutical or veterinary compo-sition containing, as active principle, at least one aminoalkoxyphenyl derivative according to claim 9, in combination with a pharmaceutical vehicle or a suita-ble excipient.

17 - A pharmaceutical or veterinary compo-sition according to one of claims 15 and 16 for the treatment of pathological syndromes of the cardiovas-cular system, containing from 50 mg to 500 mg of active principle.

18 - The use of at least one aminoalkoxy-phenyl derivative according to anyone of claims 1 to 9 for preparing a medicine.

19 - The use of at least one aminoalkoxy-phenyl derivative according to anyone of claims 1 to 9 for preparing a medicine for treating pathological syndromes of the cardiovascular system.

- The use of at least one aminoalkoxy-phenyl derivative according to anyone of claims 1 to 9 for preparing a medicine for treating ocular diseases.

21 - The use of at least one aminoalkoxy-phenyl derivative according to anyone of claims 1 to 9 for preparing a medicine for potentiating anticancer drugs.