CA1064504A

CA1064504A - Sulphur- and oxygen-containing diaryl compounds

Info

Publication number: CA1064504A
Application number: CA236,205A
Authority: CA
Inventors: Victor Lafon; Louis Lafon
Original assignee: Laboratoire L Lafon SA
Current assignee: Cephalon France SAS
Priority date: 1974-09-30
Filing date: 1975-09-23
Publication date: 1979-10-16
Also published as: DK437075A; DK146336B; NL176776C; DK146336C; CH609024A5; DE2543179A1; IE42609B1; IE42609L; NL176776B; DE2560602C2; NL7511452A

Abstract

ABSTRACT OF THE DISCLOSURE
The sulphur- and oxygen-containing diaryl compounds of the formula:
I
in which A is O, S, SO or SO2, B is O or, when A is O, S, Alk is a C1-C4 hydrocarbon radical with a straight or branched chain, R represents COOH, an esterified COOH group, a carboxy-lic amide group, OH, O-SO2CH3, NH2, NHR1, NR1R2, NHZOH, NHZNR1R2, C(=NH)NH2, C(=NH)NHOH or 2-.DELTA.2-imida?olinyl, z is a C2-C4 hydrocarbon radical with a straight or branched chain, and R1 and R2 each represent a C1-C3 lower alkyl group, and their addition salts with bases when R is COOH, and their addition salts with acids when R is a basic radical, are use-ful pharmacological agents in the treatment of circulatory complaints such as cardio-vascular illnesses.

Description

~ ` ~
5~
The present lnvention relates to sulphur- .lnd oxyc~en-containing diaryl compoun~ls, their preparation and their appli-cation in therapy.
The present invention provides the sulphur- and oxygen-containing diaryl compouncls o~ the formula:
~ e~ ~-Alk-R
in which A is O, S, SO or SO2, B is O or, when A is O, S, Alk is a Cl-C4 hydrocarbon radical with a straight or branched chain, R represents COOH, an esterified COOH group, a carboxylic 10 amide group, OH, O-SO2CH3, NH2, NHRl, MR~R2, NHZOH, . ~- .
NHZNRlR2, C(=NH)NH2, C(=NH)NHOH or 2- ~2-imidazolinyl~ z is a C2-C4 hydrocarbon radical with a linear or branched !~
chain, and Rl and R2 each represent a Cl-C3 lower alkyl group, and their addition salts with bases when R is COOH, and their addition salts with acids when R is a basic radical.
In the text which follows, the generic term "amidine"
is to be understood to~ include not only the group C(-NH)NH2 but also the amidoxime group C(=NH)NHOEI and cyclic amidine groups such as the 2-~ 2-imidazolinyl group.
20 ~ ~ The term "Alk" represents in particular the groups ~ ~-

2 3 ~ ( 3)2' CH2CEI2, CH(CH3)CH2, C~CH ) CH
CH2CH(CH3) or~CH2C(CH3)2. The group Z is in particular, : CN2C~2~ CE~(cE~3)cH2t C~CH3)2CH2~ C~2C~I~CH3) or CH2C~CH3)2~ .

The expression "esteriied COOH group" is to be understood to mean~any group COOX, wherein X is either a .
~ ` ' ~ 2 , ~7 .. . ..

~;4~

Cl-C3 lower alkyl group (such as rnethyl, ethyl, propyl or isopropyl) or a CI-12CH2NRlR2 group (wherein NRlR2 is defined as above) or an ester radical which results from the esterification of a bis-[tS-hydroxyalkyl)thio]-alkane as in British Specification No. 1,307,227.
Amorlg the acid: addition salts of the acids of the formula I (R=COOH) are included first the salts obtained with the usual organic bases and secondly the salts obtained with the bis-[(N-hydroxyalkyl)amino-alkylthio]-alkanes of the formula:
x ( 2)n x NRo Bo IX
described in French Application No. 75/02,307 o~ 24th January 1975, wherein Bo is a C2-C4 hydroxyalkyl group or C2~C4 dihydroxyalkyl group, Ao is a C2-C6 alkylene group, Ro is H, alkyl, acyl or Bo and x:is 0, 1 or 2.
The expresslon "carboxylic amide group" is to be understood to mean a group chosen from CONH2, CONHRl, ..
CONRlR2, CONHZOH and CONHZNRlR2, wherein Rl, R2 and Z are : ~ defined as above, and the amides which xesult from the ~ ~
condensation of an acid of formula I tR=COOH), in the form ~ `
of the acid chloride, with an amine of the above formula IX.
; Preferred compounds accordin~ to the invention are:
a) the acids of the formula:
:

Cl ~3 A ~ </ \ ~ B-~-COOH Ia . ~

5~
Ln which A i~ O, S, So or so2, B is o, or S lf A is O, Y iq CH2, CH(CH3) and C(CH3)2, and the adc3ition salts obtained by reaction oE the said acids with organic bases, especially with the biS-~(N-hydroxya]kyl)amlnoalkylthio~-alkanes of the Eormula IX mentioned above.
b) The esters of the formula:
C 1 {~ ~3 B-Y-COOX Ib wherein A is o, S, So or So2, B is o, or S if A i~ O, Y is CH2, CH(CH3) and C(CEI3)z and X is defined as above, and their addition salts with acids, if X contains an amino group.
c) The alcohols of the formula:

Cl ~ A _ ~ ~ B Yl-OH Ic wherein A is o, S, So or SO2, B is O or S i~ A is O and Y~
is CH2CH;2, CH(CEI3)CH2, C (CH332CH2, CH2CH(CE[3) and CH~C (CH332, and their derivatives resultin~ ~rom the conversion of the , .
OH group to an O-SO2CH3 group.

d) The amides o~ the formula:
:
Cl ~3 A - ~ ~ B-Y-COXl Id in which A is o, S, SO or SO2, B :Ls O, or S i~ A :ls O, Y is : CH2, CH (CEI3) or C (CH3)2 and Xl is ~DH2t NH OEI2CH20H, NHCH2CH2N(CH3)2 or NHCH~CH2N(C2H5)2, and their addition salts.

6~5t3~

e~ The amines oE the formula:
Cl ~ A - ~ ~ B-Yl-X Ie in which A is o, s, So or so2, ~ is o or s i~ A is o, 1 H2OEI2, CH(C~3)CH2, C(C~I3)2CH2, CH2CH(CH ~
or CH2C(CH3)2, and X2 is NH2~ NHCH2CH2oH, NHCH (CH3~CH20H, NHC~CH3)2CH2H~ ~CH2cH2N(cH3)2~ ~ICH2C~2N(C2H5)2, ( ~3)2~ N(C2H5)2 or ~HCH(CH3) 2~ and their addition salts.
f) The amidines of the formula:
Cl ~ ~ A ~ B~Y-X3 I~

in which A is o, S, so or S02, B is o or s if A is o, Y is CH2, CH(CH3) and C(CH3)2 and ~3 is C(=~)NH2, ~ -;
C(=NH)NHOH and 2- ~2-imidazolinyl and their addition salts. -The compounds of the ~ormula I may be prepared by the two methods described below with their variants, where appropriate~
Method~A
- A diphenyl derivative of the formula:
Cl { ~ A ~ ~ ,BH II
wher~in A and B are de~ined aæ above, is reacted with a . ~, - .:

S~4 halogen derivative of the formula:
Hal-Alk-R' III
wherein Hal is a bromine or chlorine atom and ~' is CooC H , OH, N~I2 9 NHRl, MRIR2~ NHZOH, N~NRl 2 so as to give a compound of the formula:

Cl ~ ~ A ~ } B-Alk-R' IV ~.

Thereaftex, i~ necessaxy a) the carbox~late (IV, R'-CO0C2H5~ is converted to the corresponding acid derivative ~I, R=COOH) by hydrolysis, the said acid derivative thereafter bein~ subjected where appropriate, to amidification and esterification reactions to give the amides and ~ :
. .
the other esters;

b) the alcohol (IV, R'=OH) is converted to thé .
~- .
corresponding mesylate~derivative (I, R=O-SO2CH3:) by reaction with methanesulphonyl chloride; and~ :;
c~ ~ the cyano derivative (IV, R'=CN) is converted ~.

to the corresponding "amidine" derivative [I, R=C~=NH)NH2, C(=NH)NHOH and 2 - a -imidazolinyl] by : 20 reacting the said cyano derivative with, respectively, NH3, NH20H and.H2NCH2CH2NH2~ in the presence of an alcohol.
~: ~

~.

~,1-, - . . . . . . .

5a~

I'o carry out the reaction lI-tIII it is preferred to use a bromine derivative (III, Hal - Br) if R' is COOC2H5. Furthermo~e, if R' is CN, OH or amino, it is possible to use a chlorine or bromine derivative III, the chlorine derivative generally giving better yields than the bromine derivative in this case.
Amongst the variants vf method A there may be mentioned:
the production of amines by reduction of the corresponding amides: ;
the production o:f amines from alcohols or. ~
the mesylates (R=O-SOCH3) of the latter; :
the production of other esters by trans- :
esterification of the compound IV (R'=COOC2H5);
the production:of amides from the ester IV ~;
~:~ (R'--COOC2H5) by reaction with amines; :
the direct production of amides by reaction ~.
of II with a bromo-alkylamide of the formula III
20I (R' = carboxamido): ~ :~
the production of the alcohol b~ reduction of the corresponding acid R = COOH;
the oxidation of the sulphide group A = S
to the sulphinyl group ~ = SO and to the sulphonyl ; .;
:~ group A = SO2, by oxidation of the said sulphide by .
H2O2 in the presence of acetic acid this oxidation " ` .

, _ 7 ~

s~
:;
is carried out in accordance wi-th a method which is in itself known, and for this purpose it is recommended to carry out the reaction at a tlemperature below, or equal to, 50C to obtain the sulphinyl derivative and at a temperature above 55C (55C to 100C) to obtain the sulphonyl derivative, uslng concentrated hydrogen peroxide of at least 110 volumes strength (that is to say water containing at least 33~ by weight of hydrogen peroxide); the oxidation by means of H2O2 can be carried out at any stage of method A.
Method B
Method B, which is less general than the preceding method, comprises the reaction of a cuprous salt of the formula:

Cl ~ A'-Cu V

wherein Al is O or S, wit.h a bromine derivative of the formula:

Br _ ~ B~Y-COOC2H5 VI

!: ' in which B is O and can represent 5 if A' is O, and Y
is CH2, CH(CH3) or C(CH3~2 to give an ester of the formula:

:~; , . .
; ~ ~ , , ,, ' ;

`
~6~ 4

3 A . ~ ~ - B-y-cooc2H5 VII

which i5 hydrolysed to give -the corresponding acid Cl _ </ ~ A' _ ~ -B-Y-CoOH VIII

The acid of formula VIII is thereafter, where appropriate, subjected to the following reactions: ~ :
reduction of the acid to the corresponding alcohol, followed by treatment of the said alcohol, :
if necessary, with Cl-O-S02-CH3, to give the 10 corresponding mesylate, ~ `
estexification of the acid to give the other este~s; ;; ~:
: amidification of the acid to give the amldes, followed by reduction of the said amides, if necessary, to give the corresponding amines;
and ~ if appropriate, oxidation o the . :
: sulphide group A' or B = S to the sulphinyl group 50g~

SO and the sulphonyl yroup S02 by means oE
H20~, as indicated above. .
Amongst the variants of method B
there may be mentioned the trans-esterification and amidif.ication of the ester VII
The addition salts with acids, which can be prepared from the bases of the formula I, are:obtained by methods in themselves known, for example by reaction of the free base with an inorganic or organic acid. Amongst the acids which can be used there may especially be mentioned hydrochloric, hydrobromic, hydriodic, ~-sulphuric, formic, maleic, fumaric, oxalic, ~
ascorbic, citric, acetic, methanesulphonic, ~ ~:
p-toluenesulphonic:, lactic, succinic, benzoic sal;icyclic, acetylsalicylic, malic, tartaric, glutamic and aspartic acid.
Some of the compounds of the invention are listed in Table~I below.
The compounds of the invention are : useful in therapy in the treatment of circulator~
.
complaints, especially cardio-vascular illnesses.

Certain of them are hypo-lipidaemic agents and hypo-cholesterolaemic agents, ¢ertain of them ~ ~ are blood platelet anti-aggregation agents, and ; ~ finally, others of them are simultaneously hypo-~ lipidaemic, hypo-cholesterolaemic and anti-: , ' - 1 0 ' ' ' ~, . , .

1~16~504 aggregation agents, the property shared by all the compounds being a beneficial effect on .
circulatory complaints and in particular on - -cardio-vascular illnesses.
The invention includes within its scope therapeutic compositions comprising at least one compound of formula I as such or as one of its non-toxic addition salts in combination with a physiologically acceptable excipient.

.~' . .

~: ~: : :

. , '~ : '', ;' : ~ ; :

: ~ ' :~:

~ ' ', ;~,' - 11 - , : :

~6~
_ ~__~__ _ _ .
U~
~ ~ ~ ~n 0 00 ~ v ~ ~:
~ O ~ ~ ~ ~ oo ~ ~ o l ~ ~ ' V ~ o _ ~

. h ' ~nO ' ~
. ' ~ . , ~ , ' O ~ O ' ;t ~: o~ X~ ~
1 ~ V~ ~
t~ 3 ~ z ~ o o ~ ~ o~ o o ~ ~ v ~ v ~r . . . X
~ _ . _~ _ , . " ,, ~
. . ~ i ,.. -T ~:x~ ~ ~
¢ ~ X~ tX ~ U~ V ~ :: ~
:: ` : v c ) c,) t.) v ~ C.~ V ~ t~ ~) V ~ t? O 1 : ~:: H ~ ~ ~ ~1 3 ~ o O o O O o O o en -tn ~r~q t~ t~ cn O ~ ..
: _ ,_ ~ _ ~ .
~: ~~S ~ n ~ rJ~ r~ O O O O O o O O ~ ~1 _ _ . _._ __ ~ ~rl r_ O CO Cl~ ~I) ~ a) ' ~i ~ t~
0 I O OI C~ O O ' O I O ~ 0 0 0 ~ r~
C) ~ ~7 ~7 ~ U~ :
, ~ _,, V ~ U ~ 0 .

~1 t~ .. -- --~ ~ O ,l~ O ~ ~ ~
:

::
~ - 12 - . .

, ~; , . ; ~ . , .

., . .,, : . .. ~ , . .. ` ` .. ~

3~
_ . ~ . ~

~ ~ ,' o~ V ~, o ~ o ~ ~ ~ ~ &o ,~ o .~,~ ~ ~ ~ C`l ~ o ~ ~ CO ., U~
~ ~ Ul ~: . "

... ..... .. _ ~: . . ..
. p~ .. ',~

o o o o ~, V C~ ~, V ~, o o o o o o .
. .
_ ~ I . : ;,, ~î , . . ' g ~V ~ . ':.
,1 C~ . ..
¢ ~ ~ X~ ,, ~ , V` ~ ~ ~ ,.
: ~ ~ X ~ ,~ ,." ' - :
,: ~ ~ :,: .:
~: ~: H ~ O O O t~ O O O ~ O O ~ . ~
~ ~ ~31 _ . _._. .. _ .~
: ~ ~ZI ~ u~ ~n O ' o o o o o o o o o . ~.
~1 ~ , . . ~ `
. ~ ,~' G ,, ~ O ~'I ~ C~l o o .~ a~ o .-1 ~1 o ~
~D O C~ O O O O O O O O o O .
. . ...
V ~ , C~ ~1 _._ ~ .~ 0~ ~ .:
~ 1~ . . ..
~1 1~ ~ _~ ~ . , : ` ` ~ _ _ ..
:` , . . ~
`, .

~, ~,g r ~ r~ r ~ t~ O C.~ C.. ) U V r ~ r~ ~ r ~n O o O u~ O O O O O o O O
~ _ ~o ~ rJ ~1 V ~ ~ rY _l ~ r-l r~l . ~ ¦
~ri _ . ..... _~ C)~ C`' 113 . O~ ~ ~rl . ~ C~l N C~ 1 C.) C.) 5 ~ r ~ C~l x ~ æ z ~ ~ ~
a~ a . ~ n 5 ~`1 ~ ~ ~ c q h h S ~ O ~ ~ ~1 tH h ~: Z O X Z; Z; O X Z Z c~ r~ t.~ C~ c~J O a) a~ ~ ~
a) ~:
__ _ - .__~_~_.
. 4~
~a ~ c~l ~ ~ , C~l ~ ~ X
r~
O ~3 V rJ ~ ~ X ~ ~ ^,~
Y c~ c~ I c~ r,~ l ~ ~ V
t~ ~1 X ~ ~ S :~ O ,.
~ ~ r ~ r~ r ~ C~ 0 ~i __ __~ ~
o m c~ o c) o o o o o r~ ~ o O O O ~ ~q ~_- . ~
H ~ . E3 ~' ~ O C~ O O o o o o o o o ~ o o o -d ~
_ __~____ ~ $
~ . . O
. . ,r~ O
1~ It~ O r~ CO C~J O q~l . r ~ CJ~ t~7 r-l 1a CO O
tl~ ~I N ~ 1 ~ ~ c~l ~ c-7 trl ~1-) ~ ~
~:1 o I o o o I o o o o o o o o I ` rl h ~.
O ~`;t ~ ~ o ,s~
. ~? , _ . _ _ _~ O ~) a) . . ~ ~ , ~ ~ ..
ro r~
i ~ ~ .a a~
cr~ o ,~o ~ c~ (1) . X N ~ ~ ~tc~l ct7 c-~ ~
_ . . æ
~6gL~
.

.
. : :: :: .. .
: .. ' `: .: '.,. . . . . ~ :, : , ~ ~.\

s~

O-ther advantages and charaG-teris-tics of the inven-tion will be better understood on reading -the preparation examples which ~ollow and are given by way of illustration but without implying any limitation. In these examples, the synthesis of the compounds II, V and VI, which can be used as the starting material according to the invention, has also been illustrated. Furthermore, it is obvious that the i.somers (~) and (-) of the racemic compounds which have been described in the said examples can be isolated, in accordance with a method which is in itsel~ kno~.
Ex~mp~e_l '~

~ ~ d ~2 NH-(CH2)2~
: : , , ' A solution o~ 21.6 g (0~075 mol) o~ sodium bis-(2-methoxy-ethoxy)~aluminium hydride in 50 ml o~ benzene is run over the course o~ 30 minutes into a refluxing solution o~ 18.3 g (0.050 mol) o~` N-hydroxye-thyl-4 (4-chlorophenyl-thio)-phenoxy-isobutyramide (prepared as indicated later in Example 7) in 75 ml o~ benzene~ The mixture is kept under re~lux ~or 1 hour 30 minu-tes and is then hydrolysed with ?
100 ml o~ ~ N sodium hydroxide solution, whilst cooling. The organic phase is decanted, washed with water and extracted ,.... ., ; ~ . , . , .; . , , , :
,; .. ~ , ~ . .~. ... .. . .. . .

~rith dilu-te hydrochloric acid, and after rendering the aqueous phase alkaline wi-th concentrated sodium hydroxide solution, 10.6 g of an orange produc-t are ob-tained.
Instantaneous mel-ting po.int (Kofler) = 50C.
_-yl~
oride Code No. CRL 40 ~ 238 10 g o~ the ~ree base of Example 1, in ethyl ace-tate, are treated with a solution o~ hydrogen chloride in e-ther.
After puri~ication of the precipitate by recrystallisation from a mixture of ethyl acetate and ethanol (1:2), 8 g of a slightly beige powder which is insoluble in water are : :~
obtained. -~
lS Instantaneous melting point (Kg~ler) = 148Co ` ~5~,,~ .
.

native ~ l~henoxy]- -z U~_ ' `

C1~ 3 : ' : Code No. CRL 40 ~ 2~9 `
A soluti.on o~ 10~75 g (0~033 mol) of p-(p-c~loro-phenylthio)-phenoxy-isobutyric acid (CRL 40,201) and of 10 ml ~; (0.100 mol) o~ hydrogen peroxide of 12.0 volumesstrength, in .

~0 6 4~ ~
50 ml o~ acetic acid, is heated at bet~een 55 and 70C for 3 hours. Therea~-ter the greater part of the solventsis driven off under reduced pressure and the residue is dissolved in diethyl ether, which is washed with water. After S evaporat1on of the solvent 7 the residual oil is solidi~ied in petroleum ether and after ~iltrat;ion gives 10.7 g o~ a white powder which is insoluble in water and soluble in alcohol.
Instan-taneous mel-ting point (K8fler) - 135C.
Yield = 91%.
Example 4 , Cl ~ s ~ 0-fH-CO2E~

~3 -~

A mixture of 13.65 g (0.050 mol) of ethyl (~)-2-~4-bromophenoxy)-propionate and 1106 g ~00056 mol) of cuprou5 ~ .
, p-chlorophenylthiolate in 100 ml of quinoline and 10 m' of anhydrous pyridine is heated to abou-t 170U~ ~or 4 hours~
Therea~ter the reaction mixture is poured onto 175 g o~ ice and 58 ml o~ concentrated hydrochloric acid. A~ter stirring overnight, the mixture is e~tracted with diethyl ether, which is washed successively with dilute hydrochloric acid and water and gives, a~ter evaporation o~ the sol~ent, 16.75 g o~ an orange-coloured oil.
Yieldr~ 100%~
' ' _ 17 - ~

, ~''' .

:.~ . . ; . . , ., ,; , , , . , " . , ~

s~

C1 ~ ~ = 9 ~ o-C~;coo~

Code No~ CRL 40, 246 A solution o~ 16.7 g (abou-t 0.05 mol) of -the pre-ceding ester and of 3 g (0.075 mol) of sodium hydroxide pellets in 50 ml of ethanol and 25 ml of wa-ter i5 heated to the reflux -temperature for 1 hour. The ethanol is then driven off under reduced pressure and the residue is ~ -diluted with 75 ml o~ wa-terO The aqueous phase is acidified~with hydrochloric acid and extracted with diethyl etherj and the extract is then washed with water. The organic phase is in turn extracted with a solution of po-tassium :
bicarbonate, and a~ter acidi~ication and filtration this aq~eous phase gives 12.4 g of a slightly grey powder.
After puri~ication of 12 g o~ this powder by crystallisation, and treatment with charcoal~ in diisopropyl ether, 8 2 g o~ a white powder which is insoluble in water and soluble in alcohol are obtained.
Instantaneous meltlng point t~B~ler) = 148C~
~0 ~
(Code No. C~L 40,248) On oxidising the acid o~ Example 5 (CRL 4Q,246) by means o~ H202 a,s describe~ in Example ~ 2~[4-(4-chloro-;. ;, ;': ~ ' , , , ., ' ~

S~

phenylsulphonyl)-phenoxy]-propio,nic acid is obtained.
Instantaneous melting point (Kofler) _ 178C.

~>~ i~7~ r-~d~, ~ ~ _ ~ lde ' Cl_ ~ ~5 ~ coNll-c~2c~l7oH

Code No. CRL 40,251 a) A mixture of 15 g (0~0465 mol) of p-(p-chlorophenyl-thio)-phenoxy-isobutyric acid (CRL 40,201) and of 16.75 ml (0.232 mol) of thionyl chloride is heated to the reflux temperature for 10 minutes. After having taken up the ?
reaction mixture in benzene, filtered the solution in the ~ presence of charcoal and evaporated the solvent, 16 g of an orange-coloured oil are obtained.
Yield = about 100%.
b) ~ -A solution of 16 g (0.040 mol) of the preceding acicl chloride in 25 ml of benzene is run over the course of 15 minutes into a suspension of 13.4 g (0.220 mol) of 2-amino-ethanol in 30 m:L of benzene at between 20 and 55C. The reaction mixture is heated to the reflux temperatur? for -- 19 -- ' . ~ . .., .; .: ,; ,.. . . . . .. . .. ..
, .. . . . . . . .
. .

2 hours and is evaporated to dryness under reduced pressure, The residue is dissolved in ethy~l acetate, which is washed successively with water, dilute hydrochloric acid and a solution o~ potassium carbonate. The oil obtained, after evaporation of the solvent, is puri~ied by washing in diîsopropyl ether (sic), giving 10.6 g o~ a powder which is insoluble in water.
Instantaneous melting point (KUfler) = 66C.
Yield = 62.8%.
Example 8 xy-~J

(C32~1o ~ 5-(CK~2-o-~-f-~o-G s~ ~

.
Codç No. CRL 40,253 a) ~
I5 A mixture of 15 g (0.0465 mol) o~ p-(p-chlorophenyl-thio)-phenoxy-isobutyric acid (GRL 40,201) and of 16~75 ml ~0.232 mol) of thion~l chloride is heated to the re~lux ternpera-ture for 10 minutes. A~ter having^taken up the reaction mixture in benzene, filtered the solution in the presence of carbon black and evaporated the solvent, 16 g of an orange-- coloured oil are obta.ined.
Yield = about 100%.

.~ : '.
~ - 20 _ .

b) ~
A solution of 13 g (0.038 mol) of the preceding acid chloride in 25 ml of benzene is run o~er -the course of 15 minutes into a suspension o~ 5 g (0 017 mol) o~ bis-1,10-(2-hydroxy-ethylthio)-decane in ZO ml of benzene and 3 g (0 038 mol) of pyridine at between 20 and 55C me reactants ar~ left in contact overnight at ambient temperature and the reaction mixture is then washed with dilute hydroahloric acid.
After drying over dry sodium sulphate and evapora-~ing the solvent, 17 5 g of an orange-coloured oil are obtained.
This oil is dissolved in diethyl ether and purified by 2 successive washes with potassium carbonate followed by dilute sodium hydroxide solution, giving 15.55 g of an orange~
coloured oil which is insoluble in water.
~ Yield = 94%, : ~-' ~@F~ ;
On reacting ethyl a-bromoacetate with p-(p-chloro-phenoxy)-thiophenol in acoordance with the process described . .
in Example 13 below, ethyl 4-(4-chlorophenoxy) phenylthio- ,,!, acetate is obtained in the form of an oil.
0 ' Cl- ~ ~ S-CH~-Coo~

~ ' ';
~ 25 Code No. CRL ~0,271 '.

Hydrolysis of -the product of Exa~ple 9 in accordance with the working me-thod described in Example 14 gives 4-(4-chlorophenoxy)-phenylthioacetic ,acid~
Ins-tantaneous melting point (Kofler) - 87C
~m~

Code No. CRI~ 40,272 On subjecting the acid of Example 10 to an amidifica~-tion reaction with 2-amino-e-thanol in accordance with the working method described in Example 8) CRL 40,272 is obtained.
Instantaneous melting point (Kofler) = 98C, Cl ~ _ ~ cH2 CH2-NH-cH~-c~x-oH

Code No. 40,274 a) ~ ) 3 ml (0.030 mol) o~ 10 N sodium hydroxide solution are run over the course of 10 minutes into a solu-tion of 6.85 g (0.029 mol) o~ 4-(4-chlorophenoxy)-thiophe~ol and 2~58 g (0.032 mol) o~ 2-chloroethanol in 20 ml oE ethanol, at between 20C and 42C. The mixture is stirred ~or 2 hours at ambient temperature and the solvent is then driven of'~ under reduced pressure. A~ter having dissolved the residue ~ 22 , . . ,, - -.
, . .

in diethyl ether, washed the organic phase ob-talned with dilute sodium hydroxide solu-tion and water and then evaporated -the solvent, 7.9 g of a fragrant pink powder are obtained.
This powder is purified by crys-tallisation ~rom cy-lohexane to give 6.6 g of a pale pink powder.
Instan-taneous melting poin-t (K8fler) ~ 6~C
Yield = 81. 2%.
~ L~Y~chloroethane 2 ml (0.0278 mol) of thionyl chloride are run over the course of 5 minutes into a solution of 6.5 g (0.0232 mol) o~ the preceding product in 15 ml of benzene and the mixture is then heated to the refl~ temperatùre ~or 1 hour. The reaction mixt~e is then evaporated to dryness under reduced pressure and the residue is dissolved in diethyl ether.
The organic phase obtained is washed with water and a -~
potassium carbonate solu-tion, dried over dry sodium sulphate and treated with charcoal, and the solvent is then evaporated to give 6.75 g of a white powder~
~ Instantaneous melting point (Kofler) = 59C
Yield = 97. 2%.
c) CR~ o 274 ~ .
A mixture of 6.7 g (0.022~ mol) of the preceding produc-t and of 6.85 g (0.112 mol) of 2-amino ethanol is heated slowly -to 170C (over the course o~ 30 minutes) Thereafter the reaction mixture is taken up in chloro~orm and the chloroform solution is washed successively with water, dilute sodil~ hydroxide solution and water. After drying, and evapora-ting the solven-t, 7.05 g of an oil which - 2~ ~

. ', : ': '` - " ` `

~L~64SC~

crystallises are obtained. 6.8 g o~ this product are purified by two successive cryst:allisations from diisopropyl ether to give 4.8 g of a ~hite powder which is insoluble in water.
Instantaneous melting point (K8fler) = 67-68C.
Yield of stage c = 70%.

~ _ .

~ ~ nat_ 9.05 g (0,0464 mol) vf ethyl a~bromoisohutyrate are run over the course of 15 minutes, at about 60C, into a solution o~ 10 g (0.0422 mol) o~ p (p-chlorophenoxy)-thio-phenol and 1 g (0.0422 mol) of sodium in 40 ml of anhydrous ~ ethanol. The mixt~re is stirred for 1 hour at ambient temperature and is evaporated to dryness under reduced ~; pressure~ After having dissolved the residue in diethyl ether, and washed the organic phase obtained with water and dried it over dry sodium sulphate, the solvent is evaporated, to ~20~ ~ ` glve 14~2 g of a limpid pale yellow oil.
Yield = 96%.

~b~n ~ e 2s propionic-acid C~}~_5-bP~00~

- 2~ -.

.
.

~6~S~9~
, Code No. CRL 40,275 - A solu-tion o:f 14 g (0.04 mol) o~ the ester of Example 13 and o~ 3~36 g (0.06 mo]) of po-tassium hydroxide pelle-ts in 20 ml of water and 40 ml o~ e-thanol :is hea-ted to -the reflux -temperature for 1 hour~ The ethanol is evapora-ted under reduced pressure and the residue is diluted with 50 ml of wa-ter, The solution is acidi~ied ~o Congo Red and the insoluble matter is extracted wi-th diethyl ether.
The organic phase obtained is in turn ex-tracted with a 0 ' potassium bicarbonate solution. A~ter acidifying this aqueous phase with concentra~ed hydrochloric acid, 10 g o~
a white powder which is insoluble in water are isolated by extraction with diethyl ether.
Instantaneous melting point (Kofler) = 131-132C
Yield = 77.5,b.

_15 . . ~ ' p~ ~

C1- ~ -o - ~ 9 .

2~ Code No. CRL 40,276 A solution o~ 9 g (0.027~ mol) o~ p-(p-chiorophenoxy)-phenylthio-isobutyric acid (CRL 40,275) in 75 ml o~' diethyl ether and 7~5 ml o~ tetrahydro:Eurane is run over the course , . .

, ~ ~ ~ 4S~ ~

of 30 minutes in-to a suspension o~ 2.4 g (0,0617 mol) of lithium aluminium hydride in 20 rnl o~ diethyl e-ther and the mixture is then s-tirred ~or 1 hour a-t the reflux temperature, The excess hydride is neutralised with ethyl acetate and the product is hydrolysed wi-th a dilute hydrochloric aoid solution, whils-t cooling. Af-ter washing the organic phase obtained with water and dilute sodium hydroxide solution, drying it and evaporating the solvent, 8.6 g o~ a limpid pale ycllow oil are obtained.
Yield: about 100%~
~ e~ _16 . ~

~} ~3S ~ CU2~NH-(C~)2-OH
.

Code No. CRL 40,~79 2.25 ml (0.031-l mol) of thionyl chloride are run over the course o~ 5 minu-tes into a solution of` 8 g (0.0259 mol) o~ p-(p-chlorophenoxy)phenyl-thio-isobutanol (CRL 40,276) in 30 ml o~ anhyclrous benzene ancl 0.5 ml o~ anhydrous pyridine.
The mixture is heated to the reflux temperature ~or 30 minutes and is evaporated to dryness under reduced pre,ssure.
A~ter dissolving the residue in diethyl ether, washing the e,ther solution with water and drying it over dry sodium .

,, sulphate, and evapora-ting the solvent, 8.05 g of 4-(4-chloro-phenoxy)-phenylthio-isobutyl chloride are obtained in the forM
of a limpid orange-yellow oil Yield = 95.2%.
A mix-ture o~ 8 g (0~024 mol) of the preceding product and 7.35 g (0.120 mol~ o~ 2-amino ethanol i3 gradua:Lly heated to 170 over the course of 30 minutes. The reaction mixture is taken up in diethyl ether, which is washed wlth water. The organic phase i5 extracted with a dilute hydrochloric acid solution, which is in turn rendered alkaline to permit the extraction of 6.85 g o~ a pale yellow oil which is insoluble in water and crystallises on cooling.
Melting point ~ 50C.
Yield = 81.5%
Total yield = 77.5%.
Erxample 7 nomencIature: 2-r4-(4-chlQro~henvlthio)-~henoxvl-2-methvl-, .
.
'. ~,'' C1~ S ~ I-COOH ;~

Code No. CRL 40,201 23.8 g (0.115 mol) o~ cuprous 4-chlorophenylthiolate (p-Cl~C6HL~-S-Cu) are added to a solution o~ 28.7 g (0.1 mol) o~ethyl 4-bromophenoxy-isobutyrate in 75 ml of quinoline and ., ~ 27 : . .. .

~45(~

25 ml of pyridine. The mixture is heated to 170~C
whilst stirring ~or ~ hours~ The solution is poured in-to ice containing 80 ml o:f concentrated HCl, the mixture is stirred for 1 hour and ex-tractecl with ethyl acetate, -the extract is washed with water.and. then with dilute bicarbonate and is dried, and the ethyl acetate is driven o~ in vacuo.
The oil thus obtained is dissolved in 120 ml o~ ethanGl and is treated for 1 hour, at the re~lux temperature, with 6 g (0.15 mol) o~ NaOH pellets in 75 ml of water, The ethanol is evaporated in vacuo, 200 ml of wa-ter are added to the residue and the acid is precipi-tated by means of concentrated HCl. It is filtered of~, washed with water, dried and .
recrystallised from diisopropyl ether. CRL 40,201 is obtained in a yield of 56%~
15: Melting point = 146-148C~ -: : Exa~le 18 ~ ~ro~ionic acid :; ~ ~ ' .
:~ .

al_~350 ~0 F 3 Code No. CRL 40,202 6.45 g (0,02 mol) of 4-(4~chlorophenylthio)-phenoxy- ;~
isobutyric acid dissolved in 25 ml o~ acetic acid are oxidised with Z ml (0.02 mol) of hydrogen peroxide o~ 110 volumes "
~ - 28 , .. .. . .. . . . . . .
, . , , . - ..
, . . .

~6~

stre}lg-th. The mixture is heated for 1 hour at 50C and is evaporated to dryness in vacuo, and the residue is taken up in diisopropyl ether, filtered off and recrystallised from ethyl aceta-te~ This gives CRL 40,202 in a yield of 86%.
Melting point - 140-142C.

4~ Chlor ~ d ~ - - ~ 2 Code No. CRL 40,333 ~ `
aj p-B
~ 25 g ~0.20 mol) o~ dimethyl sulphate are run over the `~
course of 45 minutes into a refluxing suspension of 34.4 g (0.20~mol) of p-bromophenol and 27.5 g (0.20 mol~ of potassium ;~ -carbonate in 150 ml of acetone. The re~lux is maintained Por a further hour, the inorganic salts are removed by fil-15~ tration and the filtrate is evaporated to dryness under reduced pressure. The residue is dissolved in diethyl ether,~ the ether solution is washecl with d:i].u-te sodium hydroxide solution and water and is dried over ~r~ sodium ` sulphate, and the solvent is evaporated to give 37.2 g of a slightly yelLow oil which is insoluble in water.
Yield - 99.5%
Boiling point/13 mm Hg _ 95C.
b) ~
A mixture of 67 g (0~520 mol) oP p~chlorophenol and .

.. :: , , : . . , , : . , 29~5 g (0.520 mol~ of KO~I pellets is heated to 100C for 2 hours ~nder a pressure of about 5 mm Hg. Thereafter 117 g (0.625 mol) of p-bromoanisole anrl 1 g of copper powder are added and the mixture is then heated to abou-t 220-230C for 5hou~.
The cooled rea¢tion mixture is -taken up in die-thyl e-ther and after removing the inorganic salts by filtration -the filtrate is washed with 2 N sodi~n hydroxide solution and with wa-ter.
The solvent is driven of~ under reduced pressure~drying is carried ou-t with sodium sulpha-te and 133 g of an orange-coloured oil are obtained. Purification of this oil by distillation under reduced pressure gives 70 g of a wnite crystalline mass which is insoluble in water Boiling point/2-3 mm ~Ig = 150C
Yield = 57.3%.
C) ~e~h~
A solution of 69 g ~0.294 mol) of the preceding product and~of 265 ml of 48% strength hydrobromic acid in 630 ml of acetic acid is heated to the reflux temperature for 2 hours and is then evaporated to d~yness under reduced pressure.
20 ; The residue is dissolved in diethyl ether, which is washed successively with water and a potassium bicarbonate solution.
~fter drying over dry sodium sulphate and evaporating the solvent o~ the organic phase, 64.7 g o~ a slightly beige powder are obtained. Purification of -this pcwder by crystallisation from cyclohexane gives 60.5 g of a white crystalline powder which is insoluble in water.
Instantaneous melting point (Kofler) - 82C
Boiling point/0.4 mm I-I~ = 143C
Yield = 93 5%.

1(J 6~5~

d) ~ ~
A solu-tion o~ 7.1 g (0.075 mol) of chloroacetic acid in 20 ml of ethanol is run over the course o~ 30 minu-tes into a solution, kept at about 60C, of 15 g (0.068 mol) o~ -the preceding produc-t and 6.3 g (0.157 mol) of sod.ium hydroxide pellets in 50 ml of water. The mixture is hea-ted to the reflux temperature for 2 hours, -the ethanol is driven o~f under reduced pressure and the residue ls acidified to Congo `I Red with dilute hydrochloric acid. The precipitate obtained is filtered off and dried. The purification of this pre-cipi~-te by washing with hot diisopropyl ether gives 10 g of a slightly pink crystalline powder which is insoluble in water Instantaneous melting point (Ko~ler) = 162C -;
; . Yield of stage d) = 53% ~ -Total yield = 21.2%~ ~ ~

Ci~ o~ CH-CooH
H

~:
Code No. CRL 40,299 a) ~ ~ n te 2009 g (0.115 mol) of ethyl 2~bromo-propionate are run over the ~ourse o~ 30 minutes into a hot solution of 23 g (0~10~5 mol~ o~ p-(p-chlorophenoxy)-phenol and 2.4 g (0.1045 mol) of sodi~n in 90 ml of anhydrous e-thanol and the mixture - 31 ~

.

.
.

, - ~ 6 ~

is then heated -to the reflux ternpera-ture for 2 hours. The inorganic sal-ts are removed by f`iltration'and the ethanol is driven off under reduced pressure. After having dis-solved the xesidue in die-thyl ether, washed the solut:ion with water, dried the organic phase over dry sodium sulphate and evaporated the solvent, 32.5 g o* an orange~coloured oil which is insoluble in water are obtained. -, Yield 97%.
b) ~ 9 , A solution o~ 32 g (0.10 mol) o~ the preceding produc-t and o~ 8.4 g (0.15 mol) o~ po-tassium hydroxide pellets in ~' lO0 ml of ethanol and 50 ml of demineralised water is heated ' -; to the,re~lux temperature ~or 2 hours. The ethanol is ,-, , -' ;~ driven off under reduced pressure and the residue is taken ,~'~
1,5 ~up~in wa-ter. The solution obtained is acidified to Congo Red and the insoluble matter is extracted with die~hyl ether.
~; The organic phase obtalnsd is in turn e'xtracted with a potassium bicarbonate solution. After acidi~ying thi.s '~
aqueous phase with concentrated hydrochloric acid, 25 g o~ a white powder which is insoluble in water are isolated by extraction with diethyl ether.
~; ` Instantaneous melting point (Ko~ler) = 121C
Yield of stage b) = 85.6%. "
_21 , ~ . AOY'~
d .. , . `:
:~ ~
.
32 _ , :

c~ o~ o~ 3Oo Code No. CRL 40~308 17.5 ml (0.1530 mol) o~ chlorof'orm are run (over the course of 30 minutes) in-to a hot suspension o~ 25.9 g (0.1175 mol) o~ p-(p-chlorophenoxy)-phenol and 28.2 g (0.7050 mol) o~ sodium hydro~:ide pellets in 152 ml (2.3500 mols) o~ acetone and the re~lux is ~hen maintained ~or 4 hours. me reaction mixture is evapora-ted to dryness under reduced pressure, the residue is taken up in water and -the mlxture is acidifled to Congo Red with concentrated , hydroohloric acid. ~ me insoluble matter is extracted with die-thyl. ether and the~organio phase is in -turn ex~ . :;.
; traoted with a potassium bicarbonate solution~ Acidifi~
cation of the aqueous phase with concentrated hydrochloric aoid liberates a precipitate which is isolated by filtration~
15 : ~Purificat1on o~ this precipitate by -two successive crystalli~ :`
sations and treatment with charcoal (CXA) in cyclohexane gives 25.6 g of a slightly yellow powder which is insoluble in water.
~ ~ :Instantaneous melting point (Ko~leL) , 131C
: Yield - 74%.

, ~ 33 -~

. . .

~6450~

Cl ~ 0 ~ 3 S~ COOH

Code No. CRL 40,281 a) ~ e 56 g (0.400 mol) of potassium carbonate and 5.6 g of pur.ified copper are added to a lukewarm solution (~60C) of 51.5 g (0.400 mol) of p-chlorophenol and 72 g (0,456 mol) -o~ p-chloronitrobenzene in 40 ml of dimethylformamide and the mixture is then heated to the reflux -temperature for .~

5 hours. The inorganic salts are removed by filtering -. .
the reaction mixture and the dime-thylformamide is evaporated under reduced pressure, . The residue is purified by er~rstallisation from methanol to give 83.2 g of a yellow bei~e powder. ~ .
Instantaneous melting point (Ko:~ler) - 73C
Yield = 83.2%.
b) 91 g (0.364 mol) of the preceding product and 54.5 g (l.O90 mols) of hydrazine hydrate are dissolved in 900 ml of methanol at about 50C. This tempe.rature is malntained ; ~.
and a su~ficien-t amoun-t of Raney nickel to decompose the : ~
. ~
~; hydrazine is added in small portions over the course of 5 hours, after which the m~.xture is heated to the reflux :~ , ~ ' , .
~ 3 :

. . ..

4S6~

tempera-ture for 1 hour. Af-ter having removed t~e catalyst by filtration in the presence o~ charcoal (CXA) and evaporated the solvent, puri:Eication by crystallisation from cyclohexane gives 60 g of l:ight beige needles.
Instan-taneous melting po:int (Ko~ler) = 101C
Yield = 75%.
c ) ~
59.5 g (0.270 mol) of the preceding product are introduced, all at once, into a hot solution o~ 5~ ml (0.675 mol) o~ l2.5 N hydrochloric acid and o~ 375 ml of water. The mixture is cooled and a solution o~ 22.6 g ~ ;
(0.298 mol) of sodium ni-trite (taken to be 90% pure) in 100 ml of water is run in over the course o~ 45 minutes at between 0 and ~5C. The excess nitrous acid is ~ r ~ - ' L~ ~ destroyéd with a pinch o~ urea (negative reactive on an ~ ~
iodine/starch paper). me reaction mixture is kept ~-at about ~5C and is run in portions, over the course of l hour 15 minutes, into a solution o~ 56 g (0.351 Imol) of potassium ethyl-xanthate in 60 ml o~ water, kept a-t 40C.
, Thereafter the oily suspension obtained is heated ~or 1 hour to 60C and thè insoluble ma-tter is extracted with diethyl e-ther to give, after evapora-tion of the solve1lt, 90.2 g of an orange-red oil.
This oil is treated for 4 hours with 38 g (0.675 2S mol~ o~ potassium hydroxide pellets and 200 ml o~ water at the bol1, then acidified to Congo Red with 6 N sulphuric acid a~d again treated at the boil ~or 4 hours in the presence of 5 g of zinc powder. The mix-ture is rendered alkaline ~ .

wi.th NaOH, the aqueous phase is washed with diethyl ether and acidi~ication o~ the latter gives 45,85 g o~ a yellow powder.
Instan-taneous mel-ting poin-t (Kofler) = 55C
Yield = 72,2%, (d) ~ eno~ ate 8.4 g (0.0464 mol) of ethyl a-bromopropiona-te are run over -the course of 10 minutes9 at about 50C, in-to a solu-tion o~ 10 ~ ~0.0~22 mol) of the preceding product and 1 g (0,0422 mol~ o~ sodium in 40 ml o~ anhydrous ethanol, The mix-ture is heated -to the re~l~ temperature ~or 30 minutes, the inorganic salts are ~r~ved ky~tra-tion and the ethanol is driven of~ ~lder reduced pressure. The residue is taken up in diethyl ether; the organic phase obtained is washed wi-th water, dried over dry sodium sulphate and treated with char-coal (CXA), After ev~poration o~ the solven-t, 14.2 g ~ of a limpid pale yellow oil which is insoluble in wa-ter are ,: ~~ . . ..
obtai~ed.
Yield = about 100%.
e) ~
~ A solution of 14~2 g (0.042c mol) o~ the preceding ~ ~;
product and of 3.54 g (0.0635 mol) of potassiwm hydroxide pe`llets in 20 ml o~ wa-ter and 40 ml o~ ethanol is heated to ~ -~
the reflux temperature ~or 2 hours. The ~lcohol ls evaporated ~mder reduced pressure and the reaction mixture is diluted with wa-ter. The solution is acidi~ied to Congo Red and -the insoluble matter is extrac-ted wlth diethyl ether~ T:he organic phase obtained is in turn ex-tracted with a potassium bicarbonate solution. After acidi~ying ~. ,, ..
~, ~

. . . . . . .

45~

.
this aqueous phase with concentrated hydrochloric acid, 12~25 g o~ a pale yellow powder are isola-ted by extraction with diethyl ether. 12 g of this powder are purified by crystallisa-tion and trea-tment wi-th CXA charcoal in cyclohexane, to give lO g o~ a ~hite powder which is insoluble in water.
Instan-taneous melting point (Kofler) _ 103C
Yield of stage ~ = 83.l~%
Total yield - 35.4%.
Example 23 , ; Cl _ ~ 0 ~ o-c~2-c~ o~ ;~

Code No. CRL 40,293 ;

6.6 g (0.082 mol) o~ 2-chloro-ethanol are run over the course of 5 minutes into a hot solution oE 15 g (0.068 ~ ; mol) oE p-(p-chlorophenoxy~-phenol and 2.75 g (0~068 mol) ; ~ 15~ of sodium hydro$ide pellets in 40 ml o~ anhydrous ethanol.
The mix-ture is heated to the reflux ternperature ~or 4 hours, the inorganic salts are removed by ~iltration and the ethanol is driven oE:E under reduced pressure. A~ter having ta~en up the reaction mixture in diethyl ether, washed the 20 organic phase thus obtained with 2 N sodium hydroxide solu-tlon and with water, dried it and evaporated the solven-t, ll g o~ pasty crystals are obtained.
10.5 g of these crys-tals are puriEied by crystallisa-, : .

., .. ,, . ; .. ; . . .. ,, ..... . ~ . . . . .

1~645~9~

tion from diisopropyl ether to give 6.7 g of shiny white flakes.
Instantaneous melting point (Kofler) = 78C' Yield = ~95~.
~E~
', clature: 2- ~ ~ ; i :: .
. .

Cl - ~ - o - ~ o-C-cH~OU
~3 :, .
Cvde No. CRL 40,310 A solutlon of 12 g (0,0392 mol) of 4-(4-chlorophenoxy)-~pheno~y-isobutyrlc acid (CRL 40,308) in 80 ml o~ anhydrous diethyl ether and 2~ml of tetrahydrofurane is run over the course of 30 minutes~into a suspension of 3,35 g (0,088~ mol) o~ L1AlH4 1n 30 ~1 o~ anh~drous diethyl ether and the reflux is Ihen maintained~or l hour 30 minutes, The excess 5~ ; h~dr1de~ lS ~neutralised with ethyl acetate and the complex is hydrol~Jsed with a dilute hydrochloric acid soluticn. The , organic~phase is decanted and washed wi-th water and dilute sodium hydroxide solution, and a~ter drying and e~aporation , .. .
o~ the solvent gives ll.5 g o~ a thick yellow oil ~hich is insoluble in water, Yield about 10~/o.
Example 25 ;~`
4-(4-Chlorcphenoxy)-phenoxy-isobutyl mesylate alt~rnative , !
, , : ' ' :' " ' ' ; : ., ': " ' ' , ' , ' ' ' ' ' ''.' . :, .'. ' 5(~4 pro~l methanesulphonate Cl ~ - o- < ~ o-l~C~l2~50~l3 , . Code No. CR.L 40,312 4.1 g (0.0356 mol) of methanesulphonyl chloride are run (over the course of 8 minutesj into a solutlon, kept at about 10C, of 10.4 g (0.0356 mol) of 4 (4 chlorophenoxy)- `
phenoxy-isobutanol (CRL 40,310) in 17.5 ml o~ a~h~drous , ' .
pyridine, and the mixture is stirred ~or 1 hour at ~mbient ..
temperature. The reaction mixture is poured onto ice and is acidified to Congo Red wlth ooncentrated.hydrochloric-acid. , ~
The insoluble matter is extracted with ethyl aceta~e and the. . ~ :
organic phase thus obtained is washed wlth~water~ dried and~
evaporated , to dryness ~nder reduced pressure, to give 13.7 g of a yellow powder. The puri~ication of thls ~ }5 powder by crys-talllsation and treat,ment with charcoal (CXA) ; : in diisopropyl ether gives 10.5 g o~ a white powde.r which is ~ . .
insoluble in water.
; ~ Instantaneous melting point (Ko~ler) = 85C ,.
: Yield i 78.3%.
~ a~
: ' ' , . , ''' Cl~O_~S ~-C~2~
.
: - 39.-, ''' ' .

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

lL~6~4 Code No. CRL 40,282 A solution of 9 g (0~292 mol) of (~)-2~[4-(4-chloro-phenoxy)-phenylthiopropionic acid (CRL 40,281) in 75 ml of ;
anhydrous diethyl ether and 2 ml of dried tetrahydrofurane is run over the course of 50 minutes into a suspension of 2.5 g (0.0656 mol) of LiAlHL~ in 20 ml of anhydrous diethyl ether.
The mixture is heated to the re~lux temperature for 1 hour, the excess hydride is destroyed with ethyl ace-ta-te and hydrolysis is carried out with a dilute hydrochloric acid solution. ~f-ter washing the organic phase thus obtained with water and dilute sodium hydroxide solution, then drying it over dry sodium sulphate and evaporating the solvent, 8.6 g o~ a water-insoluble colourless oil having a yellow sheen is obtained. -15 : Yield = about lOOyo.

o~ zc~l2o~

:' :
Code No. CRL 40,300 A solution o~ 22.5 g (0.077 mol) o~ 2-[4-(4-chlorophenoxy)-phenoxy]-propionic acid (CRL 40299) in 150 ml of anhydrous dieth~l ether is run over the course of 1 hour 30 minutes into a suspension of 6.6 g (0.173 mol) o~ LiAlH4 in 50 ml o~ anh~drous diethyl ether. Thereafter the , - 40 _ , .. .. . ... . . . .. .. .. ... . ...
~, ~ . , ,,, ,, . ;
~ ~ : . : . , ., . - . : .--.
.. ... .. . . .. .. . ....

so~

reflux is maintained for 1 hour 30 minutes, the excess hydride is neu-tralised with ethyl acetat;e and the complex is hydroly-sed with dilute hydrochloric acid. The organic phase is decanted, washed with water and dilute sodium hydroxide solution and gives, a~ter drying over dry sodium sulphate and evaporation of the solvent, 21.4 g of a crystalline white mass, which is insoluble in water.
Melting point ~50C
Yield about 100%u ~ . ;

Cl _ ~ o ~ ~ -5~2~ ~l Code~No. CRL 40,332~
A solution of 8.15 g (0.075 mol) of 1-chloro-2-methyl- ~-15 ~ 2-propanol in 20 ml of ethanol is run over -the course o~ ;
:
25 minutes into a solution, kept at about 60C, of 15 g (0.068 mol3 of p-(p-chlorophenoxy)phenol ~d ~3 g (0.075 mol) o~ sodium hydroxide pellets in 20 ml of water and 2~ ml o~
.
~ ethanol. rme mixture is heated to the reflux tempera-; 20 ~ ture for 2 hours and the ethanol is driven o~ under reduced ; pressure. The residue is extracted with diethyl ether and after drying and evaporation o~ the solvent gives 7.3 g of a yellow oil. This oil is puri~ied by crystallisa-:
tion from a mixture o~ cyclohexane and petroleum ether (1:2 by volume) followed by washing with 2 N NaOH~ 4 g of a ~:

.

~ 5~ ~

white powder ~hich is insoluble in water are obtained.
Instantaneous melting point (Ko~ler) = 55C
Yield: 20.3%.
~ .
~ ~ e~b~ e _ b'o~.de Cl ~ ~ 0 _ _ ~ o-(cH2)2-NH2 ~ ~Cl Code No. CRL 40,317 a) ~
A solution o~ 3,78 g (0.0500 mol) of chloroaceto- ~ -nitrile in 10 ml o~ anhydrous ethanol is run over the course of 20 minut~s into a solution o~ 1,04 g (0.0453 mol) of sodiwQ andllO g (o, 04s3 mol) of p-(p-chlorophenoxy)-phenol in .. . ~ .
50 ml of anhydrous ethanol and the mixture is then heated to ~the reflux temperature for 4 hours. It is evaporated -to dryness under reduced pressure and the residue is dis~
sol~ed in diethyl ether, which is washed ~ith water and wi-th dilute sodium hydroxide solution~ ~fter drying over dry sodium sulphate and evaporating the solvent ~rom the organic phase, 12 g of a~ orange-coloured oil are obtained.
Puri~ication o~ this oil ~y dis-tillation under reduced ~ pressure gives 9.5 g of a limpid pa]e yellow oil which is insoluble in water~ ;
Boiling point/0.4 mm Hg ~ 165C
Yield - 81%.
b) ~ 7 A solutio~l of g g (0,0347 mol) of the preceding .
~2 nitrile in 50 ml o~ anhydrous diethyl ether is run over the course of 50 minutes into a suspension o~ 3O3 g (0.0868 mol) of LiAlH4 in 40 ml of anhydrous diethyl ether, The mix-ture is heated to the reflux temperature for 1 hour, the excess hydride is neutralised with eth~l acetate and the complex is then hydrolysed wi-th dilute sodium hydroxide solution. The organic phase is decanted, wa~hed with water, dried over dry sodium sulphate and evaporated to give

7.5 g of a limpid pale yellow oil which crystallises.
4.5 g of this product in diethyl ether are treated with a solution of hydrogen chloride in ether. A~ter puri~ication o~ the Frecip~*eoktained,by crystallisation and treatment with CXA charcoal, in a mixture of isopropanol and cyclohexane (1:1 by volume~, 2 g of a beige powder which is ~ r ~ , soluble in water are obtained~
Instantaneous melting poln~ (Ko~ler) - 215C
Yield of stage b) - 21.4%

~ .

~ Cl ~ ~ ~ C~l2-C~2- S0~-CH3 :~ . , , , 2.6 g (0.0227 mol) of methanesulphonyl chloride are run over the course of 5 minutes, at about-~10C, into a solution of 6 g (0.0227 mol) of 2-[4-(4-chloropheno~y)-phenoxy]~ ethanol (CRL ~0,293) in 11 ml o~ pyridine and the . .
_ 43 _ 5~

mixture is then stirred ~or 1 hour a-t ambient temperature.
Thereafter -the reaction mix-ture is poured on-to ice and acidified to Congo Red with concentra-ted hydrochloric acid.
After extracting the insoluble ma-tter wi-th e-thyl acetate, washing the organic phase obtai.ned with water and drying it over dry sodium sulphate, evaporation of -the solvent gives 7.8 g of a white powder.
Instantaneous mel-ting point (Kofler) = 68C
Yield about 100%.
10 ~3~, , .. . ' ' ~
:(cH ) -NH_(CH2)2-OH~ ~Cl ~ ~;

Code NoO CRL 40 295 A mixture of 7.8 g (0 0227 mol) o~ the preceding pro-lSduct and o~ 13.8 g (0.2270 mol) of 2 aminoethanol is heated slowly to 170G. The reaction mixture is allowed to return to ambient temperature and is taken up in water.
A~ter extracting the insoluble matter with diethyl ether, washing the extract with water, drying it and evaporati.ng the solvent, 6.55 g o~ a white powder which is insolu~le in water are obtained~
Instantaneous melting point (Ko~ler) = 98C ~ !
6 g of this product, in ethyl ace-tate, are treated with a solution of hydrogen chloride in ether and the product ' , . ., ; , ~ ~ .

~1~6~ 4 is then purified by crys.tallisation from a mixture of ethanol and ethyl acetate (1:~ by volu~le), to give 5.6 g of a hydro-chloride which is in the form of white flakes soluble in water to the extent of 200 g/l.
Instantaneous mel-ting point (Kofler) - 141C
. Yield = 77~5%
~ , ' ", C ~ __O ~ cH2)-N(c2N5)2 J

:-Code No. CRL 40 330 A solution of 13.2 g to 075 mol) o~ 2-(N,N-diethyl- : ;:;
amino)-l-chloroethane hydrochloride in 30 ml of water is run over the course of 3Q minutes into a solu-tion, kep~ at about 60C,~of:15 g (0.06~ mol) of p-(~-chlorophenoxy)-phenol and ~:; 15 6.~ g~0.157 molj of sodium hydroxide pellets in 20 ml of water and 20 ml of ethanol. The mixture is heated -to the reflux temperature for 1 hour and the ethanol is evaporated . ...... under reduced pressure~ The aqueous phase is extracted with diethyl ether and the organic phase obtained is washed , with water until neutral, dried over dry ~odium sulphate and evapora~ed to d:ryness under reduced pressure The oily : . : .
: residue is treated in a sblution of hydrogen chloride in ~: diethyl. e-ther, to give 20 g of a white powder, Recrystalli ~- , :, .
.
~5 i . ' .

5 ~ ~

sation f.rom ethyl aceta-te gives :18 g of CRL 40 3~0 Instantaneous lilelting po.int (Kofler) = 119C
Yield 74.3%

~ .
~ . .
, .Cl_~0 ~0-~-CH2-NH-tCil2)2-OH~ HCl Code No. CRL 40 311 ,A,solution o~ 7.8 g (0.0386 mol~ of sodium bis-(2-methoxy-ethoxy)-aluminium hydride in 25 ml of henzene is run 1~ ~ over the course of 45 minutes into a solu-tion, at the re~lux ~ .
temperature, of 9 g (0.0257 mol) of M-ethanol-2-[4-(4-chloro-phenoxy)-phenoxy~-2~methyl~1-propionamide ~CRI, 40 309), pre parRd as indicated in Example 38, in 40 ml o~ anhydrous : ,benzene, and the reflux is maintained for a further 45 minutes.
1,5 me co~piex is.hydrolysed with dilute sodium hydroxide solu-tion and the organic phase is decanted, washed with water and dried; evaporation o~ the solvent gives an orange-coLoured oil.' This oil :Ls treated with a solution of hydrogen chlor-Z0 ' ,ide in diethyl ether, the precipitate obtained is isolated by ~iltration and the mother liquor is evaporated so as to ' : reco~er the unreacted starting amide. Purification o~
the precipitate by a further conversion to -the hase and then ' - 46 --.~ .

~6i4S~4 : to the salt, and by a crystallisation ~ro~ a mixture of ethyl acetate and ethanol (1:1) in -the presence o~ charcoal (CXA) i gives 1.6 g of a white powder wh:ich is soluble in water, Instantaneous melting po:int (Kofler) = 133C
S
(+)-2-~ y~ r~yl me~

Cl - ~ 0 ~ Cll2-o-so2-Cll3 .8:~1 g (0.07 mol) o~ methanesulphonyl chloride are run, at about 10C, into a solution o~ 19.5 g (0,07 mol) o~ 2-[4-(4-chlorophenoxy)-phenoxy]~ propanol (CRL 40 300)prepared '~
as indicated in Example 27, in 35 ml of pyridine. The reaction mixture is~stirred for~l hour at ambient temperature and is poured onto ice, The insolubie matter is extracted with diethyl ether and~the organlc phase obtained is washed with dilute hydrochloric acid and dried, to,give a white pasty 15~ residue a~ter evaporation o~ the solvent. me solidi~ica-tion of this residue in petroleum ether gives 24 g o~ a whi-te , powder whioh is insoluble ln water.
Melting point below 50C, Yleld: 96.2%, - 20 ~

: amine h~ clloride ~ ~ .
..
47 ~

.... , , ., . ... ~. . ~ . .

5~

O~ 0-C~I-C~12-NH-~cH2)2-OH~ HCl Code No. CRL 40 301 A mix-ture o~ 10 g (0.028 mol) o~ -the mesylate of Example 34 and of 17 g (0.280 mol) of 2-aminoethanol is slowly heated to 170C. The reactio~ mlx~ure is S allowed to return to ambient -temperature and is taken up in water. A~ter extracting the insoluble matter with diethyl ether, washing the organic phase with water and drying ;~
it o~er dry sodium sulphate, 8.7 g of a pale yellow oil are cbtained.after evaporation of the solvent. 8.4 g of :
10 this product, in ethyl acetate, are treated with a solution : of hydrogen chloride in ether and the product is then purified by crystallisation from a mixture of ethyl acetate and anhydrous e-thanol (7:2 by volume) to give 8.3 g of white flakes which are sol.uble in water -to.the extent of 200 g/l.
lS ~ : InstantanPous melting point (Kofler) = 145CC
.Yield = 86%
' ' ' ' ~, ' .

C _O{~-CIl-cN2-NN-c-c1120~1, NFl Code No. CRL 40 302

8 ~
' , ~064S~

A mixture of 13 g (0.0365 mol) of the mes~flate of Example 34 and of 32~5 g ~0.365 mol) o~ 2~amino-2-me-thyl-1-propanol is heated 510wly to 170C The reac-tion mix-ture is allowed to return to amb.ient temperature and is taken up in water. The insoluble mat-ter is extracted with diethyl ether and the organic phase obtained is washed with water and dried over dry sodium ~sulphate to give, after evaporation of the solvent, 1207 g o~ a limpid pale yellow oil. After treating 12 g of this oil in a solution of hydrogen chloride in diethyl ether, and purifying the produot by crystallisation from ethy] acetate, 11.2 g of a whlte powder which is soluble in water to the extent of 200 g/l are obtained. :
:~ Instantaneous melting polnt (Kofler) = 125C .
lS ~ Yield = 84. 2%

.

_ ~ J-~l-C~2-~-(cll2)2 ON

Code No. 40 2~3 a) ~
2.35 ml (0.0326 mol) of thionyl chloride are run, over .the course of 7 minu-tes, into a solution of 8 g (0.0271 mol) of (~)-2-[4-(4-chlorophenoxy)-phenylthio~ l-propanol (CRL

. - 49 ~

i:; ~ . . . .

40 282~ prepared as lndicated in Example 26 and o~ 0 5 ml of pyridine in 30 ml of anhydrous ~enzene The reaction mixture is heated to the reflux temperature for 1 hour and - is washed with wa-ter and with a potassium bicarbonate solution.
Af-ter drying over dry sodium sulphate and evaporating the sol-vent, 8.05 g of a limpid pale yell~w oil which is insoluble in water are obtained.
Yield 95%~
b) ~
A mix-ture o~ 7.95 g (0.0254 mol) of the preceding product and of 7.75 g (0~1270 mol) of 2-aminoethanol is heated gradually to 170C over the course of 1 hour. The re-~action mixture is taken up with diethyl ether, which is washed with water. me aqueous phase is extracted with a dilute hydrochloric acid solution; the insoluble oil ~;~ between the two phases is lsolated7 taken up in water and extracted with diethyl ether in the presence of potassium carbonate. After drying the organic phase over dry sodium sulphate, treating it with CXA charcoal, and evapora-ting the solvent, 7.8 g of a yellow oil are obtain~d. 6 g of this oil are purified by a f~r~erbase/salt conversion to give 5.75 g of a pale yellow oil which is soluble in an aqueous hydrochloric acid solution at between pH 3 and pH 7.
Yield o~ stage b) = 87~2%
Total yield - 83%

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

.

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

Cl ~ 0 - ~ o~ C ~ (CN2)2-~

Code No. 40 309 a) A mixture of 12 g (0.0392 mol) o~ 4-(4-chlorophenoxy)-phenoxy-isobutyric acid (CRL 40 308) prepared as described in Example 21, and of 14.15 ml (0.1960 mol) of thiony1 chloride is heated to the reflux temperature for 50 minutes The reaction mixture is tàken up in benzene, the solution is , ~iltered in the presence of CXA charcoal, and a~-ter having evaporated the solvent under reduced pressure 12.5 g of - 10 a brown-red~ oil are obtained.' Yield = 95,5%.
' b) ~
A solution of 12 g (0.0369 mol~ o~ the preceding product in 40 ml of anh~drous benæene is run(over the course of ' 15 minutes), at between 20 and 36C, into a suspension o~ 11.3 g ~' (0.1850 mol) o~ ethanolamine in 30 ml o~ anhydrous ben~ene.
The reaction mixture is heated to 'the re~lux temperature ~or 1 hour and is then washed s'uccessively with water, dilute ~odiu~ hydroxide solution and a dilute hydrochloric acid solution. A~ter drying over dry sodium sulphate, filtering, and evaporating the solvent ~rom -the organic phase, .
an orange-red crystalline mass is obtained. CRL 40 309 is : ~ .

~L~6~50~

purif.ied by crystallisat.ion, and.-treatment with CXA charcoal, in diisopropyl e-ther, to give 10.25 g of a slightly yellow powder which is insoluble in water.
Instantaneous melting poin-t (Kofler) = 77C
s Yield of stage b) = 79.5%
To-tal yield = 76%.
, ~ .
hydrochlor1de ~:

, C ~ o ~ o-c~2-coN~ cu2)~-N \ ~ilC1 Code No. CRL 40 334 a) A mixture of 8~3 g (0.029B mol~ o~ 4~(4-ohlorophenoxy)~
phenoxy-acetic acid (CRL 40 ~33) prep.ared as indisated in Example l~ and of 10 8 ml (0~1500 mol) o~ -thionyl chloride is - ~ :
; heated to the re~lux temperature for 30 minutes~ After , having taken up the reaction mixture in benzene and evaporated the solution -to cLryness under reduced pressure, 8.7 g of a beige powder are.obtained.
. ~ Instantaneous melting point (Kofler) = 64C
20 : Yield = ~8.3%
b) ~
; , .~ : : A solut;ion of 8.5 g (0.0286 mol) of the preced.ing . :
: product in 20 ml of anhydrous benzene is run over -the course o~ 15 minutes, at between 20C and 40C, into a solution of -' ~ ', ';:

' '" ;' , ' ~4~0~

16.6 g (0.14~0 mol) o~ N,N~diethyl-ethylenediamine in ~0 rnl of anhydrous benzene. The reaction mixture is heated to the reflux temperature for 30 minutes and is then washed with water After drying, and evaporating the solvent from the organic phase, 10.75 g o~ an orange-coloured oil are obtained.

9.5 g of this oil 9 in diisopropyl ether, are treated with a solution of hydrogen chloride in ether and the pre-cipi-tate obtained is puri~ied by crystallisation ~rom ethyl acetate to give 9.8 g of a slightly beige powder ~hich is soluble in water.
Instantaneous mel-ting point (Kofler) - 120C
Yield o~ s-tage b = 94.5%
Total yield = 93%

Cl ~ 0 - ~ 0-C~2-C-, ~ . HCl OI~

Code No. CRL 40 337 A ~uspension of 5~37 g (0.0772 mol~ of hydrox~rlamine hydrochloride and of 7.72 g (0.0772 mol) of potassium bicarbon-ate 1~ 8 ml o~ wa-ter is added, all at once, -to a suspension o~ 10 g (0.0385 mol) of 4-(4-chlorophenoxy)-phenoxy-ace-to-nitrile prepared as indicated in Example 29a)~ .in 24 ml of n-butanol. The mixture is heated to the reflux tempera-ture ~or 1 hour, the butanol is driven of~, the re~sidue is , - 53 ~

-~ 50 ~
taken up in wa-ter ancl the insolu'ble matter is extracted with die-thyl ether. The organic phase is washed with water, dried over dry sodium sulpha-te and evaporated, and the residue obtained ,is p~lrified by washing ~with ho-t diisopropyl ether to give 10 g of brilliant white needles.
Instantaneous melting point (Kofler) = 99C ?
After treating 9.5 g o~ this product in a solution of hydrogen chloride in diethyl ether and purifying -the product by crystallisation from isopropanol, 10.15 g o~ a white powder which is partially soluble in water are obtained.
Instantaneous melting point (Kofler) = 148C ~ ;
- Yield = 85% - `' Example'41 4-~4-Chlorophenoxy~=phenoxy-acetamidine hydrochloridev ' .

~ 1 ~ o ~ o-CH2-C \ . ~Cl .- . , , ..
Code No~ CRL 40 338 1' ``
. ~ . ': ' a) Ethyl 4~(4-ch~orophenox~ -phenoxy-acetimidate hydrochl_ride A solution of 15 g (0.0578 mol) o~ 4-(4-chlorGphenoxy)-phenoxy-acetonitrile prepared a.s indicated in Exa~ple 29a) and ,~
o~ 3.7 ml (0.0637,mol) of anhydrous ethanol in 75 ml of '' anhydrous diethyl ether is kept at about -5C and a stream of ,~
dry hydrogen chloride gas is F~ssed intoi~ for 2 hours.
.
Therea~ter -the reaction mix-ture' is left ~or 4 hours at about 2C and 19.25 g o~ a white powder are isolated by ~iltration~
, :

~6~5~
Instantaneous melting point (Ko~ler) ~ 148C
Yield = 97.5%
` b) ~
A stream o~ NH3 is passed over the course of 1 hour at abou-t 10C into a soluti.on o~ 10 g (0.0292 mol) o~ the preceding pr3duct .in 100 ml o.~ anhydrous ethanol, m e reaction mixture is s-t.irred for 4 hours at am~ient temperature and is then evaporated to dryness under reduced pressure.
', After puri~ying the residue by washing it wi-th diethyl ether, 8.55 g of a white powder are obtained. 7.55 g of this po~der are again purified by a crystallisation and a treat-ment with CXA charcoal in isopropar.lol, to give 6.05 g o~ a white product which is soluble in water.
Instantaneous melting point (Kofler) = 166C -lS Yield o~ stage b~ = 75.5%

~; chloride : : :
~ CL_ ~ 0-CH ~ 3 .71Cl . . ~ , I
:~ }I ....
.
Code No CRL 40 322 ~ A solution o~ 6 g (0.0175 mol) o~ the product o~ ;
Example 41a) and o~ 1.25 ml ~000184 mol) of et~ylenediamine in 40 ml o~ anhydrous ethanol is heated to the reflux tempera-ture for 2 hou~ 30 minutes. The ethanol is driven off .:
' . ::' ~4504 under reduced pressure, -the residue is taken up in dilute sodium hydroxide solution and the insoluble ma-t-ter is extracted with diethyl ether~ The product obtained a~ter evapora-tion of the solvent is puri~i.ed by washing i.t with diisopropyl ether, to give 4 g of a white po~wder which is insoluble in water~
Instantaneous melting point (Kofler) = 117C
After treating 3.8 g of this powder, in ethyl acetate, with a sol.uti.on of hydrogen chloride in ether, 3~8 g of a white powder which is soluble in hot water are obtained.
Instantaneous melting point (Kofler) = 166C
Yield = 80.5%~
The examples which ~ollow illustrate the production of a) addition salts with acids (compare Examples 43-45 and 47-48) ~.
lS and b) an ester (compare Example 46) ~rom an acid of the formula I (R = COOH) and from a free base belonging to the ~.:
: group of bis-[(N-hydroxyalkyl)-amino-alkylthio]-alkanes of ~ the formula: .
, Bo-NRo-A~-sox-(cH2)n-sox-~o-NRo-go 20 : More precisely, the acids which were used are~
fcr Examples 43 and 46, CRL 40 201, which has been described in Example 17, . '~
~or Example 44, CRL 40 239 which ha~ been described in .
~xample 3, " c: ' for Exa,~ple 45, CRL 40 248 which has been described in . Example 6, ~or Example 47, CRL 40 202 which has been been described in Exampie 18, and ~ 56 - :.

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

~45~4 for Example 48, CRL 40 246 which has been described in Example 5.
The free ~ase used in Examples 43-48 is 6,17-dithia-3,20-diaza-1,22-docosanediol, wh:ich in the ~orm o~ the dihydro-S chloride has been given Code No. LL 1,770.

'b~

(C~ rs-(ca2)2-~2-(c}~2~2-o~l]2~ 2C ~ ~ ~C-Coo Code No CRL 40 240 A hot solution o~ 6.45 g (0 02 mol) o~ p-(p-chloro-phenylthio3-phenQxy~isobutyric acid in 25 ml o~ anhydrous ethanol is run into a hot solution of 3.8 g (0.01 mol) of 6,17-dithia-3?20-diaza-1,22-docosanediol ~free base of LL
15 ~ 1,770j in 25 ml of anhydrous e-thanol. I'he mlxture is stirred for 2 hours at ambient tempera-ture and the solvent then evaporated under reduced pressure. Af-ter having :: :
washed the residue with acetonitrile, 8,~ g o~ a slightly beige powder which is insoluble in wa-ter but soluble in alsohol are obtained. Instantaneous melting point (Ko~ler) - 75C. Yield - 82/~
Exam~le 1~l~

' ~ ' .
` 7 ' LS~

~C~Z~ CII2)2 ~2-(CII2)2-0H72 2C1 ~ 2 ~ -c-CoO

Code No. CRL 40241 A hot solu-tion o~ 6.6 g (0.0186 mol) of p-(p-chloro-phenylsulphonyl)-phenoxy-isobu-tyric acid in 25 ml o~ anhydrous ethanol is run into a hot solution of 3.54 g (0.0093 mol) of 6,17-dithia-3,20-diaza-1,22-docosanediol in 25 rnl of anhydrous ethanol. The mixture is stirred for 2 hours at ambient temperature and the solvent is then evaporated under reduced pressure. After having washed the residue with aceto-~ nitrile, 9~9 g of a slightly pir~ powder which is insoluble in water and soluble in hot alcohol are obtained. Instan-taneous melting point (Kofler) = 137C. Yield 98%.

:: :

2) L(~S (CH2)2~NH2-(CH2)2_o~1~ , 2Cl{~S02~0-CH-COO
,. :

Code No~ CRL 4024g A hot solutiorl of 5.10 g (0.0150 mol) of (~)-2-[p- ;
(p-chlorophenylsulphonyl)-phenox~-propionic acid in 20 ml of ar~drous ethanol is run into a hot solution of 2.84 g ; ~ - 5~ _ .; , ~,.. ,:: ` : . .:.:, .

~ ~f~04 (0.0075 mol~ of 6,17-dithia-3,20-diaza-1,22-docosanedio] (free base of LL 1,770) in 20 ml of anhydrous ethanol. APter having left the reactan-ts in contact ~or 15 minutes the solvent is evaporated under reduced pressure. The crystalline residue is then washed wi-th acetonitrile to give 7.8 g of a white powder which is insoluble in water and in alcohol. Instantaneous melting point (Ko~ler) =
149-150C. Yield: 98.3%.
~ .

10 ~ ~
~*~ ' :' 2 2 ~
2)10 S~(CH2)2-N \ _CH3 ~ /==~

~ ~ bH3~5--~C~

Code No. CRL 40 25 a) ~A mixture o~ 15 g (0~0465 mol) o~` p~(p-chlorophenyl-~
15thio)phenoxy-isobutyric acid and of 16.75 ml (0.2320 mol~ of thionyl chloride is heated to the reflux temperature for 10 minutes. A~ter havlng taken up the reaction mixture in benzene, filtered the solution in the presence of charcoal and evaporated the solvent, 16 g of an orange-coloured oil are obtained. ~ield: 100%.
b) CRL 40 254 A solution o.f 17 g (0~050 mol) of the acid chloride .

~L~69LS~

obtained as above, in 50 ml of chloroform, is run over the ; course of 50 minutes, at 0C, into a suspension o~ 9,5 g (O.OZ5 mol) of 6,17-dithia-3,20-diaza-1,22-docosanediol (free base of LL 1~770) and of 5 g (0.050 mol) o~ triethylamine in 75 ml of chloroform. After having stirred the reaction mixture overnight a-t ambient temperature~ it is washed successively with water, a dilute hydrochloric acid solution and a potassium bicarbonate solution, and the solvent is then evaporated under reduced pressure, to give 23 g of a thick orange-coloured oil. A~ter puri~ication o~ 15 g o~
this oil by chromatography on a si.lica column, 7.7 g o~ a limpid orange-coloured oil which is insoluble in water are ~ ,~
obtained.
~ Total yield ~ 48%.

~ ~, o 1 ~-(C3~2~ r~c~ 2~ ]2' 2C~O~ oo~) Code No~ CRL 40 242 A hot solution o~ 6.77 g (0.02 mol) o~ CRL 40 202 in 25 ml of ethanol is run into a hot ~olution o~ 3.8 g (0.01 mol) of 6,17-dithia-3,20-diaza-1,22-docosanediol in 25 ml of ~ e~hanol. The mixture is stirred ~or 30 mi~utes at ;~ ambient ternperature and the solvent is then evaporated under ~ - 60 -, .- ,. . .... . . . .. ...

reduced pressure ~ter having solidified the resldue in diisopropyl ether, 10.4 g of a white po~Jder which is insoluble in water and soluble in alcohol are obtained.
Instan-taneous melting point (Kofler) = about 85C
Yield = 98.5%

6 17-Dithi^ ',~J~ l Z2-docos ~ -phenyl ~ te]
'' /==~\ /~\ I CH3 ~3 (CH2)10rS (CH2)2-NH2-(C~l2)2-o}l]2~ 2 C1 ~ S ~ 0-~H~Coo Code No~ CRL 40 247 A hot solution of 4.62 g ~0.015 mol) of CRL 40 246 in 20 ml of anhydrous ethanol is run into a hot solution o~
2.84 g~: (o~bo7s mol) of 6,17-dithia-3,20 diaza-1,22-docosane diol in~20~.1 of anhydrous ethanol A~ter having left 15` ~ the reactants in contact for 15 minutes, the so]vent is evaporated wnder reduced pressure. The residue is then solidi~ied in acetonitrile to give 7 2 g of a whi-te powder which is insoluble in water and soluble in alcohol.
In~tantaneous melting point (Kofler) - about ~0C
Yield = 96,5%.

:: ~ :
; ,~
~: . ;

' ~

. ~ ..

;4S~4 The results of the pharmacological tests which were undertaken both in respec-t of the hypo-lipidaemic properties and hypo-cholesterolaemic properties, on the one hand, and of the anti-aggregation proper-t:ies, on the other, have been summarised below.
The hypo-lipidaemic ac-tion and hypo-cholesterolaemlc action have been demonstrated by s-tudying various battches of i Wistar rats: ~
` A. A batch of rats receiving a normal diet (percentage :
inhibition = 100%);
B. a batch of rats receiving a hyper-lipid diet (percentage inhibition = 0%);
C. a batch of rats receiving -the hyper-lipid diet B with ~ .
a daily dose, of 0.1 g/kg) of a reference product having a lipidaemia-normalising action, namely Lipavlon [ethyl 2-(p~
: chlorophenoxy)-2-methyl-propionate];
D.~ a;batch of rats receiving the hyper-lipid diet B with a ~; ~ daily dose7 of 0.1 g/kg, of another product having a lipidaemia~normalising ac-tion, namely LL 1558 Cl,10-bis-(2-hydroxyethyl-thlo)-decane]; and E, a batch of rats receiving the hyper-lipid diet B with a daily dose of 10 mg/kg and 25 mg/kg and, where necessary, higher doses. ~
m e ant;i-aggregation action has been demonstrated by studying the pardmeters which characterise -the curve ~or the aggregation of platelets induced;
a~ by collagen : the inhibition o~ aggregation (which corres-ponds to the % transmission), the la~ency period and the : .
~ - 6~ -.i:

.
: .

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

~/l9645~*

speed; and ; b) by ADP: the inhibi-tion o~ aggrega-tion (that is to say the % -transmission).
In Table II which follows have been shown the results S relating to CRL 40,201 (the ~roduct of ~xample 17) and CRL 40,202 (the product of Example 18) in respect of the , hypo-lipidaemic action and hypo-cholesterolaemic action.
,, Table II shows that CRL 40,201 and CRL 40,202 are very active hypo-lipidaemic and hypo-cholesterolaemic agents because at a dose of 0.025 g/kg they each have an activity comparable to the two reference products administered at a dose of 0.1 g/kg.
In Table III which ~ollows have been shown the results -.
relating to the antl-aggregation action o~ some products on `
~15 the blood o~ male Wistar rats, the aggregating agents used -being collagen/acetic acid diluted lllO, and A M at 1 ~ M.

: : :

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

63 - ~

,1 ' ' ~ ''~'.
, .

1~4~

_ __ . .. __ _ . .. ~. __ __ h O

rl O rl ~) ~ ~ ~ N
~ ~r .
r~ _ , ____ __ _ _ __ __ __ .,, l ~ ~o -! ~ 0 oo E~ ~0 O ~ ~ ~ ~ r~ t~i ~
_ ~ ____ ._ _ ._ _ _ .

u~ r~ .
~d O ' O ~ ~ ~t C:) ~ 1~_ ~ '' ' ' ~ ~ .
-- u~ __ .~._ _ :. _ . ,.~ , E~ ~ O ~D ~: ~ O 0 . . .
~;bO ~ ~ ~ C' :~ C~ ~ ~
rl~ __ ______ : : ~ ~ h ~ . .
~d ~ O O O O O O

h: : ~i ~1 rd ~11 ~: ~ ~ ~ h rl +3 Pi'o ~Q ~lo ~ . ~ 1~ ~ ~ Lt~ ~ ~ ~ ~ I~ ~ ~
O ~:1 ~ ~rl rl ~ .~1 'dl ~1 ~rl ~d~l Pl r ~ ~ 11 ~ 0 11~ I bO rl ~ rl ~) ~ ~0 ~ :

o h h ~ ~! ~ ~N h o h hO

~ 64 5~4 __ ~1 ~ .~ ~ o~ o~
o ~ ~
.~ _ ~ ......... _ ~ ."
~ .1 ~J N ~ . .

~0 bO E~ ~
. ~l d N~1 0 ~ O ~

~ ~ __ . __ . . ., " ''.
$ h rl ~\1 ~I rl C~l ~ ~ ~ ~1 ~ + ' + ~ + ~
_ _ , ,~
:; -: ~ ~ : ,.~. `'' :
o Q) a) u~ a .
H ~ ~ q I ~ h h ~ h J ~ O h ~ ;t ~ ;1 . ~.

:~,~~ O O O O O O
: ~ o~ ~ o ~ ol ~ ` .,` ~-: O ~___ : ~
. a) ~ \I J ~D ^
~; C~ ~ ~ ~

:; - . _ , ~,~
' ~j' ~ ;t' .:. _................... .

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

.

51~4 The results of Table III show -that the products studied are anti-aggregation agents, the most interesting ~ :
amongst them being CRL 40,23~ (Example 2) and CRL 40,276 (Example 14) and above all CRL 40,271 (Example 10), which in addition to the anti-aggregation effect exhibi-ts a h~po-lipidaemic action (total lipids : 35% inhibi-tion) and hypo-cholesterolaemic action (cholesterol : 54% inhibition) at a dose o~ 0.1 g/kg in rats.
The results o~ the anti-aggregation test and of the hypo-lipidaemic action and hypo-cholesterolaemic action tests of other products of the invention have been lised in Table IV which follows, the code used being the following (for ~: each dose shown): . ' zero activity ~ signi~icant activity : +
: intense activity : +*
ery intense activit~ : ++~
:: :

:

:~ : ' : :

" .
' ' , ~ ' ~:; ' ' , ~ . - 66 -3164~0~

~: ._ ~ __ . _ ... . .
rl . .
~ . ,,' .(r) ., 2~ `2ci~ ~ 2~
r~ ~t ~ I J ;i J ~J
'E~ h ,, " ., .. ,. ,. ,. ., +' u~ ta cq ~ a~ 'd rOI ~:11 rO ~,dl rO 'd rO~ l l l J .
rl r~ ~ h ~ o ~ ~1 a) ,~ a r ~ O r~ + r~ ~1 1-> r~
l l r-l a~ r~l O r-l O r~ ~ . :
O O t~ r~ 1~ r~ ~ r-l 1~ r-l 1~4 +'o ~o ~o ~1~0 ~ E~ ~ E~ ~ E~ ~ E~ ~
_, . __ . . .. ~ ~__ ..... - : _ ~ ~ _~ '~ ' :
~rl S: ~ ~ : .
. I ~ 0~ ~ . _ +~a~ t + . , h t~) -~ .t ~ - I ~ + + +
h' : .~ ~
- - - ~.. - - - - - : :-:

: ~ ~ h ~ h ~ ~d ~d ~ ~d ~d .

:h ~ I q~ ~ ~

r~ ~ ~0 El ~ ~ ~ ~ 13 t~l r~ r~ O rl 0~ rl r~ 0~

~: : ... ~ _ ____ ___ . __ _-_ ~ ~ ' ~ ' ~ ~ ~I ~ .~ 0~ O c~l . "
~ ~ ~d ~ ;l ~ ~ ~J ;l ~ ~
~ ~ ~ v ~ v ~ ~ ~! ~! ~ ~ ~!
_ _ .. __ ... ___ _ _ _ _ ,, ,,;, :, .
r-l . . ~;
~ 1~1 -_ 0~ -_~ _ ~ 1:- O ~:'''~
:. ~ : , ~. .

:: ;~

- 67 ~
, ~ , . ~
.

. ~.. . . . . . . .. . . .

:`~
:`
+~l r~ .
~ E~ ~ ~ ~ ~ (~ ~ ~ ~ ~c~
O r~ ~ L~ rl ~ ~\1 ~ r Ir-l rll rll r h .
a) -1~ u~ M u~ u~ u~
O.) ~r O ~rl O rl O rl O 'd ~I rO
~ 4 r~ r~ +~ r a) rl(V r (l) rl (1~
O O E-l V E C~ E~ C ) E ~ 1: E O
~__ . ._ __~ _ . __ _ ~............. _ _._ rl g .
rl td r + + + + + + + h t~ bO ~ ~
_ _ ___ _ _ ~__ h rd ~ ~1 ~ ~ ~d rd~ ~d ~0 ~_ ul ;~ ;~ ;~ ~ ~ ;~ ~!; h H 1>7 h tO tH r~~ h O h h r¦ X ~ ;~ ~ r~C
r-l ~3 ~ El E3 ~3 ~i ~1 O
:h r~ O O rl oo O t-l tH
~._._ ~. _ . ._ __ ~. . _ _ O

æ ~ ~ ~ o oo ~ ~ ~On ~> J ;l J ~O ;I ~ ~O . ~:) ~ ~! ~ ~! ~! Ei~! ~ ~! ~ ~ ., rl ~ ___ __ __ .
~ C`J r I ~ ~ C~ O~ ;i' .
~:1 _~ _ ~; ~ .
. ____ _ _ -~

-- 68 -- .

i ~:, . . . .

: :. .
.

-:
The other pharmacological tests which have been carried out with CRL 40,293 (ExaMple 23) have been lis-ted below. :
Toxicity In female mice~ the L~--50 on oral adminis-tration is 2,050 mg/kg. In male rats, the LD-O, on oral administration?
i~ i5 grea-ter than 600 mg/kg.
It has fur-thermore been observed that CRL 40,293 is a well-tolerated subs-tance. In fasting rats (a batch o~ 3 animals) which receive 1 g/kg o~ the product -through a probang, no ulceratlon or inflammation of the stomac.l and of the duodenum is observed after killing the animals 8 hours a~ter administration.
Cardio-vascular activity Three anaesthetised dogs are used for this study.
e product is administered intraduodenally as a gum suspen~
sion. ~
Two dogs with the thorax closed and respiring spon-taneously are given CRL 40~93 at a dose of 100 mg/kg 20~ ollowed by 200 mg/kg, this second dose being administered ` -~
- 1 hour 30 minutes to 2 hours after the .~irst. None of the . parameters measured changed during the 2 hours' observation (arterial pressure 7 pulse rate, le~t intra-ventricular pressure, dp/dt, vertebral and ~emoral arterial flow rates and respiration).
One do~ wi-th -the thorax opened is given 100 mg/kg, followed a~ter 1 hour by 200 mg/kg, of CRL 40,293. None of the parame-ters measured changed during the 2 hours' , ~Ll)64S~

observation (arterial pressure9 pulse ra-te, left intra-ventricular pressure, dp/dt~ aorta flow rate, work of` the left ven-tricle, coronary ar-terial flow ra-te) In these animals -the effec-ts of in~ections of nor-adrenalin , acetylcholine, t~raminet DMPP, his-tamine and serotonine were unchanged and the same is true o~ the e~fects of occlusion of the carotids and of stimulation of the central end and peripheral end of the vagus~
The product has a good hypo-lipidaemic and hypo-cholesterolaemic activi-ty as indicated in Table IV for an oral dose of 50 mg/kg. Fur-thermore, at a daily oral dose of 10 mg/kg the decrease in total lipids and in cholesterol is 20% after 3-4 days' treatment.
The clinical tests have made it possible to confirm the pharmacological tests, mus~ ln man9 CRL 40,293 (Example 23) in the form of gela-tine-coated pills containing 400 m6 Of active ingredient administered at the rate of 2 such pills~twice daily has given good results in the treatment of cirGulatory complaints and especially of lipid clisturbances.
~ ~ CRL 40,317 (Examp1e 2~) and CRL 40~295 (Example 31) each in the form of a -tablet containing 250 to 500 mg of active ingredient~ and administered -to man to prevent cardio--vascular accidents, were well tolerated, especially in -the treatment of coronary insuf~iciency.
CRL 40,271 (Example 10) was well lolera-ted in man and has proved efficient in the treatment of circulatory com-plaints due to hyperlipidaemias when used in the ~orm of a gelatine~coated pill containing 200 to 400 mg of active ingredient and taken at the ra-te of 1 -to 2 such pills per day.

.
.

;" ~ - "
. . ~ .. . . .

Claims

The embodiments of the invention in which an exclu-sive property or privilege is claimed, are defined as follows:

1. Process for the preparation of sulphur- and oxygen-containing diaryl compounds of the formula:

I

in which A is O, S, SO or SO2, B is O or, when A is O, S, Alk is a C1-C4 hydrocarbon radical with a straight or branched chain, R represents COOH, an esterified COOH group, a carboxylic amide group, OH, O-SO2CH3, NH2, NHR1, NR1R2, NHZOH, NHZNR1R2, C(=NH)NH2, C:(=NH)NHOH or 2-.DELTA.2-imidazolinyl, Z is a C2-C4 hydrocarbon radical with a straight or branched chain, and R1 and R2 each represent a C1-C3 lower alkyl group, and their addition salts with bases when R is COOH, and their addition salts with acids when R is a basic radical, which comprises reacting a diphenyl derivative of the formula:

II

in which A and B are as defined above, with a halogen compound of the formula:
Hal - Alk - R' III
in which Alk is as defined above, Hal represents halogen, and R' is COOC2H5, OH, NH2, NHR1, NR1R2, NHZOH, NHZNR1R2, or CN to produce a compound of the formula:

IV

followed, if desired, by:

(a) hydrolysing a carboxylate (IV, R' = COOC2H5) to the corresponding acid (R = COOH) which may then be converted into an amide or other ester;
(b) converting an alcohol (IV, R' = OH) into the corresponding mesylate (R = OSO2CH3) by reaction with methane-sulphonyl chloride; or (c) reacting a cyanide (IV, R' = CN) with NH3, NH2OH or H2NCH2CH2NH2 in the presence of an alcohol to produce an amidino compound in which R is C(:NH)NH2, C(:NH)NHOH, or 2-.DELTA.2-imidazolinyl.

2. Process according to claim 1 for the preparation of a compound of the formula:

Ia in which A is O, S, SO or SO2, B is O or, when A is O, S, and Y is CH2, CH(CH3) or C(CH3)2, and its addition salts with organic bases, which comprises reacting a compound of the formula:

with a bromo compound of the formula:
Br - Y - COOC2H5 and hydrolysing the ester obtained.

3. Process according to claim 1 for the preparation of an amine of the formula:

Ie in which A is O, S, SO or SO2, B is O or, when A is O, S, Y1 is CH2CH2, CH(CH3)CH2, C(CH3)2CH2, CH2CH(CH3) or CH2C(CH3)2, and X2 is NH2, NHCH2CH2OH, NHCH(CH3)CH2OH, NHC(CH3)2CH2OH, NHCH2CH2N(CH3)2, NHCH2CH2N(C2H5)2, N(CH3)2, N(C2H5)2 or NHCH(CH3)2, and its addition salts with acids, which comprises reacting a diphenyl derivative of the formula:

with a chloroalkylamine of the formula:

where A, B, Y1, and X2 are as hereinbefore defined.

4. Sulphur- and oxygen-containing diaryl compounds of the formula:
I

in which A is O, S, SO or SO2, B is O or, when A is O, S, Alk is a C1-C4 hydrocarbon radical with a straight or branched chain, R represents COOH, an esterified COOH group, a carboxylic amide group, OH, O-SO2CH3, NH2, NHR1, NR1R2, NHZOH, NHZNR1R2, C(=NH)NH2, C(=NH)NHOH or 2-.DELTA.2-imidazolinyl, Z is a C2-C4 hydrocarbon radical with a straight or branched chain, and R1 and R2 each represent a C1-C3 lower alkyl group, and their addition salts with bases when R is COOH, and their addition salts with acids when R is a basic radical, when prepared by the process claimed in claim 1 or any obvious chemical equi-valent thereof,

5. Sulphur- and oxygen-containing diaryl compounds of the formula:

Ia in which A is O, S, SO or SO2, B is O or, when A is O, S, and Y is CH2, CH(CH3) or C(CH3)2, and its addition salts with organic bases, when prepared by the process claimed in claim 2 or any obvious chemical equivalent thereof.

6. Sulphur- and oxygen-containing diaryl compounds of the formula:

Ie in which A is O, S, SO or SO2, B is O or, when A is O, S, Y1 is CH2CH2, CH(CH3)CH2, C(CH3)2CH2, CH2CH(CH3) or CH2C(CH3)2, and X2 is NH2, NHCH2CH2OH, NHCH(CH3)CH2OH, NHC(CH3)2CH2OH, NHCH2CH2N(CH3)2, NHCH2CH2N(C2H5)2, N(CH3)2, N(C2H5)2 or NHCH(CH3)2, when prepared by the process claimed in claim 3, or any obvious chemical equivalent thereof.