Note: Descriptions are shown in the official language in which they were submitted.
3~
The present invention relates to the use of 2,4-
dichlorophenyl-triazolyl-ethan-ones and ols as antimicrobial
agents, in particular as antimycotics.
It has already been disclosed that phenoxy-triazolyl
derivatives have a good antimycotic action tcompare German
Offenlegungsschriften (German Published Specifications)
2,247,18~ and 2,324,424). However, their action, in particular
against dermatophytes, is not always completely satisfactory.
The present invention provides a pharmaceutical
composition comprising an effective amount of an active
ingredient which is a 2~4-dichlorophenyktriazolyl-ethan-one or
; ol compound of the following general formula or its salt
Cl
- O - ~H - A - ~ - Cl (I)
~n ~N
N
in which A is a keto group or a CH(OH) group, each X is independ-
ently of any other X present, halogen, alkyl or optionally
~ substituted phenyl, and n is an integer having a value of
`/ 0, 1, 2 or 3, together with a pharmaceutically acceptable
carrier or diluent.
Those compounds of the formula (I) in which A repre-
sents the CH(OH) ~roup have two asymmetric carbon atoms; theycan therefore exist in the form of the two geometric isomers
(erythro form and threo form), which can be obtained in various
proportions. In both cases, they exist in the form of optical
isomers. All the isomers are included within the scope of the
presenk invention.
Surprisingly, the 2,4~dichlorophenyl-triazolyI-ethan-
:
~3~1~3~&i
ones and -ols which can be used according to the invention
exhibit a better antimycotic, therapeutically useful activity
then the phenoxy-triazolyl derivatives known from the state
o~ the art, which are the most closely related compounds
chemically and from the point of view of their activity.
The ~ub~tances which can be u~ed according to the invention
thus represent an enrichment of pharmacy.
Pre~erred compounds according to the invention
include compo~ds o~ formula (I) in which each X is one of
lG halogen e~pecially ~luorine 9 chlorine, bromine or iodine,
straight-chain or branched alkyl having 1 to 4 carbon atoms
and phenyl which is optionally substituted by halogen,
especially chlorine; n is an inte~er having a value of 0, 1
or 2, and A has the 3ame meaning a~ defined hereinbefore.
~xamples which ~ay be mentioned of particularly active
representatives o~ the active compounds according to the
invention~ in addition to those of the preparation examples
and the examples o~ Table 1, are the following: 1-(2-
chlorophenoxy)-2-(2~4-dichlorophenyl)~ 1,2,4-tria~ol-1-yl)-
ethan~2-one and ol, 1-(2-Isopropylphenoxy)-2-(2,4-dichloro
phenyl)~ 294-triazol 1-yl3-ethan 2-one and -ol, 1-(2-
methylphenoxy)D2-(2,4-dichlorophenyl)-1-(1,2,4-triazol-1-yl)-
ethan-2 one and -ol, 1-(2~chloro-4-methylphenox~)-2-(274-
dlc110rophenyl)w1-(172,4-triRzol-l-yl)-ethan-2 one and -ol,
1-(4~bromophenoxy)~2-(2,~-dichlorophenyl)-1-(1,2,4-triazol~l-
yl)-ethan-2-one and -ol 9 1- ~ 4-iodophenoxy) 2~(2,4~dichloro-
phenyl)-l-(l 9 2,4-triazol-l~yl) ethan~2-one and -ol, 1-(2,
6-dichlorophenoxy)-2-(2,4-dichlorophenyl)-1-(1,2,4-triazol 1-
yl~-ethan-2-one and -ol 9 1-( 2,5-dichlorophenoxy)-2-(2 9 4-
dichlorophenyl)-1~(1,2,4-triazol~l-yl)-ethan-2-one and ~ol,
~ - 3 -
36
1,(5 fluorophenoxy)-2 (2,4-dichlorophenyl) 1-(192,4-triazol_
l-yl)-ethan-2-one and -ol~ 1-(3-~romopheno~y3-2-(2,4-dich-
lorophenyl)-1-(1,2~4 triazol-1-yl)-ethan-2-one and -ol,
1-(4-methylphenoxy)-2-(2,4-dichlorophenyl)-1-(ly2,4-triazol
l-yl)~ethan 2~one and -ol, 1-(4-ethylphenoxy~-2-(2 9 4-dichloro-
phenyl)-1~(192,4-triazol-l-yl)-ethan-2 one and -ol, 1-(3-
methylphenoxy~-2-(2~4-dichlorophenyl)-1-(1,2,4-triazol-1-yl~-
ethan-2-one and -ol, 1-(2-methylphenoxy)-2-(2,4-dichlorophen-
~ 2,4-triazol l yl)-ethan-2-one and -ol, 1~(4-chloro-
2-methylphenoxy)-2-(2g4-dichlorophenyl)-1-(1~2,4-triazol-1-
yl)-ethan-2-one and -ol~ 1-(4-bromo-2-methylphenoxy)-2-
(2,4 dichlorophenyl)~ 2,4-triazol-1-yl)-ethan-2-one and
ol, 1~(4-fluoro-2-methylphenoxy)-2-(2,4-dichlorophenyl) 1-
(1,2,4-triazol 1-yl)-ethan-2~one and -ol~ 1-(4-iodo-2~methyl-
phe~o2y)~2-(2,4-dichlorophenyl)-1-(1,2,4 triazol-l yl~-
eth~n-2-one and ol, 1-(2,~dimethylphenoxy);2-(2,4-dichloro- .
phenyl~ (1,2,4-triazol-1-yl)-ethan~-2-one and -ol, 1-(4-2',
4'-dlchlorobiphenylyloxy)-2-(2,4-dichlorphenyl3-1-(1,2,4- -
~ : triazol-l-yl)-ethan-2-one and -ol, 1-(4-2,4'-dichlorobipheny~
20~ ~loxy)-2-(2~4-dichlorophenyl)-1-(1,2,4-triazol-1-yl3-ethan-2-
one and -ol, 1-(4-4'-bromobiphenylyloxy)-2-(294-dichloro-
. phenyl)~ 2,4 triazol-1-yl~-ethan~2-one and -ol and~l
~4~2-chlorobiphenylyloxy~-2-(2,4-dichloro~hen~ 1,2~4-
~:~ triazol-l~yl) ethan-2-one and -ol~
: However~ they can be prepared accor~ing to our own
proposal, by reacting 1-bromo-2-(2~4-dichlorophenyl)-1-phenoxy-ethan-
2~ones o the formula
,
~ - .
3~
- 0 - CH - C0 - ~ - Cl
~I' '
(II)
in which
X and n have the same meaning as defined hereinbefore
in form~la (I~ with 19294-triazole in the presence of an
inert organic solvent, for example acetonitrile, and in the
presence of an acid-billding agent, for example potassium
carbonate or an excess o~ 1,2,4-triazole, at a temperature
of from 0 to 150C, preferably at 60 to 1~0C~ and where
necessary reducing the 1,2,4-triazolyl-ethanones, thereby
obtained, with a complex borohydride~ for example sodium
borohydride, in a manner which is in itself known in the
presence of a polar organic solvent, for example methanol,
at temperature of from 0 to 30C so as to produce the corres-
pond m g 1,2~4-triazolyl-ethanols. The compounds of the
formula (I) may be isolated b;y conventional techniques.
~he l-bromo-2-(2,4~dichlorophenyl)-1-phenoxy-ethan-2-
ones of the ~ormula `(II) to be used as starting substances
:20~ are not yet known~ However, -they can be prepared by known
: processes~ by reacting ~ppropriate phenols wlth ~bromo-2,
4-diohlorQscetophenone and~subsequently replaclng the~active
hydrogen~atom which still remains bY brcmine by conventional~
techniques O
~ : ~Preferred salts o~ the compounds cf the formula (I~
are salts with physiologically acceptable acids~ Thess
:: include, preferably~ ~alts~wlth hydrogen halide aclds, such~;
as, for example, hydrochloric acid and hydrobromic acid, in~
particular h~drochloric acid, phcsphoric acid, nitric~acid,~
monofunctional and bi~unctional carboxylic acids and hydrcxy_
~ 5
3~
carboxylic acids, such as, -for example, acetic acid, citric
acid, sorbic acid and lactic acid, and 1,5-naphthalene-di-
sulphonic acid.
The new compounds of formula (I) and their salts can
~e interconverted in any suitable manner; methods for such in-
terconversion are known in the art.
The compounds of the formula (I)~ which can be used
according to the invention, and their salts, exhibit anti-
microbial, in particular powerful antimycotic9 effec~s. The~
1~ possess a ver~ broad spectrum of antimyco~ic activity, especi-
ally agains~ dermatophytes and blastomyces as well as bi-
phase fungi, for example against varieties of Candida, such
as Candida albicans, varieties of Epidermophyton, such
Epidermophyton floccosum, varieties of Aspergillus, such as
Aspergillus niger and Aspergillus fumigatus, varieties of
Trichop~yton, such as Trichophyton mentagrophytes, varieties
of Microsporon, such as Microsporon felineum and varieties of
Penicillium, such as Penicillium communc. The recital of
these micro-organisms in no way implies a limitation of t~e
2~ germs which can be combated but is only of illustrative
character.
The following may be mentioned as examples of fields
; of indication in human medicine: dermatomycoses and systemic
mycoses caused by Trichophyton mentagrophytes and other varie-
ties of Trichlophyton, varieties of Microsporon, Epidermophyton
floccosum, blastomyces and biphase fungi as well as moulds.
The following may be mentioned as examples of fields
of indication in veterinary medicine: generally all dermato-
mycoses and systemic mycoses, especially those caused by the
3Q above mentioned pathogens.
- 6 -
,~ "
".~",
36
As stated above, the invention also ~lates to the
use in human and veterinary medicine of the compounds of the
invention.
The present invention pro~ides a pharmaceutical compo-
sition containing as active ingredient a compound of the
invention in admixture with a solid or liquefied gaseous
diluent) or in admixture with a liquid diluent other than a
solvent of a molecular weight less than 200 (preferably less
than 350) e~cept in the presence of a sur~ace active agent.
The invention further provides a pharmaceutical
composition containing as active ingredient a compound of
the invention in the form of a sterile and/or isotonic aqueous
solution.
The invention also provides a medicament in dosage
unit form comprising a compound of the invent~on.
~he invention also provides a medicament in the form
of tablets (including lozenges;and granules~, dragees, cap-
sules 9 pills ~ ampoules or suppositories comprising a com-
pound of the inventionO
2~ "Medicament" as used in this Specifica~ion means
: ~ :
ph~sically discrete coherent portions suitable for medlcal
;administration. "Medicament in dosage unit~form" as used
:
in this Specification means physically discrete coherent
units suitable for medical administration each containing~a
daily dose~or a multiple (up to ~our times) or sub-multiple
(down to a ~orbieth) of a daily dose of the compound of~ the
~; invention in association with a carrier and/or enclosed wibhin
;an envelope~ Whether the medicament contains a dally dose
or7 ~or example, a hal~9 a third9 or a quarter of a daily dose~
7~ill depend on whether~the medicament is to be administered
:
once or, for example, twice, three times or four times a
day respectlvely.
The pharmaceutical compositions according to the
invention may, for example, take the form of ointments, gels,
pastes, creams, sprays (including aerosols), lotions,
suspensions, solutions and emulsions of the active ingred
ient in aqueous or non-aqueous diluents, syrups, granulates
or powders~
~he diluents to be used in pharmaceutical compositions
(e.g. granulates) adapted to be formed into tablets, dragees7
capsules and pills include the following:
(a) fillers and extenders, e.gt starch, sugars, mannitol,
and silicic acid; (b) bindin~ agents, e~g. carboxymethyl
cellulose and other cellulose derivatives, alginates, gela-
tine and polyvinyl pyrrolidone; (c) moisturizing a~ents,
e.~. glycerol; (d) disintegrating agents, e.g. agar-agar,
calcium carbonate and ~odium bicarbonate; (e~ agents ~or
retarding di~solution e.g. par~ffin; (f) resorption accelera-
tors, e.g. quaternary ammonium compounds3 (g) sur~ace
; 20 active agents, e.g. cetyl alcohol, glycerol monostearate;
(h) adsorptive carriers, e.gO kaolin and bentonite; (i~ lub-~
ricants, e.g~ talc, calcium and magnesium stearate and solid
polyethylene glycols~
The tablets ? dragees, oapsules and pills formed ~rom
the pharmaceutical compositions of the invention can have
the customary coatings, e~velopes and protectiye matrices,
which may contain opaoi~iers. They can be so constituted
that they release the active ingredient only or preferably
in a particular part of the intestinal tract, possibly over
~0 a period o~ timeO The coatings, envelopes and proteotive
8 -
:
, ' . ' .
3~
matrices may be made~ for e~ample 7 of polymeric substances
or waxes
The ingredient can also be made up in microencapsula-
ted form together with one or several of the above men-tioned
diluent~.
~he diluents to be used in pharmaceutical compositions
adapted to be formed into suppositories can, for example,
be the usual water-soluble or water-insoluble diluents, such
as polyethylene glycols and fats (e~g. cocoa oil and high
esters Le.g~ nl4 -alcohol with C16-fatty acid]~ or mixtures
of these diluents.
The pharmaceutical compositions which are ointments,
pastea, creams and gels can, for example, contain the usual
diluents9 eOg animal and vegetable fats9 waxes, paraffins,
starch, tragacanth, cellulose derivatives, polyethylene
glycols, silicones, bentonites, silicic acid, talc and 2inc
oxide or mixtures of these substances.
The pharmaceutical compositions which are powders and
sprays can~ for example? contain the usual diluents, e.g.
: ~
~ 20 lactose9 talc, silicic ~cid? aluminium hydro~ide, calcium
:
silicate, and polyamide powder or mixtures o~ these substances~
Ae~osol sprays~can, for example9 contai:n the usual propel-~
lants, e~g.~chlorofluorohydrocarbonsO
~he pharmaceutioal compositions which are solutions
and emulsions can, for example, contain the customar~ diluents~
(with~ of course, the above~mentioned exclusion of solvents
having a molecular weight below 200 except in the presence
o~ a ~ur~ace-active agen~), such as solvents~ dissolving
agents and ~emulsi~iers; specific eæamples of such diluents ~
are water? ethyl alcohol, isopropyl aloohol, ethyl carbooate,
_ g _
eth;yl acetate, benzyl alcohol5 benzyl benzoate, propylene
glycolt 1,3-butylene glycol, dimethylformamide, oils Lfor
e~ample ground nut oil], glycerol, tetrahydrofurfuryl alcohol,
polyethylene glycols and fatty acid esters of sorbitol or
mixtures thereof.
For parenteral administration, solutions and emul-
sions should be sterile, and, if appropriate, blood-isotonic.
~he pharmaceutical compositions which are suspensions
can contain the usual diluents, such as liquid diluents, e,g.
water~ ethyl alcohol, propylene glycol9 surface-active a~nt~
(e,~ ethoxvlated isostearyl alcohols, polyoxyeth~lene sorbite
and sorbitane esters), microcr~stalline cellulose, aluminium
metahydro~ide, bentonite, agar-agar and tragacanth or mixtures
thereof~
All the pharmaceutical compositions according to the
invention can also contain colouring agents and preservatives
as well as perfumes and flavouring additions (e.g. peppermint
oil and eucalyptus oil) and sweetening agents (e.g. saccharin).
The pharmaceutical compositions according to the
invention generally contain from 0.1 to 9995 usually from
0.5 to 95% of -the active ingredient by weight of the total
composition.
In addition to a compound of the invention, the pharma-
ceutical compositions and medicaments according to the
invention can also contain other pharmaceutically active
compounds. ~hey may also ccntain a plurality of compounds
of the invention,
Any diluent in the medicaments of the present in~ention
may be any of those mentioned above in relation to the pharma-
ceutical compositions of the present invention. Such medioa;
~e A ~ - 10 -
3~i
ment~ may include solvents of molecular weight less ~han 200
as 301e diluent.
The discrete coherent portions constituting the
medicament according to the invention will generally be
adapted, by virtue of their shape or packaging, for medical
admini~tration and may be, for example7 any of the following:
tablets, (including lozenges and granulates), pills, dragees,
capsules, suppositories and ampoule~. Some of these ~orms
may be made up for delayed release of the active ingredient~
Some, such as capsules, include a protective envelope which
- renders the portion~ of the medicament physically discrete
and coherent.
'rhe pre~erred daily dose for admini~tration of the
medicaments o~ the invention is from 0.5 to 15 g preferably
from 2.5 to 10 g o~ ac-tive ingredientO
~he production of the above mentioned pharmaceutical
compositions and medicaments i~ carried out by any method
known in the art, for example, by mixing the active ingred-
ient(s3 with the diluent(s) to form a pharmaceutical compo-
2G sition (e.g. a granulate) and then fol~ing the composition
into the medicament (e.g~ tablets).
~his invention further provides a method of combating
(including prevention, relief and cure of) the above mentioned
di~eases in human and non-human animals~, which comprises
administering to the animals a compound of the invention
alone or in admixture with a diluent or in the form of a
~ medicament according to the lnvention.
O It is envisaged that these active compounds will be
administered perorally, parenterally (for e~ample intra-
muscularly, intraperitoneally, or intravenously)~ rectally
e~ a~
:
or locally, pre~erably parenterally, especially intravenously.
Pre~erred pharmaceutical compositions and medicaments are
therefore those adapted for intravenous administration, such
as sterile and blood-isotonic solutions and emulsions and
ampoules containing them. Administration in the method of
the invention is pre~erably intravenously.
In general it has proved advantageous to administer
amol~ts of from 10 mg to 300 mg/kg of body weight most
pre~erably from 50 to 200 mg/kg of body weight per day to
achieve e~ective results. Nevertheless, it can at times
be necessary to deviate from those dosage rates, and in
partic~ar to do so as a function of the nature and body
weight of the human or animal subject to be treated, the
individual reaction of this subject to the treatment, the
type of formulation in which the active ingredient is admini-
stered and the mode in which the administration is carried
out, and the point in the progress o~ the disease or interval
at which it is to be administered. Thus it may in some case
suffice to use less than the above mentioned minimum dosage
ratej whilst other cases the upper limit mentioned must be
e~ceeded to achieve the desired results. Where larger amounts
are administered it can be advlsable to divide these into
several individual administrations o~er the course o~ the
day.
~ 3~_~
Description of the e~periment:
The in vitro tests were carried out in a series diluN
tion test with germ inocula o~ an average o~ 5 ~ 104 germs/ml
o~ substrateO The nutrient medium was (a) ~or dermato~h~tes
~ ~ a~ 12 -
.
36
and moulds: Sabouraud's milieu d'épreuve and (b) for yeasts:
meat e~tract/glucose broth.
~ he incubation temperature was 28C and the duration
of incubation was 24 to 96 hours.
The results of the tests o-f the activity o~ various
compounds of t.l~e invention against diverse micro-organism
are given in the following Table A,
::
: . ~ :
~: : : : :
~e A_L~ 13 -
., . : ~ , ' . ' ' ' : '
..,
3~
o o ~
q~ rl h
~ ~ l l l
h
'~ o ~ O O
-rl O
o
b~
rl
~
qD~ O *
.~ a) e) o 8 o
,,
CQ
o ~ a)
~ O O O
~ ~` o . o o
~;
O ~d ~
~ ~,, o o
,., ~,
O
,~
h !~ ~ ~
~a H C)
h t~
¦ ~_ b~
~1 ~ ~ I ~) o \~;_
E~ D ~ D ~ ~9 D
I,.. ~ - 14 -
03~
b~
.,,
v~ ~d
h
o o ~
h I l I
0 ~
.,1 ~ bD
a
h h s::
~1 a>
'Ho
bO ~
H O
'~ H ,1 d
~ , ';~ ` d
O /~
s~
~ ~ ~ o
V
O
Z;
0~ h
h
d ~1~ æ ~ ~ æ
~P 1 Ç ~
~aL~ - 15 - ~
, . . . . , , ,i
~ ~1303~
- 91 -
O ~ ~ X ,~ Y
Z
.
~i ~,
(D ;i3 H
J~, ~ p A r r ~y ~ C,
`C H
P~
~ ~ ~ ''C t~
:' 00
v v v v a~ v ~o ~ .
~ -~ r ~ r ~ ~
c~ V ~
r r ~ (P oq 3
(n
: b~
: . : ~ ~ ~
: ~ ~ ~ a ~ :
~ .
:
,
.
, . .
36
PreP~3Sb~I:L
E~m~
Cl- ~ -0 CH-C0- ~ -Cl
~ I S03H
N--
' x 1/2 ~
~o3~
24406 g (0~62 mol) of 1-bromo-1-(4-chlorophenoxy)-2-
(2,4-dichlorophenyl)-ethan-2-one are added dropwise, at the
boil, to 149 g (2.13 mols) of 1,2,4-triazole in 1,5G0 ml of
acetonitrile. The mi~ture is heated under reflux for ~0
hours~ Thereafterp the solvent is distilled off in vaouo,
the residue is taken up in 1,000 ml of methylene chloride and
the methylene chloride i~s- extracted by shakin~ with three
tirles 500 ml of water. '~he aqueous phase is again e~trac~-
ted by shaking with 500 ml of methylene chloride. The com-
bined methylene chloride phases are dried over sodium sulphate
and concentrated by distilling off the solvent in vacuo.
he residue is dissolved in 300 ml of acetone and 100 g of
~lp5lnaphthalenedisulphonic acid hexahydrate in 200 ml of
acetone are added. ~his gives 270 g (41~% of theory) of
(4-chlorophenoxy)-2-(2,4 dichlorophenyl~ (1,2,4-triazol-
yl) ethan~2~one na~halene-1,5-disulphonate of melting
polnt 198C.
25 ~3~a~ ~ ~
~1
0-C~-~0 ~ -Cl
Np:
~N J x HCl
~0 ~ :
17
36
The base is liberated from the 1-(4-chlorophenoxy)-2-
(2,4~dichlorophenyl)-1-(1,2~4-triazol-1-yl~ethan-2-one
naphthalene 1,5-disulphonate9 obtained according to Example 1,
by adding sodium bicarbonate solution, and is taken up in
ethyl acetate and converted with ethereal hydrochloric acid
into the hydrochlo~ide, which crystallises out after standi~g
in ether ~or a prolonged period, This gives 1-(4~chloro-
phenoxy)-2-(2,4-dichlorophenyl)-1-(1,2,4-triazol-1 yl)-ethan-
2-one hydrochloride of melting point 138~140a~ quantitatively.
~3a~
Cl
Cl- ~ -0-CH-CH- ~ -Cl
N. Il x HCl . .
226 g (0.42 mol) of 1-(4-chlorophenoxy)-2-t2,4-dichloro-
phenyl)-1~ 2,4~triazol~1-yl)-ethan-2-one naphthalene-1,5-
disulphonate (Example 1) are suspended in 500 ml of methylene
: chloride, 1,000 ml of saturated sodium bicarbonate solution
.
:20 ~ are added and the mixture is stirred for 5 hours. '~he
isolated organic phase is dried over sodium sulphate and
concentrated in vacuo. '~he residue is taken up in 1.5 1 o~
methanol, 17 g (0.45 mol) of sodium borohydride are added in
portions of about 1 B at about 0 to 5C and the mixture is
stirred ~or 15 hours at room temperature. 200 ml~of con~en-
trated hydrochloric acid are then added dropwise at 0C
and the mixture is again stirred ~or 15 hours at room tempera~
ture. 'l'he reaction mixture is~then stirred into 1,000 ml
G~ saturated sodium:bicarbonate solution, the aqueous phase
is extracted by shaking with twice 500 ml o~methylene chloride
`
2 - 18 -
~g~ ~9~ ~
and 1;he organic phase is extracted by shaking with -twice 200
ml o:~ water. The combined organic phases are dried over
SOdil1m sulphate and concentrated by distilling off the solvent
in vacuo. The oil which remains is dissolved in 800 ml of
ether and dry hydrogen chloride is added in excess~ This
gives 113.5 g (64% of theory) o~ 1-(4-chlorophenoxy)-2-(29
4~dichlorophenyl)-1 (1,2y4-triazol~l-yl)-ethan-2-ol hydrochlo-
ride as an isomer mixture o~ melting point 157 - 172C.
The ~ollowing compounds in Table 1 are obtained by
methods analog~us to tho3e of the example~ given above.
.
. .
:
,:
` : '
. ~ ~
`~
19- .
.
: - . . .,, :. , . . ' . ~
36
Tabl~s 1
~ - O CH ~ A - ~ - Cl
Xn ~N~N
N 11
Example Xn A Melting po nt (C)
4 2,4-C12 CO 173-83 (x HC1~
4 ~ CO 205~08 (~ ~Cl)
6 4 ~ -Ol ao 138 (decomposition) (x HCl)
7 4-~ ao 83-~6
8 2,6-al2 co 176 (~ Ha
-Cl ao 140-42 (x HCl)
,
- CO 86-88
11 4-CH~ CO 172 (x HCl)
12 4-Cl, 2-C~3 CO 138 ~ HCl)
~;~13 4~I ao 156 (x Ha
14 ~4-al2 CH(O~) 68-85 (x HCl)~ isomer
15: 4- ~~ CH(OH)~148-50 (x HaI)~ mlxture
16 ~4- ~ -ClCH(OH) 170-74 , "~
17~ ~ ~ 4-~oH(OH) 139-43: (~ H~
18 :~ CH(OH) 171-73 :~
~ l9~ 3-a~ CH(OH) 155-58 ~(x HCl),
; ~ ~ : : : ,' ~ :
- 20 _
:
:
.
