Note: Descriptions are shown in the official language in which they were submitted.
2 ~ 9 ~ 6 ~ 1
The present invention is concerned wi~h amino acid
5 derivatives. In particular, it is concerned wi~h amino acid
deriva~ives of the general formula
A~S(:~ N ~
0 wherein R1 signifies imidazolylme~hyl or pyridylmethyl and
A signifies carboxyl, benzyloxycarbonyl, hydroxymethyl or
alkylcarbonyloxymethyl,
in the form of optically pure diastereomers, rnixtures of dia-
stereomers, dias~ereomeric racemates or mixtures of dias~ereo-
meric racemates as well as ph~rmaceutically usable salts of
~hese compounds.
:
These compounds are distinguished by valuable pharma-
codynamic properties and can be used for the control or
20 prevention of illnesses. In particular, they have a renin-
inhibiting activity and are accordillgly suitable for the treatment
of high blood pressure and cardiac insufficiency.
,; .
- Objects of the present invention are the compounds of
25 formula I and their pharrraceutically usable sal~s per se and for
use as therapeutically active substances, the manufacture of
~hese compounds, medicaments containing these and the manu-
facture of such medicaments as well as the use of the compounds
of formula I and their pharmaceutically usable salts in the
30 control or prevention of illnesses or in the improvemen~ of
health, especially in the control or prevention of high blood
pressure and cardiac insufficiency.
Kbr/1 5.2.93
~r"
'~
2093S71
The compounds of formula I above are already generically
known frnrn, for example, EP-A-0,309,766 and ~P-A-0,377,139,
but i~ has surprisingly been found tha~ lthey are distinguished by
a pronounced oral activi~y. Of ~he compounds specifically named
5 in the two European Pa~en~ Public~tions only two are described as
being orally active, namely ~he end produc~ of Example 16 of EP-
A-0,309,766 and, respec~ively, the end product of Examp~e 1 Qf
EP-A-0,377,139. A comparison of the oral activity of the
compounds in accordance with the invention with the more active
o previously described compound (Example 1 of EP-A-0,377, 1 39)
shows a significantly higher oral activity for ~he compounds of
formula 1, as can be coneluded readily from Figures 1-3 disoussed
below.
The alkyi residues which appear in the term "alkylcarbonyl-
oxymethyl" or "alkylcarbonyl" in the present description are
straight-chain and branched, saturated hydrocarbon residues with
1-8, preferably 1-4, carbon atoms sueh as methyl, ethyl, n-
propyl, isopropyl, n-butyl, isobutyl, sec.-butyll tert-butyl, pentyl,
20 hexyl and the like.
The term "pharmaceutically usable salts" embraces salts
with inorganic or organic acids such as hydrochloric acid, hydro-
bromic acid, nitric acid, sulphuric acid, phosphoric acid, citric
25 acid, formic acid, maleic acid, ace~ic acid, succinic acid, tartaric
acid, methanesulphonic acid, p-to5uenesulphonic acid and the like
or, where A signifies carboxyl, also with inorganic or organic
bases such as sodium or potassium hydroxide, ammonia,
triethylamine, diisopropylethylamine, pyridine and the like. Such
30 salts ean be manufactured readily by any person skilled in the art
having regard to the state of the art and taking into consideration
the nature of the compound to be converted into a salt.
The compounds of formula I have a~ least four asymmetric
35 carbon atoms and are therefore presen~ in the forrn of optically
pure diastereomers, mixtures of diastereomers, diastereomeric
racemates or mixtures of diastereorneric racemates. The present
invention embraces all forms. Mixtures of diastereomers, dia-
2 ~ 7 ~
stereomeric racemates or mixtures of dias~ereomeric racerna~escan be separated according to usual methods, e.g. by column
chromatography, thin-layer chroma~ography, HPLC and the like.
Those compounds of formuia I in which A signifies hydroxy-
methyl or alkylcarbonyloxymethyl~ especially alkylcarbonyloxy-
methyl, particularly C~ 4-alkylcarbonyloxymethyl, are preferred.
Where A does no~ have ~he foregoing significances, then those
compounds of formula I in which A signifies carboxyl are
o pre~erred.
From the foregoing it will be evident that those compounds
of formula I in which A signifies C1 4-alkylcarbonyloxymethyl
are particularly preferred.
Specially preferred compounds of formula I are:
2,2-Dimethylpropionic acid 2-[(S)- or 2-[~R)-2-[~S3-1
t(1 S~2R~3s~-1-cyclohexylmethyi-3-cyclopropyl-2~3-dihydr
20 propylcarbamoyl3-2-imidazol-4-yl-e~hylcarbamoyl]-3-phenyl-
propylsulphonyl~-2-methylpropyl ester,
2,2-dimethylpropionic acid ~-~(R)- or 2-~S)-Z-[(S)-1-
[(1 S,2R,3S)-1 -cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxy-
25 propylcarbamoyl~-2-pyridirl-3-yl-e~hylcarbamoyl]-3-phenyl-
propylsulphonyl]-2-methylpropyl es~er and
2,2-dimethylpropionic acid 2-[~S)- or 2-~(R)-2-~(S)-1-
[(1 S,2P~,3S)-1-cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxy-
30 propylcarbamoyl]-2-pyridin-3-yl ethylcarbamoyl]-3-phenyl-
propylsulphonyl]-2-methylpropyl es~er.
Compounds of forrnula I in the form of optically pure
diastereomers, mixtures of dias~ereomers, dias~ereomeric
35 racemates or mixtures of diastereomeric racemates as well as
pharmaceutically usable salts thereof can be manufac~ured by
a) reacting a compound of the general forrnula
' :
';
2 ~ 9 ~ 6 71
2 ~ ~ 11
wherein R1 has the ~ignificance given above,
5 with an acid of the general formula
Al ~SQ~i::)H lll
'13 -
wherein A1 signifies ben~yloxycarbonyl, hydroxymethyl or
o alkylcarbonyloxymethylJ
or an activated derivative thereof, or
b) reacting the compound of the ~ormula
OH ~
H2N~ IV
OH
with an acid of the general formula
O Rl
A~ ~SO~ N ~OH V
wherein A1 and R1 have the si~nificance given above,
or an ac~ivatecl derivative thereof, or
2~5Çi7~
s
c) for the manufacture of a compound of formula I ;n which A
signifies carboxyl, cleaving off ~he benzyl group in a compound of
formula I in which A signifies ben~yloxycarbonyi, and
d) if desired, separating a rnixture of diastereomeric
racemates into the diastereomeric racema~es or optically pure
diastereomers, and/or
0 e) if desired, separating a mixture of dias~ereomers into the
optically pure diastereomers, and/or
f) if desired, conver~ing a compound obtained into a pharma-
ceuticaily usable salt.
The acylation of a compound of forrnula ll with an acid of
forrnula lll or an aetivated derivative thereof is effec~ed
according to methods known per se in peptide chemistry. Suitable
acylating agents are activated deriva~ives such as esters, mixed
20 esters, acid halides, acid anhydrides or mixed anhydrides. The
reaction is carried out in an or~anic solvent or solvent mixture
which is inert under the reaction conditions at a temperature
between about 0C and room tempera~ure. As solvents ~here some
into consideration especially aromatic hydrocarbons such as
25 benzene, ~oluene or xylene, chlorinated hydrocarbons such as
methylene chloride or chloroform, ethers such as cliethyl e~her,
tetrahydrofuran or dioxan, and the like. Furthermore, the
acylation can be effected in the presence of a condensation agent
such as HBTU [O benzotriazolyl-N,N,N',N-tetramethyluronium
30 hexafluorophosphate, BOP [benzotrlazol-1-yloxy-
bis(dimethylamino)phosphonium hexafluorophosphate], BOP~
[bis(2-oxo-2-oxazolidinyl)phosphine chloride], HOBT ~N-
hydroxybenzotriazole}, DCC CdicYclohexYlcarbodilmide
hydrochloridel, EDC ~N-(3-dirnethylaminopropyl)-N'-
3s ethylcarbodiimide hydrochloride] and the like. The reac~ion isconveniently carried out in an organic solvent or solvent mixture
which is inert under the reaction conditions at a ~ernperature
between about 0 and 50C, preferably at about room tempera~ure.
~.:
2~ 671
As solvents there come into consideration especially dimethyl-
forrnamide, methylene chloride, acetonitrile, tetrahydrofuran and
the like.
The reaction of a compound of formula IV with an acid of
formula V or an activated derivative thereof is also effected
according to me~hods which are known per se in peptide
chemistry, i.e. under the same conditions as given above for the
acylation of a compound of formula ~I. Examples of suitable
0 activated compounds of formula V are iikewise acid halides, acid
anhydrides, mixed anhydrides, esters, mixed esters and the like.
The cleavage of ~he benzyl group in accordance with process
variant c) is also effected according to methods known per se,
conveniently hydrogenolytically.
The starting ma~erials of formula ll are ,oartly novel and
partly known. These cornpounds can be prepared by reacting the
compound of formula IV with a compound of the general formula
o
H2N ~ Vl
R1
wherein R1 has the significance given above.
This reaction is effected according to methods which are known
2s in pep~ide chemistry, i.e. under the reaction conditions which are
described above for the acylation of a compound of formula ll.
The starting material of formula IV~ i.e. 3-amino-4-cyclo-
hexyl-1-cyclopropyl-1,2-blltanediol, is known.
The compounds of formuia Vl are known or can be obtained
in analogy to the preparation of the known compounds.
The acids of formula lll and their activated derivatives are
35 novel and are also an object of the present invention. The prepar-
ation of the acids of formula lll is presented by way or formulae
':
2 ~ 9 .~ ~ 7 1
in the following Reaction Scheme. The ac~ivated derivatives can
be prepared readily by any person skilled in the art having regard
to the state of the art and taking into consideration the nature of
the activated deriva~ive.
The acids of formula V and ~heir activated derivatives are
also novel and are an objeet of the present invention. They can be
prepared readily by reacting an acid of formula lil wi~h a
compound of formula Vl. The reaction is effected aecording to
0 me~hods which are known in peptide chemis~ry, i.e. under ~he
reaction conditions which are described above for the aeyl~tion
of a compound of formula 11. The ac~ivated derivatives o~ ~he
acids of formuia V can be prepared readily by any person skilled
in the art in ~he same manner as those of the acids of ~ormula 111.
The steps which are presented in the Reaction Scheme are
without exeeption reactions which are usual in synthetic
chemistry, all of whieh are carrie~ out according ~o methods
known per se. With respect to the pr~cise reaction condi~ions for
20 the steps pr~sented in the Reaction Scheme, reference is made to
the experimen$al section. In the Reac~ion Scheme the symbol R2
signKies aralkyl, especially benzyl, or alkyl, especially ~-butyl,
R2l signifies alkyl, especially ~-butyl, R3 signifies benzyl and
signifies alkylcarbonyl.
- 25
The starting materials of formulae Vll and Vlll used in the
Reaction Scheme are known.
: :.
"
2~9~6~
Scheme
H~SH ~ o ?
Vll ~lli 111~
ll l
J~SOJ~R: '
~X Xlll
I
o
~ o
X
_lo~5;0~0R2- --D zo~S J's
Xl X~l
~; J's ZO~;OEJ~SOH
Illa Illb
2~ 671
The compounds of formula I and their pharmaceutically
usable salts have an inhibitory activity on the natural enzyme
renin. The latter passes from the kidneys into the blovd and there
brings about the cleavage of angiotensinogen with the formation
5 of the decapeptide angiotensin I which is then cleaved in the
lungs, the kidneys and other organs to the octapeptide angiotensin
Il. Angiotensin ll increases the blood pressure not only directly
~y ar~crial constriction, but also indirectly by the liberation of
the sodium ion-retaining hormone aldosterone from the adrenal
0 gland, with which is associated an increase in the extracelluiar
fluid volume. This increase is attributed to the action of angio-
tensin ll itself or to the heptapeptide angiotensin lll which is
formed therefrom as a cleavage product. Inhibition of ~he en~y-
ma~ic ac~ivity of renin bFings about a decrease in the formation
of angiotensin I and as a consequence thereof the forma~ion of a
smaller amoullt of angiotensin ll. The reduced concentration of
this active peptide hormone is the actual reason for ~he blood
pressure-lowering ac~ivity of renin inhibitors.
The activity of renin inhibitors can be demonstrated
experimentally by means of the in vivo test described hereinaf~er:
BloQd pre~sure-lowerins~ ~tivi~y in thç a,~ mQdç~
The blood pressure-lowering effect of the compounds was
measured in normotensive squirrel monkeys of both sexes (weight
400-700 g). The sodium depletion was achieved by the subcu-
taneous iniection of in each case 5 mg/kg of furosemide 66, 42
and 18 hours prior to the experiment.
The compounds were administered orally ~s tlhe methane
sulphonate salts in aqueous solution in a dosage of 3 mg/kg. The
arterial blood pressure was measured according ~o the procedure
published in Hypertension 1991; 18: 22-31.
The results obtained in this test are cornpiled in the
following Figures 1-3.
- l O ~ 2 Q 9 ~ 6 r~ 1
oo oo
Il 11 11 11 11
¢ ~ ~ ~ u s; ~
+ ~ ~ t ~ '
~ '~
r~ " ~
r' ~ ~,
~ ~ ",
~ -~ _
H
_~ _,~
'- ~ _
a~
I ~
O O O O ~ ~
~ N ~I')
(6H~W~ d~W ~ L~3a
2~9 ~ 6 ~1
n : N(lmber of tes~s
A : Control
B : (2S,3R,4S)-4-CL-N-~(ZS)-3-[(2S or R)-2,3-
Diacetoxypropyl~sulphonyl-2 (1-naphthyl-
methyi)propionyl]norleucyl]amino-5-cyclohexyl-
1 -morpholino-2,3-pen~anediol
~O C : (2S,3R,4$)-4-[L-N-[~2$)-3-~2R or S)-2,3-
Diace~o~ypropyl3sulphonyl-2-( 1 -naphthyl-
methyl)propionyl~norleucyl~amino-5-oyclohexyl-
1 -morpholino-Z,3-pentanediol
D : (S or R)-2-Benzyl-N-[(S)-l-C(lS,2P~,3S)-1
cyclohexylmethyl-3-cyclQpropyl-2,3-dihyclroxy-
propylcarbarnoyl~-Z-imidazol-4-y5e~hyl]-3 -(2-
hydroxy-1 ,1 -dimethylethylsulphonyl)propion-
amidc
zo
E : Acetic acid 2-~(S)- or 2-~(R)-2-L(S)-1-
[~1 S,2R,3S)-1 -cyclohexylmethyl-3-cyclopropyl-
2 ,3-dihydroxypropylcarbamoyl]-2-imidazol-4-
ylethylcarbamoyl]-3-phenylpropylsulphonyl~-2-
methylpropyl ester
2~9~fi71
- 12 -
Il 11 11 11 11 11
+ t ~ t I ~
t ~ ~
.
~"
~i ,'q~\ L
1 ~
w~
~:
[
o o ~ - ~
~ ~ t
( 6HWW) dVW ~1~3a
2~9a671
13
A : Control
B : (2S,3R,4S)-4-[L-N-r(2S)-3-~(2S or R)-253-
Diacetoxypropyl3sll1phonyl-2-( 1 -naphthyl-
methyl)propionyl]norleucyl]amino-5-cyclohexyl-
1 -morpholino-2, 3-pentanediol
C : (2S,3R,4S)-4-EL-N-[(2S)-3-~2R or S)-2,3-
Diacetoxypropyl]sulphonyl-2-1~ 1 -naphthyl-
o methyl~propionyl3norleucyl]amino-5-Gyclohexyl-
1 -morpholino-2,3-pentanediol
F : Benzyl 2-~(S)- ur 2-~(R)-2-~(S)~ l S,ZR,~S)-1-
cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxy-
propylcarbamoyl~-2-imidazol-4-ylethylearba-
moyl3-3-phenylpropylsulphonyl]-2-rnethyl-
propionate
G : 2-~S)- or 2-l[(R)-2-[~S)-1-~(1 S,2R,3S)-1 -Cyclo-
hexylmethyl-3-cyclopropyi-2,3-dihydroxy-
propylcarbamoyl]-2-imidazol-4 ~ylethylcarba-
moyl3-3-phenylpropylsulphonyl~-2-methyl-
propionic acid
:`
H : 2-(R)- or 2-[(S)-2-[(S)-1-~(1 S,2R,3S)-1-Cyclo-
hexylmethyl-3-cyclopropyl-2 ,3-dihydroxy-
propylcarbamoyll-2-imidazol-4-ylethylcarba-
rnoyl~-3-phenylpropylsulphonyl]-2-me~hyl-
propionic acid
1 ~ 2 ~ .9 ~ ~ 7 1
~ P
+ t ~ t t 4
~aD
,~
~, 2
o
H
- N
~ ' O
o 0 ~ !
(6HWul~ dYW Yl~a
209Cj6 l1
1s
Q : Control
B : (2S,3R,4S)-4-~L-N-~2S3-3-~(2S orR)-2,3-
Diacetoxypropyl]sulphonyl-2-(1 naphthyl-
methyl)propionyl]norleucyl]amino-5-cyclohexyl-
1 -morpholino-2,3-pen~anediol
C : (2S,3R,4S)-4-[L-N-~25)-3-1~(2R or S)-Z,3-
Diacetoxypropyl}slJlphonyl-2-( 1 -naphthyl-
1 o methyl)propionyl]norleucyl3ctmino-5-cyclohexyl-
l -morpholino-2 9 3-pentanediol
2,2-Dimethylpropionic acid 2-[(S)- or 2-[~R)-2-
~(S~ (1 S,ZR,3S)-1 -cyclohexylmethyl-3-
cyciopropyl-2,3-dihydroxypropylcarbamoyl]-2-
imidazol-4-yle~hylcarbamoyl]-3-phenylpropyi-
sulphonyl~-~-methylpropyl ester
J : 2,Z-Dirnethylpropionic acid 2-[(R~- or 2-[(S)-2-
E(S)-l -E(l S,2R,3S)-l-cyclohexylmethyl-3
cyclopropyl-2,3-dihydroxypropylcarb3moyl]-2-
~` pyridin-3-ylethylcarbamoyl]-3-phenylpropyl-
sulphonyl3-2-methylpropyl es~er
K : 2,2-Dimethylpropionic acid 2-[(S~-or2-[(R)-2-
~` [(S)-1-[(1 S,2R,3S)-1-cyclohexylmethyl-3-
cyclopropyl-2,3-dihydroxypropylcarbamoyl~-2-
',: pyridin-3-ylethylcarbamoyl]-3-phenylpropyl-
sulphonyl]-2-rne~hylpropyl ester
2 0 ~ 7 ~
16
The compounds oF formula I as well as their pharmaceuti-
cally usable salts can be used as medicaments, e.g. in the form of
pharmaceu~ical preparations. The pharmaceutical preparations
can be administered enterally such as orally, e.g. in the form of
5 tablets, coated tablets, drag~es, hard and soft gela~ine capsules,
solu~ions~ emulsions or suspensions, nasally, e.g. in the form of
nasal sprays, or rec~ally, e.g. in ~he form of suppositories.
However, the administration can also be effected parenterally
such as intramuscularly or intravenously, e.g. in the forrn of
o injection solutions.
The compounds of formula i as well as ~heir pharmaeeuti-
cally usable salts can be processed with pharmaceutically inert,
inorganic or organic excipients for ~he manufacture of tablets,
5 coated tablets, dragees and hard gelatine capsules. Lac~ose, curn
starch or derivatives thereof, talc, stearic acid or its salts etcO
can be used e.g. as such excipients for tabiets, dragées and hard
gelatine capsules.
Sui~able excipien~s for soft gelatine capsules are e.g.
vegetable oils, waxes, fats, semi-solid and liquid polyols e~c.
~uitable excipients for ~he manufacture of solutions and
syrups are e.g. water, polyols, saocharose, invert sugar, glucose
25 etc.
Suitable excipients for injec~ion solutions are e.g. water,
alcohols, polyols, glycerol, vegetable oils etc.
Suitable excipients for suppositories are e.g. natural or
hardened oils, waxes, fats, semi-liquid or liquid polyols etc.
Moreover, the pharmaceutical preparations can contain
preservatives, solubilizers, viscosity-increasing substances,
35 stabilizers, wetting agents, emulsifiers, sweeteners, colorants,
flavorants, salts for varying the osmotic pressure, buffers,
coating agents or antioxiclants. They can also contain still other
therapeu~ically valuable substances.
2 0 9 ~ ~ 71
17
In ~ccordance with the invention the compounds of general
formula I as well as their ph~rmaceutically usable salts can be
used in ~he control or prevention of high blood pressure and
s cardiac insufficiency. The dosage can vary within wide limits
and will, of course, be fi~ted ~o the individual requirements in
eaeh par~icular case. In general, in the case of oral admini-
stration there should suffiee a daiiy dosage of about 3 mg to
about 3 g, preferably about 10 mg to about 1 g, e.g. approxi-
0 mately 300 my per person, divided in preferably 1-3 unit doses,
which ean e.g. be of the same amount, whereby, however, the
upper limi~ just given can also be exceeded when this is found ~o
be indioa~ed. Usually, ehildren receive half of the adult dosa~e.
The following Exarnples illustra~e ~he present invention, but
are not intended to be limiting in any manner. All temperatures
are given in deyrees Celsius. The following abbrevia~ion~ are
used:
zo His-OH = L-Histidine
Fmoc = 9-Fluorenylmethoxycarbonyl
DBU = 1,8-Diazabicyclo[5.4.0]undee-7-ene[1,5-5]
,~
, ~m~
2s
A mixture of 2.33 9 (6.06 mmol) of (RS)-2-benzyl-3-[2
~2,2-dimethylpropionyloxy) 1,1-dimethylethylsulphonyl]propionic
aeid, 2.0 g (5.49 mmol) of (S~-2-amino-N-[(1 S,2R,3S)-1-
30 cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxypropyl]-3-
imidazol-4-ylpropionamide, 0.61 g (6.06 mmol) of triethyl-
amine, 0.95 g (6.06 mmol) of HOBT and 2.3 9 (6.06 mmol) of
HBTU in 50 ml of dimethylformamicle was stirred a~ room
~emperature overnight. Thereafter, the reaction mixture was
35 evaporated in a high vacuum. The residue was taken up in 500 ml
of ethyl acetate and washed twice with 200 ml of saturated
sodium hydrogen carbonate solution each time. The ethyl acetate
phase was dried over sodium sulphate and subsequently evapor-
2~9a~71
18
a~ed under reduced pressure. For purification and separation ofthe two epimeric produc~s, the residue (4.98 g) was chromato-
graphed twice on 400 ~ of silica gel using a 97:3:0.1 mixture of
methylene chloride, methanc~l and pyridine as the eluent. The less
5 polar 2,2-dimethylpropionic acid 2-[(S)- or 2-[~P~)-2-[(S)-l-
[(1 S,2R,3S)-1 -cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxy-
propylcarbamoyl]-Z-imidazol-4-ylethylcarbamoyl~-3-phenyl-
propylsulphonyl3-2-methylpropyl ester was precipitated from
ethyl acetate/hexane and gave 1.3 9 of a colourless solid, MS:
10 731 (M~H~+. The more polar 2,2-dimethylpropionic acid Z-~(R)- or
2-[(S)-2-C~S)-l-[(1 S,2R,3S)-1-cyclohexylmethyl-3-eyclopropyl-
2,3-dihydroxypropylearbamoyl]-2 -imidazol-4-ylethylcarbamoyl]-
3-phenylpropylsulphonyl]-2-me~hylpropyl ester gave, after
Iyophilization from dioxan/water, 1.08 g of a colourless powder,
15 MS: 731 (M+H)+.
The 2-amino-N-[(1S,2R,3S)-1-cyclohexylrnethyl-3-cyclo-
propyl-2,3~dihydroxypropyl]-3-irnidazol-4-ylpropionamide used
as ~he starting material was prepared as ~ollows:
(a) tert-Butyl ~4S,5Ps)-4-cyclohexylmethyl-5-~(S)-cyclo-
propylhydroxymethyl3-2,2-dimethyl-3-oxazolidinecarboxylate and
tert~butyl (4S,5R)-4-cyclohexylmethyl-5-[~R)-cyclopropyl
hydroxymethyl]-2,2-dimethyl-3-oxazolidinecarboxylate:
A solution of 3.21 9 olF ter~-butyl (4S,5R)-4-cyclohexyl-
methyl)-5-formyl-2,2-dimethyl-3-oxazolidinecarboxylate [W0
87/05302] in 25 ml of tetrahydrofuran was added dropwise at
about 15 to a ~irignard compound, prepared from 3.94 ml
30 (49 mmol) of bromoeyclopropane and 1.2 g ~0.049 gram atom) of
magnesium shavings in 22 ml of te~rahydrofuran, and the
reaction mixture was subsequently stirred at room temperature
under argon for 16 hours. Thereafter, the reaction mixture was
poured into 40 ml of an ice-cold saturated ammonium c~loride
35 solution and extracted twice with 50 ml of ethyl acetate each
time. The ethyl acetate extracts were washed with 40 ml of
ice-cold saturated ammonium chloride solution, then combined,
dried over sodium sulphate and evaporatecl under reduced
~9;~6~1
lg
pressure. For purification, the residue (4.33 9) was chromato-
graphed over a column of 1 10 g of silica gel, prepared with
toluene anà 1% triethylamine, using a 95:5 mixture of ~oluene and
ethyl acetate as the eluen~. There were ob~ained 1.9 g of ~er~-
5 butyl (4S,5R)-4-cyclohexylrnethyl-5-[(R)-cyclopropylhydroxy-
methyl]-2,2-dimethyl-3-oxa~olidinecarboxylate, MS: 368 (M+H)+,
and 0.5 g of tert-butyl (4S,SR)-4-cyclohexylmethyl-5-[(S3-
cyclopropylhydroxymethyl]-2 ,2-dimethyl-3-oxazolidinecarboxyl-
a~e, MS: 368 ~Ivl+H)+, each as a colourless oil.
(b) ~1S,2R,3S~-3-Amino-4-cyclohexyl-1-cyclopropyl-
bu~ane-1 ,2-diol:
1.42 g (3.86 mmol) of ~ert-butyi (4S,5R)-4-cyclohexy!-
methyl-5-[(R)-cyclopropylhytlroxyme~hyl]-2,2-dlime~hyl-3-
oxazolidinecarboxyia~e dissolved in 15 ml of methanol and 10 ml
of wat~r were treated wi~h 4 ml of 7.5N hydrochloric acid and
s~irred a~ 50O for 3 hours. The reac~ion solution was cooled to 3O
in an ice bath, treated dropwise with 4 ml of 7.5N sodium
20 hydroxide solution and s~irred for 1 hour. The suspension
obtained was evaporated under reduced pressure, water was
removed azeotropically twice with 10 ml of ~oluene and the
`~ residue was stirred three times with 10 ml of a 95:5 mix~ure of
methylen~ chloride and methanol. The insoluble residue was
2s filtered off and ~he filtrate was ~vaporated under reduced
pressure. The resulting crude produç~ (1.14 9) was suspended in
15 ml of ether and ~hen fil~ered off under suction. There was
ob~ained 0.58 9 of (lS,2R,3S~-3-amino-4-cyclohexyl-1-cyclo-
propylbutane-1,2-dioi as colourless crystals, rn.p. 141-142.
(S)-Z-Amino-N-[(1 S,2R,3S)-1 -cyclohexylmethyl-3-cyclo-
propyl-2 ,3-dihydroxypropyl]-3-imidazol-4-ylpropionamide:
A mix~ure of 343 mg (1.51 mmol) of (1 S,2R,3S)-3-amino-
35 4-cyclohexyl-1-cyclopropylbutane-1,Z-diol, 995 mg (1.66 mmol)
of (Fmoc)2His-OH, 0.21 ml (1.61 mmol) of 4-ethylmorpholine,
449 mg (3.22 mrnol) of HOBT ancl 347 mg (1.81 mmol) of EDC in
20 ml of dimethylformamide was left to stand at room
2 ~ 9 ~ 6 7 ~
temperature overnight. Thereafter, the reaction mixture was
evapora~ed in a high vacuum, the residue was poured into a
mixture of i~e and 90 ml of sodium bicarbonate solution and
ex~raoted three times with 150 ml of ethyl ace~a~e each time.
s The three ethyl acetate extrac~s were washed in succession wi~h
70 ml of saturated ammonium chloride solution, 70 ml of 2N
sodium bicarbonate solution and 70 ml of satur~ted soclium
chloride solution, çombined, dried over magnesium sulphate,
filtered and evaporated. The crude product ob~ained was stirred
o at room tempera~ure for 3 hours in 60 ml of methylene chloride
and 2 ml of piperidine. Thereaf~er, the reaction mixture was
evaporated and the residue was tri~urated with 50 ml of hexane
and filtered off. The filtra~e was chromatoyraphed on 70 9 of
silica gel using a 65:10:1 mixture o~ methylene chloride,
methanol and ammonia as the eluent, whereby there were
obtained 390 mg of (S)-2-amino-N-[(1 S,2R,3S)-1-cyclohexyl
methyl-3-cyciopropyl-2,3-dihydroxypropyl]-3-imidazol-4
ylpropionamide as a colourless foam; MS: 365 (M+H)+.
2() The (RS)-2-benzyl-3-[2-(Z,2-dimethylpropionyloxy)-1,1-
dimethylethylsulphonyl]propionie acid used as the starting
rna~erial was prepared as ~ollows:
(d) (RS~-2-(2-Benzyloxycarbonyl-3-phenylpropylsulphonyl)-
25 2-methylpropionic acid:
8.4 g (55.4 rnmol) of DBU were added dropwise to a
solution of 3.3 9 ~27.7 mmol) of 2-rnercaptoisobutyric acid ~Can.
J. Chem. Çl (8), 1872] and 6.9 9 (27.7 mmol) of benzyl 2-benzyl-
30 acrylate [EP-A 0,1 17,429~ while holding the temperature of the
reaction mix~ure between 5 and 10. After completion of the
addition the mixture was stirred a~ 10 for a fur~her 5 hours.
Subsequently, the reaction mixture was treated dropwise, while
cooling with ice and holding the temperature below 10, with
35 Z2.5 9 (36.6 mmol) of potassium monopersulpha~e triple salt
suspended in 450 ml of water. Thereafter, the mix~ure was
stirred at the same temperature for one hour, then coolecl to 0
and a further Z2.5 g (36.6 mmol~ of potassium rnonopersulphate
2~3~1~7~
21
triple salt were added spatula-wise. The mixture was left to
warm slowly to room ~emperature and stirred for a further
15 hours. For the working-wp, ~he mix~ure was diluted with
200 ml of water and extracted four times with 60 ml of ethyi
5 acetate each time. The eombined organic extracts were dried
over sodium sulphate and evaporated under reducecl pressure until
~he product began to crystallize. Then, 30 ml of hexane and
20 ml of ether were added while stirring and ~he precipitated
produc~ was subsequently filtered off under suction and dried.
o There were obtained 9.7 g of ~RS)-2-(2-benyloxycarbonyl-3-
phenyipropylswlphonyl)-2-methylpropionic acid as a colourless
solid; MS: 42~ ~M+NH4)+.
(e) (RS)-2~(2-Benzyloxycarbonyl-3-phenylpropylsulphonyl)-
2-methylpropionyl chloride:
A solution of 9.0 9 (22.2 mmol~ of (RS)-2-~2-benzyloxy-
carbonyl-3-phenylpropylsulphonyl)-Z-methylpropionic acid and
9.6 ml (112.3 rnmol) of oxalyl chloride in 18 ml of te~rahydro-
20 furan was heated to 500 for 18 hours. Thereafter, ~he reactionsolution was evaporated under reduced pressure. The residue was
~aken up twice with 250 ml of toluene each time and evaporated
under reduced pressure. The (RS)-2-(2-benzyloxycarbonyl-3-
phenylpropylsulphonyl)-2-methylpropionyl chloride was obtained
25 as a yellowish oil in quanti~ative yield and was used in the next
step without purification and characterization.
~ f) Benzyl (RS)-2-benzyl-3-(2-hydroxy-1 ,1 -dimethyl-
ethylsulphonyl)propionate:
A solution of 9.4 9 (22.2 mmol) o~ (RS)-2-(2-benzyloxy-
carbonyl-3-phenylpropylsulphonyl)-2-methylpropionyl ehloride in
45 ml of tetrahydrofuran was treated dropwise at 0 within
15 minutes with 2.3 ml ~23.3 mmol) of 1 OM borane-dimethyl
35 sulphide complex and subsequently stirred at room temperature
for 3 hours. Thereafter, the mixture was cooled to oo and about
2 ml of methanol, 30 rnl of water and 30 ml of sa~urated sodium
hydrogen carbonate solution were added in succession. The
2~95671
22
mix~ure was then extracted ~hree times with 35 ml of ether each
time and the combined organic phases were subsequent3y dried
over sodium sulphate and evaporated under reduced pressure. The
crude product was digested in 50 ml of ether and, after suction
5 filtration and drying, there were obtained 6.7 g of benzyl (RS)-2-
benzyl-3-(2-hydroxy~ dimethylethylsulphonyl~propiona~e as a
colourless solid; MS: 408 (M~NH4)~.
(g) Benzyl (~S)-2-Benzyl-3-[2-(2,2-dimethylpropionyloxy)-
10 1,1-dim~thylethylsulphonyÇ~propionate:
0.74 g (6.14 mmol, 1.2 mol eq.) of pivaloyl chloride were
added at room tempera~ure ~o a solution of 2.0 g (5.12 mmol) of
benzyl (RS)-2-benzyl-3-(2-hydroxy-1,1-dimethyle~hylsulphonyl)-
propionate and 60 mg (0.5 mrnol3 of N,N'-dime~hylaminopyridine
in 20 ml of dry pyridine. The reaction mix~ure was warmed ~o
40 and stirred at this temperature for a further 6 hours. For ~he
working-up, the cooled reaction solution was evaporated in a
wa~erjet vacuum. For purification, the residue was chromato-
20 graphed on silica gel using a 99:1 mixture of methylen@ chlorideand methanol as the eluent. There were obtained 2.18 g (90% of
. theory) of benzyl (RS)-2-benzyl-3-[2-(2,2-dimethylpropionyl-
oxy)-1,1~ime~hyle~hylsulphonyl~propionate as colourless
crystals; MS: 475 ~M+H)~.
(h) (RS)-2-Benzyl-3-[2-(2,2-dimethylpropionyloxy)~
dimethylethylsuiphonyl]propionic acid:
A solution o~ 2.17 9 (4.57 mmol) of benzyl (RS)-2-benzyl-
30 3-[2-(2,2-dimethylpropionyloxy)-1 ,1-dimethylethylsulphonyl~-
propionate in 100 ml of methanol was treated wi~h 0.5 9 of
palladium/charcoal (5%~ and hydrogenated at room temperature
under normal pressure for 90 minutes. For the working-up, the
ca~alyst was filtered o ff and rinsed three times with 30 rnl of
35 methanol each time. After evaporation in a waterjet vacuum
there were obtained 1.55 9 (88% of theory) of (RS)-2-ben~yl-3-
[2-(2 ,Z-dirnethylpropionyloxy)-1 ,1 -dimethylethylsulphonyl3-
propionic acid as colourless crystals; MS: 385 (M-~H)+.
23 2~ 671
E~
The following compound~ were manufactured in an analo-
s gous manner to that described in Example l
- From (RS)-2-benzyl-3-~2-(2~2-dimethylpropionyloxy)
1,1-dimethylethylsulphonyl]propionic acid and ~S)-2 amino-N-
[(1 S,2R,3S)-1 -cycioh~xylme~hyl-3-cyc3Opropyl-2,3-dihydroxy-
10 propyl]-3-pyridin-3-ylpropionamide ~he less polar epimer 2,2-
dimethylpropionic acid 2-[(R)- or 2-[(S~-2-[~S)-1-[~ S,2R,3S)-1-
cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxypropylcarbamoyl]-
2-pyridin-3-yle~hylcarbamoyl~-3-phenylpropylsulphonyl]-2-
methylpropyl ester, MS: 742 (M~H)+, and ~he more polar epimer
2,2-dimethylpropiQnic acid 2-[(S)- or 2-~(R~-2-[(S~-1-
[(l S,2R,3S)-1 -cyclohexylmethyl-3-cyclopropyl-2,3-
dihydroxypropylcarbamoyl]-2-pyridin-3-ylethylcarbamoyl]-3-
phenylpropylsulphonyl~-2-methylpropyi ester, MS: 742 (M+H)~,
each as a colouriess foam;
- from (RS)-3-(2-acetoxy-1,1-dimethylethylsulphonyl)-2-
benzylpropionic acid and (S)-2-amino-N-[~1 S,ZR,3S)-1 -cyclo-
hexylmethyl-3-cyclopropyl-2 ,3~dihydroxypropyl]-3-imidazol-4-
ylpropionamide the less polar epimer ace~ic acid 2-~R)- or 2-
25 [(S~-2-[(S)-1-[( 1 S,2R,3S)-1 -cyclohexylmethy3-3-cyciopropyl-
2,3-dihydroxypropylcarbamoyl~-2-imidazol-4-ylethylcarbamoyl~
3-phenylpropylsulphonyl]-2-methylpropyl ester, MS: 689 (M~H~+,
and the more polar epimer acetic acid 2-[(S)- or 2-[(R) 2-~(S)-l-
~(1 S,2R,3S)-1 -cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxy-
30 propylcarbamoyl]-2-imidazol-4-ylethy3carbarr~yl]-3-phenyl-
propylsulphonyl~-2-methylpropyl ester, MS: 689 ~M~H)~, each as a
colourless amorphous solid;
- from (RS)-2-benzyl-3-(2-hydroxy-lJl-dirnethylethyl-
3s sulphonyl)propionic acid and (S)-2-amino-N-[(1 S,2R,3S)-l-cyclo-
hexylmethyl-3-cyclopropyl-2 ,3-dihydroxypropyl]-3-imidazol-4-
ylpropionamide the less polar epimer ~R or S)-2-benzyl-N-~(S)-1-
~(1 S,2R,3S)-l-cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxy-
209.~'71
24
propylcarbamoyl]-2-imidazol-4-ytethyl]-3-(2-hydroxy-1, 1-
dimethylethylsulphonyl)propionamide, MS: 647 (M~H)~, and the
more polar epimer (S or R)-2-benzyl-N-~($)-1-~(1 S,2R~3S~
cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxypropylearbamoyl~
5 2-imida701-4-yle~hyl]-3-(2-hydroxy-1, 1 -dimethyle~hyl-
sulphonyl)propionamide, MS: 647 (M~H)+, each as an amorphous,
colourless solid.
The (S)-2-amino-N-~lS,2R,3S~-l-cyclohexylmle~hyl 3-
o cyclopropyl-213-dihydroxypropyl~-3-pyridin-3-yl-propionamide
used as the starting ma~erial was prepared as ~llows:
1.27 g (3.3 mmol) of HBTU ancl 0.45 ml (3.3 mmol) of
trie~hylamine were added to a solution of 878 mg ~3.3 mmol) o~
15 N-(tert-butoxycarbonyl)-3-(pyridin-3-yl)-L-alanine (DE
3,640,535) and 750 mg (3.3 mmol) of (1 S,2R,3S)-3-amino-4-
cyclohexyl-1-cyclopropylbutane~1,2-diol in 33 ml acetonitrile
and the mixture was stirred at room temperatwre overnight. The
colourless clystals obtained af~er fil~ration were dissolved in
20 30 ml of ethanol and Z3.3 ml of 1 N hydrochloric acid were added
~hereto. A~er 24 hours at 500 the solution was made basic with
2N sodium hydroxide solution, evaporated under reduced pressure
and the residue was parti~ionecl between water and e~hyl acetate.
The aqueous phase was ex~raeted ~hre~ times with ethyl acetate
2s and the combined organic phases were dried over magnesiurn
sulpha~e, filtered and evaporated under reduced pressure.
Chromatographic purification of the residue (silica gel,
methylene chloride/methanol/ammonia 14û:10:1) yielded 436 mg
of (S)-Z-amino-N-[(1 S,2R,3S)-1 -cyclohexylmethyl-3-cyclo-
30 propyl-2,3-dihydroxypropyl~-3~pyridin-3-ylpropionamide, MS:
267 (M+H)+, as a colourless foam.
The dihydrocinnamic acid derivatives used as the starting
ma~erials were prepared as follows:
3s
(a) (RS)-3-(2-Acetoxy-l, l-dimethylethylsulphonyl)-2-
benzylpropionic acid:
2 ~ 9 ~ 6 ~ 1
In an analogous manner to tha~ described in Example 1 (g-h),
by aeylating benzyl (RS)-2-benzyl-3-(2-hydroxy-1,1~dimethyl-
ethylsulphonyl)propionate with acetyl chloride in pyridine there
was obtained benzyl ~RS)-3-(2-acetoxy-1,1-dimethyle~hyl-
5 sulphonyl)-2-benzylpropionate, MS: 341 (M-benzyl)+, as a colour-
less oil. Subsequen~ ca~alytic hyd~ogena~ion yielded (RS)-3-(2-
acetoxy~ dimethylethylsulphonyl~-2-benzylpropionic acid, MS:
296 (M-l ICOOH)~, as a colourless oil.
0(b) (RS)-2-Benzyl-3-~2-hydroxy-1 ,1-dimethylethyl-
sulphonyl~propionic acid:
In an analogous manner to that describedl in Example 1 ~h),
by catalytically hydrogenating the benzyl (RS)-2-benzyl-3-(2-
15 hydroxy-1,1-dimethylethylsulphonyl)propionate described in
Example 1 (f) over palladium/eharcoal ~5%~ the~ was ob~ained
(RS)-2-benzyl-3-(2-hydroxy-1 ,1 -dimethylethylsulphonyl)-
propionic acid as a eolourless solid; MS: 300 (M)+.
20~e~
In an analogous manner to that described in Example 1, by
condensing (RS)-2-benzyl-3-(1-benzyloxycarbonyl-1-methyl-
ethylsulphonyl)propionic aoid with (S)-2-amino-N-[(1 S,2R,3S)-1-
zs cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxypropyl]-3-
imidazol-4-yipropionamide there were obtained the less polar
epimer benzyl 2-[(S)- or 2-[(R)-2-~(S)-1-[(1 S,2R,3S)-1 cyclo-
hexylme~hyl-3-cyclopropyl-2 ,3-dihydroxypropylcarbamoyl]-2-
imidazol 4-ylethylcarbamoyl]-3-phenylpropylsulphonyl]-2-
30 methylpropionate, MS: 751 (M+tl)+, and the more polar epimerbenzyl 2-~(R)- or 2-[(S)-2-~(S)-1 [(1 S,2R,3S)-1-cyclohexyl-
methyl-3-cyclopropyl-2,3-dihydroxypropylcarbamoyl3-2-
imidazol-4-ylethylcarbamoyl3-3-phenylpropylsulphonyl]-2 -
methylpropionate, MS: 751 (M~H)~, each as a colourless foam.
3s
The (RS)-2-benzyl~3-~1-benzyloxycarbonyi-1-methylethyl-
sulphonyl)propionic acid used as the starting rnaterial was
prepared as follows:
2 ~ 9 5 6 r~ L
2~
~ a~ (RS)-2-~2-tert-Bu~oxycarbonyl-2-benzylethyl-
sulphonyl)-Z-methylpropionic acid:
In an analogous manner ~o that described in Examp!e 1 (d~,
by the addition of 2-mercaptoisobutyric acid to tert-butyl 2-
benzylacrylate, prepared according to a generally known
proeedure from 2-benzylacrylic acid and N,N-dimethylformamide
di~tert-butyl acetal [Tetrahedron 1979, ~5, 1675)], there was
10 obtai~ed (RS)-2-(2-tert-butoxycarbonyl-2-benzylethyl-
sulphonyl)-2-methylpropionic acid as a yellowish oil; MS: 282 ~M-
H2C-C(CH3)2]+-
(b) Benzyl (RS~-2-~2-tert-butoxycarbonyl-2-benzylethyl-
sulphonyl)-2-methylpropionate:
A solution of 500 mg (1.3 mmol) of (RS)-2-(Z-ter~-
butoxycarbonyi-2-benzylethyisulphonyl)-2-methylpropionic acid
in 5 ml of acetonitrile was treated with 197 mg (1.3 mmol) of
20 DBU and 222 mg (1.3 mmol) of benzyl bromide were added
dropwise thereto a~ room temperature. The yellowish reaction
solution was stirred for a fur~her 3 hours, ~hen treated with
10 ml of water and extracted twi~e with 10 ml of ethyl ace~ate
each time. The combined ethyl ace~ate phases were washed twice
25 with S ml of water each time, subsequently dried over sodium
sulphate and evaporated under reduced pressure. The thus-
obtained benzyl ester was used in the following oxidation step in
the form o~ a yellow oil (580 mg) without further purification
and characteriza~ion.
The oxidation with potassium monopersulphate triple salt
was effected analogously ~o Example 1 (d) and gave benzyl (RS)-
2-~2-tert-butoxyoarbonyl-2-benzylethylsulphonyl)-2-methyl-
propionate as a colourless oil; MS: 461 ~M~H)~.
(c) (RS)-2-Benzyl-3-(1-benzyloxycarbonyl-1-methylethyl-
sulphonyl)propionic acid:
2 7 2 ~ ~ ~ 6 7 1
A mixture of 401 mg (0.87 mmol) of benzyl (RS)-2~(2-
tert-butoxycarbonyl-2-benzyie~hylsulphonyl)-2-methyl-
propionate and 5 ml of anhydrous formic acid was s~irred at
room temperature. After 6 hours the initially turbid solution
5 became clear. This solution was evaporated at 40 under recluced
pressure and ~he residue was ~aken up in 10 ml of ethyl ~cetate
and washed with 3 ml of water. After drying over sodium
sulphate and evaporation in a waterjet vacuum there were
obtained 340 mg of (RS)~2-benzyl-3-(1-benzyloxycarbonyl-1-
o methylethylsulphonyl)propionic acid, MS: 313 (M-benzyl)~, as a
colourless oil which was used in the followin~ step without
~urther purification.
~m~
The foilowing compounds were rnanufactured by cataly~ic
hydrogena~ion in an analogous manner to tha~ described in
Example 1 (h):
- From benzyl 2~[(S)- or 2-~(R)-2-[(S~-l-[(lS,2R,3S)-1-
cyclohexylmethyJ-3-cyclopropy5-2,3-dihydroxypropylcarbamoyl]-
~-imidazol-4-ylethylcarbamoyl~-3 -phenylpropylsulphonyl~-2-
methylpropionate the 2-~(S)- or Z-~(R~-2~[(S)-1 -[(l S,2R,3S)-1-
cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxypropyl-
25 carbamoylJ-2~imidazol-4-ylethylcarbamoyl]-3-phenylpropyl-
sulphonyl]-2-methylpropionic acid as a colourless, amorphous
solid; MS: 661 (M+H)'~, and
- from benzyl 2-[(R)- or 2-[~S)-2-[(S)-l -[(1 S,ZR,3S)-1-
30 cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxypropylcarbamoyl]-
2-imidazol-4-ylethylcarbamoyl]-3-phenylpropylsulphonyl]-2-
methylpropionate the 2-~(R)- or 2-~(S)-2-[~S)-1-[(1 S/2R,3S)-1-
cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxypropyl-
carbamoyl]-2-imidazol-4-ylethylcarbamoyl]-3-phenylpropyl-
35 sulphonyl]-Z-methylpropionic acid as a colourless, amorphous
solid; MS: 661 (M+H)+.
2 1~ ' 7 ~
28
~m~
~Q~e~
5 CQmp~.siti~;
2,2-Dimethylpropionic acid 2-~(S~- or 2-L(R)-2-~(S)-l-
[~1 S,ZR,3S)-1 -cyclohexyimethyl-3-cyclopropyl-7,3-
dihydroxypropylcarbamoyl~-2-imidazol-4-ylethyl-
o carbamoyl~-3-phenylpropylsulphonyl]-Z-snethylpropyl
es~r, micronized 5.0 g
Polysorba~e 80 0.3 g
Hydro)(ypropylmethylcellulose 1.0 g
Flavour q.s.
Methylparaben 0.2 g
Propylparaben 0~04 g
Water ad 100.0 ml
Ex~m~le B
Qral.~Leous solll~ion
Com~ition
2,2-Dimethylpropionic acid 2-[(S)- or 2-[(R)-2-[(S)-1-
[(1S,2R,3S)-l-cyclohexylmethyl-3 eyclopropyl-2,3-
dihydroxypropylcarbamoyl]-2-imidazol-4 -ylethyl-
carbamoyl~-3-phenylpropylsulphonyl] ~2-methylpropyl
35 ester, 1.0 g
Methylparaben 0.2 g
2 ~3 9 i ) & r~ ~L
29
Propylparaben o 04 g
Flavour q.s.
5 Water ad 100.0 ml
.~m~
0
ÇQmQQ~;
1 ) 2,2-Dirne~hylpropionic acid Z-[(S) or 2-~(R)-
2-[(S)-1-[(1 S,2R,3S)-1-cyclohexylmethyl-3-
cyelopropyl-2,3-dihydroxypropylearbamoyl]-2-
imidazol-4-ylethylcarbamoyl~3-phenylpropyi-
sulphonylll~2-methylpropyl es~er 200 mg
2) Anhydrous lactose 160 mg
3) Hydroxypropylme~hylcellulose 18 mg
4) Sodium carboxymethylcellulose 20 mg
2s 5) Magnesium stearate ~mg
Tablet weight 400 mg
0
1 ) and 2) are mixed in~ensively. The mixture is thereafter
moistened with an aqueous solution of 3) and kneaded, and the
resul~ing mass is granulated, dried and sieved. The granula~e is
mixed with 4) and 5) and pressed to tablets of suitable size.
3s
2~9~7 ~
E~am~
C~mp~ n
1 ) Z~2-Dlmetnylpropionic aeid 2-[(S)- or 2-[(R)-20[(S)-l -
[~1 S,2R,3S)-1 -cyc~ohexylmethyl-3-cyolopropyl-2,3-
dihydroxypropylcarbamoyl]-2-imidazol-4-ylethyl-
o carbamoyl]-3-phenylpropylsulphonyl~-2-methyl-
propyl ester 200 mg
2) Anhydrous lactose 160 mg
33 Hydroxypropylmethylcellulose 18 mg
4) Sodiumcarboxymethyicellulose 20 mg
5) Magnesiumstearate 2
Capsule fill weigh~ 400 mg
Manuf~[j~LQr~ res
1 ) and 2) are mixed intensively. The mixture is thereafter
moistened with an aqueous solution of 3~ and kneaded, and the
resulting mass is granulated, dried and sieved. The granula~e is
mixed with 4) and 5) and the mixtur~ is Fiiled into capsules of
suitable size.
~mQIQ~
Inieçtion sql~ion
35 ~m~i~
2,~-Dimethylpropionic acid 2-[(S)- or 2-[(R) 2-
~(S)-1-[(1 S,2R,3S)-1-cyclohexylmethyl-3-cyclo-
2~9~7~
31
propyl-2,3 dihydroxypropylcarbamoyl~-2-imidazol-
4-ylethylcarbamoyl]-3-phenylpropylsulphonyl]-2-
methylpropyl ester 20 mg
5 Pyrogen-free D-mannitol 10 mg
Water ~r injection ad 1.0 ml
The active substance and the mannitol are dissolved in
nitrogen-gassed water and subse~uently Iyophilized according to
a conventional procedure.
~E
When the procedures described in Examples A-E are
~ollowed, corresponding galenical preparations can be
manufactured fr~m the following, likewise preferred comp~unds
zo and their pharmaceutically usable salts:
2,2-Dime~hylpropionic acid 2-r(R)- or Z-[(5)-2-[(S)-1-
[(1 S,2R,3S)-1 -cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxy-
propylcarbamoyl]-2-pyridin-3-ylethylc3rbamoyl]-3-phenyl-
25 propylsulphonyl~-2-methylpropyl ester and
2,2-dimethylpropionic acid 2-~(S)- or 2-[(R)-Z-[(S)-1-
[(1 S,2R,3S)-1-cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxy-
propylcarbamoyl]-2-pyridin-3-ylethylcarbamoyl]-3~phenyl-
30 propylsulphonyl~-2-methylpropyl ester.
