Substituted cyclohexanol esters, their use for treating diseases, and pharmaceutical preparations

Cyclohexanol esters of the formula I ##STR1## are described in which the radicals have the given meaning. The compounds are pharmacologically active and may therefore be used as pharmaceuticals, in particular for treating diabetes and other diseases which are characterized by an elevated secretion of glucose from the liver or by an elevated activity of the glucose-6-phosphatase system.

The disease picture of diabetes is characterized by elevated blood sugar 
values. In the case of insulin-dependent or type I diabetes, the cause is 
the death of the insulin-producing .beta. cells of the pancreas; this 
condition is therefore treated by administering insulin (substitution 
therapy). By contrast, non-insulin-dependent or type II diabetes is 
characterized by insulin having a diminished effect on muscle tissue and 
fat tissue (insulin resistance) and by an increased production of glucose 
in the liver. The causes of these metabolic disturbances are to a large 
extent still unclear. While the established therapy using sulfonylureas 
attempts to compensate for the insulin resistance by increasing the 
endogenous liberation of insulin, this does not in all cases lead to 
normalization of the blood sugar level and is not able to halt the 
progress of the disease; many type II diabetics eventually become 
insulin-dependent as a result of the .beta. cells becoming "exhausted", 
and suffer from late damage such as cataracts, nephropathies and 
angiopathies. 
For this reason, novel therapeutic principles for treating type II diabetes 
are desirable. 
In the fasting state, the concentration of glucose in the blood is 
determined by the glucose production of the liver. A variety of research 
groups have been able to demonstrate that the increase in the blood sugar 
values in type II diabetes is correlated with a proportionally elevated 
output of glucose from the liver. The glucose which is secreted by the 
liver into the blood can be formed both by degrading liver glycogen 
(glycogenolysis) and by gluconeogenesis. 
Glucose-6-phosphate is the common end product of both gluconeogenesis and 
glycogenolysis. The terminal step in the hepatic liberation of glucose 
from glucose-6-phosphate is catalyzed by glucose-6-phosphatase (EC 
3.1.3.9). Glucose-6-phosphatase represents a multienzyme complex present 
in the endoplasmic reticulum (ER). This enzyme complex comprises a 
glucose-6-phosphate translocase which is present in the ER membrane, a 
glucose-6-phosphatase which is located on the luminal side of the 
endoplasmic reticulum and a phosphate translocase [for a review, see: 
Ashmore J. and Weber G., "The Role of Hepatic Glucose-6-phosphatase in the 
Regulation of Carbohydrate Metabolism", in Vitamins and Hormones, Vol XVII 
(Harris R. S., Marrian G. F., Thimann K. V., Edts.), 92 to 132, (1959); 
Burchell A., Waddell I. D., "The molecular basis of the hepatic microsomal 
glucose-6-phosphatase system", Bio-chim. Biophys. Acta 1092, 129 to 137, 
(1990)]. The extensive literature which is available shows that the 
activity of this multienzyme complex is also elevated under all 
investigated conditions which, in animal experiments, lead to elevated 
blood sugar values, e.g. streptozotocin, alloxan, cortisone, thyroid 
hormones and starvation. In addition to this, a large number of 
investigations indicate that the elevated production of glucose observed 
in type II diabetics is associated with elevated glucose-6-phosphatase 
activity. The importance of the glucose-6-phosphatase system for normal 
glucose homeostasis is also underscored by the hypoglycemic symptoms of 
patients suffering from glycogen storage disease type Ib, who lack the 
translocase component of the glucose-6-phosphate system. 
The use of suitable active compounds (inhibitors) to diminish 
glucose-6-phosphatase activity should result in a decreased liberation of 
glucose from the liver. These active compounds should be able to adapt the 
production of glucose by the liver to the actual peripheral consumption. 
In addition to this, the lower blood glucose values thereby produced in 
type II diabetics in the fasting state ought also to exert a preventive 
effect with regard to late damage in diabetes. 
A series of non-specific inhibitors of glucose-6-phosphatase has been 
described in the literature, e.g. phlorrhizin [Soodsma, J. F., Legler, B. 
and Nordlie, R. C., J. Biol. Chem. 242, 1955 to 1960, (1967)], 
5,5'-dithiobis-2-nitrobenzoic acid [Wallin, B. K. and Arion, W. J., 
Biochem. Biophys. Res. Commun. 48, 694 to 699, (1972)], 
2,2'-diisothiocyanatostilbene and 2-isothiocyanato-2'-acetoxystilbene 
[Zoccoli, M. A. and Karnowski, M. L., J. Biol. Chem. 255, 1113 to 1119, 
(1980)]. The first therapeutically utilizable inhibitors of the 
glucose-6-phosphatase system are proposed in European Patent Applications 
No. 93 114 260.8 and No. 93 114 261.6. 
The cyclohexane derivatives which are characterized in detail below are 
novel compounds which have not previously been described in the chemical 
and biological literature. We have now found that esters of certain 
cyclohexanol derivatives, e.g. the compound according to Example 4, are 
very good inhibitors of the glucose-6-phosphatase system. 
The invention therefore relates to cyclohexanol esters of the formula I 
##STR2## 
in which the radicals have the following meaning: R.sup.1 is 
CONHCOR.sup.15, CSNHR.sup.15 , CONHSO.sub.2 R.sup.14, CSNHSO.sub.2 
R.sup.14 or CH.sub.2 NHSO.sub.2 R.sup.14, or 
R.sup.1 is a radical selected from the following formulae: 
##STR3## 
in which V is N or CH, W is N or CH, U is O or S, E is NR.sup.14, O, S or 
NH, G is --N.dbd., --O--, --S-- or 
##STR4## 
M is NR.sup.14, NH, CH.sub.2 or CR.sup.8 R.sup.9, and aromatic rings can 
be substituted once or more than once by F, Cl, Br, I, OH, O--C.sub.1 
-C.sub.4 -alkyl, C.sub.1 -C.sub.4 -alkyl, CF.sub.3, NO.sub.2 or CN, or 
R.sup.1 forms, together with R.sup.2, the ring 
##STR5## 
R.sup.2 is C.sub.1 -C.sub.10 -alkyl (R.sup.11) n, O--C.sub.1 -C.sub.10 
-alkyl(R.sup.11)n, C.sub.2 -C.sub.10 -alkenyl(R.sup.11)n, O--C.sub.3 
-C.sub.10 -alkenyl(R.sup.11)n, C.sub.2 -C.sub.10 -C.sub.10 
-alkynyl(R.sup.11)n, O--C.sub.3 -C.sub.10 -alkynyl(R.sup.11)n, S--C.sub.1 
-C.sub.10 -alkyl (R.sup.11)n, S--C.sub.3 -C.sub.10 -alkenyl(R.sup.11)n, 
S--C.sub.3 -C.sub.10 -alkynyl(R.sup.11)n, NH--C.sub.1 -C.sub.10 
-alkyl(R.sup.11)n, NH--C.sub.3 -C.sub.10 -alkenyl(R.sup.11)n or 
NH--C.sub.3 -C.sub.10 -alkynyl(R.sup.11)n, where R.sup.11 is optionally 
substituted by R.sup.12; 
R.sup.3, R.sup.11 and R.sup.13 are alkyl having from 1 to 10 carbon atoms, 
cycloalkyl having from 3 to 8 ring carbon atoms, phenyl, naphthyl, 
phenanthryl, pyridyl, thienyl, furyl, pyrimidyl, indolyl, imidazolyl, 
coumarinyl, phthaliminyl, quinolyl, piperazinyl, tetrazolyl, triazolyl, 
oxazolyl or their thieno-fused, pyridino-fused, pyrimidino-fused or 
benzo-fused derivatives, where the aromatic radical or heteroaromatic 
radical can be substituted once or more than once, identically or 
differently, by F, Cl, Br, I, OH, --NO.sub.2, CN, C.sub.1 -C.sub.4 
-alkoxy, C.sub.1 -C.sub.4 -alkyl, NR.sup.8 R.sup.9, phenyl, benzyl, 
thienyl, furyl, imidazolyl, pyridyl, O-phenyl or O-benzyl, and R.sup.3, 
R.sup.11 and R.sup.13 are identical or different; 
R.sup.4, R.sup.5 and R.sup.6 are H, OH, an OH group protected by customary 
alcohol protective groups, F, Cl or Br, or have the meanings given for 
R.sup.2, where R.sup.4, R.sup.5 and R.sup.6 are identical or different; 
R.sup.7 is C.sub.1 -C.sub.4 -alkyl, phenyl or benzyl; R.sup.8 and R.sup.9 
are H, C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -alkanoyl or phenyl which 
is optionally substituted by F, Cl, Br, I, OH, O--C.sub.1 -C.sub.4 -alkyl, 
CF.sub.3, --NO.sub.2 or CN, where R.sup.8 and R.sup.9 are identical or 
different, or R.sup.8 and R.sup.9 form, together with the nitrogen atom, a 
4- to 10-membered, saturated heterocyclic ring in which a CH.sub.2 group 
can be optionally replaced by O, S or NR.sup.10, 
R.sup.10 is H, C.sub.1 -C.sub.4 -alkyl, phenyl or benzyl; 
R.sup.12 is phenyl, naphthyl, phenanthryl, pyridyl, thienyl, furyl, 
thiazolyl, pyrimidyl, indolyl, imidazolyl, coumarinyl, phthaliminyl, 
quinolyl, piperazinyl, tetrazolyl, triazolyl, oxazolyl or their 
thieno-fused or benzo-fused derivatives, where the aromatic radical or 
heteroaromatic radical can be substituted once or more than once, 
identically or differently, by F, Cl, Br, I, OH, CF.sub.3, --NO.sub.2, CN, 
C.sub.1 -C.sub.4 -alkoxy, C.sub.1 -C.sub.4 -alkyl, NR.sup.8 R.sup.9, 
phenyl, benzyl, thienyl, furyl, imidazolyl, pyridyl, O-phenyl or O-benzyl; 
R.sup.14 is hydrogen, C.sub.1 -C.sub.10 -alkyl, phenyl, naphthyl, 
phenanthryl, pyridyl, thienyl, furyl, thiazolyl, pyrimidyl, indolyl, 
imidazolyl, coumarinyl, phthaliminyl, quinolyl, piperazinyl, tetrazolyl, 
triazolyl, oxazolyl or their thieno-fused or benzo-fused derivatives, 
where the aromatic radical or heteroaromatic radical can be substituted 
once or more than once, identically or differently, by F, Cl, Br, I, OH, 
CF.sub.3, --NO.sub.2, CN, C.sub.1 -C.sub.4 -alkoxy, C.sub.1 -C.sub.4 
-alkyl, NR.sup.8 R.sup.9, phenyl, benzyl, thienyl, furyl, imidazolyl, 
pyridyl, O-phenyl or O-benzyl, or R.sup.14 is a radical of the formula 
##STR6## 
R.sup.15 is C.sub.3 -C.sub.10 -alkenoyl, C.sub.3 -C.sub.10 
-alkenoyl(R.sup.12), C.sub.1 -C.sub.10 -alkanoyl(R.sup.12), phenyl, 
naphthyl, phenanthryl, pyridyl, thienyl, furyl, thiazolyl, pyrimidyl, 
indolyl, imidazolyl, coumarinyl, phthaliminyl, quinolyl, piperazinyl, 
tetrazolyl, triazolyl, oxazolyl or their thieno-fused or benzofused 
derivatives, where the aromatic radical or heteroaromatic radical can be 
substituted once or more than once, identically or differently, by F, Cl, 
Br, I, OH, CF.sub.3, --NO.sub.2, CN, C.sub.1 -C.sub.4 -alkoxy, C.sub.1 
-C.sub.4 -alkyl, NR.sup.8 R.sup.9, phenyl, benzyl, thienyl, furyl, 
imidazolyl, pyridyl, O-phenyl or O-benzyl; 
R.sup.16 is C.sub.1 -C.sub.10 -alkyl (R.sup.11)n, C.sub.3 -C.sub.10 
alkenyl(R.sup.11)n or C.sub.3 -C.sub.10 -alkynyl(R.sup.11)n, where 
R.sup.11 is optionally substituted by R.sup.12, X is (CH.sub.2)m, 
--CH.dbd.CH--, --C.tbd.C--, --CH.sub.2 --O--CH.sub.2 --, --CH.sub.2 
--S--CH.sub.2 -- or 
##STR7## 
Y is (CH.sub.2).sub.m, O, S or NR.sup.8, Z is (CH.sub.2).sub.m, S, O, 
S--C.sub.1 -C.sub.10 -alkyl, O--C.sub.1 -C.sub.10 -alkyl, CH.dbd.CH, 
CH.dbd.CF, CH.dbd.CCl, CH.dbd.CBr, CH.sub.2 --CO, CH.sub.2 --CHF, CH.sub.2 
--CHCl, CH.sub.2 --CHBr, CH.sub.2 --CHI, C.sub.3 -C.sub.10 -cycloalkylene, 
C.sub.3 -C.sub.10 - cycloalkenylene, where from 1 to 3 ring carbon atoms 
can be replaced by sulfur atoms, oxygen atoms or nitrogen atoms, 
COOR.sup.7, C.tbd.C, CH.dbd.C (C.sub.1 -C.sub.4 -alkyl), CH.dbd.C (CN), 
CH.dbd.C (NR.sup.8 R.sup.9), CH.dbd.C (C.sub.1 -C.sub.4 -alkanoyl), 
CH.dbd.C (R.sup.13) or NR.sup.8, and, if Y is oxygen, 
##STR8## 
can together be an amino acid residue, selected from the group consisting 
of Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lye, Phe, Pro, 
Ser, Thr, Trp, Tyr and their derivatives protected by customary protective 
groups, 
n is zero, 1 or 2, 
m is zero, 1, 2, 3 or 4. 
Insofar as they contain a carboxyl group, the novel compounds of the 
formula I can form salts with inorganic or organic bases. The invention 
also relates, therefore, to the physiologically tolerated salts of 
compounds of the formula I. The novel compounds of the formula I contain a 
number of stereocenters. The invention relates to all possible enantiomers 
and diastereomers. They are all represented by the formula I. 
Unless otherwise indicated, the following applies to the statements made 
above and below: 
The alkyl, alkanolyl and alkoxy radicals given under R.sup.1, R.sup.3, 
R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, 
R.sup.15, R.sup.16 and Z are straight-chain or branched. 
The alkyl, alkenyl and alkynyl groups given under R.sup.2 and R.sup.14 are 
straight-chain, branched or cyclic, it also being possible for only a part 
of the radical to form a ring. In addition, one of the CH.sub.2 groups can 
be replaced by O, S, SO, SO.sub.2 or NR.sup.8, R.sup.11 can be substituted 
by R.sup.12, and, when n is 2, the two radicals R.sup.11 are identical or 
different. 
Unsaturated radicals are unsaturated once or more than once. 
Alcohol protective groups are: 
Substituted ethers, such as methoxymethyl, methylthiomethyl, 
t-butylthiomethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, 
t-butoxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 1-ethoxyethyl, allyl, 
benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, 
p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, 
p-phenylbenzyl, 2-picolyl and 4-picolyl. 
Protective groups for the amino acid are: 
a) Carbamates, such as methyl and ethyl, 9-fluorenylmethyl; 
9-(2-sulfo)fluorenylmethyl, 9-(2,7-dibromo)fluorenylmethyl, 
2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl, 
4-methoxyphenacyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 
2-phenylethyl, 1-(1-adamantyl)-1-methylethyl, 1-dimethyl-2-haloethyl, 
1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl, 
1-methyl-1-(4-biphenyl)ethyl, 1-(3,5-di-t-butylphenyl)-1-methylethyl, 
2-(2'- and 4'-pyridyl)ethyl, 2-(N,N-dicyclohexylcarboxamido)ethyl, 
t-butyl, 1-adamantyl, vinyl, allyl, 1-isopropylallyl, cinnamyl, 
4-nitrocinnamyl, 8-quinolyl, N-hydroxypiperidinyl, alkylthio, benzyl, 
p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 
2,4-dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl and 
diphenylmethyl, t-amyl, S-benzylthiocarbamate, p-cyanobenzyl, cyclobutyl, 
cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyclobenzyl, 
diisopropylmethyl, 2,2-dimethoxycarbonylvinyl, 
o-(N,N-dimethylcarboxamido)benzyl, 
1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl, 1,1-dimethylpropynyl, 
di-(2-pyridyl)methyl, 2-furanylmethyl, 2-iodoethyl, isobornyl, isobutyl, 
isonicotinyl, p-(p'-methoxyphenylazo)benzyl, 1-methylcyclobutyl, 
1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl, 
1-methyl-1-(3,5-dimethoxyphenyl)ethyl, 
1-methyl-1-(p-phenylazophenyl)ethyl, 1-methyl-1-phenylethyl, 
1-methyl-1-(4-pyridyl)ethyl, phenyl, p-(phenylazo)benzyl, 
2,4,6-tri-t-butylphenyl, 4-(trimethylammonium)benzyl and 
2,4,6-trimethylbenzyl. 
b) Urea derivatives, such as phenothiazinyl-(10)-carbonyl derivatives, 
N'-p-toluenesulfonylaminocarbonyl and N'-phenylaminothiocarbonyl. 
c) Amides, such as N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl, 
N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-picolinoyl, 
N-3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, N-benzoyl and 
N-p-phenylbenzoyl. 
Compounds of the formula I are preferred in which 
R.sup.1 is CONHCOR.sup.15, CSNHR.sup.15, CONHSO.sub.2 R.sup.14, 
CSNHSO.sub.2 R.sup.14 or CH.sub.2 NHSO.sub.2 R.sup.14, or is a radical of 
the following formulae: 
##STR9## 
in which E is O, S or NH, R.sup.14 is H, U is O or S, V is N or CH, W is 
N or CH, and aromatic rings can be substituted once or more than once by 
F, Cl, Br, I, OH, O--C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -alkyl, 
CF.sub.3, NO.sub.2 or CN, 
or R.sup.1 forms, together with R.sup.2, the ring 
##STR10## 
R.sup.2 has the following meanings: O--C.sub.1 -C.sub.10 -alkyl 
(R.sup.11).sub.n, (n is 0, 1 or 2), where the alkyl moiety is unbranched, 
branched or cyclic, and R.sup.11 can be substituted by R.sup.12, and, when 
n is 2, the two radicals R.sup.11 are identical or different, O--C.sub.3 
-C.sub.10 -alkenyl(R.sup.11).sub.n, (n is 0, 1 or 2), where the alkenyl 
moiety is unbranched, branched or cyclic, and is unsaturated once or more 
than once, and R.sup.11 can be substituted by R.sup.12, 
O--C.sub.3 -C.sub.10 -alkynyl(R.sup.11).sub.n, (n is 0, 1 or 2), where the 
alkynyl moiety is unbranched, branched or cyclic, and is unsaturated once 
or more than once, and R.sup.11 can be substituted by R.sup.12, 
R.sup.3 to R.sup.15 have the meanings given above, and X, Y, Z and R.sup.16 
have the following meanings: 
X is (CH.sub.2).sub.m, (m is 0, 1, 2, 3 or 4), CH.dbd.CH, C.tbd.C, CH.sub.2 
OCH.sub.2 or CH.sub.2 SCH.sub.2, 
Y is (CH.sub.2).sub.m, (m is 0, 1, 2, 3 or 4), O, S or NR.sup.8, 
Z is (CH.sub.2).sub.m, (m is 0, 1, 2, 3 or 4), S, O, S--C.sub.1 -C.sub.10 
-alkyl, CH.dbd.CH, CH.dbd.CF, CH.dbd.CCl, CH.dbd.CBr, CH.sub.2 --C(O), 
CH.sub.2 --CHF, CH.sub.2 --CHCl, CH.sub.2 --CHBr, CH.sub.2 --CHI, C.sub.3 
-C.sub.10 -cycloalkylene, C.sub.3 -C.sub.10 -cycloalkenylene, COOR.sup.7, 
C.tbd.C, CH.dbd.C(C.sub.1 -C.sub.4 -alkyl), CH.dbd.C(CN), 
CH.dbd.C(R.sup.13) or NR.sup.8. 
R.sup.16 is C.sub.1 -C.sub.10 -alkyl(R.sup.11)n, C.sub.3 -C.sub.10 
-alkenyl(R.sup.11)n or C.sub.3 -C.sub.10 -alkynyl(R.sup.11)n, with n in 
each case being zero or one. 
In formula I, the radicals have, in particular, the following meanings: 
R.sup.1 is CONHCOR.sup.15, CSNHR.sup.15, CONHSO.sub.2 R.sup.14, 
CSNHSO.sub.2 R.sup.14 or a radical of the formulae: 
##STR11## 
in which E is O, S or NH, R.sup.14 is H, U is O or S, V is N or CH, W is 
N or CH, and aromatic rings can be substituted once or more than once by 
F, Cl, Br, I, OH, O--C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -alkyl, 
CF.sub.3, NO.sub.2 or CN, 
or R.sup.1 forms, together with R.sup.2, the ring 
##STR12## 
R.sup.2 is O--C.sub.1 -C.sub.10 -alkyl(R.sup.11).sub.n, (n is 0, 1 or 2), 
where the alkyl moiety is unbranched, branched or cyclic, and R.sup.11 can 
be substituted by R.sup.12, 
O--C.sub.3 -C.sub.10 -alkenyl(R.sup.11).sub.n, (n is 0, 1 or 2), where the 
alkenyl moiety is unbranched, branched or cyclic, and is also unsaturated 
once or more than once, and R.sup.11 can be substituted by R.sup.12, 
O--C.sub.3 -C.sub.10 -alkynyl(R.sup.11).sub.n, (n is 0, 1 or 2), where the 
alkynyl moiety is unbranched, branched or cyclic, is unsaturated once or 
more than once, and R.sup.11 can be substituted by R.sup.12, 
R.sup.3 to R.sup.15 have the meanings given above, 
X is (CH.sub.2).sub.m, (m is 0, 1, 2, 3 or 4), CH.dbd.CH, C.tbd.C, CH.sub.2 
OCH.sub.2 or CH.sub.2 SCH.sub.2, 
Y is (CH.sub.2).sub.m, (m is 0, 1, 2, 3 or 4), O, S or NR.sup.8, 
Z is (CH.sub.2).sub.m, (m is 0, 1, 2, 3 or 4), S, O, S--C.sub.1 -C.sub.10 
-alkyl, (unbranched or branched), CH.dbd.CH, CH.dbd.CF, CH.dbd.CCl, 
CH.dbd.CBr, CH.sub.2 --C(O), CH.sub.2 --CHF, CH.sub.2 --CHCl, CH.sub.2 
--CHBr, CH.sub.2 --CHI, C.sub.3 -C.sub.10 -cycloalkylene, C.sub.3 
-C.sub.10 -cycloalkenylene, COOR.sup.7, C.tbd.C, CH.dbd.C(C.sub.1 -C.sub.4 
-alkyl) (unbranched or branched), CH.dbd.C(CN), CH.dbd.C (R.sup.13) or 
NR.sup.8, 
R.sup.16 is C.sub.1 -C.sub.10 -alkyl(R.sup.11).sub.n, C.sub.3 -C.sub.10 
-alkenyl(R.sup.11).sub.n or C.sub.3 -C.sub.10 -alkynyl(R.sup.11).sub.n, 
with n in each case being zero or 1. 
The following meanings of the radicals in formula I are very particularly 
preferred: 
R.sup.1 is CONHSO.sub.2 R.sup.14 or a radical of the following formulae: 
##STR13## 
in which E is O, V is N and W is N, or R.sup.1 forms, together with 
R.sup.2, the ring 
##STR14## 
in which U is oxygen, R.sup.2 is O--C.sub.1 -C.sub.6 -alkyl(R.sup.11) (n 
is 1), where the alkyl moiety is unbranched, branched or cyclic, or 
O--C.sub.3 -C.sub.6 -alkenyl(R.sup.11).sub.n, (n is 1) where the alkenyl 
moiety is unbranched, branched or cyclic, 
R.sup.3, R.sup.11 and R.sup.13 are phenyl, phenyl substituted by OH or 
chlorine, imidazolyl or benzo-fused or pyridino-fused imidazolyl, where 
R.sup.3, R.sup.11 and R.sup.13 are identical or different. 
R.sup.4, R.sup.5 and R.sup.6 are H or OH, where R.sup.4, R.sup.5 and 
R.sup.6 are identical or different. 
R.sup.8 and R.sup.9 are C.sub.1 -C.sub.4 -alkyl. 
R.sup.14 is C.sub.1 -C.sub.4 -alkyl, phenyl, naphthyl, thiazolyl or its 
benzo-fused derivatives, where the aromatic radical or heteroaromatic 
radical can be monosubstituted or disubstituted by chlorine, CF.sub.3, 
NO.sub.2, C.sub.1 -C.sub.4 -alkoxy or NR.sup.8 R.sup.9, or R.sup.14 is a 
radical of the formula 
##STR15## 
R.sup.16 is C.sub.1 -C.sub.4 -alkyl(R.sup.11).sub.n, with n being 1. 
Insofar as they contain a carboxyl group, the novel compounds of the 
formula I can form salts with inorganic or organic bases. Salts with 
inorganic bases are preferred, particularly the physiologically harmless 
alkali metal salts, especially sodium salts and potassium salts. The 
compounds of the formula I inhibit the glucose-6-phosphatase system of the 
liver in mammals. The compounds are therefore suitable for use as 
pharmaceuticals. The invention also relates, therefore, to pharmaceuticals 
based on the compounds of the formula I, where appropriate in the form of 
the physiologically tolerated salts. 
The invention furthermore relates to the use of compounds of the formula I, 
or of the salts, for treating diseases which are associated with an 
elevated activity of the glucose-6-phosphatase system. 
The invention also relates, therefore, to the use of compounds of the 
formula I, or of the salts, for treating diseases which are associated 
with an elevated production of glucose from the liver. 
The invention also relates to the use of compounds of the formula I, or of 
the salts, for treating type II diabetes (non-insulin-dependent or 
maturity-onset diabetes). 
The invention furthermore comprises the use of compounds of the formula I, 
or of the salts, for preparing pharmaceuticals for treating diabetes and 
other diseases which are characterized by an elevated secretion of glucose 
from the liver or by an elevated activity of the glucose- 6-phosphatase 
system. 
The effect of the novel compounds on the glucose-6-phosphatase system was 
investigated in an enzyme test using liver microsomes. 
Fresh livers from male Wistar rats were used for preparing the microsome 
fraction containing glucose-6-phosphatase and were processed as described 
in the literature [Canfield, W. K. and Arion, W. J., J. Biol. Chem. 263, 
7458 to 7460, (1988)]. This microsome fraction can be stored at 
-70.degree. C. for at least 2 months without any significant loss of 
activity. The glucose-6-phosphatase activity was detected, as described in 
the literature (Arion, W. J. in Methods Enzymol. 174, Academic Press 1989, 
pages 58 to 67), by determining the phosphate liberated from 
glucose-6-phosphate. 0.1 ml of test mixture contained glucose-6-phosphate 
(1mmol/l), the test substance, 0.1 mg of microsome fraction and 100 mmol/l 
HEPES buffer (4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid), pH 7.0. 
The reaction was started by adding the enzyme. After proceeding at room 
temperature for 20 minutes, the reaction was stopped by adding 0.2 ml of 
phosphate reagent. The sample was incubated at 37.degree. C. for 30 
minutes and the absorption (A) of the blue color was then measured at 570 
nm. The inhibitory activity of the test substance was obtained by 
comparing with a control reaction which did not contain any test 
substance, according to the formula 
##EQU1## 
If necessary, the inhibitory activity of the test substance was determined 
as a function of the concentration of the test substance employed and, 
from this, the concentration was calculated which was required to inhibit 
the enzyme activity by 50% (IC.sub.50). 
The IC.sub.50 value was determined for the compounds listed below: 
______________________________________ 
Compound IC.sub.50 [.mu.m]: 
______________________________________ 
4 0.02 
9 0.3 
19 0.8 
______________________________________ 
The invention also relates to a pharmaceutical which contains one or more 
novel compounds of the formula I and/or its/their pharmacologically 
tolerated salts. 
The pharmaceuticals are prepared by processes which are known per se and 
with which the person skilled in the art is familiar. As pharmaceuticals, 
the novel, pharmacologically active, compounds (.dbd. active compound) are 
either employed as such or, preferably, in combination with suitable 
pharmaceutical auxiliary substances, in the form of tablets, coated 
tablets, capsules, suppositories, emulsions, suspensions, granules, 
powders, solutions or preparations having a protracted release of active 
compound, with the content of active compound advantageously being from 
0.1 to 95%. 
Owing to his specialist knowledge, the person skilled in the art is 
familiar with those auxiliary substances which are suitable for the 
desired pharmaceutical formulation. In addition to solvents, gel formers, 
suppository bases, tablet adjuvants and other active compound excipients, 
antioxidants, dispersants, emulsifiers, defoamers, taste corrigents, 
preservatives, solubilizers or dyes can, for example, also be used. 
The active compounds may be administered topically, orally, parenterally or 
intravenously, with the preferred mode of administration depending on the 
disease to be treated. Oral administration is preferred. 
For a form for oral use, the active compounds are mixed with the additives 
which are suitable for this purpose, such as carrier substances, 
stabilizers or inert diluents, and brought by customary methods into 
suitable forms for administration, such as tablets, coated tablets, hard 
gelatin capsules, aqueous, alcoholic or oily suspensions, or aqueous, 
alcoholic or oily solutions. Examples of inert excipients which can be 
used are gum arabic, magnesium hydroxide, magnesium carbonate, potassium 
phosphate, lactose, glucose or starch, in particular corn starch. In this 
context, the formulation can be effected as a dry granulate or as a wet 
granulate. Suitable oily carrier substances or solvents are vegetable or 
animal oils, such as sunflower oil or cod liver oil. 
For subcutaneous or intravenous administration, the active compounds, or 
their physiologically tolerated salts, are brought into solution, 
suspension or emulsion, if desired together with the substances which are 
customary for this purpose, such as solubilizers, emulsifiers or other 
auxiliary substances. Examples of suitable solvents are water, 
physiological sodium chloride solution or alcohols, e.g. ethanol, propanol 
or glycerol, and, in addition, also sugar solutions such as glucose 
solutions or mannitol solutions, or else a mixture of different solvents. 
Eyedrops, which contain the active compound in aqueous or oily solution, 
are suitable pharmaceutical preparations for topical and local use. 
Aerosols and sprays, and also coarse powders, which are administered 
through the nostrils by means of rapid inhalation, and especially nose 
drops, which contain the active compounds in aqueous or oily solution, are 
suitable for use on the nose. 
The dosage of the active compound of the formula I to be administered, and 
the frequency of administration, depend on the strength and the duration 
of the effect of the novel compound used; also on the nature and severity 
of the disease to be treated and on the sex, age, weight and individual 
responsiveness of the mammalian subject to be treated. On average, the 
recommended daily dose of a novel compound is, in the case of a mammalian 
subject--most importantly a human patient--of approximately 75 kg in 
weight, in the range of from about 1 to 500 mg, preferably from about 10 
to 250 mg, it being possible, according to requirement, for the 
administration to take place in several doses per day, and also, where 
appropriate, to be lower or higher. 
The preparation of the novel compounds of the formula I is elucidated by 
the examples. Room temperature denotes a temperature of from 20.degree. to 
25.degree. C.

EXAMPLE 1 
##STR16## 
Preparation of compound 2 from 1 
3.7 g (0.054 mol) of the carboxylic acid 1 (preparation cf. EP Application 
No. 93 114 261.6, reaction scheme method A, structural element 68B) were 
dissolved in 36 ml of anhydrous dimethylformamide, and 1.81 g (0.011 mol) 
of N,N'-carbonyldi-(1,2,4-triazole) were added, at room temperature and 
under argon, to this solution, which was then heated at from 50.degree. to 
60.degree. C. for 1.5 hours. After it had been cooled down, the 0.15 molar 
solution of 2 was employed in the subsequent step without any further 
working-up. 
Preparation of compound 3 from 2 
0.057 g (0.006 mol) of methanesulfonamide was dissolved in 3 ml of 
anhydrous dimethylformamide, and 0.02 g (0.0066 mol) of sodium hydride 
(80% in oil) was added at room temperature. The suspension was stirred at 
from 50.degree. to 60.degree. C. for 45 minutes. 3.1 ml (0.00047 mol) of 
the 0.15 molar triazolide solution 2 were then added dropwise at this 
temperature. The reaction mixture was stirred at 60.degree. C. for 1 hour. 
It was then added to a saturated solution of ammonium chloride, whereupon 
the product 3 precipitated out as an amorphous solid. The precipitate was 
filtered off with suction and then washed with distilled water; the solid 
thus obtained was then dried over calcium chloride at 10.sup.- 2 Torr and 
40.degree. C. for 3 hours. 0.248 g of compound 3 was obtained. 
Preparation of compound 4 from 3 
0.24 g (0.000316 mol) of cyclohexylidene ketal 3 was initially introduced 
in 10 ml of dioxane, and 1.6 ml (0.0032 mol) of 2 molar hydrochloric acid 
were added at room temperature while stirring vigorously. The clear 
solution was stirred at from 50.degree. to 60.degree. C. for 2 hours. The 
reaction solution was then cooled down to from 10.degree. to 20.degree. C. 
and titrated with 1 molar sodium hydroxide solution to pH 3; the reaction 
mixture was then diluted with 20 ml of distilled water and concentrated in 
vacuo until no further dioxane distilled off. On being stirred up with 
water, a precipitate slowly crystallized and was filtered off with suction 
and washed with water. After drying at 40.degree. C. under high vacuum, 
0.18 g of compound 4 was obtained as a colorless solid. 
In this manner, the following compounds of the formula I were synthesized: 
##STR17## 
EXAMPLE 2 
##STR18## 
Preparation of compound 14 from 13: 
5.0 g (0.012 mol) of lactone 13 (preparation cf. EP Application No. 93 114 
261.6, reaction scheme method A, structural element 68B) were dissolved in 
80 ml of anhydrous toluene, and 10 ml (0.012 mol) of a 1.2 molar solution 
of diisobutylaluminum hydride in hexane were added dropwise at -78.degree. 
C. and under an argon atmosphere. After 1 hour at -50.degree. C., 
hydrolysis was carried out using a saturated solution of ammonium 
chloride. The mixture was extracted with ethyl acetate and the combined 
organic phases were washed with a saturated solution of sodium chloride 
and dried using magnesium sulfate. The organic phase was concentrated in 
vacuo and the lactol 14 thus obtained was employed in the subsequent step 
without any further purification. 
Preparation of compound 15 from 14: 
4.6 g (0.011 mol) of lactol and 0.761 g (0.011 mol) of hydroxylamine 
hydrochloride were dissolved in 50 ml of methanol. 750 mg (0.014 mol) of 
potassium hydroxide were added. This solution was stirred at room 
temperature for 1 hour. 300 ml of methyl tert-butyl ether were then added 
to the solution, and this was followed by washing with water and with a 
saturated solution of sodium chloride; after drying with magnesium 
sulfate, the organic phase was concentrated in vacuo. The residue was 
purified by chromatography on silica gel (eluent: ethyl acetate/n-heptane 
1:2). 3.6 g of oxime 15 were obtained as a colorless oil. 
Preparation of compound 16 from 15: 
20.0 g (0.046 mol) of oxime 15 were initially introduced in 200 ml of 
anhydrous dichloromethane, and 23.0 g (0.14 mol) of 
N,N'-carbonyldiimidazole were added. There followed a powerful evolution 
of gas. After 14 hours at room temperature, 100 ml of methanol were added 
to the reaction solution, and the mixture was heated under reflux for a 
further 4 hours. For the working-up, the solution was brought to dryness 
by rotary evaporation and the residue was taken up in methyl tert-butyl 
ether. The organic phase was washed with a mixture of water/0.1M solution 
of potassium hydrogen sulfate, dried using magnesium sulfate and 
concentrated in vacuo. The residue was purified by chromatography on 
silica gel (silica gel particle size: 35 to 70 .mu.m, eluent system: ethyl 
acetate/n-heptane 1:5, towards the end, the proportion of n-heptane was 
decreased: 1:3). 12.9 g of nitrile 16 were obtained as a colorless oil. 
Preparation of compound 17 from 16: 
12.9 g (0.0286 mol) of nitrile 16 were dissolved in 250 ml of anhydrous 
toluene and heated at 110.degree. C. 5.89 g (0.0286 mol) quantities of 
trimethyltin azide were added at 24-hour intervals over a period of three 
days. The reaction solution was then concentrated in vacuo, and 50 ml of 
10 molar sodium hydroxide solution and 20 ml of tetrahydrofuran were added 
to the residue while stirring vigorously. The resulting sodium salt of 17 
was filtered off with suction and then suspended in distilled water and 
this suspension was acidified with 2 molar acetic acid. It was extracted 
with ethyl acetate and the combined organic phases were dried using 
magnesium sulfate and concentrated in vacuo. 7.7 g of tetrazole 17 were 
obtained. 
##STR19## 
Preparation of starting compound B from A: 
274 mg (0.001 mol) of carboxylic acid A (preparation cf. EP Application No. 
93 114 261.6, method I) were dissolved, under an argon atmosphere and at 
room temperature, in 20 ml of anhydrous dimethylformamide, and 180.4 mg 
(0.0011 mol) of N,N'-carbonyldi-(1,2,4-triazole) were added. The reaction 
solution was stirred at 60.degree. C. for 1 hour. The resulting solution 
of compound B was employed in the subsequent step without any further 
working-up. 
Preparation of compound 18 from 17: 
3.0 g (0.00652 mol) of compound 17 were dissolved, under an argon 
atmosphere, in 30 ml of anhydrous dimethylformamide, and 0.70 g (0.023 
mol) of sodium hydride (80% dispersion in oil) was added at room 
temperature. After 1 hour, 157 ml (0.0078 mol) of an 0.5 molar solution of 
B in dimethylformamide were added dropwise, and the mixture was stirred 
once again at room temperature for 1 hour. The reaction solution was 
subsequently added to a saturated solution of ammonium chloride, and this 
mixture was extracted with ethyl acetate. The combined organic phases were 
washed with a saturated solution of sodium chloride, dried over magnesium 
sulfate and concentrated in vacuo. The crude product was purified by 
chromatography. (Silica gel particle size: 35 to 70 .mu.m, eluent system: 
ethyl acetate/n-heptane/methanol/glacial acetic acid 30:10:2:1). The ester 
18 was obtained as an amorphous solid. 
Preparation of compound 19 from 18: 
3.8 g (0.0053 mol) of cyclohexylidene compound 18 were taken up in 150 ml 
of dioxane, and 10 ml (0.02 mol) of 2 molar hydrochloric acid were added 
while stirring. This solution was heated at 60.degree. C. for 2 hours. The 
pH of the reaction solution was then adjusted to 3 using 18 ml of 1N molar 
sodium hydroxide solution and the solvent was removed by rotary 
evaporation. The residue was taken up in ethyl acetate and the precipitate 
which developed was filtered off. The filtrate was concentrated in vacuo 
and the residue was purified by chromatography on silica gel (silica gel 
particle size: 35 to 70 .mu.m, eluent system: ethyl 
acetate/methanol/water/glacial acetic acid 4:1:1:0.5). 2.5 g of compound 
19 were obtained as a colorless amorphous solid. 
In this manner, the following compounds of the formula I were synthesized: 
##STR20## 
EXAMPLE 3 
##STR21## 
Preparation of compound 22 from 21: 
2.26 g (0.01 mol) of the ketone 21 which is known from the literature (cf. 
J. C. Barrier et al., Helv. Chim. Acta 66, 296 (1983)) and 4.29 g (0.025 
mol) of 3-phenylpropylamine hydrochloride were initially introduced, under 
an argon atmosphere, in 5 ml of methanol and 3 ml of distilled water. The 
mixture was cooled to 0.degree. C. and a solution of 1.63 g (0.025 mol) of 
potassium cyanide in 4 ml of distilled water was added dropwise. The 
reaction mixture was stirred at 0.degree. C. for 4 hours and at room 
temperature for 1 hour and was then added, while stirring, to ice/water; 
this mixture was extracted three times with ethyl acetate. The combined 
organic phases were washed three times with distilled water and once with 
a saturated solution of sodium chloride and then dried using magnesium 
sulfate and concentrated in vacuo. 5.0 g of crude product 22 were 
obtained, which product was employed in the subsequent step without any 
further purification. 
Preparation of compound 23 from 22: 
3.7 g (0.01 mol) of cyano compound 22 were dissolved in 8 ml of glacial 
acetic acid, and a solution of 1.62 g (0.02 mol) of potassium cyanate in 4 
ml of distilled water was added at room temperature and while stirring. 
The reaction solution was stirred at room temperature for 75 minutes and 
then added to a mixture of ice and waters this new mixture was extracted 
twice with ethyl acetate, and the combined organic phases were washed once 
with distilled water and once with a saturated solution of sodium 
chloride. After the organic phase had been dried with magnesium sulfate, 
it was concentrated in vacuo; the oily residue thus obtained was dissolved 
in 4 ml of dioxane, and 10 ml of 2 molar hydrochloric acid were added to 
this solution while stirring. After stirring at 55.degree. C. for one 
hour, the reaction mixture was poured onto an ice/water mixture and the 
whole was extracted three times with ethyl acetate. The organic phases 
were washed three times with water and once with a saturated solution of 
sodium chloride, dried over magnesium sulfate and concentrated in vacuo. 
The oily residue was purified by chromatography on silica gel (silica gel 
particle size: 35 to 70 .mu.m, eluent: ethyl 
acetate/n-heptane/methanol/glacial acetic acid 20:10:2:1), and 0.36 g of 
product 23 was obtained. 
Preparation of compound 24 from 23: 
0.36 g (0.00106 mol) of compound 23 was dissolved in 1.09 ml (0.0106 mol) 
of dimethoxypropane and 20 ml of anhydrous dichloromethane. 26 mg (10 mol 
%) of pyridinium para-toluenesulfonate were added. The mixture was heated 
at 40.degree. C. for 45 minutes. The reaction solution was then added to a 
saturated solution of sodium hydrogen sulfate and this mixture was 
extracted with ethyl acetates the combined organic phases were dried using 
magnesium sulfate. The residue was purified by chromatography on silica 
gel (silica gel particle size: 35 to 70 .mu.m, eluent system: ethyl 
acetate/n-heptane 2:1), and 0.24 g of compound 24 was obtained as a 
colorless solid. 
Preparation of compound 25 from 24: 
230 mg (0.0006 mol) of hydroxy compound 24 were dissolved in 10 ml of 
anhydrous dimethylformamide, and 55 mg (0.00184 mol) of sodium hydride 
(80% dispersion in oil) were added at room temperature and under an argon 
atmosphere. After 30 minutes at room temperature, 22 ml of a 0.5 molar 
solution of B in dimethylformamide were added dropwise. After a further 30 
minutes at this temperature, a clear solution was obtained; a saturated 
solution of ammonium chloride was added to this clear solution, whereupon 
the product 25 precipitated out as an amorphous solid. This solid was 
filtered off with suction and dried in vacuo. 310 mg of compound 25 were 
obtained. 
Preparation of compound 26 from 25: 
290 mg (0.00047 mol) of compound 25 were dissolved in 30 ml of dioxane, and 
4 ml (0.008 mol) of 2 molar hydrochloric acid were added, at room 
temperature and while stirring vigorously, to this solution. After 
stirring at 50.degree. C. for two hours, the reaction solution was cooled 
down to from 10.degree. to 20.degree. C. and titrated to pH 3 using 1 
molar sodium hydroxide solution. The solution was concentrated in vacuo 
and the oily residue was taken up in isopropanol; the precipitate of salt 
was-filtered off and the filtrate was concentrated once again in vacuo. 
The residue was stirred up with methyl tert-butyl ether and the amorphous 
precipitate was filtered off with suction. After drying in vacuo, 140 mg 
of compound 26 (end product of the formula I) were obtained. 
##STR22## 
EXAMPLE 4 
##STR23## 
Preparation of compound 28 from 27: 
6.4 g (14.5 ml, 0.161 mol) of 2-bromothiazole were dissolved, under an 
argon atmosphere, in 500 ml of anhydrous diethyl ether, and 107.5 ml of 
n-butyllithium in hexane (1.5 molar solution) were added dropwise at 
-78.degree. C. The mixture was stirred at -78.degree. C. for 30 minutes 
and a solution of 25.0 g (0.081 mol) of ketone 27 (cf. EP Application No. 
92 114 260.8, formula scheme 4, compound 23B) in 50 ml of anhydrous 
tetrahydrofuran was then added dropwise. The reaction solution was allowed 
to heat up to -30.degree. C. within the space of 30 minutes. After that, 
the reaction solution was added to ammonium chloride solution, and this 
mixture was extracted with ethyl acetate and the combined organic phases 
were washed with a saturated solution of sodium chloride and dried using 
sodium sulfate. The organic phase was concentrated in vacuo and the 
residue was purified by chromatography on silica gel (eluent: ethyl 
acetate/heptane 1:2, particle size: 35 to 70 .mu.m). 23.3 g (77%) of 
compound 28 were obtained as a viscous oil. 
Preparation of compound 30 from 28: 
15.0 g (0.038 mol) of alcohol 28 were dissolved in 250 ml of anhydrous 
dimethylformamide, and 1.5 g (0.05 mol) of sodium hydride were added at 
from 0.degree. to 10.degree. C. The mixture was stirred at 10.degree. C. 
for 1.5 hours and then cooled down to 0.degree. C., when 13.2 g (0.057 
mol) of cis-3-(4-chlorophenyl)propenyl bromide (29), dissolved in 30 ml of 
anhydrous dimethylformamide, were added dropwise. The reaction solution 
was allowed to warm to room temperature and was stirred at this 
temperature for 2 hours. The reaction solution was subsequently added to a 
saturated solution of ammonium chloride and this mixture was extracted 
with ethyl acetates the combined organic phases were washed with a 
saturated solution of sodium chloride. After having been dried using 
sodium sulfate, the organic phase was concentrated in vacuo and the 
residue was purified by chromatography on silica gel (eluent: ethyl 
acetate/n-heptane 1:2, particle size: 35 to 70 .mu.m). 19.0 g of thiazole 
30 were obtained as a viscous oil. 
Preparation of compound 31 from 30: 
56.6 ml of a 1.1 molar solution of diethylzinc in toluene were added 
dropwise, at 0.degree. C. and under an argon atmosphere, to 250 ml of 
anhydrous dichloroethane, and 9.0 ml (0.125 mol) of chloroiodomethane were 
then added at 0.degree. C. The reaction solution was stirred at the same 
temperature for 30 minutes and, after that, 17.0 g (0.031 mol) of olefin 
30, dissolved in 30 ml of anhydrous dichloroethane, were added dropwise. 
The mixture was allowed to warm slowly to room temperature. After 2 hours, 
the reaction solution was added to a saturated solution of ammonium 
chloride and this mixture was extracted with ethyl acetates the combined 
organic phases were washed with a saturated solution of sodium chloride. 
After the organic phase had been dried using sodium sulfate, it was 
concentrated in vacuo and the residue was stirred thoroughly with methyl 
tert-butyl ether. The precipitate was filtered off (methylation of the 
nitrogen in the thiazole ring took place as a side reaction) and the 
filtrate was concentrated once again. 4.2 g (24%) of compound 31 were 
obtained as a viscous oil. 
Preparation of compound 32 from 31: 
4.2 g (0.008 mol) of 31 were dissolved in 100 ml of methanol and 150 ml of 
dichloromethane, and 0.7 g (0.003 mol) of pyridinium p-toluenesulfonate 
was added at room temperature. The clear solution was allowed to stand at 
room temperature for 14 hours and 20 ml of a 1N solution of sodium 
hydrogen carbonate were then added to it; this mixture was concentrated 
until only the aqueous phase remained. This phase was extracted with ethyl 
acetate and the combined organic phases were washed with a saturated 
solution of sodium chloride, dried using sodium sulfate and concentrated 
in vacuo. The residue was purified by chromatography on silica gel 
(eluent: ethyl acetate/n-heptane 1:1, particle size: 35 to 70 .mu.m). 1.82 
g (51%) of compound 32 were obtained as a colorless oil. 
Preparation of compound 33 from 32: 
In analogy with the preparation of compound 19 from compound 17, as 
described in Example 2, compound 33 of the formula I was obtained, as an 
amorphous solid, from 32 in 2 stages. MS (FAB): m/z=542 (M+H.sup.+)