Note: Descriptions are shown in the official language in which they were submitted.
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Sulfamoyl Sulfonate Prodrugs
The invention relates to sulfamoyl sulfonate prodrugs of general formula I,
//O
X ~=0
js~ NH 2
p ~\
O
Drug ; Gruppe Z
[Group Z] (I),
a process for the production of these prodrugs, pharmaceutical compositions
that contain
these compounds, and their use for the production of orally available
pharmaceutical agents.
From WO 01/91797, steroidal compounds that are bonded via an -S02NR1R2 group
to erythrocytes and that accumulate there are known. The concentration ratio
of the
compounds between erythrocytes and plasma is 10-1000:1, preferably 30-1000:1,
so that a
depot formation in the erythrocytes can be mentioned. Because of the strong
binding of the
compounds to the erythrocytes, metabolization is avoided during passage
through the liver.
Disadvantageously, no therapy-relevant active ingredient levels are given
despite a reduced
metabolization with the indicated dosages. Reasons for this can be sought in
excessive
binding to erythrocytes, an enzyme-induced cleavage and in low solubilities.
It is the object of the invention to provide new prodrugs that are orally
available and
that, in comparison to the prior art, ensure a therapy-relevant active
ingredient level even at a
low dosage.
This object is achieved by sulfamoyl sulfonate prodrugs of general formula
(I), in
which a sulfamoyl radical is bonded to the drug that is to be released via a
spacer X by means
of a sulfonate bond.
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2
Sulfamoyl sulfonate prodrugs of general formula (I) are
//0
X S=0
S NHZ
p~ \0
Drug Gruppe Z
[Group Z] (I),
in which
X is a C1_12-alkanediyl-, a CPFZp group where p= 1-5, a C3_g-cycloalkanediyl-,
an
arylene-, a heteroalkanediyl-, a C1.4-alkanediylaryl-, a C1_4-alkanediyl-C3_8-
cycloalkyl- or a C3_8-cycloalkanediyl-C1_4-alkyl group, and
Drug is a pharmaceutical active ingredient that can form a sulfonate via an OH
group, such as steroids, anti-malaria agents, nucleosides, or isoflavonoids,
which can optionally be substituted.
The sulfamoyl sulfonate compounds according to the invention bond to
erythrocytes,
are readily water-soluble and are hydrolytically cleaved without assistance
from enzymes.
For the purpose of this invention, "C1_12-alkanediyl group" is defined as a
double-
bonded, branched or straight-chain alkylene radical with up to 12 carbon atoms
that
optionally can be substituted with, e.g., halogen atoms, hydroxy groups, or
nitrile groups. As
examples, a methane-l,l-diyl-, ethane-1,2-diyl, propane-1,3-diyl-, butane-l,4-
diyl-, pentane-
1,5-diyl-; hexane-1,6-diyl-, octane-l,8-diyl-, and undecane-1,11-diyl group
can be
mentioned.
For the purpose of this invention, CPF2P group with p = 1-5 is defined as a
branched or
straight-chain perfluorinated alkyl radical with up to 5 carbon atoms. As
examples, a
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3
perfluoropropane-1,3-diyl-, perfluorobutane-1,4-diyl-, and perfluoropentarie-
1,5-diyl group
can be mentioned.
The above-mentioned "C3_8-cycloalkanediyl group" means, according to the
invention, a double-bonded, mono- or bicyclic, carbocyclic group with 3 to 8
carbon atoms
that optionally can be substituted with halogen atoms, hydroxy groups, and
nitrile groups,
such as, for example, with a cyclobutane-1,3-diyl-, cyclopentane-1,3-diyl- or
a cyclohexane-
1,4-diyl group.
The above-mentioned "arylene group" means, according to the invention, a
double-
bonded, aromatic mono- to tricyclic, carbocyclic group with 6 to 15 carbon
atoms that
optionally can be substituted with halogen atoms, hydroxy groups, nitrile
groups, and alkyl
groups, such as, for example, with an m-phenylene-, p-phenylene-,
phenanthrylene- or a
naphthalene group.
The heteroarylene radical includes, in each case, 5-16 ring atoms and
contains,
instead of carbon, one or more heteroatoms that are the same or different,
such as oxygen,
nitrogen or sulfur, in the ring. The heteroaryl radical can be mono-, bi- or
tricyclic.
For example, there can be mentioned: thienyl, furanyl, pyrrolyl, oxazolyl,
thiazolyl,
imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,
thiadiazolyl,
benzofuranyl, benzothienyl, benzothiazole, benzoxazolyl, benzimidazolyl,
indazolyl, indolyl,
isoindolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolyl,
and isoquinolyl.
For the purpose of the invention, a heteroalkanediyl group is a double-bonded,
straight-chain or branched, saturated or unsaturated heteroalkyl radical with,
in each case, 1-6
carbon atoms and can contain, instead of carbon, one or more heteroatoms that
are the same
or different, such as oxygen, nitrogen or sulfur, such as, for example, a bis-
ethylenoxy
radical.
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The "C14-arylalkanediyl group" is an aryl group that is bonded to a skeleton
via a C1
C4-alkanediyl group, whereby the alkanediyl group can be straight-chain or
branched. For
example, benzyl or phenethylene can be mentioned.
The "C3_8-cycloalkyl-C1_4-alkanediyl group" means, for example, cycloalkyl-
(CH2)-,
cycloalkyl-(C2H4)-, cycloalkyl-(C3H6)-, cycloalkyl-(C4Hg)-, or cycloalkyl-
(C5H,o)-. In this
case, cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl or
cyclooctyl.
"C1_4-Alkyl-C3_8-cycloalkanediyl group" is defined as methylcycloalkanediyl,
ethyl-
cycloalkanediyl, propylcycloalkanediyl, butylcycloalkanediyl, or
pentylcycloalkanediyl. In
this case, cycloalkanediyl can be cyclopropane-1,3-diyl, cyclobutane-1,4-diyl,
cyclopentane-
1,5-diyl, cyclohexane-1,6-diyl, cycloheptane-1,7-diyl or cyclooctane-1,8-diyl.
In the context of this invention, the term "halogen atom" is defined as a
fluorine,
chlorine, bromine or iodine atom, preferably a fluorine, chlorine, or bromine
atom.
A pharmaceutical active ingredient that can form a sulfonate via an OH group
means,
for the purpose of the invention, the following:
Steroids: Estrogens, for example estradiol or estriol, or
androgens, for example testosterone, MENT (7 a-methyl-19-
nortestosterone), eF-MENT (11 -fluoro-7 a-methyl-l9-nortestosterone),
nandrolone, DHT (dihydrotestosterone), or
gestagens, for example norethisterone, dienogest or levonorgestrel,
or corticoids, for example cortisol
Anti-malaria agents: quinine, cinchonidine, hydroxychloroquine, primaquine,
mefloquine;
or
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Nucleosides: consisting of a sugar, such as ribose or deoxyribose, and a base,
such
as adenine, guanine, cytosine, thymine or uracil, and also zidovudine,
brivudine, indinavir, and nelfinavir;
Isoflavonoids: genisteine.
Especially preferred compounds are specified as follows:
1) 3-hydroxyestra-1,3,5(10)-trien-17(3-y13'-sulfamoylphenyl sulfonate,
2) 3-acetoxyestra-1,3,5(10)-trien-17(3-yl 3'- sulfamoylphenyl sulfonate,
3) 3-tert-butyldimethylsilyloxyestra-1,3,5(10)-trien-170-yl 3'-sulfamoylphenyl
sulfonate,
4) 3-hydroxyestra-1,3,5(10)-trien-l7R-y14'-sulfamoylphenyl sulfonate,
5) 2-methoxy-3-hydroxyestra-1,3,5(10)-trien-170-yl 3'-sulfamoylphenyl
sulfonate,
6) 3,16a-dihydroxyestra-1,3,5(10)-trien-17(3-yl 3'-sulfamoylphenyl sulfonate,
7) 3,170 -dihydroxyestra-1,3,5(10)-trien-16a-y13'-sulfamoylphenyl sulfonate,
8) 3-benzoyloxyestra-1,3,5(10)-trien-170-yl 3'-sulfamoylphenyl sulfonate,
9) quinine-3'-sulfamoylphenyl sulfonate,
10) cinchonidine-3'-sulfamoylphenyl sulfonate,
11) zidovudine-3'-sulfamoylphenyl sulfonate,
12) 3-oxoandrost-4-en-170-yl 3'-sulfamoylphenyl sulfonate,
13) 3-oxoandrostan-17P-yl 3'-sulfamoylphenyl sulfonate,
14) 3-oxo-7a-methylandrost-4-en-170-yl 3'-sulfamoylphenyl sulfonate,
15) 3-oxoestr-4-en-17(3-yl 3'-sulfamoylphenyl sulfonate, and
16) brivudine-3'-sulfamoylphenyl sulfonate.
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The therapeutically relevant drug compound is released through hydrolysis from
the
compounds according to the invention.
In-Vitro Tests:
Carbonic Anhydrase Inhibition
Test Principle:
Photometric determination of the inhibition of human carbonic anhydrase I or
II with
sulfonamides or sulfamates on microtiter plates with the aid of enzymatic
conversion of
nitrophenyl acetate with a color change from colorless to yellow.
Table 1: IC50 Inhibiting Values of Human Carbonic Anhydrase I
CAII CAI
Inhibitor IC50 (nM) IC50 (nM)
Estradiol-3-sulfamat 34 157 10.6
3-Oxoandrost-4-en-17R-yI 120 2300
3'-aminosulfonylphenyl-
sulfonat
3-Oxo-7a-methylandrost-4- 120 2300
en-170-yi 3'-aminosulfonyl-
hen Isulfonat
3-Hydroxyestra-1,3,5(10)- 81 1700
trien-17p-yl 3'-aminosulfo-
n I hen Isulfonat
Zidovudinsulfonat 1100 2900
Acetazolamid 61 1200
bekannter CA-Hemmer) 190
Literature: 1) C. Landolfi, M. Marchetti, G. Ciocci, and C. Milanese, Journal
of
Pharmacological and Toxicological Methods 38, 169-172 (1997).
[Key to Table 1:]
Estradiol-3-sulfamat = Estradiol-3-sulfamate
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3-Oxoandrost-4-en-17R-yl 3'-aminosulfamoylphenylsulfonat = 3-Oxoandrost-4-en-
170-yl 3'-
sulfamoylphenyl sulfonate
3 -Oxo-7a-methylandrost-4-en-17 0-yl 3'-aminosulfamoylphenylsulfonat = 3 -Oxo-
7a-
methylandrost-4-en-17(3-yl 3'-aminosulfamoylphenyl sulfonate
3-Hydroxyestra-1,3,5(10)-trien-17(3-yl 3'-aminosulfonylphenylsulfonat = 3-
Hydroxyestra-
1,3,5(10)-trien-l7R-yl 3'-aminosulfonylphenyl sulfonate
Zidovudinsulfonat = Zidovudine Sulfonate
Acetazolamid (bekannter CA-Hemmer) = Acetazolamide (Known CA Inhibitor)
It was found that the sulfamoyl sulfonate prodrugs according to the invention
surprisingly readily inhibit the carbonic anhydrase II. A concentration of the
prodrugs,
according to the invention, in the erythrocytes can be deduced from this.
Physicochemical Data
Solubility in Water
a) Kinetic Measurement:
The compounds according to the invention were measured as 10 mmol DMSO
solution in a 0.01 M phosphate buffer solution at pH 7.4 and 25 C with
nephelometry and
turbidity.
While in a turbid state, the solution to be tested was added drop by drop to
the buffer
solution until a precipitate settled.
The precipitate was detected in a dilution series (compounds in a phosphate
buffer
solution according to the invention) by nephelometry.
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b.) Thermodynamic Measurement:
The compounds in solid form according to the invention were added to an excess
of
an aqueous buffer system of various pH values. It was stirred 24 hours at 25
C. After
centrifuging, the solution was examined with HPLC (HPLC: column: Xterra MS C18
2.5
m, 30 x 4.6 mm). Two standard gradient systems were used based on the
compounds to be
measured:
Acidic gradient: A: water/0.01 % trifluoroacetic acid, B: acetonitrile/0. 0 1
%
trifluoroacetic acid - 0 min 5% B, 0-3 min 65% B, 3-5 min 65% B, 5-6 min 5% B
Alkaline gradient: A: water/0.025% ammonia, B: acetonitrile/0.025% ammonia - 0
min 20% B, 0-3 min 80% B, 3-5 min 80% B, 5-6 min 20% B.
Table 2: Water Solubility
Substance Solubility in Water
Estradiol-3-sulfamate 0.15 mg/100 ml
Testosterone Propionate Insoluble
3-Hydroxyestra-1,3,5(10)-trien-170-y13'- 3 mg/1
sulfamoylphenyl Sulfonate
3-Oxoandrost-4-en-170-yl 3'-sulfamoyl- 5 mg/l
phenyl Sulfonate
3-Oxo-7a-methylandrost-4-en-17(3-yl 3'- About 6 mg/1
sulfamoylphenyl Sulfonate
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The compounds according to the invention show a higher solubility when
compared
to sulfamate- and carboxylic acid ester prodrugs, which allows for better
absorption in the
intestine.
Hydrolysis
The compounds according to the invention were measured as a DMSO solution in
an
aqueous buffer of various pH values at 37 C.
The quantification took place through HPLC (HPLC column: Xterra MS C18 2.5 m
4.6 x 30mm). Based on the test substances to be measured, the following
gradient system was
used for the HPLC:
Acidic gradient: A: water/0.01 % trifluoroacetic acid, B: acetonitrile/0. 0 1
%
trifluoroacetic acid - 0 min 5% B, 0-3 min 65% B, 3=5 min 65% B, 5-6 min 5% B
Alkaline gradient: A: water/0.025% ammonia, B: acetonitrile/0.025% ammonia - 0
min 20% B, 0-3 min 80% B, 3-5 min 80% B, 5-6 min 20% B. The quantification
took'
place after 1 and 2 hours and after 24 hours.
Stability in Simulated Gastric Juice:
Solutions of the compounds according to the invention were incubated at 37 C
in
simulated gastric juice (aqueous NaCI solution with pepsin, pH- 1.2).
The quantification took place through HPLC (HPLC-column: Xterra MS C18 2.5 m
4.6 x 30mm) using the gradient system:
A: water/0.01 % trifluoroacetic acid, B: acetonitrile/0.01 % trifluoroacetic
acid - 0 min
5% B, 0-3 min 65% B, 3-5 min 65% B, 5-6 min 5% B.
The quantification took place after 0.5, 1, 1.5 and 2 hours.
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Table 3: Hydrolysis/Stability in Gastric Juice
Decomposition in %
pH =1, 37 C pH = 7.4, 37 C
Substance 30 min 1 h 2 h 24 h 1 h 2h. 24 h
3-Hydroxyestra-1,3,5 4 7 14 80 6 13 84
(10)-trien-17(3-yl3'- (pH=1.2)
sulfamoyl-phenyl
sulfonate
3-Oxoandrost-4-en- 3 6 11 78 6 12 75
17 (3-y13'-sulfamoyl- (pH=1.2)
phenyl sulfonate
3-Oxo-7a-methyl- 6 11 71 6 11 70
androst-4-en-17p-yl
3'-sulfamoylphenyl
sulfonate
3-Oxoandrost-4-en- 0 0 0 0 0 0 0
17(3-yl n-propionate
Carboxylic acid esters are relatively stable in gastric juice (pH - 1) and in
the
intestine (pH - 7.4), but are cleaved when passing through the intestine by
esterases that exist
there. During passage through the stomach, however, the stable prodrug remains
almost
complete.
The cleavage of the carboxylic acid ester thus takes place when passing
through the
intestine and in the liver.
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No enzymes (esterases) are known for sulfonic acid ester. It was therefore
surprising
that the sulfonates are still cleaved, whereby a simple hydrolysis takes
place. Although a slow
hydrolysis already takes place in the gastric juice and when the pH = 7.4, the
sulfonates have
adequate stability to pass through the stomach and the intestine. An esterase
cleavage does
not take place in the intestine wall. The first-pass effect in the liver is
avoided since the
sulfonates are bonded with the sulfonamide group to the erythrocytes.
The compounds of general formula (I) according to the invention can, as a
function of
the meaning of "drug," be used for the treatment and/or prophylaxis of various
clinical
pictures. For example, the compounds of general formula (I) can be used if the
"drug" is a
steroid, such as androgen or estrogen, in hormone replacement therapy (HRT) in
women and
men, or in the treatment of hormonally-induced diseases in men (prostrate
cancer, breast
cancer, hypogonadism) and in women (endometriosis, breast cancer). In
addition, the
compounds of general formula (I) according to the invention, in which "drug,"
for example,
stands for an androgen or estrogen, can he used for birth control in men and
women.
The use of additional active ingredients mentioned for "drug," such as
quinine,
cinchonidine, hydroxychloroquine, primaquine or mefloquine, relates to the
treatment of
malaria.
Compounds of general formula (I) according to the invention, in which "drug"
means
a cortisol derivative, can be used for the treatment and prophylaxis of
inflammatory and/or
allergic diseases that are influenced by immunosuppressive agents and/or
antiproliferative
agents.
Prodrugs according to the invention, in which "drug" means a nucleoside
(zidovudine,
brivudine, indinavir, nelfinavir), can be used for the treatment of viral
diseases (herpes, HIV).
In addition, subjects of the invention are the pharmaceutical compositions
that contain
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the compounds of general formula (I) according to the invention and optionally
additional
active ingredients, for example gestagens (norethisterone, dienogest,
drospirenone,
levonorgestrel), antigestagens (mifepristone, onapristone) and/or progesterone
receptor
modulators (mesoprogestins, such as asoprisnil).
These pharmaceutical compositions and pharmaceutical agents are preferably
administered orally. In addition to the usual vehicles and/or diluents, they
contain at least one
compound of general formula I.
Dosage
The prodrugs according to the invention can be administered orally.
Generally, satisfactory results are to be expected both for the treatment
and/or
prophylaxis of the above-mentioned indications or for birth control if the
dosage is carried
out in such a way that after the administration of the prodrugs, an amount of
the
corresponding active ingredient ("drug") is released that corresponds to the
highest
pharmaceutically used maximum dose of the respective "drug" substance.
The pharmaceutical agents of the invention are produced in a known way with
the
usual solid or liquid vehicles or diluents and the commonly used
pharmaceutical-technical
adjuvants corresponding to the desired form of administration with a suitable
dosage. The
preferred preparations are in a dispensing form that is suitable for oral
administration. Such
dispensing forms are, for example, tablets, film tablets, coated tablets,
capsules, pills,
powders, solutions or suspensions or else depot forms.
Corresponding tablets can be obtained by, for example, mixing the active
ingredient
with known adjuvants, for example inert diluents such as dextrose, sugar,
sorbitol, mannitol,
polyvinylpyrrolidone, explosives such as corn starch or alginic acid, binding
agents such as
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13
starch or gelatin, lubricants such as magnesium stearate or talc, and/or
agents for achieving a
depot effect, such as carboxylpolymethylene, carboxylmethyl cellulose,
cellulose acetate
phthalate or polyvinyl acetate. The tablets can also consist of several
layers.
Coated tablets can accordingly be produced by coating cores, which are
produced
analogously to the tablets, with agents that are commonly used in tablet
coatings, for example,
polyvinylpyrrolidone or shellac, gum arabic, talc, titanium oxide or sugar. In
this case, the
shells for the coated tablets can also consist of several layers, whereby the
adjuvants
mentioned above with the tablets can be used.
Solutions or suspensions with the compounds of general formula I according to
the
invention can contain additional taste-improving agents such as saccharin,
cyclamate or
sugar, as well as, e.g., flavoring substances such as vanilla or orange
extract. In addition,
they can contain suspending adjuvants such as sodium carboxymethyl cellulose
or
preservatives such as p-hydroxybenzoate.
The capsules that contain compounds of general formula I can be produced by,
for
example, the compound(s) of general formula (I) being mixed with an inert
vehicle such as
lactose or sorbitol and encapsulated in gelatin capsules.
The prodrugs according to the invention can be synthesized according to the
following examples, whereby the latter are used for a more detailed
explanation without
limiting the invention.
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General Synthesis Instructions
Variant 1
Reaction with Disulfonic Acid Chlorides
A disulfonic acid chloride of general formula S02-X-SO2Cl is dissolved under a
cover
gas in a base, such as, e.g., pyridine. The corresponding amount of a drug
substance is added
to the solution. The reaction mixture is stirred until the reaction is
completed. Then, the
reaction mixture is stirred into a concentrated NH3 solution. The precipitate
is filtered off,
washed with water and dried. The residue is extracted with an organic solvent,
such as, e,g.,
ethyl acetate, the organic phase is washed, and it is dried with a desiccant
such as, e.g.,
MgSO4. After filtration, it is concentrated by evaporation and chromatographed
on silica gel.
Corresponding sulfamoyl sulfonates are obtained.
Variant 2
Reaction with Sulfamoyl Sulfonic Acid Halides
A drug substance, as defined above, is dissolved under a cover gas in a base,
such as,
e.g., pyridine, and an inert solvent, such as, e.g., chloroform. While being
cooled, the
corresponding amount of a sulfamoyl sulfonic acid halide of general formula
NH2SO2-X-
SO2Hal is added to the solution. The reaction mixture is stirred until the
reaction is
completed. Then, water is added, and it is optionally acidified with an acid,
such as, e.g., 10%
HCI. It is extracted with an organic solvent, such as, e,g., ethyl acetate,
the organic phase is
washed, and it is dried with a desiccant, such as, e.g., MgSO4. After
filtration, it is
concentrated by evaporation and chromatographed on silica gel. Corresponding
sulfamoyl
sulfonates are obtained.
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The corresponding sulfamoyl sulfonic acid halides or disulfonic acid chlorides
are
commercially available or can be produced by methods that are known to one
skilled in the
art.
Synthesis Examples
Example 1
3 -tert-Butyldimethylsilyloxyestra-1 3 5(10)-trien-17(i-y13'-sulfamoylphenyl
Sulfonate
1.9 g of 1,3-benzenedisulfonyl chloride is dissolved under argon in 5 ml of
pyridine.
Then, 1.0 g of 3-tert=butyldimethylsilyloxyestra-1,3,5(10)-trien-17(3-ol is
added. After 2
hours, the reaction mixture is stirred into 25 ml of a concentrated ammonia
solution. After 10
minutes, it is suctioned off, washed with water and dried. The residue is
chromatographically
purified on silica gel. 3-tert-Butyldimethylsilyloxyestra-1,3,5(10)-trien-17(3-
yl 3'-
sulfamoylphenyl sulfonate is obtained.
'H-NMR (DMSO-D6): 0.14 (s, 6 H, SiMe), 0.77 (s, 3 H, 18-Me), 0.93 (s, 9 H, t.-
Bu),
4.43 (t, 1 H, 17-H), 7.68 (s, 2 H, NHZ).
Example 2
3 -Hydroxyestra-1 3 5(10)-trien-l7R-yl 3'-sulfamoylphenyl Sulfonate
300 mg of 3-tert-butyldimethylsilyloxyestra-1,3,5(10)-trien-17(3-y13'-
sulfamoylphenyl sulfonate is dissolved in 20 ml of THF. While being stirred,
200 mg of
tetrabutyl ammonium fluoride is added at room temperature. After 1 hour, 20 ml
of water is
stirred in. The substance is extracted with ethyl acetate. The organic phase
is washed with
saturated NaCI solution, dried on MgSOa, filtered, concentrated by evaporation
and
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16
chromatographed on silica gel. 3-Hydroxyestra-1,3,5(10)-trien-17(3-y13'-
sulfamoylphenyl
sulfonate is obtained.
1H-NMR (DMSO-d6): 0.76 (s, 3 H, 18-Me), 4.43 (t, 1 H, 17-H), 7.68 (s, 2 H,
NH2),
8.98 (s, 1H, 3-OH).
Example 3
3 -Oxo-7a-methylestra-4-en-17 D-y13'-sulfamoylphenyl Sulfonate
1.9 g of 1,3-benzenedisulfonyl chloride is dissolved under argon in 5 ml of
pyridine.
Then, 1.0 g of MENT is added. After 2 hours, the reaction mixture is stirred
into 25 ml of
concentrated ammonia solution. After 10 minutes; it is suctioned off, washed
with water and
dried. The residue is chromatographically purified on silica gel. 3-Oxo-7a-
methylestr-4-en-
17(3-yl 3'-sulfamoylphenyl sulfonate is obtained.
'H-NMR (DMSO-D6): 0.66 (d, 3 H, 7-Me), 4.38 (t, 1 H, 17-H), 5.69 (s; 1 H, 4-
H),
7.67 (s, 2 H, NH2), 7.83 - 8.28 (m, 4 H, H-Ar).
Example 4
3-Oxo-androst-4-en-17p-yl 3'-sulfamoylphenyl Sulfonate
Variant 1
2.0 g of 1,3-benzenedisulfonyl chloride is dissolved under argon in 5.5 ml of
pyridine.
Then, 1.0 g of testosterone is added. After 2 hours, the reaction mixture is
stirred into 25 ml
of concentrated ammonia solution. After 10 minutes, it is suctioned off,
washed with water
and dried. The residue is chromatographically purified on silica gel. 3-Oxo-
androst-4-en-
17R-y13'-sulfamoylphenyl sulfonate is obtained.
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Variant 2
1.0 g of testosterone is dissolved under argon in 5.5 ml of pyridine. Then,
1.8 g of 3-
aminosulfonylphenylsulfonyl chloride is added. After 2 hours, the reaction
mixture is stirred
into 25 ml of water and acidified with 10% HCI. After 10 minutes, it is
suctioned off, washed
with water and dried. The residue is chromatographically purified on silica
gel. 3-Oxo-
androst-4-en-17(3-yl 3'-sulfamoylphenyl sulfonate is obtained.
1H-N1VIR (DMSO-D6): 0.78 (s, 3 H, 18-Me), 1.11 (s, 3 H, 19-Me), 4.34 (t, 1 H,
17-
H), 5.60 (s, 1 H, 4-H), 7.67 (s, 2 H, NH2), 7.83 - 8.28 (m, 4 H,
H-Ar).
Example 5
Zidovudine-sulfamoylphenyl Sulfonate
2.0 g of 1,3-benzenedisulfonyl chloride is dissolved under argon in 5.5 ml of
pyridine..
Then, 1.0 g of zidovudine is added at 0 C. After 2 hours of stirring at room
temperature, the
reaction mixture is added to 25 ml of concentrated ammonia solution. After 10
minutes of
stirring, it is evaporated to the dry state and extracted with EE. The organic
phase is
concentrated by evaporation and the residue is chromatographically purified on
silica gel.
Zidovudine-sulfamoylphenyl sulfonate is obtained.
1H-NMR (DMSO-D6): 1.17 (s, 3 H, Me), 2.40 (m, 2 H, CH2), 4.00 (m, 1 H, CH),
4.42 (m, 2 H, CH2), 6.09 (m, 1 H, CH), 7.40 (s, 1 H, CH),
7.66 (s, 2 H, NH2), 7.85-8.30 (3 m + s, 5 H, 4-H), 11.35 (s,
1 H, NH).
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Example 6
Cinchonidine-sulfamoylphenyl Sulfonate
2.0 g of 1,3-benzenedisulfonyl chloride is dissolved under argon in 5.5 ml of
pyridine.
Then, 1.0 g of cinchonidine is added at 0 C. After 2 hours of stirring at room
temperature, the
reaction mixture is added to 25 ml of concentrated ammonia solution. After 10
minutes of
stirring, it is evaporated to the dry state and extracted with EE. The organic
phase is
concentrated by evaporation, and the residue is chromatographically purified
on silica gel.
Cinchonidine-sulfamoylphenyl sulfonate is obtained.
'H-NMR (DMSO-D6): 4.99 (m, 2 H, CH=CH2), 5.94 (m, 1 H, CH=CH2),
7.58 (s, 2 H, NH2).
Without further elaboration, it is believed that one skilled in the art can,
using the
preceding description, utilize the present invention to its fullest extent.
The following
preferred specific embodiments are, therefore, to be construed as merely
illustrative, and not
limitative of the remainder of the disclosure in any way whatsoever.
In the foregoing and in the following examples, all temperatures are set forth
uncorrected in degrees Celsius, and all parts and percentages are by weight,
unless otherwise
indicated.
The preceding examples can be repeated with similar success by substituting
the
generically or specifically described reactants and/or operating conditions of
this invention
for those used in the preceding examples.
From the foregoing description, one skilled in the art can easily ascertain
the essential
characteristics of this invention and, without departing from the spirit and
scope thereof, can
CA 02632272 2008-05-26
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make various changes and modifications of the invention to adapt it to various
usages and
conditions. -
