Sulfamoyl sulfonate prodrugs
The invention relates to sulfamoyl sulfonate prodrugs of general formula I, a process for their production, pharmaceutical compositions that contain these compounds, and their use for the production of orally available pharmaceutical agents. The compounds according to the invention bind to carbonic anhydrases and inhibit these enzymes.
1 . Sulfamoyl sulfonate prodrugs of general formula I
[Group Z] (I)
in which
X is a C1-12-alkanediyl-, a CpF2p group where p=1-5, a C3-8-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 with an OH group, such as steroids, anti-malaria agents, nucleosides, or isoflavonoids,
which can optionally be substituted.
2 . Sulfamoyl sulfonate prodrugs according to claim 1 , whereby
Drug means steroids, such as estrogens, for example estradiol or estriol, or
androgens, for example testosterone, MENT (7α-methyl-19-nortestosterone), eF-MENT (11-fluoro-7α-methyl-19-nortestosterone), nandrolone, DHT (dihydrotestosterone), or
gestagens, for example norethisterone, dienogest or levonorgestrel, corticoids, for example cortisol
anti-malaria agents, for example quinine, cinchonidine, hydroxychloroquine, primaquine, mefloquine or
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, nelfinavir isoflavonoids, for example genisteine.
3 . Sulfamoyl sulfonate prodrugs according to claim 1 , whereby X is an arylene group.
4 . Sulfamoyl sulfonate prodrugs according to claim 3 , whereby X is a phenylene-, pyridylene- or thiophenylene radical that is unsubstituted or that is substituted with a chlorine.
5 . Sulfamoyl sulfonate prodrugs according to claim 3 , namely
1) 3-hydroxyestra-1,3,5(10)-trien-17β-yl 3′-sulfamoylphenyl sulfonate,
2) 3-acetoxyestra-1,3,5(10)-trien-17β-yl 3′-sulfamoylphenyl sulfonate,
3) 3-tert-butyldimethylsilyloxyestra-1,3,5(10)-trien-17β-yl 3′-sulfamoylphenyl sulfonate,
4) 3-hydroxyestra-1,3,5(10)-trien-17β-yl 4′-sulfamoylphenyl sulfonate,
5) 2-methoxy-3-hydroxyestra-1,3,5(10)-trien-17β-yl 3′-sulfamoylphenyl sulfonate,
6) 3,16α-dihydroxyestra-1,3,5(10)-trien-17β-yl 3′-sulfamoylphenyl sulfonate,
7) 3,17β-dihydroxyestra-1,3,5(10)-trien-16α-yl 3′-sulfamoylphenyl sulfonate,
8) 3-benzoyloxyestra-1,3,5(10)-trien-17β-yl 3′-sulfamoylphenyl sulfonate,
9) quinine-3′-sulfamoylphenyl sulfonate,
10) cinchonidine-3′-sulfamoylphenyl sulfonate,
11) zidovudine-3′-sulfamoylphenyl sulfonate,
12) 3-oxoandrost-4-en-17β-yl 3′-sulfamoylphenyl sulfonate,
13) 3-oxoandrostan-17β-yl 3′-sulfamoylphenyl sulfonate,
14) 3-oxo-7α-methylandrost-4-en-17β-yl 3′-sulfamoylphenyl sulfonate,
15) 3-oxoestr-4-en-17β-yl 3′-sulfamoylphenyl sulfonate, and
16) brivudine-3′-sulfamoylphenyl sulfonate.
6 . Compounds according to claim 1 , whereby the active ingredient is an anti-malaria agent, such as arteether, artemether, artesunate, chloroquine, pamaquine, primaquine, pyrethamine, mefloquine, proguanil, cinchonidine, cinchonin, hydroxychloroquine, pamaquine, primaquine, pyrimethamine, quinine, or a quinine derivative, such as quinine-bisulfate, quinine-carbonate, quinine-dihydrobromide, quinine-dihydrochloride, quinine-ethylcarbonate, quinine-formate, quinine-gluconate, quinine-hydroiodide, quinine-hydrochloride, quinine salicylate or quinine-sulfate.
7 . Use of the compounds according to claim 6 for the prevention of a parasitic attack of erythrocytes.
8 . Compounds according to claim 1 , whereby the therapeutically desired effect takes place by release, especially hydrolytic cleavage of the active ingredient contained in the prodrug or its metabolites.
9 . Pharmaceutical composition containing at least one compound of general formula I according to claim 1 and optionally at least one additional active ingredient together with pharmaceutically compatible adjuvants and/or vehicles.
10 . Pharmaceutical composition according to claim 9 , whereby the additional active ingredient is a steroidal compound.
11 . Pharmaceutical composition according to claim 10 , whereby the additional steroidal compound is a gestagen, antigestagen or a progesterone receptor modulator.
12 . Pharmaceutical composition according to claim 11 , in which the included gestagens are norethisterone, dienogest, drospirenone, or levonorgestrel; antigestagens are mifepristone, onapristone, and progesteron receptor modulators, for example, mesoprogestins, such as asoprisnil.
13 . Use of the compounds according to claim 1 for the production of a pharmaceutical agent.
14 . Use according to claim 13 for the production of a pharmaceutical agent for hormone replacement therapy.
15 . Use of the compounds according to claim 1 for female birth control.
16 . Use according to claim 13 for the production of a pharmaceutical agent for therapy and/or prophylaxis of hormonally-induced diseases in men and women.
17 . Use according to claim 13 for the production of a pharmaceutical agent for therapy and prophylaxis of endometriosis, breast cancers, prostate cancers or hypogonadism.
18 . Use according to claim 13 for the production of a pharmaceutical agent for therapy and/or prophylaxis of diseases that are positively influenced by the inhibition of carbonic anhydrase activity.
19 . Use according to claim 13 for the production of a pharmaceutical agent for therapy and/or prophylaxis of inflammatory and/or allergic diseases.
20 . Process for the production of sulfamoyl sulfonate prodrugs of general formula (I) according to claim 1 by reaction of a corresponding active ingredient “Drug” according to claim 1 , with a disulfonic acid chloride SO2-X—SO2Cl in the presence of a base, and subsequent treatment with ammonia, or by reaction of the corresponding active ingredient “Drug” according to claim 1 with a sulfamoylsulfonic acid halide NH2SO2-X—SO2Cl in the presence of a base.
21 . Process according to claim 20 , whereby the base is pyridine.