Compounds with sulphonamide group and pharmaceutical compositions containing these compounds

• US 20040014781A1
• Filed: 08/01/2003
• Published: 01/22/2004
• Est. Priority Date: 05/31/2000
• Status: Active Grant

• Current Assignee: Schering Ag (Merck & Co., Inc.)
• Original Assignee: Schering Ag (Merck & Co., Inc.)
• Inventors: Hillisch, Alexander, Schwarz, Sigfrid, Elger, Walter, Schollkopf, Klaus, Hedden, Annemarie
• Granted Patent: US 7,507,725 B2
• Time in Patent Office: Days
• US Class Current: 514/304
• CPC Class Codes: A61P 33/06 Antimalarials
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07J 41/0038 with an androstane skeleton, including 18- or 19-substituted derivatives, 18-nor derivatives and also derivatives where position 17-beta is substituted by a carbon atom not directly bonded to a further carbon atom and not being part of an amide group
• CPC Class Codes: C07J 41/0044 with an estrane or gonane skeleton, including 18-substituted derivatives and derivatives where position 17-beta is substituted by a carbon atom not directly bonded to another carbon atom and not being part of an amide group
• CPC Class Codes: C07J 41/005 the 17-beta position being substituted by an uninterrupted chain of only two carbon atoms, e.g. pregnane derivatives
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention relates to compounds which, acting as a prodrug and/or support, enable an active agent to be taken up by the erythrocytes and/or an active agent to bind to the erythrocytes. The uptake of these compounds by and/or the binding thereof to the erythrocytes is made possible by a group of formula —SO2NR1R2, wherein R1 and R2, independently of each other, mean a hydrogen atom, an acyl group, an alkyl group, a cycloalkyl group, an aryl group, a cyano group or a hydroxy group. The inventive prodrugs enable active agents such as endogenic substances, natural substances and synthetic substances with therapeutically useful properties which have a high “first path” effect, to be administered orally effectively or significantly improve the oral activity thereof.

Claims

1. Compound that as a prodrug and/or vehicle makes it possible to take up an active ingredient into erythrocytes and/or to bind an active ingredient to erythrocytes, characterized in that the uptake of the compound into erythrocytes and/or the binding of the compound to erythrocytes is made possible by a group

—

SO₂NR¹R²

whereby R¹ and R², independently of one another, is a hydrogen atom, an acyl radical, an alkyl radical, a cycloalkyl radical, an aryl radical, a cyano group or a hydroxy group;

2. Compound according to claim 1, whereby the uptake of the compound into erythrocytes and/or the binding of the compound to erythrocytes is carried out via hemoglobin, membrane proteins and/or carboanhydrase.

3. Compound according to claim 1 and/or 2, whereby a depot of the active ingredient in the erythrocytes is formed by the uptake of the compound into erythrocytes and/or by the binding of the compound to erythrocytes, whereby an essential part of the active ingredient is present in the body in erythrocytes.

4. Compound according to claim 3, whereby the compound is enriched in the erythrocytes by a factor 10 to 1000 above the plasma level.

5. Compound according to one of claims 1 to 4, whereby the compound is a compound that exerts its action in the erythrocytes.

6. Compound according to one of claims 2 to 5, wherein the compound is a prodrug that has the following structure:

Active ingredient-[Spacer]n-SO₂NR¹R²

whereby n means a number 0 or 1, R¹ and R² have the meaning that is given in claim 1, and the active ingredient in its free form has a functional group.

7. Compound according to claim 6, whereby one of radicals R¹ and R² means a hydrogen atom.

8. Compound according to claim 7, whereby R¹ and R² mean a hydrogen atom.

9. Compound according to one of claims 6 to 8, whereby the compound and/or the active ingredient that is contained in the compound prevents the parasitic attack of the erythrocytes.

10. Compound according to claim 9, whereby the active ingredient is an anti-malaria agent, such as arteether, artemether, artesunate, chloroquine, pamaquine, primaquine, pyrethamine, mefloquine, proguanil, cinchonidine, cinchonine, hydroxychloroquine, pamaquine, primaquine, pyrimethamine, quinine or a quinine derivative, such as quinine-bisulfate, quinine-carbonate, quinine-dihydrobromide, quinine-dihydro chloride, quinine-ethylcarbonate, quinine-formate, quinine-gluconate, quinine-hydroiodide, quinine-hydrochloride, quinine-salicylate or quinine-sulfate.

11. Compound according to one of claims 1 to 10, whereby the therapeutically desired action is carried out by release, especially hydrolytic cleavage, of the active ingredient that is contained in the prodrug and/or its metabolites.

12. Compound according to one of claims 6 to 8, whereby n is 0, and the functional group is a group —

OH, which forms a group —

O—

SO₂NH₂ with the group —

SO₂NH₂;

a group ═

O, which is converted into a group ═

N—

OH or ═

N—

NH₂ and forms a group ═

N—

O—

SO₂NH₂ or ═

N—

NH—

SO₂NH₂ with the group —

SO₂NH₂;

a group —

NHR, which forms a group —

NR—

SO₂NH₂ with the group —

SO₂NH₂, whereby R is a hydrogen atom or an alkyl radical or NR is part of a heterocyclic ring system, or

a group —

SH, which forms a group —

S—

SO₂NH₂ with the group —

SO₂NH₂.

13. Compound according to claim 6, whereby n is 1, and the functional group is a group —

COOH, which together with the spacer and with the group —

SO₂NH₂ forms a group —

C(O)-spacer-SO₂NH₂.

14. Compound according to claim 11, whereby the spacer is a group -A-B-(O)_s, whereby s is a number 0 or 1, A stands for S, O or NR³, whereby R³ is a hydrogen atom, an alkyl radical or an acyl radical, and B is selected from an alkylene group, an arylene group, an alkylene arylene group or an alkylene arylenealkylene group, which optionally are substituted.

15. Compound according to claim 8, whereby n is 1, and the functional group is a group —

YH, which together with the spacer and with the group —

SO₂NH₂ forms a group —

Y-spacer-SO₂NH₂, whereby Y stands for S, O or NR , whereby R⁴ is a hydrogen atom, an alkyl radical or an acyl radical, or NR⁴ is part of a heterocyclic ring system.

16. Compound according to claim 15, whereby the spacer is a group

17. Compound according to claim 15, whereby the spacer means a group

18. Compound according to claim 13, whereby the spacer means a group

19. Compound according to one of claims 16 to 18, whereby the functional group is a group —

OH.

20. Compound according to one of claims 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 and/or 20, whereby the active ingredient is selected from androgens, anabolic agents, anti androgens, estrogens, gestagens glucocorticoids, amoebicides;

anti-diuretic agents, antigonatropines, ulcer therapeutic agents, neuropharmaceutical agents, dopamine receptor antagonists, dopamine, apomorphine, melatonin and peptides, such as GnRH, and other hypothalamic, regulatory active peptides.

21. Compound according to claim 20, whereby the active ingredient is an androgen, and the functional group is the 17-hydroxy group or the 3-carbonyl group of the androgen.

22. Compound according to claim 21, whereby the androgen is testosterone.

23. Compound according to claim 20, whereby the active ingredient is an estrogen, and the functional group is a 3-, 16- or 17-hydroxy group or 17-carbonyl group.

24. Compound according to claim 23, whereby the active ingredient is selected from estradiol, estriol or estrone.

25. Compound according to claim 20, whereby the active ingredient is a gestagen, and the functional group is a 17-hydroxy group or a 3-carbonyl group.

26. Compound according to claim 25, whereby the active ingredient is selected from norethisterone, dienogest, drospirenone or levonorgestrel.