CN101321535A - Heteroaromatic sulfonamide prodrugs - Google Patents

Heteroaromatic sulfonamide prodrugs Download PDF

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CN101321535A
CN101321535A CNA2006800450153A CN200680045015A CN101321535A CN 101321535 A CN101321535 A CN 101321535A CN A2006800450153 A CNA2006800450153 A CN A2006800450153A CN 200680045015 A CN200680045015 A CN 200680045015A CN 101321535 A CN101321535 A CN 101321535A
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sulfamoyl
beta
carboxylate
triolefins
female
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R·维尔瓦
R·努比迈尔
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Bayer Pharma AG
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Schering AG
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J33/00—Normal steroids having a sulfur-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton

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Abstract

The invention relates to the sulfonamide prodrugs of formula (I), comprising a heteroaromatic linker, to a method for producing the same, to pharmaceutical compositions containing said compounds and to their use for producing orally available drugs. The compounds according to the invention bind to carboanhydrases and inhibit these enzymes.

Description

Heteroaromatic sulfonamide prodrugs
Technical field
The present invention relates to the sulfonamide prodrugs of general formula (I):
Figure A20068004501500061
Wherein X is assorted armaticity.The invention still further relates to the method for these prodrugs of preparation, the pharmaceutical composition that comprises these chemical compounds and their application in the preparation oral drugs.
Background technology
WO 01/91797 has disclosed by group-SO 2NR 1R 2And combine and accumulate on this steroidal compounds with erythrocyte.The concentration ratio of these chemical compounds between erythrocyte and blood plasma is 10-1000: 1, be preferably 30-1000: and 1, we can be described as the durative action preparation in the erythrocyte thus.Because these chemical compounds and erythrocyte have strong combination, so can avoid the metabolism during liver passes through.Disadvantageously, can reduce metabolism, the reactive compound of treatment related levels is not provided although show the use said preparation.Its reason is considered to and erythrocytic fracture strong, that enzyme brings out and the low dissolubility of combining.
The purpose of this invention is to provide novel prodrug, it can be oral and be compared with the prior art the reactive compound that also can guarantee to treat related levels under low dosage.
Summary of the invention
This purpose is that the heterocyclic sulfonamide prodrug of general formula (I) is realized, wherein sulfamoyl is connected on the medicine to be discharged by the carboxylic acid ester bond via the assorted fragrance basic X in interval,
Figure A20068004501500071
Wherein
X is assorted aromatic radical or the assorted aromatic radical of alkyl that does not replace or replace, and
Drug is the pharmaceutical active compounds that can form carboxylate by the OH group, and as steroidal compounds, anti-malarial agents, nucleoside, isoflavonoid (isoflavanoids), they can be chosen wantonly and be substituted.Sulfonamide prodrugs with assorted fragrant linking group X according to the present invention combines with erythrocyte, and is soluble in water, and can be hydrolyzed fracture under the situation that does not have enzyme to participate in.
The specific embodiment
Within the scope of the invention, assorted aromatic radical for example is thiophene, pyridine, pyrroles, furan or by C 1-4Thiophene, pyridine, pyrroles or furan that-alkyl or halogen replace.For substituted assorted aromatic group, it can be 2-bromothiophene, 2 acetyl thiophene, N-methylpyrrole and 2-bromopyridine.
C 1-4-alkyl is methyl, ethyl, propyl group, butyl or isopropyl.
Term " halogen " is meant fluorine, chlorine, bromine or iodine atom in category of the present invention, wherein preferred fluorine, chlorine or bromine.
Above-mentioned term " alkyl mix aromatic radical " is meant and passes through C 1-3-alkylidene and be connected assorted aromatic radical in the described ester functional group.Assorted aromatic radical is the group described in the above-mentioned assorted aromatic group.
C 1-3-alkylidene is methylene, ethylidene or propylidene bridge
Preferred assorted aromatic group is pyridine and thiophene.
Preferred chemical compound is as follows:
1) the 3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl 6 '-sulfamoyl nicotinate (1),
2) the 3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl 5 '-sulfamoyl nicotinate (2),
3) the 3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl 2 '-ethyl-5 '-sulfamoyl thiophene-3 '-carboxylate (3),
4) the 3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl 2 '-bromo-5 '-sulfamoyl thiophene-3 '-carboxylate (4),
5) 3-oxo hero-4-alkene-17 beta-yl 6 '-sulfamoyl nicotinate (5),
6) 3-oxo hero-4-alkene-17 beta-yl 5 '-sulfamoyl nicotinate (6),
7) 3-oxo hero-4-alkene-17 beta-yl 2 '-ethyl-5 '-sulfamoyl-thiophene-3 '-carboxylate,
8) 3-oxo hero-4-alkene-17 beta-yl 5 '-sulfamoyl thiophene-3 '-carboxylate,
9) the 3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl 5 '-sulfamoyl thiophene-3 '-carboxylate,
10) the 3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl 6 '-sulfamoyl thiophene-3 '-carboxylate,
11) 3-oxo hero-4-alkene-17 beta-yl 5 '-sulfamoyl thiophene-3 '-carboxylate,
12) 3-oxo-7 Alpha-Methyl hero-4-alkene-17 beta-yl 5 '-sulfamoyl-nicotinate,
13) 3-oxo-7 Alpha-Methyl hero-4-alkene-17 beta-yl 6 '-sulfamoyl-nicotinate,
14) 3-oxo-7 Alpha-Methyl hero-4-alkene-17 beta-yl N-ethyl-5 '-sulfamoyl thiophene-3 '-carboxylate,
15) the 3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl N-methyl-5 '-sulfamoyl-1H-pyrroles-2 '-carboxylate.
According to the present invention, the relevant medical compounds of described treatment by hydrolysis by discharging in these chemical compounds.
Experiment in vitro
A) carbonic anhydrase inhibitory action
The experiment principle:
On microtitration plate, by means of the enzymic transformations of acetic acid nitrobenzophenone ester, color is used spectrphotometric method for measuring sulfonamide compounds or the sulfamate compounds thing inhibitory action to people's carbonic anhydrase I or II thus by the colourless yellow that becomes.
Table 1: the IC of people's carbonic anhydrase I 50Inhibiting value
Inhibitor CA II IC 50(nM) CA I IC 50(nM)
Estradiol 3-sulfamate 34 157±10.6
The 3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl 6 '-sulfamoyl nicotinate (1) 31 2900
The 3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl 5 '-sulfamoyl nicotinate (2) 160 2100
3-oxo hero-4-alkene-17 beta-yl 5 '-sulfamoyl nicotinate (6) 250 2900
3-oxo hero-4-alkene-17 beta-yl 6 '-sulfamoyl nicotinate (5) 41 3200
The 3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl 2 '-ethyl-5 '-sulfamoyl thiophene-3 '-carboxylate (3) 42 3400
The 3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl 2 '-bromo-5 '-sulfamoyl thiophene-3 '-carboxylate (4) 47 3300
Acetazolamide (known CA inhibitor) 61 1200 19001)
Document: 1) C.Landolfi, M.Marchetti, G.Ciocci, and C.Milanese, Journal ofPharmacological and Toxicological Methods 38,169-172 (1997).
Find that the sulfamoyl prodrug of general formula (I) is very shockingly good to the inhibitory action of carbonic anhydrase II.Can derive prodrug according to the present invention concentrating in erythrocyte thus.
B) blood-plasma concentration ratio-experiment principle and experiment are described:
According to the SO in the material of the present invention 2-NH 2Group since with the combining of carbonic anhydrase, can cause concentrating on erythrocyte.
The experiment principle:
By the reactive compound processing that newly obtains in the rat and use limited amount through the blood of heparinization.With respect to calibration curve (having known activity compound concentration), measure the concentration of described reactive compound in the blood plasma that obtains thus through the blood plasma of admixture.Calculate blood-blood plasma ratio by measured concentration and theoretical concentration.
Table 2: the blood/plasma ratio of selected prodrug
Prodrug The blood/plasma ratio
Estradiol 3-sulfamate About 50
The 3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl 5 '-sulfamoyl nicotinate (2) 2
3-oxo hero-4-alkene-17 beta-yl 5 '-sulfamoyl nicotinate (6) 5.7
3-oxo hero-4-alkene-17 beta-yl 6 '-sulfamoyl nicotinate (5) 3.6
The 3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl 2 '-ethyl-5 '-sulfamoyl thiophene-3 '-carboxylate (3) 1.8
The 3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl 2 '-bromo-5 '-sulfamoyl thiophene-3 '-carboxylate (4) 9.5
Opposite with disclosed result among the WO 01/91797, The compounds of this invention at the concentration ratio between erythrocyte and the blood plasma not at 10-1000: in 1 the scope, but＜10: in 1 the scope.For the reactive compound of realizing the treatment related levels, this itself shows it is a critical defective.Can be best blood/plasma ratio by selecting suitable linking group to regulate for preceding drug compound.
Depend on the definition of " Drug ", these experimental results show that general formula of the present invention (I) chemical compound has and treat and/or prevent different syndromic various probabilities.For example, if " Drug " is steroidal such as androgen or estrogen, then the chemical compound of general formula (I) can be used for the Hormone Replacement Therapy (HRT) among women and the male or is used for the treatment of the disease that hormone brings out among the male (carcinoma of prostate, breast carcinoma, hypogonadism), and the disease that hormone brings out among the women (endometriosis, breast carcinoma).In addition, wherein " Drug " for example is androgen or estrogenicly can be used for birth control among male or the women according to general formula of the present invention (I) chemical compound.
When the treatment malaria, can use other reactive compounds as " Drug ", for example quinine, cinchonidine, oxychloroquine, primaquine or mefloquine mefloquine.
Wherein " Drug " for hydrocortisone derivative can be used for treating and preventing to be subjected to inflammatory diseases and/or the allergic disease that immunosuppressant and/or antiproliferative influence according to general formula of the present invention (I) chemical compound.
Wherein " Drug " can be used for treating viral disease (herpes, HIV) for the prodrug of the present invention of nucleoside compound (zidovudine, brivudine, English ground guiding principle Wei, Nai Fennawei).
The invention still further relates to general formula (I) chemical compound that comprises according to the present invention and the pharmaceutical composition of other reactive compounds randomly, described other reactive compounds for example are progestogen (norethindrone, dienogest, drospirenone, levonorgestrel), gestation (mifepristone, onapristone) and/or progesterone receptor modulator (middle progesterone (mesoprogestins) is as asoprisnil).
These therapeutic combinations and the administration of medicine preferred oral.Except that the carrier and/or diluent of routine, they also comprise the chemical compound of at least a general formula I.
Dosage
According to prodrug Orally-administrable of the present invention.
Generally, if behind the described prodrug of administration, its dosage can make the burst size of corresponding reactive compound (" Drug ") farthest be equivalent to the maximum dose level of this medicinal corresponding " Drug " material, then all can expect gratifying result for treating and/or preventing above-mentioned indication or being used for birth control.
Medicine of the present invention be in known manner with proper dosage with conventional solid or liquid carrier or diluent and according to desirable administration type and normally used drug excipient is prepared.Preferred preparation comprises the form of administration that is suitable for oral administration.These form of administration for example are tablet, thin membrane coated tablet, coated tablet, capsule, pill, powder, solution or suspensoid or can are long-acting dosage forms.
Suitable tablet can for example followingly make: mixed active chemical compound and known excipient, as inert diluent such as glucose, sucrose, sorbitol, mannitol, polyvinylpyrrolidone, disintegrating agent such as corn starch or alginic acid, binding agent such as starch or gelatin, lubricant such as magnesium stearate or Talcum, and/or be used to realize material such as carboxyl polymethylene, carboxymethyl cellulose, acetic acid terephthaldehyde acid cellulose or the polyvinyl acetate of long-acting.These tablets also can comprise a plurality of layers.
Correspondingly, coated tablet can be prepared as follows: with normally used material in the coated tablet coating core that is similar to above-mentioned tablet and makes is carried out coating, described coating substance for example is polyvinylpyrrolidone or Lac, arabic gum, Talcum, titanium oxide or sugar.At this, the shell of this coated tablet also can comprise a plurality of layers, wherein also can use the excipient of mentioning in the above-mentioned tablet.
The solution or the suspensoid that comprise the present invention's compound of Formula I also can comprise flavour enhancer such as glucide, cyclamate or sucrose in addition, and flavoring agent for example, as vanillin or mandarin orange extract.They also can comprise suspension excipient such as sodium carboxymethyl cellulose or antiseptic such as p-Hydroxybenzoate.
The capsule that comprises compound of Formula I can for example be prepared as follows: the compound of Formula I that makes one or more and inert carrier such as lactose or sorbitol mix, then with their encapsulates in gelatine capsule.
Can synthesize according to following examples according to prodrug of the present invention, but these embodiment are used for more detailed explanation, rather than limitation of the scope of the invention.
This corresponding sulfamoyl heteroaryl carboxylic acid can commercially availablely obtain or can be prepared by method known to those skilled in the art by the sulfoacid compound or derivatives thereof.The junctional complex that can not commercially availablely obtain can synthesize according to the description in following examples.
6-sulfamoyl nicotinic acid
The 6-sulfo-nicotinic acid of 5g is dissolved in the concentrated hydrochloric acid and 9ml water of 41ml.This solution is cooled to 0-5 ℃, then to wherein leading to people's chlorine 4 hours.Subsequently reaction solution is added in the 100g ice, and the material that is settled out filters and is added in the cold dense NH3 solution of 100ml.After 1 hour, this mixture is concentrated into 1/3, and is acidified to pH=3 with HCl.The material that sucking filtration is settled out washes with water and drying.Then, carry out pure system, obtain 6-sulfamoyl nicotinic acid by column chromatography.
1H-NMR(DMSO-d 6)：7.62(s，2H，NH 2)；8.03(m，1H，CH)；8.50(m，1H，CH)；9.08(m，1H，CH).
5-sulfamoyl nicotinic acid
1.) beta-picoline-5-sulfonic acid
At first introduce the oleum (25%) of 200ml.Under cooling, drip the beta-picoline of 97ml.At 40 ℃ of HgSO that add 3.12g down 4, this mixture heated 16 hours down at 225-235 ℃ subsequently.Distill the H of about 100ml 2SO 4(160 ℃, 2mbar).Then this mixture is added in the ice of 400g and with the water dilution of 2l.Use CaCO subsequently 3Neutralize.This mixture filters out inorganic constituents, and residue washs with 2l boiling water.Aqueous solution concentrates, and residue carry out chromatographically pure system on silica gel then.Obtain beta-picoline-5-sulfonic acid.
1H-NMR(DMSO-d 6)：2.31(s，3H，CH 3)；7.75(s，1H，CH)；8.36(s，1H，CH)；8.57(s，1H，CH).
2.) 5-sulfamoyl-beta-picoline
Make the beta-picoline-5-sulfonic acid of 3.5g and the PCl of 6.5g 5POCl with 2.5ml 3Under protective gas, mix, then this mixture was heated 3 hours down at 120 ℃.Vacuum filtration goes out POCl 3, under cooling, add the 3ml frozen water then.This mixture under agitation is added into the NH of 150ml 3In the solution, then this solution concentration is extremely done.Residue extracts with MeOH, and the product that obtains after concentrating carries out pure system by column chromatography on silica gel.Obtain 5-sulfamoyl-beta-picoline.
1H-NMR(DMSO-d 6)：2.39(s，3H，CH 3)；7.56(s，2H，NH 2)；8.00(s，1H，CH)；8.62(s，1H，CH)；8.77(s，1H，CH).
3.) 5-sulfamoyl nicotinic acid
At first the 5-sulfamoyl-beta-picoline with 8.0g is introduced in the water of 250ml.The KMnO that adds 12.5g 4After, this mixture is warmed to 70 ℃.After the decolouring, add the KMnO of 12.5g again 4, then this mixture is warmed to 70 ℃ totally 12 hours.Heat filtering also is concentrated into about 20ml.Residue concentration is that 10% HCl carries out acidify (pH～2).Sucking filtration goes out cooling crystalline material down, washes with water and drying.Obtain 5-sulfamoyl nicotinic acid.
1H-NMR(DMSO-d 6)：7.76(s，2H，NH 2)；8.62(m，1H，CH)；9.15(m，1H，CH)；9.23(m，1H，CH).
Synthetic embodiment
Embodiment 1:3-t-butyldimethylsilyl oxygen base is female-1,3,5 (10)-triolefins-17 beta-yl 6 '-ammonia sulphur The acyl group nicotinate
Under argon that the 3-t-butyldimethylsilyl oxygen base of 0.5g is female-1,3, the 6-sulfamoyl nicotinic acid of 5 (10)-triolefins-17 β-pure and mild 0.5g is dissolved in the pyridine of 7ml.Then add the p-Tos-OH of 0.1g, and finally at 0 ℃ of DCC that adds 0.5g down.After 48 hours, reactant mixture at room temperature stirs.During post processing, add the water of 40ml, the HCl with 10% concentration is adjusted to pH～6 with this mixture then.Filter out sedimentary material, wash with water and drying.Carry out chromatographically pure system on silica gel, it is female-1,3 to obtain 3-tert-butyl group dimethyl-silicyl oxygen base, 5 (10)-triolefins-17 beta-yl 6 '-sulfamoyl-nicotinate.
1H-NMR(DMSO-d 6)：0.16(s，6H，SiMe)，0.938(s，9H，t-Bu)，0.944(s，3H，18-Me)，4.90(t，1H，17-H)，6.50-7.15(3m，3H，CH Ar)，7.69(s，2H，NH 2)，8.06，8.55，9.16(3m，3H，CH Py).
Embodiment 2:3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl 6 '-sulfamoyl-nicotinate (1)
The 3-t-butyldimethylsilyl oxygen base of 300mg is female-1,3, and 5 (10)-triolefins-17 beta-yl 6 '-sulfamoyl nicotinate is dissolved among the THF of 20ml.Under stirring at room, add the TBAF of 250mg.After 1 hour, stir the water that adds 20ml.This material ethyl acetate extraction.Organic facies is with saturated NaCl solution washing, at MgSO 4Last dry, filter, concentrate and on silica gel, carry out chromatographically pure system, it is female-1,3 to obtain the 3-hydroxyl, 5 (10)-triolefins-17 beta-yl 6 '-sulfamoyl nicotinate.
1H-NMR(DMSO-d 6)：0.94(s，3H，18-Me)，4.90(t，1H，17-H)，6.40-7.15(3m，3H，CH Ar)，7.69(s，2H，NH 2)；8.06，8.55(2m，2H，CH Py)，9.02(s，1H，3-OH)，9.17(1s，1H，CH Py).
Embodiment 3:3-t-butyldimethylsilyl oxygen base is female-1,3,5 (10)-triolefins-17 beta-yl 5 '-ammonia sulphur The acyl group nicotinate
Under argon that the 3-t-butyldimethylsilyl oxygen base of 0.55g is female-1,3, the 5-sulfamoyl nicotinic acid of 5 (10)-triolefins-17 β-pure and mild 0.55g is dissolved in the pyridine of 7ml.Then add the p-Tos-OH of 0.12g, and finally at 0 ℃ of DCC that adds 0.55g down.After 48 hours, reactant mixture at room temperature stirs.During post processing, add the water of 40ml, the HCl with 10% concentration is adjusted to pH～6 with this mixture then.Filter out sedimentary material, wash with water and drying.Carry out chromatographically pure system on silica gel, it is female-1,3 to obtain 3-tert-butyl group dimethyl-silicyl oxygen base, 5 (10)-triolefins-17 beta-yl 5 '-sulfamoyl-nicotinate.
1H-NMR(DMSO-d 6)：0.16(s，6H，SiMe)，0.94(s，9H，t-Bu)，0.95(s，3H，18-Me)，4.92(t，1H，17-H)，6.5-7.2(3m，3H，CH Ar)，7.79(s，2H，NH 2)，8.6-9.3(3m，3H，CH Py).
Embodiment 4:3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl 5 '-sulfamoyl-nicotinate (2)
The 3-t-butyldimethylsilyl oxygen base of 250mg is female-1,3, and 5 (10)-triolefins-17 beta-yl 5 '-sulfamoyl nicotinate is dissolved among the THF of 20ml.Under stirring at room, add the TBAF of 220mg.After 1 hour, stir the water that adds 15ml.This material ethyl acetate extraction.Organic facies is with saturated NaCl solution washing, at MgSO 4Last dry, filter, concentrate and on silica gel, carry out chromatographically pure system, it is female-1,3 to obtain the 3-hydroxyl, 5 (10)-triolefins-17 beta-yl 5 '-sulfamoyl nicotinate.
1H-NMR(DMSO-d 6)：0.94(s，3H，18-Me)，4.91(t，1H，17-H)，6.4-7.1(3m，3H，CH Ar)，7.92(s，2H，NH 2)；8.61(s，1H，CH Py)，9.00(s，1H，3-OH)，9.17，9.26(2s，2H，CH Py).
Embodiment 5:3-t-butyldimethylsilyl oxygen base is female-1,3,5 (10)-triolefins-17 beta-yl 2 '-second Base-5 '-sulfamoyl thiophene-3 '-carboxylate
Under argon that the 3-t-butyldimethylsilyl oxygen base of 0.75g is female-1,3, the 5-(amino-sulfonyl) of 5 (10)-triolefins-17 β-pure and mild 0.8g-2-ethyl-3-thiophene carboxylic acid is dissolved in the pyridine of 10ml.Then add the p-Tos-OH of 0.2g, and finally at 0 ℃ of DCC that adds 0.75g down.After 48 hours, reactant mixture at room temperature stirs.During post processing, add the water of 60ml, the HCl with 10% concentration is adjusted to pH～6 with this mixture then.Filter out sedimentary material, wash with water and drying.Carry out chromatographically pure system on silica gel, it is female-1,3 to obtain 3-t-butyldimethylsilyl oxygen base, 5 (10)-triolefins-17 beta-yl 2 '-ethyl-5 '-sulfamoyl thiophene-3 '-carboxylate.
1H-NMR(CDCl 3)：0.19(s，6H，SiMe)，0.92(s，3H，18-Me)，0.97(s，9H，t-Bu)，1.34(t，3H，Et)，3.26(q，2H，Et)，4.86(t，1H，17-H)，5.12(s，2H，NH 2)，6.50-7.15(3m，3H，CH Ar)，7.92(s，1H，CH Th).
Embodiment 6:3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl 2 '-ethyl-5 '-sulfamoyl thiophene-3 '-carboxylic Acid esters (3)
The 3-t-butyldimethylsilyl oxygen base of 440mg is female-1,3, and 5 (10)-triolefins-17 beta-yl 2 '-ethyl-5 '-sulfamoyl thiophene-3 '-carboxylate is dissolved among the THF of 20ml.Under stirring at room, add the TBAF of 400mg.After 1 hour, stir the water that adds 20ml.Reactant mixture concentrates, and sucking filtration goes out sedimentary material, washes with water and carry out chromatographically pure system on silica gel, and it is female-1,3 to obtain the 3-hydroxyl, 5 (10)-triolefins-17 beta-yl 2 '-ethyl-5 '-sulfamoyl thiophene-3 '-carboxylate (3).
1H-NMR(DMSO-d 6)：0.89(s，3H，18-Me)，1.27(t，3H，Et)，3.20(q，2H，Et)，4.79(t，1H，17-H)，6.35-7.05(3m，3H，CH Ar)，7.72(s，1H，CH Th)，7.76(s，2H，NH 2)，9.01(s，1H，3-OH).
Embodiment 7:3-t-butyldimethylsilyl oxygen base is female-1,3,5 (10)-triolefins-17 beta-yl 2 '-bromo- 5 '-sulfamoyl thiophene-3 '-carboxylate
Under argon that the 3-t-butyldimethylsilyl oxygen base of 0.75g is female-1,3, the 5-(amino-sulfonyl) of 5 (10)-triolefins-17 β-pure and mild 0.8g-2-bromo-3-thiophene carboxylic acid is dissolved in the pyridine of 10ml.Then add the p-Tos-OH of 0.2g, and finally at 0 ℃ of DCC that adds 0.75g down.After 48 hours, reactant mixture at room temperature stirs.During post processing, add the water of 70ml, the HCl with 10% concentration is adjusted to pH～6 with this mixture then.Filter out sedimentary material, wash with water and drying.Carry out chromatographically pure system on silica gel, it is female-1,3 to obtain 3-t-butyldimethylsilyl oxygen base, 5 (10)-triolefins-17 beta-yl 2 '-bromo-5 '-sulfamoyl thiophene-3 '-carboxylate.
1H-NMR(CDCl 3)：0.19(s，6H，SiMe)，0.94(s，3H，18-Me)，0.97(s，9H，t-Bu)，4.88(t，1H，17-H)，5.22(s，2H，NH 2)，6.50-7.10(3m，3H，CH Ar)，7.85(s，1H，CH Th).
Embodiment 8:3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl 2 '-bromo-5 '-sulfamoyl thiophene-3 '-carboxylic acid Ester (4)
The 3-t-butyldimethylsilyl oxygen base of 330mg is female-1,3, and 5 (10)-triolefins-17 beta-yl 2 '-bromo-5 '-sulfamoyl thiophene-3 '-carboxylate is dissolved among the THF of 30ml.Under stirring at room, add the TBAF of 300mg.After 1 hour, stir the water that adds 30ml.Reactant mixture concentrates, and sucking filtration goes out sedimentary material, washes with water and carry out chromatographically pure system on silica gel, and it is female-1,3 to obtain the 3-hydroxyl, 5 (10)-triolefins-17 beta-yl 2 '-bromo-5 '-sulfamoyl thiophene-3 '-carboxylate (4).
1H-NMR(DMSO-d 6)：0.96(s，3H，18-Me)，4.84(t，1H，17-H)，6.40-7.15(3m，3H，CH Ar)，7.75(s，1H，CH Th)，8.05(s，2H，NH 2)，9.01(s，1H，3-OH).
Embodiment 9:3-oxo hero-4-alkene-17 beta-yl 6 '-sulfamoyl nicotinate (5)
The testosterone of 0.4g is dissolved in the pyridine of 2ml.Behind the dicyclohexylcarbodiimide (DCC) of the 6-sulfamoyl nicotinic acid of interpolation 0.4g, the p-toluenesulfonic acid of 50mg and 0.4g, this mixture at room temperature stirred 72 hours.Add the water of 10ml subsequently.This mixture carries out acidify (pH=5) slightly with the HCl of 10% concentration.Filter out precipitation, use saturated NaHCO 3Solution and water washing 2 times.Desirable residue ethyl acetate extraction.Organic facies is with the NaHCO of 10% concentration 3Solution and saturated NaCl solution washing, dry on magnesium sulfate, filter, concentrate, on silica gel, carry out chromatographically pure system then, obtain 3-oxo hero-4-alkene-17 beta-yl 6 '-sulfamoyl-nicotinate (5).
1H-NMR(DMSO-d 6)：0.95(s，3H，Me)；1.17(s，3H，Me)；5.64(s，1H，4-H)；7.68(s，2H，NH 2)；8.06，8.53，9.15(3m，3H，CH Ar).
Embodiment 10:3-oxo hero-4-alkene-17 beta-yl 5 '-sulfamoyl nicotinate (6)
The testosterone of 0.4g is dissolved in the pyridine of 2ml.Behind the dicyclohexylcarbodiimide (DCC) of the 5-sulfamoyl nicotinic acid of interpolation 0.4g, the p-toluenesulfonic acid of 50mg and 0.4g, this mixture at room temperature stirred 72 hours.Add the water of 10ml subsequently.This mixture carries out acidify (pH=5) slightly with the HCl of 10% concentration.Filter out precipitation, use saturated NaHCO 3Solution and water washing 2 times.Desirable residue ethyl acetate extraction.Organic facies is with the NaHCO of 10% concentration 3Solution and saturated NaCl solution washing, dry on magnesium sulfate, filter, concentrate, on silica gel, carry out chromatographically pure system then, obtain 3-oxo hero-4-alkene-17 beta-yl 5 '-sulfamoyl-nicotinate (6).
1H-NMR(DMSO-d 6)：0.96(s，3H，Me)；1.17(s，3H，Me)；5.64(s，1H，4-H)；7.76(s，2H，NH 2)；8.59，9.17，9.24(3s，3H，CH Ar).
Embodiment 11:3-t-butyldimethylsilyl oxygen base is female-1,3,5 (10)-triolefins-17 beta-yl N-first Base-5 '-sulfamoyl-1H-pyrroles-2 '-carboxylate
Under argon that the 3-t-butyldimethylsilyl oxygen base of 0.50g is female-1,3, the N-methyl-5 ' of 5 (10)-triolefins-17 β-pure and mild 0.50g-sulfamoyl-1H-pyrroles-2 '-carboxylic acid is dissolved in the pyridine of 7ml.Then add the p-Tos-OH of 0.12g, and finally at 0 ℃ of DCC that adds 0.5g down.After 48 hours, reactant mixture at room temperature stirs.During post processing, add the water of 40ml, the HCl with 10% concentration is adjusted to pH～6 with this mixture then.Filter out sedimentary material, wash with water and drying.Carry out chromatographically pure system on silica gel, it is female-1,3 to obtain 3-t-butyldimethylsilyl oxygen base, 5 (10)-triolefins-17 beta-yl N-methyl-5 '-sulfamoyl-1H-pyrroles-2 '-carboxylate.
1H-NMR(CDCl 3)：0.18(s，6H，SiMe)，0.92(s，3H，18-Me)，0.97(s，9H，t-Bu)，3.95(s，3H，NMe)，4.83(t，1H，17-H)，4.95(s，2H，NH 2)，6.5-7.3(5m，5H，CH Ar).
Embodiment 12:3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl N-methyl-5 '-sulfamoyl-1H-pyrroles- 2 '-carboxylate
The 3-t-butyldimethylsilyl oxygen base of 300mg is female-1,3, and 5 (10)-triolefins-17 beta-yl N-methyl-5 '-sulfamoyl-1H-pyrroles-2 '-carboxylate is dissolved among the THF of 20ml.Under stirring at room, add the TBAF of 250mg.After 1 hour, stir the water that adds 20ml.Reactant mixture concentrates, and sucking filtration goes out sedimentary material, washes with water and carry out chromatographically pure system on silica gel, and it is female-1,3 to obtain the 3-hydroxyl, 5 (10)-triolefins-17 beta-yl N-methyl-5 '-sulfamoyl-1H-pyrroles-2 '-carboxylate.
1H-NMR(DMSO-d 6)：0.89(s，3H，18-Me)，3.88(s，3H，NMe)，4.76(t，1H，17-H)，7.12(s，2H，NH 2)，8.99(s，1H，3-OH).
Claims (according to the modification of the 19th of treaty)
1, the sulfonamide prodrugs of general formula I
Figure A20068004501500191
Wherein
X is assorted aromatic radical or the assorted aromatic radical of alkyl that does not replace or replace, and
Drug is the pharmaceutical active compounds that can form carboxylate by the OH group, as steroidal compounds,
They can be chosen wantonly and be substituted.
2, according to the sulfonamide prodrugs of claim 1, wherein X is pyridine or thienyl.
3, according to the sulfamoyl sulfonate prodrugs of claim 1, wherein
Drug is a steroidal compounds, estrogen for example is as estradiol or estriol, perhaps androgen, as testosterone, MENT (7 Alpha-Methyls-19-nortestosterone), eF-MENT (11-fluoro-7 Alpha-Methyls-19-nortestosterone), nandrolone phenylpropionate, DHT (dihydrotestosterone), perhaps
Progestogen, for example norethindrone, dienogest or levonorgestrel,
Adrenocortical hormone, for example hydrocortisone.
4, according to the sulfamoyl sulfonate prodrugs of claim 1 or 2, it is:
1) the 3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl 6 '-sulfamoyl nicotinate (1),
2) the 3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl 5 '-sulfamoyl nicotinate (2),
3) the 3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl 2 '-ethyl-5 '-sulfamoyl thiophene-3 '-carboxylate (3),
4) the 3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl 2 '-bromo-5 '-sulfamoyl thiophene-3 '-carboxylate (4),
5) 3-oxo hero-4-alkene-17 beta-yl 6 '-sulfamoyl-nicotinate (5),
6) 3-oxo hero-4-alkene-17 beta-yl 5 '-sulfamoyl-nicotinate (6),
7) 3-oxo hero-4-alkene-17 beta-yl 2 '-ethyl-5 '-sulfamoyl thiophene-3 '-carboxylate,
8) 3-oxo hero-4-alkene-17 beta-yl 5 '-sulfamoyl thiophene-3 '-carboxylate,
9) the 3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl 5 '-sulfamoyl thiophene-3 '-carboxylate,
10) the 3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl 6 '-sulfamoyl thiophene-3 '-carboxylate,
11) 3-oxo hero-4-alkene-17 beta-yl 5 '-sulfamoyl-thiophene-3 '-carboxylate,
12) 3-oxo-7 Alpha-Methyl hero-4-alkene-17 beta-yl 5 '-sulfamoyl nicotinate,
13) 3-oxo-7 Alpha-Methyl hero-4-alkene-17 beta-yl 6 '-sulfamoyl nicotinate,
14) 3-oxo-7 Alpha-Methyl hero-4-alkene-17 beta-yl N-ethyl-5 '-sulfamoyl thiophene-3 '-carboxylate,
15) the 3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl N-methyl-5 '-sulfamoyl-1H-pyrroles-2 '-carboxylate.
5, according to the chemical compound of one of claim 1-6, the effect of wishing in the wherein said treatment is to realize by the described reactive compound or its metabolite that comprise in release, the especially described prodrug of hydrolytic cleavage.
6, pharmaceutical composition, it comprises at least a compound of Formula I and acceptable excipient of materia medica and/or carrier according to one of claim 1-4, and optional comprises at least a other reactive compound.
7, pharmaceutical composition according to Claim 8, wherein said other reactive compound is a steroidal compounds.
8, according to the pharmaceutical composition of claim 9, wherein said steroidal compounds is progestogen, gestation or progesterone receptor modulator.
9, according to the pharmaceutical composition of claim 10, wherein the progestogen that comprised are norethindrone, dienogest, drospirenone, levonorgestrel, described gestation is mifepristone, onapristone, and progesterone receptor modulator such as middle progesterone, as asoprisnil.
10, according to the application in the preparation medicine of the chemical compound of one of claim 1-7.
11, according to the application of claim 12, it is the medicine that preparation is used for Hormone Replacement Therapy.
12, according to the application of chemical compound in women's birth control of one of claim 1-7.
13, according to the application of claim 12, it is that preparation is used for the treatment of and/or prevents the medicine of the disease that hormone causes in the masculinity and femininity.
14, according to the application of claim 12, it is that preparation is used for the treatment of and prevents the medicine of endometriosis, breast carcinoma, carcinoma of prostate or hypogonadism.
15, according to the application of claim 12, it is that preparation is used for the treatment of and/or prevents and can produce the medicine of the disease of positive impact to it by suppressing the carbonic anhydrase activity.
16, according to the application of claim 12, it is the medicine that preparation is used for the treatment of and/or prevents inflammatory and/or allergic disease.
17, preparation is according to the method for the sulfonamide prodrugs of the general formula (I) of claim 1, it is in the presence of dicyclohexylcarbodiimide or EDC (N-(3-dimethylaminopropyl)-N '-ethyl carbodiimide), choose wantonly and use catalyst, make the carboxylic acid NH of corresponding assorted fragrant linking group 2SO 2-X-COOH and suitable reactive compound reaction, or in the presence of alkali, preferred pyridine, make the sulfamoyl-carboxylic acid chloride of corresponding assorted fragrant linking group and suitable reactive compound coupling.
18, according to the method for claim 19, wherein said alkali is pyridine.
19, according to the method for claim 20, wherein said catalyst is a p-methyl benzenesulfonic acid.

Claims (21)

1, the sulfonamide prodrugs of general formula I
Figure A2006800450150002C1
Wherein
X is assorted aromatic radical or the assorted aromatic radical of alkyl that does not replace or replace, and
Drug is the pharmaceutical active compounds that can form carboxylate by the OH group, and as steroidal compounds, anti-malarial agents, ucleosides, isoflavonoid, they can be chosen wantonly and be substituted.
2, according to the sulfonamide prodrugs of claim 1, wherein X is pyridine or thienyl.
3, according to the sulfamoyl sulfonate prodrugs of claim 1, wherein
Drug is a steroidal compounds, estrogen for example is as estradiol or estriol, perhaps androgen, as testosterone, MENT (7 Alpha-Methyls-19-nortestosterone), eF-MENT (11-fluoro-7 Alpha-Methyls-19-nortestosterone), nandrolone phenylpropionate, DHT (dihydrotestosterone), perhaps
Progestogen, for example norethindrone, dienogest or levonorgestrel,
Adrenocortical hormone, hydrocortisone for example,
Anti-malarial agents, for example quinine, cinchonidine, oxychloroquine, primaquine, mefloquine, or
Ucleosides, it is selected from sugar as ribose or deoxyribose and alkali such as adenine, guanine, cytosine, thymus pyrimidine or uracil, and zidovudine, brivudine, English ground guiding principle Wei, Nai Fennawei,
Isoflavonoid, for example genistein.
4, according to the sulfamoyl sulfonate prodrugs of claim 1 or 2, it is:
1) the 3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl 6 '-sulfamoyl nicotinate (1),
2) the 3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl 5 '-sulfamoyl nicotinate (2),
3) the 3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl 2 '-ethyl-5 '-sulfamoyl thiophene-3 '-carboxylate (3),
4) the 3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl 2 '-bromo-5 '-sulfamoyl thiophene-3 '-carboxylate (4),
5) 3-oxo hero-4-alkene-17 beta-yl 6 '-sulfamoyl-nicotinate (5),
6) 3-oxo hero-4-alkene-17 beta-yl 5 '-sulfamoyl-nicotinate (6),
7) 3-oxo hero-4-alkene-17 beta-yl 2 '-ethyl-5 '-sulfamoyl thiophene-3 '-carboxylate,
8) 3-oxo hero-4-alkene-17 beta-yl 5 '-sulfamoyl thiophene-3 '-carboxylate,
9) the 3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl 5 '-sulfamoyl thiophene-3 '-carboxylate,
10) the 3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl 6 '-sulfamoyl thiophene-3 '-carboxylate,
11) 3-oxo hero-4-alkene-17 beta-yl 5 '-sulfamoyl-thiophene-3 '-carboxylate,
12) 3-oxo-7 Alpha-Methyl hero-4-alkene-17 beta-yl 5 '-sulfamoyl nicotinate,
13) 3-oxo-7 Alpha-Methyl hero-4-alkene-17 beta-yl 6 '-sulfamoyl nicotinate,
14) 3-oxo-7 Alpha-Methyl hero-4-alkene-17 beta-yl N-ethyl-5 '-sulfamoyl thiophene-3 '-carboxylate,
15) the 3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl N-methyl-5 '-sulfamoyl-1H-pyrroles-2 '-carboxylate.
5, according to claim 1,2 or 4 chemical compound, wherein said reactive compound is an anti-malarial agents, as arteether, Artemether, artesunate, chloroquine, pamaquine, primaquine, pyrethamine, mefloquine, proguanil, cinchonidine, cinchonine, oxychloroquine, pamaquine, primaquine, pyrimethamine, quinine or quinine derivative such as neutral quinine sulphate, aristochin, quinine dihydrobromide, quinine dihydrochloride, quinine ethylcarbonate, Quinaform, quinin(e) gluconate, quinin iodide, quinin hydrochloride, quinin salicylate or quinine sulfate.
6, the chemical compound according to claim 5 is preventing parasite to the application in the erythrocytic attack.
7, according to the chemical compound of one of claim 1-6, wherein treating and going up the effect of wishing is to realize by the described reactive compound or its metabolite that comprise in release, the especially described prodrug of hydrolytic cleavage.
8, pharmaceutical composition, it comprises at least a compound of Formula I and acceptable excipient of materia medica and/or carrier according to one of claim 1-4, and optional comprises at least a other reactive compound.
9, pharmaceutical composition according to Claim 8, wherein said other reactive compound is a steroidal compounds.
10, according to the pharmaceutical composition of claim 9, wherein said steroidal compounds is progestogen, gestation or progesterone receptor modulator.
11, according to the pharmaceutical composition of claim 10, wherein the progestogen that comprised are norethindrone, dienogest, drospirenone, levonorgestrel, described gestation is mifepristone, onapristone, and progesterone receptor modulator such as middle progesterone, as asoprisnil.
12, according to the application in the preparation medicine of the chemical compound of one of claim 1-7.
13, according to the application of claim 12, it is the medicine that preparation is used for Hormone Replacement Therapy.
14, according to the application of chemical compound in women's birth control of one of claim 1-7.
15, according to the application of claim 12, it is that preparation is used for the treatment of and/or prevents the medicine of the disease that hormone causes in the masculinity and femininity.
16, according to the application of claim 12, it is that preparation is used for the treatment of and prevents the medicine of endometriosis, breast carcinoma, carcinoma of prostate or hypogonadism.
17, according to the application of claim 12, it is that preparation is used for the treatment of and/or prevents and can produce the medicine of the disease of positive impact to it by suppressing the carbonic anhydrase activity.
18, according to the application of claim 12, it is the medicine that preparation is used for the treatment of and/or prevents inflammatory and/or allergic disease.
19, preparation is according to the method for the sulfonamide prodrugs of the general formula (I) of claim 1, it is in the presence of dicyclohexylcarbodiimide or EDC (N-(3-dimethylaminopropyl)-N '-ethyl carbodiimide), choose wantonly and use catalyst, make the carboxylic acid NH of corresponding assorted fragrant linking group 2SO 2-X-COOH and suitable reactive compound reaction, or in the presence of alkali, preferred pyridine, make the sulfamoyl-carboxylic acid chloride of corresponding assorted fragrant linking group and suitable reactive compound coupling.
20, according to the method for claim 19, wherein said alkali is pyridine.
21, according to the method for claim 20, wherein said catalyst is a p-methyl benzenesulfonic acid.
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IL191563A0 (en) 2009-08-03
AU2006319381A1 (en) 2007-06-07
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ZA200805660B (en) 2009-11-25
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