CN101316858A - Sulfamoyl sulfonate prodrugs - Google Patents
Sulfamoyl sulfonate prodrugs Download PDFInfo
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- CN101316858A CN101316858A CNA2006800449086A CN200680044908A CN101316858A CN 101316858 A CN101316858 A CN 101316858A CN A2006800449086 A CNA2006800449086 A CN A2006800449086A CN 200680044908 A CN200680044908 A CN 200680044908A CN 101316858 A CN101316858 A CN 101316858A
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- Prior art keywords
- sulfamyl
- sulfonic acid
- acid ester
- phenylbenzimidazole sulfonic
- beta
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0072—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the A ring of the steroid being aromatic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/26—Androgens
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/30—Oestrogens
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0038—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 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
Abstract
The invention relates to the sulfamoyl sulfonate prodrugs of general formula (I), to a method for producing them, to pharmaceutical compositions containing the same and to their use for producing orally available drugs. The compounds according to the invention bind to carboanhydrases and inhibit these enzymes.
Description
Technical field
The present invention relates to the sulfamoyl sulfonate prodrugs of general formula (I),
The invention still further relates to the method for these prodrugs of preparation, the pharmaceutical composition that comprises these compounds and their application in the preparation oral pharmaceutical.
WO 01/91797 has disclosed by group-SO
2NR
1R
2And combine and accumulate on this steroidal compounds with red corpuscle.The concentration ratio of these compounds between red corpuscle and blood plasma is 10-1000: 1, be preferably 30-1000: and 1, we can be described as the prolonged action preparation in the red corpuscle thus.Because these compounds and red corpuscle have strong keying action, so can avoid the metabolism during liver passes through.Disadvantageously, can reduce metabolism, the active 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 solubleness of combining.
The purpose of this invention is to provide novel prodrug, it can be oral and be compared with the prior art the active compound that also can guarantee to treat related levels under low dosage.
Summary of the invention
This purpose is that the sulfamoyl sulfonate prodrugs of general formula (I) realizes that wherein sulfamyl is connected on the medicine to be discharged by the sulfonic acid ester bond via spacer X.
The sulfamoyl sulfonate prodrugs of general formula (I) is
Wherein
X is C
1-12-alkane 2 basis, the C of p=1-5 wherein
pF
2pGroup, C
3-8-cycloalkanes two bases, arylidene, assorted alkane 2 basis, C
1-4-alkane 2 basis aryl, C
1-4-alkane 2 basis-C
3-8-cycloalkyl or C
3-8-cycloalkanes two bases-C
1-4-alkyl, and
Drug is the active constituents of medicine that can form sulphonate by the 0H group, and as steroidal compounds, anti-malarial agents, nucleosides, isoflavonoid (isoflavanoids), they can be chosen wantonly and be substituted.
Sulfamoyl sulfonate compound according to the present invention combines with red corpuscle, and is soluble in water, and can be hydrolyzed fracture under the situation that does not have enzyme to participate in.
In the present invention, " C
1-12-alkane 2 basis " be meant straight or branched alkylidene group with two connecting keys, it has maximum 12 carbon atoms, and can randomly be replaced by for example halogen atom, hydroxyl or itrile group.Its example can be a methane-1,1-two bases, ethane-1,2-two bases, propane-1,3-two bases, butane-1,4-two bases, pentane-1,5-two bases, hexane-1,6-two bases, octane-1,8-two base and undecanes-1,11-two bases.
In the present invention, the C of p=1-5 wherein
pF
2pBase is meant the straight or branched perfluoroalkyl with maximum 5 carbon atoms.It for example can be a perfluoropropane-1,3-two bases, perfluorinated butane-1,4-two base and perflenapents-1,5-two bases.
According to the present invention, above-mentioned " C
3-8-cycloalkanes two bases " be meant monocycle or bicyclic carbocyclic group with two connecting keys, it has 3-8 carbon atom, and can randomly be replaced by halogen atom, hydroxyl and itrile group; for example be tetramethylene-1; 3-two bases, pentamethylene-1,3-two bases or hexanaphthene-1,4-two bases.
According to the present invention, above-mentioned " arylidene " is meant that the monocycle with two connecting keys is to the tricyclic aromatic carbon ring group, it has 6-15 carbon atom, and can be randomly replaced by halogen atom, hydroxyl, itrile group and alkyl, for example is metaphenylene, to phenylene, phenanthrylene or naphthylidene.
Heteroarylidene comprises 5-16 annular atoms in various situations, and alternative carbon atom comprises one or more identical or different heteroatomss such as oxygen, nitrogen or sulphur in ring.This heteroaryl can be monocyclic, bicyclic or tricyclic.For example can be thienyl, furyl, pyrryl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazole base, triazolyl, thiadiazolyl group, benzofuryl, benzothienyl, benzothiazolyl, benzoxazolyl, benzimidazolyl-, indazolyl, indyl, pseudoindoyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl, quinolyl and isoquinolyl.
In the present invention, assorted alkane 2 basis is meant the assorted alkyl of the saturated or unsaturated straight or branched with two connecting keys, it has 1-6 carbon atom in various situations, and alternative carbon atom comprises one or more identical or different heteroatomss such as oxygen, nitrogen or sulphur, for example is acetylene oxygen base.
" C
1-4-aryl alkane 2 basis " be meant and pass through C
1-C
4-alkane 2 basis is connected to the aryl on the skeleton, and wherein alkane 2 basis can be a straight or branched, for example can be benzyl or styroyl.
" C
3-8-cycloalkyl-C
1-4-alkane 2 basis " for example be meant cycloalkyl-(CH
2)-, cycloalkyl-(C
2H
4)-, cycloalkyl-(C
3H
6)-, cycloalkyl-(C
4H
8)-or cycloalkyl-(C
5H
10)-.In the case, cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl or ring octyl group.
" C
1-4-alkyl-C
3-8-cycloalkanes two bases " be meant methyl cycloalkanes two bases, ethyl cycloalkanes two bases, propyl group cycloalkanes two bases, butyl cycloalkanes two bases or amyl group cycloalkanes two bases.In this situation, cycloalkanes two bases can be cyclopropane-1,3-two bases, tetramethylene-1,4-two bases, pentamethylene-1,5-two bases, hexanaphthene-1,6-two bases, suberane-1,7-two bases or cyclooctane-1,8-two bases.
Within the scope of the invention, term " halogen atom " is meant fluorine, chlorine, bromine or iodine atom, is preferably fluorine, chlorine or bromine atom.
In the present invention, can be following person by the active constituents of medicine of OH group formation sulphonate:
Steroidal compounds, oestrogenic hormon for example, as estradiol or trihydroxy-oestrin,
Male sex hormone is as testosterone, MENT (7 Alpha-Methyls-19-nortestosterone), eF-MENT (11-fluoro-7 Alpha-Methyls-19-nortestosterone), Nrolone Phenylpropionate, DHT (Standone), perhaps
Progestogen, for example Norethisterone, dienogest or Levonorgestrel,
Adrenocortical hormone, hydrocortisone for example,
Anti-malarial agents, for example quinine, Cinchonidune, Oxychloroquine, primaquine, Mefloquine hydrochloride, perhaps
Ucleosides is selected from sugar as ribose or ribodesose and alkali such as VITAMIN B4, guanine, cytosine(Cyt), thymus pyrimidine or uridylic, and zidovudine, brivudine, English ground guiding principle Wei, Nai Fennawei,
Isoflavonoid, for example genistein.
Particularly preferred compound is following person:
1) the 3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
2) the 3-acetoxyl group is female-1,3,5 (10)-triolefins-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
3) 3-t-butyldimethylsilyloxy base is female-1,3,5 (10)-triolefins-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
4) the 3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl 4 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
5) 2-methoxyl group-3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
6) 3,16 alpha-dihydroxy-s are female-1,3,5 (10)-triolefins-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
7) 3,17 beta-dihydroxyies are female-1,3,5 (10)-triolefins-16 α-Ji 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
8) 3-benzoyl oxygen base is female-1,3,5 (10)-triolefins-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
9) quinine-3 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
10) Cinchonidune-3 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
11) zidovudine-3 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
12) 3-oxo hero-4-alkene-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
13) 3-oxo androstane-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
14) 3-oxo-7 Alpha-Methyl hero-4-alkene-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
15) the 3-oxo female-4-alkene-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester, and
16) brivudine-3 '-sulfamyl phenylbenzimidazole sulfonic acid ester.
The relevant medical compounds of described treatment by hydrolysis by these according to discharging in the compound of the present invention.
Experiment in vitro
A) carbonic anhydrase restraining effect
The experiment principle:
On microtiter plate, by means of the enzymic transformations of acetate nitrophenyl ester, color is used spectrphotometric method for measuring sulfonamide compounds or the sulfamate compounds thing restraining effect 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 |
| 3-oxo hero-4-alkene-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester | 120 | 2300 |
| 3-oxo-7 Alpha-Methyl hero-4-alkene-17 beta-yl 3 '-amino sulfamyl phenylbenzimidazole sulfonic acid ester | 120 | 2300 |
| The 3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl 3 '-amino-sulfonyl phenylbenzimidazole sulfonic acid ester | 81 | 1700 |
| The zidovudine sulphonate | 1100 | 2900 |
| 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, very shockingly be easy to suppress carbonic anhydrase II according to sulfamoyl sulfonate prodrugs of the present invention.Can derive prodrug according to the present invention concentrating in red corpuscle thus.
The materialization data
Solubleness in the water
A) kinetic measurement:
Compound according to the present invention is measured with turbidometer and turbidity down in pH 7.4 and 25 ℃ with the 10mmol DMSO solution in the 0.01M phosphate buffered saline buffer.
Under muddy state, drips of solution to be tested is added in the described damping fluid, until depositing throw out.
This throw out detects with turbidometer according to a series of extent of dilution (compound according to the present invention is in phosphate buffered saline buffer).
B.) thermodynamics is measured:
The compound of solid form that will be according to the present invention is added in the water-containing buffering liquid system of excessive various pH values.Stirred 24 hours down at 25 ℃.After centrifugal, (HPLC: post: Xterra MS C182.5 μ m, 30 * 4.6mm) check this solution with HPLC.The compound that gene is measured, use two normal gradients systems:
Acid gradient: A: water/0.01% trifluoroacetic acid, B: acetonitrile/0.01% trifluoroacetic acid-0min 5%B, 0-3min 65%B, 3-5min 65%B, 5-6min 5%B
Alkali gradient: A: water/0.025% ammoniacal liquor, B: acetonitrile/0.025% ammoniacal liquor-0min 20%B, 0-3min 80%B, 3-5min 80%B, 5-6min 20%B.
Table 2: water solubility
| Material | Solubleness in the water |
| Estradiol-3-sulfamate | 0.15mg/100ml |
| Testosterone propionate | Insoluble |
| The 3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester | 3mg/l |
| 3-oxo hero-4-alkene-17 beta-yl 3 '-sulfamyl-phenylbenzimidazole sulfonic acid ester | 5mg/l |
| 3-oxo-7 Alpha-Methyl hero-4-alkene-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester | About 6mg/l |
Compound according to the present invention is compared with the carboxylicesters prodrug with the thionamic acid ester prodrugs has higher solubleness, and this can realize better absorbing in enteron aisle.
Hydrolysis
Compound according to the present invention is measured under 37 ℃ with the DMSO solution in the water-containing buffering liquid of various pH values.
Quantitatively (the HPLC post: Xterra MS C182.5 μ m 4.6 * 30mm) carries out by HPLC.Based on test substances to be measured, use following gradient system to be used for HPLC:
Acid gradient: A: water/0.01% trifluoroacetic acid, B: acetonitrile/0.01% trifluoroacetic acid-0min 5%B, 0-3min 65%B, 3-5min 65%B, 5-6min 5%B
Alkali gradient: A: water/0.025% ammoniacal liquor, B: acetonitrile/0.025% ammoniacal liquor-0min 20%B, 0-3min 80%B, 3-5min 80%B, 5-6min 20%B.Carrying out after 1 and 2 hour and after 24 hours quantitatively.
Stability in simulated gastric fluid:
According to the solution of compound of the present invention under 37 ℃ in simulated gastric fluid (containing the pepsic NaCl aqueous solution, pH～1.2) incubation.
Quantitatively by HPLC (the HPLC-post: Xterra MS C18 2.5 μ m 4.6 * 30mm) carry out in order to following gradient system:
A: water/0.01% trifluoroacetic acid, B: acetonitrile/0.01% trifluoroacetic acid-0min 5%B, 0-3min65%B, 3-5min 65%B, 5-6min 5%B.
After 0.5,1,1.5 and 2 hour, carry out quantitatively.
Table 3: the hydrolysis/stability in gastric juice
Carboxylicesters is all comparatively stable in gastric juice (pH～1) and enteron aisle (pH～7.4), but in by enteron aisle by the time esterase fracture that wherein existed.Yet when passing through in by stomach, stable prodrug still almost is kept perfectly.
When being passed through by enteron aisle and liver, this carboxylicesters ruptures thus.
It is known not having enzyme (esterase) for sulphonate.Therefore surprisingly, described sulphonate is still ruptured, and simple hydrolysis takes place thus.Though hydrolysis has slowly taken place in gastric juice and during pH=7.4, these sulphonates are for being that enough stability is arranged for stomach and enteron aisle.The esterase fracture does not occur in the intestines wall.Because these sulphonates and erythrocytic sulphonamide base key connect, so can avoid the first pass effect in liver.
Depend on the definition of " Drug ", these experimental results show that general formula of the present invention (I) compound has and treat and/or prevent different syndromic various possibilities.For example, if " Drug " is steroidal such as male sex hormone or oestrogenic hormon, then the compound of general formula (I) can be used for the Hormone Replacement Therapy (HRT) among the women and the male sex or is used for the treatment of the disease that hormone brings out among the male sex (prostate cancer, mammary cancer, hypogonadism), and the disease that hormone brings out among the women (endometriosis, mammary cancer).In addition, wherein " Drug " for example is male sex hormone or estrogenicly can be used for birth control among the male sex or the women according to general formula of the present invention (I) compound.
When the treatment malaria, can use other activeconstituentss as " Drug ", for example quinine, Cinchonidune, Oxychloroquine, primaquine or Mefloquine hydrochloride.
Wherein " Drug " for hydrocortisone derivative can be used for treating and preventing to be subjected to inflammatory diseases and/or the allergic disease that immunosuppressor and/or antiproliferative influence according to general formula of the present invention (I) compound.
Wherein " Drug " can be used for treating virus disease (bleb, HIV) for the prodrug of the present invention of nucleosides (zidovudine, brivudine, English ground guiding principle Wei, Nai Fennawei).
In addition, the invention still further relates to general formula (I) compound that comprises according to the present invention and the pharmaceutical composition of other activeconstituentss randomly, described other activeconstituentss for example are progestogen (Norethisterone, dienogest, drospirenone, Levonorgestrel), antiprogestin (mifepristone, onapristone) and/or progesterone receptor modulator (middle progesterone compound (mesoprogestins) is as asoprisnil).
These therapeutic compositions and the administration of medicine preferred oral.Except that the carrier and/or thinner of routine, they also comprise the compound of at least a general formula I.T
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 activeconstituents (" 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 thinner 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, coating tablet, capsule, pill, powder, solution or suspensoid or can are long-acting dosage forms.
Corresponding tablet can for example followingly make: mixed active composition and known vehicle, as inert diluent such as glucose, sucrose, sorbyl alcohol, N.F,USP MANNITOL, polyvinylpyrrolidone, disintegrating agent such as W-Gum or alginic acid, tackiness 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, acetate terephthaldehyde acid cellulose or the polyvinyl acetate of long-acting.These tablets also can comprise a plurality of layers.
Correspondingly, coating tablet can be prepared as follows: with normally used material in the coating tablet dressing core that is similar to above-mentioned tablet and makes is carried out dressing, described coating substance for example is polyvinylpyrrolidone or shellac, gum arabic, talcum, titanium oxide or sugar.At this, the shell of this coating tablet also can comprise a plurality of layers, wherein also can use the vehicle 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 odorant such as asccharin, cyclamate or sucrose in addition, and seasonings for example, as Vanillin or citrus extract.In addition, they also can comprise suspension vehicle such as Xylo-Mucine or sanitas 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 support such as lactose or sorbyl alcohol 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.
General synthetic guide
Method 1
React with disulfonic acid chloride
Under shielding gas with general formula SO
2-X-SO
2The disulfonyl halogen of Cl is dissolved in alkali such as the pyridine.In this solution, add the medicine of respective amount.This reaction mixture is stirred to and reacts completely.Then reaction mixture is stirred and be added in the concentrated ammonia solution.Throw out filters, and washes with water, and is dry then.Residue extracts with organic solvent such as ethyl acetate, and organic phase is washed, and uses siccative such as dried over mgso then.After the filtration, evaporation concentration, and on silica gel, carry out chromatographically pure system, obtain corresponding sulfamoyl sulfonate compound.
Method 2
React with the sulfamyl sulfonic acid halide
Under shielding gas with aforesaid medicine dissolution in alkali such as pyridine and inert solvent such as chloroform.Under cooling, in this solution, add the general formula NH of respective amount
2SO
2-X-SO
2The sulfamyl sulfonic acid halide of Hal.This reaction mixture is stirred to and reacts completely.Then add water, and randomly carry out acidifying as 10%HCl with acid.Extract with organic solvent such as ethyl acetate, organic phase is washed, and uses siccative such as dried over mgso then.After the filtration, evaporation concentration, and on silica gel, carry out chromatographically pure system, obtain corresponding sulfamoyl sulfonate compound.
These corresponding sulfamyl sulfonic acid halides or disulfonic acid chloride can commercially availablely obtain or can prepare according to method known to those skilled in the art.
Synthetic embodiment
Embodiment 1:3-t-butyldimethylsilyl is female-1,3,5 (10)-triolefins-17 beta-yl 3 '-sulfamyl
The phenylbenzimidazole sulfonic acid ester
With 1 of 1.9g, the 3-benzene-disulfo-chloride is dissolved in the pyridine of 5ml under argon gas.It is female-1,3 to add the 3-t-butyldimethylsilyl of 1.0g then, 5 (10)-triolefins-17 β-alcohol.After 2 hours, the reaction mixture stirring is added in the concentrated ammonia solution of 25ml.After 10 minutes, suction filtration washes with water and drying.Residue carry out chromatographically pure system on silica gel, it is female-1,3 to obtain the 3-t-butyldimethylsilyl, 5 (10)-triolefins-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester.
1H-NMR(DMSO-D
6)：0.14(s，6H，SiMe)，0.77(s，3H，18-Me)，0.93(s，9H，t.-Bu)，4.43(t，1H，17-H)，7.68(s，2H，NH
2).
Embodiment 2:3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester
The 3-t-butyldimethylsilyl of 300mg is female-1,3,5 (10)-triolefins-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester is dissolved among the THF of 20ml.Under agitation, add the tetrabutyl ammonium fluoride of 200mg in room temperature.After 1 hour, stir the water that adds 20ml.This material extracts with ethyl acetate (EE).Organic phase is washed with saturated nacl aqueous solution, and dry on sal epsom, evaporation concentration carry out chromatographically pure system then on silica gel, and it is female-1,3 to obtain the 3-hydroxyl, 5 (10)-triolefins-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester.
1H-NMR(DMSO-d
6)：0.76(s，3H，18-Me)，4.43(t，1H，17-H)，7.68(s，2H，NH
2)，8.98(s，1H，3-OH).
Embodiment 3:3-oxo-7 Alpha-Methyl is female-4-alkene-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester
With 1 of 1.9g, the 3-benzene-disulfo-chloride is dissolved in the pyridine of 5ml under argon gas.Add the MENT of 1.0g then.After 2 hours, the reaction mixture stirring is added in the concentrated ammonia solution of 25ml.After 10 minutes, suction filtration washes with water and drying.Residue carry out chromatographically pure system on silica gel, obtain 3-oxo-7 Alpha-Methyl female-4-alkene-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester.
1H-NMR(DMSO-D
6)：0.66(d，3H，7-Me)，4.38(t，1H，17-H)，5.69(s，1H，4-H)，7.67(s，2H，NH
2)，7.83-8.28(m，4H，H-Ar).
Embodiment 4:3-oxo-hero-4-alkene-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester
Method 1
With 1 of 2.0g, the 3-benzene-disulfo-chloride is dissolved in the pyridine of 5.5ml under argon gas.Add the testosterone of 1.0g.After 2 hours, the reaction mixture stirring is added in the concentrated ammonia solution of 25ml.After 10 minutes, suction filtration washes with water and drying.Residue carry out chromatographically pure system on silica gel, obtain 3-oxo-hero-4-alkene-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester.
Method 2
Testosterone with 1.0g under argon gas is dissolved in the pyridine of 5.5ml.Add the 3-amino-sulfonyl phenyl SULPHURYL CHLORIDE of 1.8g.After 2 hours, stir reaction mixture in the water be added into 25ml and use the 10%HCl acidifying.After 10 minutes, suction filtration washes with water and drying.Residue carry out chromatographically pure system on silica gel, obtain 3-oxo-hero-4-alkene-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester.
1H-NMR(DMSO-D
6)：0.78(s，3H，18-Me)，1.11(s，3H，19-Me)，4.34(t，1H，17-H)，5.60(s，1H，4-H)，7.67(s，2H，NH
2)，7.83-8.28(m，4H，H-Ar).
Embodiment 5: zidovudine-sulfamyl phenylbenzimidazole sulfonic acid ester
With 1 of 2.0g, the 3-benzene-disulfo-chloride is dissolved in the pyridine of 5.5ml under argon gas.At 0 ℃ of zidovudine that adds 1.0g down.After at room temperature stirring 2 hours, reaction mixture is added in the strong aqua of 25ml.Stir after 10 minutes, be evaporated to driedly, and extract with EE.Organic phase is carried out evaporation concentration, and residue carry out chromatographically pure system on silica gel, obtains zidovudine-sulfamyl phenylbenzimidazole sulfonic acid ester.
1H-NMR(DMSO-D
6)：1.17(s，3H，Me)，2.40(m，2H，CH
2)，4.00(m，1H，CH)，4.42(m，2H，CH
2)，6.09(m，1H，CH)，7.40(s，1H，CH)，7.66(s，2H，NH
2)，7.85-8.30(3m+s，5H，4-H)，11.35(s，1H，NH).
Embodiment 6: Cinchonidune-sulfamyl phenylbenzimidazole sulfonic acid ester
With 1 of 2.0g, the 3-benzene-disulfo-chloride is dissolved in the pyridine of 5.5ml under argon gas.At 0 ℃ of Cinchonidune that adds 1.0g down.After at room temperature stirring 2 hours, reaction mixture is added in the strong aqua of 25ml.Stir after 10 minutes, be evaporated to driedly, and extract with EE.Organic phase is carried out evaporation concentration, and residue carry out chromatographically pure system on silica gel, obtains Cinchonidune-sulfamyl phenylbenzimidazole sulfonic acid ester,
1H-NMR(DMSO-D
6)：4.99(m，2H，CH＝
CH 2 )，5.94(m，1H，
CH＝CH
2)，7.58(s，2H，NH
2).
Need not further description, believe that those skilled in the art state under the situation of specification sheets in the use can intactly utilize the present invention.Therefore, preferred specific embodiments only is to be used for explanation, and is absolutely not the restriction of the scope of the invention.
In the above-described embodiments, all temperature all are without gauged degree centigrade, and all umbers and per-cent all calculate according to weight, except as otherwise noted.
These embodiment can successfully be repeated to implement by the general or specifically described reactant that uses among these embodiment that replace the present invention and/or operational condition.
By foregoing description, those skilled in the art can easily determine essential characteristic of the present invention, and under the situation that does not depart from its spirit and scope, can carry out various changes and improvements to adapt to various application and condition to the present invention.
Claims (according to the modification of the 19th of treaty)
Statement according to the 19th of treaty
The applicant is willing to the basis of appended modified claims as further international inspector at this, and it is further being transmitted in the flow process in selected or appointment office.
For eliminating the clearly objection of shortage according to the 6th of PCT treaty, the applicant submits modified claim 1-21.
This new claim 1-21 can find to support with upper/lower positions.
Claim 1: former claim 1 and specification sheets the 2nd and 3 pages, described in the written notice in 21 days Mays in 2007 of International Search Department
Claim 20: the general formula of disulfonic acid chloride is corrected, and this is conspicuous for those skilled in the art.
Claim 2-19 and 21 does not become.
Claim 1 has been carried out following modification: to C
1-12-alkane 2 basis, C
3-8Features such as-cycloalkanes two bases, arylidene and assorted alkane 2 basis limit, and have eliminated inconsistent between claim 1 and the specification sheets 2-3 page or leaf, and this claim is clearly according to the 6th of PCT treaty thus.
In claim 20, the general formula of the apparent error of disulfonic acid chloride is corrected.Shown in the embodiment on the specification sheets 12-14 page or leaf, benzene-disulfo-chloride is used to prepare sulfamoyl sulfonate.Because this benzene-disulfo-chloride only can obtain (seeing http:/www.chemexper.com) by dichloride, it is evident that for the technician in organic synthesis field it only can mean general formula at this
Cl-SO
2-X-SO
2The disulfonic acid chloride of-Cl.Therefore the applicant is this mistake of request report, and submits through the 11st page in the specification sheets of corrigendum.
On Instructions Page 3, deleted the definition that has nothing to do with the application to heteroaryl.The implication of heteroaryl is not have that this is substituent in this application.Therefore the applicant submits the Instructions Page 3 through corrigendum.
1, the sulfamoyl sulfonate prodrugs of general formula I
Wherein
X is C
1-12-alkane 2 basis, the C of p=1-5 wherein
pF
2pGroup, optional monocycle or the dicyclo C that is replaced by halogen atom, hydroxyl or itrile group
3-8-cycloalkanes two bases, optional monocycle to the three ring C that is replaced by halogen atom, hydroxyl, itrile group or alkyl
6-15-arylidene, have 1-6 carbon atom and alternative carbon atom contains one or more identical or different heteroatomic assorted alkane 2 basis, C
1-4-alkane 2 basis aryl, C
1-4-alkane 2 basis-C
3-8-cycloalkyl or C
3-8-cycloalkanes two bases-C
1-4-alkyl, and
Drug is the active constituents of medicine that can form sulphonate by the OH group, and as steroidal compounds, anti-malarial agents, nucleosides, isoflavonoid, they can be chosen wantonly and be substituted.
2, according to the sulfamoyl sulfonate prodrugs of claim 1, wherein
Drug is a steroidal compounds, oestrogenic hormon for example, and as estradiol or trihydroxy-oestrin, or
Male sex hormone, as testosterone, MENT (7 Alpha-Methyls-19-nortestosterone), eF-MENT (11-fluoro-7 Alpha-Methyls-19-nortestosterone), Nrolone Phenylpropionate, DHT (Standone), or
Progestogen, for example Norethisterone, dienogest or Levonorgestrel,
Adrenocortical hormone, hydrocortisone for example,
Anti-malarial agents, for example quinine, Cinchonidune, Oxychloroquine, primaquine, Mefloquine hydrochloride, perhaps
Ucleosides is made up of as ribose or ribodesose and alkali such as VITAMIN B4, guanine, cytosine(Cyt), thymus pyrimidine or uridylic sugar, and zidovudine, brivudine, English ground guiding principle Wei, Nai Fennawei,
Isoflavonoid, for example genistein.
3, according to the sulfamoyl sulfonate prodrugs of claim 1, wherein X is an arylidene.
4, according to the sulfamoyl sulfonate prodrugs of claim 3, wherein X be not substituted or the phenylene that replaced by chlorine-, pyridylidene-or inferior thienyl.
5, according to the sulfamoyl sulfonate prodrugs of claim 3 or 4, it is:
1) the 3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
2) the 3-acetoxyl group is female-1,3,5 (10)-triolefins-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
3) 3-t-butyldimethylsilyloxy base is female-1,3,5 (10)-triolefins-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
4) the 3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl 4 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
5) 2-methoxyl group-3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
6) 3,16 alpha-dihydroxy-s are female-1,3,5 (10)-triolefins-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
7) 3,17 beta-dihydroxyies are female-1,3,5 (10)-triolefins-16 α-Ji 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
8) 3-benzoyl oxygen base is female-1,3,5 (10)-triolefins-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
9) quinine-3 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
10) Cinchonidune-3 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
11) zidovudine-3 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
12) 3-oxo hero-4-alkene-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
13) 3-oxo androstane-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
14) 3-oxo-7 Alpha-Methyl hero-4-alkene-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
15) the 3-oxo female-4-alkene-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester, and
16) brivudine-3 '-sulfamyl phenylbenzimidazole sulfonic acid ester.
6, according to claim 1,3 or 4 compound, wherein said activeconstituents is an anti-malarial agents, as arteether, Artemether, Artesunate, chloroquine, pamaquine, primaquine, pyrethamine, Mefloquine hydrochloride, chloroguanide, Cinchonidune, cinchonine, Oxychloroquine, pamaquine, primaquine, Pyrimethamine hcl, quinine or quinine derivative such as neutral quinine sulphate, aristoquin, quinine dihydrobromide, quinine dihydrochloride, quinine ethylcarbonate, Quinoform, quinin(e) gluconate, quinin iodide, quinine hydrochloride, quinin salicylate or Quinine Sulphate Di HC.
7, the compound according to claim 6 is preventing parasite to the application in the erythrocytic attack.
8, according to the compound of one of claim 1-7, wherein treating and going up the effect of wishing is to realize by the described activeconstituents or its metabolite that comprise in release, the especially described prodrug of hydrolytic cleavage.
9, pharmaceutical composition, it comprises at least a compound of Formula I and acceptable assistant agent of pharmacology and/or carrier according to one of claim 1-5, and optional comprises at least a other activeconstituents.
10, according to the pharmaceutical composition of claim 9, wherein said other activeconstituents is a steroidal compounds.
11, according to the pharmaceutical composition of claim 10, wherein said steroidal compounds is progestogen, antiprogestin or progesterone receptor modulator.
12, according to the pharmaceutical composition of claim 11, wherein the progestogen that is comprised is Norethisterone, dienogest, drospirenone, Levonorgestrel, and antiprogestin is mifepristone, onapristone, and progesterone receptor modulator such as middle progesterone, as asoprisnil.
13, according to the application in the preparation medicine of the compound of one of claim 1-8.
14, according to the application of claim 13, it is the medicine that preparation is used for Hormone Replacement Therapy.
15, according to the application of compound in women's birth control of one of claim 1-8.
16, according to the application of claim 13, 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.
17, according to the application of claim 13, it is the medicine that preparation is used for the treatment of and prevents endometriosis, mammary cancer, prostate cancer or hypogonadism.
18, according to the application of claim 13, it is to prepare to be used for the treatment of and/or to prevent by suppressing the carbonic anhydrase activity it to be produced the medicine of the disease of positive influence.
19, according to the application of claim 13, it is the medicine that preparation is used for the treatment of and/or prevents inflammatory and/or allergic disease.
20, preparation is according to the method for the sulfamoyl sulfonate prodrugs of the general formula (I) of claim 1, and it is the corresponding activeconstituents " Drug " and disulfonic acid chloride ClSO that makes in the presence of alkali according to claim 1 and 2
2-X-SO
2Ammonia treatment is used in the Cl reaction subsequently, or makes corresponding activeconstituents " Drug " and sulfamyl sulfonic acid halide NH according to claim 1 and 2 in the presence of alkali
2SO
2-X-SO
2The Cl reaction.
21, according to the method for claim 20, wherein said alkali is pyridine.
Claims (21)
1, the sulfamoyl sulfonate prodrugs of general formula I
Wherein
X is C
1-12-alkane 2 basis, the C of p=1-5 wherein
pF
2pGroup, C
3-8-cycloalkanes two bases, arylidene, assorted alkane 2 basis, C
1-4-alkane 2 basis aryl, C
1-4-alkane 2 basis-C
3-8-cycloalkyl or C
3-8-cycloalkanes two bases-C
1-4-alkyl, and
Drug is the active constituents of medicine that can form sulphonate by the OH group, and as steroidal compounds, anti-malarial agents, nucleosides, isoflavonoid, they can be chosen wantonly and be substituted.
2, according to the sulfamoyl sulfonate prodrugs of claim 1, wherein
Drug is a steroidal compounds, oestrogenic hormon for example, and as estradiol or trihydroxy-oestrin, or
Male sex hormone, as testosterone, MENT (7 Alpha-Methyls-19-nortestosterone), eF-MENT (11-fluoro-7 Alpha-Methyls-19-nortestosterone), Nrolone Phenylpropionate, DHT (Standone), or
Progestogen, for example Norethisterone, dienogest or Levonorgestrel,
Adrenocortical hormone, hydrocortisone for example,
Anti-malarial agents, for example quinine, Cinchonidune, Oxychloroquine, primaquine, Mefloquine hydrochloride, perhaps
Ucleosides is made up of as ribose or ribodesose and alkali such as VITAMIN B4, guanine, cytosine(Cyt), thymus pyrimidine or uridylic sugar, and zidovudine, brivudine, English ground guiding principle Wei, Nai Fennawei,
Isoflavonoid, for example genistein.
3, according to the sulfamoyl sulfonate prodrugs of claim 1, wherein X is an arylidene.
4, according to the sulfamoyl sulfonate prodrugs of claim 3, wherein X be not substituted or the phenylene that replaced by chlorine-, pyridylidene-or inferior thienyl.
5, according to the sulfamoyl sulfonate prodrugs of claim 3 or 4, it is:
1) the 3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
2) the 3-acetoxyl group is female-1,3,5 (10)-triolefins-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
3) 3-t-butyldimethylsilyloxy base is female-1,3,5 (10)-triolefins-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
4) the 3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl 4 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
5) 2-methoxyl group-3-hydroxyl is female-1,3,5 (10)-triolefins-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
6) 3,16 alpha-dihydroxy-s are female-1,3,5 (10)-triolefins-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
7) 3,17 beta-dihydroxyies are female-1,3,5 (10)-triolefins-16 α-Ji 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
8) 3-benzoyl oxygen base is female-1,3,5 (10)-triolefins-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
9) quinine-3 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
10) Cinchonidune-3 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
11) zidovudine-3 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
12) 3-oxo hero-4-alkene-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
13) 3-oxo androstane-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
14) 3-oxo-7 Alpha-Methyl hero-4-alkene-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester,
15) the 3-oxo female-4-alkene-17 beta-yl 3 '-sulfamyl phenylbenzimidazole sulfonic acid ester, and
16) brivudine-3 '-sulfamyl phenylbenzimidazole sulfonic acid ester.
6, according to claim 1,3 or 4 compound, wherein said activeconstituents is an anti-malarial agents, as arteether, Artemether, Artesunate, chloroquine, pamaquine, primaquine, pyrethamine, Mefloquine hydrochloride, chloroguanide, Cinchonidune, cinchonine, Oxychloroquine, pamaquine, primaquine, Pyrimethamine hcl, quinine or quinine derivative such as neutral quinine sulphate, aristoquin, quinine dihydrobromide, quinine dihydrochloride, quinine ethylcarbonate, Quinoform, quinin(e) gluconate, quinin iodide, quinine hydrochloride, quinin salicylate or Quinine Sulphate Di HC.
7, the compound according to claim 6 is preventing parasite to the application in the erythrocytic attack.
8, according to the compound of one of claim 1-7, wherein treating and going up the effect of wishing is to realize by the described activeconstituents or its metabolite that comprise in release, the especially described prodrug of hydrolytic cleavage.
9, pharmaceutical composition, it comprises at least a compound of Formula I and acceptable assistant agent of pharmacology and/or carrier according to one of claim 1-5, and optional comprises at least a other activeconstituents.
10, according to the pharmaceutical composition of claim 9, wherein said other activeconstituents is a steroidal compounds.
11, according to the pharmaceutical composition of claim 10, wherein said steroidal compounds is progestogen, antiprogestin or progesterone receptor modulator.
12, according to the pharmaceutical composition of claim 11, wherein the progestogen that is comprised is Norethisterone, dienogest, drospirenone, Levonorgestrel, and antiprogestin is mifepristone, onapristone, and progesterone receptor modulator such as middle progesterone, as asoprisnil.
13, according to the application in the preparation medicine of the compound of one of claim 1-8.
14, according to the application of claim 13, it is the medicine that preparation is used for Hormone Replacement Therapy.
15, according to the application of compound in women's birth control of one of claim 1-8.
16, according to the application of claim 13, 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.
17, according to the application of claim 13, it is the medicine that preparation is used for the treatment of and prevents endometriosis, mammary cancer, prostate cancer or hypogonadism.
18, according to the application of claim 13, it is to prepare to be used for the treatment of and/or to prevent by suppressing the carbonic anhydrase activity it to be produced the medicine of the disease of positive influence.
19, according to the application of claim 13, it is the medicine that preparation is used for the treatment of and/or prevents inflammatory and/or allergic disease.
20, preparation is according to the method for the sulfamoyl sulfonate prodrugs of the general formula (I) of claim 1, and it is the corresponding activeconstituents " Drug " and disulfonic acid chloride SO that makes in the presence of alkali according to claim 1 and 2
2-X-SO
2Ammonia treatment is used in the Cl reaction subsequently, or makes corresponding activeconstituents " Drug " and sulfamyl sulfonic acid halide NH according to claim 1 and 2 in the presence of alkali
2SO
2-X-SO
2The Cl reaction.
21, according to the method for claim 20, wherein said alkali is pyridine.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102005057408.4 | 2005-11-30 | ||
| DE102005057408A DE102005057408A1 (en) | 2005-11-30 | 2005-11-30 | New sulfamoylsulfonate prodrugs e.g. useful for protecting red blood cells from attack by parasites or for hormone replacement therapy, female fertility control or treating hormone-associated diseases |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101316858A true CN101316858A (en) | 2008-12-03 |
Family
ID=37983623
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800449086A Pending CN101316858A (en) | 2005-11-30 | 2006-11-27 | Sulfamoyl sulfonate prodrugs |
Country Status (15)
| Country | Link |
|---|---|
| EP (1) | EP1957513A2 (en) |
| JP (1) | JP2009517424A (en) |
| KR (1) | KR20080072956A (en) |
| CN (1) | CN101316858A (en) |
| AU (1) | AU2006319380A1 (en) |
| BR (1) | BRPI0619253A2 (en) |
| CA (1) | CA2632272A1 (en) |
| CR (1) | CR10003A (en) |
| DE (1) | DE102005057408A1 (en) |
| EA (1) | EA200801306A1 (en) |
| EC (1) | ECSP088489A (en) |
| IL (1) | IL191570A0 (en) |
| NO (1) | NO20082915L (en) |
| WO (1) | WO2007062874A2 (en) |
| ZA (1) | ZA200805659B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101987101A (en) * | 2009-08-05 | 2011-03-23 | 天津金耀集团有限公司 | Anti-inflammatory eye composition with glucocorticoid aromatic sulfamoyl sulfonic acid ester as active ingredient |
| CN101987104A (en) * | 2009-08-05 | 2011-03-23 | 天津金耀集团有限公司 | Ophthalmic composition of heteroaryl sulfamoyl carboxylic ester carbonic anhydrase inhibitor |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010110747A1 (en) * | 2009-03-24 | 2010-09-30 | National University Of Singapore | Use of artemisinin derivatives for the treatment of asthma and chronic obstructive pulmonary disease (copd) |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10027887A1 (en) * | 2000-05-31 | 2001-12-13 | Jenapharm Gmbh | Compounds with a sulfonamide group and pharmaceutical compositions containing these compounds |
| DE102004025966A1 (en) * | 2004-05-21 | 2005-12-15 | Schering Ag | Estradiol prodrugs |
| DE102004025985A1 (en) * | 2004-05-21 | 2005-12-15 | Schering Ag | Estriol and estetrol prodrugs |
| DE102004025986A1 (en) * | 2004-05-21 | 2005-12-15 | Schering Ag | Steroid prodrugs with androgenic effects |
-
2005
- 2005-11-30 DE DE102005057408A patent/DE102005057408A1/en not_active Ceased
-
2006
- 2006-11-27 JP JP2008542678A patent/JP2009517424A/en active Pending
- 2006-11-27 WO PCT/EP2006/011726 patent/WO2007062874A2/en active Application Filing
- 2006-11-27 BR BRPI0619253-0A patent/BRPI0619253A2/en not_active Application Discontinuation
- 2006-11-27 EP EP06829354A patent/EP1957513A2/en not_active Withdrawn
- 2006-11-27 KR KR1020087015775A patent/KR20080072956A/en not_active Application Discontinuation
- 2006-11-27 EA EA200801306A patent/EA200801306A1/en unknown
- 2006-11-27 CA CA002632272A patent/CA2632272A1/en not_active Abandoned
- 2006-11-27 AU AU2006319380A patent/AU2006319380A1/en not_active Abandoned
- 2006-11-27 CN CNA2006800449086A patent/CN101316858A/en active Pending
-
2008
- 2008-05-20 IL IL191570A patent/IL191570A0/en unknown
- 2008-05-21 CR CR10003A patent/CR10003A/en not_active Application Discontinuation
- 2008-05-30 EC EC2008008489A patent/ECSP088489A/en unknown
- 2008-06-27 NO NO20082915A patent/NO20082915L/en not_active Application Discontinuation
- 2008-06-27 ZA ZA200805659A patent/ZA200805659B/en unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101987101A (en) * | 2009-08-05 | 2011-03-23 | 天津金耀集团有限公司 | Anti-inflammatory eye composition with glucocorticoid aromatic sulfamoyl sulfonic acid ester as active ingredient |
| CN101987104A (en) * | 2009-08-05 | 2011-03-23 | 天津金耀集团有限公司 | Ophthalmic composition of heteroaryl sulfamoyl carboxylic ester carbonic anhydrase inhibitor |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1957513A2 (en) | 2008-08-20 |
| EA200801306A1 (en) | 2008-10-30 |
| AU2006319380A1 (en) | 2007-06-07 |
| WO2007062874A3 (en) | 2007-07-12 |
| IL191570A0 (en) | 2008-12-29 |
| WO2007062874B1 (en) | 2007-09-27 |
| DE102005057408A1 (en) | 2007-05-31 |
| BRPI0619253A2 (en) | 2011-09-27 |
| CA2632272A1 (en) | 2007-06-07 |
| KR20080072956A (en) | 2008-08-07 |
| NO20082915L (en) | 2008-06-27 |
| WO2007062874A2 (en) | 2007-06-07 |
| JP2009517424A (en) | 2009-04-30 |
| ZA200805659B (en) | 2009-10-28 |
| CR10003A (en) | 2008-08-21 |
| ECSP088489A (en) | 2008-06-30 |
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