CN100432077C - N-sulfonylaminothiazole - Google Patents
N-sulfonylaminothiazole Download PDFInfo
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- CN100432077C CN100432077C CNB2003801029331A CN200380102933A CN100432077C CN 100432077 C CN100432077 C CN 100432077C CN B2003801029331 A CNB2003801029331 A CN B2003801029331A CN 200380102933 A CN200380102933 A CN 200380102933A CN 100432077 C CN100432077 C CN 100432077C
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Abstract
N-(4,5,6,7-tetrahydro-thiazolo-[5,4-c]pyridin-2-yl)-(C6-18)arylsulfonamides, wherein the nitrogen atom of the pyridine is substituted, and wherein the pyridine ring is optionally bridged, useful as a pharmaceutical related to steroid sulfatase.
Description
The present invention relates to the N-sulfonylaminothiazole, for example can be used for treating N-sulfonylaminothiazole by the disease of the effect mediation of steoid sulfatase.
On the one hand, the invention provides the nitrogen-atoms of pyridine wherein be replace, for example and wherein pyridine ring randomly is N-(4,5,6,7-tetrahydrochysene-thiazole is pyridine-2-yl also-[5, the 4-c])-(C of bridging
6-18) aryl sulfonic acid amides in preparation treatment by the disease of the effect mediation of the steoid sulfatase purposes in the medicine of acne for example.
Wherein the nitrogen-atoms of pyridine be replace, for example and wherein pyridine ring randomly is N-(4,5,6,7-tetrahydrochysene-thiazole is pyridine-2-yl also-[5, the 4-c])-(C of bridging
6-18) aryl sulfonic acid amides be called as in this article " (according to) thiazole of the present invention also-pyridine-aryl sulfonic acid amides ".So the former replacement of the nitrogen of pyridine, for example replaced: (C by following group
1-12) alkoxy carbonyl, (C
1-6) alkyl-carbonyl, (C
3-6) cycloalkyl (C
1-6) alkyl-carbonyl, the unsubstituted or (C that replaces
6-18) for example phenyl of aryl, list or multiple replacement, for example by aminocarboxyl, halogen or halo (C
1-6) alkyl, for example by aminocarboxyl or halo (C
1-6) (the C that replaces of alkyl
6-18) aryl.Preferably, the nitrogen-atoms of pyridine is by (C
1-12) alkoxy carbonyl, (C
3-6) cycloalkyl (C
1-6) alkyl-carbonyl, the unsubstituted or (C that replaces
6-18) the aryl replacement.Pyridine ring be bridging not or bridging, for example by (C
1-4) alkylidene group, (C for example
1-2) alkylidene group such as ethylidene bridging.Thiazole of the present invention also-pyridine-aryl sulfonic acid amides comprises for example N-(4,5,6,7-tetrahydrochysene-thiazole is [5,4-c] pyridine-2-yl also)-benzsulfamide.(the C that is connected with sulphonamide
6-18) aryl can be unsubstituted or replace, for example by group conventional in organic chemistry halo (C for example
1-4) alkyl or halogen replacement.
On the other hand, the thiazole of the present invention of use provided by the present invention also-pyridine-aryl sulfonic acid amides is the compound of formula I:
Wherein:
R
1Be (C unsubstituted or that replace
6-18) aryl, for example by aminocarboxyl, halogen or halo (C
1-6) the alkyl replacement, preferably by halogen or halo (C
1-6) the alkyl replacement,
R
2Be (C
1-12) alkoxy carbonyl, (C
1-6) alkyl-carbonyl, (C
3-6) cycloalkyl (C
1-6) alkyl-carbonyl or (C unsubstituted or that replace
6-18) aryl, for example by aminocarboxyl, halogen or halo (C
1-6) the alkyl replacement, and
-R
3, R
4And R
5Be hydrogen
Perhaps
-R
3And R
5Be (C together
1-4) alkylidene group and R
4Be hydrogen.
Be used to prepare thiazole that treatment comprises formula I compound by the medicine of the disease of the effect mediation of steoid sulfatase of the present invention also-pyridine-aryl sulfonic acid amides is called as " (according to) be used for compound of the present invention " hereinafter.
Thiazole of the present invention also-pyridine-aryl sulfonic acid amides in defined each independent substituting group can itself be preferred substituted, be independent of defined other substituting group.
On the other hand, the invention provides formula I compound into formula II compound:
Wherein:
R
1Be (C unsubstituted or that replace
6-18) aryl, for example by aminocarboxyl, halogen or halo (C
1-6) the alkyl replacement,
R
2` is (C
1-12) alkoxy carbonyl, (C
1-6) alkyl-carbonyl, (C
3-6) cycloalkyl (C
1-6) alkyl-carbonyl or (C unsubstituted or that replace
6-18) aryl, for example by aminocarboxyl, halogen or halo (C
1-6) the alkyl replacement, and
R
3And R
5Be (C together
1-4) alkylidene group and R
4Be hydrogen.
On the other hand, the invention provides and be formula II
AThe formula II compound of compound:
Wherein:
R
1By halo (C
1-4) phenyl that replaces of alkyl or halogen, and
R
2` is (C
1-8) alkoxy carbonyl, (C
3-6) cycloalkyl (C
1-4) alkyl-carbonyl or phenyl unsubstituted or that replace, for example by aminocarboxyl, halogen or halo (C
1-6) phenyl of alkyl list or multiple replacement.
On the other hand, the invention provides and be formula II
A1The formula II of compound or II
ACompound:
On the other hand, the invention provides formula I compound into the formula III compound:
Wherein:
R
1Be (C unsubstituted or that replace
6-18) aryl, for example by aminocarboxyl, halogen or halo (C
1-6) the alkyl replacement, and
R
2`` is (C
1-12) alkoxy carbonyl, (C
3-6) cycloalkyl (C
1-6) alkyl-carbonyl, unsubstituted (C
6-18) aryl or by aminocarboxyl, halogen or halo (C
1-6) (the C that replaces of alkyl
6-18) aryl.
On the other hand, the invention provides and be formula III
AThe formula III compound of compound:
Wherein:
R
1By halo (C
1-4) phenyl of alkyl or halogen list or multiple replacement, and
R
2`` is (C
1-6) alkoxy carbonyl, (C
3-6) cycloalkyl (C
1-2) alkyl-carbonyl or by aminocarboxyl or halo (C
1-4) phenyl that replaces of alkyl.
On the other hand, the invention provides formula III
A1Compound:
On the other hand, the invention provides formula II compound, it is N-(3-thia-5,11-diaza-three ring [6.2.1.0
*2,6
*] 11 carbon-2 (6), 4-diene-4-yl)-benzsulfamide.
On the other hand, the invention provides and be selected from following formula III compound:
-2-[2-(3,5-couple-trifluoromethyl-phenylsulfonamido)-6,7-dihydro-4H-thiazole is [5,4-c] pyridine-5-yl also]-4-trifluoromethyl-benzamide,
-2-[2-(2,3-two chloro-phenylsulfonamido)-6,7-dihydro-4H-thiazole is [5,4-c] pyridine-5-yl also]-4-trifluoromethyl-benzamide,
-2-[2-(3,5-two chloro-phenylsulfonamido)-6,7-dihydro-4H-thiazole is [5,4-c] pyridine-5-yl also]-4-trifluoromethyl-benzamide,
-2-(3,5-couple-trifluoromethyl-phenylsulfonamido)-6,7-dihydro-4H-thiazole is [5,4-c] pyridine-5-t-butyl formate also,
-2-(2,3-two chloro-phenylsulfonamido)-6,7-dihydro-4H-thiazole is [5,4-c] pyridine-5-t-butyl formate also,
-2-(3,5-two chloro-phenylsulfonamido)-6,7-dihydro-4H-thiazole also [5,4-c] pyridine-5-t-butyl formate and
-N-[5-(2-cyclopentyl-ethanoyl)-4,5,6,7-tetrahydrochysene-thiazole be [5,4-c] pyridine-2-yl also]-3,5-pair-trifluoromethyl-benzsulfamide.
If not definition in addition herein, then
-(C
6-18) aryl comprises (C unsubstituted and that replace
6-18) aryl, for example phenyl, for example for example comprised aminocarboxyl, halogen or halo (C
1-6) alkyl in interior organic chemistry conventional group list or the (C of multiple replacement
6-18) aryl.
-halo (C
1-6) alkyl comprises halo (C
1-4) alkyl, for example CF
3,
-halogen comprises fluorine, chlorine, bromine and iodine, chlorine for example,
-(C
1-12) alkoxyl group comprises (C
1-8) alkoxyl group, for example (C
1-4) alkoxyl group, tert.-butoxy for example,
-(C
3-6) cycloalkyl comprises (C
5-6) cycloalkyl, cyclopentyl for example,
-(C
1-6) alkyl-carbonyl comprises (C
1-4) alkyl-carbonyl, for example methyl carbonyl.
Compound provided by the present invention is formula II, II for example
A, II
A1, III, III
AAnd III
A1Compound be called as " (according to) compound of the present invention " hereinafter.Each independent substituting group defined above can itself be a preferred substituted in the compound of the present invention, is independent of defined other substituting group.Formula II compound comprises formula II
AAnd II
A1Compound.The formula III compound comprises formula III
AAnd III
A1Compound.
Compound of the present invention comprises any type of compound, for example the compound of free form, salt form, solvate form thereof and salt and solvate form thereof.
On the other hand, the invention provides the compound of the present invention of salt form.
Being used for compound of the present invention can be used in any form, for example free form, salt form, solvate form thereof and salt and solvate form thereof.
The salt of compound of the present invention or the salt that is used for compound of the present invention comprise pharmacologically acceptable salt, for example comprise metal-salt and acid salt.Metal-salt comprises for example an alkali metal salt or alkaline earth salt, for example sodium salt; Acid salt comprises compound of the present invention or is used for compound of the present invention and the sour for example salt of HCl.
The compound of the present invention of free form or be used for the respective compound that compound of the present invention can be converted to salt form; And vice versa.The compound of the present invention of free form or salt form or solvate form thereof or be used for the respective compound that compound of the present invention can be converted to free form or salt form or non-solvent compound form; And vice versa.
Compound of the present invention or be used for compound of the present invention and can exist with the form of mixtures of isomeric forms and they.Isomer mixture for example comprises that the isomer mixture of mixture of enantiomers or non-enantiomer mixture can for example suitably be separated to obtain pure isomer according to ordinary method.The present invention includes the compound of the present invention of any isomeric forms and any isomer mixture form or be used for compound of the present invention.
On the other hand, the invention provides the method for preparation compound of the present invention, for example or preparation be used for the method for compound of the present invention, this method comprises makes 4,5,6,7-tetrahydrochysene-thiazole is [5,4-c] pyridine-2-base-amine, for example formula IV compound also:
Wherein X has R defined above
2, R
2` or R
2The implication of `` and R
3, R
4And R
5As defined above,
With suitable sulfonic acid halide for example SULPHURYL CHLORIDE, R wherein for example
1Formula R as defined above
1-SO
2The reaction of the compound of Cl is to obtain compound of the present invention for example or be used for compound of the present invention.
In a preferred embodiment of the invention, compound of the present invention or be used for compound of the present invention can be by the preparation of following step:
A. making wherein, X is tert-butoxycarbonyl and R
3, R
4And R
5Formula IV compound as defined above and R wherein
1Formula R as defined above
1-SO
2The reaction of Cl compound is to obtain wherein R
1, R
3, R
4And R
5As defined above and X be the formula I of tert-butoxycarbonyl or formula II or formula HI compound and
B. the tert-butoxycarbonyl that ruptures, for example by handling, to obtain formula V compound with the HCl diethyl ether solution:
R wherein
1As defined above, for example obtain with salt form example hydrochloric acid salt form,
C. make formula V compound
C1. with the reaction of (replacement) phenyl-fluoride, to obtain wherein R
1As defined above and R
2, R
2` or R
2`` is formula I or the formula II or the formula III compound of (replacement) phenyl, or
C2. with (C
3-6) cycloalkyl (C
1-6) for example carbonyl chloride reaction of alkyl carbonyl halide, to obtain wherein R
1As defined above and R
2, R
2` or R
2`` is (C
3-6) cycloalkyl (C
1-6) the formula I of alkyl-carbonyl or formula II or formula III compound and
D. from reaction mixture, isolate the formula I or the formula III compound that are obtained.
Formula IV and V compound can be used as the intermediate of preparation formula I or formula III compound.Formula IV compound also constitutes a part of the present invention.
On the other hand, the invention provides the compound of formula IV:
Wherein X has R defined above
2The implication of `` for example provides the formula IV compound of salt form example hydrochloric acid salt form, for example as the intermediate of preparation formula III compound.
On the other hand, the invention provides preparation compound of the present invention for example or be used for the method for compound of the present invention, this method comprises makes 4,5,6, and 7-tetrahydrochysene-thiazole is [5,4-c] pyridine-2-base-amine, for example formula VI compound also:
Wherein X has R defined above
2The implication of `,
With sulfonic acid halide for example SULPHURYL CHLORIDE, R wherein for example
1Formula R as defined above
1-SO
2Cl compound reaction is to obtain compound of the present invention for example or be used for compound of the present invention, for example formula I or formula II compound.
The compound of formula VI and VII can be used as the intermediate of preparation formula I or formula II or formula III compound, and also constitutes a part of the present invention.
On the other hand, the invention provides the compound of formula VI:
Wherein X has R defined above
2The implication of ` for example provides the formula VI compound of salt form example hydrochloric acid salt form, for example as the intermediate of preparation formula I or formula II compound.
On the other hand, the invention provides the compound of formula VII:
R wherein
1As defined above, for example provide the formula VII compound of salt form example hydrochloric acid salt form, for example be used as the intermediate of preparation formula I or formula II compound.
Above-mentioned reaction is an acylation reaction, can be carried out suitably, for example in suitable solvent and under suitable temperature, for example according to for example with similar method of ordinary method or as described herein carrying out.
Formula I or formula II or formula III compound can be converted to its sodium-salt form, and for example the nitrogen-atoms of sulfuryl amine group is to have formula I or formula II or the formula III compound of Na as cationic anionic form to obtain wherein for formula I by for example handling free alkali form in EtOH with NaOH or formula II or formula III compound.
Can obtain formula IV compound when suitable, for example, for example under sulphur exists, for example react in the pyridine at polar solvent by piperidone and the cyanamide that N-is replaced according to for example obtaining with the similar method of ordinary method.
When suitable, can prepare any compound as herein described, the intermediate that for example comprises compound of the present invention or be used for compound of the present invention and for example comprise its preparation of formula IV, V, VI or VII, for example according to for example with the similar method of ordinary method, for example or specifically described herein method obtain.
In intermediate of the present invention, if there is functional group, it randomly can be protected form or salt form (if having salt forming group).The optional protecting group that exists can be removed in the suitable stage, for example according to for example being removed with the similar method of ordinary method.
Steroid hormone in the particular organization is relevant with numerous disease, for example for example acne, androgenetic alopecia and hirsutism of the disease of mammary gland, uterine endometrium and tumor of prostate and pilosebaceous unit.The local important as precursors that produces these steroid hormones is a steroid 3-O-sulfuric ester, and it is desulfurized by steoid sulfatase in target tissue.Inhibition to this enzyme causes corresponding active steroid hormone local horizontal to reduce, and estimates that this has the treatment dependency.In addition, the steoid sulfatase inhibitor can be used as immunosuppressor, verified can hypermnesis when it is delivered to brain.
Acne is the multi-pathogenesis disease that the interaction by many factors causes, and described factor is heredity, sebum, hormone and bacterium for example.For acne, most important risk factor is that sebum produces; With physiognomy ratio with healthy skin, the bigger and more sebums of generation of sebiferous gland in nearly all patients with acne.The degree that the growth of sebiferous gland and sebum produce is carried out hormone control by androgens; Therefore, androgens is brought into play keying action in the pathogenesis of acne.In the male sex, have two main sources to supply androgens to target tissue: (i) secrete the sexual gland of testosterone, (ii) produce the suprarenal gland of dehydroepiandrosterone (DHEA), dehydroepiandrosterone is secreted with sulfuric ester conjugates (DHEAS) form.Testosterone and DHEAS for example all are converted to the active male sex hormone-dihydrotestosterone of tool (DHT) at target tissue in skin.Evidence suggests that and directly provide the active androgens class to compare, the local synthetic paths of these DHT in the skin are even more important from circulation.Therefore, the endogenous male sex hormone level that reduces in the target tissue with specific inhibitor should have the treatment benefit to acne and stearrhea.In addition, it has been opened and has regulated local androgens level by topical therapeutic but not influence the prospect that the circulating hormone level is treated these diseases by systemic treatment.
Usually see by right and wrong in white people for male sex's androgenetic alopecia, accounts for about 95% of all types of alopecias.Male pattern alopecia is by the hair follicle quantity increase that enters telogen in the scalp with by elongated causing of time length telogen.It is the hair forfeiture that determines in the heredity that realizes by androgens.It is reported, compare, in the male sex of alopecia, have the serum DHEA of rising still normal testosterone levels to be arranged, hinted that the generation of the male sex hormone in the target tissue is very important in androgenetic alopecia with non-alopecia contrast.
Hirsutism is that the pathologic of hair thickens and density, it is characterized in that the male pattern of children and women's hair growth.Hirsutism form to increase by androgens or androgenic susceptibility is increased and is brought out by male sex hormone by hair follicle.Therefore, the treatment that causes middle endogenous androgens of target tissue (skin) and/or estrogens level to reduce should be effective to acne, androgenetic alopecia and hirsutism.
As mentioned above, the active male sex hormone of tool of DHT-is synthetic by competent general precursor DHEAS in skin, and the first step is by steoid sulfatase the DHEAS desulfurization to be produced DHEA in the metabolic pathway from DHEAS to DHT.The existing description claims to exist this enzyme in keratinocyte and skin deutero-inoblast.For example oestrone 3-O-sulfamate and 4-methylcoumarin-7-base (umbelliferyl)-O-sulfamate have been proved conclusively the potential use that steoid sulfatase is used for reducing skin endogenous steroid hormone level to utilize known steoid sulfatase inhibitor.The inhibitor that we have found that the placenta steoid sulfatase also suppresses the steoid sulfatase by people's keratinocyte (HaCaT) or human skin deutero-fibroblast (1BR3GN) preparation.Prove that also described inhibitor can block the steoid sulfatase in the complete individual layer HaCaT keratinocyte.
Therefore, the inhibitor of steoid sulfatase can be used for reducing male sex hormone and the estrogen level in the skin.The inhibitor that they can be used as steoid sulfatase comes the androgen-dependent disorders (for example acne, stearrhea, androgenetic alopecia, hirsutism) and the topical therapeutic squamous cell carcinoma of topical therapeutic pilosebaceous unit.
In addition, estimate that on-steroidal sex steroid sulfatase inhibiting agent can be used for treating the disease by the effect mediation of steroid hormone, wherein sulfatase splitted steroid product plays a role.The indication of these new inhibitors comprises the androgen-dependent disorders (for example acne, stearrhea, androgenetic alopecia, hirsutism) of pilosebaceous unit; Oestrogenic hormon-or male sex hormone-dependent tumors, for example squamous cell carcinoma and knurl, for example mammary gland, uterine endometrium and prostatic squamous cell carcinoma and knurl; Inflammatory diseases and autoimmune disorder, for example organ rejection response after rheumatoid arthritis, I type and type ii diabetes, systemic lupus erythematous, multiple sclerosis, myasthenia gravis, thyroiditis, vasculitis, ulcerative colitis and regional ileitis, psoriatic, contact dermatitis, graft versus host disease (GVH disease), eczema, asthma and the transplanting.The steoid sulfatase inhibitor also can be used for treating cancer, in particular for treatment oestrogenic hormon-and male sex hormone-dependence cancer, for example mammary cancer, carcinoma of endometrium and squamous cell carcinoma and prostate cancer.The steoid sulfatase inhibitor also can be used to strengthen cognitive function by the DHEAS level that increases in the central nervous system, in particular for the treatment senile dementia, comprises alzheimer's disease.
Compound can confirm in following pilot system in the activity aspect the inhibition steoid sulfatase activity:
The purifying of human steroid sulfatase
Giving a birth and separating the fresh acquisition people placenta in back with reticular tissue with film.In order to store, this material is chilled under-70 ℃.After thawing, all further steps all carry out under 4 ℃, regulate the pH value down at 20 ℃ simultaneously.400g should be organized in 1.2 liters of buffer A (50mM Tris-HCl, pH7.4,0.25M sucrose) homogenize.With the homogenate that obtains under 10,000 * g centrifugal 45 minutes.The taking-up supernatant liquor retains and the throw out that obtains is homogenized in the 500ml buffer A again.After centrifugal, two supernatant liquors that obtain are merged and carry out ultracentrifugation (100,000 * g, 1 hour).Be resuspended in the buffer A throw out that obtains and repeated centrifugation.The throw out that obtains is suspended among the 50mM Tris-HCl of 50ml pH7.4, and is stored under-20 ℃ until further handling.
After thawing, collect microsome and it is suspended in the 50ml buffer B (10mM Tris-HCl, pH 7.0,1mM EDTA, the 2mM 2 mercapto ethanol, 1% TritonX-100,0.1% presses down the enzyme peptide) by ultracentrifugation (as mentioned above).In mild stirring on ice after 1 hour, with suspension centrifugal (100,000 * g, 1 hour).Collection contains the supernatant liquor of enzymic activity and with 1M Tris pH is adjusted to 8.0.The solution that obtains is carried in hydroxyapatite column, and (2.6 * 20cm) go up and with the buffer B balance of pH 8.0.Post is washed with the flow velocity of buffer B with 2ml/ minute.In flowing, reclaim active.To merge thing is adjusted to pH 7.4 and is that equilibrated concanavalin A agarose column among the damping fluid C (20mM Tris-HCl, pH 7.4,0.1% TritonX-100,0.5M NaCl) (separate by 1.6 * 10cm) enterprising circumstances in which people get things ready for a trip spectrums.With damping fluid C flushing post, and with the albumen of 10% the methyl mannoside elution of bound in damping fluid C.Dialyse with the active fraction merging and with damping fluid D (20mM Tris-HCl, pH8.0,1mM EDTA, 0.1%Triton X-100,10% glycerine (v/v)).
The retentate that obtains is carried in (on 0.8 * 10cm), the flushing post also carries out wash-out with the linear gradient of the NaCl in damping fluid D of damping fluid D to 2M with the blue agarose column of damping fluid D equilibrated.Active fraction is merged, concentrate (Centricon 10) as required, be stored under-20 ℃ with damping fluid D dialysis and with aliquot.
The analysis of human steroid sulfatase
The human steroid sulfatase of known purifying not only can cracking steroid sulfuric ester, and cracking aromatic yl acid ester 4-methylcoumarin-7-base sulfuric ester for example easily, and it is used as active indicator in this pilot system.By preparing analysis of mixtures in the hole that in proper order following solution is added white microtiter plate:
1) 50 μ l substrate solutions (at 0.1M Tris-HCl, the 1.5mM 4-methylcoumarin among the pH 7.5-7-base sulfuric ester)
2) 50 μ l test compounds are at 0.1M Tris-HCl pH 7.5, (the stock solution of preparation test compound in DMSO of the diluent among the 0.1%Triton X-100; The ultimate density of solvent is no more than 1% in analysis of mixtures)
3) 50 μ l enzyme diluents (about 12 unit of enzyme/ml)
We are defined as when the initial substrate concentration 500 μ M under 37 ℃ a unit of enzyme at 0.1MTris-HCl, and pH 7.5, the amount of the steoid sulfatase of hydrolysis 1nmol 4-methylcoumarin-7-base sulfuric ester per hour among the 0.1%Triton X-100.
With plate 37 ℃ of following incubations 1 hour.Then by adding 100 μ l 0.2M NaOH stopped reaction.In Titertek Fluoroskan II instrument, use λ
Ex=355nm and λ
Em=460nm measures fluorescence intensity.
Relative IC
50The calculating of value
Calculate the concentration (IC of 50% inhibitory enzyme activity in order to the fluorescence intensity data (I) of acquisition under the different concns (c) of test compound during equation is analyzed by above-mentioned human steroid sulfatase down
50):
I wherein
100Be that observed intensity and s are not slope factors when having inhibitor.As reference compound, measure its IC abreast with the oestrone sulfamate with all other test compounds
50Value.Relative IC
50Value is defined as follows:
According to our test and calculating, the IC of oestrone sulfamate
50Value is about 60nM.
The compound of the present invention that is used for that comprises compound of the present invention all demonstrates activity in described analysis.
CHO/STS analyzes
Microtiter plate is gone in Chinese hamster ovary celI (CHO/STS) inoculation of personnel selection steoid sulfatase stable transfection.Reach about 90% merge after, with they being incubated overnight with gradient concentration for trying material (compound for example of the present invention or be used for compound of the present invention).Then they are at room temperature fixed 10 minutes with 4% Paraformaldehyde 96 and, before with 100 μ l/ hole 0.5mM 4-methylcoumarins-7-base sulfuric ester (MUS) incubation, it is dissolved in 0.1M Tris-HCl, among the pH 7.5 with PBS washing 4 times.Under 37 ℃, carry out enzyme reaction 30 minutes.Every then hole add 50 μ l stop buffers (1M Tris-HCl, pH10.4).With enzyme reaction solution be transferred to white plate (Microfluor, Dynex, Chantilly, VA) in and read reading in the plate device in Fluoroskan II fluorescence micro titer plate.From all values, deduct reagent blank.For drug test, use flat fluorescent (FU) divided by cell protein being used sulforhodamine B (OD
550) optical density readings after the dyeing is so that proofread and correct the cell count deviation.Measure IC by the linear interpolation method between two scaling points (bracketing point)
50Value.In each of carrying out with inhibitor analyzed, with oestrone 3-O-sulfamate as reference compound, and with oestrone 3-O-sulfamate with IC
50Marking of value (relative IC
50=IC
50Compound/IC
50Oestrone 3-O-sulfamate).
The compound of the present invention that is used for that comprises compound of the present invention all demonstrates activity in described analysis.
The analysis of carrying out with human skin homogenate
Cut refrigerated people corpse skin samples (the about 100mg of each sample) into pieces (about 1 * 1mm) with sharp scissors.The small pieces that obtain are suspended in the damping fluid (20mM Tris-HCl, pH 7.5) that 10 volumes (w/w) contain 0.1%Triton X-100.Adding is by the test compound of the gradient concentration of the stock solution in ethanol or DMSO preparation (compound for example of the present invention or be used for compound of the present invention).The second, add DHEAS (1 μ C/ml[as substrate
3H] DHEAS, specific activity: about 60Ci/mmol and the unlabelled DHEAS of 20 μ M).With sample 37 ℃ of following incubations 18 hours.When incubation period finishes, add 50 μ l 1M Tris, pH 10.4 and 3ml toluene.Take out the organic phase of 1ml aliquots containig and it is carried out liquid scintillation counting(LSC).The dpm-value that to measure in aliquots containig per hour changes into the nmol number of every gram skin cracked DHEA.
The compound of the present invention that is used for that comprises compound of the present invention all demonstrates activity in described analysis.
The compound of the present invention that is used for that comprises compound of the present invention all demonstrates activity in experimental system defined above.The compound exhibits of the present invention that is used for that comprises compound of the present invention of salt and/or solvate form thereof goes out with the compound of the present invention of free form and/or non-solvent compound form or is used for the activity of compound same levels of the present invention.
Therefore, the disease that compound of the present invention is adapted at treating by the effect mediation of steoid sulfatase that is used for that comprises compound of the present invention is used as the steoid sulfatase inhibitor, described disease for example comprises the androgen-dependent disorders of pilosebaceous unit, as
-acne,
-stearrhea,
-androgenetic alopecia,
Hirsutism;
-cancer, for example oestrogenic hormon and male sex hormone-dependence cancer;
-cognition dysfunction for example comprises the senile dementia of alzheimer's disease.
The compound of the present invention that is used for that comprises compound of the present invention is preferred for treating acne, stearrhea, androgenetic alopecia, hirsutism; Oestrogenic hormon for example and androgen-dependent-cancer more preferably is used for the treatment of acne.Described treatment comprises therapeutic treatment and prevention.
The compound of embodiment 1 is a preferred compound of the present invention.
For example, after measured the compound of embodiment 1 in the analysis of carrying out with human skin homogenate as herein described, demonstrate the IC of 160nm
50
On the other hand, the invention provides formula II or the formula III compound that for example in the disease of treatment, is used as medicine by the effect mediation of steoid sulfatase.
On the other hand, the invention provides treatment and for example treat acne, stearrhea, androgenetic alopecia, hirsutism by the disease of the effect mediation of steoid sulfatase; Oestrogenic hormon for example and the method for male sex hormone-dependence cancer, this method comprise to the thiazole of the present invention of the individual administering therapeutic significant quantity of this treatment of needs also-pyridine-aryl sulfonic acid amides, for example comprise formula I or formula II or formula III compound.
For described purposes, the dosage of use certainly changes according to for example used particular compound, method of application and required treatment.Yet, generally speaking, if with the per daily dose administered compound of about 0.1mg/kg to about 100mg/kg the weight of animals (for example about 0.0625mg/kg extremely about 62.5mg/kg), for example easily with every day 2 to 4 times divided dose use, then can obtain gratifying result.For the big Mammals of major part, total per daily dose is extremely about 5000mg of about 5mg, can be easily for example to be no more than 4 times divided dose every day or to use with the delay form.Unit dosage form comprises for example about 1.25mg to about 2000mg compound of the present invention and at least a pharmaceutically acceptable vehicle of blended, for example carrier, thinner with it.
The compound of the present invention that is used for that comprises compound of the present invention can be with pharmaceutical acceptable salt for example with acid salt or metal-salt; Or with free form; Randomly use with solvate form thereof.
Comprise being used for compound of the present invention and can using of compound of the present invention in the mode similar to the known standard thing that is used for described indication.Compound of the present invention or be used for compound of the present invention can with for example pharmaceutically useful vehicle of routine for example carrier and thinner and randomly other vehicle mix mutually.Comprise being used for compound of the present invention and can for example using by following approach of compound of the present invention with pharmaceutical compositions:
-Orally administered, for example Orally administered with tablet, Capsule form;
-parenteral, intravenously are used, and for example use with liquid form such as solution, suspension form parenteral, intravenously;
-topical application is for example with ointment, the topical application of ointment form.
The concentration of active substance certainly for example changes according to used compound, required treatment and the character of compositions for use in the pharmaceutical composition.Generally speaking, in topical compositions, to the concentration of about 90%w/w, can obtain gratifying result with about 1%w/w with about 0.05 to about 5% for example about concentration of 0.1 to about 1%w/w with in oral, parenteral or intravenously composition.
On the other hand, the invention provides the pharmaceutical composition of compound at least a of the present invention that comprises pharmacy effective dose and at least a pharmaceutically acceptable vehicle that makes up with it.
Pharmaceutical composition of the present invention can comprise one or more compounds of the present invention, for example at least a compound of the present invention is as activeconstituents.
Except at least a compound of the present invention, pharmaceutical composition of the present invention can also comprise one or more other forms of pharmacologically active agents.Described other forms of pharmacologically active agents comprises for example retinene derivative, and vitamin A acid for example is as isotretinoin; Vitamin A acid (Roche); Adapalene (6-[3-(1-adamantyl)-4-p-methoxy-phenyl]-the 2-naphthoic acid); Oral contraceptive, it is pregnant-1,3 that for example 19-removes first-17a-, 5 (10)-triolefins-20-alkynes-3,17-glycol, 6-chloro-17-hydroxyl-1a, 2a-methylene radical-4,6-pregnant diene-3, the 20-diketone, as
(Schering), antimicrobial drug as erythromycin, comprises Erythromycin A, Azythromycin, clarithromycin, Roxithromycin; Tetracyclines, lincosamide-microbiotic, as clindamycin (methyl 7-chloro-6,7,8-three deoxidations-6-(anti-form-1-methyl-4-propyl group-L-2-tetramethyleneimine-formamido group)-1-sulfo--L-Soviet Union-a-D-gala-Xin pyranoside (octopyranosid)), nonane diacid (nonane diacid), that husky star in ground; Dapsone, benzoyl peroxide; Keratolytic agent is as Whitfield's ointment; Anti-inflammatory agent is as reflunomide, pimecrolimus; The steroid 5 inhibitor.
For treatment mammary cancer and carcinoma of endometrium, other forms of pharmacologically active agents comprises aromatase inhibitor, as Anastrozole, letrozole, Exemestane.
Combination comprises
-fixed combination, wherein two or more forms of pharmacologically active agents in same pharmaceutical composition,
-medicine box, wherein two or more forms of pharmacologically active agents of independent composition forms are sold in same packing, for example contain the specification sheets of using jointly; With
-independent assortment, wherein forms of pharmacologically active agents is packed separately, but provides the specification sheets of while or sequential application.
On the other hand, the invention provides compound of the present invention or be used for compound of the present invention and at least a other pharmaceutically effectively combination of promoting agent, as comprise at least a compound of the present invention or be used for compound of the present invention and at least a other the pharmaceutically combination of effective promoting agent and pharmaceutical composition of at least a pharmaceutically acceptable vehicle as medicine.
On the other hand, the invention provides formula I
P1Compound:
Wherein:
R
1P1Be (C
6-18) aryl, and
R
2P1Be (C
1-12) alkoxy carbonyl, or phenyl unsubstituted or that replace, for example by one or more phenyl that are selected from following group replacement:
-aminocarboxyl,
-halogen,
-(C
1-6) haloalkyl.
On the other hand, the invention provides formula I
P2Compound:
Wherein:
R
1Be (C
6-18) aryl, and
R
2Be (C
1-12) alkoxy carbonyl, (C
1-4) alkyl-carbonyl or phenyl unsubstituted or that replace, for example phenyl that is replaced by one or more following groups:
-aminocarboxyl,
-halogen,
-(C
1-6) haloalkyl.
Be used for illustrating following examples of the present invention, mentioned temperature is degree centigrade and is not calibrated.
Used following shortenings:
The BOC tert-butoxycarbonyl
The c-Hex hexalin
The DMSO methyl-sulphoxide
DMAP N, the N-dimethyl aminopyridine
The DIEA diisopropyl ethyl amine
The EtAc ethyl acetate
EtOH ethanol
M.p. fusing point
The RT room temperature
Embodiment 1
2-[2-(3,5-couple-trifluoromethyl-phenylsulfonamido)-6,7-dihydro-4H-thiazole is [5,4-c] pyridine-5-yl also]-4-trifluoromethyl-benzamide
A. free alkali
With 3.3g 2-(3,5-couple-trifluoromethyl-phenylsulfonamido)-4,5,6,7-tetrahydrochysene-thiazole is [5,4-c] pyridine-5-hydrochloride, 1.545g 2-fluoro-4-trifluoromethyl-benzamide and 3.3g K also
2CO
3In DMSO, heated 5 hours down in 150 ℃.From the gained mixture, steam and desolventize, the evaporation residue of gained is dissolved among the EtAc/MeOH (9/1) and with HCl and the salt solution extraction gained mixture of 50ml 1M.Obtain two-phase and it is separated, the organic layer that the concentrates gained circumstances in which people get things ready for a trip spectrum of going forward side by side is separated.Obtain 2-[2-(3,5-couple-trifluoromethyl-phenylsulfonamido)-6,7-dihydro-4H-thiazole is [5,4-c] pyridine-5-yl also]-4-trifluoromethyl-benzamide, use the EtAc recrystallization.
Fusing point: 225-228 ℃;
1H-NMR/CD
3OD:8.35 (s, 2H), 8.03 (s, 1H), 7.92 (d, J=8.0Hz, 1H), 7.40 (dd, J=8.0,1.1Hz, 1H), 7.35 (s, 1H), 4.06 (t, J=1.8Hz, 2H), 3.44 (t, J=5.6Hz, 2H), 2.69 (m, 2H);
13C-NMR/CD
3OD:168.83,149.35,144.47,133.37,133.11,131.99,131.72,131.08,130.83,126.07,124.89,123.27,119.90,116.27,116.24,113.20,49.44,47.90,22.76.
B. sodium salt
The NaOH aqueous solution of 1.9ml 0.1M is added 118mg 2-[2-(3,5-pair-trifluoromethyl-phenylsulfonamido)-6,7-dihydro-4H-thiazole is [5,4-c] pyridine-5-yl also]-solution of 4-trifluoromethyl-benzamide in 10ml EtOH in, the gained mixture was at room temperature stirred 5 minutes.From the gained mixture, steam and desolventize the also evaporation residue of lyophilize gained.Obtain [2-(3,5-couple-trifluoromethyl-phenylsulfonamido)-6,7-dihydro-4H-thiazole is [5,4-c] pyridine-5-yl also]-4-trifluoromethyl-benzamide sodium salt.
Be similar to the method described in the embodiment 1A, but use suitable starting raw material, obtained the compound of formula EX1:
R wherein
1As defined in Table 1.
1H-NMR and
13The C-NMR data also provide in table 1.
Table 1
Embodiment 4
2-(3,5-couple-trifluoromethyl-phenylsulfonamido)-6,7-dihydro-4H-thiazole is [5,4-c] pyridine-5-t-butyl formate also
With 8.5g 2-amino-6,7-dihydro-4H-thiazole is [5,4-c] pyridine-5-t-butyl formate, 15.6g3 also, and 5-pair-trifluoromethyl-benzene sulfonyl chloride and the mixture of 8.1g DMAP in the 100ml pyridine stirred 4 hours down at 80 ℃.From the gained mixture, steam and desolventize, handle the evaporation residue of gained and use NaHSO with EtAc
4The aqueous solution and salt solution extraction gained mixture.With gained organic layer drying, from gained solution, steam and desolventize and with EtAc and c-Hex mixture (+5%MeOH) processing gained resistates.With 2-(3,5-couple-trifluoromethyl-phenylsulfonamido)-6,7-dihydro-4H-thiazole also [5,4-c] pyridine-5-t-butyl formate throw out leaches and is dry.
Be similar to the method described in the embodiment 4, but use suitable starting raw material, obtained the compound of formula EX2:
R wherein
1As defined in Table 2:
1H-NMR and
13The C-NMR data also provide in table 2.
Table 2
Embodiment 7
Be similar to the method described in the embodiment 4, but use suitable starting raw material, obtained the compound of following formula:
13C-NMR：133.04，132.70，132.36，129.39，127.24，126.09，124.33，121.61，81.24，52.70，51.50，32.30，28.64。
Embodiment 8
N-[5-(2-cyclopentyl-ethanoyl)-4,5,6,7-tetrahydrochysene-thiazole be [5,4-c] pyridine-2-yl also]-3,5-pair-trifluoromethyl-benzsulfamide
Under 0 ℃, DIEA and cyclopentyl Acetyl Chloride 98Min. added 75mg 2-(3,5-is two-trifluoromethyl-phenylsulfonamido)-4,5,6,7-tetrahydrochysene-thiazole also [5,4-c] pyridine-5-hydrochloride at CH
2Cl
2In mixture in.The gained mixture was at room temperature stirred 4 hours, add the NaHSO of 2ml 1M
4The aqueous solution also separates the two-phase that forms.The gained organic layer is concentrated and is prepared HPLC (RP-18).Obtain N-[5-(2-cyclopentyl-ethanoyl)-4,5,6,7-tetrahydrochysene-thiazole is [5,4-c] pyridine-2-yl also]-3,5-pair-trifluoromethyl-benzsulfamide.
1H-NMR/CDCl
3(2 kinds of rotational isomers): 12.3 (bs, 1H), 8.28 (s, 2H), 7.92 (s, 1H), 4.44 (s, 1.2H), 4.32 (s, 0.8H), 3.79 (t, J=5.5Hz, 0.8H), 3.16 (t, J=5.6Hz, 1.2H), 2.55 (m, 1.2H), 2.48 (m, 0.8H), 2.32 (t, J=6.3Hz, 1.2H), 2.17 (m, 1H), 1.78 (m, 2H), 1.52 (m, 4H), 1.07 (m, 2H);
13C-NMR/CDCl
3: 172.12,168.95,145.48,132.84,132.50,129.85,127.03,125.64,124.40,121.68,114.06,43.27,42.49,40.41,40.18,39.69,38.65,36.90,33.08,25.28,24.44,23.37.
The preparation of starting raw material
S1.2-amino-6,7-dihydro-4H-thiazole also [5,4-c] pyridine-5-t-butyl formate (wherein Y is the formula IV of tert-butoxycarbonyl
ACompound)
19.9g 1-BOC-piperidin-4-one-, 8.4g cyanamide and the mixture of 6.4g sulphur in the 100ml pyridine were refluxed 100 minutes under inert atmosphere.Steaming desolventizes and the gained evaporation residue is carried out flash chromatography at silica gel from the gained mixture.Obtain 2-amino-6,7-dihydro-4H-thiazole is [5,4-c] pyridine-5-t-butyl formate also.
1H-NMR/CDCl
3/d
6-DMSO：5.95(bs，2H)，4.39(s，2H)，3.67(t，J＝5.2Hz，2H)，3.08(bs，2H)，1.43(s，9H)；
13C-NMR/CDCl
3/d
6-DMSO：166.17，153.87，79.19，28.86，27.69，26.01。
Be similar to the method described in the embodiment S1, but use suitable starting raw material, prepared the compound among embodiment S2 and the S3:
S2.4-amino-3-thia-5,11-diaza-three ring [6.2.1.0
*2,6
*] 11 carbon-2 (6), 4-diene-11-t-butyl formate
13C-NMR：80.24，53.09，52.67，36.70，36.19，28.78。
S3.2-(3,5-is two-trifluoromethyl-phenylsulfonamido)-4,5,6,7-tetrahydrochysene-thiazole be [5,4-c] pyridine-5-hydrochloride (R wherein also
1Be 3, the formula V compound of 5-trifluoromethylbenzene)
Hydrochloric acid diethyl ether solution that 50ml is saturated adds 9.95g 2-(3,5-is two-trifluoromethyl-phenylsulfonamido)-6,7-dihydro-4H-thiazole also [5,4-c] pyridine-5-t-butyl formate at 150ml CH
2Cl
2In solution in and the gained mixture at room temperature stirred 4 hours.From the gained mixture, steam the evaporation residue that desolventizes and handle gained with ether.Solid sediment is leached and drying.Obtain 2-(3,5-couple-trifluoromethyl-phenylsulfonamido)-4,5,6,7-tetrahydrochysene-thiazole is [5,4-c] pyridine-5-hydrochloride also.
1H-NMR/CDCl
3/d
6-DMSO：13.30(bs，1H)，9.86(bs，2H)，8.43(s，2H)，8.29(s，1H)，4.04(s，2H)，3.21(t，J＝5.8Hz，2H)，2.70(t，J＝5.7Hz，2H)；
13C-NMR/CDCl
3/d
6-DMSO：168.35，145.15，132.17，131.83，131.50，131.17，130.20，127.02，126.66，126.47，124.31，121.59，118.87，109.47，20.30。
Be similar to described in the embodiment S3, but use suitable starting raw material, obtained the compound among embodiment S4 and the S5:
S4.2-(2,3-two chloro-phenylsulfonamido)-4,5,6,7-tetrahydrochysene-thiazole be [5,4-c] pyridine-5-hydrochloride (R wherein also
1Be 2, the formula V compound of 3-dichlorophenyl)
13C-NMR：168.03，141.31，134.17，134.06，129.33，129.23，128.56，128.33，108.80，19.95。
S5.2-(3,5-two chloro-phenylsulfonamido)-4,5,6,7-tetrahydrochysene-thiazole be [5,4-c] pyridine-5-hydrochloride (R wherein also
1Be 3, the formula V compound of 5-dichlorophenyl)
13C-NMR：168.03，141.31，134.17，134.06，129.33，129.23，128.56，128.33，108.80，19.95。
Claims (7)
1. the compound of formula I:
Wherein:
A)
R
1It is unsubstituted phenyl or by aminocarboxyl, halogen or halo C
1-6The phenyl that alkyl replaces,
R
2Be C
1-12Alkoxy carbonyl, C
1-6Alkyl-carbonyl, C
3-6Cycloalkyl C
1-6Alkyl-carbonyl or unsubstituted phenyl or by aminocarboxyl, halogen or halo C
1-6The phenyl that alkyl replaces, and
R
3And R
5Be C together
1-4Alkylidene group and R
4Be hydrogen; Perhaps
B)
R
1It is unsubstituted phenyl or by aminocarboxyl, halogen or halo C
1-6The phenyl that alkyl replaces,
R
2Be C
1-12Alkoxy carbonyl, C
3-6Cycloalkyl C
1-6Alkyl-carbonyl, unsubstituted phenyl or by aminocarboxyl, halogen or halo C
1-6The phenyl that alkyl replaces, and
R
3, R
4And R
5Be hydrogen.
2. the compound of claim 1, it is N-(3-thia-5,11-diaza-three ring [6.2.1.0
*2,6
*] 11 carbon-2 (6), 4-diene-4-yl)-benzsulfamide
Or be selected from following compound:
-2-[2-(3,5-couple-trifluoromethyl-phenylsulfonamido)-6,7-dihydro-4H-thiazole is [5,4-c] pyridine-5-yl also]-4-trifluoromethyl-benzamide,
-2-[2-(2,3-two chloro-phenylsulfonamido)-6,7-dihydro-4H-thiazole is [5,4-c] pyridine-5-yl also]-4-trifluoromethyl-benzamide,
-2-[2-(3,5-two chloro-phenylsulfonamido)-6,7-dihydro-4H-thiazole is [5,4-c] pyridine-5-yl also]-4-trifluoromethyl-benzamide,
-2-(3,5-couple-trifluoromethyl-phenylsulfonamido)-6,7-dihydro-4H-thiazole is [5,4-c] pyridine-5-t-butyl formate also,
-2-(2,3-two chloro-phenylsulfonamido)-6,7-dihydro-4H-thiazole is [5,4-c] pyridine-5-t-butyl formate also,
-2-(3,5-two chloro-phenylsulfonamido)-6,7-dihydro-4H-thiazole also [5,4-c] pyridine-5-t-butyl formate and
-N-[5-(2-cyclopentyl-ethanoyl)-4,5,6,7-tetrahydrochysene-thiazole be [5,4-c] pyridine-2-yl also]-3,5-pair-trifluoromethyl-benzsulfamide.
3. the compound of the following formula of claim 1:
4. the compound of each salt form in the claim 1 to 3.
5. each compound is used for the treatment of by the purposes in the medicine of the disease of the effect of steoid sulfatase mediation in preparation in the claim 1 to 4.
6. comprise at least a claim 1 to 4 of pharmacy effective dose each the compound and the pharmaceutical composition of at least a pharmaceutically acceptable vehicle.
7. the compound of formula VI:
Wherein X has claim 1 A) in defined R
2Implication, perhaps
The compound of formula VII:
R wherein
1As defined in claim 1.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3533331A1 (en) * | 1985-09-18 | 1987-03-26 | Heumann Ludwig & Co Gmbh | Pyridothiazole derivatives, process for their preparation, and medicaments containing these compounds |
| WO2001090094A1 (en) * | 2000-05-22 | 2001-11-29 | Biovitrum Ab | Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1 |
-
2002
- 2002-11-14 GB GB0226602A patent/GB0226602D0/en not_active Ceased
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2003
- 2003-11-13 CN CNB2003801029331A patent/CN100432077C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3533331A1 (en) * | 1985-09-18 | 1987-03-26 | Heumann Ludwig & Co Gmbh | Pyridothiazole derivatives, process for their preparation, and medicaments containing these compounds |
| WO2001090094A1 (en) * | 2000-05-22 | 2001-11-29 | Biovitrum Ab | Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1 |
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