CN101583608A - Chromene S1P1 receptor antagonist - Google Patents
Chromene S1P1 receptor antagonist Download PDFInfo
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- CN101583608A CN101583608A CNA2008800025942A CN200880002594A CN101583608A CN 101583608 A CN101583608 A CN 101583608A CN A2008800025942 A CNA2008800025942 A CN A2008800025942A CN 200880002594 A CN200880002594 A CN 200880002594A CN 101583608 A CN101583608 A CN 101583608A
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- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 125000002345 steroid group Chemical group 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000004114 suspension culture Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 229960000235 temsirolimus Drugs 0.000 description 1
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical group CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000005891 transamination reaction Methods 0.000 description 1
- TUCIOBMMDDOEMM-RIYZIHGNSA-N tyrphostin B42 Chemical compound C1=C(O)C(O)=CC=C1\C=C(/C#N)C(=O)NCC1=CC=CC=C1 TUCIOBMMDDOEMM-RIYZIHGNSA-N 0.000 description 1
- HIYSWASSDOXZLC-HKOYGPOVSA-N undecylprodigiosin Chemical compound N1C(CCCCCCCCCCC)=CC=C1\C=C\1C(OC)=CC(C=2NC=CC=2)=N/1 HIYSWASSDOXZLC-HKOYGPOVSA-N 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 229950009819 zotarolimus Drugs 0.000 description 1
- CGTADGCBEXYWNE-JUKNQOCSSA-N zotarolimus Chemical compound N1([C@H]2CC[C@@H](C[C@@H](C)[C@H]3OC(=O)[C@@H]4CCCCN4C(=O)C(=O)[C@@]4(O)[C@H](C)CC[C@H](O4)C[C@@H](/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C3)OC)C[C@H]2OC)C=NN=N1 CGTADGCBEXYWNE-JUKNQOCSSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A compound of formula (I) wherein R1, R2, R3 and R4 are as defined in the specification, processes for their production, their uses, in particular in transplantation, and pharmaceutical compositions containing them.
Description
The present invention relates to the polycyclic compound, they the preparation method, they are as the purposes of medicine and the pharmaceutical composition that comprises them.
More specifically, in first aspect, the invention provides hydrolyzable derivative, its salt, hydrate and/or solvate on formula I compound or its physiology:
Wherein
R
1And R
2Be selected from following group independently of one another: hydrogen; Halogen; Nitro; The optional C that replaces
1-8Alkyl is (for example by aryl, C
3-6Cycloalkyl or C
1-8Alkoxyl group replaces); The optional halo C that replaces
1-8Alkyl; The optional C that replaces
1-8Alkoxyl group is (for example by C
1-8Alkoxyl group, C
3-8Cycloalkyl, aryl replace); The optional halo C that replaces
1-8Alkoxyl group;
R
3For comprising the saturated heterocyclic of at least one ring N atom, and it passes through R
3Ring C atom is connected with ring A, this ring carbon atom or any other ring C atom is chosen wantonly and is substituted (for example by halogen, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkyl C
1-6Alkoxyl group replaces); And
R
3On 3 or 4 of described ring A, preferably on 4;
R
4Be hydrogen; Hydroxyl; Halogen; Halo C
1-8Alkyl; The optional C that replaces
1-6Alkyl; C
1-6Alkoxyl group; Or halo C
1-6Alkoxyl group; And
R
4On 2 (ortho positions) or 3 (position).
Halogen can be fluorine, chlorine or bromine, preferred fluorine or chlorine.
As group or the alkyl that exists in group or alkoxyl group can be straight or branched.Alkylidene group can be a straight or branched.
As group or the alkyl that exists in group can be substituted, is for example replaced by hydroxyl, halogen, alkoxyl group.
As group or the alkoxyl group that exists in group can be substituted, is for example replaced by hydroxyl.
When alkyl or alkoxyl group were replaced by hydroxyl, then hydroxyl was preferably at the terminal position of alkyl or alkoxyl group.
Alkenyl can for example be replaced by alkyl, hydroxyl.
As herein defined haloalkyl and halogenated alkoxy refer to respectively by 1 to 5 halogen replace as group or alkyl that in group, exists and alkoxyl group, for example CF
3-, CHF
2-, CH
2F-or CF
3-CH
2-O-, CHF
2-CH
2-O-, CH
2F-CH
2-O-.
Haloalkyl and halogenated alkoxy can for example be replaced by hydroxyl.
Aryl can be a phenyl or naphthyl arbitrarily, preferred phenyl.
As group or the C that in group, exists
3-8Cycloalkyl, for example R
1, R
2, be meant three to eight yuan, preferred five do not comprise the heteroatoms non-aromatic ring to heptatomic.
R preferably
3Be following formula (Ia)
Wherein X is selected from N, O, C and S atom.
R preferably
3Be three to eight yuan of saturated heterocyclics as shown in the formula (Ib)
Wherein X is selected from NR, O, CH
2With the S atom, wherein
R and R ' are H or C independently of one another
1-4Alkyl, and
Wherein said R
3Link to each other by any carbon atom in formula (Ib) ring of band hydrogen atom with the described A ring in the formula (I), this hydrogen is replaced by described connection then.
In formula (Ib), described variable can be independently, jointly or its arbitrary combination ground have following preferred implication:
R is H, methyl or ethyl;
R ' is H or methyl;
X is selected from NR, O and CH
2, wherein R is H or C
1-4Alkyl or more preferably be H, methyl or ethyl;
The residue of formula (Ib) can be a chirality, and for example R-or S-enantiomorph perhaps can be its racemic mixtures.
The present invention relates to the metabolite of formula (I) compound on the other hand, for example R wherein
3Be formula (Ic) or (Id) formula of residue (I) compound
Wherein X is selected from O and S atom,
R is H or C
1-4Alkyl, and
The wave key table shows R-or S-enantiomorph or its mixture.
For example, R
3Preferably be selected from N, O and S heteroatomic three to eight yuan for comprising 1 or 2, be preferably five to eight yuan of saturated heterocyclics.Those skilled in the art are to be understood that the size when ring is five to eight atomic time, usually can have 2 heteroatomss in the heterocycle.Therefore three and/or the quaternary heterocycle in usually have no more than 1 heteroatoms.
On the other hand, R
3Pass through R
3Ring C atom with the ring A link to each other, make it at R
3Ring N atom (perhaps R
3A plurality of ring N atoms in one) an ortho position or a position.
Preferred R
3Be selected from morpholinyl, 2-morpholinyl, 2-piperazinyl, 2-piperidyl, 3-piperidyl, 3-thio-morpholinyl, 2-thio-morpholinyl, 2-pyrrolidyl and 3-pyrrolidyl.
R randomly
3For substituted.Work as R
3When substituted, it can be substituted on one or more ring carbon atoms and/or the theheterocyclic nitrogen atom when existing.Substituent example on the ring carbon atom comprises for example C
1-4Alkyl, C
1-6Alkoxyl group, halogen, halo C
1-4Alkyl.Substituting group example on the ring hetero atom comprises for example C
1-4Alkyl.
Ring A does not comprise heteroatoms.
Independently, jointly or with arbitrary combination or subgroup close preferred following meaning:
1.R
1And R
2Be independently from each other hydrogen; The optional C that replaces
1-8Alkyl; The optional halo C that replaces
1-8Alkyl; The optional C that replaces
1-8Alkoxyl group; The optional halo C that replaces
1-8Alkoxyl group;
2.R
1And R
2Be independently from each other hydrogen; C
1-8Alkyl; C
1-8Alkoxyl group;
3.R
1And R
2Both not all are hydrogen;
4.R
1And R
2Both are C
1-8Alkoxyl group;
5.R
3Be morpholinyl, 2-piperazinyl, 2-piperidyl or 2-pyrrolidyl;
6.R
3Be 3-S-morpholinyl, 2-S-piperazinyl, 2-R-piperidyl or 2-R-pyrrolidyl;
7.R
3At 4;
8.R
1And R
2Be independently from each other hydrogen; C
1-8Alkyl; C
1-8Alkoxyl group; R
3Be selected from morpholinyl, 2-piperazinyl, 2-piperidyl and 2-pyrrolidyl;
9.R
1And R
2Be independently from each other C
1-8Alkyl; C
1-8Alkoxyl group; R
3Be selected from 3-S-morpholinyl, 2-S-piperazinyl, 2-R-piperidyl and 2-R-pyrrolidyl; And R
4Be hydrogen;
10.R
1And R
2Be independently from each other the optional C that replaces
1-8Alkyl; The optional halo C that replaces
1-8Alkyl; The optional C that replaces
1-8Alkoxyl group; With the optional halo C that replaces
1-8Alkoxyl group;
11.R
1And R
2Be independently from each other C
1-8Alkyl; Halo C
1-8Alkyl; C
1-8Alkoxyl group; With halo C
1-8Alkoxyl group;
12.R
1And R
2Be independently from each other C
1-8Alkyl; And C
1-8Alkoxyl group;
13.R
3For the chirality residue and be R-or S-enantiomorph or its mixture (raceme);
14.R
3Be the S-enantiomorph;
15.R
3Be the R-enantiomorph;
16.R
4Be hydrogen.
Formula I compound can exist with free form or salt form, described salt form for example has: with the additive salt of for example organic acid or mineral acid example hydrochloric acid or acetate formation, perhaps with alkali form when R5 be COOH or available salt when comprising COOH, alkali salt for example is such as sodium or sylvite or replacement or unsubstituted ammonium salt.
Should be appreciated that formula I compound can exist with the form of optically active isomer, racemoid or diastereomer.Should be appreciated that and the present invention includes all enantiomers and conformer and composition thereof.Similarly consider the raw material that is applied to demonstrate unsymmetrical carbon like that as mentioned above.
Hydrolyzable derivative is illustrated under the physiological condition hydrolyzable production I compound and this is the compound of acceptable by product on the physiology of formula I compound on physiology, for example hydrolysis production I compound and the ester of nontoxic alcohol on the required dosage level.
The present invention also comprises the method for preparation I compound, and these methods comprise makes formula II compound (R wherein
1, R
2As defined above) with formula III compound (R wherein
3And R
4Reaction as defined above) is shown in approach A (scheme 1).
Scheme 1: approach A
Institute responds and all carries out in solvent, described solvent is all if any methyl alcohol, ethanol, tetrahydrofuran (THF), toluene, methylene dichloride, 1,2-ethylene dichloride, N-Methyl pyrrolidone, dimethylbenzene, ethyl acetate, ether, hexane, hexanaphthene, dimethyl formamide, acetone, dimethyl sulfoxide (DMSO), t-butyl methyl ether.All compounds all can use method known to those skilled in the art to separate (for example crystallization, silica gel chromatography, HPLC).
The 2-hydroxy benzaldehyde of formula IV under the existence of suitable alkali (for example secondary amine, such as piperidines) in The suitable solvent with the diethyl malonate condensation, obtain 2-oxo-2H-chromene-3-manthanoate of formula V.If R2 is a hydroxyl, then can this stage use under the alkaline condition alkylogen as electrophilic reagent in the presence of suitable alkali such as triethylamine, piperidines, sodium hydride, salt of wormwood or cesium carbonate in the presence of suitable solvent, perhaps make and use up (Mitsunobu) condition of prolonging with corresponding pure in the presence of triphenylphosphine and DEAD reagent, making hydroxy alkylated and making R2 is alkoxyl group.
2-oxo-2H-chromene-3-manthanoate with formula V carries out saponification in The suitable solvent in the presence of lithium hydroxide or sodium hydroxide then, obtains 2-oxo-2H-chromene-3-formic acid of formula II.
For forming amido linkage, use reagent such as thionyl chloride or 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide or 1,1 '-N,N'-carbonyldiimidazole or propane phosphonic acid acid anhydride are at suitable alkali such as triethylamine, N, in The suitable solvent, make formula II compound activating under the existence of N-diisopropylethylamine or sodium bicarbonate, itself and formula III compound (anils) are reacted, obtain required formula I compound.If R4 or R5 contain nitrogen functional group's blocking group such as t-butyl carbamate functional group, then, it realizes deprotection in The suitable solvent by being reacted with all example hydrochloric acids of acid or trifluoroacetic acid.
The method that employing approach A and other method relevant with the present invention prepare 2-oxo-2H-chromene-3-formic acid and formula I compound is well known by persons skilled in the art and at document (Horing, E.C. wait people (1955) organic synthesis, set volume III, 165, Livingstone, R. (1977); Rodd ' s Chemistry of carbon compounds, IV volume, the 96th page, Staunton, J. (1979); Heterocyclic Chemistry (editor P.G.Sammes), the 4th the volume) in summarize.
Under the situation that the preparation of raw material is not described especially, compound is known or can be similar to methods known in the art or prepares according to disclosed method hereinafter.
The 2-hydroxy benzaldehyde compound (R wherein for preparing non-commercially available formula IV
1Be allyl group or propyl group) facilitated method be presented in the flow process 2 (approach B).Can use wherein R of electrophilic reagent such as allyl bromide 98
1The 2-hydroxy benzaldehyde that is the formula IV of H carries out the O-alkylation in The suitable solvent in the presence of suitable alkali such as salt of wormwood or cesium carbonate, obtain formula VI compound.The claisen (Claisen) of formula VI compound under heat condition (oil bath or microwave heating) reset and can be carried out under the neat solvent condition or in The suitable solvent, obtains wherein R
1It is allylic formula IV compound.In the presence of aldehyde, two keys are carried out selective reduction, obtain wherein R
1Be the formula IV compound of propyl group, this process can use Raney nickel to realize in The suitable solvent as catalyzer under the standard hydrogenation conditions.
Perhaps, as shown in flow process 2 (approach C), if R
2It is alkoxyl group, formula VII compound and highly basic such as butyllithium and alkylogen or carboxylic acid halides are reacted, obtain formula VIII compound, it is carried out the O-dealkylation by acting on of all example hydrochloric acids of acid, Hydrogen bromide or boron tribromide in The suitable solvent, obtain formula IX compound (phenol).Formula X compound is used for example POCl under Wei Ersi Mel (Vilsmeier) condition
3And N, dinethylformamide is converted into formula IV compound (R wherein as the carbonyl source in The suitable solvent
1Be alkyl or-CO alkyl and R
2Be OH).
Scheme 2:
The 2-hydroxy benzaldehyde intermediate (R wherein for preparing non-commercially available formula IV
2Be hydroxyl) facilitated method be presented in the flow process 3 (approach D).According to literature method (Synthetic Communications, 20 (12), 1869-1876) imitated formula XI compound is synthetic.Formula X compound is used for example POCl under Wei Ersi Mel (Vilsmeier) condition
3And N, dinethylformamide is converted into formula IV compound (R wherein as the carbonyl source in The suitable solvent
2Be hydroxyl).
Scheme 3:
Approach D:
The aniline intermediate of formula III can be bought or each nitro-compound is bought, and is reduced into the aniline of formula III in The suitable solvent by the effect of palladium charcoal and hydrogen or palladium charcoal and sodium borohydride or tin protochloride.If R
4Or R
5The band amido functional group, it is in The suitable solvent, in the presence of suitable alkali such as the triethylamine, diethyl Isopropylamine, and use is as the protected one-tenth tert.-butoxy of the BOC acid anhydride carbamate of electrophilic reagent.
The aniline of formula III can be reduced under the effect by palladium charcoal and hydrogen or palladium charcoal and sodium borohydride or tin protochloride in The suitable solvent by corresponding nitro or bromo phenyl XI and obtain, or uses nitrogenous source such as ammonia, hexamethyldisilazane or imino-diacetic benzophenone to carry out bromine or transamination under the Pd of standard catalytic condition and be reduced and obtain.General introduction in formula XI nitrophenyl or bromo phenyl such as the scheme 4 (approach E) can obtain from the corresponding phenyl compound of formula XII under the nitrated of standard or bromination condition.
Scheme 4:
Approach E:
Following examples have illustrated the present invention.
Being concentrated on the rotary evaporator of solution under reduced pressure carried out.Conventional flash chromatography carries out on silica gel.Also use Biotage fast chromatographic instrument or Flashmaster instrument to carry out flash chromatography.
Used is abbreviated as:
The TBME=t-butyl methyl ether
The BOC=tert-butoxycarbonyl
The DMF=dimethyl formamide
The LiOH=lithium hydroxide
HCl=hydrochloric acid
The THF=tetrahydrofuran (THF)
CH
2Cl
2=methylene dichloride
The RT=room temperature
NaOH=sodium hydroxide
Min=minute
Embodiment 1: 7-methoxyl group-2-oxo-8-propyl group-2H-chromene-3-formic acid (4-tetramethyleneimine-2-base-phenyl)-acid amides
A) preparation of 2-allyl group oxygen base-4-methoxyl group-phenyl aldehyde
To 2-hydroxyl-4-methoxyl group-phenyl aldehyde (5g, 32.8mmol) and allyl bromide 98 (3.89ml, 46mmol) add in the solution in acetone (50ml) salt of wormwood (6.8g, 49.3mmol).Then reaction mixture was stirred 3 hours under refluxing.Reaction mixture is concentrated, between 200ml TBME and 150ml 1NNaOH, distribute layering.With organic layer 150ml salt solution and 150ml water washing, drying concentrates.Use flash chromatography (eluent: CH
2Cl
2/ hexane 8/2) behind the purifying, isolates 2-allyl group oxygen base-4-methoxyl group-phenyl aldehyde.
B) preparation of 3-allyl group-2-hydroxyl-4-methoxyl group-phenyl aldehyde
(5g, 26mmol) solution in NMP (10ml) carried out microwave heating 30 minutes with 2-allyl group oxygen base-4-methoxyl group-phenyl aldehyde in 230 ℃.Then reaction mixture is poured in ice/water (200ml) mixture, added TBME (200ml), separate organic layer,, concentrate with 150ml salt solution and 150ml water washing, drying.Use flash chromatography (eluent: CH
2Cl
2/ hexane 8/2) behind the purifying, isolates 3-allyl group-2-hydroxyl-4-methoxyl group-phenyl aldehyde.
C) preparation of 2-hydroxyl-4-methoxyl group-3-propyl group-phenyl aldehyde
(5g 26mmol) adds 10% weight Pt/C in the solution in THF (25ml) to 3-allyl group-2-hydroxyl-4-methoxyl group-phenyl aldehyde.In room temperature reaction mixture is stirred until consuming 1 equivalent hydrogen then.Then reaction mixture is passed through diatomite filtration, concentrate.2-hydroxyl-4-methoxyl group-3-propyl group-phenyl aldehyde uses without being further purified.
D) preparation of 7-methoxyl group-2-oxo-8-propyl group-2H-chromene-3-ethyl formate
To 2-hydroxyl-4-methoxyl group-3-propyl group-phenyl aldehyde (15g, 77.2mmol) add in the solution in ethanol (450ml) diethyl malonate (11.7ml, 77.2mmol) and piperidines (7.6ml, 77.2mmmol).In room temperature the reaction mixture stirring is spent the night.Use ice/water-bath that reaction mixture is cooled to 0 ℃ then, the throw out that forms is filtered, use washing with alcohol.Mother liquor is concentrated, use flash chromatography (eluent: ethyl acetate/hexane 3/7) carry out purifying, obtain 7-methoxyl group-2-oxo-8-propyl group-2H-chromene-3-ethyl formate.
E) preparation of 7-methoxyl group-2-oxo-8-propyl group-2H-chromene-3-formic acid
(15.4g 53.0mmol) adds 1N NaOH solution (120ml) in the solution in THF (300ml), in room temperature reaction mixture is stirred then and spend the night to 7-methoxyl group-2-oxo-8-propyl group-2H-chromene-3-ethyl formate in 0 ℃.Use ice/water-bath that reaction mixture is cooled to 0 ℃, use 1N HCl solution to make pH reduce to 1.In 0 ℃ reaction mixture was stirred 30 minutes, the throw out that forms is filtered, wash with water.After drying precipitate, isolate 7-methoxyl group-2-oxo-8-propyl group-2H-chromene-3-formic acid.
F) 2-{4-[(7-methoxyl group-2-oxo-8-propyl group-2H-chromene-3-carbonyl)-amino]-phenyl }-preparation of tetramethyleneimine-1-t-butyl formate
(150mg is 0.572mmol) at CH to 7-methoxyl group-2-oxo-8-propyl group-2H-chromene-3-formic acid
2Cl
2Add in the solution (6ml) diisopropylethylamine (147ul, 0.858mmol) and the solution of propane phosphonic acid acid anhydride in ethyl acetate (456ul, 0.858mmol).In room temperature reaction mixture was stirred 30 minutes then.With 2-(4-amino-phenyl)-(150mg 0.572mmol) joins in the reaction mixture tetramethyleneimine-1-t-butyl formate.In room temperature it was stirred 4 hours.Reaction mixture is with methylene dichloride (40ml) dilution, with the NaHCO of 40ml
3Saturated solution, the water washing of 40ml salt extract organic layer then, and be dry and concentrated.Separate 2-{4-[(7-methoxyl group-2-oxo-8-propyl group-2H-chromene-3-carbonyl at post precipitation)-amino]-phenyl }-tetramethyleneimine-1-t-butyl formate, obtain light yellow solid with hexane wash.
G) preparation of 7-methoxyl group-2-oxo-8-propyl group-2H-chromene-3-formic acid (4-tetramethyleneimine-2-base-phenyl)-acid amides
To 2-{4-[(7-methoxyl group-2-oxo-8-propyl group-2H-chromene-3-carbonyl)-amino]-phenyl }-(194mg 0.38mmol) is added in 4N HCl in the diox (1mL) to tetramethyleneimine-1-t-butyl formate in the solution in methylene dichloride (5ml).Reaction mixture is at room temperature stirred 2h (generating precipitation after adding HCl).With the reaction mixture concentrating under reduced pressure, solid grinds with ether then.Isolate 7-methoxyl group-2-oxo-8-propyl group-2H-chromene-3-formic acid (4-tetramethyleneimine-2-base-phenyl)-acid amides after the filtration.
All following examples are synthetic according to above-described method.
By the method described among the above embodiment 1 and use the method for describing among the approach A, and use suitable starting raw material to obtain formula Xa compound
R wherein
1, R
2, R
3And R
4Such as in the following table 1 definition.
Table 1
| Ex | R1 | R2 | R3 | R4 | (M+H) + |
| 2 | Propyl group | OEt | Rac-4-tetramethyleneimine-2-base- | H | 421.3 |
| 3 | Propyl group | OMe | 4-tetramethyleneimine-2-base- ＊ | H | 407.3 |
| 4 | Propyl group | OMe | 4-tetramethyleneimine-2-base- ＊ | H | 407.4 |
| 5 | Ethyl | OMe | 4-tetramethyleneimine-2-base- ＊ | H | 393.3 |
| 6 | Ethyl | OMe | 4-tetramethyleneimine-2-base- ＊ | H | 393.3 |
| 7 | iPr | OMe | 4-tetramethyleneimine-2-base- ＊ | H | 407.3 |
| 8 | OEt | OMe | 4-(R)-tetramethyleneimine-2-base- | H | 409.1 |
| 9 | OEt | OMe | 4-tetramethyleneimine-2-base- ＊ | H | 409.1 |
| 10 | OiPr | OMe | 4-tetramethyleneimine-2-base- ＊ | H | 423.8 |
| 11 | Propyl group | OMe | 4-1-methyl-tetramethyleneimine-2-base- ＊ | H | 421.4 |
| 12 | Propyl group | OMe | 4-1-methyl-tetramethyleneimine-2-base- ＊ | H | 421.4 |
| 13 | Propyl group | OMe | Rac-4-(1-methyl-tetramethyleneimine-2-yl)- | H | 421.3 |
| 14 | Ethyl | OMe | 4-1-methyl-tetramethyleneimine-2-base- ＊ | H | 407.4 |
| 15 | Ethyl | OMe | 4-1-methyl-tetramethyleneimine-2-base- ＊ | H | 407.4 |
| 16 | Propyl group | OEt | Rac-4-(1-methyl-tetramethyleneimine-2-yl)- | H | 435.3 |
| 17 | Propyl group | OMe | 4-[1-(2-hydroxyl-ethyl)-tetramethyleneimine-2-yl]- ＊ | H | 451.4 |
| 18 | Sec.-propyl | OMe | 4-1-methyl-tetramethyleneimine-2-base- ＊ | H | 421.3 |
| 19 | Propyl group | OMe | Rac-4-piperidines-2-base- | H | 421.3 |
| 20 | Ethyl | OMe | Rac-4-piperidines-2-base- | H | 407.3 |
| 21 | OEt | OMe | 4-piperidines-2-base- ＊ | H | 423.1 |
| 22 | OEt | OMe | 4-piperidines-2-base- ＊ | H | 423 |
| 23 | OiPr | OMe | 4-piperidines-2-base- ＊ | H | 437 |
| 24 | OiPr | OMe | 4-piperidines-2-base- ＊ | H | 437 |
| 25 | Propyl group | OMe | Rac-4-(1-methyl-piperidines-2-yl)- | H | 435.4 |
| 26 | Ethyl | OMe | Rac-4-(1-methyl-piperidines-2-yl)- | H | 421.3 |
| 27 | Propyl group | OMe | 4-(S)-morpholine-3-base- | H | 423.2 |
| 28 | Ethyl | OMe | 4-(S)-morpholine-3-base- | H | 409.1 |
| 29 | OEt | OMe | 4-(S)-morpholine-3-base- | H | 425.1 |
| 30 | OEt | OMe | 4-(R)-morpholine-3-base- | H | 425 |
| 31 | OiPr | OMe | 4-(S)-morpholine-3-base- | H | 439.2 |
| 32 | OCH 2Cyclopropyl | OMe | 4-(S)-morpholine-3-base- | H | 451 |
| 33 | OEt | OMe | 4-(S)-4-methyl-morpholine-3-base- | H | 439.8 |
| 34 | Methyl | OMe | Rac-4-morpholine-2-Ji- | H | 395.1 |
| 35 | Ethyl | OMe | Rac-4-morpholine-2-Ji- | H | 409.5 |
| 36 | Ethyl | OMe | 4-morpholine-2-Ji- ＊ | H | 409.1 |
| 37 | OEt | OMe | Rac-4-morpholine-2-Ji- | H | 425.1 |
| 38 | OEt | OMe | 4-morpholine-2-Ji- ＊ | H | 425.1 |
| 39 | OEt | OMe | 4-morpholine-2-Ji- ＊ | H | 425.1 |
| 40 | OiPr | OMe | Rac-4-morpholine-2-Ji- | H | 439.6 |
| 41 | OiPr | OMe | 4-morpholine-2-Ji- ＊ | H | 439.1 |
| 42 | OiPr | OMe | 4-morpholine-2-Ji- ＊ | H | 439.1 |
| 43 | Propyl group | OMe | Rac-4-piperazine-2-base- | H | 422 |
| 44 | Ethyl | OMe | 4-piperazine-2-base- ＊ | H | 408 |
| 45 | Ethyl | OMe | 4-piperazine-2-base- ＊ | H | 408 |
| 46 | OEt | OMe | 4-(R)-tetramethyleneimine-2-base- | 2-Me | 423 |
| 47 | OiPr | OMe | 4-(R)-tetramethyleneimine-2-base- | 2-Me | 437 |
| 48 | OEt | OMe | 4-(R)-tetramethyleneimine-2-base- | 3-Me | 423 |
| 49 | OiPr | OMe | 4-(R)-tetramethyleneimine-2-base- | 3-Me | 437 |
| 50 | OEt | OMe | 4-(R)-tetramethyleneimine-2-base- | 3-Et | 437 |
| 51 | OiPr | OMe | 4-(R)-tetramethyleneimine-2-base- | 3-Et | 451 |
| 52 | OiPr | OMe | 4-(R)-tetramethyleneimine-2-base- | H | 423.8 |
| 53 | OEt | OMe | 4-piperazine-2-base- ＊ | H | 424.0 |
| 54 | OEt | OMe | 4-piperazine-2-base- ＊ | H | 424.0 |
| 55 | OiPr | OMe | 4-piperazine-2-base- ＊ | H | 438 |
| 56 | OiPr | OMe | 4-piperazine-2-base- ＊ | H | 438 |
| 57 | OEt | OMe | 4-(R)-tetramethyleneimine-2-base- | 3-F | 427.8 |
| 58 | OiPr | OMe | 4-(R)-tetramethyleneimine-2-base- | 3-F | 441.8 |
| 59 | OEt | OMe | Rac-4-(2-Me-piperidines-2-yl)- | H | 437.2 |
| 60 | OiPr | OMe | 4-(R)-tetramethyleneimine-2-base- | 2-OMe | 453.17 |
| 61 | OEt | OMe | 4-(R)-tetramethyleneimine-2-base- | 2-OMe | 439.18 |
| 62 | Ethyl | OMe | 4-(R)-tetramethyleneimine-2-base- | 2-Me | 407.2 |
| 63 | Ethyl | OMe | 4-(R)-tetramethyleneimine-2-base- | 3-F | 411.17 |
| 64 | OiPr | OMe | 4-(R)-tetramethyleneimine-2-base- | 2-F | 441.18 |
| 65 | OEt | OMe | 4-(R)-tetramethyleneimine-2-base- | 2-F | 427.19 |
| 66 | OEt | OMe | 4-(R)-N (Me) tetramethyleneimine-2-base- | 3-Me | 437.2 |
| 67 | OiPr | OMe | 4-(R)-N (Me) tetramethyleneimine-2-base- | 3-Me | 451.3 |
| 68 | Ethyl | OMe | 4-(R)-N (Me) tetramethyleneimine-2-base- | 3-Me | 421.3 |
| 69 | Ethyl | OMe | 4-(R)-tetramethyleneimine-2-base- | 3-Me | 407.22 |
| 70 | Ethyl | OMe | 4-(R)-tetramethyleneimine-2-base- | 2-F | 411.17 |
| 71 | Methyl | OMe | 4-(R)-tetramethyleneimine-2-base- | 3-Me | 393.21 |
| 72 | Methyl | OMe | 4-(R)-tetramethyleneimine-2-base- | 3-F | 397.16 |
| 73 | OEt | OMe | 4-(R)-N (Et) tetramethyleneimine-2-base- | 3-Me | 451.2 |
| 74 | OiPr | OMe | 4-(R)-N (Et) tetramethyleneimine-2-base- | 3-Me | 465.2 |
| 75 | Methyl | OMe | 4-(R)-tetramethyleneimine-2-base- | H | 379.18 |
| 76 | Methyl | OMe | 4-(R)-tetramethyleneimine-2-base- | 2-F | 397.18 |
| 77 | Methyl | OMe | 4-(R)-tetramethyleneimine-2-base- | 2-Me | 393.21 |
| 78 | Propyl group | (S)OCH(Me)Et | 4-(R)-tetramethyleneimine-2-base- | H | 449.1 |
| 79 | Propyl group | (S)OCH(Me)Et | 4-(R)-tetramethyleneimine-2-base- | 3-Et | 477.1 |
| 80 | Propyl group | (S)OCH(Me)Et | 4-(R)-tetramethyleneimine-2-base- | 2-Me | 463.1 |
| 81 | OiPr | OiPr | 4-(R)-tetramethyleneimine-2-base- | H | 451.6 |
| 82 | OiPr | OiPr | 4-(R)-tetramethyleneimine-2-base- | 2-Me | 465.2 |
| 83 | Propyl group | (S)OCH(Me)Et | 4-(R)-tetramethyleneimine-2-base- | 3-Me | 463.3 |
| 84 | Propyl group | EtO | 4-(R)-tetramethyleneimine-2-base- | H | 421.2 |
| 85 | Propyl group | EtO | 4-(R)-tetramethyleneimine-2-base- | 2-Me | 435.3 |
| 86 | Propyl group | EtO | 4-(R)-tetramethyleneimine-2-base- | 3-Me | 435.3 |
| 87 | EtO | EtO | 4-(R)-tetramethyleneimine-2-base- | H | 423.2 |
| 88 | EtO | EtO | 4-(R)-tetramethyleneimine-2-base- | 2-Me | 437.3 |
| 89 | EtO | EtO | 4-(R)-tetramethyleneimine-2-base- | 2-F | 441.5 |
| 90 | OiPr | OMe | 4-(S)-morpholine-3-base- | 3-Me | 453.3 |
| 91 | OiPr | OMe | 4 (2-Me-piperidines-2-yl)- ＊ | H | 451.3 |
| 92 | OiPr | OMe | 4 (2-Me-piperidines-2-yl)- ＊ | H | 451.3 |
| 93 | EtO | OMe | 4 (2-Me-piperidines-2-yl)- ＊ | H | 437.3 |
| 94 | EtO | OMe | 4 (2-Me-piperidines-2-yl)- ＊ | H | 437.3 |
| 95 | EtO | OMe | 3-(S)-morpholine-3-base- | H | 425.3 |
| 96 | OiPr | OMe | 3-(S)-morpholine-3-base- | H | 439.3 |
| 97 | Methyl | OMe | 4-(S)-morpholine-3-base- | H | 395.1 |
| 98 | CH 2OMe | OMe | 4-(S)-morpholine-3-base- | H | 425.2 |
| 99 | EtO | EtO | 4-(S)-morpholine-3-base- | H | 439.2 |
| 100 | OiPr | OiPr | 4-(S)-morpholine-3-base- | H | 467.2 |
| 101 | EtO | CH 2OMe | 4-(S)-morpholine-3-base- | H | 439.3 |
| 102 | CH 2OMe | EtO | 4-(R)-tetramethyleneimine-2-base- | H | 409 |
| 103 | EtO | CH 2OMe | 4-(R)-tetramethyleneimine-2-base- | H | 423.4 |
| 104 | OiPr | OiPr | 4-(R)-tetramethyleneimine-2-base- | 2-F | 469.5 |
| 105 | OiPr | EtO | 4-(R)-tetramethyleneimine-2-base- | H | 437.3 |
| 106 | OiPr | EtO | 4-(S)-morpholine-3-base- | H | 453.3 |
The explanation that convention is represented in the last table:
* the chipal compounds of representing unknown absolute configuration.
Rac represents the racemic mixture of S and R enantiomorph.
The formula I compound exhibits of free form or pharmaceutical acceptable salt goes out valuable pharmacological character, for example as the S1P1 receptor stimulant, for example in test in vitro and in vivo as indicated in like that, so it shows and can be used for treating.
A. external
Formula I compound has binding affinity to individual people S1P acceptor, as measuring in the following test:
A.1 external: mensuration GTP [γ-
35
S] combine with film by the preparation of the Chinese hamster ovary celI of expressing human EDG acceptor
The GPCR activation experiment
S1P
1(EDG-1) GTP[γ-
35S] in conjunction with testing: the film that has prepared homogenize by the Chinese hamster ovary celI clone of the terminal c-myc mark of stably express people EDG-1N-.Before collection, with cell at two 850cm
2Roll in the bottle suspension culture 3 or 4 days.Cell centrifugation is got off, with cold PBS washing 1 time, be resuspended in≤the 20ml buffer A in (10mM EDTA does not contain the adequate proteins enzyme inhibitors mixture [1/25ml] of EDTA for 20mM HEPES, pH7.4).Use the Polytron homogenizer with 30000rpm, with 3 intervals (each is 15 seconds) with cell suspension in homogenize on ice.At first with homogenize thing on the table-type low-speed whizzer centrifugal 10 minutes with 2000rpm.Behind the cell nutsche filter, then in 4 ℃ with 50,000 * g with upper strata liquid recentrifuge 25 minutes.Throw out is resuspended in the buffer B (pH7.4,0.1mM EDTA does not contain the adequate proteins enzyme inhibitors mixture [1/10ml] of EDTA for 15% glycerine, 20mMHEPES).Use BCA protein determination test kit (Pierre Si (Pierce) company), use BSA as standard test the protein concn of prepared product.Film is carried out five equilibrium, freezing in-80 ℃ of maintenances.
Having prepared scope with DMSO is the test-compound solution of 10mM to 0.01nM.Use the 4%BSA solution dilution as positive control S1P.With the membrane prepare thing of aequum with ice-cold mensuration damping fluid (20mM HEPES, pH7.4,100mM NaCl, 10mM MgCl
2, 0.1% BSA of fatty acids not, 5 μ M GDP) and dilution, fully vortex.2 μ l or compound still less are assigned in each hole of round bottom 96 hole polystyrene assay plate, add the film (3-10 μ g/ hole) of 100 μ l dilution then, keep on ice until adding hot GTP γ S.Will [
35S]-GTP γ S 1: 1000 (v/v) of cold measurement damping fluid dilution, 100 μ l are joined in each hole.React on room temperature and carried out 90 minutes, use the Filtermate collector of packard company (Packard) that film is collected perkin elmer (Perkin-Elmer) then
On the GF/B-96 filter plate.With lavation buffer solution (20mM HEPES, pH7.4,100mMNaCl, 10mM MgCl
2) washing is for several times and with behind 95% alcohol flushing, with strainer drying 30 minutes in 37 ℃ of loft drier.Add MicroScint-20, the plate sealing is used for the enterprising line flicker counting at TopCount.By with GraphPad Prism dose response curve match instrument with GTP[γ-
35S] binding curve (raw data) match and obtain the EC50 value.Used 6 or 12 kind of different concns to produce concentration-response curve (every kind of concentration is used 3 data points).
Use from the film of the terminal c-myc of stably express c-Chinese hamster ovary celI mark or unlabelled acceptor with S1P1GTP[γ-
35S] in conjunction with the test suitable mode carried out S1P3 ,-5 ,-6 and-8GTP[γ-
35S] in conjunction with test.For each membrane prepare thing, at first carried out the dosage escalation experiment with definite optimum quantity that will add the film of each test holes with the S1P contrast.
According to above mensuration formula I compound is tested, these compound exhibits go out S1P acceptor such as S1P1 acceptor to be had selectivity, its EC
50＜1 μ M.
In addition, compare with S1P5 with S1P3, S1P4, formula I compound can demonstrate the selectivity to the S1P1 acceptor, and for example, formula I compound can be to S1P3, S1P4 and S1P5 optionally at least 20 times to the selectivity of S1P1.
Equally usually, formula I compound can be that S1P3 and S1P4 have so-called double selection than other hypotypes to S1P1 and S1P5 acceptor.Described selectivity generally is about 20-30 (representing with receptor affinity).Such S1P1/S1P5 acceptor dual agonists also has the valuable pharmacological effect.
| Ex | S1P-1EC 50[μM] |
| 1 | 0.0001 |
| 3 | 0.0016 |
| 8 | 0.0075 |
| 23 | 0.0755 |
| 27 | 0.0002 |
| 41 | 0.0029 |
| 43 | 0.0001 |
| 44 | 0.0002 |
| 53 | 0.0046 |
| 62 | 0.0005 |
| 72 | 0.0018 |
| 82 | 0.0024 |
| 89 | 0.0128 |
| 90 | 0.0062 |
| 96 | 0.0028 |
A.2FLIPR calcium current analysis
With the assay determination of FLIPR calcium current the agonist activity of compound of the present invention to S1P1, S1P3, S1P5 and S1P6.In brief, the Chinese hamster ovary celI of expressing the S1P acceptor is kept in containing the F-12K substratum (ATCC) of 5%FBS and 500ug/ml G418.Before test, cell is layered in the plate at the bottom of the 384 hole black transparents with the density of 10,000 cells/well/25 μ l in containing the F-12K substratum of 1%FBS.Second day, cell is washed 3 times (25 μ l/ are each) with lavation buffer solution.About 25 μ l dyestuffs are joined in each hole, at 37 ℃ and 5%CO
2Under hatched 1 hour.Then cell is washed 4 times (25 μ l/ are each) with lavation buffer solution.Measure calcium current at each Kong Zhonghou that 25 μ l SEW2871 (open by people such as Rosen, with for referencial use) solution is joined cell.The cell of expressing variant S1P acceptor has been carried out identical test.Writing down increasing progressively in the analysis of FLIPR calcium current at interval through 3 minutes, quantitatively is with respect to the maximum peak height percentage ratio response of S1P-1 activated with it.Compound of the present invention this test in 10
-12To 3.10
-5Has activity under the concentration of nM.
For example, the EC that has of 13 couples of S1P-1 of embodiment
50=92nM, the EC that all other isoforms (S1P-2, S1P-3, S1P-4, S1P-5) are had
50＞1um.
B. in the body: measure the shaker test that blood lymphocytes is subdued
The mensuration of circulating lymphocyte: test-compound is dissolved among the DMSO/PEG200, further dilutes with deionized water.Per os is used to rat (Louis's strain, female, age in 6-12 week) and is applied in the 1mg/kg test-compound among 4ml carrier/kg (the maximum 2%PEG200/ water of maximum 2%DMSO/).DMSO/PEG200/ water and FTY720 (0.3mg/kg) are included respectively as feminine gender and positive control.
After using, gathering blood by sublingual vein under the isoflurane anesthesia in short-term in 2,6,24 and 48 hours.Whole blood sample is carried out analysis of Hematology Changes.Use automatic analyzer to measure the periphery lymphocyte counting.By of the subgroup dyeing of fluorescence dye bonded specific antibody, use fluorescence activated cell sorter (Facscalibur) that it is analyzed with peripheral blood lymphocyte.Used two rats to subdue activity with the lymphocyte of estimating each compound that screens.The result is ED
50, it is defined as and demonstrates 50% blood lymphocytes and subdue required effective dose.Formula I compound is tested the ED that it has according to above mensuration
50Below 10mg/kg.For example, the ED that had at 6 hours of the compound of embodiment 9
50=1.4mg/kg.
Therefore, formula I compound can be used for treating and/or preventing disease or the obstacle by the lymphocytes interactions mediation, for example: in transplanting, such as cell, acute or chronic rejection or the graft function delayed recovery (delayed graft function) of tissue or organ allogeneic or heterograft, graft versus host disease (GVH disease), autoimmune disorder, rheumatoid arthritis for example, systemic lupus erythematosus, Hashimoto thyroiditis, multiple sclerosis, myasthenia gravis, I type or type ii diabetes and the obstacle relevant with it, vasculitis, pernicious anemia, Sjogren syndrome, uveitis, psoriatic, graves' ophthalmopathy, alopecia circumscripta and other, allergic disease, atopic asthma for example, atopic dermatitis, rhinallergosis/conjunctivitis, contact dermatitis, choose wantonly and have the inflammatory diseases of potential abnormal response, inflammatory bowel for example, Crohn's disease or ulcerative colitis, intrinsic asthma, the inflammatory injury of lung, the inflammatory liver injury, the inflammatory glomerular injury, atherosclerosis, osteoarthritis, irritant contact dermatitis and also have eczematoid dermatitis, seborrheic dermatitis, the cutaneous manifestations of disorder mediated on the immunology, inflammatory eye disease, keratoconjunctivitis, myocarditis or hepatitis, ischemia/reperfusion injury, myocardial infarction for example, apoplexy, intestinal ischemia, renal failure or hemorrhagic shock, traumatic shock, cancer, breast cancer for example, t cell lymphoma or T chronic myeloid leukemia, infectious diseases, toxic shock (for example superantigen causes) for example, septic shock, adult respiratory distress syndrome or virus infection such as AIDS, viral hepatitis, chronic bacterial infection, perhaps senile dementia.The example of cell, tissue or solid organ transplantation thing for example comprises pancreas islet, stem cell, marrow, cornea tissue, nervous tissue, heart, lung, the heart-lung associating, kidney, liver, intestines, pancreas, tracheae or oesophagus.For above purposes, required dosage will change according to mode of administration, the concrete illness of being treated and required effect certainly.
Usually, the per daily dose systemic administration with about 0.03 to 5.0mg/kg body weight is instructed to obtain gratifying result.Be about 0.5mg about 500mg extremely at bigger Mammals such as the indication per daily dose among the people, can for example four times separate doses or delay form be used at the most with one day easily.Be applicable to that Orally administered unit dosage form comprises about 0.1 to 50mg activeconstituents.
Formula I compound can be used by any conventional route, particularly use through intestines, for example Orally administered, for example use with the form of tablet or capsule, perhaps gi tract are used outward, for example use topical application with the form of injection solution or suspension, for example use, perhaps use with the form of intranasal or suppository with the form of lotion, gelifying agent, ointment or ointment.The pharmaceutical composition that comprises the formula I compound of free form or pharmaceutical acceptable salt and at least a pharmaceutically acceptable carrier or thinner can be in a usual manner by preparing with pharmaceutically acceptable carrier or mixing diluents.
Formula I compound can with free form or pharmaceutical acceptable salt, for example as above show those use.This class salt can prepare and demonstrate the activity with the free cpds same levels in a usual manner.
According to above, the present invention also provides:
1.1 prevention or treatment are by the obstacle of cell mediated or disease, those the method that for example as above shows in the individuality of this treatment of needs, this method comprises the formula I compound or pharmaceutically acceptable salt thereof of using significant quantity to described individuality;
1.2 prevention or treat acute or chronic transplanting rejection or inflammatory that T-is cell-mediated or autoimmune disorder, those the method that for example as above shows in the individuality of this treatment of needs, this method comprises the formula I compound or pharmaceutically acceptable salt thereof of using significant quantity to described individuality;
2. be used as medicine, for example be used as the free form of medicine or the formula I compound of pharmaceutical acceptable salt in above 1.1 or 1.2 any means that show.
3. for example be used for above 1.1 or the pharmaceutical composition of 1.2 any means, the pharmaceutically acceptable diluent or the carrier that comprise the formula I compound of free form or pharmaceutical acceptable salt and be used for this.
4. be used for preparing and be used for above 1.1 or the formula I compound or pharmaceutically acceptable salt thereof of the pharmaceutical composition of 1.2 any means.
Formula I compound can be used as independent activeconstituents or for example as the assistant agent of other medicines and co-administered with other medicines, described other medicines for example have: immunosuppressor or immunomodulator or other anti-inflammatory agent, for example be used for the treatment of or prevent allogeneic or heterograft is acute or chronic rejection or inflammatory or autoimmunization sexual dysfunction, perhaps chemotherapeutic such as malignant cell antiproliferative.For example, formula I compound can use with following drug regimen: calcineurin inhibitor, for example ciclosporin A or FK 506; MTOR inhibitor, for example rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, CCI779, ABT578, AP23573, biolimus-7 or biolimus-9; Ascosin with immunosuppression character, for example ABT-281, ASM981 etc.; Reflunomide; Endoxan; Azathioprine; Methotrexate; Leflunomide; Mizoribine; Mycophenolic Acid or salt; Mycophenolate mofetil; 15-Gusperimus or its immunosuppression homologue, analogue or derivative; Pkc inhibitor, those disclosed for example as in WO 02/38561 or WO 03/82859, for example embodiment 56 or 70 compound; The JAK3 kinase inhibitor, N-benzyl-3 for example, 4-dihydroxyl-benzylidene-malonamide nitrile alpha-cyano-(3, the 4-dihydroxyl)-] N-benzyl cinnamide (Tyrphostin AG 490), prodigiosin 25-C (PNU156804), [4-(4 '-hydroxy phenyl)-amino-6, the 7-dimethoxyquinazoline] (WHI-P131), [4-(3 '-bromo-4 '-hydroxy phenyl)-amino-6, the 7-dimethoxyquinazoline] (WHI-P154), [4-(3 ', 5 '-two bromo-4 '-hydroxy phenyl)-amino-6, the 7-dimethoxyquinazoline] WHI-P97, KRX-211,3-{ (3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-amino]-piperidines-1-yl }-3-oxo-propionitrile, be free form or pharmaceutical acceptable salt, for example single citrate (also is called CP-690,550), or as in WO 04/052359 or WO 05/066156 disclosed compound; S1P receptor stimulant or conditioning agent, for example choose FTY720 or its analogue of phosphorylation wantonly, for example choose 2-amino-2-[4-(3-benzyl oxygen base the thiophenyl)-2-chloro-phenyl-of phosphorylation wantonly] ethyl-1, ammediol or 1-{4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyl oxygen base imino-)-ethyl]-2-ethyl-benzyl }-azetidine-3-formic acid or its pharmacologically acceptable salt; Immunosuppression monoclonal antibody, for example monoclonal antibody of leukocyte receptors such as MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40, CD45, CD52, CD58, CD80, CD86 or its part; Other immunomodulatory compounds, the reorganization binding molecule that for example has at least a portion extracellular domain of CTLA4 or its mutant, for example has the reorganization binding molecule with the outside part of born of the same parents at least, for example CTLA4Ig (for example specified ATCC 68629) or its mutant of non-CTLA4 protein sequence bonded CTLA4 or its mutant, for example LEA29Y; Adhesion molecule inhibitor, for example LFA-1 antagonist, ICAM-1 or-3 antagonists, VCAM-4 antagonist or VLA-4 antagonist; Or chemotherapeutic, for example taxol, gemcitabine, cis-platinum, Dx or 5 FU 5 fluorouracil; Or anti-infection agent.
When formula I compound and other immunosuppression/immune modulating treatment, anti-inflammatory, chemotherapy or anti-infective therapy are co-administered, the dosage of the immunosuppressive compounds of using jointly, immunomodulatory compounds, anti-inflammatory compound, chemotherapy compound or anti-infective compounds will change according to the type (for example it is steroid or calcineurin inhibitor) of the concomitant medication that is adopted, the concrete medicine that is adopted, the illness of being treated or the like certainly.According to above, the present invention also provides on the other hand:
5. method as defined above, this method comprise jointly use, for example formula I compound parallel or the effective nontoxic amount of administering therapeutic successively and at least the second kind of medicine, for example immunosuppressive drug, immunomodulator, antiphlogiston or chemotherapeutic drug, for example as above show those.
6. drug regimen, for example medicine box, comprise a) first kind of material, this material is the I of the formula as disclosed herein compound of free form or pharmaceutical acceptable salt, and b) at least a shared material, for example immunosuppressor, immunomodulator, anti-inflammatory agent, chemotherapeutic or anti-infection agent.This medicine box can comprise it and use specification sheets.
Term " is used " or " combined administration " etc. is intended to comprise selected therapeutical agent is applied to single patient jointly as used herein, and is intended to comprise that material wherein is not necessarily by identical route of administration or the treatment plan used simultaneously.
Term " drug regimen " expression comprises the fixing of activeconstituents and on-fixed combination by more than one activeconstituentss being mixed or merging resulting product as used herein.Term " fixed combination " expression all is applied to the patient with activeconstituents, for example formula I compound and shared material simultaneously with the form of single entities or dosage.Term " on-fixed combination " expression with activeconstituents, for example formula I compound and shared material as independent entity simultaneously, parallel or do not have specified time restrictedly all to be applied to the patient successively, wherein this uses the treatment level of significance that these 2 kinds of compounds can be provided in patient's body.The latter also can be applicable to drug cocktail therapy (treatment), for example uses 3 kinds or more kinds of activeconstituents.
Claims (10)
1. hydrolyzable derivative, its salt, hydrate and/or solvate on formula I compound or its physiology:
Wherein
R
1And R
2Be selected from independently of one another: hydrogen; Halogen; Nitro; The optional C that replaces
1-8Alkyl; The optional halo C that replaces
1-8Alkyl; The optional C that replaces
1-8Alkoxyl group; With the optional halo C that replaces
1-8Alkoxyl group;
R
3For comprising the saturated heterocyclic of at least one ring N atom, and it is connected with ring A by ring C atom, and this ring carbon atom or any other encircle the C atom and choose wantonly and be substituted;
R
3On 3 or 4, preferably on 4;
R
4Be hydrogen; Hydroxyl; Halogen; Halo C
1-8Alkyl; The optional C that replaces
1-6Alkyl; C
1-6Alkoxyl group; Or halo C
1-6Alkoxyl group; Preferred R
4Be hydrogen;
R
4On 2 (ortho positions) or 3 (position).
2. according to the compound of claim 1, R wherein
3Be three to eight yuan of saturated heterocyclics as shown in the formula (Ib)
Wherein X is selected from NR, O, CH
2With the S atom, wherein
R and R ' are H or C independently of one another
1-4Alkyl, and
Wherein said R
3Link to each other by any carbon atom in formula (Ib) ring of band hydrogen atom with the described A ring in the formula (I), this hydrogen is replaced by described connection then.
3. the compound of claim 1, wherein R
3Preferably be selected from N, O and S heteroatomic three to eight yuan for comprising 1 or 2, be preferably four to the heptatomic saturated heterocyclic.
4. the compound of claim 1, wherein R
3Via forming described R
3Carbon atom with the ring A be connected.
5. the compound of claim 4, wherein the carbon atom of Lian Jieing is at R
3Heteroatomic two or three-digit.
6. the compound of claim 1, wherein R
1And R
2Be selected from independently of one another: the optional C that replaces
1-8Alkyl; The optional halo C that replaces
1-8Alkyl; The optional C that replaces
1-8Alkoxyl group; The optional halo C that replaces
1-8Alkoxyl group.
7. the compound of claim 1, wherein R
1And R
2Be independently from each other C
1-8Alkyl and C
1-8Alkoxyl group; Preferred R
1And R
2Both are C
1-8Alkoxyl group.
8. the compound of claim 1, wherein R
3Be 3-S-morpholinyl, 2-S-piperazinyl, 2-R-piperidyl or 2-R-pyrrolidyl; And R
34 connections at ring A.
9. be used as any one compound according to aforementioned claim of medicine.
10. as any one compound according to aforementioned claim of medicine, wherein said purposes is disease or the obstacle that treats and/or prevents by the lymphocytes interactions mediation; For example: in transplanting, such as cell, acute or chronic rejection or the graft function delayed recovery of tissue or organ allogeneic or heterograft, graft versus host disease (GVH disease), autoimmune disorder, rheumatoid arthritis for example, systemic lupus erythematosus, Hashimoto thyroiditis, multiple sclerosis, myasthenia gravis, I type or type ii diabetes and the obstacle relevant with it, vasculitis, pernicious anemia, Sjogren syndrome, uveitis, psoriatic, graves' ophthalmopathy, alopecia circumscripta and other, allergic disease, atopic asthma for example, atopic dermatitis, rhinallergosis/conjunctivitis, contact dermatitis, choose wantonly and have the inflammatory diseases of potential abnormal response, inflammatory bowel for example, Crohn's disease or ulcerative colitis, intrinsic asthma, the inflammatory injury of lung, the inflammatory liver injury, the inflammatory glomerular injury, atherosclerosis, osteoarthritis, irritant contact dermatitis and also have eczematoid dermatitis, seborrheic dermatitis, the cutaneous manifestations of disorder mediated on the immunology, inflammatory eye disease, keratoconjunctivitis, myocarditis or hepatitis, ischemia/reperfusion injury, myocardial infarction for example, apoplexy, intestinal ischemia, renal failure or hemorrhagic shock, traumatic shock, cancer, breast cancer for example, t cell lymphoma or T chronic myeloid leukemia, infectious diseases, toxic shock (for example superantigen causes) for example, septic shock, adult respiratory distress syndrome or virus infection such as AIDS, viral hepatitis, chronic bacterial infection, perhaps senile dementia.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP07101669.5 | 2007-02-02 | ||
| EP07101669 | 2007-02-02 | ||
| EP07118310.7 | 2007-10-11 |
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| Publication Number | Publication Date |
|---|---|
| CN101583608A true CN101583608A (en) | 2009-11-18 |
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| CNA2008800025942A Pending CN101583608A (en) | 2007-02-02 | 2008-01-31 | Chromene S1P1 receptor antagonist |
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| CN (1) | CN101583608A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014048165A1 (en) * | 2012-09-27 | 2014-04-03 | 上海先声药物研究有限公司 | Compound as potassium channel modulator |
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2008
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014048165A1 (en) * | 2012-09-27 | 2014-04-03 | 上海先声药物研究有限公司 | Compound as potassium channel modulator |
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