CN1646520A - 1,3,5-triazine derivatives as ligands for human adenosine-A3 receptors - Google Patents
1,3,5-triazine derivatives as ligands for human adenosine-A3 receptors Download PDFInfo
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- CN1646520A CN1646520A CNA038090937A CN03809093A CN1646520A CN 1646520 A CN1646520 A CN 1646520A CN A038090937 A CNA038090937 A CN A038090937A CN 03809093 A CN03809093 A CN 03809093A CN 1646520 A CN1646520 A CN 1646520A
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Abstract
The invention relates to a group of novel triazine derivatives which are ligands for human adenosine-A3 receptors, as well as to pharmaceutical compositions containing a pharmacologically active amount of at least one of these compounds as an active ingredient. The invention relates to compounds of the general formula (1) wherein Y represents a group of the general formula (A), (B) or (C) and all other symbols have the meanings as given in the description.
Description
The present invention relates to one group of new pyrrolotriazine derivatives, it is people adenosine-A
3The part of acceptor.The invention still further relates at least a pharmaceutical composition in these new pyrrolotriazine derivatives that contain pharmacological activity amount as active ingredient.
Two kinds of well-known natural compounds caffeines and theophylline are brought into play its pharmacological activity by interacting with Adenosine Receptors.Research produces a very large impact to Adenosine Receptors in this discovery.At present, differentiated four class Adenosine Receptorss, and they have been appointed as A respectively
1, A
2A, A
2BAnd A
3All these four classes Adenosine Receptorss all belong to seven superfamilies of striding film G-protein linked receptor.Adenosine Receptors is ubiquitous, and relates to many kinds of bioprocesss.Therefore, in the many decades in the past, the treatment potentiality of adenosine receptor ligands cause the research interest that people are very big.Nearest summary is: S.Hess, Recent advances in adenosine receptor antagonist research, Expert Opin.Ther.Patents, 11,1,547 1562,2001, and M.A.Jacobson, adenosine receptor agonists, Expert Opin.Ther.Patents, 12 (4), 489-501,2002.
The part of various Adenosine Receptorss is themes of a large amount of patent applications and patent.In these patent applications and patent, have only in two pieces to disclose triaizine compounds.WO 991163 discloses a series of adenosine-A to the people that shown
12 of the nM level affinity of acceptor, the triazine that the 4-phenylbenzene replaces.
The patent application of second piece of open triaizine compounds is JP 11158073, and it is immediate prior art.This patent application discloses the 1,3,5-triazines of a series of replacement, and they are people adenosine-A
3The part of acceptor, wherein compounds effective has the affinity of about 15nM.
Surprisingly, have now found that in a series of pyrrolotriazine derivatives with the combination of new substituting group, one group of compound has shown to have adenosine-A to the people in low nM level scope
3The affinity of acceptor.
The present invention relates to the compound and the pharmacologically acceptable salt thereof of general formula (1),
Wherein
R
1The expression halogen, alkyl (1-3C), O-alkyl (1-3C), CF
3, NH
2, N-(two)-alkyl (1-3C), N-(two)-thiazolinyl (1-3C), N-(two)-alkynyl (1-3C), N-alkyl (1-3C) thiazolinyl (1-3C), N-alkyl (1-3C) alkynyl (1-3C), N-thiazolinyl (1-3C) alkynyl (1-3C) or the optional C that replaces
2-C
8The cycloalkyl amino group,
R
2, R
3And R
4Represent H independently, halogen, alkyl (1-3C), CF
3, OH, O-alkyl (1-3C), phenoxy group, hydroxyalkyl (1-3C), alkoxyl group (1-2C)-alkyl (1-2C), phenyl, N-(two)-alkyl (1-3C), 1-morpholinyl, piperidino, 1-piperazinyl, OCF
3, SCH
3, SOCH
3, SO
2CH
3, perhaps R
2And R
3Represent the optional cumarone that replaces with the phenyl ring that they connected, Dihydrobenzofuranes, benzodioxan, benzo dioxolane or naphthalene nucleus system,
X represents NH, N-alkyl (1-3C), CH
2, O, S or C-C,
Y represents general formula (A), (B) or group (C):
Wherein:
R
5Be OH or CH
2OH,
R
6Expression H, alkyl (1-3C), phenyl, NH
2, N-(two)-alkyl (1-3C), OH, O-alkyl (1-3C) or hydroxyalkyl (1-2C),
N is 0,1 or 2,
R
7Expression alkyl (1-3C), benzyl, hydroxyalkyl (1-2C) or methoxyl group alkyl (1-2C),
R
8And R
9Represent H independently, halogen, alkyl (1-3C), CF
3, OH, O-alkyl (1-3C), N-(two)-alkyl (1-3C), 1-morpholinyl, piperidino, 1-piperazinyl, OCF
3, SCH
3, SOCH
3, or SO
2CH
3,
R
10Expression H or alkyl (1-3C),
R
11Expression H, alkyl (1-3C), benzyl, hydroxyalkyl (1-2C) or methoxyl group alkyl (1-2C),
Z represents NOH, NO alkyl (1-3C), O or S.
In described substituent description, abbreviation ' alkyl (1-3C) ' is meant ' methyl, ethyl, n-propyl or sec.-propyl '.
In this manual, ' C
2-C
8Cycloalkyl amino ' be meant any cyclic amine that in ring, contains 2-8 carbon.The cycloalkyl amino ring can contain other atom, and randomly can be substituted.C
2-C
8The example of cycloalkyl amino comprises pyrrolidyl, piperidyl, morpholinyl, aziridinyl, pyrrolinyl etc.
In this manual, ' the optional replacement ' be meant a group can by or can be selected from following one or more groups and further be replaced: alkyl, thiazolinyl; alkynyl, aryl, fluorine; chlorine, bromine, hydroxyl; alkoxyl group, alkene oxygen base, aryloxy; acyloxy, amino, alkylamino; dialkyl amido, arylamino, sulfo-; alkylthio, arylthio, cyano group; oxo, nitro, acyl group; amido, alkyl amido, dialkyl group amido; carboxyl, perhaps two optional substituting groups can form with the carbon atom that they connected and contain 0; 1 or 2 is selected from nitrogen; the heteroatomic 5-of oxygen or sulphur or 6-unit's fragrance or non-aromatic ring.Optional substituting group itself can have additional optional substituting group.The substituting group of preferred optional comprises C
1-3Alkyl such as methyl, ethyl and trifluoromethyl, fluorine, chlorine, bromine, hydroxyl, C
1-3Alkoxyl group such as methoxyl group, oxyethyl group and trifluoromethoxy, and amino.
Wherein the compound that is all formulas (1) of R-configuration or S-configuration of the substituting group on unsymmetrical carbon all belongs to the present invention.
Prodrug, promptly when by any known approach during to people's administration metabolism be the compound of formula (1) compound, also belong to the present invention.Especially, this relates to the compound with primary amino or secondary amino group or hydroxyl, and representative instance is compound and its enantiomorph (seeing below) of formula (9).It can metabolism be the compound of formula (1) compound that such compound can obtain with organic acid reaction.
The present invention be more particularly directed to formula (1) compound, wherein R
1The expression halogen, alkyl (1-3C), O-alkyl (1-3C), CF
3, NH
2Or N-(two)-alkyl (1-3C), and all other symbols have the implication that provides above.
More particularly, the present invention relates to formula (1) compound, wherein R
1=Cl, R
2=H, X=NH, Y are group (A), (B) or (C), and R
6=H, n=1, Z=O, R
10=H and R
3, R
4, R
5, R
7, R
8, R
9And R
11Have the implication that provides above, comprise all possible steric isomer and above-mentioned prodrug, therefore as general formula (2), shown in (3) and (4):
More particularly, the present invention relates to general formula (2), the compound of (3) or (4), wherein R
5=3-CH
2OH; R
7=CH
3R
8=H; R
9=H; R
11=CH
3, and R
3And R
4Have the implication that provides above, comprise all possible steric isomer and above-mentioned prodrug, therefore as general formula (5), shown in (6) and (7):
The more preferably compound of formula (8) and its enantiomorph:
The most preferred embodiment of the present invention is the compound of formula (9) expression:
This compound has pK
i9.0 ± 0.3 to people adenosine-A
3The affinity of acceptor.
The compounds of this invention and salt thereof can obtain according to general routes outlined as described below.R wherein
1Those compounds of=Cl are synthetic according to route 1:
Route 1
The experimental detail of the first step in this general routes outlined can be referring to following document:
● for X=NH, referring to J.Amer.Chem.Soc.116,1994,4326;
● for the X=N-alkyl, referring to Chem.Pharm.Bull.45,1997,291;
● for X=CH
2, referring to Tetrahedron 56,2000,9705;
● for X=O, referring to Pol.J.Chem.74,2000,837;
● for X=S, referring to J.Chem.Soc.C 1967,466 and
● for the X=C-C, referring to Tetrahedron 56,2000,9705.
R wherein
1The The compounds of this invention of=F or Br can obtain from corresponding three halo derivatives like the complete class.Experimental detail can be referring to following document:
● for R
1Be F, referring to J.Med Chem.36 (26), 4195-4200,1993 and
● for R
1=Br, referring to J.Prakt.Chem.82,536,1910.
R wherein
1=O-alkyl (1-3C) or any amino substituting group: NH
2, N-(two)-alkyl (1-3C), N-(two)-thiazolinyl (1-3C), N-(two)-alkynyl (1-3C), N-alkyl (1-3C) thiazolinyl (1-3C), N-alkyl (1-3C) alkynyl (1-3C), N-thiazolinyl (1-3C) alkynyl (1-3C) or the optional C that replaces
2-C
8The The compounds of this invention of cycloalkyl amino group can be as described in the following route 2, and the further replacement by chlorinated derivative obtains:
Route 2
Experimental detail can be referring to following document:
● for R
1=alkoxyl group, referring to Heterocycles 31 (5), 895-909,1990 and
● for R
1=(replacement) amino, referring to Tetrahedron, 54 (1998) 4051-4065.
R wherein
1=alkyl (1-3C), CF
3Or the The compounds of this invention of iodine can obtain by following route 3 described order synthesis steps.
Route 3
Experimental detail can be referring to following document:
● for R
1=alkyl, referring to J.Med Chem 42 (5), 805-818,1999,
● for R
1=CF
3, referring to J.Chem Soc., Chem Comm 1988, (10) 638-639 and
● for R
1=iodine, referring to Eur.J.Org.Chem., 2002,4181-4184.
Can use standard program well-known in the art, for example, obtain pharmacologically acceptable salt by The compounds of this invention is mixed with suitable acid.
Suitable acid salt can be with mineral acid hydrochloric acid for example, sulfuric acid, and phosphoric acid and nitric acid, or with organic acid citric acid for example, fumaric acid, toxilic acid, tartrate, acetate, trifluoroacetic acid, phenylformic acid, tosic acid, methylsulfonic acid and naphthene sulfonic acid form.
The compound of general formula of the present invention (1) with and salt have adenosine-A
3Antagonism or agonist activity.They can be used for treatment and wherein relate to adenosine-A
3The disease of acceptor perhaps can be by regulating the disease that these acceptors are treated.For example be used for: acute and chronic pain; Struvite disease comprises sacroiliitis, multiple sclerosis, asthma and psoriasis; Stomach-intestines obstacle, as ulcer, inflammatory bowel (crohn) and ulcerative colitis; Anaphylaxis is eczema for example, atopic dermatitis and rhinitis; Cardiovascular diseases is myocardial infarction for example, irregular pulse, hypertension, thrombosis, anaemia, arteriosclerosis, stenocardia; Dermatosis is urticaria for example, lupus erythematosus and itch; Ophthalmic diseases such as glaucoma; Dyspnoea comprises chronic obstructive pulmonary disease, bronchitis and cystic fibrosis; Central nervous system disease comprises various forms of epilepsies, apoplexy, dysthymia disorders, sleep apnea; Impaired with cognitive and memory is the illness alzheimer's disease for example of feature, Ke-Ya syndromes, Huntington Chorea, Parkinson's disease and neural rehabilitation (post-traumatic cerebral lesion); Acute brain or Spinal injury; Diabetes; Osteoporosis; Disease of immune system; Various cancers and leukemia; Bacterium and virus infection.
Adenosine-the A of The compounds of this invention
3Receptor antagonist or exciting character adopt method as described below to measure.
With people adenosine-A
3The receptors bind of acceptor
Described compound and people adenosine-A
3The affinity of acceptor adopts C.A.Salvatore et al.:Molecular cloning and characterization of the human A
3Adenosinereceptor, Proc.Natl.Acad.Sci.USA,
90, 10365-10369, the receptor binding assay described in 1993 is measured.Briefly, from people adenosine-A
3People's reconstitution cell (HEK 293) that acceptor is expressed therein with being stabilized obtains the membrane prepare thing.Not or the concentration of diluting in the damping fluid that is fit to is arranged is in the presence of the test compound of 10 μ M to 0.1nM, with film usefulness [
125I]-AB-MECA cultivated 90 minutes at 22 ℃.By filtering with Packard GF/B glass fibre filter, use the Packard cell harvestor, with ice-cold damping fluid washing several, carry out separating of binding radioactivity and free radioactivity.(Topcount, Packard), (Microscint 0, Packard) measures binding radioactivity to adopt the liquid scintillation cocktail with scintillometer.The radioactivity of measuring is figure to the test compound concentration of replacing, and calculates the replacement curve, obtain IC by four parameter logistic regressions
50Value, the replacement compound concentrations when promptly 50% radioligand is replaced.Affinity pK
IValue is by using radioligand concentration correction IC
50Value is calculated, and it is to people adenosine-A
3The affinity of acceptor is calculated according to the Cheng-Prusoff equation:
pK
I=-log(IC
50/(1+S/K
d))
IC wherein
50As mentioned above, S for the test in employed [
125I]-AB-MECA concentration, represent (being generally 0.1nM) with mol/L, and K
dFor [
125I]-AB-MECA and people adenosine-A
3The balance dissociation constant (0.22nM) of acceptor.
In conjunction with in testing, compound of the present invention has high adenosine-A above-mentioned
3Receptor affinity.This character makes them can be used for treatment wherein to relate to adenosine-A
3The disease of acceptor perhaps can be by regulating the disease that these acceptors are treated.
Embodiment
(1S, 2R)-2-{[4-chloro-6-(3,4-methylenedioxyphenyl base amino)-[1,3,5] triazine-2-yl]-amino }-1-phenyl-third-1-alcohol
Under agitation, in remaining on-20 ℃ the solution of cyanuryl chloride (1.84g) in acetonitrile (20ml), drip 3 in succession, solution and diisopropyl ethyl amine (DIPEA) (1.29g) the solution in acetonitrile (20ml) of 4-methylenedioxyphenyl amine (1.37g) in acetonitrile (20ml).-20 ℃ stir 1 hour after, drip in succession again the solution of DIPEA (1.29g) in acetonitrile (20ml) and (1S, 2R)-(+)-solution of norephedrine (1.51g) in acetonitrile (20ml).Make this mixture be warming up to room temperature naturally, and restir 2 hours.The reaction mixture that vacuum concentration obtains.After adding ethyl acetate (250ml), with organic layer use in succession the HCl aqueous solution (1M, 100ml), the NaOH aqueous solution (1M, 100ml) and salt solution (50ml) wash.The organic layer dried over sodium sulfate is filtered and vacuum concentration.The product that obtains is by purification by silica gel column chromatography, and use heptane: the mixture of ethyl acetate (3: 1) is as elutriant.Obtain pure product (formula (9), referring to top, Embodiment B-44 is referring to table), be white solid, yield is 80%.
Further illustrate the present invention by specific embodiment listed, that represent by following general formula in the following table:
Wherein Y represents general formula (A), (B) or group (C):
These embodiment only are in order further to illustrate the present invention in more detail, therefore the scope that does not limit the present invention in any way.
????A-23 | ????Cl | ????NH | ????H | ????H | ????H | ??(A) | ??1 | ????4-OH | ????H |
????A-24 | ????Cl | ????NH | ????H | ????CH 3 | ????H | ??(A) | ??1 | ????4-OH | ????H |
????A-25 | ????Cl | ????NH | ????Cl | ????H | ????H | ??(A) | ??1 | ????4-OH | ????H |
????A-26 | ????Cl | ????NH | ????OCH 3 | ????H | ????H | ??(A) | ??1 | ????4-OH | ????H |
????A-27 | ????Cl | ????NH | ????H | ????OCH 3 | ????H | ??(A) | ??1 | ????4-OH | ????H |
????A-28 | ????Cl | ????NH | ????OC 2H 5 | ????H | ????H | ??(A) | ??1 | ????4-OH | ????H |
????A-29 | ????Cl | ????NH | ????H | ????OC 2H 5 | ????H | ??(A) | ??1 | ????4-OH | ????H |
????A-30 | ????Cl | ????NH | ????H | ????(CH 2) 2OH | ????H | ??(A) | ??1 | ????4-OH | ????H |
????nr | ????R 1 | ????X | ????R 2 | ????R 3 | ????R 4 | ??Y | ??n | ????R 5 | ????R 6 |
????A-31 | ????Cl | ????NH | The O-phenyl | ????H | ????H | ??(A) | ??1 | ????4-OH | ????H |
????A-32 | ????Cl | ????NH | ????H | The O-phenyl | ????H | ??(A) | ??1 | ????4-OH | ????H |
????A-33 | ????Cl | ????NH | ????H | The 1-morpholinyl | ????H | ??(A) | ??1 | ????4-OH | ????H |
????A-34 | ????Cl | ????NH | ????CH 3 | ????CH 3 | ????H | ??(A) | ??1 | ????4-OH | ????H |
????A-35 | ????Cl | ????NH | ????F | ????CH 3 | ????H | ??(A) | ??1 | ????4-OH | ????H |
????A-36 | ????Cl | ????NH | ????F | ????OCH 3 | ????H | ??(A) | ??1 | ????4-OH | ????H |
????A-37 | ????Cl | ????NH | ????OCH 3 | ????H | ????CF 3 | ??(A) | ??1 | ????4-OH | ????H |
????A-38 | ????Cl | ????NH | ????OCH 3 | ????H | ????OCH 3 | ??(A) | ??1 | ????4-OH | ????H |
????A-39 | ????Cl | ????NH | -phenyl- | ????H | ??(A) | ??1 | ????4-OH | ????H | |
????A-40 | ????Cl | ????NH | ????????-O-CH 2-O- | ????H | ??(A) | ??1 | ????2-CH 2OH | ????H | |
????A-41 | ????Cl | ????NH | ????OCH 3 | ????H | ????H | ??(A) | ??1 | ????2-CH 2OH | ????H |
????A-42 | ????Cl | ????NH | ????H | ????OCH 3 | ????H | ??(A) | ??1 | ????2-CH 2OH | ????H |
????A-43 | ????Cl | ????NH | ????H | ????OC 2H 5 | ????H | ??(A) | ??1 | ????2-CH 2OH | ????H |
????A-44 | ????Cl | ????NH | ????H | The 1-morpholinyl | ????H | ??(A) | ??1 | ????2-CH 2OH | ????H |
????A-45 | ????Cl | ????NH | ????CH 3 | ????CH 3 | ????H | ??(A) | ??1 | ????2-CH 2OH | ????H |
??A-46 | ????Cl | ????NH | ????F | ????OCH 3 | ????H | ??(A) | ??1 | ????2-CH 2OH | ????H |
??A-47 | ????Cl | ????NH | ????OCH 3 | ????H | ????OCH 3 | ??(A) | ??1 | ????2-CH 2OH | ????H |
??A-48 | ????Cl | ????NH | ?????????-O-CH 2-O- | ????H | ??(A) | ??1 | ????3-CH 2OH | ????H | |
??A-49 | ????CH 3 | ????NH | ?????????-O-CH 2-O- | ????H | ??(A) | ??1 | ????3-CH 2OH | ????H | |
??A-50 | ????OCH 3 | ????NH | ?????????-O-CH 2-O- | ????H | ??(A) | ??1 | ????3-CH 2OH | ????H | |
??A-51 | The 1-morpholinyl | ????NH | ?????????-O-CH 2-O- | ????H | ??(A) | ??1 | ????3-CH 2OH | ????H | |
??A-52 | The 1-tetramethyleneimine | ????NH | ?????????-O-CH 2-O- | ????H | ??(A) | ??1 | ????3-CH 2OH | ????H | |
??A-53 | The NH-propargyl | ????NH | ?????????-O-CH 2-O- | ????H | ??(A) | ??1 | ????3-CH 2OH | ????H | |
??A-54 | ????Cl | ????NCH 3 | ?????????-O-CH 2-O- | ????H | ??(A) | ??1 | ????3-CH 2OH | ????H | |
??A-55 | ????Cl | ????O | ?????????-O-CH 2-O- | ????H | ??(A) | ??1 | ????3-CH 2OH | ????H | |
??A-56 | ????Cl | ????S | ?????????-O-CH 2-O- | ????H | ??(A) | ??1 | ????3-CH 2OH | ????H | |
??A-57 | ????Cl | ????CH 2 | ?????????-O-CH 2-O- | ????H | ??(A) | ??1 | ????3-CH 2OH | ????H | |
??A-58 | ????Cl | Key | ?????????-O-CH 2-O- | ????H | ??(A) | ??1 | ????3-CH 2OH | ????H | |
??A-59 | ????Cl | ????NH | ?????????-O-CH 2-O- | ????H | ??(A) | ??1 | ????4-CH 2OH | ????H | |
??A-60 | ????Cl | ????NH | ?????????-O-CH 2-O- | ????H | ??(A) | ??0 | ????3-OH | ????H | |
??A-61 | ????Cl | ????NH | ????CH 3 | ????H | ????H | ??(A) | ??0 | ????3-OH | ????H |
??nr | ????R 1 | ????X | ????R 2 | ????R 3 | ????R 4 | ??Y | ??n | ????R 5 | ????R 6 |
??A-62 | ????Cl | ????NH | ????Cl | ????H | ????H | ??(A) | ??0 | ????3-OH | ????H |
??A-63 | ????Cl | ????NH | ????OCH 3 | ????H | ????H | ??(A) | ??0 | ????3-OH | ????H |
??A-64 | ????Cl | ????NH | ????H | ????OCH 3 | ????H | ??(A) | ??0 | ????3-OH | ????H |
??A-65 | ????Cl | ????NH | ????H | ????OC 2H 5 | ????H | ??(A) | ??0 | ????3-OH | ????H |
??A-66 | ????Cl | ????NH | ????H | The 1-morpholinyl | ????H | ??(A) | ??0 | ????3-OH | ????H |
??A-67 | ????Cl | ????NH | ????CH 3 | ????CH 3 | ????H | ??(A) | ??0 | ????3-OH | ????H |
??A-68 | ????Cl | ????NH | ????F | ????CH 3 | ????H | ??(A) | ??0 | ????3-OH | ????H |
??A-69 | ????Cl | ????NH | ????F | ????OCH 3 | ????H | ??(A) | ??0 | ????3-OH | ????H |
??A-70 | ????Cl | ????NH | -phenyl- | ????H | ??(A) | ??0 | ????3-OH | ????H | |
??A-71 | ????Cl | ????NH | ????-O-CH 2-O- | ????H | ??(A) | ??0 | ????3-CH 2OH | ????H |
?B-17 | ????Cl | ????NH | ????OCH 2CH 3 | ??H | ????H | ????(B) | ????CH 3 | ????H | ????H | ??CH 3 | ????1R,2R |
?B-18 | ????Cl | ????NH | ????CH 3 | ??H | ????H | ????(B) | ????CH 3 | ????H | ????H | ??H | ????1S,2R |
?B-19 | ????Cl | ????NH | ????Cl | ??H | ????H | ????(B) | ????CH 3 | ????H | ????H | ??H | ????1S,2R |
?B-20 | ????Cl | ????NH | ????Cl | ??H | ????H | ????(B) | ????CH 3 | ????H | ????H | ??CH 3 | ????1R,2R |
?B-21 | ????Cl | ????NH | ????CH(OH)CH 3 | ??H | ????H | ????(B) | ????CH 3 | ????H | ????H | ??H | ????1S,2R |
?B-22 | ????Cl | ????NH | ????CH(OH)CH 3 | ??H | ????H | ????(B) | ????CH 3 | ????H | ????H | ??CH 3 | ????1R,2R |
?B-23 | ????Cl | ????NH | The O-phenyl | ??H | ????H | ????(B) | ????CH 3 | ????H | ????H | ??H | ????1S,2R |
?B-24 | ????Cl | ????NH | The O-phenyl | ??H | ????H | ????(B) | ????CH 3 | ????H | ????H | ??CH 3 | ????1R,2R |
?B-25 | ????Cl | ????NH | ????H | ??OCH 3 | ????H | ????(B) | ????CH 3 | ????H | ????H | ??H | ????1S,2R |
?B-26 | ????Cl | ????NH | ????H | ??OCH 3 | ????H | ????(B) | ????CH 3 | ????H | ????H | ??H | ????1R,2S |
?B-27 | ????Cl | ????NH | ????H | ??OCH 3 | ????H | ????(B) | ????CH 3 | ????H | ????H | ??CH 3 | ????1R,2R |
?B-28 | ????Cl | ????NH | ????H | ??OCH 2CH 3 | ????H | ????(B) | ????CH 3 | ????H | ????H | ??H | ????1S,2R |
?B-29 | ????Cl | ????NH | ????H | The 1-morpholinyl | ????H | ????(B) | ????CH 3 | ????H | ????H | ??H | ????1S,2R |
?B-30 | ????Cl | ????NH | ????H | ??CH 3 | ????H | ????(B) | ????CH 3 | ????H | ????H | ??H | ????1S,2R |
?Nr | ????R 1 | ????X | ????R 2 | ??R 3 | ????R 4 | ????Y | ????R 7 | ????R 8 | ????R 9 | ??R 10 | Three-dimensional |
?B-31 | ????Cl | ????NH | ????H | ??CF 3 | ????H | ????(B) | ????CH 3 | ????H | ????H | ??H | ????1S,2R |
?B-32 | ????Cl | ????NH | ????H | The O-phenyl | ????H | ????(B) | ????CH 3 | ????H | ????H | ??H | ????1S,2R |
?B-33 | ????Cl | ????NH | ????H | The O-phenyl | ????H | ????(B) | ????CH 3 | ????H | ????H | ??CH 3 | ????1R,2R |
?B-34 | ????Cl | ????NH | ????H | ????(CH 2) 2OH | ????H | ????(B) | ????CH 3 | ????H | ????H | ??CH 3 | ????1R,2R |
?B-35 | ????Cl | ????NH | ????F | ????CH 3 | ????H | ????(B) | ????CH 3 | ????H | ????H | ??H | ????1S,2R |
?B-36 | ????Cl | ????NH | ????F | ????OCH 3 | ????H | ????(B) | ????CH 3 | ????H | ????H | ??H | ????1S,2R |
?B-37 | ????Cl | ????NH | ????F | ????OCH 3 | ????H | ????(B) | ????CH 3 | ????H | ????H | ??CH 3 | ????1R,2R |
?B-38 | ????Cl | ????NH | ????F | ????OCH 3 | ????H | ????(B) | ????CH 3 | ????H | ????H | ??CH 3 | ????1R,2S |
?B-39 | ????Cl | ????NH | ????OCH 3 | ????H | ????CF 3 | ????(B) | ????CH 3 | ????H | ????H | ??H | ????1S,2R |
?B-40 | ????Cl | ????NH | ????OCH 3 | ????H | ????OCH 3 | ????(B) | ????CH 3 | ????H | ????H | ??H | ????1S,2R |
?B-41 | ????Cl | ????NH | ????OCH 3 | ????H | ????OCH 3 | ????(B) | ????CH 3 | ????H | ????H | ??CH 3 | ????1R,2R |
?B-42 | ????Cl | ????NH | ????CH 3 | ????CH 3 | ????H | ????(B) | ????CH 3 | ????H | ????H | ??H | ????1S,2R |
?B-43 | ????Cl | ????NH | -phenyl- | ????H | ????(B) | ????CH 3 | ????H | ????H | ??H | ????1S,2R | |
?B-44 | ????Cl | ????NH | ??????-O-CH 2-O- | ????H | ????(B) | ????CH 3 | ????H | ????H | ??H | ????1S,2R | |
?B-45 | ????Cl | ????NH | ??????-O-CH 2-O- | ????H | ????(B) | ????CH 3 | ????H | ????H | ??H | ????1R,2S | |
?B-46 | ????Cl | ????NH | ??????-O-CH 2-O- | ????H | ????(B) | ????CH 3 | ????H | ????H | ??CH 3 | ????1S,2R | |
?B-47 | ????Cl | ????NH | ??????-O-CH 2-O- | ????H | ????(B) | ????CH 3 | ????H | ????H | ??CH 3 | ????1S,2S | |
?B-48 | ????Cl | ????NH | ??????-O-CH 2-O- | ????H | ????(B) | ????CH 3 | ????H | ????H | ??CH 3 | ????1R,2S | |
?B-49 | ????Cl | ????NH | ??????-O-CH 2-O- | ????H | ????(B) | ????CH 3 | ????H | ????H | ??CH 3 | ????1R,2R | |
?B-50 | ????Cl | ????NCH 3 | ??????-O-CH 2-O- | ????H | ????(B) | ????CH 3 | ????H | ????H | ??H | ????1S,2R | |
?B-51 | ????Cl | ????O | ??????-O-CH 2-O- | ????H | ????(B) | ????CH 3 | ????H | ????H | ??H | ????1S,2R | |
?B-52 | ????Cl | ????S | ??????-O-CH 2-O- | ????H | ????(B) | ????CH 3 | ????H | ????H | ??H | ????1S,2R |
?B-53 | ????Cl | ????CH 2 | ??????-O-CH 2-O- | ????H | ????(B) | ????CH 3 | ????H | ????H | ???H | ????1S,2R | |
?B-54 | ????Cl | Key | ??????-O-CH 2-O- | ????H | ????(B) | ????CH 3 | ????H | ????H | ???H | ????1S,2R | |
?B-55 | ????Cl | ????NH | ??????-O-CH 2-O- | ????H | ????(B) | ????CH 3 | ????3-OH | ????H | ???H | ????1R,2S | |
?B-56 | ????Cl | ????NH | ??????-O-CH 2-O- | ????H | ????(B) | ????CH 3 | ????4-OH | ????H | ???H | ????1S,2R | |
?B-57 | ????Cl | ????NH | ??????-O-CH 2-O- | ????H | ????(B) | ????CH 3 | ????3-OH | ????4-OH | ???H | ????1R,2S | |
?B-58 | ????Cl | ????NH | ??????-O-CH 2-O- | ????H | ????(B) | ????CH 3 | ????2-OCH 3 | ????5-OCH 3 | ???H | Racemic | |
?B-59 | ????NH 2 | ????NH | ??????-O-CH 2-O- | ????H | ????(B) | ????CH 3 | ????H | ????H | ???H | ????1R,2S | |
?B-60 | ????N(CH 3) 2 | ????NH | ??????-O-CH 2-O- | ????H | ????(B) | ????CH 3 | ????H | ????H | ???H | ????1R,2S | |
?B-61 | The 1-pyrrolidyl | ????NH | ??????-O-CH 2-O- | ????H | ????(B) | ????CH 3 | ????H | ????H | ???H | ????1S,2R | |
?Nr | ????R 1 | ????X | ????R 2 | ????R 3 | ????R 4 | ????Y | ????R 7 | ????R 8 | ????R 9 | ???R 10 | Three-dimensional |
?B-62 | The 1-morpholinyl | ????NH | ??????-O-CH 2-O- | ????H | ????(B) | ????CH 3 | ????H | ????H | ???H | ????1S,2R | |
?B-63 | Piperidino | ????NH | ??????-O-CH 2-O- | ????H | ????(B) | ????CH 3 | ????H | ????H | ???H | ????1S,2R | |
?B-64 | The NH-propargyl | ????NH | ??????-O-CH 2-O- | ????H | ????(B) | ????CH 3 | ????H | ????H | ???H | ????1S,2R | |
?B-65 | ????N(CH 3) propargyl | ????NH | ??????-O-CH 2-O- | ????H | ????(B) | ????CH 3 | ????H | ????H | ???H | ????1S,2R | |
?B-66 | ????CH 3 | ????NH | ??????-O-CH 2-O- | ????H | ????(B) | ????CH 3 | ????H | ????H | ???H | ????1S,2R | |
?B-67 | ????OCH 3 | ????NH | ??????-O-CH 2-O- | ????H | ????(B) | ????CH 3 | ????H | ????H | ???H | ????1S,2R |
The embodiment of prodrug
The notion of " prodrug " is described for example, has prepared the compound of following formula (10):
Embodiment | The R-group |
Preceding-1 | Propionyl |
Preceding-2 | Valeryl |
Preceding-3 | Nicotinoyl |
Preceding-4 | N-ethanoyl-different piperidine formyl base |
Preceding-5 | The methoxyl group ethanoyl |
Preceding-6 | The acetoxyl group ethanoyl |
Preceding-7 | Nonanoyl |
To the affinity of people's adenosine-A3 acceptor, still after hydrolysis, their do not produce the compound (see above) of the very high formula (9) of activity to the prodrug of formula (10).
Claims (14)
1. the compound of general formula (1), its pharmacologically acceptable salt and wherein the substituting group on potential asymmetric carbon atom be the compound of all formulas (1) of R-configuration or S-configuration, with and prodrug,
Wherein
R
1The expression halogen, alkyl (1-3C), O-alkyl (1-3C), CF
3, NH
2, N-(two)-alkyl (1-3C), N-(two)-thiazolinyl (1-3C), N-(two)-alkynyl (1-3C), N-alkyl (1-3C) thiazolinyl (1-3C), N-alkyl (1-3C) alkynyl (1-3C), N-thiazolinyl (1-3C) alkynyl (1-3C) or the optional C that replaces
2-C
8The cycloalkyl amino group,
R
2, R
3And R
4Represent H independently, halogen, alkyl (1-3C), CF
3, OH, O-alkyl (1-3C), phenoxy group, hydroxyalkyl (1-3C), alkoxyl group (1-2C)-alkyl (1-2C), phenyl, N-(two)-alkyl (1-3C), 1-morpholinyl, piperidino, 1-piperazinyl, OCF
3, SCH
3, SOCH
3, SO
2CH
3, perhaps R
2And R
3Represent the optional cumarone that replaces with the phenyl ring that they connected, Dihydrobenzofuranes, benzodioxan, benzo dioxolane or naphthalene nucleus system,
X represents NH, N-alkyl (1-3C), CH
2, O, S or C-C,
Y represents general formula (A), (B) or group (C):
Wherein:
R
5Be OH or CH
2OH,
R
6Expression H, alkyl (1-3C), phenyl, NH
2, N-(two)-alkyl (1-3C), OH, O-alkyl (1-3C) or hydroxyalkyl (1-2C),
N is 0,1 or 2,
R
7Expression alkyl (1-3C), benzyl, hydroxyalkyl (1-2C) or methoxyl group alkyl (1-2C),
R
8And R
9Represent H independently, halogen, alkyl (1-3C), CF
3, OH, O-alkyl (1-3C), N-(two)-alkyl (1-3C), 1-morpholinyl, piperidino, 1-piperazinyl, OCF
3, SCH
3, SOCH
3, or SO
2CH
3,
R
10Expression H or alkyl (1-3C),
R
11Expression H, alkyl (1-3C), benzyl, hydroxyalkyl (1-2C) or methoxyl group alkyl (1-2C),
Z represents NOH, NO alkyl (1-3C), O or S.
2. the compound of the described general formula of claim 1 (1), wherein R
1The expression halogen, alkyl (1-3C), O-alkyl (1-3C), CF
3, NH
2Or N-(two)-alkyl (1-3C); R
2, R
3And R
4Represent H independently, halogen, alkyl (1-3C), CF
3, OH, O-alkyl (1-3C), phenyl, N-(two)-alkyl (1-3C), 1-morpholinyl, piperidino, 1-piperazinyl, OCF
3, SCH
3, SOCH
3, SO
2CH
3, perhaps R
2And R
3Represent cumarone with the phenyl ring that they connected, benzodioxan or benzo dioxolane ring system, X represents NH, N-alkyl (1-3C), CH
2, O, S or C-C, Y represent general formula (A) or group (B), wherein R
5Be OH or CH
2OH; R
6Expression H, alkyl (1-3C), phenyl, NH
2, N-(two)-alkyl (1-3C), OH, O-alkyl (1-3C) or hydroxyalkyl (1-2C); N is 0,1 or 2; R
7Expression alkyl (1-3C), benzyl or hydroxyalkyl (1-2C); R
8And R
9Represent H independently, halogen, alkyl (1-3C), CF
3, OH, O-alkyl (1-3C), N-(two)-alkyl (1-3C), 1-morpholinyl, piperidino, 1-piperazinyl, OCF
3, SCH
3, SOCH
3, or SO
2CH
3And R
10=H.
3. the compound of the described general formula of claim 1 (1), wherein Y is the group of general formula (A), and R
1, R
2, R
3, R
4, R
5, R
6, X and n have the implication described in the claim 1.
4. the compound of the described general formula of claim 1 (1), wherein Y is the group of general formula (A), and R
1, R
2, R
3, R
4, R
5, R
6, X and n have the implication described in the claim 2.
5. the compound of the described general formula of claim 1 (1), wherein Y is the group of general formula (B), and R
1, R
2, R
3, R
4, R
7, R
8, R
9, R
10Has the implication described in the claim 1 with X.
6. the compound of the described general formula of claim 1 (1), wherein Y is the group of general formula (B), and R
1, R
2, R
3, R
4, R
7, R
8, R
9, R
10Has the implication described in the claim 2 with X.
7. the compound of the described general formula of claim 1 (1), wherein Y is the group of general formula (C), and R
1, R
2, R
3, R
4, R
8, R
9, R
10, R
11, X and Z have the implication described in the claim 1.
8. the compound of the described general formula of claim 1 (1), wherein R
1=Cl, R
2=H, X=NH, Y are group (A), (B) or (C), and R
6=H, n=1, Z=O, R
10=H, and R
3, R
4, R
5, R
7, R
8, R
9And R
11Has the implication described in the claim 1.
9. the compound of the described general formula of claim 1 (1), wherein R
1=Cl, R
2=H, X=NH, Y are group (A), (B) or (C), and R
5=3-CH
2OH, R
6=H, n=1, R
7=CH
3R
8=H; R
9=H, Z=O, R
10=H, R
11=CH
3, and R
3And R
4Has the implication described in the claim 1.
11. the described compound of claim 1 with general formula (9)
12. pharmaceutical composition, contain pharmacological activity amount, among at least a claim 1-11 any described compound as activeconstituents.
13. any described compound is used for the treatment of in preparation and wherein relates to adenosine-A among the claim 1-11
3The disease of acceptor or can be by the purposes in the pharmaceutical composition of regulating the disease that these acceptors treat.
14. the described purposes of claim 13, wherein said disease are acute and chronic pain; Struvite disease comprises sacroiliitis, multiple sclerosis, asthma and psoriasis; Stomach-intestines obstacle, as ulcer, inflammatory bowel (crohn) and ulcerative colitis; Anaphylaxis is eczema for example, atopic dermatitis and rhinitis; Cardiovascular diseases is myocardial infarction for example, irregular pulse, hypertension, thrombosis, anaemia, arteriosclerosis, stenocardia; Dermatosis is urticaria for example, lupus erythematosus and itch; Ophthalmic diseases such as glaucoma; Dyspnoea comprises chronic obstructive pulmonary disease, bronchitis and cystic fibrosis; Central nervous system disease comprises various forms of epilepsies, apoplexy, dysthymia disorders, sleep apnea; Impaired with cognitive and memory is the obstacle alzheimer's disease for example of feature, Ke-Ya syndromes, Huntington Chorea, Parkinson's disease and neural rehabilitation (post-traumatic cerebral lesion); Acute brain or Spinal injury; Diabetes; Osteoporosis; Disease of immune system; Various cancers and leukemia; Bacterium and virus infection.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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EP02077310 | 2002-05-30 | ||
EP02077310.7 | 2002-05-30 |
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Publication Number | Publication Date |
---|---|
CN1646520A true CN1646520A (en) | 2005-07-27 |
CN1329388C CN1329388C (en) | 2007-08-01 |
Family
ID=29595045
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CNB038090937A Expired - Fee Related CN1329388C (en) | 2002-05-30 | 2003-05-28 | 1,3,5-triazine derivatives as ligands for human adenosine-A3 receptors |
Country Status (16)
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EP (1) | EP1513827A1 (en) |
JP (1) | JP4590260B2 (en) |
CN (1) | CN1329388C (en) |
AR (1) | AR040231A1 (en) |
AU (1) | AU2003250232B2 (en) |
BR (1) | BR0304925A (en) |
CA (1) | CA2484981C (en) |
HK (1) | HK1075045A1 (en) |
HR (1) | HRP20040970A2 (en) |
IL (1) | IL164240A (en) |
MX (1) | MXPA04011948A (en) |
PL (1) | PL372418A1 (en) |
RU (1) | RU2312859C2 (en) |
UA (1) | UA77816C2 (en) |
WO (1) | WO2003101980A1 (en) |
ZA (1) | ZA200408029B (en) |
Families Citing this family (5)
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CA2533397A1 (en) * | 2003-07-22 | 2005-02-03 | Neurogen Corporation | Substituted pyridin-2-ylamine analogues |
WO2005028467A1 (en) | 2003-09-15 | 2005-03-31 | Anadys Pharmaceuticals, Inc. | Antibacterial 3,5-diaminopiperidine-substitute aromatic and heteroaromatic compounds |
GB2465405A (en) * | 2008-11-10 | 2010-05-19 | Univ Basel | Triazine, pyrimidine and pyridine analogues and their use in therapy |
ES2665561T3 (en) | 2012-07-04 | 2018-04-26 | Agro-Kanesho Co., Ltd. | Ester derivative of 2-aminonicotinic acid and bactericide containing the same as active ingredient |
GB201810668D0 (en) | 2018-06-28 | 2018-08-15 | Stiftelsen Alzecure | New compounds |
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GB9226735D0 (en) * | 1992-12-22 | 1993-02-17 | Ici Plc | Azole derivatives |
DE19735800A1 (en) * | 1997-08-18 | 1999-02-25 | Boehringer Ingelheim Pharma | Use of known and new triazine derivatives |
JPH11158073A (en) * | 1997-09-26 | 1999-06-15 | Takeda Chem Ind Ltd | Adenosine a3 antagonist |
-
2003
- 2003-05-28 RU RU2004138803/04A patent/RU2312859C2/en not_active IP Right Cessation
- 2003-05-28 UA UA20041210642A patent/UA77816C2/en unknown
- 2003-05-28 AU AU2003250232A patent/AU2003250232B2/en not_active Ceased
- 2003-05-28 PL PL03372418A patent/PL372418A1/en not_active Application Discontinuation
- 2003-05-28 WO PCT/EP2003/050203 patent/WO2003101980A1/en active Application Filing
- 2003-05-28 EP EP03755982A patent/EP1513827A1/en not_active Withdrawn
- 2003-05-28 BR BR0304925-6A patent/BR0304925A/en not_active IP Right Cessation
- 2003-05-28 MX MXPA04011948A patent/MXPA04011948A/en active IP Right Grant
- 2003-05-28 JP JP2004509671A patent/JP4590260B2/en not_active Expired - Fee Related
- 2003-05-28 CN CNB038090937A patent/CN1329388C/en not_active Expired - Fee Related
- 2003-05-28 CA CA2484981A patent/CA2484981C/en not_active Expired - Fee Related
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-
2004
- 2004-09-23 IL IL164240A patent/IL164240A/en not_active IP Right Cessation
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- 2004-10-15 HR HR20040970A patent/HRP20040970A2/en not_active Application Discontinuation
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Also Published As
Publication number | Publication date |
---|---|
AR040231A1 (en) | 2005-03-23 |
AU2003250232A1 (en) | 2003-12-19 |
JP2005531600A (en) | 2005-10-20 |
IL164240A (en) | 2010-12-30 |
AU2003250232B2 (en) | 2008-09-11 |
CA2484981A1 (en) | 2003-12-11 |
ZA200408029B (en) | 2005-10-06 |
UA77816C2 (en) | 2007-01-15 |
PL372418A1 (en) | 2005-07-25 |
CA2484981C (en) | 2011-07-26 |
WO2003101980A1 (en) | 2003-12-11 |
RU2004138803A (en) | 2005-06-10 |
RU2312859C2 (en) | 2007-12-20 |
EP1513827A1 (en) | 2005-03-16 |
MXPA04011948A (en) | 2005-03-31 |
CN1329388C (en) | 2007-08-01 |
BR0304925A (en) | 2004-09-28 |
JP4590260B2 (en) | 2010-12-01 |
HRP20040970A2 (en) | 2005-06-30 |
IL164240A0 (en) | 2005-12-18 |
HK1075045A1 (en) | 2005-12-02 |
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