CN101516882B - Selective antagonists of A2A adenosine receptors - Google Patents
Selective antagonists of A2A adenosine receptors Download PDFInfo
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- CN101516882B CN101516882B CN2007800343349A CN200780034334A CN101516882B CN 101516882 B CN101516882 B CN 101516882B CN 2007800343349 A CN2007800343349 A CN 2007800343349A CN 200780034334 A CN200780034334 A CN 200780034334A CN 101516882 B CN101516882 B CN 101516882B
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- propargyl
- group
- phenyl
- piperidines
- purine
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Abstract
The present invention provides compounds of formulae (Ia) and (Ib): wherein R<1-5>, Q, X, Y, Z, p, q, and r are as defined herein. The compounds are potent and selective antagonists of A2A adenosine receptors (ARs). The invention further includes pharmaceutical compositions containing these compounds and methods of using the same.
Description
Related application data
The rights and interests that No. the 60/807th, 545, the U.S. Provisional Application that the application requires to submit on July 17th, 2006, the disclosure of this provisional application is all incorporated at this.
Technical field
The present invention relates to is A
2AThe compound and the pharmaceutical composition of the selective antagonist of Adenosine Receptors (AR).These compounds are effective as medicament.
Background technology
Confirmed A
2AThe selective antagonist of Adenosine Receptors is all effectively treated parkinson's disease (PD) in animal model and people's test.(see Hauser etc., Neurology 2003,61,297-303).First kind relative selectivity A
2AThe AR antagonist is a 8-styryl xanthine, KW-6002 for example, and it is to A
2AAR has low nmole avidity, and to A
2AThe selectivity ratios of AR is to A
1The selectivity of AR＞100 times.KW-6002,2002 as PD therapeutical agent entering clinical trial.(see Bara-Jimenez etc., Neurology 2003,61, and 293-296) SCH58261, pyrazolo [4,3-e]-1,2,4-triazoles also [1,5-c] pyrimidine are the prototypes of a series of s-generation verivates, said s-generation verivate external also to A
2AAR have low nmole avidity and good selectivity (see Zocchi etc., Br.J.Pharmacol.1996,117,1381-1386).The antagonist 1,2 of the 3rd type of appearance, 4-triazolo [4,5-e]-1,3,5-triazines, with ZM241385 representative, in inferior nmole scope to A
2AAR effectively but have some cross reactivities.(see Keddie etc., Eur.J.Pharmacol., 1996,301,107-113).
These effective A
2AAntagonist has been important research tool, greatly promotes A in vitro and in vivo
2AThe pharmaceutical research of AR function, and significantly strengthen us to A
2AThe understanding of AR neurobiology.Yet each in these antagonists all has important shortcoming.KW-6002 is the concurrent third contact of a total solar or lunar eclipse isomerizing of photosensitivity, tautomerizes to active low 800 times Z isomer from active E isomer.SCH58261 solubleness is extremely low, even and the bioavailability of its s-generation verivate also limited.It is limited that ZM241385 is not only selectivity, and bioavailability is also low.Other nitrogen heterocyclic is for example from 1,2 of ICI, and 4-triazolo [4,3-α] quinoxaline-1-ketone and oxazole also [4,5-d] pyrimidine also are nonselective, and their bioavailability of the unknown.(see Colotta etc., Arch.Pharm. (Weinheim) 1999,332,39-41).
Though for A
1, A
2A, A
2BAnd A
3AR can obtain Adenosine Receptors subtype-selective probe, but seldom obtains having the selective antagonist of character in acceptable body outer property and the body.Therefore, so exist to selectivity A
2AThe lasting demand of the compound of receptor antagonist.
Summary of the invention
The invention provides as A
2AThe acting compound of adenosine receptor antagonists and steric isomer and pharmacy acceptable salt.
The present invention also provides pharmaceutical composition, and this pharmaceutical composition comprises and pharmaceutically acceptable carrier-bound compound of the present invention or its steric isomer or pharmacy acceptable salt.
In addition, the invention provides and be used to treat Mammals such as people's pathological condition or the treat-ment of symptom, wherein adenosine A
2AFor example overactivity (over-activity) involves into pathological one or more symptoms to the activity of acceptor and expectation improves said symptom to their active antagonistic action (i.e. blocking-up).Therefore; The invention provides the method for treatment disease; Said method comprises at least a The compounds of this invention or its steric isomer or the pharmacy acceptable salt of administering therapeutic significant quantity, and wherein said disease is selected from dyspraxia, cancer, habituation venereal disease disease (addictive disorder) (for example smoking, alcohol, medicine).
The invention provides the The compounds of this invention that confession is used in therapeutic treatment.
The present invention also provides The compounds of this invention to be used to prepare the purposes of medicine.
Other purpose of the present invention, feature and advantage will become obvious by following detailed description.Yet; Having pointed out each side of the present invention although should be understood that detailed description and specific embodiment, only is to provide for explanation; Because described in detail by this for a person skilled in the art, various variations in spirit and scope of the invention and change will become obvious.
The best mode of embodiment of the present invention
The applicant finds that compound of the present invention can be used for treatment and deleterious A
2AReceptor activation or active diseases associated.
On the one hand, the invention provides novel formula Ia or compound or its steric isomer or the pharmacy acceptable salt of Ib:
Wherein:
(CH
2)
n(CH
2)
q(CH
2) part be selected from independently OH ,=O, C
1-4Alkyl, C
3-6The 0-2 of naphthenic base and benzyl group replaces;
Q is O or S;
X is CH or N;
Y is selected from by O, NY
1, OCH
2CH
2OCH
2, OCH
2CH
2OCH
2CH
2OCH
2, OCH
2CH
2OCH
2CH
2OCH
2CH
2OCH
2, NY
1CH
2CH
2OCH
2, NY
1CH
2CH
2OCH
2CH
2OCH
2And NY
1CH
2CH
2OCH
2CH
2OCH
2CH
2OCH
2The group of forming;
Selectively, Y does not exist;
Y
1Be selected from by H, C
1-4Alkyl, benzyl, C
3-6Naphthenic base and (C
3-6Naphthenic base) C
1-4The group that alkylidene group is formed;
Z is selected from the group of being made up of aryl and heteroaryl, and wherein Z is via the carbon atom connection and by 1-4 Z
1Group replaces;
Z
1Be independently selected from by F, Cl, Br, I, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl ,-(CH
2)
aOR
a,-(CH
2)
aNR
aR
a,-(CH
2)
aNHOH ,-(CH
2)
aNR
aNR
aR
a,-(CH
2)
aNO
2,-(CH
2)
aCN ,-(CH
2)
aCO
2R
a,-(CH
2)
aC (O) R
a,-(CH
2)
aOC (O) R
a,-(CH
2)
aCONR
aR
a, CF
3And OCF
3The group of forming;
R
aBe independently selected from by H, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
3-8Naphthenic base, (C
3-8Naphthenic base) C
1-8Alkylidene group, aryl, (aryl) C
1-8Alkylidene group, heteroaryl and (heteroaryl) C
1-8The group that alkylidene group is formed, the selectively selected freedom-O-of wherein said alkyl and naphthenic base ,-S (O)
0-2-with-NR
c1-2 heteroatoms of the group of-composition at interval;
R
1Be independently selected from by H, C
1-8Alkyl, C
3-8Naphthenic base, (C
3-8Naphthenic base) C
1-8Alkylidene group, aryl, (aryl) C
1-8Alkylidene group, heteroaryl, (heteroaryl) C
1-8Alkylidene group, (aryl) (aryl)-C
1-8Alkylidene group, (heteroaryl) (heteroaryl)-C
1-8Alkylidene group and (aryl) (heteroaryl) C
1-8The group that alkylidene group is formed, the selectively selected freedom-O-of wherein said alkyl and naphthenic base ,-S (O)
0-2-with-NR
c1-2 heteroatoms interval of the group of-composition, and R
1Group be independently selected from by F, Cl, Br, I, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl ,-(CH
2)
aOR
a,-(CH
2)
aNR
aR
a,-(CH
2)
aNHOH ,-(CH
2)
aNR
aNR
aR
a,-(CH
2)
aNO
2,-(CH
2)
aCN ,-(CH
2)
aCO
2R
a,-(CH
2)
aC (O) R
a,-(CH
2)
aOC (O) R
a,-(CH
2)
aCONR
aR
a, CF
3And OCF
30-4 group of the group of forming replaces;
R
2Be selected from by H, C
1-6Alkyl, OR
a, N (R
a)
2, C
3-8The group that naphthenic base, aryl, heterocycle and heteroaryl are formed, wherein said alkyl, naphthenic base, aryl, heterocycle and heteroaryl selectively are independently selected from by F, Cl, I, Br, CH
3, CF
3And CH
31-2 group of the group that O forms replaces;
R
3Do not exist or C
1-8Alkylidene group, the selectively selected freedom-O-of wherein said alkylidene group ,-S (O)
0-21-2 the heteroatoms interval of-group formed with-NH-;
R
3Selected free F, Cl, Br, I ,-OR
d,-SR
d,-N (R
d)
2, C
3-6Naphthenic base, (C
3-6Naphthenic base) C
1-4Alkylidene group, aryl, (aryl) C
1-4Alkylidene group, heteroaryl and (heteroaryl) C
1-40-2 group of the group that alkylidene group is formed replaces, the selectively selected freedom-O-of wherein said alkylidene group and naphthenic base ,-S (O)
0-2-with-NR
c1-2 heteroatoms of the group of-composition at interval;
R
4Be selected from by C
1-8Alkyl, C
2-8Thiazolinyl, C
2-8Alkynyl, C
3-12Naphthenic base, (C
3-12Naphthenic base) C
1-8Alkylidene group, aryl, (aryl) C
1-8Alkylidene group, heteroaryl, (heteroaryl) C
1-8Alkylidene group, CF
3,-CO
2R
b, R
bC (O)-, (R
b)
2NC (O)-, R
bOC (S)-, R
bC (S)-and R
bS (=O)-group formed, the selectively selected freedom-O-of wherein said alkyl and naphthenic base ,-S (O)
0-21-2 the heteroatoms interval of-group formed with-NH-, and said alkyl, thiazolinyl, alkynyl, naphthenic base, aryl and heteroaryl are independently selected from by F, Cl, Br, I, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl ,-(CH
2)
aOR
a,-(CH
2)
aNR
aR
a,-(CH
2)
aNHOH ,-(CH
2)
aNR
aNR
aR
a,-(CH
2)
aNO
2,-(CH
2)
aCN ,-(CH
2)
aCO
2R
a,-(CH
2)
aC (O) R
a,-(CH
2)
aOC (O) R
a,-(CH
2)
aCONR
aR
a, CF
3, OCF
3With-OS (O
2) R
a0-4 group of the group of forming replaces;
Selectively, work as R
3When existing, R
4Be selected from addition by H, F, Cl, Br, I, N (R
b)
2, OR
b, SR
b,-CN, NO
2, CF
3O, R
bC (O) O-,-OCO
2R
b, (R
b)
2NC (O) O-, R
bOC (O) NR
b-, R
bC (O) NR
b-, (R
b)
2NC (O) NR
b-and (R
b)
2NC (S) NR
bThe group of-composition;
Condition is to work as R
2Be H and R
3When not existing, R so
4Be not
Wherein:
(a) " * " is tie point;
(b) R
zBe-CH
2OR ,-CO
2R ,-OC (O) R ,-CH
2OC (O) R ,-CH
2SR ,-C (S) OR ,-CH
2OC (S) R ,-CH
2NRR ,-C (S) NRR or-C (O) NRR; And,
(c) R is H or substituting group;
R
bBe independently selected from by H, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
3-8Naphthenic base, (C
3-8Naphthenic base) C
1-8Alkylidene group, aryl, (aryl) C
1-8Alkylidene group, heteroaryl and (heteroaryl) C
1-8The group that alkylidene group is formed, the selectively selected freedom-O-of wherein said alkyl and naphthenic base ,-S (O)
0-21-2 the heteroatoms interval of-group formed with-NH-, and the selected free F of wherein said alkyl, naphthenic base, aryl and heteroaryl, Cl, Br, I, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl ,-(CH
2)
aOR
a,-(CH
2)
aNR
aR
a,-(CH
2)
aNHOH ,-(CH
2)
aNR
aNR
aR
a,-(CH
2)
aNO
2,-(CH
2)
aCN ,-(CH
2)
aCO
2R
a,-(CH
2)
aC (O) R
a,-(CH
2)
aOC (O) R
a,-(CH
2)
aCONR
aR
a, CF
3And OCF
30-4 substituting group of the group of forming replaces;
R
cBe independently selected from by H, C
1-6The group that alkyl and benzyl are formed;
R
dBe independently selected from by H, C
1-6Alkyl, C
3-6Naphthenic base, (C
3-6Naphthenic base) C
1-4The group that alkylidene group, phenyl and benzyl are formed;
R
5Be independently selected from by H, F, Cl, Br, I ,-OR
c,-N (R
c)
2, C
1-6Alkyl, C
3-6Naphthenic base, aryl and (aryl) C
1-4The group that alkylidene group is formed, the selectively selected freedom-O-of wherein said alkyl and naphthenic base ,-S (O)
0-2-with-NR
b1-2 heteroatoms of the group of-composition at interval;
R
6Be selected from by CH
2CH
2, the group formed of CH=CH and C ≡ C;
A is independently selected from the group of forming by 0,1 and 2;
N is independently selected from the group of forming by 0,1 and 2;
P is independently selected from the group of forming by 0,1 and 2;
Q is independently selected from the group of forming by 0,1 and 2; And,
R is independently selected from the group of forming by 0,1 and 2.
On the other hand, work as R
2Be H, R
5Be that C ≡ C and Y are O or NY
1The time, at least one Z so
1Be different from-CN, OR
aAnd NR
aNRa, wherein R
aBe H or C
1-6Alkyl;
On the other hand, the invention provides novel formula IIa or IIIa compound:
Y is selected from by O, NY
1, OCH
2CH
2OCH
2And NY
1CH
2CH
2OCH
2The group of forming;
Selectively, Y does not exist;
Y
1Be selected from by H and CH
3The group of forming;
Z is selected from the group of being made up of 5-6 unit's heteroaryl and phenyl, and wherein Z is via the carbon atom connection and by 1-4 Z
1Group replaces;
Z
1Be independently selected from by F, Cl, C
1-4Alkyl, C
2-4Thiazolinyl, C
2-4Alkynyl ,-(CH
2)
aOR
a,-(CH
2)
aNR
aR
a,-(CH
2)
aNHOH ,-(CH
2)
aNR
aNR
aR
a,-(CH
2)
aNO
2,-(CH
2)
aCN ,-(CH
2)
aCO
2R
a,-(CH
2)
aC (O) R
a,-(CH
2)
aOC (O) R
a,-(CH
2)
aCONR
aR
a, CF
3And OCF
3The group of forming;
R
aBe independently selected from by H, C
1-4Alkyl, C
2-4Thiazolinyl, C
2-4Alkynyl, C
3-6Naphthenic base, (C
3-6Naphthenic base) C
1-2Alkylidene group, aryl, (aryl) C
1-2Alkylidene group, heteroaryl and (heteroaryl) C
1-2The group that alkylidene group is formed, the selectively selected freedom-O-of wherein said alkyl and naphthenic base ,-S (O)
0-2-with-NR
c1-2 heteroatoms of the group of-composition at interval;
R
1Be independently selected from by H, C
1-4Alkyl, C
3-6Naphthenic base, (C
3-6Naphthenic base) C
1-4Alkylidene group, aryl, (aryl) C
1-4Alkylidene group, heteroaryl, (heteroaryl) C
1-4Alkylidene group, (aryl) (aryl)-C
1-4Alkylidene group, (heteroaryl) (heteroaryl)-C
1-4Alkylidene group and (aryl) (heteroaryl) C
1-2The group that alkylidene group is formed, the selectively selected freedom-O-of wherein said alkyl and naphthenic base ,-S (O)
0-2-with-NR
c1-2 the heteroatoms interval of-group formed, and said aryl and hetero-aromatic ring are independently selected from by F, Cl, C
1-4Alkyl, C
2-4Thiazolinyl, C
2-4Alkynyl ,-(CH
2)
aOR
a,-(CH
2)
aNR
aR
a,-(CH
2)
aNHOH ,-(CH
2)
aNR
aNR
aR
a,-(CH
2)
aNO
2,-(CH
2)
aCN ,-(CH
2)
aCO
2R
a,-(CH
2)
aC (O) R
a,-(CH
2)
aOC (O) R
a,-(CH
2)
aCONR
aR
a, CF
3And OCF
30-2 group of the group of forming replaces;
R
2Be selected from by H, C
1-4Alkyl, OR
a, N (R
a)
2, C
3-6The group that naphthenic base, aryl, heterocycle and heteroaryl are formed, wherein said alkyl, naphthenic base, aryl, heterocycle and heteroaryl are independently selected from by F, Cl, CH
3, CF
3And CH
30-2 group of the group that O forms replaces;
R
4Be selected from by C
1-4Alkyl, C
2-4Thiazolinyl, C
2-4Alkynyl, C
3-6Naphthenic base, (C
3-6Naphthenic base) C
1-2Alkylidene group, aryl, (aryl) C
1-2Alkylidene group, heteroaryl, (heteroaryl) C
1-2Alkylidene group, CF
3,-CO
2R
b, R
bC (O)-, (R
b)
2NC (O)-, R
bOC (S)-, R
bC (S)-and R
bS (=O)-group formed, the selectively selected freedom-O-of wherein said alkyl and naphthenic base ,-S (O)
0-21-2 the heteroatoms interval of-group formed with-NH-, and said alkyl, thiazolinyl, alkynyl, naphthenic base, aryl and heteroaryl are independently selected from by F, Cl, C
1-4Alkyl, C
2-4Thiazolinyl, C
2-4Alkynyl ,-(CH
2)
aOR
a,-(CH
2)
aNR
aR
a,-(CH
2)
aNHOH ,-(CH
2)
aNR
aNR
aR
a,-(CH
2)
aNO
2,-(CH
2)
aCN ,-(CH
2)
aCO
2R
a,-(CH
2)
aC (O) R
a,-(CH
2)
aOC (O) R
a,-(CH
2)
aCONR
aR
a, CF
3, OCF
3With-OS (O
2) R
a0-3 group of the group of forming replaces;
Selectively, work as R
3When existing, R
4Optional in addition free H, F, Cl, N (R
b)
2, OR
b, SR
b,-CN, NO
2, CF
3O, R
bC (O) O-,-OCO
2R
b, (R
b)
2NC (O) O-, R
bOC (O) NR
b-, R
bC (O) NR
b-, (R
b)
2NC (O) NR
b-and (R
b)
2NC (S) NR
bThe group of-composition;
Condition is to work as R
2Be H and R
3When not existing, R4 is not so
Wherein:
(a) " * " is tie point;
(b) R
zBe-CH
2OR ,-CO
2R ,-OC (O) R ,-CH
2OC (O) R ,-CH
2SR ,-C (S) OR ,-CH
2OC (S) R ,-CH
2NRR ,-C (S) NRR or-C (O) NRR; And,
(c) R is H or substituting group;
R
bBe independently selected from by H, C
1-4Alkyl, C
2-4Thiazolinyl, C
2-4Alkynyl, C
3-6Naphthenic base, (C
3-6Naphthenic base) C
1-2Alkylidene group, aryl, (aryl) C
1-2Alkylidene group, heteroaryl and (heteroaryl) C
1-2The group that alkylidene group is formed, the selectively selected freedom-O-of wherein said alkyl and naphthenic base ,-S (O)
0-21-2 the heteroatoms interval of-group formed with-NH-, and the selected free F of wherein said alkyl, naphthenic base, aryl and heteroaryl, Cl, C
1-4Alkyl, C
2-4Thiazolinyl, C
2-4Alkynyl ,-(CH
2)
aOR
a,-(CH
2)
aNR
aR
a,-(CH
2)
aNHOH ,-(CH
2)
aNR
aNR
aR
a,-(CH
2)
aNO
2,-(CH
2)
aCN ,-(CH
2)
aCO
2R
a,-(CH
2)
aC (O) R
a,-(CH
2)
aOC (O) R
a,-(CH
2)
aCONR
aR
a, CF
3And OCF
30-2 substituting group of the group of forming replaces;
R
3Do not exist or C
1-4Alkylidene group, the selectively selected freedom-O-of wherein said alkylidene group ,-S (O)
0-2The heteroatoms of-the group formed with-NH-at interval;
R
3Selected free F, Cl ,-OR
d,-SR
d,-N (R
d)
2, C
3-6Naphthenic base, (C
3-6Naphthenic base) C
1-2Alkylidene group, aryl, (aryl) C
1-2Alkylidene group, heteroaryl and (heteroaryl) C
1-20-1 group of the group that alkylidene group is formed replaces, the selectively selected freedom-O-of wherein said alkylidene group and naphthenic base ,-S (O)
0-2-with-NR
c1-2 heteroatoms of the group of-composition at interval;
R
cBe independently selected from by H and C
1-4The group that alkyl is formed;
R
dBe independently selected from by H, C
1-4Alkyl, (C
3-6Naphthenic base) C
1-2The group that alkylidene group and benzyl are formed;
R
5Be independently selected from by H, F, Cl ,-OR
c,-N (R
c)
2, C
1-4Alkyl, C
3-6Naphthenic base, aryl and (aryl) C
1-2The group that alkylidene group is formed, the selectively selected freedom-O-of wherein said alkyl and naphthenic base ,-S (O)
0-2-with-NR
b1 heteroatoms of the group of-composition at interval;
A is independently selected from the group of forming by 0 and 1;
N is independently selected from the group of forming by 0 and 1;
P is independently selected from the group of forming by 0 and 1;
Q is independently selected from the group of forming by 0 and 1; And,
R is independently selected from the group of forming by 0 and 1.
On the other hand, the invention provides novel compound, wherein:
Y is selected from by O and OCH
2CH
2OCH
2The group of forming;
Selectively, Y does not exist;
Z is selected from the group of being made up of phenyl, pyridyl and pyrimidyl, and wherein Z is via the carbon atom connection and by 1-3 Z
1Group replaces;
Z
1Be independently selected from by F, Cl, C
1-4Alkyl, C
2-4Thiazolinyl, C
2-4Alkynyl, OR
a, NHOH, NR
aNR
aR
a, NO
2, CO
2R
a, C (O) R
a, OC (O) R
a, CONR
aR
a, CF
3And OCF
3The group of forming;
R
1Be independently selected from by H, C
1-4Alkyl, (cyclopropyl) CH
2-, benzyl, pyridyl-CH
2-, (phenyl) (phenyl)-C
1-4Alkylidene group, (pyridyl) (pyridyl)-C
1-4Alkylidene group and (phenyl) (pyridyl) C
1-4The group that alkylidene group is formed, wherein said benzyl, phenyl and pyridyl ring are independently selected from by F, Cl, CH
3, OH, OCH
3, NH
2, NHCH
3, N (CH
3)
2, NHOH, NHNH
2, NO
2, CN, CO
2CH
3, C (O) CH
3, CONH
2, C (O) NHCH
3, C (O) N (CH
3)
2, CF
3And OCF
30-2 group of the group of forming replaces;
R
2Be selected from by H, OR
a, N (R
a)
2, the group formed of phenyl and 5-6 unit heteroaryl, wherein said phenyl and heteroaryl are independently selected from by F, Cl, CH
3, CF
3And CH
30-2 group of the group that O forms replaces;
R
3Do not exist or C
1-2Alkylidene group;
R
4Be selected from by C
2-4Thiazolinyl, C
2-4The group that alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, heteroaryl are formed, wherein the selectively selected freedom-O-of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl ,-S (O)
0-2The heteroatoms of-the group formed with-NH-at interval, and said thiazolinyl, alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl and heteroaryl are independently selected from by F, Cl, CH
3, OH, OCH
3, NH
2, NHCH
3, N (CH
3)
2, NHOH, NHNH
2, NO
2, CN, CO
2CH
3, C (O) CH
3, CONH
2, C (O) NHCH
3, C (O) N (CH
3)
2, CF
3And OCF
30-2 group of the group of forming replaces;
R
5Be independently selected from by H and CH
3The group of forming;
N is 1;
P is 1;
Q is independently selected from the group of forming by 0 and 1; And,
R is independently selected from the group of forming by 0 and 1.
On the other hand, the invention provides novel compound, wherein:
Z is selected from the group of being made up of phenyl, pyridyl and pyrimidyl, and wherein Z is via the carbon atom connection and by 1 Z
1Group replaces; And,
Z
1Be independently selected from by F, Cl, CH
3, CH
2CH
3, OH, OCH
3, NH
2, NHCH
3, N (CH
3)
2, NHOH, NHNH
2, NO
2, CN, CO
2CH
3, C (O) CH
3, CONH
2, C (O) NHCH
3, C (O) N (CH
3)
2, CF
3And OCF
3The group of forming.
On the other hand, the invention provides novel compound, wherein said compound has formula IIa.
On the other hand, the invention provides novel compound, wherein p is 1.
On the other hand, the invention provides novel compound, wherein r is 0.
On the other hand, the invention provides novel compound, wherein Y is O.
On the other hand, the invention provides novel compound, wherein said compound has formula IIb:
On the other hand, the invention provides novel compound, wherein said compound has formula III a.
On the other hand, the invention provides novel compound, wherein p is 1.
On the other hand, the invention provides novel compound, wherein r is 0.
On the other hand, the invention provides novel compound, wherein Y is O.
On the other hand, the invention provides novel compound, wherein said compound has formula III b:
On the other hand, the invention provides novel compound, said compound is selected from:
4-[3-(6-amino-9-Propargyl-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 2-benzyloxy-ethyl ester;
4-[3-(6-amino-9-cyclopentyl-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 2-benzyloxy-ethyl ester;
4-[3-(6-amino-9-Propargyl-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 3-trifluoromethyl-phenyl ester;
4-[3-(6-amino-9-cyclopentyl-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 3-trifluoromethyl-phenyl ester;
4-[3-(6-amino-9-Propargyl-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 2-fluoro-phenyl ester;
4-[3-(6-amino-9-Propargyl-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 4-nitro-phenyl ester;
4-[3-(6-amino-9-Propargyl-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 4-methoxycarbonyl-phenyl ester;
4-[3-(6-amino-9-Propargyl-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 4-chloro-phenyl ester;
4-[3-(6-amino-9-Propargyl-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 4-methoxyl group-phenyl ester;
4-[3-(6-amino-9-Propargyl-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 4-methyl-phenyl ester;
4-[3-(6-amino-9-Propargyl-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 4-nitro-benzyl ester;
4-[3-(6-amino-9-Propargyl-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 2-chloro-phenyl ester;
4-[3-(6-amino-9-Propargyl-9H-purine 2-yl)-Propargyl]-piperidines-1-carboxylic acid 2-methoxyl group-phenyl ester;
2-{3-[1-((3, the 4-dimethyl-) carbobenzoxy) piperidin-4-yl] propine-1-yl }-9-propargyl VITAMIN B4;
2-{3-[1-((3, the 4-difluoro) carbobenzoxy) piperidin-4-yl] propine-1-yl }-9-propargyl VITAMIN B4; And,
2-{3-[1-((3, the 4-dichloro) carbobenzoxy) piperidin-4-yl] propine-1-yl }-9-propargyl VITAMIN B4.
In another aspect of this invention, pharmaceutical composition is provided, this pharmaceutical composition comprises: the compound of the present invention and the pharmaceutically acceptable carrier of treatment significant quantity.
In another aspect of this invention, provide to be used to treat the mammiferous adenosine A that wherein involves
2AReceptor active and need produce the pathological condition of antagonism or the treat-ment of symptom to its effect, said treat-ment comprises: the The compounds of this invention that will treat significant quantity is applied to Mammals.
In another aspect of this invention; The method of treatment disease is provided; This method comprises at least a The compounds of this invention or its steric isomer or the pharmacy acceptable salt of administering therapeutic significant quantity, and wherein said disease is selected from dyspraxia, cancer and habituation venereal disease disease (for example smoking, alcohol, medicine).
In another aspect of this invention, dyspraxia is selected from: Huntington's disease, catalepsy, parkinson's disease, nona, stein-leventhal syndrome, MSA, corticobasal degeneration, Wilson's disease (wilson ' s disease), HallervordenSpatz Disease (Hallervorden-Spatz disease), carrying out property pallidal atrophy, DOPA-reactive myodystonia-parkinson (Dopa-responsive dystonia-Parkinsonism) and spasticity.
In another aspect of this invention, provide to be used for prevention or to treat the mammiferous adenosine A that wherein involves
2AReceptor active and need the pathological condition of antagonism receptor acting or the treat-ment of symptom, said treat-ment comprises: the The compounds of this invention of significant quantity is applied to Mammals.
In another aspect of this invention, the The compounds of this invention that provides confession in therapeutic treatment, to use.
In another aspect, provide The compounds of this invention to be used to prepare purposes to the useful medicine of treatment mammalian diseases.
Any aspect of the present invention or characteristic, no matter be characterized as being preferably or be not characterized as being preferred, can with any others of the present invention or characteristics combination, no matter such further feature is characterized as being preferably or is not characterized as being preferably.
Work as R
4-R
3-when being H, the imidazole ring of The compounds of this invention can exist or exist as tautomer (for example the alkynyl substituted base can be positioned at 7-position or 9-position) with tautomeric forms so.The technician will recognize that these tautomers are included in the scope of the present invention.For example, also mean the corresponding tautomer of this compound through naming or pointing out a kind of compound.
Definition
Except as otherwise noted, the example right and wrong that provided among the application are exclusive.They are including, but not limited to cited group.
In being used in the present specification that comprises claims, only if specify in addition, indefinite article " (a) " and " one (an) " expression " at least one " or " one or more ".
The example of the molecular weight of The compounds of this invention can comprise that (a) is less than about 500 gram/moles, 550 gram/moles, 600 gram/moles, 650 gram/moles, 700 gram/moles, 750 gram/moles, 800 gram/moles, 850 gram/moles, 900 gram/moles, 950 gram/moles or 1000 gram/moles; (b) less than about 950 gram/moles; (c) less than about 850 gram/moles, and (d) less than about 750 gram/moles.
Term " substituted " is illustrated in any one or a plurality of hydrogen of specifying on the group (or atom) by from the candidate replacement of specifying in the group, and condition is normal valency and the stable compound of this replacement generation that does not exceed specified atom.When substituting group is that (promptly=O) time, 2 hydrogen are replaced ketone group on this atom so.The ketone group substituting group does not exist on the aromatics part.Comprise each number of this scope if allow so individually more than a substituting group (for example 0-4).For example, (a) 0-4 comprises 0,1,2,3 and 4, and (b) 0-2 comprises 0,1 and 2.
This compound of stably expressed is suitable for pharmaceutical use.
Stable compound is contained in the present invention, therefore except as otherwise noted, avoids following of bonding: heteroatoms-halogen, N-S, O-S, O-O and S-S.
The present invention includes all isotropic substances of the atom that appears in the The compounds of this invention.Isotropic substance comprises those atoms that have identical ordination number but have different total mass numbers.The isotropic substance of hydrogen comprises tritium and deuterium.The isotropic substance of carbon comprises C-13 and C-14.
" alkyl " comprises representative examples of saturated aliphatic alkyl side chain and straight chain with the carbon atom that specifies number.For example, the C1-6 alkyl comprises C
1, C
2, C
3, C
4, C
5And C
6Alkyl.The example of alkyl comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec.-butyl, the tertiary butyl, n-pentyl and sec.-amyl sec-pentyl secondary amyl.When alkyl by NH at interval the time, if the substituting group of definition alkyl, this NH group can be substituted so.
" thiazolinyl " is included in the straight chain with one or more unsaturated C-Cs or props up the hydrocarbon atom that specifies number in the chain configuration, and said unsaturated C-C can appear at any stable point along this chain, like vinyl and propenyl.C
2-6Thiazolinyl comprises C
2, C
3, C
4, C
5And C
6Thiazolinyl.
" alkynyl " is included in the straight chain with one or more carbon-to-carbon three keys or props up the hydrocarbon atom that specifies number in the chain configuration, and said carbon-to-carbon three key can appear at any stable point along this chain, like ethynyl and proyl.C
2-6Alkynyl comprises C
2, C
3, C
4, C
5And C
6Alkynyl.
" halo " or " halogen " refers to fluoro, chloro, bromo and iodo.
" naphthenic base " is included in the hydrocarbon atom that specifies number in the saturated rings, like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl group.C
3-8Naphthenic base comprises C
3, C
4, C
5, C
6, C
7And C
8Naphthenic base.Naphthenic base also comprises bicyclic alkyl and tricyclic alkyl, and bicyclic alkyl and tricyclic alkyl both comprise condensed ring and bridged ring (for example norcamphane and diamantane).Although naphthenic base is not an aromatics, also can be undersaturated (for example 1-2 two keys).The example of unsaturated naphthenic base comprises cyclopentenyl and cyclohexenyl.When naphthenic base by NH at interval the time, if the substituting group of definition alkyl, this NH group can be substituted so.
" aryl " refers to any stable 6,7,8,9,10,11,12 or 13 yuan of monocyclic, bicyclic or trinucleated ring, if when wherein existing more than a ring, at least one ring is an aromatics.The example of aryl comprises fluorenyl, phenyl, naphthyl, indanyl and tetralyl.
Any stable ring that " heterocycle " refers to be made up of carbon atom and 1,2,3 or 4 heteroatoms or saturated or part is undersaturated (promptly with specified atom number; Non-aromatics) 3,4,5,6,7,8,9,10,11 or 12 yuan of monocyclic, bicyclic or trinucleated ring, said heteroatoms is independently selected from the group of being made up of N, O and S.As an example, if heterocycle is a 5-6 unit, it is made up of carbon atom and 1-2 heteroatoms so, and said heteroatoms is independently selected from the group of being made up of N, O and S.If heterocycle is bicyclic or trinucleated, so this two the ring or three the ring at least one ring must contain heteroatoms, although all two the ring or all three the ring each can contain one or more heteroatomss.The N group can be N, NH or N-substituting group, depends on whether selected ring and substituting group are mentioned.Nitrogen heteroatom and sulfur heteroatom can be selectively oxidized (for example S, S (O), S (O)
2And N-O).Heterocycle can be at any heteroatoms that produces rock steady structure or the side group that the carbon atom place is connected to it.Heterocycle described herein can be substituted on the carbon or on nitrogen-atoms, as long as the compound of gained is stable.Usually, when the overall number of S atom in the heterocycle and O atom surpassed 1, these heteroatomss were not adjacent to each other so.The heterocyclic example comprises those heterocycles when the overall number of S atom in the heterocycle and O atom is 0-1.The heterocyclic example comprises decahydroquinolyl, dihydrofuran-, imidazolidyl, imidazolinyl, morpholinyl, piperidyl, pyrrolidyl and tetrahydrofuran base.What also comprise is to contain for example above-mentioned heterocyclic condensed ring and spirocyclic compound.
" heteroaryl " refers to be aromatics and any stable 5,6,7,8,9,10,11 or 12 yuan of monocyclic, bicyclic or trinucleated heterocycle that be made up of carbon atom and 1,2,3,4,5 or 6 heteroatoms, and said heteroatoms is independently selected from the group of being made up of N, O and S.If heteroaryl is bicyclic or trinucleated, so this two the ring or three the ring at least one ring must contain heteroatoms, although all two the ring or all three the ring each can contain one or more heteroatomss.If heteroaryl is bicyclic or trinucleated, at least one ring in this ring must be an aromatics so.The N group can be N, NH or N-substituting group, depends on whether selected ring and substituting group are mentioned.Nitrogen heteroatom and sulfur heteroatom can be selectively oxidized (for example S, S (O), S (O)
2And N-O).Hetero-aromatic ring can be at any heteroatoms that produces rock steady structure or the side group that the carbon atom place is connected to it.Hetero-aromatic ring described herein can be substituted on the carbon or on nitrogen-atoms, as long as the compound of gained is stable.
The example of heteroaryl comprises acridyl, a word used for translation octyl group (azocinyl), benzimidazolyl-, benzofuryl, benzothienyl (benzothiofuranyl), benzo thiophenyl (benzothiophenyl), benzoxazolyl, benzoxazole quinoline base, benzothiazolyl, benzotriazole base, benzo tetrazyl, benzoisoxazole base, benzisothiazole base, benzimidazoline base, carbazyl, 4aH-carbazyl, carbolinyl, chromanyl, chromenyl, cinnolines base, decahydroquinolyl, 2H, 6H-1,5; 2-dithiazine base, dihydrofuran-[2,3-b] THF, furyl, furazan base, imidazolyl, 1H-indazolyl, indoles thiazolinyl (indolenyl), indolinyl, pyrrocoline base (indolizinyl), indyl, 3H-indyl, isatin acyl group (isatinoyl), isobenzofuran-base, different chromanyl, iso indazolyl, iso-dihydro-indole-group, pseudoindoyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazole base, 1,2; 3-oxadiazole base, 1,2,4-oxadiazole base, 1; 2,5-oxadiazole base, 1,3; 4-oxadiazole Ji 、 oxazolidinyl 、 oxazolyl, oxindole base, pyrimidyl, phenanthridinyl, phenanthroline base, phenazinyl, phenothiazinyl, phenoxanthein base (phenoxathinyl) 、 phenoxazinyl, 2 base, pteridyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, Bi Ding Bing oxazole, pyridine-imidazole, pyrido thiazole, pyridyl (pyridinyl), pyridyl (pyridyl), pyrimidyl, 2H-pyrryl, pyrryl, quinazolyl, quinolyl, 4H-quinolizinyl 、 quinoxalinyl, quinuclidinyl, tetrazyl, 6H-1,2; 5-thiadiazine base, 1,2,3-thiadiazolyl group, 1; 2; 4-thiadiazolyl group, 1,2,5-thiadiazolyl group, 1; 3; 4-thiadiazolyl group, thianthrenyl, thiazolyl, thienyl, thieno-thiazolyl, thiophene Bing oxazolyl, Thienoimidazole base, thiophenyl, triazinyl, 1,2,3-triazoles base, 1; 2; 4-triazolyl, oso-triazole base, 1; 3,4-triazolyl and xanthenyl.
Mammals and patient are contained usually the warm-blooded mammals under medical treatment and nursing (the for example animal of the mankind and domestication).Mammiferous example comprises (a) cat, dog, horse, ox and human and (b) mankind.
" treatment (treating) " or " treatment (treatment) " contained the treatment of mammalian diseases state; And comprise: (a) prevention morbid state occurs in the Mammals, especially when such Mammals easy infection morbid state but N during for this morbid state of trouble; (b) suppress morbid state, for example stop its development; And/or (c) alleviate morbid state, for example impel morbid state to disappear until the terminal point that reaches expectation.Treatment also comprises improve (for example the easing the pain or discomfort) of disease symptoms, and wherein such improvement can or cannot directly influence disease (for example cause, propagation, expression etc.).
" pharmacy acceptable salt " refers to the verivate of disclosed compound, and wherein parent compound is modified through forming its hydrogen salt or subsalt.The example of pharmacy acceptable salt including, but not limited to, such as the inorganic acid salt or the organic acid salt of the alkaline residue of amine; An alkali metal salt or organic salt such as the acidic residues of carboxylic acid; And analogue.Pharmacy acceptable salt for example comprises the non-toxic salt or the quaternary ammonium salt of the routine of the parent compound that is formed by nontoxic mineral acid or organic acid.For example; Conventional like this non-toxic salt including, but not limited to; Those salt that obtain by mineral acid that is selected from following acid and organic acid: 1,2-ethane disulfonic acid, 2-acetoxy-benzoic acid, 2-hydroxyethanesulfonic acid, acetate, xitix, Phenylsulfonic acid, phenylformic acid, heavy carbonic, carbonic acid, Hydrocerol A, YD 30, ethane disulfonic acid, ethane sulfonic acid, fumaric acid, glucoheptonic acid, glyconic acid, L-glutamic acid, oxyacetic acid, bismuth glycolyl arsanilate (glycollyarsanilic), Sucrets (hexylresorcinic), sea crust acid (hydrabamic), Hydrogen bromide, hydrochloric acid, hydroiodic acid HI, oxaloacetic acid, hydroxynaphthoic acid, hydroxyethylsulfonic acid, lactic acid, lactobionic acid, lauryl sulfonic acid, toxilic acid, oxysuccinic acid, racemic melic acid, methanesulfonic, naphthene sulfonic acid (napsylic), nitric acid, oxalic acid, pounce on acid, pantothenic acid, toluylic acid, phosphoric acid, polygalacturonic acid, propionic acid, Whitfield's ointment (salicylic), Triple Pressed Stearic Acid, inferior acetate (subacetic), succsinic acid, thionamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartrate and toluenesulphonic acids.
Can synthesize pharmacy acceptable salt of the present invention by the parent compound that contains alkalescence or tart part through the chemical process of routine.Normally, through with the free acid of these compounds or free alkali form and stoichiometric suitable alkali or acid in water or in organic solvent or in the mixture of water and organic solvent, react, can prepare such salt; Normally, non-aqueous media is fit to like ether, ETHYLE ACETATE, ethanol, Virahol or acetonitrile.At Remington ' s Pharmaceutical Sciences (pharmaceutical science of Lei Mingdun), 18 editions, Mack Publishing Company; Easton, PA, 1990; Find the tabulation of suitable salt in the 1445th page, its disclosure in view of the above by reference mode incorporate into.
" treatment significant quantity " comprises the amount of when independent or co-administered, effectively treating at the The compounds of this invention of this cited indication." treatment significant quantity " also comprises the amount of combination of the claimed compounds of effective treatment expection indication.Combination of compounds can be a synergistic combination.When co-administered during the additive effect of the effect of compound compound when using separately as single medicament, Adv.Enzyme Regul., 1984, the described synergy of 22:27-55 take place as by for example Chou and Talalay.Usually, when the suboptimal concentration (sub-optimal concentration) of compound, clearly illustrate synergistic effect.Synergy can be lower cytotoxicity, increase are compared in combination with independent component effect or some other useful effect.
The compounds of this invention can have one or more asymmetric centers, and can optically-active form and racemic form existence and separated with optically-active form and racemic form.Some compounds can show heteromorphism.The present invention comprises the form of any racemic, optically-active, the polymorphous or steric isomer of The compounds of this invention, or its mixture, and they have useful properties as herein described; (for example how to prepare the optically-active form; Through recrystallization technology resolution of racemic form; Through synthetic by the starting substance of optically-active; Synthetic through chirality, perhaps through using the chromatographic separation of chiral stationary phase) and how to use standard test as herein described or use other similar test determination therapeutic activity well known in the art, be known in the art.
The example of steric isomer of the present invention comprises formula A-F compound (and unshowned tautomeric form).
For the cited occurrence of radical, substituting group and scope only is in order to explain; They do not get rid of radical and substituent other limit value or other value in limited range.
Dosage and preparation
The compounds of this invention can be mixed with pharmaceutical composition; And be applied to mammalian hosts with the various forms that is suitable for selected route of administration such as human patients, said route of administration for example orally or the stomach and intestine other places, through intravenous, intramuscular, partial, suction or subcutaneous approach.Exemplary pharmaceutical composition is at " Remington:The Science and Practice of Pharmacy (Lei Mingdun: pharmaceutical science with put into practice) ", and A.Gennaro edits, 20 editions; Lippincott; Williams& Wilkins, Philadelphia, open among the PA.
This compound can with pharmaceutically acceptable carrier or the assimilable edible carrier combinations systemic administration such as inert diluent, for example oral.Can they be encapsulated in duricrust gelatine capsule or the soft shell gelatin capsules, can they be pressed into tablet or can they directly be combined with the food of patient's diet.Use for oral administration, active compound can use with one or more carrier combinations and with the form of ingestible tablet, buccal tablet, lozenge, capsule, elixir, suspension agent, syrup, wafer (wafer) and analogue.Such compsn and preparation should contain at least 0.1% active compound.The percentage ratio of compsn and preparation can change, and can be aptly between about 2% to about 60% of the weight of given unit dosage.The amount of the active compound in such treatment in the useful compsn is with the amount that obtains the effective dose level.
Tablet, lozenge, pill, capsule and analogue also can contain following material: tackiness agent, like tragacanth gum, gum arabic, W-Gum or gelatin; Carrier is like Lin Suanergai; Disintegrating agent is like W-Gum, yam starch, alginic acid and analogue; Lubricant is like Magnesium Stearate; And sweeting agent, like sucrose, fructose, lactose or aspartame, perhaps can add seasonings such as peppermint, wintergreen oil or cherry seasonings.When unit dosage was capsule, except above types of materials, capsule also can contain liquid vehicle, like vegetables oil or polyoxyethylene glycol.Various other materials can be used as dressing and exist, and perhaps various other materials can exist so that otherwise change the physical form of solid unit dosage form.For instance, tablet, pill or capsule can be coated with gelatin, wax, shellac or sugar and analogue.Syrup or elixir can contain active compound, as the sucrose of sweeting agent or fructose, as the Tegosept M of sanitas and propylben, dyestuff with such as the seasonings of the spices of cherry or orange.Should be understood that employed any material should be pharmaceutically acceptable during in employed amount and be nontoxic basically in any unit dosage of preparation.In addition, during active compound can be incorporated extended release preparation into and install.
Also can through infusion or the injection with active compound intravenously ground or intraperitoneal use.The solution of active compound or its salt can be prepared in water, selectively mixes with nontoxic tensio-active agent.Dispersion-s also can glycerine, liquid polyethylene glycol, triactin, and composition thereof in preparation and in oil, preparing.Under common storage and working conditions, these preparations contain sanitas to prevent microorganism growth.
Be suitable for injecting or the pharmaceutical dosage form of infusion can comprise aseptic aqueous solution or dispersion-s or the sterilized powder that contains activeconstituents; But this activeconstituents is suitable for the solution or the dispersion-s of the aseptic injectable or infusion of instant preparation, selectively is encapsulated in the liposome.In all scenario, final formulation should be aseptic, fluidic and stable under the condition of preparation and storage.Liquid vehicle or vector can be solvent or liquid dispersion medium, and it comprises water for example, ethanol, polyvalent alcohol (for example glycerine, Ucar 35, liquid polyethylene glycol, and analogue), vegetables oil, nontoxic glyceryl ester and suitable mixture thereof.For example, can keep suitable flowability through forming liposome, using tensio-active agent through in the dispersion-s situation, keeping required granularity or passing through.Can pass through various antiseptic-germicides and anti-mycotic agent, for example nipagin esters (parabens), butylene-chlorohydrin, phenol, Sorbic Acid, Thiomersalate and analogue produce the prevention to microbial process.In many situations, possibly expect to comprise isotonic agent, for example sugar, damping fluid or sodium-chlor.Can be through in compsn, use postponing absorption agent, for example aluminum monostearate and gelatin, the prolongation that produces injectable compsn absorbs.
Through will the active compound of the required amount in the solvent that is fit to required more than cited various other compositions mix, subsequent filtration is sterilized, and prepares aseptic injectable solution.Under the situation of the sterilized powder of the solution that is used to prepare sterile injectable; Suitable compound method comprises vacuum drying technique and Freeze Drying Technique, and these technological activeconstituentss that produce in the solution that is present in previous sterile filtration add the powder of any required composition in addition.
For topical application, this compound can be used with pure form, that is, and and when they are liquid.Yet, usually need with they with possibly be that the acceptable carrier combination is applied to skin as compsn or preparation on the dermatology of solid or liquid.
Useful solid carrier comprises fine particle solid (finely divided solid), like talcum, clay, Microcrystalline Cellulose, silicon-dioxide, aluminum oxide and analogue.Useful liquid vehicle comprises water, alcohol or glycol or water-alcohol/glycol blends, and this compound can selectively be dissolved or dispersed in the said liquid vehicle with level of significance by nontoxic tensio-active agent.The adjuvant that can add such as flavouring agent and additional biocide to optimize character to given purposes.The liquid compsn of gained can use from absorbent pads, be used for infiltrating bandage and other dressing or use pump type atomizer or aerosol atomizer to be sprayed on the involved area.
Thickening material also can use paste, gel, ointment, soap and the analogue that can be coated with out to form with liquid vehicle; Be used to be applied directly to user's skin, said thickening material such as synthetic polymer, lipid acid, soap and fatty ester, Fatty Alcohol(C12-C14 and C12-C18), modified-cellulose or modified inorganic material.
The example of compsn that can be used for The compounds of this invention is delivered to the useful dermatology of skin is known in the art; For example, see people (US 4,559,157) and Wortzman (US 4,820,508) such as people such as Jacquet (US 4,608,392), Geria (US4,992,478), Smith.The useful dosage of The compounds of this invention can be confirmed through comparing their external activity and activity in vivo in animal model.It is known in the art that effective dose in mouse and other animal is extrapolated to human method; For example, see U.S. Patent number 4,938,949.
Usually, the concentration of the The compounds of this invention in liquid compsn such as lotion will be from (a) about 0.1wt%-25wt% and (b) about 0.5wt%-10wt%.Concentration in semi-solid combination or solids compsn such as gel or powder will be (a) about 0.1wt%-5wt% and (b) about 0.5wt%-2.5wt%.
Being used to treat the amount of required compound or its active salt or verivate will be not only change along with selected particular compound or salt; And along with the character of route of administration, the situation of just being treated and patient's age and situation and change, and will finally be doctor on duty or clinician's judgement.Yet generally speaking, the dosage that is fit to will be from every day (a) about 1.0mg/kg body weight every day-100mg/kg body weight, (b) every day about 10mg/kg body weight every day-75mg/kg body weight, and (c) in the scope of every day about 5mg/kg body weight every day-20mg/kg body weight.
Can be with unit dosage; For example contain (a) about 4mg-400mg, (b) about 10mg-200mg and (c) tablet, the capsule sheet (caplets) of the activeconstituents per unit formulation of about 20mg-100mg wait administered compound expediently.
Ideally, should use activeconstituents to reach from (a) about 0.02 μ M-20 μ M, (b) about 0.1 μ M-10 μ M and (c) plasma peak concentration of the active compound of about 0.5 μ M-5 μ M.For example perhaps Orally administered as the bolus of the activeconstituents that contains the 4mg-400mg that has an appointment through the solution of intravenous injection 0.005%-0.5% activeconstituents, can reach these concentration.
The compounds of this invention also can be used through sucking from sucker, insufflator, spraying gun or compression wrap (pack) or other device of sending aerosol spray.Compression wrap can comprise suitable propelling agent, like carbonic acid gas or other suitable gas.In the situation of pressurised aerosol, dose unit can be confirmed through the value that the amount of sending metering is provided.At drug reference book such as Remington ' s Pharmaceutical Sciences (pharmaceutical science of Lei Mingdun), volume 16 (1980) or roll up among 18 (1990) (the Mack Publishing Co.) has fully been described sucker, insufflator, spraying gun.
Required dosage can with single dose or as the divided dose of using with proper spacing for example as providing expediently two of every days, three, four or more a plurality of sub-doses (sub-dose).Sub-doses itself can further be divided into, for example using of discontinuous loose interval repeatedly; As repeatedly sucking from insufflator or being applied to the eye through many.
All patents, patented claim, book and the document in specification sheets, quoted are incorporated into its full content with way of reference in view of the above.Why not under the consistent situation in office, will be as the criterion with the disclosure (comprising any definition wherein).
With reference to various concrete and detailed aspects and technical description the present invention.However, it should be understood that and to carry out many variations and change, also fall in the spirit and scope of the present invention.Therefore common described the present invention will be understood with reference to the following example more easily, and it is in order to explain and and not mean that the following example limits the present invention that the following example is provided.
Embodiment
Pharmacology
Can use pharmacology model known in the art to confirm that The compounds of this invention is as A
2AThe acting ability of adenosine receptor antagonists (for example, seeing U.S. Patent Application Publication No. 2005/0282831).
The compounds of this invention is expected to become A
2AAdenosine receptor antagonists.If The compounds of this invention has the IC that is less than or equal to 1 μ M
50Value, The compounds of this invention is considered to A so
2AAdenosine receptor antagonists.Tested representational compound, and shown that they are active, because find their IC
50Value is in the scope of≤1 μ M.Useful in the present invention A
2AThe other example of the activity level of the expectation of adenosine receptor antagonists comprises (a) 0.1 μ M or lower IC
50Value, (b) 0.01 μ M or lower IC
50Value, (c) 0.001 μ M or lower IC
50Value, and (d) 0.0001 μ M or lower IC
50Value.
Also can be advantageously, than other Adenosine Receptors A
1, A
2BAnd A
3, The compounds of this invention is to A
2AAcceptor is optionally.Compare A
1To A
2A3 times of selectivity will be, for example to A
2A100nM and to A
1300nM (300/100=3).Compare A
1To A
2AOptionally example comprise that (a) is to A
2AAt least 3 times; (b) to A
2AAt least 4 times; (c) to A
2AAt least 5 times; (d) to A
2AAt least 10 times; (e) to A
2AAt least 20 times; And (f) to A
2AAt least 100 times.Compare A
2BTo A
2AOptionally example comprise that (a) is to A
2AAt least 3 times; (b) to A
2AAt least 4 times; (c) to A
2AAt least 5 times; (d) to A
2AAt least 10 times; (e) to A
2AAt least 20 times; And (f) to A
2AAt least 100 times.Compare A
3To A
2AOptionally example comprise that (a) is to A
2AAt least 3 times; (b) to A
2AAt least 4 times; (c) to A
2AAt least 5 times; (d) to A
2AAt least 10 times; (e) to A
2AAt least 20 times; And (f) to A
2AAt least 100 times.
Embodiments of the invention are shown in the following Table A.
Table A
* embodiment 1 is for purpose relatively with embodiment 2.
Synthesize and sign
On the Varian-300MHz spectrograph, carry out proton NMR spectrometry, using CD
3OD, CDCl
3Or DMSO-d
6Obtain spectrum in the solution as solvent.Only if indicate, chemical shift is expressed as from CD
3OD (3.30ppm), CDCl
3(7.26ppm) or DMSO-d
6(2.5ppm) to the ppm that hangs down the field.Use ThermoFinnigan LCQ mass spectrograph to carry out electro-spray ionization (ESI) mass spectroscopy.
The amino substituted exemplary steps of N6-: 2-iodo adenosine.
With 6-chloro-2-iodo-9-(2 ', 3 ', 5 '-O-triacetyl furyl glycosyl (triacetylfuranosyl))-(14.70g, 0.02729mol) suspension-s in MeOH (300mL) cools off on ice bath the 9H-purine.Then the ammonia bubbling is passed through this mixture until saturated.Sealed reaction vessel and 40 ℃ the heating 18 hours and 60 ℃ the heating 5 days.With mixture in cooled on ice, and with nitrogen bubble through this solution, allow mixture is warmed to room temperature.Solvent is removed in decompression then, and from contain the water that 3-4 drips Glacial acetic acid min. 99.5 the recrystallization crude product.Filter the gained throw out, and water and ether washing precipitate are to obtain white solid: yield 7.167g, 67%.
The exemplary steps of C2 coupling: 2-{3-[1-((2-chlorine) carbobenzoxy) piperidin-4-yl] propine-1-yl } adenosine.
To the 2-iodo adenosine in the DMF (20mL) of new degasification (0.602g, 1.531mmol) solution, add degasification triethylamine (1.20mL, 8.54mmol), Pd (PPh
3)
4(85mg, 0.074mmol), CuI (catalyzer) and 2-chloro-phenyl-4-(Propargyl) piperidines-1-carboxylicesters (0.588g, 2.117mmol).This mixture was stirred 20 hours under inert atmosphere in room temperature.Add Pd (II) the scavenging agent Si-mercaptan (400mg) and Pd (0) the scavenging agent Si-TAAcOH (619mg) of silica bound and continue to stir extra 72h.Suspension-s passes through diatomite filtration, and makes the gained solution evaporation to dry.Through column chromatography purifying crude product, with the gradient elution of DCM/MeOH (0-4%), obtain pure products: yield 0.733g, 88% into white solid.
Ribose cracked exemplary steps: 4-[3-(6-amino-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 2-chloro-phenyl ester.
2-{3-[1-((2-chlorine) carbobenzoxy) piperidin-4-yl] propine-1-yl } (0.720g, 1.326mmol) solution in methyl alcohol (25mL) and 1.0M HCl (2.50mL) stirred 22 hours in 90 ℃ in pressure assembly adenosine.With 1.0M NaOH pH is adjusted to 5, and under reduced pressure removes methyl alcohol.After the cooling, filter the gained throw out, use water washing, obtain pure products: yield 1.481g, 88% into white solid.
Use suitable haloalkane or alkyl tosylate to carry out the alkylating exemplary steps of N9-:
The unsubstituted VITAMIN B4 of suitable 9-(0.099mmol) is dissolved among the DMF (10mL).(38mg 0.275mmol) with suitable haloalkane (0.121mmol) or alkyl tosylate, and stirs this mixture 17-71 hour in 25-100 ℃ to add Anhydrous potassium carbonate.Reaction mixture is attached on the silicon-dioxide, and through the column chromatography purifying, the gradient elution with DCM/MeOH (0-6%) obtains pure products.
Embodiment 1:4-[3-(6-amino-9-Propargyl-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid phenyl ester.
Use the alkylating exemplary steps of above-mentioned N9-, 4-[3-(6-amino-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid phenyl ester (42mg) is generated as the title compound of white solid: yield 16mg, 35%.
1H?NMR(CD
3OD)δ8.21(s，1H)，7.39-7.32，7.22-7.16，7.10-7.06(3xm，5H)，5.03(d，2H，J＝2.6Hz)，4.41-4.12(m，2H)，3.07，2.93(2xm，2H)，2.98(t，1H，J＝2.6Hz)，2.49(d，2H，J＝6.2Hz)，2.02-1.81，1.53-1.33(2xm，5H)。
13CNMR(CD
3OD)δ157.1，155.5，152.9，150.5，147.9，142.6，130.3，126.4，122.9，119.3，86.3，82.5，77.6，75.9，45.7，45.4，36.5，33.9，32.6，32.3，26.5。LRMS?ESI(M+H
+)415.2。
Embodiment 2:4-[3-(6-amino-9-cyclopentyl-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid phenyl ester.
Use the alkylating exemplary steps of above-mentioned N9-, 4-[3-(6-amino-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid phenyl ester (47mg) is generated as the title compound of white solid: yield 30mg, 53%.
1H?NMR(CD
3OD)δ?8.20(s，1H)，7.39-7.32，7.23-7.16，7.11-7.06(3xm，5H)，4.90(m，1H)，4.42-4.14(m，2H)，3.08，2.93(2xm，2H)，2.49(d，2H，J＝6.3Hz)，2.32-1.18，2.07-1.73，1.55-1.32(3xm，13H)。
13C?NMR(CD
3OD)δ157.0，155.5，152.9，150.9，147.5，141.2，130.3，126.4，122.9，119.7，85.9，82.7，57.5，45.7，45.5，36.6，33.6，32.6，32.4，26.5，24.8。LRMS?ESI(M+H
+)445.2。
Embodiment 3:4-[3-(6-amino-9-Propargyl-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 2-benzyloxy-ethyl ester.
Use the alkylating exemplary steps of above-mentioned N9-, 4-[3-(6-amino-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 2-benzyloxy-ethyl ester (25mg) is generated as the title compound of white solid: yield 20mg, 74%.
1H?NMR(CD
3OD)δ8.20(s，1H)，7.32-7.20(m，5H)，5.01(d，2H，J＝2.6Hz)，4.53(s，2H)，4.27-4.09(m，4H)，3.67(t，2H，J＝4.7Hz)，2.98(t，1H，J＝2.6Hz)，2.91-2.73(m，2H)，2.42(d，2H，J＝6.3Hz)，2.91-1.73，1.37-1.20(2xm，5H)。
13C?NMR(CD
3OD)δ157.0(x2)，150.4，147.9，142.5，139.5，129.4，128.8，128.7，119.3，86.3，82.5，77.6，75.9，74.0，69.5，65.8，45.1，36.6，33.9，32.5，26.5。LRMS?ESI(M+H
+)473.2。
Embodiment 4:4-[3-(6-amino-9-cyclopentyl-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 2-benzyloxy-ethyl ester.
Use the alkylating exemplary steps of above-mentioned N9-, 4-[3-(6-amino-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 2-benzyloxy-ethyl ester (21mg) is generated as the title compound of white solid: yield 10mg, 41%.
1H?NMR(CD
3OD)δ8.19(s，1H)，7.33-7.20(m，5H)，4.88(m，1H)，4.53(s，2H)，4.29-4.10(m，4H)，3.67(t，2H，J＝4.7Hz)，2?83(m，2H)，2.42(d，2H，J＝6.0Hz)，2.30-2.16，2.05-1.70，1.38-1.21(3xm，13H)。
13C?NMR(CD
3OD)δ157.0(x2)，150.9，147.5，141.4，139.5，129.4，128.8，128.7，119.7，85.9，82.7，74.0，69.5，65.8，57.5，45.1，36.6，33.6，32.5，26.5，24.8。LRMS?ESI(M+H
+)503.4。
Embodiment 5:4-[3-(6-amino-9-Propargyl-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 3-trifluoromethyl-phenyl ester.
Use the alkylating exemplary steps of above-mentioned N9-, 4-[3-(6-amino-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 3-trifluoromethyl-phenyl ester (48mg) is generated as the title compound of white solid: yield 34mg, 65%.
1H?NMR(CD
3OD)δ8.21(s，1H)，7.60-7.35(m，4H)，5.03(d，2H，J＝2.6Hz)，4.40-4.29，4.25-4.14(2xm，2H)，3.08，2.93(2xm，2H)，2.98(t，1H，J＝2.6Hz)，2.48(d，2H，J＝6.5Hz)，2.01-1.80，1.54-1.33(2xm，5H)。
13C?NMR(CD
3OD)δ157.1，154.7，153.2，150.5，147.9，142.6，132.7(q)，131.3，126.8，123.4，123.1，120.1，119.3，86.2，82.6，77.6，75.9，45.8，45.5，36.5，33.9，32.6，32.3，26.5。LRMS?ESI(M+H
+)483.3。
Embodiment 6:4-[3-(6-amino-9-cyclopentyl-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 3-trifluoromethyl-phenyl ester.
Use the alkylating exemplary steps of above-mentioned N9-, 4-[3-(6-amino-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 3-trifluoromethyl-phenyl ester (38mg) is generated as the title compound of white solid: yield 16mg, 37%.
1H?NMR(CD
3OD)δ8.20(s，1H)，7.61-7.35(m，4H)，4.89(m，1H)，4.35，4.20(2xm，2H)，3.09，2.94(2xm，2H)，2.48(d，2H，J＝6.3Hz)，2.32-2.17，2.06-1.72，1.55-1.34(3xm，13H)。
13C?NMR(CD
3OD)δ157.0，154.7，153.2，150.9，147.4，141.4，132.7(q)，131.3，126.8，123.4，123.1，120.1，119.7，85.9，82.7，57.5，45.8，45.5，36.5，33.6，32.3，26.5，24.8。LRMS?ESI(M+H
+)513.4。
Embodiment 7:4-[3-(6-amino-9-Propargyl-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 2-fluoro-phenyl ester.
Use the alkylating exemplary steps of above-mentioned N9-, 4-[3-(6-amino-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 4-fluoro-phenyl ester (77mg) is generated as the title compound of white solid: yield 50mg, 59%.
1H?NMR(CD
3OD)δ8.21(s，1H)，7.10(s，2H)，7.07(d，2H，J＝1.6Hz)，5.03(d，2H，J＝2.6Hz)，4.32，4.19(2xm，2H)，3.06，2.91(2xm，2H)，2.98(t，1H，J＝2.6Hz)，2.48(d，2H，J＝6.3Hz)，2.00-1.80，1.52-1.31(2xm，5H)。
13C?NMR(CD
3OD)δ163.1，159.9，157.1，155.4，150.5，148.9(d)，147.9，142.6，124.6，124.4，119.3，116.9，116.6，86.2，82.6，77.6，75.9，45.7，45.4，36.5，33.9，32.6，32.3，26.5。LRMS?ESI(M+H
+)433.2。
Embodiment 8:4-[3-(6-amino-9-Propargyl-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 4-nitro-phenyl ester.
Use the alkylating exemplary steps of above-mentioned N9-, 4-[3-(6-amino-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 4-nitro-phenyl ester (64mg) is generated as the title compound of white solid: yield 29mg, 42%.
1H?NMR(CDCl
3)δ8.23(d，2H)，8.08(s，1H)，7.29(d，2H)，6.44(br?s，2H)，4.98(d，2H)，4.29(m，2H)，3.03，2.89(2xm，2H)，2.55(t，1H)，2.52(d，2H)，2.05-1.85，1.51-1.32(2xm，5H)。
13C?NMR(CDCl
3)δ156.4，154.6，152.2，149.5，145.3，144.8，140.7，125.0，122.2，118.7，86.5，80.8，77.2，75.5，44.8，44.4，35.1，33.3，31.7，31.3，26.1。LRMS?ESI(M+H
+)460.2。
Embodiment 9:4-[3-(6-amino-9-Propargyl-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 4-methoxycarbonyl-phenyl ester.
Use the alkylating exemplary steps of above-mentioned N9-, 4-[3-(6-amino-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 4-methoxycarbonyl-phenyl ester (57mg) is generated as the title compound of white solid: yield 34mg, 55%.
1H?NMR(CDCl
3)δ8.06(s，1H)，8.02(d，2H，J＝8.7Hz)，7.17(d，2H，J＝8.8Hz)，6.36(br?s，2H)，4.97(d，2H，J＝2.6)，4.29(m，2H)，3.89(s，3H)，2.99，2.86(2xm，2H)，2.54(t，1H，J＝2.6Hz)，2.48(d，2H，J＝6.5Hz)，2.02-1.82，1.49-1.30(2xm，5H)。
13C?NMR(CDCl
3)δ166.4，155.2，154.9，152.8，149.5，145.8，140.5，130.9，126.9，121.5，118.7，86.1，81.1，75.6，75.4，52.0，44.6，44.3，35.2，33.2，31.7，31.4，26.2。LRMS?ESI(M+H
+)473.2。
Embodiment 10:4-[3-(6-amino-9-Propargyl-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 4-chloro-phenyl ester.
Use the alkylating exemplary steps of above-mentioned N9-, 4-[3-(6-amino-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 4-chloro-phenyl ester (41mg) is generated as the title compound of white solid: yield 30mg, 67%.
1H?NMR(CD
3OD)δ8.21(s，1H)，7.34(d，2H，J＝8.9Hz)，7.09(d，2H，J＝8.9Hz)，5.02(d，2H，J＝2.6Hz)，4.31，4.18(2xm，2H)，3.06，2.91(2xm，2H)，2.98(t，1H，J＝2.6Hz)，2.47(d，2H，J＝6.3Hz)，2.00-1.79，1.51-1.31(2xm，5H)。
13C?NMR(CD
3OD)δ157.1，155.0，151.6，150.4，147.9，142.6，131.7，130.3，124.5，119.3，86.2，82.5，77.6，75.9，45.7，45.4，36.5，33.9，32.6，32.3，26.5。LRMS?ESI(M+H
+)449.1。
Embodiment 11:4-[3-(6-amino-9-Propargyl-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 4-methoxyl group-phenyl ester.
Use the alkylating exemplary steps of above-mentioned N9-, 4-[3-(6-amino-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 4-methoxyl group-phenyl ester (39mg) is generated as the title compound of white solid: yield 32mg, 75%.
1H?NMR(CD
3OD)δ8.21(s，1H)，6.98(d，2H，J＝9.1Hz)，6.87(d，2H，J＝9.1Hz)，5.02(d，2H，J＝2.5Hz)，4.32，4.18(2xm，2H)，3.76(s，3H)，3.04，2.89(2xm，2H)，2.99(t，1H，J＝2.6Hz)，2.47(d，2H，J＝6.3Hz)，2.00-1.79，1.51-1.30(2xm，5H)。
13C?NMR(CD
3OD)δ158.6，157.1，155.9，150.4，147.9，146.3，142.5，123.6，119.3，115.3，86.3，82.5，77.6，75.9，56.1，45.6，45.4，36.5，33.9，32.6，32.3，26.5。LRMS?ESI(M+H
+)445.2。
Embodiment 12:4-[3-(6-amino-9-Propargyl-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 4-methyl-phenyl ester.
Use the alkylating exemplary steps of above-mentioned N9-, 4-[3-(6-amino-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 4-methyl-phenyl ester (38mg) is generated as the title compound of white solid: yield 27mg, 65%.
1H?NMR(CD
3OD)δ8.21(s，1H)，7.14(d，2H，J＝8.5Hz)，6.94(d，2H，J＝8.4Hz)，5.02(d，2H，J＝2.6Hz)，4.33，4.19(2xm，2H)，3.05，2.90(2xm，2H)，2.98(t，1H，J＝2.6Hz)，2.47(d，2H，J＝6.3Hz)，2.00-1.79，1.51-1.32(2xm，5H)。
13C?NMR(CD
3OD)δ157.1，155.7，150.6，150.4，147.9，142.5，136.2，130.7，122.6，119.3，86.3，82.5，77.6，75.9，45.6，45.4，36.5，33.9，32.6，32.3，26.5，20.8。LRMS?ESI(M+H
+)429.2。
Embodiment 13:4-[3-(6-amino-9-Propargyl-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 4-nitro-benzyl ester.
Use the alkylating exemplary steps of above-mentioned N9-, 4-[3-(6-amino-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 4-nitro-benzyl ester (43mg) is generated as the title compound of white solid: yield 37mg, 79%.
1H?NMR(CD
3OD)δ8.24(d，2H，J＝8.8Hz)，8.21(s，1H)，7.59(d，2H，J＝8.9Hz)，5.24(s，2H)，5.02(d，2H，J＝2.5Hz)，4.22(m，2H)，2.98(t，1H，J＝2.6Hz)，2.91(m，2H)，2.46(d，2H，J＝6.2Hz)，1.96-1.78，1.43-1.26，(2xm，5H)。
13C?NMR(DMSO)δ155.7，154.0，149.1，146.9，145.8，144.9，140.8，128.0，123.5，117.9，83.4，82.4，78.2，75.9，64.9，43.4，34.5，32.2，30.9，24.8。LRMS?ESI(M+H
+)474.2。
Embodiment 14:4-[3-(6-amino-9-Propargyl-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 2-chloro-phenyl ester.
Use the alkylating exemplary steps of above-mentioned N9-, 4-[3-(6-amino-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 2-chloro-phenyl ester (68mg) is generated as the title compound of white solid: yield 46mg, 62%.
1H?NMR(CD
3OD)δ8.21(s，1H)，7.41-7.46，7.34-7.27，7.24-7.17(3xm，4H)，5.03(d，2H，J＝2.5Hz)，4.38，4.18(2xm，2H)，3.11，2.94(2xm，2H)，2.98(t，1H，J＝2.6Hz)，2.48(d，2H，J＝6.4Hz)，2.03-1.82，1.59-1.32(2xm，5H)。
13C?NMR(CD
3OD)δ157.1，154.3，150.4，148.9，147.9，142.5，131.1，129.0，128.4，128.0，125.4，119.3，86.2，82.6，77.6，75.9，46.0，45.6，36.5，33.9，32.6，32.4，26.5。LRMS?ESI(M+H
+)449.2。
Embodiment 15:4-[3-(6-amino-9-Propargyl-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 2-methoxyl group-phenyl ester.
Use the alkylating exemplary steps of above-mentioned N9-, 4-[3-(6-amino-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 2-methoxyl group-phenyl ester (63mg) is generated as the title compound of white solid: yield 49mg, 71%.
1H?NMR(CD
3OD)δ8.20(s，1H)，7.20-7.12，7.05-6.98，6.93-6.85(3xm，4H)，5.02(d，2H，J＝2.6Hz)，4.34，4.16(2xm，2H)，3.78(s，3H)，3.05，2.90(2xm，2H)，2.99(t，1H，J＝2.6Hz)，2.48(d，2H，J＝6.0Hz)，1.98-1.80，1.56-1.30(2xm，5H)。
13C?NMR(CD
3OD)δ157.1，155.5，153.1，150.4，147.9，142.5，141.9，127.6，124.1，121.7，119.3，113.6，86.3，82.6，77.6，75.9，56.4，46.0，45.5，36.6，33.9，32.6，32.4，26.6。LRMS?ESI(M+H
+)445.2。
Embodiment 16:2-{3-[1-((3, the 4-dimethyl-) carbobenzoxy) piperidin-4-yl] propine-1-yl }-9-propargyl VITAMIN B4.
Using the alkylating exemplary steps of above-mentioned N9-, 2-{3-[1-((3, the 4-dimethyl-) carbobenzoxy) piperidin-4-yl] propine-1-yl } VITAMIN B4 (33mg) is generated as the title compound of white solid: yield 23mg, 64%.
1H?NMR(CD
3OD)δ8.21(s，1H)，7.08(d，1H，J＝8.2Hz)，6.84(d，1H，J＝2.3Hz)，6.78(dd，1H，J＝8.2Hz，J＝2.5Hz)，5.02(d，2H，J＝2.6Hz)，4.42-4.12(m，2H)，3.13-2.84(m，3H)，2.48(d，2H，J＝6.5Hz)，2.23(s，3H)，2.22(s，3H)，2.02-1.81，1.52-1.32(2xm，5H)。
13C?NMR(CD
3OD)δ157.1，155.8，150.8，150.5，147.9，142.5，138.8，134.7，131.1，123.7，119.9，119.3，86.3，82.6，77.2，75.9，45.5(x2)，36.5，33.9，32.5(x2)，26.5，19.8，19.1。LRMSESI(M+H
+)443.2。
Embodiment 17:2-{3-[1-((3, the 4-difluoro) carbobenzoxy) piperidin-4-yl] propine-1-yl }-9-propargyl VITAMIN B4.
Using the alkylating exemplary steps of above-mentioned N9-, 2-{3-[1-((3, the 4-difluoro) carbobenzoxy) piperidin-4-yl] propine-1-yl } VITAMIN B4 (32mg) is generated as the title compound of white solid: yield 15mg, 43%.
1H?NMR(CD
3OD)δ8.22(s，1H)，7.25(m，2H)，7.13(m，1H)，6.93(m，1H)，5.03(d，2H，J＝2.5Hz)，4.30，4.18(2xm，2H)，3.06，2.92(2xm，2H)，2.99(t，1H，J＝2.6Hz)，2.48(d，2H，J＝6.3Hz)，2.00-1.80，1.53-1.31(2xm，5H)。Carry out 13C, but fluorine divides many peaks.LRMS?ESI(M+H
+)451.2。
Embodiment 18:2-{3-[1-((3, the 4-dichloro) carbobenzoxy) piperidin-4-yl] propine-1-yl }-9-propargyl VITAMIN B4.
Use the alkylating exemplary steps of above-mentioned N9-, 2-{3-[1-((3, the 4-dichloro) carbobenzoxy) piperidin-4-yl] propine-1-yl }-VITAMIN B4 (37mg) obtains the title compound into white solid: yield 11mg, 28%.
1H?NMR(CD
3OD)δ8.22(s，1H)，7.50(d，1H，J＝8.8Hz)，7.36(d，1H，J＝2.6Hz)，7.08，(dd，1H，J＝2.6Hz，J＝8.8Hz)，5.03(d，2H，J＝2.6Hz)，4.31，4.19(2xm，2H)，3.07，2.93(2xm，2H)，2.99(t，1H，J＝2.6Hz)，2.48(d，2H，J＝6.2Hz)，2.00-1.81，1.54-1.33(2xm，5H)。LRMS?ESI(M+H
+)483.1。
Representative compound of the present invention is shown in the following table 1.The present invention includes these compounds and their steric isomer and pharmacy acceptable salt.
Table 1
| Instance number | Y | R 2 | R 4-R 3- | -(CH 2) qZ |
| 1 | NH | H | ≡-CH 2- | 4-CH 3-phenyl |
| 2 | NH | H | ≡-CH 2- | The 4-Cl-phenyl |
| 3 | NH | H | ≡-CH 2- | 3-CH 3-phenyl |
| 4 | NH | H | ≡-CH 2- | 3-CF 3-phenyl |
| 5 | NH | H | THF-3-base | 4-CH 3-phenyl |
| 6 | NH | H | THF-3-base | The 4-Cl-phenyl |
| 7 | NH | H | THF-3-base | 3-CH 3-phenyl |
| 8 | NH | H | THF-3-base | 3-CF 3-phenyl |
| 9 | NH | H | Cyclopentyl | 4-CH 3-phenyl |
| 10 | NH | H | Cyclopentyl | The 4-Cl-phenyl |
| 11 | NH | H | Cyclopentyl | 3-CH 3-phenyl |
| 12 | NH | H | Cyclopentyl | 3-CF 3-phenyl |
| 13 | NH | Furans-2-base | ≡-CH 2- | 4-CH 3-phenyl |
| 14 | NH | Furans-2-base | ≡-CH 2- | The 4-Cl-phenyl |
| 15 | NH | Furans-2-base | ≡-CH 2- | 3-CH 3-phenyl |
| 16 | NH | Furans-2-base | ≡-CH 2- | 3-CF 3-phenyl |
| 17 | NH | Furans-2-base | THF-3-base | 4-CH 3-phenyl |
| 18 | NH | Furans-2-base | THF-3-base | The 4-Cl-phenyl |
| 19 | NH | Furans-2-base | THF-3-base | 3-CH 3-phenyl |
| 20 | NH | Furans-2-base | THF-3-base | 3-CF 3-phenyl |
| 21 | NH | Furans-2-base | Cyclopentyl | 4-CH 3-phenyl |
| 22 | NH | Furans-2-base | Cyclopentyl | The 4-Cl-phenyl |
| 23 | NH | Furans-2-base | Cyclopentyl | 3-CH 3-phenyl |
| 24 | NH | Furans-2-base | Cyclopentyl | 3-CF 3-phenyl |
| 25 | NH | 2-fluoro-phenyl | ≡-CH 2- | 4-CH 3-phenyl |
| 26 | NH | 2-fluoro-phenyl | ≡-CH 2- | The 4-Cl-phenyl |
| 27 | NH | 2-fluoro-phenyl | ≡-CH 2- | 3-CH 3-phenyl |
| 28 | NH | 2-fluoro-phenyl | ≡-CH 2- | 3-CF 3-phenyl |
| 29 | NH | 2-fluoro-phenyl | THF-3-base | 4-CH 3-phenyl |
| 30 | NH | 2-fluoro-phenyl | THF-3-base | The 4-Cl-phenyl |
| 31 | NH | 2-fluoro-phenyl | THF-3-base | 3-CH 3-phenyl |
| 32 | NH | 2-fluoro-phenyl | THF-3-base | 3-CF 3-phenyl |
| 33 | NH | 2-fluoro-phenyl | Cyclopentyl | 4-CH 3-phenyl |
| 34 | NH | 2-fluoro-phenyl | Cyclopentyl | The 4-Cl-phenyl |
| 35 | NH | 2-fluoro-phenyl | Cyclopentyl | 3-CH 3-phenyl |
| 36 | NH | 2-fluoro-phenyl | Cyclopentyl | 3-CF 3-phenyl |
| 37 | O | H | ≡-CH 2- | 4-CH 3-phenyl |
| 38 | O | H | ≡-CH 2- | The 4-Cl-phenyl |
| 39 | O | H | ≡-CH 2- | 3-CH 3-phenyl |
| 40 | O | H | ≡-CH 2- | 3-CF 3-phenyl |
| 41 | O | H | THF-3-base | 4-CH 3-phenyl |
| 42 | O | H | THF-3-base | The 4-Cl-phenyl |
| 43 | O | H | THF-3-base | 3-CH 3-phenyl |
| 44 | O | H | THF-3-base | 3-CF 3-phenyl |
| 45 | O | H | Cyclopentyl | 4-CH 3-phenyl |
| 46 | O | H | Cyclopentyl | The 4-Cl-phenyl |
| 47 | O | H | Cyclopentyl | 3-CH 3-phenyl |
| 48 | O | H | Cyclopentyl | 3-CF 3-phenyl |
| 49 | O | Furans-2-base | ≡-CH 2- | 4-CH 3-phenyl |
| 50 | O | Furans-2-base | ≡-CH 2- | The 4-Cl-phenyl |
| 51 | O | Furans-2-base | ≡-CH 2- | 3-CH 3-phenyl |
| 52 | O | Furans-2-base | ≡-CH 2- | 3-CF 3-phenyl |
| 53 | O | Furans-2-base | THF-3-base | 4-CH 3-phenyl |
| 54 | O | Furans-2-base | THF-3-base | The 4-Cl-phenyl |
| 55 | O | Furans-2-base | THF-3-base | 3-CH 3-phenyl |
| 56 | O | Furans-2-base | THF-3-base | 3-CF 3-phenyl |
| 57 | O | Furans-2-base | Cyclopentyl | 4-CH 3-phenyl |
| 58 | O | Furans-2-base | Cyclopentyl | The 4-Cl-phenyl |
| 59 | O | Furans-2-base | Cyclopentyl | 3-CH 3-phenyl |
| 60 | O | Furans-2-base | Cyclopentyl | 3-CF 3-phenyl |
| 61 | O | 2-fluoro-phenyl | ≡-CH 2- | 4-CH 3-phenyl |
| 62 | O | 2-fluoro-phenyl | ≡-CH 2- | The 4-Cl-phenyl |
| 63 | O | 2-fluoro-phenyl | ≡-CH 2- | 3-CH 3-phenyl |
| 64 | O | 2-fluoro-phenyl | ≡-CH 2- | 3-CF 3-phenyl |
| 65 | O | 2-fluoro-phenyl | THF-3-base | 4-CH 3-phenyl |
| 66 | O | 2-fluoro-phenyl | THF-3-base | The 4-Cl-phenyl |
| 67 | O | 2-fluoro-phenyl | THF-3-base | 3-CH 3-phenyl |
| 68 | O | 2-fluoro-phenyl | THF-3-base | 3-CF 3-phenyl |
| 69 | O | 2-fluoro-phenyl | Cyclopentyl | 4-CH 3-phenyl |
| 70 | O | 2-fluoro-phenyl | Cyclopentyl | The 4-Cl-phenyl |
| 71 | O | 2-fluoro-phenyl | Cyclopentyl | 3-CH 3-phenyl |
| 72 | O | 2-fluoro-phenyl | Cyclopentyl | 3-CF 3-phenyl |
According to above-mentioned instruction, many changes of the present invention and variation are possible.Therefore, should be understood that within the scope of the appended claims, can by with this paper in specifically described different mode embodiment of the present invention.
Claims (6)
1. compound, it is compound or its pharmacy acceptable salt with formula III a:
Wherein:
Y is O or NH;
Z is a phenyl, and wherein Z is via the carbon atom connection and by 1-4 Z
1Group replaces;
Z
1Be independently selected from by F, Cl, C
1-4Alkyl and CF
3The group of forming;
R
1Be H;
R
2Be selected from the group of being made up of H, phenyl and furyl, said phenyl and furyl are independently selected from by F, C1, CH
3, CF
3And CH
30-2 group of the group that O forms replaces;
R
4Be selected from by C
1-4Alkyl, C
2-4Thiazolinyl, C
2-4Alkynyl, C
3-6The group that naphthenic base is formed, wherein said naphthenic base selectively be selected from-1-2 the heteroatoms interval of O-;
R
3Do not exist or for C
1-C
4Alkylidene group;
N is 1;
P is 1;
Q is 0; And,
R is 0.
2. compound according to claim 1, wherein Y is O.
3. compound, it is selected from:
4-[3-(6-amino-9-Propargyl-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 2-benzyloxy-ethyl ester;
4-[3-(6-amino-9-cyclopentyl-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 2-benzyloxy-ethyl ester;
4-[3-(6-amino-9-Propargyl-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 3-trifluoromethyl-phenyl ester;
4-[3-(6-amino-9-cyclopentyl-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 3-trifluoromethyl-phenyl ester;
4-[3-(6-amino-9-Propargyl-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 2-fluoro-phenyl ester;
4-[3-(6-amino-9-Propargyl-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 4-nitro-phenyl ester;
4-[3-(6-amino-9-Propargyl-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 4-methoxycarbonyl-phenyl ester;
4-[3-(6-amino-9-Propargyl-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 4-chloro-phenyl ester;
4-[3-(6-amino-9-Propargyl-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 4-methoxyl group-phenyl ester;
4-[3-(6-amino-9-Propargyl-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 4-methyl-phenyl ester;
4-[3-(6-amino-9-Propargyl-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 4-nitro-benzyl ester;
4-[3-(6-amino-9-Propargyl-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 2-chloro-phenyl ester;
4-[3-(6-amino-9-Propargyl-9H-purine-2-yl)-Propargyl]-piperidines-1-carboxylic acid 2-methoxyl group-phenyl ester;
2-{3-[1-((3, the 4-dimethyl-) carbobenzoxy) piperidin-4-yl] propine-1-yl }-9-propargyl VITAMIN B4;
2-{3-[1-((3, the 4-difluoro) carbobenzoxy) piperidin-4-yl] propine-1-yl }-9-propargyl VITAMIN B4; And,
2-{3-[1-((3, the 4-dichloro) carbobenzoxy) piperidin-4-yl] propine-1-yl }-9-propargyl VITAMIN B4.
4. compound, it is selected from the following table compound:
5. pharmaceutical composition, it comprises: each described compound and pharmaceutically acceptable carrier among the claim 1-4 of treatment significant quantity.
6. each the described compound among the claim 1-4 is used for preparation to treatment and deleterious A
2AThe purposes of the medicine that Adenosine Receptors activation or active diseases associated are useful.
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|---|---|---|---|
| US80754506P | 2006-07-17 | 2006-07-17 | |
| US60/807,545 | 2006-07-17 | ||
| US11/879,133 | 2007-07-16 | ||
| US11/879,133 US7985754B2 (en) | 2006-07-17 | 2007-07-16 | Selective antagonists of A2A adenosine receptors |
| PCT/US2007/016164 WO2008011007A2 (en) | 2006-07-17 | 2007-07-17 | Selective antagonists of a2a adenosine receptors |
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|---|---|---|---|---|
| CN1358190A (en) * | 1999-06-22 | 2002-07-10 | Cv治疗公司 | Propargyl phenyl ether A2A receptor agonists |
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