US2004063727A1PendingUtilityA1
6-Substituted biaryl purine derivatives as potent cyclin/cdk inhibitors and antiproliferative agents
Priority: Mar 17, 1999Filed: Aug 13, 2003Published: Apr 1, 2004
Est. expiryMar 17, 2019(expired)· nominal 20-yr term from priority
Inventors:Michael P. Trova
A61P 35/00A61P 37/06A61P 3/10A61P 7/02A61P 43/00A61P 35/02A61P 25/00C07D 473/18C07D 473/16C07D 473/24A61P 19/06A61P 19/02C07D 401/12A61K 31/52C07D 213/06
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Claims
Abstract
The present invention is directed to compounds useful in inhibiting cellular proliferation. Processes of preparing such compounds are also disclosed.
Claims
exact text as granted — not AI-modifiedWhat is claimed:
1 . A compound of the following formula:
wherein:
R 1 are the same or different and independently selected from the group consisting of:
H;
C 1 -C 4 -straight chain alkyl; and
C 3 -C 4 -branched chain alkyl;
X=CH;
R 2 =phenyl;
substituted phenyl, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of R 1 , OR 1 , SR 1 , S(O)R 1 , S(O 2 )R 1 , NHR 1 , NO 2 , OC(O)CH 3 , NHC(O)CH 3 , F, Cl, Br, CF 3 , C(O)R 1 , C(O)NHR 1 , phenyl, and C(O)NHCHR 1 CH 2 OH;
1-naphthyl;
2-naphthyl;
heterocycles selected from the group consisting of:
2-pyridyl;
3-pyridyl;
4-pyridyl;
5-pyrimidyl;
thiophene-2-yl;
thiophene-3-yl;
2-furanyl;
3-furanyl;
2-benzofuranyl;
benzothiophene-2-yl;
2-pyrrolyl;
3-pyrrolyl;
2-quinolinyl;
3-quinolinyl;
4-quinolinyl;
1-isoquinolinyl;
3-isoquinolinyl; and
4-isoquinolinyl; or
substituted heterocycle, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of Br, Cl, F, R 1 , and C(O)CH 3 ;
R 3 are the same or different and independently selected from the group consisting of:
H;
C 1 -C 4 -straight chain alkyl;
C 3 -C 4 -branched chain alkyl;
C 2 -C 4 -alkenyl chain;
(CH 2 ) n Ph; and
(CH 2 ) n -substituted phenyl, wherein the phenyl substituents are as defined above in R 2 ;
R 4 =H;
C 1 -C 4 -straight chain alkyl; or
C 3 -C 4 -branched chain alkyl;
R 3 and R 4 can be linked together by a carbon chain to form a 5-8-membered ring;
n=0-3;
Y=H;
OR 1 ;
NHR 1 ;
NHC(O)R 3 ;
NHSO 2 R 3 ;
NHC(O)NHR 3 ;
NHC(O)R 5 ; or
NHC(O)OR 6 ;
R 5 ═C 3 -C 7 -cycloalkyl;
R 6 =C 1 -C 4 -straight chain alkyl;
C 3 -C 4 -branched chain alkyl;
C 2 -C 4 -alkenyl chain;
(CH 2 ) n Ph; or
(CH 2 ) n -substituted phenyl, wherein the phenyl substituents are as defined above in R 2 ; or a pharmaceutically acceptable salt thereof;
with the proviso that when R 1 =CH(CH 3 ) 2 , and R 2 =Ph, and X=CH, then R 3 ≠H, and n≠0, and R 4 ≠H, and Y≠OH.
2 . A compound according to claim 1 , wherein
R 3 are the same or different and independently selected from the group consisting of:
H;
C 1 -C 4 -straight chain alkyl; and
C 3 -C 4 -branched chain alkyl;
Y=H;
OR 1 ;
NHR 1 ;
NHC(O)R 3 ;
NHSO 2 R 3 ; or
NHC(O)NHR 3 ; or a pharmaceutically acceptable salt thereof.
3 . A compound of the following formula:
wherein:
R 1 are the same or different and independently selected from the group consisting of:
H;
C 1 -C 4 -straight chain alkyl; and
C 3 -C 4 -branched chain alkyl;
X=CH;
R 2 =phenyl;
substituted phenyl, wherein the substituents (1-2 in number) are in any position and independently selected from the group consisting of R 1 , OR 1 , SR 1 , S(O)R 1 , S(O 2 )R 1 , NHR 1 , NO 2 , OC(O)CH 3 , NHC(O)CH 3 , F, Cl, Br, CF 3 , C(O)R 1 , C(O)NHR 1 , phenyl, and C(O)NHCHR 1 CH 2 OH;
heterocycles selected from the group consisting of:
2-pyridyl;
3-pyridyl;
4-pyridyl;
5-pyrimidyl;
thiophene-2-yl;
thiophene-3-yl;
2-furanyl;
3-furanyl;
2-benzofuranyl;
benzothiophene-2-yl;
2-pyrrolyl;
3-pyrrolyl;
2-quinolinyl;
3-quinolinyl;
4-quinolinyl;
1-isoquinolinyl;
3-isoquinolinyl; and
4-isoquinolinyl; or
substituted heterocycle, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of Br, Cl, F, R 1 , and C(O)CH 3 ;
Y=OR 1 ;
NHR 1 ;
NHC(O)R 1 ;
NHSO 2 R 1 ;
NHC(O)NHR 1 ; or
NHC(O)OR 1 ;
R 6 =C 1 -C 4 -straight chain alkyl;
C 3 -C 4 -branched chain alkyl;
C 2 -C 4 -alkenyl chain; or
or a pharmaceutically acceptable salt thereof.
4 . A compound according to claim 3 , wherein the compound has the following formula:
or a pharmaceutically acceptable salt thereof.
5 . A compound according to claim 3 , wherein the compound has the following formula:
or a pharmaceutically acceptable salt thereof.
6 . A compound according to claim 3 , wherein the compound has the following formula:
or a pharmaceutically acceptable salt thereof.
7 . A compound according to claim 3 , wherein the compound has the following formula:
or a pharmaceutically acceptable salt thereof.
8 . A compound according to claim 3 , wherein the compound has the following formula:
or a pharmaceutically acceptable salt thereof.
9 . A compound according to claim 3 , wherein the compound has the following formula:
or a pharmaceutically acceptable salt thereof.
10 . A pharmaceutical composition of matter comprising the compound of claim 1 and one or more pharmaceutical excipients.
11 . A pharmaceutical composition of matter comprising the compound of claim 3 and one or more pharmaceutical excipients.
12 . A process for preparation of a purine derivative compound of the formula:
wherein:
R 1 are the same or different and independently selected from the group consisting of:
H;
C 1 -C 4 -straight chain alkyl; and
C 3 -C 4 -branched chain alkyl;
X=CH;
R 2 =phenyl;
substituted phenyl, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of R 1 , OR 1 , SR 1 , S(O)R 1 , S(O 2 )R 1 , NHR 1 , NO 2 , OC(O)CH 3 , NHC(O)CH 3 , F, Cl, Br, CF 3 , C(O)R 1 , C(O)NHR 1 , phenyl, and C(O)NHCHR 1 CH 2 OH;
1-naphthyl;
2-naphthyl;
heterocycles selected from the group consisting of:
2-pyridyl;
3-pyridyl;
4-pyridyl;
5-pyrimidyl;
thiophene-2-yl;
thiophene-3-yl;
2-furanyl;
3-furanyl;
2-benzofuranyl;
benzothiophene-2-yl;
2-pyrrolyl;
3-pyrrolyl;
2-quinolinyl;
3-quinolinyl;
4-quinolinyl;
1-isoquinolinyl;
3-isoquinolinyl; and
4-isoquinolinyl; or
substituted heterocycle, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of Br, Cl, F, R 1 , and C(O)CH 3 ;
R 3 are the same or different and independently selected from the group consisting of
H;
C 1 -C 4 -straight chain alkyl;
C 3 -C 4 -branched chain alkyl;
C 2 -C 4 -alkenyl chain;
(CH 2 ) n Ph; and
(CH 2 ) n -substituted phenyl, wherein the phenyl substituents are as defined above in R 2 ;
R 4 =H;
C 1 -C 4 -straight chain alkyl; or
C 3 -C 4 -branched chain alkyl;
R 3 and R 4 can be linked together by a carbon chain to form a 5-8-membered ring;
n=0-3;
Y=H;
OR 1 ;
NHR 1 ;
NHC(O)R 3 ;
NHSO 2 R 3 ;
NHC(O)NHR 3 ;
NHC(O)R 5 ; or
NHC(O)OR 6 ;
R 5 =C 3 -C 7 -cycloalkyl;
R 6 =C 1 -C 4 -straight chain alkyl;
C 3 -C 4 -branched chain alkyl;
C 2 -C 4 -alkenyl chain;
(CH 2 ) n Ph; or
(CH 2 ) n -substituted phenyl, wherein the phenyl substituents are as defined above in R 2 ; or a pharmaceutically acceptable salt thereof;
with the proviso that when R 1 =CH(CH 3 ) 2 , and R 2 =Ph, and X=CH, then R 3 ≠H, and n=0, and R 4 ≠H, and Y≠OH, said process comprising:
reacting a first intermediate compound of the formula:
where
Z=Br or I
with a compound of the formula: R 2 —B(OH) 2 , R 2 —Sn(n-Bu) 3 , R 2 —Sn(Me) 3 , or mixtures thereof, under conditions effective to form the purine derivative compound.
13 . A process according to claim 12 further comprising:
reacting a second intermediate compound of the formula:
with a second compound of the formula:
under conditions effective to form the first intermediate compound.
14 . A process according to claim 13 , wherein if Y in the second compound is NH 2 , said process further comprises:
reacting the purine derivative compound with R 3 C(O)Cl or R 3 SO 2 Cl or R 3 NCO or R 3 OC(O)Cl under conditions effective to form a final product having the same formula as the purine derivative compound except that Y is NHC(O)R 3 or NHSO 2 R 3 or NHC(O)NHR 3 or NHC(O)OR 6 .
15 . A process according to claim 13 further comprising:
reacting a third intermediate compound of the formula:
with a compound of the formula R 1 -Z under conditions effective to form the second intermediate compound.
16 . A process according to claim 15 further comprising:
reacting a first starting compound of the formula:
with a second starting compound of the formula
under conditions effective to form the third intermediate compound.
17 . A process according to claim 12 , wherein the purine derivative compound has the formula:
18 . A process for preparation of a purine derivative compound of the formula
wherein:
R 1 are the same or different and independently selected from the group consisting of:
H;
C 1 -C 4 -straight chain alkyl; and
C 3 -C 4 -branched chain alkyl;
X=CH;
R 2 =phenyl;
substituted phenyl, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of R 1 , OR 1 , SR 1 , S(O)R 1 , S(O 2 )R 1 , NHR 1 , NO 2 , OC(O)CH 3 , NHC(O)CH 3 , F, Cl, Br, CF 3 , C(O)R 1 , C(O)NHR 1 , phenyl, and C(O)NHCHR 1 CH 2 OH;
1-naphthyl;
2-naphthyl;
heterocycles selected from the group consisting of:
2-pyridyl;
3-pyridyl;
4-pyridyl;
5-pyrimidyl;
thiophene-2-yl;
thiophene-3-yl;
2-furanyl;
3-furanyl;
2-benzofuranyl;
benzothiophene-2-yl;
2-pyrrolyl;
3-pyrrolyl;
2-quinolinyl;
3-quinolinyl;
4-quinolinyl;
1-isoquinolinyl;
3-isoquinolinyl; and
4-isoquinolinyl; or
substituted heterocycle, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of Br, Cl, F, R 1 , and C(O)CH 3 ;
R 3 are the same or different and independently selected from the group consisting of
H;
C 1 -C 4 -straight chain alkyl;
C 3 -C 4 -branched chain alkyl;
C 2 -C 4 -alkenyl chain;
(CH 2 ) n Ph; and
(CH 2 ) n -substituted phenyl, wherein the phenyl substituents are as defined above in R 2 ;
R 4 =H;
C 1 -C 4 -straight chain alkyl; or
C 3 -C 4 -branched chain alkyl;
R 3 and R 4 can be linked together by a carbon chain to form a 5-8-membered ring;
n-=0-3;
Y=H;
OR 1 ;
NHR 1 ;
NHC(O)R 3 ;
NHSO 2 R 3 ;
NHC(O)NHR 3 ;
NHC(O)R 5 ; or
NHC(O)OR 6 ;
R 5 =C 3 -C 7 -cycloalkyl;
R 6 =C 1 -C 4 -straight chain alkyl;
C 3 -C 4 -branched chain alkyl;
C 2 -C 4 -alkenyl chain;
(CH 2 ) n Ph; or
(CH 2 ) n -substituted phenyl, wherein the phenyl substituents are as defined above in R 2 ; or a pharmaceutically acceptable salt thereof;
with the proviso that when R 1 =CH(CH 3 ) 2 , and R 2 =Ph, and X=CH, then R 3 ≠H, and n≠0, and R 4 ≠H, and Y≠OH, said process comprising:
reacting a first intermediate compound of the formula:
with a second compound of the formula:
under conditions effective to form the purine derivative compound.
19 . A process according to claim 18 , wherein if Y in the second compound is NH 2 , said process further comprises:
reacting the purine derivative compound with R 3 C(O)Cl or R 3 SO 2 Cl or R 3 NCO or R 3 OC(O)Cl under conditions effective to form a final product having the same formula as the purine derivative compound except that Y is NHC(O)R 3 or NHSO 2 R 3 or NHC(O)NHR 3 or NHC(O)OR 6 .
20 . A process according to claim 18 further comprising:
reacting a third intermediate compound of the formula:
with a compound of the formula R 1 -Z under conditions effective to form the first intermediate compound.
21 . A process according to claim 20 further comprising:
reacting a first starting compound of the formula:
with a second starting compound of the formula
under conditions effective to form the third intermediate compound.Join the waitlist — get patent alerts
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