IP Library › Granted Patent US 6,949,559

Granted Patent B2

US 6,949,559 · App. 10/680,832 · Granted Sep 27, 2005

Nitrogen substituted biaryl purine derivatives as potent antiproliferative agents

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Quick Facts

Patent No.: US 6,949,559
App. No.: 10/680,832
Granted: Sep 27, 2005
Kind: B2

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Abstract

The compounds of the present invention are 2,6,9-trisubstituted purine derivatives which are inhibitors of cyclin/cdk complexes. The compounds of the current invention also are potent inhibitors of human cellular proliferation. As such, the compounds of the present invention constitute pharmaceutical compositions with a pharmaceutically acceptable carrier. Such compounds are useful in treating a disorder mediated by elevated levels of cell proliferation in a mammal compared to a healthy mammal by administering to such mammal an effective amount of the compound. Examples of the compounds of the present invention are represented by the following chemical structures: with X, Y, D, Q, V, A, R 1 , R 2 , R 3 , R 4 , and n 1 defined herein.

Claims (425)

1. A compound of the following formula:

wherein:

R 1 are the same or different and independently selected from the group consisting of:

C 1 -C 6 -straight chain alkyl;

C 2 -C 6 -straight alkenyl chain;

C 3 -C 6 -branched alkyl chain;

C 3 -C 6 -branched alkenyl chain;

C 3 -C 7 -cycloalkyl;

CH 2 —(C 3 -C 7 -cycloalkyl);

CH 2 CF 3 ;

CH 2 CH 2 CF 3 ; and

CH(CF 3 ) 2 ;

Q=N and D=X=CH;

V=NH;

S; or

CH 2 ;

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;

2-pyrimidyl;

4-pyrimidyl;

5-pyrimidyl;

thiophene-2-yl;

thiophene-3-yl;

2-furanyl;

3-furanyl;

oxazol-2-yl;

oxazol-4-yl;

oxazol-5-yl;

thiazol-2-yl;

thiazol-4-yl;

thiazol-5-yl;

imidazol-2-yl;

imidazol-4-yl;

pyrazol-3-yl;

pyrazol-4-yl;

isoxazol-3-yl;

isoxazol-4-yl;

isoxazol-5-yl;

isothiazol-3-yl;

isothiazol-4-yl;

isothiazol-5-yl;

1,3,4-thiadiazol-2-yl;

benzo[b]furan-2-yl;

benzo[b]thiophene-2-yl;

2-pyrrolyl;

3-pyrrolyl;

1,3,5-triazin-2-yl;

pyrazin-2-yl;

pyridazin-3-yl;

pyridazin-4-yl;

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:

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 with intervening atoms a 5-8-membered saturated or unsaturated ring;

n 1 =0-3;

n=0-3;

A=CH 2 ;

(CH 2 ) 2 ;

(CH 2 ) 3 ;

OCH 2 CH 2 ; or

CHCH 3 ;

Y=H;

OR 1 ;

N(R 1 ) 2 ;

N(R 1 )C(O)R 3 ;

N(R 1 )C(O)R 5 ;

N(R 1 )C(O)CH(R 6 )NH 2 ;

N(R 1 )SO 2 R 3 ;

N(R 1 )C(O)NHR 3 ; or

N(R 1 )C(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.

2. A compound according to claim 1 , wherein

R 3 are the same or different and independently selected from the group consisting of:

C 1 -C 4 -straight chain alkyl; and

C 3 -C 4 -branched chain alkyl;

Y=H;

OR 1 ;

N(R 1 ) 2 ;

N(R 1 )C(O)R 3 ;

N(R 1 )SO 2 R 3 ; or

N(R 1 )C(O)NHR 3 .

3. A compound of the following formula:

wherein:

R 1 are the same or different and independently selected from the group consisting of:

C 1 -C 6 -straight chain alkyl;

C 2 -C 6 -straight alkenyl chain;

C 3 -C 6 -branched alkyl chain;

C 3 -C 6 -branched alkenyl chain;

C 3 -C 7 -cycloalkyl;

CH 2 —(C 3 -C 7 -cycloalkyl);

CH 2 CF 3 ;

CH 2 CH 2 CF 3 ; and

CH(CF 3 ) 2 ;

Q=N and D=X=CH;

V=NH;

S; or

CH 2 ;

R 2 =phenyl;

1-naphthyl;

2-naphthyl;

heterocycles selected from the group consisting of:

2-pyridyl;

3-pyridyl;

4-pyridyl;

2-pyrimidyl;

4-pyrimidyl;

5-pyrimidyl;

thiophene-2-yl;

thiophene-3-yl;

2-furanyl;

3-furanyl;

oxazol-2-yl;

oxazol-4-yl;

oxazol-5-yl;

thiazol-2-yl;

thiazol-4-yl;

thiazol-5-yl;

imidazol-2-yl;

imidazol-4-yl;

pyrazol-3-yl;

pyrazol-4-yl;

isoxazol-3-yl;

isoxazol-4-yl;

isoxazol-5-yl;

isothiazol-3-yl;

isothiazol-4-yl;

isothiazol-5-yl;

1,3,4-thiadiazol-2-yl;

benzo[b]furan-2-yl;

benzo[b]thiophene-2-yl;

2-pyrrolyl;

3-pyrrolyl;

1,3,5-triazin-2-yl;

pyrazin-2-yl;

pyridazin-3-yl;

pyridazin-4-yl;

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 ;

n=0-3;

A=CH 2 ;

(CH 2 ) 2 ;

(CH 2 ) 3 ;

OCH 2 CH 2 ; or

CHCH 3 ;

Y=H;

OR 1 ;

N(R 1 ) 2 ;

N(R 1 )C(O)R 3 ;

N(R 1 )C(O)R 5 ;

N(R 1 )C(O)CH(R 6 )NH 2 ;

N(R 1 )SO 2 R 3 ;

N(R 1 )C(O)NHR 3 ; or

N(R 1 )C(O)OR 6 ;

R 3 are the same or different and independently selected from the group consisting of:

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 5 =C 3 -C 7 -cycloalkyl;

R 6 =C 1 -C 4 -straight chain alkyl;

C 3 -C 4 -branched chain alkyl; or

C 2 -C 4 -alkenyl chain;

or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition of matter comprising the compound of claim 1 and one or more pharmaceutical excipients.

5. A pharmaceutical composition of matter comprising the compound of claim 3 and one or more pharmaceutical excipients.

6. 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:

C 1 -C 6 -straight chain alkyl;

C 2 -C 6 -straight alkenyl chain;

C 3 -C 6 -branched alkyl chain;

C 3 -C 6 -branched alkenyl chain;

C 3 -C 7 -cycloalkyl;

CH 2 —(C 3 -C 7 -cycloalkyl);

CH 2 CF 3 ;

CH 2 CH 2 CF 3 ; and

CH(CF 3 ) 2 ;

Q=N and D=X=CH;

V=NH;

S; or

CH 2 ;

R 2 =phenyl;

1-naphthyl;

2-naphthyl;

heterocycles selected from the group consisting of:

2-pyridyl;

3-pyridyl;

4-pyridyl;

2-pyrimidyl;

4-pyrimidyl;

5-pyrimidyl;

thiophene-2-yl;

thiophene-3-yl;

2-furanyl;

3-furanyl;

oxazol-2-yl;

oxazol-4-yl;

oxazol-5-yl;

thiazol-2-yl;

thiazol-4-yl;

thiazol-5-yl;

imidazol-2-yl;

imidazol-4-yl;

pyrazol-3-yl;

pyrazol-4-yl;

isoxazol-3-yl;

isoxazol-4-yl;

isoxazol-5-yl;

isothiazol-3-yl;

isothiazol-4-yl;

isothiazol-5-yl;

1,3,4-thiadiazol-2-yl;

benzo[b]furan-2-yl;

benzo[b]thiophene-2-yl;

2-pyrrolyl;

3-pyrrolyl;

1,3,5-triazin-2-yl;

pyrazin-2-yl;

pyridazin-3-yl;

pyridazin-4-yl;

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:

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 with intervening atoms a 5-8-membered saturated or unsaturated ring;

n 1 =0-3;

n=0-3;

A=CH 2 ;

(CH 2 ) 2 ;

(CH 2 ) 3 ;

OCH 2 CH 2 ; or

CHCH 3 ;

Y=H;

OR 1 ;

N(R 1 ) 2 ;

N(R 1 )C(O)R 3 ;

N(R 1 )C(O)R 5 ;

N(R 1 )C(O)CH(R 6 )NH 2 ;

N(R 1 )SO 2 R 3 ;

N(R 1 )C(O)NHR 3 ; or

N(R 1 )C(O)OR 3 (;

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;

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 , or R 2 —Sn(Me) 3 , or mixtures thereof, under conditions effective to form the purine derivative compound.

7. A process according to claim 6 , wherein if Y is NHR 1 , said process further comprises:

reacting the purine derivative compound with R 3 C(O)C 1 or R 5 C(O)C 1 or R 3 SO 2 C 1 or R 3 NCO or R 6 OC(O)Cl under conditions effective to form a final product having the same formula as the purine derivative compound except that Y is NR 1 C(O)R 3 or NR 1 C(O)R 5 or NR 1 SO 2 R 3 or NR 1 C(O)NHR 3 or NR 1 C(O)OR 6 .

8. 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:

C 1 -C 6 -straight chain alkyl;

C 2 -C 6 -straight alkenyl chain;

C 3 -C 6 -branched alkyl chain;

C 3 -C 6 -branched alkenyl chain;

C 3 -C 7 -cycloalkyl;

CH 2 —(C 3 -C 7 -cycloalkyl);

CH 2 CF 3 ;

CH 2 CH 2 CF 3 ; and

CH(CF 3 ) 2 ;

Q=N, and D=X=CH;

V=NH;

O; or

R 2 =phenyl;

1-naphthyl;

2-naphthyl;

heterocycles selected from the group consisting of:

2-pyridyl;

3-pyridyl;

4-pyridyl;

2-pyrimidyl;

4-pyrimidyl;

5-pyrimidyl;

thiophene-2-yl;

thiophene-3-yl;

2-furanyl;

3-furanyl;

oxazol-2-yl;

oxazol-4-yl;

oxazol-5-yl;

thiazol-2-yl;

thiazol-4-yl;

thiazol-5-yl;

imidazol-2-yl;

imidazol-4-yl;

pyrazol-3-yl;

pyrazol-4-yl;

isoxazol-3-yl;

isoxazol-4-yl;

isoxazol-5-yl;

isothiazol-3-yl;

isothiazol-4-yl;

isothiazol-5-yl;

1,3,4-thiadiazol-2-yl;

benzo[b]furan-2-yl;

benzo[b]thiophene-2-yl;

2-pyrrolyl;

3-pyrrolyl;

1,3,5-triazin-2-yl;

pyrazin-2-yl;

pyridazin-3-yl;

pyridazin-4-yl;

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:

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 with intervening atoms a 5-8-membered saturated or unsaturated ring;

n1=0-3;

n=0-3;

A=CH 2 ;

(CH 2 ) 2 ;

(CH 2 ) 3 ;

OCH 2 CH 2 ; or

CHCH 3 ;

Y=H;

OR 1 ;

N(R 1 ) 2 ;

N(R 1 )C(O)R 3 ;

N(R 1 )C(O)R 5 ;

N(R 1 )C(O)CH(R 6 )NH 2 ;

N(R 1 )SO 2 R 3 ;

N(R 1 )C(O)NHR 3 ; or

N(R 1 )C(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; said process comprising:

reacting a first intermediate compound of the formula:

with a compound of the formula:

where V 1 =NH 2 ;

OH; or

SH;

under conditions effective to form the purine derivative compound.

9. A process according to claim 8 , wherein if Y is NHR 1 , said process further comprises:

reacting the purine derivative compound with R 3 C(O)C 1 or R 5 C(O)C 1 or R 3 SO 2 C 1 or R 3 NCO or R 6 OC(O)C1 under conditions effective to form a final product having the same formula as the purine derivative compound except that Y is NR 1 C(O)R 3 or NR 1 C(O)R 5 or NR 1 SO 2 R 3 or NR 1 C(O)NHR 3 or NR 1 C(O)OR 6 .

10. A process according to claim 8 further comprising:

reacting a second intermediate compound of the formula:

with a compound of the formula R 1 -Z under conditions effective to form the first intermediate compound.

11. A process according to claim 10 further comprising:

reacting a third intermediate compound of the formula:

with a compound of the formula 2,6-dichloropurine under conditions effective to form the second intermediate compound.

12. A process according to claim 11 further comprising:

reacting a fourth intermediate compound of the formula:

with a compound of the formula: R 2 —B(OH) 2 , R 2 —Sn(n-Bu) 3 , or R 2 —Sn (Me) 3 , or mixtures thereof, under conditions effective to form the third intermediate compound.

13. A process according to claim 8 , wherein the purine derivative compound has the formula:

Assignments (14)

ASSIGNMENT OF SECURITY INTEREST IN INTELLECTUAL PROPERTY, RECORDED ON SEPTEMBER 1, 2017, AT REEL/FRAME 043746/0621 Recorded Mar 17, 2025

From: BARCLAYS BANK PLC, AS EXISTING AGENT

To: APOLLO ADMINISTRATIVE AGENCY LLC, AS SUCCESSOR AGENT

Reel/Frame 070531/0279 →

SECURITY INTEREST Recorded Sep 6, 2021

From: CURIA GLOBAL, INC. (FKA ALBANY MOLECULAR RESEARCH, INC.); CURIA MASSACHUSETTS, INC. (FKA AMRI BURLINGTON, INC.); CURIA WISCONSIN, INC. (FKA CEDARBURG PHARMACEUTICALS, INC.); CURIA INDIANA, LLC (FKA AMRI SSCI, LLC); CURIA NEW MEXICO, LLC (FKA OSO BIOPHARMACEUTICALS MANUFACTURING, LLC); CURIA IP HOLDINGS, LLC

To: WILMINGTON TRUST, NATIONAL ASSOCIATION, AS COLLATERAL AGENT

Reel/Frame 057423/0665 →

RELEASE OF SECURITY INTEREST Recorded Oct 29, 2020

From: MORGAN STANLEY SENIOR FUNDING, INC., AS COLLATERAL AGENT

To: ALBANY MOLECULAR RESEARCH, INC.; AMRI BURLINGTON, INC.; CEDARBURG PHARMACEUTICALS, INC.; EUTICALS INC.; OSO BIOPHARMACEUTICALS MANUFACTURING, LLC

Reel/Frame 054252/0687 →

CORRECTIVE ASSIGNMENT TO CORRECT THE INCORRECT PATENT NO. 7541537 PREVIOUSLY RECORDED AT REEL: 034045 FRAME: 0951. ASSIGNOR(S) HEREBY CONFIRMS THE SECURITY INTEREST. Recorded Aug 14, 2018

From: ALBANY MOLECULAR RESEARCH, INC.; ALO ACQUISITION LLC; AMRI BURLINGTON, INC.; AMRI RENSSELAER, INC.; CEDARBURG PHARMACEUTICALS, INC.; OSO BIOPHARMACEUTICALS MANUFACTURING, LLC

To: BARCLAYS BANK PLC, AS THE COLLATERAL AGENT

Reel/Frame 046796/0352 →

FIRST LIEN SECURITY AGREEMENT Recorded Sep 1, 2017

From: ALBANY MOLECULAR RESEARCH, INC.; AMRI BURLINGTON, INC.; CEDARBURG PHARMACEUTICALS, INC.; EUTICALS INC.; OSO BIOPHARMACEUTICALS MANUFACTURING, LLC-BY ITS SOLE MEMBER: ALO ACQUISITION LLC

To: BARCLAYS BANK, PLC AS COLLATERAL AGENT

Reel/Frame 043746/0621 →

SECOND LIEN SECURITY AGREEMENT Recorded Sep 1, 2017

From: ALBANY MOLECULAR RESEARCH, INC.; AMRI BURLINGTON, INC.; CEDARBURG PHARMACEUTICALS, INC.; EUTICALS INC.; OSO BIOPHARMACEUTICALS MANUFACTURING LLC-BY ITS SOLE MEMBER:ALO ACQUISITION LLC

To: MORGAN STANLEY SENIOR FUNDING, INC.

Reel/Frame 043746/0657 →

RELEASE OF SECURITY INTEREST Recorded Aug 31, 2017

From: BARCLAYS BANK PLC, AS COLLATERAL AGENT

To: ALBANY MOLECULAR RESEARCH, INC.; ALO ACQUISITION LLC; AMRI BURLINGTON, INC.; AMRI RENSSELAER, INC.; CEDARBURG PHARMACEUTICALS, INC.; OSO BIOPHARMACEUTICALS MANUFACTURING, LLC; AMRI SSCI, LLC; EUTICALS INC.

Reel/Frame 043742/0085 →

SECURITY INTEREST Recorded Oct 24, 2014

From: ALBANY MOLECULAR RESEARCH, INC.; ALO ACQUISITION LLC; AMRI BURLINGTON, INC.; AMRI RENSSELAER, INC.; CEDARBURG PHARMACEUTICALS, INC.; OSO BIOPHARMACEUTICALS MANUFACTURING, LLC

To: BARCLAYS BANK PLC, AS THE COLLATERAL AGENT

Reel/Frame 034045/0951 →

RELEASE OF SECURITY INTEREST Recorded Jul 9, 2014

From: WELLS FARGO

To: ALBANY MOLECULAR RESEARCH, INC.

Reel/Frame 033283/0357 →

SECURITY AGREEMENT Recorded Apr 20, 2012

From: ALBANY MOLECULAR RESEARCH, INC.; AMRI BURLINGTON, INC.; AMRI BOTHELL RESEARCH CENTER, INC.; AMRI RENESSELAER, INC.

To: WELLS FARGO BANK, NATIONAL ASSOCIATION

Reel/Frame 028078/0227 →

TERMINATION Recorded Apr 19, 2012

From: BANK OF AMERICA, N.A.