Piperidinyl compounds that selectively bind integrins

• US 8,110,683 B2
• Filed: 12/22/2010
• Issued: 02/07/2012
• Est. Priority Date: 08/16/2002
• Status: Expired due to Fees

• Current Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: De Corte, Bart, Kinney, William A., Maryanoff, Bruce E., Ghosh, Shyamali, Liu, Li
• Primary Examiner(s): Solola, Taofiq A
• Application Number:
  US12/975,900
• Publication Number:
  US 20110092528A1
• Time in Patent Office: 412 Days
• Field of Search: 544/335
• US Class Current: 544/335
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/4523 containing further heterocyclic ring systems
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 51/0455 having six-membered rings with one nitrogen as the only ring hetero atom
• CPC Class Codes: A61K 51/0459 having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 27/00 Drugs for disorders of the senses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: Y02P 20/582 Recycling of unreacted starting or intermediate materials

Abstract

The invention is directed to piperidinyl compounds that selectively bind integrin receptors and methods for treating an integrin mediated disorder.

Claims

1. A compound of Formula (I) or Formula (II):

2. The compound of claim 1 wherein R₇ is one to two substituents independently selected from the group consisting of hydrogen, —

C_1-4alkoxy(R₉), —

NH₂, —

NH—

C_1-4alkyl(R₉), —

N(C_1-4alkyl(R₉))₂, —

C(═

O)H, —

C(═

O)—

C_1-4alkyl(R₉), —

C(═

O)—

NH₂, —

C(═

O)—

NH—

C_1-4alkyl(R₉), —

C(═

O)—

N(C_1-4alkyl(R₉))₂, —

C(═

O)—

NH-aryl(R₁₀), —

C(═

O)-cycloalkyl(R₁₀), —

C(═

O)-heterocyclyl(R₁₀), —

C(═

O)-aryl(R₁₀), —

C(═

O)-heteroaryl(R₁₀), —

CO₂H, —

CO₂—

C_1-4alkyl(R₉), —

CO₂-aryl(R₁₀), —

C(═

NH)—

NH₂, —

SH, —

S—

C_1-4alkyl(R₉), —

S—

C_1-4alkyl-S—

C_1-4alkyl(R₉), —

S—

C_1-4alkyl-C_1-4alkoxy(R₉), —

S—

C_1-4alkyl-NH—

C_1-4alkyl(R₉), —

SO₂—

C_1-4alkyl(R₉), —

SO₂—

NH₂, —

SO₂—

NH—

C_1-4alkyl(R₉), —

SO₂—

N(C_1-4alkyl(R₉))₂, —

SO₂-aryl(R₁₀), cyano, (halo)_1-3, hydroxy, nitro, oxo, -cycloalkyl(R₁₀), -heterocyclyl(R₁₀), -aryl(R₁₀) and -heteroaryl(R₁₀).

3. The compound of claim 1 wherein R₇ is one to two substituents independently selected from the group consisting of hydrogen, —

C_1-4alkoxy(R₉), —

NH₂, —

NH—

C_1-4alkyl(R₉), —

N(C_1-4alkyl(R₉))₂, (halo)_1-3, hydroxy and oxo.

4. The compound of claim 1 wherein R₇ is hydrogen.

5. The compound of claim 1 wherein R₈ is one to four substituents independently selected from the group consisting of hydrogen, —

C_1-4alkyl(R₉), —

C(═

O)H, —

C(═

O)—

C_1-4alkyl(R₉), —

C(═

O)—

NH₂, —

C(═

O)—

NH—

C_1-4alkyl(R₉), —

C(═

O)—

N(C_1-4alkyl(R₉))₂, —

C(═

O)—

NH-aryl(R₁₀), —

C(═

O)-cycloalkyl(R₁₀), —

C(═

O)-heterocyclyl(R₁₀), —

C(═

O)-aryl(R₁₀), —

C(═

O)-heteroaryl(R₁₀), —

CO₂H, —

CO₂—

C_1-4alkyl(R₉), —

CO₂-aryl(R₁₀), —

C(═

NH)—

NH₂, —

SO₂—

C_1-4alkyl(R₉), —

SO₂—

NH₂, —

SO₂—

NH—

C_1-4alkyl(R₉), —

SO₂—

N(C_1-4alkyl(R₉))₂, —

SO₂-aryl(R₁₀), -cycloalkyl(R₁₀) and -aryl(R₁₀) when attached to a nitrogen atom; and

, wherein R₈ is one to four substituents independently selected from the group consisting of hydrogen, —

C_1-4alkyl(R₉), —

C_1-4alkoxy(R₉), —

O-cycloalkyl(R₁₀), —

O-aryl(R₁₀), —

C(═

O)H, —

C(═

O)—

C_1-4alkyl(R₉), —

C(═

O)—

NH₂, —

C(═

O)—

NH—

C_1-4alkyl(R₉), —

C(═

O)—

N(C_1-4alkyl-R₁₁)₂, —

C(═

O)—

NH-aryl(R₁₀), —

C(═

O)-cycloalkyl(R₁₀), —

C(═

O)-heterocyclyl(R₁₀), —

C(═

O)-aryl(R₁₀), —

C(═

O)-heteroaryl(R₁₀), —

CO₂H, —

CO₂—

C_1-4alkyl(R₉), —

CO₂-aryl(R₁₀), —

C(═

NH)—

NH₂, —

SO₂—

C_1-4alkyl(R₉), —

SO₂—

NH₂, —

SO₂—

NH—

C_1-4alkyl(R₉), —

SO₂—

N(C_1-4alkyl(R₉))₂, —

SO₂-aryl(R₁₀), —

SH, —

S—

C_1-4alkyl(R₉), —

S—

C_1-4alkyl-S—

C_1-4alkyl(R₉), —

S—

C_1-4alkyl-C_1-4alkoxy(R₉), —

S—

C_1-4alkyl-NH—

C_1-4alkyl(R₉), —

NH₂, —

NH—

C_1-4alkyl(R₉), —

N(C_1-4alkyl(R₉))₂, cyano, halo, hydroxy, nitro, oxo, -cycloalkyl(R₁₀), -heterocyclyl(R₁₀), -aryl(R₁₀) and -heteroaryl(R₁₀) when attached to a carbon atom.

6. The compound of claim 1 wherein R₈ is one to four substituents independently selected from the group consisting of hydrogen, —

C_1-4alkyl(R₉), —

C(═

O)H, —

C(═

O)—

NH₂, —

C(═

O)—

NH—

C_1-4alkyl(R₉), —

C(═

O)—

N(C_1-4alkyl(R₉))₂, —

CO₂H, —

CO₂—

C_1-4alkyl(R₉) and —

SO₂—

NH₂ when attached to a nitrogen atom; and

, wherein R₈ is one to four substituents independently selected from the group consisting of hydrogen, —

C_1-4alkyl(R₉), —

C_1-4alkoxy(R₉), —

O-aryl(R₁₀), —

C(═

O)H, —

C(═

O)—

NH₂, —

C(═

O)—

NH—

C_1-4alkyl(R₉), —

C(═

O)—

N(C_1-4alkyl(R₉))₂, —

CO₂H, —

CO₂—

C_1-4alkyl(R₉), —

SO₂—

NH₂, NH₂, —

NH—

C_1-4alkyl(R₉), —

N(C_1-4alkyl(R₉))₂, cyano, halo, hydroxy, nitro and oxo when attached to a carbon atom.

7. The compound of claim 1 wherein R₈ is one to four substituents independently selected from the group consisting of hydrogen and —

C_1-4alkyl(R₉) when attached to a nitrogen atom; and

, wherein R₈ is one to four substituents independently selected from the group consisting of hydrogen, —

C_1-4alkyl(R₉), —

C_1-4alkoxy(R₉), —

O-aryl(R₁₀), —

NH₂, —

NH—

C_1-4alkyl(R₉), —

N(C_1-4alkyl(R₉))₂, halo, hydroxy and oxo when attached to a carbon atom.

8. The compound of claim 1 wherein R₈ is one to four substituents independently selected from the group consisting of hydrogen and —

C_1-4alkyl(R₉) when attached to a nitrogen atom; and

, wherein R₈ is one to four substituents independently selected from the group consisting of hydrogen, —

C_1-4alkyl(R₉), —

C_1-4alkoxy(R₉), —

O-aryl(R₁₀) and hydroxy when attached to a carbon atom.

9. The compound of claim 1 wherein R₉ is selected from the group consisting of hydrogen, —

C_1-4alkoxy, —

NH₂, —

NH—

C_1-4alkyl, —

N(C_1-4alkyl)₂, —

C(═

O)H, —

C(═

O)—

NH₂, —

C(═

O)—

NH—

C_1-4alkyl, —

C(═

O)—

N(C_1-4alkyl)₂, —

CO₂H, —

CO₂—

C_1-4alkyl, —

SO₂—

C_1-4alkyl, —

SO₂—

NH₂, —

SO₂—

NH—

C_1-4alkyl, —

SO₂—

N(C_1-4alkyl)₂, cyano, (halo)_1-3, hydroxy, nitro and oxo.

10. The compound of claim 1 wherein R₉ is selected from the group consisting of hydrogen, —

C_1-4alkoxy, —

NH₂, —

NH—

C_1-4alkyl, —

N(C_1-4alkyl)₂, —

C(═

O)H, —

CO₂H, —

C(═

O)—

C_1-4alkoxy, (halo)_1-3, hydroxy and oxo.

11. The compound of claim 1 wherein R₉ is selected from the group consisting of hydrogen, —

C_1-4alkoxy, —

NH₂, —

NH—

C_1-4alkyl, —

N(C_1-4alkyl)₂, (halo)_1-3 and hydroxy.

12. The compound of claim 1 wherein R₁₀ is one to four substituents independently selected from the group consisting of hydrogen, —

C_1-4alkyl, —

C(═

O)H, —

C(═

O)—

C_1-4alkyl, —

C(═

O)—

NH₂, —

C(═

O)—

NH—

C_1-4alkyl, —

C(═

O)—

N(C_1-4alkyl)₂, —

CO₂H, —

CO₂—

C_1-4alkyl, —

SO₂—

C_1-4alkyl, —

SO₂—

NH₂, —

SO₂—

NH—

C_1-4alkyl and —

SO₂—

N(C_1-4alkyl)₂ when attached to a nitrogen atom; and

, wherein R₁₀ is one to four substituents independently selected from the group consisting of hydrogen, —

C_1-4alkyl, —

C_1-4alkoxy, —

C(═

O)H, —

C(═

O)—

C_1-4alkyl, —

C(═

O)—

NH₂, —

C(═

O)—

NH—

C_1-4alkyl, —

C(═

O)—

N(C_1-4alkyl)₂, —

CO₂H, —

CO₂—

C_1-4alkyl, —

SO₂—

C_1-4alkyl, —

SO₂—

NH₂, —

SO₂—

NH—

C_1-4alkyl, —

SO₂—

N(C_1-4alkyl)₂, —

NH₂, —

NH—

C_1-4alkyl, —

N(C_1-4alkyl)₂, cyano, halo, hydroxy, nitro and oxo when attached to a carbon atom.

13. The compound of claim 1 wherein (R₁₀)_1-4 is selected from the group consisting of hydrogen, —

C_1-4alkyl, —

C_1-4alkoxy, —

C(═

O)H, —

C(═

O)—

C_1-4alkyl, —

CO₂H, —

CO₂—

C_1-4alkyl, —

NH₂, —

NH—

C_1-4alkyl, —

N(C_1-4alkyl)₂, halo, hydroxy, nitro and oxo when attached to a carbon atom.

14. The compound of claim 1 wherein R₁₀ is hydrogen.

15. The compound of claim 1 wherein R₂ is selected from the group consisting of hydrogen, —

C_1-4alkyl(R₇), —

C_2-4alkenyl(R₇), —

C_2-4alkynyl(R₇), -cycloalkyl(R₈), -heterocyclyl(R₈), -aryl(R₈) and -heteroaryl(R₈).

16. The compound of claim 1 wherein R₂ is selected from the group consisting of hydrogen, -cycloalkyl(R₈), -heterocyclyl(R₈), -aryl(R₈) and -heteroaryl(R₈).

17. The compound of claim 1 wherein R₂ is selected from the group consisting of hydrogen, -cycloalkyl(R₈), -heterocyclyl(R₈), -phenyl(R₈), -naphthalenyl(R₈) and -heteroaryl(R₈).

18. The compound of claim 1 wherein R₂ is selected from the group consisting of hydrogen, -tetrahydropyrimidinyl(R₈), -1,3-benzodioxolyl(R₈), -dihydrobenzofuranyl(R₈), -tetrahydroquinolinyl(R₈), -phenyl(R₈), -naphthalenyl(R₈), -pyridinyl(R₈), -pyrimidinyl(R₈) and -quinolinyl(R₈).

19. The compound of claim 1 wherein q is 1, 2 or 3.

20. The compound of claim 1 wherein Z is selected from the group consisting of hydroxy, —

NH₂, —

NH—

C_1-8alkyl, —

N(C_1-8alkyl)₂, —

O—

C_1-8alkyl, —

O—

C_1-8alkyl-OH, —

O—

C_1-8alkylC_1-4alkoxy, —

O—

C_1-8alkylcarbonylC_1-4alkyl, —

O—

C_1-8alkyl-CO₂H, —

O—

C_1-8alkyl-C(O)O—

C_1-6alkyl, C_1-8alkyl-OC(O)—

C_1-6alkyl, —

O—

C_1-8alkyl-NH₂, —

O—

C_1-8alkyl-NH—

C_1-8alkyl, —

O—

C_1-8alkyl-N(C_1-8alkyl)₂, —

O—

C_1-8alkylamide, C_1-8alkyl-C(O)—

NH—

C_1-8alkyl, —

O—

C_1-8alkyl-C(O)—

N(C_1-8alkyl)₂ and —

NHC(O)C_1-8alkyl.

24. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

21. A compound of Formula (I):

22. A compound of claim 21 wherein the compound is selected from the group consisting of:

a compound of Formula (I) wherein W is —

CH₂-Ph(3-R₁);

R₁ is

-1,4,5,6-tetrahydro-pyrimidin-2-yl;

R₂ is H, q is , and Z is OH;

0;

a compound of Formula (I) wherein W is —

(CH₂)₂-Ph(3-R₁);

R₁ is

-1,4,5,6-tetrahydro-pyrimidin-2-yl;

R₂ is H, q is 0 and Z is OH;

a compound of Formula (I) wherein W is —

CH₂-Ph(3-R₁);

R₁ is

-1,4,5,6-tetrahydro-5-OH-pyrimidin-2-yl;

R₂ is -3-quinolinyl, q is 0 and Z is OH;

a compound of Formula (I) wherein W is -Ph(3-R₁);

R₁ is

—

NH-1,4,5,6-tetrahydro-pyrimidin-2-yl;

R₂ is -3-pyridinyl, q is 2 and Z is OH;

a compound of Formula (I) wherein W is -Ph(3-R₁);

R₁ is

—

NH-1,4,5,6-tetrahydro-5-OH-pyrimidin-2-yl;

R₂ is -3-pyridinyl, q is 2 and Z is OH;

a compound of Formula (I) wherein W is -Ph(3-R₁);

R₁ is

—

NH-1,4,5,6-tetrahydro-5-OH-pyrimidin-2-yl;

R₂ is -(6-MeO)pyridin-3-yl, q is 2 and Z is OH;

a compound of Formula (I) wherein W is -Ph(3-R₁);

R₁ is

—

NH-1,4,5,6-tetrahydro-pyrimidin-2-yl;

R₂ is -3-quinolinyl, q is 2 and Z is OH;

a compound of Formula (I) wherein W is -Ph(3-R₁);

R₁ is

—

NH-1,4,5,6-tetrahydro-5-OH-2-pyrimidinyl;

R₂ is -1,3-benzodioxol-5-yl, q is 1 and Z is OH;

a compound of Formula (I) wherein W is -Ph(3-R₁);

R₁ is

—

NH-1,4,5,6-tetrahydro-5-OH-pyrimidin-2-yl;

R₂ is -3-quinolinyl, q is 2 and Z is OH;

a compound of Formula (I) wherein W is -Ph(3-R₁);

R₁ is

—

NH-3,4,5,6-tetrahydro-pyrimidin-2-yl;

R₂ is -1,3-benzodioxol-5-yl, q is 2 and Z is OH; and

a compound of Formula (I) wherein W is -Ph(3-R₁);

R₁ is

—

NH-1,4,5,6-tetrahydro-5-OH-pyrimidin-2-yl;

R₂ is -1,3-benzodioxol-5-yl, q is 2 and Z is OH.

23. A compound of Formula (I.3):