Pyridine mercapto carboxylic acids as carboxypeptidase U inhibitors

• US 7,071,175 B1
• Filed: 05/03/2000
• Issued: 07/04/2006
• Est. Priority Date: 05/03/1999
• Status: Expired due to Fees

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Astrazeneca AB (Astrazeneca PLC)
• Inventors: Linschoten, Marcel, Polla, Magnus
• Primary Examiner(s): McKenzie, Thomas C.
• Application Number:
  US09/600,661
• Time in Patent Office: 2,253 Days
• Field of Search: 514/63, 514/89, 514/277, 514/340, 514/345, 514/352, 514/354, 514/357, 546/13, 546/22, 546/268.4, 546/301, 546/309, 546/323, 546/341
• US Class Current: 514/63
• 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 38/57 from animals; from humans A61K38/553, A61K38/556 take precedence
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

The present invention relates to compounds of Formula I, and pharmaceutically acceptable salts or solvates thereof, or solvates of such salts,
which compounds inhibit carboxypeptidase U and thus can be used in the prevention and treatment of diseases associated with carboxypeptidase U. In further aspects, the invention relates to compounds of the invention for use in therapy; to processes for preparation of such new compounds: to pharmaceutical compositions containing at least one compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, as active ingredient; and to the use of the active compounds in the manufacture of medicaments for the medical use indicated above.

Claims

1. A compound of Formula I

or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt,

wherein:

R₁ is pyridyl substituted with one or more basic groups;

R₂ is selected from the group consisting of H, acyl, acylamino, alkyl, alkylcarbamoyl, alkylthio, alkoxy, aroyl, aroylamino, aryloxy, arylthio, amidino, amino, aryl, carbamoyl, carboxy, cyano, cycloalkyl, formyl, guanidino, halogen, heterocyclyl, hydroxy, oxo, nitro, thiol, a Z₂N—

CO—

O—

group, a ZO—

CO—

NZ—

group, and a Z₂N—

CO—

NZ—

group;

R₃ is selected from the group consisting of COOR₅, SO(OR₅), SO₃R₅, P═

O(OR₅)₂, B(OR₅)₂, P═

OR₅(OR₅), tetrazole, and a carboxylic acid isostere which is an acidic group having a pKa of from about −

5 to about 25;

R₄ is SH, S—

CO—

C₁-C₆ alkyl, or S—

CO-aryl;

R₅ is H, C₁-C₆ alkyl, or aryl;

R₆ is H or C₁-C₆ alkyl;

X is selected from the group consisting of O, S, SO, SO₂, C(Z)₂,

N (Z), NR₆SO₂, SO₂NR₆, NR₆CO, and CONR₆;

Y is C(Z)₂; and

Z is independently selected from the group consisting of H, C₁-C₆ alkyl, aryl, cycloalkyl, and heterocyclyl.

2. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt,

wherein:

R₂ is selected from the group consisting of H, acyl, acylamino, alkyl, alkylcarbamoyl, alkylthio, alkoxy, aroyl, aroylamino, aryloxy, arylthio, amidino, amino, aryl, carbamoyl, carboxy, cyano, cycloalkyl, formyl, guanidino, halogen, heterocyclyl, hydroxy, oxo, nitro, thiol, Z₂N—

CO—

O—

, ZO—

CO—

NZ—

, and Z₂N—

CO—

NZ—

;

R₃ is COOR₅;

R₄ is SH, S—

CO—

C₁-C₆ alkyl, or S—

CO-aryl;

R₅ is H, C₁-C₆ alkyl, or aryl;

R₆ is H or C₁-C₆ alkyl;

X is selected from the group consisting of O, S, SO, SO₂, C(Z)₂,

N(Z), NR₆SO₂, SO₂NR₆, and CONR₆;

Y is C(Z)₂; and

Z is independently selected from the group consisting of H, C₁-C₆ alkyl, aryl, cycloalkyl and heterocyclyl.

3. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt,

wherein:

R₂ is selected from the group consisting of H, C₁-C₃ alkyl, amino, halogen, and hydroxy;

R₃ is COOR₅;

R₄ is SH, S—

CO—

C₁-C₆ alkyl, or S—

CO-aryl;

R₅ is H, C₁-C₆ alkyl, or aryl;

X is C(Z)₂;

Y is C (Z)₂; and

Z is independently H or C₁-C₆ alkyl.

4. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt,

wherein:

R₂ is H, F, or C₁ alkyl;

R₃ is COOR₅;

R₄ is SH, S—

CO—

C₁-C₆ alkyl, or S—

CO-aryl;

R₅ is H, C₁-C₆ alkyl, or aryl;

X is C (Z)₂;

Y is C(Z)₂; and

Z is independently H or C₁-C₆ alkyl.

5. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, wherein:

R₂ is H, F, or C₁ alkyl;

R₃ is COOR₅;

R₄ is SH;

R₅ is H;

X is CHZ;

Y is CHZ; and

Z is independently H or C₁-C₆ alkyl.

6. The compound according to any one of claims 1-5, wherein the basic group is selected from the group consisting of amino, amidino, and guanidino.

7. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 5 as active ingredient in combination with a pharmaceutically acceptable adjuvant, diluent or carrier.

8. A pharmaceutical formulation, comprising:

(i) a compound of Formula I according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt; and

(ii) one or more antithrombotic agents selected from the group consisting of an antiplatelet agent, thromboxane receptor inhibitor, synthetase inhibitor, fibrinogen receptor antagonist, prostacyclin mimetic, phosphodiesterase inhibitor, and an ADP-receptor (P₂T) antagonist,

in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier.

9. A method for inhibiting carboxypeptidase U, comprising administering an effective amount of a compound according to any one of claims 1-5.

10. A method both for inhibiting carboxypeptidase U and for achieving an antithrombotic effect via a different mechanism, which method comprises administering a therapeutically effective total amount of:

(i) a compound of Formula I according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier; and

(ii) one or more antithrombotic agents selected from the group consisting of an antiplatelet agent, thromboxane receptor inhibitor, synthetase inhibitor, fibrinogen receptor antagonist, prostacyclin mimetic, phosphodiesterase inhibitor, and an ADP-receptor (P₂T) antagonist,

in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier.

11. A method both for inhibiting carboxypeptidase U and for achieving an antithrombotic effect via a different mechanism, which method comprises administering the formulation according to claim 8.

12. A method for treatment of thrombosis and hypercoagulability, comprising administering to a patient in need of such treatment an effective amount of a compound according to any one of claims 1-5.

13. A process for the preparation of a compound according to claim 1, wherein X is C(Z)₂, and R₂ is H, comprising the step of:

reacting a compound of Formula VI,

 

wherein R₁, R₃ and Y are as defined in claim 1 and X is C(Z)₂, with a compound of Formula IX,

R5-SH 

 

(IX)

 

wherein R₅ is a protecting group, optionally in the presence of a base or a free-radical initiator.

14. A process for the preparation of a compound according to claim 1, wherein Y is CH₂, and X is O, S, C(Z)₂, or N(Z), comprising the step of:

reacting a compound of Formula XIV,

 

wherein R₁, R₂, and R₃ are as defined in claim 1, and X is O, S, C(Z)₂, or N(Z), with a compound of general Formula IX,

R5-SH 

 

(IX)

 

wherein R₅ is a protecting group, in the presence of a suitable reagent, under standard conditions.

15. A process for the preparation of a compound according to claim 1, wherein X is NR₆CO or NR₆SO₂, comprising the step of:

reacting a compound of Formula XV,

 

wherein R₂, R₃, R₆ and Y are as defined in claim 1 and R₅ is a protecting group, with a compound of Formula XVI,

 

R1-X 

 

(XVI)

 

wherein R₁ is as defined in claim 1 and X is COOH or SO₂Cl, in the presence of a coupling reagent, under standard conditions.

16. The process according to claim 13, wherein the protecting group is selected from the group consisting of acetate (Ac), benzoyl (Bz), benzyl (Bn), and 4-methoxybenzyl (PMB).

17. The process according to claim 13, wherein the base is selected from the group consisting of NaOMe, NaH, and triethylamine.

18. The process according to claim 13, wherein the free-radical initiator is α

,α

′

-azoisobutyronitrile (AIBN).

19. The process according to claim 14, wherein the protecting group is acetate (Ac) or benzoyl (Bz).

20. The process according to claim 14, wherein the reagent is PPh₃/diisopropyl azodicarboxylate (DIAD).

21. The process according to claim 15, wherein the protecting group is selected from the group consisting of acetate (Ac), benzoyl (Bz), benzyl (Bn), and 4-methoxybenzyl (PMB).

22. The process according to claim 15, wherein the coupling reagent is selected from the group consisting of:

(i) (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP)/diisopropylethylamine (DIPEA);

(ii) dicyclohexylcarbodiimide (DCC)/1-hydroxybenzotriazol (HOBt);

(iii) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC)/triethylamine (TEA)/N,N-dimethyl amino pyridine (DMAP); and

(iv) pyridine.

23. A kit of parts comprising:

(i) a pharmaceutical formulation comprising a compound of Formula I according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier; and

(ii) a pharmaceutical formulation comprising one or more antithrombotic agents selected from the group consisting of an antiplatelet agent, thromboxane receptor inhibitor, synthetase inhibitor, fibrinogen receptor antagonist, prostacyclin mimetic, phosphodiesterase inhibitor, and an ADP-receptor (P₂T) antagonist,

in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier,

wherein compound (i) and agent (ii) are each formulated for administration in conjunction with the other.