2-(3-sulfonylamino-2-oxopyrrolidin-1-yl)propanamides as factor xa inhibitors

This application is filed pursuant to 35 U.S.C. § 371 as a United States National Phase Application of International Application No. PCT/GB02/05134 filed Nov. 13, 2002, which claims priority from GB 0127568.4 filed Nov. 16, 2001.

FIELD OF THE INVENTION

The present invention relates to a novel class of chemical compounds, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine, particularly use in the amelioration of a clinical condition for which a Factor Xa inhibitor is indicated.

BACKGROUND OF THE INVENTION

Factor Xa is a member of the trypsin-like serine protease class of enzymes. It is a key enzyme in the coagulation cascade. A one-to-one binding of Factors Xa and Va with calcium ions and phospholipid converts prothrombin into thrombin. Thrombin plays a central role in the mechanism of blood coagulation by converting the soluble plasma protein, fibrinogen, into insoluble fibrin. The insoluble fibrin matrix is required for the stabilisation of the primary hemostatic plug. Many significant disease states are related to abnormal hemostasis. With respect to the coronary arterial vasculature, abnormal thrombus formation due to the rupture of an established atherosclerotic plaque is the major cause of acute myocardial infarction and unstable angina. Both treatment of an occlusive coronary thrombus by thrombolytic therapy and percutaneous transluminal coronary angioplasty (PTCA) are often accompanied by an acute thrombotic reclosure of the affected vessel which requires immediate resolution. With respect to the venous vasculature, a high percentage of patients undergoing major surgery in the lower extremities or the abdominal area suffer from thrombus formation in the venous vasculature which can result in reduced blood flow to the affected extremity and a pre-disposition to pulmonary embolism. Disseminated intravascular coagulopathy commonly occurs within both vascular systems during septic shock, certain viral infections and cancer and is characterised by the rapid consumption of coagulation factors and systemic coagulation which results in the formation of life-threatening thrombi occurring throughout the vasculature leading to widespread organ failure.

Beyond its direct role in the formation of fibrin rich blood clots, thrombin has been reported to have profound bioregulatory effects on a number of cellular components within the vasculature and blood, (Shuman, M. A., Ann. NY Acad. Sci., 405: 349 (1986)).

A Factor Xa inhibitor may be useful in the treatment of acute vascular diseases such as coronary thrombosis (for example myocardial infarction and unstable angina), thromboembolism, acute vessel closure associated with thrombolytic therapy and percutaneous transluminal coronary angioplasty, transient ischemic attacks, pulmonary embolism, deep vein thrombosis, peripheral arterial occlusion, prevention of vessel luminal narrowing (restenosis), and the prevention of thromboembolic events associated with atrial fibrillation, e.g. stroke. They may also have utility as anticoagulant agents both in-vivo and ex-vivo, and in oedema and inflammation. Thrombin has been reported to contribute to lung fibroblast proliferation, thus, Factor Xa inhibitors could be useful for the treatment of some pulmonary fibrotic diseases. Factor Xa inhibitors could also be useful in the treatment of tumour metastasis, preventing the fibrin deposition and metastasis caused by the inappropriate activation of Factor Xa by cysteine proteinases produced by certain tumour cells. Thrombin can induce neurite retraction and thus Factor Xa inhibitors may have potential in neurogenerative diseases such as Parkinson's and Alzheimer's disease. They have also been reported for use in conjunction with thrombolytic agents, thus permitting the use of a lower dose of thrombolytic agent.

DESCRIPTION OF THE INVENTION

The present invention provides compounds of formula (I):

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wherein:

R¹represents hydrogen or —C_1-3alkylCONR^aR^b;
One of R²and R³represents —C_1-3alkyl and the other represents hydrogen;
R⁴represents hydrogen, —C_1-4alkyl, —C_3-4alkenyl, —C_2-4alkylOH, —C_2-4allkylOC_1-4alkyl, —C_1-4alkylCN or —C_0-4alkylC_3-6cycloalkyl;
R⁵represents —C_2-4alkylOH, —C_1-4alkyl, —C_2-4alkylOC_1-4alkyl, —C_1-4alkylCN, —C_1-4alkylCONR^cR^d, —C_2-4alkylNR^aR^b, —C_2-4alkylNHCOC_1-3alkyl, —C_2-4alkylNHCONR^aR^b, —C_2-4alkylNHSO₂R^e, —C_2-4alkylSO₂NR^aR^b, —C_2-4alkylNHCO₂C_1-4alkyl, —C_2-4alkylNHC(NH₂)═NR^f, or a group X—Y;
X represents —C_1-4alkylene- optionally substituted by —OH, or a direct link, with the proviso that when X is substituted by —OH, X represents C_2-4alkylene and the —OH group is not alpha with respect to the amide N atom to which the group X is attached;
Y represents —C_3-6cycloalkyl, phenyl, or an aromatic or non-aromatic 5-, 6- or 7-membered heterocyclic group containing at least one heteroatom selected from O, N or S and optionally substituted at C and/or N atoms by —C_1-3alkyl, C_1-3alkoxy, C_1-3alkylOH, halogen, —CN, —CF₃, —NH₂, —CO₂H and —OH;
R^aand R^bindependently represent hydrogen or —C_1-4alkyl;
R^cand R^dindependently represent hydrogen or —C_1-4alkyl or together with the N atom to which they are attached form a non-aromatic 5-, 6- or 7-membered heterocyclic group optionally substituted by a heteroatom selected from O, N or S;
R^erepresents —C_1-4alkyl or —CF₃;
R^frepresents NO₂or CN;
R⁶represents a group selected from:

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Z represents an optional substituent halogen,

alk represents alkylene or alkenylene,

T represents a heteroatom selected from S or N;

and pharmaceutically acceptable derivatives thereof.

Further aspects of the invention are:

- A pharmaceutical composition comprising a compound of the invention together with a pharmaceutical carrier and/or excipient.
- A compound of the invention for use in therapy.
- Use of a compound of the invention for the manufacture of a medicament for the treatment of a patient suffering from a condition susceptible to amelioration by a Factor Xa inhibitor.
- A method of treating a patient suffering from a condition susceptible to amelioration by a Factor Xa inhibitor comprising administering a therapeutically effective amount of a compound of the invention.

The compounds of formula (I) contain chiral (asymmetric) centres. The individual stereoisomers (enantiomers and diastereoisomers) and mixtures of these are within the scope of the present invention.

The present invention also provides certain compounds of formula (I) which are represented by formula (IA):

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wherein:

R¹represents hydrogen or —C_1-3alkylCONR^aR^b;
One of R²and R³represents —C_1-3alkyl and the other represents hydrogen;
R⁴represents —C_1-4alkyl, —C_2-4alkylOH, —C_1-4alkylCN, —C_3-6cycloalkyl;
R⁵represents —C_2-4alkylOH, —C_1-4alkyl, —C_2-4alkylOC_1-3alkyl, —C_1-4alkylCN, —C_1-4alkylCONR^aR^b, —C_2-4alkylNR^aR^b, —C_2-4alkylNHCOC_1-3alkyl, —C_2-4alkylNHCONR^aR^b, —C_2-4alkylNHSO₂R^a, —C_1-4alkylSO₂NR^aR^b, or a group X—Y;
X represents —C_1-4alkylene- or a direct link;
Y represents —C_3-6cycloalkyl, phenyl, or an aromatic or non-aromatic 5-, 6- or 7-membered heterocyclic group containing one or two O, N or S atoms and optionally substituted at C and/or N atoms by —C_1-3alkyl;
R^aand R^bindependently represent hydrogen or —C_1-3alkyl;
R⁶represents a group selected from:

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Z represents an optional substituent halogen,

alk represents alkylene or alkenylene,

T represents a heteroatom selected from S or N;

and pharmaceutically acceptable salts and solvates thereof.

Preferably R¹represents hydrogen or —C_1-3alkylCONH₂. More preferably R¹represents hydrogen or —CH₂CONH₂.

Preferably, one of R²and R³represents methyl and the other represents hydrogen.

Preferably, R⁴represents —C_1-4alkyl, —C_3-4alkenyl, —C_2-4alkylOH, —C_2-4alkylOC_1-4alkyl, —C_1-4alkylCN or —C_0-4alkylC_3-6cycloalkyl. More preferably, R⁴represents —C_1-3alkyl, —C_1-3alkylCN or —C_0-4alkylC_3-6cycloalkyl. Even more preferably, R⁴represents —C_1-3alkyl, —CH₂CH₂CN, —CH₂cyclopropyl or —C_3-5cycloalkyl.

In another preferred aspect, R⁴represents —C_1-4alkyl, —C_2-4alkylOH or —C_1-4alkylCN.

Preferably R⁵represents —C_2-4alkylOH, —C_1-4alkyl, —C_2-4alkylOC_1-4alkyl, —C_1-4alkylCN, —C_1-4alkylCONR^cR^d, —C_2-4alkylNR^aR^b, —C_2-4alkylNHCOC_1-3alkyl, —C_2-4alkylNHCONR^aR^b, —C_2-4alkylNHSO₂R^e, —C_2-4alkylSO₂NR^aR^b, —C_2-4alkylNHCO₂C_1-4alkyl, —C_2-4alkylNHC(NH₂)═NR^f, or a group X—Y.

X represents —C_1-4alkylene- optionally substituted by —OH, or a direct link, with the proviso that when X is substituted by —OH, X represents C_2-4alkylene and the —OH group is not alpha with respect to the amide N atom to which the group X is attached;
Y represents phenyl, or an aromatic or non-aromatic 5-, 6- or 7-membered heterocyclic group containing one or two heteroatoms selected from O, N or S atoms and optionally substituted at C and/or N atoms by —C_1-3alkyl.

More preferably, R⁵represents —C_2-4alkylOH, —C_1-4alkyl, —C_2-4alkylOC_1-3alkyl, —C_1-4alkylCN, —C_1-4alkylCONR^cR^d, —C_2-4alkylNR^aR^b, —C_2-4alkylNHCOC_1-3alkyl, —C_2-4alkylNHCONR^aR^b, C_2-4alkylNHSO₂R^e, —C_2-4alkylSO₂NR^aR^b, —C_2-4alkylNHCO₂C_1-4alkyl, —C_2-4alkylNHC(NH₂)═NR^f, or a group X—Y;

X represents —C_1-3alkylene-;
Y represents phenyl, or an aromatic or non-aromatic 5-, 6- or 7-membered heterocyclic group containing one or two heteroatoms selected from O, N or S atoms and optionally substituted at C and/or N atoms by —C_1-3alkyl.

Even more preferably, R⁵represents —C_2-4alkylOH, —C_1-4alkyl, —C_2-4alkylOC_1-3alkyl, —C_1-3alkylCN, —C_1-4alkylCONR^cR^d, —C_2-4alkylNR^aR^b, —C_2-4alkylNHCOC_1-3alkyl, —C_2-3alkylNHCONR^aR^b, —C_2-3alkylNHSO₂R^e, —C_2-4alkylSO₂NR^aR^b, —C_2-4alkylNHCO₂C_1-4alkyl, —C_2-4alkylNHC(NH₂)═NR^f, or a group X—Y;

X represents —C_1-3alkylene-;
Y represents phenyl, or a heterocyclic group selected from thiophene, tetrahydrofuran, pyrrolidine, imidazole, pyridine, piperidine, morpholine, piperazine, pyrazole or hexamethyleneimine.

Most preferably, R⁵represents —C_1-3alkyl, —C_2-3alkylOH, —C_1-2alkylCN, —C_2-3alkylOCH₃, —C_2-3alkylNR^aR^b, —C_1-2alkylCONH₂, —CH₂CH₂NHCOCH₃, —C_2-3alkylNHSO₂CH₃, —CH₂CH₂SO₂NH₂, —C_2-3alkylNHCONH₂, —C_2-3alkylNHCO₂C₄alkyl, —C_2-3alkylNHC(NH₂)═NNO₂, or —C_1-3alkylW wherein W represents thiophene, pyridine, piperidine, morpholine, piperazine, pyrazole or hexamethyleneimine.

In another preferred aspect, R⁵represents —C_2-4alkylOH, —C_1-4alkyl, —C_2-4alkylOC_1-3alkyl, —C_1-4alkylCN, —C_1-4alkylCONR^aR^b, —C_2-4alkylNR^aR^b, —C_2-4alkylNHCOC_1-3alkyl, —C_2-4alkylNHCONR^aR^b, C_2-4alkylNHSO₂R^a, —C_1-4alkylSO₂NR^aR^b, or a group X—Y;

X represents —C_1-3alkylene- or a direct link;
Y represents —C_3-6cycloalkyl, phenyl, or a heterocyclic group selected from thiophene, tetrahydrofuran, pyrrolidine, imidazole, pyridine, piperidine, morpholine or hexamethylencimine and optionally substituted at C and/or N atoms by —C_1-3alkyl.

When Y is a heterocycle selected from thiophene, tetrahydrofuran or pyridine, the heterocyclic ring is C-linked to X. When Y represents a heterocycle selected from imidazole, pyrrolidine, piperidine, morpholine, piperazine, pyrazole or hexamethyleneimine, the heterocyclic ring is C-linked or N-linked to X. Preferably, when Y represents a heterocyclic ring selected from pyrrolidine, piperazine, morpholine or hexamethyleneimine, the heterocyclic ring is N-linked to X.

Preferably, R⁶represents a group selected from: chloronaphthylene, chlorobenzothiophene, chlorobithiophene, chlorophenylethene or (chlorothienyl)ethene. More preferably, R⁶represents 6-chloronaphthylene, 5′-chloro-2,2′-bithiophene, (4-chlorophenyl)ethene, or 5′-(chlorothienyl)ethene. Most preferably, R⁶represents 6-chloro-1-benzothiophene, 6-chloronaphthylene, 5′-chloro-2,2′-bithiophene or (4-chlorophenyl)ethene.

Preferably, R^aand R^bindependently represent hydrogen or methyl.

Preferably, R^cand R^dindependently represent hydrogen or —C_1-3alkyl;

Preferably, R^frepresents NO₂.

It is to be understood that the present invention covers all combinations of preferred, more preferred, even more prefered and most preferred groups described herein above.