WO2008155335A1

WO2008155335A1 - Protease activated receptor-1 antagonists for the treatment of atrial fibrillation

Info

Publication number: WO2008155335A1
Application number: PCT/EP2008/057645
Authority: WO
Inventors: Michel Perez; Bruno Le Grand; Robert Letienne
Original assignee: Pierre Fabre Medicament
Priority date: 2007-06-19
Filing date: 2008-06-18
Publication date: 2008-12-24
Also published as: FR2917622A1; PA8784901A1; AR067061A1; CL2008001795A1; TW200908977A; FR2917622B1

Abstract

The present invention relates to the use of a protease-activated receptor-1 (PAR-1) antagonist for the manufacture of a drug to prevent or treat atrial fibrillation.

Description

PROTEASE ACTIVATED RECEPTOR-I ANTAGONISTS FOR THE TREATMENT OF ATRIAL FIBRILLATION

The present invention relates to the use of a protease-activated receptor-1 (PAR-I) antagonist, also called thrombin receptor, for the manufacture of drugs to treat or prevent atrial fibrillation (AF) . The present invention also relates to combinations of the compounds divulged herein with other cardiovascular agents, or in parallel with electrical cardioversion, to treat AF.

AF is relatively common and it affects roughly 3.5% of patients aged 65 to 74. If it persists over time, it can cause a cerebral vascular accident or even sudden death by total myocardial arrhythmia. AF is an abnormally fast type of atrial tachycardia. A normal, regular heart rate generally comprises 60 to 80 beats per minute for a subject at rest. In the case of AF, the frequency of atrial impulses can vary from 300 to 600 beats per minute. These very fast irregular signals can be the source of a number of problems. On the one hand, palpitation of the auricles reduces their pumping efficiency and a portion of the blood can remain in the auricle with each heartbeat. Accumulated blood may coagulate, which increases the risk of a cerebral vascular accident. On the other hand, the numerous impulses from the auricles attempt to follow the electrical pathway towards the ventricles, thus causing them to contract at the same abnormal frequency (ventricular fibrillation) . The atrioventricular node limits the number of signals effectively reaching the lower chambers, and thus the entire heart generally does not contract at a frequency of 300 beats per minute. Nevertheless, AF can cause the heart to race and certainly reduces its pumping efficiency. Like other forms of arrhythmia, AF can prevent the heart from pumping sufficient blood and oxygen to meet the organism's needs. In the case of volume overload in the cardiac cavities associated with post-infarction or valve leaks, the right and left auricles dilate, which constitutes the substrate for the genesis of AF: the structural remodeling concept. The understanding of the mechanisms of AF recently demonstrated the dominant role of atrial remodeling in this pathology (Nattel et al., Circ. Arrhythmia Electrophysiol . 2008, 1:62-73). "Atrial remodeling" means any persistent change in the structure or function of the atrium. Several forms of atrial remodeling favor the frequency or the persistence of AF by acting either on the electrical mechanisms or on the structure of the atrium. Thus, a new approach for treating AF may be to intervene directly on one or more of these atrial remodeling mechanisms .

The disturbance of hemostasis in the chamber of the dilated (remodeled) auricle of a patient suffering from AF leads to an abnormal concentration of thrombin, the principal pro-coagulation and pro-aggregation mediator. Thrombin also plays the role of proliferative agent in the underlying atrial tissue. Antagonizing the effects of thrombin in AF thus constitutes a mechanism against the genesis of remodeling.

The current treatments for AF include various families of drugs such as beta-blockers, some calcium channel blockers (diltiazem, verapamil) and antiarrhythmics (amiodarone, sotalol) , but many have adverse effects and none of these treatments protects against thrombotic risk. To treat this risk, certain oral anticoagulants are used, notably heparin and anti- vitamin K (AVK) , but they have a significant impact on hemorrhagic risk. To limit hemorrhagic risk, which requires close patient monitoring, a clinical study was recently undertaken to compare the activity of two antiplatelet agents (clopidogrel and aspirin) administered jointly with an oral anticoagulant for the treatment of AF (ACTIVE W study, Lancet, 2006, 367:1903-12). The study was stopped prematurely due to the clear superiority of the oral anticoagulant treatment. The use of an antiplatelet agent is thus not an obvious approach to treat AF, and it is clearly inadequate to prevent atrial remodeling.

Protease-activated receptors-1 (PAR-I) were recently cloned (Vu et al . , Cell, 1991, 64:1057-1068) and their mechanism of action elucidated (Coughlin et al., J. Clin. Invest. 1992, 89 (2) : 351-355) . These receptors, notably present on the surface of platelets but also on the surface of endothelial cells (O'Brien et al., J. Biol. Chem. 2000, 275:13502-13509), of smooth muscle cells (Hamilton et al., Br. J. Pharmacol.

2000, 130:181-188) and of fibroblasts (Hung et al., J. Cell. Biol. 1992, 116 (3) : 827-832) , are activated by thrombin and thus are also called thrombin receptors. The N-terminus of the protein is cleaved by thrombin between arginine 41 and serine 42 to free a new end which will act, after folding upon the active site, as a receptor agonist (Vu et al., Nature, 1991, 353:674- 677). With respect to platelets, this specific PAR-I receptor activation mechanism leads to thrombin- mediated platelet aggregation.

The blocking of this activation, for example with a receptor antagonist, can inhibit thrombin-mediated platelet aggregation (Ahn et al., Drug of the Future,

2001, 26:1065-1085). The blocking of these receptors can thus lead to the treatment or prevention of thrombosis (Derian et al., J. Pharmacol. Exp. Ther., 2003, 855-861), of acute coronary syndromes (Ossovskaya et al., Physiol. Rev., 2004, 84:579-621) of restenosis

(Maryanoff et al., Curr. Med. Chem. Cardiovasc.

Hematol. Agents., 2003, 13-36) or of reducing myocardial necroses during infarction or reperfusion (Steinberg et al., MoI. Pharmacol. 2005, 67:2-11). PAR-

1 antagonist activity can prevent certain inflammatory diseases in the pulmonary system (Moffatt et al., Curr.

Op. Pharmacol., 2004, 221-229). PAR-I antagonist activity can prevent certain inflammatory diseases in the gastrointestinal system, (Vergnolle et al., J. Clin. Invest., 2004, 1444-1456). These PAR-I antagonists can also be of use in the treatment of fibroses in patients with chronic liver diseases (Fiorucci et al., Hepatology, 2004, 39:365-375). They can also be of use as anti-cancer agents given that they act to control cellular proliferation and metastases (Evan-Ram et al., Nat. Med., 1998, 909-914; Boire et al., Cell, 2005, 120:303-313). Finally, these PAR-I antagonists can be of interest in dermatology to treat certain skin diseases (Schechter et al., J. Cell. Physiol., 1998, 176:365-373; Algermissen et al., Arch. Dermatol. Res., 2000, 292:488-495; Meyer-Hoffert et al., Exp. Dermatol., 2004, 13:234-241).

However, among the various therapeutic applications cited, none describes or even suggests the use of PAR-I antagonists to treat or prevent AF or the remodeling of the atrial substrate (fibrosis) .

We have shown that accumulation of thrombin in the auricles is responsible for up-regulation of PAR-I, which can trigger dilation, fibroblast proliferation and formation of platelet thrombi. By their mechanism of action, PAR-I antagonists can thus prevent or treat all of these phenomena in a patient suffering from AF and even prevent progressing from paroxysmal AF to chronic AF. These compounds can also be used in co- therapy with the conventional treatments mentioned above or in parallel with electrical cardioversion.

The present invention relates to the use of compounds described as PAR-I antagonists such as the phenylpentadienoyl derivatives divulged in French patent application 06 05418 (FR2902427, WO2007147822) of general formula I :

(I) wherein :

Ri and R₂, identical or different, represent: an atom of hydrogen or halogen, CN or NO₂, with Ri and R2 not representing hydrogen simultaneously, m represents:

1 or 2 n represents:

0, 1 or 2

R₃ represents: phenyl unsubstituted or substituted by one or more residues selected among halogen, hydroxyl or (Ci- Cε) alkyl; (C₂-Ce) alkyl unsubstituted or substituted by one or more residues selected among halogen or hydroxyl; cycloalkyl; pyridine; thiophene; pyrrole unsubstituted or substituted by (Ci-Cε) alkyl; thiazole; furan; as well as the therapeutically-acceptable salts or solvates thereof.

The derivatives of the cinnamoyl-piperazine divulged in French patent application 06 05419 (FR2902426, WO2007147824 ) of general formula II:

(ii: wherein :

Ri represents: halogen, CN or NO₂;

R₂ represents: hydrogen or halogen; n represents:

1 or 2;

R₃ represents: phenyl substituted by one or more halogen or (Ci-Cε) alkyl; or a cyclohexyl; as well as the therapeutically-acceptable salts or solvates thereof.

The present invention also relates to himbacine derivatives of general formula:

with X is selected among the groups:

H, -OH, -NHCO₂Et , NHCOMe , -NHCO-cyclopropyl , -NHCONHMe , -NHSO₂Me , -NHCO₂CH₂CO₂H, -NHCO₂CH₂CONH₂ , CH₂NHCO₂Et , CONHEt and Z represents: a hydrogen or a hydroxy group. When Y2=H, Yi is selected among the groups:

with Ri chosen among:

H, F, Cl, CF₃, -NHSO₂Et and R₂ chosen among: H, F, CF3.

Yi and Y₂ can form a ring with the meaning -CH=CH- C(OH)=CH- as described in US 6,063,847; US 2002/2049350; WO03/089428; Chackalamanil et al . , J. Med. Chem. (2005) 48 (19) : 5884-87) , and in particular compound SCH-530348 of formula:

The present invention also relates to cyclic amidine derivatives and iminopyrrolidine derivatives of general formula:

with Ri and R₄, identical or different, represented by: hydrogen, a (Ci-₆) alkoxy, a (Ci-₆) alkyl or a halogen with R₂ selected among the following groups:

H, -CO-NH-CH₃, CN, halogen, (Ci-C₆) alkylaminocarbonyl, (Ci-C₆) alkylamino with R₃ selected among the groups:

H, -O-Et, halogen, (Ci-C₆) alkoxy with R₅ selected among the groups:

H, -CN, halogen with R₆ selected among the groups:

- (CH2 )_m-C0-Ar with m varying from 1 to 3 and Ar representing: a substituted or unsubstituted aryl ring, notably a phenyl optionally substituted by Xi, X₂ and X₃ radicals such as:

with Xi and X₃, identical or different, represented by:

H, CN, halogen, (Ci-C₆) alkyl and in particular - C(CH₃)₃, and

X₂ selected among:

H, OH, CN or halogen.

Moreover, X₂ and X₃ can form a ring with the meaning -O-CH2-CH2-NH-, and

R₇ represents:

H, -OH, a (Ci-C₆) alkyl, an acyl, a carbamoyl, a (Ci-C₆) alkoxy, as described in documents WO02/085850, WO02/088092, WO02/088094, WO02/085855 and the European equivalent EP 1 391 451.

Notably, the present invention relates to the compound ER-129614-06 of formula:

and to the compound ER-121958-06 of formula:

In the case of post-infarction volume overload in the cardiac cavities, the right and left auricles dilate, which constitutes the substrate for the genesis of AF. The disturbance of hemostasis in the chamber of the dilated auricle of a patient suffering from AF leads to an abnormal concentration of thrombin. We have shown that this accumulation of thrombin is responsible for up-regulation of PAR-I, which can trigger, on the one hand, atrial structural remodeling via fibroblast proliferation and, on the other hand, the formation of platelet thrombi.

By their mechanism of action, PAR-I antagonists can thus prevent atrial dilation, fibroblast proliferation and thrombi formation in the auricle of a patient suffering from AF.

As a result, a PAR-I antagonist should constitute an effective preventive or curative treatment for atrial fibrillation. The compounds described in the present invention have shown that they are capable of antagonizing PAR-I receptors and preventing dilation of the left auricle.

Materials

The studies are carried out in male rats. Due to their better tolerance of surgery, the weight range of the rats chosen for experimentation is 180-200 g on arrival. Measurements of the various myocardial cavities are taken by echocardiography on anesthetized animals .

Methods

The animal is anesthetized by a 3.5% mixture of oxygen and isoflurane (Aerrane, Baxter Laboratories) . A thoracotomy perpendicular to the sternum of roughly 2 cm is performed at the fourth intercostal space towards the left front paw. A ligature (4/0 silk, CCl needle, Ethicon®) is passed around the left coronary artery at 1 mm from its origin. A surgical knot is made around the left coronary artery sufficiently tight to completely occlude the vessel. A continuously-recording electrocardiogram is used to verify that the ligature is properly positioned. After 30 minutes of ligature, the knot is removed in order to reperfuse coronary circulation. Two months after the procedure, the animals are anesthetized again to carry out an echocardiographic measure of the cardiac chambers and to measure blood velocity within the myocardium using pulsed Doppler. Finally, the animals are euthanized by sodium pentobarbital overdose 160 mg/kg i.p. for various histological measurements. The animals are force-fed daily with PAR-I antagonists in solution in a 1% water/methyl cellulose (MC) vehicle from the first 24 h of reperfusion after infarction until the animal is sacrificed.

Results

Certain compounds described in the present invention demonstrate that they are able, after administration by oral route in doses ranging from 10 to 100 mg/kg/d for 60 days, to reduce by 20% to 90% the surface of the left auricle (LA, measured by echocardiography) compared to untreated animals (SHAM) that undergo anesthesia, opening of the thorax, isolation and ligature of the coronary artery but without the ligature being tight.

An example of the activity observed with one of the compounds described in French patent application 06 05419 (FR 2902426, WO2007147824 ) , example 1, 3- (2- chloro-phenyl) -1- [4- (4-fluoro-benzyl) -piperazin-1-yl] - propenone of formula:

is represented in figure 1 in the appendix. As shown in this figure, compound A administered at a dose of 40 mg/kg/d for two months induces a significant reduction in the volume of the left auricle compared to untreated animals (sham) .

A second example of activity on atrial remodeling is given with one of the compounds described in French patent application 06 05418 (FR2902427, WO2007147822) , example 1, 2- [5-oxo-5- (4-pyridin-2-yl-piperazin-l-yl) penta-1, 3-dienyl] -benzonitrile of formula:

As shown in figure 2 in the appendix, the compound B administered at a dose of 40 mg/kg/d for two months induces a significant reduction in the volume of the left auricle compared to untreated animals (sham) . These two examples perfectly illustrate the potential of PAR-I antagonists to act on atrial structural remodeling and thus atrial fibrillation as well .

The present invention also relates to pharmaceutical compositions containing as an active ingredient a compound according to the invention described above, or a pharmaceutically-acceptable salt thereof, mixed or combined with a suitable excipient. Such compositions can assume the form, for example, of solid or liquid compositions, emulsions, lotions or creams .

As solid compositions for oral administration, tablets, pills, powders (in gelatin capsules or in packets) or granules can be used. In such compositions, the active ingredient according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, under an argon flow. Such compositions may also include substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a colorant, a coating (for sugar-coated pills) or a varnish. As liquid compositions for oral administration, the following can be used: pharmaceutically-acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or liquid paraffin. Such compositions can include substances other than diluents, for example wetting, sweetening, thickening, flavoring or stabilizing agents.

Sterile compositions for parenteral administration can be, preferably, aqueous or non-aqueous solutions, suspensions or emulsions. As a solvent or vehicle, the following can be used: water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other suitable organic solvents. Such compositions can also contain additives, in particular wetting agents, isotonic agents, emulsifiers, dispersants and stabilizers. Sterilization can be achieved in several ways, for example by sterilizing filtration, by incorporating sterilizing agents in the composition, by irradiation or by heating. Such compositions can also be prepared in the form of sterile solid compositions that can be dissolved in sterile water or in any other injectable sterile medium just before use.

Compositions for rectal administration are suppositories or rectal capsules that contain, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

Compositions for topical administration can be creams, lotions, eye drops, mouth washes, nose drops or aerosols, for example.

Doses depend on desired effect, treatment duration and administration route, and are generally between 0.001 g and 1 g (preferably between 0.005 g and 0.75 g) per day, preferably by oral route for an adult, with unit doses ranging from 0.1 mg to 500 mg of active substance . Generally, the doctor will establish suitable dosing according to the patient's age, weight and other specific factors of the case.

According to another aspect of the invention, the present application relates also to a product containing at least one PAR-I antagonist compound and a beta-blocker, a calcium channel blocker such as diltiazem and verapamil, and/or an antiarrhythmic such as amiodarone and sotalol, as a combination product for use simultaneously, separately or extended over time to treat or prevent atrial fibrillation.

The invention relates also to a therapeutic combination, containing as an active ingredient at least one PAR-I antagonist compound in combination with electrical cardioversion, for use simultaneously, separately or extended over time to treat or prevent atrial fibrillation.

Claims

1. Use of a protease-activated receptor-1 (PAR-I) antagonist for the manufacture of a drug to treat or prevent atrial fibrillation.

2. Use according to claim 1, characterized in that the PAR-I antagonist is a compound of general formula I:

:D

wherein :

Ri and R₂, identical or different, represent: an atom of hydrogen or halogen, CN or NO2, with Ri and R2 not representing hydrogen simultaneously, m represents:

1 or 2 n represents:

0, 1 or 2

R₃ represents: phenyl unsubstituted or substituted by one or more residues selected among halogen, hydroxyl or (Ci-Cε) alkyl;

(C2-C6) alkyl unsubstituted or substituted by one or more residues selected among halogen or hydroxyl; cycloalkyl; pyridine; thiophene; pyrrole unsubstituted or substituted by

(Ci-C_δ) alkyl; thiazole or furan; as well as the therapeutically-acceptable salts or solvates thereof.

3. Use according to claim 1, characterized in that the PAR-I antagonist is a compound of general formula II:

:ii)

wherein :

Ri represents: halogen, CN or NO₂;

R₂ represents: hydrogen or halogen; n represents:

1 or 2;

4. Use according to claim 1, characterized in that the PAR-I antagonist is a himbacine derivative of formula:

5. Use according to claim 1, characterized in that the PAR-I antagonist is a cyclic amidine derivative or iminopyrrolidine derivative of formula:

6. Use according to claim 1, characterized in that the PAR-I antagonist is a cyclic amidine derivative or iminopyrrolidine derivative of formula:

7. A product containing at least one PAR-I antagonist compound and a beta-blocker, a calcium channel blocker such as diltiazem and verapamil, and/or an antiarrhythmic such as amiodarone and sotalol, as a combination product for use simultaneously, separately or extended over time to treat or prevent atrial fibrillation.

8. A therapeutic combination, containing as an active ingredient at least one PAR-I antagonist compound in combination with electrical cardioversion, for use simultaneously, separately or extended over time to treat or prevent atrial fibrillation.