JP2002538226A - Treatment of thrombosis by using a combination of factor Xa inhibitor and aspirin, tissue plasminogen activator (TPA), GPIIb / IIIa antagonist, low molecular weight heparin or heparin - Google Patents

Abstract

  (57) [Summary] A method of treating thrombosis in a mammal, comprising treating a combination of (i) a factor Xa inhibitor and (ii) a compound selected from the group consisting of aspirin, TPA, a GPIIb / IIIa antagonist, low molecular weight heparin and heparin. Provided is a method wherein at least one dose of (i) and (ii) is a sub-therapeutic dose. Preferably, the combination of (i) and (ii) above provides a synergistic effect.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] The treatment of thrombosis in mammals, more particularly (i) factor Xa inhibitors and (i)
i) treatment by co-administration of a compound selected from the group consisting of aspirin, TPA, GPIIb / IIIa antagonist, low molecular weight heparin and heparin,
A treatment wherein at least one dose of i) and (ii) is a sub-therapeutic dose.

BACKGROUND OF THE INVENTION Selected classes of factor Xa inhibitors and aspirin, GPIIb / IIIa
Antagonists, tissue plasminogen activator (TPA), low molecular weight heparin and selected classes of heparin are essential as component parts of the novel compositions of the present invention. Aspirin and GPIIb / IIIa antagonists are known in the art as antiplatelet agents. Tissue plasminogen activator (TPA) is known as a thrombolytic agent. Low molecular weight heparin and heparin are known as anticoagulants.

[0003] Factor Xa is a blood clotting protein. It plays a major role in blood coagulation because of its central position at the convergence of the intrinsic and extrinsic pathways of coagulation. It is believed that inhibition of factor Xa can decrease thrombin production by either the extrinsic or intrinsic pathway without interfering with the basal levels of thrombin activity required for normal hemostasis (Harke LA, Hanson SR and Kelly AB.A
antithrombotic strategies targeting t
rombin activities, thrombin receptor
s and thrombin generation. Thrombosis
and Haemostasis 78: 736-741, 1997).

[0004] Both peptide and non-peptide factor Xa inhibitors are currently available (K
aiser B. Thrombin and factor Xa inhib
itors. Drugs of the Future 23: 423-436
, 1998). Examples of peptide factor Xa inhibitors are antistasin and tic anticoagulant peptides; non-peptide factor Xa inhibitors are described in WO98 / 2326, Th
romb Haemost 1994; 71: 314-9, Thromb Ha.
emost 1994; 72: 393-6, and Thromb Haemos.
t 1998; 79: 859-64. The antithrombotic effects of these peptide and non-peptide factor Xa inhibitors have been well demonstrated in various experimental models of arterial and venous thrombosis (Kaiser B. Thrombin and f).
actor Xa inhibitors. Drugs of the Fut
ure 23: 423-436, 1998).

SUMMARY OF THE INVENTION One object of the present invention is a method of treating thrombosis in a mammal, comprising (i)
Administering to said mammal a therapeutically effective amount of a combination of a factor Xa inhibitor and (ii) a compound selected from the group consisting of aspirin, TPA, a GPIIb / IIIa antagonist, low molecular weight heparin or heparin, (i) And (ii) at least one dose is a sub-therapeutic dose.

Another object of the present invention is to provide a method of treating thrombosis in a mammal wherein the combination of (i) and (ii) above is administered in an amount that provides a synergistic effect.

[0007] These and other objects, which will become apparent during the detailed description set forth below, include the factor Xa inhibitors (i), (ii) aspirin, tissue plasminogen activator (TPA), Administration in combination with one of the GPIIb / IIIa antagonist, low molecular weight heparin or heparin is administered at a dose that is a sub-therapeutic dose when at least one, and preferably both, of (i) and (ii) are administered alone. It was achieved by the discovery that

DETAILED DESCRIPTION Combinations of the active compounds (i) and (ii) of the present invention are useful in treating cerebrovascular diseases such as atherosclerosis, valvular heart disease, heart failure, stroke, atrial fibrillation, myocardial infarction. And coronary artery disease such as unstable angina, coronary artery bypass grafting, peripheral vascular disease, thromboembolic complications of prosthetic cardiovascular devices such as heart valve and vascular transplantation, and major plastic surgery, large fractures and / or It is useful in treating thrombotic disorders, including deep vein thrombosis after abdominal surgery. These combinations are also expected to be useful in combination with endovascular stenting, such as percutaneous transluminal coronary dilatation to prevent subsequent arterial thrombosis and reocclusion.

[0009] Factor Xa inhibitor compounds (i) useful in the present invention are well known in the prior art. Preferred factor Xa inhibitors are described in PCT application US9 filed December 15, 1997.
No. 7/22895 (published on Jul. 2, 1998 as WO 98/28269), the disclosure of which is incorporated herein by reference. WO 98/2826
Particularly preferred compounds in 9 are compounds (1):

[0010]

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Compound (2):

[0012]

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Compound (3):

[0014]

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[0015]

Another Factor Xa inhibitor compound is Thromb Haemost 1994;
1: 314-9 and Thromb Haemost 1994; 72: 393.
DX-9065a described in -6. DX-9065a is (+)-
2S-2 [4-[[(3S) -1-acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- [7-amidino-2-naphthyl] propanoate hydrochloride pentahydrate. Additional factor Xa inhibitor compounds include Thromb Haemost 1
998; 79: 859-64. YM-
60828 is [N- [4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] -N-[(7-amidino-2-naphthyl) methyl] sulfamoyl) acetic acid dihydrochloride. Other factor Xa inhibitor compounds will be readily known to those skilled in the art.

The compounds (ii) of the present invention are commercially available and / or are well known in the prior art. Aspirin, Fragmin (Pharmacia AB, Stockholm, Sweden), Heparin (Upjohn, Kalamazoo, MI)
, And TPA (Genentech, San Francisco, CA) are commercially available. Fragmin is a low molecular weight heparin. Standard heparin has a molecular weight of 750 to 1000 kDa, while an average molecular weight of 4.5.
It is separated from standard heparin as kDa. Low molecular weight heparins, such as fragmin, differ from heparin in both pharmacokinetic properties and mechanism of action. Fragmin titers are expressed in units of anti-factor Xa activity. Each mg of fragmin has about 150 U of anti-factor Xa activity.

Preferred GPIIb / IIIa antagonist compounds useful as component (ii) of the combination are described in PCT Application Publication WO 95/14683, issued June 1, 1995 as a second embodiment. Preferred compounds described therein are
formula:

[0019]

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Or a pharmaceutically acceptable salt thereof, wherein R¹Is R^2a(R^Three) N-, R^Two(R^Three) N (R^TwoN =) C-, R^2a(R^Three) N (CH _Two )_{p ′}Z-, R^Two(R^Three) N (R^TwoN =) C (CH_Two)_{p ''}Z-, R^Two(R^Three) N (
R^TwoN =) CN (R^Two)-, R^Two(R^Three) NC (O)-, R^Two(R^FiveO) N (R^TwoN =
) C-, R^Two(R^Three) N (R^FiveON =) C-,

[0021]

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Wherein Z is selected from a bond, O, or S;

R^TwoAnd R^ThreeIs H; C₁~ C₆Alkyl; hydroxy, halogen, C₁~ C₆A
Lucoxy, C₁~ C₆Alkyl, CF_Three, S (O)_mCH_Three, -N (CH_Three)_Two, C₁~
C_FourSelect from haloalkyl, methylenedioxydiyl, ethylenedioxydiyl
Optionally substituted with 0 to 3 groups₇~ C₁₁Arylalkyl; (C₁~ C _Ten ) Alkoxycarbonyl; the aryl group is hydroxy, halogen, C₁~ C₆Al
Coxy, C₁~ C₆Alkyl, CF_Three, S (O)_mCH_Three, -N (CH_Three)_Two, C₁~ C _Four Selected from haloalkyl, methylenedioxydiyl, ethylenedioxydiyl
Aryl (C) optionally substituted with 0 to 3 groups₁~ C_TenAlkoxy) cal
Carbonyl, or a heteroaryl group is hydroxy, halogen, C₁~ C₆Alkoxy
, C₁~ C₆Alkyl, CF_Three, S (O)_mCH_Three, -N (CH_Three)_Two, C₁~ C_FourHalo
0 selected from alkyl, methylenedioxydiyl and ethylenedioxydiyl
A heteroaryl (C₁~ C_Five) Independent from alkyl
Selected

R ^2a is R ² or R ² (R ³ ) N (R ² N =) C;

U is a single bond,

[0026] V represents a single bond; substituted with 0-3 groups selected from R ⁶ or R ⁷ independently, - (C ₁ -C ₇ alkyl) -; the R ⁶ or R ⁷ independently -(C ₂ -C ₇ alkenyl)-substituted with 0 to 3 groups selected;-(C substituted with 0 to 3 groups independently selected from R ⁶ or R ^7. Phenyl substituted with 0 to 2 groups independently selected from R ⁶ or R ⁷ ,-( _2- C ₇ alkynyl)-;
Phenyl) -Q-; pyridyl substituted with 0 to 2 groups independently selected from R ⁶ or R ⁷ ,-(
Or pyridazinyl is substituted with 0 to 2 groups independently selected from R ⁶ or R ⁷ ,
-(Pyridazinyl) -Q-;

Q is a single bond, -O-, -S (O)_m-, -N (R¹²)-,-(CH_Two)_m−, −
C (= O)-, -N (R^5a) C (= O)-, -C (= O) N (R^5a)-, -CH _Two O-, -OCH_Two-, -CH_TwoN (R¹²)-, -N (R¹²) CH_Two-, -CH_TwoC
(= O)-, -C (= O) CH_Two-, -CH_TwoS (O)_m-Or -S (O)_mC
H_Two-Selected from

However, when b is a single bond, and R ¹ -UV- is a substituent on C5 of the central 5-membered ring of formula Ic, Q is -O-, -S (O) _m ^{-, - N (R 12)} -, - C (=
^{O) N (R 5a) -} , - CH 2 O -, - CH 2 N (R 12) - or -CH ₂ S (O) _m - rather,

W is-(C (R ⁴ ) ₂ ) -C (= O) -N (R ^5a )-or -C (= O) -N
^{(R 5a) - (C (} R 4) 2) - are selected from,

X is —C (R ⁴ ) (R ⁸ ) —CHR ^4a —,

R ⁴ is selected from H, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkylcarbonyl, aryl, arylalkyl, cycloalkyl, or cycloalkylalkyl;

R ^4a is hydroxy, C ₁ -C ₁₀ alkoxy, nitro, —N (R ⁵ ) R ^5a , —N (
R ¹² ) R ¹³ , or —N (R ¹⁶ ) R ¹⁷ , selected from aryl substituted with 0 to 3 R ⁶ or (C ₁ -C ₁₀ alkyl) carbonyl;

R ^4b is H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, hydroxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkylsulfinyl, C ₁ -C ₆ alkylsulfonyl, nitro, (C ₁ -C ₆ alkyl) carbonyl, C ₆ -C ₁₀ ^{aryl, -N (R 12) R 13} , _{halo, CF 3, CN, (C} 1 ~ C ₆ alkoxy) carbonyl, carboxy, piperidinyl, selected from morpholinyl or pyridyl,

R ⁵ is selected from H or C ₁ -C ₁₀ alkyl substituted with 0-6 R ^4b ,

R ^5a is hydrogen, hydroxy, C ₁ -C ₈ alkyl, C ₂ -C ₆ alkenyl, C ₃
C ₁₁ cycloalkyl, C ₁₁ cycloalkylmethyl from C _4, C ₁ ~C ₆ alkoxy, benzyloxy, C ₁₀ aryl from C _6, heteroaryl, heteroarylalkyl, C ₁₁ arylalkyl from C ₇ or adamantylmethyl, from , 0
Selected from C ₁ -C ₁₀ alkyl substituted with two R ^4b ,

Alternatively, R ⁵ and R ^5a together are 3-azabicyclononyl, 1,2
, 3,4-Tetrahydro-1-quinolinyl, 1,2,3,4-tetrahydro-2
-Isoquinolinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl,
Thiamorpholinyl, thiazolidinyl or 1-piperazinyl, each optionally being C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, heteroaryl, C ₇ -C ₁₁ arylalkyl, (C ₁ -C ₆ alkyl) carbonyl, (C ₃ -C ₇ cycloalkyl) carbonyl, (C ₁ -C ₆ alkoxy) carbonyl or (C ₇ -C ₁₁ arylalkoxy) carbonyl,

R ^5b represents C ₁ -C ₈ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₁₁ cycloalkyl,
Selected from C ₄ -C ₁₁ cycloalkylmethyl, C ₆ -C ₁₀ aryl, C ₇ -C ₁₁ arylalkyl, or C ₁ -C ₁₀ alkyl substituted with 0 to 2 R ^4b ,

[0038] Y is hydroxy, C ₁₀ alkyloxy from C _1, C ₁₁ cycloalkyloxy from C _3, C ₁₀ aryloxy from C _6, C ₁₁ aralkyloxy from C _7, C _{1 0} alkylcarbonyloxy alkyl from C ₃ Oxy, C ₃ to C ₁₀ alkoxycarbonyloxyalkyloxy, C ₂ to C ₁₀ alkoxycarbonylalkyloxy, C ₅ to C ₁₀ cycloalkylcarbonyloxyalkyloxy, C ₅ to C ₁₀ cycloalkoxycarbonyloxyalkyloxy, C ₅ to C ₁₀ cycloalkoxycarbonylalkyloxy, C ₇ to C ₁₁ aryloxycarbonylalkyloxy, C ₈ to C ₁₂ aryloxycarbonyloxyalkyloxy, C ₈ to C ₁₂ arylcarbonyloxyalkyloxy, C ₅ to C ₁₀ alkoxyalkylcarbo D Oxy alkyloxy, from C ₅ C ₁₀ (5- alkyl-1,3-dioxa - cyclopenten-2-one - yl) C ₁₄ (5 from methyloxy or C _10,
-Aryl-1,3-dioxa-cyclopenten-2-one-yl) methyloxy,

R ⁶ and R ⁷ are each H, C ₁ -C ₁₀ alkyl, hydroxy, C ₁ -C ₁₀ alkoxy, nitro, (C ₁ -C ₁₀ alkyl) carbonyl, —N (R ¹² ) R ¹³ , cyano , Or halo, independently selected from

R ¹² and R ¹³ are each H, C ₁ -C ₁₀ alkyl, (C ₁ -C ₁₀ alkoxy)
Independent from carbonyl, (C ₁ -C ₁₀ alkyl) carbonyl, C ₁ -C ₁₀ alkylsulfonyl, aryl (C ₁ -C ₁₀ alkyl) sulfonyl, arylsulfonyl, heteroarylsulfonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl or aryl is selected, the aryl group is optionally substituted C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halo, optionally with CF _3, and 0-3 groups selected from the group consisting of NO ₂ ,

R ¹⁵ is H, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₁ -C ₁₀ alkoxy, aryl, heteroaryl or (C ₁ -C ₁₀ alkoxy) carbonyl , CO ₂ R ⁵ or —C (＝ O) N (R ⁵ ) R ^5a ,

R¹⁶Is -C (= O) -OR^18a, -C (= O) -R^18b, -C (= O) N (R ^18b )_Two, -SO_Two-R^18aOr -SO_Two−N (R^18b)_TwoSelected from

R ¹⁷ is selected from H or C ₁ -C ₅ alkyl;

[0044] R ^18a is 0-2 C ₁ -C ₈ alkyl substituted with R ^19, 0-2 C ₂ -C ₈ alkenyl substituted with R ^19, with 0-2 R ¹⁹ substituted C ₂ -C ₈ alkynyl, 0-2 C ₃ substituted by R ¹⁹ of -C ₈ cycloalkyl, aryl substituted with 0-4 R ^19, at 0-4 R ¹⁹ Substituted aryl (C ₁ -C ₆ alkyl)-,

Pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-
Indolyl, pyrrolidinyl, piperidinyl, indolinyl, or heterocyclic ring system selected from morpholinyl, (said heterocycle is substituted with 0-4 R ^19),

Pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, isoxazolinyl, benzofuranyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, indolyl , A C ₁ -C ₆ alkyl substituted with a heterocyclic system selected from pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, wherein said heterocycle is substituted with 0-4 R ¹⁹ .

R ^18b is selected from R ^18a or H;

R ¹⁹ is H, halogen, CF ₃ , CN, NO ₂ , NR ¹² N ¹³ , C ₁ -C ₈ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₁
Cycloalkyl, C ₄ -C ₁₁ cycloalkylalkyl, aryl, heteroaryl, aryl (C ₁ -C ₆ alkyl)-, (C ₁ -C ₄ alkyl) sulfonyl, aryl-sulfonyl, or C ₁ -C ₄ alkoxycarbonyl Selected from

N is 0-4, p ′ is 1-7, p ″ is 1-7, and r is 0-3.

More preferred compounds have the formula:

[0051]

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Or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is R ^2a (R ³ ) N—, R ² NH (R ² N =) C—, R ² NH (R ² N =) CNH
^{-, R 2a (R 3)} N (CH 2) p 'Z-, R 2 NH (R 2 N =) C (CH 2) p''Z
^{-, R 2 (R 3)} NC (O) -, R 2 (R 5 O) N (R 2 N =) C-, R 2 (R 3) N
(R ⁵ ON =) C-,

[0054]

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Selected from

N is 0 to 1, p 'is 4 to 6, p' 'is 2 to 4,

Z is selected from a bond or O;

V is a single bond,-(phenyl)-or-(pyridyl)-,

W is selected from — (C (R ⁴ ) ₂ ) —C (＝ O) —N (R ^5a ) — and —C (＝ O) —N (R ^5a ) —CH ₂ —

X is —CH ₂ —CH (N (R ¹⁶ ) R ¹⁷ ) — or —CH ₂ —CH (NR ⁵ R ^5a )
-Selected from

Y is hydroxy, C ₁ to C ₁₀ alkoxy, methylcarbonyloxymethoxy-, ethylcarbonyloxymethoxy-, t-butylcarbonyloxymethoxy-, cyclohexylcarbonyloxymethoxy-, 1- (methylcarbonyloxy) ethoxy-, 1- (ethylcarbonyloxy) ethoxy-, 1- (t-butylcarbonyloxy) ethoxy-, 1- (cyclohexylcarbonyloxy) ethoxy-, i-propyloxycarbonyloxymethoxy-, t-butyloxycarbonyloxymethoxy-, 1- (i-propyloxycarbonyloxy) ethoxy-, 1- (cyclohexyloxycarbonyloxy) ethoxy-, 1- (
t-butyloxycarbonyloxy) ethoxy-, dimethylaminoethoxy-,
Diethylaminoethoxy-, (5-methyl-1,3-dioxacyclopentene-
2-one-4-yl) methoxy-, (5- (t-butyl) -1,3-dioxacyclopenten-2-one-4-yl) methoxy-, (1,3-dioxa-5-phenyl- Cyclopenten-2-one-4-yl) methoxy-, 1- (2- (2-
Methoxypropyl) carbonyloxy) ethoxy-,

[0062] R ¹⁶ is -C (= O) -O-R 18a, -C (= O) -R 18b, -S (= O) 2 -R 1 8a or -SO ₂ -N (R ^18b) ₂ Selected from

R ¹⁷ is selected from H or C ₁ -C ₅ alkyl;

[0064] R ^18a is 0-2 C ₁ -C ₈ alkyl substituted with R ^19, 0-2 C ₂ -C ₈ alkenyl substituted with R ^19, with 0-2 R ¹⁹ substituted C ₂ -C ₈ alkynyl, 0-2 C ₃ substituted by R ¹⁹ of -C ₈ cycloalkyl, aryl substituted with 0-4 R ^19, at 0-4 R ¹⁹ Substituted aryl (C ₁ -C ₆ alkyl)-

Pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-
Indolyl, pyrrolidinyl, piperidinyl, indolinyl, or heterocyclic ring system selected from morpholinyl, (said heterocycle is substituted with 0-4 R ^19),

Pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, isoxazolinyl, benzofuranyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, indolyl, indolyl , pyrrolidinyl, piperidinyl, is selected indolinyl or heterocyclic ring system selected from morpholinyl (the heterocycle is being substituted with 0 to 4 R ¹⁹⁾ C ₁ ~C ₆ alkyl substituted with from.

A particularly preferred compound has the formula: Compound (4):

[0068]

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Has the following formula:

Other salts of the present compounds are also particularly preferred.

Specific examples of other GPIIb / IIIa antagonist compounds are described in Graul et al.
carbourough (Graul A, Martel AM and Casta
ner J .; Drugs of the Futu
re 22: 508-517, 1997; Scarborough RM; E
ptifibatide. Drugs of the Future 23:
585-590, 1998), abciximab (abciximab)
, Eptifibatide, tirofiban, ramifiban, lefradafiban, sibrafiban
rafiban) (Ro-48-3657), orbofiban and or xemilofiban. Others will be apparent to those skilled in the art.

“Therapeutically effective amount” is intended to include the amount of the combination of compounds that is effective in treating thrombosis in a mammal. The combination of compounds is preferably a synergistic combination. See, for example, Chou and Talalay, Adv. Enzyme Re
gul. 22: 27-55 (1984).
Occurs when the effect of the compound when administered in combination (in this case, an antithrombotic effect) is greater than the additive effect of the compound when administered alone as a single agent. In general, a synergistic effect is most apparent at suboptimal concentrations of the compound. A synergistic effect may be an anti-hypertensive effect, an anti-thrombotic effect, or other non-additive combined benefit compared to the individual components.

“Concurrent administration”, “combination” or “combined” when referring to component (i) and component (ii) of the present invention means that the component is administered together to the mammal to be treated. I do. In the case of co-administration, the components can be administered simultaneously or sequentially in any order or at different times. Thus, component (i) and component (ii)
Can be administered separately, but are administered sufficiently close in time to provide the desired therapeutic effect.

The “subtherapeutic dose (subt) when referring to component (i) and component (ii) of the present invention
"Herapeutic dose" means that the components when administered alone to a mammal do not have the desired therapeutic effect on the disease being treated.

The present invention can be further understood by the following examples in which compounds (1) to (4) are shown above. The saline solution (0.9% by mass NaCl)
It is a vehicle in all examples.

Example 1 Combination of Aspirin and Factor Xa Inhibitor Rabbits are anesthetized with ketamine (50 mg / kg, im) and xylazine (10 mg / kg, im) and then surgically using arterial and venous catheters. Prepared. An electromagnetic flowmeter probe was placed over the isolated segment of the carotid artery to monitor blood flow. Using an external stainless steel bipolar electrode at 4 mA for 3 minutes,
Thrombus formation was induced by electrical stimulation of the carotid artery. Carotid artery blood flow was measured continuously over 90 minutes to monitor thrombotic occlusion. Electrical stimulation of carotid artery 1
The time before the test drug was infused intravenously and continued for 90 minutes.

As shown in FIG. 1, in animals treated with saline vehicle, thrombus formation was induced after electrical stimulation and carotid artery blood flow gradually decreased. Approximately 40 minutes after stimulation, the artery was completely occluded and blood flow was zero. Aspirin at 1 mg / kg / hr (0.167 mg / ml in saline) or 0.1 mg / kg / hr
Compound (1) (Factor Xa inhibitor) at IV (concentration 0.017 mg / ml in saline) does not prevent arterial occlusion, and the blood flow in these animals is similar to that in vehicle-treated animals. At almost the same time it dropped to zero. Surprisingly, 1 mg / kg / h
0.1 mg / kg / hr intravenous compound (1) in combination with intravenous aspirin prevented arterial occlusion and maintained blood flow for at least 90 minutes. Compound (1
These results indicate that the combination of Aspirin) and aspirin at their subtherapeutic doses produced a surprisingly significant antithrombotic effect in a rabbit model of arterial thrombosis.

Example 2 Combination of Compound (4) (GP-IIb / IIIa Antagonist) and Factor Xa Inhibitor The experimental protocol was described as in Example 1. As shown in FIG. 2, 0.03 mg / kg / hr of intravenous compound (4) (GP-IIb / IIIa antagonist) and 0.1 mg / kg / hr of intravenous compound (3) (Xa Factor inhibitor) did not prevent arterial occlusion, and blood flow in these animals was reduced to zero almost simultaneously with vehicle-treated animals. Surprisingly, 0.1 m combined with compound (4) at 0.03 mg / kg / hr intravenously (concentration in physiological saline 0.005 mg / ml)
g / kg / hr intravenous injection (concentration in physiological saline is 0.017 mg / ml)
3) prevented occlusion of the artery and maintained blood flow for at least 90 minutes. These results indicate that the combination of compound (3) and compound (4) at their sub-therapeutic dose resulted in a surprisingly significant antithrombotic effect in a rabbit model of arterial thrombosis.

Example 3 Combination of Fragmin (Low Molecular Weight Heparin) and Factor Xa Inhibitor The experimental protocol was described as in Example 1. As shown in FIG. 3, 60 U / kg / hr intravenous fragmin (low molecular weight heparin) had moderate activity. 0.1 mg / kg / hr intravenous compound (3) (factor Xa inhibitor) did not prevent arterial occlusion, and blood flow in these animals was zero, similar to that in vehicle-treated animals. Down to Surprisingly, 0.1 mg / kg / hr IV (in saline) was combined with 60 U / kg / hr IV (in saline: 0.067 mg / ml or 10 U / ml) of fragmin. 0.017mg / ml)
Compound (3) prevented arterial occlusion and maintained blood flow for at least 90 minutes. These results indicate that the combination of sub-therapeutic dose of compound (3) and an intermediate dose of fragmin produces a significant antithrombotic effect in a rabbit model of arterial thrombosis.

Example 4 Combination of Recombinant Tissue Plasminogen Activator (TPA) and Factor Xa Inhibitor Experiments were performed on rats. Similar to the rabbit protocol described in Example 1, except that Compound (2) and / or TPA were given 5 minutes after the formation of the preformed clot. The parameter to be measured is its opening time. As shown in FIG. 4, 5.6 mg / kg (concentration 0.23 mg / ml in saline) and 1.4 mg / kg / hr intravenous compound (2) 5 minutes after induction of occlusive thrombus Neither nor TPA at 1 mg / kg iv (concentration 1 mg / ml in saline) had a therapeutic effect on patency time. However, the combination of 5.6 mg / kg and 1.4 mg / kg / hr intravenous compound (2) with 1 mg / kg intravenous TPA increased patency time to 70%. This result indicates that Xa such as compound (2)
Factor inhibitors have been shown to be promising and useful adjuvants to accelerate thrombolysis induced by TPA or other thrombolytic agents. Compound (2) enhances thrombolysis induced by sub-therapeutic doses of TPA.

Example 5 Combination of Heparin and Factor Xa Inhibitor The experiment was performed in male guinea pigs anesthetized with a mixture of ketamine (90 mg / kg, im) and xylazine (12 mg / kg, im). The carotid artery and the jugular vein were connected by an arteriovenous shunt. Exposure of flowing blood to silk resulted in significant thrombus formation. After 30 minutes, the shunt was cut and the silk thread covered with the thrombus was weighed. Compounds or saline vehicle were given as a continuous intravenous infusion starting 1 hour before circulating blood to the shunt and continuing throughout the experiment (ie, 90 minutes). As shown in FIG. 5, heparin at 4 U / kg / hr intravenously (concentration in physiological saline: 0.667 U / ml) did not have an antithrombotic effect. However, 4 U / kg / hr intravenous heparin is 0.3, 1 or 3
mg / kg / hr intravenously (concentration in saline for 0.05 mg dose is 0.05
mg / ml) of compound (3) (factor Xa inhibitor) enhanced the antithrombotic effect. This result indicates that in a guinea pig model of venous thrombosis, a subtherapeutic dose of heparin was
It shows that the antithrombotic effect of 3) is enhanced.

These results indicate that factor Xa inhibitors and aspirin, TPA, GPIIb / III
a Combination therapy comprising an antagonist, low molecular weight heparin or one of heparin has been shown to be effective in treating thrombosis in a patient. The methods of the present invention provide significant advantages over currently available treatments for thrombosis.

Dosage and Formulation The factor Xa inhibitor (i) and compound (ii) of the present invention may be used to treat thrombosis by any means of contacting the active agent with the site of action in the mammalian body, ie, factor Xa. Can be administered as They can be administered as individual therapeutic agents or in combination with therapeutic agents by conventional methods that can be used for pharmaceuticals. These can be administered alone, but are preferably administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and normal pharmaceutical practice.

The pharmacodynamic properties of the individual drugs and their mechanism and route of administration, as well as the dose to be administered; age, health and weight of the recipient; nature and extent of symptoms; type of concurrent treatment; frequency of treatment And depending on known factors such as the desired effect. The daily dose of the active ingredient can be from about 0.001 to about 1000 mg / kg of body weight, with the preferred dose being from about 0.01 to about 30 mg / kg.

[0085] Dosage forms of compositions suitable for administration contain from about 1 mg to about 100 mg of active ingredient per unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight relative to the total weight of the composition. The active ingredient can be administered orally, in solid dosage forms such as capsules, tablets and powders, or in liquid dosage forms such as elixirs, syrups and suspensions. It can also be administered parenterally, in sterile liquid dosage forms.

Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Compressed tablets can be manufactured using diluents as well. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar-coated or film-coated to mask the unpleasant taste and protect the tablet from the atmosphere, or enteric-coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration may contain coloring and flavoring to increase patient acceptance.

Typically, glycols or polyethylene glycols, such as water, suitable oils, saline, aqueous dextrose (glucose) and related sugar solutions and propylene glycol, are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizers and if necessary, buffer substances. Antioxidants, alone or in combination, such as sodium bisulfite, sodium sulfite or ascorbic acid are suitable stabilizers. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions may contain preservatives, such as benzalkonium chloride, methyl- or propylparaben, and chlorobutanol. Suitable pharmaceutical carriers are standard textbooks in this field, Remington's Pharmaceutical Science.
ces, 17th ed. (Mack Publishing Company
, Easton, PA, 1985), which description may be incorporated by reference.

Pharmaceutical dosage forms useful for administering the compounds of the present invention are as follows.

[0089] Capsules standard two-piece hard each powdered active ingredient in a gelatin capsule 0.1-10
By filling 0 mg, lactose 150 mg, cellulose 50 mg and magnesium stearate 6 mg, many unit capsules can be manufactured.

Soft Gelatin Capsules A mixture of the active ingredients in a digestible oil, such as soybean oil, cottonseed oil or olive oil, is prepared and injected into the gelatin using a positive displacement pump to give the active ingredient 0.1-1.
A soft gelatin capsule containing 00 mg can be formed. The capsule must then be washed and dried.

Tablet dosage unit is 0.1-100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide
A number of tablets can be prepared by conventional methods, for example, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.

0.1 to 100 mg of the active ingredient in which 5 ml of each suspension is finely dispersed, 200 mg of sodium carboxymethylcellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, S. P. Aqueous suspensions for oral administration can be prepared so as to contain 0.025 mg of vanillin.

Injection Parenteral compositions suitable for administration by injection can be prepared by stirring 0.1-100 mg of the active ingredient in 10% by volume of propylene glycol and water. The solution is sterilized by commonly used techniques.

Combination of Components (i) and (ii) Each therapeutic component of the present invention may independently be in a dosage form as described above, and may be administered in various ways as described above. . In the following description, it is to be understood that component (ii) represents one or more agents as described above. Thus, if components (i) and (ii) are to be treated similarly or separately, each agent of component (ii) can be treated similarly or separately.

The components (i) and (ii) of the present invention may be formulated together as a combination product in a single dosage unit (ie, combined into one capsule, tablet, powder or liquid or the like). Can be. If components (i) and (ii) are not formulated together in a single dosage unit, component (i) can be administered simultaneously with component (ii) or in any order. For example, component (i) of the invention can be administered first, followed by component (ii), or they can be administered in reverse order. When component (ii) contains one or more drugs, such as aspirin and heparin, these drugs can be administered together or in any order.
If not administered simultaneously, preferably administration of components (i) and (ii) is not more than about one hour apart. Preferably, the route of administration of components (i) and (ii) is intravenous (iv). The terms oral agent, oral inhibitor, oral compound and the like as used herein mean a compound that can be administered orally. It is preferred to administer both component (i) and component (ii) in the same route (ie, for example, both orally) or in the same dosage form, but if desired, they can each be administered in a separate route (
Thus, for example, one component of the combination product can be administered orally and the other compound can be administered intravenously) or in another dosage form.

As will be appreciated by those skilled in the art, the dose of the combination therapy of the present invention will depend on the pharmacodynamic properties of the individual agents and their mode of administration and route of administration, the age, health and It can vary depending on various factors such as weight, the nature and extent of the symptoms, the type of concurrent treatment, the frequency of treatment and the desired effect.

[0097] The appropriate dose of components (i) and (ii) of the present invention should be readily ascertained by one skilled in the art based on the present disclosure. As a general guideline, the daily dose will typically be from about 0.01 mg to about 1 g of each component. When component (ii) represents one or more compounds, typically the daily dose will be from about 0.01 mg to about 0.1 mg of each agent of component (ii).
g. As a general guideline, when the compounds of component (i) and component (ii) are administered in combination, they may take into account the synergistic effect of the combination when administered alone as a single agent for the treatment of thrombosis Compared to the usual dose of the components, the dose of each component can be reduced by 70-80%.

While combining the active ingredients into a single dosage unit, the combination products of the present invention can be formulated so as to minimize physical contact between the active ingredients. One of the active ingredients can be enteric coated, for example, to minimize contact when the product is administered orally. Enteric coating of one of the active ingredients not only minimizes contact between the combined active ingredients, but also ensures that one of these ingredients is not released in the stomach but is released in the intestine The release of these components in can be controlled. Another embodiment of the present invention, wherein oral administration is desired, is a combination wherein one of the active ingredients is coated with a sustained release material that provides sustained release through the gastrointestinal tract and minimizes contact between the combined active ingredients. Bring product. In addition, the sustained release component may additionally be enteric coated so that release of the component occurs only in the intestine. Yet another approach is that one component is coated with a sustained and / or enteric release polymer and the other component is a polymer such as hydroxypropyl methylcellulose or a low viscosity polymer to further separate the active ingredient. Includes combination product formulations that are coated with suitable materials known to those skilled in the art. The polymer coating serves to create an additional barrier to interaction with the other component. In each formulation where contact between components (i) and (ii) is prevented via a coating or some other material, the individual agents of component (ii) may also prevent contact with each other. it can.

The dosage form of the combination product of the present invention, wherein one active ingredient is enteric coated, can be prepared by blending the enteric coated ingredient and the other active ingredients together and then compressing them into tablets, or Enteric coated ingredients may be in tablet form, such that the active ingredient is compressed into one tablet layer and the other active ingredients are compressed into additional layers. Optionally, one or more placebo layers may be present such that a placebo layer is between the layers of the active ingredient to further separate the two layers. In addition, the dosage forms of the present invention may be in the form of capsules wherein the active ingredient is compressed into tablets, or in the form of multiple microtablets, particles, granules or non-peril additionally enteric coated. May be. These enteric-coated microtablets, particles, granules or non-peril are then encapsulated or compressed into granules with other active ingredient granules.

As with other methods of minimizing contact between the components of the combination products of the present invention, administered in a single dosage form or in separate dosage forms, but simultaneously or concurrently in the same manner These will be readily understood by those skilled in the art based on the description of the present invention.

Obviously, many modifications and variations of the present invention are possible in light of the above teachings. Therefore, within the scope of the appended claims, the invention may be practiced otherwise than as specifically described.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1: Carotid artery blood flow versus time for saline vehicle, aspirin alone, factor Xa inhibitor alone, and combinations of aspirin with the same factor Xa inhibitor. It is. FIG. 2 is a graph showing carotid artery blood flow versus time for a saline vehicle, a GPIIb / IIIa antagonist alone, a factor Xa inhibitor, and a combination of the same GPIIb / IIIa antagonist and a factor Xa inhibitor. FIG. 3 is a graph showing carotid artery blood flow versus time for saline vehicle, fragmin, factor Xa inhibitor alone and in combination with fragmin and the same factor Xa inhibitor. FIG. 4 is a bar graph showing the opening periods for saline vehicle, factor Xa inhibitor alone, TPA alone, and the same combination of TPA and factor Xa inhibitor. (FIG. 5) Saline vehicle and heparin alone, heparin and three different Xa
4 is a bar graph showing the antithrombotic effect of a combination of factor inhibitors.

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Claims (8)

[Claims] 1. A method for treating thrombosis in a mammal, comprising administering to said mammal (i) a factor Xa inhibitor and (ii) aspirin, TPA, GPIIb / II.
Administering a therapeutically effective amount of a combination of a compound selected from the group consisting of an Ia antagonist, low molecular weight heparin and heparin, wherein at least one dose of (i) and (ii) is a sub-therapeutic dose. Features method. 2. The method of claim 1, wherein the combination of (i) and (ii) provides a synergistic effect. 3. The method according to claim 2, wherein (ii) is aspirin. 4. The method according to claim 2, wherein (ii) is TPA. 5. The method according to claim 2, wherein (ii) is a GPIIb / IIIa antagonist. 6. The method of claim 2, wherein (ii) is low molecular weight heparin. 7. The method according to claim 2, wherein (ii) is heparin. 8. A compound selected from the group consisting of (i) a factor Xa inhibitor and (ii) aspirin, TPA, a GPIIb / IIIa antagonist, low molecular weight heparin and heparin for the manufacture of a medicament for treating thrombosis. Use of combinations.