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    • 专利摘要:
    A combination of (i) a factor Xa inhibitor, and (ii) aspirin, a TPA, a GPIIb / IIIa antagonist, a low molecular weight heparin and a heparin, is administered to a mammal in a therapeutically effective amount, wherein (i) and A method of treating thrombosis in a mammal, wherein the dosage of at least one of (ii) is a sub-therapeutic dose. Preferably, the combination of (i) and (ii) provides a synergistic effect.
    公开号:KR20020005614A
    申请号:KR1020017011454
    申请日:2000-03-10
    公开日:2002-01-17
    发明作者:판크라스 씨. 웡
    申请人:블레어 큐. 퍼거슨；듀폰 파마슈티컬즈 컴퍼니；
    IPC主号:
    专利说明:

    Treatment of Thrombosis by Combined Use of a Factor X Inhibitor and Aspirin, Tissue Plasminogen Activator with Aspirin, Tissue Plasminogen Activator (TPA), WPIIｂ / IIIa Antagonist, Low Molecular Weight Heparin or Heparin (TPA), a GPIIb / IIIa Antagonist, Low Molecular Weight Heparin or Heparin}
    [2] Selected classes of Xa factor inhibitors and selected classes of aspirin, GPIIb / IIIa antagonists, tissue plasminogen activators (TPA), low molecular weight heparin and heparin are essential as members of the novel compositions of the invention. Aspirin and GPIIb / IIIa antagonists are known in the art as antiplatelets. Tissue plasminogen activator (TPA) is known as thrombolytics. Low molecular weight heparin and heparin are known as anticoagulants.
    [3] Factor Xa is a blood coagulation protein. This plays an important role in blood coagulation because its central location is at the point of aggregation of the endogenous and exogenous pathways of coagulation. Inhibiting the factor Xa does not interfere with the baseline thrombin activity required for normal hemostasis, It is believed that the production of thrombin can be excluded [Harke LA, Hanson SR and Kelly AB. Antithrombotic strategies targeting thrombin activities, thrombin receptors and thrombin generation. Thrombosis and Haemostasis 78: 736-741, 1997.
    [4] Both peptide and non-peptide Xa factor inhibitors are commonly available [Kaiser B. Thrombin and Factor Xa inhibitors. Drugs of the Future 23: 423-436, 1998]. Examples of peptide Xa factor inhibitors include antistasis and tick anticoagulant peptides, and non-peptide Xa factor inhibitors are described in WO 98/2326, Thromb Haemost 1994; 71: 314-9, Thromb Haemost 1994; 72: 393-6, and Thromb Haemost 1998; 79: 859-64. The antithrombotic effect of the peptide and nonpeptide Xa factor inhibitors has been demonstrated in various experimental models of arterial and venous thrombosis [Kaiser B. Thrombin and factor Xa inhibitors. Drugs of the Future 23: 423-436, 1998].
    [5] <Overview of invention>
    [6] One of the objectives of the present invention is to administer to a mammal a therapeutically effective amount of a combination of a compound selected from the group consisting of (i) a factor Xa inhibitor and (ii) aspirin, TPA, a GPIIb / IIIa antagonist, a low molecular weight heparin and a heparin Wherein the dosage of one or more of (i) and (ii) is a sub-therapeutic dose, to provide a method of treating thrombosis in a mammal.
    [7] Another object of the present invention is to provide a method for treating thrombosis in a mammal, wherein the combination of (i) and (ii) described above is administered in an amount that provides a synergistic effect.
    [8] These and other objects (which will become apparent from the detailed description below) may include Xa factor inhibitor (i) (ii) aspirin, tissue plasminogen activator (TPA), GIIb / IIIa antagonist, low molecular weight heparin or heparin. Administration in combination with any one of them, with the discovery that at least one of (i) and (ii), preferably both, is administered at a sub-therapeutic dose when administered alone.
    [1] The present invention relates to the treatment of thrombosis in mammals, more specifically by administering a combination of (i) a factor Xa inhibitor and (ii) a compound selected from the group consisting of aspirin, TPA, GPIIb / IIIa antagonist, low molecular weight heparin and heparin. To a treatment wherein the dosage of one or more of (i) and (ii) is a sub-therapeutic dose.
    [9] 1 is a graph showing the blood flow of the carotid artery over time in the case of saline vehicle, aspirin alone, Xa factor inhibitor alone, and the same combination of Xa inhibitor and aspirin.
    [10] FIG. 2 is a graph showing the flow of carotid artery over time for saline vehicle, GPIIb / IIIa antagonist alone, Xa factor inhibitor alone, and the same combination of GPIIb / IIIa antagonist and Xa factor inhibitor.
    [11] FIG. 3 is a graph showing the blood flow of the carotid artery over time for saline vehicles, fragmin, Xa factor inhibitors, and combinations of the same Xa inhibitors and pragmin.
    [12] 4 is a bar chart showing the open duration for saline vehicle, Xa factor inhibitor alone, TPA alone, and a combination of the same TPA and Xa factor inhibitor.
    [13] FIG. 5 is a bar chart showing the antithrombotic effect of saline vehicle, heparin alone, and combination with heparin and three different doses of Xa factor inhibitor.
    [14] Combinations of the active compounds (i) and (ii) of the present invention include atherosclerotic arterial disease, valve heart disease, heart failure, cerebrovascular diseases such as stroke, atrial fibrillation, coronary artery disease such as myocardial infarction and Thromboembolic disease, including thromboembolic complications of artificial cardiovascular devices, such as unstable angina, coronary circuitry, peripheral vascular disease, heart valves and vascular grafts, orthopedic surgery, large fractures, and / or deep vein thrombosis after abdominal surgery Useful in the treatment of The combination is also expected to be useful in preventing subsequent arterial thrombus formation and reclosure in combination with intravascular stent implantation, such as percutaneous transvascular coronary angioplasty.
    [15] Factor Xa inhibitor compounds useful in the present invention are well known in the prior art. Preferred Xa factor inhibitors are disclosed in PCT Patent Application No. US97 / 22895, filed Dec. 15, 1997 and published on Jul. 2, 1998 as WO 98/28269, the disclosures of which are incorporated herein by reference. Included as. Particularly preferred compounds disclosed in WO 98/28269 are compounds of the formulas 1 to 3 below.
    [16]
    [17]
    [18]
    [19] Another Xa factor inhibitor compound is described by Thromb Haemost 1994; 71: 314-9 and Thromb Haemost 1994; 72: 393-6, DX-9065a. DX-9065a is (+)-2S-2 [4-[[(3S) -1-acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- [7-amidino-2-naphthyl] Propanoic acid hydrochloride pentahydrate. Another Xa factor inhibitor compound is described by Thromb Haemost 1998; 79: 859-64, YM-60828. YM-60828 is [N- [4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] -N-[(7-amidino-2-naphthyl) methyl] sulfamoyl] acetic acid 2 Hydrochloride. Other Xa factor inhibitor compounds are readily apparent to those skilled in the art.
    [20] Compounds (ii) useful in the combinations of the present invention are commercially available and / or are well known in the prior art. Aspirin, pragmin (Pharmacia AB, Stockholm, Sweden), heparin (Upjohn, Kalamazoo, Michigan) and TPA (Genentech, San Francisco, Califonia) are commercially available. Pragmine is a low molecular weight heparin. It is separated from standard heparin with an average molecular weight of 4.5 kDa, and the molecular weight of standard heparin is between 750 and 1000 kDa. Low molecular weight heparin, such as pragmin, differs from heparin in both pharmacokinetic properties and mechanisms of action. The efficacy of pragmin is expressed in units of anti-Xa factor activity. Each mg of pragmin has an anti-Xa factor activity of about 150 U.
    [21] Preferred GPIIb / IIIa antagonist compounds useful as component (ii) of the combinations of the present invention are disclosed as a second embodiment in PCT Patent Application WO 95/14683, published on June 1, 1995. Preferred compounds or pharmaceutically acceptable salts thereof described in these documents are those having the structure of Formula 1a.
    [22]
    [23] Where
    [24] R 1 is R 2a (R 3 ) N-, R 2 (R 3 ) N (R 2 N =) C-, R 2a (R 3 ) N (CH 2 ) p ' Z-, R 2 (R 3 ) N (R 2 N =) C (CH 2 ) p " Z-, R 2 (R 3 ) N (R 2 N =) CN (R 2 )-, 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-,
    [25]
    [26] Is selected from,
    [27] Z is selected from a bond, O or S,
    [28] R 2 and R 3 are independently H; C 1 -C 6 alkyl; Hydroxy, halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S (O) mCH 3 , —N (CH 3 ) 2 , C 1 -C 4 haloalkyl, methylenedioxydiyl, C 7 -C 11 arylalkyl optionally substituted with 0 to 3 groups selected from ethylenedioxydiyl; (C 1 -C 10 alkoxy) carbonyl; Aryl (C 1 -C 10 alkoxy) carbonyl, wherein the aryl group is hydroxy, halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S (O) m CH 3 , -N (CH 3 ) optionally substituted with 0 to 3 groups selected from 2 , C 1 -C 4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl); Or heteroaryl (C 1 -C 5 ) alkyl, wherein the heteroaryl group is hydroxy, halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S (O) m CH 3 , -N ( CH 3 ) 2 , optionally substituted with 0 to 2 groups selected from C 1 -C 4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl),
    [29] R 2a is R 2 or R 2 (R 3 ) N (R 2 N =) C,
    [30] U is a single bond,
    [31] V is a single bond; -(C 1 -C 7 alkyl)-substituted with 0 to 3 groups independently selected from R 6 or R 7 ; -(C 2 -C 7 alkenyl)-substituted with 0 to 3 groups independently selected from R 6 or R 7 ; -(C 2 -C 7 alkynyl)-substituted with 0 to 3 groups independently selected from R 6 or R 7 ; -(Phenyl) -Q-, wherein phenyl is substituted with 0 to 2 groups independently selected from R 6 or R 7 ; -(Pyridyl) -Q-, wherein said pyridyl is substituted with 0 to 2 groups independently selected from R 6 or R 7 ; Or-(pyridazinyl) -Q-, wherein said pyridazinyl is substituted with 0 to 2 groups independently selected from R 6 or R 7 ,
    [32] Q is a single bond, -O-, -S (O) m- , -NH (R 12 )-,-(CH 2 ) m- , -C (= O)-, -N (R 5a ) C (= O)-, -C (= O) N (R 5a )-, -CH 2 O-, -OCH 2- , -CH 2 N (R 12 )-, -N (R 12 ) CH 2- , CH 2 Is selected from C (= 0)-, -C (= 0) CH 2- , -CH 2 S (O) m -or -S (O) m CH 2- ,
    [33] Provided that when b is a single bond and R 1 -UV is a substituent on C 5 of the central 5-membered ring of formula (Ic), Q is -O-, -S (O) m- , -N (R 12 )-, -C ( Is not = O) N (R 5a )-, -CH 2 O-, -CH 2 N (R 12 )-or -CH 2 S (O) m-,
    [34] W is selected from-(C (R 4 ) 2 ) -C (= 0) -N (R 5a )-and -C (= 0) -N (R 5a )-(C (R 4 ) 2 )- ,
    [35] X is -C (R 4 ) (R 8 ) -CHR 4a- ,
    [36] R4Is H, COne-C10Alkyl, COne-C10Alkylcarbonyl, aryl, arylalkyl, cycloalkyl and cycloalkylalkyl,
    [37] R 4a is substituted with hydroxy, C 1 -C 10 alkoxy, nitro, —N (R 5 ) R 5a , —N (R 12 ) R 13 or —N (R 16 ) R 17 , 0 to 3 R 6 Aryl and (C 1 -C 10 alkyl) carbonyl,
    [38] 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, morpholinyl and pyridyl,
    [39] R5Is H and 0-6 R4bSubstituted by COne-C10Selected from alkyl,
    [40] R 5a is hydrogen, hydroxy, C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylmethyl, C 1 -C 6 alkoxy, benzyloxy, C 6 -C 10 aryl, heteroaryl, heteroarylalkyl, C 7 -C 11 arylalkyl, adamantylmethyl, and C 1 -C 10 alkyl substituted with 0 to 2 R 4b , or
    [41] 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 of which is 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- Optionally substituted with C 11 arylalkoxy) carbonyl,
    [42] R 5b is C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylmethyl, C 6 -C 10 aryl, C 7 -C 11 arylalkyl, And C 1 -C 10 alkyl substituted with 0 to 2 R 4b ,
    [43] Y is hydroxy, C 1 -C 10 alkyloxy, C 3 -C 11 cycloalkyloxy, C 6 -C 10 aryloxy, C 7 -C 11 aralkyloxy, C 3 -C 10 alkylcarbonyloxyalkyloxy , C 3 -C 10 alkoxycarbonyloxyalkyloxy, C 2 -C 10 alkoxycarbonylalkyloxy, C 5 -C 10 cycloalkylcarbonyloxyalkyloxy, C 5 -C 10 cycloalkoxycarbonyloxyalkyloxy, C 5 -C 10 cycloalkoxycarbonylalkyloxy, C 7 -C 11 aryloxycarbonylalkyloxy, C 8 -C 12 aryloxycarbonyloxyalkyloxy, C 8 -C 12 arylcarbonyloxyalkyloxy, C 5 -C 10 alkoxyalkylcarbonyloxyalkyloxy, C 5 -C 10 (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl) methyloxy and C 10 -C 14 (5-aryl -1,3-dioxa-cyclopenten-2-one-yl) methyloxy,
    [44] R 6 and R 7 are each independently 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, and halo,
    [45] R 12 and R 13 are each independently H, C 1 -C 10 alkyl, (C 1 -C 10 alkoxy) carbonyl, (C 1 -C 10 alkyl) carbonyl, C 1 -C 10 alkylsulfonyl, aryl (C 1 -C 10 alkyl) sulfonyl, arylsulfonyl, heteroarylsulfonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl and aryl, wherein the aryl groups are C 1 -C 4 alkyl, C 1 -C 4 optionally substituted with 0 to 3 substituents selected from the group consisting of alkoxy, halo, CF 3 and NO 2 ;
    [46] 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, (C 1 -C 10 alkoxy) carbonyl , CO 2 R 5 and -C (= 0) N (R 5 ) R 5a ,
    [47] R 16 is -C (= 0) -OR 18a , -C (= 0) -R 18b , -C (= 0) N (R 18b ) 2 , -SO 2 -R 18a and -SO 2 -N (R 18b ) 2 is selected from
    [48] R 17 is selected from H and C 1 -C 5 alkyl,
    [49] R 18a is C 1 -C 8 alkyl substituted with 0 to 2 R 19 ; C 2 -C 8 alkenyl substituted with 0 to 2 R 19 ; C 2 -C 8 alkynyl substituted with 0 to 2 R 19 ; C 3 -C 8 cycloalkyl substituted with 0 to 2 R 19 ; Aryl substituted with 0 to 4 R 19 ; Aryl (C 1 -C 6 alkyl)-substituted with 0 to 4 R 19 ; Pyridinyl, furanyl, thiazolyl, thienyl. Pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, benzimidazolyl, piperidinyl, Heterocyclic ring system selected from tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl, pyrrolidinyl, piperidinyl, indolinyl, and morpholinyl and substituted with 0 to 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, pyrrolidinyl, piperidinyl, indolinyl and morpholinyl and are selected from 0 to 4 R Selected from C 1 -C 6 alkyl substituted with a heterocyclic ring system substituted with 19 ,
    [50] R 18b is selected from R 18a and H,
    [51] R 19 is H, halogen, CF 3 , CN, NO 2 , NR 12 R 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 and C 1- C 4 alkoxycarbonyl,
    [52] n is 0 to 4,
    [53] p 'is 1 to 7,
    [54] p "is 1 to 7,
    [55] R is 0-3.
    [56] More preferred compounds are the compounds of formula (Ib) or their pharmaceutically acceptable salts.
    [57]
    [58] Where
    [59] 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-,
    [60]
    [61] Is selected from,
    [62] n is 0 to 1,
    [63] p 'is 4 to 6,
    [64] p "is 2 to 4,
    [65] Z is selected from a bond and O,
    [66] V is a single bond,-(phenyl)-or-(pyridyl)-,
    [67] W is selected from — (C (R 4 ) 2 ) —C (═O) —N (R 5a ) — and —C (═O) —N (R 5a ) —CH 2 —,
    [68] X is selected from -CH 2 -CH (N (R 16 ) R 17 )-and -CH 2 -CH (NR 5 R 5a )-,
    [69] Y is hydroxy, C 1 -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-dioxacyclopenten-2-one-4-yl) Methoxy-, (5- (t-butyl) -1,3-dioxacyclopenten-2-one-4-yl) methoxy, (1,3-dioxa-5-phenyl-cyclopentene-2- On-4-yl) methoxy-, 1- (2- (2-methoxypropyl) carbonyloxy) ethoxy-,
    [70] R 16 is selected from -C (= 0) -OR 18a , -C (= 0) -R 18b , -S (= 0) 2 -R 18a and -SO 2 -N (R 18b ) 2 ,
    [71] R 17 is selected from H and C 1 -C 5 alkyl,
    [72] R 18a is C 1 -C 8 alkyl substituted with 0 to 2 R 19 ; C 2 -C 8 alkenyl substituted with 0 to 2 R 19 ; C 2 -C 8 alkynyl substituted with 0 to 2 R 19 ; C 3 -C 8 cycloalkyl substituted with 0 to 2 R 19 ; Aryl substituted with 0 to 4 R 19 ; Aryl (C 1 -C 6 alkyl)-substituted with 0 to 4 R 19 ; Pyridinyl, furanyl, thiazolyl, thienyl. Pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, benzimidazolyl, piperidinyl, Heterocyclic ring system selected from tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl, pyrrolidinyl, piperidinyl, indolinyl, and morpholinyl and substituted with 0 to 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, pyrrolidinyl, piperidinyl, indolinyl and morpholinyl and are selected from 0 to 4 R And C 1 -C 6 alkyl substituted with a heterocyclic ring system substituted with 19 .
    [73] Particularly preferred compounds are those having the structure of formula (4).
    [74]
    [75] Other salts of the compounds are also particularly preferred.
    [76] Specific examples of other GPIIb / IIIa antagonist compounds are described in Graul et al. and Scarborough (Grual A, Martel AM and Castaner J. Xemilifiban; Drugs of the Future 22: 508-517, 1997; Scarborough RM; Eptifibatide.Drugs of the Future 23: 585-590, 1998) Typivatid, tyropivan, ramipivan, lepradaffivan, sibrapivan (Ro-48-3657), orbopiban and gemifivan, others are readily apparent to those skilled in the art.
    [77] A "therapeutically effective amount" includes an amount of a combination of compounds that is effective for treating thrombosis in a mammal. The combination of compounds is preferably a combination having a synergistic effect. See, eg, Chou and Talalay, Adv. Enzyme Regul. 22: 27-55 (1984), the synergy is the effect of the compound when administered in combination (in the case of the present invention), rather than the additional effect of the compound when the compound is administered alone as a single agent. Anti-thrombotic effect). In general, synergistic effects are most evident at concentrations below the optimal concentration of the compounds of the invention. Synergy can be said to be an antihypertensive effect, an antithrombogenic effect or other non-additive beneficial effects of the combination over the individual components.
    [78] The terms "concomitant administration", "combination" or "in combination" with respect to components (i) and (ii) of the present invention mean that the components are administered together to the mammal to be treated. When administered in combination, the components may be administered simultaneously or sequentially at any order or at different times. Thus, component (i) and component (ii) can be administered separately but within a sufficiently close time to provide the desired therapeutic effect.
    [79] The term "subtherapeutic dose" for components (i) and (ii) of the present invention does not provide the desired therapeutic effect for the disease to be treated when administered alone to a mammal. Means that.
    [80] The invention can be understood in more detail from the following examples, in which the compounds 1 to 4 are as indicated above. Brine (0.9 wt% NaCl) is the vehicle in all examples.
    [81] Example 1
    [82] Combination of Aspirin and Xa Factor Inhibitors
    [83] Rabbits were anesthetized with ketamine (50 mg / kg i.m.) and xylazine (10 mg / kg i.m.) and surgically prepared arterial and venous catheters. Electromagnetic probes were placed in the isolated carotid artery and blood flow was monitored. Thrombus formation was induced by electrical stimulation of the carotid artery at 4 mA for 3 minutes using an external stainless steel bipolar electrode. Carotid artery blood flow was continuously measured over 90 minutes to monitor thrombus occlusion. The test agent was injected intravenously over a 90 minute period 1 hour prior to electrical stimulation of the carotid artery.
    [84] As shown in FIG. 1, in animals treated with saline vehicles, thrombus formation was induced after electrical stimulation, thereby gradually decreasing carotid blood flow. About 40 minutes after stimulation, the artery was completely occluded and the blood flow was zero. Compound 1 (Xa factor inhibitor) of 1 mg / kg / hr (intravenous) (concentration in saline is 0.167 mg / ml) or 0.1 mg / kg / hr (intravenous) (concentration in saline is 0.017 mg / ml) ) Did not prevent the occlusion of the arteries and the blood flow of these animals decreased to zero at approximately the same time as in the vehicle treated animals. Surprisingly, the combination of 1 mg / kg / hr (intravenous) aspirin and 0.1 mg / kg / hr (intravenous) Compound 1 prevented occlusion and maintained blood flow for at least 90 minutes. These results show that the combination of Compound 1 and aspirin at sub-dose doses results in significant antithrombotic effects that are unexpected in the rabbit model of arterial thrombosis.
    [85] Example 2
    [86] Combination of Compound 4 (GP-IIb / IIIa Antagonist) and Xa Factor Inhibitor
    [87] The experimental protocol is as described above for Example 1. As shown in FIG. 2, compound 4 (GP-IIb / IIIa antagonist) at 0.03 mg / kg / hr (intravenous)) and compound 3 (Xa factor inhibitor) at 0.1 mg / kg / hr (intravenous) are arterial Occlusion was not prevented and blood flow in these animals decreased to zero at the same time as in vehicle-treated animals. Surprisingly, compound 3 of 0.1 mg / kg / hr (intravenous) (concentration in saline is 0.017 mg / ml) and 0.3 mg / kg / hr (intravenous) (concentration in saline is 0.005 mg / ml) The combination prevented occlusion of the artery and maintained blood flow for at least 90 minutes. These results show that sub-therapeutic doses of Compound 3 and Compound 4 result in significant antithrombotic effects that are unexpected in rabbit models of arterial thrombosis.
    [88] Example 3
    [89] Combination of Fragmine (Low Molecular Weight Heparin) and Xa Factor Inhibitor
    [90] The experimental protocol is as described above for Example 1. As shown in FIG. 3, 60 U / kg / hr (intravenous) pragmin (low molecular weight heparin) has moderate activity. Compound 3 (Xa factor inhibitor) at 0.1 mg / kg / hr (intravenous) did not prevent arterial occlusion and blood flow in these animals decreased to zero at the same time as in vehicle-treated animals. Surprisingly, a combination of compound 3 of 0.1 mg / kg / hr (intravenous) (concentration in saline is 0.017 mg / ml) and pragmin of 60 U / kg / hr (intravenous) (concentration in saline is 0.067 mg / ml) Prevented blockage of the artery and maintained blood flow for at least 90 minutes. These results show that the combination of sub-therapeutic doses of compound 3 and medium doses of pragmine leads to significant and unexpected antithrombotic effects in the rabbit model of arterial thrombosis.
    [91] Example 4
    [92] Combination of Combination Tissue Plasminogen Activator (TPA) and Factor Xa Inhibitor
    [93] Experiments were performed on rats. Similar to the rabbit protocol described in Example 1, except that Compound 2 and / or TPA were administered 5 minutes after forming preformed thrombus. The measured parameter was the duration of opening. As shown in FIG. 4, 5 minutes after the induction of thrombus occlusion, 5.6 mg / kg (concentration in saline is 0.23 mg / ml) and 1.4 mg / kr / hr (intravenously) of compound 2 or 1 mg / kg (intravenous) Neither TPA (concentration in saline was 1 mg / ml) provided a therapeutic effect on the duration of opening. However, the combination of 5.6 mg / kg and 1.4 mg / kg / hr (intravenous) Compound 2 with 1 mg / kg (intravenous) TPA increased the duration of opening by 70%. These results suggest that Xa factor inhibitors such as Compound 2 are promising useful adjuvants that accelerate thrombolysis induced by TPA or other thrombolytics. Compound 2 augments thrombolysis induced by sub-therapeutic TPA doses.
    [94] Example 5
    [95] Combination of Heparin and Xa Factor Inhibitor
    [96] Experiments were performed with male guinea pigs anesthetized with a mixture of ketamine (90 mg / kg intramuscular) and xylazine (12 mg / kg intramuscular). Arterio-venous shunts were connected between the carotid artery and the jugular vein. Blood flow was exposed to silk thread to induce significant thrombosis. After 30 minutes, the shorts were separated and the silk thread covered with thrombus was weighed. The compound or saline vehicle was fed in a continuous intravenous infusion continuously 1 hour before blood circulation in the short circuit and throughout the experimental period (ie 90 minutes). As shown in FIG. 5, heparin showed no antithrombotic effect at 4 U / kg / hr (intravenous) (concentration in saline was 0.667 U / ml). However, heparin at 4 U / kg / hr (intravenous) was 0.3, 1 or 3 mg / kg / h (intravenous) (concentration in saline for dose 0.3 was 0.05 mg / ml) of Compound 3 (Xa factor). Inhibitors) had an antithrombotic effect. This result suggests that heparin enhances the antithrombotic effect of Compound 3 at sub-dose doses in the guinea model of venous thrombosis.
    [97] The results presented indicate that a combination therapy comprising one of aspirin, TPA, GPIIb / IIIa antagonist, low molecular weight heparin or heparin and factor Xa inhibitors would be effective in treating thrombosis in patients. The methods of the present invention provide significant advantages over currently available thrombosis therapeutics.
    [98] Dosage and Formulation
    [99] Factor Xa inhibitors (i) and compounds of the present invention (ii) may be administered as therapeutic agents for thrombosis by any method of bringing the active agent into contact with the active agent site, ie factor Xa, in the body of a mammal. These may be administered by any conventional means that can be used with the medicament as individual therapeutic agents or combinations of therapeutic agents. These may be administered alone, but are preferably administered with a pharmaceutical carrier selected based on the chosen route of administration and standard pharmaceutical practice.
    [100] Naturally, the dosage may be based on known factors such as the pharmacokinetic characteristics and mode and route of administration of the particular agent, the age, health and weight of the recipient, the nature and extent of the symptoms, the type of treatment used, the frequency of treatment and the desired It may vary depending on the effect. The daily dosage of the active ingredient is expected to be from about 0.001 to about 1000 milligrams per kg of body weight, with a preferred dosage of about 0.01 to 30 mg / kg.
    [101] Dosage forms of a composition suitable for administration contain from about 1 mg to about 100 mg of active ingredient per unit. In such pharmaceutical compositions the active ingredient will typically be present in an amount of about 0.5 to 95 weight percent, based on 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 may also be administered parenterally in sterile liquid dosage form.
    [102] Gelatin capsules contain the active ingredient and powder carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules may be prepared in sustained release formulations to provide continuous release of the medication for a period of time. To hide any unpleasant taste and to protect the tablet from the surrounding environment, the compressed tablet may be in dragee or film coating form or enteric coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration may contain colorants and flavoring agents to increase tolerance to the patient.
    [103] In general, water, suitable oils, saline, aqueous dextrose (glucose) and related sugar solutions and glycols (such as propylene glycol or polyethylene glycol) are suitable carriers for parenteral solutions. The solution for parenteral administration preferably contains a water soluble salt of the active ingredient, a suitable stabilizer, and a buffer material if necessary. Antioxidants such as sodium hydrogen sulfite, sodium sulfite or ascorbic acid are suitable stabilizers, alone or in combination. Citric acid and its salts and sodium EDTA are also used. Parenteral solutions may also contain preservatives such as benzalkonium chloride, methyl- or propyl-parabens and chlorobutanol. Suitable pharmaceutical carriers are those described in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, which are standard references in the art and the disclosure of which is incorporated herein by reference.
    [104] Useful pharmaceutical dosage forms for the administration of the compounds of the invention can be illustrated as follows.
    [105] capsule
    [106] A large number of unit capsules are prepared by filling each of the standard two-piece hard gelatin capsules with 0.1 to 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate. can do.
    [107] Soft gelatin capsules
    [108] Mixtures of the active ingredients in digestible oils, such as soybean oil, cottonseed oil or olive oil, can be prepared and injected into gelatin using a positive displacement pump to produce soft gelatin capsules containing from 0.1 to 100 mg of the active ingredient. The capsules are then washed and dried.
    [109] refine
    [110] According to the usual procedure, the unit dose will be 0.1 to 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg of lactose. Numerous tablets can be made. Suitable coatings may be applied to enhance flavor suitability or slow down absorption.
    [111] Suspension
    [112] Aqueous suspension for oral administration so that each 5 ml contains 0.1 to 100 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution (US Pharmacopoeia) and 0.025 mg of vanillin Can be prepared.
    [113] Injection
    [114] Parenteral compositions suitable for injection administration can be prepared by stirring 0.1 to 100 mg of the active ingredient in 10% by volume propylene glycol and water. The solution is sterilized by commonly used techniques.
    [115] Combination of Components (i) and (ii)
    [116] Each of the therapeutic agent components of the present invention may be independently any dosage form as described above, and may also be administered by various routes as described above. In the following description component (ii) is to be understood to represent one or more of the previously described agents. Thus, if components (i) and (ii) are treated identically or independently, each agent of component (ii) may also be treated identically or independently.
    [117] Components (i) and (ii) of the present invention can be combined together and formulated together into a single dosage unit (ie, one capsule, tablet, powder or liquid, etc.). If components (i) and (ii) are not formulated together in a single dosage unit, component (i) is administered at the same time as component (ii) or in any order, e.g. It may be administered first followed by the administration of component (ii) or in reverse order. If component (ii) contains one or more agents, ie aspirin and heparin, these agents may be administered together or in any order. When not administered simultaneously, components (i) and (ii) are preferably administered at about 1 hour intervals. Preferably, the route of administration of components (i) and (ii) is intravenous administration (i.v.). As used herein, the term oral medicament, oral inhibitor, oral compound and the like refer to compounds that can be administered orally. It is preferred to administer both component (i) and (ii) by the same route (ie, both orally) or in the form of administration, but if desired, orally administer a different route (ie, one component of the combination product, for example). And the remaining ingredients can be administered intravenously) or in a dosage form.
    [118] As will be apparent to a medical practitioner of ordinary skill in the art, the dosage of the combination therapy of the present invention may vary depending on the pharmacokinetic characteristics of the particular agent as described above, the mode and route of administration thereof, the age, health condition of the recipient, It may vary depending on various factors such as body weight, nature and extent of symptoms, type of treatment in combination, frequency of treatment and the desired effect.
    [119] Appropriate dosages of components (i) and (ii) of the present invention can be readily ascertained from the disclosure herein by those of ordinary skill in the art. As a general guideline, typically the daily dosage is from about 0.01 mg to about 1 g per component. If component (ii) represents one or more compounds, the daily dosage is typically from about 0.01 mg to about 0.1 g of component (ii) per each drug. As a general guideline, in view of the synergistic effect of the combination, when the compounds of component (i) and component (ii) are administered together, they are compared to conventional dosages when they are administered alone as a single agent to treat thrombosis. The dosage of each component can be reduced by 70 to 80%.
    [120] Although the active ingredients are combined in a single dosage unit, the combination products of the present invention can be formulated to minimize physical contact of the active ingredients. In order to minimize contact, for example when oral administration of a product, one active ingredient may be enterically coated. Enteric coating of one of the active ingredients not only minimizes contact between the active ingredients in combination, but also releases one of these ingredients in the gastrointestinal tract so that one of these ingredients is released in the intestine rather than in the stomach. I can regulate it. Another embodiment of the invention where oral administration is preferred provides a combination product wherein one of the active ingredients has a sustained release effect throughout the gastrointestinal tract and is also coated with a sustained release material that contributes to minimizing physical contact between the combined active ingredients. do. Furthermore, the sustained release component may further be enterically coated such that release of this component occurs only in the intestine. Yet another approach is to coat one component with sustained release and / or enteric polymers to further separate the active ingredients and the other component also polymers such as low viscosity grade hydroxypropyl methylcellulose or other suitable materials known in the art. Formulation of a combination product coated with. Polymeric coatings contribute to forming additional barriers to interaction with other components. In each formulation in which contact between components (i) and (ii) is prevented by a coating or other material, the contact between the respective components of component (ii) can also be prevented.
    [121] Dosage forms of the combination product of the present invention in which one active ingredient is enteric coated may be mixed together with the enteric coated component and other active ingredients and then compressed into tablets or the enteric coated component is compressed into one tablet layer and the remaining active ingredient is compressed. It may be in the form of a tablet compressed into an additional layer. Optionally, one or more placebo layers may be placed such that a placebo layer exists between the layers of the active ingredients to further separate the two layers. In addition, the dosage form of the present invention may be in the form of a capsule in which one active ingredient is compressed into tablets or in the form of a plurality of microtablets, particles, granules or non-perils (these are then enterically coated). The enteric coated microtablets, particles, granules or biferyls can then be encapsulated or compressed into capsules with granulation of other active ingredients.
    [122] The above and other methods for minimizing contact between the components of the combination product of the present invention, whether administered in a single dosage form or simultaneously or in the same manner in separate forms, are described in the art based on the description herein. Will be obvious to you.
    [123] Obviously, many modifications and variations of the present invention described above are possible in light of the above teachings. It is, therefore, to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.
    权利要求:
    Claims (8)
    [1" claim-type="Currently amended] A therapeutically effective amount of a combination of a compound selected from the group consisting of (i) a factor Xa inhibitor and (ii) aspirin, a tissue plasminogen activator (TPA), a GPIIb / IIIa antagonist, a low molecular weight heparin and a heparin, is administered to a mammal in a therapeutically effective amount A method of treating thrombosis in a mammal, wherein the dosage of at least one of (i) and (ii) is a sub-therapeutic dose.
    [2" claim-type="Currently amended] The method of claim 1, wherein the combination of (i) and (ii) provides a synergistic effect.
    [3" claim-type="Currently amended] The method of claim 2, wherein (ii) is aspirin.
    [4" claim-type="Currently amended] The method of claim 2, wherein (ii) is TPA.
    [5" claim-type="Currently amended] The method of claim 2, wherein (ii) is a GPIIb / IIIa antagonist.
    [6" claim-type="Currently amended] The method of claim 2, wherein (ii) is low molecular weight heparin.
    [7" claim-type="Currently amended] The method of claim 2, wherein (ii) is heparin.
    [8" claim-type="Currently amended] Use of a combination of (i) a factor Xa inhibitor and (ii) aspirin, a TPA, a GPIIb / IIIa antagonist, a low molecular weight heparin and a heparin compound for the manufacture of a medicament for the treatment of thrombosis.
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    同族专利:
    公开号 | 公开日
    IL144798D0|2002-06-30|
    EP1161279A1|2001-12-12|
    AU3525400A|2000-09-28|
    ZA200106360B|2002-08-02|
    JP2002538226A|2002-11-12|
    BR0010381A|2002-02-05|
    CN1346292A|2002-04-24|
    CA2361650A1|2000-09-14|
    AU766089B2|2003-10-09|
    WO2000053264A1|2000-09-14|
    EA200100966A1|2002-02-28|
    NZ513217A|2003-11-28|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1999-03-11|Priority to US12381599P
    1999-03-11|Priority to US60/123,815
    2000-03-10|Application filed by 블레어 큐. 퍼거슨, 듀폰 파마슈티컬즈 컴퍼니
    2000-03-10|Priority to PCT/US2000/006451
    2002-01-17|Publication of KR20020005614A
    优先权:
    申请号 | 申请日 | 专利标题
    US12381599P| true| 1999-03-11|1999-03-11|
    US60/123,815|1999-03-11|
    PCT/US2000/006451|WO2000053264A1|1999-03-11|2000-03-10|Treatment of thrombosis by combined use of a factor xa inhibitor and aspirin, tissue plasminogen activator , a gpiib/iiia antagonist, low molecular weight heparin or heparin|
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