WO2002051445A2

WO2002051445A2 - An oral and parenteral pharmaceutical formulation comprising a low molecular weight thrombin inhibitor prodrug

Info

Publication number: WO2002051445A2
Application number: PCT/EP2001/015029
Authority: WO
Inventors: Helmut Mack; Wilfried Hornberger
Original assignee: Abbott Gmbh & Co. Kg
Priority date: 2000-12-22
Filing date: 2001-12-19
Publication date: 2002-07-04
Also published as: WO2002051445A3; DE10064797A1

Abstract

According to the invention there is provided a kit of parts comprising: (a) a parenteral pharmaceutical formulation including a low molecular weight thrombin inhibitor prodrug, or a pharmaceutically acceptable derivative thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier; and (b) an oral pharmaceutical formulation including a prodrug of a low molecular weight thrombin inhibitor, or a pharmaceutically acceptable derivative of that prodrug, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other, as well as the use of such a kit of parts in the treatment of a condition in which inhibition of thrombin is required or desired.

Description

AN ORAL AND PARENTERAL PHARMACEUTICAL FORMJLATION COMPRISING A LOW MOLECULAR WEIGHT THROMBIN INHIBITOR PRODRUG

This invention relates to a new use of low molecular weight thrombin inhibitor prodrugs as combination of an oral and parenteral application.

Blood coagulation is the key process involved in both haemostasis (i.e. the prevention of blood loss from a damaged vessel) and thrombosis (i.e. the formation of a blood clot in a blood vessel, sometimes leading to vessel obstruction) .

Coagulation is the result of a complex series of enzymatic reactions . One of the ultimate steps in this series of reactions is the conversion of the proenzyme prothrombin to the active enzyme thrombin.

Thrombin is known to play a central role in coagulation. It activates platelets, leading to platelet aggregation, converts fibrinogen into fibrin monomers, which polymerize spontaneously into fibrin polymers, and activates factor XIII, which in turn crosslinks the polymers to form insoluble fibrin. Furthermore, thrombin activates factor V and factor VIII leading to a "positive feedback" generation of thrombin from prothrombin.

Effective inhibitors of thrombin are thus known, and/or are expected, to be useful as anticoagulants and therefore useful in the therapeutic treatment of thrombosis and related disorders .

The early development of low molecular weight inhibitors of thrombin has been described by Claesson in Blood Coagul. Fibrinol. (1994) 5, 411.

Low molecular weight thrombin inhibitors have been described more recently in US Patent 4,346,078; International Patent Applications WO 93/11152, WO 93/18060, WO 93/05069, wo^" 94/20467, WO 94/29336, WO 95/35309, WO 95/23609, WO 96/03374, WO 96/06832, WO 96/06849, WO 96/25426, WO 96/32110, WO 97/01338, WO 97/02284, WO 97/15190, WO 97/30708, WO 97/40024, WO 97/46577, WO 98/06740, WO 97/49404, WO 97/11693, WO 97/24135, WO 97/47299, WO 98/01422, WO 98/57932, WO 99/29664, WO 98/06741, WO 99/37668, WO 99/37611, WO 98/37075, WO 99/00371, WO 99/28297, WO 99/29670, WO 99/40072, WO 99/54313, WO 96/31504, WO 00/01704 and WO 00/08014; European Patent Applications 648 780, 468 231, 559 046, 641 779, 185 390, 526 877, 542 525, 195 212, 362 002, 364 344, 530 167, 293 881, 686 642, 669 317, 601 459 and 623 596; and German Patent Applications DE 19829964, DE 19834751, DE 19851421, DE 19857202, DE 19858029 and DE 19907813.

In particular, international patent application WO 94/29336 discloses a group of compounds, including HOOC-CH₂- (R)Cgl-Aze- Pab-H (in which Cgl represents cyclohexylglycine, Aze represents S-azetidine-2- carboxylic acid and Pab-H represents 4-amino- methyl-amidinobenzene) , which is also known as melagatran (see Example I of WO 94/29336) . International Patent Application WO 97/23499 discloses prodrugs of inter alia melagatran.

WO 00/64470 discloses a combination treatment with drug and prodrug.

In particular, international patent application WO 95/35309, WO 96/25426, WO 98/06740, WO 98/06741, WO 00/61577, and

WO 00/61609 disclose a group of compounds which are prodrugs of oral thrombin inhibitors. The preferred compounds of those application are also preferred in this application. More preferred are the preferred compounds of WO 00/61577 and WO 00/61609.

None of the above-mentioned documents disclose or suggest the parenteral administration of a thrombin inhibitor prodrug in conjunction with an oral administration of a prodrug of that thrombin inhibitor, or indeed in conjunction with a prodrug of any thrombin inhibitor.

Deep venous thrombosis (DVT) and pulmonary embolism (PE) are major health problems, which may give rise to serious outcomes. In particular, PE may be fatal, or may result in the development of pulmonary hypertension and heart failure from recurrent embolism. DVT may result in post-thrombotic venous insufficiency and ulcers in the affected part of the body (e.g. leg). Both are conurion conditions , which have a great impact on worldwide healthcare costs.

There is a considerable incidence of DVT and PE following ortho_¬ paedic surgery. For example, in patients undergoing total hip replacement, the incidence of DVT in the absence of thrombo- prophylaxis may be as high as to 57%. Further, the incidence of proximal DVT may be between 23 and 36%, and that of fatal PE 0.34 to 6%. In patients undergoing total knee replacement in the absence of thromboprophylaxis , the postoperative incidence of DVT is between 40 and 84%, of proximal DVT is between 9 and 20%, and of fatal PE is between 0.2 and 0.7%. in patients undergoing' general surgery in the absence of thromboprophylaxis, the post_¬ operative incidence of DVT is about 25%. (Reference: Chest (1998) 114, 531S to 560S.) Low-dose, subcutaneous (s.c.) unfractionated heparin is the most widely used current prophylactic treatment for venous thromboembolism resulting from orthopaedic and general surgery. The incidence of DVT after total hip replacement has been shown to be reduced (see Chest reference above) .

The use of low-molecular weight heparin (LMWH) in the prophylaxis of DVT following total hip and knee replacement operations has been shown to further the reduce incidence (when compared to low dose unfractionated heparin) , without a concomitant increase in bleeding (see Chest reference above) .

However, prolonged treatment with heparins has been shown to give rise to an increased risk of osteoporosis. Heparins may also give rise to "heparin- induced thrombocytopeaia" (HIT) , are dependent on the plasma level of the endogenous thrombin inhibitor, anti- thrombin, and do not inactivate clot-bound thrombin.

Oral anticoagulants, such as warfarin (a vitamin K antagonist) , has also been shown to be effective in reducing DVT after major surgery (see Chest reference above) . However, due to the risk of bleeding, and the need for frequent laboratory control, the use of this substance is generally reserved for high risk patients, and/or for long term use. Vitamin K antagonists also demonstrate a notable risk of interaction with other drugs and certain foods^, and their use requires monitoring of the patient's blood coagulation status .

Antiplatelet agents, such as aspirin, have been shown to have limited efficacy in preventing DVT (see Chest reference above)

Comparative clinical studies carried out during the course of total hip replacement operations have shown that subcutaneous administration of the thrombin inhibitor hirudin is superior to unfractionated heparin and LMWH in reducing, the frequency of total and proximal DVT with no corresponding increase in bleeding (see Eriksson et al in Lancet, 347, 635 1 (1996) and J. Bone Joint. Surg., Sep., 11 (1996)). However, hirudin is expensive and has an immunogenic potential .

Thus, there is a need for effective treatments of thrombotic conditions such as DVT. It was found, surprisingly, that parenteral administration of a prodrug of a low molecular weight thrombin inhibitor in conjunction with an oral administration of a prodrug of a (or a prodrug of that) thrombin inhibitor gives rise to a notable anticoagulant effect.

According to a first aspect of the invention there is provided a kit of parts comprising components :

(a) a parenteral pharmaceutical formulation including a prodrug of a low molecular weight thrombin inhibitor, or a pharma_¬ ceutically acceptable derivative thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier_; and

(b) an oral pharmaceutical formulation including a prodrug of a low molecular weight thrombin inhibitor, or a pharmaceutically acceptable derivative of that prodrug, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.

It is preferred that the prodrug of component (b) is identical to the prodrug of component (a) .

According to a further aspect of the invention, there is provided a method of making a kit of parts as defined herein, which method comprises bringing a component (a) , as defined above, into association with a component (b) , as defined above, thus rendering the two components suitable for administration in conjunction with each other.

By bringing the two components "into association with" each other, we include that components (a) and (b) may be:

(i) provided as separate formulations (i.e. independently of one another) , which are subsequently brought together for use in conjunction with each other in combination therapy; or

(ii) packaged and presented together as separate components of a "combination pack" for use in conjunction with each other in combination therapy. Thus, there is further provided a kit of parts comprising:

(1) one of components (a) and (b) as defined herein; together with

(2) instructions to use that component in conjunction with the other of the two components .

The kits of parts defined herein may comprise more than one parenteral formulation including an appropriate quantity/dose of the thrombin inhibitor prodrug, and/or more than one oral formulation including an appropriate quantity/dose of respective prodrug, in order to provide for repeat dosing. If more than one formulation (comprising oral or parenteral trombin inhibitor prodrug) is present, such formulations may be the same, or may be different in terms of the dose of thrombin inhibitor prodrug, chemical composition and/or physical form.

A further aspect of the invention provides a method of treatment of a condition in which inhibition of thrombin is required or desired, which comprises administration of:

(a) a pharmaceutical parenteral formulation including a prodrug of low molecular weight thrombin inhibitor, or a phar aceuti- cally acceptable derivative thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier; in conjunction with

(b) an oral pharmaceutical formulation including a prodrug of a low molecular weight thrombin inhibitor, or a pharmaceutically acceptable derivative of that prodrug, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, - to a patient suffering from, or susceptible to, such a condition.

For the avoidance of doubt, as used herein, the term "treatment" includes therapeutic and/or prophylactic treatment.

"Pharmaceutically acceptable derivatives" of thrombin inhibitor prodrugs includes salts (e.g. pharmaceutically acceptable non- toxic organic or inorganic acid addition salts) and solvates . It will be appreciated that the term pharmaceutically acceptable derivatives of active thrombin inhibitor prodrugs includes those derivatives that have the same biological function and/or activity as that thrombin inhibitor prodrug. By "administration in conjunction with", we include that respective formulations comprising thrombin inhibitor prodrug are administered, sequentially, separately and/or simultaneously, over the course of treatment of the relevant condition, which condition may be acute or chronic. Preferably, the term includes that the two formulations are administered (optionally repeat_¬ edly) sufficiently closely in time for there to be a beneficial effect for the patient, that is greater, over the course of the treatment of the relevant condition, than if either of the two formulations are administered (optionally repeatedly) alone, in the absence of the other formulation, over the same course of treatment .

Determination of whether a combination provides a greater beneficial effect in respect of, and over the course of treatment of, a particular condition, will depend upon the condition to be treated or prevented, but may be achieved routinely by the skilled person.

Thus, the term "in conjunction with" includes that one or other of the two formulations may be administered (optionally repeatedly) prior to, after, and/or at the same time as, administration with the other component.

When used in this context, the terms "administered simultaneously" and "administered at the same time as" include that individual doses of parenteral and oral thrombin inhibitor prodrug are administered within 48 hours (e.g. 24 hours) of each other.

The term "low molecular weight thrombin inhibitor" will be understood by those skilled in the art. The term may also be understood to include any composition of matter (e.g. chemical compound) which inhibits thrombin to an experimentally determinable degree in in vivo and/or in in vitro tests, and which possesses a molecular weight of below 2,000, preferably below 1,000.

Preferred low molecular weight thrombin inhibitors include low molecular weight peptide-based, amino acid-based, and/or peptide analogue-based, thrombin inhibitors.

The term "low molecular weight peptide-based, amino acid-based, and/or peptide analogue-based, thrombin inhibitors" will be well understood by one skilled in the art to include low molecular weight thrombin inhibitors with one to four peptide linkages, and includes those described in the review paper by Claesson in Blood Coagul. Fibrin. (1994) 5, 411, as well as those disclosed in US Patent N' 4,346,078; International Patent Applications WO 93/11152, WO 93/18060, WO 93/05069, WO 94/20467, WO 94/29336, WO 95/35309, WO 95/23609, WO 96/03374, WO 96/06832, WO 96/06849,' WO 96/25426, WO 96/32110, MO 97/01338, WO 97/02284, WO 97/15190,' WO 97/30708, WO 97/40024, WO 97/46577, WO 98/06740, WO 97/49404^ WO 97/11693, WO 97/24135, WO 97/47299, WO 98/014222, WO 98/57932, WO 99/29664, WO 98/06741, WO 99/37668, WO 99/37611, WO 98/37075,' WO 99/00371, WO 99/28297, WO 99/29670, WO 99/40072, WO 99/54313,' WO 96/31504, WO 00/01704 and WO 00/08014; European Patent

Applications 648 780, 468 231, 559 046, 641 779, 185 390, 526 877, 542 525, 195 212, 362 002, 364 344, 530 167, 293 881, 686 642, 669 317, 601 459 and 623 596; German Patent Applications DE 19829964, DE 19834751, DE 19851421, DE 19857202, DE 19858029 and DE 19907813, the disclosures in all of which documents are hereby incorporated by reference.

Preferred low molecular weight peptide-based thrombin inhibitors include HOOC-CH₂- (R) Cha-Pic-Nag-H (wherein Cha represents cyclo- hexylalanine, Pic represents (S) -pipecolinic acid and Nag represents noragmatine,- known as inogatran; see International Patent Application WO 93/11152) and, especially, HOOC-CH₂- (R₎ Cgl- Aze-Pab-H (known as melagatran; see above and International Patent Application WO 94/29336) . Other preferred low molecular weight thrombin inhibitors are disclosed in international patent applications WO 95/35309, WO 96/25426, WO 98/06740 and WO 98/06741.

The term "prodrug" of a low molecular weight thrombin inhibitor includes any compound that, following oral or parenteral administration, is metabolised in vivo to form a low molecular weight thrombin inhibitor (as defined herein) , in an experimentally-detectable amount, and within a predetermined time (e.g. within a dosing interval of between 6 and 24 hours ⁽i.e. once to four times daily)), following oral or parenteral administration. Prodrugs of the thrombin inhibitor melagatran that may be mentioned include those disclosed in international patent application WO 97/23499. Preferred prodrugs are those of the formula R'OOC-CH₂- (R) Cgl-Aze-Pab-OH (see the list of abbreviations above or in WO 97/23499), wherein R' represents C₃-C₈-cycloalkyl, Cι--C₄-alkyl-C₃-C₈-cycloalkyl, Cι_₁₀ alkyl or benzyl, such as linear or branched C_x_₆ alkyl (e.g. C^ alkyl, especially methyl, propyl and, particularly, ethyl) and the OH group replaces one of the amidino hydrogens in Pab. Other preferred "prodrugs" are disclosed in WO 00/61577 and WO 00/61609. The term "condition in which inhibition of thrombin is required or desired" will be understood by those skilled in the art to include the following:

The treatment and/or prophylaxis of thrombosis and hyper- coagulability in blood and tissues of animals including, man. It is known that hypercoagulability may lead to thrombo- embolic diseases. Conditions associated with hypercoagulability and thrombo-embolic diseases which may be mentioned include inherited or acquired activated protein C resistance, such as the factor V-mutation (factor V Leiden) , and inherited or acquired deficiencies in antithrombin III, protein C, protein S, heparin cofactor II. Other conditions known to be associated with hypercoagulability and thrombo-embolic disease include circulating antiphospholipid antibodies (Lupus anticoagulant), homocysteinerni, heparin induced thrombocytopenia and defects in fibrinolysis .

The treatment of conditions where there is an undesirable excess of thrombin without signs of hypercoagulability, for example in neurodegenerative diseases such as Alzheimer's disease.

Particular disease states which may be mentioned include the therapeutic and/or prophylactic treatment of venous thrombosis (e.g. DVT) and pulmonary embolism, arterial thrombosis (e.g. in myocardial infarction, unstable angina, thrombosis-based stroke and peripheral arterial thrombosis) and systemic embolism usually from the atrium during arterial fibrillation or from the left ventricle after trans ural myocardial infarction, or caused by congestive heart failure prophylaxis of re- occlusion

(i.e. thrombosis) after thrombolysis, percutaneous trans-luminal angioplasty (PTA) and coronary bypass operations; the prevention of re-thrombosis after microsurgery and vascular surgery in general .

Further indications include the therapeutic and/or prophylactic treatment of disseminated intravascular coagulation caused by bacteria, multiple trauma, intoxication or any other mechanism; anticoagulant treatment when blood is in contact with foreign surfaces in the body such as vascular grafts, vascular stents, vascular catheters, mechanical and biological prosthetic valves or any other medical device; and anticoagulant treatment when blood is in contact with medical devices outside the body such as during cardiovascular surgery using a heart-lung machine or in haemodialysis; the therapeutic and/or prophylactic treatment of idiopathic and adult respiratory distress syndrome, pulmonary fibrosis following treatment with, radiation or chemotherapy, septic shock, septicemia, inflammatory responses, which include, but are not limited to, edema, acute or chronic atherosclerosis such as coronary arterial disease, cerebral arterial disease, peripheral arterial disease, reperfusion damage, and restenos'is after percutaneous trans-lu inal angioplasty (PTA) .

Preferred conditions include thrombosis, especially DVT, including distal and proximal DVT. The present invention finds particular utility in the prophylactic treatment of DVT resulting from surgery, such as gastrointestinal, or orthopaedic, surgery (e.g. hip or knee replacement) . This includes DVT resulting from immobilisation after surgery.

In accordance with the invention, prodrugs of thrombin inhibitors, and derivatives thereof, may be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, topically, by any other parenteral route, or via inhalation, in the form of a pharmaceutical preparation comprising the thrombin inhibitor prodrug in a pharmaceutically acceptable dosage form. Depending on the disorder, and the patient, to be treated, as well as the route of administration, the compositions may be administered at varying doses .

Preferred modes of delivery are systemic. For the first prodrug preferred modes of administration are parenteral, more preferably intravenous, and especially subcutaneous. For the second prodrugs preferred modes of administration are oral. The prodrugs are preferred the same.

In the therapeutic treatment of mammals, and especially humans, prodrugs of thrombin inhibitors, and derivatives of either will generally be administered as a pharmaceutical formulation in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, which may be selected with due regard to the intended route of administration and standard pharmaceutical practice.

Suitable formulations for use in administering thrombin inhibitors are known in the art, and include those known from US Patent NO 4,346,078; International Patent Applications O 93/11152, WO 93/18060, WO 93/05069, WO 94/20467, WO 94/29336, O 95/35309, WO 95/23609, WO 96/03374, WO 96/06832, WO 96/06849^ O 96/25426, WO 96/32110, WO 97/01338, WO 97/02284, WO 97/15190^ O 97/30708, WO 97/40024, WO 97/46577, WO 98/06740, WO 97/49404, O 97/11693, WO 97/24135, WO 97/47299, WO 98/01422, WO 98/57932^ O 99/29664, WO 98/06741, WO 99/37668, WO 99/37611, WO 98/37075^ O 99/00371,. WO 99/28297, WO 99/29670, WO 99/40072, WO 99/54313' WO 96/31504, WO 00/01704 and WO 00/08014; and European Patent Applications 648 780, 468 231, 559 046, 641 779, 185 390, 526 877, 542 525, 195 212, 362 002, 364 344, 530 167, 293 881, 686 642, 669 317, 601 459 and 623 596, the disclosures in all 'of which documents are hereby incorporated by reference.

Suitable formulations for use with melagatran, derivatives and prodrugs thereof are described in the literature, for example as described in inter alia international patent applications WO 94/29336, WO 96/14084, WO 96/16671, WO 97/23499, WO 97/39770, WO 97/45138, WO 98/16252, WO 99/27912 and WO 99/27913, the disclosures in which documents are hereby incorporated by reference. Other prodrugs as disclosed, e.g. in WO 00/61577 and WO 00/61609 can be formulated in an analogous way.

Otherwise, the preparation of suitable formulations may be achieved non-inventively by the skilled person using routine techniques .

The amounts of thrombin inhibitor prodrug, or derivative thereof , in the formulation will depend on the severity of- the condition, and on the patient, to be treated, as well as the compound (s) which is/are employed, but may be determined non-inventively by the skilled person.

Suitable doses of thrombin inhibitors prodrugs and derivatives thereof, in the therapeutic and/or prophylactic treatment of mammalian, especially human, patients may be determined routinely by the medical practitioner or other skilled person, and include the respective doses discussed in the prior art documents disclosing thrombin inhibitors that are mentioned hereinbefore, the disclosures in which are hereby incorporated by reference.'

In the case of thrombin inhibitor prodrugs, suitable doses of active compound, prodrugs and derivatives thereof, in the thera_¬ peutic and/or prophylactic treatment of mammalian, especially human, patients include those which give a mean plasma" concentra_¬ tion of up to 5 μmol/L, for example in the range 0.001 to μmol/L over the course of treatment of the relevant condition. Suitable doses may thus be in the range 0. 1 mg once daily to 100 mg three times daily, and/or up to 100 mg infused parenterally over a 24 hour period.

In any event, the physician, or the skilled person, will be able to determine the actual dosage which will be most suitable for an individual patient, which is likely to vary with the condition that is to be treated, as well as the age, weight, sex and response of the particular patient to be treated. The above- mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.

The sequence in which the formulations comprising oral and parenteral thrombin inhibitor prodrug, may be administered (i.e. whether, and at what point, sequential, separate and/or simultaneous administration takes place) may be determined by the physician or skilled person. For example, the sequence may depend upon many factors that will be evident to the skilled person, such as whether, at any time during the course or period of treatment, one or other of the formulations cannot be administered to the patient for practical reasons (e.g. the patient is unconscious and thus unable to take an oral formulation comprising either thrombin inhibitor prodrug₎ .

For example, in the treatment of thrombosis (e.g. DVT) resulting from surgery, such as gastrointestinal, or orthopaedic surgery, it is preferred that the formulation comprising thrombin inhibitor prodrug is administered parenterally within two days (e.g. within 24 hours) of surgery (either prior to or after surgery), and particularly immediately prior to (e.g. within 2 hours), and/or within up to 12 hours after, surgery (e.g. at least one hour after surgery) , and thereafter for up to between 3 and 7 (e.g. between 0 and 2, such as between 1 and 2) days after that surgery, and that the formulation comprising prodrug is administered orally within 7 days following that surgery ⁽preferably once administration of parenteral thrombin inhibitor prodrug has been terminated) for up to e.g. between 11 and 40 days, preferably 9 days, more preferably up to 8 days.

The method described herein may have the advantage that, in the treatment of conditions in which inhibition of thrombin is required or desired, it may be more convenient for the physician and/or patient than, be more efficacious than, be less" toxic than, have a broader range of activity than, be more potent than, produce fewer side effects than, or that it may have_, other useful pharmacological properties over, similar methods known in the prior art for the treatment of such conditions . Suitable thrombin inhibitors of the invention respective their prodrugs are compounds with the general structure:

wherein

R^l: H-, d-Cie-alkyl-, H₃C- [0-CH₂-CH₂]_q (q = 1-4), C₇-C₁₂-bicyclo- alkyl-, Cι₀-tricycloalkyl-, C₃-C₈-cycloalkyl-, C₃-C₈-cycloal- kyl-Cι-C₃-alkyl-, pyranyl-, 4-piperidinyl-, aryl- oder phe- nyl-Cι-C₄-alkyl-, (all these residues besides H may be substi- tuted by up to three identical or different residues of the group Cι-₄-alkyl-, CF₃-, C₁_₄-Alkoxy- , F- or Cl-)or R¹ may be 2-Oxo-l,3-dioxolen-4-yl-methyl- which may be substituted in 5-position by Cι-Cι_S-alkyl or aryl,

R2_: -H, -OH, -0C(0)R³, -C(0)OR⁴,with

R³: -H, -Cι_₈-alkyl, -C₃-C₈-cycloalkyl, -Cι-C₃-alkyl-C₃-C₈-cycloal- kyl, -aryl or -C-^*.-C₃-alkylphenyl, (all these residues besides H may be substituted by up to three identical or different residues of the group C-^-alkyl-, CF₃-, C₁_₄-alkoxy-, F- or C1-),

R⁴: -Cι_₈-alkyl, -CH₂CC1₃, -Cι-C₃-alkyl-C₃-C₈-cycloalkyl,

-C₃-C₈-eyeloalkyl, -phenyl or -Cι-C₃-alkylphenyl, which all may be substituted by up to three identical or different residues of the group Cι_-alkyl-, CF₃-, C_X--₄-alkoxy-, F- or C1-)

Spacer: chemical group which inhibits together with the two end groups thrombin to an experimentally determinable degree in in vivo and/or in in vitro tests, and which possesses a molecular weight of below 2,000, preferably below 1,000,

whereas R¹ and R² are not hydrogen at the same time. Prefered are following prodrugs :

Inogatran prodrugs

Melagatran prodrugs

BIBR 1048 prodrugs

Napsagatran prodrugs

UK 156406 prodrugs

wherein R¹ and R² have the above mentioned meanings:

and compounds with the general formula

_R ^l H-, d-d^β-alkyl-, H₃C- [0-CH₂-CH₂]_g (q = 1-4), C₇-C₁₂-bicyclo- alkyl-, C₁₀-tricycloalkyl-, C₃-C₈-cycloalkyl-, C₃-C₈-cyclo- alkyl-Cι-C₃-alkyl-, pyranyl-, 4-piperidinyl-, aryl- oder phenyl-C₁-C₄-alkyl-, (all these residues besides H may be substituted by up to three identical or different residues of the group C^-alkyl-, CF₃-, Cι,-₄-Alkoxy-, F- or Cl-)or R_l may be 2-Oxo-l, 3-dioxolen-4-yl-methyl- which may be substituted in 5-position by Cι-C₁₆-alkyl or aryl,

R²: -H, -OH, -0C(0)R³, -C (0) OR*, with

R³ _: -H, -d-^g-alkyl, -C₃-C₈-cycloalkyl, -Ci-C-j-alkyl-C-_j-C₈-cyclo- alkyl, -aryl or -Cx-Cs-alkylphenyl, (all these residues- besides H may be substituted by up to three identical or different residues of the group Cι--₄-alkyl-, CF₃-, Cι_₄-alkoxy-, F- or C1-) ,

R⁴ _: -Cι-8-alkyl, -CH₂CC1₃, -C₁-C₃-alkyl-C₃-C₈-cycloalkyl,

-C₃-C₈-cycloalkyl, -phenyl or -Ci-Ca-alkylphenyl, which all may be substituted by up to three identical or different residues of the group C-^-alkyl-, CF₃-, C-^-alkoxy- _F- or C1-)

whereas R^l and R² are not hydrogen at the same time.

Chain ¹ : C_!_₄ alkyl

Gl :

with Ar³.-five or six membered aromatic or heteroaromatic ring, preferable phenyl, pyridyl, naphthyl Alk: Cι_₆ alkyl, G²: bond or C₁-₄ alkyl or C₃_₅ cycloalkyl

Ar¹:

Chain²: Cι_₄ alkyl, in which one carbon atom can be replaced by oxygen, nitrogen or sulfur

Ar²: six membered aromatic or heteroaromatic ring, preferable phenyl, pyridyl , naphthyl and compounds with the general formula II:

R1

where m , n, p, R^l, R², R⁵, A and B are

m 1, 2, 3, 4,

n 0, 1, 2,

p 1, 2, 3,

R^l H-, Ci-Ci_S-alkyl-, H₃C- [0-CH₂-CH₂]_q (g = 1-4), C₇-C₁₂-bicyclo- alkyl-, C₁₀-tricycloalkyl-, C₃-C₈-cycloalkyl-, C₃-C₈-cycloal- kyl-Cι-C₃-alkyl-, pyranyl-, 4-piperidinyl-, aryl- oder phe_¬ nyl-Cι-C₄-alkyl-, (all these residues besides H may be substi- tuted by up to three identical or different residues of the group d-4-alkyl-, CF₃-, C₁_₄-Alkoxy- , F- or Cl-)or Rl may be 2-Oxo-l,3-dioxolen-4-yl-methyl- which may be substituted in 5-position by Cι-Cι₆-alkyl or aryl,

R²: -H, -OH, -0C(0)R³, -C (O) OR* , with

R³: -H, -d-s-alkyl, -C₃-C₈-cycloalkyl, -Cι-C₃-alkyl-C₃-C₈-cycloal- kyl, -aryl or -d-C₆-alkylphenyl, (all these residues besides H may be substituted by up to three identical or different residues of the group d-4-alkyl-, CF₃-, C₁_₄-alkoxy-, F- or C1-),

R⁴: -d_₈-alkyl, -CH₂CC1₃, -d-C₃-alkyl-C₃-C₈-cycloalkyl,

-C₃-C₈-cycloalkyl, -phenyl or -C₁-C₃-alkylphenyl, which all may be substituted by up to three identical or different residues of the group d_₄-alkyl-, CF₃-, d_₄-alkoxy-. F- or C1-) whereas R and R² are not hydrogen at the same t ime.

R⁵ H-,Cι_8^~alkyl-, phenyl- (which may be substituted by up to three identical or different residues of the group Cι-₄-al- kyl-, CF₃-, Ci-4-Alkoxy-, F- or C1-) , C₃_₈-cycloal- kyl-,C₇-C₁₂-bicycloalkyl- or Cι₀-tricycloalkyl-, (C₆H₅)₂CH-

-CH₂-CH₂-, -CH₂-CH2-CH₂-, -CH₂-CH₂-CH₂-CH₂-, -CH₂-CHOH-CH₂- -CH₂-CH=CH-, -CH₂-CH-CH-CH₂-, CH₂-S-CH₂-, -CH₂-CH₂-S-

B

where q, L¹ , L², L³, L⁴, L⁵, X,Y,Z are

0, 1,

L^l, L², L³ and L⁴ are independent of each other and are =N-, -CH= or -CR⁶= with R⁶ C₁_₄-aikyl, C1-, F, Cι-C₄-alkoxy, OH,

L⁵ -CH- or -N-

X 0, S, -NH-, -N-Cχ-₄-alkyl- ,

Y -N= or -CR⁷= (R⁷ = H-, Cι_₄-alkyl-, Cl, CF₃),

Z -N= or -CR⁷= (R⁷ = H-, d_₄-alkyl-, Cl, CF₃₎. More preferred compounds are:

where m , n, p, R¹, R², R⁵, A and B are

m 1, n 0, 1, P 1,

R¹ H-, Cι-C₁₅-alkyl-, C₃-C₈-cycloalkyl-, C₃-C₈-cycloal- kyl-Cχ-C₃-alkyl-,

R²: -H, -OH, -0C(0)R³, -C (0) OR⁴, with

R³: -H, -Cχ-8-alkyl, -C₃-C₈-cycloalkyl,

R⁴: -C^χ_₈-alkyl, -C₁-C₃-alkyl-C₃-C₈-cycloalkyl, -C₃-C₈-cycloalkyl

whereas R^l and R² are not hydrogen at the same time

R⁵ Cι-₈-alkyl- , C₃_₈-cycloalkyl- , C₇-C₁₂-bicycloalkyl- , ( C₅H₅ ) ₂CH- , (C₆H_X1)₂CH-,

A -CH₂-CH₂-, -CH₂-CH₂-CH₂-, -CH₂-CH₂-CH₂-CH₂-, -CH₂-CH=CH- ' B

where L¹, L², X,Y,Z are

L^l and L² are independent of each other and are =N-or -CH=,

X 0, S

-N= or -CH=,

-N= or -CH=

Following compounds are mentioned especially:

1. EtOOC-CH₂- (D) -Chg-Aze-NH-CH₂- [2-am- (OH) ] -phen

2. CH₃OOC-CH₂-(D)-Chg-Pyr-NH-CH2-5-[2-am-(OH) ] -thioph

3. EtOOC-CH₂- (D) -Chg-Pyr-NH-CH₂-5- [2-am- (OH) ] -thioph nPrOOC-CH₂- ⁽D) -Chg-Pyr-NH-CH₂-5- f∑-a - (QH) J -thioph iPrOOC-CH₂- (D) -Chg-Pyr-NH-CH₂-5- [2-am- (OH) ] -thioph

6. nBuOOC-CH₂- (D) -Chg-Pyr-NH-CH₂-5- [2-am- (OH)] -thioph tBuOOC-CH₂- (D) -Chg-Pyr-NH-CH₂-5 [2-am- (OH) ] -thioph

JBuOOC-CH₂- (D) -Chg-Pyr-NH-CH₂-5- [2-am- (OH) ] -thioph

9. nPentOOC-CH₂- (D) -Chg-Pyr-NH-CH₂-5- [2-am- (OH) ] -thioph

10 iPentOOC-CH₂- (D) -Chg-Pyr-NH-CH₂-5- [2-am- (OH) ] -thioph

11. neoPentOOC-CH₂- (D) -Chg-Pyr-NH-CH₂-5- [2-am- (OH) ] -thioph

12 nHexOOC-CH₂- (D) -Chg-Pyr-NH-CH₂-5- r2-am- (OH) ] -thioph

13 cHex-OC-CH₂- (D) -Chg-Pyr-NH-CH₂-5- [2-am- (OH) ] -thioph

14. nHeptOOC-CH₂- (D) -Chg-Pyr-NH-CH₂-5- [2-am- (OH) ] -thioph

15. nOctOOC-CH₂- (D) -Chg-Pyr-NH-CH₂-5- [2-am- (OH) ] -thioph

16. CH₃OOC-CH₂- (D) -Chg-Pyr-NH-CH₂-5- [3-am- (OH) J -thioph

17. EtOOC-CH₂- (D) -Chg-Pyr-NH-CH₂-5- [3-am- (OH) ] -thioph

18 nPrO0C-CH₂- (D) -Chg-Pyr-NH-CH₂-5- [3-am- (OH) ] -thioph

19 iPrOOC-CH₂- (D) -Chg-Pyr-NH-CH₂-5- [3-am- (OH) ] -thioph

20 nBuOOC-CH₂- (D) -Chg-Pyr-NH-CH₂-5- [3-am- (OH) ] -thioph 21 . tBuOOC-CH₂- (D) -Chg-Pyr-NH-CH₂-5- [3-am- (OH) ] -thioph

22 . iBuOOC-CH₂- (D) -Chg-Pyr-NH-CH₂-5 - [ 3 -am- ( OH ) ] -thioph

23 nPentOOC-CH₂- (D) -Chg-Pyr-NH-CH₂-5- [3-am- ( OH) ] -thioph

24 . iPentOOC-CH₂- (D) -Chg-Pyr-NH-CH₂-5- [3-am- ( OH) ] -thioph

25 . neoPentOOC-CH₂- (D) -Chg-Pyr-NH-CH₂-5- [3-am- (OH) ] -thioph

26 , nHexOOC-CH₂- (D) -Chg-Pyr-NH-CH₂-5- [3-am- ( OH) ] -thioph

27 cHex-OC-CH₂- (D) -Chg-Pyr-NH-CH₂-5- [3-am- ( OH) ] -thioph

28 . nHeptOOC-CH- (D) -Chg-Pyr-NH-CH₂-5- [3-am- (OH) ] -thioph

29 nOctOOC-CH₂- (D) -Chg-Pyr-NH-CH₂-5- [3-am- (OH) ] -thioph

30 CH₃.OOC-CH₂-(D) -Cha-Pyr-NH-CH₂-2- [4-am- (OH) ] -thiaz

31 . EtOOC-CH₂-(D) -Cha-Pyr-NH-CH₂-2- [4-am- (OH) ] -thiaz

32 nPrOOC-CH₂-(D) -Cha-Pyr-NH-CH₂-2- [4-am- (OH) ] -thiaz

33 iPrOOC-CH₂- (D) -Cha-Pyr-NH-CH₂-2- [4-am- (OH) ] -thiaz

34 . nBuOOC-CH₂- (D) -Cha-Pyr-NH-CH₂-2- [4-am- (OH) ] -thiaz

35 . tBuOOC-CH₂- (D) -Cha-Pyr-NH-CH₂-2-[4-am- (OH) ] -thiaz

36 . iBuOOC-CH₂- (D) -Cha-Pyr-NH-CH₂-2- [4-am- (OH) ] -thiaz

37 nPentOOC-CH₂- (D) -Cha-Pyr-NH-CH₂-2- [4-am- (OH) ] -thiaz

^•38 . iPentOOC-CH₂- (D) -Cha-Pyr-NH-CH₂-2- [4-am- (OH) ] -thiaz

39 neoPentOOC-CH₂- (D) -Cha-Pyr-NH-CH₂-2- [4-am- (OH) ] -thiaz

40 nHexOOC-CH₂- (D) -Cha-Pyr-NH-CH₂-2- [4-am- (OH) ] -thiaz

41 . cHex-OC-CH₂- (D) -Cha-Pyr-NH-CH₂-2- [4-am- (OH) ] -thiaz

42 nHeptOOC-CH₂- (D) -Cha-Pyr-NH-CH₂-2- [4-am- (OH) ] -thiaz

43 nOctOOC-CH₂- (D) -Cha-Pyr-NH-CH₂-2- [ 4-am- (OH) ] -thiaz

44 . CH₃OOC-CH₂- (D) -Cha-Pyr-NH-3- ( 6-am-OH) -pico

45 EtOOC-CH₂- (D) -Cha-Pyr-NH-3- ( 6-am-OH) -pico

46 nPrOOC-CH₂- (D) -Cha-Pyr-NH-3- ( 6-am-OH) -pico

47 . iPrOOC-CH₂- (D) -Cha-Pyr-NH-3- ( 6-am-OH) -pico 8 nBuOOC-CH₂-(D) -Cha-Pyr-NH-3- ( 6-am-OH) -pico 9 . tBuOOC-CH₂-(D) -Cha-Pyr-NH-3- ( 6-am-OH) -pico 0 , iBuOOC-CH₂- (D) -Cha-Pyr-NH-3- ( 6-am-OH) -pico 1 , nPentOOC-CH₂- (D) -Cha-Pyr-NH-3- ( 6-am-OH) -pico 2 iPentOQC-CH₂- (D) -Cha-Pyr-NH-3- ( 6-am-OH) -pico 3 neoPentOOC-CH₂- (D) -Cha-Pyr-NH-3- ( 6-am-OH) -pico 4 , nHexOOC-CH₂- (D) -Cha-Pyr-NH-3- ( 6-am-OH) -pico 5 cHex-OC-CH₂- (D) -Cha-Pyr-NH-3- ( 6-am-OH) -pico 6 , nHeptOOC-CH₂- (D) -Cha-Pyr-NH-3- ( 6-am-OH) -pico 7 . nOctOOC-CH₂- (D) -Cha-Pyr-NH-3- ( 6-am-OH) -pico Abbreviations

am: amidino

Azt: azetidincarbonic acid Cha: eye1ohexylalanine

Chg: cyclohexylglycine

Pab: p-amidinobenzyl

Phen: phenyl

Pico: picolyl Pro: proline

Pyr: 3 , 4-dehydroproline thiaz : thiazol thiop : thiophen

The above mentioned inhibitors and antagonists can be synthesised according standard procedures. Particulars are given e.g. in WO 9535309, WO 9625426, WO 9806740, WO 9806741, WO 9611914, O 9738981, WO 9809953, WO 00/61577 and WO 00 /61609.

Claims

1. A kit of parts comprising: 5

(a) a parenteral pharmaceutical formulation including a low molecular weight thrombin inhibitor prodrug, or a pharmaceutically acceptable derivative thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or

10 carrier; and

(b) a oral pharmaceutical formulation including a prodrug of a low molecular weight thrombin inhibitor, or a pharmaceutically acceptable derivative of that prodrug,

15 in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.

20 2. A kit of parts as claimed in Claim 1, wherein the prodrug of the thrombin inhibitor of component (a) and (b) are the same.

3. A kit of parts as claimed in Claim 1 or Claim 2, wherein components (a) and (b) are suitable for sequential, separate

25 and/or simultaneous use in the treatment of a condition in which inhibition of thrombin is required or desired.

4. A kit of parts as claimed in Claim 3 , wherein the condition is deep venous thrombosis .

30

5. A kit of parts as claimed in any one of Claims 1 to 4, wherein the thrombin inhibitor prodrug is

^R2

40

45 0480/932/2000 AP/gb 22.12.2000 wherein R^l, R², R³, R⁴ and spacer are:

R^l: H-, Cχ-C₁₆-alkyl-, H₃C- [0-CH₂-CH₂]_g (q =^' 1-4) ,

C₇-Cχ₂-bicycloalkyl-, C₁₀-tricycloalkyl-, C₃-C₈-cyclo- alkyl-, C₃-C₈-cycloalkyl-Cχ-C₃-alkyl-, pyranyl-,

4-piperidinyl-, aryl- oder phenyl-Cχ-C₄-alkyl-, (all these residues besides H may be substituted by up to three identical or different residues of the group Cχ_₄-alkyl-, CF₃-, Cχ-₄-Alkoxy-, F- or Cl-)or l may be 2-Oxo-l, 3-dioxolen-4-yl-methyl- which may be substituted in 5-position by Cχ-Cχ₆~alkyl or aryl,

R²: -H, -OH, -0C(0)R³, -C(0)OR⁴, with

R³: -H, -Cχ_₈-alkyl, -C₃-C₈-cycloalkyl, -Cχ-C₃-alkyl-

C₃-C₈-cycloalkyl, -aryl or -Cχ-C₆-alkylphenyl, (all these residues besides H may be substituted by up to three identical or different residues of the group Cι_₄-alkyl-, CF₃-, Cχ-₄-alkoxy-, F- or C1-) ,

R⁴: -Ci-s-alkyl, -CH₂CC1₃ , -Cχ-C₃-alkyl-C₃-C₈-cycloalkyl,

-C₃-C₈-cycloalkyl, -phenyl or -Cχ-C₃-alkylphenyl, which all may be substituted by up to three identical or different residues of the group Cχ_₄-alkyl-, CF₃-, Cχ_₄-alkoxy-, F- or C1-)

whereas R^l and R² are not hydrogen at the same time.

A kit of parts as claimed in any one of Claims 1 to 4, wherein at least one of the thrombin inhibitor prodrugs is

where m , n, p, R¹, R² , R⁵, A and B are

m 1, 2, 3, 4,

n 0, 1, 2,

p 1, 2, 3,

R^l H-, Cχ-Cχ6-alkyl-, H₃C- [0-CH₂-CH₂] _g (q = 1-4),

C₇-Cχ -bicycloalkyl-, Cχo-tricycloalkyl-, C₃-C₈-cyclo- alkyl-, C₃-C8-cycloalkyl-Cχ-C₃-alkyl-, pyranyl-, 4-piperidinyl-, aryl- oder phenyl-Cχ-C₄-alkyl-, (all these residues besides H may be substituted by up to three identical or different residues of the group Cι-₄-alkyl-, CF₃-, Cχ-₄-Alkoxy-, F- or Cl-)or Rl may be 2-Oxo-l, 3-dioxolen-4-yl-methyl- which may be substituted in 5-position by Cχ-Cχ₆-alkyl or aryl,

R²: -H, -OH, -0C(0)R³, -C(0)0R⁴, with

R³: -H, -Cχ-₈-alkyl, -C₃-C₈-cycloalkyl, -C₁-C₃-alkyl-C₃-C₈- cycloalkyl, -aryl or -Cχ-C₅-alkylphenyl, (all these residues besides H may be substituted by up to three identical or different residues of the group Cχ_₄-alkyl-, CF₃-, Cι_₄-alkoxy-, F- or C1-) , R⁴: -Cχ_₈-alkyl, -CH₂CC1₃, -C₁-C₃-alkyl-C₃-C₈-cycloalkyl,

-C₃-C₈-eyeloalkyl, -phenyl or -C -C₃-alkylphenyl, which all may be substituted by up to three identical or different residues of the group Cχ_₄-alkyl-, CF₃-, Cχ_₄-alkoxy-, F- or C1-)

whereas R^l and R² are not hydrogen at the same time .

R⁵ H-,Cχ_₈-alkyl-, phenyl- (which may be substituted by up to three identical or different residues of the group

Cχ--₄-alkyl-, CF₃-, Cχ_₄-Alkoxy-, F- or C1-) , C₃_₈-cyclo- alkyl-,C₇-Cχ₂-bicycloalkyl- or C₁₀-tricycloalkyl-, (C₆H₅)₂CH-, (C₆Hu)₂CH-.

A -CH₂-CH₂-, -CH₂-CH₂-CH₂-, -CH₂-CH₂-CH₂-CH₂-, -CH₂-CHOH-CH₂- -CH₂-CH=CH-,-CH₂-CH-=CH-CH₂-,CH₂-S-CH₂-, -CH₂-CH₂-S-

B

where q, L^x, L², L³ , L⁴, L⁵, X,Y,Z are

q 0, 1,

L¹, L², L³ and L⁴ are independent of each other and are =N-, .-CH= or -CR⁶= with R⁵ Cχ_ -alkyl, C1-, F, Cχ-C₄-alkoxy, OH,

L⁵ -CH- or -N-

X 0, S, -NH-, -N-Cχ_₄-alkyl-,

Y -N= or -CR⁷= (R⁷ -= H-, Cι_₄-alkyl-, Cl, CF₃),

Z -N= or -CR⁷= (R⁷ = H-, Cχ_₄-alkyl-, Cl, CF₃ ) .

7. A kit of parts as claimed in any one of the Claims 1 to 4, wherein at least one of the prodrugs is of the formula R 0₂C-CH₂-(R)Cgl-Aze-Pab~OH, wherein Rⁱ represents linear or branched Cχ-6 alkyl and the OH group replaces one of the

5 amidino hydrogens in Pab.

8. A kit of parts as claimed in Claim 7, wherein Ri represents methyl , ethyl or propyl .

10 9. A method of making a kit of parts as defined in any one of Claims 1 to 8, which method comprises bringing a component (a) according to any one of Claims 1 to 8 , into association with a component (b) according to any one of Claims 1 to 8, thus rendering the two components suitable for administration

15 in conjunction with each other.

10. A kit of parts comprising:

(1) one of components (a) and (b) as defined in any one of 20 Claims 1 to 8; together with

25.11. A method of treatment of a condition in which inhibition of thrombin is required or desired, which comprises administration of

(a) a parenteral pharmaceutical formulation including a low 30 molecular weight thrombin inhibitor prodrug, or a pharmaceutically acceptable derivative thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier; in conjunction with

5 ^• (b) an oral pharmaceutical formulation including a prodrug of a low molecular weight thrombin inhibitor, or .a pharmaceutically acceptable derivative of that prodrug, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, to a patient suffering from, or 0 susceptible to, such a condition.

12. A method as claimed in Claim 11 in which component (a) is administered prior to commencement of administration of component (b) . 5

13. A method of treatment of a condition in which inhibition of thrombin is required or desired, which comprises administration of a formulation as defined in Claim 10 to a patient suffering from, or susceptible to, such a 5 condition.

14. A method as claimed in any one of Claims 11 to 13, wherein the condition is deep venous thrombosis .

10 15. A method as claimed in Claim 14, wherein the thrombosis results from surgery.

16. A method as claimed in Claim 15, wherein the surgery is gastrointestinal surgery or orthopaedic surgery.

15

17. A method as claimed in Claim 15 or Claim 16, wherein component (a) is administered subcutaneous prior to and/or after surgery and component (b) is administered orally following that surgery. 0

18. The use of a thrombin inhibitor prodrug, or a pharmaceutically acceptable derivative thereof, in the manufacture of a medicament for the treatment or prophylaxis of a condition in which inhibition of thrombin is required 5 or desired, which treatment or prophylaxis comprises administration of:

(a) a parenteral pharmaceutical formulation including a low molecular weight thrombin inhibitor prodrug, or a pharma- 0 ceutically acceptable derivative thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier; in conjunction with

(b) an oral pharmaceutical formulation including a prodrug 5 of a low molecular weight thrombin inhibitor, or a pharmaceutically acceptable derivative of that prodrug, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, to a patient suffering from, or susceptible to, such a condition. 0

5