Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/05—Dipeptides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

• This invention relates to a new use of low molecular weight thrombin inhibitors.
• Cholesterol is involved in the production and maintenance of cell membranes, as well as the production of sex hormones (including progesterone, testosterone, estradiol and cortisol), bile salts and Vitamin D. It is formed primarily in the liver, but also in other parts of the body, such as the small intestine.
• LDLs low-density lipoproteins
• HDLs protective high-density lipoproteins
• VLDLs very low-density lipoproteins
• triglycerides are substances that are found endogenously in the bloodstream, and may be deposited in adipose tissue. Triglycerides contain high- energy fatty acids which provide much of the fuel needed for normal cellular function. However, an excessive amount of triglycerides, or VLDLs, in the bloodstream can result in similar problems to those associated with high cholesterol and LDL levels, as well as obesity and diabetes.
• levels of HDLs, LDLs, total cholesterol and triglycerides are all key indicators in determining the risk of atherosclerosis and associated cardiovascular disorders, such as coronary artery diseases (e.g. angina pectoris, myocardial infarction, etc.), stroke (including cerebro-vascular accident and transient ischaemic attack), peripheral arterial occlusive disease, obesity and diabetes.
• coronary artery diseases e.g. angina pectoris, myocardial infarction, etc.
• stroke including cerebro-vascular accident and transient ischaemic attack
• peripheral arterial occlusive disease e.g. a favourable HDL level.
• Patients with normal cholesterol levels but low HDL levels are also at increased risk.
• Apolipoprotein B which carries lipids in VLDLs and LDLs
• ApoA-I low levels of apolipoprotein A-I
• cholesterol and triglyceride levels There are numerous factors that influence cholesterol and triglyceride levels, including diet, age, weight, gender, genetics, diseases (such as diabetes) and lifestyle.
• cholesterol- and/or triglyceride-lowering medication may be prescribed.
• Drugs that reduce LDL levels in serum can prevent or reduce the build-up of artery blocking plaques, and can reduce the risk of plaque rupture and associated thrombo-embolic complications.
• drugs that can help reduce blood cholesterol levels The most commonly prescribed are the statins, HMG-CoA reductase inhibitors, such as lovastatin, pravastatin, fluvastatin, simvastatin, atorvastatin, pitavastatin and rosuvastatin (e.g. rosuvastatin-calcium). These drugs prevent directly the formation of cholesterol in the liver and thus reduce the risk of cardiovascular disease.
• Other prescribed drug categories include resins
• B vitamin niacin has been reported at high doses to lower triglycerides and LDL levels in addition to increasing HDL levels.
• Fibrates (such as gemf ⁇ brozil and fenof ⁇ brate) are known to lower triglycerides and can increase HDL levels.
• international patent application WO 94/29336 discloses a group of compounds, including HOOC-CH 2 -(R)Cgl-(S)Aze-Pab-H (in which Cgl represents cyclohexylglycyl, Aze represents azetidine-2-carboxyl and Pab-H represents 4-amidinobenzylamino), which is also known as melagatran (see Example 1 of WO 94/29336).
• International Patent Application WO 97/23499 discloses prodrugs of inter alia melagatran.
• a low molecular weight thrombin inhibitor may give rise to reduced levels of lipids, such as total cholesterol, LDLs (i.e. LDL-cholesterol) and triglycerides in the bloodstream, in addition to increasing HDL (i.e. HDL-cholesterol) levels.
• LDLs i.e. LDL-cholesterol
• HDL-cholesterol high HDL
• cholesterol-lowering therapy includes any therapy that results in beneficial modifications of serum profiles of total cholesterol, lipids (including triglycerides), lipoproteins or apolipoproteins, and will thus be understood to encompass the terms “lipid-modifying therapy” and “lipid- (and triglyceride-) lowering therapy", as well as the treatment of hyperlipidaemias (i.e. the elevation of lipids in the bloodstream), including hypercholesterolaemia (high cholesterol levels in the blood; including primary and secondary (combined) hypercholesterolaemia), hyperlipoproteinemia (elevated plasma lipoproteins levels) and/or hypertriglyceridemia (high triglyceride levels in the blood).
• hyperlipidaemias i.e. the elevation of lipids in the bloodstream
• hypercholesterolaemia high cholesterol levels in the blood; including primary and secondary (combined) hypercholesterolaemia
• hyperlipoproteinemia elevated plasma lipoproteins levels
• hypertriglyceridemia high
• the term will thus be understood to include types I, II (Ila and lib), III, IV and/or V hyperlipoproteinaemia, as well as secondary hypertriglyceridaemia and/or familial lecithin cholesterol acyltransferase deficiency, but in principle includes any treatment of a patient which results in a decrease in serum levels of cholesterol, LDLs, VLDLs, triglycerides and/or ApoB, and/or an increase in serum levels of HDLs and/or ApoA-I.
• a cholesterol-lowering therapy method which method comprises the administration of a low molecular weight thrombin inhibitor, or a pharmaceutically acceptable derivative thereof, to a patient in need of such therapy.
• treatment includes the therapeutic and/or prophylactic treatment of patients in need of modifications of cholesterol, lipid (including triglyceride), lipoprotein and/or apolipoprotein profiles.
• “Pharmaceutically acceptable derivatives” of thrombin inhibitors includes salts (e.g. pharmaceutically-acceptable non-toxic organic or inorganic acid addition salts) and solvates. It will be appreciated that the term further includes derivatives that have, or provide for, the same biological function and/or activity as any relevant inhibitor. Thus, for the purposes of this invention, the term also includes prodrugs of thrombin inhibitors.
• 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.
• 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,
• Preferred low molecular weight peptide-based thrombin inhibitors include those described generically and specifically in international patent application WO 98/37075, including the compound that is the subject of Claim 8 of that application as published (l-methyl-2-[N-(4-amidinophenyl)aminomethyl]- benzimidazol-5-yl-carboxylic acid, N-(2-pvridyl)-N-(2-hydroxycarbonyl- ethyl)amide) and prodrugs thereof, such as the compound that is the subject of Claim 10 of that application as published (l-methyl-2-[N-[4-(N-n- hexyloxycarbonylamidino)phenyl]aminomethyl]benzimidazol-5-yl-carboxylic acid, N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide) and those described in international patent application WO 04/014894.
• Preferred low molecular weight peptide-based thrombin inhibitors also include HOOC-CH 2 -(R)Cha-Pic-Nag-H (wherein Cha represents cyclohexylalanine, Pic represents ( - ⁇ ipecolinic acid and Nag represents noragmatine; known as inogatran; see International Patent Application WO 93/11152) and, especially, HOOC-CH 2 -(R)Cgl-(»S)Aze-Pab-H (known as melagatran; see above and International Patent Application WO 94/29336).
• thrombin inhibitors include those of the formula I,
• R a represents -OH or -CH 2 OH
• R 1 represents at least one optional halo substituent
• R 2 represents one or two C 1-3 alkoxy substituents, the alkyl parts of which substituents are themselves substituted with one or more fluoro substituents (i.e. R 2 represents one or two fluoroalkoxy(C ⁇ -3 ) groups);
• Y represents -CH 2 - or -(CH 2 ) 2 -;
• R 3 represents a structural fragment of formula I(i) or I(ii):
• R .4 4 represents H or one or more fluoro substituents; and one or two of X b X 2 , X 3 and X 4 represent -N- and the others represent
• Preferred compounds of formula I include:
• 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)).
• parenteral administration includes all forms of administration other than oral 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 I O 2 C-CH 2 -(R)Cgl-(»S)Aze-Pab- OH (see the list of abbreviations above or in WO 97/23499), wherein R 1 represents C O alkyl or benzyl, such as linear or branched C ⁇ _ 6 alkyl (e.g. C ⁇ _ 4 alkyl, especially methyl, propyl and, particularly, ethyl) and the OH group replaces one of the amidino hydrogens in Pab.
• R 1 represents C O alkyl or benzyl, such as linear or branched C ⁇ _ 6 alkyl (e.g. C ⁇ _ 4 alkyl, especially methyl, propyl and, particularly, ethyl) and the OH group replaces one of the amidino hydrogens in Pab.
• Preferred prodrugs of compounds of formula I that may be mentioned include those of formula la,
• R ,3a represents a structural fragment of formula I(iii) or I(iv): l(i ⁇ ) l(iv)
• R represents OR or C(0)OR ;
• R 6 represents H, C 1-10 alkyl, C 1-3 alkylaryl or C 1-3 alkyloxyaryl (the alkyl parts of which latter two groups are optionally. interrupted by one or more oxygen atoms, and the aryl parts of which latter two groups are optionally substituted by one or more substituents selected from halo, phenyl, methyl or methoxy, which latter three groups are also optionally substituted by one or more halo substituents);
• R represents C ⁇ -10 alkyl (which latter group is optionally interrupted by one or more oxygen atoms), or C 1-3 alkylaryl or C 1 - 3 alkyloxyaryl (the alkyl parts of which latter two groups are optionally interrupted by one or more oxygen atoms, and the aryl parts of which latter two groups are optionally substituted by one or more substituents selected from halo, phenyl, methyl or methoxy, which latter three groups are also optionally substituted by one or more halo substituents); and R a , R 1 , R 2 , Y, R 4 , X 1? X 2 , X 3 and are as hereinbefore defined.
• Preferred prodrugs of compounds of formula I are methoxyamidine prodrugs thereof.
• preferred compounds of formula la include:
• 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 or prodrug in a pharmaceutically acceptable dosage form.
• the compositions may be administered at varying doses.
• Preferred modes of delivery are systemic.
• preferred modes of administration are parenteral, more preferably intravenous, and especially subcutaneous.
• preferred modes of administration are oral.
• thrombin inhibitors In the therapeutic treatment of mammals, and especially humans, thrombin inhibitors, 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 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 96/17860, WO 96/24609, 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 98/579
• 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, WO 99/27913, WO 00/12043 and WO 00/13671, the disclosures in which documents are hereby incorporated by reference. Otherwise, the preparation of suitable formulations may be achieved non-inventively by the skilled person using routine techniques.
• thrombin inhibitor or derivative 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 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 relevant prior art documents that are mentioned hereinbefore, the relevant disclosures in which are hereby incorporated by reference.
• suitable doses of active compound, prodrugs and derivatives thereof, in the therapeutic and/or prophylactic treatment of mammalian, especially human, patients include those which give a mean plasma concentration of up to 5 ⁇ mol/L, for example in the range 0.001 to 5 ⁇ mol/L over the course of treatment of the relevant condition.
• Suitable doses may thus be in the range 0.1 mg once daily to 25 mg three times daily, and/or up to lOO .
• suitable daily doses of compounds in the therapeutic treatment of humans are about 0.001-100 mg/kg body weight at peroral administration and 0.001-50 mg/kg body weight at parenteral administration.
• 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 severity of 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.
• Low molecular weight thrombin inhibitors may be employed in the method described herein by way of co-administration along with other cholesterol- lowering, or lipid-lowering/modifying, drugs/therapies that are mentioned hereinbefore, such as the statins (HMG-CoA reductase inhibitors) and particularly any one of those statins specifically mentioned hereinbefore, in combination therapy.
• statins HMG-CoA reductase inhibitors
• a combination product comprising:
• Such combination products provide for the administration of low molecular weight thrombin inhibitor/derivative in conjunction with the other therapeutic agent, and may thus be presented either as separate formulations, wherein at least one of those formulations comprises thrombin inhibitor/derivative, and at least one comprises the other therapeutic agent, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including thrombin inhibitor/derivative and the other therapeutic agent).
• a pharmaceutical formulation including a low molecular weight thrombin inhibitor, or a pharmaceutically-acceptable derivative thereof; another cholesterol-lowering, or lipid lowering/modifying, therapeutic agent; and a pharmaceutically-acceptable adjuvant, diluent or carrier; and (2) a kit of parts comprising components:
• a pharmaceutical formulation including another cholesterol-lowering, or lipid lowering/modifying, therapeutic agent 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.
• the method described herein may have the advantage that, in cholesterol- lowering therapy, 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 (treatments) known in the prior art for use in such therapy.
• Figure 1 illustrates the difference in mean values (with 95% Confidence Intervals) of total cholesterol levels in serum as between patients receiving ximelagatran (36 mg bid) or warfarin (INR levels between 2 and 3) during the course of a clinical trial over a 21 month period.
• Figure 2 illustrates the difference in mean values (with 95% Confidence Intervals) of levels of total triglycerides in serum as between patients receiving ximelagatran (36 mg bid) or warfarin (INR levels between 2 and
• Figure 3 illustrates the difference in mean values (with 95% Confidence Intervals) of LDL (i.e. LDL-cholesterol) levels in seram as between patients receiving ximelagatran (36 mg bid) or warfarin (INR levels between 2 and 3) during the course of a clinical trial over a 21 month period.
• LDL i.e. LDL-cholesterol
• Figure 4 illustrates the difference in mean values (with 95% Confidence Intervals) of HDL (i.e. HDL-cholesterol) levels in seram as between patients receiving ximelagatran (36 mg bid) or warfarin (INR levels between 2 and 3) during the course of a clinical trial over a 21 month period.
• HDL i.e. HDL-cholesterol
• Ximelagatran is a prodrug of the low molecular weight thrombin inhibitor, melagatran (see Example 1 of international patent application WO 94/29226).
• the clinical trial protocol was similar to that described in international patent application WO 02/36157, with the following major differences: (a) the study objective was to show that the efficacy of ximelagatran is non- inferior to that of dose-adjusted warfarin, aiming for an INR 2.0-3.0 (with INR measurements taken at least every 28 ⁇ 3 days), in the prevention of all strokes (fatal and non-fatal) and systemic embolic events in patients with chronic non- valvular atrial fibrillation;
• the total number of patients in the trial was 3407 (as opposed to 220 in the study described in WO 02/36157).
• the study was a multicentre, multinational, IVRS-randomised, open-label, parallel- group study carried out across approximately 300 centres in approximately 25 countries.
• melagatran and derivatives thereof e.g. prodrugs, such as ximelagtran
• prodrugs such as ximelagtran
• low molecular weight thrombin inhibitors and derivatives/prodrugs thereof in cholesterol-lowering therapy.

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