WO2004082667A1 - Traitement du diabete insulino-dependant a l'aide d'inhibiteurs de pde5 - Google Patents

Traitement du diabete insulino-dependant a l'aide d'inhibiteurs de pde5 Download PDF

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WO2004082667A1
WO2004082667A1 PCT/IB2004/000696 IB2004000696W WO2004082667A1 WO 2004082667 A1 WO2004082667 A1 WO 2004082667A1 IB 2004000696 W IB2004000696 W IB 2004000696W WO 2004082667 A1 WO2004082667 A1 WO 2004082667A1
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composition
substantial
inhibiting activity
diabetes
kit according
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PCT/IB2004/000696
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English (en)
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Gillian Munro Burgess
Earl Michael Gibbs
Christopher Peter Wayman
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Pfizer Products Inc.
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Priority to JP2006506327A priority Critical patent/JP2006520777A/ja
Priority to BRPI0408500-0A priority patent/BRPI0408500A/pt
Priority to MXPA05009242A priority patent/MXPA05009242A/es
Priority to CA002519357A priority patent/CA2519357A1/fr
Priority to EP04717183A priority patent/EP1605925A1/fr
Publication of WO2004082667A1 publication Critical patent/WO2004082667A1/fr

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    • 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
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • 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
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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

Definitions

  • the invention described herein relates to the treatment of Type 1 diabetes, in particular to the treatment, including prophylaxis, palliative treatment and cure of Type 1 diabetes with an inhibitor of cGMP phosphodiesterase type 5 (also referred to as cGMP PDE5 or simply PDE5) without substantial PDE2 inhibiting activity.
  • an inhibitor of cGMP phosphodiesterase type 5 also referred to as cGMP PDE5 or simply PDE5
  • Type 1 diabetes is usually diagnosed in children and young adults and is also known as juvenile diabetes, Type 1 diabetes mellitus (DM), insulin-dependent DM (IDDM) and juvenile- onset diabetes and may be known by other names. The term is used interchangeably herein.
  • the peak time for developing diabetes is during puberty, although it can occur at any age.
  • Type 1 diabetes the body does not produce insulin, or does not produce insulin in sufficient amounts. Insulin is necessary for the body to be able to use glucose, the basic fuel for the cells in the body, and insulin takes the glucose from the blood into the cells. The pancreas produces insulin in ⁇ -cells. Sometimes, the ⁇ -cells get destroyed or damaged and cannot produce (sufficient) insulin anymore.
  • DKA diabetic ketoacidosis
  • diabetes Common complications associated with or caused by diabetes include microvascular complications, retinopathy, nephropathy, peripheral and autonomic neuropathies, polyneuropathies, macrovascular complications including atherosclerotic coronary and peripheral arterial disease, foot ulcers and joint problems (e.g.Charcot's joints), increased risk of infection from fungi and bacteria (e.g. peripheral skin infections and oral and vaginal thrush) and renal failure.
  • microvascular complications retinopathy, nephropathy, peripheral and autonomic neuropathies, polyneuropathies, macrovascular complications including atherosclerotic coronary and peripheral arterial disease, foot ulcers and joint problems (e.g.Charcot's joints), increased risk of infection from fungi and bacteria (e.g. peripheral skin infections and oral and vaginal thrush) and renal failure.
  • Type 1 diabetics are typically dependent on insulin (usually by injection) to control their blood sugar levels.
  • JP 08208475 describes a nitrogen mono oxide inhibitor comprising 2-imino piperidine for treating type 1 diabetes, etc.
  • WO02/13798 discloses the use of PDE5 inhibitors in the treatment of type 2 diabetes, the insulin resistance syndrome, insulin resistance, and impaired glucose tolerance.
  • US Patent 6,479,493 discloses a method of treating Type 1 diabetes with a PDE2 inhibitor, optionally in the presence of a PDE5 inhibitor. Also disclosed therein is a use of a combined PDE2/PDE5 inhibitor in said treatment. The disclosure therein is said to be based on the presence of PDE2 and PDE5 in macrophages, the inhibition of which leads to apoptosis if said macrophages.
  • sildenafil PDE5-specific Inhibitor
  • the inhibition of only ...PDE5 alone i.e. without the inhibition of PDE2 is not sufficient to induce apoptosis in U397 cells.
  • a cGMP PDE5 inhibitor without substantial PDE2 inhibiting activity, can be used in the treatment of Type 1 diabetes.
  • the invention is illustrated by the data below, which describes the effect of chronic delivery of sildenafil on blood sugar levels in rats pre-treated with streptozotocin (STZ).
  • STZ is a nitrosamine which is toxic to the pancreatic ⁇ -cells and STZ-treated rats have been used as an experimental model for Type 1 diabetes (see e.g. Ari et al, Clin Sci (Colch) 1999:96:365).
  • Type 1 diabetes rats of 200-250g were injected intra-peritoneally with streptozotocin (60mg/kg) in citrate phosphate buffer, pH4.5 or the equivalent volume of vehicle.
  • streptozotocin 60mg/kg
  • citrate phosphate buffer pH4.5 or the equivalent volume of vehicle.
  • STZ-treated rats were excluded from the study if their serum glucose levels were below below 15- 20nmol/L.
  • Body weight was monitored weekly (diabetic rats fail to gain weight compared to control rats), but care was taken that their weight loss did not exceed 20%.
  • the dosing regimen consisted of sildenafil mesylate ( « SIL ») or the equivalent volume of vehicle ( « VEH » physiological saline) given subcutanously, 20 mg/kg, three times a day targeted to give therapeutically meaningful plasma concentrations.
  • the treatment with sildenafil commenced 48h after administration of STZ and continued for a period of 8 weeks.
  • the Sildenafil-treated rats were divided in two group - normal and STZ-treated. In addition, there were two non-sildenafil groups -again normal and STZ treated. Throughout this period blood samples were taken from the tail vein on a weekly basis. These samples were taken prior to dosing so that trough concentrations could be estimated (ie at 6-8h post dose).
  • Type 1 diabetes The use of a PDE5 inhibitor without substantial PDE2 inhibiting activity, or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of Type 1 diabetes; 2.
  • a method of treating Type 1 diabetes in an individual suffering from Type 1 diabetes which method comprises administering to said individual an effective amount of a PDE5 inhibitor without substantial PDE2 inhibiting activity, or a pharmaceutically acceptable salt thereof;
  • a pharmaceutical composition for use in the treatment of Type 1 diabetes comprising a PDE5 inhibitor without substantial PDE2 inhibiting activity, or a pharmaceutically acceptable salt thereof admixed with a pharmaceutically acceptable carrier, diluent or excipient;
  • a pharmaceutical combination for simultaneous, separate or sequential administration for the treatment of Type 1 diabetes in an individual comprising sildenafil or a pharmaceutically acceptable salt thereof and one or more additional agents active vs Type 1 diabetes or a condition caused by Type 1 diabetes; and
  • a kit for the treatment of Type 1 diabetes comprising a PDE5 inhibitor without substantial PDE2 inhibiting activity, or a pharmaceutically acceptable salt thereof, in an effective amount, optionally one or more pharmaceutically acceptable carrier, excipient or diluent, and one or more of: a. a means for testing for Type 1 diabetes; b. one or more additional agents agents active vs Type 1 diabetes or a condition caused by
  • Type 1 diabetes and/or c. instructions for the treatment of Type 1 diabetes.
  • a PDE5 inhibitor without substantial PDE2 inhibiting activity we mean compounds with PDE5 inhibition IC 50 's of less than 100 nanomolar, more preferably, at less than 50 nanomolar, more preferably still at less than 10 nanomolar, and that the compound has a selectivity for inhibiting PDE5 vs PDE2 of at least 30X as measured by comparing the IC 50 values vs these enzymes, i.e. the IC 50 value vs PDE5 for the compound is at least 30 times smaller than the corresponding IC 50 value vs PDE2.
  • the PDE5/PDE2 selectivity is at least 100X, more preferably at least 1000X.
  • the cGMP PDE5 inhibitors without substantial PDE2 inhibiting activity used in the pharmaceutical combinations according to the present invention are also selective vs other PDEs.
  • they Preferably they have a selectivity of PDE5 over PDE3 of greater than 100 more preferably greater than 300. More preferably the PDE5 has a selectivity over both PDES and PDE4 of greater than 100, more preferably greater than 300.
  • IC50 values for the PDE3 and PDE4 enzyme may be determined using established literature methodology, see S A Ballard ei al, Journal of Urology, 1998, vol. 159, pages 2164-2171 and as detailed herein after.
  • Compounds suitable for use in accordance with the present invention are potent and selective PDE5 inhibitors without substantial PDE2 inhibiting activity.
  • In vitro PDE inhibitory activities against cyclic guanosine 3',5'-monophosphate (cGMP) and cyclic adenosine 3',5'- monophosphate (cAMP) phosphodiesterases can be determined by measurement of their IC 50 values (the concentration of compound required for 50% inhibition of enzyme activity).
  • the required PDE enzymes can be isolated from a variety of sources, including human corpus cavemosum, human and rabbit platelets, human cardiac ventricle, human skeletal muscle and bovine retina, essentially by the method of W.J. Thompson and M.M. Appleman (Biochem., 1971 , 10, 311 ).
  • the cGMP-specific PDE (PDE5) and the cGMP- inhibited cAMP PDE (PDE3) can be obtained from human corpus cavemosum tissue, human platelets or rabbit platelets; the cGMP-stimulated PDE (PDE2) can be obtained from human corpus cavemosum; the calcium/calmodulin (Ca/CAM)-dependent PDE (PDE1 ) from human cardiac ventricle; the cAMP-specific PDE (PDE4) from human skeletal muscle; and the photoreceptor PDE (PDE6) from bovine retina.
  • Phosphodiesterases 7-11 can be generated from full length human recombinant clones transfected into SF9 cells.
  • Assays can be performed either using a modification of the "batch" method of W.J. Thompson et al. (Biochem., 1979, 18, 5228) or using a scintillation proximity assay for the direct detection of AMP/GMP using a modification of the protocol described by Amersham pic under product code TRKQ7090/7100.
  • the final assay volume is made up to 100 ⁇ l with assay buffer [20 mM Tris-HCI pH 7.4, 5 mM MgCI 2 , 1 mg/ml bovine serum albumin]. Reactions are initiated with enzyme, incubated for 30-60 min at 30°C to give ⁇ 30% substrate turnover and terminated with 50 ⁇ l yttrium silicate SPA beads (containing 3 mM of the respective unlabelled cyclic nucleotide for PDEs 9 and 11 ). Plates are re-sealed and shaken for 20 min, after which the beads are allowed to settle for 30 min in the dark and then counted on a TopCount plate reader (Packard, Meriden, CT). Radioactivity units are converted to % activity of an uninhibited control (100%), plotted against inhibitor concentration and inhibitor IC o values obtained using the 'Fit Curve' Microsoft Excel extension.
  • assay buffer 20 mM Tris-HCI pH 7.4, 5 mM MgCI 2 , 1 mg/ml bo
  • IC5 0 values the concentration of compound required for 50% inhibition of enzyme activity.
  • pharmaceutically may include “veterinary” and “veterinarily”, respectively.
  • treatment includes one or more of curative, palliative and prophylactic treatment.
  • treatment includes at least curative treatment and/or palliative treatment.
  • the treatment provides a chronic level of PDE5 inhibition without substantial PDE2 inhibition in the treatment of Type 1 diabetes.
  • Chronic levels of PDES inhibition may be provided by daily multidosing of PDES inhibitors, by use of a PDE5 inhibitor which has a long half-life, by use of a formulation or device which provides for sustained or controlled or pulsatile release of the PDES inhibitor, or other means well-known in the art.
  • Suitable PDES inhibitors without substantial PDE2 inhibiting activity for the use according to the present invention may be any that satisfy the definition given above, and may include: the pyrazolo [4,3-d]pyrimidin-7-ones disclosed in EP-A-0463756; the pyrazolo [4,3- d]pyrimidin-7-ones disclosed in EP-A-0526004; the pyrazolo [4,3-d]pyrimidin-7-ones disclosed in published international patent application WO 93/06104; the isomeric pyrazolo [3,4-d]pyrimidin-4-ones disclosed in published international patent application WO 93/07149; the quinazolin-4-ones disclosed in published international patent application WO 93/12095; the pyrido [3,2-d]pyrimidin-4-ones disclosed in published international patent application WO 94/05661 ; the purin-6-ones disclosed in published international patent application WO 94/00453; the pyrazolo [4,3-
  • PDE5 inhibitors PDE5 inhibitors
  • (+)-3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxy-1 (R)-methylethoxy)pyridin-3- yl]-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one also known as 3-ethyl-5- ⁇ 5-[4- ethylpiperazin-1-ylsulphonyl]-2-([(1 R)-2-methoxy-1-methylethyl]oxy)pyridin-3-yl ⁇ -2-methyl- 2,6-dihydro-7H-pyrazolo[4,3-d] pyrimidin-7-one (see WO99/54333); 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6- dihydr
  • Still other type cGMP PDE5 inhibitors which may be useful in conjunction with the present invention include:4-bromo-5-(pyridylmethylamino)-6-[3-(4-chlorophenyl)-propoxy]-
  • the PDES inhibitor without substantial PDE2 inhibiting activity is selected from sildenafil, tadalafii, vardenafil, DA-8159 and 5-[2-ethoxy-5-(4-ethylpiperazin-1- ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin- 7-one.
  • the PDE5 inhibitor without substantial PDE2 inhibiting activity is sildenafil.
  • compositions for use in the invention may additionally comprise one or more additional active agents.
  • present invention further comprises the use of combinations of the PDE5 inhibitor without substantial PDE2 inhibiting activity for the treatment of Type 1 diabetes with one or more additional active agents (for simultaneous, separate or sequential administration) effective in the treatment of Type 1 diabetes and/or its downstream consequences/conditions.
  • references herein to the use of PDE5 inhibitors without substantial PDE2 inhibiting activity for use according to the present invention also includes combination of PDE5 inhibitors without substantial PDE2 inhibiting activity with other additional (active) agents.
  • Such additional agent may be another Type 1 diabetes drug as detailed herein, such as for example clomid.
  • the method of the present invention may also be used in conjunction with hormone therapy.
  • the present invention may be used in conjunction with one or more hormones or steroids - such as those mentioned in WO-A-99/21562.
  • Additional active agents which may be suitable for use in the present invention include the following:
  • NO-donor (NO-agonist) compounds or NO synthase substrate such as organic nitrates, such as mono- di or tri-nitrates or organic nitrate esters including glyceryl trinitrate (also known as nitroglycerin), isosorbide 5-mononitrate, isosorbide dinitrate, pentaerythritol tetranitrate, erythrityl tetranitrate, sodium nitroprusside (SNP), 3- morpholinosydnonimine molsidomine, S-nitroso- N-acetyl penicilliamine (SNAP) S-nitroso-N- glutathione (SNO-GLU), N-hydroxy - L-arginine, amylnitrate, linsidomine, linsidomine chlorohydrate, (SIN-1) S-nitroso - N-cysteine, diazenium diolates,
  • potassium channel openers or modulators include nicorandil, cromokalim, levcromakalim, lemakalim, pinacidii, cliazoxide, minoxidil, charybdotoxin, glyburide, 4-amini pyridine, BaCI 2 ; and/or
  • angiotensin receptor antagonists such as losartan
  • one or more antiplatelet and antithrombotic agents e.g. tPA, uPA, warfarin, hirudin and other thrombin inhibitors, heparin, thromboplastin activating factor inhibitors; and/or
  • one or more insulin sensitising agents such as Rezulin, Avandia or Actos and hypoglycaemic agents such as, but not limited to, glipizide (sulfonylureas), metformin, or acarbose; and/or
  • one or more estrogen receptor modulators and/or estrogen agonists and/or estrogen antagonists preferably raloxifene or lasofoxifene, (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl- ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-o! and pharmaceutically acceptable salts thereof (compound A below) the preparation of which is detailed in WO 96/21656.
  • NEP inhibitor one or more of an NEP inhibitor, preferably wherein said NEP is EC 3.4.24.11 and more preferably wherein said NEP inhibitor is a selective inhibitor for EC 3.4.24.11 , which has an IC 50 vs NEP of less than 100nM (e.g. ompatrilat, sampatrilat) - suitable NEP inhibitor compounds are described in EP-A-1097719; and/or (xi) one or more compounds which inhibit angiotensin-converting enzyme such as enalapril, and one or more combined inhibitors of angiotensin-converting enzyme and neutral endopeptidase such as omapatrilat; and/or
  • AMP-activated protein kinase such as 5-amino-4- imidazolecarboxamide ribonucleoside
  • weight loss agents such as sibutramine or orlistat; and/or (xviii) one or more dipeptidyl peptidase IV inhibitors such as NVP DPP728 or P32/98; and/or
  • glucagon antagonists such as NNC25-2504; and/or (xx) one or more agents that inhibit PTP1 B such as PTP112; and/or (xxi) one or more agents that reduce PTP1 B levels using antisense technology; and/or (xxii) one or more glycogen synthase kinase-3 inhibitors such as Chir98014; and/or
  • WO00/59510 and/or (xxviii) one or more aldose reductase inhibitors such as 6-(5-chloro-3-methyl-benzofuran- 2-sulphonyl)-2H-pyridazin-3-one (see e.g. WO02/079198), zopolrestat, zenarestat, or fidarestat; and/or (xxix) soluble guanyl cyclase (sGC) activators such as BAY 41-8543 and BAY 41-2272.
  • aldose reductase inhibitors such as 6-(5-chloro-3-methyl-benzofuran- 2-sulphonyl)-2H-pyridazin-3-one (see e.g. WO02/079198), zopolrestat, zenarestat, or fidarestat
  • sGC soluble guanyl cyclase activators
  • the antilipemic agents mentioned in (iv) above can be selected from the group consisting of:
  • o HMG-CoA-reductase inhibitors o squalene synthase inhibitors, o bile acid absorption inhibitors (also referred to as “bile acid anion exchangers" or bile acid sequestrants),
  • HMG-CoA denotes "3- hyd roxy methylg I uta ryl-coenzyme A” .
  • statins preference according to the invention is given, in particular, to the substance class of the vastatins - which, for the sake of simplicity, are in most cases referred to in the literature simply as "statins".
  • statins preference according to the invention is given to the substance class of the vastatins - which, for the sake of simplicity, are in most cases referred to in the literature simply as "statins".
  • atorvastatin commercially available under the name Lipitor ® from Parke- Davis/Pfizer
  • fluvastatin commercially available under the name Lescol ® from Novartis
  • lovastatin commercially available under the name Mevacor ® from Merck
  • pravastatin commercially available under the name Lipostat ® from Bristol- Myers squibb
  • simvastatin commercially available under the name Zocor ® from Merck
  • itavastatin also called “nisvastatin”; NK-104; systematic name: [S-[R*,S*- (E)]]-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]- 3,5-dihydroxy-6- heptenoic acid); o dalvastatin;
  • cerivastatin and atorvastatin and their respective salts, hydrates, alkoxides, esters and tautomers.
  • statins very particular preference is given to cerivastatin and atorvastatin and their respective salts, hydrates, alkoxides, esters and tautomers.
  • salts refers in eac case to physiologically acceptable salts of the compounds in question: these can, for example, be salts with mineral acids, carboxylic acids or sulfonic acids, in particular with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid, or else mixed salts thereof.
  • the salts ca also be salts with customary bases, such as, for example, alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example calcium or magnesium salts) or ammonium salts, derived from ammonia or organic amines, such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1- ephenamine or methyl-piperidine, and also mixed salts thereof.
  • customary bases such as, for example, alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example calcium or magnesium salts) or ammonium salts, derived from ammonia or organic amines, such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-
  • statin salts which can be used according to the invention are fluindostatin (the monosodium salt of fluvastatin); the monopotassium salt and the calcium salt of itavastatin; and the calcium salt of (+)-(3R,5S)-bis-(7-(4-(4- fluorophenyl)-6-isopropyl-2-(N-methyl-N-methane-sulfonylamino)-pyrimidin-5-yl)-3,5- dihydroxy-6(E)-hept ⁇ noic acid ("ZD 4522” or "S 4522” from Shionogi and AstraZeneca, respectively).
  • statin salts which can be used according to the invention are the monosodium and the monopotassium salts and also the calcium salts of cerivastatin, atorvastatin and pravastatin.
  • HMG-CoA-reductase inhibitors are described in EP-A-0 325 130 and EP-A-0-491 226, both in the name of Bayer AG, the content of which is hereby included by way of reference.
  • EP-A-0 325 130 provides substituted pyridines
  • EP-A-0-491 226 describes substituted pyridyldihydroxyheptenoic acid derivatives and their salts, and among these in particular cerivastatin, which is particularly preferred according to the invention (claim 6 of EP-A-0-491 226).
  • Preference according to the invention is also given to the statins mentioned in WO- A-99/11263, the disclosure of which is included by way of reference.
  • cholestyramine commercially available under the name Questran ® from Bristol-Myers Squibb
  • colestipol commercially available under the name Colestid ® from Pharmacia & Upjohn
  • fibric acid derivatives mentioned above preference according to the invention is given to ciprofibrate (commercially available under the name Modalim from Sanofi Winthorp), fenofibrate (commercially available under the name Lipantil 1® from Fournier), gemfibrozil (commercially available under the name Lopid ® from Parke-Davis), bezafibrate and chlofibrate (see also Exp. Opin. Invest. Drugs (1998), 7(5), pages 715-727.
  • acipimox commercially available under the name Olbetam ® from Pharmacia & Upjohn
  • Olbetam ® from Pharmacia & Upjohn
  • Preferred specific combinations for use in accordance with the invention comprise: any PDE5 inhibitor without substantial PDE2 inhibiting activity selected from sildenafil, tadalafil, vardenafil, DA-8159 and 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]- 3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one and their respective salts, solvates,
  • insulin with any one of : insulin, raloxifene, lasofoxifene, (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl- ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol, atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, itavastatin, simvastatin and (+)-(3R,5S)-bis-(7-(4-(4- fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)-pyrimidin-5-yl)-3,5- dihydroxy-6(E)-heptenoic acid and their respective salts, hydrates, alkoxides, esters and tautomers.
  • atorvastatin cerivastatin, fluvastatin, lovastatin,
  • agents of the invention are referred to as "agents of the invention”. If a combination of active agents is administered, they can be delivered to the treatment subject in the same formulation and in the same administration method, or they can be delivered in separate formulations and by the same or different methods.
  • Pharmaceutically acceptable salts of the agents of the invention include the acid addition and base salts (including disalts) thereof.
  • Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate, camsylate, citrate, edisylate, esylate, fumarate, gluceptate, gluconate, glucuronate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, hydrogen phosphate, isethionate, D- and L- lactate, malate, maleate, malonate, mesylate, methylsulphate, 2-napsylate, nicotinate, nitrate, orotate, palmoate, phosphate, saccharate, stearate, succinate sulphate, D- and L- tartrate, and tosylate salts.
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
  • suitable salts see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Wiley-VCH, Weinheim, Germany (2002).
  • a pharmaceutically acceptable salt of an agent of the invention may be readily prepared by mixing together solutions of the agent and the desired acid or base, as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • solvates for use in accordance with the invention include hydrates and solvates wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 O, de-acetone, d 6 -DMSO.
  • references to agents of the invention include references to salts thereof and to solvates and clathrates of agents of the invention and salts thereof.
  • the invention includes the use of all polymorphs of the agents of the invention as hereinbefore defined.
  • prodrugs of the agents of the invention.
  • certain derivatives of agents of the invention which have little or no pharmacological activity themselves can, when metabolised upon administration into or onto the body, give rise to agents of the invention having the desired activity.
  • Such derivatives are referred to as "prodrugs”.
  • Prodrugs for use in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the agents of the invention with certain moieties known to those skilled in the art as "pro-moieties” as described, for example, in “Design of Prodrugs” by H Bundgaard (Elsevier, 1985).
  • agents of the invention may themselves act as prodrugs of other agents of the invention.
  • Agents of the invention containing one or more asymmetric carbon atoms can exist as two or more optical isomers. Where an agent of the invention contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible, and where the compound contains, for example, a keto or oxime group, tautomeric isomerism ('tautomerism') may occur. It follows that a single compound may exhibit more than one type of isomerism.
  • Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, fractional crystallisation and chromatography.
  • Conventional techniques for the preparation/isolation of individual stereoisomers include the conversion of a suitable optically pure precursor, resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral HPLC, or fractional crystallisation of diastereoisomeric salts formed by reaction of the racemate with a suitable optically active acid or base, for example, tartaric acid.
  • the present invention also includes the use of all pharmaceutically acceptable isotopic variations of agents of the invention.
  • An isotopic variation is defined as one in which at least one atom is replaced by an atom having the same atomic number, but an atomic mass different from the atomic mass usually found in nature.
  • isotopes suitable for inclusion in the agents of the invention include isotopes of hydrogen, such as H and 3 H, carbon, such as 13 C and 14 C, nitrogen, such as 15 N, oxygen, such as 17 O and 18 O, phosphorus, such as 32 P, sulphur, such as 35 S, fluorine, such as 18 F, and chlorine, such as 36 CI.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Isotopic variations of the agents of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in prior art mentioned herein using appropriate isotopic variations of suitable reagents.
  • the agents of the invention may be freeze-dried, spray-dried, or evaporatively dried to provide a solid plug, powder, or film of crystalline or amorphous material. Microwave or radio frequency drying may be used for this purpose.
  • the agents of the invention may be administered alone or in combination with other drugs and will generally be administered as a formulation in association with one or more pharmaceutically acceptable excipients.
  • excipient is used herein to describe any ingredient other than the compound of the invention. The choice of excipient will to a large extent depend on the particular mode of administration.
  • the agents of the invention may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, films (including muco-adhesive), ovules, sprays and liquid formulations.
  • Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet. The agents of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, V ⁇ _ (6), 981-986 by Liang and Chen (2001).
  • composition of a typical tablet in accordance with the invention may comprise:
  • a typical tablet may be prepared using standard processes known to a formulation chemist, for example, by direct compression, granulation (dry, wet, or melt), melt congealing, or extrusion.
  • the tablet formulation may comprise one or more layers and may be coated or uncoated.
  • excipients suitable for oral administration include carriers, for example, cellulose, calcium carbonate, dibasic calcium phosphate, mannitol and sodium citrate, granulation binders, for example, polyvinylpyrrolidine, hydroxypropylcellulose, hydroxypropylmethylcellulose and gelatin, disinteg rants, for example, sodium starch glycolate and silicates, lubricating agents, for example, magnesium stearate and stearic acid, wetting agents, for example, sodium lauryl sulphate, preservatives, anti-oxidants, flavours and colourants.
  • carriers for example, cellulose, calcium carbonate, dibasic calcium phosphate, mannitol and sodium citrate
  • granulation binders for example, polyvinylpyrrolidine, hydroxypropylcellulose, hydroxypropylmethylcellulose and gelatin
  • disinteg rants for example, sodium starch glycolate and silicates
  • lubricating agents for example, magnesium stearate and stearic
  • Solid formulations for oral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled dual-, targeted and programmed release. Details of suitable modified release technologies such as high energy dispersions, osmotic and coated particles are to be found in Verma et al, Pharmaceutical Technology On-line, 25(2), 1-14 (2001). Other modified release formulations are described in US Patent No. 6,106,864.
  • the agents of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ.
  • Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous.
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen- free water.
  • excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9)
  • a suitable vehicle such as sterile, pyrogen- free water.
  • parenteral formulations under sterile conditions may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • solubility of agents of the invention used in the preparation of parenteral solutions may be increased by suitable processing, for example, preparation of an appropriate salt, the use of high energy spray-dried dispersions (see WO 01/47495) and/or by the use of appropriate formulation techniques, such as the use of solubility-enhancing agents.
  • Formulations for parenteral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled dual-, targeted and programmed release.
  • the agents of the invention may also be administered topically to the skin or mucosa, either dermally or transdermally.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions.
  • Liposomes may also be used.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin and propylene glycol.
  • Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999).
  • Other means of topical administration include delivery by iontophoresis, electroporation, phonophoresis, sonophoresis and needle-free or microneedle injection.
  • Formulations for topical administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled dual-, targeted and programmed release.
  • compounds of the invention may be formulated in a more solid form for administration as an implanted depot providing long-term release of the active compound.
  • the agents of the invention may also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as dichlorofluoromethane.
  • a dry powder either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids
  • atomiser preferably an atomiser using electrohydrodynamics to produce a fine mist
  • nebuliser with or without the use of a suitable propellant, such as dichlorofluoromethane.
  • the pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the active compound comprising, for example, ethanol (optionally, aqueous ethanol) or a suitable alternative agent for dispersing, solubilising, or extending release of the active, the propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate or an oligolactic acid.
  • the active compound comprising, for example, ethanol (optionally, aqueous ethanol) or a suitable alternative agent for dispersing, solubilising, or extending release of the active, the propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate or an oligolactic acid.
  • the drug product Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
  • comminuting method such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
  • a suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1 ⁇ g to 10mg of the compound of the invention per actuation and the actuation volume may vary from 1 ⁇ l to 100 ⁇ l.
  • a typical formulation may comprise an agent of the invention, propylene glycol, sterile water, ethanol and sodium chloride.
  • Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
  • Capsules, blisters and cartridges made, for example, from gelatin or HPMC) for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as /-leucine, mannitol, or magnesium stearate.
  • the dosage unit is determined by means of a valve which delivers a metered amount.
  • Units in accordance with the invention are typically arranged to administer a metered dose or "puff containing the agent of the invention.
  • the overall daily dose will typically be administered in a single dose or, more usually, as divided doses throughout the day.
  • Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled dual-, targeted and programmed release.
  • the agents of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema.
  • Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
  • Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled dual-, targeted and programmed release.
  • the agents of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline.
  • Other formulations suitable for ocular and andial administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes.
  • a polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride.
  • a preservative such as benzalkonium chloride.
  • Such formulations may also be delivered by iontophoresis.
  • Formulations for ocular/andial administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled dual-, targeted, or programmed release.
  • agents of the invention may be combined with soluble macromolecular entities such as cyclodextrin or polyethylene glycol-containing polymers to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability.
  • soluble macromolecular entities such as cyclodextrin or polyethylene glycol-containing polymers
  • Drug-cyclodextrin complexes are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used.
  • the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in International Patent Applications Nos. WO 91/11172, WO 94/02518 and WO 98/55148.
  • the total daily dose of the agents of the invention is typically in the range 1mg to 100mg depending, of course, on the mode of administration.
  • oral administration may require a total daily dose of from 1mg to 100mg, while an intravenous dose may require a different amount.
  • the total daily dose may be administered in single or divided doses.
  • These dosages are based on an average human subject having a weight of about 65 to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.
  • Formulation 1 A tablet is prepared using the following ingredients:
  • the components are blended and compressed to form tablets each weighing 665mg.
  • Formulation 2 An intravenous formulation may be prepared as follows:
  • Formulation 3 A tablet is prepared using the following ingredients :
  • Sildenafil citrate 50 mg is blended with cellulose (microcrystalline), silicon dioxide, stearic acid (fumed) and the mixture is compressed to form tablets.

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Abstract

Utilisation d'un inhibiteur de PDE5 n'ayant sensiblement aucune activité inhibitrice de PDE2, ou de son sel pharmaceutiquement acceptable, dans la préparation d'un médicament destiné au traitement du diabète insulino-dépendant. Procédé de traitement du diabète insulino-dépendant chez un sujet souffrant de diabète insulino-dépendant, ce procédé consistant à administrer audit sujet une quantité efficace d'un inhibiteur de PDE5 n'ayant sensiblement aucune activité inhibitrice de PDE2, ou de son sel pharmaceutiquement acceptable.
PCT/IB2004/000696 2003-03-17 2004-03-04 Traitement du diabete insulino-dependant a l'aide d'inhibiteurs de pde5 WO2004082667A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
JP2006506327A JP2006520777A (ja) 2003-03-17 2004-03-04 Ｐｄｅ５阻害剤を用いる１型糖尿病の治療
BRPI0408500-0A BRPI0408500A (pt) 2003-03-17 2004-03-04 tratamento do diabetes do tipo 1 com inibidores de pde5
MXPA05009242A MXPA05009242A (es) 2003-03-17 2004-03-04 Tratamiento de la diabetes tipo 1 con los inhibidores de la pde5.
CA002519357A CA2519357A1 (fr) 2003-03-17 2004-03-04 Traitement du diabete insulino-dependant a l'aide d'inhibiteurs de pde5
EP04717183A EP1605925A1 (fr) 2003-03-17 2004-03-04 Traitement du diabete insulino-dependant a l'aide d'inhibiteurs de pde5

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EP2213289A1 (fr) 2006-09-07 2010-08-04 Nycomed GmbH Combinaison pour le Traitement de mellitus de diabète
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EP1737465A4 (fr) * 2004-04-19 2007-10-03 Univ Loma Linda Composition et procede de reduction de dommages ischemiques renaux
WO2007010337A2 (fr) * 2005-07-15 2007-01-25 Proxomed Medizintechnik Gmbh Utilisation d'inhibiteurs de phosphodiesterase type 5 pour la prevention et le traitement de maladies ou de troubles, et systemes d'administration associes
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JP2009515816A (ja) * 2005-08-04 2009-04-16 トランスフオーム・フアーマシユーチカルズ・インコーポレーテツド フェノフィブレートおよびスタチンを含んでなる新規調合物、ならびに関連する処置方法
EP2213289A1 (fr) 2006-09-07 2010-08-04 Nycomed GmbH Combinaison pour le Traitement de mellitus de diabète
US9670138B2 (en) 2007-06-04 2017-06-06 Ben-Gurion University Of The Negev Research And Development Authority Telomerase activating compounds and methods of use thereof
US10214481B2 (en) 2007-06-04 2019-02-26 Ben-Gurion University Of The Negev Research And Development Aithority Telomerase activating compounds and methods of use thereof
US9663448B2 (en) 2007-06-04 2017-05-30 Ben-Gurion University Of The Negev Research And Development Authority Tri-aryl compounds and compositions comprising the same
CN108452311A (zh) * 2012-11-13 2018-08-28 纽斯尔特科学公司 用于增强能量代谢的组合物和方法
WO2014105655A1 (fr) 2012-12-24 2014-07-03 Neurogastrx, Inc. Méthodes de traitement d'affections du tractus digestif
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US9132134B2 (en) 2012-12-24 2015-09-15 Neurogastrx, Inc. Methods for treating GI tract disorders
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WO2015068156A1 (fr) 2013-11-05 2015-05-14 Ben-Gurion University Of The Negev Research And Development Authority Composés pour le traitement du diabète et des complications pathologiques qui en résultent
US10111880B2 (en) 2013-11-05 2018-10-30 Ben-Gurion University Of The Negev Research And Development Authority Compounds for the treatment of diabetes and disease complications arising from same
US9844554B2 (en) 2014-06-24 2017-12-19 Neurogastrx, Inc. Prodrugs of metopimazine
CN111491630A (zh) * 2017-12-19 2020-08-04 马莱西尔研究与技术有限责任公司 糖尿病足溃疡的治疗方法
US10836757B1 (en) 2020-04-02 2020-11-17 Neurogastrx, Inc. Polymorphic forms of metopimazine
US11390620B2 (en) 2020-04-02 2022-07-19 Neurogastrx, Inc. Polymorphic forms of metopimazine
US11834445B2 (en) 2020-04-02 2023-12-05 Neurogastrx, Inc. Polymorphic forms of metopimazine

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CA2519357A1 (fr) 2004-09-30
JP2006520777A (ja) 2006-09-14
EP1605925A1 (fr) 2005-12-21
TW200503666A (en) 2005-02-01
MXPA05009242A (es) 2006-04-18
BRPI0408500A (pt) 2006-03-07

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