EP1429760A1 - Nouvelle combinaison - Google Patents

Nouvelle combinaison

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Publication number
EP1429760A1
EP1429760A1 EP02794744A EP02794744A EP1429760A1 EP 1429760 A1 EP1429760 A1 EP 1429760A1 EP 02794744 A EP02794744 A EP 02794744A EP 02794744 A EP02794744 A EP 02794744A EP 1429760 A1 EP1429760 A1 EP 1429760A1
Authority
EP
European Patent Office
Prior art keywords
carbon atoms
chain
straight
substituted
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP02794744A
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German (de)
English (en)
Inventor
Hilmar Bischoff
Johannes-Peter Stasch
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer AG
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Bayer Healthcare AG
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Publication date
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Publication of EP1429760A1 publication Critical patent/EP1429760A1/fr
Withdrawn legal-status Critical Current

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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
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a new combination preparation comprising at least one lipid-lowering agent and at least one compound which is able to stimulate the soluble guanylate cyclase.
  • cGMP cyclic guanosine non-phosphate
  • NO nitrogen monoxide
  • cGMP forms the NO / cGMP system.
  • the guanylate cyclases catalyze the biosynthesis of cGMP from guanosine triposphate (GTP).
  • GTP guanosine triposphate
  • the soluble guanylate cyclases consist of two subunits and most likely contain one heme per heterodimer, which is part of the regulatory center. This is of central importance for the activation mechanism. NO can bind to the iron atom of the heme and thus significantly increase the activity of the enzyme. CO is also able to attack the central iron atom of the heme, whereby the stimulation by CO is significantly less than that by NO.
  • guanylate cyclase plays a decisive role in different physiological processes, in particular in the relaxation and proliferation of smooth muscle cells, platelet aggregation and adhesion and neuronal signal transmission as well as in diseases, which based on a disturbance of the above-mentioned processes.
  • compounds such as organic nitrates have been used for the therapeutic stimulation of soluble guanylate cyclase, the effect of which is based on the release of NO. This is formed by bioconversion and activates the soluble guanylate cyclase by attacks on the iron central atom of the heme.
  • the development of tolerance is one of the decisive disadvantages of this type of treatment.
  • WO 98/16507, WO 98/23619, WO 00/06567, WO 00/06568, WO 00/06569 and WO 00/21954 pyrazolopyridine derivatives are described as stimulators of soluble guanylate cyclase.
  • the present invention further relates to the use of lipid-lowering agents to enhance the action of direct stimulators of soluble guanylate cyclase in the treatment of diseases which can be influenced by stimulating soluble guanylate cyclase.
  • the amount of the direct stimulator of soluble guanylate cyclase required for the treatment of diseases or the amount of lipid-lowering agent required can be reduced and thus the potential for side effects can be reduced.
  • the present invention relates to a combination preparation containing
  • At least one direct stimulator of soluble guanylate cyclase as active ingredient component A At least one direct stimulator of soluble guanylate cyclase as active ingredient component A;
  • combination preparation means that the two active ingredient components A and B can be used either simultaneously or in a chronological manner (i.e. separately from one another).
  • the term “combination preparation” comprises constituents A and B either in a functional unit, ie as a true combination (for example as a mixture, mixture or batch), or else (spatially) separately from one another, ie as a so-called “kit-of- parts ".
  • the present invention thus furthermore also relates to a combination therapy for diseases which can be influenced by stimulation of the soluble guanylate cyclase with a combination preparation which comprises at least one direct stimulator of the soluble guanylate cyclase and at least one lipid-lowering agent.
  • the combination according to the invention can be administered in this way, ie the combination therapy according to the invention can be carried out by administering the active ingredient components A and B simultaneously.
  • the active ingredient components A and B can either be in a functional unit (ie as a true combination such as a mixture, mixture or mixture). quantity) or also (spatially) separated from each other (ie as a so-called "kit” or "kit-of-parts").
  • the active ingredient components A and B are administered separately from one another, in particular in terms of time.
  • lipid-lowering agent can also be continued before and parallel to the administration of the direct stimulator of the soluble guanylate cyclase.
  • the active ingredient components A and B of the combination preparation according to the invention are administered in a chronologically graduated manner, preferably the lipid-lowering agent in advance, i.e. before the direct stimulator of soluble guanylate cyclase was administered.
  • the improvement in the effect of the direct stimulator of soluble guanylate cyclase_ by the simultaneous or graded or parallel administration of lipid-lowering agents can probably be explained by the fact that the lipid-lowering agents disrupt the endothelial function by generating Improve nitrogen monoxide (NO) (Current Opinion in Lipidology, 1997, Vol. 8, pages 362-368 and Circulation 1998, 97, pages 1129-1135). It was shown that direct stimulators of soluble guanylate cyclase in Combination with NO show a synergistic effect (see, for example, WO 00/06569, Fig. 1).
  • the lipid-lowering agent can be selected from the group of:
  • Bile acid absorption inhibitors also called “bile acid anion exchangers” or “bile acid sequestrants”
  • fibric acid and its derivatives are also called “bile acid anion exchangers” or “bile acid sequestrants”.
  • HMG-CoA reductase inhibitors are preferred according to the invention.
  • the abbreviation "HMG-CoA” stands for "3-hydroxymethylglutaryl-coenzyme A”.
  • the substance class of Vastatine - for the sake of simplicity mostly referred to in the literature as "statins" - is preferred.
  • Atorvastatin commercially available under the name Lipitor® from Parke-Davis
  • Cerivastatin commercially available under the name Lipobay® or Baycol® from Bayer
  • 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-
  • AstraZeneca systematic name: (+) - (3R, 5S) -Bis- (7- (4- (4-fluorohenyl) -6-isopropyl-2- (N-memyl-N-memanesulfonylamino) -pyrimidine-5- yl) -3,5-dihydroxy-6 (E) -heptenic acid);
  • atorvastatin cerivastatin, fluvastatin, lovastatin, pravastatin, pitavastatin, simvastatin and rosuvastatin and their respective salts, hydrates, alcoholates, esters and tautomers are very particularly preferred.
  • Cerivastatin and atorvastatin and their respective salts, hydrates, alcoholates, esters and tautomers are very particularly preferred.
  • salts in the sense of the present invention means physiologically acceptable salts of the respective compounds: These can be, for example, 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 mixed salts thereof, but they can also be salts with conventional bases, such as, for example, alkali metal salts (for example sodium or potassium salts) , Alkaline earth metal salts (eg calcium or magnesium salts) or ammonium salts derived from ammonia or organic amines such as, for example, diethylamine, triethylamine, ethy
  • 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 pitavastatin; and the calcium salt of (+) - (3R, 5S) -Bis- (7- (4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methanesulfonylamino) pyrimidine) 5-yl) -3,5-dihydroxy-6 (E) - heptenoic acid ("Rosuvastatin", "ZD 4522” or “S 4522” from Shionogi or AstraZeneca). Further examples of statin salts which can be used according to the invention are the monosodium and the monopotassium salts and the calcium salts of cerivastatin, atorvastatin and pravastatin.
  • EP-A-0 325 130 and in EP-A-0-491 226, the content of which is hereby incorporated by reference.
  • EP-A-0 325 130 relates to substituted pyridines
  • EP-A-0-491 226 relates to substituted pyridyldihydroxyheptenoic acid derivatives and described their salts, including in particular the cerivastatin which is particularly preferred according to the invention (claim 6 of EP-A-0-491 226).
  • statins mentioned in WO-A-99/11263 are also preferred according to the invention.
  • HMG-CoA reductase inhibitors which are described in the publication Bioorganic & Medicinal Chemistry, Vol. 2, pages 437-444 (1997), the disclosure of which is hereby fully incorporated by reference.
  • HMG-CoA reductase inhibitors A further overview of HMG-CoA reductase inhibitors is available in pharmacy in our time, 28th year, No. 3, pages 147-1152 (1999).
  • Preferred bile acid sequestrants according to the invention are cholestyramine (commercially available under the name Qestran® from Bristol-Myers Squibb) and colestipol (commercially available under the name Colestid® from Pharmacia & Upjohn) (bile acid sequestrants). see also Exp. Opin. Invest. Drugs (1998), 7 (5), pages 715-727).
  • Preferred among the aforementioned fibric acid derivatives according to the invention are ciprofibrate (commercially available under the name Modalim® from Sanofi Winthrop), fenofibrate (commercially available under the name Lipantil® from Fournier), gemfibrozil (commercially available under the name Lopid® from Parke-Davis), bezafibrate and clofibrate (see also Exp. Opin. Invest. Drugs (1998),
  • Acipimox (commercially available under the name Olbetam® from Pharmacia & Upjohn) is preferred among the nicotinic acid analogs mentioned above (see also Exp. Opin. Invest. Drugs (1998), 7 (5), pages 715-727). According to the invention, preferred among the aforementioned co3 fatty acids is Maxepa (sold by Seven Seas) (see also Exp. Opin. Invest. Drugs (1998), 7 (5), pages 715-727).
  • the direct stimulator of soluble guanylate cyclase can preferably be selected from those described in published patent applications WO 98/16223, WO 98/16507, WO 98/23619, WO 00/06567, WO 00/06568, WO 00/06569 and WO 00/21954 described compounds. Reference is expressly made to the content of these published documents.
  • R 1 represents a saturated, partially unsaturated or aromatic 5- or 6-membered heterocycle with up to 3 heteroatoms from the series S, N and / or O, which can be bonded via a nitrogen atom, and optionally up to 3 times is identical or differently substituted by
  • Cyano, halogen optionally by straight-chain or branched Alkyl with up to 4 carbon atoms substituted C 6-10 aryl, NO, NHCO-C 1-6 alkyl, N (CO-C 1-6 alkyl) 2 , NHSO 2 -C 1-6 alkyl; a radical of the formula R'NCOR 11 which is bonded to the rest of the molecule via the nitrogen atom, where
  • 8- cycloalkyl ring in which optionally two carbon atoms are connected to one another via an oxygen atom, can be fused; a radical from the group consisting of -OSO 2 -C 1-6 alkyl, -OSO - C 3-8 cycloalkyl, -OSO 2 -phenyl, where the phenyl ring may optionally be substituted; is a radical of the formula -O-CX-NR ⁇ R TM, wherein
  • X represents O or S
  • R ffl and R IV may be the same or different and, for a radical from the group consisting of H, optionally substituted C 1-6 -alkyl, optionally substituted C ⁇ e-alkoxy-Ci-e-alkyl, optionally substituted hydroxy- C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 1-6 alkylcarbonyloxy-C 1-6 alkyl, optionally substituted hydroxycarbonyl C 1-6 alkyl, optionally with a C 1 -6 -Alkylsubstituted phenyl, a saturated five- to seven-membered heterocycle which is optionally bonded to the nitrogen atom via a C 1-6 -alkyl radical or optionally substituted C 3-8 -cycloalkyl, where R 3 and R 4 are not simultaneously H could be; - ⁇ ' ⁇ -
  • R m and ⁇ A together with the nitrogen atom to which they are attached form a five- to seven-membered saturated heterocycle which may optionally contain a further hetero atom from the group N, O, S and / or optionally substituted or fused with a phenyl ring can; a radical of the formula NR v SO 2 R VI , wherein
  • R v and R VI together with the heteroatoms to which they are attached form a five- to seven-membered heterocycle which can be saturated or partially unsaturated, optionally containing one or more further heteroatoms from the group N, O, S and optionally can be substituted; straight-chain or branched alkenyl or alkynyl having up to 10 carbon atoms or straight-chain or branched alkyl having up to 20 carbon atoms, which in turn, if appropriate, by
  • n 1 or 2;
  • a 5- or 6-membered ring which contains two oxygen atoms as ring members and forms a bicyclic unit or a spiro unit with the 3-8-membered ring, and / or Hydroxy, cyano, straight-chain or branched alkyl, acyl or alkoxycarbonyl each having up to 6 carbon atoms, where alkyl, acyl and alkoxycarbonyl, by hydroxy, amino, halogen, carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino, each with up to can be substituted to 5 carbon atoms, a rest of the formula
  • R5 denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms
  • c represents a number 1 or 2
  • R "and R ' are the same or different and are hydrogen or straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or by aryl having 6 to 10 carbon atoms, which in turn can be substituted by halogen , or aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, or cycloalkyl having 3 to 7 carbon atoms, or R ⁇ and R ⁇ together with the nitrogen atom form a 5- to 7-membered saturated heterocycle which can optionally contain a further oxygen atom or a radical -NR °, wherein
  • R8 is hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or a radical of the formula
  • d represents a number 1 or 2
  • R 9 straight-chain or branched alkyl with 1 to 10 carbon atoms, cycloalkyl with 3 to 8 carbon atoms, aryl with 6 to 10 carbon atoms or a saturated or unsaturated 5- to 6-membered heterocycle with up to 3 heteroatoms from the series S, N and / or O means, the ring systems optionally being substituted by halogen or by straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms, a radical of the formula PO (OR 10 ) (OR 11 ), in which
  • R 10 and R 11 are the same or different and are hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms or benzyl,
  • e represents a number 0 or 1
  • R 12 and R 13 are the same or different and are hydrogen, straight-chain or branched alkyl having up to 14 carbon atoms or cycloalkyl having 3 to 14 Are carbon atoms, aryl having 6 to 10 carbon atoms or a saturated or unsaturated 3 to 10-membered ring having up to 5 heteroatoms from the series N, O, S, where the radicals mentioned may be aryl having 6 to 10 carbon atoms, heterocyclyl, Cycloalkyl with 3 to 7 carbon atoms, hydroxy, amino or straight-chain or branched alkoxy, acyl or alkoxycarbonyl, each with up to 6 carbon atoms, can be substituted,
  • R 12 and R 13 including the nitrogen atom to which they are attached, can form a 5- or 6-membered ring with up to 3 heteroatoms from the series N, O, S, which may be substituted up to 3 times can be hydroxyl, alkoxy or alkyl, each with up to 8 carbon atoms,
  • R 12 and R 13 can also mean straight-chain, branched or cyclic acyl having up to 14 carbon atoms, hydroxyalkyl, straight-chain or branched alkoxycarbonyl or acyloxyalkyl each having up to 6 carbon atoms or a radical of the formula —SO 2 R 14 , in which
  • A represents phenyl or a 5- to 6-membered aromatic or saturated heterocycle with up to 3 heteroatoms from the series S, N and / or O, which each optionally up to 3 times through the same or different
  • Mercaptyl hydroxy, formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl, each having up to 6 carbon atoms, nitro, cyano, trifluoromethyl, azido, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms , which in turn can be substituted by hydroxy, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl each having up to 5 carbon atoms, and / or by a group of the formula - (CO) f -NR 15 R 16 , where
  • d represents a number 0 or 1
  • R 15 and R 16 are identical or different and denote hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl, each having up to 5 carbon atoms,
  • R 1 represents a saturated or unsaturated, optionally substituted C 3-8 cycloalkyl, or
  • R m NCOR ⁇ m represents a radical of the formula R m NCOR ⁇ m which is bonded to the rest of the molecule via the nitrogen atom, R 1 and R 111 together with the amide group to which they are bonded forming a five- or six-membered saturated heterocycle, which may optionally contain a further oxygen atom and may have one to five further substituents from the group consisting of oxo, C 1-4 -alkyl or may be fused to a phenyl ring; or represents 4-pyridinyl or 3-pyridinyl; R "represents H, halogen or NH 2 , or
  • R 1 for an optionally substituted cyclopropyl, cyclobutyl, cyclopentenyl, cyclopentyl, cyclohexyl, 1-hydroxycyclopropyl or 1- (fluoromethyl) cyclopropyl radical or for optionally substituted morpholino, piperidine, piperazine, pyrrolidine, 4- Pyridinyl or 3-pyridinyl, triazolyl or
  • R represents H, halogen or NH 2 , or
  • R 1 represents a cyclopropyl radical, a 1-hydroxy 1-cyclopropyl radical, morpholino, 4-pyridinyl or 3-pyridinyl,
  • R represents H or NH 2 , or
  • the compounds of the general formula (I) according to the invention can also be present in the form of their salts.
  • salts with organic or inorganic bases or acids may be mentioned here.
  • Physiologically acceptable salts are preferred in the context of the present invention.
  • Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or
  • Be sulfonic acids For example, particular preference is given to Salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
  • Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention which have a free carboxyl group.
  • Sodium, potassium, magnesium or calcium salts are particularly preferred, and ammonium salts derived from ammonia, or organic amines such as ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylenediamine.
  • the compounds according to the invention can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or do not behave like image and mirror image (diastereomers).
  • the invention relates both to the enantiomers or diastereomers and to their respective mixtures.
  • the racemic forms can be uniformly standardized into the stereoisomerically, for example by chromatographic separation
  • Double bonds present in the compounds according to the invention can be in the eis or trans configuration (Z or E form).
  • Invention includes.
  • the compounds according to the invention can exist in the form of their hydrates, the number of water molecules bound to the molecule depending on the particular compound according to the invention.
  • Alkyl generally represents a straight-chain or branched hydrocarbon radical having 1 to 20 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl and isooctyl, nonyl, decyl, dodeyl, eicosyl.
  • Alkenyl generally represents a straight-chain or branched hydrocarbon radical having 2 to 20 carbon atoms and one or more, preferably with one or two double bonds. Examples include allyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl, isohexenyl, heptenyl, isoheptenyl, octenyl and isooctenyl.
  • Alkynyl generally represents a straight-chain or branched hydrocarbon radical having 2 to 20 carbon atoms and one or more, preferably with one or two triple bonds. Examples include ethynyl, 2-butynyl, 2-pentynyl and 2-hexynyl.
  • Acyl generally represents straight-chain or branched lower alkyl having 1 to 9
  • Carbon atoms which is bonded via a carbonyl group.
  • Examples include: acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl and isobutylcarbonyl.
  • Alkoxy generally represents a straight-chain or branched hydrocarbon radical having 1 to 14 carbon atoms which is bonded via an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, heptoxy, isoheptoxy, octoxy or iso-octoxy.
  • alkoxy and “alkyloxy” are used synonymously.
  • Alkoxyalkyl generally represents an alkyl radical having up to 8 carbon atoms which is substituted by an alkoxy radical having up to 8 carbon atoms.
  • Alkoxycarbonyl can, for example, by the formula
  • Alkyl here generally represents a straight-chain or branched hydrocarbon radical having 1 to 13 carbon atoms.
  • alkoxycarbonyl radicals methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl or isobutoxycarbonyl.
  • Cycloalkyl generally represents a cyclic hydrocarbon radical having 3 to 8 carbon atoms. Cyclopropyl, cyclopentyl and cyclohexyl are preferred.
  • Examples include cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • Cvcloalkoxy stands in the context of the invention for an alkoxy radical, the hydrocarbon radical of which is a cycloalkyl radical.
  • the cycloalkyl radical generally has up to 8 carbon atoms. Examples include: cyclopropyloxy and cyclohexyloxy.
  • cycloalkoxy and “cycloalkyloxy” are used synonymously.
  • Aryl generally represents an aromatic radical having 6 to 10 carbon atoms.
  • Preferred aryl radicals are phenyl and naphthyl.
  • Halogen in the context of the invention represents fluorine, chlorine, bromine and iodine.
  • heterocycle generally represents a saturated, unsaturated or aromatic 3- to 10-membered, for example 5- or 6-membered, heterocycle which can contain up to 3 heteroatoms from the S, N and / or O series and which in the case of a nitrogen atom can also be bound via this.
  • Examples include: oxadiazolyl, thiadiazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, furyl, pyrrolyl, pyrrolidinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuranyl, 1,2,3 triazolyl, thiazolyl, oxazolyl, oxazolyl, oxazolyl, oxazolyl, oxazolyl, oxazolyl , Thiazolyl, furyl, oxazolyl,
  • heteroaryl stands for an aromatic heterocyclic radical.
  • the combination preparation according to the invention can also contain any other active ingredients, so provided that these do not run counter to the indication area and do not impair the action of the direct stimulator of soluble guanylate cyclase and the lipid-lowering agent.
  • organic nitrates or NO donors - that is to say compounds which stimulate the synthesis of cGMP - or compounds which inhibit the breakdown of cyclic guanosine monophosphate (cGMP) can be added to the composition according to the invention.
  • Organic nitrates and NO donors in the context of the invention are generally substances which develop their therapeutic effect via the release of NO or NO species.
  • Sodium nitroprusside, nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, molsidomine and SIN-1 are preferred.
  • the invention also includes combination with compounds that inhibit the degradation of cyclic guanosine monophosphate (cGMP).
  • cGMP cyclic guanosine monophosphate
  • These are in particular inhibitors of phosphodiesterases 1, 2 and 5; Nomenclature according to Beavo and
  • Active ingredient components A and B - are either present as a true mixture together with A and / or B or are also spatially separated from them. They can be administered in parallel or simultaneously or at different times to the active ingredient component (s) A and / or B.
  • compositions according to the invention include, for example:
  • cGMP PDE inhibitors such as, for example, sildenafil (EP-B-0 463 756), IC 351 (WO 95/19978) or vardenafil (WO 99/24433), ⁇ -adrenergic antagonists such as eg yohimbine or Vasomax® from Zonagen; or such sub- punches as mentioned in WO-A-98/52569, the content of which is hereby incorporated by reference; or Prostaglandine-El; or seretonin antagonists;
  • the application is preferably oral, perlingual, sublingual, nasal, transdermal, buccal, intravenous, rectal, inhalative or parenteral.
  • the application is preferably oral, sublingual or nasal. Oral application is particularly preferred.
  • the two active ingredient components A and B - together or spatially separated - can each be converted in a manner known per se into the customary formulations, such as tablets, dragées, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert ones toxic, pharmaceutically suitable carriers or solvents.
  • the therapeutically active components A and B should each be present in a concentration of about 0.5 to 90% by weight of the total mixture, i.e. in amounts sufficient to achieve the dosage range indicated.
  • formulations are made by stretching the two
  • dosages of 0.001 to 50 mg / kg preferably 0.001 mg / kg to 20 mg / kg, in particular 0.001 to 10 mg / kg body weight, particularly preferably 0.001 mg / kg to 5 mg / kg, are used for oral administration , the respective active ingredient component A or B administered to achieve effective and meaningful results.

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Abstract

L'invention concerne une préparation combinée contenant comme constituants actifs sur le plan pharmaceutique, au moins un constituant de principe actif A et au moins un constituant de principe actif B. Le constituant de principe actif A est un stimulant direct de guanylate cyclase et le constituant de principe actif B est un réducteur lipidique. Les deux constituants de principe actif A et B peuvent s'utiliser soit simultanément, soit de manière décalée dans le temps, c.-à-d. sous forme d'unité fonctionnelle ou séparément l'un de l'autre.
EP02794744A 2001-08-17 2002-08-05 Nouvelle combinaison Withdrawn EP1429760A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10140421 2001-08-17
DE10140421A DE10140421A1 (de) 2001-08-17 2001-08-17 Neue Kombination
PCT/EP2002/008701 WO2003015770A1 (fr) 2001-08-17 2002-08-05 Nouvelle combinaison

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EP1429760A1 true EP1429760A1 (fr) 2004-06-23

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US (1) US20040186163A1 (fr)
EP (1) EP1429760A1 (fr)
JP (1) JP2005501846A (fr)
KR (1) KR20040032922A (fr)
CN (1) CN1571669A (fr)
BR (1) BR0211954A (fr)
CA (1) CA2457041A1 (fr)
DE (1) DE10140421A1 (fr)
IL (1) IL160161A0 (fr)
MX (1) MXPA04001470A (fr)
PL (1) PL367864A1 (fr)
WO (1) WO2003015770A1 (fr)

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DE19944226A1 (de) * 1999-09-15 2001-03-29 Aventis Pharma Gmbh Verfahren zum Nachweis von oxidierten Formen der löslichen Guanylatzyklase und Verfahren zum Screening nach Aktivatoren der löslichen Guanylatzyklase mit oxidiertem Hämeisen
DE10351903A1 (de) * 2003-11-06 2005-06-09 Bayer Healthcare Ag Neue Kombination
WO2008124505A2 (fr) * 2007-04-05 2008-10-16 Ironwood Pharmaceuticals,Inc. Modulateurs de la guanylate soluble (scg) pour le traitement de troubles liés aux lipides

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DE19834045A1 (de) * 1998-07-29 2000-02-03 Bayer Ag (4-Amino-5-ethylpyrimidin-2-yl)-1-(2-fluorbenzyl)-1H-pyrazolo[3,4-b]pyridin
MXPA01012125A (es) * 1999-05-27 2002-06-04 Pfizer Prod Inc Profarmacos mutuos de amilodipino y atorvastatina.
HN2000000050A (es) * 1999-05-27 2001-02-02 Pfizer Prod Inc Sal mutua de amlodipino y atorvastatina

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Title
See references of WO03015770A1 *

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US20040186163A1 (en) 2004-09-23
WO2003015770A1 (fr) 2003-02-27
JP2005501846A (ja) 2005-01-20
DE10140421A1 (de) 2003-03-06
MXPA04001470A (es) 2005-02-17
BR0211954A (pt) 2004-09-21
CA2457041A1 (fr) 2003-02-27
CN1571669A (zh) 2005-01-26
PL367864A1 (en) 2005-03-07
KR20040032922A (ko) 2004-04-17
IL160161A0 (en) 2004-07-25

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