EP1335723A1 - Verwendung von stimulatoren der löslichen guanylatcyclase zur behandlung von osteoporose - Google Patents
Verwendung von stimulatoren der löslichen guanylatcyclase zur behandlung von osteoporoseInfo
- Publication number
- EP1335723A1 EP1335723A1 EP01992572A EP01992572A EP1335723A1 EP 1335723 A1 EP1335723 A1 EP 1335723A1 EP 01992572 A EP01992572 A EP 01992572A EP 01992572 A EP01992572 A EP 01992572A EP 1335723 A1 EP1335723 A1 EP 1335723A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- osteoporosis
- compounds
- salts
- medicament
- treatment
- 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.)
- Withdrawn
Links
Classifications
-
- 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
- A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
-
- 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
- A61K31/395—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
- 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
Definitions
- the present invention relates to the use of stimulators of the soluble
- Guanylate cyclase for the manufacture of a medicament for the treatment of osteoporosis.
- Osteoporosis is a systemic disease of the skeleton, which is characterized by bone loss, i.e. characterized by a reduction in bone mass. This leads to a deterioration in the quality of the microarchitecture of the bone tissue and an increased risk of bone fracture.
- osteoporosis A distinction is made between different forms of osteoporosis. About 5% of patients are affected by secondary osteoporosis, which mainly results from endocrine, renal and hepatic diseases (e.g. Cushing's syndrome). Most patients (95%), however, suffer from primary osteoporosis, in which a distinction is made between primary idiopathic osteoporosis, type I osteoporosis and type II osteoporosis. Primarily idiopathic osteoporosis occurs in children or young adults. Type I osteoporosis is also referred to as postmenopausal osteoporosis and type II osteoporosis as senile osteoporosis. These types of osteoporosis occur primarily in old age, with the likelihood of the disease increasing with increasing age.
- fluoride or calcium preparations to stimulate new bone formation
- estrogen, progestogen or calcitonin to inhibit bone resorption
- biphosphonates such as alendronate (to reduce bone loss) or, in old age, anabolics are used to treat osteoporosis. It is believed that osteoporosis is caused by the increased breakdown of bone by osteoclasts. Osteoclasts are cells that specialize in the secretion of HC1 and thereby break down bone. In the normal state, as part of the constant renewal of the bone substance in the body, bone tissue is broken down by the osteoclasts and new bone is formed by the osteoblasts.
- Osteolytic diseases such as osteoporosis are triggered by an imbalance between bone formation and bone loss, ie bone loss by the osteoclasts predominates. Bone degradation is controlled by changes in the number and activity of the osteoclasts (cf. Suda et al., J. Bone Miner. Res. 12 (1997), 869-879).
- cGMP cyclic guanosine monophosphate
- cGMP together with nitrogen monoxide (NO), which is released from the endothelium and transmits hormonal and mechanical signals, cGMP forms the NO / cGMP system.
- the guanylate cyclases catalyze the biosynthesis of cGMP from guanosine triphosphate (GTP).
- GTP guanosine triphosphate
- the previously known representatives of this family can be divided into two groups according to structural features and the type of ligand: the particulate guanylate cyclases that can be stimulated by natriuretic peptides and the soluble guanylate cyclases that can be stimulated by NO.
- 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.
- Hem-free preparations cannot be stimulated by NO.
- 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 phosphodiesterases, ion channels and protein kinases play 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 are based on a disturbance of the above-mentioned processes.
- the present invention relates to the use of compounds of the formula (I)
- R 1 is a saturated or unsaturated, optionally substituted C 3 . 8 - cycloalkyl or a saturated, unsaturated or partially unsaturated 3-8-membered heterocycle which contains 1-4 heteroatoms from the series N, O, S, SO, SO 2 and can optionally be substituted;
- R 2 represents H or NH 2 ; and salts, isomers and hydrates thereof, for the manufacture of a medicament for the treatment of osteoporosis.
- R 1 for an optionally substituted cyclopropyl, cyclobutyl, cyclopentenyl, cyclopentyl, cyclohexyl, 1-hydroxycyclopropyl or 1- (fluoromethyl) cyclopropyl radical or for optionally substituted morpholino,
- R 2 represents H or NH 2 ;
- R 1 represents a cyclopropyl radical
- R 2 represents H
- R 1 represents morpholino
- R 2 represents NH 2 ;
- 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 sulfonic acids.
- 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 sulfonic acids.
- 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.
- metal or ammonium salts which are derived from ammonia, or organic amines such as emylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimerylaminoethanol, arginine, lysine or ethylene diamine.
- 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 racemes, like the diastereomers, can be prepared in a known manner, for example Separate into the stereoisomerically uniform constituents 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).
- 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.
- 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.
- heterocycle generally represents a saturated, unsaturated or aromatic 3- to 8-membered, for example 5- or 6-membered, heterocycle which can contain up to 4 heteroatoms from the series S, N and / or O 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, imazolyl, imid , Thiazolyl, furyl, oxazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl and tefrahydropyranyl are preferred.
- heteroaryl stands for an aromatic heteroeyclic radical.
- the invention includes the use of a combination of
- Stimulators of soluble guanylate cyclase in particular the compounds of the general formula (I) according to the invention, with organic nitrates and NO donors for the manufacture of a medicament for the treatment of osteoporosis.
- the invention encompasses the use of a combination of stimulators of soluble guanylate cyclase, in particular of the compounds of the general formula (I) according to the invention, with compounds which inhibit the breakdown of cyclic guanosine monophosphate (cGMP) for the manufacture of a medicament for the treatment of osteoporosis.
- cGMP cyclic guanosine monophosphate
- the stimulators of soluble guanylate cyclase can be administered in pharmaceutical preparations which, in addition to the stimulators of soluble guanylate cyclase, in particular the compounds of the general formula (I) according to the invention, contain non-toxic, inert pharmaceutically suitable excipients.
- the active compounds can also be present in microencapsulated form in one or more of the above-mentioned carriers.
- the therapeutically active compounds in particular the compounds of the general formula (I), should be present in the pharmaceutical preparations listed above in a concentration of about 0.1 to 99.5, preferably about 0.5 to 95% by weight of the total mixture to be available.
- the pharmaceutical preparations listed above can also contain further active pharmaceutical ingredients.
- the active ingredient (s) according to the invention in total amounts of about 0.01 to about 700, preferably 0.01 to 100 mg / kg body weight per 24
- a single dose contains the active ingredient (s) according to the invention preferably in amounts of about 0.1 to about 80, in particular 0.1 to 30 mg / kg body weight.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10054278 | 2000-11-02 | ||
DE10054278A DE10054278A1 (de) | 2000-11-02 | 2000-11-02 | Verwendung von Stimulatoren der löslichen Guanylatcyclase zur Behandlung von Osteoporose |
PCT/EP2001/012159 WO2002036120A1 (de) | 2000-11-02 | 2001-10-22 | Verwendung von stimulatoren der löslichen guanylatcyclase zur behandlung von osteoporose |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1335723A1 true EP1335723A1 (de) | 2003-08-20 |
Family
ID=7661878
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP01992572A Withdrawn EP1335723A1 (de) | 2000-11-02 | 2001-10-22 | Verwendung von stimulatoren der löslichen guanylatcyclase zur behandlung von osteoporose |
Country Status (7)
Country | Link |
---|---|
US (1) | US20040053915A1 (ja) |
EP (1) | EP1335723A1 (ja) |
JP (1) | JP2004512366A (ja) |
AU (1) | AU2002223633A1 (ja) |
CA (1) | CA2427551A1 (ja) |
DE (1) | DE10054278A1 (ja) |
WO (1) | WO2002036120A1 (ja) |
Families Citing this family (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10232572A1 (de) * | 2002-07-18 | 2004-02-05 | Bayer Ag | Neue 2,5-disubstituierte Pyrimidinderivate |
JP2005089457A (ja) * | 2003-09-03 | 2005-04-07 | Yung Shin Pharmaceutical Industry Co Ltd | 骨成長を促進するまたは骨吸収を阻害するための薬剤組成物 |
DE102007015034A1 (de) * | 2007-03-29 | 2008-10-02 | Bayer Healthcare Ag | Lactam-substituierte Dicarbonsäuren und ihre Verwendung |
US8741910B2 (en) * | 2008-11-25 | 2014-06-03 | Merck Sharp & Dohme Corp. | Soluble guanylate cyclase activators |
US9284301B2 (en) | 2010-03-25 | 2016-03-15 | Merck Sharp & Dohme Corp. | Soluble guanylate cyclase activators |
PT2576548E (pt) * | 2010-05-26 | 2015-09-16 | Adverio Pharma Gmbh | Utilização de estimuladores de sgc, activadores de sgc, por si sós ou em combinação com inibidores de pde5 para o tratamento de esclerose sistémica (sgc) |
ES2564503T3 (es) | 2010-05-27 | 2016-03-23 | Merck Sharp & Dohme Corp. | Activadores de la guanilato-ciclasa soluble |
KR20180002657A (ko) | 2015-05-06 | 2018-01-08 | 바이엘 파마 악티엔게젤샤프트 | 전신 경화증 (SSc)에 수반되는 수족지 궤양 (DU)의 치료를 위한 sGC 자극제, sGC 활성화제 단독 및 PDE5 억제제와의 조합물의 용도 |
FI3325013T4 (fi) | 2015-07-23 | 2023-10-11 | Liukoisen guanylaattisyklaasin (sgc) stimulaattoreita ja/tai aktivaattoreita yhdistelmänä neutraalin endopeptidaasin estäjän (nep-estäjä) ja/tai angiotensiini aii -antagonistin kanssa ja niiden käyttö | |
US20180344735A1 (en) | 2015-12-14 | 2018-12-06 | Ironwood Pharmaceuticals, Inc. | USE OF sGC STIMULATORS FOR THE TREATMENT OF GASTROINTESTINAL SPHINCTER DYSFUNCTION |
US10682210B1 (en) | 2016-08-20 | 2020-06-16 | Hybridge, Llc | Digital full arch method for immediate definitive dental prostheses |
CA3039734A1 (en) | 2016-10-11 | 2018-04-19 | Bayer Pharma Aktiengesellschaft | Combination containing sgc stimulators and mineralocorticoid receptor antagonists |
WO2018069148A1 (de) | 2016-10-11 | 2018-04-19 | Bayer Pharma Aktiengesellschaft | Kombination enthaltend sgc aktivatoren und mineralocorticoid-rezeptor-antagonisten |
US20190381039A1 (en) | 2016-12-13 | 2019-12-19 | Cyclerion Therapeutics, Inc. | USE OF sGC STIMULATORS FOR THE TREATMENT OF ESOPHAGEAL MOTILITY DISORDERS |
EP3498298A1 (en) | 2017-12-15 | 2019-06-19 | Bayer AG | The use of sgc stimulators and sgc activators alone or in combination with pde5 inhibitors for the treatment of bone disorders including osteogenesis imperfecta (oi) |
AU2019269047A1 (en) | 2018-05-15 | 2020-11-26 | Bayer Aktiengesellschaft | 1,3-thiazol-2-yl substituted benzamides for the treatment of diseases associated with nerve fiber sensitization |
SG11202100092QA (en) | 2018-07-11 | 2021-02-25 | Cyclerion Therapeutics Inc | USE OF sGC STIMULATORS FOR THE TREATMENT OF MITOCHONRIAL DISORDERS |
WO2020164008A1 (en) | 2019-02-13 | 2020-08-20 | Bayer Aktiengesellschaft | Process for the preparation of porous microparticles |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU736303B2 (en) * | 1996-10-14 | 2001-07-26 | Bayer Aktiengesellschaft | New heterocyclylmethyl-substituted pyrazol derivates |
DE19642255A1 (de) * | 1996-10-14 | 1998-04-16 | Bayer Ag | Verwendung von 1-Benzyl-3-(substituierten-hetaryl) -kondensierten Pyrazol-Derivaten |
US6043252A (en) * | 1997-05-05 | 2000-03-28 | Icos Corporation | Carboline derivatives |
US6451805B1 (en) * | 1997-11-14 | 2002-09-17 | Bayer Aktiengesellschaft | Substituted pyrazole derivatives for the treatment of cardiocirculatory diseases |
DE19834047A1 (de) * | 1998-07-29 | 2000-02-03 | Bayer Ag | Substituierte Pyrazolderivate |
DE19834044A1 (de) * | 1998-07-29 | 2000-02-03 | Bayer Ag | Neue substituierte Pyrazolderivate |
WO2000051597A1 (en) * | 1999-03-05 | 2000-09-08 | Merck Frosst Canada & Co. | Methods for inhibiting cathepsin k activity for the treatment of diseases related to bone loss |
-
2000
- 2000-11-02 DE DE10054278A patent/DE10054278A1/de not_active Withdrawn
-
2001
- 2001-10-22 WO PCT/EP2001/012159 patent/WO2002036120A1/de not_active Application Discontinuation
- 2001-10-22 CA CA002427551A patent/CA2427551A1/en not_active Abandoned
- 2001-10-22 AU AU2002223633A patent/AU2002223633A1/en not_active Abandoned
- 2001-10-22 JP JP2002538932A patent/JP2004512366A/ja active Pending
- 2001-10-22 US US10/415,708 patent/US20040053915A1/en not_active Abandoned
- 2001-10-22 EP EP01992572A patent/EP1335723A1/de not_active Withdrawn
Non-Patent Citations (1)
Title |
---|
See references of WO0236120A1 * |
Also Published As
Publication number | Publication date |
---|---|
JP2004512366A (ja) | 2004-04-22 |
DE10054278A1 (de) | 2002-05-08 |
US20040053915A1 (en) | 2004-03-18 |
WO2002036120A1 (de) | 2002-05-10 |
AU2002223633A1 (en) | 2002-05-15 |
CA2427551A1 (en) | 2003-05-10 |
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Extension state: AL LT LV MK RO SI |
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RIN1 | Information on inventor provided before grant (corrected) |
Inventor name: STRAUB, ALEXANDER Inventor name: STASCH, JOHANNES-PETER Inventor name: SANDER, ERICH Inventor name: GEISS, VOLKER |
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RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: BAYER HEALTHCARE AG |
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