EP1919464A1 - Oxadiazole compounds as urokinase inhibitors - Google Patents
Oxadiazole compounds as urokinase inhibitorsInfo
- Publication number
- EP1919464A1 EP1919464A1 EP06791713A EP06791713A EP1919464A1 EP 1919464 A1 EP1919464 A1 EP 1919464A1 EP 06791713 A EP06791713 A EP 06791713A EP 06791713 A EP06791713 A EP 06791713A EP 1919464 A1 EP1919464 A1 EP 1919464A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- compounds
- alkyl
- alkynyl
- substituted
- unsubstituted
- 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- Withdrawn
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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
- A61K31/425—Thiazoles
-
- 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
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- 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
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- 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
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- 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
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
- C07D271/07—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
Definitions
- the present invention relates to novel compounds for inhibiting urokinase plasminogen activator (uPA) with high bioavailability and oral administration and to their use as therapeutic agents for the treatment of urokinase or / and urokinase receptor-associated diseases, such as e.g. Tumors and metastasis.
- uPA urokinase plasminogen activator
- the invention particularly relates to compounds containing oxadiazole groups.
- uPA urokinase-type plasminogen activator
- benzamidine-type uPA inhibitors are disclosed in EP 1 098 651, arylguanidine-type uPA inhibitors in WO 01/96286 and WO 02/14349.
- a common feature of these synthetic inhibitors is a basic residue consisting of an amidino or / and guanidino group.
- the known urokinase inhibitors have the disadvantage that they are poorly absorbed by oral administration and thus can exert little pharmacological activity in the body in this mode of administration. Pharmaceutical preparations are therefore usually given once, but up to twice a week, to the patient intravenously over a period of several hours. This is associated with a high burden on the patient, as this is associated with considerable time and frequent hospital visits and requires a high degree of cooperation of the patient.
- Intramuscular and subcutaneous routes of administration also offer no advantages, since here often severe pain at the puncture sites and irritation to tissue necrosis may occur, which also require a lengthy follow-up treatment.
- amidine and guanidine-containing urokinase inhibitors show only a slight pharmacological action when administered orally.
- a prerequisite for the therapeutic effect of an active ingredient is its bioavailability. For example, it must be taken from the gastrointestinal tract after oral administration.
- An important mechanism for such membrane penetration is passive diffusion (Gangvar S. et al., DDT (1997) 148-155). It has been hypothesized in the literature that the lipophilicity of a drug plays an important role in passive diffusion across the membrane barriers of the gastrointestinal tract.
- EP 0 708 640 describes a modification of amidine functions to amidoxime, amidoxime esters and oxadiazole for anthelmintically active pentamidines, preference being given to using the amidoxime esters and oxadiazole as suitable modifications.
- the degree of lipophilicity alone is not sufficient (Hansch et al., J. Am. Chem. Soc. 86 (1964) 1616-1626) and an increase in the lipophilicity of the compounds is not a suitable parameter for prediction represents the passage of the membrane.
- a direct relation between lipophilicity and membrane permeation could not be determined (Conradi et al., Pharm. Res. 9 (1992) 435-439).
- An object of the present invention was to provide novel drugs for the inhibition of urokinase, which have a significantly increased bioavailability and activity in the organism when administered orally.
- B represents -SO 2 - or -CO-
- X represents -NR 1 - or -CHR 1 -
- Z is -R 4 , -OR 4 or -NH-R 4
- Y is -OR 2 or -NHR 2
- R 1 are each independently -H, branched or straight-chain -Ci-C 6 -
- R 2 is -H, -R 1 , -COR 1 , -COOR 1 or -CON (R 1 ) 2
- R 3 is H or -OR 8 ,
- R 8 is -H, -C 1 -C 6 -alkyl, -C 2 -C 6 -alkenyl or -C 2 -C 6 -alkynyl, unsubstituted or substituted or -COR 6 or -COOR 6 or an oligo- or Poylalkylenoxyrest with eg 2-50 -C 2 -C 4 -
- Alkyleneoxy, e.g. Ethyleneoxy groups means
- R 4 is H, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl or C 2 -C 6 -alkyl, unsubstituted or substituted, or a cyclic radical,
- R 5 is -H, -d-Ce-alkyl, -C 2 -C 6 -alkenyl or -C 2 -C 6 -alkyl, unsubstituted or substituted, or a cyclic radical,
- R 6 is -H, branched or straight-chain C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl or -C 2 -C 6 -alkynyl, unsubstituted or substituted, or denotes a cyclic radical,
- R 7 is H, branched or straight-chain, linear, mono-, bi- or polycyclic alkyl, alkenyl, alkynyl, carboxyalkyl,
- the drug is an orally administrable agent.
- the medicament is particularly preferably used for inhibiting the urokinase-plasminogen activator.
- X, Y, R 4 , R 5 and R 7 are as defined above, or their salts.
- the group E is preferably in the para position of the phenyl ring in the compounds I and II. Particular preference is given to compounds of the general formula I 1 in which E represents N-oxa or oxa.
- the compounds according to the invention have an oxadiazole group. It has surprisingly been found that such compounds are outstandingly orally available.
- the compounds according to the invention have at least one ester, more preferably two ester groups at the positions Y and R 3 or R 7 .
- the compounds may be present as salts, preferably as physiologically acceptable acid salts, for example salts of mineral acids, more preferably as hydrochlorides or as salts of suitable organic acids.
- the compounds may be present as optically pure compounds or as mixtures of enantiomers or / and diastereomers.
- Cyclic radicals may contain one or more saturated, unsaturated or aromatic rings.
- Preferred examples of cyclic radicals are cycloalkyl radicals, aryl radicals, alkylaryl radicals, heteroaryl radicals and bicyclic radicals. Particularly preferred are mono- or bicyclic radicals.
- the cyclic radicals preferably contain 4 to 30, in particular 5-10 carbon and hetero atoms as ring atoms, and optionally one or more substituents as indicated above.
- Heterocyclic systems preferably contain one or more O, S or / and N atoms.
- Preferred bicyclic ring systems are those with a -CO-radical.
- Most preferred examples of cyclic radicals are an adamantyl radical or a benzyl radical.
- Alkyl, alkenyl and alkynyl groups preferably contain up to 6, in particular up to 4 carbon atoms.
- R 1 is preferably H or an optionally substituted dC 4 alkyl, eg -CH 3, or a Ci-C 6 - alkylaryl so that CO-X-NR 5, for example, may represent a glycyl, alanyl, phenylalanyl or Homophenylalanylrest.
- R 1 is more preferably CH 3 such that X is -CH (CH 3 ) -.
- R 2 is more preferably COR 1 such that Y represents an ester group.
- R 1 is particularly preferably a branched alkyl radical, in particular ferf-butyl.
- R 3 is particularly preferably -OR 8 , wherein R 8 is again preferably -COR 6 , so that the group R 3 preferably comprises an ester group.
- R 6 is preferably a branched alkyl radical, in particular for fer-butyl.
- R 6 is preferably a cyclic radical, in particular adamantyl.
- R 4 is more preferably para-chlorobenzyl (CI-C 6 H 5 -CH 2 -).
- R 5 is preferably -H or dC 3 -alkyl, in particular CH 3 .
- R 4 is an alkyl radical having a cyclic substituent, for example an optionally substituted phenyl radical or a bicyclic radical, such as
- R 4 is a substituted or unsubstituted C 1 -C 3 -alkyl-aryl radical, for example a benzyl radical which may optionally be substituted in the meta or para position by halogen or / and -NO 2 , the Halogen is selected from F, Cl, Br and I, more preferably Cl and Br.
- suitable substituents are each halogen, in particular F, Cl, Br or I, C 1 -C 4 -alkyl, OR 6 , in particular OH 1 OCOR 6 , COOR 6 , N (R 6 ) 2 , NR 6 COR 6 or NR 6 CON (R 6 ) 2 .
- the compounds of the invention may optionally be used together with suitable pharmaceutical excipients or carriers for the preparation of medicaments.
- suitable pharmaceutical excipients or carriers for the preparation of medicaments.
- an administration in combination with other active ingredients such as other urokinase inhibitors, such as such as antibodies and / or peptides, but also with chemotherapeutic agents and cytostatics and / or cytostatic agents possible.
- the compounds of the general formula I and / or II according to the invention can likewise be used and used in the sense of a prodrug.
- a prodrug is a pharmaceutically inactive derivative of the corresponding pharmaceutically active substance which is converted or transformed spontaneously or enzymatically after oral administration to release the pharmaceutically active substance.
- the medicaments can be administered topically, rectally or parenterally in humans and animals, e.g. intravenous, subcutaneous, intramuscular, intraperitoneal, sublingual, nasal or / and inhalation, e.g. in the form of tablets, dragees, capsules, pellets, suppositories, solutions, emulsions, suspensions, liposomes, inhalation sprays or transdermal systems, such as patches, and more preferably orally, e.g. be administered as a slow-release / sustained-release formulation.
- the compounds of the invention are useful for controlling diseases associated with pathological overexpression of uPA or / and urokinase plasminogen activator receptor (uPAR). For example, they are able to highly efficiently inhibit the growth and / or spread of malignant tumors as well as the metastasis of tumors. Examples include tumor diseases such as breast cancer, lung cancer, bladder cancer, gastric cancer, cervical cancer, ovarian cancer, kidney cancer, prostate cancer and soft tissue sarcomas, especially tumors associated with a high metastasis rate.
- the compounds may optionally be used together with other tumor agents or with other types of treatment, eg radiation and / or surgical interventions.
- the compounds according to the invention are also active for other uPA-associated and / or uPAR-associated diseases.
- diseases are, for example, pulmonary hypertension and / or heart diseases (eg WO 02/00248), gastric and intestinal diseases, such as inflammatory bowel disease, premalignant colon adenomas, inflammatory diseases, such as septic arthritis, osteoarthritis, rheumatoid arthritis, or other diseases, such as osteoporosis, cholesteatomy, skin and eye diseases and viral or bacterial infections, with express reference to the diseases mentioned in EP-A-0 691 350, EP-A-1 182 207 and US Pat. No. 5,712,291.
- the compounds of the general formula I can be prepared, for example, as in the synthesis schemes in FIG.
- the uPA inhibitors according to the invention not only have improved bioavailability, but also significantly improved activity against a primary tumor.
- the substances according to the invention can be used alone or in combination with other physiologically active substances, e.g. with radiotherapeutics or with cytotoxic and / or cytostatic agents, e.g. Chemotherapeutic agents, such as cisplatin, doxorubicin, 5-fluorouracil, taxol derivatives, and / or other chemotherapeutic agents, for example selected from the group of alkylating agents, antimetabolites, antibiotics, epidophyllotoxins and vinca alkaloids. Also possible is a combination with radiotherapy and / or surgical interventions.
- cytotoxic and / or cytostatic agents e.g. Chemotherapeutic agents, such as cisplatin, doxorubicin, 5-fluorouracil, taxol derivatives, and / or other chemotherapeutic agents, for example selected from the group of alkylating agents, antimetabolites, antibiotics, epidophyllotoxins and vinca alkaloids.
- chemotherapeutic agents such
- the invention provides a process for inhibiting urokinase in animals, in particular humans, by administering an effective amount of at least one compound of general formula I.
- the dose to be administered depends on the type and severity of the disease treating disorders. For example, the daily dose is in the range of 0.01-100 mg / kg of active ingredient.
- the invention relates to novel inhibitors of the urokinase-plasminogen activator of the general formula I.
- Figure 1 shows a synthetic scheme for WX-770 and the synthesis of derivatives.
- Figure 2 shows the oral availability of WX-770 in rat.
- FIG. 3 shows the in vitro metabolic activation of WX-770 to WX-582.
- FIG. 4 shows the effectiveness of the compound WX-770 according to the invention in the BN-472 rat tumor model.
- FIG. 5 shows the rearrangement to the oxadiazole.
- FIG. 6 shows the kinetics of tumor growth for treatment with soya phosphatidylcholine (control), subcutaneous administration of WX-340 and oral administration of WX-771 (FIG. 6A) and WX-781 (FIG. 6B) and for WX-780 (FIG. Figure 6C) at doses of 0.2 mg / kg and 2 mg / kg, respectively.
- Figure 7 shows the effects on the size and weight of the primary tumor.
- Figure 8 shows the antimetastatic effects.
- Compound 3 was prepared from 4-chlorobenzyl chloride.
- 4-chlorobenzyl magnesium bromide was prepared therefrom by classical Grignard reaction, which was then reacted in a highly exothermic reaction with sulfuryl chloride according to: Bhattacharya, S.N .; Eaborn, C; Walton, D.R.M. J. Chem. Soc. 1968, 1265-1267. At least in smaller quantities, however, the product is also commercially available.
- the free amine 9 (3.86 g, 7.9 mmol) was suspended under ice-cooling in 4 M hydrogen chloride in dioxane (7.8 mL) and then methanof (10 mL) was added until a clear solution had formed. After cooling for 30 minutes under ice cooling, 4 M HCl in dioxane (7.8 ml) were added again and the mixture was stirred at 0 ° C. for a further 1 h. The reaction solution was concentrated and the solid was dried in vacuo (4.19 g, 82%).
- the urokinase-type plasminogen activator (uPA), its cellular receptor (uPAR) and its inhibitor (PAI-1) are essential components of the plasmin activation cascade. Plasmin plays an essential role in tissue remodeling and cell migration, as well as in tumor-associated proteolytic activity through the activation of other enzymes, e.g. of matrix metalloproteinases (MMPs). For example, in breast cancer, high levels of expression of these components promote invasion, metastatic spread, and neo-angiogenesis of tumors. Thus, the inhibition of tumor-associated proteolytic activity is a novel concept for the development of antitumor and anti-metastatic agents for cancer patients.
- MMPs matrix metalloproteinases
- the BN-472 metastatic breast tumor was used in brown Norwegian rats.
- the type of tumor tissue used is described, for example, in Kort et al., J. Natl. Cancer Inst. 72 (1984) 709-713.
- the rats were purchased from Harlan Nederland, NL 5960-AD Horst, The Netherlands, and were six to eight weeks old and 128g to 170g in weight.
- a phosphatidylcholine vehicle was obtained by introducing 400 mg of soy phosphatidylcholine in 20 ml of phosphate buffered saline and 400 ⁇ l of absolute ethanol. 0.8 ml of the suspension was administered orally to the rats as a control.
- 7.5 mg of WX-771 was added to 20 ml of a soy phosphatidylcholine solution as used in the control.
- 0.8 ml of this suspension was orally administered.
- the stock solution was diluted 1:10 to receive a dose of 0.2 mg / kg when administered also 0.8 ml per rat.
- 7.5 mg WX-780 were placed in 20 ml of a soy phosphatidylcholine suspension corresponding to the control suspension described above.
- 0.8 ml of this suspension was administered to the rats.
- the stock solution was diluted 1:10, with further administration of 0.8 ml per rat.
- 7.5 mg of WX-781 was introduced into 20 ml of a soy phosphatidylcholine suspension corresponding to the control suspension described above.
- the rats were given 0.8 ml orally administered.
- the stock solution was diluted 1:10, with 0.8 ml / rat still being administered orally.
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- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Proteomics, Peptides & Aminoacids (AREA)
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- Genetics & Genomics (AREA)
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- Biochemistry (AREA)
- Rheumatology (AREA)
- Oncology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Communicable Diseases (AREA)
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Abstract
Description
Claims
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP06791713A EP1919464A1 (en) | 2005-08-29 | 2006-08-29 | Oxadiazole compounds as urokinase inhibitors |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP05018732 | 2005-08-29 | ||
PCT/EP2006/008451 WO2007025718A1 (en) | 2005-08-29 | 2006-08-29 | Oxadiazole compounds as urokinase inhibitors |
EP06791713A EP1919464A1 (en) | 2005-08-29 | 2006-08-29 | Oxadiazole compounds as urokinase inhibitors |
Publications (1)
Publication Number | Publication Date |
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EP1919464A1 true EP1919464A1 (en) | 2008-05-14 |
Family
ID=37307288
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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EP06791713A Withdrawn EP1919464A1 (en) | 2005-08-29 | 2006-08-29 | Oxadiazole compounds as urokinase inhibitors |
Country Status (11)
Country | Link |
---|---|
US (1) | US20090286837A1 (en) |
EP (1) | EP1919464A1 (en) |
JP (1) | JP2009506087A (en) |
KR (1) | KR20080038443A (en) |
CN (1) | CN101378744A (en) |
AU (1) | AU2006286752B2 (en) |
BR (1) | BRPI0615290A2 (en) |
CA (1) | CA2620683A1 (en) |
MX (1) | MX2008002702A (en) |
RU (1) | RU2008112208A (en) |
WO (1) | WO2007025718A1 (en) |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE4321444A1 (en) * | 1993-06-28 | 1995-01-05 | Bernd Prof Dr Clement | Pharmaceutical preparation |
DE10029014A1 (en) * | 2000-06-15 | 2001-12-20 | Univ Schiller Jena | Urokinase inhibitor, useful for treatment, prophylaxis or diagnosis of thromboembolic disease, comprising acylated 3- or 4-amidino-benzylamine derivative |
DE10029015A1 (en) * | 2000-06-15 | 2001-12-20 | Curacyte Ag | Coagulation Factor Xa inhibitor, useful for treatment, prophylaxis or diagnosis of thromboembolic disease, comprising acylated 3- or 4-amidino-benzylamine derivative |
CA2387002A1 (en) * | 2000-08-11 | 2002-02-21 | Corvas International, Inc. | Non-covalent inhibitors of urokinase and blood vessel formation |
WO2003070229A2 (en) * | 2002-02-22 | 2003-08-28 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Use of proteinase inhibitors in the treatment of autoimmune diseases |
DE10212555A1 (en) * | 2002-03-15 | 2003-09-25 | Univ Schiller Jena | Detecting and suppressing growth of malignant tumors and their metastases, comprises administration of coagulation factor Xa inhibitors |
DE10342108A1 (en) * | 2003-09-11 | 2005-04-14 | Curacyte Chemistry Gmbh | Basic substituted benzylamine analogs as coagulation factor Xa inhibitors, their preparation and use |
-
2006
- 2006-08-29 AU AU2006286752A patent/AU2006286752B2/en not_active Expired - Fee Related
- 2006-08-29 JP JP2008528406A patent/JP2009506087A/en not_active Withdrawn
- 2006-08-29 KR KR1020087007482A patent/KR20080038443A/en not_active Application Discontinuation
- 2006-08-29 EP EP06791713A patent/EP1919464A1/en not_active Withdrawn
- 2006-08-29 RU RU2008112208/04A patent/RU2008112208A/en not_active Application Discontinuation
- 2006-08-29 US US11/991,268 patent/US20090286837A1/en not_active Abandoned
- 2006-08-29 MX MX2008002702A patent/MX2008002702A/en not_active Application Discontinuation
- 2006-08-29 CA CA002620683A patent/CA2620683A1/en not_active Abandoned
- 2006-08-29 BR BRPI0615290-2A patent/BRPI0615290A2/en not_active IP Right Cessation
- 2006-08-29 CN CNA2006800317284A patent/CN101378744A/en active Pending
- 2006-08-29 WO PCT/EP2006/008451 patent/WO2007025718A1/en active Application Filing
Non-Patent Citations (1)
Title |
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See references of WO2007025718A1 * |
Also Published As
Publication number | Publication date |
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JP2009506087A (en) | 2009-02-12 |
AU2006286752B2 (en) | 2011-10-06 |
WO2007025718A1 (en) | 2007-03-08 |
MX2008002702A (en) | 2008-03-18 |
BRPI0615290A2 (en) | 2011-05-17 |
US20090286837A1 (en) | 2009-11-19 |
CN101378744A (en) | 2009-03-04 |
RU2008112208A (en) | 2009-10-10 |
CA2620683A1 (en) | 2007-03-08 |
KR20080038443A (en) | 2008-05-06 |
AU2006286752A1 (en) | 2007-03-08 |
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