US20010020042A1 - Fluorophenyl-substituted alkenylcarboxylic acid guanidides, process for their preparation, their use as a medicament or diagnostic, and medicament containing them - Google Patents
Fluorophenyl-substituted alkenylcarboxylic acid guanidides, process for their preparation, their use as a medicament or diagnostic, and medicament containing them Download PDFInfo
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- US20010020042A1 US20010020042A1 US09/778,899 US77889901A US2001020042A1 US 20010020042 A1 US20010020042 A1 US 20010020042A1 US 77889901 A US77889901 A US 77889901A US 2001020042 A1 US2001020042 A1 US 2001020042A1
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- 0 *C(=O)C(C)=C(C)C1=C(C)C(C)=C(C)C(C)=C1C.II Chemical compound *C(=O)C(C)=C(C)C1=C(C)C(C)=C(C)C(C)=C1C.II 0.000 description 3
- PHQRCDLVPODXTQ-UHFFFAOYSA-N [H]N([H])C(=[H]C(=O)C(C)=C(C)C1=C(C)C(C)=C(C)C(C)=C1C)N([H])[H] Chemical compound [H]N([H])C(=[H]C(=O)C(C)=C(C)C1=C(C)C(C)=C(C)C(C)=C1C)N([H])[H] PHQRCDLVPODXTQ-UHFFFAOYSA-N 0.000 description 3
- DFBZVJLADDKRGF-QHHAFSJGSA-N C/C(=C\C1=CC(F)=CC(F)=C1)C(=O)N=C(N)N Chemical compound C/C(=C\C1=CC(F)=CC(F)=C1)C(=O)N=C(N)N DFBZVJLADDKRGF-QHHAFSJGSA-N 0.000 description 1
- RXMUPNVSYKGKMY-UHFFFAOYSA-N CN(C)C1=C(Cl)N=C(C(=O)NC(=N)N)C(N)=N1 Chemical compound CN(C)C1=C(Cl)N=C(C(=O)NC(=N)N)C(N)=N1 RXMUPNVSYKGKMY-UHFFFAOYSA-N 0.000 description 1
- GVZPQNVDRZEJRU-DAFODLJHSA-N NC(N)=NC(=O)/C=C/C1=C(F)C=CC(F)=C1 Chemical compound NC(N)=NC(=O)/C=C/C1=C(F)C=CC(F)=C1 GVZPQNVDRZEJRU-DAFODLJHSA-N 0.000 description 1
- FGLKXTSTMPDAMW-AATRIKPKSA-N NC(N)=NC(=O)/C=C/C1=C(F)C=CC=C1 Chemical compound NC(N)=NC(=O)/C=C/C1=C(F)C=CC=C1 FGLKXTSTMPDAMW-AATRIKPKSA-N 0.000 description 1
- UTGOZEAYAZYVTF-OWOJBTEDSA-N NC(N)=NC(=O)/C=C/C1=CC(F)=CC(F)=C1 Chemical compound NC(N)=NC(=O)/C=C/C1=CC(F)=CC(F)=C1 UTGOZEAYAZYVTF-OWOJBTEDSA-N 0.000 description 1
- OLALSUPQCJAGAU-SNAWJCMRSA-N NC(N)=NC(=O)/C=C/C1=CC=CC(F)=C1 Chemical compound NC(N)=NC(=O)/C=C/C1=CC=CC(F)=C1 OLALSUPQCJAGAU-SNAWJCMRSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
- C07C279/22—Y being a hydrogen or a carbon atom, e.g. benzoylguanidines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
- C07C279/10—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by doubly-bound oxygen atoms
-
- 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
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- 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
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- 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
- A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
-
- 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
- A61P9/06—Antiarrhythmics
-
- 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
- This invention relates to fluorophenyl-substituted alkenylcarboxylic acid guanidides, process for their preparation, their use as a medicament or diagnostic, and medicament containing them
- the invention further relates to alkenylcarboxylic acid guanidides carrying fluorophenyl groups, of the formula I:
- R(6) is hydrogen, (C 1 -C 8 )-alkyl, (C 3 -C 8 )-cycloalkyl or phenyl, the phenyl group being unsubstituted or substituted by 1 - 3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR(9)-R(10);
- R(9) and R(10) are hydrogen, (C 1 -C 4 )-alkyl or (C 1 -C 4 )-perfluoroalkyl;
- R(7) is independently defined in the same way as R(6);
- R(1), R(2), R(3), R(4) and R(5) independently of one another are hydrogen or F, it being necessary, however, for at least one of the radicals R(1), R(2), R(3), R(4) and R(5) to be fluorine;
- Preferred compounds of the formula I are those in which:
- R(6) is hydrogen, (C 1 -C 4 ) -alkyl or (C 3 -C 6 ) -cycloalkyl;
- R(7) is independently defined in the same way as R(6);
- R(1), R(2), R(3), R(4) and R(5) independently of one another are hydrogen or F, it being necessary, however, for at least one of the radicals R(1), R(2), R(3), R(4) and R(5) to be fluorine;
- R(6) is hydrogen or CH 3 ;
- R(7) is hydrogen
- R(1), R(2), R(3), R(4) and R(5) independently of one another are hydrogen or F, it being necessary, however, for at least one of the radicals R(1), R(2), R(3), R(4) and R(5) to be fluorine;
- the compounds of the formula I contain one or more centers of asymmetry, these can have either the S or the R configuration.
- the compounds can exist as optical isomers, as diastereoisomers, as racemates or as mixtures thereof.
- the double bond geometry of the compounds of the formula I can be either E or Z.
- the compounds can exist as a mixture of the double bond isomers.
- the indicated alkyl radicals can be either linear or branched.
- the invention further relates to a process for the preparation of the compound I, which comprises reacting a compound of the formula II:
- R(1) to R(7) being defined as indicated and L being a leaving group readily susceptible to nucleophilic substitution.
- the activated acid derivatives of the formula II, in which L is an alkoxy group, preferably a methoxy group, a phenoxy group, a phenylthio, methylthio or 2-pyridylthio group or a nitrogen heterocycle, preferably 1-imidazolyl, are advantageously obtained in a manner known per se from the corresponding carboxylic acid chlorides (formula II, L ⁇ Cl), which can in turn be prepared in a manner known per se from the corresponding carboxylic acids (formula II, L ⁇ OH), for example with thionyl chloride.
- the reaction is advantageously carried out with the addition of an acid acceptor, e.g. in the form of excess guanidine, in order to bind the hydrohalic acid.
- an acid acceptor e.g. in the form of excess guanidine
- the compounds I are substituted acylguanidines.
- the most prominent representative of the acylguanidines is the pyrazine derivative amiloride, which is used in therapy as a potassium-sparing diuretic.
- amiloride pyrazine derivative amiloride
- Numerous other compounds of the amiloride type are described in the literature, examples being dimethylamiloride or ethylisopropylamiloride.
- halogen is only mentioned in general terms as a substituent on the phenyl ring and, although it is defined as “all four halogens”, no individual example with fluorine substitution is given.
- the compounds according to the invention have very good antiarrhythmic properties but no undesirable or disadvantageous salidiuretic properties.
- the compounds are outstandingly suitable for the prophylaxis and treatment of infarction and for the treatment of angina pectoris, said compounds also preventively inhibiting or greatly reducing the pathophysiological processes associated with the occurrence of ischemically induced damage, especially with the production of ischemically induced cardiac arrhythmia.
- the compounds of the formula I according to the invention by inhibiting the cellular Na + /H + exchange mechanism, can be used as drugs for the treatment of any acute or chronic damage produced by ischemia or diseases primarily or secondarily induced by said damage.
- This relates to their use as drugs for operative procedures, e.g. in organ transplants, it being possible for the compounds to be used for protecting the organs in the donor before and during removal and for protecting removed organs, for example when treated with or stored in physiological baths, as well as during transfer into the recipient organism.
- the compounds are also valuable drugs, with a protective action, when carrying out angioplastic operative procedures, for example on the heart and on peripheral vessels.
- the compounds are also suitable as drugs for the treatment of ischemia of the nervous system, especially the CNS, and are suitable e.g. for the treatment of stroke or cerebral edema.
- the compounds of the formula I according to the invention are also suitable for the treatment of forms of shock, for example allergic, cardiogenic, hypovolemic and bacterial shock.
- Another feature of the compounds of the formula I according to the invention is their potent inhibitory action on cell proliferation, for example the proliferation of fibroblasts and the non-striated vascular myocytes.
- the compounds of the formula I are therefore suitable as valuable therapeutic agents for diseases where cell proliferation is a primary or secondary cause, and consequently can be used as antiatherosclerotics and agents for combating late diabetic complications, carcinosis, fibrotic diseases like pulmonary fibrosis, hepatic fibrosis or renal fibrosis, and organic hypertrophy and hyperplasia, especially hyperplasia and hypertrophy of the prostate.
- the compounds according to the invention are effective inhibitors of the cellular sodium/proton exchanger (Na + /H + exchanger), which, in numerous diseases (essential hypertonia, atherosclerosis, diabetes etc.) , is also high in cells which are readily accessible for measurement, for example in erythrocytes, thrombocytes or leukocytes.
- the compounds according to the invention are therefore suitable as outstanding and simple scientific tools, for example in their use as diagnostics for determining and distinguishing between specific forms of hypertonia, as well as atherosclerosis, diabetes, proliferative diseases etc.
- the compounds of the formula I are further suitable for preventive therapy to prevent the genesis of high blood pressure, for example essential hypertonia.
- Drugs containing a compound I can be administered orally, parenterally, intravenously, rectally or by inhalation, the preferred administration depending on the particular characteristics of the disease.
- the compounds of the formula I can be administered on their own or together with galenic adjuncts, in both veterinary and human medicine.
- adjuncts are suitable for the desired drug formulation.
- the active compounds are mixed with the appropriate additives, such as excipients, stabilizers or inert diluents, and converted by the customary methods to the appropriate forms of administration, such as tablets, coated tablets, hard gelatin capsules or aqueous, alcoholic or oily solutions.
- excipients such as gum arabic; magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, especially corn-starch.
- the product can be formulated as either dry or wet granules.
- suitable oily excipients or solvents are vegetable or animal oils such as sunflower oil or cod-liver oil.
- the active compounds are brought into solution, suspension or emulsion, if desired together with the substances conventionally used for this purpose, such as solubilizers, emulsifiers or other adjuncts.
- suitable solvents are water, physiological saline or alcohols, e.g. ethanol, propanol or glycerol, as well as sugar solutions such as glucose or mannitol solutions, or else a mixture of the various solvents mentioned.
- Suitable pharmaceutical formulations or compositions for administration in the form of aerosols or sprays are solutions, suspensions or emulsions of the active substance of the formula I in a pharmaceutically acceptable solvent, such as ethanol or water in particular, or in a mixture of such solvents.
- the formulation can also contain other pharmaceutical adjuncts such as surfactants, emulsifiers and stabilizers, as well as a propellant gas.
- a formulation conventionally contains the active substance in a concentration of about 0.1 to 10% by weight, especially about 0.3 to 3% by weight.
- the dosage of the active substance of the formula 1 to be administered, and the frequency of administration, depend on the potency and duration of action of the compounds used, on the type and severity of the disease to be treated and on the sex, age, weight and individual responsiveness of the mammal to be treated.
- the daily dose of a compound of the formula I for a patient weighing about 75 kg is at least 0.001 mg/kg, preferably 0.01 mg/kg, up to at most 10 mg/kg, preferably 1 mg/kg of body weight.
- dosages may be necessary, e.g. up to 4 individual doses per day.
- i.v. administration for instance to an infarction patient in intensive care, up to 200 mg per day may be necessary.
- [0070] was prepared according to variant 1 A from metafluorocinnamic acid.
- [0073] was prepared according to variant 1 A from 2,5-difluorocinnamic acid.
- [0076] was prepared according to variant 1 A from 3,5-difluorocinnamic acid.
- [0079] was prepared according to variant 1 A from orthofluorocinnamic acid.
- E-3- (2-Fluorophenyl) -2-methylacrylic acid guanidide was synthesized from 2-fluorobenzaldehyde analogously to Example 5 and isolated as the hydrochloride.
- E-3-(4-Fluorophenyl)-2-methylacrylic acid guanidide was synthesized from 4-fluorobenzaldehyde analogously to Example 5 and isolated as the hydrochloride.
- E-3-(2,3,6-Trifluorophenyl)-2-methylacrylic acid guanidide was synthesized from 2,3,6-trifluorobenzaldehyde analogously to Example 5 and isolated as the hydrochloride.
- E-3-(2,3,5,6-Tetrafluorophenyl)-2-methylacrylic acid guanidide was synthesized from 2,3,5,6-tetrafluorobenzaldehyde analogously to Example 5 and isolated as the hydrochloride.
- E-3-(2,3,4,5,6-Pentafluorophenyl)-2-methylacrylic acid guanidide was synthesized from 2,3,4,5,6-pentafluorobenzaldehyde analogously to Example 5 and isolated as the hydrochloride
- E-3-(2,4,6-Trifluorophenyl)-2-methylacrylic acid guanidide was synthesized from 2,4,6-trifluorobenzaldehyde analogously to Example 5 and isolated as the hydrochloride.
- E-3-(2 ,6-Difluorophenyl)-2-methylacrylic acid guanidide was synthesized from 2,6-difluorobenzaldehyde analogously to Example 5 and isolated as the hydrochloride
- New Zealand white rabbits received a standard diet with 2% of cholesterol for six weeks in order to activate the Na + /H + exchange and thus be able to determine by flame photometry the Na+ influx into the erythrocytes via Na + /H + exchange.
- the blood was taken from the auricular arteries and rendered incoagulable with 25 IU/ml of heparin potassium. Part of each sample was used for double determination of the hematocrit by centrifugation. 100 ⁇ l aliquots were used for measurement of the initial Na + content of the erythrocytes.
- the net Na + influx was calculated from the difference between the initial sodium values and the sodium content of the erythrocytes after incubation.
- the sodium influx capable of inhibition by amiloride was calculated from the difference in the sodium content of the erythrocytes after incubation with and without 3 ⁇ 10 ⁇ 4 mol/l of amiloride. The same procedure was also adopted for the compounds according to the invention.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Diabetes (AREA)
- Urology & Nephrology (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Surgery (AREA)
- Vascular Medicine (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Reproductive Health (AREA)
- Gastroenterology & Hepatology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/778,899 US20010020042A1 (en) | 1995-05-22 | 2001-02-08 | Fluorophenyl-substituted alkenylcarboxylic acid guanidides, process for their preparation, their use as a medicament or diagnostic, and medicament containing them |
US10/024,388 US6504057B2 (en) | 1995-05-22 | 2001-12-20 | Fluorophenyl-substituted alkenylcarboxylic acid guanidides, process for their preparation, their use as a medicament or diagnostic, and medicament containing them |
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19518796.2 | 1995-05-22 | ||
DE19518796A DE19518796A1 (de) | 1995-05-22 | 1995-05-22 | Fluorphenylsubstituierte Alkenylcarbonsäure-guanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
US65119696A | 1996-05-20 | 1996-05-20 | |
US94751797A | 1997-09-29 | 1997-09-29 | |
US24417799A | 1999-02-04 | 1999-02-04 | |
US41347899A | 1999-10-06 | 1999-10-06 | |
US09/778,899 US20010020042A1 (en) | 1995-05-22 | 2001-02-08 | Fluorophenyl-substituted alkenylcarboxylic acid guanidides, process for their preparation, their use as a medicament or diagnostic, and medicament containing them |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US41347899A Continuation | 1995-05-22 | 1999-10-06 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/024,388 Continuation US6504057B2 (en) | 1995-05-22 | 2001-12-20 | Fluorophenyl-substituted alkenylcarboxylic acid guanidides, process for their preparation, their use as a medicament or diagnostic, and medicament containing them |
Publications (1)
Publication Number | Publication Date |
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US20010020042A1 true US20010020042A1 (en) | 2001-09-06 |
Family
ID=7762597
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
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US09/778,899 Abandoned US20010020042A1 (en) | 1995-05-22 | 2001-02-08 | Fluorophenyl-substituted alkenylcarboxylic acid guanidides, process for their preparation, their use as a medicament or diagnostic, and medicament containing them |
US10/024,388 Expired - Fee Related US6504057B2 (en) | 1995-05-22 | 2001-12-20 | Fluorophenyl-substituted alkenylcarboxylic acid guanidides, process for their preparation, their use as a medicament or diagnostic, and medicament containing them |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
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US10/024,388 Expired - Fee Related US6504057B2 (en) | 1995-05-22 | 2001-12-20 | Fluorophenyl-substituted alkenylcarboxylic acid guanidides, process for their preparation, their use as a medicament or diagnostic, and medicament containing them |
Country Status (29)
Country | Link |
---|---|
US (2) | US20010020042A1 (de) |
EP (1) | EP0744397B1 (de) |
JP (1) | JP3924018B2 (de) |
KR (1) | KR960041152A (de) |
CN (1) | CN1063437C (de) |
AR (1) | AR002744A1 (de) |
AT (1) | ATE192431T1 (de) |
AU (1) | AU701493B2 (de) |
BR (1) | BR9602394A (de) |
CA (1) | CA2177007C (de) |
CZ (1) | CZ291622B6 (de) |
DE (2) | DE19518796A1 (de) |
DK (1) | DK0744397T3 (de) |
ES (1) | ES2147629T3 (de) |
GR (1) | GR3033416T3 (de) |
HR (1) | HRP960230B1 (de) |
HU (1) | HUP9601358A3 (de) |
IL (1) | IL118327A (de) |
MY (1) | MY113803A (de) |
NO (1) | NO305552B1 (de) |
NZ (1) | NZ286622A (de) |
PL (1) | PL183431B1 (de) |
PT (1) | PT744397E (de) |
RU (1) | RU2164913C2 (de) |
SI (1) | SI0744397T1 (de) |
SK (1) | SK281527B6 (de) |
TR (1) | TR199600421A2 (de) |
TW (1) | TW415936B (de) |
ZA (1) | ZA964035B (de) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6399824B1 (en) | 2000-09-22 | 2002-06-04 | Aventis Pharma Deutschland Gmbh | Substituted cinnamic, acid guanidides, process for their preparation, their use as a medicament, and medicament comprising them |
US20090099239A1 (en) * | 2005-06-24 | 2009-04-16 | Gary Dinneen Ewart | Antiviral Compounds and Methods |
Families Citing this family (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6011059A (en) * | 1997-12-24 | 2000-01-04 | Bristol-Myers Squibb Company | Acyl guanidine sodium/proton exchange inhibitors and method |
US6160134A (en) * | 1997-12-24 | 2000-12-12 | Bristol-Myers Squibb Co. | Process for preparing chiral cyclopropane carboxylic acids and acyl guanidines |
JP2002542291A (ja) | 1999-04-23 | 2002-12-10 | ブリストル−マイヤーズ スクイブ カンパニー | ジ環式アシルグアニジン・ナトリウム/プロトン交換抑制剤および方法 |
CA2529949C (en) * | 2003-06-26 | 2013-08-06 | Biotron Limited | Antiviral compounds and methods |
AU2013205388B2 (en) * | 2005-06-24 | 2016-05-05 | Biotron Limited | Antiviral compounds and methods |
WO2018129556A1 (en) | 2017-01-09 | 2018-07-12 | Ardelyx, Inc. | Compounds and methods for inhibiting nhe-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders |
WO2010078449A2 (en) | 2008-12-31 | 2010-07-08 | Ardelyx, Inc. | Compounds and methods for inhibiting nhe-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders |
US20150336892A1 (en) | 2012-08-21 | 2015-11-26 | Ardelyx, Inc | Compounds and methods for inhibiting nhe-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders |
US10376481B2 (en) | 2012-08-21 | 2019-08-13 | Ardelyx, Inc. | Compounds and methods for inhibiting NHE-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders |
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- 1996-05-14 DE DE59605101T patent/DE59605101D1/de not_active Expired - Lifetime
- 1996-05-14 DK DK96107622T patent/DK0744397T3/da active
- 1996-05-14 ES ES96107622T patent/ES2147629T3/es not_active Expired - Lifetime
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- 1996-05-14 PT PT96107622T patent/PT744397E/pt unknown
- 1996-05-15 PL PL96314252A patent/PL183431B1/pl unknown
- 1996-05-17 SK SK651-96A patent/SK281527B6/sk unknown
- 1996-05-17 RU RU96109699/04A patent/RU2164913C2/ru not_active IP Right Cessation
- 1996-05-20 CN CN96100265A patent/CN1063437C/zh not_active Expired - Fee Related
- 1996-05-20 AU AU52373/96A patent/AU701493B2/en not_active Ceased
- 1996-05-20 HU HU9601358A patent/HUP9601358A3/hu unknown
- 1996-05-20 CZ CZ19961450A patent/CZ291622B6/cs not_active IP Right Cessation
- 1996-05-20 NZ NZ286622A patent/NZ286622A/xx unknown
- 1996-05-20 TR TR96/00421A patent/TR199600421A2/xx unknown
- 1996-05-20 IL IL11832796A patent/IL118327A/en not_active IP Right Cessation
- 1996-05-20 HR HR960230A patent/HRP960230B1/xx not_active IP Right Cessation
- 1996-05-20 AR ARP960102622A patent/AR002744A1/es unknown
- 1996-05-21 JP JP12523696A patent/JP3924018B2/ja not_active Expired - Fee Related
- 1996-05-21 ZA ZA9604035A patent/ZA964035B/xx unknown
- 1996-05-21 KR KR1019960017109A patent/KR960041152A/ko not_active Application Discontinuation
- 1996-05-21 BR BR9602394A patent/BR9602394A/pt not_active Application Discontinuation
- 1996-05-21 CA CA002177007A patent/CA2177007C/en not_active Expired - Fee Related
- 1996-05-21 NO NO962063A patent/NO305552B1/no not_active IP Right Cessation
- 1996-05-22 MY MYPI96001926A patent/MY113803A/en unknown
- 1996-06-14 TW TW085107133A patent/TW415936B/zh not_active IP Right Cessation
-
2000
- 2000-05-16 GR GR20000401106T patent/GR3033416T3/el not_active IP Right Cessation
-
2001
- 2001-02-08 US US09/778,899 patent/US20010020042A1/en not_active Abandoned
- 2001-12-20 US US10/024,388 patent/US6504057B2/en not_active Expired - Fee Related
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US20090099239A1 (en) * | 2005-06-24 | 2009-04-16 | Gary Dinneen Ewart | Antiviral Compounds and Methods |
US8669280B2 (en) | 2005-06-24 | 2014-03-11 | Biotron Limited | Antiviral compounds and methods |
US9440926B2 (en) | 2005-06-24 | 2016-09-13 | Biotron Limited | Antiviral compounds and methods |
US10683263B2 (en) | 2005-06-24 | 2020-06-16 | Biotron Limited | Antiviral compounds and methods |
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