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 PDF

Info

Publication number
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
Authority
US
United States
Prior art keywords
formula
compound
administering
effective amount
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.)
Abandoned
Application number
US09/778,899
Other languages
English (en)
Inventor
Jan-Robert Schwark
Hans-Jochen Lang
Heinz-Werner Kleemann
Andreas Weichert
Wolfgang Scholz
Udo Albus
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.)
Hoechst AG
Original Assignee
Hoechst AG
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Hoechst AG filed Critical Hoechst AG
Priority to US09/778,899 priority Critical patent/US20010020042A1/en
Publication of US20010020042A1 publication Critical patent/US20010020042A1/en
Priority to US10/024,388 priority patent/US6504057B2/en
Abandoned legal-status Critical Current

Links

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.

Landscapes

  • 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)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Diabetes (AREA)
  • Urology & Nephrology (AREA)
  • Endocrinology (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Emergency Medicine (AREA)
  • Vascular Medicine (AREA)
  • Surgery (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Reproductive Health (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)
US09/778,899 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 Abandoned US20010020042A1 (en)

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
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
DE19518796.2 1995-05-22
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
US20010020042A1 true US20010020042A1 (en) 2001-09-06

Family

ID=7762597

Family Applications (2)

Application Number Title Priority Date Filing Date
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
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 (cs)
EP (1) EP0744397B1 (cs)
JP (1) JP3924018B2 (cs)
KR (1) KR960041152A (cs)
CN (1) CN1063437C (cs)
AR (1) AR002744A1 (cs)
AT (1) ATE192431T1 (cs)
AU (1) AU701493B2 (cs)
BR (1) BR9602394A (cs)
CA (1) CA2177007C (cs)
CZ (1) CZ291622B6 (cs)
DE (2) DE19518796A1 (cs)
DK (1) DK0744397T3 (cs)
ES (1) ES2147629T3 (cs)
GR (1) GR3033416T3 (cs)
HR (1) HRP960230B1 (cs)
HU (1) HUP9601358A3 (cs)
IL (1) IL118327A (cs)
MY (1) MY113803A (cs)
NO (1) NO305552B1 (cs)
NZ (1) NZ286622A (cs)
PL (1) PL183431B1 (cs)
PT (1) PT744397E (cs)
RU (1) RU2164913C2 (cs)
SI (1) SI0744397T1 (cs)
SK (1) SK281527B6 (cs)
TR (1) TR199600421A2 (cs)
TW (1) TW415936B (cs)
ZA (1) ZA964035B (cs)

Cited By (2)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
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
EP1180029A4 (en) 1999-04-23 2002-10-02 Bristol Myers Squibb Co BICYCLIC ACYL IHIBITORING SODIUM / PROTON EXCHANGER AND RELATED PROCEDURE.
KR101153254B1 (ko) * 2003-06-26 2012-07-02 바이오트론 리미티드 항바이러스 화합물 및 방법
AU2013205388B2 (en) * 2005-06-24 2016-05-05 Biotron Limited Antiviral compounds and methods
EP2384318B1 (en) 2008-12-31 2017-11-15 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
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
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
HK1211469A1 (en) 2012-08-21 2016-05-27 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
PT2983667T (pt) 2013-04-12 2019-07-11 Ardelyx Inc Compostos e métodos de ligação ao nhe3 para inibir o transporte de fosfato
JP2020505333A (ja) 2017-01-09 2020-02-20 アルデリックス， インコーポレイテッド Ｎｈｅ媒介性アンチポートの阻害薬
CN110267944B (zh) 2017-01-09 2024-03-08 阿德利克斯股份有限公司 可用于治疗胃肠道病症的化合物
EP4397366A3 (en) 2017-08-04 2024-11-20 Ardelyx, Inc. Glycyrrhetinic acid derivatives for treating hyperkalemia
ES2953233T3 (es) 2019-02-07 2023-11-08 Ardelyx Inc Derivados del ácido glicirretínico para su uso en el tratamiento de la hiperpotasemia
US20200368223A1 (en) 2019-05-21 2020-11-26 Ardelyx, Inc. Methods for inhibiting phosphate transport

Family Cites Families (70)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2734904A (en) 1956-02-14 Xcxnhxc-nh
US564937A (en) * 1896-07-28 Culm-loader
US2743904A (en) 1950-11-07 1956-05-01 Loren F Scott Excavating apparatus
US3571861A (en) * 1968-11-26 1971-03-23 Famco Inc Bag closure means
US3612475A (en) * 1969-04-02 1971-10-12 Amp Inc Flexible tube closure
US3713622A (en) * 1971-02-26 1973-01-30 Amp Inc Closure device for flexible tubing
US3874042A (en) * 1973-01-22 1975-04-01 Biospectrum Inc Clamp for thin walled tubing
US3857396A (en) * 1973-08-22 1974-12-31 C Hardwick Suture clamp
US4547202A (en) * 1982-02-02 1985-10-15 Atlantic Richfield Company Hydrocarbon oils with improved pour points
US4454875A (en) * 1982-04-15 1984-06-19 Techmedica, Inc. Osteal medical staple
US4548201A (en) * 1982-04-20 1985-10-22 Inbae Yoon Elastic ligating ring clip
US4544670A (en) 1982-08-24 1985-10-01 William H. Rorer, Inc. Method of treating coccidiosis with acyl guanidines
US4534350A (en) * 1983-06-20 1985-08-13 Ethicon, Inc. Two-piece tissue fastener with compressible leg staple and retaining receiver
US4612923A (en) * 1983-12-01 1986-09-23 Ethicon, Inc. Glass-filled, absorbable surgical devices
US4646741A (en) * 1984-11-09 1987-03-03 Ethicon, Inc. Surgical fastener made from polymeric blends
US4955913A (en) * 1985-03-28 1990-09-11 Robinson Walter C Surgical tie
US4889119A (en) * 1985-07-17 1989-12-26 Ethicon, Inc. Surgical fastener made from glycolide-rich polymer blends
US5366459A (en) * 1987-05-14 1994-11-22 Inbae Yoon Surgical clip and clip application procedures
US4960420A (en) * 1988-08-23 1990-10-02 Marlowe Goble E Channel ligament clamp and system
US4932962A (en) * 1989-05-16 1990-06-12 Inbae Yoon Suture devices particularly useful in endoscopic surgery and methods of suturing
US4955959A (en) * 1989-05-26 1990-09-11 United States Surgical Corporation Locking mechanism for a surgical fastening apparatus
US4997433A (en) * 1990-01-16 1991-03-05 Marlowe Goble E Endosteal fixation stud and system
US5013316A (en) * 1990-03-26 1991-05-07 Marlowe Goble E Soft tissue anchor system
US5078731A (en) * 1990-06-05 1992-01-07 Hayhurst John O Suture clip
US5152034A (en) * 1990-10-19 1992-10-06 Konings Frederikus J J Click-clip
US5425489A (en) * 1990-12-20 1995-06-20 United States Surgical Corporation Fascia clip and instrument
US6102921A (en) * 1990-12-21 2000-08-15 University Of New Mexico Nerve anastomosis sling and method
US5203864A (en) * 1991-04-05 1993-04-20 Phillips Edward H Surgical fastener system
US5217472A (en) * 1991-05-07 1993-06-08 United States Surgical Corporation Surgical fastening device
US5257713A (en) * 1991-05-07 1993-11-02 United States Surgical Corporation Surgical fastening device
GB9111972D0 (en) * 1991-06-04 1991-07-24 Clinical Product Dev Ltd Medical/surgical devices
US5290217A (en) * 1991-10-10 1994-03-01 Earl K. Sipes Method and apparatus for hernia repair
US5289963A (en) * 1991-10-18 1994-03-01 United States Surgical Corporation Apparatus and method for applying surgical staples to attach an object to body tissue
US5497933A (en) * 1991-10-18 1996-03-12 United States Surgical Corporation Apparatus and method for applying surgical staples to attach an object to body tissue
US5356064A (en) * 1991-10-18 1994-10-18 United States Surgical Corporation Apparatus and method for applying surgical staples to attach an object to body tissue
US5333624A (en) * 1992-02-24 1994-08-02 United States Surgical Corporation Surgical attaching apparatus
US5171251A (en) * 1992-03-02 1992-12-15 Ethicon, Inc. Surgical clip having hole therein and method of anchoring suture
US5425737A (en) * 1992-04-08 1995-06-20 American Cyanamid Co. Surgical purse string suturing instrument and method
US6312442B1 (en) * 1992-06-02 2001-11-06 General Surgical Innovations, Inc. Method for developing an anatomic space for laparoscopic hernia repair
CA2104345A1 (en) * 1992-09-02 1994-03-03 David T. Green Surgical clamp apparatus
US5362294A (en) * 1992-09-25 1994-11-08 Seitzinger Michael R Sling for positioning internal organ during laparoscopic surgery and method of use
US5282832A (en) * 1992-10-09 1994-02-01 United States Surgical Corporation Suture clip
US5464416A (en) * 1992-11-10 1995-11-07 Ethicon, Inc. Ligating clip
US5328077A (en) * 1992-11-19 1994-07-12 Lou Ek Seng Method and apparatus for treating female urinary incontinence
US5649939A (en) * 1992-12-08 1997-07-22 Reddick; Eddie J. Laparoscopic suture introducer
EP0612723B1 (de) * 1993-02-20 1997-08-27 Hoechst Aktiengesellschaft Substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament, als Inhibitoren des zellulären Na+/H+-Austauschs oder als Diagnostikum sowie sie enthaltendes Medikament
US5354292A (en) * 1993-03-02 1994-10-11 Braeuer Harry L Surgical mesh introduce with bone screw applicator for the repair of an inguinal hernia
US5474543A (en) * 1993-05-17 1995-12-12 Mckay; Hunter A. Single needle apparatus and method for performing retropublic urethropexy
CA2124651C (en) * 1993-08-20 2004-09-28 David T. Green Apparatus and method for applying and adjusting an anchoring device
US5507754A (en) * 1993-08-20 1996-04-16 United States Surgical Corporation Apparatus and method for applying and adjusting an anchoring device
DE4328869A1 (de) * 1993-08-27 1995-03-02 Hoechst Ag Ortho-substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament
US5542594A (en) * 1993-10-06 1996-08-06 United States Surgical Corporation Surgical stapling apparatus with biocompatible surgical fabric
US5618290A (en) * 1993-10-19 1997-04-08 W.L. Gore & Associates, Inc. Endoscopic suture passer and method
US5776147A (en) * 1993-10-20 1998-07-07 Applied Medical Resources Corporation Laparoscopic surgical clamp
AU1011595A (en) * 1994-01-13 1995-07-20 Ethicon Inc. Spiral surgical tack
US5452836A (en) * 1994-02-07 1995-09-26 Ethicon Endo-Surgery, Inc. Surgical stapling instrument with improved jaw closure and staple firing actuator mechanism
US5425740A (en) * 1994-05-17 1995-06-20 Hutchinson, Jr.; William B. Endoscopic hernia repair clip and method
DE4421536A1 (de) 1994-06-20 1995-12-21 Hoechst Ag Perfluoralkylgruppen tragende phenylsubstituierte Alkenylcarbonsäure-guanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament
US5569306A (en) * 1995-06-06 1996-10-29 Thal; Raymond Knotless suture anchor assembly
DE69736174T2 (de) * 1996-04-19 2007-05-16 Applied Medical Resources Corp., Laguna Hills Vorrichtung zum anbringen von halteklammern
US5816258A (en) * 1996-06-13 1998-10-06 General Surgical Innovations, Inc. Bladder neck suspension method
US6024748A (en) * 1996-07-23 2000-02-15 United States Surgical Corporation Singleshot anastomosis instrument with detachable loading unit and method
US6109500A (en) * 1996-10-04 2000-08-29 United States Surgical Corporation Lockout mechanism for a surgical stapler
JP2002514100A (ja) * 1996-10-24 2002-05-14 スピナル コンセプツ，インク． 脊椎を固定するための方法および装置
US5766250A (en) * 1996-10-28 1998-06-16 Medicinelodge, Inc. Ligament fixator for a ligament anchor system
US5954057A (en) * 1997-02-12 1999-09-21 Li Medical Technologies, Inc. Soft tissue suspension clip, clip assembly, emplacement tool and method
US5904692A (en) * 1997-04-14 1999-05-18 Mitek Surgical Products, Inc. Needle assembly and method for passing suture
US5960522A (en) * 1997-05-21 1999-10-05 Micron Electronics, Inc. Ribbon cable alligator clamp
US6099552A (en) * 1997-11-12 2000-08-08 Boston Scientific Corporation Gastrointestinal copression clips
JP2002514463A (ja) * 1998-05-12 2002-05-21 サイムド ライフ システムズ， インコーポレイテッド 手動骨アンカ配置デバイス

Cited By (5)

* Cited by examiner, † Cited by third party
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
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

Also Published As

Publication number Publication date
NO962063L (no) 1996-11-25
AU5237396A (en) 1996-12-05
HRP960230B1 (en) 2000-12-31
CN1063437C (zh) 2001-03-21
TW415936B (en) 2000-12-21
SK65196A3 (en) 1996-12-04
ZA964035B (en) 1997-11-21
PL314252A1 (en) 1996-11-25
ES2147629T3 (es) 2000-09-16
MY113803A (en) 2002-05-31
IL118327A (en) 2002-12-01
HU9601358D0 (en) 1996-07-29
CN1138029A (zh) 1996-12-18
SI0744397T1 (en) 2000-08-31
JP3924018B2 (ja) 2007-06-06
EP0744397B1 (de) 2000-05-03
HUP9601358A3 (en) 1997-10-28
DE59605101D1 (de) 2000-06-08
SK281527B6 (sk) 2001-04-09
US20020123529A1 (en) 2002-09-05
JPH08319266A (ja) 1996-12-03
DK0744397T3 (da) 2000-08-28
BR9602394A (pt) 1998-10-06
HUP9601358A2 (en) 1997-05-28
IL118327A0 (en) 1996-09-12
PT744397E (pt) 2000-09-29
PL183431B1 (pl) 2002-06-28
HRP960230A2 (en) 1997-12-31
KR960041152A (ko) 1996-12-19
EP0744397A2 (de) 1996-11-27
CA2177007A1 (en) 1996-11-23
NZ286622A (en) 1997-08-22
GR3033416T3 (en) 2000-09-29
RU2164913C2 (ru) 2001-04-10
CZ291622B6 (cs) 2003-04-16
ATE192431T1 (de) 2000-05-15
AU701493B2 (en) 1999-01-28
NO962063D0 (no) 1996-05-21
US6504057B2 (en) 2003-01-07
CA2177007C (en) 2009-01-06
AR002744A1 (es) 1998-04-29
CZ145096A3 (en) 1996-12-11
TR199600421A2 (tr) 1997-03-21
DE19518796A1 (de) 1996-11-28
NO305552B1 (no) 1999-06-21
EP0744397A3 (de) 1997-03-26

Similar Documents

Publication Publication Date Title
US6504057B2 (en) Fluorophenyl-substituted alkenylcarboxylic acid guanidides, process for their preparation, their use as a medicament or diagnostic, and medicament containing them
US6025349A (en) Phenyl.-substituted alkenylcarboguanidides carrying perfluoroalkyl groups, a process for their preparation, their use as a medicament or diagnostic agent, and also a medicament containing them
JPH07304729A (ja) ペルフルオロアルキル−置換ベンゾイルグアニジン類、その製造方法、医薬または診断剤としてのその使用およびそれを含有する医薬
JPH06345643A (ja) 置換ベンゾイルグアニジン、その製造方法、医薬または診断薬としてのその使用およびそれらを含有する医薬
US5559153A (en) Urea-substituted benzoylguanidines, process for their preparation, their use as pharmaceutical or diagnostic, and pharmaceutical containing them
US5631293A (en) Preparation of amino acid-substituted benzoylguanidines as diagnostic agents
US5883133A (en) Substituted cinnamic acid guanidides, a process for their preparation, their use as medicaments or diagnostic agents and medicaments comprising them
CA2140989C (en) Phenyl-substituted alkylcarboguanidides carrying perfluoroalkyl groups, a process for their preparation, their use as a medicament or diagnosticagent, and a medicament containing them
US5747541A (en) Substituted benzoylguanidines, a process for their preparation, their use as medicament of diagnostic agent, and medicament comprising them
US5641792A (en) Benzoylguanidines substituted by heterocyclic N-oxide, process for their preparation and pharmaceutical compositions containing them
CA2152878A1 (en) Ortho-amino-substituted benzoylguanidines, a process for their preparation, their use as a medicament or diagnostic agent, and also a medicament containing them
US5665739A (en) Substituted benzoylguanidines, process and their preparation, their use as pharmaceutical or diagnostic, and pharmaceutical containing them
US5756535A (en) Substituted thiophenylalkenylcarboxylic acid guanidines, processes for their preparation, their use as a medicament or diagnositc, and a medicament containing them

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION