Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
  • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
  • C07D223/16—Benzazepines; Hydrogenated benzazepines
• • 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
• • 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
  • 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
  • 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
  • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides

Definitions

• the invention relates to a group of novel salts of compounds with the formula
• EP 0733642 is related to compounds with the formula (l) and their physiologically acceptable salts as such and to the use of the compound in heart insufficiency.
• EP 0830863, WO00/48601 and WO01/03699 are related to the use of the above compounds in the improvement of gastrointestinal blood flow, in the treatment of hypertension and in the treatment and prophylaxis of cardiac damages induced by adriamycin and comparable anti-cancer drugs, respectively.
• Preferred benzazepines are the compounds wherein Ri is a phenylethyl group or a 1-naphtylethyl group, R 2 and R 3 are both hydrogen and wherein R 4 is a biolabile ester group.
• Suitable groups forming biolabile esters include (C C 6 )-alkyl groups, phenyl or phenyl-(C C 6 )-alkyl groups which are optionally substituted in the phenyl ring by (CrC 6 )-alkyl or by a (C 2 -C 6 )-alkylene chain bonded to two adjacent carbon atoms, dioxolanylmethyl groups which are optionally substituted in the dioxolane ring by (C-r C 6 )-alkyl or (C 2 -C 6 )-alkanoyloxymethyl groups which are optionally substituted on the oxymethyl group by (C 1 -C 6 )-alkyl.
• the group R 4 is a by (C C 6 )-alkyl this is preferably an unbranched (C 1 -C 4 )-alkyl group. In the most preferred compounds R 4 is ethyl.
• bivalent metal salts are calcium, magnesium and zinc salts. Most preferred is the calcium salt.
• these salts contrary to the sodium and potassium salts mentioned in EP0733642 have highly desirable properties, as they can be isolated in solid (amorphous) form and have a solubility in an isotonic fluid of pH 7.4 which is at least a factor of 10 higher than the corresponding acid. Further the bivalent salts can be prepared without racemisation.
• metal salts preferably L ⁇ or the bivalent Ca 2+ , Mg 2+ or Zn 2+ salts. It has surprisingly been found that lithium salts and bivalent metal salts of the compound of formula I are very soluble in slightly polar aprotic solvents at room temperature, such as cyclohexane, toluene, methyl tertiairy butyl ether and ethyl acetate.
• the salts of the present invention can be easily obtained by mixing hydroxide or a suitable salt of the desired metal with a solution or slurry of the compound of formula I in one of the above mentioned slightly polar aprotic solvents.
• a small amount of water can be added to the solution or slurry in the organic solvent and the water can be removed by azeotropic destination.
• an apolar aprotic solvent which forms an azeotrope with water has to be selected.
• the metal can be added in the form of an ethoxide (e.g.
• the preferred solvent for the above method is methyl tertiairy methyl ether or ethyl acetate.
• a precipitant is defined as a second liquid that is added to a solution to reduce the solubility of the dissolved compound, causing its precipitation/crystallization and maximizing the yield of product. It is necessary for the two liquids (the original solvent and the added precipitant) to be completely miscible with one another in all proportions.
• the salt is isolated in the form of a non-crystalline precipitate, which appears in all cases to be homogeneous, it is sometimes desirable to have a real crystallisation step in order to improve the purity of the active compound whichhas to meet strict requirements.
• the S- ⁇ -methylbenzyl amine salt of the compound of formula I is extremely suitable in the purification of these compounds, as said salt is crystalline and can be easily recrystallised in high yields from organic solvents, preferably alcohols such as ethanol or isopropyl alcohol. Therefore the present invention is also related to S- ⁇ -methylbenzylamine salts of the compounds of formula I. Said salts are only suitable as intermediates in a purification step, as the S- ⁇ -methylbenzylamine appears to be too toxic to be used.
• the S- ⁇ -methylbenzylamine salts of the compounds of formula I can be prepared by adding S- ⁇ -methylbenzylamine to a solution of the compound of formula I in ethanol or isopropanol or another suitable alcohol. The salt will crystallize from that solution upon standing and cooling (dependent on concentration)
• the pharmaceutically acceptable salts of the present invention can be formulated according to state-of-the art formulation processes.
• Customary formulations can be used, such as, e.g. tablets, capsules or suppositories.
• These pharmaceutical formulations can be produced by known methods such as direct compression, granulation, extrusion, moulding using conventional solid excipients such as fillers e.g. celluloses, lactoses and starches, binders e.g. celluloses and polyvinylpyrrolidon (pvp), desintegrants e.g. starches and cross-linked pvp, glidiants e.g.
• colloidal silica e.g magnesium stearate or conventional liquid and semi-solid excipients such as poly ethylene glycols, caster oil derivates, triglycerides and paraffins. Additionally preservatives e.g. parabens and emulsifiers e.g. poly sorbates can be added.
• the pharmaceutically acceptable salts of the present invention are suitable as medicaments for larger mammals, especially humans, for in the treatment of heart failure and for promoting diuresis/natriuresis, especially in patients suffering from heart failure, for the improvement of gastrointestinal blood flow, in the treatment of hypertension and in the treatment and prophylaxis of cardiac damages induced by adriamycin and comparable anti-cancer drugs.
• the compounds of the invention can be used in medicinal forms which can be administered parenterally, especially i.v., orally or as suppository.
• the doses to be used may vary individually and vary with the nature of the condition to be treated, the particular substance used and the mode of administration.
• Medicinal forms with an active substance content of from 1 to 800 mg per individual dose are generally suitable for administration to larger mammals, especially humans.
• the following examples are only intended to further illustrate the invention, in more detail, and therefore these example are not deemed to restrict the scope of the invention in any way.
• the filtered solution was dosed to hexane and, when a solid product was formed, it was collected on a filter. When a tar or oil was formed the largest part of the solvent was decanted and the remaining solvent was evaporated to yield a solid foam.
• the properties of the salts prepared are summarised in Table 2.
• the metal content was determined by a complexometric titration with ethylenediamine-tetra-acetic acid disodiumsalt solution for Calcium and with Atomic Emission Spectroscopy (AES) for all other metals.
• AES Atomic Emission Spectroscopy
• Li, Ca, Mg and Zn salts which were isolated as a solid powder are soluble in slightly polar aprotic solvents.
• these solvents are ethyl acetate, toluene, cyclohexane and methyl t-butyl ether.
• the compounds are also soluble in polar aprotic solvents such as THF, acetone, acetonitril, DMF and DMSO.
• the metal contents found in the salt are somewhat higher than the theoretical amounts, but this is normal in these types of work-up and analyses.
• salt formation with the strongly basic monovalent hydroxides degradation of the active substance occurs, leading to a low compound content in the final salt.
• Example 2 Preparation of the S- ⁇ -methylbenzylamine salt of 1H-1-Benz- azepine-1 -acetic acid, 3-[[[1 - ⁇ (2R)-2-(ethoxycarbonyl)-4-phenylbutyl]-cyclo- pentyl]carbonyl]amino]-2,3,4,5-tetrahydro-2-oxo-, (3S)-.
• the layers were separated and the organic layer was washed two times with 50 ml of water.
• the organic layer was concentrated to an oil, 15 ml of ethyl acetate was added and the solution obtained was again concentrated to an oil.
• the oil was solved again in 80 ml of ethyl acetate and 2 ml of water was added.
• An amount of 0.56 g Ca(OH) 2 95% was added and the mixture was refluxed during 4 hours via a water trap (Dean-Stark apparatus).
• the solution was filtered and reduced in volume to 40 ml.
• the solution was cooled down to 30-35°C and dosed in 30 minutes to 250 ml of cold hexane (10°C) and stirred for an additional 30 minutes at 10°C.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Medicinal Chemistry (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Animal Behavior & Ethology (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Veterinary Medicine (AREA)
• Pharmacology & Pharmacy (AREA)
• Public Health (AREA)
• Biochemistry (AREA)
• Molecular Biology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Engineering & Computer Science (AREA)
• Biophysics (AREA)
• Genetics & Genomics (AREA)
• Heart & Thoracic Surgery (AREA)
• Cardiology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Peptides Or Proteins (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

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• 2003
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  • 2003-01-15 AU AU2003206755A patent/AU2003206755B2/en not_active Ceased
  • 2003-01-15 RU RU2004124840/04A patent/RU2303041C2/ru not_active IP Right Cessation
  • 2003-01-15 WO PCT/EP2003/000515 patent/WO2003059939A1/en not_active Ceased
  • 2003-01-15 EP EP03704436A patent/EP1468010A1/en not_active Withdrawn
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• 2004
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