Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D291/00—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms
  • C07D291/02—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms not condensed with other rings
  • C07D291/04—Five-membered rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
  • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
  • C07K5/022—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2
  • C07K5/0222—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2 with the first amino acid being heterocyclic, e.g. Pro, Trp
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• N-sulfoxy anhydrides a process for the preparation thereof and its use for the preparation of bioactive substances having ACE inhibitory action
• the second type uses e.g. N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-N- carboxy-anhydride (NCA; see the formula (II) below) as reactant.
• NCA N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-N- carboxy-anhydride
• EP 0215335 A2 the reaction of N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine of the formula (I)
• R 1 represents PhCFH 2 -CH 2 - or CH 3 CH 2 CH 2 - and R 2 represents methyl or R 3 -NH-(CH 2 ) 3 -CH 2 ,-, R 3 being an amino protecting group, preferably CF 3 CO-.
• the second object of the invention is a process for the preparation of novel N-sulfoxy anhydrides of the formula (III), characterized in that a compound of the formula (IV)
• R 1 in R 2 have the above meanings
• R 4 represents the rest of imidazole, of alkyl imidazole, of benzimidazole, of tetrazole and of similar other heterocyclic compounds.
• the reaction between the compound of the formula (IV) and the compound ot the general formula (V) is carried out in dry organic solvents (humidity ⁇ 0.04% ). preferably in chlorinated organic solvents such as methylene chloride, or non- chlorinated organic solvents such as ethyl acetate, dimethyl carbonate, diethyl carbonate, acetonitrile etc.
• the formed hydrochloride of a heterocyclic compound e.g. imidazole HCl . methyl- imidazole HCl , benzimidazole HCl , tetrazole HCl etc., is filtered off or sucked ott. Organic bases may be regenerated and recycled.
• a heterocyclic compound e.g. imidazole HCl . methyl- imidazole HCl , benzimidazole HCl , tetrazole HCl etc.
• the third object of the invention is a process for the preparation of corresponding ACE inhibitors, wherein NSA (III) is reacted with corresponding derivatives ot amino acids defined below. More particularly, the object of the invention is a process for the preparation of ACE inhibitors of the formula
• R 1 and R 2 are defined as above and R has the following meanings
• inorganic salts e.g. potassium or sodium salts are used.
• organic salts preferably salts of DBU (1.8-diazabicyclo[5.4.0]undec-7-ene).
• DBN (1,5-diazabicyclo[4.3.0]non-5-ene).
• TEA triethylamine
• tetramethylguanidine imidazole. methylimidazole etc. are used.
• octahydro-1H-indole-2-carboxylic acid a pure isomer is used such as 2S,3aS,7aS or 2S,3aR,7aS, SSS or SRS trandolapril is obtained (see J. Med. Chem. 1987, 30, 992-998).
• Synthetised ACE inhibitors are recrystallized from acetonitrile or are purified by reprecipitation in ethyl acetate thus achieving high yields at purification (about 94 %).
• the mother liquor contained the novel compound N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-N- sulfoxy- anhydride or NSA, which was analyzed.
• NSA is oily liquid, unstable in humidity and air. and has a molecular weight 325 determined by iodometric titration on the basis of the following Scheme:
• NSA thus prepared may be used as starting material for the synthesis of ACE inhibitors.
• Trimethylchlorosilane (5.7 ml: 0.045 mole) was added to a mixture of L-proline (2.47 g; 0.0215 mole), anhydrous methylene chloride (90 ml) and triethylamine (2.5 ml: 0.018 mole) and the mixture was stirred for 2 hours.
• Thionylchloride (0.73 ml; 0.01 mole) was added to dry methylene chloride mixture (25 ml: H 2 O ⁇ ⁇ 0.04 % ) and the mixture was cooled to AC. Then imidazole (2.72 g: 0.04 mole) was added. The mixture was stirred for 65 minutes at a temperature between -5°C and room temperature 20°C.
• opalescent solution A (the preparation thereof is disclosed below) of siiylated (2S.3aS.7aS)- octahydro- 1 H-indole-2-carboxylic acid was added to the filtrate and an opalescent yellow solution was obtained. This solution was stirred for 1 to 6 hours at room temperature (21°C). Then the solution of H 2 O (10 ml) and NaCl (3 g) was added and 35% HCl was added to achieve pH 0.8. It was decanted and the organic phase was washed with water (5 ml). A solution of H 2 O (10 ml) and NaCl (3 g) was added to the organic phase and 33% NaOH was added to achieve pH 4.33.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Biochemistry (AREA)
• Biophysics (AREA)
• General Health & Medical Sciences (AREA)
• Genetics & Genomics (AREA)
• Medicinal Chemistry (AREA)
• Molecular Biology (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Peptides Or Proteins (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Priority Applications (1)

Applications Claiming Priority (2)

Publications (1)

Family

ID=20431608

Family Applications (1)

Country Status (4)

Cited By (5)

Families Citing this family (2)

Citations (3)

• 1995
  • 1995-04-24 SI SI9500140A patent/SI9500140A/sl not_active IP Right Cessation
• 1996
  • 1996-04-22 CA CA002203435A patent/CA2203435A1/en not_active Abandoned
  • 1996-04-22 WO PCT/SI1996/000009 patent/WO1996033984A1/en active Application Filing
  • 1996-04-22 AU AU52944/96A patent/AU5294496A/en not_active Abandoned

Patent Citations (3)

Non-Patent Citations (2)

Also Published As

Similar Documents

Legal Events