Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
  • C07D213/32—Sulfur atoms
  • C07D213/34—Sulfur atoms to which a second hetero atom is attached
• • 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
  • A61P11/06—Antiasthmatics

Definitions

• cAMP cyclic AMP
• the level of intracellular cAMP is regulated through both its synthesis by adenyl cyclases and degradation by cyclic nucleotide phosphodiesterases (PDE).
• PDEs form a family of at least seven enzyme isotypes (I-VII) which differ in their affinity for cAMP and/or cGMP, subcellular localisation and regulation (Beavo J.A.
• PDE isotype selective inhibitors have enabled the role of PDEs in a variety of cell types to be investigated.
• PDE IV controls the breakdown of cAMP in many inflammatory cells, for example, basophils (Peachell P.T. et al, (1992) J. Immunol. 148 2503-2510) and eosinophils (Dent G. et al, (1991) Br. J. Pharmacol 103 1339-1346) and that inhibition of this isotype is associated with the inhibition of cell activation.
• Consequendy PDE IV inhibitors are currently being developed as potential anti-inflammatory drugs particularly for the prophylaxis and treatment of asthma.
• This invention is concerned with a novel process for the preparation of a compound of structural formula I
• Rl is phenyl, substituted phenyl, Cl-6 alkyl or C2-6 alkenyl which is an important antiasthmatic agent which comprises the key step of the addition of Rl to an intermediate 2:
• Rl is Cl-6 alkyl, C2-6 alkenyl, phenyl, either unsubstituted or substituted with one or two substituents, which can be the same or different, selected from the group consisting of R2 and Alk(R2) m; wherein
• Alk is straight or branched chain Cl-6 alkylene, C2-6 alkenylene or
• C2-6 alkynylene optionally interrupted by one, two or three -O-, -S-, -S(0)p or -N(R3)-;
• R3 is hydrogen or Cl-6 alkyl or C2-6 alkenyl
• R 4 is l) C3-6 cycloalkyl
• Cl-3 alkoxy R6 is 1) tolyl, 2) phenyl,
• M is ZnLi or ZnMgBr.
• m is zero or an integer selected from 1, 2 and 3; and
• p is an integer selected from 1 and 2.
• the process comprises treating the olefin 2, and a catalyst, nickel acetylacetonate, Ni(acac)2, in an ethereal solvent such as THF, diethyl ether, glyne, or diglyme, preferably THF cooling to about -35 to - 15°C and adding a slurry of the zincate, RI3M, in the same ethereal solvent also at -35 to -15°C while maintaining the temperature below about -15°C.
• an ethereal solvent such as THF, diethyl ether, glyne, or diglyme
• the mixture is quenched with ammonium chloride solution and ethyl acetate and the pH adjusted to about 10 with a base, such as ammonium hydroxide, sodium or potassium hydroxide, a sodium or potassium carbonate.
• a base such as ammonium hydroxide, sodium or potassium hydroxide, a sodium or potassium carbonate.
• the product 4 is isolated from the organic layer, dissolved in an ethereal solvent preferably THF and an organic acid such as acetic acid, pivalic acid, trifluoroacetic chloroacetic acid, or propionic acid and treated with Zn metal.
• an immiscible organic solvent such as methylene chloride, chloroform toluene, or ethylacetate is added and the pH is adjusted to about 6.
• the product, 1, is isolated from the organic layer.
• the starting material, 2 is obtained according to the following reaction scheme:
• alkyl means straight or branched alkyl with the indicated number of carbon atoms.
• Halo means chloro, bromo, fluoro or iodo.
• Menthyltoluene Sulfinate 2a 30 g 294.46 102
• a solution of picoline in THF (351 mL) was cooled to -50°C and treated with n-BuLi while maintaining the intenral temperature -45°C.
• the deep orange reacion mixture was warmed to ambient temperature and aged for 1 hr.
• the resulting dark solution was treated at 22°C with a solution of the sulfinate in THF (120mL) while maintaining the temperature ⁇ 27°C.
• the reaction was aged for 30 min upon which time HPLC analysis indicated disappearance of the sulfinate 2a.
• the reaction mixture was quenced with IM aqueous NH4CI (700mL), CH2CI2 (lOOOmL) was added and the layers were partitioned.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Pulmonology (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Pharmacology & Pharmacy (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines Containing Material From Animals Or Micro-Organisms (AREA)

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Publications (1)

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Cited By (2)

Citations (2)

• 1997
  • 1997-04-07 AR ARP970101372A patent/AR006550A1/es unknown
  • 1997-04-14 BR BR9708684A patent/BR9708684A/pt unknown
  • 1997-04-14 AU AU24592/97A patent/AU2459297A/en not_active Abandoned
  • 1997-04-14 WO PCT/US1997/006131 patent/WO1997038976A1/en not_active Application Discontinuation
  • 1997-04-14 CN CN97193932A patent/CN1216532A/zh active Pending
  • 1997-04-14 SK SK1431-98A patent/SK143198A3/sk unknown
  • 1997-04-14 EA EA199800931A patent/EA000877B1/ru not_active IP Right Cessation
  • 1997-04-14 CZ CZ983332A patent/CZ333298A3/cs unknown
  • 1997-04-14 EP EP97920379A patent/EP0898564A1/en not_active Withdrawn
  • 1997-04-15 TW TW086104869A patent/TW426669B/zh not_active IP Right Cessation

Patent Citations (2)

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