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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
  • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
  • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C323/56—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • 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

Definitions

• This invention relates to certain amine salts of leukotriene antagonists and the use of certain amines to form these salts as a means for crystallizing selectively optical isomers of the leukotriene antagonists recited herein.
• SRS-A Slow Reacting Substance of Anaphylaxis
• SRS-A has been shown to be a highly potent bronchoconstricting substance which is released primarily from mast cells and basophils on antigenic challenge.
• SRS-A has been proposed as a primary mediator in human asthma.
• SRS-A in addition to its pronounced effects on lung tissue, also produces permeability changes in skin and may be involved in acute cutaneous allergic reactions. Further, SRS-A has been shown to effect depression of ventricular contraction and p ⁇ tentiation of the cardiovascular effects of histamine. Antagonists to SRS substances have been developed in an attempt to provide relief from the disease conditions giving rise to or resulting from these compounds.
• A is 1 and X is 1 or 2;
• Rl is C8 to C1 3 alkyl, C ⁇ to C 1 2 alkoxy, C7 to C12 alkylthio, Cio to C 12 1-alkynyl, 10-undecynyloxy, 11-dodecynyl, phenyl-C4 to Ci o alkyl, phenyl-C3 to C9 alkoxy, phenylthio-C ⁇ to C9 alkyl with the phenyl optionally mono substituted with bromo, chloro, trifluoromethyl, Ci to C4 alkoxy, methylthio or trifluoromethylthio, furyl-C4 to Cio alkyl, trifluoromethyl-C7 to C 12 alkyl or cyclohexyl-C4 to Cio alkyl; q is 0, 1 or 2, with the proviso that Ri is not alkylthio or phenylthioalkyl when q is 1 or 2;
• Y is COR3, C(R4)H(CH 2 ) m COR3, or (CH2) ⁇ -l-C-tetrazolyl;
• R3 is 0"» amino, or Ci to C ⁇ alkoxy,
• R4 is hydrogen, methyl, C to C4-alkoxy, fluoro or hydroxy; m is 0, 1, or 2; R is (CH 2 ) n COR6; n is 0 to 6;
• R is O", amino, or Ci to C6-alkoxy; with the proviso that at least one of Y or R must have an R 3 or R6 group respectively which is O".
• This invention also relates to a process for separating a single isomer, either the R or S form, from a racemic mixture of a compound of formula II
• R, Ri, q and Y are defined above with the proviso that R3 and R ⁇ are R3' and R & where R 3 1 and R ⁇ ' are independently -OH, amino, or C i to CO alkoxy, with the further proviso that at least one of R 3 > or R ⁇ $ must be -OH or a salt thereof, which process comprises treating a racemic mixture of formula II with about 0.5 to 2.5 equivalents, relative to the number of carboxylic acid groups in the formula, of either (R)-4-nitro- ⁇ -methylbenzenemethanamine or (S)-4-nitro- ⁇ - methylbenzenemethanamine, recovering a crystalline salt, and converting the salt to an acid or a pharmaceutically acceptable salt. It is preferred to use 0.5 to 1.5 equivalents of the nitro compound per carboxylic acid group in formula II. This process yields a substantially pure single enantiomer from a racemic mixture.
• a preferred class of salts are those of formula (IA)
• A is 1, X is 1 or 2, and Ri and R are described above.
• Ri is defined above, particularly where Ri is phenylalkyl.
• Most preferred among the salts of this group are: the bis-(R)-4-nitro- ⁇ -methylbenzenemethanamine salt of (S)- ⁇
• Ri is described above, particularly where Ri is phenylalkyl.
• the salts of the formula (IC) are exemplified by the following compounds: the bis-(R)-4-nitro- ⁇ -methylbenzenemethanamine salt of (R)- ⁇ - [(2-carboxyethyl)thio]-2-(l-dodecyl)benzeneacetic acid; and the bis-(R)-4-nitro- ⁇ -methylbenzenemethanamine salt of (R)- ⁇ -[(2- carboxyethyl)thio]-2-(8-phenyloctyl)benzeneacetic acid.
• Ri is defined above, particularly where Ri is phenylalkyl.
• the compounds of formula (ID) are exemplified by the following compounds : the bis-(R)-4-nitro- ⁇ -methylbenzenemethanamine salt of [R- (R*,S*)]- ⁇ -[(2-carboxyethyl)thio]- ⁇ -hydroxy-2-(8-phenyloctyl)- benzenepropanoic acid; and the bis-(R)-4-nitro- ⁇ -methylbenzenemethanamine salt of [R-(R*,S*)]- ⁇ -[(2-carboxyethyl)thio]- ⁇ -hydroxy-2-(l -dodecyl)- benzenepropanoic acid.
• racemates of formula II In a process for resolving racemates of formula II, the following sets of general and specific compounds are preferred. A set of preferred racemates are those of formula (IIB),
• Ri is a phenyl-C_
• Most particularly racemates of formula (IIB) can be treated with the (R)-4- nitro- ⁇ -methylbenzenemethanamine to obtain, after further manipulation, the isomers (S)- ⁇ -[(2-carboxyethyl)thio]-2-(l - dodecyl)berizenepropanoic acid and (S)- ⁇ -[(2-carboxyethyl)thio]-2-(8- phenyloctyl)benzenepropanoic acid.
• racemates of formula (IID) can be treated with (R)-4- nitro- ⁇ -methylbenzenemethanamine to obtain, after further manipulation, the isomer [R-(R*,S*)]- ⁇ -[(2-carboxyethyl)thio]- ⁇ - hydroxy-2-(8-phenyloctyl)benzenepropanoic acid.
• the racemates of this invention can be prepared according to the disclosure set out in United States Patent number 4,820,719 issued April 11, 1989. That disclosure, in full, is incorporated herein by reference as if set out herein.
• the amine, (R)-4-nitro- ⁇ -methylbenzenemethanamine can be purchased as a hydrochloride salt from a commercial source such as Chiron, a Norwegian company. Or the hydrochloride salt may be made by the process of Baker, J. W. & Ingold, C.K., J. Chem. Soc. 261-264, 1927, and the R and S isomers fractionally crystallized by the method of Nerdel, F. and Liebeg, H., Ann 621 :42-50, 1959. A more recent process for making the hydrochloride salt of this amine is given in Perry, C.W. et al, Synthesis 492-494, 1977.
• the amine can be prepared by treating the hydrochloride salt with a strong base and extracting the amine into an organic solvent, for example methylene chloride or toluene. Amine prepared in this manner may be stored prior to use. Alternatively, the amine can be liberated in-situ by treating the hydrochloride salt with a strong base in an aqueous alcoholic solvent, and then used immediately.
• an organic solvent for example methylene chloride or toluene.
• Amine prepared in this manner may be stored prior to use.
• the amine can be liberated in-situ by treating the hydrochloride salt with a strong base in an aqueous alcoholic solvent, and then used immediately.
• This amine is a particularly effective resolving agent for separating out a particular isomer from a racemic mixture of compounds denoted by formula II.
• a salt is formed between the amine and the carboxylate function. This salt can be fractionally crystallized, giving a salt comprising the amine and just one isomer of the acid. An alcohol is the preferred solvent for crystallization. This method provides excellent selectivity for the desired isomer.
• salts may be converted to the corresponding acid by means of a dilute acid. Or they may be converted to another salt, such as an alkali metal salt, by treating a solution of the isolated salt with a base.
• the salt can be converted to the free acid by treating a solution of that salt with dilute mineral acid, for example 0.5N HC1 at room temperature or thereabouts. The mixture is then extracted with an appropriate organic solvent, or subjected to other convenient separatory means, and the pure isomer obtained as the free acid after removing the solvent.
• Racemic ⁇ -[(2-carboxyethyl)thio] -2-(8-phenyloctyl)- benzenepropanoic acid [6.05 g (60.7% assay, 8.3 mmol)] was dissolved in 80 mL of 2-propanol and treated with a solution of 1.48 g (8.9 mmol) of (R)-4-nitro- ⁇ -methylbenzenemethanamine in 2-propanol. The mixture was heated to reflux, then allowed to cool to 0°C. The resulting solids were isolated by filtration to afford, after drying, 2.33 g of crude product. Chiral HPLC analysis indicated 97.7% of the desired S-enantiomer.
• Example 3 Determination and Confirmation of Absolute Configuration Both (S)- ⁇ -[(2-carboxyethyl)thio]-2-(8-phenyloctyl)- benzenepropanoic acid and [R-(R*,S*)]- ⁇ -[(2-carboxyethyl)thio]- ⁇ - hydroxy-2-(8-phenyloctyl)benzenepropanoic acid react with two molar equivalents of (R)-4-iodo- ⁇ -methylbenzenemethanamine to produce highly crystalline salts. In each of these salts, the absolute configuration of the diacid portion was determined unambiguously by single crystal x-ray analysis.
• each salt was treated with aqueous acid and extracted with ethyl acetate.
• HPLC column cellulose tris-3,5-dimethylphenylcarbamate chiral stationary phase, coated on silica gel

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