Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Patent
1993-04-22
1994-02-22
Dees, Jose G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
548253, 549496, 560 11, 560 15, 562406, 562429, C07B 5700, C07C31706, C07C32316, C07D25704, C07D30702
Patent
active
052889009
DESCRIPTION:
BRIEF SUMMARY
SCOPE OF THE INVENTION
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.
BACKGROUND OF THE INVENTION
"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 potentiation 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 number of the compounds developed are normally prepared as a racemic mixture, though activity lies primarily or completely in just one of the optical isomers. Resolving these mixtures is a useful, if not necessary step in preparing a useful formulation for treating these diseases. It has now been found that for certain compounds, the ones set out below, this can be accomplished most readily and inexpensively by means of (R)-4-nitro-.alpha.-methylbenzenemethanamine. This amine is uniquely suited to resolving certain enantiomers of the compounds given below so that the most active isomer can be obtained for use in treating SRS-related diseases.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of this invention are (R)-4-nitro-.alpha.-methylbenzenemethanamine salts of formula I ##STR1## where: A is 1 and X is 1 or 2; to C.sub.12 alkylthio, C.sub.10 to C.sub.12 1-alkynyl, 10-undecynyloxy, 11-dodecynyl, phenyl-C.sub.4 to C.sub.10 alkyl, phenyl-C.sub.3 to C.sub.9 alkoxy, phenylthio-C.sub.3 to C.sub.9 alkyl with the phenyl optionally mono substituted with bromo, chloro, trifluoromethyl, C.sub.1 to C.sub.4 alkoxy, methylthio or trifluoromethylthio, furyl-C.sub.4 to C.sub.10 alkyl, trifluoromethyl-C.sub.7 to C.sub.12 alkyl or cyclohexyl-C.sub.4 to C.sub.10 alkyl; phenylthioalkyl when q is 1 or 2; (CH.sub.2).sub.0-1 -C-tetrazolyl; R.sub.6 group respectively which is O.sup.-.
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 ##STR2## where R, R.sub.1, q and Y are defined above with the proviso that R.sub.3 and R.sub.6 are R.sub.3' and R.sub.6' where R.sub.3' and R.sub.6' are independently --OH, amino, or C.sub.1 to C.sub.6 alkoxy, with the further proviso that at least one of R.sub.3' or R.sub.6' 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-.alpha.-methylbenzenemethanamine or (S)-4-nitro-.alpha.-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) ##STR3## wherein A is 1, X is 1 or 2, and R.sub.1 and R are described above.
Another preferred group of these salts are 3-aryl-propionates of formula (IB) ##STR4## wherein R.sub.1 is defined above, particularly where R.sub.1 is phenylalkyl. Most preferred among the salts of this group are: (S)-.beta.-[(2-carboxyethyl)thio]-2-(1-dodecyl)benzenepropanoic acid; and the (S)-.beta.-[(2-carboxyethyl)thio]-2-(8-phenyloctyl)benzenepropanoic acid.
Another preferred group of salts are the aryl-acetates of formula (IC). ##STR5## where R.sub.1 is described above, particularly where R.sub.1 is phenylalkyl.
The
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Laird Trevor
Mills Robert J.
Clarke Vera C.
Dees Jos,e G.
Kanagy James M.
Lentz Edward T.
SmithKline Beecham Corporation
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