Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-11-12
1999-11-30
Jones, Dwayne C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548465, 548468, 548469, A01N 4338, C07D20902
Patent
active
059943874
DESCRIPTION:
BRIEF SUMMARY
This invention relates to the fumarate salt of (R)-5-(methylaminosulphonylmethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1 H-indole of the structure: ##STR1##
Compound (I) in its free base form is described in Example 5A of WO-A-92/06973. The fumarate salt of (I) has not previously been described, although fumarate salts are mentioned in general terms only in a list of suitable pharmaceutically acceptable acid addition salts in WO-A-92/06973.
We have now found that the fumarate salt of (I) has unexpectedly improved stability to oxidative degradation. Also, and again unexpectedly, it has excellent solubility and solid state stability and is non-hygroscopic.
Accordingly, the present invention provides the fumarate salt of (R)-5-(methylaminosulphonylmethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-3-(N- methylpyrrolidin-2-ylmethyl)-1 H-indole, pharmaceutical compositions containing It, and its use in treating migraine.
The salt can be prepared by the reaction of compound (I) with fumaric acid, typically about 1 equivalent, in a suitable organic solvent or mixture of solvents as is illustrated in the following Example.
It can be formulated and administered to humans to treat migraine and other indications as described in WO-A-92/06973, which is incorporated herein by reference.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph of the stability of Compound (I) in 90% PEG 400 at 40.degree. C. with and without oxidative stress (mean.+-.stand. dev., n=3) .
EXAMPLE
(R)-5-(Methylaminosulphonylmethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-ind
ole
To a suspension of (R)-5-(methylaminosulphonylmethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-in dole (16.25 g, 0.0506 mol) in methanol (81.25 ml) was added, in one portion, fumaric acid (5.87 g, 0.0506 mol) at ambient temperature giving a fine suspension that was filtered and washed with methanol (16 ml). The stirred liquors were heated to reflux and diluted with acetonitrile (50 ml). Solvent was removed by distillation at atmospheric pressure and replaced with acetonitrile up to a vapour temperature of 80.degree. C. During distillation the solution was seeded with (R)-5-(methylaminosulphonylmethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-in dole fumarate and a slurry was produced. The slurry was allowed to cool to ambient temperature then granulated at 0.degree. C. for 1 hour. Filtration gave the product (21.45 g, 97%) as off-white crystals, m.p. 159.degree. C. (by DSC). Rf. 0.2 (silica, diethyl ether/ethyl acetate/DEA/MeOH, 10:10:1:1); [.alpha]sub.d +13.17.degree. (c=1,H.sub.2 O).
Found: C,54.94;H,6.35;N,9.60% C.sub.16 H.sub.23 N.sub.3 O.sub.2 S;C.sub.4 H.sub.4 O.sub.4 requires: C,54.91;H,6.22;N,9.60%
.sup.1 H-NMR (300 MHz. DMSO-d.sub.6): .delta.=1.50-1.90 (m, 4H), 2.50-2.54 (d, 3H), 2.54-2.60 (s, 3H), 2.62-2.74 (m, 1H), 2.82-2.96 (m, 1H), 3.08 (dd, 1 H), 3.20-3.30 (m, 1H), 4.28-4.36 (s, 2H), 6.48-6.54 (s, 2H) 6.70-6.80 (q, 1H), 7.02-7.12 (d, 1H), 7.16-7.22 (s, 1H), 7.28-7.36 (d, 1H), 7.48-7.56 (s, 1H), 10.86-10.94 (s, 1H).
For both the free base and fumarate salt, approximately 50 mg of solid bulk material was accurately weighed into a 1.5 mL plastic "Eppendorf" tube (Sigma). 0.3 mL of water (MilliQ) was then added to the tubes. The tubes were then vortex mixed at 1,300 rpm ("LKB") for 16 hours at room temperature. The supematant was separated from undissolved material by centrifugation at 13,000 rpm for 20 minutes ("Heraeus Biofuge 13"), then diluted and assayed for Compound (I) by HPLC. This assay used a mobile phase of acetonitrile (20%), water (80%) and trifluoroacetic acid (0.1%) and a 150.times.4.2 mm "Zorbax SB CN" column at 40.degree. C. with U.V. detection at 220 nm. The results are set out below.
Approximately 10 mg of each of the free base and fumarate salts of Compound (I) were exposed to 8 different relative humidities (RHs) between 0 and 94% at 30.degree. C. in the Surface Measurement Systems Ltd moisture microbalance. The samples were allowed to reach equilibrium at each of these RHs and the change in weight from the initial value when the sample was first placed
REFERENCES:
patent: 5039679 (1991-08-01), Herman
patent: 5545644 (1996-08-01), Macor et al.
Berge, et al., J. Pharm. Sci. 66(1), 1-19 (1977).
Fuller Jr. Grover F.
Ginsburg Paul H.
Jones Dwayne C.
Pfizer Inc.
Richardson Peter C.
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