Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-12-16
2003-09-30
Morris, Patricia L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S406000, C546S167000, C548S369700
Reexamination Certificate
active
06627643
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to methods of preparing sodium-hydrogen exchanger type 1 (NHE-1) inhibitors and methods of preparing pharmaceutical compositions comprising the NHE-1 inhibitors.
BACKGROUND OF THE INVENTION
Sodium-hydrogen exchanger type 1 (NHE-1) inhibitors of formula I′
are useful for the prevention and treatment of myocardial ischemic injury. Myocardial ischemic injury can occur in out-patient as well as in perioperative settings and can lead to the development of sudden death, myocardial infarction or congestive heart failure. It is anticipated that therapies using the NHE-1 inhibitors of formula I′ will be life-saving and reduce hospitalizations, enhance quality of life and reduce overall health care costs of high risk patients.
Commonly assigned WO 99/43663A1, discloses a variety of NHE-1 inhibitors including NHE-1 inhibitors relating to the methods of the present invention.
Baumgarth, et al. (1997)
J. Med. Chem.
40, 2017-2034 discloses synthesizing acyl guanidine via coupling of an ester and guanidine, in addition to an acid chloride and guanidine wherein the substrates are aromatic monocyclic structures.
Ferlin, et al. (1989)
II Famraco
44:12, 1141-1156 disclose a method of synthesizing 5-hydrazinoquinoline by reacting quinolin-5-ylamine with stannous chloride and sodium nitrite.
Colored impurities are produced when N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl)-guanidine, an NHE-1 inhibitor of formula I′, is prepared by the previously known processes. For example, aqueous solutions of N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl)-guanidine made by the previously known processes have a distinct yellow color. The impurities responsible for such coloration have not been identified.
From a commercial and regulatory point of view, discoloration of pharmaceutical products containing N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl)-guanidine is undesirable. In the case of pharmaceutical products that are administered to patients, especially those administered by injection, it is considered commercially advantageous that such products be substantially colorless and in as pure a form as possible. For example, a colorless product is helpful for conducting blinded clinical research using a placebo, ensuring that the placebo is visually indistinguishable from the active product.
SUMMARY OF THE INVENTION
This invention provides improved processes for preparing NHE-1 inhibitors of formula
wherein R
1
is methylsulfonyl or hydrogen, R
2
is hydrogen or a halogen, R
3
is hydrogen, R
4
is hydrogen or a halogen, or R
3
and R
4
, together with the carbon atoms to which they are attached, form a six member fully unsaturated ring having one hetero atom that is nitrogen.
In one aspect, this invention provides methods of preparing a compound of formula I′
comprising: combining a mixture of acetonitrile and a compound of formula IX′
with thionyl chloride to form a mixture comprising a compound of formula X′;
evaporating excess thionyl chloride from said mixture to form an evaporated mixture; and combining said evaporated mixture with guanidine to form a compound of formula I′, wherein R
1
is methylsulfonyl or hydrogen, R
2
is hydrogen or a halogen, R
3
is hydrogen, R
4
is hydrogen or a halogen, or R
3
and R
4
form, together with the carbon atoms to which they are attached, a six member fully unsaturated ring having one hetero atom that is nitrogen.
In another aspect, the invention provides methods of preparing a pharmaceutical composition comprising: combining a mixture of acetonitrile and a compound of formula IX′
with thionyl chloride to form a mixture comprising a compound of formula X′;
evaporating of excess thionyl chloride from said mixture to form an evaporated mixture; combining said evaporated mixture with guanidine to form a final mixture comprising a compound of formula I′
isolating said compound of formula I′ from said final mixture; and combining said compound of formula I′, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable vehicle, diluent or carrier, wherein R
1
is methylsulfonyl or hydrogen, R
2
is hydrogen or a halogen, R
3
is hydrogen, R
4
is hydrogen or a halogen, or R
3
and R
4
form, together with the carbon atoms to which they are attached, a six member fully unsaturated ring having one hetero atom that is nitrogen.
In a preferred embodiment of the invention, the compound of formula IX′ is 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid, the compound of formula X′ is 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl chloride and the compound of formula I′ is N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl)-guanidine.
In a more preferred embodiment, the 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid in acetonitrile is combined with thionyl chloride at a temperature of about 25° C. for at least about one hour and preferably for at least about one-half hour.
In another preferred embodiment, the evaporation of thionyl chloride reduces the volume of the mixture by about 10%. More preferably, said evaporation is performed under vacuum and at a temperature of about 85° C.
Unless otherwise defined below, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs.
“Halogen” means an atom of one of the elements of Group 18 of the periodic table of elements, preferably fluorine, bromine or chlorine.
“Pharmaceutically-acceptable salt” refers to nontoxic anionic salts containing anions such as (but not limited to) chloride, bromide, iodide, sulfate, bisulfate, phosphate, acetate, maleate, fumarate, oxalate, lactate, tartrate, citrate, gluconate, methanesulfonate and 4-toluene-sulfonate. Where more than one basic moiety exists, multiple salts (e.g., di-salt) are included. The expression also refers to nontoxic cationic salts such as (but not limited to) sodium, potassium, calcium, magnesium, ammonium or protonated benzathine (N,N′-dibenzylethylenediamine), choline, ethanolamine, diethanolamine, ethylenediamine, meglamine (N-methyl-glucamine), benethamine (N-benzylphenethylamine), piperazine or tromethamine (2-amino-2-hydroxymethyl-1,3-propanediol).
Those skilled in the art will recognize, based on the present description, that certain compounds of this invention will contain one or more atoms that may be in a particular stereochemical or geometric configuration, giving rise to stereoisomers and configurational isomers. All such isomers and mixtures thereof are included in this invention.
DETAILED DESCRIPTION OF THE INVENTION
Reaction Scheme A illustrates processes of preparing compounds of formula VI′. Scheme B illustrates processes of preparing compounds of formula I′ using compounds of formula VI′ from Scheme A. These processes are used to make NHE-1 inhibitors, including, for example, N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl)-guanidine.
According to Scheme A, a diazonium salt of a compound of formula II′ is combined with L-ascorbic acid (formula III) to form a lactone intermediate compound of formula IV′ as a transient intermediate, which decomposes to an oxalic acid intermediate compound of formula V′. At elevated reaction temperatures, above about 35° C. and preferably above about 50° C. and most preferably above about 80° C., a compound of formula IV′ converts to a formula VI′ compound as a one-pot reaction. At lower temperatures, the oxalic acid intermediate compounds of formula V′ are not converted to compounds of formula VI′. An oxalic compound of formula V′ may be converted to a hydrazino compound of formula VI′ using a hydrolyzing agent, preferably hydrochloric acid. Using concentrated hydrochloric acid will result in formation of a compound of formula VI′ as the hydrochloride salt.
As noted above, the lactone intermediates of formula IV&pri
Busch Frank R.
Withbroe Gregory J.
Catania R. L.
Ginsburg P. H.
Morris Patricia L.
Pfizer Inc.
Richardson P. C.
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