Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-11-27
2004-06-22
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S167000, C546S171000
Reexamination Certificate
active
06753334
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to methods of preparing sodium-hydrogen exchanger type 1 (NHE-1) inhibitors, intermediates of NHE-1 inhibitors and a new almost colorless form of the NHE-1 inhibitor, N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl)-guanidine.
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, the disclosure of which is hereby incorporated by reference, discloses a variety of NHE-1 inhibitors including the NHE-1 inhibitors of the present invention.
J. Med. Chem. 1997, 40, 2017-2034 “(2-Methyl-5-(methylsulfonyl)benzoyl)guanidine Na+/H+ Antiporter Inhibitors” and Arzneim.-Forsch. (Drug Res.) 25, Nr. 10 (1975) “Substituted Phenylacetylguanidines: a New Class of Antihypertensive Agents” disclose 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.
J. Heterocyclic Chem., 24, 1669 (1987) “Reaction of 2-Dimethylaminomethylene-1,3-diones with Dinucleophiles. VI. Synthesis of Ethyl or Methyl 1,5-Disubsittuted 1H-Pyrazole-4-carboxylates” discloses the preparation of esters of 5-substituted 1-phenyl-1H-pyrazole-4-carboxylic acids.
Ferlin, et al., II Famraco, 44:12, pp 1141-1156 (1989) discloses a method of synthesizing 5-hydrazinoquinoline by reacting quinolin-5-ylamine with stannous chloride and sodium nitrite.
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, colored impurities are produced. 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 products that are injected in patients' bodies, it is advantageous to have products that are almost colorless and whose active ingredient is in as pure a form as possible.
SUMMARY OF THE INVENTION
This invention relates to a novel process using ascorbic acid to prepare NHE-1 inhibitors 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.
It has been discovered that when the NHE-1 inhibitor, N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl)-guanidine, is prepared by the ascorbic acid process of this invention, the final product has fewer colored impurities and is obtained in higher yield than that made by previous processes. It has also been discovered that by using citric acid in the preparation of N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl)-guanidine, these colored impurities are further reduced.
One aspect of this invention is methods of preparing compounds of formula VI′
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, comprising reducing, with ascorbic acid, compounds of formula II′
wherein X is chloride, bromide, iodide, ½(SO
4
)
2−
or tetrafluoroborate and R
1
, R
2
, R
3
and R
4
are as defined for formula VI′ above.
Another aspect of the invention is methods of preparing compounds of formula VI′, comprising combining compounds formula II′, with ascorbic acid to form compounds of formula V′
wherein R
1
, R
2
, R
3
and R
4
are as defined for formula VI′ above, and heating the compound of formula V′ to a temperature above about 50° C. to form compounds of formula VI′.
A further aspect of the invention is methods of preparing compounds of formula I′
wherein R
1
, R
2
, R
3
and R
4
are as defined for formula VI′ above, comprising combining the compound of formula VI′ made by a method of this invention, with &agr;-[(dimethylamino)methylene]-&bgr;-oxo-cyclopropanepropanoic acid, (&agr;Z)-methylester to form compounds of formula VIII′
wherein R
1
, R
2
, R
3
and R
4
are as defined for formula VI′ above, and coupling said formula VIII′ compound with guanidine to form the compound of formula I′.
A still further aspect of this invention is compounds of formula V′
wherein R
1
, R
2
, R
3
and R
4
are as defined for formula VI′ above.
Another aspect of this invention is compounds of formula IV′
wherein R
1
, R
2
, R
3
and R
4
are as defined for formula VI′ above.
A further aspect of this invention is methods of preparing 5-hydrazinoquinoline comprising reduction of a diazonium salt of 5-aminoquinoline with ascorbic acid.
An additional aspect of this invention is methods of preparing 5-hydrazinoquinoline comprising combining a diazonium salt of 5-aminoquinoline with ascorbic acid to form [2-(5-quinolinyl)hydrazide]-ethanedioic acid and heating said [2-(5-quinolinyl)hydrazide]-ethanedioic acid to a temperature above about 35° C., preferably above about 50° C. and most preferably above about 80° C., in an aqueous solution containing a hydrolyzing agent, preferably hydrochloric acid.
Another aspect of this invention is methods of preparing [2-(5-quinolinyl)hydrazide]-ethanedioic acid comprising combining a diazonium salt of 5-aminoquinoline with ascorbic acid to form a reaction mixture and maintaining said reaction mixture at a temperature below about 25° C.
A further aspect of this invention is the compound [2-(5-quinolinyl)hydrazide]-ethanedioic acid.
A still further aspect of this invention is the compound of formula IV
An additional aspect of this invention is methods of preparing N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl)-guanidine comprising:
combining 5-hydrazinoquinoline made by a method of this invention with &agr;-[(dimethylamino)methylene]-&bgr;-oxo-cyclopropanepropanoic acid, (&agr;Z)-methyl ester to form 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid methyl ester; and
coupling said 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid methyl ester with guanidine to form N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl)-guanidine.
Another aspect of this invention is methods of preparing N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl)-guanidine comprising:
combining 5-hydrazinoquinoline made by a method of this invention with &agr;-[(dimethylamino)methylene]-&bgr;-oxo-cyclopropanepropanoic acid, (&agr;Z)-methyl ester to form 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid methyl ester;
hydrolyzing said 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid methyl ester with an inorganic base to form 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid; and
coupling said 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid with guanidine to form N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl)-guanidine.
A further aspect of this invention is methods of preparing N-(5-cyclopropyl-1-quinolin-5-
Lambert John F.
Norris Timothy
Pfizer Inc.
Scully Scott Murphy & Presser
Seaman D. Margaret
LandOfFree
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