Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-08-10
2002-08-27
Huang, Evelyn Mei (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S171000, C560S124000, C564S230000
Reexamination Certificate
active
06441176
ABSTRACT:
BACKGROUND OF INVENTION
This invention relates to sodium-hydrogen exchanger type 1 (NHE-1) inhibitors and methods of making such inhibitors.
Mycardial 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. There is an unmet medical need to prevent or minimize myocardial ischemic injury, particularly perioperative myocardial infarction. Such a therapy is anticipated to be life-saving and reduce hospitalizations, enhance quality of life and reduce overall health care costs of high risk patients.
Pharmacological cardioprotection would reduce the incidence and progression of myocardial infarction and dysfunction occurring in these surgical settings (perioperatively). In addition to reducing myocardial damage and improving post-ischemic myocardial function in patients with ischemic heart disease, cardioprotection would also decrease the incidence of cardiac morbidity and mortality due to myocardial infarction and dysfunction in patients “at risk” (such as greater than 65 years, exercise intolerant, coronary artery disease, diabetes mellitus, hypertension) that require non-cardiac surgery.
The mechanism(s) responsible for the myocardial injury observed after ischemia and reperfusion is not fully understood.
A variety of publications have disclosed the use of guanidine derivatives as useful for the treatment of, for example, arrhythmias.
A recent published patent application, PCT/IB99/00206 published as WO 99/43663 on Sep. 2, 1999, the disclosure of which is hereby incorporated by reference, discloses a variety of NHE-1 inhibitors including [5-cyclopropyl-1-(quinolin-5-yl)-1H-pyrazole4-carbonyl]guanidine.
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.
Further, J. Heterocyclic Chem., 24, 1669 (1987) “Reaction of 2-Dimethylaminomethylene-1,3-diones with Dinucleophiles. VI. Synthesis of Ethyl or Methyl 1,5-Disubstituted 1H-Pyrazole4-carboxylates” discloses the preparation of esters of 5-substituted 1-phenyl-1H-pyrazole-4-carboxylic acids.
Thus, there is clearly a need and a continuing search in this field of art for compounds for the treatment of perioperative myocardial ischemia, and accordingly methods for making such compounds.
SUMMARY OF THE INVENTION
One aspect of this invention is directed to a process for preparing N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole4-carbonyl)-guanidine, monomesylate salt comprising combining N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole4-carbonyl)-guanidine with methanesulfonic acid.
Preferably the combination is performed in a polar aprotic solvent at a temperature of about 40° C. to about 80° C. It is also preferred that the solvent is a mixture of acetone and 1-methyl-2-pyrrolidinone.
Another aspect of this invention is directed to a process for preparing N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl)-guanidine comprising:
a. combining 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid and thionyl chloride in toluene to form 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid chloride; and
b. combining guanidine hydrochloride and sodium hydroxide with a suspension of 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole4-carboxylic acid chloride in tetrahydrofuran at a temperature of about −10° C. to about 10° C. for about 1 hour to about 3 hours.
Preferably the 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid and thionyl chloride are combined at a temperature of about 60° C. to about 90° C. for about one to about three hours. It is also preferred that the 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole4-carboxylic acid is prepared by hydrolysis with methanol in the presence of sodium hydroxide at reflux.
Another aspect of this invention is directed to a process for preparing 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid methyl ester comprising: combining quinolin-5-yl-hydrazine and methyl-3-cyclopropyl-2-dimethylenamino-3-oxopropanoate in a reaction-inert solvent in the presence of an amine base.
Preferably the solvent is ethanol, the amine base is triethylamine and the combination occurs at a temperature of about 50° C. to about reflux.
Another aspect of this invention is directed to a process for preparing methyl-3-cyclopropyl-2-dimethylenamino-3-oxopropanoate comprising: combining methyl-3-cyclopropyl-3-oxopropanoate and N,N-dimethylformamide dimethylacetal at a temperature of about 50° C. to about 110° C. for about one to about five hours under neat conditions.
Another aspect of this invention is directed to a process for preparing N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole4-carbonyl)-guanidine, monomesylate salt comprising:
a. combining methyl-3-cyclopropyl-3-oxopropanoate and N,N-dimethylformamide dimethylacetal at a temperature of about 50° C. to about 110° C. for about one to about five hours under neat conditions;
b. combining quinolin-5-yl-hydrazine and methyl-3-cyclopropyl-2-dimethylenamino-3-oxopropanoate in a reaction-inert solvent in the presence of an amine base to form 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole4-carboxylic acid methyl ester;
c. hydrolyzing the 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid methyl ester with methanol in the presence of sodium hydroxide at reflux to form 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid;
d. combining 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole4-carboxylic acid and thionyl chloride to form 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole4-carboxylic acid chloride;
e. combining guanidine hydrochloride and sodium hydroxide with a suspension of 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole4-carboxylic acid chloride in tetrahydrofuran at a temperature of about −10° C. to about 10° C. for about 1 hour to about 3 hours to form N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole4-carbonyl)-guanidine; and
f. combining N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole4-carbonyl)-guanidine with methanesulfonic acid to form N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl)-guanidine, monomesylate salt.
In comparison to the procedures disclosed in WO99/43663 published on Sep. 2, 1999, the instant invention provides various advantages. For example, formation of the acid chloride with thionyl chloride in toluene is preferred because the HCl salt of the acid chloride is isolated as a solid directly from the reaction. Treatment of the acid chloride in tetrahydrofuran (THF) with guanidine HCl and aqueous sodium hydroxide at lower temperatures results in increased purity and higher yields. Higher temperatures result in increased hydrolysis of the acid chloride as well as formation of other by-products.
By “pharmaceutically acceptable” it is meant the carrier, diluent, excipients, and/or salt must be compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof.
As used herein, the expressions “reaction-inert solvent” and “inert solvent” refers to a solvent or mixture of solvents which does not interact with starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product.
The chemist of ordinary skill will recognize that certain compounds of this invention will contain one or more atoms which 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. Hydrates and solvates of the compounds of this invention are also included.
Other features and advantages will be apparent from the description and claims which describe the invention.
DETAILED DESCRIPTION OF THE INVENTION
In general the compound of this invention, &l
Benson Gregg C.
Huang Evelyn Mei
Musser Arlene K.
Pfizer Inc.
Richardson Peter C.
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