Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-10-10
2001-11-06
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S159000
Reexamination Certificate
active
06313142
ABSTRACT:
This invention relates to cholesteryl ester transfer protein (CETP) inhibitors, and method for making such inhibitors.
Atherosclerosis and its associated coronary artery disease (CAD) is the leading cause of mortality in the industrialized world. Despite attempts to modify secondary risk factors (smoking, obesity, lack of exercise) and treatment of dyslipidemia with dietary modification and drug therapy, coronary heart disease (CHD) remains the most common cause of death in the U.S., where cardiovascular disease accounts for 44% of all deaths, with 53% of these associated with atherosclerotic coronary heart disease.
Risk for development of this condition has been shown to be strongly correlated with certain plasma lipid levels. While elevated LDL-cholesterol may be the most recognized form of dyslipidemia, it is by no means the only significant lipid associated contributor to CHD. Low HDL-C is also a known risk factor for CHD (Gordon, D.J., et al.,: “High-density Lipoprotein Cholesterol and Cardiovascular Disease”, Circulation, (1989), 79: 8-15).
High LDL-cholesterol and triglyceride levels are positively correlated, while high levels of HDL-cholesterol are negatively correlated with the risk for developing cardiovascular diseases. Thus, dyslipidemia is not a unitary risk profile for CHD but may be comprised of one or more lipid aberrations.
Among the many factors controlling plasma levels of these disease dependent principles, cholesteryl ester transfer protein (CETP) activity affects all three. The role of this 70,000 dalton plasma glycoprotein found in a number of animal species, including humans, is to transfer cholesteryl ester and triglyceride between lipoprotein particles, including high density lipoproteins (HDL), low density lipoproteins (LDL), very low density lipoproteins (VLDL), and chylomicrons. The net result of CETP activity is a lowering of HDL cholesterol and an increase in LDL cholesterol. This effect on lipoprotein profile is believed to be pro-atherogenic, especially in subjects whose lipid profile constitutes an increased risk for CHD.
No wholly satisfactory HDL-elevating therapies exist. Niacin can significantly increase HDL, but has serious toleration issues which reduce compliance. Fibrates and the HMG CoA reductase inhibitors raise HDL-C only modestly. As a result, there is a significant unmet medical need for a well-tolerated agent which can significantly elevate plasma HDL levels, thereby reversing or slowing the progression of atherosclerosis.
Commonly assigned U.S. application Ser. No. 09/391,152 filed Sep. 7, 1999 entitled 4-CARBOXYAMINO-2-SUBSTITUTED-1,2,3,4-TETRAHYDROQUINOLINES, the disclosure of which is hereby incorporated by reference, is directed to compounds of the following general formula:
Specifically, the compound [2R,4S]4-[(3,5bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester is described. A process for making this compound is also described in Example 7.
Thus, although there are a variety of anti-atherosclerosis therapies, there is a continuing need and a continuing search in this field of art for compounds for the treatment of atherosclerosis, and accordingly methods for making such compounds.
SUMMARY OF THE INVENTION
One aspect of this invention is 4-(3,5bis-trifluoromethylbenzylamino)-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxyl add ethyl ester, 4-toluene -sulfonate.
Another aspect of this invention is (−)-(2R,4S)-4-(3,5-bis-trifluoromethylbenylamino)-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxyl acid ethyl ester or pharmaceutically acceptable salts thereof, preferably the 4-toluene-sulfonate salt thereof.
Another aspect of this invention is cis-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester and pharmaceutically acceptable salts thereof, preferably the (−)di-benzoyl-L-tartrate salt or (−)di-p-toluoyl-L-tartaric acid salt thereof.
Another aspect of this invention is (−)(2R,4S)-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester and pharmaceutically acceptable salts thereof, preferably the (−)di-benzoyl-L-tartrate salt or (−)di-p-toluoyl-L-tartaric acid salt thereof.
Another aspect of this invention is directed to a process for preparing (−)-(2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester comprising combining (−)-(2R,4S)-4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, 4-toluene-sulfonate and sodium carbonate in tetrahydrofuran at a temperature of about 20° C. to about 25° C. in the presence of methyl chloroformate.
Another aspect of this invention is directed to a process for preparing (−)-(2R,4S)-4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-6-trifluoromethyl-3,4-dihydro -2H-quinoline-1-carboxylic acid ethyl ester, 4-toluene-sulfonate comprising
a. combining 4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester and (−) dibenzoyl-L-tartaric acid (anhydrous) or (−)di-p-toluoyl-L-tartaric acid to form the (−) dibenzoyl-L-tartaric acid salt or di-p-toluoyl-L-tartaric acid salt thereof;
b. combining the resulting salt, 1,2-dichloroethane and an aqueous base with 3,5-bis(trifluoromethyl)benzaldehyde, followed by the addition of sodium triacetoxyborohydride; and
c. adding 4-toluene sulfonic acid monohydrate.
Preferably the (−) dibenzoyl-L-tartaric acid (anhydrous) is used.
Another aspect of this invention is directed to a process for preparing 4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester comprising; combining cis-4-benzyloxycarbonylamino-2-ethyl-6-trifluoromethyl-3,4dihydro-2H-quinoline-1-carboxylic acid ethyl ester and ammonium formate in methanol with palladium/carbon to form a slurry and heating the resulting slurry at a temperature of about 35° C. to about 60° C. for about 30 minutes to about 3 hours.
Another aspect of this invention is directed to a process for preparing cis-(2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin4-yl)-carbamic acid-R
1
-ester, wherein R
1
is benzyl,t-butyl or C
1
-C
4
(alkyl), comprising: combining vinyl-carbamic acid-R
1
, (1-benzotriazol-1-yl-propyl)-(4-trifluoromethyl-phenyl)-amine and 4-toluene-sulfonic acid monohydrate in toluene at a temperature of about 50° C. to about 90° C. Preferably the process includes the additional step of combining the resulting cis-(2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid-R
1
-ester with pyridine and ethyl choroformate in dichloromethane to prepare cis-4-R
1
-oxycarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester.
Another aspect of this invention is directed to a process for preparing (−)-(2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester comprising
a. combining vinyl-carbamic acid-R
1
, wherein R
1
is benzyl, (1-benzotriazol-1-yl-propyl)-(4-trifluoromethyl-phenyl)-amine and 4-toluene-sulfonic acid monohydrate in toluene at a temperature of about 50° C. to about 90° C. to prepare cis-(2-ethyl-6trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid-R
1
-ester wherein R
1
is benzyl;
b. combining the resulting cis-(2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid-R
1
-ester with pyridine and ethyl choroformate in dichloromethane to prepare cis-4-R
1
-oxycarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester;
c. combining cis-4-R
1
-oxycarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester and ammonium formate in methanol with palladium/carbon to form a slurry and heating the resulting slurry at a temperature of about 35° C
Damon David B.
Dugger Robert W.
Benson Gregg C.
Covington Raymond
Musser Arlene K.
Pfizer Inc.
Richardson Peter C.
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